." ... .

. .. .." .
. ."
 Essentials of
NUCLEAR MEDICINE
SCIENCE
Edited by
William B . Hladik 111, M . S . , R .Ph.
Associate Professor of Pharmacy and Director of Radiopharmacy
College of Pharmacy
University of New )Mexico
Albuquerque, New Mexico

Gopal B . Saha, Ph.D.

Staff Radiochemist
Department of Nuclear Medicine
The Cleveland Clinic Foundation
Cleveland, Ohio

Kenneth T. Study, B.S. , C.N.M.T.

Medical Accounts Manager
Digital Equipment Corporalion
Albuquerque, New Mexico

With the technical assistance of

Blair E . Friedman, M.A.
Senior Technical Sales Representative
Medi-Physics,Inc.
Lake Worth, Florida

WILLIAMS & WlLKlNS

Balllmore London Los Angeles Sydney

I
1
Edimr: John Butler
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Copy Ediror: Bill Cady
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Prodrdorz: Raymond E. Rcler

To our wives:
Leslie
Sipra
Linda

and our children:

Copyright 0 I987 Billy and Anya
JVi\liams & Wilkins
428 East Preston Street Pranlik and Trina
BaItimore, MD 21202, U . S . A . Jessica

without whose love,

encouragement and patience
this project would
have never been completed
All rightsreserved This book is protectedby copyright. Nopart oi this book maybe
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Accurm indicatlons. adverse reactions, and dosage scheduIes for drugs arc provided in this
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Prirmd irl Ihe Uniied S l a m of America

Library of Congress Cataloging-in-PublicationData

Main entry under title:

Essentials of nuclear medicine science.

Includes bibliographies and index.

1. Radiopharmaceuricals. 2 . Nuclear medicine. 1. Hladik.William B.. 1 9 5 G , 11.

Saha. Gopal 8. III. Study, Kenncth T. [DNLM: 1 . NuclcarMedicine. WN 440 E781

R M 852.E87 I987 616.07'57
8517978
ISBN 0-683-04051-0

Printed at the 87 88 89 90 91
Waverly Press. Inc 1 0 9 8 7 6 5 4 3 2 1
 Foreword

Science in the service of the clinical practiceof nuclear medicine oftenutilizes a variety
of problem-solving techniques. The biodistribution of a radioactive tracer can provide
significant physiologic, biochemical,and anatomic information regarding the health status
of a patient. However, many parameters can influence the biodistribution of a radiotracer
and confound the diagnostic information. In addition to theintrinsic biological factors that
determine the basic distribution pattern, thereare extrinsic factors (e.g., procedural errors,
instrumentation errors, and adverse reactions) which can influence the presentation of the
data and, thus,theultimateoutcome of the study. By knowing what these potential
confounding factors are and how they operate, tough diagnostic questions can often be
resolved.
When examining an individual study, we are often faced with the problem of differ-
entiating what is unique from what is a repeated pattern. As more experience is gained, the
once unique event becomes a known and repeated, but often rare, pattern. The sharing of
information from various branchesofnuclearmedicinescience is a powerful way to
improve our skills in dealing with these day-to-day unusual patterns. In turn, the diag-
nosticpotential of radiotracerstudies is improved.The objective of collectingand
organizing the idormationwhich helps us to recognizeand understand the quirks of tracer
biodistribufons (and external variables which influence data capture) has been a major
undertaking-an undertaking essential to the preparation of thisvolume. The various
authors have done well to provide the reader with this collection of data and its synthesis
into a basic reference.
The task which culminates with this book was started many years ago. In 1977, the
1
faculty and staff of the University of New Mexico (UNM) Radiopharmacy realized that
there was a critical needto teach radiopharmacy students theclinical side of their specialty
practice more effectively. Theefforttoachieve a more clinicallyoriented teaching
program required that data be collected from the various scientific specialists who serveon
nuclear medical teams. As theinformation grew and waspassedon to studentsand
associates in the field, its value became increasingly apparent. Thisinformation has been
shared via informal telephone exchange fora number of years. What the staff of the UNM
Radiopharmacy was doing was also being done by other professionals at various nuclear
! medicine institutions. In time, itbe.came more and more evident that there was a real need
to compile the information that was being networked into a reference book. A number of
authors have combined their efforts and information into a collection of manuscripts which
will serve well those who are faced with the task of interpreting biodistribution studies-
studies which may have been influenced by possible, and sometimes rare, confounding
parameters.

Buck A. Rhodes, Ph.D.

Albuquerque, New Mexico
 Preface

The nuclear medicine physician, in arriving at a diagnostic conclusion, uses multiple

sources of information, UsuaIly the data (images or numerical values) are evaluated, de
novo,as the primarysource of infomationtoinsure that theinitialimpressionsare
unbiased. Next, the anciilary information is obtained. This may include: (a) comments
from the referring physician and other information regarding the patient, (b) procedural
information suppliedbythetechnologystaff,(c)datafromphysicists,computerspe-
cialists,or other nuclearmedicinescientists who may have had involvement in the
procedure, and (d) pharmaceutical information from thestaff responsible forpreparing the
radioactive Lracer drugs. Thephysician’s interpretation results from an integration of these
primary and ancillary information sources plus knowledge gained from previous training
and experience.
This book provides the reader with a wide scope of ancillary information on radiophar-
maceuticah (and related subjects) that can beused to strengthen both the nuclear medicine
clinical decision-making process as well as the radiopharmaceuticalevaluation process. In
general, chapter topics compensate for current deficiencies in the secondary literature
relative to radiopharmaceuticals and other technological and biological parameters that
must be taken into consideration by nuclear medicine professionalsin their daily practice.
The format of this book is such that physicians, pharmacists, Lechnologists, and other
scientists in the specialty area of nuclear medicine can utilize it as a textbook when they
are students and then as a reference volume when they are carrying out their respective
clinical functions.
It seems apparent that nuclear medicine, more than most othermedical specialties,
brings together quite a variety of scientists and professionals. Depending on the mix of
scientists in a particular department, any one individual maytake on a variable number of
clinical responsibilities and thus must be familiar with a broad scope of topics beyond his
or her specific area of expertise. Chapters in this book are intended to supply information
which will assist nuclear medicine professionals with varied backgrounds and strengths to
become more active and competent consultants in the clinical setting. Even with this in
mind, this book is certainly not all-inclusive; rather, it touches on those areas about which
the professional is frequently called upon to act as a source of information.
The use of the word “essentials” in the title of this book should not be construed to
mean “basics.” We assume that those who use this book will already be well trained in Lhe
basic concepts of their primary discipline related to nuclear medicine, i.e.,health physics,
technology, chemistry, pharmacy, medicine, etc.,and thus there is no need to include such
information in this book. However, all of lhe material herein is essential if he individual is
to communicate effectively and serve as a source of current and relevant information.
The stimulus for the development of this book was primarily forthcoming from inqui-
ries directed to the University of New Mexico (UNM) Radiopharmacy. The UNM group
has operated a consultation service for local, state,and national callers seeking answers to
 questions or problems ~ I lhry I t w cncountering in nuclear medicine, particularly specific
and detailed information pcrhining to physical, pharmacologic, physiologic, pharmacoki-
netic, or quality CO~IIIUIp;ll’;llncters which influence the invivo performance of radioactive
tracers. This 11;~s providcrl 11s with the opportunity to collect and organize the data into a
bank of rcxlily ~ r ~ r i c v ; ~ information,
ble which served as the nucleus €or the book.
Aulhrrs (11 tach chapter were selected on the basis of their individual expertise in the
p;u.ticul;u a ~ a Chapters
. havebeenwritten with asmuch up-to-dateinformation as
possihlc and are adequatelyreferenced.Becauseeachchapter is written by different
Acknowledgments
:luthors on relatedmatter, thereissome inadvertent overlap of contents in different
chapters despite ourcareful editing. Due io the rapid pace of nuclear medicine growth and
the long procress of editing and publishing, certain recentIy released information couid not
be included in the book. The editorswould like to thank particularly BuckA . Rhodes, Ph.D., who suggested the
need for this type of book and helpedto develop its “character.” His foresight and
William B. HIadik 111 inspiration are deeply appreciated.
Gopal B. Saha We are indebtedtoBlair E. Friedman, M . A . , whowas instrumental in contacting
Kenneth T. Study potential authors, making arrangements with the publisher, and proofreading the typeset
COPY.
We would also like to acknowledge Kay L. Hicks, Elva G. Giron, Sharon 1. Ramirez,
and Jennifer A. Farenbaugh for their s u p x b secretarial assistance.
For her photography expertise, we acknowledge and thank Chris Martin, Albuquerque,
New Mexico, who supplied the iamge ultimately selected for the book cover.
Our sincerest thanks go to Zophia Pastuszyn, C.N.M.T., Ruth Snyder, and the entire
staff in thenuclearmedicinedepartment at Lovelace Medical Center, for providing
scintiscans considered for the book cover.
Special credit is extended to the staff of Williams & Wilkins for their advice and
patience during the development and production of this book.
We gratefully acknowledgeCarnlan A . Bliss,Dean of theCollege of Pharmacy,
University of New Mexico, and the management of Digital Equipment Corporation for
their support of this task.
Finally,theeditors extendtheir deepestappreciation to thecontributors who have
cooperated fully in ali aspects of the preparation of this text.

xi
 Contributors

Neil Abel, M.S., M.B.A. Donald A. Bille, Ph.D., R.N.

ReviewingPharmacist Nursing School Professor
Food and Drug Administration Graduate Faculty
Rockville,MaryIand Graduale Department of Nursing Education,
Administration, and Heallh Policy
School of Nursing
Harold L. Atkins, M.D. University of Maryland
Professor of Radiology Baltimore, Maryland
School of Medicine
Health Sciences Center Doyle W, Canfrell, B.A., R.T.(N), C.N.M.T.
Stale University of New York at Stony BI.oak Director of Medical Imaging
Stony Brook, NewYork Park Lane Medical Cenler
and Kansas City, Missouri
Chief, Division of Nuclear Medicine
Department of Radiology Teresa J. Cantrell, B.A., R.T.(N), C.N.M.T.
University Hospital at Stony Brook Supervisor of Nuclear Medicine/Ullrasound
Stony Brook, New York Department of Radiology
St. Luke5 Hospital
Kansas Cily, Missouri
William J. Baker, M.S.
Associate Professor of Nuclear Pharmacy and Henry M. Chilton, PharmD.
Director, Intermountain Radiopharmacy AssociateProfessor
College of Pharmacy Division of Nuclear Medicine
University of Utah Health Sciences Center Department of Radiology
Salt Lake City, Ulah Bowman Gray School of Medicine
Wake Forest University
Winston-Salem, North Carolina
Robert W.Beightol, Pharm.D., B.C.N.P.
Director, Nuclear Pharmacy Senices Jeffrey A. Clanton, M.S., B.C.N.P.
Roanoke Memorial Hospitak Associate in Radiology and
Roanoke,Virginia Chief of Radiopharmacy Services
Vanderbilt University Medical Center
Nashville, Tennessee
Ralph Blumhardt, M.D.
Associate Professor of Radiology and Jack L. Coney, M.S., C.H.P.
Head of Division of Nuclear Medicine HealthPhysicist
University of Texas Health Science Center at San Syncor International Corporation
Antonio Albuquerque, New Mexico
San Antonio,Texas
Larry T. Cook, Ph.D.
Associate Professor of Diagnostic Radiology
Terry L. Braun, B.S., R.Ph. Division of Diagnostic Imaging and Radiological
Radiochemisl Science
Cancer Therapy Inslitute Department of Diagnostic Radiology
King hisal Specialist Hospital University of Kansas Medical Center
Riyadh, Saudia Arabia Kansas City, Kansas
xiii
 xiv t Contributors

M. Annette Cordova, M S . , R.Ph. Allan H. Gobuty, Pharm,D., M.S. Jack L. Lancaster, Ph.D. Brookhaven NationaI Laboratory
Assistanl Director Assistant Professor of Radiology Assistant Professor of Radiology and Upton, NewYork
Department of Pharmacy Medical School Head of Diagnostic Radiology Physics Section
Northeast Community Hospital University of Texas Health Science Center at University of Texas Health Science Center at San James A. Ponto, M.S., R.Ph., B.C.N.P.
Sedford, Texas Houston Antonio Nuclear Pharmacist
Houston, Texas San Antonio, Texas Department of Radiology
John J. Coupal, Ph.D. and University of Iowa Hospitals and Clinics
Assistant Clinical Professor of Radiation Medicine John C. Lasher, M.D. Iowa City, Iowa
Hospital
College
Hermann
of Medicine Assistant Professor of Radiology and
Universitv
Texas Houston,
of Kentuckv University of Texas Health Science Center at San ClinicaI Associate Professor
Lexington,Kentucky Antonio College of Pharmacy
and Ned Gregorio, R.Ph., B.C.N.P. San Antonio, Texas University of Iowa
Nuclear Pharmacist Nuclear Pharmacist Iowa City, Iowa
Nuclear Medicine Service Radiopharmacy David L. Laven, C.R.Ph. F.A.S.C.P.
Veterans Administration Medical Center College of Pharmacy Director,NuclearPharmacyService David F. Preston, M.D.
Lexington,Kentucky University of New Mexico Nuclear Medicine Department F’rofessorof Diagnostic Radiology
Albuquerque, New Mexico Veterans Administration Medical Center Division of Nuclear Medicine
Bay Pines, Fbrida Departrnenl of Diagnostic Radiology
Robert J. Cowan, M.D. Ned D. Heindel, Ph.D. University of Kansas Medical CenteI
Professor of RadioIogy Professor, Department of Chemistry and KansasCity,Kansas
Division of Nuclear Medicine Brian C. Lentle, M.D., F.R.C.P.(C)
Director, Center for Health Sciences Director, Departmenl of Nuclear Medicine
Department of Radiology Lehigh University Bock A. Rhodes, PhD.
Bowman Gray School of Medicine Vancouver General Hospilal President
Bethlehem,Pennsylvania Vancouver, BritishCoIumbia
WakeForest University and RhoMed, Inc.
Winston-Salem, North Carolina and Albuquerque, New Mexico
Adjunct Professor Head, Division of Nuclear Medicine
Department of Radiation Oncology and Nuclear Department of Radiology
Medicine Gopal B. Saha, Ph.D.
Frederick L. Datz, M.D. University of British Columbia Staff Radiochemist
Associate Professor of Radiology and Hahnemann University Vancouver. British Columbia
Philadelphia,Pennsylvania Department of Nuclear Medicine
Clinical Director of Nuclear Medicine The Cleveland Clinic Foundation
School of Medicine Geoffrey Levine, Ph.D., B.C.N.P. Cleveland, Ohio
University of Utah
Health
Sciences
Center
William
B. Hladik 111, M S . , R.Ph. Associate Professor of Radiology
Associate
Professor
Utah
City,
LakeSalt of Pharmacy
and School of Medicine Pranlika Som, D.V.M., Sc.M.
Director of Radiopharmacy University of Pittsburgh Scientist
College of Pharmacy Pittsburgh,Pennsylvania Brookhaven Nalional Laboratory
Natalie Foster, Ph.D. University of New Mexico
AssistantProfessor and Uplon, NewYork
Albuquerque, New Mexico Clinical Associate Professor of Pharmaceutical
Department of Chemistry and
Center for Health Sciences Sciences Research Associate Professor of Radiology
Robert Hodges, PharmD. School of Pharmacy School of Medicine
Lehigh University Staff Pharmacist
BethIehem,Pennsylvania University of Pittsburgh HeaIth Sciences Center
Washington Regional Medical Center Pittsburgh, Pennsylvania State University of New York at Stony Brook
and Fayetteville, Arkansas
Adjunct Assistant Professor and Stony Brook, New York
Department of Radiation Oncology and Nuclear Director of Nuclear Pharmacy
Karl F. Hubner, M.D. Presbyterian-University Hospital Michael G. Stabin, M.E.
Medicine Professor of Radiology and
Hahnemann University Pittsburgh,Pennsylvania Radiopharmaceutical Internal Dose Information
Director of Research Cenler
PhiladeIphia,Pennsyivania Department of Radiology
University of Tennessee Hospital
Zvi €I. Oster, M.D. Manpower Education, Research and Training
Professor o€ Radiology Division
John E. Freilas, M.D. Knoxville.Tennessee School of Medicine Oak Ridge Associated Universities
Nuclear Medicine Deparhent Health Sciences Center Oak Ridge, Tennessee
William Beaumont Hospital Xobert C. Jost, M.S., R.Ph. State University o€ New York at Stony Brook
Royal Oak, Michigan Pharmacist Stony Brook, NewYork Victor J. Slathis, B.S., R.Ph.
and University of New Mexico Hospital and Nuclear Pharmacist
Clinical Associate Professor Albuquerque, New Mexico Co-Chief, Division of Nuclear Medicine Pharmacy Department
University of Michigan Medical SchooI Department of Radiology N . T. Enloe Memorial Hospital
Ann Arbor, Michigan E. Edmund Kim, M.D., M.S. University Hospital at Stony Brook Chico,California
and Professor of Radiology and Medicine, and Stony Brook, NewYork
Clinical Associate Professor Direclor, Division of Nuclear Medicine and Kenneth T. Study, B.S., C.N.M.T.
School of Medicine University of Texas Health Science Center at Research Collaborator and Medical Accounts Manager
Wayne State University Houston Visiting Clinician Digital Equipment Corporation
Detroit,Michigan Houston, Texas MedicalDeparlmenl Albuquerque, New Mexico
xvi I Contributors

Colin B. Styles, M.D. Roger W. TaR, B.S., C.N.M.T.

Department of Nuclear Medicine Section Supervisor
St. Vincent’sHospital Division of Nuclear Medicine
Victoria Parade Department of Radiology
Fitzroy 3065, Australia Heights General Hospital

Dennis P. Swanson, MS.,R.Ph., B.C.N.P.

Albuquerque, New Mexico
James E Vandergrift, M.S.
Contents
Department of Diagnoslic Radiology and Medical Assistant Professor of Radiology (Physics) and
Imaging Radiation Safety Officer
Henry Ford HospitaI College of Medicine
Detroit,Michigan University of Arkansas for Medical Sciences
and Little Rock, Arkansas Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Clinical Associate Professor of Pharmacy
College of Pharmacy Evelyn E. Watson Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
University of Michigan Program Manager Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
AM Arbor, Michigan RadiopharmaceuticaI Internal Dose Information ...
and Center Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x111
Adjunct Associate Professor of Pharmacy Practice Manpower Education, Research and Training
SchooI of Pharmacy Division
Wayne State University Oak Ridge Associated Universities I
Detroit,Michigan Oak Ridge,Tennessee Considerations for the Clinical Use
of Radiopharmaceuticals

Chapter 1
Normal Biodistribution of Diagnostic Radiopharmaceuticals
G o ~ n l B . S r r h a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Chapter 2
Radiopharmacokinetics in Nuclear Medicine
JeffreyA.Clanton .................................................. 20
Chapter 3
Biodistribution and Structure in Radiodiagnostics
N e d D . Heildei m d N a t a l i eF o s t e r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Chapter 4
Metabolic Fate of Radiopharmaceuticals
RoberiC.Josi ............................. 44
Chapter 5
Radiopharmaceutical Absorbed Dose Consideralions
Jack L . Coffeer, E v e l y n E. Watson, Karl F. Hubrrer, arrd Michael G . Stabin . . . I 51
Chapter 6
Considerations and Controversies in the Selection of Radiopharmaceuticals
Henry M . C h i l t o n and Robert J. ConIan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Chapter 7
Therapeutic Applications of Radiopharmaceuticals
William J. Baker, F r e d e r i c k L. Dalz, and Robert W.Beightol x4
Chapter 8
Preparation and Clinical Utility of Labeled Blood Products
Willirrm J. B a k e r and F r e d e r i c k L . Dalz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Chapter 9
Nuclear Medicine Procedures for Monitoring Patient Therapy
Alla?~H . Goblrty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
 Chapter 21
Chapter 10 Regulatory Problems in Nuclear Medicine
Interventional Studies in Nuclear Medicine James F. Vandergrifl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 1
Gopal B . Saha, Dennis P. Swar~son,and William B . Hladik III . . . . . . . . . . . . . 115
Chapter 11
Medical Decision Making III
David F. Preston and Larry T. Cook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Considerations for the Preclinical and the Clinical Investigation
of New Radiopharmaceuticals
Chapter 12
Computer Applications in Nuclear Medicine Chapter 22
Jack L. Larrcaster, John C . Lasher,and Ralph Bllrrnhardr . . . . . . . . . . . . . . . . . . 145 Animal Models of Human Disease
Prantika Son1 and Zvi H . Oster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
I1 Chapter 23
Problems and Pitfalls Encountered Considerations in the Assembly and Submission of the Physician-sponsored
with the Use of Radiopharmaceuticals Investigational New Drug Application
Geoffrey Levine and Neil Abel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Chapter 13
Iatrogenic Alterations in the Biodistribution of Radiotracers as a R e d of Drug
Therapy: Theoretical Considerations
IV
Interactions among Nuclear Medicine
RobertHodges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Health Care Professionals and Patients
Chapter 14
Iatrogenic Alterations in the Biodiswibulion of Radiotracers as a ResuIt of Drug Chapter 24
Therapy: Reported Instances Radiopharmaceutical Information and Consultation Services
William B . Hlodik lli, James A . Ponfo, Brian C. Lentle, William B . Hladik iii, Ned Gregorio, Terry L. B r a m , Victor J. Stathis, and
and David L . Laven . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 JamesA.Ponto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Chapler 15 Chapter 25
Iatrogenic Alterations in the Biodistribution of Radiotracers as a Result of Issues of Patient Education
Radiation Therapy, Surgery, and Other Invasive Medical Procedures Donald A . B i l k . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
Brian C . Lenfle and Colin B . SijJles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Chapter 26
Chapter 16 Patient Preparation for Nuclear Medicine Studies
Normal Clinical Variation in Anatomic Structure and Physiologic Function and Its Victor J. Stathis, Doyle W. Canrrell, and Teresa J. Cantre11 . . . . . . . . . . . . . . . . 411
Effect on Radiopharmaceutical Biodistribution
John J, Coupal and E . Edn~undKim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Chapter 17
Unusual or Unanticipated Alterations in the Biodistribution of
Radiopharmaceuticals as a Result of Pathologic Mechanisms
E . Edtnrcnd Kin? arzd John J. Coupal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Chapter 18
Clinical Manifestations of Radiopharmaceutical Formulation Problems
James A . Ponto, Demis P. Swanson, ami John E. Freilas . . . . . . . . . . . . . . . . . . 268
Chapter 19
Instrumentation and Procedural Problems in Nuclear Medicine
Kenneth T, Study and Roger W. Taff . . . . . . . . . . . . . . . . . . 290
Chapter 20
Adverse Reactions Associated with Radiophannaceulicals
M . Annette Cordovn, William B . Hladik i i I , Brrck A . Rhodes, and
HaroidL.Atkim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
 1
Normal Biodistribution of Diagnostic
Radiopharmaceuticak

Nuclearmedicineas a diagnosticmodality generalorswithisotonicsaline.Sodium

has grown to such an extent that it is practiced in [99mTc]pertechnetate and many 9 9 m Tproducts ~
almosl all hospitals nationwide. In the practice account for almost 80% of the radiopharmaceu-
of nuclear medicine: physicians set norms for ticals used in nuclear medicine procedures. The
morphology or physiologic function of each reason for such a preeminent position for 9 9 m T ~
organ by studying a largenumber of normal is thatits electronemissionis negligibleand
palienls. For every procedure, there is in these thus the radiation dose to patients is minimal.
diagnostic data a range of normal variations that They-rayenergy of 140 keVissuitablefor
are familiar to the physicians. Nuclear medicine scintigraphy with a gamma camera.
practitionersinterpret diseasesorpathologies After intravenous administration, 99mTc-per-
that are attributed on the basis of the deviations technetate* initially distributes itself in the vas-
from the limits of these variations. cular compartment. Radiopertechnetate most
As indicated in thePreface, this book pri- closely resemblesiodide in biologic behavior
marily focuses on ancillary information in the and becomes plasma protein bound, mostly to
interpretation of nuclear medicine studies. Be- albumin (1). Plasmaclearance is very rapid,
fore learningaboutabnormalitiesalong with and equilibrium between vascular compartment
various pitfalls and artifacts in a nudear medi- and interstitial fluid is achieved in as shorta
cinestudy, however, one ought to be familiar time as 2 to 3 minutes. The plasma clearance
with the normal biodistribution of different ra- half-time is approximately 30 minutes. Approx-
diopharmaceuticals. This chapter highlightsthe imately 30% of theadministered doseis ex-
expected normal biodistributions of various rou- creted in the first 24 hours. The total urinary
tinely used radiopharrnaceuticals. Detaiied and fecalexcretion of 9 9 m Tactivity~ isabout
pharmacokineticandmetabolicaspects of ra- 50% in 3 days and almost 70% in 8 days.
diopharmaceuticals have not been presented, as Beasley et al. (2) observed that pertechnetate is
they are discussed in the following chapters. In secreted by thesalivaryglandsandgastric
afew instances,scintiphotographsiiluslraling mucosa and isexcreted to a significant degreein
normal biodistribution have been included. Fa- the feces. The distribution of pertechnelate is
miliarity with the material in this chapter shouldsomewhat different from iodide distribution in
provide betterunderstandingandappreciation that iodide is reabsorbed once it passes into the
of the contents of later chapters. small intestine. Also, about 1% of the admin-
istered dose of pertechnetate is trapped by the
SODIUM [99mTc]PERTECHNETATE thyroid glands.
99mTc decays with a half-life of 6 hours and
emits y-rays of 140 keV with an abundance of *Although [99"Tclpertechnetateis preferred by IUPAC,
90%. This radionuclideis obtained in thechern- gQmTc-pertechnetale is standard, and both ax used through-
ical form of NaTcO, by eluting the 9 9 M ~ - 9 9 m Tout
~ this chapter.
 4 f Essentials of NuclearMedicineScieljce
The administered dose varies with the type of
study: 10-20 mCi for brain imaging, 1-5 mCi
for thyroid studies, and 20-25 mCi for in vivo
red bloodcelllabeling for gated bloodpool
sludies. In brain and thyroid studies, imaging is
performed about 20-30 minutes or longer after
injection, whereas in gated blood pool studies,
it is performcd 5-10 minutesafterinjection.
Brain imaging with 99mTc0, is governed by
theblood-brain barrier(BBB) which prevents
wmTcO, from entering normal brain cells. The
BBB breaks down, however, in abnormal cells
such asoccurintumors,infarcts, and other
conditions, and thus the tracer localizes in le-
sions. 99mTcO; localizes in the choroid plexus,
and thus artifacts are seen in normal brain im-
ages; this is prevented by oral administration of
250 mg potassium perchlorate topatients just
prior to injection of thetracer (3). Potassium
perchlorate saturates the choroid plexus and
leaves no binding sites for 99mT~O;I
The normalbrain scintigraphs do notshow
activity within thecerebrum itself due to the
blood-brain barrier. The periphery of the hemi-
spheres, however, is outlined by increased ac-
tivity in the subarachnoid space, calvaria, and
softtissues of the scalp. Increasedactivityis
also seen in the sagittal and transverse sinuses.
On h e posterior views, the transverse sinuses
aregenerally symmetric. Onlateral views, ac-
tivity is seen in the suprasellarandsylvian
regions.
Figure 1.1. A normal thyroid scinligraph obtained at
60 minutes after administration of 5 mCi of
9 9 m ~ ~ o ~ - .
99mTc07is trapped in the thyroid but, unlike
iodide, is not organified. Administration of per-
chlorate, Lugol's solution, and thiocyanate re-
duces the 9 9 m Tuptake
~ by the thyroid glands.
Normalthyroiduptake of 99mTc0, isonly
0.3-3 .O% at 20 minutes after administration. A
normal scintigraph exhibits a homogeneous dis-
tribution of radioactivity in both thyroid lobes
whichhave a butterflyor a wide "V" ap-
pearance. The size of the isthmus vanes from
thin and barely visible, to wide with an intense
image. The pyramidal lobe can be visualized in
a small percentage of norma1 scans. A normal
thyroidscintigraphobtained with 9 9 m T ~ 0is4
shown in Figure 1.1.
99mT~-
DIETHYLENETRIAMJNEPENTAACETIC
ACID
99mTc-diethylenetriaminepentaaceticacid
(DTPA) isprimarily used for brain andrenal
imaging and for measurement of glomerular fil-
tration rate (GFR). After intravenous injection,
it is excreted entirely by glomerular filtration.
Hauser et al. (4) andAtkins et a!. ( 5 ) have
studied the pharmacokineticcharacteristics of
this radiopharmaceutical in dogs and humans.
The plasma disappearance curve consists of
threecomponents with tms of 12 minutes, 98
minutes, and 14.8 hours. The protein binding is
approximately 5-10% at 1 hour. Maximum re-
nal uptake (5%)occurs 5 minutes after adminis-
tration.Urinary excretion isabout 90% in 24
hours.
Because DTPA is entireIyfilteredby
glomeruli, GFR can be determined by use of
this radiopharmaceuticd (6, 7). Plasma protein
binding of DTPA yields somewhaterroneous
GFR values, however. 99mT~-DTPA also is used
for renal imaging. Because of this radiopharma-
ceutical'srapid elimination by filtration,early
images of the kidney allow good demonstration
of the parenchyma primarily due to blood sup-
ply in the kidneys (8).
Brain imaging with 99mTc-DTPAhasbeen
successfully accomplished by many investiga-
tors and is now accepted as a routine procedure,
The mechanism of localization is governed by
the blood-brain barrier, as isS9mTcO; uptake in
thebrain. DTPA does not accumulate in the
Normal Biodismriburion uf DiugrmficRadiopharmaceuticals
choroid plexus and, thus, has an advantage over
99mT~O;as a brain imaging agent.
""Tc-GLUCEPTATE
""Tc-gluceptate (GH)? is used for brain and
renal imaging. After intravenous administra-
tion, it is excreted by both glomerular filtration
and tubular secretion. A comparative study of
99mTc-labeledGH, DTFA, and dimercaptosuc-
cinic acid (DMSA) has been made by Arnoldet
ai. (8). Its plasma clearance is very rapid for the
first 2 hours and becomes slower thereafter. The
99mT~-GH is loosely bound to proteins initially
and increases in binding to about 75% after 6
hours. Approximately 12% of the administered
dose accumulates in the kidney, largely in the
cortex.Urinaryexcretionisnearly 50% in 2
hours and 70% in 24 hours. The brain and renal
scintigraphs show a distribution of activity sim-
ilar to that of DTPA. Like DTPA, GH does not
accumulate in the choroid plexus.
""Tc-LABELED MACROAGGREGATED
ALBUMIN OR ALBUMIN
MICROSPHERES
9mTc-labeledmacroaggregatedalbumin
(MAA) or albumin microspheres commonlyare
used for lung perfusion imaging. The particles
are about 10-90 prn in size, and in a dose of
3-4 mCi, approximately 100.000-500,000 par-
licles are administered per injection. The parti-
cles are lodged in capillaries and precapillary
arteries during the first transit of blood circula-
tion through the lungs. Larger particles (> 150
pm) should not be administeredbecause they
may occlude precapillary arteries and cause re-
gional pulmonary embolism.
Theclearance of particles fromthelungs
depends onthesize andnumber of particles
administered. Approximately 50% of 50- 100
million MAA partides in the 10-70-pm range
is cleared from human lungs in about 4-6 hours
(9, IO). Albumin microspheres are cleared more
slowly than are MAA particles, because they are
more rigid and their clearance is slower (of the
order of 12-24 hours) (11). Mechanical move-
? Glucep~ateis the official (USAN) name for what was
previously known as glucoheptonate; the commonly used
abbreviation "GH" comes from this latrer lenn.
I 5
ment and certain enzymatic action in the lungs
break down the aggregated particles into smaller
ones which are then removed by the reticuloen-
dothelial system (RES) (12, 13). Some radioac-
tivity is excreted bythe kidney,and urinary
excretion is about 42-46% in 48 hours (14).
In normal lung scintigraphs, labeled particles
are evenly distributed in anterior and posterior
projections.Somewhatless activity is seen in
the upper zones due to less lung voiume. The
well-defined defecl due Lo the heart is seen on
anterior and lateral views. The lungs look rela-
tively smaller in obesepatients.Minor varia-
tions in thedistribution of particles,due to
slight abnormalities in the pattern of blood flow,
particularly in the right lung, are observed in
about 20-25% of apparently hearthy subjects
(15). Perfusion defects also are seen in elderly
subjects, which is perhaps related lo undetected
obstructive airway diseases (16, 17). The posi-
tion of thepatientalso affects the distribulion
pattern of MAA particles. If patients in an up-
right position are given injections, particles set-
tle at the bottom of the lungs and less activily is
seen in the upper part of the lungs. Normal lung
scintigraphs are shown in Figure 1.2.
99"T~-LA3ELED
COLLQIDS
99mTc-labeledsulfur colloid is the most com-
monly used radiolabeledcolloidinnuclear
medicine. The size of these particles varies be-
tween 50 rm and 500 nrn, with a mean of 150 -
nm, and [hey are removed bythe RES (liver,
spleen, and bone marrow).
After intravenous injection, about 80-85% of
the dose accumulates in the liver; lo%, in the
spleen; and the rest, in the bone marrow. Vari-
ousfactorssuch as hepatic blood flow, RES
integrity, the size and the number of parlicles,
and the physical characteristics of particles af-
fect the in vivo distribution of the colloid (18,
19). Theparticles are lodged permanently in the
reliculoendotherial cells and the effective half-
life is almost equal to the physical half-life of
99111T~. The plasma clearance half-time is about
2-5 minutes, and themaximumliver uptake
occurswithin10-15minutes.Theclearance
rate of colloid particles depends on the blood
volume perfusing the liver and on the number of
particles. As the number of particles increases,
6 I Essentials of Nuclear Medicine Science Normol Biudisrribulion of Diagnostic RatliopkarmacelrticnEs 1 7

q$

POST RAO LPO RL ANT POST ANT/MARK

ANT RAO LAO .tL RL LL R A0

Figure 1.2. Normal lung scintigraphs obtainedin different projections after administration
of 4 mCi of 99mTc-
MAA. POST, posterior; RAO, righlanterioroblique; LPO, left posterioroblique; RL, right lateral; ANT,
anterior; LAO, left anterior obIique; L L , left laleraI.

the clearance rate falls, reaching minimum val- of estrogen,endotoxin,heparin, and perhaps
ues withprogressivesaturation of the pha- other substances(22). Normal liver scintigraphs
gocytic capacity. In normal adults,themax- obtained with use of 3 mCi of 99mTc-labeled
imum clearance in each passage is about 94% sulfur colloid are shown in Figure 1.3.
(20). Anothercolloid of importanceis94mTc-la-
In normal subjects, there are wide variations beled antimonysulfidecolloid whichis com-
in the distribution of radioactive colloids due to monlyused forlymphoscintigraphy.The par-
various contours of theliverand spleen. In ticle size of this colloid ranges between 10 nm
decreased hepatocellularfunction, Ihe colloid and 20 nm. Subcutaneous injections are made Figure 1.3. Norma1 liver scintigraphs obtained in different projections after administration
of 3 mCi of WmTc-
uptakeis shifted toward thespleenandbone betweenthefirstandsecondmetatarsalsfor labeled sulfur colloid. ANT, anterior; POST posterior; ANTIMARK, anteriortmarker; RL, right lateral; LL, left
marrow. Often, the uptake at the junction of the imaging of lymphatic flow in the legs, between lateral; RAO, rightanterioroblique; LAO, left anterior oblique; RPO, rightposterioroblique; LPO, left
poslerior oblique.
right and left lobes is diffuse dueto the thinness the first and second metacarpals for imaging of
of the connective tissues. The densityof spleen the arms, and at both sides of the xyphoid pro- -~ phomaorpartialblockade ofthe lymphatics. Indroxymethylene diphosphonate (HDP)are com-
activity usually is the same asor somewhat less cess for imaging o€ the parasternal nodes. Ap- parasternal lymphnodescintigraphy, 96% re- monly used for this purpose. Approximately 20
than that of right posterior activity. The most proximately 80%of the colloid is transported by producibility was obtained by Ege (23). mCi of *"Tc-MDP or WmTc-HDP are admin-
"

commonlyencounteredartifact is dueto the thelymphaticsystem. At 24 hours after and istered intravenously to the patient, and scinti-
scatter of 140 keV y-rays of 9 9 m T in~overlying depending on the site of injection, the inguinal, 99mT~-LABELED PHOSPHATE graphic
images
are
obtained 2-3 hours after
structures,suchasfemalebreasts.Another iliac,andperiaorticregions,severallymph COMPOUNDS in-jection. Immediately
prior to imaging, the
common linding is the lung uptake of colloids. nodes in the parasternal region, and other lymph Several99n'Tc-labeled phosphatecomplexes patient should void in-order to reduce the back-
This uptake has been atlributed to phagocylosis nodes are seen.Discontinuity in the flow of havebeen investigated for bone imaging; cur- ground from the bladder activity.
by macrophages in thelungs (21) or by RES radioactivity may result from metastasis; in- rentiy,however, only99mTc-Iabeledmethylene A comparative study of four phosphate com-
cells migrated into the lungs under the influence creased activity in any area may be due to lym- diphosphonate (MDP) and 99111Tc-labeled hy- pounds(wg"Tc-labeledpolyphosphate,pyro-
 8 1 Esseutials of Nuclenr MedicineScience
phosphate (PYP), hydroxyethylidene diphos-
phonate (HEDP), and MDP) has been made by
Subramanian et al. (24). At 2 hours after admin-
istration to rabbits, the boneuptake of both
HEDP and MDP is about 7-9% of the admin-
islered dose per 1% of total body weight, but the
absoluleboneconcenkation was significantly
higher for both diphosphonates than for PYP. In
humans, the blood clearance of HEDP is some-
what slower than that of MDP for the first 6
hours, but at 24 hr the blood level of HEDP is
slightly lower than that of MDP. Theblood
clearance was much slower forPYP than for
either diphosphonate. The 24-hour urinary ex-
cretion of HEDP and MDP is about 7s-8095,
while that of PYP is about 60%. Protein-binding
of MDP and PYP has been reported to be ap-
I
proximately 22% ( 2 5 ) and 42% (26), respec-
tively, 2 hours after injection. Theprotein-bind-
ing of HEDP is aboul 30% at 3 hours (24).
Recently, 99mTc-HDP has been inlroduced
and shown to have better bone localization than
does MDP (27, 28). Rib uptake values of HDP
and MDP in dog are 5.4% and 4.3%, respec-
tively, ofthe administereddose per 1 gm of
body weight. Urinary excretion inrdog is about
59% in 24 hours.The relativelylow urinary
excrelion of HDP compared with MDP, how-
ever, is primarily due to skeletal uptake rather
than to protein binding. A comparative study of
whole-body retention reflecting skeletal uptake
of threediphosphonates(HEDP,MDP,and
HDP) has been made in humans by Fogelman et
al. (29). This study has shown that the whole-
bodyretention of thesethreecompoundsis
18.4%, 30.3%, and 36.696, respectively, which
indicates greater uptake for HDP. Clinical stud-
ies also have proved this material to be some-
what superior to MDP.
Increasedblood flow, reactive boneforma-
tion, and extraction efficiency of the bone min-
eral are the determining factors for bone uptake
of %"'Tc-labeled phosphate complexes. Uptake
ishigher in thegrowing skeleton of children
than in the skeleton of adults.Boneuptake
decreases with increasing age. Symmetric areas
of increased concentration are seen in the meta-
physeal zones in the growing skeleton. Ankles,
knees, elbows,wrists, shoulderjoints,pelvic
bones. and vertebrae are all seen with increased
Normal Biodistributiotg of Dingnostic Rndiophart?lace;lficaIs I 9
uptake.Approximately 2-4% of theinjected
doseaccumulates in thenormalkidneys,al-
thoughtheisotopemaylocalizeinnormal
breasts, softtissues,tumors,and sites of in-
flammaiion and injeclion. Norma1 anterior skel-
etal scintigraphs obtained with 99mTc-HDP are
shown in Figure 1.4.
Wilrerson et a]. (30) has shown that 9 9 m T ~ -
ik- i
PYP accumulates in myocardial infarct to such
an extent that meaningful imaging could be
made of the infarcts. It has alsobeen shown that
[here is reasonable accumulation of 99mTc-HDP
in myocardial infarcts (28). In the canine, the
uptake values of 99mTc-HDPand 99mTc-PYPare
5.1% and4.4%, respectively, of theadmin-
istered doseper 1 g m of body weight in in-
farcted myocardium, compared with 0.15% and
0.13% in normal myocardium.
""Tc-LMELED IMINODIACETIC ACID
DERIVATIVES
lminodiacetic acid (IDA) derivatives labeled
with 99n1T~ are routinely used for evaluation of
hepatocytic function.LobergetaI.(31) first
introduceda 99mTc-Iabeled derivative of IDA ANTERIOR BONE IMAGES
for this purpose. Wistow et al. (32) developed
andevaluated such IDA derivatives as 2,6-di-
ethyl, p-ethoxy, andp-iodo-DA and found that
all hadexcellenthepatobiliaryspecificity and
differed primarily in blood clearance and urin- minutesafteradministration ( 3 3 , 34). As 99mTc-diethyi-IDAhasprovedtobevery
ary excretion. Newer derivatives are p-isopropyl hepatocellular funclion decreases and bilirubin useful as a hepatobiliary agent (38-40). In rab-
(PIPIDA) and diisopropyl-substituted iminodia- level progressively increases, hepatobiliary ex- bits, its blood content is about 1.2%, and urin-
cetic acid (DISIDA) that have been shown to cretion decreases and renal excretion increases. ary excretion is 9.0% of the administered dose
have belter hepatobiliary characteristics. Lenglhening the alkyl chain on the benzene 30 minutes after administration (35). The subse-
Approximately 3-5 mCi of a 99mTc-labeled ring of the IDA molecule resuits in increased quenldevelopment of DISIDAderivalives,
IDA derivativeisinjected intravenously into hepatobiliary excretion and reduced urinary ex- however, has addedsignificantly io hepalobil-
humans who have fasted for 2-4 hr, and irnag- cretion.PIPIDAbehavessimilarlytoHIDA, iaryimaging, and currentlyit is the agent of
ing is performed at different time intervals up to except that it gives slightly better visualization choiceforthispurpose.Thirtyminutesafter
1-4 hours, which indicates liver function and of the biliary system when the biIirubin level is intravenous administration,nearly 8% of the
biliary patency. The liver activity is seen within 20-25 mgldl (35). The common bile duct isnot dose remains in the circulation. Approximately
a few minutes, is cleared rapidly, and appears in well visualized by PIPIDA, however. Its urinary 9% is excreted in the urine in the first 2 hours
thegallbladderandthenintheintestine. In excretion in rabbits is about 7.5% of the dose 30 after injection. In fasting individuals, maximum
dogs, the blood clearance half-time of WmTc- minutes after administration (36).99mTc-labeled liver uptakeoccursby 10 minutes,and peak
HIDA is only a few minutes, with only 3% of butyl irninodiacetic acid (BIDA) has somewhat gallbladder activity, by 30-40 minutes after in-
the injected dose remaining in the blood at 30 slower plasma clearance and liver uptake and jection (41). 99mTc-DISIDAprovidessuperior
minutes,andcumdativeurinary excretion is muchlessrenalclearancethanhasPIPIDA images when the bilirubin level is 20-30 mgldl.
about 17% of the administered dose at 2 hours (37). Urinary excretion is of the order of 0.7% In normal scinligraphs, the liver is well vis-
after administration. The hepatobiliary system of the injected dose 30 minutes after adminisIra- uaIizedwithin 5 minutesafteradministration.
is visible with a bilirubin level as high as 5-8 tion (36). It is useful when the bilirubin level is Afler this, the tracer is cleared from the liver
rng/dl. The gallbladder could b e seen within 30 10-20 mgldl (35). andexcretedinto thebiliarytree,the hepalic
 x
'_- -
. , -
.=
<-
~-
10 I Essentials of Nncleur Medicine Science Normal Biodistriburion of Dingrzosiic Rndiophar?naceuticols t Ii

ductsand, later, the gallbladder. In normally tainedwith""Tc-DISIDA are showninFigure quently been made by Subrarnanian et al. (8). pool, whereas a separation of the heart from the
f u n c t i o n i n hg e p a t idc u c t sa,c t i v i t w
y i l1l . 5 . After intravenous injection, it is excreted in the surrounding lung blood pool by more than 2 cm
promptly flow into the duodenal sweep and urine by both glomerular fiitration and tubular raises the probability of effusion (48).
proximalsmall bowel. The total timefor this 99"TC~D1MERCAPT~SUCC1N1C secretion. In humans, the renal uptake is about When99mTc-labeledRBC are denatured by
complete flow of IDAcompoundsshould not 99mTc-dimercaptosuccinicacid (DMSA) isa 12% of the administered dose at 1 hourafter heating at 50" for 15 minutes, they accumulate
exceed 45-60 minutes in normal patients. Nor- renal agent which was first introduced by Lin et injection, with most of the dose localizingin the selectively in the spleen. Twenty minutes after
mal scintigraphs of the hepatobiliary system ob- al. (42); a detailed study of this agent has subse- cortex, which results in a very high cortex-to- injection, blood radioactivity falls below 50%
medulla activity ratio. This value is somewhat of its maximum value (49). The plasma clear-
lower than the 48% quoted by Kawamura et al. ance curve is biphasic, and the ratio of unit area
(43). The blood clearance of 99mTc-DMSAin spleen-to-liver activity at the body surface ex-
humans is slow Itl? = -10 minutes), and there ceeds 4:l in normal patients (49).
is no diffusion of the tracer into red cells. Ap-
proximately 75% of 99mTc-DMSAisloosely 99"T~-ALBUMIN
bound to plasma proteins initially. The amount Humanserumalbuminlabeled with 99mTc
of 99mTc-DMSA bound increases to 90% at 24 was introduced by McAfee et al. (50) for imag-
hours.Urinaryexcretion is about 37% at 24 ingpracenta. A15-mCidosegiven by intra-
hours. venous injection has been used for blood pool
Approximately 2-5 mCi of %"Tc-DMSA is imaging. McAfee et al. (50) has observed that 5
ANT(5') ANTCIO') ANTCIS) injected intravenously, and renal images are ob- minutes after injection, the first biological half-
tained at theposteriorposition. Bothkidneys life of 99mTc-albumin is about 6 hours, with a
arewell visualized, with defectsseenascold subsequentcomponent with ahalf-time of 3
spots. A number of investigators (43-46) have days. In normal humans, less than 0.5% of the
usedthis agent and havefound that excellent injected radioactivity isrecovered in the urine or
renalimagesusedtoassessthedifferenlial feces within the first 24 hours after injection.
slatus of both left and right kidneys have been The placenta contains about 1% of the admin-
obtained. istereddoseper 1% of thematernalbody
weight.
99"T~-LABELEDRED BLOOD CELLS Cardiacchambersarewellvisualized by
Red blood cells (RBC) are labeled with ssmTc 99mTc-albumin.This tracer is not as goodas
byboth in vitro and in vivomethods.99mTc- WmTc-labeled RBC for cardiac imaging, how-
labeled RBC are primarily used for bIood pool ever, because albumin has a larger extravascular
visualization and asdenatured red cellsfor comparlment of distributionthandoRBC,
spleen imaging. which compromises the resolution of cardiac
ANT(30'1 LAOC30'1 R L (30'1 The biodistribution of 99mTc-labeledRBC in images. It has been pointed out by Rhodes (51)
humans has been studied by Larson et al. (47). thal various methodologies in the preparationof
The blood disappearance curve has two compo- 99mTc-albumininfluencethedistribution of
nents: onewitha tlr,of 29hours(95%)and 99mTc-albuminprimarily due to the presence of
another with a t @of 20 minutes. Approximately free and reduced technetium.
5% of the activity is observed in the spleen due
to either sequestrationof damaged RBC or equi- SODIUM [luI] OR ['3'I]IODIDE
libration with splenic blood pool. The cardiac Iodide normally is absorbedfromfoodinto
chambers are well visualized. In most cases, a the blood through the gastrointestinal tract, and
myocardial halo of decreasedactivity is seen, its bloodcontent reaches maximumwithin 3
lying between the left ventricular chamber and hours. Radioiodide in blood is found mostly in
the lung blood pool. The ratio of the left ven- plasmaandto a lesserextent in RBC.The
tricular activity to background activity is about plasma clearance of iodide is exponentiai and
2.5-2.7.Thenormalcardiacblood pool oc- rapid.
M45') POST(2-h r) cupies less than half of the total diameter of the For thyroid studies, approximately 50 pCi of
Figure 1.5. Normal scintigraphs of the hepatobiliary system obtained after adminislration of 5 mCi of WmTc- chest at its widest dimension. Cardiomegaly is Nal3]I or 300 p,Ci of Natz3I isadministered
DISIDA. ANT, anterior; LAO, left anterior oblique; RL, right lateral; POS7; posterior. seenasanenlargement of thecardiacblood orally, and uptake and imagingare performed at
 12 t Esserltials of Nuclear Medicine Science
24 hours.The thyroidgland extracts aImost
20% of the iodide in asinglepassfromthe
blood that perfuses the gland. The iodide trap or
pump concentrates iodide almosl 25 times the
plasma level, but the concentration may be in-
creased asmuchas 500 timesundercertain
conditions, such as iodide deficiency. The trap-
pediodide is oxidizedbyan enzyme to form
iodine which then iodinates tyrosine to produce
moniodotyrosine (MIT) and diiodotyrosine
(DIT).Thisprocess of iodination is called
organification. MIT and DIT further condense
toform T, and T4 which are then bound to
thyroglobulin, part of which is reIeased in the
blood circulation under the influence of thyroid-
stimulating hormone (TSH).
The normal 24-hour thyroid uptake of iodine
is 10-35%, butuptakevaries because of the
"cold" iodine content in food in different en-
demic areas. Thehigh plasma level of iodide, or
the presence of perchlorate, thiocyanate, chlo-
rate, or iodate, or theadministrationofmeth-
imazole or propylthiouracil can reduce the thy-
roid uptake of iodide, whereas the administra-
tion of TSH would increase the uptake.
Other glands, such as salivary andgastric
glands, concentrate iodide about as efficiently
as the thyroid, although iodide in salivary and
gastricsecretionsis not lost from the body,
since it is reabsorbed from the intestinal tract
(52). Iodide alsoaccumulates in thekidneys,
sinceitis fiiteredby thekidneys,andabout
73% normallyis reabsorbedbythe tubules.
Urinary excretion is 37-75% (53), fecal excre-
tion is about lo%, and sweat excretion is almost
negligibIe in 24 hours. The morphological dis-
tribution of iodide in the thyroid glands is sim-
ilar to that of pertechnetate.
u-~'~'I]IODO~IPPURATE (HIPPURAN)
The primary use of I3'I-hippuranis in the
assessment of renal function. When renography
is perfonned, approximately 40-50 pCi of I3lI-
hippuran is administered intravenously. If both
renography and renal imaging are intended,
however, about 250-300 pCi are injected. Re-
nograms are obtained by tracing the flow of
activitythrougheach kidney againstthetime
afterinjection.Imaging is performedevery 5
minutes or so over a period of 45-60 minutes.
Hippuraniseliminatedbythekidneys
through glomerular filtration(20%) and tubular
secretion (80%). The plasma clearance is very
rapid (about 30 minutes). Normal adult hip-
puran clearance approximates 500-600 ml
plasma per 1 minute, and 70% of the injected
dose is excreted in the urine 35 minutes after
injection. Depending on the degree of hydration
of the patient, the peak renal concentration oc-
curs in 2-5 minutes after injection (54-56). A
dehydrated patient will demonstrate peakpar-
enchymalactivityslightlylater andmayhave
deIayedclearance.Proteinbindingisabout
60-70%, but the bond is very weak and thus
dissociates rapidly. Whenever renal function is
to be measured, free iodide in the 1311-hippuran
shouldbeless than 3%; otherwise,effective
renaI plasma flow would be reduced consider-
ably (57). Anactivetransportmechanism ac-
countsfortheexcretion of hippuran by renal
tubules (58).
6P-I'311]IODOMETHYL-19-
NORCHOLESTEROL (NP-59)
Thecompound 6P-11311]iodomethyl-19-nor-
cholesterol (NP-59) isavailable from the Uni-
versity of Michigan and is used in a dose of 2
mCi for adrenaI gland imaging. In dogs, 5%kg
dose/gm$ accumulates in the adrenal cortex as
early as 2 days after the dose; the peak value of
8%kg doselgm is reached at 10 days (59). Most
accumulates in the cortex of the adrenal gland.
The highest concentration of NP-59 is found in
thethyroidglandsandamounts to about
12-14%kg doselgm at 1 0 days. Urinary excre-
tion is about 29% in 9 days.
Images are obtained at 4-8 days after injec-
tion. Adrenal glands are seen as ovoid areas of
persistent and fairly equal activity near the mid-
line. Liver uptake is seen superior and lateral to
the right adrenal gland. The gallbladder also is
seenprior to 7 daysafteradministration. A efficiencyfor201Tlindogsisapproximately
repeat scan after a fatty meal helps clarify most
of these situations. Often bowel activity, partic-
ularly that seen on early images, can be elimi-
nated by laxatives (60).
$ %kg d o s e l g ~ ~ ~
X body weight in kg
- pCi in organlgm
- X
pCi administered dose
Normal Biudistribution of DiagnosticRadiopharmaceulicals I I3
lz5I-LABELEDFIBRINOGEN A normal thallium image is characterized by
1251-labeledfibrinogen is primarily used for uniform distributionof ?OIT1activity throughout
the left ventricular myocardium.A Iarge area of
thedetection of venousthrombus.Approx-
decreased activity in the center is dueto the left
imately 100 pCi of this agent are injected intra-
venously, and venous thrombi are detected by ventricularcavity. Decreased activity may be
external counting at various sites over the lower seen in the cardiac apex due to thinness of the
extremities. The biological half-life normally is posterior basal areaof themyocardium.The
proximal portions of the septum and posterior
about 3.5-4.1 days, but about 33% of the ad-
lateral wall, as seen in the LAO images, show
ministereddosehasahalf-life of about 12
somewhat nonuniform distribution ofactivity.
hours. Almost 80% of thebody'sfibrinogen
pool is within the circulating plasma volume. Its The right ventricle often is seen on the exercise
images, withIittle or no activityseen on the
uptakeis not specific for venousthrombosis
redistribution views.
because it alsoaccumulates in surgicalinci-
The quality of zolTl images can be greatly
sions,inflammatorylesions,andgrossedema
of lower extremities (61). Detection of thrombi enhancedby computerprocessing.Thecom-
with this agent is more accurate in postoperative mon methods involve background subtraction,
patients than in patients with overt clinical man- contrast enhancement, and image filtering. An-
other approach has beento define quantitatively
ifestations.
the relative distribution of 201T1 in the myocar-
[ 201T~JTHALLOUS CHLORIDE dium as a function of space and/or time. This
Variouscardiovascular diseases are detected method has been accomplished with use of the
by several radiotracers, depending on the type computer and is called the washout technique.
of physiological handling of each radiotracer. With this technique, one can assess the change
of activity in a given area of the myocardium
Functioning myocardial celIs can be imaged
with time or the rerative distribution of activity
with radiopotassium or its analogs, such as43K,
s2Rb, 129Cs,13NH4+,and zO'Tl. Of these, 20'T1 in different segments of themyocardium in a
has been the radiotracer of choice (62-64) be- givenprojection.Anewapproach to to-
cause Kt and T1+ are both monovalent cations mographic imaging with use o€ a seven-piahole
of the same ionic size and therefore concentrate collimator, with which multiple tomographic
equally in the myocardium. slices of the heart can be obtained, has been
Approximately1.5-2mCi of 20'T1 in the suggested. Positioning of theheart(i.e., the
form of thallous chloride are injected intra- patient) and loss in depth resolution are major
venously. Imaging is performed with a camera disadvantages in the tomographic technique.
at different projections (mostly anterior, left an- The extraction of thallium ion bymyocytes
terior oblique (LAO), and left lateral) with the requires that the cations traverse the capillary
patient under resting and stress conditions. The wall, interstitial space, and myocyte membrane.
blood clearance exhibits a biexponential curve The barrier at the capillary wall is dependent on
consisting of components with t M of 5 minutes blood flow, and cations are transported across
(92%) and 40 hours (8%) (65). The24-hour the cell membraneby the active transport rnech-
urinary excretion is about 3-8% of the admin- anism via the Na+-K+-ATPase pump (68, 69).
istered dose (64, 65). The myocardial extraction Since the viable cells take up these radiotracers,
myocardial infarcts would be seen as cold spots.
SS% in asinglepassunderbasalconditions Myocardialimaging during peak exercise and
(66). Maximum myocardial uptake is about 4% then at rest can distinguish between infarcts and
of theadministereddose10-25minutesafter ischemicregions. A coldarea in both sets of
injection (67). Thethyroiduptake isabout images would indicate an infarct, while a cold
0.2%, and the activity disappears in 24 hours. area that fills in at rest would suggest ischemia.
Approximately 0.15% of the dose accumulates The thalliumuptake is decreased in ischemic
in the testicles; 3%, in the kidneys; and3-7% in hypoxia resulting from a decreased blood flow
100
the liver (65). (70).
14 f Essenriols ojNuclear Medicine Science
[47G~]GALLIUMCITRATE
[67Ga]galliumcitrate is most commonly used
for the diagnosis of neoplasms, Hodgkin's dis-
ease,andabscesses. For imaging,approx-
imately 2-10 mCi areinjectedintravenously,
and whole-body imaging is performed at 24, 48
and,sometimes, 72 hours later to obtain un-
equivocal information.Thebiodistribution of
67Ga has been studied extensively by Hayes and
his group (71-73).
When carrier-free [67Ga]galliumcitrate is ad-
ministered intravenously, most of 67Ga is bound
to plasma protein, specifically totransferrin.
Urinary excretion is nearly 15% in 24hours,
fecal excretion is nearly 10% in 24 hours, and
the remainingaclivity stays in thebody (74).
Gallium is secreled by the large bowel and be-
comes prominent after 1 or 2 days. During the
scanning period (i .e., between 24 hours and 72
hours), thehighestconcentrations are seen in
the bone, liver, and spleen. About one third of
Figure 1.6. A normal 67Ga
the tracer is excretedover the first week, and the
remaining two thirds is distributed in the liver
(6%), spleen (l%), kidney (2%), skeleton (in-
cluding marrow) (24%), andother soft tissues
(34%). Relatively high concentrations are also
observed in the adrenals, the large bowel, and
the lungs.Undercertainphysiologicalcondi-
tions, intense localization may occur within the
breast and long bones, and these variations may
mimic malignant tumors (75). Slight uptake of
67Ga in normal lungs has been noted by Braude
et al. (76). The normaldistribution of 67Ga is
affected by various agents, such as iron dextran,
deferoxamine, chemotherapeulic agents, antibi-
otics, and estrogens (77). A normal distribution
of [67Ga]gallium citrate is shown in Figure 1.6.
Subcellular fractionation studies by Hayes
and Carlton (78) showed that 67Ga is primarily
bound to two proteins with molecular weights of
about 100,000 and 50,000 daltons in rat tumor
and liver. The 'j7Ga uptakeisinfluencedby
vascularity, increasing permeability, andrapid
proliferation of thetumor cells. Hoffer et al.
scan at 48 hours. A . Anterior. B . Posterior.
(79) proposed that 'j7Ga binds 10 the lactoferrin theconventionally used SICr-labeledplatelets.
present in body tissues and polymorphonuclear The in vivo kinetics and distribution of Illln-
leukocyles and that the 67Ga-bound lactoferrin Iabeled platelets in humans have been reported
pcrhaps is responsible for gallium Iocalization by several investigators (S8-93). The mean sur-
~ I I tumors, inflammatorydiseases,andab- vival time of [ I 'In-labeled autologous platelets,
scesses. Larson (SO), however, proposed that the based on h e a r fitting of the data, is 8.S days
'I'Ga uptake is mediated by transferrin-specific (91)which is thesameasthatreportedby
receptors on the cell membrane. Wahner et a1 (90). Shorter survival times are
obtained if the data are fitted with an exponen-
"'IN-LABELED LEUKOCYTES tial function.Themean recovery of l['Jn-la-
' I ] In-labeled leukocytes are used for the de- beled pIateIets varies from 57% to 75% (88, 92,
tection of inflammatorydiseasessuchasab- 93). Much of the variation is due to differences
scesses (81-84). Autologousleukocytesare in methodoIogies applied to measure the platelet
labeled with [IIIn-oxine (85), and 200-500 pCi recovery.
of labeIedcellsareinjectedintravenously. Immediately after injection, *"In activity de-
lmaging is commonly performedat 24 hoursbut creases rapidly in the blood but increases in the
can be performed asearly as 12 hoursafter spleen and the liver to relatively plateau values
injection. within 20-30 minutes (90). Thelattervalues
The plasma disappearance half-time is of the change only a little over a long period of time.
order of 5-7 hours (81, 86). Urinary excretion The spleen uptake is found to be approximately
is negligible (86). The in vivodistribution of 40% at 7-9 days, while the liver uptake ranges
ll[In-labeled leukocytes reflects thenormal pat- between 13% and 25% (90, 91). The liver ac-
tern of distribution of leukocytes.Approx- tivity is due to sequestration of damaged plate-
imately 50% of the cells accumulate in the liver; lets. There is no discernible accumulation in the
about 1 I % , in the spleen; and about 8%, in the lungs or in the abdomen outside the spleen or
lungs. Most of the activity in the lungs repre- liver. At a latertime (9 days afterinjection),
sents background activity over the entire chest slight visualization of bone marrow is observed.
area and does not appear on the scan as a focal
spot (87). [75S~]SELENOMETHIONINE
A variety of inflammatorydiseasescanbe P a n c r e a si m a g i n g is p e r f o r m e dw i l h
detected by the use of I 'In-labeled leukocytes. [7SSe]selenomethionine; theusualintravenous
Abdominal abscesses, renal inflammation, and dose is 250 pCi. Approximately6-7% of the
active colitis, among others, are the most com- adminislered dose accumulates in the pancreas
mon. Disadvantages in the use of lllIn-labeled within 1 hourafter administration (94). The
leukocyles are long time of preparation (-2 biologic half-life is about 47 days. Urinary ex-
hours) and high radiation dose to the liver and cretion and fecal excretion are about 80% and
spleen (4 rad and 24 racUmCi) (86). 1.57'0, respectively.
The leukocyte uptake in the abscesses or in- Selenomethionine is utilized in the synthesis
flammatory diseases is effected by the migra- of pancreatic enzymes in the pancreas. As an
tion of these cells through the capillary waIl lo amino acid, however, it accumulates in the sali-
the point of injury or infection. This migration vary glands, liver, and small intestine. For these
is caused by the release of a polypeptide known reasons, often the pancreatic image is obscured
as leukotoxine which increases the capillary by the liver and surrounding activities.
permeability.
lJ3XE
1111~-LA3ELED PLATELETS l3jXe is an inert gas relatively insoluble in
lL[ln-labeledplatelets have been used in hu- water but slightly soluble in blood and fat. 133Xe
mans for the deteclion of thrombi, measurement gas is used for thelung ventilalion study in
of platelet survival, and other kinetics, and in order to delemine the ainvaypatency of the
severallaboratories,this methodhas replaced lungs. Ten to 15 mCi of 133Xegas are mixed
I6 I Esselzrial.7 of NrrcleorMedicineScience
BREATHOLD EO 1
wo1 wo 2
Figure 1.7. Normal lung ventilation scintigraphs obtainedafter administration of
washout.
with air in a closed-system xenon machine for
eachpatient.Thepatient is asked to inhale
'33Xe from the machine and to hold the breath
for 15-35 seconds. At this time, a single-breath
image is obtained. For the next 4-5 minutes,
the patient rebreathes the mixture in the closed
system, and equilibriumimages are obtained.
The next phase of the study is the "washout" in
which the patient inhales fresh air and exhales
133Xe into the system containing a xenon-ab-
sorbing charcoal filter. Several images are ob-
tained over a period of 4-5 minutes during this
"washout" phase.Imagingisperformedwith
the patient in the uprighl position, and posterior
viewsare obtained.The'33Xegasdistributes
itself throughout the lungs in a uniform pattern
in patients with normal ventilation, and the even
distributioncorresponds to the lungvolume.
Clearance of xenon from the lungs is rapid, and
in normal men, lung outlines are not seen 3-5
minutesafter initiation of washout. '33Xe ac-
€02-
WO 3
133Xe. EQ,equilibrium; WO,
tivity may be seen in the liver during the wash-
out period due to fatty content of the liver and
thus gives the appearance of delayed clearance
from theright base (95). Any airway obstruction
is indicated by retention of activities in the area.
Regions with decreased activity on thesingle-
breath view are considered abnormal (96-99).
Normalventilationscintigraphs are shown in
Figure 1.7.
ACKNOWLEDGMENTS
Scinligraphs for Figures 1.1, 1.2, 1 . 3 , 1.5,
and 1.7 were kindlysuppliedbyRobertA.
Johnson, M.D., Presbyterian Hospital, Albu-
querque, NM.
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donunal abscess. Am J Surg 13999-104, 1980. dose to humansfrom'SSe-selenomethionine. J Nucl
64. SchelbertHR.Henning H, Rig0 P, et aI: Considera-
83. Carroll B , Silverman PM, Goodwin DA: et al: Ultra- Med (MIRD suppl 6, pamphlet 9): 10, 1972.
tions of "IT1 as a myocardial radionuclide Imaging
sonography and indium-l 1I whlte blood cell scanning 95. Carey JE, Purdy IM, Moses DC: Localization of lJ3Xe
agcnrin man. Irwesr Rndiol 11:163-17I, 1976.
for the detection of intraabdominalabscesses. Rndi- inliverduringventilationstudies. f l v d Med
65.Alkins HL, BudingerTF,LebowilzE,et al:
ology 140:155-160.1981. 15:1179-1181.1974.
Thallium-201 for medical use.Pan 3.Human disuibu-
lion and physicalimagingproperties. J NrclMed
84.Bicknell TA, Kohatsu S , Goodwin DA: Use of in- 915. Alderson PO, Secker-Walker RH. Forrest JV: Detection
dium- 111 -labeled autologous leukocytesin differentiat- of pulmonary disease. Radiology 11 1643-648, 1978.
18:133-140,1977.
ing pancreaticabscess lrom pseudocyst. Am J Srrrg 97. Alderson PO, Lee H, Summer WR, et al: Comparison
66. WeichHF, StraussHW,Pilt B: Theextraction of
142:312-316, 1981. of Xe-133 washout and single breath imaging for the
thallium-201 by the myocardium. Circrhtiorz 56:
85. Clay ME, McCullough J, Forstrom LA: Indium-lll- detection of ventilationabnormalities. J N~rclMed
188-191, 1977.
labeled leukocytes: preparationand labeling technique. 20:917-922,1979.
67.Bradley-Moore PR, Lebowitz E, Greene MW, et al:
In WahnerHW, Goodwin DA (eds): 11I-hdium-~Q- 98. Milic-Emile J: Radioactive xenon In the evaluation or
Thallium-201 for medical use. 11. Biologic behavior. J
beied Platelets a t d L e ~ k o c y f e sCrystal
. Lake, IL, Cen- regionallungfunction. Semin Nucl Med 1:246-252,
NuclMed 161.56-160, 1975.
tral Chapter, Society of Nuclear Medicine, 1981, p 57. 1971.
68. Tancrcdi RG, Yipinlsoi T, Bassingthwaighte: Capillary
86. Williams LE, Forstrom LA, Weiblen BJ, et al:Esti- 99.Anderson PO, Bruce R L Scintigraphicevaluation of
and cell wall permeabilily to potassium in isolated dog
mates of dosimetrv for In-1 11 granulocytes. In Wahner regional pulmonary ventilation. Semin Nucl Med
hearts. Am J Physiol 229:537-544. 1975.
H W , Goodwin DA (eds): Ill-Irldilrm-labeledPlarelets 10:218-242. 1980.
69.Strauss H W , Harrison K , Langan J K , etal:
Thallium-201 for myocardialimaging:relation of
thallium-201 to regional myocardial perfusion. Cir-
culatiorr 51:641-645, 1975.
70. Levenson WI, Adolph RJ, Romhilt DW, et al: Effects of
myocardial hypoxia and ischemia on myocardial scinti-
gwphy. Am J Cardiol 35:251-257, 1975.
71. Harbman RE, Hayes RL: The binding of gallium and
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sociatcdUniversities,1967.
 2
Radiophar.macokinetics in Nuclear Medicine
Jeffrey A ClantonI
Radiopharmacokineticsisthestudy of the
time course of radiopharmaceutical distribution
in the various fluids, organ systems, and excreta
of the body and the use of mathematical rela-
lionships to mode1 and inlerpret these data. The
ultimate goal of radiopharmacokinetics is as di-
verse as its definition. To some, the goal is to
develop a better or more selective radiopharma-
ceutical. Others may use the models and infor-
mation derived from the data to calculate radia-
lion dosimetry. The mostprevalent use of the
data, however, is to assessorganfunction for
diagnostic purposes.
BASICS
In order to develop an appropriatemathe-
matical model after experimental datahave been
collected. assumptions regarding compartmen-
tal distribution of the tracer must be made. The
most common method employed forp h m a c o -
kinetic modeling is to represent the body as a
series of compartments ( I ) . This, like other
methods, is not without limitation. The major
problem is tofind a sufficient, yetnot ex-
haustive, method of mathematically describing
one or more groups of pharmacodynamic data.
A “compartmentalizedsystem” is, therefore,
anaverage of thephysiologicalsystemrather
than an exact representation (2).
There are three major steps in the complete
kinetic evaluation of experimental data (3):
1. Choice of themost appropriatepharmaco-
kinetic model
2. Fitting of the model curve(s) to the experi-
mental data
3. Use of derived rnodel(s) and parameters for
prediction
20
This chapter is focusedon the details of the first
andthird steps of kinetic analysis, withintro-
duclory informalion provided on step 2.
Single Compartmental Analysis
Of the compartmentalmodelsthalcanbe
utilized,theone-compartmentmodel is the
most simple. In this model, lhe body is depicted
as one largehomogeneousunit, and ilisas-
sumed that changes in plasma drug levels quan-
litatively reflect changes in tissue drug levels. It
is also assunled that the drug is eliminated in a
single-exponential or first-orderfashion(Fig.
2.1). After it has been determined that the one-
compartment model is suitable for theexperi-
mental data, the following equation can be ap-
plied:
X = Xoe-kr Equation
2.1
where X , is the amount of drug injected, X is the
amount of drug remaining in the compartment
at time t, and k is the first-order eliminationrate
constant.
Equation 2.1 is of litlle imporlance, however,
because X cannot be determined in vivo. With
this model, it isassumed that the total biological
system is onecomparlment;itcanbefurther
assumed, therefore, that there is a relationship
between the drug concentration in plasma (C)
and the amountof drug (X)in the compartment.
This assumption leads to the following equation
(1):
X = VC Equation 2.2
In this equation,theconstant V hasunits of
volume and is known as the volume of distribu-
tion. The volume of distributionusuallydoes
not have direct physiologicaI significance or re-
i lntravosculor\
1
1
Rodiopharmoceutical~
I
I
1 1 I I
I’ I
IO 20 30 40
TI ME
Figure 2.1. Semilogarithmic graph ol plasma concentration as a function of time. The data follow a single-
exponential decline that is described by Equation 2.3.
fer to actual blood volumes, however, as I.‘ may
be as much as several hundred liters in a 70-kg
man. The relationship (Equation 2.2) between
the amount of drug ( X ) in the compartment and
the drug concentration (C) enables the conver-
sion of Equation 2.1 from an amount-time Lo a
concentration-time relationship as follows:
kt
L o g C = Loge,- - Equation 2.3
2.303
where C, is the plasma concentration immedi-
ately after injection. SinceX, equals the amount
of the drug injected and C, can be extrapolated
from the plot of the data generated with Equa-
tion 2.3, the volume of the distribution can be
estimated with the following equation:
Intravenous dose
V = Equation 2.4
co
Radiopharmaceuticals that can be sludied with
use of the one-compartment model include: Ia-
beled albumin or red blood cells for blood pool
imaging, 133Xe for pulmonary ventilation, la-
beledparticles for lungperfusion studies, and
3 H 2 0for total body water detemlinations (4).
Multicompartmental Analysis (Passive)
Often, radiopharmaceutical distributionis too
complex to be interpreted by a single-compart-
I I I 4 I J
50 60 70 80 90 100
ment model. In these cases, it becomes neces-
sary to include two or more compartments in
the modeltoobtaina moredefinitiveassess-
ment. Normally, kinelic data can be separated
into two large but different compartments. The
larger (central) compartment would be consid-
ered the blood and all highly vascular organs. A
smaller (peripheral) compartment consisting of
all poorly perfused tissue (i.e., lean tissue and
fat) could then be established. As with the sin-
gle-compartmentpassivediffusionmodel,
elimination is assumed to be firstorder, as is the
distribution between the two (or more) compart-
ments ( 5 ) (Fig. 2.2).
As would be expected, the mullicompartlnenl
model is used to analyze a radiopharmaceutical
when the plasma clearance is multiexponential
(Fig. 2.3). If a two-compartment model is used,
plasma clearance of the radiopharmaceutical is
biexponential. If the model is further defined to
have excretion out of the central compartment
(Fig. 2.2A), its mathematical model would re-
semble the following equation:
Equation 2.5
where X, is the amount of drug in the central
22 f Essentials of Nuclear Medicine Science

nlent or multicompartment nonlinear model lor UTILIZATION OF

CENTRAL PERIPHERAL i111alysis (Fig. 2.4). Theseprocesses may be RADIOPHARMACOKINETIC DATA
capxcity limited, which requires the use of spe- Dosimetry Calculations
cialized techniques to describe their kinetics.
Radiation dose calculations are essential for
The equation used most frequently for their
A. B. mathematical description is the Michaelis-Men-
the development of anyradiopharmaceutical.
The primary need for performing lhese calcula-
lcn equation (7, 8):
tions is to determinetheapproximate risk a
patient poplalion will be exposed to as a result
of their diagnostic or therapeutic study. There-
fore, the proper kinetic information is needed to
obtain the most accurate dosimetry calculations
where -dC/dr is therate of decrease of the possible.
C. radiopharmaceuticalfrom the compartment at For proper radiation dose estimates, three
time I , is the theoretical maximum rate of the data basesmust be available for thecalcula-
Figure 2.2. A diagrammatic representation of three types of two-compartment systemsthat consist of a central tions. First, the pharmacokinetics of the radio-
and peripheralCompartment. A demonstratesexcretion from the central compartment, B demonstrales
active processbeingstudied,and K,,, isthe
excretion from the peripheral compartment, and C demonstrates excretion from both cornparlments. Michaelis-Menten constant. pharmaceutical must be known. Second, a value
Radiopharmaceuticals that require the use of forthemass of distribution in the "average"
noillinear analysis for accurate modeling in- man must be decided on, and lastly, the type of
compartment, X, is the amount of drug in the S7mSr, W a , and 99mTc-labeled phosphorus com-
clude the following: "'TI and 86Rb for myocar- radiation emitted by theradionuclide with its
central compartment at lime zero, and 1y and p pounds for bone imaging, 9 9 m T or ~ - "'In-DTPA
dial imaging,radioiodinatedhippuran, 9 9 m T ~ - equivalent energy deposition in tissue must be
are complex constants used to replace other con- for cisternography, and *"'Tc-DTPA for renal
DMSA, and 99mTc-gluconate for renal studies, available.
stants(i.e., a = (Kz1K 3 1 ) / P p
, = FJ,, , andstudies (4, 6).
radioiodineand 4 9 m T ~ 0for 4 thyroid, salivary The first phase of this process, the pharmaco-
F , = fraction of the drug in the central compart-
gland, a n ds t o m a c hi m a g i n g ,[ 7 5 S e l s e - kineiics,normally is accomplished by use of
ment). Active or Nonlinear Analysis
lenomethionine for pancreas and parathyroid various animalmodels.Unfortunately,due to
Radiopharmaceuticals that require analysis All radiopharmaceuticals that undergo bio-
by a passive diffusion multicompartment model transformation or otheractiveprocesses (i.e., imaging, I3'J-labeled rosebengaland 9 9 m T ~ - species variation, theanimalkineticdata (if
includethefollowing:99mTc-DTPA, *"Tc- renal tubular secretion and certain hepatobiliary labeled iminodiaceticacid (IDA) compounds extrapolateddirectly to humans) can be the
gluconate, and 99mTcO;for brain imaging, 18F, secretionprocesses)require a single-compart-
for hepatobiliarystudies, [1311]iodomethylnor- largesl single source of error in the calculation
cholesterol and 1251-labeledfibrinogen (4). of radiation dosimetry (9). If, however, a phar-

A=Central
Compartmeni
B=PeripheralCompartment

5
Q
Q

IO 20 30 40 50 60 70 80 90 100
TIM E
Figure 2.4. A semitogarithmic graph of drug levels in a single-compartment modef that exhibits Michaelis-
Menlen kinetics as a function of time.
 :=-=
24 I Essentials of Nuclear Medicine Science Radiopllnr.rnacokillefics in Nuclear. Medicine I 25

macokinetic model based on data obtained from Since the introduction of the IDA compounds, Butyl and dimethyl substitutions on the ben-
lower animals by invasive techniquesiscon- much information regardingthepharmacoki- zene ring have been used to study steric effects
structed and the model is then modified to ac- netics of these compounds has been established. and the rate of hepatobiliary clearance (K4J (14,
cept the compartmental masses, interconnecting VASCULAR VASCULAR Once the kinetic information fora radiophar- 3 1, 32). Whensubstitutions are made in the
pathways, and rate constants applicable to man, Inaceutical has been established, in vitro models ortho position, changes in radiochemical com-
accurate results may be obtained. can be created to test new compounds prior to position as well as in increasedhepatobiliarp
Loberg and Buddemeyer (10) haverecently heir introduction and kinetic study in animals. transit time occur as the alkyl chain length of
demonstrated this approach with the 99mTc-IDA The time, effort, and monetary advantage de- thesubstitution is increased (33-35). Inail
compounds for hepatobiliary imaging. With use rived from use of this type of approach is ob- cases, meta-subslituted derivatives perform the
of indwelling catheters for collection of blood, vious. Nunn (15) established a method of test- best (35). Substitutions made between the ring
bile, andurinefrom dogs (1 I , 12), a four- ing IDA derivatives by using high-performance and the amide group have no effect on in vivo
compartment model was constructed (Fig. 2.5). liquid chromatography (HPLC). distribution (36). If the chain length between the
Then, with use of limited blood and urine data When the radiopharmacokinetic model for amide and imino nitrogen is increased, however,
in combinalion with gammacameraimaging h e 99mTc-labeled compounds is care€ulIy stud- muhiple radioactive species that adverselyaf-
data obtained from normal subjects, the elim- Figure 2.5. Schematic of the pharmacokinetic model ied, severalimportantprinciplescan be ob- fect distribution are produced (14, 36).
for the biological distribution o€ 99mTc-IDA com-
ination rate constants were modified to fit the pounds. served. If there is an increase in the rate con- As with many other compounds, the distribu-
human experimental data (Table 2.1). stant K,, or a decrease in the rate constant K,, tion of the IDA derivatives are affected by net
(Fig. 2.5), hepatobiliary specificity is im- electrical charge.Loberg(37)has shownthat
Table 2.1. Ihe IDA-benzenering. With these biological proved. Further, theprincipaldeterminant of hepatobiliary clearance ( K I 2and K d 2 ) is de-
Inkrspecies-related Variations in the Elimination of changes induced by drug modificalion, an in- hepatic transit time (which is affecled by olher creased,whilerenalclearance ( K 3 , ) isin-
SmTc-HIDA crease in the liver extraction rate constant and a rate constants) is theratefunction K,, (16). creased, when the molecule has a net positive
reduction in the renal excretionrateconstant With use of the kinetic model, the problem of charge (Fig. 2.5). ChiotellisandVarvarigou
Rate Constants
could be obtained to calculate radiation dosime- [he chemical structural requirements can be ad- (14) demonstrated simiiar results with nega-
Species K,? Kza X,? try if the proposed alkyl-substituted IDA com- dressed, In order to achieve hepatobiliary excre- tively charged groups or substilutes capable of
pounds were used in man. lion, the IDA compound must have the follow- hydrogen bonding.
Normaldogs 6.0 14.4 0.56 1.1
Normal man 2.0 6.0 0.49 1.6 ing: (a) diacetatesubstitution on theamine With thisradiopharmacokineticinformation
Radiopharmaceutical Design nilrogen,(b)anelectron-pullinggroupsub- used in conjunction with the SDRs, athird-
In thepast,radiopharmaceuticalstended to stituted beta to the amine, and (c) a lipophilic generation IDA compound (mebrofenin) has
With this type of approach, much of the am- be discovered by trial and error rather than by group separated by substanlial distance €rom the been described by Nunn et al. (38). This com-
biguity of lraditional pharmacokinetics can be careful design. More recently, however. radio- hydrophilic group (29). poundexhibits kineticproperties that enhance
eliminated. Even though the data obtained from pharmacokinetics and structure-distribution re- As the dilferenl sections of the compound are clinical imaging.(Mebrofeninisdiscussed in
humanscannotbeascomplete,therelative lationships (SDRs) h a x become important for changed, the effecls onits pharmacokinetics more detail in Chapter 3 . )
clearance from [he major organs of accumula- thedevelopment of morespecific anduseful can be determined. Results of these studies Unfortunately,theuse of radiopharmaco-
tion,blood,and urinecan beexternallyana- drugs.(SeeChapter 3 foradditionaldetails.) should lead to the development of an agent with kinetic modeling for the development of radio-
lyzed for comparison with the previously con- Recentexamples of radiopharmaceuticals de- high hepalobiiiary specificily, rapid liver transit pharmaceuticals is not without pitfalls. First, it
structed animal model. signedinthisfashionincludehepatobiliary times, and good radiochemical stability. In ad- must be assumed or experimentally proven that
Another advantage of lhis approach, in addi- (14-19), heart (ZO), brain (21-23), and adrenal dition, the agent should be only minimaIly af- the compound does not undergo melabolism in
tionto the increasedaccuracy fordosimetry agents (24, 25). Of these,thekinetics of the ~- fectedby
competingmoeities,
such
high
as vivo and the observed distribution is not that of
calculations, isthe ability to alter theknown hepatobiliary agents have received lhe most bilirubin levels. a metabolite (39). Second, as demonstrated and
kinetics in order to anticipate the changes in comprehensive study and provide the best ex- It is accepted that nonspecific protein binding described by Nunn (15), proteinbindingand
dosimetry that would occur if thedrug were amples for discussion. influences the renal clearance (K31),and is asso- other pharmacokinetic data cannot be modeled
pharmacoIogically improved or if the excretion Hepatobiliary agents have been used in nu- ciated with the lipophilicity, of the drug. Nunn with absolutecertaintywhensubtlechemical
ofthe drug were changed due to disease. Loberg clearmedicinesince1955when Taplin et al. (15, 30) has demonstrated that para-substituted changes are made. Presumably,this isdue to
and Buddemeyer (10) demonstrated this ability (26)introduced 1311-Iabeledrosebengal. De- IDA compounds show the most protein binding. unpredicted steric effects or radiolabeling dif-
withtheirfour-compartment model of 99mT~- spite its limitations, this iodinated agent found When the lipophilicity was compared wilh the ferences. FinalIy, because radiopharmaceuticals
dimethyliminodiacetic acid (HIDA). widespread clinical use (27) as investigators renal clearance, a predictablemodelcouldbe aretypically labeled with “no-carrieradded”
Severalinvestigators (12, 13) havereported strove to discover an agent with better imaging generatedforpara- and diortho-substituted (nnnomolar) radionuclides, it is difficult or im-
thepharmacodynamicchangesseen in animal characteristics (16). In 1975, thefirst 99mTc- cornpounds, but therenal elimination of the possible to directlydeterminethestructure of
models if molecular modifications are made to labeled derivative of IDA was introduced by monoor~ho-substituted compounds couldnot be the resultant compound and isolate a single radi-
the IDA compounds by alkyl substitutions on Harvey etal. (28) forhepatobiliaryimaging. predicled ex vivo. ochemical for injection (34).
-
~~~~

.”
26 / Essentials of NldenrMedicineScience
Diagnosis
The primary function of nuclear medicine in
the medical community isthe diagnosis of func-
tional abnormalities in various organ systems.
Thisdiagnosis is accomplishedby review of
serial images of the uptake and clearance of a
radiopharmaceutical or by review of a static
image in order to screen for functional homoge-
neity. With few exceptions, all diagnostic pro-
cedures in nuclear medicine are performed by
observing the in vivo pharmacokinetics of the
radiopharmaceuticaI.With use of theIDA
model (Fig. 2.5), the kinetics of a normal and
abnormal study can be discussed. Lf liver func-
tion is normal, rapidaccumulation (2-3 min-
utes) of the IDA compound in the liver ( K 1 2 ) ,
visualization of the biliary system (K4J within
10-15 minutes, and activity in the gallbladder
and duodenum 15-30 minutesafter injection
should be seen (Fig. 2.6).
Abnormal function can be observed in a vari-
ety of ways. The most common indications for
the use of the IDA compounds are to rule out
acute cholecystitis or bile duct obstruction. If
there is an obstruction in the common bile duct
(Fig. 2.7), cIearance of I D A fromthe blood
(K,,) and hepatobiliary clearance ( K 4 ? )may b e
fairIy normal. The clearance of the bile out of
the commonduct will be impeded, however,
resulting in increased transit time and an abnor-
mal scan. If the patienthasahighbilirubin
level, the radiopharmaceutical and the bilirubin
will compete for hepatocyte function. The result
will be a decreased K,, and an increased K,,. If
the patient has severe liver disease, K,,and K4,
are decreased and K31is increased. In short, the
actual radiopharmacokinetics are the phenome-
non observed during a nuclear medicine proce-
dure.
Another exampleof diagnosis based on kinet-
ics is the radionuclide renogram. The distribu-
tion andkinetics of radioiodinated o-iodohip-
puric acid (OIH) is a six-comparhnentmodel
(40) too complex to present in detail in this
chapter. The normalkinetics observedduring
Rodiophannacokinefics in NtlcIectr Medicine 1 27
the scanning procedure can be described, how-
ever. The normal plasma clearance half-time of R L
OIH is about 30 minutes, with the peak kidney
activityoccurring 3-5 minutesafterintra-
venous injection. During thenext 10-15 min-
utes, the OIH is cleared from the kidneys in an
exponential fashion (41). In order to obtain
properdata,imagesarenormallycollected
every 30 seconds for 30 minutes, and the infor-
mation is stored fortheconstruction of func-
tional curves (Fig. 2.8). Abnormal renal func-
tion will cause a delay in peak kidney activity, a
delay in visualization of bladder acfvity, andlor 5 min
an abnormal clearance curve (Fig. 2.9).
Pharmacological Intervention
In addition to disease or observed functional
abnormalities,certaindrugscancause altera-
tions in the observed radiopharmacokinetics
(42). For more information on this subject, see
Chapter 10.
CONCLUSIONS
Practical radiopharmacokinetics (i.e., the ob-
servation of in vivo kinetics) has been the basis
of nuclearmedicinesince its inception.The
clinician's knowledge of normaldrugkinetics
withallowablevariance isthemethod that is
still used today for functional diagnosis. It was
not until 1979 that Wolf et al. (43) introduced
the term "radiopharmacokinetics"to describe ~~
the mathematical modeling of radiolabeled
drugs.
Radiopharmacokineticresearchhas the po-
tential €or improving diagnostic roles and dos-
imetry calculations as well as thedesignand
evaluation of radiopharmaceuticals. To date, the
most significant realization of this polential has
been in improved diagnostic techniques and
dosimetrycalculations.
Due to the
polential .~
problems cited previously, radiopharmaceutical
design based on radiopharmacokineticmodel-
ing has been disappointing. With the introduc- Figure 2.6. A normal hepatobiliary scan performed with 5'9mTc-disofenin.There is promptuptake of the drug
tion of new analytical tools, however, this ave- in the hepatic parenchyma, with visualization of the gallbladder and rhe duodenum within 25 minutes of
nue may soon prove its potential. injection.
~~
~.
~
 28 f Essentials ojNlrclear MedicilwScielzce i n Nuclear Medicine
Rndio~harrr~acokinetics I 29

5 rnin 0-5rnin 5-10min 10.15 min

10 min
R

._
15 min 20min '_

L 15.20rnin R 20.25min 125-30rnin

. -

Figure 2.7. An abnormal hepatobiliary scan performed with SmTc-disofenin. Then: is prompt uptake of the
drug, but the gaIlbladder is not visualized (possible acute cholecys~itis),and there is persistent activity in Ihe
conlmon bile duct (possible partial obstruction). In addition, activity is seen in the region of the stomach,
which suggests duodenal-gastric reflux.
.~
.~
I ,
i
I .
30 / Essemials of Nuclenr Medicirie Science
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1 . Gibaldi M , Perrier D: Plznnnacokinelics. New York,
Marcel DeWter, 1975, pp 1-43.
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cukifrrrics. Hamilton, IL. Drug Intehgence Publica-
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J M (ed): Kinefirs ofDrug Acrior~.Nen York, Springer-
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4. Wellman HN, Appeldom C R A kinetic approach lothe
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15. Nunn A Struclure-distributionrelationships of radio-
Time t o washout
pharmaceuticals correlationbetween the reversed-phase
to 75% (minutes) 10.7 22.3 .5
YOClearance 71.1 13.0 c a p a c l tfya c t o r s f o r g m Tpch e n y l c a r -
5.5
'Could not be found banloylmethyliminodiaceticacids and their renal elim-
ination. J Chrurnalogr 255:91-100, 1983.
Figure 2.9. An abnormal bilateral renogram pcrformed with o-['3'I]iodohippurate.The time to peak was 6.3
16, Chenw LK, Nunn AD, Loberg MD: Radiopharmaceu-
minutes for the left kidney and 15.0 minutes for the right kidney, with clearance times being 10.7 and 22.3
ticals for hepatobiliary imaging. Senlirr Nucl Med
minutes, respectively. This represcnls a bilaleraI decrease in funclion (on the right to a greatcr cxtenl than on
the left). 125-17, 1982.
Radioyhnr~t~ncokir~erics
i17 N?lrdenrMedicine I 31
17, Hun1 FC, Maddalena Dl, Wilson JG: Technetium-99m
beozlmidazolyl iminodiacetic acid hepatobiliary radio-
pharmaceuticals: structure biodistribulionstud~cs.1111J
Nucl Med Biol 11:219-223, 1984.
18. Vera DR. Krohn KA, Stadalnik RC, et a!: Tc-99m
ealaclosylneoglycoalbulfiin: in vitro characterization of
receptor-mediated bmding. J N I Med ~ 25-779-787,
1984.
19. Kato-Azuma M-Lipophilic derivalives of 9PmTc(Sn)
pyridoxylidenc-phenylalanine: a slructuredistribution
relationship (SDR) study on lechnetium-99mcom-
lug~.
20. Deursch E, Bushong WV,Glavan KA, et al: Heart imag-
ing wilh cationiccomplexes or technetium. Science
214:85-86,1981.
21. Kung HE Molnar M. Billings J, et al: Synthesisand
of
biodistribution of neutral lipid-soluble wsmTc complexes
r h a r crosstheblood-brainbarrier. J Nrrcl Med
25:326-332,1984.
22. Sokolofr L, Reivich M.Kennedy C, et al: The (14C)
deoxyglucose method for the measurement of local
cerebral glucose utilization:theory, procedure. and nor-
mal values in the conscious and anesthetized alblnorat
J Nenrockem 5:897-916, 1977.
23. Heiss WD, Parvlik G, Herholz K, et al: Regional ki-
netic constants and cerebral metabolic rate for glucose
in normalhumanvolunteersdetermined by dynamic
positron emission tomography of (18F)-2-fluoro-2-de-
oxy-D-glucose. JCerebB/oorlFlowMerab2:212-223.
1984.
24. Wieland DM,Manager TI,Inbasekaran MN, et al:
Adrenal medula imaging agents: a structure-distribution
relationship study of radiolabeled aralkylguanidincs. J
Med Chern 27:149-155, 1984.
25. Knapp FF, Ambrose KP, Callahan AP: The eflect of
srrucluralnlodiiications on theadrenaluplake of
steroids labeled in the side chain with 12'm rellurium. J
N K / Med 21:258-263, 1980.
26. Taplin GV, Meredith OM, Kade H: The radioactive "'1
Lagged rose bengal uptake excretion lest for liver func-
tionusing external gammaray scintillationcounting
techniques. d Lab Clin Meed 45655-678. 1955.
27. Winston MA, Blahd WH: 1-133 rose bengal imaging
techniques in the differentialdiagnosis of jaundiced
patients. Semirl Nrrcl Med 2367-175, 1972.
new radiopharmaceutical for hepatobiliary imaging. J
Nucl Med 16533, 1975.
hepatobiliaryimagingagents.InFreeman LM,
Weissman MS (eds): A'uclear Medicine Aallrnual 1981,
New York, Raven Press, 1981, pp 1-33.
30. Nunn AD: In: Proceedirrgs of rhe 3rd Ir~lernaiiorral
Syrnposiurn or! Radiophartnnoceurical Clrerrfisrry. S I
Louis, CV Mosby. 1980.
31. Molter M, Kluss G: Properties of various IDA deriva-
tives. JLabelIed Compd Radiopkarm 1856-58, I981
I
32. Van Wyk AJ, Fourie PJ, Van Zy) WH, el al: Synthesis
of Iivc new *lnTc-HIDA isomers and comparison with
"mTc-HIDA. Eur J Nucl Med 4445-448, 1979.
32 I Essenlials of Nuclear Medicine Scierrce
33. Fonda U:Pedersen B. Tc-99m-diethyl HIDA. A contn-
bution lo the study of its S t N C l U R . Eur J N d Med
3:87-89. 1978.
34. Nicholson RW. Herman KJ, Shields RA, et al: The
preparation and composilion of HIDA , E w J Ahcl Med
3313-317, 1980.
35. Nunn AD, Loberg MD: Hepatobiliaryagents. In
Spencer RP (ed): Radiophar/nacell?iculs: Srrfrcrure-Ac-
riviry Relariorfships. New York,Grune & Stratton.
1581, pp 539-548.
36. Fields AT, Porter DW,Callery PS, et al: Synthesis and
radiolabeling or technetiumradiopharmaceuticals
based on 11-substituted iminodiacelic acid effect of
radiolabelmg conditionson radiochemical purity. J La-
belled Coalpd Radioplfarm 15:387-399. 1578.
37. Loberg MD: Radiolabeleddruganalogs basedon If-
substituted iminadiacetiac acid. In Heindel ND, Bums
DH, Honda T (eds): The CllemisrlT o[Radiopharmo-
cefrricols. New York, Masson Publishing, 1978, pp
191-204.
38. Nunn AD. Lobcrg MK. Conley RA: A structure-dis-
tribution-relationship approach leading LO the develop-
ment of 99"Tc-mebrofenin: an improvedcholescin-
tigraphic agent. J A'ucl Med 24:423-430, 1983.
39. Eckelman WC, Vulkeri WA: In vivo chemistry or
*mTc-chelates. I ~ r rJ Appl Rodiur lsor 33:945-951,
1982.
40. Delucia R, Lara PF,VaHe LB, et a 1 Distribution and
kinetics of hippuran l 3 I I in rats. Acru Physiol La/ A m
31:235-235, 1981.
4 1 , Saha GB: Fultdumenlals of Nuclear Pharrrracy. ed 2 .
New York, Springer-Verlag.1984, pp 228-236.
42. Hladik WB, Nigg K K , Rhodes BA: Drug-induced
changes in the biological distribution of radiopharma-
ceulicals. Semi11 Nucl &fed 12: 184-21 8, 1982.
43. Woif W , Manaka R, Young D, et al:Nuclear phar-
macologylradiopharmacokineLics.A nen dimension of
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land DR, Allen DR, et a! (eds): Rudiophanrracerlriab
I I . New York, Society of Nuclear Medicine, 1979, p
405,
3
Biodistributiolz and Structure in
Radiodiagnostics*
Ned D.Heindel and Natalie Foster
Amajorobjective of modernproducti\:e
drugdiscoveryisuncovering thequanlitative
relationshipsbetween a set of organic com-
pounds and their pharmacological potencies.
Academic and corporate pharmaceutical devel-
opmentgroups employthe underlyingstruc-
tural correlates of molecules-compared in a
standard biological assay-as predictive guides
to dictate the synthesis of the optimally potent
member of a series. Although there are several
quantitative structure-activity relationships
(SARs), the most widelyexploitedsystemis
that developed by Hansch (1). Formulated from
pharmacological empiricism, a molecular-lever
view of transmembrane passage by small mole-
cules, and enlightenedintuition, the Hansch
methodhasbeenlested experimentally in sev-
eral hundred sets of drugcandidatesand has
becomeacornerstone of drug discovery.Sev-
eral key reviews of its utility have appeared (2,
3).
When the Hansch hypothesis is expressed as
an equation, it may lake several forms; the €01-
lowing is one of the more common:
1
log -
C
= -k,(log P)' + kz(IOg P)
+ pcI + k,E, + k4
This equation statesthat there is a relation-
ship within a series of compounds of the meas-
ured concentration to produce a defined biolog-
* This work was supported. in part, by grants from the
Elsa U. Pardeeand W. W. SmithFoundations (0 Ned D.
Heiltdel and by PHs Grnnl CA31426horn rhe National
Canccr Instime, DHHS. to Natalie Foster.
33
ical effect (C) to the partilion coefficient (P)of
anygivenmemberbetweenalipidandan
aqueous phase, a polar electronic factor (pu), a
steric parameter (E5), and a constant &). Sim-
ply stated, drug effects relate to membrane par-
tilioning,polarity, and the size of themole-
cule.
In the full form of the Hansch equation, not
all termsactuallyare as equallyimportant.
Often. log P andlor(log P)*, where P isthe
partilion coefficient measured between oclanol
and saline layers, shows a more significant cor-
relalion with the biological potency than do the
other terms. For example, the activity of a se-
ries of alcohols as inhibitors of Slaphylucocclts
aweus maybeexpressedas log (1IC) =
0.67(1og P ) + 0.07, with a correlalion coeffi-
cient of 0.964 (4). The data from a study of the
localization of fourteen arylboronic acids in
mouse brainsfit theexpressionlog (IIC) =
-0.53(log P): + 2.47(log P) - 1.05, with a
correlation coefficient of 0.9 15 ( 5 ) . Correlated
in a simple bioassay, electronic and steric fac-
torsoftenappearlessimportantwithina
limitedset of similarstmctures.The relalive
solubility of a drug for lipid or blood phases
(P) constitutes the major factor not only in po-
tency but also in transport andlor distribution.
Quantitative SARs have made the discovery
of therapeutic drugs easier for more than LWO
decades but have been applied to imaging ra-
diopharmaceuticals only recently. In the devel-
opment or radiodiagnostics, the goal is not en-
hancing therapeutic actionbut rather optimiz-
ing target site delivery. WieIand has called this
objective a structure-distribution relationship
34 I Esserdnls of Nuclear. Medicirw Science
(SDR) and has pointed out h a t often there is a
markedparallelbetweenthe SAR inphar-
macologically active agents and the SDR of a
radiolabeled analog (6). Several radiopharma-
ceuticalresearch groups have recently shown
that with use of aHansch-like approach, in
vivobiodistributioncanbecorrelatedwilh
structure within a molecular set (7, 8).
Most of the current clinically successful ra-
diopharmaceuticals are theproducts of en-
lightened serendipily. Those investigators who
have searched for new radiopharmaceuticals
have often entered the field from classical me-
dicinal chemislry and are atluned lo using ther-
apeuticallyactiveagenls as likely modelson
whichto base new imaging candidates. There
are'severalinstancesinwhichcompounds
known to produce a biological effect in a target
tissue concentraie within that tissue lo a suffi-
cient degree to permit imaging (when these
substances bear a y- or positron-emitting radio-
tracer). Counsel1 and Ice (9) called the applica-
tion of this concept the"pharmacological ap-
proach'' toradiopharmaceutical design.Oth-
ers, however, have cautioned against assuming
that simply because a pharmaceutical produces
a biologicaleffect in a specifiedbiological
tissue,itsconcentration in thattissue is ele-
vated above that of any proximalbackground
tissues (IO). This nole of caution nolwithstand-
ing, radiolabeled small molecules such as
drugs, natural metabolites, and enzyme inhib-
itors have been a fruitful class for discovery of
valuable radiodiagnostics.
Theapplication of quantitativestructure-
distribution correlationsis likelyto make fu-
ture radiopharmaceutical development much
more effective, but it is unlikely to be applica-
ble to all imaging diagnostics. Fundamentaily,
agents may be divided into two groups on the
basis of their mechanism of localization: those
agents that demonstratetruechemical avidity
for the target tissue and those agents that parti-
tion by physical processes. It is necessary lo
understand these differing mechanisms in order
to apply successfully the quantitative structure-
distributiontheory to the design of potential
imagingagents.
A RATIONAL GROUPING OF
RADIOPHARMACEUTICALS
Substrate-specific Agents
In a modem classification system for radio-
pharmaceuticals, which is merely the most re-
cent of a number of proposed codifications, the
pharmacologicaIly derived agents and receplor-
binding drugs are referredto as subsirate spe-
cific (11). Theseagentsparticipate in definite
chemical reactions or in specificligand-sub-
stratebindingwithinthetargetlocus.Fatty
acids forheartimaging,carbohydrateanalogs
for brain or tumorimaging,steroidsfores-
trogenorandrogenreceptortissues,and a Cholinergic blockingagents
plethora of enzyme inhibitors for delineation of
nonubiquilousenzyme sites-when converted
to radiolabeled analogs-constitute the sub-
strate-specific class of radiopharrnaceuticaIs
(see Table 3.1).
An isotopically substituted biochetnical,
most often bearing a I T for anative I2C,can
track a metabolic pathway and then image ana-
tomica1 lociknownastargets for thatbio-
chemical. For example, the incorporation of
aminoacids into pancreaticaIly produceddi-
gestive enzymes providesawell-characterized
metabolic pathway, and the use of ~ - [ " C l t r p
lophan (andother ]IC aminoacids)for pan-
creas imaging is a derivative development (12).
Whentheagent employed is not anative
biochemical but a close structural analog capa-
ble of serving as an enzynte substrafe or inhib-
itor. there can still be marked target uptake in
tissue in which enzymes utilizing thal analog
are found. m - [ 1311]iodobenzylguanidine( l3lI-
mIBG) (Fig. 3. I ) was proposedasan adre-
nomeduIIary imagingagentbecause it repre-
sented a structuralapproximation of aralkyl-
guanidine known to display antiadrenergic
effects (13). Recentevidenceshowsthat l3lI-
NH
II
O C H * - NH-C -NH*
)=/
I
Figure 3.1. Structure of m-[1311]iodobenzylguani-
dine (mIBG).
Table 3.1.
Classes of Radiopharmaceuticals*
Subsfrate specific?
Isotopically substituted biochemical
[ llC]palmitic acid
[ LT]glucose
Metabolic trapping
2-deoxy-2-[ laF]fluoro-~-ghcose
Enzyme inhibitor or enzyme substrate
[IT]isoxazole
(?)
6-[1~~I]iodomethyl-l9-norcholesterol
[Yjelselenomethionine (?)
Receptor-binding biochemical or drug
Steroids
Adrenergic blocking agents
Antibodies to tumor-associated antigens
CEA antibody
Substrole uorlspeciJic$
Diffusion
S m T c 0 ~for brain tumor imaging
133Xe
and for lung
ventilation
studies
Compartmentalspace
WmTc-DTPA for ECF measurements
WmTc-labeledRBC for red cell volume
13II-labeled human semm aIbumin for plasma vol-
ume
Capillary blockade and cell sequestration
99nlTc-labeIed rnacroaggregaled albumin for re-
gional perfusion studies
Damaged 99mTc-labeled RBC for splenic se-
questration studies
Phagocytosis
99mTc-labeled sulfur coIloid for phagocytic func-
tion measurements
WaTc-labeledantimonysulfurcolloid
lymphoscintigraphy
* From W. C. Eckelman and R. C. Reba: The
classification of radiotracers. J . Nrtcl. M e d .
19:1179-1181, 1978, wilhpermission of the Soci-
ety of Nuclear Medicine.
7 The substrate must participate in a definite
chemicalreaction or in a definiteligand-substrate
interaction.
$ The compound does not participate in a specific
chemical reaction.
mIBG has a similar uptake and retention mech-
anism tothat of norepinephrine (14). The ra-
tionale for use of labeled enzyme substrates or
inhibitors,usually tagged with radiohalogens,
has been a valuabledesignconcept in radio-
pharmaceutical science.
Biodistriburion and Strrtciure inRodiodingnosrics I 35
A few circumstances are known in which the
radiotracer is scavengedfromtheblood and
trappedwithina target tissue as a metabolite,
which therebyestablishes a concentration of
nuclide against the blood gradient. This mew
bolic trapping has been observed for 2-deoxy-
D-[ 14C]glucose and for- the clinically useful 2-
deoxy-2-[ lsF]fluoro-~-giucose, both of which
experience the biotransport of glucose but be-
come trapped within the cell apparently as the
nonmetabolizable6-phosphates (15). TheI8F
sugar,withitspositron-emittingfluorine
nuclide, allows a tomographic visuaIization of
regionsofhigh glucoseuptake:metabolically
active brain, tumors, and funclioning well-per-
fused myocardium (16).
The designation of a specificradiopharma-
ceutical as a receprur-binding biochemical
must, ofnecessity, be somewhatarbitrary in
that undoubtedly many of those agents whose
partilioning mechanisms class them as enzyme
inhibitors andlor substrates or as metabolically
trappedtracersalsoexperience a specific
ligand-receptorinteraction in vivo. It is, how-
ever, the prime objective of the receptor-bind-
ing class of radiopharmaceuticals to probe only
the binding phase of the receptor action.
Typical receptor densities vary, but the con-
centration of a-adrenoceptors in the heart is
indicated in femtornoles (lO-I5 moles) per mil-
ligram,while the concentration of muscarinic
for
cholinergic receptors is indicated in picomoles
(10-12 moles) permilligram of protein. Simi-
Iarly, bindingavidities of Iigandscanvary
widely but for most pharmaceuticals are in [he
108-10~oM - ' range. Low receptor densities
andhigh bindingaffinities dictatethatcandi-
date imaging radiopharmaceuticals must be of
high punty and high specific activity and must
containnegligibleconcentrations of non-
radiolabeled contaminants competing for these
receptor loci. Ultimate imagequalityappears
to depend on high specific activity (17, 18).
Specialradiolabelingmethodsandchro-
matographic purification techniques have been
developed to producethesehigh-specific-
activity products.Choice of suitable radionu-
clide for attachment to a potential receptor-spe-
 36 I Essentials of NuclearMedicineScience
cific imaging diagnostic has been a major con-
cern.Priorresearchinradioimmunoassay
development had shown h a t the substitution of
halogen(usually 1251) forhydrogenseldom
negated the utility of the modified tracer as an
in vitro probe of an analyte concentration. Al-
though in vivoreceptors are expected to be
more complex and more demanding of spatial
geomelry andmatched lipophilicity, [he dem-
onstration that radiohalogenated estrogens con-
centrate in breast tumors and radiohalogenated
dopamineantagonists display favorablebrain
uptakehas convincedmost radiophmaceuti-
cal investigators that the halide-for-hydrogen
substitution can be successful (19, 20).
In the search for synthetic models to be la-
beled as imaging diagnostics, the usua1 proce-
dure has been toevaluate firstthe tritium-la-
beledcandidates in vitrobycompetitive
bindingassaysperformedonisolated receptor
protein. In theory,thecompoundwiththe
highestbindingavidity shouldconstitutethe
best in vivo candidate(aftertaggingwith a labeled antibodies currenlly is in tumor detec-
radiohalogen) for imaging that receptor sys-
tem. The use of tritialed compounds with iso-
lated receptor preparations aIIows avoidance of
extensive screening in animals which would
otherwise be required. A recent editorial points
out how theuse of in vitrobindingdataon
triliated compounds (haloperidol and spiroperi-
dol)can lead (and has led in at least onein-
stance) to incorrect conclusions about the rela-
tive site-directed behavior in vivo (21). Several
explanationshavebeenadvanced;onepos-
sibility is a differential metabolic exchange of
tritium from the ligand. Despite this caveat, it
seems certain that extrapolations from high-af-
finity, tritium-labeled ligands tested in vitro to
radiohalogenatedcandidatesprobed i n vivo
will continue to be made.
Unfortunately, forreasonsto be discussed
shortly,noradiopharmaceuticalscontaining
metal ion nuclideshaveyetdemonstrated re-
ceptor-specific uptake in vivo.High-specific-
activity radiopharmaceuticaIs should, in the-
ory, be more readily obtainable by complexa-
tion of imaging candidates 10 cationic radionu-
clides such as indium, gallium, and technetium
than by radiohalogenation with lSF, lZ3I, l3II,
77Br,or other suitable halogens. Most metallic
Biodisiribution nnd Siruciwe irr Radiodioglmiics I 37
radionuclides are conveniently available on site
nabletoquantitativestructure-distribution cor- kidney fall into three categories as a function
at high specific activities as eIuants from gen-
relations in a Hansch-styIe approach, with the of their mode of elimination: those that are fil-
eratorsand,onchelation to a carrierligand,
possible exception of labeled antibodies and tered (99mTc complexes of diethylenetriamine-
are readily purified from unbound tracer.
macromolecules. The labeled small molecules pentaacetic acid (DTPA) and ethylenediamine-
Perhaps the ultimate in the substrate-specific
can take part in definite chemical reactions or tetraaceticacid(EDTA)),thosethatare
class of radiodiagnostics will be those based on
engage in a specific molecule-receptor binding secreted (99mTc-N,N'-bis(mercantoacetyl)ethyl-
labeled antibodies raised to targetassociated
and therefore should b e sensitive to the same enediamine (wmTc-DADS)), and those that ex-
antigens. The potential antigens can be tumor
factorsthatHanschidentifiedinthequan- perience filtration, secretion, and binding to
markers, normal organ-associated proteins
titative SAR studies of therapeutic pharmaceu- the kidneys (among others, 9 9 m T ~
complexes of
such ascardiacmyosin,cocci,or otherbac-
ticals, i.e., Iipophilicity, electronicpoiar fac- mannitol, citrate, tetracycline, and dirnercapto-
leria,orhormonalregulatorssuchashuman
tors, and molecular size. succinic acid (DMSA)) (26). In general, those
chorionicgonadotropin.Antibodiescanbe
compoundsfilteredthroughtheglomerular
raised as the ciassic poIyclonals or may be the Substrate-nonspecific Agents membrane must be relatively small molecules.
m o n o c l o n a lp r o d u c t so fc o n t e m p o r a r y
Substratenonspecificagents do notrequire A modestamount of proteinbindingcanbe
hybridoma technology. Radionuclidescan be
chemical events to provideattachment 10 the tolerated,butthe charge on thecompound is
the halogens (usually l3II) or metal ions (such
ultimate deliverysite. In fact, no technetium critical. For example, neulral dextran can cross
as 9hTc,"'In, or 67Ga) chelated to ligands
attachedto the IgG backbone.In two recent chelate has yet been shown to engage in sub- the membrane, whereas dextran sulfate is com-
strate-specific binding to a receptor protein, al- pletely rejected (29).
articles, the background and the clinical prom-
lhough manyattempts IO developsuchagents Few definite conclusions on the mechanisms
ise of this emerging field of radioimmunoimag-
have been made (26, 27). Nevertheless, such of localization have been drawn, and very few
ing have been reviewed (22, 23).
radiopharmaceuticals-in particular 99mTc che- predictions have been made with use of quan-
Although the most significant application of
lates-may have a biodistribution that is rnark- titative SDR, even in tightly controlled experi-
edly sensitive to relative lipid-TFersus-blood sol- ments.Forcorrelation of thestructureof
tion in animal models and humans, impressive
ubility and for that reason may display an SDR 99mTc-labeledcomplexestotheir biodistribu-
uptakes of a wmTc-labeledantibacterial anti-
that correlates with eitherthe P term of the lion, the actual structure of the complex must
body in an endocarditislesion and of l 3 I l - ,
Hansch equation or with a quantity derived be known, andthe assumption must be made
l 1 h - , and wmTc-labeled antimyosin fragments
from it. that this structure does not change in vivo (26,
( h b ) in acute myocardial infarctionsindicate
The net elimination patterns of radiopharma- 30). Neither of these concerns is lrivial, since
that antibody transport of nuclides will have far
ceulicals are often viewed as a competition be- structuralstudies(massspectroscopy, x-ray
widerdiagnostic possibilities thanjusttumor
tween the renal and hepatobiliary systems. The diffraction) are impossible under the conditions
imaging (24, 25). Thisarea, however, is too
factorsdetermining biliaryversus urinary ex- prevailing i n thesolutionsasadminislered
nascent to yield quantitative structure-distribu-
cretion of agents are not clearly definable, but and conclusions about structure can only be in-
tion studies, butseveral conclusionsdoseem
four properlies-polarity, molecular size, mo- ferred from mass level experiments irl which a
possible. Nonspecific targeting of the labeled
lecularweight, and molecular structure-are carrier is used. Many 9 9 m Tchelates
~ used for
antibodiesand highbloodbackgroundlevels
most influential (28). The first breakthroughs renal studies are mixtures thathavenotbeen
can be partially overcome by computer enhan-
in the application of quantitalive SDRs to ra- fully characterized chemically.
cement through subtraction of the nontarget ac-
diopharmaceuticalshavecomewiththose For example, the high-performance liquid
tivitywith a dual-tracertechnique.Further-
agents that can evaluate the excretory organs, c h r o m a t o g r a p h y (HPLC) e v a l u a t i o no f
more,smallerantibodyfragments(Fab)
presumablybecausetheHanschpartitionco- "mTc-N,N'-bis(mercaptoacetyl)-2,3-diamino-
produced by papaindigestion of theoriginal
efficient-a paramount factor in drug trans- propanoate (wmTc-CO,-DADS) (Fig. 3.2) has
IgGs oftenretain target specificity, reduce the
port-is exceedingly sensitive to the same fOUT shown thepresence of twocomponents,one
nonspecific binding, and provide a more rapid
factors that dictate excretion pathway. with a specificity for renal excretion higher
blood background clearance.Sincemore than
Forextensive biliary excretion tooccur, a than that for ~ - [ ' ~ ~ I j i o d o h i p p u r (OIH)
a t e and a
50% of the publications in 1983 on new fumor-
moleculeseems to require a criticalbalance secondwithcomparablespecificity butwith
seekingradiopharmaceuticals dealt with anti-
between polar and nonpolar aspects of its char- slightly slower renal excretion kinetics (31).
body transporl,analogs withinthis classifica-
acter. The molecular size seiectivity for either These two majorcomponents are thought to
tion of site-directedtracers seemdestinedto
urine or biliary excretion appears to be inherent result from chelate ring isomerization. Knowl-
increase markedly.
intheorgansthemselves,andmanycom- edge of theirindividualmolecularstructures
Intuitively, one expects that all the substrate-
pounds appear to have equal affinity for both will aid in understanding how these complexes
specific classes (see Table 3.1) might be ame-
routes. Those compounds cleared through lhe are handled by the renal tubular system, which
~ .
~.
~~
-. .
"
38 I Esaenfiais of Nuclear Medicine Scieltce

lower for "good" excreters like rats, dogs, and

hens),conjugation,andincreasedlipid soi-
_I
ubility. Themolecules also shouldcontain at
leasttwoplanarlipophiiicstructuresplus a
polar group and must be protein bound (26). It
is thought that classic receptor-binding mecha-
nisms are not likely 10 operate because of the
diverse types of compounds that seem to share
the same hepatobiliarypathway; nevertheless,
thedevelopment of SDRs has been possible
and has become crucial to the logical design of
Figure 3.2. Structure of Tc-N,N'-bis(rnercaptoac- better radiopharmaceuticals for hepatobiliary
etyl)-2.3-diaminopropanoate(Tc-C0,-DADS).
imaging.
The iminodiacetic acid (IDA)complexes of A - CH3 -4 935,42 -I 684
0 - H -I E79.28 -I 6.7~
differsessentiallyonly in thekinetics.This 99mTchave been successfullyused ashepato-
preparation hassignificantly improved param- biliary agents, and a considerable body of data
C - cn3 - Br 041.42 -1 6.73
D -n -NO2 717.50 -I 6.58
eters for evaluation of renal function with re- from which SDRs were developedhas been E -H - C02H 7L5.52 -3 5.47
gard to 99n'Tc-N,N'-bis(mercaptoacetyl)ethy- collected. Burns etal. (7) showedthat there F - CH3 -H 603.60 -I 6.52

lene diamine (99"mTc-DADS)which has been was a linear relationshipbetween the netbili- G -H - CH3 655.56 -I 6.49
H -ti -H 627.52 -I 6.44
suggested as a potential replacement for OIH. ary excrelion found for 9 9 n i Tcomplexes
~ of I x = -H Y =-C02H 671.52 -2 5.62
The source of the improved characteristics of IDA derivatives and the nalural log of the mo- X" - CH3 yl. H -
(he new carboxylate analog is thought to b e the lecular weight divided by the charge (Fig. 3.3).
a Unless olharwira indicated X = X' and Y = Y'
increasedprotein binding of the agent, which Withinalimitedconlpound series, in which
vastly decreases its glomerular filtration. variations in molecular weight are obtained by
Another interesting aspect of the biodistribu- simple functional substitutions (H, CH,, I, Br,
lOOr
tion of these mixed agents is the effect of slan- NO,) at a site remote from the metal ion-bind-
now ion (often used in kits to reduce the high inglocus, increases in the overall molecular
oxidation states of the available Tc to the Iower weight would be expected to reflect increasing
states needed forcomplexformalion)on the lipophilicity.Furthermore,increases in overall
retention of the radiopharmaceutical in the re- charge would be expecled to parallel decreases
nal corlex. For a series of chelating agents, an in lipophilicity. Thus, for some limited series
increase in divalent tin concentration causes an of radiopharmaceuticals the log P or log (OC-
increasedretention in thekidneysapparently Ianollsaline) as employed in the Hansch equa-
by altering the permeability of the membranes tion canbeapproximatedby log (molecular
(32). weightholecular charge).
Nunn et al. {X) tested 33 IDA derivatives
EXAMPLES OF QUANTITATIVE SDR
anddrew correlations between physicochemi-
HepatobiIiary Imaging Agents cal parameters,structuraleffects,andinvivo
Radiopharmaceuticalsthatlocalizewithin characteristics.They showed that lipophilicity Figure 3.3. Biliary excretion of IDA analogs as 99mTc compIexes in mice. MW, molecular weight; 2.
charge. (From H. D. Burns et al.: Design of technetiumradiopharmaceuticals. In N , D. Heindel et al.
the hepatobiliary system are a noninvasive di- can be used to predict protein binding and in reds.): The Chernisfy ofRndiupharmacellticuI. New York, Masson Publishing, 1978, pp. 268-289, with
agnosticmeans of evaluatingmanyclinical vivodistribution of 94mTc-IDAderivatives. permission of Masson Publishing.)
problems.Unlike the excretion of many com- Their linear SDRs were used to develop a new
pounds by thekidney,(hepassage of com- compound with excellent properties as a cho-
pounds through the hepatobiliary system is an lescintigraphic agent. The resultant compound,
activesecretoryprocess (33). A number of mebrofenin(Fig. 3.4) or3-bromo-2,4,6-
generalizationsregardingtheproperties neces- trimethylphenylcarbamoylmethyliminodiacetic
sary for a highlevel of biliary ralher than acid, exhibited: (a) high specificity for the hep-
kidney excretionhavebeen proposed: amini- a t o b i l i a r ys y s t e m , ( b ) rapidtransittime
Figure 3.4. Structure of 3-bromo-2,4,6-tri-
mum ~nolecularweight of around 500 daltons through the hepatobiliary system, and (c) high acid
n~ethylphenyIcarbamoyln~ethyli~ninodiacetic
(thisnumber is speciesrelatedandmaybe resistance to competition from compounds (mebrofenin).
40 I Essenriais of Nlucleur Medicilse Scieme Biodisrribution and Structure in Rodiodiagnosfics I 41

such as bilirubin. In the context of the study it
was shown that orthosubstituentscontributed
less to the measured lipophilicity than the clas-
sicHansch-approachtheoryhadpredicted.
IDAderiviativeswithsmall alkylsubstituents
in the ortho position had faster hepatoceilular
transit times than did their unsubstituled coun-
terparts.
In a study of the SDRs in 9 9 m Tcomplexes
~ radiopharmaceuticals, subtle differences of
of pyridoxyiidenephenylalanine (Fig. 3 . 5 ) ,
Kato-Azuma (34, 35) noted thatthe halogens
or alkyl groups placed on phenyl ring positions
on the phenylalanine moiety increased the total
lipophilicity and invariably decreased the urin-
aryexcretion.Suchsubstituentsinthepara
position, however, delayed hepatobiliary tran-
sit, while those in the ortho position appeared
to accelerate it. If both ortho andpara posi-
tions were occupied by lipophilic substituents,
the effect of the ortho substituent (acceleration)
predominated over the effect (inhibition) of the
para substituent with regard to thehepatobil-
iary transit. Among the three pyridoxplami-
i
nates studied in rats(amino acid moieties in-
cludedphenylalanine,tryptophan,and 5-
methyltryptophan), use of the5-methyltrypto-
phanderivative (9qmTc(Sn)-PHMT)(Fig. 3.6)
resulted in the highest biliary excretion, lowest
blood and renal retention, and the smallest uri-
nary output. Thus, as hasoften been seen in
slruclure-distribution studies of melallonuclide
structure canproducemajorallerations in in
vivo behavior and can frustrate quanlitative
SDRs .
A radiohalogenatedfamily of hepatobiliary
imagingcandidates, however, displayed more
regular SDRs. Reiffers et al. (36) prepared five
indotricarbocyanines labeled with I 3 l 1 in the 5-
positionand H, F, C1, 3r, and I in the 5'-
positions (Fig. 3.7). A small change in the 5'-
substituenthad a pronouncedeffect on the
liverclearance of themolecule in mice.
Whether the conwolling mechanism was due to
steric andlor electronic effects was not obvious
from the results, but a correIation between liver
activity 30 min postinjection and both the van chemical and structural configuration of the
derWaalsradiusandthePaulingelec- compound (38). In general,forthepolyphos-
lronegativity of the substituent in the 5"posi- phate agents (pyrophosphate, tripolyphosphate,
tion was shomln. It was noted also that the more polyphosphate),uptakeinboneisinversely
polarizablethehalogen,the slower the liver proportional to chain length (39). Only a single
clearance (Fig. 3,s). phosphate moiety appears necessary for good
bone uptake by candidate imaging agents, even
Bone Imaging Agents though most currently utilized radiopharma-
SDRs havealsobeenstudiedfor 9 9 m T ~ceuticals havemorethan onesuchfunction,
bone-imaging agents. From the original reports e.g., methylene diphosphonate (MDP) and hy-
in 1971 by Subramanian and McAfee (37) and droxymethylene diphosphonate (HDP) (40)
manysubsequentevaluations,thecriteriafor (Fig. 3.9). The importance of additional func-
uptake have been determined. These structure- tional groups may lie in theirability to keep
affinity relationships depend on both the proc- the stannous ion, which was used to reduce the
essesinvolved in bonemetabolismand the pertechnetate, in solution (26).
I IB
r I
0 40
m

//
CH
I H I I 1
lo I
t
H
1 - I I
1.0 1.5 2.0, 2.0 3.0 4.0
VAN D E R W A A L S R A D I U S ( A I ELECTRONEGATIVITY

Figure 3.8. A . Correlation of the 30-min retention of the 1311 monohalo-bis salts in mice with the van der
Waals radius of the 5-halogen substituent. B . Correlation of the 30-min retention of I3l1monohalo-bis salts
in mice with the PauIing electronegativily of the 5-halogen substiluent. (From S. Reiffers et al.: Cyclotron
Figure 3.5. Structure of pyridoxylidenephenylala- Figure 3.6. Structure of pyridoxylaminate Of 5- isolopesand radiopharmaceuticals-XXXIII. In!. J . Appl. i s o t . 34:1383-1393, 1983, withpermission of
nine, methyltryptophan. the Brookhaven National Laboratory and Pergamon Press.)

0 RI 0
131 H I II
I\ HO-P-C-P-OH
I I 1
HO R2 OH

MOP (rnethylenediphosphonate 1: RI = H I R e = H
HEDP (hydroxyethylidenediphosphonate):RI=CHSRfOH
HDP (hydroxymethylenediphosphonate): R I =H, R2=0H
Figure 3.7.Structurc of indotricarbocyanine radiolabeled with I"I at the 5-position and substituted a1 the
5'-position. ~~
Figure 3.9. Structure of diphosphonate ligand for 9gmTc-labeIed bone imaging agents.
~.
 p
Ij
li

42 I E s s t ~ ~ t i odf sNuclearMedicitreSciexce Biodisrribution ond Structure i n Rodiodiagnostics 1 43

SUMMARY
Whether it be in myocardial agents,bone-
affiniccompounds, eswogen receptor-specific
tracers. hepatobiliaryradionuclide chelates, or
any of the myriad of other radioactive in vivo
diagnostics, more and more investigators have
beentestingtheprinciples of SDR in their
search for improved radiopharmaceuticals.
When the structural variationsacrossa com-
pound set are not exlensive, a linear correlation
may be observedbetween one or more phys-
icochemical propertiesandbiodistribution (7,
36). When the compound set is structurally di-
verse, however, it is thefortunate investigator
who can make even a qualitativecorrelation
(29, 31). In the final analysis, radiopharmaceu-
tical researchers probe for correlations not jus1
as an academic exercise but to assist in prepar-
ingtheoptimumcandidateimagingagent.
Therehavebeensuccesse (8, 34, 36) and
there surely wifl be others, for while the ap-
I glucosemetabolism in man:techniqueandresults.
plication of structure-distribution studies to ra-
: diopharmaceuticals
is a budding
endeavor, the
seedhasgerminatedandfurtherfruitswill
surely be born.
. .
- I .
ill
~
men1 of ""Tc-mebrofenin:an improvedcholescinti-
graphic agent. J N~rclMed 24:423-430. 1983.
9. Counsel1 RE.Ice RD: The design of organimaging
radiophannaceutlcak In Ariens El (ed): Drub D e -
sign. New York, Academic Press. 1974. vol 6, pp
172-259.
IO. Andrew GA, KniseIey RM. Wagner HN Jr: (Editors
remarks). In: Radioactive Pharmocertriculs. USAEC
Publication,CONF-651111.SpringCield,VA,
USAEC,1971, p 116.
11. EckelmanWC, Reba R C The classification or ra-
diotracers. JM,clMed 19:1179-1181, 1978.
12. Washburn LC, Hubner KF, Sun T T , et al: ~'C-L-
tryptophan,apotential agent for diagnosis of pan-
creatic disease using PET. J Nrrcl Med 24:P121, 1983.
13. Wieland DM. Wu JL. Brown LE, el al: Radiolabeled
adrenergic neuron-blocking agents: adrenomedullary
maging with l~~I-iodobenzylguanidine. J h'zrcl Med
21349-353, 1980.
14.Jaques S Jr, Tobes MC,Sisson JC, Wicland DM:
Mcchanisms of uptake and retention of meta-iodo-
benzylguanidine (mlBG) intheadrenalmedulla. J rial repIacement for I3'I o-iodohippurate. J NucI Med
N'ucl Med 24: 1 17, 1983
15. Reivich M. Alavi A . Greenberg J, et al: 'BF Fluoro-
deoxyglucose methodfor measuring localcerebral
Prog Nrrcl Med 7:138-148. 1981.
16. Alavi A, Reivich M, Greenberg J, Wolf AP: Cerebral
functional activity mapped with '*F-2-deoxy-2-fluoro-
o-glucose.InLambrecht RM, Marcos N (eds): A p
pikafiords of Ntrcleor urzd Radiochemistry. New Yo&
27. Dannals RF, Bums HD, Marzilli LG, et ai: The use of
T c and 99mTc in the development and characteriza-
lion of new radiotracers for diagnostic nuclear rnedi-
cine. In Lambrecht RM, Marcos N (eds): Applicalions 34. Kato-Azuma M: WmTc(Sn)-N-pyridoxylaminates:a
of Nuclear arrd Radiochcmislq?. New York, Fergamon
Press,1982, pp127-138.
28. Chervu LR, Nunn AD, Loberg M D Radiopharmaceu-
ticals for hepatobiliary imaging. Sernirz N'ucl Med
125-17, 1982.
29. Blaufox MD, ChervuLR:Analysis of structure-ac-
tivity relationship or renal Imaging agents. In Spencer
RP [ed): Rndioplrar~nacr.u~ica~s: ~ r r ~ 4 c l ~ ~ ~ eRe-
- A c ~ ~ ~ ,isotopes
lationships. New York. Grune & Stratton,1981,pp
521-537.
30.Chiotellis E, StassinopoulouCI, Varvarigou A ,
Vavouraki H: Structure-activity relationships of some
Wechnetium labeled thioethylaminocarboxylates. J
M e d Chem 25:1370-1374, 1982.
31. Fritzberg AR, Kuni CC, Clingensmith WC 111, el al:
Synthesisandbiologicalevaluation of""Tc NN-
bis(merceptoacetyl)-2,d-diaminopropanoate: a paten-
23592-598, 1982.
32. Steigman J, Chin EV, SolomonNA:Scintiphotosin
rabbitsmadewithgPmTc-preparationsreducedwith
electrolysis and SnC1,: concise communication. I Nrrd
Med 20:766-770, 1979.
33. N u n n AD, Loberg MD: Hepatobiliaryagents. In
Spencer RP (ed): Radiopharrnaceuricals: Slructure-
Activily Relariorzships. NewYork, Gmne t Slratton,
1981, pp 539-556.
new series of hepatobiliaryagents. J N d Med
23517-524, 1982.
35.Kato-Azuma M: Lipophilicderivatives of 99"Tc(Sn)
pyridoxylidene phenylalanine: a structure distribution
relationship (SDR) study on 9"'lechnetium complexes.
lrrl J Appl Rodiar Isor 33:937-944, 1982
36. Reiffcrs S , Lambrccht RM, Wolf AP, et al: Cyclorron
i r ~ and radiopharmaceulicals"XXXII1. Syn-
them and structural eIIects 01 seleclive biliary excre-
tion of halogenated indotricarbocyanines. In1 J Appl
Radiut Zsor 341383-1393, 1983.
37. Subramanian G . Mc Afee JG: A new complex of P 3 m T ~
for skeletalimaging. Radiology 99: 192- 196, 1971.
38. HosainP,Wang TST: Bone imaging compounds w i t h
specialreferencetoswcture-affinityrelationship. In
Spencer RP (ea): Radiopharmacerrticals: Sfrrrcrure-
Acriviry Relarionships. New York, GNne & Slratlon,
1981,521-537.
39. Jones AJ. FrancisMD,Davis MA: Bonescanning:
radionuclidicreactionmechanisms. Sernin Nfrcl Med
6:3-18, 1976.
40. Hosain P, Spencer RP, Ahlquist KJ, Sripada PK: Bone
accumulation of the %Tc complex of carbamyl phos-
phate and its analogs. J N r d Med 19530-533, 1978.

: ,,?:.'
I,. .
Pergamon Press, 1982, pp 239-250.
_. ,
, I .
17.EckelmanWC: Receptor-Bblding Radiurracers. Boca
. I
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,
:i,..,
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chemistry. J 18. Eckelman WC: Receptor-Binding Radiofracers. Boca
. .I
Med Chrn 19:l-6. 1976.
~ I._ Raton, FL, CRC Press. 1982, vol 11.
...l
I .
2 . Hansch C: A quanliratlveapproach to biochemical 19. Delesus O T , Friedman AM, Rasad A, Revenaugh IR:
i2'
~

I I . struclurc-activity
relationships. Arc Chenr Res Preparation and purification of 77Br labded p-bromo-
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2232-239, 1969.
I.

> 1,:- spiroperidol for in vivo dopamine receplor sludies. J

.-. , I'...-
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~. 3. Leo A, Hansch Elkins
C. D: Partition coefficienls and Labelled Cornpd Rodiopharm 20(6):745-756,1983.
.~2
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use.
their Clrenz Rev 71(6):525-554,
1971. 20.McElvany DK,Katzenellenbogen JA, Shafer KE. el
, -
4. Lien El. Hansch C, Anderson SM: Structure-activity al: 16aJ'Brbromoestradiol:dosimetry and prelimi-
. -.
. i correlations
antibacterial
for agents on Gram-positive nary clinical studies. J N d Mcd 23:425-430, 1982.
i ,1 ,
21. Tervson TJ: RadiopharmaceuticalsforreceptorImag-
! -s and Gram-negative
cells. J Med Cllern 11:430-441,
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5. Hansch C, Steward AT(, Iwass J: The correlation of 22.Goldenberg DM: Tumor imaging withmonoclonal
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I
~ ,, ..
._
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with
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constanls. Mol Phar- 23.Sfakianakis GN, Deland FH:Radioimmunodiagnosis
..-
1
,~
.

andradioimmunotherapy,1982. I Nrrcl M e d
.. ,=.
!" macol 137-92, 1965.
:z", 23:840-850. 1982.
~

7.~=.:, ,
.~
I ~ ..
I
6 . Wieland DM, Brown LE, Mangner TI, et al: Ra-
., . <-. ? I / dioiodinated
aralkylgoanidines:
synlhesis and clinical 24. Wahl RL, Parker CW. Philpolt G W Improvedradio-
, , ? I
I
I
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.C
potential.ln~emationalSymposium on Radioiodines, imaging and tumorlocalizationwithmonoclonal
i .3 ;I
~
Banff,
Alberta,
Canada, 22-24.
1980.
pp F(ab')>. J N:rcl M d 24:316-325, 1983.
,ji'
~

i 7. Rums HD. WorlepP,WagnerHN Jr, et aI: Design of 2 5 . Yasuda T , Leinbach RC, Khaw BA, et a): Prediction
, ,._
:-
.:
~
~

, _
_ c
lechneliumradiopharmnceuticals. In HeindelND. of inhrctvolume in patlcnts undcrgomgreperfusion
. .".
I
i:"
_ & ,
bums HD. Handa T, Brady LW (eds): The ChemisIry therapy by "Tc-antimyosin SPECT. f N'ucl Med .~

,-
i ;2.
~

. .:-
,r=
::$
.
.>.- .
,:,i
afRadiophannacerr,ir/~.Ncw York, Masson
ing, 1978, pp 268-289.
F'ublish-

8. Nunn AD, Loberg MD, Conley RA: A stmcturc-dis-

425:P20, 1984.
26. Eckclman W C , Voklert WA: Invivo chemistry of
*~Tc-chelales. 11rr J Appl Radiar Isor 33:945-952,
". .
.~
~~
._
~-

.~
~

; i:;p
~. . -"- -.
-
-~
__
1
i :;;.: tribution-relat~onship approach leadingto the develop- 1982.
{ ;..: "

_"-2=:-:
~

I I@
~

~. =
~
 Metabolic Fate of Radioplrarmacerrtica!s I 45

1 . Gases: 133Xe and 8 1 m K r 67Ga-labeIedproteincomplex of unknown

2. Cations: 67Ga, ZolTI,"'In, and 113mIn
3. Anions: [ 51Cr]chromate,[99mTc]pertechne-
4 tate, [3'P]phosphate, [ 1231]iodide,or [ 1311]-
iodide
4. 99mTc-Iabeled compounds:pyrophosphate,
Metabolic Fate of Radiopharmaceuticals diphosphonates , sulfur colloid, macroaggre-
gated albumin, serum albumin, iminodiace-
nature. As isdiscussedinChapter 1, radi-
ogalliumisalsoeliminated to someextent in
the bowel.
[201Tl]thallouschloride is used tomeasure
myocardial perfusion in patients with suspected
myocardia1 ischemiaorinfarction.Much
dence supports the beliefthat the in vivo uti-
evi-

Robert C, Jost tic acid derivatives, gluceptate, dimercapto-

i : Afterabsorptionorintravenousinjection,a
drug is distributed into intersdtial and cellular
fluids of thebody. This distributionis influ-
enced by the various physiological factors and
physiochemicalproperties of the drug. These
include cardiac output, regional blood flow,
lipid solubility, and protein binding. Drug ac-
tion usuallyis terminated by excretion of the
unchanged drug or by metabolism of the drug
followed by excretion of pharmacologically ac-
live or inactive metabolites.Drugsoften are
nonpolar, lipid-solubleorganic acids or bases
thatare no1 readily eliminated from the body.
Metabolic reactions commonly, resuIt in more
polar and less lipid-soluble metabolites that are
moreeasilyexcretedthanaretheoriginal
drugs.
Metabolicreactionsinvolvingdrugshave
been classifiedaseithernonsynthetic or syn-
thetic (1). Nonsynthetic reactions includeox-
idation, reduction, and hydrolysis and may re-
sultinactivation,changeinactivity,or
deactivation of the parent compound. Synthetic
reactions involve the conjugation of the drug or
metaboliteto an endogenoussubstancesuch
asglucuronicacid,aceticacid,glycine, or
sulfate.
Metabolic reactions are further classified as
eithernonmicrosoma1ormicrosomal. Non-
microsomal metabolic reactions include acety-
lation reactions,glycineandsulfateconjuga-
tions,andmethyrationreactionsinvolving
oxygen, sulfur, and nitrogen. In addition, non-
microsomal enzymes are irivolved in the catal-
ysis of some oxidation, reduction, and hydro-
lysis reactions. Nonmicrosomal enzymes are
primarily found in the liver but may also occur
inplasma,intestines,andredbloodcells
44
(RBC). Microsomal enzymes are found pri-
marily in the smooth endoplasmic reticulum of
theliver and,additionally, in the kidney and
gastrointestinaiepithelium.Microsomalen-
zymescatalyzeglucuronideconjugations of
phenols, alcohols, and carboxylic acids as well
asmanyoxidativereactions.Theseoxidative
reactions include nitrogen andoxygen dealky-
lation,deamination of primary and secondary
amines,anddesulfuration.Enzymes that are
coIlectively called mixed function oxidases are
utilized in oxidativereactions of the hepatic
endoplasmicreticulum.Theterminaloxidase
in the system is cytochrome P-450. The reac-
tions require nicotinamide adenine dinucleotide
phosphate (NADPH) as theprimaryelectron
donor and molecular oxygen.
METABOLISM OF
RADIOPHARMACEUTICALS
The general metabolic reactions discussed
previously also act on radiopharrnaceuticals.
Detailed chemical characterizations of radio-
pharmaceuticalmetabolitesandmetabolic
pathway studiesarescant, however. This lack
of research into the metabolism of radiophar-
maceuticals may reflect the difficulties encoun-
tered in the anaIysis of tracer amounts of the
drugs and their metabolites. Alternatively, the
generally held clinical opinion that a radiophar-
maceutical need only be stable until it reaches
its target organ may prevent generation of the
necessaryinterestandfundingrequiredfor
these studies.
The radiopharmaceuticals used commonly in
nuclearmedicinemaybeclassifiedintofive
groups:
succinic acid (DMSA), and diethylenetri-
lization of thalliumisclosely
tassiumutilization.Studies
related to po-
in ratsand dogs
aminepentaacetic acid (DTPA) have demonstratedincreasedurinarythallium
5 . Radioiodinatedcompounds:o-iodohippuric excretion with increased dietary potassium (5).
acid, iodomethyinorcholesterol (NP-59), fi- Ithasalsobeenshown that thalliumuptake,
brinogen, andserumalbumin likepotassiumuptake,occurs by anactive
transportmechanismand that once inside the
Gases
cell, thallium is released at a slower rate than is
Theradioactivegases,133Xeand81mKr, are potassium.Theinitialmyocardialuptake of
no1 metabolized andareexcreted in themo- thallium is dependentonmyocardialblood
lecular form. The biodistribution of these gases flow distribution and the extraction of thallium
is discussed in Chapter 1. by themyocardium (6). Redistribution of
thallium begins immediately and continues un-
Cations tilequilibriumisreached with thecirculating
Thecationicradionuclides used innuclear thallium pool (7).
medicine include [67Fa]gallium citrate, Studies on the metabolic fate of l1IIn in rats
[ZolTl]thallous chloride,["[In]or [1131n]indium haveshownthatfollowinginuavenousinjec-
chloride, ll'In-oxine, and "'In-diethylenetri- tion of [lllIn]indium chloride, the lllln tri-
aminepentaacetic acid (DTPA). valent cation isbound to transferrin and not
Gallium is found in group XI1 of the periodic preferentially localized in any one tissue (8). It
tabIebelow aluminum and aboveindiumand was suggested that IlLIn is bound to connective
normallyisfound as a trivalent cation. It has tissue via polyanionic mucopolysaccharides.
no known trace element function (2). After in-
travenous injection of [67Ga]gallium citrate, Anions
67Ga rapidlybindstoplasmaproteins,es- The anionic radiopharmaceuticals are repre-
pecially to transferrin. It also binds to ferritin, s e n t e d b y s o d i u m [ T r J c h r o m a t e , s o d i u m
lactoferrin, and siderophores.Thereismuch [99mTc]pertechnetate,sodium[32P]phosphate,
controversy concerning the mechanism(s) of and chromic [ 32P]phosphate suspension.
galliumuptake by tumorsandinflammatory T r in the form of sodium chromate iabels
tissue. It appears that the biological behavior RBCforuse in determining red cell survival
of gallium is closely related to Iigands found in time,measuring blood volumemeasurements,
vivo and, more significantly, to the metabolic and imaging the spleen. It is thought that the
pathways of related cations (3). Unbound gal- labelingmechanismprobablyinvolves diffu-
lium is deposited in the bone and excreted in sion of theanionichexavalentchromium
the urine. It has been shown that in the urine, (CrO;) through the red cell membrane where it
67Gainiiially occurs in citrateform (4).Also isthenenzymaticallyreducedtoCr3+ (9).
found are gallium hydroIysis products, gallium Spontaneous elution of radioactivity occurs at a
hydroxide, and gallate. In addition, 50% of the rate of more than 1% a day. The released radio-
67Ga activity has been found to be retained by activity in the Cr3+ form is not capable of ia-
membrane ultrafiltration when the urine is col- belingothercells butmaybind plasma pro-
lectedandanalyzed at 1 weekpostinjection; teins. Trivalent chromium is an essential trace
this retained fraction is believed to represent a element. It is a factor for the action of insulin
i : !
.- 46 t Essentials o i N l d e a r Medicitre Science
in conrrolling glucose metabolism. It is bound
in a complexligandknownasthe"glucose
tolerance factor" (GTF) (IO). Chromium also
is found in ribonucleicacid (RNA). It is not
known whelherinjectedchromiumiscapable
of being incorporated into GTF or RNA.
Seventy to eighty percent of the pertechne-
(ate anion (TcO;)is protein bound in plasma
(11): with the majority being bound to serum
albumin (12).The 20-30% that isunbound
actsas a highlydiffusiblesmallmolecule
which can be found in many organs including
thethyroid,salivaryglands,gastricmucosa,
andthe choroid plexus of the brain.The un-
bound pertechnetate is removed from the blood
by loss to the extracellular fluid or to specific
tissue entrapment as in the thyroid. As the con-
centration of free TcO; decreases, ihe equi-
librium shifts torelease more TcO, from its
protein-binding sites until equilibrium is re-
established. Pertechnetate is excretedinthe
urine, feces,saliva, andlacrimal fluid.The
administration of perchlorate ((30;) results in
tissue redistribution of TcO;. This result may
be due to eilher release of TcO, from plasma
protein-binding sitesandredistribution to ex-
tracellular spaces or a partial intracellular shift
of TcO; (13). I n the presence of perchlorate,
TcO; moves into RBC.
Phosphorusisfound in organicandin-
organic forms in all tissues. Ninety percent of
the body's phosphorus is found in bone as
in thehydroxyapatitecrystalwhere its
turnoverisnormally slow (14).Phosphorus
alsois found in nucleicacids,phospholipids,
plasma, and extracellular fluids. The biological
half-life ( t 3 of 32P in bone is 1155 days, and
the tl/?for thewhole body is257days.The
biological tw for soft tissues is approximately
90 days (14). Additionalinformation on phos-
phates is presented in the section of this chap-
ter on bone imaging agents.
The metabolism of iodine has been studied
extensively (15, 16) and, therefore, is not dis-
cussed in detail. Cerlain aspects of iodine me-
tabolism,however,arepertinent to nuclear
medicine studies.
Theaveragedailyiodineintakeisapprox-
imately150pglday.Degradation of thyroid
hormones contribules another 70 pglday to this
inorganiciodine pool.Inorganiciodinecircu-
lales as iodide (I-) until it is taken up by the
thyroid where it is enzymatically oxidizedto
iodine (17). Thyroid uptake accounts for about
70 pg of iodine per day. The remainder is ex-
cretedthroughthekidney,except for small
amounts excreted in thefeces.Thyroid hor-
mone synthesis is inhibited by thiourea or thio-
amide-lype drugs(propylthiouracil,methima-
zole). Thyroid trapping of iodide is blocked by
thiocyanates and perchlorate. Increased dietary
iodine decreases the thyroid uprake of I3'I- or
1231- during nuclear medicine procedures.
99mTc-labeledCompounds
The use of 99mTc-labeled sulfur colloid for
imaging the spleen, liver, and bone marrow is
basedonthepremisethatcells of the re-
ticuloendothelial system (RES) are able to re-
move colloid particles from the circulation.
Fixed macrophages are believed to be the pri-
mary RES cell responsible for colloid uptake.
Autoradiographic techniques were unable to
demonstrate *'"Tc activity within KupFfer ceIIs
(18). Evidence that macrophages do, in fact,
phagocytize 99mTc-labeled sulfur colloid parti-
cles, however, has come from studies that have
demonstrated osmium-stained colloid particles
with liver macrophages of the rat (19). This
result is in contrast to the results of studies
whichshowedthat neulrophils are not labeled
by phagocytosis of 99mTc-labeled sulfur colloid
but are labeled by adhesion of colloid at their
external surface (20).
Factors affectingthephagocytosis of suifur
colloid particles have been divided into (a) par-
ticlefactors and (b) host factors (21). Particle
factorsincludecharge,surfacecharacteristics
(foreignness), size,anddose.Sizeappears to
have the most influence on the biodistribution
of sulfur colloid particles. With a mean parti-
cle size of 100 nm, 80-90% of the activity is
seenintheliver,with 5-10% seen in the
spleen and the remainder seen in the bone mar-
row (22, 23). Largerpartidesresultinin-
creased splenic uptake, whereas smaller parti-
cleslocalize in thebone marrow (23). Host
factorsincludeorgan blood flow andre-
ticuloendothelialcellintegrity.Increased
splenicuptakehasbeenseen with malignant
melanoma (24). portalhypertension (25), and
cirrhosis (21).
Notingthe in vitro instability of sulfur col-
loid particles in the presence of serum, Frier et
al. (26) examined the biodistribution of sulfur
colloid labeled with both 9 g m Tand
~ 35S. It was
found that the biodistribution of the two labels
differed considerably.With 99mTc-labeled sul-
fur colloid, liver uptake was more than 80% of
therecovereddose,withalmostcomplete
blood clearance of activity occurring by 10
minutes after injection. On the other hand, 35S
showed slowand incomplete blood clearance
and no specific concenlration of activity in any
tissue examined. The authors believed that the
differingbiodistributions of thetwotracers
could be duetoeither loss of sulfurcontent
from the particles before they reached the liver
or loss of sulfur from particles following pha-
gocytosis in the liver. It appears that the pres-
ence of 9 9 m Tmay~ modify the in vivo behavior
of thesulfur coIloidcarrier.Alternatively, the
in vivo environment may alter the physical and
chemical properties of theradiopharmaceuti-
cal. These observations do not appear to have
any major clinical significance.
The intracellular handling of sulfur colloid
particles is no1 well understood. In general,
engulfed material is containedwithin a pha-
gosome or phagocyticvacuolewhichfuses
with a lysosome L O form a phagolysosome.
The ukimatefate of the colloid particlede-
pends on its susceptibility to enzymatic diges-
tion. Lysosomes are known to contain a wide
variety of hydrolyticenzymesincluding both
acid and alkalinephosphatases,ribonuclease,
deoxyribonuclease, nucleotidase, sulfatase, ca-
thepsins, andglucosidases.Colloids may re-
main within the macrophages indefinitely,
probably many times longer than the half-life
of the radiolabels (23) or until the cell dies. It
has been reported, however, that 99mTc-labeIed
sulfur colloid may be metaboli7,ed and digested
by the lysosomal enzyme sulfatase (27).
The use of 49mTc-labeledmacroaggregated
albumin (MAA) is a w.11-established technique
for the assessment of pulmonary perfusion and
the deteclion of pulmonary emboli. After intra-
venous injeclion of MAA, particles ranging in
diameter from 10 pm 10 100 pm are trapped in
theprecapillaryarterioles of thelungs.Al-
buminmacroaggregates, being looselyjoined
fragments of smallerparticles, are malleable
and may change shape. With use of cinemicro-
scopic techniques in the capillary beds of rab-
bit omentum, it was shown that MAA particles
are forced through thearteriolesbyconslant
cellular bombardment and continuous forward
and backward movement due to changing intra-
arteriolar pressure (28), Similar conditions un-
doubtedly occur in the pulmonary vasculature
and, along withmechanical movement of the
lungs and proteolytic action, result in fragmen-
tation of the macroaggregates. Phagocytosis
and enzymatic digestion of these smaller parti-
cles in a manner similar to digestion of colloid
particles results in the release of ionic 9 9 m T ~
andlor 99mTc-labeled albumin fragments. With
I3'I-MAA, free iodide and iodinatedalbumin
breakdownproductsarereleased intothe cir-
culation (23). Labeled human serumalbumin
has been used for measuring blood volume and
cardiac output. A significantfraction of al-
bumin is lostintothe gut where it is digested
(29). After digestion, thelabel (99mTc or I3'l)
could be redistributed into the body.
99mTc-labeledphosphateandphosphonate
compounds are used in bone imaging and myo-
cardialinfarctimaging.Thesecompounds in-
clude pyrophosphate (PYP), l-hydroxyethyl-
idene diphosphonate (HEDP), methylene di-
phosphonate (MDP), and hydroxymethylene
diphosphonate (HDP). These compounds have
replaced the polyphosphale compounds used
earlier in nuclear medicine.
*"Tc-labeled phosphate and phosphonale
compounds are metastable in vivo (30). Com-
plex stability increases in succession from tri-
polyphosphate, to PYP, to MDP, and to HEDP.
Stability is associated with more protein bind-
ing.Complexbreakdownoccurs primarily in
the extravascuIar space. Studies have shown
that in rats, hydrolysis of 99mTc-labeledphos-
phate complexes leads to the formation of two
compounds (31). Thefirst,thoughtto be hy-
drated 99'1'Tc-dioxide, has no affinity for bone,
is notproteinbound,andisexcretedby
glomerularfiltration. The second compound,
whichisderived from thefirst, is a charged
9 9 m T(1V)
~ compound which is protein hound.
48 I Esseutials of NuclearMedicineScience
Thislattercompoundisthought tobind the
organic bone matrix.
The stability characteristics of the phosphate
and phosphonatecompoundsalso are depen-
dentontheorder of linking of their aloms.
Pyrophosphates have a P-0-P linkage which is
readilyhydrolyzed b y pyrophosphatase to
orthophosphate (32). Diphosphonates have a P-
C-Plinkagewhich is stableandresistant to
hydrolysis (33). In fact,there are no known
serum enzymes that hydrolyze disphosphonates
(34).
Evaluationof the hepatobiliary systemcan
beaccomplishedbyuse of various N-sub-
stituted derivatives of iminodiacetic acid
(IDA). 95mTc-labeled IDA derivativesare
cleared by an anionic clearance mechanism in
a manner similar to that involved in bilirubin
clearance (35). Increased bilirubinlevels may
decreasetheclearance of these radiopharrna-
ceuticals to varying degrees.Theaddition of
high-molecular-weight substituents on the aro-
matic ring has been shown to increase hepato-
biiiaryspecificity (36). Studies in mice have
shown that the in vivo kinetics of N-substituted
iminodiacetic acid complexes may vary, de-
pending on the structure, the polarity, orthe
molecularweight of thearomaticsubstituent
(37). Liver affinity is decreased by increasing
polarity, and substitution in the ortho position
leads to complexes with increasedurinary ex-
c r e t i o nr a t e s .9 m T c - l a b e l e d N[N'-(2,6-
dimethylphenyl)carbamoylmethyl]iminodi-
aceticacid(95mTc-HIDA)isexcreted i n the
original radiochemical form and is not dissoci-
ated or metabolized (38).
99mT~-DTPA isa well-established radiophar-
rnaceutica1 for brain and kidney imaging. "'In-
DTPA is used in cisternographystudies.In
studies in which 14C-DTPA was used in rats, it
was demonstrated thatafter intravenous injec-
tion, 84% of ?he injected activity was excreted
in the urine and 10% was excreted in the feces
during the first 24 hours (39). In addition, the
activity in the tissues was below 1% of the
administered dose at 24 hours, and only 0.15%
of theadministered activity remained in the
tissue at 39 dayspostinjection.Inanother
study, 90- 100% of an intravenously admin-
istered dose of I4C-DTPA was found inthe
urine at 24 hour postinjection (40). The biolog-
ical stability of wmTc-DTPA was studied in hu-
mans (41). One hour after injection of 9 9 m T ~ -
DTPA, more than 98% of the 9 9 m Tactivity
~ in
the urinewas in the form of the labeled che-
late. In plasma samples, 80-90% of the 9 9 m T ~
activity was in thelabeledchelateform,
5-10% was associated with serum proteins,
1-4% was found as an unidentified compound,
andlessthan 3% was foundas uncomplexed
[49mTc]pertechnetate(41).
Radioiodinated Pharmaceuticals
The use of radioiodinated (I3'[) pharmaceuti-
cals in nuclearmedicine has decreased in re-
centyearsduetoitsless-than-idealenergy
characteristics and long physical half-life. l3lI-
labeled compounds are still used in renal imag-
ing (0-[1311]iodohippurate),howelper, and most
recenlly have been used in studies of the adre-
nalmedullaandcortex(rn-[1311]iodobenzyl-
guanidine(mlBG)andI3'I-NP-59,respec-
tively).
The metabolism of ~ - [ ~ ~ ~ I ] i o d o h i p p uin-
volves four possible pathways (42). It may be
(a) deiodinated, (b) deiodinatedandsimul-
taneously cleared to benzoic acid, glycine, and
freeiodide,(c) hydrolyzed to [1311]-iodoben-
zoic acid and13'I-glycine, or (d) excreted in
the unmetabolized form. The latter pathway
probablypredominates due to the rapid dear-
ance of the compound in the urine.
The imaging of the adrenal cortex with 1311-
NP-59 (6p-['311]iodomethyl-19-nor-
cholest-5(10)-en-3~-oI) is based on the idea
that NF-59, with a structure similar to choles-
terol, will enter the biosynthetic pathway that
utilizescholesteroltoproducesteroid
mones. Theconversion of thecholeslerolto
the varioussteroid hormones involves the hy-
droxylation of the side chain of cholesterol and
thesubsequentcleavage of the moleculebe-
tween C, and C,, by the enzyme desmolase.
I3'I-NP-59 has greater stability to deiodination
than does 19-[1311]iodocholesterol (43).
Themetabolism of theadrenalmedulla
imaging agent, 13'I-mIBG, has been studied by
use of 1251-pIBGin dogliverhomogenates
(44). These studies have shown veryslow en-
zymatic dehalogenation which is stimulated by
addition of glutathione (GSH). Itwassug-
gestedthatthisdehalogenationisdueto
GSH-S-transferaseinthe liver. It was shown
that in vivo dehalogenation also occurs.
SUMMARY
The metabolism of radiopharmaceuticals has
been shown to be generally similar to the me-
tabolism of nonradioactivedrugs in many re-
spects, including the enzyme systems utilized
in biotransformation reactions. Detailed studies
of radiopharmaceuticalmetabolism, however,
arefewer and less extensive than studies of
nonradioactive drugmetabolism.The reasons
for the overall lack of metabolic studies of ra-
diopharmaceuticaIshavebeenvariouslyat-
tributed both to(he lack of interest by c h i -
ciansandtothetechnologicalproblems
associatedwithanalysis of traceramounts of
radiochemicalcompounds.Itappears that in
[he race to develop newer and better radiophar-
maceuticaisoverthepast 20 years,clinical
rate usefulnessovershadowed morebasicresearch
areas suchasmetabolism. It ishoped that in
the future a balancewillbereached between
applied and basic research, with the end result
being a reexamination of manyradiopharma-
ceutical~ in terms of metabolism and kinetics.
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5
Radiupharmuceutical Absorbed Dose
Consideratioas*
GENERAL PRINCIPLES
Thenumber of radionuclides with suitable
physical and chemical properties acceptable as
indicators in radiopharmaceuticals (radiophar-
maceuticaldrugproducts, RDP) islimited.
Compromises have to be made in the develop-
ment of radiopharmaceuticals,since boththe
chemical and the physical characteristics of ra-
dionuclides have lo be considered. Many times,
some of the specificity of the RDP has to be
given up when radiopharmaceuticals are se-
lected for clinical use,
Important criteria for determining the accept-
ability and clinical usefulness of diagnostic and
therapeutic applications of radiopharmaceuti-
c a l ~are [he potential risk, the practicabiiity, and
the diagnostic or therapeutic result that can be
expected. Practicability and potenlial diagnostic
or therapeulic benefits are imporlant factors in
determiningwhethertherisks are acceptable.
The risks involved in the clinical use of radio-
pharmaceuticals are essentially the consequence
of radiation exposure and, to some extent, the
potential side effects of complications resuIting
fromthechemical,biological, or physical
nature of the radiopharmaceuticals.
Manyrisks that are of concern withother
diagnosticprocedures play only a secondary
* This workwas perfomledunderInleragcncyAgree-
ment No. FDA 224-75-3016, DOE 40-286-71, Oak Ridge
Associated Universities pedorms complementary work for
the U.S. Department or Energyundercontrac[ DE-
AC05-760R00033.
role in nuclear medicine. More than 95% of the
diagnosticnuclearmedicineproceduresare
noninvasive,Handling of thepatientisre-
stricted to administering the radiopharmaceuti-
cal (intravenousinjection,oralapplication, or
inhalation) and, possibly, taking blood samples
for radioassay.
Side effects from the chemical nature of the
radiopharmaceutical are rare because the chem-
ical amount of the radiotracer used is extremely
small. The incidence of complications from ra-
diophannaceuticals has been found to be about
1 in 10,000 procedures. In comparison, side
effects from contrast media in conventional ra-
diography occur at a rate of approximately 1 5 . 5
Lo 1:250 procedures.
Thus, radiation exposure from the injected
radioactivetracer to the patient and, specifi-
cally, the polential somatic and genetic effects
of this exposure are the main concern. The risks
from lherapeutic applications of radionuclides
are more easily accepted than are those resulting
from diagnostic nuclear medical procedures.
The additional radiation load to the popula-
tion fromnuclearmedicalproceduresis less
than 10%. There is no epidemiologic evidence
that this 10% increase would result in somatic
damage withinthe population. So we are lefc
with the general genetic risk which is primarily
a collective risk and not of much concern to the
individual.
Although the somatic risk is extremely low
and thegenetic risk is negligibre with use of
radionuclides in nuclearmedicine,the physi-
 Radiopharrnaceutical Absorbed Dose Considerafiorls I 53
52 I Essmrials of NuclearMedicine Science

tions, such as acceptance of a linear dose-effect new drug provisions was ended, radiopharma-
cian who orders these tests should always weigh fect the pharmacokinetic pathways and, conse- relationship for low doses and the use of a statis- ceuticals have been regdated in the sameway as
the resuks of the test against the radiation ex- quently, change the dose distributionand possi- tical approach for measuring the benefit from all other drugs. Review groups in the Center for
posureriskto the patient. The dose from the bly the target organ dose. nuclear medicineanddeterminingtheproba- Drugs and Bioiogics(formerlythe Bureauof
radionuclide should be as low as possible, and The patient's age andweightare important bility of the development of radiation-induced Drugs) of the FDA evaluateapplicalionsfor
the optimal test would always b e one in which a considerations when a decision on [he amount
neoplasticdiseases,aremade.Thebenefits marketing (NDAs) and investigationalnew drug
radionuclide with a short half-life is used. On of activity to be administered is to be made. gained from nuclear medical tests outweigh the exemptions (INDs) of radiopharmaceuticals. An
the other hand, too small an amount of activity Age,especially in children,is a determining risks, however, provided the indication for the NDA is approved only if the applicant shows
results in insufficient information and a repeti- factor in thisdecision.Simply to adjustthe test is justified and modem principles of radio- that thedrugissafe,effective, andproperly
tion of the test, which in the long run increases activity on the basis of body weight is not satis- pharmaceutical applications and high-standard manufactured. Substantial evidence of effec-
the radiation exposure. It is much easier to de- factory and could resull in unnecessarilyhigh quality control procedures are used. tiveness is required by law and must consist of
fine ageneticaliy significantdoseasonefor radiation-absorbed doses in children, since the adequate and well-controlled investigations, in-
whichnuclear medicineprocedure is clearly mass of certain organs relative to the body over- RESPONSIBILITIES AND VIEWS OF cluding clinical investigations, conducled by
indicated. If the decision of whether or not to all is quite different in a small child than in an REGULATORY AGENCIES persons considered to be qualified to evaluate
order a nuclearmedical test is basedon this adult. Furthermore, children have an overall in- Licensed physicians can use any method or the effectiveness of the drug when used accord-
principre, the number of nonproductive tests or creasedradiosensitivityandincreasedfunc- agent they believe would help in managing their ing tothe proposedlabeling(package insert).
noninformative tests will be reduced and the usetionalandphysiologicactivities in certain patients, including devices or agents that have In addition to the FDA which regulates the
of higher doses may even b e justified. tissues of the growingbody(i.e.,bone, thy- risks associatedwith their use. The physician manufacture and use of radiopharmaceuticals,
The radiation exposure in nuclear medicine is roid). A safer approach to calculating a reason- has the responsibility of weighing the benefits the U.S. NuclearRegulatoryCommission
withinthe samerange as theexposurefrom ableradiopharmaceuticaladministrationfor to be derived from a device or agent againstany (NRC)hasauthorityoverby-product,special
conventional radiographic examinalions, and children is probably the body surface area, or risks in order to determine whether its use is nuclear, and source material but not over natu-
some diagnostic radiotracer studies result in a Webster's rule (the pediatric dose = x + 1 over warranted. Although regulatory agencies do not rally occurring and accelerator-produced radio-
much lower exposure than do radiographic pro- x -I-7 times the adult dose, where x = age in prevent physicians from practicing medicine ac- active materials. By-product material is material
cedures. It may be said thatthe riskis lower years), or a simple and practical ruIe of thumb cording to their judgment,the agencies do have made radioactive by exposure to radiation from
withlowerdosesandthatasthedoseap- approach (children under5 years receive 25% of responsibility for issuing guidelines for the use the use or production of special nuclear mate-
proaches zero, the risk also comes close to zero. (heactivity thatwould begiven toanadult; of drugs, biologic products, and devices and to rials and uranium mill tailings. Special nuclear
Even the small fraction of additional radiation those 5-10 years old, 50%; those 10-15 years ensure that these guidelines are safe and effec- material is 233U or plutonium or uranium en-
dose froma nuclear medicinetest may represent old, 75%; andthoseolder than 15years,the riched with 233U or 235U; source material is
tive.
a risk, however, andwe shouldmakeevery same activity as adults). For manyyearsafter World War 11, radio- uranium or thorium in any form. Because ura-
efforttoreducethatrisk as much as possible Otherfactors that may affecttheradiation pharmaceuticals were exempted from the reg- nium and transuranics are not used in nuclear
and practical. During the past 15 years, short- dose from radiopharmaceuticals to patients are ulationsthat applied to nonradioactive drugs medicine, only radiopharmaceuticals that con-
lived radionuclides havebeen used Lo reduce the thepatient's physicalconditionand abilityto
and were distributed under the regulatorysuper- tainby-product material are subject to NRC
radiation exposure to patients, to the point that cooperate. If a nuclear medicine study cannot vision of the U.S. Atomic Energy Commission. regulations.
now it is even possible to use nuclear medical be completed because of those reasons, the This exemption began with the introduction of Thevariousstatesalsohaveregulalory
procedures with children. study may have to be repeated, which leads to radioactive drugs containing by-product radio- powers overtheuse of radioactivematerials.
A key question concerned with reducingradi- addilional radiation exposure of the patienl. nuclides and became official in 1963 (1) when The kind of control that is exercised depends on
ation exposure to the patient is whether another Poor or inadequate preparation in general, and the Investigational New Drug Regulations were the individual state; the state programs can be
test can givetheanswer withouttheuse of forspecifictestsin particular, may result in put in force. In 1971, the Food and Drug Ad- divided into three basic types, however. Agree-
radiation and without the undue risks associated unsatisfactory studies and unnecessaryradiation
ministration (FDA) which is the federal regu- ment states have reached an agreement with the
withotherkinds of invasive diagnostic ap- doses. In addition, poor quality assurance pro- latory agency that has responsibility for the NRC to license by-product, source, and special
proaches. In many instances, nuclear medical or cedures and sloppy techniques in the radiophar-
safety of foods, cosmetics, drugs, and medical nuclear material. Licensing sfares license natu-
radiographic information, albeit of marginal maceuticallaboratory(doseprescribing,dose devicesbecamemoreinvolved in theuse of rally occurring and accelerator-produced radio-
value by itself, can give conclusive complemen- calculation,anddosecalibration) and during radiopharmaceuticals and called forthe submis- acfve materials. Registration states register nat-
tary or confirming information needed for the administration of the activity (mislabeling sy- sion of new drug applications (NDAs) for the urally occurringand accelerator-producedra-
diagnostic, prognostic, or therapeutic manage- ringes, wrong patient, etc.) result in avoidable "welI-established" radioactivedrugs (2). This dioactivematerials.Thedifferent policies of
men1of a patient. If a nuclear medical proce- misadministrations. Most of the misadministra- resulted in theapproval of a large number of these agencies that have regulatory powers tend
dure is indicated, we have to decide which ra- tionsandunnecessaryexposuresaredue to NDAs for radiopharmaceuticals that had been to make fhe use of radiopharmaceuticals partic-
diopharmaceutical to use.In this regard we need human factors in nuclear medicine quality con- used routinely by clinicians for several years. ularly difficult.Anyonewishing to use radio-
to consider the pharmacokineticsof a particular trol. Since 1975, w h e nt h ee x e m p t i o nf o r pharmaceuticals must obtain information from
radiopharmaceulical,bearing in mind that the Benefit-risk ratios can be calculated for nu-
radiopharmaceuticalsfromthe investigational the state radiological health department about
patient's disease or altered physiology may af- clear Inedical procedures if certain assump-

the applicable regulations as well as become
familiar with NRC regulations (see Chapter 21)
and FDA requirements (see Chapter 23).
Investigational New Drugs
Beforetesting any new drug,whether it is
radioactive or not, the investigator must comply
withthe Equirements that certainsafeguards
are used in the studies. One method ofdoing
this is to file a “Notice of Claimed Investiga-
tional Exemption for a New Drug, ” commonly
called an IND. Details of the IND process are
given in Chapter 23; those areas of the IND
which are pertinent toradiation dose calcula-
tions, however, arealsobrieflycovered here.
The primary requirements of an IND are:
1 . Complele information about the composition
of the drug
2. Results of all preclinical investigations of the
d w
3. The prolocol for the investigation
4. Qualifications of the investigators
5. Information on any adverse effects
6. Submission of annual progress reports
Of these requirements, the second (results of
all preclinical investigations) is ihe one that is
most relevant tothischapter. Beforehuman
studies can be initiated, studies in animals must
be carriedouttodetermine the biologic dis-
tribution and retention as well as the toxicity of
the malerial. The phrase “biologic distribution
and retention” takes into account the excretory
pattern of the radionuciide, and these factorsare
essential to making a meaningfu1 estimate of the
radiation dose to the patient. These initial esti-
matesusually are derived from studies in rats
and mice, with some limited data coming from
largeranimalstoevaluateinterspecies dif-
ferences.Theactual design of thepreclinical
studies is left to the discretion of the investiga-
tors; the studies should be planned, however, so
that virtually all of the administered activity is
accounted for at severaldifferent timesafter
administration. Distribution and retention stud-
ies in animals with induced disease conditions
represenlative of those for which the radiophar-
maceutical is intended may also be required to
show how [he radiation dose differs in abnormal
conditions. These studies also serve to demon-
stralethe effectiveness of theproposed agent.
TheFDArequests that the radiation dose
calculations be made in accordance withthe
schema (3) of theMedical Internal Radiation
Dose (MIRD) Committeeof the Society of Nu-
clear
Medicineor with
a comparable technique.
The basic equationforthe MIRD technique is
D(rl) = S(r,+ r h ) Equation 5.1
h No. 1, Revised (3), and MIRD Pamphlet No. 12
where fi is the mean dose, A is the cumulated
aclivity, and S is the absorbed dose per unit of
cumulated activity. The symbolsrk and r,?repre-
sent a targel region and source region, respec-
tively. Theequationdescribingtheabsorbed
dose per unit cumulaled activity, S, is
S(r, t T,,) = x 1
t r-,J Equation 5.2
where Ai is the mean energy of the ith type of
radiation emitled perunit cumulated activity,
and @! is the specific absorbed fraction of en-
ergy. The A value is the productof the factors k,
n , and E for each type of radiation, where k is a
constant based on the units to be used (2.13 in
MIRD schema for traditional units of radiation
dose in rad), n is the fractional abundance of the
radiationemissions,and E is theenergyin
MeV. The specific absorbed fraction, @, is the
+,
absorbed fraction, divided by the mass of the
target organ. The absorbed fraclion, +,
is the
fraclion of the total energy emitted in a source
organ which is absorbed by a targel organ. A
mathematical model of the body and its organs
is needed to calcdale absorbed fractions, spe-
cific absorbed fractions, and S values.
Values of S for a mathematical model of Ref-
erence Man have been published by the MIRD
Committee (4) and others (5-9). Although ra-
diopharmaceuticals are administered to women
and children,the radiation doseestimatesfor
Reference Man have been accepted by the FDA
as representative of the dose to any patient. If S
values for childrenbecomereadily available,
radiation dose estimates for chiIdren of various
ages may be required for radiopharmaceuticals
thal could have potentia1 value in children,
The cumulated activities, 2, usuallyare de-
terminedfrompreclinicalstudies and may re-
quire extrapolation from values obtained in ani-
mals to values expected in humans. Conse-
quently, [he animal sludies should be carefully
planned and executed so that the necessary in-
Radiopho,.}}7ncettficnlAbsorbed Dose Considernriorrs I
~~
formation will be obtained. The FDA generally
requires dose estimates for the organ or organs
receiving the highest radiation dose,forthe
gonads, for the bone marrow, and for the total
body. Techniques for calculating cumulated ac-
.~ tivities have been describedinmanydifferenl
publications, two of which are MIRD Pamphlet
(10). These are helpful in understanding the
general principles of calculating the number of
nuclear transformations h a t will occur in a
source organ over a particular time period but
do not give guidance on techniques for extrapo-
lating animaldata to humans.Severaipapers
presented at the Third International Symposium
on RadiopharmaceuticalDosimetry and pub-
lished in the Proceedirlgs are helpful in analyz-
ing data from animal studies and in using them
for estimating radiation dose in humans
(11-17).
After lhe sponsor of a ne” drug submits the
IND to the FDA, the responsible staff in the
Center forDrugsandBiologics of [heFDA
must review thedocument.Theprimary pur-
pose of this review is to evaluate the potential
problems in the proposed clinical trial; this re-
viewisperformedby a chemist, a phar-
macologist, and a physician. If the FDA does
not notify the sponsor to the contraryin 30 days
after receipt of the IND, the sponsor may initi-
ale [he clinical trials.
-
Theclinicalinvestiration is conducted in
three phases. Phase I consists of asludy in a
limited number of humansubjects to obtain
pharmacokinetic data on the radiopharmaceuti-
cal. These studies should demonstrate the nor-
mal biodistribution, clearance half-time, routes
of excretion, the organs that show the highest
concentration of the radionuclide, and the op-
timum imaging or sampling times. Children and
pregnanl or lactating women are excluded from
phase I studies. Patients with selected diseases
may be studied to evaluate distribution and ex-
cretion alterations that maybe caused by the
diseaseprocess.Thesechangesmay signifi-
cantly affect the radialion dose received by the
patient.
An alternative mechanism to the submission
of an IND for performing a limited number of
clinicaltrials is toobtainapproval by a local
institutional committee (IS). Such a committee,
55
called a Radioactive Drug Research Committee
(RDRC), is approved by the FDA to act on its
behalf. An RDRC can approve a research study
wilh the radiopharmaceutical if it is shown that
the radiation exposure to the patient is less than
the
prescribed maximums(simiIar to the max-
imumpermissibleexposures for occupational
workers); that the active ingredients in the phar-
maceutical are known not to cause any clinically
detectable pharmacologicaleffect in humans;
that the rights of human subjects will be pro-
tecled through review of theresearch by an
institutional review board; that the radiopharma-
ceutical meets chemical, pharmaceutical, radi-
ochemical, and radionuclidic standards of iden-
lity,strength,quality,andpurity; that the
researchprotocol is scientificallysound; and
that theinvestigators are qualifiedtoconduct
the proposed study and licensed to handle radio-
aclive materials,
Activities RDRCof an must be
reporled periodically to the FDA for review.
Phase I1 studies are conductedby two or
more independent investigators andare intended
toevaluate the safety and effectiveness of the
radiopharmaceulical under conditions of clini-
cal use of the drug.Thesestudiesshouldbe
designed to collect sufficient evidence to docu-
mentthenature of anyadverseeffects or the
absence of such effects and to demonstrate the
reliability of the diagnostic information ob-
tained with use of the agent.
Phase 111, the last portion of the investiga-
lion, is needed to provide statistically reliable
information on the safety and efficacy of the
drug. For [his reason, much larger numbers of
patients are used. Once the clinical evaluation of
a new drug is completed and the drug is found
to havepotential use in medicine, the sponsor
will seek to have the drug approved for market-
ing. In order to accomplishthis, a new drug
application (NDA) is filed with the FDA.
New Drug Applications
The new drug application is an extremely
voluminous document and details all of the in-
formation thal has been compiled on the drug,
including all the manufacturing and conlrol in-
formation as well as the preclinical and clinical
dala. Individual case reports are required. The
information that will be includedin the package
insert must be submitted. Adverse effects must
56 t Esserrrinls of Nuclear MedicineSciem-e
be well documented. The FDAmust analyze the
information to ascertainthe safetyandeffec-
tiveness of the drug and establish that the label-
ing (package insert) information is documented
by the studies that have been performed.
The approval of new drug applications in the
United States has been quite slow. In fact, the
average time for approving a radiopharmaceuti-
cal NDA has been about 2 years (19). Usually,
the blame for thelong lag time from initiation of
clinical studies to approval of the drug for mar-
keting is placed on the FDA; the fault must be
shared, however, with the manufacturers and the
nuclearmedicinephysicians.Accordingto
Frankel and Kawin (19), many of the phase LII
studies arenot adequateand well controlled.
Even though the studies can be used for suppor-
tive evidence, they are not sufficient for ap-
proval of an NDA. Frankel suggests two ways
to avoid this: (a) to have an adequate protocol
followedcarefullyafter it hasbeen developed
and agreed on by the FDA and theinvestigators
and (b) to have a meeting between manufactur-
ers and reviewers so that everyone understands
[he protocol and the agreements that have been
reached.
After a NDA is approved, the drug can be
distributed to licensed nuclear medicine facili-
ties for use. The package insert accompanying
the drug contains the caution that it should not
be used in pregnant or lactating women or chil-
dren unless the benefit to be gained outweighs
the risk of the study. Absorbed dose calculations
for pregnant or lactating women or children are
not included in the package insert. These cal-
culationspresent specialproblems becauseof
differences in organ size and location as well as
total body size.
PEDIATRIC RADIATION DOSE
ESTIMATION
The problem of estimating radiation dose to
childrenfrominternallydepositedradio-
nuclides, as with any radiation dose estimate,
breaks down into two simplerproblems:(a)
quantifying the biologic parameters and (b)
quantifying the physicalparameters.The for-
mer refers to the sum of the information regard-
ing the distribution and retention of the radioac-
tivecompound.Thelatterdescribesthe
characteristic decay modes of the radioisotope,
the frequency of each type of emission, and the
geometry in which the energy is releasedand
deposited.
Thephysicalparameters are muchmore
easily understood and, consequently, are better
studied, so they will be considered first. In the
MIRD technique for calculating internal radia-
tion dose ( 3 ) , a single factor describes the en-
ergydeposited in aregion of thebody. This
factoriscalled the S value,and valueshave
been calculated for a geometric model designed
to approximate the size, shape,and composition
of the adult human (4). The basic units of the S
value are absorbed dose per unit of cumulated
activity. The S value itself may be broken down
into two parts, one being the decay data for the
radionuclide (decay energy and branching) and
the other being the fraction of energy emitted in
a sourceregionwhichisabsorbed in atarget
region per unit mass of the target region (spe-
cific absorbed fraction).
For convenience in calculating S values, the
radiations emittedby a radionuclide are oflen
grouped according to thepenetrability of the
radiation. If essentially all of the energy would
be deposited in the source region, the radiation
is called nonpenetrating radiation. If the radia-
tion could be deposited in other regions, it is
called penetrating radiation. Typically, the spe-
cificabsorbed fraction forthenonpenetrating
radiation is 1 divided by the mass of' the region,
whenthesourceandtargetregionsarethe
same, and is 0, whenthesourceand target
regions are different. For penetrating radiation,
regardless of whether the source and target re-
gions are the same or are separate, the specific
absorbed fraction is the fractionof energy origi-
nating in the source region that is absorbed in
thetarget, divided by themass of thetarget
region. These fractions usuallyare calculated by
generating Monte Carlo photon histories for
several photon energies for each of the (20 or
more)sourceorgansand by correlatingthe
point of absorption with the geometries of the
target organs.
Becausethe
decay
data €or the different ra-
dionuclidesarefixed,onlythespecificab-
sorbed fractions will change for the various age
groups.Oncespecificabsorbedfractions are
~~
~ __
Radiopharmacerriica!AbsorbedDose
calculated, however, S values may be generated
for any given radionuclide. An early attempt to
generate thesespecificabsorbed fractions for
children involved shrinking of the human phan-
tom, until the weight matched lhat of the human
at the various ages, by factors related to theratio
of the cube rootof the masses (20).This resulled
in significant distortion of the true size, shape,
andorientation of manyorgans.Similarly, S dren include renal studies, lung scans, thyroid
values for 62 radionuclides, based on scaling of
the adult S values by factors related to the dis-
tancebetween the centers of mass of target-
source organ pairs, were published for five pe-
dialric age groups (21, 22). Other investigators
(23-25) remodeled the adult phantom to repre-
sent thenewborn,the 1-year-old, the 5-year-
old, and the 15-year-old and generaled specific
absorbedfractions for several energies.Cristy
(26) has designedphantomsrepresenting the
newborn, the 1-year-old, the 5-year-old, the 10-
year-old, andthe 15-year-old which arebased
on the changes in organ system size and place-
ment with age, not simply on size scaling of the
aduh phantom. Cristy and Eckerman (27) have
generated specificabsorbedfractions for the
various organs in the phantom, using 25 source
regions and 25 target regions. S values can be
easily calculated for specific radionuclides.
Biologic data describing radionuclidicbehav-
ior in children are lacking. Most biodistribulion
data used to generate pediatric absorbed doses
arebased on informationfromeither healthy
human adults or animals. Consequently, the ac-
curacy of thegeneratedestimates is open to
question. Some information is known about the
variation in biokinetics with age. For instance,
newbornshavelowerrenalbloodflow,
glomerular filtration rate, and transportof hepa-
tobiliary agents, more rapid washout of radioac-
tive gases, and greater uptake of bone-seeking
radiopharmaceulicalsthan do adults (28), a
poorly formed blood-brainbarrier, and an in-
complete enzyme complement (29). The num-
ber of alveoli increases rapidly during the first
year of life and then more gradually, reaching
the number found in adults at about 8 years of
~~
age (30). Thenumber of pulmonaryarleries
also increasesrapidlybetweentheages of 4
monthsand 3 years(31).Thesephysiologic
~~
.~
~.
-
=
parameters become closer to adult values with
Considerations I 57
maturation, but clearly the quantitation of the
changes would help to improve the accuracy of
dose estimates generated for childrenof various
intermediateages.Forshort-livedradionu-
clides, however, variations in the biologic half-
time are often unimportant in the final outcome
of effective half-time and absorbed dose.
Some radionuclide studies performed in chil-
scinligraphy, splenicscintigraphy,bonescans,
cardiac studies, and gastric emptying studies.In
renal studies, 99"Tc(Sn)-diethylenelriaminepen-
taacetic acid (DTPA) may be used to evaluate
renal perfusion,functioning renal mass,and
glomerular filtration rate, as well as to visualize
various anatomic structures. 99mTc-gluceptale is
used to visualize the renal corlex and the pel-
vicalyceal collecting systems. 99mTc-dimercap-
tosuccinic acid (DMSA) is used to outline renal
morphology andto differenliatefunction. In
addition, follow-up cystographystudiesoften
are performed with 99mTc-pertechnetate or sul-
fur colloid. slmKrand 133Xeare used for lung
ventilation studies in children, with the latter
being either inhaled or given in a saline injec-
tion. Lung perfusion studies may be performed
with 99mTc-labeied macroaggregated albumin
(MAA) or wmTc-labeled albumin microspheres.
Thyroidstudieswillcommonlyemploysome
radioactive iodineasNal.Spleenscans have
been carried out with use of 99mTc-labeledheat-
treatedredbloodcells(RBC).Liver-spleen
scans usually are performed with 99mTc-labeled
sulfur colloid. The ""Tc-labeled phosphate
compounds areused widely for bone studies,
with methylene diphosphonate (MDP) currently
beinglhemostpopular. In cardiacsludies,
99mTc-labeIed RBC, pertechnetate, or human
serumalbumin (HSA) may beemployed.In
gastricemptyingstudies,usuallysome 99mT~
compound suchas sulfur colloid taggedto some
fooditemisemployed.Carrier-free 67Ga is
widely used to image soft-tissue and bone ma-
lignancies.
Therefore, a large amountof distribution data
is needed to quantify the radiation dose to chil-
dren from these procedures. Li et al. (32) have
listed dose estimatesfor 1-year-oldsand 15-
year-olds to the lungs, gonads, and total body
for SlnlKr and '33Xe gas used for ventilation
 58 t Essenfinls of IVuclenr Medicine Science
studies. The S values used, however, were di-
rectly from absorbed fractions for the adult. The
t
distribution dala also came from adult studies.
Kereiakes et al. (33) generatedradiation dose
estimatestothethyroid for 123i,1251, l3II, and
'j21as iodide for newborns, 1-year-olds, 5-yea-
olds , 10-year-olds , and 15-year-olds . Their bio-
logic data came fromseveral sources; they con-
cluded thal the biologic half-time (68 days) did
not vary significantly with age and that a mean
uptake of 27% of theadministeredactivity
could be used for all except the newborn, for
which they used 70%. They noted that thyroid
uptake in the first 2 weeks of life can be very
high. Wellman et al. (34) found that values in
this age span could approach loo%, although
the average for all other age groups was around
30%. The biologic half-time and generated dose
estimates for the adult agreed well with the
values found in MIRD Dose Estimate Report
No. 5 (35). Henrichsetal.(22) quotedage-
specific effective half-times for I3lI in the thy-
roid, from which age-specific biologic half-
timesforiodide may be inferred (Table 5.1).
The age-specific dose estimates for the thyroid
fr0rnI~~1, which are calculated .by using the
scaled S values of Henrichs et al. (22), agree
fairly well with the values of Kereiakes et al.
(Table 5.2). Ball and Wolf (36) generated dose
estimates €or a variety of agents for newborns,
1 -year-olds, 5-year-olds , 10-year-olds , and 15-
year-olds, consideringoniyorgan self-irradia-
tion and usinggeometricfactors of Hine and
Brownell (37). James et al. (38) also published
doseestimatesforseveralradionuclidesfor
Table 5.1.
Age-specific Values of the Biologic Half-time (tb)
of Iodides in the Thyroid*
~ ~~ ~
0 14.0
0.5 23.6
1 25.3
3 29.1
5 29.1
10 44.1
15 48.7
* Extrapolated from the age-specific cffective
half-times for I'Jl
as dctcnnined by Henrichs et al.
(22).
Table 5.2.
Comparison of the Age-specific Dose Estimates for
the Thyroid from 1311 as Determined by Kereiakes
el al. (33) and Henrichs et ai. (22)
Age (yr) Kerciakes e l al. Henrichs et 01.
0 16.0 13.0
1 10.9 13.0
5 5.I 7.5
10 3.0 4.1
15 2.1 2.7
these age groups, considering only organ self-
irradialion.
Although advances have been made in quan-
tifying the physical parameters involved in cal-
culating radiation dose to children of various
ages, there is little information available cur-
rently aboul the biologic parameters. Age-spe-
cific radiation dose estimates are of great impor-
tance to the physician who wants the adminis-
tration of activity to be as low aspossible lo
achieve a suitable scan image. Both enlhusiasm
in the medical professional community and sup-
pori from the regulatory agencies are needed to
formulate and execute studies thatwill establish
the metabolic properties of these radionuclides
in children.
Radiation Risks
In virtually all animal studies, life-shortening
hasbeen shown to be more pronounced when
irradiation occurs earlier in life. This difference
may, however, be accounted for in part in that
the latent period for deaths resulting from can-
cer induction exceeded life expectancies atirra-
diation forsome of theolderagegroups.In
human studies, a generalpattern of increased
susceptibility to cancer induction with increas-
ing age is observed in those over age 20, and
lrends in those below age 20 vary with the type
of cancer (39). Typically, Iatent periods are
somewhat longer in younger age groups.
Analysis of the atomic bomb survivors has
shown that persons irradiated before age 15 had
the highest incidence of both chronic and acute
leukemia and a higher number of excess deaths
per million persons per year perrad to the bone
marrowlhan did all olheragegroups except
RadioF
chose exposedafter age 50. Theyoungerage
groupsalso seemedtohave a shorter lalent
period.
There are some indicationsthat persons under
age 20 have a higher risk of thyroid cancer per
rad than do those in olderagegroups.The
numbers from the atomic bomb survivors indi-
cate this trend but are based on a small sample
size. Medical findings among the Marshall Is-
landers show a rale of incidence of benign thy-
roid lesions in children under age 10 to be four
times that in the older exposed population.
Olher observations of the atomic bomb sur-
vivors show thal the risk for breastcancer is
highest amongfemales in the 10-19-year-old
group, declines with age until age 50, and then
increases again. For those under age 10, abso-
lutely no incidence of breastcancer was ob-
served.This pattern is understandable,since
majorhormonalchangesareoccurringin
women in the second decade of life,
RADIATION HAZARDS INVOLVING
RADIOPHARMACEUTICAL
ADMINISTRATIONS TO LACTATING
MOTHERS
Breast milkiscomposed of water, fat, lac-
tose, casein, other proteins, and ash. The con-
sistency is that of fat droplets surrounded by a
membrane, in a suspension of transudate con-
sisting of milk, proleins, sugar, salts, and water.
Immediately after birth, the loss of eslrogen and
progesterone secretion by the placenla removes
the inhibiting effect of these hormones on pro-
lactin productionby [he pituitarygland.The
prolactin stimulates synthesis of large quanlities
of fat, lactose, and casein, and breast milk pro-
duclion becomes copious within 2 to 3 days.
Milk production may continue for several years
if the mother continues to breast feed, but typ-
.~ ically
lasts only 7-9 months.
Calcium and phosphate are needed in large
~-
quantities for milk production; 2-3 gm of cal-
cium phosphate may be lost from the mother's
body each day. Fifty g m of fat and 100 gin of
lactose(thelatter derivedfromthe mother's
glucose) also are used each day. Thus, any ra-
dioactive element that maysubslitutefor ele-
ments required in the production of breast milk
~ ; . ~
r ,
may eventually reach the nursing baby's system
and present a radiological hazard.
Radionuclides Transmitted to Breast Milk
Evidence has been reported of the appearance
of b7Ga, 9 9 m T1311,
~ , 1251,and 113mln in the breast
milk after administration of compounds labeled
with one of these radionuclides. Quantitation of
theamount of activilyin themilk at various
timespostinjection (PI) is ralher easy (usually
involvingcounting of a standardquantily of
milk in a well gamma counter and comparing
the result to that of a knonln radioactive slandard
in the same volume) and is widely reported in
the lilerature. Quantitation ofthe radiation haz-
ard to the infant, however, has been hampered
by the lack of age-specific distribution and re-
lention data and by the lack of a widely accepted
phantomfor the infant.Thelaller need has
perhaps been met by Cristy and Eckerman (26,
7), with their pediatric phantoms and associ-
ated specificabsorbedfractionsforphotons.
The lack of distribution and retention data prob-
ably will not be resolved in the near future;
almost all radiation dose estimates are based on
the assumption that the infant's metabolism ei-
ther parallels or equals [hat of an adult.
67Ga has been observed in human breasl milk
after administration of [67Gajgallium citrate(48,
49), Tobin and Schneider (48) studied the con-
cenlrationsinenough delailto determine an
effeclive retention half-time. In their study, the
concentrations decreased monotonicallywith an
effective half-time of 57 hours. In the study by
Larson and Schall (491, samples taken al 96 and
120 hours showed the same concentration. Both
sludiesindicate thatthe effectivehalf-time is
close to the physical half-life of %a. The max-
imum reported concentrations, expressed as the
fraction of injected activity per unit volume of
milk, were 5.0 X 10-5/ml and 2.3 X 10-s/ml
(Table 5.3).
The mostdatareported in the literatureon
radionuclides in breast milk have been collected
on "'"Tc-labeled compounds (50-57). Admin-
islralions of 99n1Tc-labeledpertechnetate or mac-
roagreggated albumin (MAA) were followed by
measurements of w m T activity
~ in the breast
milk at various Limes PI. Table 5 . 3 lists !he
results reported by the various authors. An inter-
60 I Essentials of A'uclearMedicine Science RndiopkflrmacellricalAbsorbedDoseConsiderations I 61
~~

Table 5.3. for study of suspected venous thrombi (54, 58) is as small as at birth, whereas the milk intake
Maximum Concentrations and Effective Half-times (teff)Reported in the Literature for Various showed a mean fraction of injected lZ5I in the has increased. . . . However, the maximum ra-
Radionuclides Appearing in Breast Milk after Radiopharmaceutical Administrations breast milk of 2.2 X IO-Vml, wilh a standard diation dose mapnot coincidewiththe max-
deviation of 1.9 X 10-s/ml. The half-time for imum hazard[ ,] since gIand radiosensitivity
Maxlmum Reported Marimurn Concentralion
RadionuclideCompound Conccnlration* Time (hr)i at 5 hr+ l,, (hr) Relerencc disappearanceforthe 1251was 73.5 +- 9.2 may be greaterat birth." What is clear from the
hours. Two patients receiving l3lI-MAA for di- observeddatais that theamount of activity
5.0 X72 10-5 57 48 agnosis of suspectedpulmonaryemboli (53) entering the breast milk will be highly patient-
2.3 X 10-5 96 - 120: 78f 49
had measured fractions of injected activity of 8 specific, although theparameters involved in
4.0 x 10-5 -5 4.0 X 10-5 4.6 54 X 10-5/mI 2 8.5 X 10-5/mI, with an effective the variability are not clearly defined. It is diffi-
-1.0 x 10-4 -6.5 1.0 x 10" 3.6 54
half-lime of 19.5 ? 0.7 hours. In both patients, cult to advise a woman about how long to inter-
1.5 x 10-5 4 1.5 x 10-5 2.8 51
3.5 x 10-6 6 3.5 x 10-6 5.61 52 however, the time of maximum activity was rupt breastfeeding after a radiopharmaceutical
53
around 30 hours.Withboth of thesecom- study, because fractionaluptakespublished in
8.3 X 10-6 10 1.8 x 10-5 5.5
5.1 X 10-5 2 5.1 x 10-5 3.6 53 pounds, at least in thelimitednumber of pa- the literature may tell little or nothing about lhe
1.1 X 10-5 22 1.4 X 4.6 56 tients,thepattern seen with the99mTc-labeled behavior of thematerial in thepatientunder
I .4 x 10-211 2 1.4 X 10-2 3.4 55 compounds, of better agreementbetweenthe study. It appears that theaveragesgenerated
5.4 X 10-311 2.4 5.4 x 10-3 3.9 55 reported effective half-times than between the here for effective half-times, which were calcu-
2.0 X 10-5 5 2.0 X 10-5 57 uptake fractions, was reproduced. laled from the various studies, will be reliable
8.2 x 10-6 108 67 54 One further study from the literature de- for most patients, unless there is a known, spe-
3.5 x 10-5 40 ao 58 scribes a patient who received 0.65 GBq (17.5 cial biophysical condition. Because of the un-
1.4 x 10-4 23 20 53 mCi) of an 113m1n chelate complex for abrain certainty in the estimates of fractional uptake,
2.0 x 10-5 14 19 53 scan (60). Activity concentrations measured at however, recommendations should be on the
2.0 x 10-5 24 59 I .67 and 21.5 hours PI were 2.5 X 10-7/ml and conservative side; i.e., they should be based on
1.3 x 10-5 24 59 1.4 X lO-'/rnl, respectively. Thesedataalone longerrather than shorterinterruptiontimes.
3.9 x 10-5 6 6.5 59 would suggest an impossible effective half-time
2.5 x 10-7 1.7 23** 60 of 23 hours (no mention was made of the data Radiation Dose Estimation
beingdecay-corrected),whichwould indicate The variability of the data regarding the frac-
* Units are fraction of injected activity per milliliter of milk. that more datamust beconsideredbefore a tion of injected activity appearing in the breast
i'Time at which listed maximum was reported.
$ Same concentration reported at 96 and at 120 hours. Physical half-life for 67Ga reported for talf.
quantitative assessment of effective half-time milk suggests that a general value for absorbed
5 Curve had a shoulder similar to that reported in Reference 54. can be made. dose to themother or infant per unitinjected
!I Patient admitted for study of enlarged thyroid. In conclusion,severalradionuclideswill activitywould be unreliable. In situationsin-
1 Same patient, treated while nursing 4-month-old infmt, at two times, 2 months apart. appear, to some degree, in the breast milk of volvinglactatingmothersforwhichradi-
** Suggested from the data, but impossible; most likely Thio. lactatingmothers.Althoughthefractional onuclide administrations are unavoidable,reli-
uptake usually isvery low, on the order of able dose estimates will result only from actual
esting contrast emerges between the extremely shon4ed a clear pattern of ingrowth, often with a mI-10-4/mI, theradiation doseto the infant measurements of theactivity in the patient's
broad range of breast milk concentrations and shoulder. Therefore, it is not possible to decay- may be considerable for two reasons. First, the breast milk. Although the variability of the ef-
the rather narrow range of effective half-times correct ail of the values to time 0, and a time of infant may consume as much as 800-1500 ml fective half-times is not as great, the sampling
of the activity in themilk.Berkeetai.(51) 5 hours was chosen (Table 5,3), since itwas past of milk per day, which, in a worst case, might should be designed to measure this parameter,
studied chromatograms of the sampled milk the shoulder of the ingrowth curve in all cases. result in the infant consuming a significant per- since some patient-to-patientvariation isseen
afleradministration of ""Tc-MAA and con- Thedecaycorrection was carriedout so that cent of the injected activity. Second, on a per and the activity does not always follow a pre-
firmed that the g 9 m Taclivity
~ was: indeed, free valuesreported at longtimes PI could be in- unit activity basis, the radiation dose to an in- viouslyobservedpattern. An example of this
pertechnetate.Therefore,thefraction of in- cluded with the other values to obtain a more fant will be considerably larger than that to an deviation is the appearance of activity in breast
jecled activily appearing in the milk should be reasonable value for the average maximum frac- adult because the internal organs are in closer milk after injection of 12SI-labeledfibrinogen,
less for the MAA group than for the free per- tion of injected activity appearing in the breast proximity, which results in more cross-irradia- as described in the previous section, "Radionu-
technetate group, sincethetaggingefficiency milk. Although the average concentration in pa- ~~ tion,andbecausetheorgans are smaller, which clides Transmitted toBreastMilk."The 15-
for the MAA should be at least 90%. tients seemed to be higher €or 99mTcO; than for results in larger doses per unit activity for self- year-oId phantom of Cristy (26) is a reasonable
For all of thetechnetiumcompounds, the the ~ ~ " ~ T C - M Athe
Apatient-to-patient
, vari- irradiation. Both iodine and technetium will representation of ReferenceWoman, andthe
concentrate to some degree in the
thyroid.
As
~~

variation in the reported effectivehalf-times was ability was so large that any difference between -.~ specificabsorbed fractions generatedfor this
low; the meat1 andstandard deviation of all the means was obscured at the 0.1 significance
Li
~--~
~

noled by Wayne et aI. (61), "The maximum phanlom (27) include values forphoton self-
valuescombinedwere4.2hoursand 0.96 level. -~
._ - thyroid irradiation would occur at the age of 6 absorption in the breasts.Therefore,once S
Two patients receiving lZ51-labeIedfibrinogen __
hours, respectively.Sometimes,thecurves ~-.~
--_
c _~

monthst,]since the size of the glandat that age valuesare generated forthebreasts, absorbed
""
=
.__"
-~.
~~ -=. ~~
 Rodiopharmaceztricol Absorbed Dose Considernrims I 63
62 t Esselztials of Nucleor Medicim Science

Table 5.5.
dose estimates for the breasts may be approxi- MIRD Dose Estimate Report No. 8 (41) for the
mated.Specificabsorbedfractionsforthe nonresting population, are shown in Table 5.4. Dose Estimates for the Newborn Reported in the Lilerature for SmTc Ingested in Breast Milk
breasts as a source organ may also be used to The valuesare given on aper unitingested Esumakd Radiation Dose [mCp!,lBq)
calculatethe radiationabsorbeddose toother activity basis, with 100% absorptionintothe
Targel Organ Rclcrence 50 Rekrsnce 5 1 Relerencc 54 Relerencc 57 Relerence 38
organs of the body from activity in the breast infant's bloodstream and biokinetics identical to
milk by the standard MIRD lechnique (3). that of an adult assumed. Table 5.5 shows some Stomach 0.32 1.2
For calculation of the radiation dose tothe publisheddose estimates for the newbornfor Upper large inlestine 0.57
infant in situations in which breastfeeding was 99mTc(38, 50, 51, 54, 57). All of the aulhors Lower large inkstine 0.22 0.54
Gonads 0.048
inadvertently continued soon after a radiophar- cited in Table 5 . 5 assumed thatactivity in the Thyroid 0.95 0.8 1 1.2 0.64 0.92
maceutical adminiswation, one must determine breast milk was free pertechnetate. Rumble (50) Total body 0.038 0.041 0.048 0.026 0.038
the retention of the activity in the breast milk assumed that the kinetics were the same as those
over the interva1 during which feeding occurred. of adults, that 50% of the pertechnetate ingesled
If the situation is discovered after feeding has was absorbed, and that 2% of the activity in-
ach wall. They used theSnyderand Ford S also calculated a dose estimate for thethyroid of
occurred, samples of the milk should be taken gested went to the thyroid, with only self-irra-
values for the gonads (67). O'Connel and Sut- 5.7 X lo3 mGylMBq (2.1 X lo-' radlmCi) for
immediately and regularly until a pallern is es- diationof the target organsconsidered.The
ton (57) and James et al.(38) generated S values the newborn, with a 30% thyroid uptake at 24
tablished. The times at which the infant fed and authorslisted in Table 5.5 used thespecific
from absorbed fractions for geometric shapes hours and a 68.1-day effective half-time in the
the approximate amount of each feeding should absorbed fractions of Hwang et al. (63) fora 10-
from MIRD Pamphlet Nos. 3 and 8 . thyroid assumed. This half-time is in agreement
be established, and the observed pattern should week-old infant, except for the thyroid and gas-
CristyandEckerrnan's phantom and theresi-with the 65-day half-time used for the longest
be back-projected to estimatetheamount of trointestinal organs,for whichthey generated
dence times predicted bythemodel in MIRD compartment in themodeldescribed in MIRD
activityavailable €or uptake at eachfeeding. pholon-absorbed fractions from thegeometric
Dose Estimate Report No. 5 (35) were usedto Dose Estimate Report No. 5 . James et al. (38)
The genera1 formulafor calculatingthe total models in MIRD Pamphlet Nos. 3 and 8 (64,
eslablish the dose estimates for I3lI for the new- quoted dose estimates of WellmanandAnger
activity ingested by the infant on the basis of a 65). Berke et al. (51) scaled adult dose esti-
born that are listed in Table 5.6. For these esti- (6s) for the thyroid from I3'I administration of
monoexponential decay process would be: mates by a faclor of I O to obtain infant dose
mates, a maximumthyroiduptake of 25% was 4.3 X IO3 mGylMBq (1.4 X 10' rad/mCi).
n estimates; they assumed that the thyroid would
A, = A, exp ( - A f i ) V i Equation 5.3 receivearadiation dose 20 times higher than assumed; Wellman et al. (34)found that theCristyand Eckerrnan's phantom (27) andthe
i=l literature forNorthAmericanchildren reflected residencetimespredictedbythemodel in
that received by the total body. Mattsson et a].
where A, isthe totalactivity ingested (Bq or a mean of about 30%, except during thefirst 2 MIRD Dose Estimate Report No. 2 (69) were
(54) used S valuesfor the stomachcontents
pCi), II is the total number of feedings, A, is the weeks of life when values can approach 100%. used to establish the dose estimates for 67Gafor
irradiating thestomachwall, as calculatedby
maximum activityconcentrationinthebreast If we assume that the elimination kinetics do not the newborn that are listed in Table 5.7. James
Henrichs et al. (66), and adultvaluesfor S
milk, which is projected from [he observed data changewith an uptake of more than 2595, these el a1. (38) generaled dose estimates for 67Ga,
values for the stomachwall irradiating the stom-
(Bqlml or pCi/ml), A is the observed effective estimates may be scaled to calculale dose esti-
decay constant for the radionuclidein the breast Table 5.4. mates for these situations. Wellman et al. (34)
Table 5.7.
milk (0.693 divided by the observed effective Dose Estimates for the Newborn' for Ingested
half-time)(hour"), fi is thetime betweenthe Is'lmTclPertechnetale Dose Estimates for the Newborn* for Ingested
Table 5.6.
['JGa]Gallium Citrate
occurrence of the maximum activity concentra-
I:
EstimatedRadiation
tion and feedinglime i (hours),and V , is the ~~
=- Organ
Tareel
~
Dose (mCy/MBql Estimates
Dose for the Newborn* for Ingested 1311
L
Esrimarcd Radlatlon
volume of milkingested at feedingi.(milli- as Sodium Iodide Targcl Organ Dose (~nGy/blBq)

liters). bladder Urinary 0.26

0.20 Estima[cd Radiation Stomach 0.87
Hays (62) observed that thefraction of in- Stomach Target Organ intesline
Dose (mGylMBq) Small 0.12
Upper large intestine 0.44
gested Y 9 n 1 T ~in0 the
7 infant's bloodstream var- Lower large intestine 0.42 Upper
intestine
large 1.5
Stomach 8.2 intestine
Lower large 3.2
ied widely
from patient
to patienteven
and from Ovaries 0.068
0.033 intestine Small 4.6 Kidneys 1.1
trial to trial in the same patient. Because values Tesles Liver 1.5 Liver 1.3
didapproach 100% inmanyinstances, corn- 0.40
Ovaries 0.55 Ovaries 0.75
0.032
plete absorption in the infant
shouldprobably body Testes
2.1 0.44 Spleen
be assumed for dosimetry. * Based on residence times in5700
MIRD Dose Esti- body
Thyroid
Total body3.1
Tesles
Total
0.80
0.88
Doseestimatesforthenewbornfrom male Repor[ NO. 8 (41) for the nonresting population
'"TcO;. with Cristv and Eckerman's specific and pediatric phantom of Crisly and Eckerman (27). * Based on rcsidence limes in MIRD Dose Esli- * Based on residence times in MIRD Dose Esti-
Inale Report No. 5 (35) and the pediatric phantom of mate Report No. 2 (69) and the pediatric phantom of
Cristy andEckerman(27). One hundred percent of Cristy and Eckerman(27).Onehundredpercent of
thc ingcstcd activity was assumed to reach the blood- (he ingestcd activity was assumed to reach the blood-
strean), stream,
1; i:
I .
M I EsserlriaIs of Nrdeor Medicine Science
I .
assumingeffectivehalf-times of 70 and 61
hours for the spleen and whole body, respec-
tively. Their radiation dose estimates were 2 1
mGylMBq (7.8 rad/mCi) and 0.38 mGylMBq
(1.4 rad/mCi) for the spleen and whole body,
respectively.
RADIATION HAZARDS INVOLVING
RADIOPHARMACEUTICAL
ADMINISTRATIONS TO PREGNANT
WOMEN
The radiosensitivity of the developing fetus is months, and 7.5 in the last 3 months(76).
known to be relatively high, because of the high Watson (Ti’), in reviewing the work of Aboul-
rale of cell division and the abundance of poorly
specialized tissues. Effects of ionizing radiation
on the developing embryo and fetus include (a) would be the most conservative number which
inuauterine and extrauterine growth retardation, could be derived from h e i r data. This biologic
(b) embryonic, fetal, or neonatal death, and (c)
congenitalmalformation.Theprobabilityand
severity of these symptoms will vary with the are listed in Table 5.8.
absorbed dose and absorbeddoserate to the
embryo or fetus, as well as the stage of gestation concluded that the placental transfer of T,, T 4 ,
at which irradiation occurs (see section entitled, or TSH is very low. Values of fetal radioactivity
“Radiation Risks”).
Radiation Dosimetry
Radiation dose to the fetus from administra-
lion of radiopharmaceuticals to the mother may shorllybeforeinducedlaborshowedabout
come from two sources: irradiation of the felus
from activity in the individualorgansor lotal
body of the mother and irradiation of the fetal
tissues from radioactive materials that cross the and of L-triiodothyronine or D-triiodothyronine
placenta. The former involves only penetrating
radiation; thelatterinvolves both penetrating
and nonpenetrating radiation.
As with other radiation dose calculations, es-
timatingradiationdoses to the fetus breaks
down into two basic problems: determining the
melabolic parameters and determining the phys-
ical parameters. The first problem involves de-
termining whether the pharmaceutical behavior
in the pregnant female differs from that in the
normal adult and in whatquantitiesthe phar-
maceutical or free radioactive label crosses the
placentaand enters the fetal metabolism. The
second problem involves deriving the appropri-
ate specific absorbed fractions for irradiation of
the fetus by activity in the maternal organs and
by activity in the fetus itself.
Biologic Parameters
Many researchers have established that iodine
in the mother’s bloodslream will cross the pla-
I
centa (70-75). The fetal thyroid begins assim-
ilating iodine by the thirteenth week and con-
tinues for the remainder of the gestation. Fetal
thyroid avidity for iodide is greater than rnater-
nal avidity. At 9 months of age,theorganic
iodide concentration in the fetai blood is about
75% of that in the mother’s; the ralio of fetal to
maternalthyroidconcentration,
about 1.2 at 3 months, 1.8 from 3 months to 6
Khair et al. (78), decided that a biologic half-
time of 24 days for iodine in the fetal chyroid
half-time and an infinite biologic half-time were
used to establish the dose estimates for 13’1that
From a review of the literature, Fisher (79)
were less than 1 % of the injected activity in the
mother near term and not measurable early in
gestation.Kearns and Hutson(75)foundthal
although iodine administered as sodium iodide
equal concentration in the mother’s and the um-
bilical cord blood, the Uansfer of L-thyroxine
was around 5 % , of D-thyroxine was about 9%,
was about 25%.
Table 5.8.
Radiation Dose Estimates to the Felal Thyroid from
1 3 1 1 , Generated by Watson (77) under TWO
Assumptions
Esrirnaled Radiation Dosc (mGyMBq)
Fetal Age (mol = 6 days
3 240
4 510
5 600
6 1100
7 7 60
8 570
9 460
Rndiopl~armaceuticnlAbsorbed Dose Considerarions f
The placental transfer of [99mTcjpertechnetate
in rats is well documented (80, 81). Hahn et al.
(81) reported that 3.5% of the injected activity
crossedtheratplacenta nearterm;their esti-
mated dose to the fetus, as determined by the
geometric model of Smith and Warner (82) for
the embryo, was 5.1-6.2pGy/MBq (19-23
mradlrnCi).Wegsl et al. (SO) reportedcumu-
lated activity in the rat fetus and placenta as a
functionofgestational age; the values for the
fetus increased exponentially with age,some-
however, is
what in parallel with weight gains. Values in the
placenta increased linearly, again in rough par-
alIel toweight gain. These investigatorslisted
dose estimates to the whole fetus, baseddirectly
onthe observed cumulatedactivilies at early
stages of pregnancyand on values derived by
use of an extrapolation factor based on a human-
to-animalweight ratio. They also quoted fetal
radiation dose estimates of Kereiakes el al.(83).
Theestimatedvalue,extrapolatedvalue,and
quoted value fromWegst etal. (80) were 13
PGylMBq (48 rnradlmci), 86 pGylMBq (322
mradlmci), and 10 pGylMBq (37 mradlrnci),
respectively. Theextrapolatedvalues may be
unnecessarily high; because the cumulated ac-
tivity gains paralleled weight gains, the cumu-
latedactivityperunit weight may be a more
meaningful parameter, and a weight-related ex-
trapoladon may not be needed. Wegst et al. also
found that 9 9 m Tdistribution
~ was altered during
pregnancy. Cumulated activities in the thyroid
andovariesdecreasedduringgestation,al-
though cumulated activity values in the ovaries
showed a slight increase at the endof gestation.
Allvaluesfortheseorganswere lower than
values for the nonpregnant rats.Values in the
liver increasedduringgestationfrom normal
values to values about 15% higher than normal.
Wegst etal.alsodemonstratedplacental
crossover of 99mTc-DTPAin rats (84).Values for
the cumulated activity i n the fetus and placenta
L l f = t,
increased exponentially and linearly, respec-
tively, as did the pertechnetate values. This doc-
320 ument was still in press at the time of this
680
810
writing, so morequantitative informationand
1500 dose estimates were not available. Again, how-
1000 ever, they demonslraledaltered biodistribution
760 during pregnancy. Cumulatedactivities in the
620 thyroid increased from normal values to values
65
30% higherthannormalduringpregnancy;
cumulated activities in the ovaries and liver in-
creased from values lower than normal to values
100%and 40% higher than normal,respec-
tively.
Hayes and Byrd (85) found that 67Ga admin-
istered as citrate crossed the hamster placenta in
amounts of 0.6% and 1.2% of the administered
activily at [he ends of the secondand lhird
trimesters of gestation,respectively. The con-
centration, however, decreased,since the in-
crease in activitydid not keep up with the
weight gain. The authors explained this on the
basis of the increasing amounts of 67Gaentering
the breast milk in the late stages of gestation.
Weiner (86) also found ‘j7Ga transfer to the rat
fetusduring pregnancy.Activitylevels in the
placenta were between 0.2% and 0.24% in the
firsttrimester,between 0.75% and 4% in the
second trimester, and between 2% and 6 % in the
third trimester. Activity levels in the fetus were
between 0% and 0.25% in the second trimester
and between 0.2% and 0.6% in thethird tri-
mester. He stated that studies in humans involv-
inginadvertentadministrations to pregnant
women showed a similar pattern but with higher
percentages of transfer.
H a h ne ta l . (81) alsolistedplacental
crossover vaIues and dose estimates to the fetus
from99mTc-labeledsulfurcolloid,albumin,
iron compiex,andpolyphosphate.The max-
imumcrossovervalues were 0.05%, 0.03%,
3.6%, and 0.6% of the injected activily,respec-
tively. The associated dose estimates (again as
determined by the model of Smith and Warner
(82)) were 56 pGylMBq (210 mrad/mCi), 30
pGylMBq (110 madlmci), 59-96 pGylMBq
(220-360 mradlrnci), and 70-89 p,Gy/MBq
(260-330 mradlmci), respectiveIy.
Dyer and Brill (87) measured fetal 59Fe up-
take up to about 5 months of gestation, in cases
of therapeutic abortions. Activity was measured
in dissected liver and spleen samples as well as
in the whole fetus. The total percent of activity
injected into the mother which appears in the
fetus increased from about 0.1% to 3.0% over
fetal ages ranging from9 to 22 weeks, while the
percent uptake per gram of fetal body weight
decreased from about 0.03% to 0.007%. In the
fetalliver andspleen,accumulationalso in-
66 I Esser~tinlrof Nnclenr Mediriue Science
creased with age. I n the liver, activitylevels
varied from about 0.07%to 2.3% from 9 weeks
to 22 weeks; and in lhe spleen, activitylevels
varied from 0.0017~lo 0,03% from 13 weeks to
22 weeks. The authors generated dose eslimates
forthefetusand fetal organsapparentlyby
using [he geometricalmodels in MIRD Pam-
phlet No. 3 (64) for photonself-absorption in
small volumes and by adding the nonpenetrat-
ingconlribution as well assomepenetrating
conlribution from themother. Theirestimated
radiation dosesforthewholefetus(perunit
injected activity in the mother) ranged from 7.8
mGylMBq to 10.5 rnGylMBq (29 rad/mCi to
39 rad/mCi); estimates for the liverranged from
65 mGylM3q to 120 mGylMBq (240 radlmCi
to 430 rad/mCi); and estimates for the spleen
ranged from 16 InGylMBq to 51 rnGy/h?Bq (60
radlmCi to 190 rad/mCi).
Hibbard and Herbert(88) studied feta1 uptake
o€ radioiodine following administration of iodi-
nated serum albumin (RISA) to the mother near
term. Althoughthere was no activity in the
amniotic fluid, the umbilical cord plasma con-
centration ranged from about 1.5% to 2.5% of
the mother's plasma concentration at delivery,
with time intervals between injection and deliv-
ery ranging from 2 hours to 78 hours. Although
separate determinations of free and protein-
bound iodine were not made,theauthors as-
sumed that the low aclivity levels indicated lhat
placental crossover was realized only for iodine
liberated from the albumin in the mother's sys-
tem. In a study of the fetal thyroid uptake from
administrations of RlSA 0.1-35 days before
delivery, tbey observedan asymptotically in-
creasing uptake pattern, when corrected for ra-
dioactive decay. which would appear to reflect
the steady degradation of RISA in the mother.
This uptake would result in the release of free
iodide and increase fetal thyroid uptake to some
maximum. The equation describing the uptake
was:
v ( t ) = 2.05(1 - exp(-0.58t))exp(-hr)
Equalion 5.4
where y ( f ) is [he fetal thyroid uptake, in percent
of activity injected as RISA, r is the timein days
PI, and h is theradioactivedecaycons(ant
(day-]). As mentioned, the maximum lime be-
tween injection anddelivery was 35 days, so
(hispattern is onlyclearlyestablishedfor
feiuses older than about 7.5 months.The au-
thors generated dose estimates for the fetal thy-
roid and gonads for I3[l,assuming no biologic
removal from the fetal organs. Their dose esli-
mateswere 260 mGy/MBq (980 rad/mCi) foI
the thyroid and 0 . 3 8 mGylMBq (1.4 radlmCi)
for the gonads, Since these estimates consider
only physical decay, the resuit for the fetal thy-
roid can be directly compared to those of Wat-
son (77) (for 8 and 9 monthswith t e f f = lP).
With Hibbard and Herbert's estimate (88),it is
predicted that the dose per unit injected activity
as R E A is about 40% of that per unit injected
activity as sodium iodide. Since theplacental
crossover was assumed to be only from iodide
released from the RISA moIecule, the dose esti-
mates for RISA are probablytoohigh.Thc
maximum uptake used by Watson for 9 months
was 3.4% of the sodium iodide administered to
themolher;therefore,thepredictionthatas
much as 2 % of the activity administered to the
mother as RlSA could reach the fetal thyroid is
probably unjustified.
Sastry el al. (89)generated radialiondose
estimates for l3II-HSA, '23I-HSA, 99mTc-HSA.
and [113mIn]indium chloride, four radiopharma-
ceuticals formerly used in radionuclide placen-
tography. The doseestimates were derived from
a geometricmodelrepresentingthefetusa[
about midterm. Theirestirnales included contri-
butions from activity in the placenta and uterinc
wall, for which they developed their own mathe-
matical models. They assumed that for the iodi-
nated compounds, 5% of the iodine was re-
leased per day from the RlSA molecule, 2% of
the total injected activity crossed the placenta,
and 5% of the free iodide in either the mother's
or the fetus'bloodstream was taken up in thc
thyroid. For all of the HSA compounds, a 13-
day biologic half-time in the bloodwas as-
sumed. For wn'Tc-labeled HSA, 13.4% of the
injected activity was assumed to appear in thc
fetalbloodstream.Placentalcrossover 01'
["3Tn]indiun~chloridewasassumed to bc
O.S%, with an effective half-time of 100 min-
utes in the blood. Their estimates for the whole
fetuswere 0.57 mGy/MBq (2.1 rad/mCi), 24
pGy/MBq(87 mradlmCi), 4.9 pGy/MBq (18
Radiophor~noceuiicalAbsorbed Dose Consideratioru
: ~ I t n l h C i ) ,and 4 pGp/MBq (15 mrad/mCi),
l~.\lw~~lively, l3]I-,
for and 99"'Tc-labeled
I I Y A ; 1 n d [113"'In]indiumchloride. Their respec-
II\C cs~imatesfor the fetal thyroid for the KSA
Ilrlbpounds were 98 pGylMBq (360 mrad/
III('II. 35 pGylMBq(98mradlmci), and I2
I I ! i\!'MBHq (45 mradlmCi).This dose estimate
I 21 I Ill-labeled HSA is almost 3000 times lower
I female is required for Monte Carlo estimationof
:~I,III t11:1( of HibbardandHerbertandseems
I a t ( I c J 1 more reasonable.
K ; u l et al. (90) listed dose estimates for the
[c.[w, lor 99mTc-labeled microspheres, sulfur
I o l l \ l i d . ghceptate, and polyphosphale and for
I ' (i:llplliurn citrate. The generated dose esti-
111.tlc5 IO !he whole fetus were 1.6 pGy/MBq (6
IIII;KI/IIIC~), 1.5 pGy/MSq (5.6 mradlmci), 1.9
~a(iy/MBq(7 mradlmci), 3.5 KGylMBq (13
tllr:ldklCi), and 0.075 mGy/MBq (0.28 rad/
! [ I ( ' I ) . respectively.Neitherthisarticlenor the
I )Il p i n a l source document (9 I), however, reveals
I H W these estimates were derived.
I'tlysical Parameters
For very earlystages of pregnancy, when
I ;~rliopharrnaceuticalsmay be administered in-
dvcrtenlly, a detailed geometric model maynot
1 % nccessary
~ to provide a reasonable picture of
[ I I C dosimetry. First, the placental permeability
1 5 low in rhe earlymonths (46). Second, the
I V I L I ~ itself growsslowly at first, witharapid
tlpwing occurring after about3 monlhs (92), so
flrc geometry of theregion is not greatlyaf-
I r c ~ c r l in theearlyweeks.Therefore, normal
Illctabolic parameters are probably appropriate,
. d a n approximatedose tothefetusmay be
Ill>(:linedby caiculating the dose to the uterus.
'['IIc best model for [his application is probably
1111: 15-year-old phantom of Cristy (26).
Ailer the fetus begins to grow, the specific
;Itwrbed fractions for the fetus from maternal
Lwgans that arenotmoved from their original
pi>sitionwill probably not change significantly.
Snyder (93) has shown that the absorbed frac-
~ i u nvaries directly with the mass of the target
r u p n for photon energies above about 50 keV
1111' combinations ill which the distance between
lllc wurcc and the target organ does not vary
p x t l y as the mass of the target changes. This
IIIU:IIIS that the sprciJiic absorbed fraction wil!
11111 change. In the pregnant female, however,
I 67
many of the organs in the abdominal area will
be somewhat repositioned as thefetusgrows,
and the fetus will come considerably closer to
many of theseorgans.Therefore,quantitative
estimates of the changes in specificabsorbed
fractions formanyorganswill be difficultto
make. A phantom representing the pregnant
the absorbedfraction forthe fetus at various
stages of development.
If the amount of activity that crosses the pla-
centa is known,doseestimatesforthefetus
from self-contained activity are not difficult to
obtain,andtheabsorbedfraclionfornon-
penetrating radiations may be assumed to be I .
MlRD Pamphlet No. 3 (64) givesvaluesfor
photonself-absorption for spheres andellip-
soids of various masses, filled with water and
containing a uniform distribution of activity
throughout. The S values for the whole fetus,
once a geometric model is chosen, can rhus be
obtained from a knowledge o€the decay scheme
for [he radionuclide. If uptakein individual
organs of the fetus is known, dose estimates for
these organs may also be derived in a similar
manner.
If aclivity is known to localize in the pla-
centa, the model of Sastry et al. (89) will proba-
bly give a good approximation of the doseto the
fetus from penetrating radiations. They do not
actually give absorbed fractions or specific ab-
sorbed fractions, bui they describe the general
geometric model that can be easily adapted to a
specific situation.
Cloutier et al. (94) have generated estimates
for absorbed fraclions for photon aclivily in Ihe
urinary bladder duringpregnancy. They genera-
ted a detailed geometric model to simulate the
fetus at eachmonth of pregnancy,then ran
Monte Carlo simulations for a urinary bladder
model designed to fill and void at regular intcr-
vals. Their results were expressedforseveral
discrete photon energies. If the amount of radi-
oaclivity in the urine can be determined, esti-
mates of the dose to the fetus can be oblained
with relative ease.
In summary, current models are adequate to
estimate fetal radiation dose from maternal ac-
tivity during the early stages of pregnancy, at
leas1 up to 6-8 weeks. For later stages of preg-
 Rfldiopl
1: 5.
,$: 1;
I:#

[; ]j nancy,
models
there
are
that be
can used give
to Table 5.9.
:
i
: ?
> . the radiation dose
from activity contained in
the ministration of radioactiveiodine to pregnant rnalities, radiopharmaceutical formulation er-
Some Specifics of Organogenesis in the Human
i
! '
' ;
I.[
placenta, or the
urinary bladder, fetus
itself;
for Fetus women, however, the children exhibited only rors,misadministrations, and drug alterations
., subtle behavioral abnormalities, oflen with hy- are considered in this section.
. i.
.
. .
maternalorgans
that
are not significantly af-
i
;
Time (days) Event pothyroidism and low protein-bound iodine lev-
!: fected by the growing fetus
(e.g.,
brain, thy- Normal Variation

:
. ~

. ,:
I.

roid), dose estimates based on the dose to the 20-21 Heart appears els. These cases alsooften involved much larger
'I I
,
,:
.
Circulation of blood
apparent administered activities to the mother. Most nuclear medicine physicians recognize
. . nongravid uterus
will
constitute a first approx- 21-22
32 Limb buds appear Theplacentaisreadilypermeable to in- the differences in the appearance ofthe same
! :' irnation.
32-35 Major differentiation of heart struc- organic sodium, potassium, cesium, stronlium, type of scanindifferentpatients. Usually, a
In this area of nuclear medicine, the informa- tures and phosphorus. Animal studiesindicate that pattern of distribution is observed in the "nor-
' tionaboutthebiologic parameters needed for 37 Arm, forearm, and hand recognized
adminisbation of radioactivephosphorusand mal" studies. Within this patternof distribution
radiation dose estimationis in approximately 22-40 Development of eye
40 Digits on hand
recognizable strontium in sufficiently high amounts may re- theuptakes by specificorganswilldifferas
equal abundance to that about physical param-
! I
sult in fetal death. discussedinChapter16.These variationscan
,i . eters. Although information about the metabolic causesignificantdifferencesintheabsorbed
behavior of someradiopharmaceuticalshas Relating the quanlity of radiation which will
cause a certain endpoint in animals to a similar dose from a radiopharmaceutical. Two common
been obtained,many remain to bestudied,and very long,themostfrequent observations in-
,:
. .-.' ...,
I

i
,I

thequestionaboutaltered maternalphysiologyvolvemicrocephaly,whenexposureoccurs value in humans is virtuallyimpossible.The examples are the doses from 9 9 m Tas ~ sodium
i
,
'I
,
i
.I patterns of results related to stage of gestation pertechnetate and 1231or I3'I as sodium iodide.
. ,
during pregnancy has not beenfullyaddressed,early in pregnancy;central nervous system dis-
.
3
,i

>
i
-. I
although the animal data from Wegst et al. sug- orders, when exposure occurs in the first 2 tri- when irradiation occurs show remarkable sim- In MIRD Dose Estimate ReportNo. 8 (41), two
, ~I ,
ilarities between animals and humans, however, populations weredefined as having different
,'
gest thatthis is an important area for study. A mesters; and growth retardation. Studies on the
;
!
~

I. : I so qualitative results may be studied with some dislributions of NaggmTcO,. The absorbed doses
few of the current geometric models cangive
offspring of the Japanese bomb survivors who
F: confidence. Because of the large amount of ge- calculated from these distributions reflect these
f :
some answers about fetalradiation dose in early were irradiated while pregnant (39) showed an
i .
pregnancy; much
remains
worked
be
to on, netic and environmental variables, a threshold differences.Themoststrikingdifference is a
1 .
incidence of microcephaly which was 4 times
1-
._ I ~

at which [eratogenic effects will not occur also factor-of-5 increase in the dose to the stomach
however, to improve the dose estimates in the higher(28%)for irradiation occurringduring
~ ~

! ' _
.~
I- L is difficult to establish, but paitems in animals walI of the resting population over the nonrest-
, _ = middle and late stages of gestation. weeks 4 through 13 of gestation lhan for that
i ;-: andhumansindicatethatthereprobablyare ing population. Other differences in doses are
-~ ;.
f (7%) occurring later. For weeks 6 through 11,
i
_
>
=

Radiation Risks such thresholdsandthattheyare higherfor given in this report but are less than a factor of
5.
:, :,1 -i the measured incidence was 11%for air doses
I, ._.- . .. Duringthefirst 2 weeks of development,the of 1-9 rads, was 17% for air doses of 10-19 prolracted exposures than for acute exposures. 2. MIRD Dose EstimateReport No. 5 (35)
gives the dosesfrom different isotopes of iodine
. !*, .
'-
.~ fetus is not susceptible to teratogenic effects rad, and increased upward to 100% for air doses
administered as sodium iodide. The dose to the
:
,
~~

'.I
.
~

. induced by ionizing radialion. this

At stage,
the of more than 100 rad. The tissue doses corre- EFFECTS OF ALTERED
j. .:..
. :. radiation willeitherdamagemanycells, which sponding to thefirsttworangesaboveareabout thyroid from different iodine uptake values in
1
i..$ :. BIODISTRIBUTION ON ABSORBED the normal thyroid can be different by a factor
will result in death,oronlydamagea few cells, 1.4 rad and 5.7 rad, respectively. Althoughthe
DOSE
1
7. r
of 5. Other variations occur bur these are less
:
=
rr : I '
F
-
.
which will allow the fetus
survive
to without 1 1 % incidence was not significantly different
>- -. I. defects.Duringthe next 6 weeks of gestation,fromthe 4% controlfrequency,theauthors (39) Absorbed doseestimates for radiopharma- than a factorof 3, and the dosesare of much less
3,
1.
.2
; I- ceuticals usually are calculatedfromdata on consequence than is the dose to the thyroid.
3, .:
:i /I
,
vital organs and structures of the body are being believe that the incidence reflected "part of a
distributionandkineticsinsome"normal"
j. >i (
3:-
3, . , formed, andradialioninjurymayresult inmajordose-effectprogressionforthesensitive Anatomic or Physiologic Abnormality
I .- . morphological abnormalilies. Damage duringstages."
Growth retardalion
and
mental retarda- population.Furthermore, the calculations are
1,
- . ~

L
i:, madefortheReferenceManphantom which The radiation absorbed dose, as a result of
z . 1 :, the remaining time may result in physiological tion were only observed when doses reached 25
r:
5: ,.~: I-
:/ has standard bodyand organ masses (40). These changesindistributionbroughtabout bydis-
i .~. defects
minor
or
morphologicalabnormalities.
rad.
-2
i .i

~. . - calculations obviously do not apply to indi- ease,usually is a secondaryconsideration,

=
;, , I.. i Table 5.9 lists somespecifics about major A few observations have
been made after
I ' .:
3; -: events in development of the fetus and thestagepregnantwomenwereinadvertentlygiven viduals of a given population but rather applyto sincethepurpose of administeringtheradio-
j. .'. ._ the population asa whole. The Medical Internal pharmaceuticalis to findorconfirmdisease.
I, '5" of gestation at which they occur. therapeutic administrations of I3lI. In one re-
?: Radiation Dose (MIRD)Committee of the Soci- These alterations in distribution, retention, and
,...
1.
-. 3
-- ~ ~ Obviously,quantitativeinformationavailableportedcase (95), in which themotherreceived
.
"
ir :-
:ty of Nuclear Medicine and other groups that organ size can, however, change the dose esti-
5, /i onradiation effectstothefetuscomesfromthreeadministrations of 111 MBq (3 mCi)and
: .'
I. -7, publish dose estimates have recognized that mates.
- i
: -4 ..
~. .. . :I!
eitheranimalstudiesor inadvertent humanex-oneadministration of 44 MBq (1.2 mCi) during
4-
there are large variations in the distribution of a Two diseasestates, in additiontonormal,
:f : /. j
~

$ ~

posures.Thenumber of studies relatedto thethecourse of herpregnancy, the child eventually

radiopharmaceuticalwithin a normalpopula- were considered in MIRD Dose Estimate Report
!L.
~

j; 1;. Jj,. internal radiation dose from administered radio-exhibitedcharacteristics consistent with
cre-
;[
i.
~ ':<'
pharmaceuticals is even lower, with the bulk of tinism. These authors related another case of a tion. The recognition of this variability has led Nos. 3 and 4 (42, 43) for *"Tc-labeled sulfur
j, <.
I

1;
,I:';
, ,- i
/I
1

theinformation involvingexternal irradiation of mother who received radioiodine in the fourth to the listingof subpopulationsorranges of colloid and LY8Au-labeledcolloid. For these two
$1 ;. ).: the fetus. Although the Iist of abnormalitiesweek of pregnancyandwhose infant diedsoon values based on uptake for some radiophama- liver disease states, the size of the organs and
:i I:_ ccuticals. In adclilion to these normal variations, the distribution of the radiopharmaceuticals
i, ,.,'i
II ' resulting from in utero radiation exposureisafterbirth.In severalother casesinvolvingad- theeffects of anatomic or physiologic abnor- change. The organ receiving the highest dose
70 / Esserztials of Nuclear Medicine Science
changes, from theliver in the normal state to the
spleen in intermediate-to-advanced diffuse par-
enchymal liver disease. The magnitude of
change for 9 9 m Tand ~ 1 9 k Ais~different because
of the physical parameters of the lwo radionu-
clides.
For a radiopharmaceutical such as [67Ga]gal-
liumcitrate, the dose tonormaltissues is re-
duced when the activity is taken up by tumor,
abscess, or a metaslalic process. The dose lo a
tumor from a diagnostic procedure is rarely, if
ever, calculated. In the case of tumor, abscess,
or metastatic process, the dose to normal tissues
is assumed to be themaximum received from
the study.
The absorbed dose from studies such as those
performed with 99mTc-labeled red blood cells
are affected little by decreased perfusion in cer-
tain areas. If there is an abnormality, theab-
sorbed doses can be calculated by modifJhg the
distribution.These calculations, however, are
rarely performed on a routine basis.
Radiopharmaceutical Formulation Error
For 99mTc-labeled compounds, the errors in
fonnulation result in untagged compounds (free
pertechnetate) or undesired compounds that
cause analteration in the uptake in the target
organ. Generally, these alterations are only an-
noyances in nuclear medicine studies, but [hey
can cause the absorbed doses to the organs to be
altered. If the preparation contains some amount
of freepertechnetateandthepercentage is
known, the dose estimates for the amount of
pertechnetate can be easily obtained. In these
situalions, h e absorbed dose to the target organ
probably will be reduced and a higher absorbed
dose may be delivered to organs no1 under in-
vestigation.
In radiopharmaceutical therapy, formulation
errors can haveamoreserious impact. A for-
mulation error involving V-labeled poly-
styrene beads for treatment of metastatic liver
disease resulted in high red-marrow absorbed
doses ( 4 4 , 45). During this procedure, the
labeled beads were trapped in the capillary bed
after injection in the hepatic artery. Eightpa-
tients suffered a rapid drop in white blood cell
count shortly after injectionof the beads, which
suggests the instability of thebinding to the
beads. A test of the stability of this batch per-
formed in rats indicated that, indeed, about 50%
of theactivity leached off thelabeledbeads.
Half of this activity (25% of the total admin-
istered activity) was assumed to deposil in the
bones and bone marrow, which results in a bone
marrow dose of about 7 rad/mCi. The injected
activities of 90Y ranged from 45 mCi to 85 mCi,
with possible totalred-marrowdoses of up to
400-600 rads,Seven of the 8 patientsdied
within 3 weeks, but these were all terminally ill
patients who had already undergone various
therapeutic procedures, such as chemotherapy,
before the W Y was administered. In summary,
formulationerrors can be a seriousproblem
with therapeuticradiopharmaceuticals and can
cause differences in absorbed doses from diag-
nostic radiopharmaceuticals. (Chapter 18 deals
more €uHy with formulation problems and (he
clinical manifestations.)
Adminisiration Errors
The most common administration erroris [he
infiltrated injection; i.e., the radiopharmaceuti-
cal is injected into the tissue around a vein
rather than intothe vein itself. Theabsorbed
dose to this tissue can be calculated from the
dose equation,
if thecumulated activity, A,,, in theinjection
site is known or can becalculated from the half-
time and the amount infiltrated and the mass of
the infiltrated dose site, mk,is also known. The
othertermsinEquation 5.5 are thesameas
those in Equations 5.1 and 5.2. These absorbed
doses to theinjectionsitecanbequite high
(-100 rad) if the administered activity is high
and the mass of the injection site is small. The
calculationbecomesmorecomplicated if the
radiopharmaceutical slowly diffuses inlo a lhese altered dislributions of activity tobe deter-
larger area and thus constantly changesthe mass
of the injection site.
Anothertype of administrationerror is the
injection of particles such as M A A or albumin
nlicrospheres into an arlery instead of a vein. If
Rodiopharnzaceurical Absorbed Dose Co>rsidernrions / 71
the arm vein was the intendedsite,the particles tinely performed, probably because the ab-
are trapped in the capillary bed of the hand. The sorbed doses are within the diagnostic range and
dose equation (Equation 5.3) can be used for thebenefitto be gainedoutweighs the risk asso-
calculatingtheabsorbeddose,providedthe ciated withtheradiation dose.
cumulated activity and mass of the target area
.~ are known, F~~nonparticulate radiophmaceu-IatrogenicAlterations by Drug Interaction
ticals,the intraarterial injection usuallydelays or Invasive Medical Procedures
the appearance of the activity in thearea being The distributions fromdrug interaclion or
studied. vary proceduresmedical invasive considerably
Injection of thewrongradiopharmaceuticalfromone individualto another. These varialions
~~
does not fall under the headingofaltered dis- can evenmask disease or cause a fake positive
tribution, since the distribulion may be normal scaninterpretation. For diagnostic studies, USU-
for the radiopha~aceutica]given, but is an- allythe absorbed doses will be quite low, but
other type of administration error. Usually,the doses in individual patientscan be significantly
doseestimatehas alreadybeencalculated fordifferentbecause of changes in distribution
the misadministered drug, so the absorbeddosebroughtaboutby theseialrogenic alterations.
determination is not a problem, The problem is As for all dose calculations, the doses are de-
that organs have been irradiated and no informa- pendent on the cumulated activities for the dif-
tionbeen
obtained.
has ferent organs. If these
values
are available, [he
Injection of too muchor too little of the general dose equation (Equation 5.1) can be
proper radiopharmaceutical usually is caused by used. The uptake and mention in organsare no1
a misreading of the dose calibrator. Because the available or are sketchy, at best, for these and
absorbeddose is directlyproportional to the often fornormaldistributions.
~-~ administered activity, the absorbed
dose esli- The
physicalpropertiesfor
dose
calculations
mate for the misadministralion is made accord- (radionuclide emissions, phantoms representing
ingly. The administration of too littleactivity man, etc.), comparedwilhthebiologic data
initially can be as serious as the administration available, are relatively well known. Collecting
of too much; e.g., the administration of 50% of adequate biologic data is difficult and time con-
the required activity that results in a poor study suming but is necessary if the dose estimates are
andnecessitates arepeatstudy has thesame toreflectthesiluation for a given population.
effect as giving 150% of therequiredactivily (These topicsare discussed in more delail in
initially. Chapters 14 and 15.)
Drug Intervention SUMMARY
An increasingnumber of nuclearmedicine From the discussion in this chapter the reader
studies are being cornpIemented with drug inter- may get the impression that absorbed dose cal-
vention,asisdiscussed in Chapter 10. These culations are primarily guesswork. Admittedly,
studies are designed to cause an alteration of the assumptions must be made in some calculations
radiopharmaceutical distribution corresponding when there are gaps in the available data. These
to a specific condition. Because the distribution cakulations, however, represent an estimate of
is changed, the absorbed dose also is changed in thetrueabsorbeddose with reasonably suffi-
proportion to the amount of change in distribu- cient accuracy to assure the physician and reg-
tion. Calculation of the absorbed dose requires ulatory agencies that patients are not receiving
excessively high absorbed radiation doses. The
mined for individual patients. After the cumu- MIRD techniqueappears to be an acceptable
lated activities are calculated, the general dose method of dosecalculations, with individual
equation (Equation 5.1) could be applied. De- calculations being only as good as the input
termination of the altered distribution is diffi- information. All possiblesituationshave not
cult, and calculations of this type are not rou- been modeled, nor will they ever be, but ab-

72 t i h o ~ z r i o l uof Nrrckwr M d i c i r r e Science
sorbed dose estimation can continue to be of use
withapplication of available data, some com-
mon sense, and a few reasonable assumptions.
REFERENCES
I . Food and Drug Administration: Radioactive new drugs
[our invesligalional use. FedReg 28:183, Jan 8 , 1963.
2. Food and Drug Administration: Radioactiven e w drugs:
new-drug applicalion requirements.FedReg 36:21026,
Nov 3, 1971.
3. Loevinger R, Berman M: RevisedSchemafor CalcuIar-
ing the Absorbed Dose from Biologically Deposited
Radiorruclides, MIRD Pamphlet No I , Revised. New
York, Society of NucIear Medicine, 1976.
4. Snyder WS. Ford MR, Warner GG, Watson SB: "S',
Absorbed Dose per Unit Cumulated Acrivie for Se-
leered Radionuclides and Organs, MIRD Pamphlet No
I I . New York, Society of NuclearMedicine,1975.
5. Snyder W S , Ford MR, Warner GG, Watson SB: A
Tobrrloriorz of Dosr Eqzrivalrnr per Microcrrrie-Day for
Source alld Target Orgarzs of an A d d l for Various
Rodionuclides. O W L 5000, Parts I & 11. Contract
#W-7405-eng-26. Oak Ridge, TN, Oak RidgeNa-
tional Laboratory, 1974- 1975.
6 . InlernationalCommission on RadiologicalProtection:
Limitsfor Intakes of radionuclides by workers. In:
Anrfals of the ICRP, ICRP Publication 30. Supplement
to Par1 1. New York, Pergamon Press, 1979.
7. International Commission on Radiological Protection:
Limitsforintakes of radionuclides by workers. In:
Anffalsofrhe ICRP, ICRP Publicalion 30. Supplement
lo Part 2. New York, Pergamon Press. 1981.
8 , InternationalCommission on RadiologicalProtection:
Limlls for inlakes of radionuchdes by workers. In:
A!fnolsof fhe ICRP, ICRP Publication 30. Supplement
A lo Part 3. NewYork. Pergamon Press. 1982.
9.InternationalCommission on RadiologicalProtection:
Limits lor intakes of radionuclides by workers. In:
Arn~olsofrhe ICRP, ICRP Publicalion 30. Supplement
B lo Part 3. New York, Pegamon Press, 1982.
10. BermanM: Kirzelic Models for Absorbed Dose Cal-
culurions, nm/MlRD Pamphlet No 12. New York, So-
ciety of Nuclear Medicine, 1977.
11. Roedler H D Accuracy of internal dosecalcuIalions
with spccial consideration of radiopharmaceutical bio-
kinelics. InWaLson E, Schlafke-SteIson A, Coffey J,
Cloulier R (eds): Proceedings of Third irlrernarional
Radiophormaceuiical Dosimetry Symposirtm. HHS
Publicalion FDA-81-8166. Rockville, MD,BRH, June
1981, pp 1-20.
12.Lathrop, KA: ColIecLionand presentation or animal
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Considerations and Controversies in the
Selection of Radiopharmaceuticals
When a radiopharmaceutical is selected for a
specific study, multiple factors must be consid-
ered to ensure that optimum clinical information
will be provided with minimum radiation ex-
posure to the patient and laboratory personnel.
In this endeavor, certain questions must be con-
sidered. What are the nuclear properties of the
available radiopharmaceuhls? Fortheorgan
to be studied, are there multiple radiopharma-
ceuticaI localization pathways? If so, which is
bestsuited to providethedesireddiagnostic
information? Does the presence of certain clini-
cal factors preclude [he use of some radiophar-
maceuticals and require the use of others? Do
certain radiopharmaceuticals have overriding
radiopharmacologic properties which limit their
usefulness for the evaluation of certain clinical
siluations? Finally, how significant are non-
clinical properties such as cost, availability, and
productformulation? In h i s chapter, some of
these areas and severalsituationswhich illus-
Physical Half-life
Presently, there are more than 1,500 radionu-
clides available,with physical half-livesrang-
ing fromfractions of a secondto as long as
several thousand years. The description ofan
"ideal" physical half-life for any radionuclide
is difficult, since this property is largely deter-
mined by consideration of radiophannaceutical
uptakeand eliminationkinetics in the target
organ. In practice, however, the physicalhalf-
life of any radionuclide must be sufficiently
long to ensure that afterradiopharmaceutical
administration, enough activity remains in the
tissue at the time of imaging to obtain adequate
clinicalinformation. Generally, radionuclides
withvery long physical half-livesareundesir-
able,sincetheirpresenceinthebodyafter
imaging results in additional, unnecessary radi-
ation exposure. Very short-lived radionuclides
havelimitations: thefrequency of air freight
shimnents of theseraDidh decavine. radionu-
"

2 ==
-
=

take studies of the humanfetal

thyroid. J Nucl Med
Ric Clin Lab 10629-660, 1980.
91, Kaul A, Roedler H: Sr~.alrler~erposirio~z des Feren Drr-
Irate the radiopharmaceutical selection process elides usually is greater, and relatively larger
2. -3 ,. are discussed. amounts must be administered in order to assure
;. -:
.~ I 8:157-165, 1967. rch Radiophormaka Scl~~.angers~~afrsabbrz~ch Nach
9 -< .J. ~ li 73. Hodges R, Evans T, Bradbury J. KeetleI W : Accumula- Swahlene.rposiriolr Durcl? Medizilresclle Mnsorahrrfof.
5:
.. .
2. lion of radioactiveiodine by humanfetalthyroids. J Munich, Kolloquium im Institut fur Strahlenschutz der
.~
I .~. -
3, I -
Clirl Endocrirrol 15:66 1-667, 1955. Gesellsha[l fur Strahlen- und Urnweltforschung, 1977.
1, 19, .
!.
7'
,-
.
' 74. Dyer N, Brill A, Glasser S: Maternal-fetallransporl 92. Gillespie E Principles of uterine growth in pregnancy. pharmaceuticals were radioiodinated products able:
*
1. -1
~. ,. and
distribution of Fe-59 and
I-131 in humans. An1 J Am f Obsler Gynecol 59(5):949-959, 1950. with limited clinical applications. Over the past
;i:
. ji
%- ;L ,' A .
. Obarer Gyrecol IO3:290-296,1969 93. Snyder W Estimation of absorbedfraction of energy
3,
2, i ic
:--:.:
"

75. Kcarns J, Hutson W: Tagged isomers

and
analogues of
several decades, however, developments in ra-
.> 7- fromphoton sources in body organs. In Cloutier R .
I: ;j. i" thyroxine (their transmission
across the human
piacenta Edwards C, Snydcr W (eds): Medical Radionrtdides: dionuclide
production
technology
radio-
and Decay lWode Gamma
j ij andothcr studies). J Nzrcl Med 4:453-4611963. Radinriorz Dose arzd Eflecrs. US Atomic Energy Com- chemistry have made available a variety of ra- Emission
+ .; . . :z ?. 76. Book S , Goldmnn M : Thyroidal radiation
exposure of mission Division ofTechnical Infor~nalion,June 1970. diophartnaceuticalspreparedfromseveral dif- It is well known that radionuclides which
$ -:
1

f- the fetus. Healrlr P11y.r 29:874-877. 1975. 94. Cloutier R , Smith S , Warson E, et al: Dosc to the felus
,:;
ferent radionuclides. Because nuclear properties decay by nonparliculate emissions, such as iso-
77. Watson E Radiation dose eslimates to the human retal Irom radionuclides in the bladder. Henllh P h y s
,.; Ii , ::l significantly influence patient radiation dosime- meric transition or eleclron capture, are prefera-
i" 8: i:. thyroid at various stagesdevelopment.
of J Nucl Med 25:147-161,1973.
$ i! I try as well as clinical suilability (l), these areas ble for clinical use, since relatively lesser local
I' ;: , : .
I ./
j
24(5):~95,19x3.
78. Aboul-Khair S. Buchanan J, Crooks J, Turnbull A:
95. Gmen H , Gareis F, Shepard T, Kelley V: Cretinism
associatedwithmaternalsodiumiodide 1-131 therapy are of primaryimportance in the selection ofa tissue irradiation occurs with these decay
f ! ! ,
I.: .: j ;:
!
, Stmcturc function
and of the human fetal thyroid. C h during prcgnancy. Arlr J Dis C l d d 122:247-249. 197 1. modcs radiopharmaceutical. .
1: ., .
i
.!:.
76 f Essemitrls of Nucleor Medicim Science
Table 6.1.
Nuclear Properties of Selected Radionuclides and Photopeak Efficiencies in 0.5-inch Sodium Iodide
Radionuclide Physical Hall-lilt
99mTc 6.0 hr
"'In 2.8 days
1311 8.1 days
* Photopeak efficiency, shown for the 0.5-inch NaI (TI) scintillation crystal, represents the percentage of
pholons striking crystal which are compIetely absorbed.
For use with most currentIy availablescin-
tillation camera systems, a principal photon en-
ergy of 150 keV is near ideal. Higher energy
photons (Table 6. I ) have much lower photopeak
efficiency (2), while verylow energy photons
are attenuated by body tissues and are less ac-
cessible for external scintillation detection. Ad-
ditionally, these photons should be mono-
energetic. A radiopharmaceuticalto be em-
ployed in a patient in the presence of another
radiopharmaceutica1shouldhave a slightly
higher energy emission to allow detection with
minimal energy interference from the initial ra-
diopharmaceuticd.
Since the number of photons emitted during
decay(i.e.,theabundance)influencesthe
amount of radioactivitythat muslbe adrnin-
istered, radionuclides withuseful photons of
high abundance are most desirable for scintilla-
tion imaging.Forsomestudies, however, the
radiopharmaceuticals that have suitable biologic
distributionpropertiesmaynothave a high
abundance of usablephotons. For example,
while the myocardial perfusion agent 201TIhas
gammaemissions at 135 and 167 keV,their
Table 6.2.
Nuclear Properties of Myocardia1 Perfusion Agent,
[*O~TI]ThallousChloride*
Principal Emissions Mean Disintegration(%)
Hg x-rays (68-80 keV) 94.4
Gamma-4 (1 35 keV) 2.7
Gamma-6 (1 67 keV) 10.0
* Decay mode = electron capture; tm*y = 73.1 hr.
Considerations and Controversies in the Selection of Radiopharmaceuricais f 77
BIOLOGICAL FACTORS AFFECTING bengal, a lipophilic dye, was employed for hep-
THE CHOICE OF atobiliarp imaging ( 5 ) . Recently,I3lI-labeled
RADIOPHARMACEUTICALS rose bengal has been replaced by 99mTc-labeled
Prmcipal Emission (keV) Mean Disintegration (%) Photopeak Efficiency (%I* derivativesof iminodiacetic acid (IDA) which
In additionto nuclear properties, other fac-
140 88 91 torsinvolved in radiopharmaceuticalselection have superior imaging and biologic distribution
173 89 82 pertainto biologic distribution characteristics. properties (6-8).
247 94 50
364 82 30 These properties, which include tissue uptake
rates, rates of biologic clearance, and other ki- Kidney (Renal Imaging)
netic-type factors, significantly affect radio- Since renal function consists of several corn-
pharmaceutica1 usefulness and radiation dos- plex mechanisms, the careful selection of the
imetry. These characteristics are largely influ- radiopharmaceutical is essential in order to ob-
encedbythelocalizationmechanisms of
tain the desired diagnostic information.
relatively low abundance (Table 6.2) limits their specific radiopharmaceuticals (refer to Table Someradiopharmaceuticals, such as 9 9 m T ~ -
usefulness forimaging.Forthisreason, 201T1 3.1, page 35). Some organs contain more than diethylenetriaminepentaacetic acid (DTPA) are
imaging is performed with use of the Hg x-rays one physiologic pathway or tissue characteristic filtered by the kidneys and do not undergo lu-
which, although of lower energy than the that can be utilized as a mechanism for radio- bular reabsorption or secretion.Thistype of
gamma emissions, are available in sufficiently pharmaceutical localization. With these organs, agent is particularly suitable for evaluation of
high abundance for imaging. therefore, it is essential that the correct radio-renalblood flow and for theestimation of
pharmaceutical that enablesgeneration of the
9 9 m Tversus
~ Other Radionuclides glomerular fihation (9). Sodium [99mTc]per-
desired diagnostic information is chosen. technetate is also useful for renal blood flow
Although wmTchas nertr-ideal imaging prop-
imaging. The urinary excretion of sodium
erties (Table 6.3), it cannot be employed to label Mechanisms of Localization [99mTc]pertechnetate is relatively slow, with
somecompounds useful forimaging (3). For of Selected Organ Systems
about 85% of the filtered activity being reab-
thisreason, aitemativeradionuclidessuchas Liver (Relicuioendothelial System versus sorbedbythe renaltubules (10); therefore, it
67Ga, "'In, 1231,and 12'Xe have been used to fill HepatobiliaryImaging) cannot be employed efficiently for renal func-
clinical voids. Nevertheless, more than 90% of
In theliver, two celltypes-Kupffer and hep- tion studies.
all diagnostic radiopharmaceuticals are labeled
atocytes-provide different organ uptake mech- Radioiodinated o-iodohippurate (OIH) also is
with 9 9 m TThe
~ . majority of these 49mTc-labeled
anisms for hepatic localization. The hepatic useful for renal imaging; its distributionproper-
agentsareprepared byaddinggenerator-pro-
reticuloendothelia1 (RE)KupfferceIIs,which ties are markedly different from that of WmTc-
duced 8 9 m T(as ~ sodiumpertechnetate) to re-
phagocytize particles in blood,removeintra- labeled DTFA or pertechnetate, however. Radi-
agent "kits" that contain the nonradioactive
venously injected colloids. Since Kupffer cells oiodinated (either lZ3I or I3lI) OIH is approx-
compound to be Iabeled as well asanyother
are uniformly distributed in healthy liver, their imately 80% secreted and 20% filteredand is
additives required in the radiolabeling process
appearance,asdepictedbyscintillationimag- virtually totally extracted from the blood pass-
andlor maintenance of the radiolabeled product.
ing, yields information about liver size, shape, ing through the kidney (1 1). This efficient renal
Considerations involving the selection of 9 9 m T ~
and position. The Kupffer cells constitute the clearance makes it a very desirable radiophar-
kit-typeradiopharmaceuticalsarediscussed
Iargest proportion of the RE system ( 8 5 8 ) ; maceutical for estimation of effectiverenal
later in this chapter.
since phagocytic R E cells are also found in the plasma flow (ERPF) (12).
spleen (10%) and bone marrow (5%), however, Static images of renal anatomy can be ob-
intravenously injected radioactive colloids will tained with radiopharmaceuticals that accumu-
also be taken up by these organs (4). late in the renal cortex (13). Both 99mTc-labeled
Table 6.3. Alternalively, hepatic parenchymal cells dimercaptosuccinic acid (DMSA) and glucep-
(hepatocytes) actively remove blood breakdown tate have significant cortical retention and can
Nuclear Properties of 99mTc
products and toxins which are subsequently ex- be used for static renal cortical imaging. h a g -
Physical half-life of 6.0 hr creted in bile.Radiopharmaceuticals removed ing with either radiopharmaceutical usually is
Generator product from decay of 99M0 by hepatocytes provide diagnostic information performed approximately 2-3 hours postinjec-
Isomeric transilion decay mode
on hepatocyte function and on the palency and tion. Generally, the fraction of injected dose of
Monoenergetic 140-keV emission (88% abundance)
Low radiation dose constant (0.303 gm-rad/pCi-hr) integrity of the biliary drainage system. In the 99mTc-DMSAwhich localizes in the renal cor-
early days of nuclear medicine, 13*1-labeledrose lex is much greaterlhan that of 99mTc-gluceptate
78 I Essentials of Nuclear MedicineScience Coruiderafiorls and Conlrove,v i e s ill rhe Selection of'Radiophormacerrricals t 79

and persists for a much longer period of time 1960s for lung ventilation imaging, is less tlwn I I ~ considerations are presented be-
E T ~ I tllcse Differences in Target Uptake Rates
(13, 14). ideal, since its principal photon emission of 8 I Although two radiopharmaceuticals may
keV cannot readily be distinguished from99n11'c share the same uptake pathway, there may be
Lung (Perfusion versus Ventilation Compton scatter when the ventilation study lo1 slight variation in absolute target tissue uptake
Imaging) lows lhe 9 9 m Tperfusion
~ study. For this reasol!. orrates of uptakewhichaffecttheclinical
Because gaseous exchange in lung is a com- 133Xeventilation imaging usually is perforrncrl usefulness of these radiopharmaceuticals. Usu-
posite function involving both blood flow and either immediately prior to h e 9 9 m Tperfusion
~ ally, differences in basic pharmacologic proper-
ventilation, pulmonarynuclear medicine studies study or on the following day (17). Both I?% ties are responsible for such alterations inlocal-
employ radiopharmaceuticals that depict either (17-19) and *ImKr (20) haveprincipal photon ization kinetics.
perfusion or ventilation. energies higher than that of 99mTc and can hc
Pulmonaryperfusion imaging is performed used for ventilation imagingimmediately fol- Thyroid Imaging
with use of radiolabeled particles such as 99mTc- lowing an abnormal 99mTcperfusion study. Boil1 As previously mentioned, both radioiodides
labeled macroaggregated albumin (MAA) or Iz7Xe and 81mKrdecaybydesirable electroll and sodium[99mTc]pertechnetatecan be used
human albumin microspheres (HAM). These capture and provide minimal radiation eA forthyroidimaging.Radioiodide requires 24
parlicles are larger than red blood cells and will posure. The relatively long physical half-life (>I hours or more for maximum thyroid accumula-
be filtered and trapped in the lungs (by capillary IZ7Xe(36.4 days), however, prohibits direct lr tion, at whichtime it is relatively specific for
blockade mechanism) immediately following lease of expired IZ7Xetoatmosphere, whicl~ the thyroidtissueand provides high target-to-
intravenous injection. The appearance of these thus requires the use of some type of gas-tlap- Gji.lhruclivity commonly present in the lower backgroundratios.Sodium[99mTc]pertechne-
radiolabeled particles in lungs, provided the ping system for physical decay. 81mKr,on 1 1 ~ tate, however, reaches maximum uptake as soon
particlesare homogeneouslymixed in blood other hand, is a generator-producedradiorw as 20 minutes after administration but is much
and almost entirely extracted by the lungs dur- clide with a 13-second physical half-life m t less specific for thyroid tissue.
ing first passage, provides images of regional may be safelyexhaled by the patient directly Although both sodium [ 99mTc]pertechnetate
pulmonary perfusion (15). Areas of lung which into the room. Multiple lung views can be 011- and radioiodine areinitially "trapped" in the
do not receive blood appear as areas of dimin- lained, since thepatient breathes the gasdireclly thyroid by similarmechanisms,onlyradi-
ished activity. Although perfusion imaging with from its generator, but the short physical hall- oiodineentersfurtherintotheorganification
radiolabeled particles is a sensitive indicator of life prevents assessment of "washout" which 13 cycle by which thyroid hormone is produced.
regional lung blood flow, it is of limited specif- a sensitive indicator of obstructive airway d i h - Tissue accumulation of radioiodineisconsid-
icity, since changes in pulmonary perfusion can ease. Each generatormust be replaced daily duc ereda more specificindicator of functioning
be seen with many diseases of the lung. Greater to the relatively short parent (*'Rb) physicill thyroid tissue. Clinically useful images may be
diagnostic specificityforlungdisease usually half-life of 4.7 hours. Radioaerosols made 1ro111 obtained with either sodium [49mTc]perlech-
can be obtained by combining lung ventilation commonly available radiopharmaceuticals, SLICI~ nelateorradioiodine(especiallysodium
imaging with pulmonary perfusion imaging. as 99mTc-DTPA,also can be used to image lull; [lL3I]iodide),and selectionisoften basedon
sincepulmonaryembolioftencanbedistin- ventilation function (21). After inhalation, radii factors such as availability, cost,route of ad-
guished from most other types of lung disease oaerosol residence time in lung is sufficiently ministration, and time of maximal uptake. Be-
whichalsoproduceperfusiondefects (16) long to permit imaging in multiple views, a l ~ r l cause of its betterspecificity forfunctioning
(Table 6.4). since relatively inexpensive radiophamaccuti. thyroidtissue, however, radioiodineusually is
Among clinicians there is some controversy cals are used, the cost for the agent is rninirna preferred in the search for functioning metas-
as 10 which radiopharmaceutical is superior for RadioaerosoIspreparedfrom 9 9 m Tare~ 1101 tatic thyroid tumor, in the attempt to locale ecto-
ventilation imaging. r33Xe, used since the early ideal, since the lung perfusion agent is also iu pic thyroid tissue, and in the evaluation of func-
99mTc-labeled radiopharmaceutical. tioning thyroid nodules (24).

Table 6.4. CLINICAL DIFFERENCES RELATED TO Renal Imaging: 99mTc-DMSA versus

BIOLOGIC BEHAVIOR wmTc-Gluceptate
Characteristic Evaluation of Pulmonary Emboli and
Chronic-type Obslruclive Lung Diseases by Amongradiopharmaceuticalsuseful for ;I fore, in personswho Both *"Tc-DMSA and 99mTc-gluceptate lo-
Pulmonary Perfusion and Venlilation Imaging particular clinical indication, minor differenw calize in the renal cortex and areuseful for
in biologic behavior can become major consirl- obtaining images of renal cortical anatomy. Be-
hlnmnary Pulmonary
Lung Disease Typ Perfusion Imaging Ventilation Imaging erationswhichinfluenceoverallsuitabiliry cause 99mTc-DMSA localizesin the renal cortex
Areas in which these lypes of differences can to a much greater extent and for a longer period
Pulmonary emboli Abnormal Normal of time than does 99mTc-gluceptate, itprovides a
Chronic obstructive Abnormal Abnomlal affect the clinical selection process along with :I
discussion of radiopharmaceuticals which cx. higher radiation dose to renal cortex than does
80 1 Esserztiols of Nuclear Medicine Science
99mTc-gluceptate(1.4 radlmCi for49mTc-DMSA
versus 0.3 radlmCifor 99mTc-gluceptate). For
this reason,when99mTc-DMSAisused,the
amount of activity to be administered is limited
to 5 mCi. Since dynamic blood flow imaging
oftenrequires theinjection of at least 10-15
mCi, 99mTc-gluceptate is preferred whenever re-
nal blood flow imagingisperformed in con-
junction with delayed renal imaging.
Hepatobiliary Imaging
During the pastfew years, several 49mTc-IDA
derivatives have been developed (Table 6.5). All
these agents share the same hepatobiliary clear-
ance pathway, yet have different rates of excre-
tion. To date, there isnoclearconsensusas
to which 99mTc-IDA agent is superior forhepa-
tobiliary imaging, and it hasbeensuggested
that actual selection of a 99mTc-IDA agent might
be basedontheclinical problem at hand. Al-
though therapid clearance of these 99mTc-la-
beled agents from the liver is largely dependent
on hepatocelluIar integrity, slight structural dif-
ferences among these agents critically affectthe
rate of excretion from the hepatocytes into bile
(25). In one study (26) in which five different
99mTc-IDA agents were evaluated in a total of
115patients, it wasbelieved thatagents that
clear the hepatobiliary system slower may be
most suitable for gallbladdervisualization in
Table 6.5.
Chemical Structures of' Several 99mTc-labeled
Derivalives of Iminodiacetic Acid Which Are
Useful for Hepatobiliary Imaging
Basic SIIUC~I~S
HIDA -CH, -H - CH,
Diisopropyl -CH(CH,), -H -CHICH,),
Diclhyl -CH2CH, -H -CH,CH,
p-Isopropyl - H -CH(CH,), -H
suspectedacutecholecystitis,sincerapidly
clearingagents may not always reachaslow-
filling gallbladder.
Differences in Rates of Excretion
The amount of radiopharmaceutical remain-
ing in blood and soft tissues can seriously de-
grade image qualily by lowering the target to
nontarget ralios.Generally,radiophamaceuti-
cals that clear rapidly frombloodpermit(a)
higher qualityimages and (b) imaging to be
performed much sooner after radiopharmaceuti-
cal administration than do some slower-clearing
agents.
Bone Imaging
SinceSubrarnanianintroducedthefirst
""Tc-labeled boneseeker in 1971 (27), other
improved bone-seeking radiopharmaceuticals
havefollowed. The 99mTc-Iabeled diphospho-
nates are the agents of choice for skeletal imag-
ing; compared with previous 99mTc-labeledra-
diopharmaceuticals,theseagentshavegreater
uptake in bone'and more rapid blood clearance
(28, 29). The fraction of 99mTc-labeledbone
seekers not taken up by bone is rapidly removed
from blood and excreted via glomerular filtra-
tion. Presently, the ""Tc-labeled diphospho-
nates, medronate (MDP) and oxidronate (HDP),
arethe most widelyused 99mTc-labeledbone
imagingradiopharmaceuticals, with 9 9 m T ~ - ~ x -
idronateshowing slightlybelter boneuptake
and blood clearance (30). Thus far, no major
clinical differencehasbeen demonstrated be-
tween oxidronate and medronate. One study has
s h o w that their ability to detect skeletal lesions
is similar (31).
NONCLINICAL FACTORS AFFECTING
RADIOPHARMACEUTICAL
SELECTION
Inpractice, not all considerations in radio-
pharmaceutical selection involve purely clinical
decisions such as the dmg-related biodistribu-
tion properties of the radiodiagnostic agent or
the patient's clinical status. Often, acritical
determinant in choosing one radiopharmaceuti-
caloverallothersrnighlberelatedtodif-
ferencesinproductformulationamongcom-
mercial products, or limitations in their supply tisic acid, on the bone imaging radiopharmaceu-
and availability, or cost. tical, 99mTc-oxidronate, is shown in Figure6.1.
Stabilized formulations of 99mTc-labeled radio-
Product Formulation pharmaceuticalsresult in preparationswith
Today, mosl 99mTc-labeledradiophmaceuti- longer radiolabeled shelf lives and can be eco-
calsareavailable in "kit" form. Thesekits nomicaIly significant, since kits can be used for
contain the compound to be labeled as well as longer periods of time before serious degrada-
any necessary reagents that enhance the labeling tion which might affect image quality occurs.
reaction or maintain product integrity (i.e., pre- Over the past several years, there has been
vent breakdown of the "tagged" radiopharma- increasing interest in the minimum number of
ceutical). Slight differences in kit formulation particles that must be injected to obtain an ac-
cansignificantlyaffectradiopharmaceutical ceptable quality lung perfusion study and, con-
usefulness. sequently, in the kit formulation of the lung
For example,antioxidanlssuchasgentisic perfusionradiopharmaceuticals 99mTc-MAA
acid (32) or sodium ascorbate slow the rate of in and 99mTc-HAM.Initially, Duley and Heck (33)
vitro oxidative degradation of certain 99mT~-la- reported that no less than 65,000 particles were
beledradiopharmaceuticals,whichthus main- necessary for optimal lung imaging. More re-
tain the preferredradiolabeled form. The in cently, however, it hasbecome apparenl that
vitro stabilizing effect of the antioxidant, gen- improvedresolution of currentscintillation
401
Aa (Both p r o d u c t s
without stabilizers)
Tc.99m HEDP
Tc-99m HOP
(.Both products with
3 6 9 72 24
Tlme (hours)
added s t a b i l i z e r
g e n t i s i c acid)
Figure 6.1. Effect of the antioxidant, gentisicacid, on the in vitro slabilityoltwo bone-imaging radiopharma-
ceukals, WTc-oxidronale (HDP) and 99mTc-etidronate(HEDP). n , products without stabilizer; 6 , products
with stabilizer. (Adapted from A. J. Tofe et al.: Gentisic acid: a new stabilizer for low tin skeletal imaging
agents. Concise communication. J. N r d . Med. 21:366-370, 1980, with permission of the Society of Nuclear
Medicine .)
 82 I Essentials of Nuclear MedicineScience
cameras requires an increase in the minimum
number of particles to be injected to between
150,000 and 250,000 for an adult. Among the
several available commercial preparations of
i . . M A A and HAM, there is a wide variation in the
. i
number of MAA or HAM particles standardly
contained per vial. For larger nuclear medicine
departments, the selection of a particular prod-
uctthat contains a relativelysmall number of
particles might necessitate the daily preparation
of several vials in order to perform the desired
. .
studies in a single day. In this situation, the cost
for several vials can be significant.
Sometimes, however, it may be beneficial to
use a lung perfusion product that contains small
numbers of particles.For example,newborns
and infants up to 1 year of age have not fully
developed the number of pulmonary capillaries
found in the adult, and for this reason, it is
necessary to giveinfantsinjections of propor-
tionallyfewerparticles.If,forexample,
500,000 particles are consideredsafeforan
adult, lung perfusion scans in newborns should
be performed with no more than 50,000 parti-
cles, and infants up to 1 year of age should be
given injections of no more than' 165,000 parti-
cles (34, 35).
Ease of in Situ Preparation
Allbough the ease of in situ preparation may
initially appear to be a superficial consideration,
a review is important, since time and handling
of radiopharmaceuticals during their preparation
is likely lo, even with extreme precautions, in-
crease personnel radiation exposure.
Patient Preparation Requirements
The optimal use of some radiopharmaceuti-
cals may require patient preparationorsome
type of drug pretreatment to either enhance ra-
diopharmaceutical uptake or prevent radiophar-
maceutical accumulation by certain tissues. Ad-
ditionally, some preexisting clinicalsituations
may obviate the use of certain radiopharmaceu-
ticals; e.g., radioiodide thyroid imaging cannot
be performed satisfactorily in patients receiving
antithyroid drugs such as propylthiouracil
(PTU). In these situations, however, pertechne-
tate thyroid imaging is less affected.
cost
Radiopharmaceutical cost, which is always a
worthwhile consideration, is becoming even
more significant. Since the amount of radioac-
tivity that may be added to a single vial deter-
mines the number of studies that may be per-
formed, cost effectiveness cannot be based only
on vial cost. Subsequently, kits that contain
Iargeamounts of ligand or complexingagent
usually allow the addition of larger activities of
wmTcduringpreparation,whichpermitsa
larger number of studies to be pedormed. In
these situations, the actual cost per study per-
formed drops substantially. Manufacturer pack-
age inserts usually specify suggested maximum
levels of [99mTc]pertechnetate which can be
added to each vial during kit preparation.
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1. Wagner HN Jr, Emmons H: Characteristics of an ideal
radiopharmaceutical. In Andrews GA, Knisely RM,
WagnerHN Jr (eds): Radioaclive Pharnraceuticuls,
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1966, pp1-32.
2 . Bell EG, Maher B , McAfee JG, etal: Radiopharma-
ceuticals for gammacisternography. In Subramanian
G, Rhodes BA, Cooper JF, Sodd VI (eds): Rudiophnr-
mflcesliculs. New York, Society of Nuclear Medicine,
1975, pp 399-410.
3. McAfeeJG:Radioactivediagnosticagents:current
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4. Larson SM, Nelp WB: Radiopharmacotogy of a sim-
plified *mTc-colloid preparation for photoscanning. J
N r d Med 7:817-820, 1966.
5 . Taplin GV, Meredith OM, Kade H The radioactive
('311-tagged) rose bcngal uptake: excretion teslfor liver
function using external gamma-ray scintillation count-
ing lechniques. J Lab Clin Med 45665, 1955.
6. Loberg MD, Cooper M, Harvey E, el al: Development
of new radiophannaceuticals based uponN-substitution
of iminodiacetic acid. J NucI Med 17533-638, 1976.
7. Van Wyk AJ, Fourie PJ, Van Zyl WH, et al: Synthesis
of five new gmTc-HIDA isomers and comparison with
WmTc-HIDA. Eur J Nucl Med 4:445-448, 1979.
8 , Cbervu LR, Nunn AD, Loberg MD: Radiophamlaceu-
ticalsforhepatobiliaryimaging. Semin A ' d Med
125-17, 1982.
9. Klopper JF, Hauser W, Atkins HL, et al: Evaluation ol
SmTc-DTPA Tor the measuremenl of glomerular filtra-
tion rale. J Nftcl Med 13:107-110, 1972.
10. Dayton DA, Maher F T , Elveback LR: Renal clearance
~ )pertechnetate. M Q ~ Clin
of technetium ( g P m Tas O Proc
44:539,1969.
Considerations m d Colttrove1a i e s
11. Tubis IM.Posnick E, Nordyke R A Preparation and use
of I3'I labeled sodium iodohippurate in kidney function
tests. Proc Soc Exp Biol Med 103:497-498, 1960.
12. Zielinski FiV, Holly F E , Robinson GD Jr, et al: Total
and individual kidney function assessment with 1-123
ortho-iodohippurate. Radiology 125:753-759,1977.
13. Arnold RW, Subramanian G, McAfee JG, et al: Com-
parison of Tc-99m complexesfor renal ~maging.J Nucl
Med 16357-367, 1975.
14. Handmaker H, Young B, h e n s t e i n J: Clinical experi-
ence with Tc-99m DMSA (dimercapto succinic acid) a
new renal imaging agent. J Nucl Med 16:28-32, 1975.
15. Davis M A ParticulateradiopharmaceuticaIs for pul-
monary studies. InSubramanian G, Rhodes BA,
Cooper JE Sodd VJ (eds): Rudiopl~mfoceuriculs.New
York, Society of NuclearMedicine.1975, pp
267-281
16. McNeil BJ: A diagnosticstrategyusingventiIation-
perfusionstudies in patientssuspect for pulmonary
embolism. J Nlucl Med 1 7 6 1 3 4 1 6 . 1976.
17. Coates G, Nahmias C: Xenon-127, a comparison with
xenon-I33forventilationimaging. J Nucl Med
18:22 1-225, 1977.
18. Hoffer PB, Harper PV, Beck Rh!, et al: lmproved
xenon images with Xe-127. J N d Med 14:172-174,
1973.
19. Atkins HL, Susskind H, Kloppcr JF, et al: A clinicaI
comparison of Xe-127 and Xe-133 for lung ventilation
sludies. J Nfrcl Med 18553-659, 1977.
20. Fazio R, Jones T Assessmenl of regional ventilation by
conrinuous inhalation of radioactive krypton4 1m. Br
Med J 3673-676. 1975.
21. Taplin GV, Poe ND, Isawa T Radioaerosol inhalation
scintigraphy. In Subramanian G. Rhodes BA, Cooper
JF, Sodd VI (eds): Radioplfan~faceuficals. New York.
Sociely of Nuclear Medicme, 1975, pp 305-315.
22. Froelich JM', Swanson DP: Imaging of the infiam-
pp matory process withlabeled cells. Sernirz Hucl Med
14:128-I40, 1984.
23. Lanlieri RL, Fawcett HD, McKillop IH, et al: Ga-67 or
In-1 1 1 white blood ccIl scans for abscess deteclion: a
case of In-1 1 1 , C h Nircl Med 5: 185- 188, 1980.
24. Task force on short-livedradionuclides for medical
it1 theSelection of Radiopharmaceutical~ I 83
applications: evaluationof diseases of the thyroid gland
with i n vivo use of radionuclides. J A'lrcl Med
19107-112, 1978.
25. Bobba VR, KrishnamurthyGT,KingstonE, et al:
Comparison of biokinetics and biliary imaging param-
eters of four Tc-99m iminodiacetic acid derivatives in
normal subjects. Clin Nucl Med 8:70-75, 1983.
26. Williams W, Krishnamurlhy GT, Brar HS, et al: Scinti-
graphic variations of normal b i I i q pathology. J Nucl
Med 25:160-165, 1984.
27. Subramanian G , McAfee JG: A new complex of %Tc
forskeletalimaging. Radiology 99:192-196,1971.
28. Subramanian G , McAfee JG, Blair I u , et a1 Tech-
netium-99m-methylene diphosphonate-a superior
agent for skeletal imaging: comparison with other tech-
netium complexes. J Nucl Med 16:744-755, 1975.
29. Davis MA, Jones AG: Comparison of BmTc-labeled
phosphate and phosphonate agents for skeletal imag-
ing. Semin Nucl Med 6:19-31, 1976.
30. Bevan JA, Tofe AJ, Benedict JJ, et a1 Tc-99m HMDP
(hydroxymethylene dipbosphonate): a radiopharmaceu-
tical for skeletal and acute myocardial infarct imaging.
II. Comparison oi Tc-99m hydroxymethyIene diphos-
phonate(HMDP)withotherlechneliurn-labeled
boneimaging agents in a canine model. J Nzrcl Med
21:967-970,1980.
31. Van Duzee BE Schaelfer JA, Ball JD, et al: Relative
lesiondekctability of Tc-99m HMDP and Tc-99m
MDP: concisecommunication. J N ~ c lM e d
25:166-169. 1984.
32. Tofe AJ, 3evan IA, Fawzi MB, et 81: Gentisic acid: a
new stabilizer for low tin skeletal imaging agents. Con-
cise communicarion. f Nucl Med 21:366-370, 1980.
33. Heck LL. Duley JtV Jr: Statisticalconsiderations in
lung imaging with wmTc-albumin particles. Rodiology
113675, 1974.
34. Heyman S: Toxicity and safety factors associated with
lung perfusion sludies with Jadiobdbeied particles (lel-
ter to the editor). J A'ucl Med 20:1098-1099, 1979.
35. Davis MD,Taube RA: Re: toxicilyand safety factors
associated with lung perfusionstudieswithradiola-
beledparticles(lettertotheeditor). J Nrrcl Med
201099, 1979.

7 marily affects themultiplication of bone m a -
Therapeutic Applications of
Radiopharmaceuticals
Whether a radiopharmaceuticalhasdiag-
nostic or therapeutic application depends on
both theisotopeand pharmaceutical used. For
diagnostic applications, lhe isotope should un-
dergo only y-decay, since usually only y-radia-
tion is detected by nuclear medicine cameras.
The half-life should be justlongenough to
allowthe procedure to be performed. In con-
trast,the isotopeneededfortherapeutic pur-
poses should have particulale radiation, such as
a p-particle(electron),sincethese are locally
absorbed and increase the local radiation dose.
y-Radiation, which penetrates the tissues, pro-
duces lessradiation dose than do p-particles.
Several references dealing with radioactive de-
cay, parliculate interactions, and diagnostic and
therapeutic applicalions of radiopharmaceuti-
cals are available (1-8),
Radiopharmaceuticals can legally be used
only by physicians whoare qualified by specific
training in the safe handling of radionuclides.
The experience and training of these physicians
must be approved by theNuclear Regulatory
Commission (9) orAgreement State Agency
authorized to license the use ofradiopharmaceu-
ticals. A list of all byproduct material and pro-
cedures is available in the Code of Federal Reg-
ulations (9).
Of the many radiopharmaceuticals available
fordiagnostic and therapeuticuse,onlythose
commonly used will be discussed in this chap-
ter.
AGENTS USED FOR THERAPY
Generic Name: Sodium Phosphate P 32
Solution (U.S.P.)
Synonyms: Sodium Phosphate P 32
Therapeutic by Mal-
linckrodt
Phosphotope by E. R .
Squibb & Sons
Description
Radiophosphorus (32P)is prepared by ( T I , p )
reaction on pure sulfur (j2S). 32Phas a physical
half-life of 14.3 days and decays to 32Sby p-
emission. The maximum energy of this P-parti-
cle is 1.7 MeV, withanaverage emissionen-
ergy of 0.695 MeV. In tissue, this @-particlehas
a maximum range of approximately 8 mrn but
an average range of only 2 mm.
Sodium [32P]phosphate is available for ther-
apy as a sterile, pyrogen-free, colorless solution
containing less than 2 mg of sodium acetate per
ml as buffer and sodium chloride for isotonicity.
It may contain sodium hydroxide or hydro-
chloric acid for pH adjustment. The total phos-
phorus content is less than 0.5 rnglml. In some
instances,autoradiolysismay render the nor-
mally colorless solution a pale yellow, but this
has noeffect on itstherapeutic action.The
effective half-life of sodium [32P]phosphate is
approximately 8 days in thecellularcompo-
nents of blood and 8-10 days in all other tissues
except brain and bone.
Mechanism of Action
Certainblooddiseases are characterized by
an abnormal increase in one or more of the cell
lines of the hematopoietic system. Because the
myeloproliferative and lymphoproliferative dis-
orders are characterized by a cellular division
more rapidthan normal, anattempt has been
made to interrupt cell multiplication by the use
Therapeutic Applicarions of Radiopharmaceuticals I
of radioactivesodium[32PJphosphate.Since
sodium [32P]phosphate is deposited primarily in
boneandbonemarrow,theP-radiationpri-
row cells (4, IO).
Indications
Polycythemia vera has been treated with use
of phlebotomy, alkylatingagents,andsodium
[32P]phosphate.Therapy with alkylating agents
is often associatedwith sideeffectssuchas
nausea, vomiting,alopecia, and skinrashes.
Sodium [32Pjphosphate,on the other hand, sup-
presses myeloid proliferation with none of the
undesirable side effects associated with the al-
kylating agents ( I l - 13).
A less commontherapeutic appIication for
sodium [32P]phosphate is in the palliative treat-
ment of bone pain in patients with metastases
fromcarcinomas of theprostate,lung,and
breast (1 1-13). Because skeletal metastases
generally incite osteoblastic activity andthus
phosphate deposition, severalresearchers have
used sodium[32P]phosphatewhenanalgesics,
hormone therapy, or external radiationare no
longer feasible or effective (14-16).
Dose
For polycythemia vera, the dosage range for
theinitialtreatment is 1-5 mCi, which is de-
pendent on the severity and stage of lhe disease
and thesize of thepatient.The National In-
stitute of Health Polycythemia Vera Study
Group recommendsan initial dose of 2.3 mCiof
sodium [32P]phosphate persq m of body surface
area. Subsequentdoses arebased on patient
response. After the initial dose, a latent period
of 1-3 months usually is succeeded bya smooth
progressioninto completehematologic remis-
sion and achievement of a normal blood count
which lasts from months to years (4, 10).
For the treatment of bone painassociated with
skeletal metastases, the dosage range is 10-21
mCi of sodium [32P]phosphate given overa 3- or
4-week period, which is dependent onpatient
response. A typical dosing regimen might be 3
mCi given the first day, followed by two doses
of 2 mCi, with eachgivenevery other day
duringthefirstweek.Duringthesecond and
third weeks, two doses of 2 mCi each are given;
85
thereafter, 1 mCi is given twice a week until a
total of 21 rnCi has been administered or the
patient's bloodcountindicates a whiteblood
cell countof less than 3 , 0 0 0 1 ~mm
count of less than 5 0 , 0 0 0 1 ~mm.
~ or a platelet
~ In some in-
stances, relief of bone pain is achieved after a
total of 8 or 9 mCi has been administered.
Reduction of alkalinephosphatase levels and
radiologic evidence of bone healing have been
associated with the patient's pain relief (14-16).
In many instances in which sodium [32P]phos-
phate is used for the treatment of bone pain,
increased incorporation of sodium [32P]phos-
phate into the bone is achieved by placing the
patient on parathormone therapy prior to giving
radiophosphorus. The parathormone mobilizes
calcium and phosphates out of bone and lowers
the threshold of renal tubules for excretion of
phosphate, which results in an increased urinary
excretion of calcium and phosphorus. On dis-
continuance of treatment with parathormone, a
rebound effect whereby the renal output of cal-
cium andphosphorus is greatly decreased oc-
curs and results in the bones avidly seeking to
repiace calcium and phosphorussalts, which
enhances the incorporationof sodium [32P]phos-
phate. It has been recommended that calcium be
administered concurrently to assist in the depo-
sition of sodium [32P]phosphate in bonesand to
achievea progressiveossification ofthe dis-
eased bone (15).
Toxicity
Because sodium [32P]phosphate is actively
deposited in theblood-forming ceIIs of bone,
theprimarytoxiceffectsaretothehema-
t o p o i e t i cs y s t e m .O v e r d o s a g ew i t h so-
d i ~ m [ ~ ~ P ] p h o s p hmaya t e produce such serious
hematological effects as thrombocytopenia,leu-
kopenia, anemia, and leukemia (17, 18).
Pharmacodynamics
About 5-10% of intravenously administered
sodium [32P]phosphate is excreted in the urine
in the first 24 hours, with about 20% excreted
by the end of the first week. Only a very small
percenlage of the dose is excreted in the feces,
butthis percentageincreasessomewhat if the
dose is administered orally (17). Once sodium
[32P]phosphate is administered, it enters the
86 1 Essentinls of Nuclear MedicineScience
body pool of inorganic phosphate and is distrib-
uted fairly uniformly throughout the body over
the first 3 days. Only 12% of the dose decays
duringthisperiod.After 3 days,preferential
depositionoccurs in bone marrow,liver,and
spleen, with accumulation of up to ten times as
much sodium [32P]phosphate in these tissues as
in the rest of the body.
Therefore,thesecompartmentsreceive a gold and avoids the problems of radiation safety
greater amount of radiation-absorbed dose (4).
The kinetics of sodium [32P]phosphate require
multicompartmental analysis and may differ
from patient to patient due to variations in bone
accretion, metabolism, and renal excretion (4).
The kinetics do not lend themselves to estab-
lishing a pharmacokinetic dosing regimen.
Monitoring Parameters
Inclinicalsituationsinwhichsodium
[32P]phosphate is being used therapeutically. [he
most important parameters to be monitored are
hematologic (4, 10, 17).
In polycythemia vera, the drug should not be
administered if the leukocyte count falls below
50001cu mm or the platelet count is less than
100,000-150,000/cu mm (4, 17, 18).
In the treatment of bone pain from skeletal
metastases,sodium[32Pjphosphateusuallyis
not given when the leukocyte count is less than
2,000-5,000/cu mm and/or theplatelet count
falls below 50,000-100,000/cu mm (14-16,
18, 19).
Generic Name: Chromic Phosphate P 32
(U.S.P.); Chromic Phos-
phate P 32 Suspension
Synonym:Phosphocol P 32 by Mal-
linckrodt
Description
Chromic [32P]phosphate is commercially
available as asterile,pyrogen-free suspension
in a 30% dextrose solutionwith 2% benzyl
alcohol as apreservative (20). The suspension is
ablue-greencolorwithaparticlesize of
0.5-1.5 W ,
Mechanism of Action
The therapeutic action of chromic [3ZP]phos-
phate is accomplished by local irradiation from
thep-emission.Silver (5) haslistedseveral
possible mechanisms of action: (a) mesothelial
fibrosis, (b) fibrosis of small blood vessels, (c)
direct action on tumor seedlings, and (d) direct
radiation killing of free tumor cells in fluid.
Previously, 1 9 8 Acolloid
~ wascommonly
used.Chromic[32P]phosphatehas greater de-
structive action per disintegration than does
associated with the high-energy y- as well as 6-
emission of Ig8Au. Although the literature con-
tains extensive references to its use, 1 9 8 Acol-~
loid is no longer commercially available in the
United States.
Indications
Chromic [32P]phosphate is used for the treat-
ment of peritoneal or pleural effusions caused
by metastatic disease and, occasionally, for
treatment of primary malignancy. Chromic
phosphate is employed by either intracavity in-
stillation (for effusions) or injection directly
into the tumor for treatment of the primary ma-
lignancy.
Radiocolloids have been used in a Iarge num-
ber of malignant diseases, including prostatic
(21), bladder (22), lung (23),and cervical carci-
nomas (24). The only current significant use of
jZPis in the management of malignant effusions
(6). It should be emphasized that radiocolloids
are palliative agents that have no specific effect
on thecausative malignantprocess.Chromic
[32P]phosphate therapy is indicated in those pa-
tients whose effusions failto respond to conven-
tional radiation therapy or chemotherapy. Ther-
apy is restricted to patientsin whom centrifuged
effusionspecimens have demonstratedmalig-
nant cells, since radiocolloids areof no value in
the treatment of nonmalignant effusions (4). In
bloody effusions, the treatment with radiocol-
loid may be less effective (20). Palliativesuc-
cess with adequate control of fluid accumulation
is reportedly achieved in 5040% of cases (4).
Dose
Thesuggesteddoserangeemployed in the
average 75-kg patient is 10-20 mCi for intra-
peritonea1 instillation and 6-12 mCi for intra-
pleural instillation. Doses for inlerstitial use
should be based on the estimated gram weight
of thetumorand are about 0.3-0.5 mCilgm
(20).
Toxicity
Therapy with chromic [32P]phosphate is gen-
erally well tolerated by most patients, but un-
toward effects have been associated with its use.
These effects include bone marrow depression,
pleuritis, nausea, and abdominal cramping. Se-
vere necrosis may occur if chromic phosphate is
accidentallyinjectedinterstitially or intoa
loculation (20).
Pharmacodynamics
The physical half-life of chromic [32Pjphos-
phate is 14.3 days; the effective half-life is ?he
same.
Following the removal of fluid from the ap-
propriate cavity, the prescribed dose of radiocol-
loid is instilled. Care should be taken to ensure
that the needle or catheter is in the proper loca-
tion and that free-flowing fluid is in the cavity.
In many institutions, technetium sulfur colloid
is given first, to be certain the 32P wiII not be and the glass container may darken due to the
injected into a locuiation. Immediately follow-
ing administration and for several hours there-
after, the patient should be asked to move from
one position to another to help achieve a more
homogenousdispersionwithin thecavity.For
thebest response,theparticlesshould"plate
out" on the surface of the cavity and irradiale
the metastatic implants responsible for fluid ac-
cumulation. Treatment with chromic phosphate
should not be repeated sooner than 3 or 4 weeks
if the effusion recurs. Some investigators
Iieve that four instillations should be attempted
before the malignant effusion is considered re-
fractory (4).
Monitoring Parameters
All contaminated equipment and intravenous
lines used in instillation of the radiopharmaceu-
tical should be handled according to good radia-
tion protectionmeasures.Thecontaminated
supplies should be placed in a safe place and
storeduntilthe radioactivityhasdecayed
background or should be disposed of with other concentratedto alesser extent inthesalivary
radioactive waste in an accepted manner (25).
Gcneric Name: Sodium Iodide I 131 Cap-
sules a n d Solution (U.S.P.)
The,rupeulic Applicnliorls of R ~ d i o p ~ l a r ~ l a c e z i t i c a lIs 87
Synonyms: SodiumIodide I 131 Cap-
sules and Solution Thera-
peutic by Mallinckrodt
Iodotope I 131 Capsules
and Solution by E. R.
Squibb & S O ~ S
Description
Sodium [1311]iodideisavailable in capsules
and aqueoussolutionfor oral administration
(26-29). The physical half-life of l3II is 8.08
days. Themajory-rayemissionis 364 KeV
(80%); the predominant p-emission is 608 KeV
(87.2%). The finaldisintegrationproductis
l3lXe. Radioactive iodine (l3II)is produced by
the fission reaction of 235Uor by irradiation of
tellurium dioxide. The specific y-ray constant
for l3Il is 2.2 WmCi-hr at I cm. The half-value
layeris 3 mm of Pb.There is nosterile,
pyrogen-freeformcurrentlycommercially
available for intravenous administration. The
pH of the commercial solution may differ from
the U.S.P. limit of 7.5-9.0. The oral solution
effects of radiation (27, 29).
The solutions are shipped in lead containers
(referred to as "pigs") to decrease the external
radiation. The shielding provided by the manu-
facturer is generally not adequate, so the ''pigs"
should be stored behindadditionalshielding
until the radioactive substanceisused.Oral
solutions of sodium [1311]iodideshould be han-
dled with extreme caution, as contaminalion on
the surface of the containers and volatilization
be-
can occur (19, 30). In order to decrease radia-
tion dose to personnel, it is good practice to
handle allvolatile radiopharmaceuticais in an
approved fume hood (30).
Mechanism of Action
Sodium [1311]iodide isreadily absorbed by the
gastrointestinal tract and is handled by the body
in the same manner as stable iodide, being re-
movedfromthe blood streamalmostex-
to cIusively by the thyroid and kidney. Iodide is
glandsandstomach;itreenterstheintestinal
tract in secretions from theseorgansand is
again absorbed into the circulation. Radioiodine
can also be found in nasal secretions, nlouth,
88 I Essentinls of NuclearMedicineScience
trachea, female breast (including the nonlactat-
ing breast), gallbladder, liver, and intestine (28).
Indications
Radioactive iodine therapy is indicated in cer-
tain patients with carcinomas ofthe thyroid.
Well-differentiated carcinoma of the thyroid,
papillary or follicular carcinoma, usually accu-
mulate radioiodine. Akhough this accumulation
is generally significantly less than that in nor-
mal thyroid, large doses of radiation can still be
delivered by orally administered radioiodine
when the normal thyroid is ablated by surgery
or radioiodine therapy. Radioiodine will also be
accumulated by a small percentage of anaplastic
tumors.
Radioactive iodine isaIso used to treat benign
thyroid disease, primarily hyperlhyroidism. In
fact, l3]I is an excellent alternative to Iong-term
antithyroidtreatmentand has virtually elimi-
nated surgery as a form of therapy in patients
with Graves' disease and toxic multinodular
goiter.
Dose
The dosage required for a patient usually is
determined by the distribution of metastatic dis-
ease on an I3'I scan. Since uptake of iodine by
the [urnor tissue is low, patients are allowed to
becomehypothyroid so that theirendogenous
TSH will stimulate iodine uptake by the tumor
cells. Recent exposure Lo stableiodine in arty
form(especiallycontrast agentsused in radi-
ology) or to thyroid medications will decrease
[he amount of iodine uptake (31). Therefore, a
thorough history should be obtained before
scanning or treatment.
If the scan shows activity only inthe surgical
bed, it is difficult to determinewhether this
represents local tumor or residual thyroid. Some
clinicians will treat with 30-mCi doses, assum-
ing that the activity is residualthyroid (32).The
30-rnCi dose allows the patient to be treated as
an outpatient. A more aggressive approach is Lo
give doses in the range of 100-1 50 mCi. Usu-
ally, palients thal show activity in the lungs are
trealed with 175 mCi, and those with bone me-
tastases are treated with 200 mCi (33).
The dose should always be checked immedi-
atelyprior to administration. It should be ad-
ministered from the lead container with several
rinses of the vial with water.
The dosage for hyperthyroidism varies with
its cause. For Graves' disease, a range of 3-10
mCi is used. Although some clinicians attempt
to calculate a dose basedon the sizeof the gland
and the percentuptake of atracer amount of
iodine, many physicians find a fixed dose to be
justaseffective.Patientswithtoxicmulti-
nodular goiter are more resistant to therapy and
doses in the range of 15-30 mCi are commonly
used.
The most common side effectof a radioactive
iodine therapy is thegradualdevelopment of
hypothyroidism. There is no increasedinci-
dence of thyroid carcinoma. In fact, treated pa-
tients have a lower risk of cancer than the gen-
eralpublic.Radioiodineadministrationis
contraindicated in pregnant or nursing mothers.
Toxicity
Potential side effects, although not common,
includebone marrow depression,blooddys-
crasias,chromosomalabnormalities,andpul-
monary fibrosis (28, 29).
Pharmacodynamics
After oral administration of radioiodine, ap-
proximateiy 40% of the activity has an effective
half-life 6 0 . 3 4 days, and 60% has an effective
half-life of 7.61 days (29). The main route of
excretion is via the kidneys; therefore, the pa-
tient should be adequately hydrated to ensure
rapid elimination of the iodine that is not incor-
porated into the tumor.
Monitoring Parameters
Depression of the hematopoietic system may
occur when large doses of sodium [1311]iodide
are administered. The patientshouldbefol-
Iowed with appropriatebloodtests.Stringent
enforcement of all health physics precautions is
imperative for protection of personnel and pa-
tients. Excellent government publications con-
cerning these precautions are available (34, 35).
REFERENCES
1.Hendee WR:Medical Radiation I'hpics. Chicago,
YearBook Medical hbiishcrs, 1970.
2 . Mladjenovid M: Karliuisotope arld Radiariorl Pl~ysics.
Ncw York, Academic Prcss, 1973.
Theropeutic Applications oSRadiophormacelcticaIs
3. ParkerRP, Smith PHs, Taylor DM: Basic Science of
Nuclear Medicine. New York, Churchill Livingstone,
1978.
4. Blahd WH: Nrtcleor Medicine. New York, McGraw-
Hill, 1971.
5. Silver S: RadioacriwNuclides i f fMedicirle and B i d -
ogy: Medicine, ed 3. Philadelphia, Lea & Febiger,
1968.
6. Maynard CD: Clinical Nuclear M e d i c i m Philadel-
phia, Lea & Febiger, 1971.
7 . ShtaseI P Speak IO M e in Nuclear Medicine. Hagers-
town, MD, Harper & Row, 1976.
8.Subramanian C, Rhodes B A , Cooper JG, Sodd VJ:
Radiopharmacelrfical. New York, Society of Nuclear
1975. Medicine,
9 , Title 10: Code of Federal Regrrlutloru. Washin$on,
DC,Nuclear Rcgulalory Commission, Chap 1,Par1 35,
Secc 35.1-35.100.
10. Wasserman LR, Brown SM: Polycythemia vera. In
HollandJF,Frei E I11 (eds): Currer Medicine. Phila-
delphia. Lea & Febiger, 1974, pp 1359-1374.
11. Gardner FH: Treatment of polycythemia vera (p. vera).
Sernirr Hernarol 3220, 1966.
12. Gilbert HS: Problems relating to control of polycythe-
mia vera: the use of alkylatingagents. Bbod 32500,
1968. 1178.
13. Kenny JM, Marinelli LD, \Voodward SQ: Tracer stud-
ies with radioactivephosphorus inmalignant neoplastic
disease. Radiology 37:683-687, 1941.
14. Tong ECK, Finkelstein P The lreatment of prostalic
bone metaslases with parathormone and radloaclive
phosphorus. J Urol 109:71-75, 1973.
15. Tong ECK: Parathormone and P-32 therapy in proslatic
cancer with bone metaslases. Radiology 98:343-351,
1971,
16. Convin SH, Malament M, Small M: Experiences with
P-32 in advanced carcinoma of the prostate. J Urol
1W745-748, 1970.
17. ER Squibb & Sons: Technical Data Sheel. Medotopes.
Squibb Hospital Division,PO Box 4000, Princeton. NJ
08540.
18. Mallinckrodt: Technical Product Data. Mallinckrodt. S I
Louis, MO 63184.
19. SiIberslein EB: Radionuclide therapy of hemalologic
disorder. Sernird Nucl Meed 9:100, 1979.
20. MallinckrodtNuclear: Phosphocol P-32. Technical
Product Data Report 8/76.
I 89
21. Rusche C, Jaffc HL: Palliatative meatment of prostatic
cancer with radioactivecolloidalchromicphosphate:
three yearsexperience and resulls. I Urol 74:393,
1957.
22. Christensen WR, Weaver RG: Transcystoscopic
injec-
tion of tumors of the bladder wilh radioactivecolloldal
chromicphosphate. J [!I? Coli Surg 28:138,1957.
23. Hahn PF, Memeely GR, Carlson RI, Alsobrook W :
Adjuvant use of silver-coated radioactive gold in treat-
men1 of bronchogenic carcinomaby pneumoneclomy. J
N d Med 1:273. 1960.
24. Allen W M , Sherman AI, Amcson AN: Further results
obtained in the trealrnenl of cancer or the cervix with
radiogold: a progress report. Am J Ubster Gyrrecol
70386, 1955.
25. Title 10: Code of Federal Reg~rlu/iufrs.Washington,
DC, Nuclear Regulatory Commission, Chap 1 , P a l20.
r
26. ER Squibb & Sons: MedotopeDivision. New
Bmnswick, NJ.
27. ER Squibb & Sons: Technical Data Sheel:Iodotope.
Sodium Iodide 13'1 Capsules and Solution, April 1969.
28. PochinEE:Radioiodinelherapy of tbyroidcancer.
Semi?!Nncl Med 1(4):503, 1971.
29. MallinckrodtNuclear:Sodium Iodide 131-1 Capsules
and SolulionTherapeutic. Technical ProductReport,
117
30. Rubin LM, Miller KL, Schadt WW: A solution to the
radioiodinevolatilizationproblem. Henllll Phys
32:307,1976.
31. Hanslen P D Drug hrteractions. PhiladeIphia, Lea &
Febiger, 1976.
32. McCowen KD, Adler RA, Ghaed N, e l al: Low dose
radiodine thyroid ablation in postsurgical patients with
lhyroid cancer. Am J Med 61 5 2 , 1976.
33. 3ienualles JW: The treatment of thyroid cancer with
radioactive iodine. SeminNrrcl Med 8:79, 1978
34. National Council on Radiation Protection and Measure-
ments: Precauriom i n the Managemen/ ofPurients Who
Have Received Theraperrtic Amounts ofRadiornuclides.
Report No. 37. Nalional Council on Radiation Protec-
lion and Measurements, 1970.
35, Brodsky A: Principles and Prucrices fur Keepirzg Oc-
crrpariuml Radiarim Elposures a1 Medical Insrilurions
as Low as Reasonably Achiewble, NUREG0267.
Washington, DC, Nuclear Regulatory Commission,
1977,

8 I . Draw 15-20 ml of bIood and divide it into Iwo
,i ,
Preparation and Clinical Utility of Labeled
.
, .
Blood Products
Among thesignificantadvances in nuclear
medicine over the past decade, the one that has
had probabIy the greatest clinicaI impact is the
use of radiolabeledred cells, leukocytes, and
platelets. Labeled red bloodcells(RBC) are
used daily in mostnucIear medicinedepart-
ments.
PREPARATION OF RADIOLABELED
RED BLOOD CELLS
The agcnts available for tagging red cells are
s'Cr, %"Tc, and Illln. These agents are indis-
criminate and label circulating cells of all ages.
51Cris the isolope most commonly employed
for the measurement of red cell life-span and
mass, Red cell labeling with 51Cr has been in
use since the early 1950s when Gray and Sler-
ling first described its use (1-4), 51Cr is avail-
able as sodium chromate. Because the product
has such high specific activity, adequate red
blood cell tagging can be obtained with a mini-
mal incubation time. Chromium is available in
the hexavalent ( + 6) state, in which form it
readily penetrates the red blood cell, attaches to
the hemogIobin, and is reduced to the trivalent
( + 3) state, The chromium forms a moderately
stable label within the red cell until the cell is
sequestered. The radiolabel then can elute from
the cell and is excreted, mainly in the urine. In
the trivalent state, Y r is not reutilized in the
body for radiolabeling red cells in vivo.
The physical half-life of 51Cr is 27.8 days,
and the decay occurs mainly byK-capture. Nine
percent of total emissions is in the form of a
320-keV y-ray which,although not ideal for
imaging, allows measurements with use of a
properlyshielded well counter. Theeffective
half-life is 14.2 days. It should be noted that the
biological half-life of red bloodcellslabeled
with W r is significantly longer when the half-
life is delemined by whole body counting than
when it is determined by counting samples of
peripheral blood. This implies that the 51Cr la-
bel is not promptly excretedat the endof the red
cell life-span and that it is probably sequestered
in reticuloendothelial organs such as the spleen.
In Table 8,1, the procedure for radiolabeling
red blood cells with 51Crin current use at the
Intermountain Radiopharmacy, University of
Utah, is detailed. 51Cr-labeled red cells can be
utilized for spleen sequestration studies byheat-
ing the labeled cell for20 minutes at 49.5" C. A
recentreport indicates that thechromium-la-
beled red cellsheated in saline have shorter
clearance times than thoseheatedaspacked
cells or in plasma (5).
Redbloodcellslabeledwithlllln-oxine
(oxyquinoline)are used occasionally.Thead-
vantage of lilIn-oxine-labeled red blood cells is
that the physical half-lifeof lllIn of 2.8 days
(67.2hours)allows for serialimaging (6-8).
) j 1 h decays by electron capture with 173-keV
and 247-keV photons. The radiolabeling of red
bloodcellswith IIlIn-oxine is relatively easy
and requires only that thecellsuspensionbe
incubatedforapproximately 15 minuteswith
the lllIn-oxine solution.
Several methods to radiolabel red blood cells
with 99n1Tc are currently available. These meth-
ods usually are classified as in vitro, in vivo, or
a combination of both.
The in vivomethod of radiolabeling red
blood cells is based on the observation that the
administration of stannous compounds prior to
Preparaiion and Clinical Uriiily $Labeled Blood Products I 91
Table 8.1. from the patient, incubationwith 9 9 m T ~ ,
and
Procedure for Labeling Red Blood Cells with W r reinjection into the patient (13-16). Acid citrate
dextrose (ACD) is the anticoagulant of choice
sterile, empty vials (io ml), each of which con-
tains 2 cc of ACD solution.*
for the combined technique(17). The combined
technique is relatively simple and produces uni-
formly good results.
2, Add 25 c~Ciof sodium [Wrjchromate toeach
vial,
3. Incubate (with rotalion) for 20 minutes. RADIOLABELED RED CELLS:
4. Add approximately 50 mg of ascorbic acid (0.1
ml of Cervalin, 500 mg/rnl) to each vial to stop
CLINICAL UTILITY
the reaction. 51Cr-Iabeled red cells are used infrequently at
5 . Spin in a cenlrifuge for 5 minutes at 450 x g. the present time. They are restricted to studies
6 . Vent the vial with a needle. of red cell survival, red cell mass, and splenic
7. Draw offplasmawithasyringe (top half)and sequestration. In some patients, red cells seem
save the plasma.
8. Dilute cells with saline up to the 10-ml markin a to be destroyed at an accelerated rate. By injec-
vial and mix. tion of 51Cr-labeled red cells and then drawing
9. Spin again in the centrifuge for 5 minutes. of samples at various times, a curvecanbe
10. Draw off thesalineportion (top half) with a constructed that indicates the average survival
syringe. time for a red cell. The true mean half-life span
11. Measure the wash and plasma (from step 7) in
the dosecalibrator and calculate labeling effi- of the normal erythrocyte is 50-60 days. How-
ciency. ever, the W r study gives a normal mean half-
12. Resuspend the cells in saline up to an approxi- life valueof only 25-35 days, because about
mate 50% hemalocril (packed cell voIume). 1% of the label elutes from red cells each day
13. Dispense the twovialswithappropriatepaper-
work,
(1 8).
For a determination of whelher the spleen is
* Squibb ACD solution modified, list 10320. sequestering red cells, SICr-labeledred cells are
injected and then activityismeasured with a
probe placed over the heart and spleen. Increas-
the injection of 99mTc-pertechnetate* alters the ing countsfrom the spleenover several days
in vivo distribution of the 99nLTc-pertechnetate indicatepreferential sequestration of red cells
(9). Although99n1Tc-pertechnetatealonedoes (18).
not bind strongly to red blood cells in vivo, the 99mTc-labeledred cells are used far more fre-
pre-tinning of red cells allows the administered quently than are Wr-labeled cells. The primary
99mTc-perlechnetate to enter into the cells, be use of 99mTc-labeledred cells is for cardiovascu-
reduced, and become firmly bound to cellular lar studies. With use of a gamma camera inter-
components (10). The in vivo method requires faced to a computer, a "motion picture" of the
two injections,andnohandling of blood is heart ejecting the radiolabeled red cells can be
involved. Labeling efficiency ranges from 60% obtained. The function of the walls of the heart
to 90% with use of this method. and the amount of blood ejected can be meas-
If higher labeling efficiencies are necessary, ured. These studiesare useful in diagnosing and
in vitro radiolabeling may be used. The in vitro evaluating patients with atherosclerotic coro-
method (see Table 8.2) requires the removal of n a r ya r t e r yd i s e a s e ,c a r d i o m y o p a t h i e s ,
bloodfromthepatient,radiolabelingwith adriamycin cardiotoxicity, valvularheart dis-
9 9 m Tand ~ , reinjection into the patient ( I I , 12). ease, cardiac shunts, ventricular aneurysms,
Thecombinedmethodutilizes an in vivo and myocardial contusions (19).
tinning procedure followed bytheaddition of Theother area in which 99mTc-labeledred
99"1Tc-pertechnetateto a samplewithdrawn cells are frequently used is in diagnosing sites of
gastrointestinal (GI) hemorrhage (13). GI
bleeding is often intermittent in nature. There-
*Allhough sodium [~mTcIpcrtechnclaleis preferred by
IUPAC, wmTc-pertechnetate is slandard, and bolh are used fore, having 99mTc-labeiedred cells constantly
lhroughoul this chapkr. circulating in the body is an excellent way to
 92 1 Essentials of N d e a r Medicine Science Preparahn and Clinical Utiliry of Labeled Blood Producis I 93

Tabie 8.2. talion,settlingagentssuchashydroxyethyl engulfedtheparticles.Solubleagents, on the

. . Procedure for Preparing wmTc-Iabeled Red Blood Cells (RBC) with Use of the Brookhaven National starch can be used. other hand, allow easyseparation oftheun-
1 '
Laboratory Red Blood Cell Kit* In studies of neutrophil kinetics, it is imper- wanted activity remaining in the labeling fluid
ative that a pure neulrophil population be ob- by centrifugation and resuspension of the radio-
1 . Add 1-3 ml (smallestpossiblevolume is preferable)ofsodium[99mTc]pertechnetate to asterileand tained.Densitygradientcentrifugation is a labeled cells. Of the soluble agents tested, only
pyrogen-free 10-15-ml pharmaceutical vial and assay. Store in a lead shield.
2. Draw 4 ml of patient blood into a heparinized syringe and add to kit. Up to 6 ml blood may be used if the commonlyusedtechnique (21). Although nonpolarlipid-solublechelatesradiolabeled
i i

hematocril is low. Ficoll-Hypaque separations have been used ex- cells to a sufficient degree. Unfortunately, some
3. Mix immediately to dissolve [he freeze-dried solids in the bloodand gently rotale the tube for 5 minutes at tensively, some studies have indicated that this of the lipophilic chelates eluted from the cells
room lemperature. mixture may diminish leukocyte viability (21). before intracellular labeling occurred. One that
4 . Add1 ml ofa 4.4%EDTA (ethylenediaminetetraacetic acid,disodiumsalt)solution.Drawanequal
Thishas led some investigators to use a more did not, yet radiolabeled cellsefficiently, was
volume of air to avoid pressure buildup in the tube.
5 . Mix briefly by gently inverting about five times, and centrifuge the tube upside down for5 minutes at 1300 innocuous gradient material, Percoll. "'In-oxine.Since"lln-oxine wasfirstdeter-
X g (2900 rpm for a 14-cm spin radius; full-speed setting on InternalionaI Clinical Centrifuge CL Model Thepioneering work inleukocytelabeIing mined by McAfee and Thakur to be the best
20928m). was performed by McAfee and Thakur in 1976 radioIabeling agent, it has gone on to become
6. Maintain the tube in the inverled position to avoid disturbing the packed RBC. With a standard 20-gauge (22, 23). These investigalors looked at a large the most widely used agent for leukocyle label-
sterile needle and a 2'/2-3-m1 sterile disposable syringe, withdraw 1.25-2.0 ml of RBC (depending on
number of both soluble and particulate agents ing.
volume of whole blood used) and transfer to the premeasured lechnelium prepared in step 1. To remove the
RBC from the upside-down Vacutainer tube, make sure the plunger of the 3-ml syringe is pushed all the for labeling neutrophils.In these studies, partic- Several methods for radiolabeling leukocytes
way into (he syringe barrel before puncturing (he Vaculainer stopper-injection of air into the settledRBC ulate agentspresentedseveral problems, with with ll1In have been reported (24-27). In Table
will resuspend [he cells, Once the needle has just penetrated the Vacutainer stopper, remove [he RBC in one the major one being that of separating unbound 8 . 3 the method for radiolabeling leukocytes
smooth plunger withdrawal movement-ejection of cells from the syringe back into the Vaculainer tube radioactive parlicles and cells with particles ad- with ]"In-oxine used at lhe University of Utah
will resuspend the remaining cells, and (he operation cannot be continued without recenlrifugation.
herent to (he surface from those cells that have Medical Center is described.
7.. Incubate the 99mTc-RBC mixture for 10 minutes at room temperature wilh gentle mixing.
8 , Assay and dilute appropriately for injection. Cell separation and yield determination at this point consis- !
tently give yield of 98% or more.
9. The described procedure yields an excellent agenr for blood pool imaging and red cell mass studies.
Table 8.3.
Subslitution of the following for step 7 produces an ideal splenic agent: lncubate the technetium RBC
mixture 15 minutes at 49" C with gentle mixing. Procedure for LabeIing Autologous Leukocytes with tllIn-Oxine

1, Collect 40 cc of whole blood in a 50-cc syringe containing5 cc of ACD solulion and mix well. Add 1 part
Hespan (6% Hetastarch, a settIing agent) to 10 parts whole blood in the syringe.
2. Place the syringe in a clamp at an 80" angle, with the needle up, and allow the RBC to settle.
3. Remove the needle from the syringe and replace with a buttemy catheter.
4. Take a 50-mf sleriIe propylene centrifuge tube with a screw top and express the supernatant containine the
leukocyte-rich plasma from the syringe into the centrifuge tube, be& careful not to collect any f B C .
5 To obtain the while blood cell(s) (WBC) button, centrifuge the supernatant collected in step 4 a1 450 X g
diagnose GI hemorrhage. The other radiophar- PREPARATION OF llJI~-LABELED for 5 minutes.The WBC buttonwillcontainsomeRBC.Thisisnormalandwillnotaffectthe
maceutical used for GI bleeding studies, 99mT~- LEUKOCYTES preparation.
labeled sulfurcolloid,hasbeen shown to be Since the radioactive agents currently avail- 6 . Pour of€ the leukocyle poor plasma (LPP) and the supernatant into an identical sterile centrifuge tube and
save,
much less effeclive. This is because the clear- able radiolabel all cell types indiscriminately, it 7. Resuspend the WBC button by gently adding 5 ml of sterile saline. Agitate very genlly to resuspend the
ance half-time for sulfur colloid isso short and, is necessary first to separate the leukocytes WBC button. Spin down and discard the wash.
therefore,intermittentbleeds will bemissed. from the remainder of the blood cells. Manip- 8. Resuspend with 5 ml of saline and add 650 FCi of '[]In-oxine to the concentrated cell suspension and
, . The red cell study is most useful in evaluating ulation of the blood in vitro can decrease leuko- incubale for 20-30 minutes. Gently agitate the mixture three or four times during incubation to ensure
"
adequate mixing.
lower GI bleeding (colon). Bleeding sites in the cyte viability, so extremecaremustbe taken
9. After the incubation is compIeted, use a 10-mI disposable syringelo withdraw 5 mI of LPP from the tube
upper GI tract (esophagus and stomach) are best during cell separation. or step 6 , gently add [his lo the labeled WBC-saIine mixture, and agilate gently to resuspend the labcled
diagnosed by endoscopy ratherthan by radionu- For clinical examinations such as for abscess celIs. Centrifuge the mixture for 5 minutes at 450 X g. Four the supernatant into a separate container and
clide studies. detection,mixedleukocytepreparationsare counl each fraclion for labeling efficiency.
Occasionally, ""Tc-labeled red cells are heat adequate. McAfee et al. (21) compared the con- 10. Assay the wash and cells in the dose calibrator. The labeling efficiency is calculated by the formula:
damaged before injection, which causes them to centration of a pure preparation of radiolabeled +
E = [C/(C W)] X loo%, where C i s the activity associated wilh thecells, W is the aclivity associated
with the wash, and E is [he Iabeling efficiency.
be preferentiallytaken up bythespleen (20). leukocytes to a mixed cell suspension in experi- 1 1 . Using a 10-mI syringe, withdraw 6 ml of LPP saved from step6 , add this to the IabeIed WBC button, and
Sludies of heat-damaged red cells areused to mental abscesses and found no significant dif- agitalc gently lo resuspend the labeled cclls.
diagnosesplenomegaly,splenicinfarction, tu- ference. The simplest way to obtain mixed leu- 12. The 1"In-labeled leukocytes are now ready for injection back inlo the palient. Save the small amount of
mors of thespleen,hematomassecondary to kocyte populationsis with gravitysedimenta- labcled celIs remaining in the tube for a WBC countand microscopic examination. The amountof activity
trauma, and accessory spleens. tion of erylhrocyles. For hastening of sedimen- in the find product should be limited to 500 pCi.
 94 I Essentials of Nuclear MedicineScierrce Preparariou and Clinical Ufiliry of Labeled Blood Products f 95

The clinical utility of ll'In-oxine-labeled leu- oxine, reduces cell viability. In studies in which GI tract. Less commonly, abscesses result from cumulation of lllIn-labeledleukocytesinthe
kocytes has stimulated the development of other "'In-oxine-labeled leukocytes are directly com- complications involving the genitourinary sys- lungs and 10% of patients with diffuse pulmon-
labeling agents, especially tropolone. Tro- paredwith ll'ln-~opo~one-labeledleukocytes, tem. A mortaIity rate of 35% or higher is asso- ary uptake of radiolabeled leukocytes actually
polone is another lipophilic chelating agent that, however, no significant difference in their clini- ciated with untreated intraabdominal abscesses; have an infection.
like oxine, forms 3:1 complexes with lllIn and calability to detect abscesseshasbeen noted therefore, theimportance of prompt, accurate Finally, the scan doesnot appear to be helpful
can be used to radiolabel neutrophils (28). The (7-9). detection is obvious. Because an abscess is an indiagnosinginfectedheart valves (subacute
radiolabeling technique for lllIn-lropolone is lllln-oxineisstillthe prevalent method in accumulation of leukocytes, radiolabeling of the bacterial endocarditis (SBE)) (40). This is sig-
. .. similar to that for "'In-oxine (although some- use. This agent is no longer an investigational patient's own leukocytes with y-emitting radio- nificant because SBE is often considered in the
what simpler and quicker) with one major ex- radiopharmaceutical(since January 1986), and nuclides is a (theoretically) logical way to detect differential diagnosis of fever of unknown ori-
ception:thecells do not need to be removed therefore,itis available to all physiciansli- these focal infections. Clinical trials have con- gin.
from ulasma for cell labeling. One method cur-
I
censed to receive Il'In. firmed that leukocytescanning is a sensitive
rentlyinuseforlllIn-tropolonelabelingis means of detectingsites of infection.Sen- PREPARATION OF "'IN-LABELED
given in Table 8.4. RADIOLABELED
LEUKOCYTES: sitivities as high as 95% have been reported for PLATELETS
The advantages- of "'In-lropolone over IlLIn- CLINICAL UTILITY scans with "'In-labeled leukocytes (30, 31). "'In-labeled platelets offer several advan-
oxine as a labeling agent are controversial. Pro- The primary useof "'In-labeled leukocytes is In addition to intraabdominalabscesses, tages over5'Cr-labeled platelets: (a) higher pho-
.. ..
ponents of tropolone argue that it is less loxic
than oxine (28). More importantly, they believe
for the diagnosis of intraabdominal abscesses.
These frequently occur as cornplicalions of sur- ..
imaging with "'In-labeled leukocytes is helpful
in evalualing a number of other disorders. Ra-
, ton yield, (b) more desirable imaging energies,
: . and IC) less blood required for labeling. These
that depriving cells of plasma, as required with gery, injuries, or inflammatory diseases of the diolabeled leukocytescanbe used to evaluate advantages make "'In a more desirable radionu-
patients with inflammatory bowel disease (32). clide for imagingplatelet distribution and quan-
Attemptsto use [67Ga]gaIliumcitrate in these tifying organ uptake. The radiolabeling of plate-
'I .
patients have been suboptimal,since W a is letswithillInpresentsgreatertechnical
Table 8.4.
normally excreted in the GI tract. Leukocytes, problems thanthe radiolabeling of leukocytes
Preparation of 1I'In-Tropolone-labeled Leukocytes on the other hand, normally are not excreted in with I1'ln. In orderto ensure that platelets retain
the bowel and, therefore, have a much greater theirviabilityand do notaggregate prior to
1. Collect 40 cc of whole blood in a 50-cc syringe containing 5 cc of ACD solution and mix well.
2. Add 1 part Hespan (6%Hetastarch) to 10 parts whole blood in the syringe. potential for evaluating these diseases. In addi- reinjection, care must be taken during their ra-
3. Invert and place the syringe in'an incubator (37" C) with the needle up and allow the mixture to settlefor tion Lo imaging patients, stools can be collected diolabeling. Since the original article by Thakur
30 minules. and counted to follow the activity of the disease (41), various methods for radiolabelingplateIets
4 . Express leukocyte-rich plasma (LRP) through a 19-gauge buttemy into a 50-ml centrifuge lube. (33). have appeared in the literature (42-44). The
5 . Centrifuge [he LRP for 5 minulesat 450 X g.
Scans with "'In-labeled leukocytes are occa- radiolabeling of platelets has been the subject of
6. Pour off the supernatant into anorher 50-1111 centrifuge tube labeled platelet poor plasma (PPP).
7. Centrifuge thelubelabeled FPP for 5 minutesat 1600 X g. sionally used to diagnose transplant rejection of several symposiums (45, 46). The University of
8. Add 0.1 ml of topolone solution*(26 pg/O.1 d in HEPES buffer) to the cell button left over from step 4. both the kidneys and the hearl, since there is a Utahcurrenlly utilizesa modification of the
9. Add 700 pCi of Il'In-chloride to the bullon and tropolone solution and resuspend. leukocyte infiltrationassociated with rejection method reported by Heaton et al. (43) for the
10. Incubate the cells in the incubator at 37" C for IO minules. (34,35). In addition,radiolabeledleukocytes labeiing of autologous platelets (Table 8 , 3 .
11, "Wash" the cells with 6 ml of the supernatant in (he centrifuge tube labeled PPP. This will "scavenge"
have been used for diagnosing prosthetic graft
any free Illln-chloride left in solulion. RADIOLABELED PLATELETS:
12. Centrifuge the cells and PPP for 5 minutes at 450 X g. infections (36).
13. Pour off the supernatant into a tube labeled "wash" and assay i l for activity. The use of lllIn-labeled leukocytes in bone CLINICAL UTILITY
14. Resuspend the cell button in 6 r n I of PPP. and joint infections iscontroversial. With use of The utility of radiolabeled plalelets has been
15. Assay the cells for activity. "'In-labeledleukocytes,someinvestigators examined in a variety of diseases. At thepresent
16. Delemine tagging efficiency. havereported very high sensitivities for these
17. Dispense 500 pCi of activity associated with the leukocytes. time, however, the role of platelet scintigraphy
18. Count the number of WBC in a hemocytometer and examine microscopically. infections,whereas others havereported only in routine clinical practice has not been estab-
about 50% sensitivity in their patient popuia- lished. Because platelets are an important part
* Preparation of tropolone solution is carried out by following these steps: tions (37, 38). All investigators, however, have of the body's clotting mechanism, it is not sur-
I . Dissolve 238.3 rng of HEPES buffer (MW 238.3; Aldrich Chemical, Milwaukee, W1 53201) in 40 ml of found that when there is bone or joint uptake of prising that the main interest in using radiola-
normal saline. radiolabeled leukocytes, it is quite specific for beled platelets has been in the diagnosis of deep
2. Add 10 mg of tropolone (MW 122.12; Aldrich Chemical, Milwaukee, N'l53201) and dissolve completely infection. venousthrombosis in thelegs.Studies have
in MEPES solution. Imaging with "'In-labeled leukocytes is not indicated[hat L1lIn-labeledplateletsare a sen-
3. Adjustto pH 7.6 with 0.1 N NaOH. useful in suspected pulmonaryinfection (39).
4. Add normal saline up to a volume of 50 ml. sitive technique for diagnosing fresh clot (47).
5. Filter 20 ml into a 20-ml sterile evacuatcd vial with 0.22-p. Milliporc Alter. Unfortunately, numerous noninfectious disor- The degree of uptake of ll'ln-labeled platelets,
6 . Solution is stable for a( leas13 months; 0.1 ml of this solution yields20 pg of tropolone in a 20-ml solulion ders result in leukocyteuptake in thelungs. however,decreasesasthethrombusages.
of HEPES buffer. Onlyabout 50% of patientswithfocalac- Therefore,thescanis lessuseful in patients
96 1 Essenfiuls of Nuclear Medicine Science
Table 8.5.
Preparation of ~1~In-labeled Platelels
1. Draw 43 rnl of whole blood in 7 m l of ACD.
2. Cenkifuge at 200 X g for 15 minutes.
3. Separate pIatelet-richplasmaandcentrifugeat
2000 X g for 10 minutes.
4 . Retainplasma.
5. Resuspend plalelels in 6 ml of ACD/saline.'
6 . Centrifugeat 2000 X g for 10 minulesand
discard the rinse solution.
7. Resuspend in 5 ml of ACDlsaline and add 800
&Ci 1 11 In-oxine .
8. Incubate at room temperature for 20 minutes.
9. Add 6 ml of ACD plasma from step 4.
10. Cenlrifuge at 2000 X g for 10 minutes.
11. Save the wash and caIculate labeling efficiency.
12. Resuspendin 5 ml plasmasaved from step 4.
Radiolabeled platelets are ready for patient use.
* ACDlsaline is a 1:7 dilution of Squibb-modified
ACD solution with 0.9% NaC1 and pH adjusted lo
6.5 with 1 M NaOH, The ACD reduces the platelet
sensitivily to ADP and is used lo decrease the platelet
clumping during centrifugalion. It is difficult to esti-
mateplaleletviabilityin vitro, butaggregation to
ADP is somewhat recovcrable by adding MgCI, . bves! 29: 1604, 1950.
who have clots that are several days old. Platelet
uptakeappearsto be very specific for throm-
bosis. Theoptimal time forimagingradiola-
beled platelets is 24 hours after injection. The
effect of heparin therapy on thescan in deep
venous thrombosis is not clear in humans, al-
lhough there is evidence that it may cause false
negative studies (48).
A pulmonary embolus is a blood clot in the
extremities which has broken loose and lodged
in thelungs.One might think that platelets
would be justas useful in thisdisease as in
venous thrombosis of the extremities. Attempts
to diagnose pulmonary embolism with radiola-
beled platelets, however, have been disappoint-
ing (48). It appears that heparin does interfere
with uptake of lllIn-Iabeled platelets in pulmon-
ary embolism. The need to discontinue use of
heparin is a major disadvantage for clinical use
of thistechnique.'llln-Iabeledplatelets have
been used occasionally in patients with blood
clols in other areas, such asin the renal vein and
the superior sagitlal sinus of the brain (48).
Radiolabeled platelets have been used exten-
sively to examine patients wilh suspected alher-
osclerosis in the carotid arteries.The results
with'"In-labeledplateletshave beenmixed.
Despitehighexpectations, "'In-labeledplate-
lets have added little to our understanding of the
pathogenesis,diagnosis, or treatment of athe-
roscleroticdisease(48).ll'In-labeled platelets
have not been found to be of much help in the
diagnosis of other vascular abnormalities, such
as aortic aneurysms (49).
lllIn-labeled platelets appear LO be useful in
detecting sites of GI hemorrhage in patients
who have very low bleeding rates (50). In addi-
tion, radiolabeled platelets are used to evaluate
the thrombogenicity of various man-made mate-
rials that are used in the human body, such as
catheters (48).
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2. Gray SJ, Sterling K: The tagging of redceIlsand
plasmaproleinswithradioactivechromium. J Clin
3. Ebaugh FG lr, Emerson CP, Ross JF: The use or radio-
active chromium-51as an erythrocyte-tagging agenllor
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4. Read RC. Wilson GW, Gardner F H The use of radio-
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5 . Valk PE, Guille J: Measurement of splenicfunction
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6 . Winzelberg GG, Castronovo FP, Callahan RJ. el al:
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7 , Ferranl A, Dehasque N. Leners N , el al: Scintigraphy
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8. Beckman RL, Pitlenger GL, Swanson DP, et al: Blood
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9. McRae I. Sugar RM, Shipley, BA, et ab Allerations in
tissue distribulionof 99mTc pertechnetatein rats given
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10. Pave1 DG, Zimmer A M , Patlerson VN: In vivo labeling
of rcd blocd celk wilh 99mTc: a new approach to blood
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11. Hill IC, Dworkin IH: Syringeapparatus Cor radio-
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12, Smith TD, Richard P: A simple kit for [he preparalion
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13. Winzclberg GG, McKusick KA, Froclich JW, el al:
Prepororion and Clinical Utilig of Labeled Blood Prodrtcts
Deleclion of gaslrointestina1 bleeding with 99mTc-la-
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14.Armas R , Thakur ML, Gottschalk, A : A simple
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erythrocytes. Rudiology 132215, 1979.
15. Armas RR, Thakur ML. Gottschalk A: A simplified
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16. Callahan RJ, Froelich JW, McKusick KA, e[ al: A
modified method for the in vivo labeling ofred blood
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17. Porter WC, Stuart MD, Freilas JE, el al: Acid-citrale-
dextrose compared with heparin in the preparation of in
vivolin vitro technetium-99m rsd blood cells. J Nucl
Med 24:388. 1983.
18. McIntyre P, Dubos PE: The blood.In Rocha AFG,
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catApplicurions. Philadelphia, Lea & Febiger,1979,
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19. Berger HJ, Zarel BJ: Radionuclide assessment of car-
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3. New York, GNne & Slratton,1984, pp 364-478.
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21. McAfee JG, SubramanIan G, Gagne G: Technique of
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spectives. Sernin Nucl Med 1483-106, 1984.
22. McAfee JG, Thakur ML: Survey o l radioactive agents
for in vitro labeling of phagocytic Icukocytes. I . Solu-
bIe agenls. J Nucl Med 17:480, 1976.
23. McAfee JG, Thakur ML: Survey of radioactive agents
for in vitro labeling of phagocytic leukocytes. 11. h r t i -
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24. Thakur ML, Coleman RE, Welch MJ: Indium-I 1 1 la-
beled leukocytes for [he localization of abscesses: prep-
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with gallium47 citrateindogs. J Lab Clin Med
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26. Danpure HJ, Osman S: Cell labeling and cell damage
with indium-I I 1 acetylacelone-an allernative IO in-
dium-1 1 I oxine. Br .!Radiol 54:597, 1981.
27. Danpure HI, Osman S , Brady F: The labeling of blood
cells in plasma with I1 1-In-lropolonale. Br J Radiol
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28. Peters A M , Savcrymultu SH. Reavy HJ, et al: Imaging
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lcukocyles. J N N C I Med 2439, 1983.
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between lropolone and oxine labeled In-111 lcukocytes
Tor delecling infcclion. .!Hfrcl Med 26:469, 1985.
30. Baker WI, Datz FL: heparalion and clinical utility of
In-1 11 labeled lcukocyles. J Nucl Med Tech 12131,
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31, Datz F L , Jacobs J, Baker W,et al: Decreased sensitivity
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indetection of occultinfection. J N u c l Med
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32. Saverymuttu SH, Peters AN, Hodgson HJ, et al: 1%-
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33. Saverymultu SH, Peters AN. Lavender P, et aI: Quan-
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35.Oluwale F, WangT.Fawwaz R, etal: Evaluation of
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36. McKeown PP, MillerDC, Jarnieson SW, etal: Diag-
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38.Coleman RE, WeIch DM, Baker WJ, et al: Clinical
experience using indium-I 11 labeledIeukocytes. In
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Trivirum,1980, pp 103-118.
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experimental infectious endocarditis with indium-1 1I
labeledbloodcellularcomponents. Circulation
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41.ThakurML, Welch MJ, Joist JH,et al: Indium-Ill
labeled platelets: studies on preparation and evaluation
or in vitro and in vivo functions. Tl~ronrbRes 9:345,
1976.
42.Dewanjee M K , Rao SA, Didisheim PL: Indium-Ill
tropolone, a new high affinity pIalelet label: prepara-
tion and evaluation of labeling parameters. J Nltcl Med
22:981-987,1981.
43. Heaton WA, Harmon HD, Weich MJ, el al: In-
dium- 1 1 1 : a new radionuclide label for studying
human plalelel kinetics. Br J Huemar 42:613, 1979.
44. Thakur ML, Barry MJ: Preparalion and evaluation of a
new indium-I 1 I agent for efficient labeling of human
plalelers in plasma( 1 11-In")* (2-mercaptopyridinc 1.
oxide). J Labelled Compd Radiuphum 19: 14 11, 1982.
45.Thakur M , Gollschalk A (eds): indium-Ill Lnbeled
Nerrrropkils. Plafelets. mzd Lymphocytes. NewYork,
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4G. Wahner H, Goodwin D (eds): Ill-Indium Loheled
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 98 I Essenrials of Nucleor Medicine Science
9
Nuclear Medicine Procedures fur Monitoring
Patient Therapy
Allan H,Gobuty
One of the most useful endeavors we engage
in is LO reflect on the quality of our work. This
predisposition of lookingcritically at our ac-
complishmentshasassumedimportance in
medicine only since aboul1900 when it became
possible to routinelyperformserial measure-
ments of blood pressure, pulse, respiratory rate,
andbodytemperature.Theadvent of car-
diopulmonarybypasssurgeryandthe period
. !
.. -. ,. that followed required more accurate assessment
of the cardiovascular and pulmonary status of
the patient (1). This requirement ledto the clini-
caluse of more sensitivemethods of patient
evaluation in the late 1950s.
We expect a greater degree of exceIlence from
those who perform tasks repeatedly or who are
certified as experts. Until recently, however,
there was little notion that we should hold peo-
ple legally accountabIe for the proper perform-
ance of theirwork.This was necessarily so,
since technology hadnot yet made it possibIe to
delemine how well innovative tasks were being
performed until somecatastrophicevent took
place. For example, we couldalwaysassume
that a ship was constructed safely so long as it
remained afloat. In medicine, we may point to
[he dynamic view of chronic disease described
by Bircher (2) as another example. In that ac-
count, a long period of time is passed in a stage
referred to as compensated dysfunction. Failure
occurs afterthediseasehas progressed to the
, -
. '
stage of decompensated dysfunction which, in
the most serious instances, ends in death (Fig.
9. I). Historically, therefore, task analysis lagged
behind innovation. It appeared reasonablethat a
new idea or technique should capture the day.
-<-=
;:-
I
The thought that the new idea should be tested
againstwell-establishedmethods of accom-
plishingthe samegoal was not fully appreci-
ated, probably because it was painfulto look for
flawsand because the process of looking ap-
peared totake an inordinateamount of time.
It hasbeenobserved (3) that a significant
advance in pharmacology occurred when thera-
peutics was first correlated with clinical effects.
Therefore,itappears thatwhatwasneglected
for so long has in medicine today assumed the
importance due it. There is now a zeal for com-
paring new and old techniqueswhich more lhan
compensates for the earlier neglect. Today, ev-
erything is being tested, including the tests
themselves.Thevalue of an innovation may
now b e appreciatedbyassessingitsconse-
quences over a defined period of time. This is
accepted today as one concept of monitoring.
Authoritative dictionaries give 10 Lo 15 defini-
tions for the term. Themost appropriate for this
discussion is, "a device for observing a biolog-
ical condition or function. " In many cases, one
can monitor the effect of intermittent drug ad-
ministration, the performance of a surgical pro-
cedure, or thestate of organfunction. Used
judiciously, the results have the potential to in-
form the clinician about the stage and progres-
sion rate of disease long before clinical decom-
pensation occurs. This chapter discusses moni-
toring with use of radionuclides; i.e., how they
are being used to assess surgery, drug therapy,
organ function, and nutritional procedures. Fur-
thermore,thechapterisdesigned to place in
perspective the rationale for the use of radionu-
clidesasprognostictoolswheneverimporlant
99
 100 f Essentials oj Nrrclear Medicine Science Nuclear hredicim Procedures for Monitoring Theram I 101

100
A Complete remission bone surveys to monitor therapy of bone metas- to determinetheefficacy of anytherapeutic
tases, renal studies to monitor renal function protocol. For instance, in the treatment of thy-
I '
after transplant surgery, and radioisotope stud- roid carcinoma for which thereare several alter-
, 1
Compensaled ies to monitor changes in myocardial function natives, clinicians have sought readily available
.. .. Dysfunction duringdrug therapy.AdditionaIly, the nuclear indices of therapeutic benefits. Here scintigra-
(silent diseose) physician can use his monitoring position dur- phy has come to be regarded as an indispensable
FuncticmI
Copadty ingconsultation as a springboard to better in- prognostic tool and as an arbiter of the appropri-
and 50 - form his nonnuclear collegues about other pro- ateness of treatment (7). Thus, adequate moni-
integrity
IWl cedures that might be indicated to further clarify toringrequires a multidisciplinaryapproach
Decompensalion the clinical picture. For instance, he frequently oflen including MM inpul in which the nuclear
hasreprintsavailable as handouts to increase physician is called on to assess the attributes of
confidence in the study result.It appears appro- the scan as well as other data that may be re-
Life incompotibie
priate, therefore, to consider the monitoring quired to make a diagnosis. Figure 9.2 suggests
Y - function of NM to be a potentially significant a scheme that depicts the probable areas where
TIME AFTER DiSEASE ONSET one worthy of increased future effort on the part various members of the health careteam, in-
of the nuclear physician. cluding the nuclear physician, may interact with
Figure 9.1. Widely accepted stages in the progression of chronic disease in both previously healthy subjects The [rend today is loward more careful scru- the patientand each otherto minimize or re-
(solid line) and those wilh preexisling disease (broken line). The time frame between points A , B , and B' tiny of new and complex monitoring methods. solve such lherapeutic challenges.
represents the stage after disease onset during which prognostic monitoring has been most helpful. (Adapted This is necessary because of federally mandated
from I. Bircher: Quantitative assessment of deranged hepatic function: a missed opportunity? Sernin. Liver The clinicianmust recognize that NM may
Dis. 3:275-284, 1983.) cos1 control measures, matters related to juris- successfullybe called on formonitoring and
prudence, and the greater need to include data that the methodology is frequentlyuncompli-
that will permit useful comparisons wilh estab- cated.The clinician should also become well
diagnostic or therapeutic decisionsare at stake. appropriate and useful for a given clinical con- lished methods. Such conservatism is, in part, a acquainted with the capabilities of the local NM
Suchtestsmaybe caHed forwheninvasive dition. consequence of inadequate and misleading service. An aggressive nuclear physician should
diagnostic procedures are indicated, when ma- The literature andclinicalexperience have knowledge of bothpractical drug use and the have at his disposal a cadre of monitoring ca-
jor surgical or medical therapy is contemplated, both documented a place for nuclear medicine sequencing of palhology which occurs during a pabilities determined by the combined talents of
or when a decision must be made aboutinstitut- (NM) in monitoring. First, we now recognize a disease process. For example, in NM a patient his co-workers, their available time, the present
ing nutritional therapy. It is a complex subject. close correlation between increased awareness with suspected GI bleeding is evaluatedwith state of technology, and priorities that have been
It should appeal especially to practitioners who of how the body responds to disease and the use use of 99mTc-labeledred blood cells (RBC), and established within the service.
seek guidelines and references that will assist in of radionuclidic methods for monitoring drug, radioactivity isdetected in thecolon.Duod- Three of theimportant areas in NM today,
determining the appropriateness of using radio- nutritional,and surgicaltherap>>. Second,the enoscopy, however, subsequently identifies radioassay,imaging,andradiobiology,face
tracers as monitoring devices. choice of an appropriate NM moniloring test blood in the small bowel. The decision is then practical limitations as to the types of monitor-
depends on knowledge of how the substrate is made to intervene surgically in the small bowel, ingthat may be performed. These limitations
CONCEPT OF MONITORING IN handled by the orgaa or system to be tested. A which contradicts NM findings. It should have are technical and result from imperfectly con-
NUCLEAR MEDICINE recent review listed over three dozen ways in been known that the intravenous use of gluca- structed systems for detecting radioactivity.
Radiotracersrepresentanimpressive poten- which NM andnonradioactive drugs areused gon would have assisted in such cases (6) and Measures aimed at addressing them are continu-
tial formonitoring.Untilrecently,creative together for monitoring purposes ( 5 ) . NM mon- that repealed NM studies would have identified ously being devised. For example, as a count
thinking and the availability of personnel were itoring now assists in identifying patient non- the small-bowel bleed. The example points out rate approaches background, one may question
the only practical limitations to development of compliance with prescribed therapeutic reg- the complexity of NM monitoring of surgical whether true counts or random background vari-
moniloring techniques.There wasa growing imens. Two examples are (a)thyroidfunction and drug therapy and the rewards made in- ation is being observed. In NM monitoring, the
demandfor new monitoring methods,which testsfor monitoring thyroidmedicationcom- creasingly available by pharmacologic interven- detection of nuclear events is basic to the per-
was fueled in part by a growing legal awareness pliance and (b) gastrointestinal (GI) protein loss tion. formance of the studies. In imaging, the mini-
of the indefensibility of not judiciously using all studiesformonitoringglucocorticoidmedica- Complicationsas a result of therapyarise mumspecific activity of the tracer should be
available clinically proven diagnostic and prog- tion compliance. Life-threatening situations are when it is not possible to predict the effect on such that sufficient counts can be obtained dur-
nostictools (4). Their rapid introduction led moreeffectively dealtwith whenearly trends organ andtissuereserves.Contributionsfrom ing a reasonable performance time of the study.
initially to discrepancies, since results of two or toward organ system failure can be identified. many disciplines arerequiredto addresssuch The information obtainable from high specific
more monitoring modalities did not always cor- The intrinsic sensitivity of NM permits detec- conditions. A less-than-appropriate response to activity radiopharmaceuticals requires less
relate. There soon came recognition of the im- Lion of many abnormalities at an earlier stage therapy may result because ofan inability to countingtimeper study than that obtainable
parlance of evaluating groups of monitoring de- than is possible usingequivalent effort with adequalely monitoror evaluatethe result. A with Iow specific activity.
vices 10 determinewhichwouldbemost other methods. Examples include scintigraphic statistical labyrinth must be negotiated in order Withtheseconcepts in mind, wc can now
102 1 Essentials of Nuclear MediciueScience Muclear Medicixe Procedures for MonitoringTherum f 103

PREPARATION: the data to counts from [I4C]carbon dioxide/109 CLASSIFICATION OF THERAPIES

Prec[inicalStudies sperm. The results are presented in Table 9.1. It hlONlTORABLE WITH NUCLEAR
P,N,D canbeseenfrom thedatathat caffeineand MEDICINE
isoproterenol increased sperm metabolic ac- The outline presented in Table 9.2 provides a
tivity (except for the effect onsperm noted with general overview of the varietyof ways in which
Strategy: 5 Final
Assessment

(3
Patient
workup; i
17,900 pg of caffeine, used as a marker of NM can be used for monitoring. Knowing what
whm to Data collection
base PATIENT Adequucy of therapy, toxicity) and that propranolol decreased it dra-
Pharmowhinelic
monitor, and of monitoring to include and what to exclude is one challenge
when to Services. NP. N,NP,D,Nt maticaIly. Thus it wasshown thattherapeutic with such lists. In this regard, the large number
adjust N+,D. N concentrations (as far as can be determined) of
therapy of uses forradionuclidesastools in research
NP. WJI thethree drugs,whenplaced in conlactwith havebeen omitted because they are not clini-
Perform
ThempF:
Post-Therapy
Collection:
Data
motile sperm under theseexperimentalcondi- calIy relevant, exceptindirectly as aids in ob-
F1N N,Q tions, have effects on sperm motility that can be taining experimentaldataaboutbiologicalor
Figure 9.2. Multidisciplinary approachto the application of therapy and subsequent monitoringof the resull. evaluated quantitatively and monitored serially. chemicalprocesses.AnotherchaIlengearises
Emphasis is placed on areas of interaction with NM personnel. P, nonnuclearphysician;NP nuclear physician; To what extent these effects would manifest because of the different perceptions aboui what
D, drug specialisl; i V , nurse; hil, nutritionist. themselves in vivohas not yet beensatisfac- constitutes a relevant NM monitoring test. Im-
torily determined. A report by Zipper et al. (9), parliality and completeness are best served by
however, demonstrated that an 80-mg tablet of including tests that are offered across a world-
consider theways in which NM has fit construc- toring modalilies have been only marginally ex- propranolol is an effective conlraceptive when it widespectrum of NM clinical practice. Liver
tivelyinto the monitoring continuum. It will plored.Theircontinuedsuccessful utilization, is insertedvaginally or takenorally.Itwas function testing is included in Table 9.2 not
become apparent that NM is most useful when il however, promises 10 maintain NM monitoring found to act, in part, by immobilizingsperm for because of popularity but because it is an exam-
is providing quantitative data. within the mainstream of medical diagnosis. at least 12 hours. If evidence of the sensitivity ple of a group of tests that are of considerable
From a historical standpoinl, the introduction Althoughtheexamples citedare of in vivo of the radiometric method of evaluating the ef- interest and potentia1 importance (2). Such tests
of four NM sludies have providedthe mile- NM, there have been many practical and inter- fects of chemical substances on sperm metabo- are discriminated against because there is a
stones on which the modernpractice of NM esting recent developments in in vitro NM. For lismcontinuestoaccumulate,and if a more widespreadbeliefthatwiththepresenttech-
monitoring rests. A fifth milestone may soon be instance, radiolabeled metabolic substrates complete understanding of the relationship be- nology their utility is iimited and their use may
reached. The earliestwas the introduction of the (RMS) have been used to evahale the effectsof tween lhese test results and the fertilizing poten- constitute an excessive radiation hazard.
thyroiduptake test.Thisstudypermitted, for substances on sperm motility. Other RMS, in- tial of sperm can be confirmed, the test may
the first time, measurements of the functional cluding [14C]glucose and [14C]fructose, have prove useful as a new monitoring device. RADIONUCLIDES AS
slate of an individual organ. A1 appropriate in- also been used in other in vitro NM procedures. All of these methods provide information PHARMACODYNAMIC TRACERS
~ervals thetest could be repeated, which would For some time there has been interest in the about organ and system function, about specific The concept of utilizing radioactive tracers to
(hereby permit the documentationof changes in use of drugs for interrupting human fertility (9) aspects of bioavailability, and about the effects optimize lhe benefits from drug therapy is not
function that may have occurred as a result of to prevent implantation (10) and for determining that therapy may have on these parameters, all new. Suchpharmacokineticstudies havebeen
surgical or drug therapy. Bonescanning with their effect on sperm metabolism (1 1, 12). An of which are recognized monitoring functions. performed on animals since 1970 (13) and in
"

99mTc-labeled radiopharmaceuticals was first in vitromethod of assessingtheeffects that

usedclinically during the early 1970s. These frequently used drugs have on sperm metabolic
studies now permit serial evaluation of the pro- activity was investigated by the author with use Table 9.1.
gress of therapy for metastatic disease as it af- of dog and human semen. The purpose of this
Effects of Drugs on Sperm*
fects the involvement of osseous structures. study was to vaIidate a radiometric method of .~
More recently, the ability to quantitatively eval- assessing drug effects on sperm metabolism by Mean cpm ( ? SD)
liquid-scintillation counting of evolved I4CO,. PE or D w
uate [he effect of drug and surgical therapy on Drug per IO' S p e d Test Conml 90 Change from Conmolt
ventricular function and the assignment of cum- Semen was oblained and placed into 2-ml sterile
ulative dose ceilings for the drugs has revolu- Dosettevials.Uniformlylabeled[14C]glucose Isoproterenol 1.11 3639 (485) 2933(400) (+) 24.1
tionized NM myocardialmonitoring. Very re- was added to the samples. One of three drugs Isoproterenol 15.69 2475 (403) 1893 (567) (+) 30.8
Caffeine 170.94 2056 (252) 1871 (273) (+) 9.9
cently, it has become possible to perform serial (isoproterenol, caffeine, or propranolol) was Caffeine 317.46 3737(439) 2741 (343) (+) 36.3
studies on intermediary metabolism in the heart next added, and the systemwas allowed to incu- Caffeine 17,900.00 663 (77) 3093 (401) (-) 78.6
and brain with use of positron-emitting radio- bale for I hour at 37" C, after which the samples Propranolol 396.83 202(63) 1233 (235) (-) 83.6
isolopes. In the near future, a fifth milestone, werecounted.Differencesbetween lest and Propranolol 40.40 1501 (318) 4191(679) (-) 64.2
the ability IO target radionuclides to labe1 spe- conlrol samples were evaluated with use of the
* Value are counts per minute (cpm).
cific types of circulating blood cells, may be Student's !-test at the 0.05 level of significance. t Dah normalized to 1.0 X 109 motile s p e r d m l .
achieved. The vislas opened up by these moni- Test results were reported after normalization of $ All test values significantly different from controls ( p < 0.05).
 I04 t Essentials o j Nuclear Medicine Science NrrcleorMedicineProcedures for Monitoring Theropy / 105

humans since 1973 (14). The goa1 of the thera-
pist is to maximizedrugbenefits,andsince
intimate knowledge of biodistribution is impor-
tant €or many reasons (minimizetoxicity, evalu-
ate site penetration and biotransformation), opti-
mization of therapy requires information unique
to each patient at a specific stage of the disease.
Manaka andWolf (15) statedthat the goal of
radiopharmacokinetics is the characterization
and control of drug kinetics as much asis prac-
tical with the view toward maximizing benefits
and minimizing adverse effects. The complex-
ity of these interactions is such,however, that it
is possible to characterize only a part of drug
behavior.Forexample,belweenindividuals
there are large variations in hepatic biotransfor-
mation of drugs. Baker et al. (16) lists genetics,
environmental conditions, nutrition, drugs, and
disease as predisposing factors. In classical
pharmacokinetics,thegoalis to approximate
the biological system, with consideration given
to a series of discrete compartments, and then to
focus on the rate at which the drug enters and
exits them and the rate at which it undergoes
chemicalchange. As a practical matter, how-
ever, it has been difficult to closely approximate
actual conditions because of technical difficul-
tiesassociatedwiththepreparation of true
tracers I
To consider how facets thathavebeendis-
cussed have had animpact on NM, we may
consider how pharmacokinetic methods have
been and are now being utilized clinically. For
the most part, these have been limited to guid-
ing arterial infusion of chemotherapeutic agents
in cancer (17), the developmentof kinetic (time-
related Compartmental distribution) models
(15), and the likelihood that radiotracer forms of
drugs may be used to evaluate target penetration
andhost resistance phenomena. The purposes
of such methods are to assess:
1. the presence of collateral circulation around
the target area,
2. collaleral circulatory changes that may occur
over a specific time frame,
3. thepatency of vascuIar distribution intoa
particulararea and how h i s changes with
1."
Lllllt,
4. the extent of arteriovenous shunting in this
area,
5. whethertherehasbeenmovement of the
Theusualobjections,basedonorganand
whole-body radiation,shouldbeminimal for
patients whoserisk-benefit ratio isconsidered
acceptable.
Other examples of the use of radionuclides to
explorepharmacodynamicsmaybecited. Of
special importance today is the potential use of
drugslabeledwithshorthalf-livedpositron
emitters. In institutions in which there are pro-
duction facilities, tests of predictive value might
beperformedwhen a determinationmustbe
made about whether or not there is an adequate
drug concentration at the desired site. Also of
importance is the use of radioDharmacokinetics
for enhancing the emerging area of chronophar-
macology (19).

(E*2
Compilation of C u r k i M N o n i t o r i n g Capabilities'
catheter tip during a course of intraarterial
therapy,
6. thepotential of adjuvants(suchasstarch
RESEARCH AND SCIENTIFIC BASIS OF
NUCLEAR MEDICINE MONITORING
NM physicians frequently are presented with
microspheres) to optimize treatment effects, opportunities to participate in research and to
Rcicrence Primarily Discose-related 7. the extraclion fraction of a compound in an develop research skills. Theymay collaborate in
organortissue of interestandhowthis the design and interpretation of investigational
Brain bIood flow 46
Gastricemptying changes during disease, studies, such as clinical trials of new drugs and
Adulls 36 8. therateandextent of biotransformation diagnostictests.Thesemustbecarefully
Children 51 within a particular organ or region. planned and executed to ensure that only accu-
GI bleeding 35 rate,reproducibleinformationisadded to the
Heart As a recent promising approach 10 the indi-
pool of medical knowledge.
size Infarct 37 vidualization of drug dosages,Bayesianfore-
myocardium infarcted versus ischemic 39 Kerlinger (20) characterizes the scientific ap-
casting (18) offers an example of thetype of
with capacity
Functional use of dipyridamole 52 proach as, "a special systematized form of all
information obtainable with use of radiolabeled
tabolism Intermediary reflective thinking and inquiry." He charac-
disease Legg-CalvC-Perthes 3s drugs. Applied to drug therapy, Bayesian fore-
terizesthe scientificmethodasincludingthe
Liver function 16 castinginvolves techniqueswhoseessence is
following process:
embolism Pulmonary 42, 43 the use of both kinetic data from the patient
Prinlarlty DIU: Therapyrrlarcd Reference
abouttoundergodrugtherapy and data avail- 1. Problem-obstacle-idea-the clinician or in-
ablefromotherpatients.Thedataobtained vestigator experiences a vague unrest about
tis in treatment Antibiotic 55 from these sources is fit to an equation contain- observedandunobservedphenomena.His
measured
response therapy, with
Aslhmafunction 54 ing two terms that represent these variables. The or her objectivethen is to express the idea in
Chemotherapy, drug perfusion
in 17
goal is to use the equation to more appropriately a clear and manageable form.
response Chemotherapy, to 39
in use dipyridamole
vasodilalion,
Coronary 47 individualizedrugdosage.Themethodholds 2. Hypothesis-formulation of a conjectural
disease pulmonary Drug-induced 40, 41 promise in dealing with arbitrarydosage and statement or proposition about therelation
dosing insulin before
assessment
antibodies,
Insulin 4s sampling patterns. Its utility, however, could be between two or more phenomenaor vari-
to response
bronchiolar
inhalation,
Methacholine 44 extended to those patients about to be placed on ables. The clinician may say, "If patient A
Primarily Surgical Therapy-related Rcrercncc
therapyon whom there arenodata available continues on totalparenteralnutrition
(whichfrequently occurs). In suchpatients, a (TPN), theremay result bonedisease that
i _- Breast
cancer
treatment
prognosis,
internal mammary lymph
node
scintigraphy 49, 50 radioactive analoev ol the druev could be used to will be monitorable at an earlv statre with
'1 with use of furosemide 56 I Y
~

f_ : Nephroureteral
dilatation
x.>
2 "
~, ~'
,
, . Portal-systemic shunt,
degree of after
sclerosing
therapy 45 ~.
provide dataabout the Fraction o€ theadmin- use of NM techniques."
?I-: ,. Pulmonary
osteoarthropathy,
treatment
surgical 53 ..~.
-
istered dose extracted by a organ
specific or 3. Reasoning-deduction-deducingcome-the
I! :'
I. tissueand to show how changes in thisvaluequences of the hypothesis.Deductive rea-

lj I
i,:
f i:
j:
!:
;;'I;:
I
* For a review of pre-1482 publications, see Reference 5. may be monitored duringthecourse of therapy. soning was added to thescientific method in
106 I Essentials of Nuclear MedicineScience
the seventeenth century(21). Without it, cer-
tainbehavioralresearch problems,suchas
testing the interactive effect of TPN, bone
disease,andchanges in radioactivecount
rates, would be insoluble.
4. Observation-test-experiment--an investiga-
tion of the varidity of the relation expressed
by the hypothesis. Hypotheses are not tested
in reality; their deduced implications are.
The clinician then has the challenge of fur-
ther developing the NM knowledgebase.Al-
though all NM physicians do not have the re-
sources or opportunitytoparticipatein
scientific research, they can make a valid contri-
bution by bringing to the fore the problems that
they encounter in their practices. They may also
be involved with research activities in collab-
oration with other health care practitioners.
Much could be said aboul the importance of
precisely defined a priori research questionsand
hypotheses in the design, data collection, and
interpretive stages of new NM monitoring meth-
ads. Three characteristics that distinguish good search
hypotheses are: (a) they are declarativesen-
tences that express a relationship between two
or more variables, (b) they have clear implica-
tions for testing, and (c) the variable must be
measurable(22).With regardto our TPN il- signment of numbers to objects or events ac-
lustration, the following statement illustrates
these points:
:fl "Nuclear medicine may b e used to monitor
'I theprogression of bonediseasein patients tors
;, undergoinglong-termTPN."Thishypoth-
I esis is declarative and expresses a relationship
J betweenvariables.Thevariablescanbe
measured. The minimum criteria for a good
?! hypothesishave,therefore,beenmet.The
1
I,
power of hypotheses lies in the possible gen-
eralizedstatementsmadeaboutthemeaning
L of data that has been collectedduringthe
ourse of a particular experiment.
As important as a useful hypothesis is, a valid tionshipbetweenthe
research design or planof studycontrolsthe
investigation of the hypothesis. A good research tionship, the moreusefulthepossiblein-
design eslablishes good comparisons of the ef- ferences. Therefore, there must be due concern
fect of an independent variable and reduces the with the measurement process and its relation to
numbcr of competingexplanationsfor an ob- the concept being tesled. Similar cautions about
served result.Several research designs are ap- the need to verify the reliability and validity of
plicable for NM monitoring (23).
1. Static stimulusdesigns (SSD). All units or
members of the selected patient population
are exposed to the same manipulation (ther-
apy), so-called one-shot studies. Monitoring
is performed once before and once after the
manipulation.
2 . Nonstaticstimulusdesigns.Someunits or
members of the selected patient population
are exposed to a zero amount of a manipuia-
tion (therapy); the balance are exposed to a
non-zero amountof the manipulation. Moni-
toring is performed as in SSD. This is the
most frequently used design in NM.
3. Mixed designs. These consist of some com-
bination of the designs discussed previously.
4. Serial designs. Patients are exposed to ma-
nipulations(therapies) as describedpre-
viously. Monitoring is performed, however,
more than once before andlor after exposure
to the manipulation. This type includes the
so-called crossover design.
The most appropriatechoice of a NM re-
design will result from knowledge o€ the
possible extraneous sources of variation that
may occur during data collection (measure-
ment).
The scope of measurement includes the as-
cording to rules (24). For NM monitoring, this
definition makes sensebecause in everycase
events (counts)are measured. In reality, how-
ever, NM measures events that are only indica-
of the characteristics of events, i.e., labels
or symbols. For example, Spielberg et al. (25)
reported the assessment of toxicityto human
lymphocytes and of changes in organ distribu-
tion as a result of increasing plasma concentra-
tions of two analgesics.Theseauthors devel-
opedanobservableresponse(changesin
counts) to the underlying unobservable and di-
rectlyunmeasurableviability of thelympho-
cytes.The measurement focusedonthe rela-
observableresponse and
the underlying concept. The stronger the rela-
measurements taken as part of a NM monitoring
Nuclear Medicim Procedures for Muniloring Theramp
design may be cited. In this regard, reliability
andvalidityarematters of degreefor which
exactness is an unachievable goal.
Whentheproposed NM studyisone of a
battery of tests for a particularprocess,with
what weight should it contribute to a positive
prognosis, a negativeprognosis, or arequire-
ment for furthertesting?Thatis,whatis the
prognostic effectiveness of the proposed study?
Sequentialdataanalysismaybeemployed in
order to pennit early termination of the study if
the new method quickly proves to be superioror
inferior. In these cases, criteria must be estab-
lished before the study is begun such that it may
be terminated at the point when, with the pre-
assigned level of confidence (say 95%), there is
a significant difference in efficacy between the
twostudies as measured by x2. it shouldbe
emphasized that the investigator may either be
cumulation,tabulation,categorization, review,
and analysis (interpretation) of the data. Each of
these processes has its associated mathematical
concepts and methods of measurement, most of
which are beyond the scope of this chapter. A
recent review of these subjects which is perti-
nent for NM purposes has appeared (26).
As theforegoingdiscussionimplies,the
manyfacets [hat define the appropriateness of
new NM studies should be dealt with on more
than one level. It is one thing for a clinician to
justify to various committees the proposed use
of a new NM study on the basis that there is a
clear need for it and that statistically it stands in
a favorable light when it is compared with pres-
ent methods. Other factors should be taken into
account, however, so that more fundamental
committee concerns will not delay the study's
inauguration. These are listed in Table 9.3 and
should be considered before human use com-
mittee authorization (26) is sought.
When the basic design and method of execu-
tion of a new NM monitoring project have been
dealt with and there has been appropriate con-
sideration given to the utility of the study from
all possible perspeclives, themost difficult parts
of developing and exccuting the research pro-
tocol are behind Ihe investigator.
I 107
Table 9.3.
NM Monitoring Checklist for Human
ExperimentationCommittees
Evaluate the need for the proposed study.
Evaluate the efficacy of the proposed study (statis-
tics). the appropriateness
Consider of the reference popula-
tion and the relation between the technicaI sen-
sitivity and specificity of the test. Consider also
the "noise levels," Le., the false positives and
false negatives.
Evaluate the testing value. How effectively will the
new lest justify its cost in relation to established
Joint probability, i.e., expected proportionof cor-
tests?
rectly diagnosed subjects (true positivesand true
negatives),
Cost values, i.e., retesting cost versus the risk of
treating a nondiseasedsubject;costassociated
with the risk of depriving a diseased subject of
treatment; costof the time delay associated with
The final phase in the process is the prepara-
tion of a report to disseminate the datato others.
A good report will successfuully address the
facets of (a) organizing thoughts logically and
(b) expressing thoughtsclearly. As apractical
matter, il often is most difficult to deal properly
with the organization of the report. In this case,
clear concise advice to authors may be foundin
the Corcncil of BioLogy Editors (CBE) Style
Manrial (27), which is used as a stylebook by
many biomedical journals. Further information
about writing final reports, as well as a checklist
may be found in Zellmer (28).
COST EFFECTIVENESS OF NUCLEAR
MEDICINE MONITORING
Medical care is different from other goods
and services. The deep historic commitment to
health careworldwide is reflected in institu-
tional arrangements thathave encouraged its
growlh and development. These include income
tax deduclions for medica1 expenses and insur-
ancepremiums and governmentfinancing of
heahhcare for the poor andelderly. Broadly
speaking the differences can be grouped under
the following headings (modified from Ref. 29):
108 t Esserltinls of NuclearMedicineScience
1 . social concern attached to the need for serv-
ices;
2. positionofproviders as determiners of the
level of patient care,
3. modifiedprofit-seekingbehavior of pro-
viders;
4. risks associated with random occurrence of
illness;
5. lack o€ knowledge on the part of consumers
about the services;
6. free-market modifying effects of provider li-
censure.
These differences help to explain the unique
organization of the medical care industry with
its associated governmental and nongovemmen-
tal restrictions and the fact that health care has
come to represent a heavy financial burden for
the private sector. The uniqueness in health care
thus encompassesalllevelsof planningfrom
federalexpendiluresto bedsidedecisions. A
focus on bedside costs is thesubject of this
section.
Itis noteworthythat thereismore at stake
thanthe new procedure’simmediatecost.Its
cost must be considered as part of a continuum
of servicesdesignedforeachcase,sincethe
results of anyprocedureanditsperceived
efficacy affects the course of diagnosis and
treatment. The results of a well-estabrished, ap-
propriately timed and performed monitoring
study may convince the clinician about the pa-
tient’s condition. No other tests may be needed.
As laboratory service costs increase,it becomes
imperative to ensure wise spending of the health
care dollar. The paramount expense is the cost
of tests. What makes a good test? Most often
there is a trade-off between operational proper-
ties (ease, speed, cost) and conceptual charac-
teristics (reliability, validity, effectiveness, and
value). A selecl few tests are best by both crite-
ria.
For any new NM monitoring study, the ele-
ments of cost and their associated frequencies
are (a) the cost of retesting or therisk of treating
a nondiseased subject(falseposilive), (b) the
cost associatedwilh depriving a diseased sub-
ject of treatment (false negative), (c) the cost
causedbythe time delay associated withper-
forming a lest and reporting its results, and (d)
thecostassociatedwiththeradiationdose.
NuclearMedicineProcedures
These valuesmay beexpressedasshown in 7. For each candidate test, substitute these val-
Table 9.4 (30). ues into Equation 9.1 to compute the cost of
The five outcomes, F, N , L , D ,and X , are the test. Thetest of choice will be that which
assumed to be mutually exclusive categories of gives the minimum total cost.
the testresult. The value, of the testmay be
represented as One difficully with this sequence lies in the
fact that there is an absence of weighing of the
X
V = D i- + P,(1 - R)F + P,(R)N + PLL terms in Equation 9.1 for such things as human
Equation 9.1 suffering, societal burdens, and the recent ad-
vent of home health care and hospice services
The quadralic equation which have made home recuperation an appea1-
P, = A + BP, 4- CPF2 Equation 9.2 ingalternativetoprolongedhospitalization.
One strength of the sequence is that health care
maybeusedtoapproximatethe relation be-
providers are encouragedtobe more alertto
tween FA,and P , . The test is optimized when discovering adverse effects of therapy early in
PF = ’ - F(l - R,
2c Equation 9.3
the NM monitoring sequence. There wouldthus
result in a reduced incidence of complications
and more timely hospital release.
Implementation of the test selection method In conclusion, this discussion has several im-
isaccomplished by performing the following plications for health care economics in general
steps: and for NM monitoring in particular:
1. Estimate D ,F, N , L , and X. 1. Strategic planning ismore important now for
2. Estimate R , clinicians.From the presentcost-contain-
3. Set the desired technical sensitivity and spe- rnent climale (for areview of 1983 Medicare
cificity trade-off as shown in Equation 9.2.
legislation,seethe Federal Register, Sep-
4. Determine the optimum P, fromEquation
tember I , 1983, p. 39746ff),moreag-
9.3. gressive economic competition for new tests
5 . Compute PA, fromtheoptimum P, (use will likely emerge.
Equation 9.2). 2. Directors and managers will keep closer tabs
6 . Estimate P,.
on operational expenses.
3. Clinicians will have lo develop their political
skills.
Consideration of economic factors will help
maintain NM at the forefront of monitoring
services in medicine (see Table 9.5).
EFFICACY OF NM MONITORING
COMPARED WITH OTHER METHODS
The advent of the concept of monitoring, its
subsequentacceplance,anditsinfluence on
pharmacology can be attributed to radioisotope
methodology. Earlier in this chapter, we dis-
cussed the use of pharmacodynamic tracers.
Studies correlating serum drug concentration
with therapeutic effect were initially performed
with use of ullraviolet (UV) spectrophotometry
and, later, with gas-liquid chromatography
(GLC). Therequirement for large samples for
use of UV spectrophotometry and the complex-
ity of GLC equipment tempered advances in this
for Monitoring Tlteraml t IO9
Table 9.5.
Economic Factors to Be Considered When Any
New NM Diagnostic Procedure Is ImpIemented*
Personneltrainingrequirements: How extensive are
they?
Protocol formulation:Should protocol be designed to
maximize test utility?
Projected frequency of use of the test: Will the fre-
quency justify developmental costs,or is the test to
be viewed as an “orphan”?
Maintenancecosts of theprocedure: What a e the
projectedcosts of qualitycontrolmeasures
signed to maintain efficacy?
de-
Patient safety during the test: Will test performance
jeopardizecare thatthe patienlwouldotherwise
receive in an emergency situation?
What will be replaced by this study? The queslion,
“How will this test complement others,” may no
longer be appropriate.
Patient cooperation: Can the test be successfully per-
formed with minimal patient cooperation?
Goal definition.
Likelihood of future third party payment.
Appropriateness of the setting:Inpatient or outpa-
tient? In thefuture,outpatientsettings may be
most appropriate for instituting new tests.
* If the answers to two or more of these factors
reflectpoorlyontheproposed test, there may be
difficulty in justifying its use.
area. Radioimmunoassay permitted quantitation
in microvolumes of serum. The complexity of
the methodology, however, has limited its wide-
spread application.
Whenthereare choices for monitoringdis-
ease or the results of therapy, there arises aneed
to compare modalities. The ability to select the
most appropriate monitoring tool from the avail-
able armamentarium can thus be preserved.
When, for instance, information about hepatic
blood flow is required, an indicator infusion and
extraction technique should be considered (31).
Drugs withhigh first-passextractionmaybe
usedwhen informationaboutportalsystemic
blood flow isdesired.Finally,radioisotope
breath tests provide useful information about the
metaboliccapacity of the liver. Theneedfor
appropriateselectioncriteriaamongsuch
closely related modalities may not be satisfiable
when political or economic factors interfere or
when there is a stong bias in favor of one tech-
nique.
 110 I Essetftiols of NuclearMedicineScience Neclenr MedicineProcedures .for Monitoring Therap f I 1I

If such obstacles can be overcome, what fa- tainty stems froma lack of reliable information. ested reader is referred lo chapters dealing more into the target and decrease of radioactivity
vorable factors should NM possess in order that For instance, it is not known whether doses of specifically with radiopharmaceutical quality frombackground are describedbyfirst-order
serious consideration will be given to starting y- or x-rays of 100 mradlyr are detrimental to and its effect on imaging and laboratory proce- kinetics and then to change Equation 9.4 to the
. clinical trials? man the whole organism (32), since there are dures. The readershould be reminded, however, more familiar form,
many factors that have made risk determination of the absolute importance of using documented
I - Preclinical Testing with Appropriate Models for low-dose, low linear energy transfer (LET) high-quality radiopharmaceuticals in the most
The eliminationofdifficult-to-controlvari- radiation difficult. These include uncertainty appropriate settingduringthepreclinicaland
ables will serve to satisfy the expectation that about the shape of the dose-response curve for clinical stages of evaluation of a new NM proce- Since rg = 4 minutes (approximate half-time
results can accurately predict the success or cancer induction, the effect of age, the masking dure for monitoring. for liver extraction of blood radioactivity), and
failure of later clinical trials. The efficacy of a effects of theenvironment, andthe genotypic Probablynowherehastheimportance of since l A depends on the volume of blood being
NM study and the way in which clinicians view effect on susceptibility to injury.Therisk of high-quality, freshly prepared radiopharmaceu- lost at the bleedingsiteand so maybe dis-
test results may depend on the adequacy of the genetic effects from low-dose, low LET radia- ticals been as effectively demonstrated as in the regarded here at 10 minutes, it can be seen that
model used during preclinical trials. In most tionhavealsobeendifficult to measure. It is use of 99mTc-labeled sulfur colloid and 9 9 m T ~ -there will be 3l.'Y1 or 7 times as much back-
cases,modelselection presents seriousprob- estimated from animal datathat 1 rem of partial labeled RBC for moniloring the results of sur- groundradioactivity at 10 minuteswhenthe
lemsbecauseofquestions raisedabout rele- exposure throughout the general population will gical and pharmacologic treatment of GI bleed- preparationcontaining 3% radiochemicalim-
vance. For example, a suggestion to use normal result in the first generation in an increase of ing,especially of the lower GI tract (35). In purity is used. Furthermore, because of the
human plasma at 37" C as a suspending medium 5-75 additionalseriousgeneticdisorderslmil- those sludies,sincebleeding may be transient asymptotic nature of the line describing the de-
when the stability of a radiopharmaceutical is lion liveborn offspring. Radiation-induced and the rate of blood loss may be low (less than crease in background radioactivity, it may never
being tested wouldevoke minimalcriticism. transmitted geneticeffects, however, have not 1 mlhnin), an adequatecontrast betweenthe be possible to achieve a comparably low back-
However, testingthe efficacy of a modelfor been demonstrated in humans, and itis not bleedingsite andthe background is essential. groundradioactivitywiththe 3% product.
inflammation is more likely to draw criticismno expected that usefulinformationwill soon be The relationship between uptake of radioactivity Some may observe that if thereis substantia1
matter which of the available models is chosen. forthcoming. at the bleeding site and decrease in background bleeding at thesite of thedefect,therate of
The difficulty arises because of theneedto The question of leukocyte damage resulting radioactivity with elapsed time canbe described disappearance of background becomes insig-
identify the relative contribution of nonspecific from NM studies has been addressed (33). It can by use of the following rate constant: nificant. Such an argument, however, disregards
uptake due to increased blood flow. Of the avail- be concluded from the reports that L1lIn-oxine one strength of this procedure-the ability to
able choices, early chronic osteomyelitis seems maycauseaberrationsintissuedistribution detect changes in slow but significant GI bleed-
most appropriate,since blood flow complica- when these leukocytes are compared with non- ing and to monitor the results of therapy over
tions are largely eliminated. radiolabeled leukocytes. The clinical impor- where dNA/& and diVBtdt represent the rate of long periodsof time with use of a minimally
There will be even more difficulty on both lance of these cellular effects, however, has not change of radioactivity at the bleeding site and invasive procedure.
scientific and moralgrounds, however, when been placed in perspective against the rapidly in theblood background, respectively. There- Other examplesof the importanceof optimiz-
the clinician is faced with the need to determine increasing use of l1]ln incell-labelingproce- fore, the absolute conkast, C, is a function of ing [he characteristics of the radiopharmaceuti-
lo what extent a new chernicai or a series of its dures. The problem will no1 go away when, in these rates n~ultiplied by the elapsed time after cal could be included here. Baker et al. (1 6)
homologs is effectivein monitoring the progres- the near future, cells can be labeled in vivo by injection of the radiopharmaceutical. The rates has, for instance, provided a list of 12 charac-
sion of necrotic tissue in patients admitted to the specifically targeted radionuclides, since the ef- may be closelyapproximatedin an animal leristics possessed by an ideal breath test sub-
emergency room as a result of electrical injury. fects on cell f u n d o n are believed to be caused model by counting the radioactivityin each area strate for measurement of hepatic function (see
Symposia that address the challenges associated mostly by the radioactivity, not so much by the over some period of time. Table 9.6). Of these characteristics,adequate
with this aspect of NM monitoring have been cell isolation procedures (34). This information makes it possibleto demon- qualily control of the substrate (the radiophar-
convened (Society of Nuciear Medicine Annual Absenl from these studiesare data that would .. strate theusefulness ofa radiopharmaceutical maceutical) is essential. If even a small fraction
"

Meeting, 1982) anda publicationwhich ad- relate the cellular effects of radiation to short- that has minimal amount of radiochemical con- of the substrate is a radiochemical contaminant,
dresses this topic recently appeared (31a). It is a andlong-termeffectsonorgansandindi- tamination. In the case of ""Tc-labeled sulfur extrahepatic metabolism may occur, which ren-
focus of our attention and a subject of impor- viduals. What should be remembered is the no- colloid, since a normal liver removes radiocol- ders the test useless as a measure of liver func-
tance in other areas of our society. In the milieu tion that some tissue damage probably occurs loid from the blood at a rateapproximately tion.
o€present ethical constraints, properly modeled during the course of these studies. So long as equal to the denominator in Equation 9.4, and
preclinical [rials will promote authorization for whole-body and crilical organ doses remain be- since insignificant amounts of unreacted 9 9 m T ~ PITFALLS AND PROBLEMS IN NM
human use, while those which are faulty will be low therisk-benefit threshold, any proposed from the radiopharmaceutical wiIl be removed MONITORING
set aside. (See also Chapter 22.) NM monitoring study should be acceptable for from the blood during the firs1 10 minutes after Even if it were possible to limit one's practice
human use. injection, it is possible to predict the difference toasingle entity, such asthestate of renal
Low Radiation Doses in effectiveness between a radiopharmaceutical function after renal transplant surgery, effective
Thequestion of radiationriskinvariably Radiopharmaceutical Effcacy with 1 % rree pertechnetate and one containing monitoring would be adifficulttask for NM.
arises when the use of radioisotopes is proposed Much has already been written in this volume 3% free perlechnelale. It is necessaryonlyto These difficulties arise because it is not possible
as Dart of a new monilorine device. The uncer- aboutradiopharmaceutical efficacy. The inter- maketheassumption thatthe rates of uptake to effectivcly characterizepatients into broad
112 1 Esselnials of Nrrclear Medicine Science Nuclear MediciueProceduresfor Mof1iroring Therun> I 113

Dealh
Table 9.6. which may form the basis for study protocols.
Characteristics of an Ideal Breath Test Substrate for The omitted information is unknown to those
Measurement of Hepatic Function (Adapted from who try to duplicate the reported technique, and
A. Baker et aI.: Clinical utility of brealh tests for therefore, lengthening of the time required for
hepatic function assessment. Semin. Liver Dis. the study to come into clinical use may occur.
3:318-329, 1983)
The gastric emptying studies recently reported
Cleavage of thelabelistherate-limiting,directly byMalmudetal. (36) are oneexample. AI-
measurable step though the article remains an important contri-
Liver melabolism only bution to the NM literature, there is no mention Suboptimal
Little or no pharmacologic effecl by the substrate in it of theimportance of patientmovement (Dealhl
Rapid metabolism
Rale of excretion appropriate lo permit timely sam-
duringthestudybetweenperiods of data ac- 0.3 I 3 to x) 100
dipg ( 14C02) cumulation.It would bereasonable toexpect
CHRONOLOGIC AGE Iyeors 1
Negllglble binding to plasma proteins some clinicians IO perform the entirestudy with
Safety (toxicity, radiation safety) the patient supine. Results in such cases could Figure 9.3. Result of a given therapeutic procedure for a serious disease on subjects of increasing age. The
Infinite dislribution in total body water deviate greatly from reported literature values, czrrwd line represents the expected effect over a range of palient ages.
Low hepatic extraction efficiency
High water solubility
and some reconsideration and reflection would
Absorption rapid and consistent be necessary before further trials to obtain ac- ~
~.
.I.~_.
ceptable data would b e attempted. Difficulties .. theselectedtest cost effective? (d) Does the 7. Sisson J: Applying Ihe radioaclive eraser 1-131 to ablate
such as these should be resolved by the pub- selectedtest stand on solid experientialand/or normal thyroid tissue in palienls from whom thyroid
categories of disease and hearth, If one attempts lisher and the author before publication. factual ground? (e) How can the data obtained CA has been resected. J N d Med 24:743-745,1983.
to base amonitoringpractice on the basis of 8. Ganalra R , Buddemeyer E, Deadhar M, el ab Modifi-
. ~ _ best be handled?
~ cation in biphasic liquid scintillation vial system for
disease diagnosis, difficulties quickly arise be- SUMMARY ? >
. ~~-
"
=
~~.
~
.
__
. The widespread acceptance of these monitor- radiomeby, J N Med
~ 21:480-483,
~ ~ 1980,
-_
~- .
~-
~

cause of factors that may not have been consid- The demands of present biomedical lech- <:
" ~~
~
~~ ing tests indicates that the available rewards are 9. Zipper J, Wheeler R, Potts D. Rivera M: propranolol as
9-
ered relevant. A list of factors that can interfere nology are not trivial. Such technology has c
=+
..
". ~

greater than the demands Dlaced on us in using a novel,

effectivespermicide:preliminaryfindings. Br
with NM monitoring is included in Table 9.7. placedunaccustomeddemands on clinicians.
The data in Table 9.7 imply that if monitoring NM has been no exception. A large number of
in NM is to be effectivee:theclinicianmust new tests which havethe potentia1 for contribut-
pause before beginningthestudy to consider ingto patient management in ways unknown
1
~
~-
~-
.c
"=
~.
_
.-~~
_

1 1 , Gobuty A, Cameron W, Non-destructive radioassay of

until recently are available. _. ACKNOWLEDGMENTS
how each of the listed factors may affecthis _.
~
~.
z
. .= sperm viability (abstract). J N d Med 19:722, 1978,
.~
= -~~~

perception of the outcome. As an example, the This chapter was designed to provide as- z= ~~

.: The
author is grateful
to Stephen E. Long,
1 2 . Ruzevich M: A radiometric method of evalualing the
,~

effect of patient age on the results of a therapeu- sistance in testassessment withlhefollowing effects of isoprolerenol, propranolol and caffeine on
-? _ ~ :
I"
M . D . , Baylor
College of Medicine,St. Luke's sperm melabolism. Masters Thesis, University of Knn-
tic procedure is shown in Figure 9.3. It is ex- temporalsequence: (a) Whatquestionscan -~-
-.
~- Episcopal Hospital,
Houston, TX, for review sas, 1981.
these tests answer? (b) Which test appears to be
~

pected that not all patients will be in a position 3"

"-~
1 - ~ and technicalassistanceand to Linda Watts for 13. Tolh-Allen J: Radiopharmacokinelic studies in mice.
to undergo equally aggressive therapy. Indi- most appropriate for the question at hand? (c) Is , .
~-
"

-~
"~ manuscript
preparation. Doctorate Thesis, Michigan State University. 1970.
a i

vidualization of both drug dosage and surgical "

14. De Conti K, Tofmess B, Lange R, Creasey W : Ctinical
intervention are routinely practiced in both med- and pharmacological studies with cis-diaminedichloro-
Table 9.7. plalinum (11). Cancer Res 33: 13 10- I31 5, 1973,
icine and surgery. This should beappreciated in ~~ REFERENCES
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~. 15. Manaka R, Wolf W: Cisplatin: Current S~Q!US urd New
NM also. Figure 9.3 might appear to b e mis- '.
~

~"
~-
Performance of NM Monitoring Studies I . Del Guerico L PrincipIes of Surgery. New York, Developmenrs. New York, Academic Press, 1980, pp
:-
~.
leading because the important differences be- McGraw-Hill, 1979, p 533. 271-283.
2--
1

tween youth and age are the kinetics of meta-
bolic processes andorganfunction.Because
these are to be considered norma1 variants, how-
ever, the validity of the figure becomes appar-
ent, since disease is listed separately among the
factors that can interfere withNM monitoring in
Table 9.7.
A difficulty with some mulliple NM monitor-
ing procedures, in which all studiesmustbe
performed identically, involves information that
is uninlentionally omitted from journal arlicles
Age
Sex
Abnormal metabolic and physioIogic variants
Incompletely willen journal articles
Concurrent food and drug intake
Lack of appropriatcness of what is being monitored
Di~ficolty in obtaining informalion
Statistical difficulty
Absence of quantiriable variables among subjects
Inadequate communication with physicians
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and pa-
Presencc of disease
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_,

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"
Pharmacological interventions in nuclear excessivelevel can act on the pituitary gland to
r
.
"

27. Council of Biology Editors: Corrncil oJBiology Edirors therapeutc change in portal-systemic c~rculat~on inves- .~
"
~~
=~
.~
medicine studies havebeen in practicefor shul
a off the release of TSHwhich, in turn,
Sryle Murzual, ed 4 . Arlington, VA, American Institute ligated by TI-201 per rectal administration.JNucl Med 5"
~.
~

longtime.Thetriiodothyronine (T,) suppres-diminishes the thyroid activity. The T, levelin

"
>-
of Biological Sciences, 1978. 2 5 ~ ~ 9 71984.
, .~
-" sion, thyroid-stimulating hormone(TSH)stim-normalpersonsis 0.2-0.3 pg1100 ml of serum.
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.-_
-i

common examples of well-established

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,~
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3 1 a , Lambrecht R , Eckelman W: Aninlal Models In Radio- "-
~

in insulin-dependent diabetics before insulin treatment. c -

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Iymphoscinligraphy in palients with breast cancer. Ra-
diology 147:845-848,1983.
50. Ege G . Elhakim T The relevance of inlernal mammary
lymphoscintigraphy in the management of breast carci-
noma. Clin U w o l l0:3,1984.
51. Rosen R, Hall W : Anatysis of gastric emptying studies
in a pediatric population. J Nucl Med 24:p33, 1983.
52. Kowcy P, Friedman P, Podrid P, et al: Use of radionu-
clideventriculographyforassessment of changes in
myocardial performance induced by disopyramide
phosphate. Am Heart J 104:769-774, 1982.
53. Lopez-Majano I, Britt T: Pulmonary hypertrophic 0 5 -
teoarlhropathy:itsmodificalionandtherapy. Ef?rJ
A'ucl Med 7419-421, 1982.
54. Chopra S, Taplin G , TashkinD: Imagingsites of
obs~ruction and measuring function response to therapy
in asthma. J Nucl Med 18606, 1977.
5 5 . Graham G , Lundy M,Frederick R, el a\: Predicting the
cure of osteomyelitisundertreatment. J Nucl Med
24:llO-113,1983.
56. Koff S , Thrall J, Keyes J 11: Assessment of hydro-
ureteronephrosis in children using diuretic radionuclide
urography. J Urol 123:531-534,1980.
entiate the information obtained from conven-
tionalnucIearmedicinediagnosticstudies.
Pharmacologic interventions involve the admin-
istration of a specificdrugbefore,during, or
after the administration of radiopharmaceutical
for a given study. Thechange in information
due to intervention of the drug offers clues to
differentiatingvariousdiseaseconditions.
These changes can be brought about by phys-
iologicinterventions also, e.g., exercise in ra-
dionuclide ventriculography. In the latter inler-
ventions, the physiologic functionof an organ is
enhanced or decreased by physical maneuvers,
and the changes observed can be used lo differ-
entiate various disease conditions.
THYROID
Triiodothyronine
Triiodothyronine (T,) is a hormone produced
by (hethyroidglandthroughiodination of
tyrosine. It is bound withinthestored thyro-
globuIin of the intrafollicular colloid. It is liber-
ated by enzymaticproteolysisinloblood cir-
culationwhere i t isboundspecificallyto
proteins. The serum level of T3 is governed by
the TSH secreled by the pituiiary gland, and an
thesis in the thvroid glands, soon after [he inlrn-
duction of the yodineuptake test for the thyroid,
hom~onalmanipulation was employed to com-
plement the normal iodine uptake test in order
to delineatefunctionalstates of thethyroid
gland.
The T, suppression test is one of several hor-
monaf maneuvers thatinvolves adminisiration
of T3 in order to determine h e autonomy of a
functioning hot nodule or a diffusely enlarged
gland. In thistest,aninitial24-houriodine
uptake is obtained, followed by administration
of 75- 100 p g of T, in three divided doses daily
for 7-10 days. The residualactivity is deter-
mined on the eighth day, and then a repeat 24-
hour uptake is obtained after correction for re-
sidual activity. Innormalthyroidglands,the
repeat 24-hour l3II uptake value falls to 50% of
the presuppression value or lower. The adminis-
trationof exogenous T, produces a negative
feedback to the pituitary which, in turn, results
in cessation of TSHproduction and release.
This diminishes the thyroid function; hence
there is less l 3 I I uptake. Most, if not all, non-
toxic goiters suppress normally. Failure of thy-
roid uptake to diminish by more than 50% indi-
116 I Essentials of Nuclear MedicineScience IniervelLlionaI Studies in hkclear Medicine / 117

catesthat thetissues are functioning autono- phylacticreactions(mostlyallergic) in patients dexamethaso

technique
sion is used CARDIOVASCULAR SYSTEM
mously but not under the influence of TSH (7, (12). ( 1 9 , 2 0 6 Z e suppresses activity of\ DiDvridamok
8). Such autonomy is observed in patients with Potassium Perchlorate
hyperthyroidism produced by diffuse hyper- available in yellow, crystal-likepowderthat is
plasia ( ~ or ~by a toxic
~ disease) ~ nodule~ ~ The potassium
g perchlorate test is useful for tivity of the zona glomerulosa for aldosterone slightly soluble in waterandvery solublein
( ~ l disease)
~ or
~ in patients
~ ~ with~ eu- ’identifying
~ congenital or acquired organifica- production (3). Normal adrenal uptake is totally alcohol. It increases coronary blood flow pri-
thyroidautonomousnodule, It should be noted
that since T, produces such side effects on the
tion defects in thethyroidgland.In
suchasHashimoto’sthyroiditis,thethyroid
diseases suppressed for 5 or 6 days with dexamethasone.
In this test, 4 mg dexamethasone is admin- -marily by a selective dilation of the coronary
arteries, without significana alterins the sys-
heart as arrhythmiasand angina, the T, suppres- glandmay trap iodide but not OrganifY be- istered dailyfor 2 days prior to injection of temic blood flow (22). It increases coronary
sion test should be perfamed on cardiacpa- Cause of an uncoupling Of the trapping and [1311]-NP-59and is continued after injection un- sinus oxygen saturation without significantly
tients with caution. organificationmechanisms. In thesepatients, til imaging is cornpjeted. Adrenal scintigraphs changing myocardial oxygen consumption. It is
The T, suppression test has been largely re- perchiorate, as an anion, successfully competes are obtained serially between I and 5 days fol- mostly excreted via the bile into the feces. No
by homone (TRH) with iodide for the binding sites in the lhyroid lowing administration of NP-59 (19). In patients specific contraindication has been reported. Its
infl,sion test, This lest is relatively less time- gland and displaces nonorganified iodide from with aldosteronomas,earlierunilateraluptake usual side effects are headache, dizziness, and
consumingand requires no administration of the gland (13-15). normally is seen on the side of adenoma, with weakness. Intravenous dipyridamole may de-
radioactivity. The method involves administra- Potassium
The Perchlorate test an little ornoactivitynotedinthecontralateral creaseblood pressure and increase heartrate
{ion of TRH and then of TSH pro- initial oral administration of a rracer dose of I3’I gland (Fig. 10.1). On the other hand, patients and cardiac output due to dilation of systemic
c~uctionin hyperthyroidpatients,This pro- andsubsequentdetermination ofa baseline with proven bilateral nodular hyperplasia have resistancevessels.Dipyridamolemaycause
cedureallows assessment of gland autonomy iodineuptakeat hours. Then, at least grn shown earlyuptake in both glands by 5 or 6 vasodilation by the hydrolysis of cyclic AMP by
without the administration of T, to patients who (600 mg for children) of potassium perchlorate days after NP-59 administration (lg-21). inhibition of the enzyme phosphodiesterase or
may already be thyrotoxic (9). is administeredorally,and half-hourlyiodine
uptakes are measured for the next 2 hours. In
Thyroid-stirnulaling Hormone normal
patients, the iodine uptake after per-
Thyroid-stimulating hormone (TSH) is pro- chlorate administration is not altered, In patients
ducedby thepituitaryglandand stimulates all with organificationdefects, however, the Per-
of the thyroidenzymaticprocessesfromiodidechloratedisplacesiodidefrom the thyroid
trapping to honnone secretion. T ~ U Sits effects gland,andtheuptakevaluefalls at least
on thyroid function can be evaluated at almost 10-15% belowthe 2 - h baseline ~ value-
any level of exogenous adminisIralion. It is ADRENAL GLAND
available as a lyophilized powder that is soluble
in saline, It retains its potency in solution for at Dexamethasone
least 2 weeks if it is refrigerated. Dexamethasone is a synthetic
adrenocortical
The TSH stimulation testhas been usedto steroid that is used for therapy in adrenocortical
differentiate primary hypothyroidism fromsec- deficiency stares;it is alsoused as an anti-
ondaryhypothyroidism (10, 11). The test isinflammatoryagent.It is available inwhite,
performed by first obtaining a baseline 24-hour odorless, crystalline powder form and is insolu-
radioiodine uptake, followed immediatelybyble in water. Dexamethasoneisreadilyabsorbed
intramuscularadministration of 5-10 U of fromthegastrointestinal tract.
bovineTSHfor 3 days.Theradioiodine uptpke Cholesterolistransported,esterified,and
is then repeated on the fourth day. Normally, the synthesized into various adrenocortical steroids
latter uptake value is more than 50% above the and stored in the adrenal cortex whose function
baseline. In secondary hypothyroidism, there is is governed by the anterior pituitary adrenocor-
a defect in TSH production bythe pituitaryticotropic hormone, ACTH. Therefore,adrenal
gland, and the thyroid gland responds to exoge- scanning has been successfully performed with
nous TSH. On the other hand, in primary hypo- use of 19-[~3~I]iodocholesterol (16, 17) and later
thyroidisnl the defect is at the thyroid level, and with the superior agent, 6P-[’3’I]iodon~ethyI-
the gland does not respond to either endogenous 19-norcholesterol, NP-59 (18).
or exogenous TSH. Hyperaldosteronism
can b e caused by both
In practice, the TSH stimulation test is no1 hyperplasia or adenoma of the adrenal gland. In
very common. Bovine TSH may induce ana- order to differentiate between the two states, the
 : 8.~
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:;:$ j
T r,:
i >y :
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,
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I 318 I Enentinls of Nuclear Medicine
Science 7
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Interver1liolml Smdies irr Nudeor Medicine / 119
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* .
by inhibition of adenosine deaminase in the observed
a 60% increase in '*'Tl concentration ._-.- vasodilation with dipyridamole.
Demanpeat et the coronary blood flow and the myocardial
1 .
,~
"i blood, which thus allows accumulation of ade-
nosine, potent
a vasodilator (23).
in the left ventricle. Gouid et aL (25) compared
the effect of dipyridamole with that of treadmill
_~

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.=-
..
i

- ,~
1

al. (28) and Josephson el al. (30) found intra-function (34, 35). Inotherwords,these
venous dipyridamole to be a reliable alternative determine how a patient's coronary vessels
and
tests

p i ..~- ~~

Because of its vasodilatingeffects on coro- stress on scintigraphywith ?''TI. At an intra- ., the for20'T1studies
to exercise in accuratefunction
de- cardiac will respond to increases in
i -. L,
i
naryarteries,dipyridamolehas
myocardial scintigraphy with 201T1
beenused in
to differenti-
venousdose of dipyridamole of 0.14 rngkgl
min,given 4 minutes prior to administration of
-__
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-
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~

tection of coronaryarterystenoses. All of theseoxygendemand.Theunderlyingprincipleis

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<%
studies have shown that dipyridamolecould re- that individuals with healthymyocardium and

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ate cardiac perfusion abnorrnarities from normal 201T1, they observed images of superior or equal -~ place exercise in the ?O'TI study, particularly in coronaryvesselsrespond tophysiologicstress
__.
;I:, perfusion as an alternative IO exercise stress. An quality to stress images. Several studies on the -..=
- patients either at risk or having
doing
output
difficulty
cardiac
a in withincrease
significant and
example is illustrated in Figure 10.2. Hamilton
have
topic carried
been
out (24-30). al. et the exercise.
coronary
blood whereas
flow, patients with car-
et al. (24) studiedtheeffects of dipyridamole (26), Sochor et al. (27),andSchmoliner et al. -_ may
diac ability
disease the not have or "re-
. . , I
.~.
" .~
~~
Ir
Nitroglycerin
.~.. (0.5 rng/kg intravenously) in normal dogsby (29) successfullydetectedcoronaryartery dis- ~-
~

", to do so. The

serve" advantage of performing
use of myocardial scintigraphy with 201T1and Nitroglycerin-
ii
. - eases
by
use of scintigraphy with "'T1 after or glyceryl nitrateacts asthese
a studies
is that they provide
additional di-
<
c~-
..
i . potent vasodilalor. particularly for coronary ar- agnostic information, since at rest many patienls
-
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.~-
~~ teries, by reducingthe cardiacworkload. Its with myocardiaidisease mayshowapparently
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exact mechanism is not known, but it acts di- normal cardiovascular radionuclide studies.
.~ ~ .
5 .
-
-~
.~~-
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~

rectly on smooth muscles. It is adminislered Dynamic stress studies aremost commonly

~.
~-!
. -. sublingually; its action starts 1-3 minules after performed with use of either a treadmill or a
~~

z i administrationand lastsfor 30-60 minutes. It is bicycleergometer in conjunction with either

"

.~ most commonly used for treatingpalients with 20'T1imaging or radionuclideangiocardiogra-

~.
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c
2- -__
"
angina pectoris.Sideeffectssuchaskansienr phy. Areas of ischemia are most likely to be
.~
.-. headache, weakness, and palpitation may result observed in zolTIstudies when the individual is
.- ,~
-~
.~
__
~

,~
..
=
" from its use. stressed,andthesedefectsappearas
Sale1 et al. (31) employed pharmacologic in- deficientareasontheresulting
photon-
image. In radio-
~~
%.
~ .~ tervention with nitroglycerin in cardiac bloodnuclide ventriculography, areas of wall motion
-=. .
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pool radionuclidic angiography to evaluate

the abnormalities often become more striking at ex-
"-~
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.
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rz viability of abnormally contracting
ventricular ercise. Global ejection fraction may fall in pa-
"
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- segments in patientswith clinicalcoronary dis- tients with coronary artery disease but typically
~.
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-.
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~
ease. Responses of disordered wall motionand will increase in normal patients (34).
~-
~.
" alterations in cardiacpumpperformance to sub- Otherforms of stress testing,such as iso-
r .~
~~. lingual
nitroglycerincould
differentiate
dys- metric exercise (36), cold pressor testing (37),
_c ~..
---
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"" synergic areas of infarction andischemia. Ni- and atrial pacing (38), are available for nuclear
-
i.
~-~
.- troglycerin produced significantly grealer re- cardiology. These teslshave been reviewed in
3%
;rr
ductions in end-systolic volume in patients delail by Buda in a recent publication (34).
-
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k ==
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~

without infarction than in patients with previous

z.-
s - infardon, which thereby results in a substantial KIDNEYS
f"
-* ~

increase in ejection
fraction in the former
rather hrosemide
g% -,=~
~

ex- than lhe latter group. Rosanski et al. (32) could Furosemide, a sulfonamidederivative, is a
S"=j make accurate scintigraphic differentiation of high-ceilingdiureticthat exerts its action by
- ~- -e- reversible and nonreversible asynergic areas of inhibiting the reabsorption of sodium and chJo-
: myocardium by gated blood Pool studybefore ride ions from the ascending loop of Henle and
and after pharmacologic intervention with nitro- the distal renal tubules. Furosemide also inhibits
I glycerin. In a studyby Borer et al. 1331, nitro- the reabsorption and promotes the excretion of
- glycerin
iInProved
qualitatively
assessed re- potassium ion. The peak diuresis obtained with
-, gional asynergy in myocardium. furosemide is greater than that observed for

mide iscontraindicatedinpatients withany
condition associatedwilh fluid or electrolyte
loss(i.e.,dehydration,hypotension,hypo-
kalemia, electrolyte imbalance) and in patients
with anuric renal failure. The polassium deple-
tion associated with furosemide administration
may produce cardiotoxic effects in patients al-
lergic to sulfonamides (39).
The interventional administration of furose-
mide has been combined with renal scintigraphy
with 99mTc-diethylenetriaminepentaacetic acid
(DTPA) and/or 1231-or 13'I-Iabeled o-iodohippu-
rate (OIHj in order to differentiate between me-
chanical obstruction or muscular atony as
cause of upper urinary tract dilation (3, 41-47).
This determination is important, since renal
atrophy can occur if mechanical obstruction is
not surgicallycorrected,whereasmuscular
atony can be treated with pharmacologic agents.
This interventional procedure is based on the
hypothesisthatthe"reservoireffect"(pro-
longedretention of urine) associated with the
nonobstructed, functionally abnormal renal col-
lecting system will respond to diuretic adminis-
trationwith increasedurine flow and prompt
washout of contents. Hence, in the dilated non-
obstructed system the 99mTc-DTFA or Iz3I- or
1311-labeled OIH renogramcurve will demon-
stratea prolonged plateau consistent with the
reservoir effect, butfollowingthe intravenous
administration of furosemide (0.3-0.5 mglkg) a
rapid washout of this activity will be observed
( F i g . 10.3). In contrast, a mechanically
obstructed system will demonstratea prolonged
renogram ulateauwhich does not respond to
" mal intravenous melogram whichshowed a vessel
furosemide administration ( 3 , 40, 42).
Although this technique is highly sensitive
for the differentiation Of
mechanical obstruction versus nonobstruction
as a cause ofuDper urinary tract dilatation (44,
snond or may respond poorly to diuretic admin-
.~
teria regarding the levels of serum creatinine or
InrerventionalStudies ill NuclearMedicine I 121
BUN necessaryto renderthe testunreliable
have been established. It should be noted, how-
ever, that there may be unilateral renal dysfunc-
tion with apparently normal BUN or creatinine
values. Basically, if these laboratory results are
twice normal andlor if the renal collectingstruc-
ture(sj are not visualized following radiotracer
administration, a response failure to diuretic ad-
ministration should be viewed with caution (3,
40).
GASTROESOPHAGEAL REFLUX
Bethanechol
a Bethanechol is a synthetic ester that is chem-
ically and pharmacologically related to acetyl-
cholineandexertsitseffectsthroughthe
slimuiation of cholinergic receptors. After oral
..
or subcutaneous administration,its action is pri-
marily muscarinic in nature; nicotinicactivity
(i.e.,cardiovascularsideeffects) is minimal
unlessthe agentisinjectedintravenouslyor
intramuscularly.Unlikeacetylcholine,beth-
anechol is stableto hydrolysis by cholinesterase
enzymes (48).
Themajorgastrointestinalactions of beth-
anecholinclude an increase in tone and per-
istaltic activity of the esophagus, stomach, and
intestines;anincreaseinloweresophageal
sphincter (LES) pressure;and an increase in
pancreatic and gastrointestinalsecretions(48).
Figure 10.3. Diuretic renogram. This study was per-
formed in a patient with low back pain and an abnor-
crossing the re&< pel& of
the right kidney. The
diagnosticproblem was to determine whetherthe
vessei was significantly obstructing the renal collect-
ing system, 99mTc-DTpA was fo]Io\red
hv an inieclionof furosemide c. ~ .~several
-, _I" ~~
~ i minutes
~ )
laler. Just prior to Lasix administration, the presence
"
a e i n a E e responTe following the adminis-
E +
"--
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i
bylerian Hospital, Albuquerque, NM.)
122 I Essenrids of NuclearMediiciue Scie>m ir? NuclearMedicirle
Irnervc~~riu~~alStudies I 123

Side effectswith oral or subcutaneous admin- esophageal reflux have been directly evaluated tone of the LES. It does not stimulate gastric, GASTROINTESTINAL BLEEDING
istration are usually mild and may include ab- andquantitatedwith use of gastroesophageal biliary, or pancreatic secretions; nor does it sig-
dominal cramping, diarrhea, nausea or vomit- scintigraphy and have been compared with its nificantly affect the moliiity of thecolon or Glucagon
ing, headache,sweating,andsalivalion.The effects on LES pressure (49, 50, 53). A signifi- gallbladder. MetocIopramide can produce cen- Glucagon is a single, straight-chain polypep-
agent is contraindicated in patients with bron- cant (p < 0.01) decrease (from 11.2 ? 1.3% to tralnervous systemeffects via antagonism of tide that is produced by the (Y cells of the pan-
chial asthmadue toitsbronchial constriction 7.7 i 1.0%, n = 15) in thegastroesophageal dopaminergic receptors (54). creatic islet or Langerhans and is isolated during
effects, in patients with peptic ulcer due lo the refluxindex did no1 occur until 30 minutes Metoclopramide-induced side effects are rare the commercia1 production of insulin. Since the
stimulation of gastrointestinal secretions, and in following administration, which corresponded and are primarilyassociatedwiththe central hormonal actions of glucagon are opposite to
patients with hyperthyroidism, since it may in- to a significant (p < 0.01) decrease in LES. nervous system(dopaminergic)effects of the [hose of insulin,glucagon is traditionally ad-
duce atrial fibrillation (48). drug.Theseadversereactionsincludesom- ministeredtoincreaseblood glucose levels in
Gaviscon nolence,fatigue,lassitudeand, in thesevere
The efficacy of bethanechol for the treatment the emergency treatment of diabetic insulin
of gastroesophageal reflux has been directly Gaviscon, a preparation containing alginic form, extrapyramidal symptoms including acute overdosage. As an interventional agent for nu-
evaluated and quanlitated by gastroesophageal acid and a combination of antacids (sodium bi- dystonicreactions. In view of theselatter ef- clear medicine and/or radiology studies, how-
scintigraphywilh a solidmealcontaining carbonate, aluminum hydroxide, magnesium fects,thedrugiscontraindicated in patients ever, glucagon is administered (0.1-1 U intra-
99mTc-labeledsulfurcolioidandlor a liquid lrisilicate), is indicated in the symptomalic treat- with epilepsy and in patienls on active pheno- venously)because ofits secondaryability to
mealcontainingll‘ln-DTPA or 99mT~-DTPA ment of gastroesophageal reflux (54). Its dual thiazinetherapy. Metoclopramidemayinduce inhibit gastrointestinal perislalsis by causing re-
(49-52). After subcutaneousadministration of mechanism of action is believedto be due to extensive catecholamine release in the presence laxation of the smooth muscle of the stomach,
5 mg of bethanechol,thegastricesophageal antacid-induced reduction of intragastric pH and of pheochromocytoma. I1 should be noted that duodenum, small bowel, and colon. After intra-
refluxindex (percent of totalgastric activity the formation of an alginic acid barrier to reflux narcoticsand otheranalgesicsormechanical venous injection (0.5 U), its actions in this re-
refluxed into the esophagus) decreased from a which is associated with its floaling, viscous obstruction can counteract the effects of meto- gard are rapid in onset (1-2 minutes) and tran-
mean (n = 10) of 11.9 & 2.4% to means of 8.3 properties (55). clopramide on gastric motility (54). sientinduration (9-17 minutes). The duo-
? 1 . 3 8 (p < 0.05), 6.0 k 1.3% (p < 0.01), Quantitative gastroesophageal scintigraphy That there must be some cholinergic activity denumismostsensitive to theeffects of
and 5 . 8 ? 1.7% (p < 0.01) at 15, 30, and 45 demonstrated a significant (p < 0.05) decrease for the expression of the pharmacologic actions glucagon;thestomach is least sensitive (59,
minutes,respectively.Simultaneousdirect (from 9.9 2 1.3% to 6.5 2 0.8%) in the of meloclopramideexplainsthefailure of the 60).
measurements of LES pressure revealed corre- gastroesophageal reflux index at 5 minutes fol- drugto stimulate gastric emptying in certain Adverse reactionsfollowingtheintravenous
sponding significant increases from 8.9 k 0.08 lowingtheoral administrationof 4 Gaviscon subjects. The scintigraphic evaluation andlor injection of glucagon are infrequenl and may
mm Hg to 14.3 2 1.9 m m Hg (p < 0.01), 18.5 tablets (49, 50, 53, 55). There was no corre- quantification of gastric emptying rateswith use include nausea, vomiting, headache, and metal-
? 1.9 mm Hg (p < 0.001), and 17.4 +- 2.1 sponding increase in LES pressure. Additional of radioactive solidorliquidmeal, which is lictaste. For inhibition of gastroinleslinal par-
mm Hg, respectively,which thus corroborated studies,performed with 87mSr-labeled alginic performed prior Lo and following the adminis- istalsis,theinjeclion of glucagonisprobably
(he proposed mechanisms of action of this agent acid, revealedthatthe majority of the admin- tration of metoclopramide, provides a direct associatedwith lessadverseeffects than the
in reducing reflux (50). These resulls were sub- istered preparation remained at [he top half of method of monitoring the effectivenessof meto- adminisiration of anticholinergics. Commercial
stantiated when directly oppositeeffects were the stomach andthat the alginicacid appeared to clopramideand of prediclingresponseto glucagon is a foreign protein that can produce
notedfollowing intravenousadministration of be refluxedpreferentially to the gastricliquid chronic oral lherapy (56-58). Such rationaliza- hypersensitivity reactions. The injection of glu-
theanticholinergic(bethanechoiantagonist) contents (55). Thus it was demonstrated in vivo tion of therapy is important in consideration of cagon should, of course, be avoided in palients
agent,atropine.Hence,anticholinergicdrugs that Gaviscon reduces reflux due to its “bar- thepotential for relatively severecentral ner- with diabetes and in patienls with pheochromo-
are contraindicated in patientswith heartburn rier”(floating,foaming, and viscous) nature vous system side effects. In a study by Domstad cytomasorinsulinomas,dueto its ability to
due to gastroesophageal reflux. and prevents the associated symptoms by being el al. (561,intravenous meloclopramide(10 mg) stimulate catecholamine and insulin release, re-
refluxed preferentially to gastric acid. significantlyshortenedthebiologicgastric spectively. Glucagon can enhance the hypo-
Antacids emptying time in 9 of 12 patients with severe prothrombinemic response to warfarin (59).
GASTRIC EMPTYING STUDIES
The predominant pharmacologic action of diabeticgastroparesis. In a similarstudy per- Gastrointestinal bleeding sites are detectedby
antacids is the reduction of inlragastric pH. Metoclopramide formed on patientswithscintigraphically abdominal scintigraphyfollowingintravenous
Hence, the efficacy of antacids in the manage- Metoclopramide, a derivative of procain- proven gastroparesis, administration of oral me- administration of 99mTc-labeledsulfurcolloid
ment of gastroesophageal reflux may be dueto a amide, promotes gastric emptying by increasing toclopramide (10 mggivenfourtimesdaily) (61) or 99’nTc-labeledred blood cells (62). Inter-
direct increase in LES pressure resulting from the tone and amplitude of gastric contractions, resulted in an improvement in gastric emptying pretation of scintigraphs, however, may become
reduced stomach acidity(53), the relief of reflux relaxingthepyloricsphincterandduodenal in 60% of patients wilh no previous surgery and difficultdue to diffusebackgroundactivity
symptoms associated with the irritating effects bulb,andincreasingperistalsis of theduo- in 75% of surgical patients (57). Significant caused by perislalsis (58). Hence, transient in-
of acid, or a combination of these ormay be due denum and jejunum. It apparently exerts these improvemenls in the gastric emptying rate fol- terventionalinhibition of gastrointestinal peri-
to alternale mechanisms. effccts by sensitizing the gastric smooth muscle lowing oral or intravenous metoclopramide have stalsis may improve the scintigraphic deteclion
As with bethancchol, the effecls of oral ant- to the actions of the neurotransmitter, acetylcho- been scintigraphicaIly demonstrated in palients of the gastrointestinal bleeding sites.
acid (30 In1 aluminum hydroxide gel) on gaslro- line. Mctoclopra~nide also increasesthe resting with gaslroesophageal reflux (59). In gastroinlestinalbleedingstudiesper-

124 I h e n r i a l s of NuclenrMedicitleScience
formedbyFroelich et al. (62), 12 of 24 patientsScintigraphic
werenoted to have abnormallyincreased, dif- iesprovide a convenient, noninvasive method
fuse activity in theabdominal region. After the for
intravenous administration of glucagon (1 U), a of intravenous or intraarterial VaSOpreSSln infu-
focal accumulation of activitywas observedinsion
the small bowei of 6 of these patients. Small- bleeding
bowel bleedingsiteswere subsequentlycon- intervention,followed
firmed in 4 of these 6 patientsand were pre- hourafter initialion of Iherapy. Additionalim-
sumed to be the origin of bleeding in the re- ages may be oblained at several time intervals in
maining 2 . This preliminary study suggests that order to make clinical decisions regarding ces-
the routine intenrentiond use of glucagon may sation
enhance theaccuracy of gastrointestinalbleed- or theuse ofalternatetherapeutic
ingstudies by preventingthemigration of ac- (i,e., embolization, surgery).
tivity from the bleeding site and by improving
target-to-background radioactivity ralios.
Vasopressin
Vasopressin is a polypeptidehormonesup-
plied as an aqueous solution of an extract of the
posterior pituilarygland. Itsactivity isslan-
dardized by assayagainstaU.S.P.
pressorunit.Vasopressin, wheninfused intra-
venously or inlraarterially (superior rnesenleric
artery), actsdirectly on the smooth muscle of
the splanchnic vascular bed to produce intense
arteriolar and capillary vasoconstriction with
s i g n i f i c a n ta n ds u s t a i n e dr e d u c t i o no f
splanchnic blood flow (63). Because of this di-
rect splanchnic vasoconstrictionactivity,low-
dose (0.1 U/min) infusions of vasopressin have
been used therapeutically to control bleeding
within Ihe gastrointestinal tract (63, 64). In this
regard, systemic intravenous infusions appear to
be equallyeffectiveand are less invasive in
natureto superiormesentericarteryinfusions
(64, 65).
Largedoses of vasopressin (i.e., 1 Ulmin
intravenously) can produce significant coronary
side effects including cardiac arrhythmias and
severe reductions in cardiac output secondary to
diminished coronaryartery flow (66). Atthe
lower doses (0.2 Ulmin) used typically to con-
trol gastrointestinal bleeding, some palients
may developnon-dose-dependent cardiacside
effects including hypertension, bradycardia,
and arrhythmias. The drug is, therefore, conlra-
indicated in any patient with a history of cardio-
vascular disease. Water retention and electrolyte
imbalance typically occur after vasopressin ad-
minislralion, as do minor abdominal cramping
I L" IL1,
F
_. ~
I.
~.
-. Medicine Nuclear lnrerve?trioml
in Sttrdies I 125
- .
% -
i.
~
l_.~ -~
=
"
_ ~
gastrointestinal bleedingstud- c- therclinicalevaluation of thistechnique is tion bycompetitivelyinhibitingthe action of
a-. based
on animal
studies
which have demon- $ I s t a w
-
5;
c-
~~
skated that prior administration of pentagastrin cells
receptors of t h e m e t a l
of the gastric mucosa (71). It does not exert
directlyevaluatingthe therapeutic efficacy 5-
-,=
>
accelerated the accumulation of activity in the anticholinergicactions, nor does it have an ef-
c$"
(63). 3aseline studies to demonstratethe -
~.
"
ectopic gastricmucosaofexperimental fect on LES pressure or gastricemptyingrate
4" Meckel'sdiverticulum (69). Thisactivity (54).
site are performed prior to Vasopressin $
by a repeat studyat 1 4:- rapidly migrated from the diverticulum site, Side effects associated with the adminiswa-
k-a however, which resulted in poor target-to-back- tion of cimelidineinclude mild andtransient
groundradioactivityratiosunlessglucagon
rI diarrhea,dizziness, and headache(whichmay
(vide infra) was coadrninistered with pentagas- be severe). The drug can potentiate the effects of
f trin. After pentagastrin administration, the duo- warfarin anticoagulants by reducing their rate of
of therapy, vasopressin dosage increases, f
modalities denum was consistentlyvisualizedearlier andhepaticmetabolism (54).
iniensely and often obscured activity in the ec-
topicgaslric mucosa.
HEPATOBILIARY SYSTEM
MECKEL'S DIVERTICULUM Glucagon Phenobarbital
Pentagastrin
Pentagastrinis a syntheticpolypeptide that
contains the pharmacologically active C-termi-
nal tetrapeptidesequencefound in the natural
i
%
5
Studies in an animal model provide support Phenobarbital, a barbiturate more commonly
for the interventional administration of gluca- used for its anticonvulsant and sedative proper-
gon in the clinical evaluation of Meckel's diver- ties, has been noted to be effective in the treat-
ticulum (69). In these studies compared with the ment of neonata1 hyperbilirubinemia in those
control nonintervenlionalstudies,administra- newborns with patent extrahepatic ducts (72). It
reference hormone, gastrin. Like gastrin, pentagastrin ex- I
cites the oxyntic cells of the stomach to stimu- 3 tion of only glucagon increased target-to-back- hasalsobeenused to lower serum bilirubin
late the secretion of acid, pepsin, and intrinsic ground radioactivityratios.Glucagonadmin- levels in patients with congenita1 nonhemolytic
factor. It also producesan increase in blood flow istered withpentagastrinresulted in early(10 unconjugated hyperbilirubinemia or chronic in-
to thegastric mucosa (67). Thesecombined minutes) visualization of the ectopic gaslric trahepatic cholestasis (72).
effects explain the use of pentagastrin to pro- mucosa with a continual increase in the inten- Phenobarbital enhances the M a r y conjuga-
g sity of activity and easeof visualization. Duod- lion and excretion of bilirubin (73). The drug is
mote the increased localization of sodium
enal interference or washoul of activily was not known to increase the hepatic extraction(ab-
[*mTc]pertechnetate in the gastric m x o s a of
Meckel's diverticulum. It should be noted,how- ! observed. It hasbeen speculaied that glucagon sorplion) of 99mTc-labeled iminodiacetic acid
ever, that high doses of pentagastrin may actu- exertedtheseeffectsbyinhibitinggastric (IDA) derivatives (74) and othercompounds
ally inhibit gastric acid secretion (67) and coun- motility and preventing translocalion of activity andtoincrease canalicular bile flow (75, 76).
teract the desiredinterventional effect.Penta- secreted by the eclopic mucosa andlor by PIE- Allhough phenobarbital stimulates the en-
gastrin stimulates gastric smooth muscle, which venting an increase in background activity due zymatic glucuronidation of bilirubin by hepatic
results in anincrease ingastricmotility and tothe discharge of noma1 9 9 m Tstomach ~ ac- microsomes (77), the cholereticeffect of the
migration of activity from the site of diverticu- tivity into the small bowel (69). drug is thought to be independent of this phe-
lumsecretion (67). Hence, its useshouldbe nomenon (78, 79), in part because it promoles
I Cimetidine
combinedwith a gastrointestinalhypotonic L the excretion of organic anions such as the IDA
agent such as glucagon (vide infra).
r-
P Although cimetidinehas not been evaluated compounds which are not conjugated by the
2 clinicdly, it has been proposed that cimetidine liver (80). Furthemore, phenobarbital has been
Adverse reactions associated with the subcu-
taneous administration of pentagastrin are tran-
sient and mild and primarily consist of nausea,
e may augment the diagnosis of Meckel's diver- shown to stimulate hepatic Na- and/or K-depen-
ticuIum by preventing the appearance of normal dent ATPase activity (81), which is thought to
9 9 m Tstomach
~ activ3y in the small bowel and
vomiting, tachycardia, and palpitations. The play an additional role in organic anion clear-
agent is contraindicated for repeated use in the thus decreasing potential backgroundactivity ance (82). Therefore, phenobarbital apparently
5 (69). In this regard, ani~nal s t u z h a v e demon- actson the entire hepatic transport system for
presence of acute peptic Ulcers and pancreatic, I
hepatic, and biliary disease (67). strated that the excretion of sodium [44mTc]per- organic anions (83).
I lechnelate from the gaslricmucosaintothe gas- Theadverseeffects of phenobarbitalon the
i
It hasbeen reportedthatthe subcutaneous
administrationofpentagastrin (6 m g k ) 15 lric conlents is inhibited by prior administration central newous system include lethargy, drow-
minulespriorto theintravenous injection of of cimetidine (70). siness, vertigo, headache, and depression. Hy-
sodium [99n'Tclperlechnetate pemitted the Vis- Cimetidine, a guanidinederivative,blocks persensitivity reactions to barbiturates occur
ualization of a Meckel's diverticulum that was both basal and slimulated (i.e., food, betazole, most frequently in patients with asthma, uai-
nnt observed Dreviously (68). Support
for fur- 1 ~ penlagastrin,caffein,insulin)gastric acid secre- caria, or angioedema. Phenobarbital apparently
 126 f E s s e n f i d s of Nuclear MedicineScience

causes rashes more often lhan do other barbitu- Cholecystokinetic Agents which may result in nonfilling of the gallblad- lion is observed (or, preferably, quantitated)
rates. Gastroinlestinal side effects include nau- der. Thisnonfillingusuallyisassociated with (Fig. 10.4). Patients with acute acalculous cho-
sea, vomiting, diarrhea, and constipation (72). Although cholecystokinin (88-93), sincalide thepresence of excessiveIy viscousbile and lecystitiswiil havea distinctlyabnormalre-
The safety of Iong-term phenobarbital therapy (3, 94-110), andceruletide (11 1) have been sludge secondary to chronic cholecystitis (113), sponse, usually with a gallbladder ejection frac-
in children and infants, including newborns, has used in nuclear medicine to induce contraction prolonged fasting (IOO), or long-term parenteral tion of much Iess than 20% (80, 106).
been established (84, 85). and subsequent filling of the gallbladder, only nutriliontherapy (114). The usefulness of this Theusualdose of sincalideis 0.02 p g k g
Phenobarbital is used in conjunction with sincalide is readily available to clinicians prac- intervenlion depends on the time, in relalion to given intravenously. Although mostinvestiga-
hepatobiliary imaging primarily to increase the ticing in the United States. Therefore, sincalide the injection of the radiopharmaceutical and torshaveadministeredthe drug by slow (1-3
diagnostic accuracy of differentiating between will be discussed as being representative of the subsequentimaging, that sincalide is admin- minutes) intravenous push,Sarva et a].(107)
neonatal hepatitis and biliary atresia. Decreased cholecystokinetic agents. istered. Two approacheshave beensuggesled have found that more conlplete emptying of the
morbidity and decreased mortality are obtaina- Sincalide (Kinevac) is the synthetic C-termi- (95). gallbladder is obtainable with a 45-minute infu-
ble when extrahepatic biliary obstruclion is di- nal oclapeptide of the hormone cholecystokinin With one approach, patientsare premedicated sion of the drug.
lagnosed and surgically corrected within the first andissimilartocholecystokinininphar- with sincalideprior to injection of theradio- The peak conkactile response after an intra-
' 2 months of life (86). Without the administra- macologic action. J t causes gallbladder contrac- pharmaceutical. This intervention promotes ear- venous push dose is usually seen at 5-15 min-
tion of phenobarbital, ht-radoi- tions resulting in both reduction of gallbladder lier visualization of the gallbladder in patients utes, with the gallbladder returning to the basal
tracer through the biliary system is very slow in sizeandevacuation of gallbladderconlents with patent cystic ducts, which thus decreases size within 1 hour (112); therefore, it is neces-
neonales with hepatitis, a l t f i o m i a r y (112). The administration of this drug also re- theimagingtime required to diagnose or ex- sary to wait approximately 30-60 minutes after
tracl is patent. If radioactivity in the bowel is not sults in decreasedesophagealsphinctertone, clude acute cholecystitis (from 4 hours to less sincalideadministrationbeforethe99mTc-IDA
C visualized within a reasonable time (24 hours), decreased intestinaltransit time, inhibitionof than I hour)andsimultaneouslyavoidsfalse compound is injected (104).
it is virtualiy impossib-ils gastric secretions, stimulation of pancreatic se- positivesthatmayoccur if theabbreviated Sincalide has essentiallyreplaced the use of a
from atresia on i h e r a d i o n u c l i d e i m a c cretions, anddelayedgaslric emptying(112). imaging procedure (withoul sincalide) is used. fauymealas a means to inducegallbladder
-ing. y-W neh is inconclusive, Adverse effects of sincalide are usually asso- There is some concern, however, that sincalide, contraction, primarily because the response to
s&geons musl resort to laparotomy in order to ciated with the pharmacologic action of the drug if routinely given prior to imaging, may obscure the drug is more predictable (80).
make the diagnosis; this is particularly unfortu- and include nausea, abdominal pain or discom- the diagnosis of chronic cholecystitis or mask
nateforthose babies who arefound tohave fort, dizziness, flushing, and an urge todefe- the smallpercentage of casesin which acute SPLEEN
jaundice unassocialed with atresia. Because of cate. These effects usually occur almost imrne- cholecystitis may present as delayed gallbladder Epinephrine
thissituation,anytest that couldhelp avoid dialely after injection and may last for several visualization (95). Among its many other pharmacologic ac-
unnecessary surgery is certainly useful. In h i s minutes ( 1 12). Another approach is 10 administer sincalide tions, epinephrine causes h e spleen to decrease
regard, the interventionof phenobarbital with Withuse ofnoninterventional methods,the only if thegallbladderdoes not initiallyfill in volume (1 15), a phenomenon which may be
cholescintigraphy has significantly improved diagnosis of cholecystitis can be made with an within 1 hour, followed by another injection of related to "expulsion" of contained blood ele-
the sensitivity and specificity of thetest for extremely high degree of accuracy when imag- 99mTc-IDA.If the gallbladder still does no1 fill ments (1 16). Since the spleen does not have a
determining the cause of neonatal jaundice, sim- ing is carried out for at least 4 hours following after an additional hour, the patient is consid- muscular coat in the splenic capsule, the con-
ply by increasing the rate of excretion of 99mT~-the administration of a 99mTc-IDAcompound ered to have acute cholecystitis; if the gallblad- tractile responsemaybemedialedwiihin Ihe
IDA and thus by allowing earlier visualization (1 13). Persistent nonvisualization of radioac- der is observed now, chroniccholecystitisis spleen and its blood vessels (1 16). More specifi-
of bowel in the presence of patent biliary ducts tivity in lhe gallbladder over this 4-hour period suspected (95). This method has been shown to cally, it may be due to variable rates of blood
(83). is suggestive of acute cholecystitis, whereas de- be as effeclive as delayed imaging (without sin- flow as the smooth muscle of terminal arteries
Phenobarbital used as a pharmacologic inter- layed visualization of the gallbladder at 1%-4 calide) in detection of chronic cholecystitis and arterioles respond to epinephrine ( 1 17). A
vention with radionuclide hepatobiliary studies hours is more typical of chroniccholecystitis (95). A disadvantage of the procedure, however, d e c r e a s h bloodflow, alongwith normal si-
is administered in doses of approximately 5 mg/ (1 13). Alternatively, some physicians prefer to is that the radiation-absorbed dose is doubled in n u k d a l and capsular elasticity, couldexplain
-
/

kglday for at least 5 days prior to the imaging conclude imaging at 60-90 minutes after injec- those patients who receive a second dose of the th'e volurnetrlc-change (117).
procedure ((83). lmaging is carried out to at tion of radiotracer, with theattendant risks of radiopharmaceutical (80). Although more clinical studies are necessary
least24hoursfollowingtheinjection ofa making a few false positive diagnoses when the It has beenobserved that in somepatients to confirm the truevaIue of epinephrine, the
"'"Tc-IDA derivative. The clinician shouldlook gallbladder is not seenwithinthisshorlened with acute acalculouscholecystitis,thegall- intervention with epinephrine in splenic imag-
not only for the appearance of bowel activity but lime frame and of missing chronic cholecystitis
also forpoor hepatic uptake of the radiotracer as which otherwise would havepresented asde-
bladder is visualized on cholescintigraphy stud-
ies (94, 96). Sincalidehas beenused as an
ing-may.Dotentially
. __
provide
method to assesssplenicinvolvemen7
a noninvasive
of
evidence for neonatalhepatitis (83). Alterna- laycd gallbladder filling in some patients. adjunct to the examination of these patients H-ms' disease. Two groups of a u t h z h a v e
tively, somephysicians prefer 10 measure the The rationale for use of sincalide with choles- who, despitc normal filling of the gallbladder, shown that the volume response to epinephrine
presence or absence of radioactivityin the cintigraphy is to empty the gallbladder and remain suspect of having acutecholecystitis, appears to bc significantly less in abnormal
bowel by taking samples of duodenalfluid a1 thereby remove any functional resistance to the due totheir clinicalpresentation. In these pa- spleens than in normal spleens (117, 118). The-
various time inlervals postinjection (87). flow of radiolracerthroughthecysticduct tients, the cfFecliveness of gallbladder contrac- oretically,neoplasticinfiltration of red and
i28
S C A = @ 5 0088E white splenic pulp would decrease both the vof-
ume of the splenic sinusoids and their elasticity,
which would thus result in the diminished vol-
ume responses noted in these studies (117).
A range of 0.5-1.0 mg of epinephrine has
been used as an interventional dose by investi-
gators (117, 118). Epinephrineisknown to
cause a variety of adverse effects, andthe reader
is referred to other sources for more detailed
information on this subjecl (119).
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11
Medical Decision Making
David F, Preston and Larry T. Cook
Making decisions is a central partof a physi-
cian's work. We wouldlike to believethat,
given a specific set of circumstances, our deci-
sions are correct, appropriate and optimal. The
complexity of medicine, however, is such that
most of our decisions are made with incomplete
information. Even if the total data on a specific
clinical situation were available, there is every
reason to believephysicianswoulddiffer in
their approach to seemingly identical problems.
At this time, physicians are asked to demon-
stratetheapproprialeness of theirchoices of
diagnosticandtherapeuticmaneuvers.Blue
Cross-BlueShield,Medicare,Medicaid, and
other third-party payers now question the physi-
cian's choice of action. In the near future,we in
nuclearmedicinewill berequired to compare
our diagnosticabilitieswithotherdiagnostic
modalitksinspecificclinicalsituations,with
the hope that the most cost-effective course may
be taken. Frequently, the data are found to be
little more than opinion and often that opinionis
not accepted by physicians in other specialties.
Despitesuchdifficulties,anumber of formal
methods, proven in the areas of business, psy-
chology,andstatistics,have been found to be
appropriateforcomplexmedicalproblems.
These techniques make it possible to identify,
simplify, organize, and measure the important
variables of a problem and are considered the
tools of medical decision making. The purpose
of this chapter isto present several clinical prob-
lems, demonstrate their resolution through the
use of InedicaI decision techniques, and point
out sources for more advanced study.
PROBABILITY
Probability is the chance that a given event
will occur. It is expressed as a decimal fraction
with a range between 0.0 {it will never happen)
to 1.0 (it will always happen). The probability
of encounteringaspecificdiseaseinagiven
patient population before any testing isper-
formed is the prior probability of that disease
and will vary from practice to practice. The a
priori or prior probability of disease is desig-
nated P(D). The prior probability P(D) could be
determined from the medical records, but many
times it is not available and must be estimated
by experiencedclinicians.Differences in the
prior probabilities account for a major cause of
disagreement in conclusionsbetweenmedical
researchers studying the same problem at differ-
entinstitutions.
When the prior probability dataare not avail-
able, one approach is to create a list of diag-
nostic possibilities from previous experience
and to assign a probability to the occurrence of
each disease in a particular group. Ideally, the
disease states should be mutually exclusive.
Thisrequiresthatthepriorprobabilities must
sun] to 1.0. At the University of Kansas Divi-
sion of Nuclear Medicine, the measured prior
probabilities for thyroid status are .05 for hypo-
thyroidism, .X4 foreuthyroidism,and . l I for
hyperthyroidism. These are objeclive rather
than subjective or personal probabilities.
The validity of subjective or personal proba-
bilitiesisdiscussedbyLusted ( I ) andothers
(2-4). Despitethewell-knownproblems of
human investigators estimating subjective prob-
abilities so they are correctly ranked and lheir
total adds 10 1.O, with practice and experience
in the subject matter, useful results may be ob-
tained (5).
+ +
Conditional probabilities P(T I D ) de-
scribe the frequency with which a test is posi-
tive (T t-), given ( I ) the presence of a specific
 MedicaI Decision Making I 135

patients with the disease and with abnormal test Table 11.3.
results (positive for the disease) to all the pa- Sensitivity and Accuracy Values for Variable
tientswith thedisease.Sensitivity = #TP/ Thresholds
(#TP + #FN). This is the same as the condi-
+
tional probability P(T 1 D i- ) or 67/(67 + 31) Figure 11 1 Flgurr I I .2

= .68. Sensitivity measures the ability to detect Threshold

Point
Sensitivity
Accuracy
Sensitivity
Accuracy
patients with the disease. This is also the true
I 1 .oo .79 1.00 .56
positive ratio (TPR). 2 I .OQ .83 1.00 .59
The specificity of a test is defined as the ratio 3 .99 .87 .99 .63
of normal test results in patients without disease 4 .99 .9 1 .99 .63
to the total number of normal patients. Specif- 5 .9a .93 .98 .70
icity = #TN/(#TN + #FP) or 771/(771 + 6 .98 .94 .98 .74
7 .97 .95 .97 .78
IO) = .99. This is the same as the conditional 8 .96 .96* .95 .81
disease (D+ ). For example, in our laboratory comparison is to make a 2 X 2 decision matrix probability P ( T - I D - ) . The false positive 9 .94 .95 .94 .84
theprobability of anelevated T, radioim- as in Table 11.2. Theresults of individual T , ratio (FPR) = (#FP)/(#FP + #TN) = 10/(10 10 .90 .94 .9I .86
munoassay (RIA)is ,684 in the patientwith determinations are comparedwiththefinal + 771) = .01. Specificity = (1 - FPR). 11
12
.84
.77
.93
.91
.87
.8 1
.87*
.86
hyperthyroidism, ,014 inapatient with eu- knowndiagnosticstate of thepatient. The The predictive value of a posilive test is the
13 ,7Q ,87 .75 .84
thyroidism, and .OOO in a patient with hypothy- number of elevated T,s (T+) associated with probability that a patient has the disease, given 14 .61 .83 .67 .81
roidism. More complete information based on disease (D + 1 and without the specific disease an abnormaltestresult,andisdefined as 15 .53 .79 .59 .78
879 patients is shown in Table I 1. I . If we assign (D - ) and the number of nonelevated T4s (T - ) #TP/(#TP + #FP) or 67/(67 f 10) = .87. 16 SO .74
diagnosiscode D l to hypothyroidism, D2 to associated with disease (D+ ) and without the Thepredictivevalue of anegativetest is 17 .41 .70
euthyroidism, and D3 to hyperthyroidism, the specific disease (D -) are seen. #TN/(#TN + #FN) or 771/(771 + 31) = 18
19
.33
2 5
.66
.63
probability of an elevated T,, given that[he The true positive group (#TP) consists of the .96. 20 .I9 .59
patient has hyperchyroidism, is P(T, + 1 D3) = number (f) of patients with a positive test(T + ) Accuracyisdefined as thefraction of total 21 .I3 .53
,684. and the disease (D+). The true negative group testresultswhichare correctandis (#TP +
Posteriorprobabilities orposttestproba- (#TN) consists of the number of patients with a #TN)/(#TP + #TN -!- f F P + #FN) or (67 * Crossing point.
bilities are the probabilities of a specific disease negative test (T-) and the absence of the spe- + 771)/(67 + 771 + IO + 31) = .95.The
after a test resull is known. One measure of the cificdisease (D-). Thefalsepositivegroup Iikelihoodratio (L) is theratio of thetrue
value of a lest is 10 compare thepretestand (#FP) consists of the number of patients wiLh an positive ratio tothe falsepositiveratio. L = various cutoff poinls can be identified in which
posttest probabilities. 1f testingimprovesthe abnormal test (T +) and the absence of the spe- TPWFPR. sensitivityandspecificitycan be modified to
probability of adiagnosis,the test may have cificdisease (D-). Thefalsenegativegroup To create a 2 x 2 table requires a decision as minimize health costs,minimizeincorrect re-
value. (#FN) consists of the number of patients with a to what test value divides normal from abnor- sults, or maximizetheinformation contellt of
negative test IT-) but with the disease (Di-). mal. If the testhas acontinuum of values. the lest (6-10).
DECISION MATRIX Thelermssensitivity,specificity,predictive Figure 1 1 . 1 is an idealized distribution of test
Many problems in medical decision making value, and accuracy have been used to describe results of diseased (D + ) and nondiseased (D - )
require comparison of test results with the pres- the value of a test. Examples aregiven based on D- D-F patients. There are equal numbers of patients in

1
enceorabsence of disease. The most simple Table 11.2. Sensitivity is defined as the ratio of both groups, and eachgroupissymmetrical
about its mean. The overlappingzone of the two
distributionsproduces15differentlhresholds
Table 11.2. (V), varying from V1 to V15, which could be
2 X 2 DecisionMatrix chosen to separate normal from abnormal. The
threshold, V8, at the crossing poinl, intuitively
Hyperthyroid (D +) Nonhyperthyroid
(D - is the point where feu8est incorrectclassifica-
tions will be obtained. Calculation of sensitivity
Elevated T4 (T + ) 67 (#TP) 10 #FP) 77 elevated lest results and accuracy for each of the 15 threshold poinls
5 appears in Table 11.3. The maximum accuracy
Nonelevated T4 (T - ) 31 (#FN) 771 (#TN) 802 nonelevated test results VI V8 \i occurs at threshold V8 whichisthecrossing
98 total hyperthyroid 781 total nonllypcrthyroid 879 lotal palicnts and Figure 11.1. Distribution of test resuIts from dis- point. If the distribution were less clearly sepa-
palienis paticnk total tests eased (D+)and noodiseased (D-) patients, w i t h rated as in Figurc 11.2, there would be greater
Tittle ovcrlap of populations. overlap; nevertheless, the crossing point would
I36 I EssentidsoJhiuclearMedicitseScience MedicalDecision Making t 137

m
VI
D-
l

VI1
D+

v21

Figure 11.2. Less clear separation ol: symmetrical

populations D C and D - ,
In the real world, the selection of the thresh-
old between normal and abnormal is often se-
lected based on the relative seriousness of the
consequences of misclassifyingthepatient.
When the task is one of screening for a possibly
fatal disease with a safe treatment, a high sensi-
tivity is required.Thismeans that almost all
persons with the disease are identified but at the
price of many false positive examinations. This
would correspond to placing a threshold at V I ,
V2, orV3 in Figure 1 1.3. To determinethe
optimal cutoff point, we determine the true pos-
itive and falsepositive ratios at each point along
[he curve. A plot of these true positive to false
positiveratiosappears in Figure11.4.This
curve is known as a“ROC curve,” an abbrevia-
tion for receiver operating characteristic curve
Thrprhold Point

10
11
12
13
14
1
2
3
4
5 .93
6
7
8*
9
Table 11.4.
Sensitivity TPR,Accuracy, FPR Changes with
Threshold Valuation for Figure 11.3
Stnsilivily (“R)

1.oo
.99
.98
.96
,94
.91
.87
.82
.76
.68
.60
.52
I44
.37
Accuracy

.75
.SO
,85
.s9

.95
.96
.96
.96
,95
.95
.94
.94
.93
FFR

.28
.22
.I7
.12
.07
.05
.03
.02
.02
.o 1
.01
.00
.HI
, 00
Problems of utility, Le., the relationship of
fahe positive costs to false negative costs, are
discussed by Hill (4), Behn andVaupel (5),
McNeil et al. (6, 9), Pauker and Kassirer (13),
Bell (14), Gorry et al. (15), Thornbury et al.
(16), Galen and Gambino (17), and Pauker and
Pauker(18).Bell’s articleisespecially clear,
concise, and readable for those intimidated by
mathematics.Thisarea is quitedifficult.The
third-partypayers,thephysician,andthepa-
tient usudly will be in disagreement as to the
“best” outcome. Should money costs be mini-
mized, or should Iife expectancy,healthout-
come at 10 years, years of gainful employment,
or diagnostic efficacy be maximized?

be the optimal threshold (6, 9). Now consider
Figure 11.3 which is a modification of the thy-
roid data in Table 1 1.2. There are almost 8 times
as many normals (D +) as abnormals (D - ). In
this asymmetrical and unequal disuibution, the
threshold defined by the crossing point again
produces the greatest accuracy, as is shown in
Table 11.4.
D-
V1 V8 V14
Figurc 11.3. Modilication of thyroid data from Klble
I 1.2. D + has almost 8 times the number of patients
as D - .
BAYIS’ THEOREM
(11 , 12). At threshold (V l), all diseased patients 15 .26 .92 .00 A diagnosis is often revised with the addition
16 .19 .9 1 .00
are identified, but 28% of normal patients are 17 .15 .91 .00 of new data. Consider the prior probabilities of
falsely classified as abnormal. This is a highly hypothyroidism (P(DI) = .05), euthyroidism
sensitive threshold. At the crossing point (VX), * Crossing point. (P(D2) = .84, and hyperthyroidism (P(D3) =
82% of diseased patients are identified and only
2% of normal patients are falsely classified as
diseased.
Selection of the optimal cutoff point requires
knowledge of the prior probability of diseased
P(D +) andnondiseased P(D - patients. The
probability of hyperthyroidism is P(D + ) = .11
and, for the absence of hyperthyroidism, is
P(D-) = .89. Whentheslope of the ROC
curve equals the ratio of P(D- )/P(D +), the
maximum accuracylies in that vicinity of the
curve (Fig. 1 1.4).
The optimum threshold is also influenced by
the ratio of the cost of a false positive ($FP)
diagnosis to the cost of a false negative diag-
nosis ($FN). If the cost of afalsenegative
diagnosis is high and the cost of a false positive
diagnosis is low, the optimal threshold will shift
up the curve to the region of greater sensitivity
and less specificity. If, on the other hand, the
cos1 of treating a normal patient for the disease
is high, the optimal point will shift down the
curve to the more vertical and left-most portions
of [hecurve. In screening programs,this op- lot
timal threshold is the region of lower sensitivity
and greaterspecificity. If thecost of afalse
positive ($FP) result is twice h a t of the cost of a
false negative ($FN)resuIt, theslope at the
optimal threshold will be 16 (Fig. 11.4). Figurc 11.4. ROC curve from Figure 1 1.3. See text for explanation
138 1 Enerrrids of1Vucleor MedicineScience
,11) obtained at the University of Kansas Divi-
sion of NuclearMedicinefrom1975through
1980. Can we improve our diagnostic classifica-
tion over the prior probabilitiesof disease by the
addition of laboratory testresults from Tables
11.1 and 1 1.2? Bayes'lheorem providesthe
melhodtorevise thediagnosticprobabililies
based on the new data.
P(T+ ID+)P(D+)
P ( D t IT+) =
P(T+
P(D+ IT+) is the probability of disease,
given a positive test. P(T+ I D + ) is the proba-
bility of a positive test, given the presence of
disease, P(D+) istheprobability of finding
disease in the population,and P(T + ) is the
probability of finding an abnormal test in the
population.
For example, Bayes' theorem permits us to
determinetheprobability ofthe presence of
hypothyroidism,euthyroidism,andhyperthy-
roidism, given knowledge of an elevated T 4 .
In Table 11.2, there were 67 of 98 patients
with a n elevated T, andhyperthyroidism
P(T,+ lD3) = 67/98 = .684.Don'tconfuse
numbers of tests or numbers of patients with
probabilities. There were no elevated T,s in the
( D l ) group, i.e., P(T,+ I D l ) = 0. Ten eu-
thyroidpatients (D2) had elevated T,s, ; . e . ,
+
PIT, I D2) = .014. The probability of an ele-
vated T4 in the entire population is
P(Di)P[T,+JDl)P(T,RIAt 101)
P(D1 IT4+,T3RIA+) =
P(Dl)P(T,-IDl)P(T3RtA;[D1)
P(D3)P(T,+JD3)P(T3RIA+(D3)
P(D3]T,t .T,RlA i) =
P(Di)P(T4+~D1)P(T,RIA+101)
Figure 11.5. Bayes' theorem expanded to include resullsof an clcvaled T,RIA and an elevated T, KIA.
figure, T, RIA is labeled as such to distinguish it from the T, rcsin uptake test.
PIT4+) = P(Dl)P(T,+ / D l )
+
+ P(DZ)P(T,+ I D2) P(D3)P(T,+ I D3)
P(T,+) = (.05)(.00)
+ (.84)(.014) + (.11)(.684) = ,087
P(D1 IT,+) = (.00)(.05)/(.087) = 0
P ( D 2 \ T , + ) = (.014)(.84)/(.087) = .14
P(D3 IT4+) = (.684)(.11)/(.087) = .86
The probability of hypothyroidism, given an
elevakd T,, is 0.0. Theprobability of eu-
thyroidism,given anelevated T,, is .14. The
probability of hyperlhyroidism,givenanele-
vated T, , is .86. Given anelevated T,, the
patient is more than 6 timesaslikely Lo be
hyperthyroid as to be euthyroid. Bayes' theorem
has revised thepriorprobabilities,based on
finding an elevated T,.
For determination of the probability of hypo-
thyroidism, euthyroidism, and hyperthyroid-
ism, when both T, and T, RIAs are elevated,
Bayes' theorem is expanded as in Figure 11.5.
P(D1 1 T4+ ,T,RIA 4-) is the probability of hy-
pothyroidism, given an elevated T4 RIA and an
elevated T, RIA. Nole that the denominators are
identical and are composedof the sum of all the
numerators. The formulais long but is simple if
broken into its components. When both T4 and
T, RIAs are elevated, the probabilily of hypo-
thyroidism is 0, the probability of euthyroidism
is .002, and the probability ol hyperlhyroidism
is ,998. Withboth tests elevated, the probability
+ P(D2)P(T4+JD2)P(T,RIA&1D2) t P(D3]P(T4t\D3)P(T3RIAtlD3)
f P(D2)P(T4+lD2)P(T,RIAt~D2) + P(D3JP(T,cID3)P(T,RIA+103)
111 this
of hyperthyroidism is 499times that of eu-
thyroidism{(.998/.002) = 4991.It is, nev-
ertheless, a probabilisticdiagnosiswhich, in
theory, cannot givetotal diagnostic assurance of
P = 1.00.
It is possible to rankeachtestandeach
unique group of test results to obtain the combi-
nation of tests which yields the highest proba-
bility for identifying each disease. From Table
1 1.1, Lhere are 5 tests for each disease state,
and
there are 3 states for each test. There are 243 =
35 possible combinations. Many of the combi-
nations will be quite unusual. The combination
of low T,, low T3 resin, low T, RIA, high
effective thyroid ratio (ETR), and high 24-hour
I3'I uptakewould be unusual. Except for the
high ETR,the testresults mightindicate the
recoveryphase of subacutethyroiditis.Hun-
dreds of thousands of studies would have to be
analyzed before the rare combinations had ade-
quate numbers for meaningful analysis. Overall
and Williams (19) obtained useful results from
less than 900 patients by using the more fre-
quently occurring combinations. In laterwork
(20, 21), their accuracy in classifying patients
was between that of a general internist and an
endocrinologist specializing in thyroid disease.
Whal is important is their use of the inexpensive
historyandphysicalexaminationasthe
modalityfor achieving impressivediagnoslic
resulls.
Theprobability of correct classificalion is
influenced to some extent by the prior proba-
bility of disease.Inourinstitution, between
1976 and 1980, P(DI) = .05, P(D2) = .84,
and P(D3) = . l I . In the Division of Nuclear
Medicine at the University of Florida, Gaines-
ville, from 1958 to J967, priorprobabilities
varied fromP(D1) = (.04 to .06), P(D2) =
(.79 to .87), P(D3) = (.IO to .15), depending
on the patient population and method of deter-
mination(22).Thesefiguresareessentially
identical to those a1 h e University of Kansas,
even though they are separated by 20 years and
1000 miles.
Suppose thcpriorprobabilities were P(D1)
= .33,P(D2) = .33, and P(D3) = .33. Calcu-
lalethe Probabilities of disease,usingthese
priorprobabilities, and comparethese results
Medical Decision Making t 139
with theprevious results by utilizing theele-
vated T, data from Table 1 1 . I .
P(D 1 T,+) = P(D)P(T4 + 1 D)/P(T, +>
P(T,+) = (.33)(.00) + (.33)(.014)
+ (.33)(.684) = .23
P(D1 IT4+) = (.33)(.00)/(.23) = 0
P(DZ[T,+) = (.33)(.014)/(.23) = .02
P(D31T4+) = (.33)(.684)/(.23) = .98
Previous calculation produced P(D1 1 T4 ) +
= 0, P(D2IT,+) = .14, and P(D31T4+) =
.86.
Comparison of P(D I T, +), with use of arbi-
trarypriorprobabilities,shows a definite
changefromtheKansas and Floridaresults.
Thischangeindicates that priorprobabilities
can influence probability of disease calcula-
tions, but as wehave shown with use of real
data, different institulions may have similar
prior probabilities.
DECISION ANALYSIS
Optimal therapy is the successful conclusion
of diagnosis. The path from problem identifica-
tion to diagnosis and through therapy is com-
plex, with conflicting perceptions, opinions,
images,tests,risks,probabilities, patient val-
ues, physician values, and third-party payer val-
ues.Decisionanalysis ( 5 , 23)permits an or-
derly approach to these problems and has been
successfully applied to numerous compiex real
world medical problems. All reasonable varia-
tions OF the diagnostic pathway canbe explicitly
outlined,clinicaldecisionsidentified, proba-
bilistic and value judgments considered, and an
optimal course of events identified.
Thedecision tree (Fig. 11.6) is a graphic
method that can demonstrate the logical se-
quence of diagnosis including test results, com-
plications of tests, the effect of treatment, the
effect of withholding treatment, and the ranking
of finaloutcomes so thatthepathway with
greatestutility maybeidentified. By conven-
tion, the initial problem appears on the left and
subsequent actions flow to the right. Decisions
under the physician's control are represented by
squares (decision nodes), and events not under a
decision makers control (chance nodes) are rep-
 140 I Essentials of NuclearMedicineScience Medical Decision Making / 141

No Disease No Disease
f
f.7
No EIfect
of Disease No Comp-
I No R x
rlication
Disease 01 Disease 35 of Oisease
Uncomp-
licated
Complicated
-x@- ,Rx
SuspiciorI Suspicior
of of iicaled
Disease I Comolication Disease
"
.U3
Complication
No Disease El- No Disease

4 .7

No Health Effect
No Health Effect
r. 1

Health Effect
Health Effect
.9
Figure 11.6. Decision lree.
Figure 11.7. Decision tree with probabilities of disease, comphcalions of test, complications or therapy, and
outcomes added.

resented by circles. Final outcomes appear at
the farright. In Figure 11.6, thesuspicion of
disease results in a decision (Dl) to perform a
test or to perform no test. The testmayhave
The probabilityof disease (.3), complicalions
of the test (.05), and complications of therapy
Utility
( . 2 )are then added as in Figure 11.7. The util-
ities or value of eachoutcome must thenbe No Disease go

complications ( C l ) which result in a deleterious estimated.Thebest,worst,andintermediate c .7 No Ellect 65

health effect. In the absence of complications, outcomes must be determined and ranked. The
physician will ordinarily use the patient's val- lication
the results of the test may exclude disease (C2), 5
in which case thereare no deleterioushealth ues, at least as they are understood. Pauker and 01 Disease

effects but only the cos1 of the test. The test may Pauker (18) show Ihe usefulness of question- Uncomp- 85
Rx 8 llcated
identify disease, in which case a square decision naires 10 elicit patient values. Pauker and Kas-
Suspicior Comp- 20
node (D2) is encounlered, at which time a deci- sirer (13), in their example concerning pulmon- of licated
sion to treat or not to treat Ihe patient must be ary embolism, utilize a more complex method Disease .05 Complication 0
made. Treatment may be complicated or uncom-
plicated.Thebranchingandmultiplication of
of estimating utilitiesthat is based on life expec-
tancyandexpectedtimefree of morbidity,
while Sisson et al. (24) estimate the remaining
El- .?
No Disease 100
possibilities may become unwieldy. Note that in
Figure11.6there are somesimplifications al- years of life expected. In Figure 11.8, the utility
readymade but thatthe major pathways are values are empiric estimations. The worst out-
described. come is a complication of thetest (death), while No HealthEffect 70
Simplification is a must, especially in com- the best outcome is to do no test and have no r.1
plex business problems (5). The sheer complex- disease.
ity of the exhaustive complete decision tree will The next step is to calculate theexpected
inhibit understanding and analysis. Sisson (24) utility ateach node.Expectedutilitiesare in Health
Effect 10
and Pauker and Kassirer (13) use well-done and ovals close to theappropriatenode(Figure .9
complex decision lrees that are minimally sim- 11.9). Reading from theright of Figure 11.9,
plified. the sum of the products of the utility and proba- Figure 11.8. Decision lree with empiric ulilitics added
 142 / EsserlfiuZs of hiucZear MedicineScience MedicalDecisionMaking I 143

Utitity From P(D) = 0 to P(D) = .23, the decision to of medical decision making, and wilh education
No Disease 90 not test is superior. of the referring physician.
.7 Sensitivityanalysiscandefine athreshold In the past 6 years, the Society for Medical
65 above which one action is optimum and below Decision Making has been formed. It is a multi-
which another action is optimum. disciplinary group composed of scientists, phy-
5
.95 sicians,administrators,andeducators who
SUMMARY
85 work toward the development and applicationof
Jest An organized, logical, and probabiiisiic ap- techniques to optimize diagnostic and therapeu-
20 proach to medical management is not new. The tic medical decisions. For example, the value
Suspicion
Qf recognilion that heaIth care resources are finite judgments of medicine have been reinvestigated
.05 Complication 0
Disease is not new. The concerted effortto limit medical with the development of techniques that can aid
No Disease 100 expenditures, already accepted by the medicaf in synthesizing values related to health, money
r community, is new. The current reimbursement (25), and malpractice.Thediscipline is in a
plan is mostlikelyjustthebeginning of en- developmental stage. We in nuclearmedicine
forced attemptstocontrolexpenditureswhile must learn to speak this mathematical and log-
quality heaIth care is maintained. Nuclearmedi- ical language in order to estabIish the value of
No HealthEffect 70
cine must now show its cost-effectiveness to the functional and physiological capabilities of
third-party payers, hospital administrators, pa- nuclear medicineunique to patient care. We
tients, and referring physicians. This task wilI must demonstrate to all the value of identifying
no1 be easy. It must start with our own educa- and treating specificfunclionalabnormalities
1.9 Health Effect 10 tion, with our willingness to work at quality prior to the development of anatomical abnor-
assurance, data base acquisition, and techniques malities. The cosls of diagnosisbyvarious

Figure 11.9. Decision tree with expected utilities calculated for each node.

100

bility of each branch is the utility value of the SENSITIVITY ANALYSIS

chance node lo the left. At decision nodes, the 80
Sensitivity analysis ( 5 , 13) permits an answer
utility of the branch with the highest value is
to this question by relating the expected utility
assigned to the decision node.
(inarbitraryunits) to thepriorprobability of
The expected utility at
disease. If in Figure 11.9 the prior probability
C5 = l i [(65 X . l ) -E ( 5 X .9)], of disease were .OO, the utility of testing (Cl)
C6 = 72 [(85 X .8) +
(20 X .2)], would be 86, while the utilityof not testing (C2)
D2 = 7 2 , would be 100. In the example, when the prior
C3 = 85 [I72 X -3) 4- (90 X .7)], probability of disease is .3, C1 = 80 and C 2 =
Cl = 80 [(85 x .95) +
(0 x .OS)], 75. When the probability of disease is 1.OO, C1
I
+
C4 = 16 [(70 X .l) (10 X .9)], = 68 and C2 = 16. These changes are plotted I
C2 = 75 [(I00 X .7) -t (16 X .3)]. in Figure 11,lO. When P(D) = 0, the greatest I
Atnode D2, the physician should treat the utility isto nottest. When P(D) = 1.0, the I
I
patient, since that isthe pathway of greatest greatestutility is .to test. Thepoint of equal I
utility between testing andnot testing is P(D)= I
utility. At D l , the physician should follow the
pathway of greatest ulility and perform &he tesl. .23. Given the initial data of complication rate
These are reasonable decisions based on .3 prior of h e test, the effect of disease, and the com-
L
0
.2
L
I
1 I
.4
I 1
.%
I I
.a
I I
1.o
probability of disease. Suppose the prior proba- plication rate of the treatment, the prior proba-
bility of disease is .5 or .7. There will benumer- bilities may range from .23 to 1.0, a fourfold PROBABILITY OF THE PRESENCE OF DISEASE P(D t
ical changes in expected utility values, but will range, and throughout that range the decision to Figure 11.10. Sensitivity analysis graph. P(D) = 2 3 is the thresholdbelowwhich the greater utility is
there be a change in the decision to test? test remains the one with highest utility value. associated with no1 testing and above which the greater utility is associated with lesting.
144 I E s s e d a l s OJ Nuclenr Medicine Science
modalitiesmustbemeasured.Thecosts of
missing the diagnosis must also be measured.
14.
The problems are complex, but progress ispOS-
sible byusing techniques of medical decision
making.
15 12
REFERENCES Computer Applications in Nuclear Medicine
1, Lusted LB: Imrudldcrr’ofj10 Medical Decision 44uking.
Springfield. IL, Charles C Thomas. 1968, pp 4-5.
2. Edwards JV, Lindman H, Savage U: Bayesianstatis-
tical inference for psychological research. Psycho! Rev
7 0 193-242, 1963,
3. Kotz S , Slroup D F Edfrcured Gvessing. NewYork, Digital computers were introduced to nuclear
Marcel Dekker, 1983, pp 21-22.
4. Hill PH, Bedau H A . Chechile RA, el al: Making Deci-
medicine research asan imaging modalityin the
mid-1960s. Widespread use of imaging comput-
ers (scintigraphiccomputers) wasnot seen in
5. nuclearmedicineclinics until themid-1970s.
For the user, the ability to acquire scintigraphic
6.
images into thecornpuler for quantitative pur-
poses, with accurate selection of regions of in-
I. terest (ROIs), promisedalmostendlesscom-
putational capabifities. Investigators quickly
developed many new methods for quantitating
8.
the distributionpatterns of radiopharmaceuticals
9. within the bodyboth spatiallyandlemporally
(1-3). The computer was used to acquire data
on practically every organ that could be imaged
10 by means of gamma camerasor rectilinear scan-
ners.Methods of imageprocessing borrowed
I1 from other disciplines were applied to scinti-
graphic computer images in an attempt to im-
prove image quality (4). Image processing in
nuclear medicine hasevolved into a relatively
extensive set of tasks that can be called on by
the user to provide additional clinical informa-
lion rather than lo improve image quality.
Digitalcomputersareutilized in nuclear
medicine departments for nonimaging applica-
tions also. Patient scheduling, archiving, radio-
pharmaceutical inventory, radioimmunoassay
(RIA), and health physics are just a few of the
areas in which the digital computer has proven
helpful. The computer is useful in any area in
which a large quantityof data needs to be accu-
rately managed, especially over a long period of
lime.
Since the 1nid-I960s,thedigitalcomputer
has evolved to the point where desk-top micro-
computers are now morepowerfulthan early
syslerns used for imaging. The power of a corn-
putersystem lies in thecombination of hard-
ware and software. To utiIize this power, a user
generally needs to become knowledgeable
about the capabilities as well as the limitations
of the hardware and sofhvare. Software devel-
oped for generalpurposeuse(suchasword
processors,databasemanagers,andspread-
sheets) oftenhastutorials included to provide
training and practice such that users can become
proficienl quickly. Computer users need io be
educated in computer basics as well as in the
proper operation of sofhvare. Without both lev-
els of (raining, users willnot be able to reap [he
maximum benefits from their computer system.
Usersshouldkeepup withnewer andbeller
versions of sofrware to make optimum use of
their hardware.
COMPUTER BASICS
The basic elements of a cornpuler system are
illustrated in Figure 12.1. Of primary interest to
nuclear medicine users are the input and outpul
(VO)capabilities of the system, sincea majority
of the Lime that the user spends at the computer
is dedicated to these tasks. This is true whether
the computer is used to acquire images andlor
textual data. Once the data are acquired by the
computer and depending on lhe desired output,
various forms of processing may be performed.
The overall purpose of a computer system is to
acquire data, process data, and provide the de-
sired output.
The inputs to a digital computer include ana-
log voltages from imaging devices, data in digi-
tal format, and keyboard entry (Fig. 12.1>. For
scintigraphic computer syslems commonly uti-
lized in nuclear medicine, the inputs are gener-
ally “X” and “y” posilional signals,isotope

CPU
Figure 12.1. Block diagram of computer system illustrates the input, output, storage, and cpu components
commonly connected by the system bus.
unblank signals (indicating that x and y signals
are due to the correct energy),andmultiple
physiologic signals(Fig.12.2).Thesesignals
pass through operational amplifiers which con-
dition their gains and thereby provide voltages
acceptable to the computer circuits. Within [he
computersystem, analog-to-digital converters
(ADCs) transform the analog voltages to digital
numerical values for binary storage and subse-
quent use by the cornpuler. During acquisilion
of gamma camera images, the input can be in
the form of a “list” mode or a “frame” mode.
With list mode acquisition, digitized positional
informalion lrom the ADCs, timing marks from
a real-time clock, and other data, such as phys-
iological triggers, can be stored in the order of
receipt as a form of high-speedrecording of
gamma camera data (Fig. 12.3). List mode data
can then be reformatted into images, with selec-
tion of various parameters such as time andlor
image, isotope A or 3 , and physiological gat-
ing. The most common mode of acquisition of
g a ~ n ~ ncamera
a images is [he “frame” mode in
which the data arc sorled into a frame such that
addresses in the frame array correspond to x and
Computer Appiicotions in Nuclear Medicine I I47
ditionally, input is a~ailable through hardware digital values acceptable to the computer (Fig.
devicessuchasjoysticks,light pens, track 12.1). Additionally, each I/O device has to be
balls, and “mice. ” These devices can provide supported by software (commonly called device
interactionwith either a menu or image data. drivers) such thatdata are passed to the com-
Use of the keyboard is required for input of puter in a meaningful fashion.
alphanumericinformation. Patient data,study There are many possible output devicesused
data, operator name, and the date and time are with computers. In nuclear medicine, the most
common examples of this type of information. common output devices include a display screen
Somemicrocomputershaveatouchscreen for text, a display screen for images and graph-
menu selection, while others require a keyboard ics,andaprinter.Thedisplayscreen for text
selection from a menu. For entering of precise should provide a text font (dot pattern to pro-
positional information, such as the outlining of duce text characters)whichiseasy to read.
a ROI within an image, hardware devicesin- Addilionally, it is desirable for the text display
cluding lightpensandothersdescribed pre- to have attributessuchas reverse videoand
viously are used. Many devices have a digital bIinking, to help prompt the operator for input.
output and connect with the computer through a A printershouldproduceroughly 40 words/
serial orparalleldigitalinterface(Fig.12.1). minute and may be either a dot matrix or a daisy
All analog input devicesrequire an ADC to wheel type. If the printer is a dot matrix type
lransform the input analog voltages to discrete and is ulilizedwithmicrocomputershaving
STORAGE COMP .ea2
y coordinates from the gamma camera field of
view (Fig. 12.4). This mode of acquisition fur-
nishes instantimages for storage and display
(no reformatting asfor list mode). In frame
mode acquisition, the x and y coordinate data
are sorted into arrays of 32 x 32, 64 x 64, 128 X
128, 256 x 256, or 512 x 512 elements, The
elements arereferredto as “pixels,” meaning
picture elemenis. Most nuclear medicine frame
mode acquisition utilizes 64 x 64 to 128 x 128
pixel images. Additionally, the mode of acquisi-
tion is commonly referred to as byle mode or
word mode indicating how many counts can be
stored at apixel.Bytemodeimages allow a
range of from 0 to 255 countslpixel, while word
modeimages allow from 0 to 65535 counts/
pixel. There is some variability in the range of
counts which can be slored in pixels for various
computers. A 64 x 64 byte mode imagerequires
a total of 4096 byles (4K byte) of memory for
storage. The storage requirements and common
uses for various modes of acquisilion are given
in Table 12.1. Figure 12.2. Block diagram of ADC and line amplifier used IW interface thc analog signals from gamma
The keyboard is the most common methodof cameras and physiological monitors to the computer. The line amp provides for adjustmen1 of the x and y
operator inpul to a scintigraphic computer. Ad- galnlna camera coordinate signals to provide image size and centering of the signals lorwarded to the ADCs.

I48 I Essentials of Nuclear Medicine Science
Table 12.1.
Memory Requirements and Common Uses for Nuclear Medicine Jinages
Matrix Size and Type Memory Requirement (Bytes)
32 X 32 byte 1024
32 X 32 word 2048
64 X 64 byte 4096
64 X 64 word 8092
128 X 128 byte 16384
128 X 128 word 32768
256 X 256 byte 65536
256 X 256 word 131072
512 X512 byte 262144
512 X 512 word 524288
graphics capabilities,specialgraphicscan be
produced. Special graphics printout capabilities
have been added to some daisy wheeI printers
COMP. a03
also. These prinlouts might include a graph of
Figure 12.3. List and frame modes of acquisition. List mode acquisition stores data from a real-time clock radioactivity versus time for a 57C0calibration
(m),
the coordinates (x and y), isotope information(z), and physiological gatingor trigger information (PV. sourceor a piechartshowingthefraction of
For viewing in the frame mode, these data must be reformatted.
different types of nudear medicine studies per-
formed on a monthly basis. The display screen
for images should provide a pixel resolution as
great as thatwhich is acquired(up to 512 x
5 12). Additionally, it is useful to provide a gray
scale capability of up to 255 levels. The image
display screen should also provide textual infor-
mation pertinenl to the patient, study, date, and
lime. Color displays are useful in applications
in which counts per pixel in one region of an
image must be visually compared with counts
per pixel in another part of the image, since our
abilitytodistinguishdifferent colors is gener-
ally better than our ability to distinguish differ-
ent gray levels. If color is utilized, a black and
white display capability should be available on
either the color monitor or a separate screen.
During acquisition, processing, and display,
images and other data generally reside in com-
puter memory. At other times,thesedata are
BYTE
COMPUTER MEMORY v
W6RD
BYTE
stored on either magnetic tape or magnetic disk.
These devices are par1 of the I/O of a cornpuler
but are not directly involved in the acquisition,
processing, and display chain of events and gen-
erally are referred to as mass storage devices.
Magnetic tape is slow in storing and retrieving
data bul is the cheapest way to store large quan-
Cowpurer Applicafions in Nuclenr Medicine / 149
Common Use
R s t dynamics-low resolution
Wst dynamics-high statistics
Dynamics-medium resolution
Dynamics-high statistics
Static and dynamic-medium resolution
Static and dynamic-high slatistics
Static-highresolution
Static-high statistics
Static-ultra high resolution
Static-highstatistics
tilies of data for long periodsof time. Indexes to
tape files should be available so that information
needed for futurereferencecanbefound
quickly. It is, therefore, desirable to have in-
dexes to datastored on magnetictape(tape
indexes) which areactuallystored on disks,
since disk access Lo data is very fast. Magnetic
diskstoragerangesfromremovable floppy
disketles (1-2-megabyte storage capacity)
to sealedmultiple-platterharddiskunits
(Winchester type up to 300-megabyte storage
capacity). The speed at which dala can be read
from or written to a magnetic disk is related to
storage capacity. Disks with greater storage ca-
pacity generally read and write data at a higher
speed. For a busy clinic, it is recommended that
disk storage capacity be sufficient to handle
1-2 weeks of clinical data, a1 which lime the
disk data would be transferred to tape and the
disks cleared. Directoriescontaining infoma-
tion about patients should be maintained with
eachdisk.The directoriesshouId include pa-
tient and study information sufficient lo allow
the user to access all stored data. This directory
information should be placed in the tape index
file when patient data are transferred from disk
to tape.
The cenkal partof the computer system often
is calledthecentralprocessingunit (CPU) or
microprocessor. It is this part of the compuler in
which all conlrol, logical, and arithmetic opera-
tionsareperformed.The CPU ormicro-
processor uses a common path called a bus to
1519 1 EssentiaIs of NI/clenr Medicine Science
pass data from one location to another (see Fig.
12.1). The bus contains a number of electrical
linessufficient for addressing (16-20 bits or
lines), for data transfer (8-16 bits or lines), for
control signals(variablewith CPU), and for
electrical power (variable with CPU) to support
devices connected to it. The CPU has access to
alargequantity of random access memory
(RAM) for use in storing dataand programs.
The CPU also has access to read only memory
(ROM) which contains a setof programs andlor
data that cannot be altered and that remain intact
whenthecomputerpoweris turned off. The
CPU has a limited vocabulary with regard to the
actions that it can perform. This vocabulary is
referred to as the instruction set for the CPU or
microprocessor. A computerprogram is a se-
quence of commands from this instruction set,
withdata insertedwhereappropriate. A pro-
gramcan be slored in ROM to providethe
computer withthe capabilityto read a key-
board, to display on a screen, to load files from
disk, to executeother program, and to perform
many other menial tasks. A collection of com-
puter programs for a commoa purpose is called
“software.”The software stored in ROM is
sometimesreferred to as a “monitor”ora
“commandinterpreter.” This software allows
the user to load and execute other programsthat
are stored on disks. It would be impossible to
have all the programs necessary in clinical nu-
clear medicine reside in the computer memory
at the same time; therefore, most of the pro-
grams called into use are read from disk. The
process of loadingandexecuting a program
initialry entails the lransfer of the program from
a disk to RAM. Once the program is in RAM,
the CPU is informed of the location, and the
CPU proceeds to interpret and execute the se-
quence of instructions that comprisethe pro-
gram. A system of operation in which part of
the system software (Le., the monitor) remains
in RAM, but most system programs are loaded
from disk and executed when desired, is called
a disk operating system (DOS).
When the computer is first turned on, a pro-
gram in ROM isautomatically executed. This
program may load another program, such as the
main menu, into RAM and start that program
running.The mainmenu program is used to
A p p k a i o n s i a Nucleor Medicine f
Comp~rfcr 251
allow users to select which programs to execute Gated Ventriculography images. This form of acquisition was unique to
in order to perform the desired tasks, such as
One of the most frequently requested param- the computer in that images were acquired rela-
acquirean image, displayan image,select a
eters of cardiac performance is the ejection frac- tive to the onset of cardiac contraction rather
ROI, and generate a curve. In older computers, than for preset counts or time as with a gamma
tion(EF) of theleftventricle. The EF isthe
the system was started by “booting” the moni-
amount of volume ejected from the heart (stroke camera only. Typically, 16-32 separate images
tor program from disk. The booting procedure
volume (SV)), divided by its initial resting vol- were acquired, with eachimagerepresenting
involved setting some switcheson the computer
ume (end diastolic (ED) volume). The SV can different time intervals within the cardiac cycle
and manually starting the computer by execut-
be determined by subtracting the minimum vol- (Fig.12.5.)Geometricalassumptionsfor the
ing asmall ROM program.Thesmall ROM
ume during contraction (end systolic (ES) vol- EF calculations were not used; instead, the very
program, when executed, would load a Larger
ume) from the ED volume. In the early 1970s, powerful and unique scintigraphicassumption
program from a specific location on a specific that counts are directly proportional to volume
the EF was calculated primitively by use of an
disk drive and start execution of that program. was theunderlying basis forthe EF calcula-
electronic gating device that allowed the sepa-
The program loaded was usually the monitor. tions.
rateacquisition of ED and ES images ofthe
Systemsofiwareisintendedtoprovide
blood pool within the heart chambers. The rela- Presently, this procedure typically is accom-
smoothoperation of the hardware associated
tiveventricular long-andshort-axeschanges plished by injectingthe patient intravenously
with a computer system aswell as many utilities
were measured between ED and ES and used LO with a small amountof nonradioactive stannous
to allow for development and management of
determine the EF. This method is exactly analo- pyrophosphate. After a proper amount of time
higher levels of software. Clinical software is
gous to the presentmethods used in single-plane (approximately 20 minutes), 15-30 mCi of
commonly developed in computer languages
contrast ventriculography, including allofits [wmTc]pertechnetate is injected intravenously,
suchas FORTRAN, BASIC, and C. These
associated geometrical errors. whichresults intheradiolabeling of the red
high-level software development languages
In 1977, Bacharach and Green (6) introduced blood cellswithintheintravascularcompart-
have to be supported by specialized libraries to
a method for acquiring gated cardiac blood pool ment (blood pool). Gatedcardiac blood pool
perform tasks associated with hardware specific
to a particular computer system. Clinical soft-
ware is distinguished from system software in
that it utilizes the computer system to perform
some clinical task. Generally, clinical software
is categorized as togeneral purpose,whether
that be acquisition, processing, or display. The
quantity and quality of clinicalsoftwareisa
major factor in selection of a computer system.
CLINICAL USES FOR SCINTIGRAPHIC
COMPUTERS
The mostsuccessfulclinical application of
the scintigraphic computer has been in the area
of nuclearcardiology (5). Thisapplication
clearly justifies the use of compulers in nuclear
medicine, since in most cases it would not be
possible to acquire and process these clinically
important studies without them.
Noninvasive methods of assessing cardiac
function are greatly needed, since clinical ques-
tions frequently arise about cardiac performance
under varying conditions of rest, exercise, and
pharmacological therapy, With the possible ex-
ception of echocardiography, these questions
cannot be answeredwithout resorting to more
invasive procedures, such as contrast angiogra- Figure 12.5. Sixteen-image gated blood pool study taken from a 24-frame MUGA study. The imagcs wcrc
ncquircd in a LAO projection from a normal patient. The ED image is in frame 1, and the ES image is in frame
phy. 10.
152 I Essentials of Nuclear Medicine Science
images are then obtained in the anterior (ANT)
and left anterior oblique (LAO) projections
(Fig. 12.6). The patient can either beat rest or at
exercise equilibrium.
Thecomputer is required to correctlysyn-
chronize the collection of data with the onset o€
cardiac contraction (Fig. 12.7). The eiectrocat-
diogram (EKG) “R-wave” is an acceptable ref-
erence of the beginning of cardiac contraction
and can be sensed electronically and sent to the
computerasa timing reference or“trigger.”
Two or more triggers are used by the computer
to determine the period of time between heart
cycles.Thisperiodisdivided by thedesired
number of gated images or memory frames to
find the time interval to allocate to each frame
(aproximately 20-100 msec). For the first inter-
val of time following a trigger, all of the gamma
camera dala sent to the computer are stored in
the firs1 frame.Subsequent intervals of time
within the first cardiaccyclehaveframes of
IONE HEART BEATIQNE
Figure 12.7,Multiple-gated acquisition illustrates the development of a single set of images representing the
average heart beat.
Complrrer Appiicafions itz Nuclear Medicine I 153
acquired data that picture the heart in various
stages of contraction and relaxation. The next
R-wave signals the computerto start over inthe
firstframe of memory. It is this “multiple-
gated” process that results in a series of frames
that are representative o€ an average heart beat.
This method often is called MUGA (multiple-
gated acquistion) whichis atrademark of the
Medical Data Systems WDS) Corporalion.
The averaging process required to obtain sta-
tistically significant images brings some disad-
vantages to the technique. Patients must possess
an unvarying heart rate in order to generate R-
wave triggers separated by a constant period. If
the heart rale is allowed to vary, the frames will
notrepresent discrete segments of the cardiac
cycle; instead, an averaged picture. of many dif-
ferent heart cycles results. A minimum acquisi-
tion time of 2 minutes is required to produce
clinically useful frames, and whenpossible,
acquisition of up to 10-20 minutes is obtained.
HEART BEAT 1
6 ALVERCIGE
HEART BEAT
154 I Esserzrials of h’ucleor MedicineScierlce
This minimum amount of time (2 minutes) pre-
vents the instantaneous determination of cardiac
function.Cardiac wail motion,obtainedby
viewingthe frames in rapid sequenceas an
endless loop (cine), results in therepetitious
viewing of a single average heart cycle.
The motion of thecardiac chambersfrom
variousviewscan help assess the extent and
degree of cardiac disease, especially myocardial
ischemia or infarction resulting from coronary
arterydisease (7). Theleftventricular EF
(LVEF) is an important index of cardiac func-
tion, parljcularly theexercise function of the
heart, since it falls with progressive increases of
exercise in the presence of clinically significant
coronary artery disease.
The LVEF is calculated by identifying to the
computer which region of the image represents
the left ventricle during the ED and ES images
(Fig. 12.8). After appropriate correction for ac-
tivity not emanating from the Jeft ventricle (i.e.,
background subtraction) (8), the EF is calcu-
lated by a simple subtraction of ED counts from
ES counts, the result of which is divided by ED
counts. Typically, the LV region of the image is
marked in each of the frames, which allows the
computer to generate a LV volume curve. From
this curve, LV filling and emptying rates can be
obtained and used as a sensitive indicator of LV
dysfunction. Additionally, the lefl ventricle can
be further subdividedinto regions, which al-
lowsdiscrete segments to be analyzed for lo-
calized disease.
The absolute volume of the left ventricle can
be determined by use of various methods that
solve forthe correction factor that relates LV
counts to volume (9). From this determination,
cardiac output can be determined,sincethe
heart rate is known. An ejection image formed
from the subtraction of the ES image from the
,ED image canprovideadditiona1 information
concerning the symmetry of wall motion. A
paradox image formed from the subtraction of
the ED image from the ES image providesinfor-
mationconcerningparadoxicalwallmotion
found in ventricular aneurysms and severe myo-
cardial ischemia.
Since the contraction of the heart is a recur-
rent event, it can be analyzed by Fourier princi-
ples by which the time-activity curve for each
nixel i n the image series is fitted to a fundamen-
tal frequencydeterminedfromtheheartrate
(10). This method has aroused considerable in-
terest, since it promises to be advantageous in
detection of subtle areas of abnormal wall mo-
tion and helpful in work with patients with in-
tracardiac conduction disturbances. The data
typically are displayed as “functional images”
representing the amplitude and phase of funda-
mental cardiac motion on a pixel-by-pixel basis.
Pseudocolor displays commonly are used for
displaying these functional images.
In summary, the motion of the heart wall can
be inferred from watching a cine presentation of
the MUGA study. Additionally, various investi-
gators have shown good correlation between the
determination of EF and ventricularvolumes
with determinations from catheterizationlabo-
ratory data (9, 11). A major advantage of the
MUGA study is that it is much less traumatic
than cardiac catheterization, yet provides infor-
mation concerning wall motion, EF, and ven-
tricular volumes.
Myocardial Perfusion
The early diagnosis of coronary artery dis-
ease (CAD) is of major therapeutic concern.
CAD affects more than half of the population of
the western world and accounts for approx-
imately one third of all causes of death. The
exercise tolerance test (ETT) has been the pri-
mary test forCAD, but poorsensitivity and
specificily(rangingfrom 70% to 80%) have
beenreported in many patientssuspected of
having CAD. In particular, the ETT is poor in
patients (a) with atypical chest pain, (b) with an
uninterpretable EKG, (c) with equivocal EKG
changes, and (d) who are receiving certain car-
diac medications. It is with these patients that
myocardialperfusion imaging is most useful.
The injection of[20’Tl]thallous chloride intra-
venouslyatpeak ETT stress,followedby
gammacameraimaging,hasresultedin a
markedincrease in thesensitivity andspecif-
icity for diagnosing CAD (12).
Inilially, the 201T1 study wasperformed with-
out a computer by acquiring “planar” images
directly from the gamma camera onto film. The
patientunderwent a standard ETT during
which, at near peak exercise, he was givcn an
intravenous injection of 1.5-3.0 mCi of 201T1.
Figure 12.8. LAO gated blood pool images taken from the same normal patient as i n Figure 12.5. This I‘igure
Thecxercise was continued for an additional
illustralcs a semiautomatic ROI selection nmcesr nacd in d ~ v ~ l n n i nrhp
u ~n~llm
rl,me
p .nrl c a ~ r l l l a r ; n n t h P FE

156 1 Essenriols of Nrrclenr MedicineScience
30-60 seconds, and within 10 minutes follow-
inginjection,thepatient was moved to the
gamma camera. Imaging was performed in sev-
era1 projections,althoughusuallyin ANT,
LAO, and lateral (LAT) projections (Fig. 12.9).
Thallium is a potassium analog that, follow-
ing intravenous injection, distributes itself to all
cells of the body in accordance with the balance
Cornpuler Applications in :Vuclear Medicine / 157
of perfusion and metabolic activity. Like po- The regional differences are expressed as a per-
tassium, itisrapidlyclearedfromtheblood cent washout which can be used objectively to
stream through an active pumping mechanism differentiateischemicfromnormalandin-
and concentratesin actively workingmuscle farctedmyocardium (Fig. 12.10). This method
cells (myocardium) as well as other cells of the is particularly useful, since it is unlikely to give
body. Therefore, the concentration of radioac- a false negative examination in patients having
tive thalIium within the intial postexercise im- balanced mullivessel disease.Inaddition, h e
ages of the heart muscle represent the reIative computer is usedwithvariousforms of to-
amount of perfusion and metabolic activity of mographicimaging.There havebeen special
the myocardia1 cells. Areas of relatively de- collimator methods such as the 7-pinhole and
creased activity represent areas of diminished rotatingslanthole (RSH) m e t h o d s ( F i g .
perfusion, as in ischemic myocardium second- 12.10B).More recently, 201T1 rotating camera
ary to CAD, or areas of reduced demand, as in tomographic imaging has proved to be useful.
scar tissue secondary to a myocardial infarction
(MI) (Fig. 12.98). Additional Clinical Uses
The distinction between ischemia and MI is Early in the history of clinical applications,
important, because early recognition of ische- ihe scintigraphic computer was used for quan-
miamay lead totreatmentpreventingan im- tification of patterns produced by h e transit of
pending MI. Identical images obtained immedi- radionuclidesthrough various organsystems.
ately following and approximately 4 hours after Amongtheseapplications was cerebral blood
theinitial stress injection are useful in differ- flow analysis whichwasused to evaluate the
entiating these two disorders. This is because of timing and symmetry of blood flow patterns in
the phenomenon of "redistribution," which is the carolid arteries, the middle cerebral arteries,
the cellular exchangeof 201T1so as toreflect the and the cerebral hemispheres. These studies
changing state of perfusion over time. The pa- were acquired in a dynamic frame mode with I
tient with myocardial ischemia during exercise framelsec for roughly 60 seconds following the
usually demonstrates near-norma1 perfusion in a bolus injectionof 20 mCi of g 9 m Tas~ pertechne-
resting situation, whichresults in the "filling- tate or of a renal imaging agent to provide rapid
in" of a defect seen on the initial stress image, clearance from the blood stream. Data analysis
whereas the patient with MI wouId continue to included a time of peak count anda comparison
demonstrate an area of relatively decreased per- of total counts between corresponding left and
fusion in a resting situation, which would result right anatomical regions (16).
in the persistence of a defect seen on the initial Computer processing of the lung during ven-
stress image. The sensitivity and specificity of tilationandperfusionstudieshasbeen per-
the planar imaging methods for the detection of formed to provide a form of functiond image in
CAD are considerablyhigher (85-95%) than which each pixel is the ratio of percenl counts
are those of the ETT only. Planar imaging is not during ventilation to percent counts during per-
very good at determining the extent of the dis- fusion (17). Thesefunctionalimages are re-
ease, however. In fact, it may appear normal in ferred to as V/Q images. The ventilation sludy
patients with balancedmultivessei disease, a is performed with 133Xe,whiletheperfusion
diagnosis that, due to its poor prognosis, should study is performed with 99mTc-labeledmacroag-
not be missed. gregatedalbumin (MAA) or albuminmicro-
The computer presently is used by many in- spheres. A functional image of the lung in
stitutions to acquire planar images. Digital im- which eachpixel of theimagerepresents the
age processing such as background subtraction clearance half-time or mean transit time (1 8) of
and filtering have proven to be of some diag- 133Xeduring the washoul portion of the ventila-
noslic value. A very important use of the com- tion study can be produced.
putcr hasbeen the quantitative comparison of A number of computer methods havebeen
the stress andredistribution 201Tl images (13, utilized to quantitate kidney function. The ma-
14). The activity of the images is individually jor problem associated with kidney evaluations
maDDed and comuared on a repima1 hasis (15) is hnrkornllnd rllhtrirrtkn T h e G;rIn-v ;r P - I O ~ ~ >
 Cornpurer Applicotiorrs i>z Nucleor Medieirge I 159

ated byimagingwithradiopharmaceuticals jection of the projection images into the volume

which are cleared primarily either by glomeru- scanned.
lar filtration (9mTc-DTPA) or by a combination In order to providequantitative data in the
of glomerular filtrationand tubularsecretion reconstructed slices, attenuation correction
or ['311]iodohippurate). Several methods musl be utilized. In order to apply attenuation
used for measurement of the giomerular filka- correction, a body contour and attenuation co-
tion rate (GFR) witha scintigraphic computer efficient mustbedelermined.Generally,the
are reported (19,20). The assessmen1 of percent body contour is approximated by an eclipse and
function per kidney is possible when imaging is a constan1 attenuation coefficient equal to that
performed.The mostaccurate proceduresfor for thewater employed. Additionally, unifor-
measurement of GFR and effectiverenal plasma mity correction with the collimator on must be
flow (ERPF) are by taking timed plasma sam- made LO eliminate potential ringartifacts that
ples andutilizing a computer to resolve the may appear in the reconstructed image due 10
plasmaconcentrationcurvedatainto multiplesystem nonuniformity. A high degree of me-
comparln~ents. Observinga cine compressed in chanical accuracy is required to produce SPECT
time from many minutes to several seconds af- images that arefree from artifacts dueto error in
fords visual inspection of the time course of the the center of rotation. With modem technology,
radiopharmaceutical within and around the kid- SPECT imaging systems produce high-quality
neys. This cine often provides infornlation not tomograms. The rotating camera tomographic
extracted quantitatively from the study. systems are limited, because the collimators
The use of scintigraphic computers for time often are far from the surface of the patient, thus
compression is a tremendous diagnostic aid for yielding poor resolution. Systems with patient
study of slow-time varying processes in the conlour tracking wiII help reduce the resolution
body. Studies such as gastric emptying, gaslro- losses due to excessive distance. Most SPECT
intestinal bleeding, and hepatobiliary imaging, imagers double as planar images wilh whole-
which require continuous acquisition of data for body scan capabililies and provide the userwith
extended periods of time,can be compressed a broad flexibility in imaging modes.
into a few seconds for viewing.By viewing of a Limited-angle tomography with 7-pinhole
cine, patient motion can often be separaled from collimators was introduced by Vogel el al. (26).
the actual motion of the radiopharmaceuticals. This form of tomographycouldbe achieved
The compulercanbelhought of as adigital with a low-cost upgrade of most compuler sys-
recorderwithcompletecontrol of playback (emsandgammacameraspresently in use.
speed. Limited-angle tomography is restrictedLo imag-
ing small volumes in which most of the activity
Tomography is concentratedwithin the organ of interest. This
The scintigraphic computer system is ideally type of tomography has been most successfully
suited to provide the processing necessary for used with cardiacimaging.Seven-pinhole to-
tomographic reconstruction of gamma camera mographyrequiresuniformitycorrection to
images.Thefirstreconstruction of transverse compensatefor variation in sensitivityacross
sectionlomographicimageswithuse ofa the field of view due to the different distances
gamma camera was reported by Kuhl and Ed- from a point within an object andthecorre-
wards in 1963 (21). Thisfeatamazinglyoc- sponding image of the point within each of the
curred when imaging computers were just being 7-pinhole images.
introduced to nuclear medicine. The techniques Limited-angle RSH tomographyprovides a
for single photon emission computed tomogra- significantimprovementover7-pinhole to-
phy (SPECT) are we11 known (22-25). Basi- mography (27). This form of limited-angle to-
cally, a gamma camera rotates around an object mography is low in cost and can be acquired as
acquiring imagcs at 2-6" intervals. The images an upgrade to computers and gamma cameras
are called projections. Most current reconstmc- presently in use. Multisegment RSH collin~ators
tion techniques involve filtering of the projec- with up to four scgments have been employedlo
tion images with a high-pass filter and backpro- improve system sensitivity (28). RSH tomogra-
160 I Essentiah af Nuclear MedicineScience
phy has proven to be clinically useful in evalua- iothalomate which is primarily cleared from the
tion of myocardialperfusionwith 2oTI. This plasma by glomerularfiltration. A common
form of tomographyissomewhatimmune to method used to evaluate GFR is to take multi-
gamma camera uniformity problems. ple-timed plasma samples and resolve the
Tomography utilized with annihilation radia- plasma disappearance curve into two compart-
tion from radionuclides which decay by posi- ments (19). The GFR is then calculated from the
tronemission is unique to nuclearmedicine area under the plasma concentration curve and
imaging.One of the mostsuccessful of the the total activity injected. If ['"I] or [1311jiodo-
earlier positron emission tomography (PET) in- hippurateisinjectedandplasmasamplesare
strumentswas the PET developed at Wash- evaluated in asimilarmanner, ERPF can be
ingtonUniversity (29, 30). PETinstruments evaluated (19).
have evolved from Ihe earlier single-slice im- A potential area for use of the computer in a
agers to multiple simultaneous slice (up to nine nuclearmedicinelaboratorywould be radio-
capabilities) (31). PET imagers are believed to pharmaceuticalinventory.Records of receipt,
havealimiting,full-widthhalf-maximum use, and storage could be maintained from en-
(FWHM) resolution of approximately 4 mm. tries made by the radiopharmacist. Periodic re-
An advantage of PET imaging is the availability ports can be produced by use of database soft-
of positronemittersforelementssuch as car- ware customizedfortheindividual user.Soft-
bon, oxygen, and nitrogen which areof tremen- ware such as dBASE I1 (or HI) and UYIUS 1 ,
dous biologicalimportance.Thedisadvantage 2, 3 can beeasily configured tohelpindata
of PETimagersishighcost. In addition, a management of radiopharmaceuticals.Several
cyclotronnearby is necessary to providethe users have reported computerized record keep-
large quantities of positron emilters necessary ingand inventory programs for nuclear medi-
cine laboratories (33-35).
for imaging.
Computerscanbe used to analyzeresults
LABORATORY USES from wipe or swipe tests for removable radioac-
The digital computer is useful in laboratory tive contamination. If energy information (mul-
environments for data storage and retrieval, tiple-channel analyzer (MCA) output or multi-
curvefittingandcalculationsand, in general, ple-channel counting) for each sample is passed
any task that can be reduced to a fixed sel of to thecomputer,aquickcheckfrom known
instructions.Thecornpuler is bestsuitedto samples can provide information as to the most
solving problems that require a large numberof likely radionuclide found and an estimate of the
calculations,justthetypeproblem fOT which reporled level of radioactivity in microcuries or
humansareleast well suited.Computers are disintegrationsperminute.Thisisextremely
utilized in almost all laboratories to help with useful when many wipe testsare to be evaluated
data reduction in radioimmunoassay (RIA) pro- at once. If the gamma counter has digital oulput
cedures. In this role, the computer takes results (usually paper tape) that the computer can read,
from a gamma counter in a prearranged order the whole process can be automatedin terms of
data entry. A report can be generated that sum-
andcalculatesthestandardcurvetoapplyto
patient samples to convert from raw counts to marizes the results of the wipe tests.
units of microgram per milliliter (or whatever Althoughthecomputerhas not metwith
units were givenfor the standard samples). With much success in providing interpretation of clin-
proper curve fitting algorithms (32), thecorn- ical images, it has proven useful in providing
putercanproducequick and reproducible re- suggesteddiagnosisbased on laboratorytest
sults for RIA. results fromareas such as blood gas evahations.
The computer has also been used to evaluate If a logical approach for interpreling a test or a
plasma clearance rates of various radiopharma- combination of tests is known, the computer can
ceuticals by analysis of the plasma concentra- be useful. For some in vitrotestssuch as the
tion curve as a function of lime. GFR can be Schilling test, inlerpretative reportingof labora-
assessed from counting plasma samples of lZ51- tory data is possible (36).
Computer Applicntions in Nuclear M e d i c h e
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computed tomography. In Herman GT (ed): I m a g e Re-
currandon from Projec~ions-implerrrerrrfl,ions nrrd
Applicarions. New York, Springer-Verlag, 1979, pp
147-246.
26. Vogel RA, Kirch DL, LeFree MT, el al: A new method
of multi-planaremissionlomographyusingscvcn
pinhole collimatorand an Anger scintillation camer:l.J
A'wl Med 19648-654, 1978.
27. Goodwin P N Recent developments in inslmmenlation
for emission computed tomography. S m i n Nucl Med
10322-334, 1980.
28. Lasher JC, Blumhardt R, Kopp DT, et al:Emission
Computedtomography: versatile limitedangle sofl-
ware. In Esser PD (ed): Emission Cornpured Tornogra-
ph.v-Czrrrent Trends. New York, Seciety of Nuclear
Medicine, 1983, pp 21 1-226.
29. Phelps ME, Hoffman EJ, Mullani NA. Ter-Pogossion
Mhl: Application of annihilakion coincidence dclectlon
lo transaxialreconslrucliontomography. J Nlfcl Mcd
16210-224,1975.
30. Ter-Pogossian M M , Phelps ME. Hoffman El, el al: A
positronemissiontransaxialtomograph for nuclear
medicine imaging (PETT). Radiology 114:89-98,
1975.
31, Goodwin P N Recenl developments in instrumentation
for emission computed tomography. Sendin Nucl Med
10327-331, 1980.
32. H ~ l lCH, DworkinHJ:Computers in theradioim-
munoassaylaboratory. In Lieberman DE (ed): Cow
purer Methods: The Fundamenfals of Digital h'uclear
Medicine. St Louis,CV Mosby, 1977, pp 114-129.
33. Herron DS: A computerizedradioactivematerial in-
ventory systcm. Heulrh Phys 37598-600. 1979.
34. Richards L A small-scale computerized isotope record
monitoring systcm. Heulrh Phys 36540-642, 1979.
erized system for conlrol and management of radionu-
 13
Iatrogenic Alterations in the Biodistribution of
Radiotracers as a Result of Drug Therapy:
Theoretical considerations
Robert Hodges
For many years, radioisotopetracers were the
exclusive tool of researchers for study of bio-
dislributionandphysiologicfunctionwith
highly controlled experimental prolocols, As
their use in humans proliferated, it was found
that theseagents behaved in quite unexpected
ways in [he generally uncontrolled clinical set-
tings. In theseearlydays, only the naturally
occurring radioactive isotopes of I , P, Ca, etc.
were available. These were elements whose bio-
logical dislribution had been fairly well estab-
lished.Moreover, imaging with theseagents
was intended to identify gross physiological
manifestations such as bone demineralization or
thyroid physiology.
The advent of 99n’Tc providedthe first tool for
convenient and extensive labeling of a variety of
molecu\es. After questions of safety were re-
solved, its acceptance was so rapid and its use
so diverse that there waslittle timelo investigate
just how the bodydeals with thisunfamiliar
metal.
Although labeling of biologic molecules with
99mTcwas becoming a common practice, what
effect labeling would haveon biodistribution of
the molecule was not known. Even the nature of
the pertechnetate ion was a puzzle long after it
became a workhorse of nuclear medicine.
Although pertechnetate was similar to iodine
in much of its biologicbehavior, researchers
recognized the importance of elucidation of its
behavior, Evenas it wasbeingwidelyused,
studieswerelaunched to investigateprotein
binding (1) and organification of pertechnetate
by thethyroid (2), as we11 asthe nature of
sali\Fary secretion (3, 4), gastric and inteslinal
secretion ( 5 , 6), and the mode of excrelion (7,
8).
As thesestudiesproceeded,journals were
increasingly publishing reports by clinicians of
the bizarre behavior patternsof pertechnetate in
theirpatients.Manytimes, i I was a phar-
macologicagent that was responsible for the
unexpected behavior of the tracer. This opened
the eyes of practitioners to the fact that many
factors, including disease states, surgical proce-
dures, radiation therapy, drug therapy for con-
trol of tumor growth, and drugs for supposedly
unrelated conditions, could affect the distribu-
tion of kacers (9).
Anychemicalagentor other influence (in-
cluding a drug) which alters either the nature of
the tracer or the biochemical milieuto which the
tracer is exposed may result in unexpecled be-
havior of the tracer (10). Because “abnormal”
radiotracer behavior suggests some biochemical
anomaly which may reflect underlying pathol-
ogy: it is necessary to rule oul the possibiliiy of
an arti€act, or a physiological alteration that is
drug-induced, before diagnosis and subsequent
therapeutic decisions can be made with confi-
dence.
In addition, becausemost drugs exert (heir
lherapeulic effect by altering ongoing physio-
logical processes,someeffects of drugs can
mimicdiseasesymptomsor, in certain in-
stances,induce disease. Such induceddisease
due to d i m 1 drug toxicity, such as acute tubular
 Drug-irlduccd Alterations: Theoretical Consideratiom I 167
166 I Essentials of NuclearMedicirleScieme

necrosis, or more indirect effects, such as sys- concept will also account for the fact that op- inglysosomal enzymes and cause releaseof and nonactin, interact with lipid bilayer mem-
ticalisomers of the same molecule hequently histamines, prostaglandins, or their precursors, branes and increase their permeability to small
temic lupus erythematosus, may also affect ra-
diotracer distribution and interfere with the dif- have different bioactivity and perhaps will help or they may initiate chaotic activation of the ions via a carrier mechanism comparable with
to explain some mechanisms of tracer uptake. complement cascade with intense ramifications that in thehighly ion-permeablenerve mern-
ferential diagnosis.
Receptors have been identified for cholinergics, for membrane function. branes. Olher membrane-modifying molecules,
FACTORS THAT DETERMINE P-adrenergics,
insulin,
angiotensin 11, gonado- SeIective membrane permeability isan essen- such as gramicidin A and alamethicin, facilitate
BIODISTRIBUTION OF glycogen, prolac tin, TSH , estrogen,
topin, his- tial characteristicof the living cell. The most the passive diffusion of ions by creating a path-
RADIOTRACERS [amines,
narcotics,
steroids.
and Of these, essential active functions of membranes include way through the membrane through which ions
selective control of the movements of ions and canmovedownan electrochemicalgradient.
Physicalandchemical properties of radio- steroidreceptors appear to b e withinthecell,
other solutes,packagingandtranslocation of Other pore-forming antibiotics are nystatin and
tracers determine, in part, how the radiotracerswhilethe othersarelocalized oncellular sur-
macromolecules, groupingandorientalion of amphotericin B (20).
will localize.Binding to plasmaproteins or faces.Receptors might beexpectedtobepoly-
enzyme systems, and transmission of extra- There is extensive literature on the effects of
intracellular constituents of blood cells, relative mers or portions thereof and would include pro-
teins and nucleic acids (12). cellular informationto the ceIl interior(16). anesthetic drugs on the transmembrane flow of
lipidandlor water solubility, extraction by the
Examples of radiotracers that are thought to Sevenleen glycoenzymes havebeen identified ionsandneutral solutes. It appears h a t the
reticuloendothelial system (RES), ionicsize and
have specific receptors are the cationic isotopes on cell surfaces. Some are involved directly in aneslhetics can increase or decrease passiveand
mass, active or passive transport systems, cel-
and the metabolically active tracers. Lysosomes transport across membranes, and some prepare aclive flows. Facilitated diffusion or carrier-me-
lular metabolism, and binding to receptors may
contain an excess of anionic groups and should their substrates for transport by converting them diatedtranslocation of glucose is inhibited by
play a role in radiotracer Iocalization (10).
demonstrate a considerable capacity for binding to ploducts [hat can be handled by other trans- halothane,methoxyflurane, ether, and various
Radiotraceruptake in disease states can be
of divalent cations which mighl reach the vesi- port systems (17). alcohols and detergents. Edcilitated transfer of
conceptualized i n terms of aIteredregional
Although membranes are much less permea- amino acids is inhibited by ethanol. It appears
physiology. Neoplasms,inflammation,and in- cleinterior(13).Onegroup of compounds
ble tocations than to anions, it is known h a t that neutral anesthetics increase passive cation
farcts are characterized by microvascularization called asialoproteins are known 10 bind to recep-
immunologicalreactionsalterlhelowcation diffusion, while positively charged anesthetics
which increases perfusion and capillary bed per- lors found only on the hepatocyte membranes.
e

pemleability of membranes. In inlact cells, cat- decrease it (21).

meability, resulting in entry of macromolecules These agents have been labeled and appear to be
ion permeability is a funclion of membrane A largevariety of organicmolecules show
into interstitial fluid space. In addition, the in- excellent hepatocyte imaging agents (14).
structure and is interdependentwith cellular me- localanestheticactivity, which suggests that
creasedmacrophageactivitythat occursmay
DRUG EFFECTS ON BIOLOGICALLY labolism. Membrane cation permeabilitymay localanesthesia mustresult from a relalively
resultiningestion of radiolabeledmac-
LMPORTANT MOLECULES WHICH be modified by lectins or antibodies, by activa- nonspecific interaction rather than from a spe-
romolecules,whilepinocytosis may result in
MAY RESULT IN CHANGES IN tion or inactivation of transportsites,orby cific binding of thedrug toareceptor in the
ingestion by other cells in the lesion. There may
RADIOTRACER DISTRIBUTION changes in kinetic parameters of transport pro- membrane (22). Thisiscompatible with more
also be suecific receotor d e s on the cell ~ n e m -
Cell Membrane cesses (1s).The direcl-acting cholinergic agents recent concepts of receptors. The lraditional
brane for theradiolabeled macromolecule and
are an example of a class of drugs that increase “lock and key” model of membrane receplors
possible intraceIlular translocation of the label A wide rangeof drug classes exert their phar-
membrane permeability to cations (12). has been modified to suggest that both the drug
( 10). effects
macological
membrane. cell on the Because most neurotransmittersanddrug and receptor have three-dimensional flexibility
It is evident that thedistribution of radio- Groups such as autocoids andtheirantagonists,
moleculesarecationic at physiological p H , and that the surface topography of both can be
[racers is based onthe samepharmacokinetic localandgeneral anesthetics,diuretics,antibi-
acidiclipidsare likely candidates to serve in varied by mutua1 inductive forces or by other
principles that have been describedfor thera- otics,steroids, fat-solubie vitamins, and many
transportmechanisms or to serveasbinding chemicalspecies in the vicinity. Current con-
peutic agents, including structure activity rela- cations have supposed sites of action on the cell
sites themselves. Threerolesforlipidshave cepls of molecule-receptor interaction conform
tionships (SARs) and binding to specific recep- membrane. It is thoughtthat many drugs can
been described: (a) direct involvement in ligand tousual chemicalbondingphenomena,i.e.,
tors. relatively
cause changesmajor in the properties
binding, (b) service as cofactors for the recep- covalent, ionic,ion-dipole,hydrogen and van
According to this SAR concept,theactions of cellmembranes. It is likely that thelarge
tor, and (c) service as regulators for the receplor- der Waal bonding forces (12).
of a drugareintimatelyrelatedto chemicalmembranepermeabilitychanges that occur in
effector system, Le., lipidsthat surround recep- Many, if not most, of the membrane actions
slructure, and minor modifications in molecular the presence of some drugs represent upheava1
tor molecules modulate the three-dimensional of anestheticsandtranquilizersoccur in both
slructure may cause major changes in biologic of the membrane ullrastructure, e.g., the crea-
structure and regulate affinity for the receptor or excitable and nonexcitable membranes. It is
behavior. For instance,itshouldbepossible, tion or enlargement of poresthroughwhich
regulate the laleral mobility of the receptor and generally assumed that the primary actions of
with use of knowledge of SAR, to augmentlipid-insolubleionscanpass (15). Thisper-
lhus conk01 the ligand-receptor complex inter- anesthetics are on the cell membrane rather than
specificity of tracers for acutely infarcted myo- meability may occur through a direct interaction
action with an effector (second messenger) such on the intracellular processes (21).
cardium (1 1). between the pharmacologicand agent a particu-
as adenyl cyclase (19). A relationship between localanesthetic po-
Thc concept of a drug receptor is important to lar cell ~nen~brane by creation of a channel of an
Lipidbilayermembranesare highly imper- tency and lipid solubiIity suggests that the pri-
theunderstanding of radiotraceruptakeand appropriate size and ioniccharge to allow pas-
meable lo small inorganic ions. A variety of mary effect of local aneslhetics is on the lipid
serves ta explainthe minute quantity of some sage of the tracer. The pharmacologic agent can
molecules, including the antibiotic valinomycin component of the ceIl membrane (22). If the
drugs needed IO elicit a measurable effect. This enhance cellular expulsion of membrane alter-

membrane contains lipids in both the gel and
liquid-crystalline phases, the addition of anes-
lhetic could, by lowering the lipid phase transi-
tion temperatures, trigger a change from thegel
phase to the liquid-crystalline state resulting in
anincrease in fluidity of the membrane (22).
Whenalipid undergoes a phasetransition,
otherphysical parameters,inaddition tothe
fluidity, change, i.e., both lipid packing density
andpolarhead groups arealtered (19). Mem-
branes undergoing a phase transition have
shown increased binding of proteins and fluo-
rescent probes as well as enhanced membrane
wansport of dyes andincreased enzymatic ac-
tivity (24). Thedegree of membranefluidity
affects enzymeactivitysuchasCa+2-ATPase,
Na+-K+ATPase and lhe P-galactoside transport
system (25). The resuitant effect on the trans-
port of tracers is open to speculation.
Following the discovery that cationic, amphi-
philic drugs such as chlorpromazine (CPZ) en-
hance 32P incorporation into phosphatidic acid
and phosphatidylinositol, results of subsequent
studies have led to the realization that CPZ and
otherdrugssuchaslocalanesthetics,im-
ipramine,amphetamines, and kvorphanolact
on phosphatidate phosphohydrolase in intact
cells. These agents modify the pattern of incor-
poration of labeled glycerin into glyceroIipidsof
liver lymphocytes.Theultimateeffect is an
increased cellularphosphatidylinositolcontent
( 16).
Phosphatidylinositol, a membrane phos-
pholipid, binds divalentcalionsavidly,but
without great specificily for individualionic
species.Affinityformonovalentcationsis
much lower (16).
Great strides are beingmade in the under-
standing of the multiple roles that the Ca+2ion
plays in ihe regulation of cellfunctionand
membranefluidity.Ionized calcium may be a
mediator for a number of cell functions, such as
cellular and organellar motility or microtubule
fluxes, and may reflect surface membrane
changes or othereventscloselyrelated to cell
funclion (26).
Calciumplays acritical role in contro1 of
intracellularcyclicnucleotideconcentration
through itsability Lo inhibitadenylcyclase,
stimuiate guanyl cyclase, and regulate the phos-
phodiesterase regulator protein (27).
Calciumand acidicphospholipids are inti-
matelyinvolved in excitatory mechanisms of
biological membranes, and Ihe displacement of
membraneouscalcium results in a funclional
inslability of the membrane (27).
It is likely that in biological membranes,
Ca+2 conlrol of permeability involves specific
interactions of Ca+2 with proteins. Conforma-
tional changes in theprotein by itself or in
concert with surrounding lipids couldbe re-
sponsible for permeability changes (28).
ThedivalentandtrivalentcationsMn+2,
Mg+l, Co+l, Lai3 andthe organicmolecules
methoxyverapamil andnifedipineare calcium
channel antagonists. Some data suggest that the
calciumchannels may possessgating mech.
nismsinvolvingphosphatidylinositolbreak-
down as the initial event required to open cal-
cium channels following agonist-receptor inter-
actions.Theorganic calcium antagonists that
havebeendeveloped may block entry of cal-
cium ions from the outside to the inside of the
cell and modify the effects of various calcium-
dependentagonists. Quercitrin anddantrolene
are also Ca+2 antagonists. In the Ca+' channel,
divalent cations wilh ionic Iadii similar to Ca+*
may be expectedtosubstitute for or act as
antagonists of CaT2 permeation. Both Sr+' and
Bat* can substitute €or Cat2 (29).
Hormone-receptor interactions may result in
direct changes in thephysical, electrical,and
biological properties of the ceil membrane.
These alterations in membrane structure may
have implications in h e transport of other mole-
cules (30).
Liposome-cell interactions have induced
changes in cell membrane composition anda
variety of cellular activities. Charged liposomes
alter the carrier-mediated transport of divalent
anions. Data have indicated a specific effect on
thecarrierand not anonspecific increase in
membrane permeability. Membrane micro-
viscosity and such properties as osmoticfra-
gility, glycerol, and K t permeability have been
altered byliposome interactions with erylhro-
cytes, platelets, normal lymphocytes, andleu-
kemiccells.Liposomestudiesalso showthat
Drug-indrrced Alleratiom: Theoretical Considerorions I 169
the presence of acidic groups within the bilayer esterase,aldehydedehydrogenase,carbonic
increase permeability to cationsanddecrease anhydrase, dopa decarboxylase, monoamine
permeability to anions. The interactions be- oxidase, and xanthine oxidase.
tween liposomesandcellscan haveprofound
effech on the properties of cell membranes
MECHANISMS BY WHICH DRUGS
(31).
It is not yet possible to document the precise
MAY AFFECT DISTRIBUTION OF
SPECIFIC RADIOPHARMACEUTICALS
effect that [he previously discussed factors may
play in membrane transport, especially with re- [ 99mTc]Pertechnetate
gard to radiotracers. Technological advances After intravenous injection of pertechnetate,
are,howeler,makingpossible a muchmore a I a g e fraction of the activity leaves the blood
detailedunderstanding of membrane per- within 1 or 2 minutes and equilibrates in various
meability and transport of a variety of charged compartments (5). It is selectively taken up by
andneutral molecules and particulates. A few the stomach, thyroid gland, salivary glands,
suspected drug interactions with radiotracers mucosal lining of the nasal sinus, and choroid
will be considered later in the chapter in light of plexus (32).
the previous discussion of membrane transport. The effecliveness of pertechnetate for tradi-
tional brain imaging depends on its distribution
Blood Components in the extracellular spaces and on its exclusion
Concern about alterations in the lransport of from normalbraintissue (33). It is generally
tracers must focus not only on theeffects on believed that it is the blood-brain barrier (BBB)
membrane permeability but also on interactions that is responsible for the exclusion of perlech-
of the tracer in particularcompartments.For netate from normal brain [issue. Uptake of per-
instance,manymolecules and bloodcompo- technetate by the choroid plexus, salivary
nents found in the circulatory system can inter- glands, andoral mucosa interfereswith brain
act with tracers. No1 only can plasma proteins scan interpretation. The use of oral perchlorate
bind with the Lracer, but body tissue may pro- to block uptake in the choroid plexus is routine
duceantibodies to the tracer. The tracer may practice in nuclear medicine departments that
also interacl with red blood cells, platelets, and ulilize pertechnetate for brain scans. Perchlorate
neutrophils. The fateof the tracer is therl depen- works by competitively inhibiting the uptake of
denton the destiny of the blood component. periechnerate by the choroid plexus and salivary
Fewer binding sites may be available to tracers glands, thus preventing an increased discharge
that bind to serum prolein if therapeutic doses of intothecerebrospinalfluid (CSF) andsaliva.
drugs that are highIy protein bound are present The synthetic anticholinergic drug glycopyrro-
in the blood pool. Their presence could be ex- late has been used in place of perchlorate for
pected to alter the biologic half-life of the tracer, almost complete eliminationof activity from the
as larger numbers of the tracer molecules are choroid plexuses and mouth and for moderate
free of binding and are available for elimination reduction in parotid gland activity (34).
or for interacting with cell membranes or with The ability of perchlorate and other agents to
olher agents in the blood stream. atrenuale or block the uptake of pertechnetate at
its usual uptake sites has generaIly been advan-
Enzymes tageous. Since these agentsblock several secre-
Becausecellsareenzymaticallycontrolled, tion routes, tissue concentrations in blood, tu-
that drugs havean effect on enzyme function mor, and brainare generallyincreased. These
suggests a possibleinterference. Several en- levels decline more slowly, which results in pro-
zymes regulating synthesis of criticalcellular longed tissue concentrations. This effect may or
constituents have been shown to be affected by may no1 be advantageous,depending onthe
drugs at clinically obtainable bloodand tissue tissue ratio and the type of tumor being imaged
levels. These enzymes include acetylcholin- (35).
 Drug-i>gducedAberarions:TheoreticalConsiderations I 171
170 I Esselztials of Nuclear MedicineScierrce

Pinocytic activity in brain capillaries in those parathyroid extract prior to aluminum ingestion blood sinuses of the liver, lung,spleen, and
11 has been shown that in rabbits, perchlorate
increases intestinal absorption of aluminum in bone marrow (51). The RES is a complex sys-
causes a major tissue redistribulion of pertech- areas protected by the BBB is known to operate
rats (47). Thisobservationshould raise some tem and is far from being understood; never-
netate, probably resulting from release of per- at very low levels under normal conditions. In
question as to the degree of aluminum absorp- theless,wideuseismade of itsreactionto
technetate from plasma protein-binding siles contrast, in almosteverystudy ofpathologic
tion in hyperparathyroid patients. radiolabeled sulfur colloid and albumin colloid.
with redistribution to tissue extracellular spaces damage of the BBB during which the capillary
With use of pertechnetate in brain scans, ill- Liposomes and vesicies are coIloid dropIets
and a shift intracellularly. With regard to blood macromolecular transfer is enhanced, a consid-
defined, diffuse activity may be observed fol- which may, someday, be foundto play a signifi-
plasma, the pertechnetate contentof scalp, lum- erable increase in the numberof pinocytic vesi-
lowing contrast cerebral angiography with Re- cant role as carriers of radioactive labels (53).
bar skin, skuil, muscle, and brain is increased cles has been reported (42). That capillary ade-
nografin 60. Contrastmaterialusedforan- The physiological activities of the RES and
significantly. Pertechnetate also moves from nylcyclasecouldbeactivatedbyhistamine
giographyalterstheBBBandpermits a the factors that influence this diffuse system of
plasma into red cells within 2 or 3 minutes after receptors reflects an important pathologic phe-
detectable concentration of radioacdvity to lin- fixed and mobilemacrophages are numerous.
perchiorateadministration, and the degree of nomenon. It hasbeen proposed that in patholog-
ger in cerebral parenchyma up to 6 hours after The involvement of the RES in lipid metabo-
protein binding drops from 80% to 40% during ical cases, effectivepinocytosis giving rise to an
increase in certain lransporl processes of brain injection. The greater concentration of activity lism, protein metabolism, iron metabolism, tu-
this time (36). has been reporled to be at the perimeter, which
capillaries could be derived from the enhanced mor growth, shock,radiation therapy, infection,
Practitioners, in attempting to explain unex- would indicate that the cortex is most sensitive
pected uptake of pertechnetate-labeled ligands, cyclic adenosine monophosphate (CAMP) pro- anda variety of immunoIogica1 processes has
to Renografin 60 (48). Vascular endothelial in- been adequately documented (51).
sometimes discount the possibility of dissocia- duction occurring due to the activalion of capil- jury produced by antigen-antibody complexes
tion of tracer from the ligand because they do lary adenyl cyclase (43). Since brain CAMP can In addition, activation of the RES during bac-
may result in blood coagulation,fibrinolysis, terial infectionanddiseases of autoimmunity
not observe stomach or thyroid uptake of per- be increased by a variety of means, including and the generation of bradykinin (49).
catecholamines, histamines, serotonin, elec- has been suggested to be a physiological host
technetate.However, a rapid red bloodcell When tin comp1ex (cilrate or pyrophosphate)
(RBC) uptake of the liberated pertechnetate, as trical impulses, andother depolarizingagents defense response, while depression of the RES
suchas high potassiumconcenlration,CAMP is administered prior to perlechnetate, the dis- associatedwith circulatoryfailuresmay be a
is observed with tin during in vivo labeling of tribution of the tracer is altered, the concentra-
RBC: could conceivably occur under the right mayplay an importantrole in situations in crucial factor in the development and progres-
which the BBB breakdownoccursviapi- tion in cerebral pathology is reduced, the con- sion of a disease process (51).
conditions. cenlration in mucouscells in thestomach,
The protectionafforded by the BBB is lost nocylosis (44). The RES, as a constituent of the vascular
thyroidand salivaryglands, andthe choroid system, can be affected by at least two routes:
when tumors, cerebrovascular accidents, ab- S h d y of mammalian cell cultures define pi-
plexuses is increased, and thereis a shift of (a)vasomotorsystemand(b)substances cir-
scesses, and other abnormalities break down the nocytosis as the cellular ingestionof fluids. The pertechnetatefromplasma to the RBC. These
BBB and allow abnormal tissue accumulation of uptake of solutes during pinocytosis is due to culating in the blood and lymph. In the former,
kinetics appear to be affected by [he action of theautonomicnervoussyslem,vasoactive
radioiracers (37). The uptake of tracer often is their presence in the fluid ingested. It may be
Sn+* which seems to localize preferentially at amines, or vasotropic tissue substances may di-
much higher in brain tissue adjacent to tumors that pinocylosis takes part in the nutrition of the the sites listed, forming stable complexes capa-
than in distantareas of the brain.Thislocal cellandalsoserves as a means of recycling minish transport of substances bound forthe
ble of reducing pertechnetate anion and fixing it RES. In [he latter, shortage of plasmafactors
uptake may be as much as or evenmorethan membrane components utilized during ex-
at the tin-binding sile (50). promoting phagocytosis, blockage of pha-
that of the tumor itseif. Uptake of radioaclivity ocytosis. Agents reported to induce CAMP-me-
by edematous tissue could explain lhe widening diated pinocytosis include inorganic salts, pro- gocylic sites by cell debris or fibrin products,
RES-imaging Agents and the appearance of endotoxins or lysosomal
of the radioactivity zone surrounding some tu- teins, biological stains, macroglobulins, and
In 1924, the term reticuloendothelial system enzymes that damage the RES cells may reduce
mors (38). It is known that excessive amounts of albumin (45).
Elevated plasma aluminum has beenreported (RES) was introduced to describe abody of the ability of the RES to respond in an expected
protein may pass from the capillaries into tissue
in vivodistribution of [99mTclper- mesenchymal-derived cells that form a diffuse manner (54).
and contribute tothe localedemaand, in the toalterthe
system of sessileandwanderingmononucIear The functional state of the macrophage is a
process,transport prolein-bound pertechnetate technetate (46). In the hemodialysis patient, in
macrophages that havetheability to rapidly majorfactordeterminingtherate of intra-
LO the tumor site. Capillary damage due to the parlicular, there is the potential for interference
ingest foreign particulate matter (51). vascularphagocytosisbythe RES. Glucan,
release of loxins and to the developmentof local with pertechnetatedistribution.Hyperalumin-
RES constitutes an important part of cellular zymosan, estrogen, endotoxin, and Bacillus
lactic acidosis also contribute to the vasogenic emia sufficient to cause encephalopathy has
host defense in the removal and degradation of Cabnetre-Gukrin (BCG) are potent RES stim-
edcmaandproteinextravasation (39). Dex- been reported to result from the presence of
aluminum in the dialysate solution.In addition, bacteria,endotoxin,tumor ceIIs, andforeign ulanls, while corlisone, methyl palmitate, ethyI
amethasone has been shown to be superior to
material from the blood (52). This removal and palmitate, and antilymphocyte serum are potent
other steroids in reducing cerebral edema sec- aluminum-containing antacids are frequently
degradationprocessisaccomplished by fixed RES depressants. There are differences between
ondary to intracranial lunlors (40). It should be prescribed as phosphate binders for patients
macrophages of the RES whose anatomical negativelychargedcolloidsandpositively
noted that steroids reduce the Lumor accumula- with chronic renal disease.This situationaf-
proximity to thecirculationenablesthem to chargedcolloids,asmeasured in vitro, with
tion of 99n1Tc-dielhylenetriaminepentaacetic fords additional opportunity for development of
have direct contact wilh such blood-borne mat- respect to both the rateof vascuIar clearance and
acid (DTPA) which is not significantly protein hyperaluminemia in the dialysis patient. It has
been lurlher observed that the administration of ter. 11 includesmacrophages Iocalized in the relative hepatic distribution. Although it is rec-
bound(41).
172 I Essenfials of NuclearMedicine Science
ognized thal the chemical and physical proper-
ties of the surface of the entity being pha-
gocytized will have significant effects on its rate
of removal, the relationshipbetween the in vitro
measurements of the charge of a particle and the
actual charge of a particle circulating in vivo
remains to be ascertained, since particles with
differentelectrophoreticmobilitiesin the ab-
sence of serum have been shown to exhibit sim-
ilar charge characteristics when h e y have been
incubated with serum (51).
Data suggest that adherence of particles on
phagocyte membranes maybe a passive process
not dependent on a metabolic energy expendi-
ture, while ingestion of the particle by the re-
ticuloendothelial cellis anactive process. i n
this regard, metabolicinhibitorsseverely limit
the ingestion phase of phagocytes. In addition,
variation in age, organ size, body weight, blood
flow,temperature,cellularmetabolism, hor-
monal levels, and reticuloendothelial cellular
population dynamics can profoundly influence
intravascular phagocytic activity (5 1).
Phagocytes have the ability to discriminate
foreign macromolecules and tissue debris from
healthy endogenous matter. The ability of mac-
rophages to distinguish “self’ from “nonself”
appears IO be mediated by aplasma protein
(opsonin)thatinteractswithforeignmac-
romolecules, making them susceptible to pha-
gocytic ingestion ( 5 1).
The clearance of blood-borne particulate ma-
terial has been shown to be mediated through
interaclion of particulate matter with opsonizing
proteins in the plasma. The removal of bacleria
appears to be mediated by the action of a spe-
cific antibody complement conlponent. In con-
trast, removal of nonbacterial colloid andpartic-
ulate matter has been shown to k mediated by
an aspecific opsonin. Consumptive depletion of
both specific andnonspecific opsonic protein
has been documented and has been shown to be
the major determinant of RES function during
reticuloendothelial blockagerather than phys-
ical saturation of reticuloendothelial cells ( 5 5 ) .
SeIectivemembraneadherenceprobablyis
associated with the physical and chemical prop-
erties of theopsonizedparticles,the charac-
teristics of the membrane of the macrophages,
andlor the presence of specific receptor sites on
the macrophage (51).
Theoretically, heparin may affectthe RES
funclion by at least four mechanisms: (a) inter-
action with the surface of the particles directly,
(b) interaction with plasma opsonins, (c) bind-
ing to the cell surface of the macrophages, and
(d) influencing the lysosomal enzyme activity
of the macrophages. Heparin injected intra-
venously has been shown to accumulate mainly
in the RES, suggesting that heparin may affect
phagocyticactivity at thecellular level. The
possibility thal heparin bindsat a specific recep-
tor site on the macrophage is suggested by the
observation that heparin depressed the inter-
nalization of microaggregated albumin particles
by the RES, whichcouldbe attribuledtoan
increase in the negative charge density of the
macrophage cell surface and could result in an
impaired attachment of the negatively charged
albuminparlicles (52). Otherstudiessuggest
that heparin increases the pinocytic activity of
cells such as fibrobIasts (51).
Intravenouslyinjectedcolloidsusuallydis-
tribute withinthebodyaccording toregional
blood flow and phagocytic activity of the liver
and spleen.Occasionally, however, uptake is
observed in the lungsand kidneys. Animal stud-
ies have shown that injection of thromboplastin
or production of intensive burnsresulted in a
marked increase in uptake of colloidal carbon
bythelungs.Pretreatmentwithheparin pre-
ventedthis increaseduptake,suggestingthal
intravascular coagulation and fibrinformation
played a role in lung accumulationof colloid or,
alternatively, that heparin prevented the attach-
ment of colloidalcarbontothemacrophage
membrane. Pulmonary microcirculation studies
have shown that following the injectionof endo-
toxin, damaged endothelium can be detected by
progressive adherence of intravenously injected
colloidalcarbon to its surface.Subsequently,
the endothelial cells swell and the colloidal car-
bon appears within the cells, suggesting phago-
cytosis (56).
Theplasmacomplement (C) system is in-
volved as an antimicrobial defense mechanism.
The usual succession of evenls in compIement
activation begins with antibodies;analternate
Drug-induced Alterurioru: Theoreiical Considerations
pathwaycanbeactivatedwithoutinvolving
antibodies, however, by diverse materials such
as lipopolysaccharide(endotoxin),inulin, and
zymosan.Thesecompoundstrigger activation
of C3 directly and generate peptides that potent-
ly affectleukocyte,especiallygranulocyte,
function (57).
Some drugs may cause histamine release
from mast cells withoul antibody mediation in a
prediclable dose-relaled fashion. This includes
opiates and radiographic contrast agents. These
contrasl agents also aclivate complement via the
alternate pathway. A few cases of disseminated
intravascular coagulation have been reported in
humans followinginjection of contrastagenls
(49).
Various eiements of the complement system
areresponsible forendothelialadherenceand
chemotaxis of granulocytes as well as opsoniza-
tion. One complement component is thought to
activate granulocytes to producemicrobicidal
oxygen radicals (superoxide and hydrogen per-
oxide). It is believed that these radicals may act
as atlraclants for other phagocyles in the area.
Data suggestthat complement is activated in
shock states incited by sepsis, hemorrhage, and
Irauma. A serious and frequently fatal conse-
quence of shock thought lo be due to prolonged
activation of complement is a condilion known
as“shock lung.” One of the features of this
syndrome is a unique plugging of the lung mi-
crovasculature by granulocytes and monocytes.
Pulmonaryabnormaliliesoccurring in hemo-
dialyzed patients produced similar but less pro-
nouncedpulmonaryabnormalities. It wasre-
portedthatinanimalstudies,virtuallyall
circulating granulocytes were removed from the
circulation and were found to be in leukocytic
plugsinpulmonarymicrovasculatureinthe
early stages of hemodialysis. This finding sug-
gests the possibility of complement aclivation,
asplasma flows overthecellophanediaIyzer
coils of the hemodialysis apparatus (57).
It is not surprising that dialyzer cellophane
could activate complement, since cellophane is
a polysaccharide such as zymosan, inulin, and
endotoxin, all of which are capable of inducing
complemenl activation (58).
As mentionedpreviously,freeradicals of
I 173
oxygen are generated by granulocytesduring
complement interaction. These radicals are re-
sponsiblefortheendothelialdamage,as has
been shown by the inhibition of damage in
cultured cellsbyfreeradicalscavengers. Al-
though endotoxin alone has no deleterious ef-
fects,significantdamageoccurswhenitis
added with granulocytes, especially in the pres-
ence of complement fresh serum (57).
The mechanism of leukostatic plugs and the
nonmicrobialactivation of complement(e.g.,
by pharmacologic agents) should be considered
in the assessment of any unusual lung uptake of
radiotracers.
Experimental evidence suggests that the se-
cretion of lysosomalhydrolasesfromhuman
polymorphonuclear leukocytes can be modified
by agents that affect cyclic nucleotides and mi-
crotubules (59). There also is evidence that
agenls that activate a lymphocylecyclic nu-
cleotide (CAMP) such as isoproterenol, nor-
epinephrine, aminophyilin, and some members
of the prostaglandin family interfere with anti-
gen-induced transformation of human lympho-
cytes in vitro (60). Thus, any tracer localization
mediated by leukocytes may be affected if the
transformation is altered.
Agents that increase intracellular cAMP have
beenimplicatedintheflow of subcellular
organelles in various systems and may interact
withmicrotubule protein. Sludies indicate that
the release of enzymes from phagocyles after
parlicle ingestion is a selective process which
does not necessarily involve generalized mem-
brane damage. cAMP acts as the second mes-
senger for the effects of many polypeptide hor-
monesontargettissuesandmediatesthe
rearrangement of the vacuolar apparatus ob-
served in stimulated organs. It mediates (a) glu-
cagon-induced formation of autophagic vac-
uoles i n liver,(b)endocytosisinthyroid
following stimulation with TSH, (c) induction
of exocytosis in osteoclasts, parotid, and pan-
creasbyparathyroidhormone (PTH), cate-
cholamines,andinsulin,and(c)melanocyte-
stimulating hormone (MSH)-induced granule
dispersion in melanocytes (61).
Human leukocytes possess specific and sepa-
rate receptors for endogenous hormones includ-
174 I Essentials of NuclearMediche Science
ing P-adrenergic catecholamines, histamines,
and prostaglandins. Each of these stimulate ac-
cumulation of cAMP in suspension of mixed
human leukocytes. It has been reported that a-
adrenergic agents, which decrease cAMP lev-
els, and cholinergic agonists enhance the immu-
nologic release of histamine and SRS-A from
lung fragments (59).
Other agents have the ability to increase in-
tracellularCAMP. Prostaglandin E not only is
associated with increases in cAMPbut also has
been associated with the movement of sub-
cellular organelles andmay interact with micro-
tubuleprotein (61). Inaddition,cAMPis
thought to impair RNA or protein synthesis in
macrophages during enzyme formation (60).
Chloramphenicol and tetracycline have been
shown to affect phagocytosisbyblockage of
DNA and RNA synthesis (54), perhaps by the
samemechanism.Otheragentssuch as the
methyl xanthines have an indirect effect. These
agents are potent inhibitors of phosphodies-
terase needed for deactivation of cAMP result-
ing in sustained high levels of CAMP. Thus data
suggestingcAMPas a secondmessenger in
many humoral systems of the body; especially
in the RES, raisethepossibilitythatphar-
macologic agents known to alter cAMP levels
may affect RES function and hencethe distribu-
tion of colloids (67).
One possible interference in phagocytosis is
thealtered state of microtubules that develops
between phagocytic vacuoles andlysosomes.
Drugs with thiscapability are colchicineand
vinblastin.Thesedrugs have been shown to
inhibit urate crystal phagocytosis, intracellular
digestion,redistribution of granule-associakd
hydrolases, and antigen-induced release of his-
tamine (61).
Phagocytosis of zymosan particles by rabbit
polymorphonuclear (PMN) leukocytes was in-
hibited by hydrocortisone, methyl predniso-
lone, and chloroquine. The concentration of
drugsinhibitory to phagocytosis was substan-
tially higher than that of drugs required for inhi-
bition of chemotaxis in vitro. Thus these agents
inhibit the inflammatory process by preventing
the response of leukocytes to chemotactic stim-
uli (62).
Miscellaneous other agents have been shown
10 affect the RES, Localanestheticsparalyze
leukocytes completely at low concentrations
and decrease their hexose monophosphate shunt
activity and myeloperoxidase-mediated iodina-
tion at even lower concentrations. General anes-
thetics hamperbothphagocytic and catabolic
reticuloendothelial functions and impair im-
mune response by leukocytes. The plasma ex-
panderdextran,whichis a largecolloid,is
knowntobepartlyengulfedbyreticukoen-
dothelial cells. Total parenteral nutrition with
hypertonic amino acids and dextrose can result
in a 50% reduction of chemotactic phagocytic
andbactericidal activity of granulocytes. Pro-
tein deficiency also has been shown to result in
a diminished uptake of colloidal carbon by
Kupffer cells. Extracorporeal circulation, as in
renal dialysis, also may depress RES function
(54).
The administration of natural or synthetic es-
trogens markedly stimulated the phagocytic ac-
tivity of the RES in experimental animals and
can result in pronounced RES organ hypertro-
phy. Other studies demonstrating a dose-related
increase in reticuloendothelialphagocytic ac-
tivity without RES organ enlargement appear to
suggest that RES stimulation following estrogen
can be the result of increased RES cell activity
rather than RES proliferation (63).
Some drugs used for diverse therapeutic ef-
fects are estrogenic. Spironolactone, a diuretic
agent, has knownestrogeniceffectsandhas
been known to produce gynecomastia in males
(64).
Under normal conditions, there is only mini-
mal uptake of 99mTc-labeledsulfurcolloid in
kidney tissue, and data donot suggest migration
of reticuloendothelial cells to the kidney.Sev-
eral theories have been proposed to explain the
incidence of renal localization of radiocolloid.
The most likely of these suggests that changes
in renal flow could induce phagocytic activity in
the proximal convoluted tubular cells. Reduced
blood flow to the kidneys could occur in con-
gestiveheartfailure (65) orpotentiallyas a let functionincludetricyclicantidepressants,
result of drug therapy that causes cardiac output
to be reduced.
Renal accumulalion of 99mTc-labeledsulfur
colloid has also been reported in renal transplant
patients during rejcction and during episodes of
acute tubular necrosis (66). Several ol the com-
monly used antibiotics, especially kanamycin,
are known to cause acute tubular necrosis (67).
Blood platelets, under normal circumstances,
circulate as smooth,disk-shapednonadherent
cells. When endothelium is brokenor disruption
of vesselsallows blood to comeinto contact
with elements of the vessel wall or perivascular
space, platelet adhesion occurs which initiates a
secretory response during which subcellular
granules extrude substances from the cell. This
extrusion processresemblesthesecretory ac-
tivity of other cells such as endocrine cells and
mast cells (68).
Blood platelets have been implicatedin medi-
ating not onlyhemostasisandthrombosis but
also various types of inflammatory and immu-
nologic processes, vascular permeability, host-
defense responses, and transplant rejection reac-
tion (69).
Increased sensitivity of p!ateleis to aggregat-
ing agentssuch as ADP, epinephrine,and
collagen occurs in heart disease, type Ila hyper-
betalipoproteinemia, transienl attacks of cere-
bral ischemia,hyperlension,anginapectoris,
myocardialinfarction,andfactorssuchas
smoking and the use of oral contraceptives (70).
Manyagents that causeplatelets torelease
their granule contentsactivate phospholipase A?
of the platelet membranewhichfrees arach-
idonicacid from platelet membrane phos-
pholipid. The arachidonic acid is converled to
proslaglandin endoperoxides and thromboxane
A?. These agents can cause platelet aggregation
and the release of granule contents (70). Sub-
slances released from plarelel granules include
serolonin, a protein that can neutralize heparin,
acid hydrolases,andfactors that canmodify
vascular permeability and integrity. These fac-
tors can have wide biological implications (68).
Indomethacin and phenylbutazone inhibit re-
lease andaggregalion of plateletslemporarjly
(69), while aspirin effects last longer due to the
irreversible acetylation of cyclo-oxygenase in
platelets (71). Other drugs thal can inhibit plate-
antihistamines,ethylalcohol,clofibrate, car-
benicillin, dextran, high doses of penicillin, ni-
trofurantoin, pyrizadine compounds, phenothia-
zines, and volatile anesthetics (69).
Theenzymelipoxygenase,isolatedfrom
human platelets, gcncratcs a derivative of arach-
idonic acid which, during inflammation, exhib-
its chemotaxis for PMN leukocytes. PMN leu-
kocytes release prostaglandin (PGE,) during
phagocytosiswhich is also chemotactic for
PMN cells (72). Thromboxane A, is the most
potent aggregator metabolite of arachidonic acid
which has been identified (73). Prostacyclin is
the most powerful substance known to prevent
aggregation; it increases cAMP Levels in plate-
lets (71). Prostacyclinreleased intothe blood
stream by pulmonary circulation constantly ac-
tivates platelet adenyl cyclase and increases
platelet CAMP, thus decreasingaggregability.
Phosphodiesterase inhibitors could potentiate
the effect of circuIating prostacyclin on platelets
(74).
Bone-imaging Agents
Pyrophosphate (PYP) has been found to be
present in normal plasma, urine, and saliva and
in bone and teeth.Because of its presence in
calcified tissuesandsurroundingfluids,PYP
may protect soft tissue from mineralization,reg-
ulatetheonset of calcification,andinfluence
the rates of entry and exit of calcium and phos-
phate in bone.Hydroxyapatite (HA) crystals
have a marked ability to absorb PYP. This af-
finity mayinhibit nucleationand subsequent
growth and aggregation of crystal nuclei of HA.
Other modes of action for inhibition of miner-
alization, besides direct action on crystals, are
possible (75).
Electron microscopic observations indicate
the presence of extracellular membranous ma-
trix vesicles in epiphyseal cartilage. The very
first crystals of HA appear to be associated with
these vesicles. They containmost of the alkaline
phosphatase, ATP, and pyrophosphatase activity
of the epiphyseal cartilage. It has been postu-
lated that because of the enzyme content, mem-
branous nature, and location of these vesicles,
they may be involved in the calcification pro-
cess. Thus hydrolysisof ATP by ATPase present
in the matrix vesiclesforms orthophosphate and
facilitates Ca+Zuptake, resulting in the cal-
cification process.Similarvesicleshave been
seen in immature bone, dentine, and calcifying
aorta (76).
Hydroxyethylidenediphosphonate (HEDP),
used therapeutjcally, couldinterferewith the
functioning of these vesicles. It has been sug-
gested that low concentrations of PYP promote
176 I Essentials of NrtclearMedicineScience
theearlierstages of calcium accumulationby
the vesicles, perhaps by actingas a substrate for
the calcium pump. HEDP might compete for
PYP at thissiteandblockcalcification.
Changes in thecellpopulations of skeletal
tissues, including epiphyseal cartilage and pag-
etic bone, and in the morphology of bone cells,
especiallyosteoclasts, are seenwhendiphos-
phonates are given therapeutically (75).
Anextracellular fluid (ECF) space liesbe-
tween the capillaries and the bone surface. The
rate of tracer transfer from the ECF to osteoidin
relation to the rapid diffusion from capillariesto
the ECF is slow. Increasing velocity of blood
flow is without significanteffect on tracer depo-
sition on osteoid surfaces. If sympathetic ner-
vous control of microvasculature is blocked,
however, vessels that are normally closed will
open, and areas of osteoid not normally exposed
to tracerwill beable to participate in tracer
uptake.Computerperturbationstudiesshow
that bone is highly sensitive to changes in ex-
traction efficiency resulting from hormonal al-
terations. Thus, both hyperparathyroidism and
hyperthyroidism result in high-contrast “super-
scans” (77).
A direct role for Iysosomal enzymes in col-
lagendegradationhas been suggested. Lyso-
somal proteases may complete the degradation
o€ collagen and may benecessary to cleave
intermolecularcross-linksbetweencollagen
molecules,makingthemsusceptibleto colla-
genase.DibutyrylCAMP(DBcAMP), a bone
reabsorptionstimulator,causesanincreased
lysosomal enzymerelease.Otheragents that
increase lysosomal enzyme release and 45Ca re-
leaseincludeisobutylmethylxanthineandcal-
cium ionophore A23187 (78).
Decreased release of lysosomal enzymes oc-
curred in parallelwith decreased 45Ca release
caused by inhibitors of bone resorption such as
cortisone,colchicine,andsalmoncalcitonin.
Otherinhibitors of lysosomalenzyme release
that were also found to inhibit bone resorption
in culturesystems were stilbamidine,chloro-
quine, and dapsone (78).
Calcitonin is a hormone thatinhibitsbone
resorption and is known to cause suppression of
elevated urinary hydroxyproline excretion. Ki-
netic studies indicate that calcitonin may have a
significant effect on 99mTc-diphosphonateclear-
ance from blood, i.e., an increased rapidity of
blood clearance of the tracer. Bladder activity
was observedearlier in the calcitonin-trealed
patients than in the non-calcitonin-treatedpa-
tients, possibly due to a decrease in the prox-
imal renal tubular reabsorption of electrolytes in
patients with Paget’s disease (79).
Calcitoninhasbeenshown to convert the
lower and upper part of the small bowel from an
absorbing organ to one thal secretes water, so-
dium, chloride, and potassium (80).
The administration of 1.25 mg of vitamin D,
intravenously in ratscauseda significantde-
crease in the uptake of 99mTc-PYPand 9 9 m T ~ -
diphosphonate by bone. Administration of 1.25
mg of dihydrotachysterolbystomachtube
caused a significant increase in the ratio of in-
farcted myocardium-to-bone uptake of 9 9 m T ~ -
PYP (81). Observations such as this led to the
search €or agents that would favorably influence
the tracer distribution (82-86).
Parathyroid hormone (PTH) elevation in
serum hasbeen observedtoincreaseurinary
excretion of 99mTc-PYP(87). This observation
suggests at least the potential that drugs which
influence PTH levels may have some effect on
excretion of %“Tc-PYP or other hone-imaging
agents.
Altered distribution of theboneagentsdi-
phosphonateandpyrophosphate,inthe pres-
ence of C a k 2 and Fe+2, hasbeenobserved.
These metal ions may facilitate the dissociation
of 9 9 m Tfrom
~ the carrier ligand, resulting in
both 59mT~ deposition at the reaction site aswell
as translocation to other tissues, possibly with
the migrant wmTc boundto another ligand. The
formation of Ca-HEDP complexes in the pres-
ence of calcium gluconate could release 9 5 m T ~ ,
followed by scavenging of the liberated 9 9 m T ~
by gluconate to form a ligand with renal imag-
ing properties. In the absence of gluconate the
Ca-HEDPreactionproduces a significant
amount of liveragent,possiblycolloidal
9 9 m T ~ 0Such
2 . transchelation may account for
the fact that pyrophosphate and diphosphonate
are effective imaging agents for myocardial in-
farction (88).
Otherpotentialdruginteractionsaresug-
gested by the fact that 99”Tc(Sn) at high pH in
Drug-inducedAilerariom:TheoreiicalConsidera;ior~s I 177
the presence of appropriatedihydroxyglycols ubilization, A 1 + 3 could be absorbed(93). It has
other than gluconate, such as gluceptate, man- been suggested that should there be an altered
nitol,and ethylene gIycero1, givesessentially distribulion of wmTc-HEDP, theA 1 + 3 content of
the sametissuedistributionasobserved with 9 9 m T ~ and the patient’s serum be checked
eluant
99mTc-gluconate (88). (94).
Other glycols are present in pharmaceuticals. An atypical bonescan with use of 9 5 m T ~ -
Polyethyleneglycol is presentinGris-PEG diphosphonale was reported in a patient receiv-
(griseofulvin), and propylene glycol is present ing Phospho-Soda. The scan was characterized
as a slabilizer agent in poorIg soluble injecta- by poorskeletaluptake with increased tracer
bles such as phenytoin, digoxin, phenobarbital, activity in the stomach, thyroid, and lungs. The
and hydralazine. poor bone uptake of the tracer mightresult from
AgentscontaininggluconateincludeKaon saturation of bonebinding sites byphosphate
(potassium gluconate),quinidinegluconate by ions from thePhospho-Sodapreparation (95).
injection, and Quinaglute Dura-Tabs (quinidine Phospho-Soda contains 0.14 g m of phos-
gluconaletablets). A product that contains a phorus per ml. The recommended purgative
congener of gluconate is guaifenisin which is dose is 10-20 ml ( 1 . 5 - 3 . 0 gm of phosphorus).
found in some cough preparations. Phosphatecan lower serumcalcium with no
Uptake of 99mTc-labeledphosphates at the increased fecal or urinary excretion of calcium.
site of intramuscular injections of an iron dex- This lowering may be dueto extraskeletal depo-
tran complex has been reported (89). One expla- silion of calcium phosphate salt. Extensive cal-
nation for this phenomenon is the combination cificationhas beenreported with orallyand
of ferric hydroxide and reduced technetium, as inlravenously administered phosphate prepara-
this combination is released from Ihe iron dex- tions (96). Whateffect. if any, this may have
tran complex (90). played in the case cited above (95) is unknown.
Additionalreports of theeffect of iron on Since most radiotracers must cross biological
tissue distribution of phosphorus-containing membranes sometime during their biodistribu-
bone agents suggests a relationship between the tion, a consideration of pharmacological mem-
degreeof ironoverload and thedecrease in brane akerations seems appropriate.
skeletal uptake. Patients with a history of trans- Calcium is intimateiy involved in many as-
fusionand hemochromatosisshowedreduced pects of cellular metabolism including glycoly-
skeletal uptake of bone agent, which correlated sis, mitochondrial metabolism, junclional com-
with thedegree of expectedironoverload in munication between ceils, cell proliferation,
these patients (91). celladhesion, and numerousotherprocesses.
Liver uptake of 99mTc-Sn-HEDP has been Calcium can induce major structural changes in
demonstrated in the presence of A 1+ j ions pos- model lipid bilayers (97).
sibly leached from thetechnetium generator. Primaryinteractions of calciumwithphos-
This uptake was believed to be due to the fonna- pholipids result in secondary effects on proteins
tion of a colloidal complex, although particles embedded in the lipid phase of biological mem-
were not visibleunder light microscopy (92). branes. In general, absorptionof Ca+* and other
Tissue burdensof aluminum have been foundto bivalent cations to negatively charged bilayers
be increasedin a number of conditions. AI- reducesthesurfacecharge,“stabilizes”the
though the gastrointestinal tract is a formidable membrane, reduces its fluidity, anddecreases
hamer to the entry of aluminum, it cannot be its permeability. In membranes of mixed phos-
considered to be impervious. Plasma aluminum pholipids, however, Ca+2can induce phase sep-
levels have been reported to rise markedly dur- aration and formation of solid phospholipid is-
ing ingestionofaluminumhydroxide,alumi- lets at theinterface between fluidand solid
num carbonate, and aluminum aminoacetate. In phases (98).
conlrastto a l u n ~ i n u ~phosphate,
n these alumi- Evidence strongly suggests that psychotropic
num compounds are soluble at the pH of the drugsinduce avariety of alterations in mem-
proximalduodenumorstomach.With sol- brane transport ~nechanisms. These drugsinter-
178 I Essenrinls of NuclearMedicineScience Drug-induced Allerations: Theoreticalconsiderations / I79

acl with the sodium pump, the cyclic nucleotide andlor intracelluIar binding of gallium by neo- liferation and secretory function of lympho- Cerrain moietiesknownas Iysosornotropic
system,microtubules, and membrane calcium plastic and inflammatory cells (103). cytes. Agents that increase CAMP decrease this agents are known to be taken up selectively into
Several factors may influence leukocyte func- function. The transfer of Ca+Zinto lymphocytes lysosomes. The antimalarial drug chloroquine
(99).
It has been demonstrated that loca1 anesthet- tion. The clinical significance of theseinflu- by A23 187 bypasses physiologic membrane can reach such concentration in lysosomes that
icsandtranquilizers suchaschlorpromazine ences is only speculative; the controversy as to events,resultinginproliferation of normal it may seriously affect the aclivily of some of
cause a dramatic decreasein the ATP content of the physiological behaviorof gallium, however, human lymphocytes (108). There are otherpath- the lysosomal enzymes and thus impair lysoso-
chicken erythrocytes which is accompanied by may be rooted in the effects of suchoutside ways for A23187 action. A23187 can stimulate mal digestion. Chloroquine has been known to
an increase in membraneparticleaggregation influences on neutrophils. For instance, activa- the movement of Mg+2and K+ in mitochondria inhibit the breakdown of endogenous proteins
and exposure of membrane phospholipids (100). tion of oxidative metabolism in PMN leuko- and induces a CaT' influx and concurrent hypo- and mucopolysaccharides in fibroblasts and that
As noled previously, Ca+2mayinteractwith cytes results in increased oxygen consumption, polarization of cell membrane. The latter effect of exogenousproteinsinmacrophages. Dex-
membrane phospholipid. I n addition, arach- glucose oxidation, and generation of oxidative is not solelyduetoCa+*movement,since tran, a polysaccharide,alsoaccumulates in
idonic acid is produced from membrane phos- intermediates (superoxide anion, hydrogen per- measurements of Nat, K + , and PO;3 indicate lysosomes. Dextran has a toxicity that may be
pholipid. Arachidonic acid is converted to pros- oxide, and hydroxyl radical). Thisoxidation that A23187 also alters the fluxes of these ions related to its accumulation and very slow clear-
taglandinendoperoxides PGG,, PGH,, and "burst" can be stimulated by opsonized parti- acrossthe membrane (97). Entry of K + into ance from lysosomes.
thromboxane A,. These agents can cause plate- cles or concanavalin A (con A), cytochalasin E, lymphocytes is one of the earliestevents of Agents entering lysosomes can act by modi-
let sensitivity to aggregation and the release of and thecalciumionophoreA23187.Theab- lymphocyte activation (109). Parallel experi- fying the properties of the lysosomal membrane
granulecontents. Increasedplatelet sensitivity sence of oxidativeintermediatesis associated ments with con A reveal a similar redistribution and thus increasing or decreasing its abilily to
to aggregation by collagen has been described with depressedmicrobicidalactivity (104). of Na+, Kt,PO,3, and Cat2 (97). Levamisole containlysosomaldigestion.Anti-inflam-
in a variety of altered physiological states, sug-False negative [67Ga]gallium citrate scans may is an anthelmintic, irnmunoshulating drug ca- malory agents such as cortisone exerl their ef-
occur in chronic abscess in leukopenic palients
gesting the possibility of platelet participation in pableofalteringintracellular levels of cyclic fect, at least partly, by modifying the lysosomal
uptake in bone associated with collagen (70). (105, 106). nucleolides,which modulateslymphocyteac- membrane, rendering it less fragile and perhaps
Other studies suggest that gallium associates livation. It is known to enhance catabolism of less capable of fusing wilh plasma membranes
[ 67Ga]Gallium Citrate primarily and tenaciously with the plasma mem- CAMP and to inhibit the catabolism of cGMP to allow exocyticdischarge of thelysosome
Afterintravenous injection, 67Ga isassoci- branes of lymphocyles and that uptake appears which is implicated in lymphocyte activation contents. Investigators have extracted a sub-
ated with [ransferrin. Subsequent tissue localiz- to be associatedwith changes in the plasma (108). stancefromkidneylysosomes wilh a strong
ation may occur as a result of migrationof membrane,suchasthose that occur in phy- Acidosis, ketosis, and hyperlipidemiamay affinityfor cationic compounds which could
gallium from transferrin to other metal-binding tohemagglulinin-stimulated cells. Lymphocytes act together or independently to alter lympho- account for kidney binding of [67Gajgallium cit-
molecules, such as lactoferrin which is similar are known to be abnormal in lymphomas which cyle membrane or the internal metabolism of rate.Carrageenan, used as a food emulsifier,
to transferrin in molecular weight but differs in accumulate gallium avidly. T-lymphocytes are lymphocytes, resulting in depressed reaction to and polyvinylpyrrolidone are also known to be
tissue distribution. Tissues and secretions with ableto be transformed readily wilh mitogens. mitogens, impairedbactericidalcapacity, and slored in lysosomes (112).
highlactoferrincontent are known to concen- The degree of uptake of gallium was not associ- impairedlocalexudativecelfularresponse Incontrast to thelysosomallocalization
trate gallium (101). These include neutrophilic ated with any aspect of cell division but rather (1 IO). mechanism,anotherset of ultracentrifugation
leukocytes, bone marrow, colon, tears, and gen- with some aspect of the cell membrane which Suppression of Kt entry into lymphocytes by studies showed gallium in tumortissueto be
ital, salivary, and nasopharyngeal secretions is known to be different in normal and neo- ouabain will prevent mitosis, blastogenesis, and located in the nucIeifraction (113). More re-
(102).Increased lactoferrin isseen in breast plastic tissues.Supporlforplasmamembrane increased protein DNA and RNA synlhesis. Hu- cently, researchers have demonstratedactivity
tumorsandinthespleen of patientswith localization is provided by the observation that mans receiving 60 mg of prednisonedevelop in organelles thatare smaller than lysosomes.
Hodgkin's disease. In inflammalory lesions, 50% of the gallium can be digested from the cell lymphopenia within a few hours. Lymphocytes These granules were isolated with use of a dif-
lacloferrin is deposited by PMN leukocytes and by proteolytic enzymeswithoutincurrence of obtained after drug administration respond ferent homogenization process. Morphologi-
binds to the surface of monocytesandmac- letha1 cell damage (107). Other studies, in con- poorly to mitogens. Either circulatory lympho- cally, these particles were predominantly rough-
rophageswhere it appearstoinhibit bacterial trast to the previouslymentioned observation, cytes are being inactivated by the corticosteroid, surfaced endoplasmic reticulum fragments;
growth by removing available ferric ion needed indicate that chronic lymphocytic leukemia in a orthoselymphocytesthatrespondwell to however, small single-membrane electron-dense
by the invading organisms (101). patientwith enlargedlymphnodesfailed to mitogen have been sequesteredoutside of the granules also were present (114).
Estrogen-stimulatedplasmaproteinsare yield a positive scan (103). circulation. This sequestration prevents migra- As has been observed earlier, high tissue pro-
transporlproleinsresponsibIe for smallmole- Lymphocyte activation by mitogens such as tion into areas of inlmunologic challenge (109). lactinlevelshave a potentinfluenceon
culessuchassteroids, thyroid hormones, and con A and cytochalasin E appears to be depen- Some studies suggest that gallium localizes in [ "Ga]gaflium citrate accumulation in mammary
metals.Ceruloplasmin and transferrin are in- dent on calcium influx via endogenous calcium subcellular organellesmorphologicallyidenti- and other tissues. Hyperprolactinernia can occur
creased by eslrogen (102). ionophores that actas a signal for cyclic nu- fiable as lysosomes, phagolysosomes, or related in pituitary adenomas, primary hypothyroid-
Observation of galliumactivity withinneu- cleotides to trigger cell proliferation; therefore, particles. Recently, electron microscopic auto- ism,chestwallinjuries,carcinoma of lung
trophils of inflammatorylesionssuggeststhe agents that increase cellular levelsof cyclic gua- radiography has shown %a 10 beassociated (which secretes ectopic prolactin), emotional
possibility of a common mechanism of uptake nosine monophosphate(cGMP)promotepro- with lysosomes ( I 1 I). andphysical stress, andadvanced renal failure
180 t Essentials of h'uclearMedicineScience
and may be induced by many drugs. Included
amongthese are reserpine,methyldopa,oral
contraceplives, antidepressants, and phenothia-
zines ( 1 15).
In the use of [67Ga]gallium citrate for brain
tumor scanning, pretreatment with anti-inflam-
matory steroids showed either a disappearance
or a reduction of gallium uptake (116).
Administration of iron dextran has been dem-
onstrated to lower the whole-body retention in
intactand abscess-bearinganimals.Whenad-
ministered 24 hours after tracer injection, iron
dextran decreases background activity, resulting
in more apparent lesions. Thus, the kinetics of
[67Ga]gallium citrate distribution can be re-
markably altered by administration of iron dex-
tran which displaces the gallium from transfer-
rin andother binding proteinsand enhances
galliumexcretion, resulting in ahigh abscess-
to-muscle ratio ( 1 17).
Ethanol and benzyl alcohol have been shown
to produce a tenfold increase in cAMP in human
leukocytes.Significant but lessmarkedaug-
mentation of cAMP was observed in human
plaleletsandgranulocytes. Themechanism is
believed to be alcohol-induced membrane per-
turbalion and activation of adenyl cyclase. Par-
enteral drugs as well as bacterioslatic water and
salinefor injection, as diluents for parenteral
drugs, often contain benzyl alcohol as a preser-
vative. Although the amount of benzyl alcohol
administered under normal circumstances is
low, unusualtherapies may result in a larger
benzyl alcohol exposure. One example is that of
"methotrexaterescue"therapyinwhich
100-150 mi of methotrexate with 0.9% benzyl
alcohol can deliver 0.9-1.35 gm of preser-
vative. Several processes irnporlant in inflam-
mationand immunity are known to besup-
pressed by increases of intracellular CAMP: (a)
lysosomal enzyme release fromPMNleuko-
cytes and macrophages, (b) hislaminerelease
from mast cells and basophilic leukocytes, (c)
antibody-dependent lymphocyte-mediated
cytotoxicity,(d)lymphocyteactivation,(e)
platelei aggregration, (f) PMNleukocyte and
macrophage motility,and (g)PMNleukocyte
adherence (1 I X).
Use of oily lymphangiographic contrast ma-
terial preceding Lolal-body [67Ga]gallium citrate
scanning has resulted in radionuclide accumula-
tion in thelungs.Histologicchangesinthe
lungs of animals and in thelymphnodes of
humans following contrastlymphangiography
havebeen reported, suggesting the possibility
of irritant effects of contrastmaterial on pul-
monary parenchyma as a cause for lung uptake
( 1 19).
Thereismuch controversy as to theactual
mechanism of uptake of [67Ga]gallium citrate
into cells, and it has been suggested that with
elucidation of the exact mechanism we may
identify a set of processes of major biological
importance. Similar cellular enlry pathways are
suspected for t 'In, the rare earth elements, and
the actinides-all of which show considerable
similiarities to 67Ga in their biological behavior
(111).
Use of agenls such as the mitogens, con A
andcylochalasin B or calciumionophore
A23187 provide a model for the better under-
sianding of drug interferences with radiotracers.
Nuclear Cardiology
Three categories of nuclear imaging used for
noninvasiveevaluation of coronaryheartdis-
ease have been described: (a) study of regional
perfusioncanbe used to detecteitherfixed
alterations in bloodflowcaused by infarction
and cardiomyopathy or transient changes in per-
fusion whenthe tracer isadministered at the
time of transientischemia; (b) the totaland
regional funclion of bolh right and left ventri-
cles can be evaluated with tracers which reside
in the blood pool of the hearl, eilher from ac-
livity curves recorded during the initial passage
through the heart or from gated images of the
heart at end systoleand end diastole; ( c ) acutely
damaged muscle can be evaluated with agents
that concentrate in zones of acute severe injury
(120).
Threesequential processesare requiredfor
cerlular localization of tracers. First, some per-
fusion mustbe present in the vicinity of the
target site to transport the tracer from ils injec-
tion site;second, thetracermust beable to
diffuse from the intravascular space lhrough the
interslitid space to the site of localization; and
third, the tracershouldbecomefixed a1 the
targetsite. In myocardialinfarction (MI) the
Drrrg-ir1ducedAlierations:TheorericalConsiderntiom 1 181
target usually is dead or dying myocardial cells Hydrogenion accumulation is oneimportant
but could b e interstitial substance or anothercell end result of glycogenolysis in ischemic tissue
type,such as granulocyteorfibroblast(121). which aggravates cell damage. cAMP also ac-
That several chelate complexes show localiz- celerates lipolysis, resulting in accumulation of
ation in all infarcted or necrotic tissueof varied acelyl coenzyme A which blocks energy trans-
pathogenesis suggests that the concentration ferfrommitochondria to cytoplasm.Agents
process is mediated by influx into the damaged that inhibit cAMP accumulation such as p-ad-
area due to increased vascular permeability, fol- renergic blockers and agents which promote in-
lowed bybindingtodamagedcomponents tracellular destruction of cAMPmay prevent
( 122). metabolic alteration in ischemictissue (125).
An essential step in the identification of po- cAMP playsa role in the modulating effectof
tential effects of drugs on uptake in myocardial cardioactive drugs. Potent stimulators of adenyl
tissue is an understanding of thebiochemical cyclase and inhibitors of phosphodiesterase are
adaptations of hypoxicandotherwise stressed cardiotonic agents. The biological effects of
cells as well as abetter understanding of the cAMPareassociatedwiththeactivation of
biochemicalchangesinducedbycardioactive CAMP-dependentprotein kinases which phos-
drugs. For example, the inotropic effectof digi- phorylate a number of substrates. There is a p-
talis on cardiac muscle can be attributed to its receptor-adenyl cyclase complex that can act as
action on thesarcolemmacellmembraneto a mediator for some cardiotonic drugs.The sar-
stimuhte Ca+Z influx, thus providing a greater coplasmicreticulum (SR) may functionas a
quantity of Ca'2 to coniractile proteins, result- receptor for CAMP-dependent functions. Canine
ing in a more forceful contraction. It is believed SR fractionsrespond to CAMP, epinephrine,
that digitalisbindslospecificsarcolemma-tu- and glucagon with augmentation of Cai2 up-
bulesyslem receptors thought to be Na+-Kt take. Protein kinase was needed for this effectto
i ATPase. Thissystem is coupledwitha Na+- be observed. Further evidencesuggests alink
Ca+2 exchangesyslemwhichtransportsNa+ between intermediarymetabolismandexcita-
out of the cell in exchange forCa+2brought into tion-contraction coupling.Ischemiceventsor
the cell. When digitalis interferes with Na+-K+ sympathetic stress may alter intermediary me-
ATPase,there is an increase in intracellular tabolism and SR glycogen concentration with a
Na+ whichactivates theNat-Ca+zexchange directeffecton SR Cat2 accumulation or re-
system withaugmentalion of Ca+? influx to lease through alerations in membrane structure
conlractile protein (123). or by affecting the kinetics of cardiac enzymes
: It has been demonstrated that in digitalized (I 26).
animals,the 43K myocardium-to-blood(MIB) Methylprednisolone has been shown to accel-
ratio was enhancedduetoslowermyocardial eratepyrophosphate blood clearance, thus
clearance after digoxin. Administration of iso- lowering blood and normaI myocardial pyro-
proterenol prior to 43Kinjection reduced myo- phosphate levels ( 127).
cardial clearance. Although the initial myocar- Theanthracyclineantibiotics,suchasdox-
I dialConcentrationwaslower,the slower orubicin, are widely used as anticancer agents.
washout resulted in higher MIB ratios (124). Use of theseagents tendstoresult in serious
cAMP is thought to play an important role in myocardial damage (128), including pericardial
cardiac function. Increased concentralion of effusion, subpericardial edema, myocarditis,
cAMP within cells appears to accelerate Ca+* cytoplasmic vacuolization, and nuclear changes
inflow, causing an inotropic effect on ischemic in rabbits within 24 hours of administration of
cells and increasing oxygen demand in faceof a 20 mgdoxorubicinper kg (129).Abnormal
limited s ~ p p i yduring ischemic disease. A met- 9g"'Tc-PYP accumulation has been observed in
abolicgradientbelweenischemicandnon- patientsundergoingtreatment for neoplasia
ischemic zones would increase.During isch- with this drug (128).
emia,cAMP would accelerate glycogenolysis The cardiotoxic effects of the anthracycline
to an extent related to the severity of ischemia. agents are enhanced by prior irradiation of the
182 I Essenrials of Nuclear MedicineScience
precordium. Doxorubicin is known to aggravate
radiation-induced heart disease, resulting in
myocardial damage at lower doses of radiation
(128). It is noteworthy that doxorubicinis
known to induce peroxidation of cardiac lipids
by theformation of free radicals(130).Free
radical-lipid peroxidation occurs undera variety
of circumstances, including vitamin E defi-
ciency, intoxication with carbontetrachloride,
exposure to ionizing radiation, carcinogenesis,
the aging process and, possibly, hyperlipidemia
accompanying atherosclerosis (131). Peroxida-
tion is also observed in degranulation of Ieuko-
cytesandplatelets,ashasbeennotedpre-
viously.
201TIoften is referred to as a potassium ana-
logbecausethemonovalent Tlt ioncan
substitute for polassium on the Na+-K+ trans-
membrane exchange system (1 32). The extrac-
tion of TIt by the myocardium is probably due
to activation of the Na+-K’ ATPase system in
which T1 appears to bind to twosites on the
enzyme whereas K binds to one site. This bind-
ing may account for the prolonged clearance of
T1 rather than K from the myocardium (133).
Thus, 2otTlcan replace potassium in the activa-
tion of pyruvate kinase and Na+-K+ ATPase
(134).
,OIT1 transporl is facilitated by depolarization
and repolarization of the myocardial cell mem-
brane. During each beat of the normal aerobic
contraction, about 3% of the intracellular K+ is
exchanged for extracellular Ki and T1+. With
anaerobic metabolism, there is little or no T1”
incorporated into the cell despite high flow rate
(135).
The ability of ions topassthrough mem-
branes is associatedwiththeir crystalradius,
while their mobility in solution is associated
with their hydratedradius(136). Therate of
passive influx into erythrocytes has been shown
to increase with increasing pH. The erythrocyte
membrane barrier to TI+ contains positively
charged R-NH: groups capable of repelling ca-
tions. An increase in pH could be expected to
decrease the number of positive charges in the
barrier and perhaps facilitate cation penetration
in both directions (137).
Part of‘ the observed differences between the
behavior of T I ’ and K t can perhapsbeex-
plained by the fact that T1+, unlike the alkali
metal cations,possesses 6s electronsand is
capable of more appreciable associationwith
anions and of complex formation (137).
T1’ influx across erythrocyte membranes can
be explainedby a model consisting of two com-
ponents: a saturable ouabain-sensitive “active”
influxand a ouabain-insensitive “passive” in-
flux that is much less saturable and is not influ-
enced by potassium concentration (137).
Since myocardial uptake of 201Tl appears to
be dependent on both blood flow and cellular
ion transport, assessment of the effect of drugs
commonly used by cardiac patients on the dis-
tribution of T1+ is important (138).
In animal models of both ischemia and in-
farction, levels of radioactive potassium and
thallium uptakehavecorrelated well with mi-
crosphere estimates of regional myocardial
blood flow in exercise imaging. Under circum-
stances of increased flow such as reactive hyper-
emia, cationuptake will besubstantiallyless
than that expected from microsphere flow esti-
mates. Under other circumstances, extracted
cations can be significantly altered while flow
remains unchanged. Thus, alterations in intra-
cellular active transport of cations due to altered
cell membrane-enzyme function must be con-
sidered. Studies with canine gracilis muscle
demonstrated thal adrninisuation of propranolol
reduces muscle uplake of radiopotassiumand
thallium by 2 - 2 s times normal. This alteration
in cation uptake can be reversed by administra-
tion of isoproterenol. This phenomenon is inde-
pendent of locaI blood flow or force of contrac-
tion and appears to representanalteration in
local intrinsic membrane function. If this same
behavior occurs in cardiac muscle, it couid limit
the usefulness in quantitative imaging of myo-
cardial distribution of these radionuclides(I 39).
A study hasbeenperformedto assessthe
effects of drugs such as dipyridamole, digoxin,
furosemide, and propranolol on myocardial dis-
tributionof 201TIin cardiac patients. Of these
drugs, only dipyridamole showed a marked in-
crease in myocardialuptake of 20’T1,possibly
due toincreasedblood flow in(hecoronary
i
arteries to 3-4 limes the resting level; however,
the increasedlocalizationwasnot associated
with myocardial blood flow in a linear manncr
Drug-induced Alrerntions: Theoretical Cmsideralioos f
(138). In addition to its vasodilatory effect, di-
pyridamole is a phosphodiesterase inhibitor and
potentiates endogenous prostacyclin (PGI,) re-
sulting in antithromboticactivity (74). PGI, is
themajor product of arachidonic acid in the
walls of the arteries and veins of humans (140).
Whether this effect of dipyridamole is responsi-
ble for the observed alteration of *OIT1uptake is
open to speculation.
In the same study,propranololaltered dis-
tribution to a statislically significant degree but
resulted in only minor change to the myocardial
image. It shouldbe noted, however, that this
study was performed on resting animals without
coronary artery disease.Propranolol may alter
regional blood flow duringexerciseandde-
crease myocardia1 oxygenconsumption for a
given level of exertion. Either one of these fac-
tors couldchangetheregionaldistribution of
”’TI in theexercisinghuman with coronary
disease (138).
If,‘as was suggested(138), T1’ can activate
Nat-K+ ATPase, competitive inhibitors of this
enzyme system would be expected to decrease
the participation of T1+ in the enzyme system.
Sodium bicarbonate hasbeen used to enhance
the myocardial concentration of 20’TIin rabbits
and dogs, resulting in an increase in myocardial
uptake of 1 E-2 times thal observed without use
of sodium bicarbonate. This change in uptake
occurred with an arterial pH change of only 0.1
U (141).
Insulin and 20% glucose given with radioac-
tive potassium, rubidium, and cesium results in
a significantincrease in myocardialuptake of
these radionuclides and also prolongs the myo-
cardial half-life of 1311-labeledoleicacid. In-
sulin in hypertonic glucose has been used clini-
cally to alter the extracellular-to-intracellular
potassium distribution in patients and to amelio-
rate the effects of ischemic myocardium. There
is evidence that the combination of hypertonic
glucoseand insulinplay independentroles in
altering K+ distribution.Rapid injection of 20%
glucose can quickly lower circulating K+ levels
and has a direct effect on transmembrane poten-
tial. Insulin may alter myocardial ion transport
and does enhance inorganic phosphate uptake in
the liver, which may be accou11panied by intra-
cellular K’ migration (124).
I83
Increased endogenous TSH induced by pro-
pylthiouracil (PTU) resulted in a significant rise
in thethyroid-to-serumratio for ,OITI, while
TSH inhibitionwith 1-thyroxine resulted in a
decrease in the ratio (142).
Thyroid-scanning Agents
Thyroid-scanning agents can be used for de-
termination of thyroid size as we11 as for func-
tional assessment of thyroid nodules. Pertech-
netate,sodium[1311]iodide,andsodium
[ 1231]iodideare the primary tracers used in thy-
roid function studies and diagnosis. Since most
of theinfluence of pharmacologicagents on
pertechnetate are discussed earlier, this section
deals with iodine radiotracers.
Usually, diagnostic procedures in which ra-
dionuclides are used give an accurate picture of
the thyroid gland and the extent of the pathol-
ogy. Anything that interferes with the uptake of
the iodine or blocks its release from the thyroid,
however, gives a false indication. Several drugs,
some of which are used daily by diabetics, epi-
leptics, and allergy sufferers, have a propensity
forobscuringthesethyroidtests.Other drugs
are iodine-containing contrast media, anti-
thyroidmedications,andthyroidsupplements
(143).
It might b e expected that any pharmacologi-
caI agent that affectsthyroidfunction might
alter the uptake of thyroid-scanning agents.
Thus,antithyroiddrugssuchasmethimazole
and PTU would invalidate measurements of ra-
dioiodine uptake (144). Administration of phe-
nylbutazoneresults in a reduction of sodium
[13’I]iodide uptake by inductionof a temporary
partialsuppression of TSH.Thissuppression
subsidesas treatment continues(145).Other
nonsteroida1 anti-inflammatoryagents may be
suspect. It has been reported that morphine in-
terferes with TSH (146). Results of studies sug-
gest that antihistaminesreduce 1 3 1 1 uptakein
euthroidpatients by 50% (147). In humans,
ACTH and cortisone diminish the thyroidal ac-
cumulation of l3lI. Thesehormonesabruptly
diminishtheprotein-boundiodide (PBI), but
they do notaltertheturnover of thyroxine in
peripheral tissues (148).
A variety of drugsincludingsulfonamides,
sulfonylureas, p-aminosalicylate (PAS), p-ami-
184 I Essentials of Nlrclear Medicine Science
nobenzoicacid (PABA), andresorcinolare
known to bind active iodide formed in the thy-
roid gland (146).Tolbutamide, a sulfonylurea
hypoglycemic agent, produces a mild but defi-
nite inhibition of l 3 l 1 uptake (149). Glucocor-
ticoids, such as dexamethasone, reduce plasma
TSH concentrations with expectedeffectson
the thyroid (150).
Drugs containingiodidesinterfere with the
entry of inorganiciodideinto the thyroid. A
wide variety of pharmaceuticals contain iodide.
These include expectorants, some vaginal sup-
positories,andiopanoicacid used forcho-
lecystography. Other dyes used for radiodiag-
nostic purposes contain iodide (151).
Heavy metals (152) and some antibiotics, es-
pecially penicillin, chlortetracycline, and chlor-
amphenicol, are capable of inhibition of l3]I
uptake (143).
A summary of some of the agentsthal are
known to influence I3lI uptake in the thyroid is
given in Chapter 14.
Hepatobiliary Scanning Agents
Although mostnuclearmedicine hepalobil-
iary studies areperformedwith use of 9 9 m T ~ -tracer behavior in the presence of drugs, com-
iminodiacetic acid analogs, another cholescin-
tigraphic agent that has beenused is 9 9 m T ~ -
pencillamine(153). Penicillamine is so named
because il is a degradation product of penicillin
and is prepared by hydrolysis of penicillin. F'ro-
benecid is known to completely block the rend
tubular secretory transport of penicillin (67).
Whether this samemechanism would beap-
plicable topenicillamine is unknown, particu-
larly at the tracer levels used for scanning pur-
poses. 11 hasbeen suggested, however, that at
least in thetherapeutic use of penicillamine,
concomitantuse of probenecidshould be
avoided if possible (154).
Therapeutic doses of morphine, codeine, and
other morphinesurrogatescancausemarked
increase in biliary tract pressure. For example,
after subcutaneous administration of 10 mg of
morphine sulfate, the pressure in the common
bile duct rises from the normal of less than 20
mm of water to a level of 200-300 mm. The
response beginswithin 5 minutesafter injec-
lion, rccnches its peak in 15 minutes and persists
for 2 hours ormore.This is due toa sharp
constriction at the lower end of the common bile
duct (sphincter of Oddi). The spasm prevents
emplying and thus causes the intraductal pres-
sureto rise (67). This interaction isdiscussed
further in Chapter 14.
SUMMARY
The mechanisms bywhich drugs affect radio-
pharmaceutical biodistribution are often medi-
a t e dt h r o u g hc h a n g e si nc e l lm e m b r a n e
characteristics, interactions with blood cellular
components, or alteration of enzyme-controlled
functions. Although this chapter has presented
some of the possible ways that drugs may mod-
ify the biorouting of certain radiokacers, con-
siderable research still needsto be performed to
confirm these mechanisms and to elucidate fur-
ther informationonthesubject.In particular,
research in which chemical agents such as con
A, cytochalasin E, and A23187 are used for
pharmacological dissection of cells could be of
helpinidentifying the precisemechanisms of
radiotracer localization. At the same time, at-
tention to reports of suspected alterations of
binedwith a detailedknowledge of the phar-
macology of such drugs, constitutes a valuable
source of new knowledge about tracer behavior.
The nextfewyearswillseesomebreak-
throughs in understandingthemechanisms
uptake of radiotracers.Thisunderstanding,
whenachieved, will openthedoor
applications of radionuclides in diagnosis
organ function and will elucidate some
complex biochemical interactions about which
we can merely speculate at the present time.
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14
Iatrogenic Alterations in the Biodistribution of
Radiotrucers as a Result of Drug Therapy:
Reported Znstunces
and David L. Laven
This chapter is a compilation of reported in-
stances in which the biodistribution of a radio-
pharmaceutical has been (or could be) modified
by theadminislration of a therapeuticnon-
radioactive drug or contrast agent in such a way
as to potentially interfere with the interpretation
of the nuclear medicine study in question. This
type of phenomenon is commonly referredto as
a drug-radiopharmaceuticalinteraction (1-3).
In [his chapter, interactions are arranged accord-
ingtothe radiopharmaceuticalinvolved; each
interaction is characlerized by useof the follow-
ing descriplors:
1. InferJering drug: the interfering nonrad’loac-
tive drug that alters the kinetics of the radio-
pharmaceutical and thus changes the result-
ing diagnostic data obtained from the study.
2. Nuclear medicine study affected: the nuclear
medicinestudyinwhichtheinteraction
likely to occur.
3. Effect on image: the appearance of the image
(or the effect on diagnostic data) which re-
suhs from the interaction.
4. Signzflcunce: thepotential clinicalsignifi-
cance of the interaction. The significance of
any given inleraction depends on several fac-
t“-.
LULI).
”whether the clinician is awarethatthe
interaction hasbeenpreviouslyreported.
“whether the clinician is awarethat the
appropriatecircumstancesforthe interac-
tion to occur arepresent in the patient
being examined.
how easily the clinician is able to take into
account the changes caused by theinterac-
tion as he or she interprets the image or
data resulting from the diagnostic proce-
dure.
Since these circumstances change from
case to case, each interaction can be de-
scribed only in terms of how itcanbe
potentiaEly interfering or annoying.
In most instances,dmg-radiopharma-
ceuticalinteractionsresult in diagnostic
confusion by inducing a pattern of radio-
pharmaceuticaldistribution which either
(a) mimics that normally visualized with a
naturally occurringdiseaseprocess, (b)
diminishes the ability to identily anatu-
rally occurring disease process, or ( c )
is
demonstrates a combination of both of the
preceding items (1). This classification
will form the basis for discussion in the
“significance”section.
5 . Mechanism: theproposedmechanism by
which thedrug alters thekinetics of the
radiopharmaceutical, i.e., the mechanism
through which the interaction occurs.
6 . Mnnagernent: possible preventive or correc-
tive management of the situation, not simply
an awareness of theinteraction.
7. How documented: thespecies in which(he
altereddistributionandlordiagnoslic daia
I89
i90 t Essentials of Nuclear MedicineScience
have been reported (or the means by which
the interaction has been documented).
8. References: literature references reporting
theinteractionand supporting (or conflicl-
ing) data.
REFERENCES
HIadik M'B 111. Ponto JA, Slathts VJ: Drug-radiophar-
maceutlcalinkeractions. In Thrall JH. Swanson DP
(eds): Diagnostic Irllerverrrrons in Abclear Medicine
Chicago, Year BookMedicalPublishers, 1985, pp
226-246.
Lentle BC.Scot[ JR, Noujaim A A , el al:Iatrogenlc
alteralions in radionuclide biodistributions. Sernin A'rd
Med 9:131-143, 1979.
Hladik WB 111, Nigg KK, Rhodes BA: Drug-induced
changes in lhe biologic dislribulionof radiophannaceuli-
cals. Senrirl Nucl Med 12184-218, 1482.
99mT~-LA3ELED COLLOIDS
Interferingdrug(s): Short-termtherapy with
cancer chemotherapeutic agents,notably the ni-
trosoureas, e.g., carmustine, lomustine.
Nuclear medicine study affected: Liver andlor
spleen scintigraphy.
Effectonimage: Reported to causetransient
changes in radiocolloid distribulion sometimes;
the specificchanges observedhavebeen (a)
inhomogeneous or irregular distribution of ra-
diocolloid in the liver, (b) hepatomegaly, and (c)
a shift of radiocolloidfrom the livertothe
spleen and/or bone marrow
Significance: Since metaslases to the liver From
other primary cancers may, at times, be man-
ifested as helerogeneoushepaticuptake of ra-
diocolloid, [his drug-induced pattern of dis-
tribution may be misinterpreted as malignancy.
Distinctfocal defects onliver andlorspleen
scans (which is the more common paltern seen
wilh metastases)have not been observedas a
result of chemotherapy.
Mechanism: No1 known; but presumably toxic
effects of chemotherapeutic agents on hepato-
cytes andreticuloendothelial cells could cause
the changes observed.
Management: Perform baseline liver and/or
spleen studies prior to initiating therapy, if it is
anticipaled that additional studies wi11 be per-
formed at any time during the courseof therapy.
If necessary, repeat the sludy several weeks fol-
lowing the completion andlor discontinuationof
therapy.
How documented: Study of 15 patients receiv-
ing single-agent or combination chemotherapy
(1); also study of patients receiving methotrex-
ate for treatment of psoriasis (2).
REFERENCES
1, Kaplan WD, Drum DE, Lokich JJ: The eKecl of cancer
chemolherapyagents on the liver-spleenscan. J Nncl
Med 2I:84-87, 1980.
2. Geronemus RG. Auerbach R , Tobias H: Liver biopsies
vs liver scans in metholrexale-treated patientswith psori-
asis. Arch Den?farol I18:649-651, 1982.
Interfering drug(s): Antacid therapy; virilizing
androgen therapy.
Nuclear medicine study affected: Liver and/or
spleen scintigraphy; bone marrow scintigraphy.
Effect on image: Diffuse pulmonary accurnula-
tion of radiocolloid.
Significance: Multiple disease states as well as
formulation problems with radiocolloid have
been associated with diffuselung uptake ob-
served on liver andlor spleen studies. This pat-
tern of distribution most frequently is associated
with intrinsicliverdisease.Majordiagnostic
inlerference does not result from the interaction,
however.
Mechanism: With antacid therapy, inteslinal
absorption of abnormally high levels of alumi-
num (from aluminum-containing antacids) has
occurred in patients with boweI obstruction or
renal disease. Aluminum probably thenreacts
with the sulfur colloid to cause radioactive mac-
roaggregates which are capable of blocking the
pulmonary microcirculation (1).
The androgen therapy (or estrogen degrada-
tion products from the androgens), on the other
hand, may stimulate the reticuloendothelial sys-
tem, resulting in mobilization of large numbers
of phagocytic cells from their storage sites,
whichare subsequently irapped in the pulmo-
nary capillary bed (2). At this new location, the
cells sequester intravascular radiocolloid.
Management: Not usually necessary; monitor
plasma aluminum levels in selected cases.
How documented: Case report of liver andlor
spleen study in individual receiving high-dose
antacid thcrapy (3); study of 13 patients rcceiv-
Drq-bsduced Alteraiions: Reporred Inslances f
ing virilizing androgen therapy for chronic ane-
mia and 13 controlpatientsalso with chronic
anemia, all monitored with bone marrow imag-
ing (4).
REFERENCES
Staum MM: Incompatibility of phosphatebufferin
"mTc-sulfurcoIloidconlaining aluminum ion. J N~rcl
Med 13:386-387.1972.
Mikhael MA, Evens RG:Migration and embolizatton of
macrophages to the lung-a possiblemechanlsm for
colloid uplake in the lung during liver scanning. J N'ncl
hfed 16:22-27,1975.
Bobinel DD, Serrin R, Zurbriggen MT, et a1: Lung
uplake ol Tc-99m sulfur colloid in palienl exhbiling
presence of AI3+ In plasma. J N r d Med 15:1220-I?22,
1974.
Sayle B A , Helmer RE 111, Balachandran S , el al: Lung
uptake of Tc-99m sulfur colloid secondary lo androgen
therapy in patients with anemia. Nucl Med Curttmurl
2:1289-1293,1981.
Interfering drug(s): General anesthetic agents,
e.g., halothane.
Nuclear medicine study affected: Liver andlor
spleen scintigraphy.
Effect on image: Shift of radiocolloidfrom
liver 10 spleen.
Significance: Colloidshift is commonly ob-
served in patients with intrinsic liver disease,
e.g., cirrhosis.
Mechanism: Generalaneslheticagentscan
cause a decrease in hepaticbloodflow and.
therefore, may reduce hepatic extraction of ra-
diocolloid. In addition, these drugs are hepato-
toxic in some patients which may contribute to
decreased hepatic uptake of radiocolloid.
Management: Monitor patient closely for signs
of hepatotoxicity.
How documented: Colloid shift documented in
14 of 20 patientswith a hislory OF surgery
within the previous month (1).
REFERENCE
1 . Lentle BC, Scott JR, Noujaim AA, et al: Iatrogenic
alteriltions in radionuciide biodislributions. Serrti?! Nucl
Med 9:131-143, 1979.
Inlerfcring drug(s): Thorium dioxide.
Nuclear medicine study affected:Liver andlor
spleen scintigraphy.
Effect on image: Absence of spleen localiza-
tion.
191
Significance: Sincethoriumdioxide has not,
for many decades, been used as a radiopaque
contrasl media, this eFfect is very rarely seen.
M e n il does occur, however, it may interfere
with the differential diagnosis of functiona1 as-
plenia.
Mechanism: a-Particles emitled in the decayof
lhoriumdeliverahighradiation dose tothe
spleen, resulting in splenic atrophy.
Management: None.
How documented: Case report (1).
REFERENCE
1 . Burroughs AK, Bass NM, Wood J, et al: Absence of
splenic uptake of radiocolloid due to Thorotrast in a
palienl with Thorotrast-induced cholangiocarcinoma. 8r
f Radio/ 55:598-600, 1982.
w"T~-LABELEDIMINODIACETIC ACID
DERIVATIVES
Interfering drug(s): Narcotic (opioid) anal-
gesics (e.g., morphine, meperidine);pentobar-
bital.
Nuclear medicinestudyaffected: Cholescin-
tigraphy.
Effect on image:Deiayed biliary-to-howel tran-
sit time (i.e., delayedvisualization of radio-
tracer in intestine) with radioactivity remaining
in the gallbladder or in the common bile duct
but not released into the duodenum.
Significance: This pattern of distribution may
mimic that observedwith mechanical obstruc-
tion of thecommon b i b ductorwitholher
nonspecific gallbladder disease. The signifi-
cance of thisinteractionisincreased,since
many palients with right upperquadrant pain
are treated with narcotic analgesics in the emer-
gency roomprior to referral to nuclear medicine
for examination.
Mechanism: Narcotic analgesics increase intra-
biliary pressure and cause spasm of the sphinter
of Oddi, thus preventing the movement of radio-
lracer into the small bowel. (Neostigmine may
enhance the effect of narcotic analgesics.)
Management: An alternative type of analgesic
may he given butusually is less effective for
pain that is olien associatedwith gallbladder
disease. When it is clinically feasible, the study
may be delayed for several hours until the effect
of the drug dissipates, although this time varies
from patient to patient.

I92 f Essentials of N'nclenr Medicine Science
How documented: Study in dogs (1); several
casereports (2-5); twoprospectiveclinical
studies (6,7).
REFERENCES
1. Durakovic A. Dubois A: Effect or ketamint, pentobar-
biral, and morphine on Tc-99111 DISIDA hepatobiliary
kinetics. J N r d Med 26:P79, 1985.
2. Taylor A Jr, KipperMS,Witztum K. et a!: Abnormal
Tc-99m PlPIDA scansmistakenforcommonducl
obstruction. Rudiology 144:373-375, 1982.
3 . Sefczek DM, S h m a P, Isaacs GH,et al:Effectof
narcotic premedication on scinligraphicevaluation of
gallbladderperforation. J N z d Med 2651-53, 1985.
4 . Pope RI, Bratke I: Two Tc-HIDAcaseswithdelayed
emptying inlo duodenum. Morrrldy Scan July 1981.
5 . Lim XE,Dubovsky EV, Tim LO, et al: Morphine-Pros-
tigmin test-e[lecl on Tc-99m DISIDA cholescintigra-
phy. Clill N d M e d 7:213-214, 1982.
6. Lim RE, Yester MV, Smith B, et al: Effect of morphine
and neostigmine on cholescintigraphy. Clirz A"! Med
6P141, 1981.
7. Joehl RJ, Koch KL, Nahnvold D L Opioid drugs cause
bile duct obstruction during hepalobiliary scans. Am J
S ~ r g147: 134- 138, 1984.
Interferingdrug(s):Nicotinic acid (chronic,
high-dosetherapy).
Nuclear medicine study affected:'Cholescin-
tigraphy.
Effect on image: Poor exlraction and elimina-
tion of radioiracer.
Significance: Pattern of distribution istypical of
that observed with intrinsic hepatocellular dis-
ease. Therefore, unless one is familiar with
toxic effects of drugs, the cause for the change
in radiotracerkinetics may beeasilymissed.
(Apparently short-lerm, lowdose therapy does
not have the same effect as chronic high-dose
therapy (l).)
Mechanism: Toxic effect of drug on hepato-
cyles .
Management: Repeat study several weeks fol-
lowing discontinuation of therapy (or following
dosage reduction).
How documented: One case reporl (2).
REFERENCES
1. Shafcr KB, Knodell RG, Stanley IN, el al: Acute efrects
of nicotinic acid on hepatic transport ofTc-99m PIPIDA.
Errr J h'ircl Hcri 8:12- 14, 1983.
2. Richards AG, Brighouse R Nicotinic acid-a cause of
failed HIDA scanning. J Nucl Med 22746-747, 198 1.
Interfering drug(s): Total parenterainutrition
(TPN) therapy.
Nuclear medicine study affected: Cholescin-
tigraphy.
Effect on image: Absent or delayed visualiza-
tion of the gallbladder (in patients with no gall-
bladderdisease).
Significance: This pattern of distribution mim-
ics that typicallyobservedwith cholescystitis,
r e s u l h g in falsepositiveimagesand,some-
times, unnecessary surgery. (TPN-induced gall-
bladder stasis may, however, be a risk factor for
cholelithiasis (l).)
Mechanism: During TPN therapy, the gallblad-
der is relatively inactive, whichresults in bile
stasis and the formation of a thick viscous jelly-
like bile within thegallbladder that impedes
flow of radiotracer into the gallbladder.
Management: Theoretically, sincalide or cho-
lecystokinin may be used to clear a pathway for
radiotracer entry into the galIbladder; however,
limited clinicaI experience with sincalide in
TPN patients does not support the efficacy of
thishypothesis.Ultrasonographyshouldbe
used as an adjuncl toconfirm the presence or
absence of gallbladder disease.
How documented: Prospective study of chole-
scintigraphy in patients on TPNtherapy (2);
retrospectivechart review of 200 consecutive
patients who received99mTc-p-isopropylimino-
diacetic acid (PIPIDA) for hepalobiliary imag-
ing (3).
REFERENCES
1. Messing 8 ,Bories C, Kunstlinger F, et al: Does total
parenteral nurrilion induce gallbladder sludge lormation
andlithiasis? Gasrroenrerology 84:1012-1019,1984.
2. Potter T,McClain CJ, Shafer RB: Effect of fasting and
parenteral alimentationon PIPIDA scintigraphy.Dig Dis
Sci 28687-691, 1983.
3. Shuman WP, Gibbs P, Rudd TG, et al: PIPlDA scintigra-
phy for cholecyslitis: false positives in alcoholism and
Lotal parenteral nutrilion. AJR 138:1-5, 1982.
Intcrfering drug(s): Hepatic artery infusion
chemotherapy.
Nuclear medicine study affected: Hepatobil-
iary scintigraphy.
Effect on image: Nonvisualization of thc gall-
bladder.
Drug-induced Aleralions: Reported Insiomes
Significance: Scintigraphic evidence of cho-
lecystitis is very common, if not uniformly
present, during hepatic artery infusion chemo-
therapy. Cholecystectomy may not be indicated
in these patients, however, unless acute clinical
signsandsymptomsaccompanythescinti-
graphic findings.
Mechanism:Hepaticarteryinfusionchemo-
therapyfrequentlyinduces a chemicalcho-
lecystitis, which is not surprising since, in the
vast majority of patients receiving this therapy,
the gallbladderisincluded in theregion per-
fused.
Management: Perform confirmatory diagnostic
tesk to determine the seriousness of the cho-
lecystitis. If thepatient is not symptomatic,
surgery is probably not necessary.
How documented: Clinical study with case re-
ports (1).
REFERENCE
1, Housholder DF, Hynes HE, Dakhil SR, et al: Hepatobil-
iary scintigraphy in patientsreceivmghepaticartery
infusion chcmotherapy. J N r d &fed 26:474-477, 1985.
9g"T~-LABELEDPHOSPHATES AND
PHOSPHONATES
Interfering drug(s): Iron-containing com-
pounds; Phospho-Soda; acute administration of
diphosphonate.
Nuclear medicine study affected:Skelelal
scintigraphy.
Effect on image: Decreased osseous uptake of
boneimagingagentsand,insome cases, an
increase in intravascular activity.
Significance: It is not known to what extent
skeletal lesions,comparedwithnormalbone,
may be affe{ted by this interaction. Therefore,
the significance is uncertain. Some slight con-
fusion may result, however, since osteoporosis
and congestive hear1 failure, among other disor-
ders, may also cause a generalized decrease in
the uptake of skeletal imaging agents by bone.
In addition, in those cases in which increased
blood background is present, the ratio of bone-
lo-background radioactivity is diminished, thus
potentially decreasing lesion detectability. (Ap-
parently ihe chronic administration of therapeu-
tic diphosphonate does not affect uptake of ra-
diotracer by bone (1, 2 ) )
f 193
Mechanism: With regard to iron-containing
drugs, it hasbeen postulated that an in vivo
transchelation may occur, resulting in a 9 9 m T ~
compound that has less affinity for bone. Alter-
natively, some iron compounds (e.g., iron dex-
tran) may form an intravascular complex with
the 99mTc-labeled skeletal imaging agents which
does not readily distribute to bone but instead
remains in the blood pool.
With Phospho-Soda, the phosphate ions in
the drug may saturate bone-binding sites toa
certainextent,resulting in competitiveinhibi-
tion of skeletal binding with the 99mTc-labeIed
phosphonates.
With diphosphonate (Didronel),the mecha-
nism is unclear, but the alterations in bone up-
take probably represent changes induced by the
drug at the site of hydroxyapatitecryslalor
calcium phosphate deposition.
Management: If ciinically appropriate, discon-
tinueirontherapy or Phospho-Soda therapy
prior to skeletal scintigraphy, keeping in mind
that thebiologichalf-life of irondextran, in
particular, is relatively long. Do not administer
nonradioactive disphosphonate within a few
hours of the administration of 94mTc-phospho-
nate.
How documented: Studies in rats (3-5); case
reporls (6-8).
REFERENCES
1. Lee, JY: Bone scintigraphy in evaluation of Didronel
therapy for Paget's disease. Clin Nucl Med 6356-358,
1981.
2 Espinasse D,Mathieu L, Alexandre C , et al: The kinet-
ics of Tc-99m labeled EHDP in Paget's discase before
and after dichloromelhylene-diphosphonatetreatment.
IMetub BORCDis Re1 Res 2:321-324, 1981.
3 McRae J, Hambright P,Valk P, et al:Chemistry of
rc-99m tracers. n.In vitro conversion of tagged HEDP
and pyrophosphate (bone-seekers) into gluconate (renal
agent). Effects of Ca and Fe(l1) on in vivo distribution. J
N'rrcl Med 17:208-211 1976.
4. Choy D,Maddalena DJ, hlurray IPC: The effect of iron-
dextran on the biodistribution of technetium pyrophos-
phate. in/ J A'zrcl Med Biol 9:277-282, 1982.
65 . Wall I, Hill P: Effecl of acute adminismation of ethanc
hydroxydiphosphonate (EHDP) on skeletal scintigraphy
with technetium-99m methylene diphosphonicacid (Tc-
MDP) in thc rat. Br J Radiol54:592-596, 1481.
Parker JA, Jones AG, Davis MA. et aI: Reduced uptake
of bone-seeking radiopharmaceuticalsrelated to iron ex-
cess. Clin Nucl Med 1:267-268, 1976.
194 1 Esserlrinls of Nrtcienr Medicine Science Drug-inducedAlterafions: Reported Insiances I 195

7. Choy D. Murray IPC, Hoschl R: The effect of iron on chiIdren treated with chemotherapeutic drugs for rnalip- liver uptake of radioactivity occurs when alumi- 2. Hoogland DR, Forstrom L, Madhal AF, et al: Effects or
h e biodistribution of bone scanning agents in humans. nant disease. Radiology 128:165-167, 1978. num is mixed with bone-seeking radiotracers in pH on tissuedistribution of 99m-Tc-pyrophosphate
Radiology 140:197-202. 1981, vitro. The phenomenon also occurs when bone- (PUP) in bone imaging (abstract). Med Imuging 239,
8 . Saha GB. Herzberg DL, Boyd C M Unusual In vivo Interferingdrug(s): “Cytotoxic”cancer 1977.
distribution of Tc-99m disphosphonate. CIin h’rrcl !Wed
imaging agents are injected into rats with ele- 3. Crawford JA, Gumeman L W Alteration oT body dis-
2:303-305. 1977 chemotherapy. vated plasma levers of aluminurn. tribution of WmTc-pyrophosphateby radiographic con-
Nuclearmedicinestudyaffected: Skeletal Management: None; if liver uptake occurs on a trast material. CIin NucI Med 3:305-307, 1978.
scintigraphy. bonescan, it may be helpfultomeasure the
Interfering drug(s): Iron-containing com- Effectonimage: Diffuse activity around cal- concentration of aluminuminthepatient’s Interfering drug@): Regional chemoperfusion;
pounds; amphoterecin B ; gentamicin; cyclo- varium whichhasbeentermedthe“sickle plasma. injections of calciumgluconate, iron dextran,
phosphamide; vincristine; doxorubicin. sign. ’’ How documented: Studiesinrats (1-4) and heparin calcium, meperidine.
Nuclearmedicinestudyaffected: Skeletal Significance: This pattern of distribution can be case studies resulting from preparation of radio- Nuclearmedicine study affected: Skeletal
scintigraphy. distinguished from meningeal carcinosis and pharmaceuticals using generator eluate with ele- scintigraphy.
Effect on image: Increased renal retention of skullmetastasesonlywhen avertex view is vated aluminum levels (4). Effect on image: Extraosseous accumulation of
radiotracer. taken.Withthe vertex view, the diseasepro- radiotracer.
Significance: The presence of radiotracer in the cesses are seen as localized uptake or hetero- REFERENCES Significance: At times, the drug-induced extra-
kidneys on a bone scan may be confused with geneous distribution, whereas the drug-induced I . Jaresko GS, Zjmmer AM, Pavel DG, et a]:Effect of osseous localization of 99mTc-labeled phospho-
disease processes such as renal vascular disease changes are manifest as homogeneous distribu- circulating aluminum on the biodistribution of Tc-99m- ‘nates may be indistinguishable from disorders
or urinary tract obstruction. Sn-diphosphonateinrats. J A ’ d M e d Technol
tion of the radiotracer. of the bone, e.g., the extravasation of calcium
8:160-161, 1980.
Mechanism: With iron-containing compounds, Mechanism: Unknown. 2. Zimmer A M , Pavel DG: Experimental investigations of gluconate has been reported to simulate osteo-
an in vivotranschelation may form a 9 9 m T ~ -Management: A vertexviewshouldbein- the possible cause of liver appearance during bone scan- myelitis.Regionalchemoperfusioncauses an
labeled kidney-seeking agent. cluded in skeletal imaging protocol in patients ning. Radiology 126813-816, 1978. increase in activity in local skeletal structures
With antibiotics and cancer chemotherapeutic in whom this confusion may arise. 3. Chaudhuri TK: The elcect of aluminum and pH on al- and the surrounding soft tissue which may be
agents, the renal localization may be due to a How documented: Prospectivestudy of skel- rered body distribution of Tc-99m EHDP. Z r z f J Nrrcl >Wed
Biol 3:31, 1976.
confused with
a malignant process.Sites of
nephrotoxic effect of the drugs, i.e., tubular or etal imaging in patientsundergoingintensive extraosseous radiotracer uptake may also be
4. Chaudhuri TK: Liver uptake of Tc-99m-diphosphonate.
vascular damage. cytotoxic therapy for breastcancer, compared Radiology 119:485-486,1976. confused with other pathologies not related to
Management: None; skeletal imaging itself with patients taking hormonal therapy for pros- drug therapy.
may be a means to monitor nephrotoxic effects tatic cancer (1). Mechanism: With regional chemoperfusion of
Interfering drug(s): Sodium diatrizoate.
of drugs (I).
REFERENCE Nurlcar medicine study affected: SkeletaI cancer drugs, the resulting hyperemia may con-
How documented: Studies in rats (1,2); case tribute to increased uptake of tracer locally.
scintigraphy.
reports (3-5); retrospective study of bone imag- 1. Creutzig H . Wolfgang D: The“sickle-sign” in bone With iron dextran, the mechanism may be a
scinligraphy. Eur J Nfrcl M e d 6:99-101, 1981,
EfTect onimage: Marked renaland hepatic
ing in children receiving cancer chemotherapy local complexing of 99mTc-diphosphonatewith
localization of radiotracer.
(6). Significance: As discussed previously,several iron dextran or,alternatively,a combination of
Interfering drugls): Aluminum-containing
diseases induce this samepattern of distribution reduced technetium with either ferric hydroxide
REFERENCES antacids. or dextran afterrelease of thesecomponents
(seeothermonographsunder99mTc-Iabeled
1 . hlcAfee I G , Singh A. Roskopf M, et al: Experimental Nuclearmedicinestudyaffected: Skeletal from the iron dextran complex,
phosphales and phosphonates).
drug-induced changes in renal function and biodisuibu- scintigraphy. With extravasation of intravenous calcium
Mechanism: The osmotic effeci of the contrast
tion of Tc-99m MDP. Invesr Radio1 18:470-478, 1983. Effect on image: Appearance of liver on bone gIuconate or injection of subcutaneous calcium
2. McRae J. Hambright P, Valk P, et al: Chemistry of
material may cause the increased renal activity
scan.
Tc-99m tracers. 11. In vitro conversion of tagged HEDP by inhibilion of the normal tubular reabsorption heparin, if the concentration of calcium in the
Significance: Interaction is of minimal clinical tissue exceedsthecapabilities of local sol-
and pyrophosphate (bone-seekers) into gluconate (renal of the 99mTc-phosphate.Thehepaticandthe
significance. However, metastatic liver disease,
agenl). EIfectsof Ca and Fe(I1) on in vivo distribution.J renal uptake of thetracer could be due to an ubiiity,precipitation of calcium, which could
amyloidosis, hepatic necrosis,hypercalcemia,
Nucl Med I7:208-211, 1976. elevation of the local in vivo pH as a result of elicit an inflammatory reaction, may occur.
3. Glass EC, DeNardo GL, Hines HH: Immediate renal and a few other diseases sometimes are associ- Management: None.
imaging and renography with WmTc methylene diphos-
the administration of contrast media (1,2).
ated with this same pattern of distribution; thus,
phonate to assess renal blood flow, excretory function, Management: On any given day, perform skel- How documented: Study in rabbits (1); case
there may be some interference with the differ-
and anatomy. Radiofogy 135:I87-I90, 1980. etal scintigraphy study prior to procedures re-. reports (1 -9).
4 . Trxkler F T , Chinn RYW: Amphotericin B therapy-a ential diagnosis.
quiring the injection of contrast media.
cause of iocrcased renal uptake oi Tc-99m MDP. Clin Mechanism: It has beenproposedthat a sub- REFERENCES
How documented: Case report (3).
Nucl Med 7:293, 1982. micron (submicroscopic) colloid is formed as a Planchon CA, Donadieu A, Perez R, et al: Calcium
5 . Siddiqui AR: Increased uprake ol lechnetium-99m la- resalt of a complexingphenomenonbetween hcparilldle inducedexlraosseous uptake in bone scan-
beled bone imaging agents in the kidneys. Semin N~rcl REFERENCES ning. E u r J ~ r ~ c l M e d 8 : 1 1 3 - 1 1 1983.
7,
aluminumandtheradiopharmaceutical, al- I . Clrdudhuri TK: The cffcct of aluminum and pH on 31- Surkin SJ, Horii SC, PassaIaqua A , et al: Augmcnted
Med 12:lOl-102, 1982.
6 . Lulrin CL, McDougall IR, Goris ML: Intense concentra- though this has never been verified. Case stud- lcrcdbody distribution of 99m-Tc-EHDP. Irrr J Nucf activity on bone scan following iocal chemoperlusion.
. _ . . in the kidneys 01
tion or technetium-99m wrophosphale ies(andanimal expcriments)have shown thal Med B i d 3 3 7 , 1976. Clirr Nucl Med 2 4 5 I , 1977.

196 I Essentials of NuclearMedicineScience
3. Mazzola AL. Barker MH, Belliveau R E Accumulation
of Tc-99m diphosphonate at sites ol intramuscular iron
therapy: case rcporl. J N d Med Techrdol 4:133-135.
1976.
4. VanAnlwerp ID, Hall JN, O'Mara RE, et al: Bone scan
abnormality produced by interaclion of Tc-99m diphos-
phonate with iron dextran (Imferon).JNucl Med 16577,
1975.
5. Byun HH. Rodman S G , Chung K E Soft-tissue con-
centratlon of Tc-99m phosphales associated with mjec-
lion o l Iron dextran complex. J Nncl Med 17:374-375,
1976.
6 . Balsam D, Goldfarb CR. Stringer B , et al: Bone scinti-
graphy for neonatal osteomyelitis: simulation by extra-
vasation of intravenouscalcium. Radiology
135:185-186, 1980.
7. Go FT, Cook SA, Abu-Yousel MI et al: Etiology of sofl
tmue localization in radionuclide bone imaging. Scien-
tific exhibil presenkd at the 28th Annual Meeting ol Ihe
Society of NuclearMedicine. Las Vegas, June1981.
8 . Brill DR: Radionuclideimaging of nonneoplaslicsoft
tissue disorders. Sernirz Nucl Med 11:277-288, 1981.
9. Duong RB, Volarich DT, Fernandez-Ulloa M , et al:
Tc-991n MDP bone scan artefact-abdominal soft tissue
uptakesecondary to subcutaneousheparin injection.
Clin NucI Mcd 9:47. 1984.
Interfering drug(s): Diethystilbestrol (es-
trogens).
Nuclear medicine study affected: .Skeletal
scintigraphy.
Effect on image: Accumulation of radiotracer
in breast tissue.
Significance: Interaction is of minimal clinical
significance. However, breast uptake occurs in
normal breasts, in benign breast lesions, in pri-
mary breast carcinomas, and in melastatic ade-
nocarcinomas;thustheremaybesome inter-
ference with the differential diagnosis.
Mechanism: The mechanism of uptake is un-
known, although it has been suggested that this
uptake may result fromthebinding of phos-
phates or diphosphonatesto receptorsites on
enzymes such as phosphatases (1).
Management: None.
How documented: Case report (2).
REFERENCES
I . Schmiit GH, Holmes R A , lsilman AT, el al: A proposed
mechanism for 991"Tc-labeledpolyphosphate and diphos-
phonateuplake byhumanbreast lissue. R ~ d i ~ l o g ~ by epsilon aminocaproic acid. J Neurosurg 57:130-134,
112733-735, 1974.
2. RanISingh PS, Pujara S , Logic IR: Tc-99m pyrophos-
phale uptake in drug-induced gynecomastia. CIird N f d
Med 2:206, 1977.
Interfering drug(s): Corticosteroids.
Nuclearmedicinestudyaffected:Skeletal
scintigraphy.
Effect on images: Decreased or absent uptake
of radiotracer in bone,especially at major
joints.
Significance: Since theeffect is decreased bone
localization, it will not be confused wilh meta-
static orother common bone diseases.However,
sincethispattern of distribution is observed
with a few other disorders, there may be some
interference with differential diagnosis.
Mechanism: Steroids may cause ischemic ne-
crosis of bone.
Management: None.
How documented: Clinical study (1).
REFERENCE
1. Conklin JJ, Alderson PO, Zizic TM, el aI: Comparison
of bone scan and radiograph sensilivily in the detectton
of steroid-inducedischemic necrosis of bones. Rndi-
olog)~147:221-226, 1983.
Interrering drug(s): €-Amino caproic acid.
Nuclearmedicinestudyaffected:Skeletal
scintigraphy.
Effect on image: Markedly increased uptake of
radiotracer in muscle.
Significance:Thisinteraction is significant
only in that muscle uptake in patienls with myo-
pathy may reduce skeletal visualization.
Mechanism:Some patientson thisdrugde-
velopa myopathy, thecause of which is no1
clear. Thisconditionisapparently helped by
bed rest.
Management: Bed rest preceding the examina-
tion is recommended in affected patients if the
bone scintigraphy is to be performed for con-
ventional indications. The technique appears of
potential use, however, inthemonitoring of
myopathy.
How documented: Evidence of the myopathy is
well documented (1) with a case report of the
scintigraphy findings in humans (2).
REFERENCES
1. Brown JA, Wollmaun RL, Mullan S: Myopathy induced
1982.
2. Van Renterghcm D, De Reuck J, Schelslracle K, et al:
Epsilonaminocaproicacid rnppalhy: additional fea-
lures. Clbl Newol Neirrosurg 86153-157, i984.
Drug-inducedAlterations:ReportedInsrnnces
Interfering drug(s): Diphosphonate.
Nuclear medicine study affected: Avid infarct
scintigraphy (99mTc-pyrophosphate).
Effect on image: Decreased uptake of radio-
tracer in infarcted myocardium and an increase
.in radioactivity in normal myocardium.
Significance: If data are applicable to humans,
a decrease in lesiondetectabilitymayresult
fromtheinteraction.Furthermore,certain
pathologic conditions which are associated with
increased serum phosphate levels, altered pyro-
phosphate metabolism, andlor decreased renal
excretion of pyrophosphate also may cause sig-
nificant impairment of the diagnoslic accuracy
of 99mTc-pyrophosphate myocardial scintigra-
phy.
Mechanism: Possibly due to saturation of
SmTc-pyrophosphate-binding silesbydiphos-
phonate and dilution of 99mTc-pyrophosphatein
the circulating diphosphonate pool at the time of
99mTc-pyrophosphate injection.
Management: Avoid concomitant use of non-
radioactive diphosphonate in patients undergo-
ing 99mTc-pyrophosphate scintigraphy for local-
ization of myocardial infarci.
How documented: Study in dogs (1).
REFERENCE
1 Buja IM. Tofe AJ. ParkeyRW, et al: Effect of EHDP on
calci~~m accumulatlonandlechnelium-99mpyrophos-
pharc uptake in experimental myocardial infarction Cir-
crrlatiorf 64:1012-1017, 1981.
Interfering drug(s): Doxorubicin.
Nuclear medicine study affected:Avid infarct
scintigraphy (99mT~-pyr~phosphate).
Effect on image: Diffuse uptake of the radio-
tracer in the myocardium.
Significance: Interaction is of minimal clinicaI
significance,sincetheuptake in thiscaseis
diffuse, unlike the more localized uptake noted
in infarctions. However, sincediffuseuptake
may be observed in many other cardiac condi-
tions,includingangina, ventricuIar aneurysm,
congeslive cardiomyopathy, chest irradiation,
calcifiedintracardiacvalves, pericarditis, and
cardioversion, there may be some interference
with the differential diagnosis.
Mechanism: Doxorubicin-induced cardiac tox-
icity inilially presents asdiffusemicroscopic
damage to the myocardium. Cellulardanmge
I 197
such as this allows accumulation of 99mTc-pyro-
phosphate.
Management: None.
How documented: Prospective clinicalstudy
(1).
REFERENCE
1. Chacko AK, Gordon DH, Bennett JM, el al: Myxardial
imaging wilh Tc-99m pyrophosphate in patients on
adriamycintreatment for neoplasia. I N~rtcl Med
183680-683,1977.
""Tc-GLUCEPTATE
Interfering drug(s): Pencillin; acetaminophen;
trimethaprim-sulfamethoxazole.
Nuclear medicine study affected: Renal scinti-
graphy.
Effect on image: Enhanced excretion of radio-
tracer through the hepatobiliary system.
significance:Radioaclivity in the gallbladder
could be confused with abnormal kidney local-
izalion. (Since hepatobiliary excretion of 99mTc-
gluceptate also occurs in healthy patients in the
fasting stale(l), and since this phenomenon was
no[taken into consideration when theinlerac-
tion was studied andlorreported, thesignifi-
cance of the interaction is not known.)
Mechanism: Theoretically, in vivo transchela-
tion occurs between gluceptate and metabolites
of thedrugs,thusforming a 9 9 m Tspecies
~
which is eliminated to a large extentviathe
hepatobiliary system.
Management: None.
How documented:. Chart review and follow-up
study in rabbits (2).
REFERENCES
1, Tyler IA, PowersTA: Gallbladder visualizalion wilh
~echnetium-99111glucohep~onate: concise communica-
lion. J NrrcI Med 23:870-871, 1982.
2. Hinkle GH, Basmadjian GP, Peck C, etai:Effects of
concurrent drug therapy on technelium Tc-99rn glucep-
tale biodislribution. Am f Hasp Pharm 39:1930-1933,
1982.
99"T~-DIMERCAPTOSUCCINICACID
(DMSA)
Interfering drug(s): Ammonium chloride; so-
dium bicarbonate; mannitol.
Nuclear mcdicine study affected: Renalscinli-
graphy.
 198 I Essentials uf ~ V ~ c l eMedicine
ar Science
i. - .,
_ .
"

c. '

_. Effect on image: Administration of ammonium Mechanism: When renal perfusion pressure is thrombosis which may result in pulmonary em- num ion concentration in theserumadversely
chloridemay substantiaIly decrease renal dis- reduced by renal artery stenosis, effective filtra- boli. affects the biodistribution of [ 99mTc]pertechne-
E-
lributionand increase hepatic distribution of tion pressure and glomerular filtration normally Management: Heparin should be discontinued tale.Renalandgastrointestinaldisorders, as
q9mTc-DMSA; administration of sodium bicar- are conservedby constriction of efferent ar- immediately in palients with delayed-onset, se- well as chronic ingestion of aluminum-contain-
bonate and mannitol may also decrease the dis- terioles. This efferent arteriolar constriction is vere thrombocytopenia with heparin-dependent ingantacids,canresult in elevated levels of
tribution of theradiopharmaceutical to the mediated by angiotensin 11. Since captopril in- antibody and should be replaced with oral anti- aluminum in the blood.
kidney. hibits the formation of angiotensin 11, the drug coagulation. Both stannous ion andsulfonamidescause
"
Significance: The possibility that drugsmay may induce a reversible, functional renal insuf- How documented: Although this phenomenon radiolabeling of red bloodcells;stannousion
~..= . induce
acid-base
imbalance
andlor
dehydration docs this by reducing the pertechnetate ion in-
" ficiency.Therefore,diminished 99mTc-DMSA has not been reported in the nuclear medicine
:& and thereby affect
the distribution of 9 9 m T ~ - uplake in a stenotic kidney during captopril ther- literature, clinicians should be aware of its pos- tracellularly, whereasthemechanism for sul-
~~

~-
-
ir-
~~
DMSA shouldbeconsidered
ing
this radiopharmaceutical.
in patients
Comparison
receiv- apy may bedueto a loss of effective trans-
of se- membrane filtrationpressure on theinvolved
sible occurrence (1-3). Fonamide-induced erythrocytelabeling is un-
clear.
.";
, -
-.
~

.
I
F.

;P,
7
-
~~ ~ quential renal studies may be impaired if drug side. REFERENCES Management: When it is clinically feasible,
.) Chong BH, Pitney WR, CastaIdi PA: Heparin-induced
3. -5> therapy is initiated at some pointafter theinitial Management: It may be necessaryto replace disconlinue therapy several days prior to imag-
thrombocytopenia: association of thrombotic compIica-
- ?
.=
L1 study is performed. In addition, false overesti- captopril with another antihypertensive agent, lions with heparin-dependcnl IgG antibody that induces ing or, alternatively,useagentsotherthan
_-
~~

.. ~.
.~
gF-
-
mates of righl renal kidney activity may occur e.g., minoxidil, prior to performance of renal thromboxane synlltesis and platelet aggregation. Lancer [9mTc]pertechnetate for brain or thyroid imag-
_= 5- when there is an increased hepatic contribution scintigraphy. If a low or absent renal uptake of 1:1246-1248. 1982. ing.
3 f
I%"
-
I , to count
therate. the radiolracer is noted in a patient with proven Kapsch D N , Silver D: Heparin-inducedthrom- How documented: Study in rabbits (1); studies
*E'i bocytopeniawiththrombosis and haernorrhage. Arc11
~- -~
a; _.
i Mechanism: Arnmoniunlchloridemay exert its or suspected renal artery stenosis on captopril in rats ( 2 , 3 ) ;prospective clinical studies (43;
~

Sfrrg 116:1423-1427, 1981.

s .-
,
i effect on distribution by inducing acidosis and therapy, further investigation (e.g., with ['231] Towne JB. Bernhard V M , Hussey C, et al: White clot and several case reports (1,6,7).
E 1~

i-t
r-zz acidification of urine;
thesodium bicarbonate or [13'I]iodohippurate) may be warranted to de- syndrome: peripheral vascular complications of hepartn
$5
- =.
= _- inducesalkalinization of theurine,whereas termine whether the apparent functional loss is therapy. Arch S w g 114:372-377, 1979. REFERENCES
Fz
"

.~.
~~
1%
mannitol can
cause dehydration, both of which reversible and drug-related 1. Chervu LR, Castronuovo JJ, Huq SS, el al: Alleratious
&F
$ r-
~ .- In red celltagging with sulfonamides. J Nfrcl Med
5 t
._ may affectthedistribution of the radiolracer. How documented: Case report (I). [99mTc]PERTECHNETATE
"

i.L 7'
"
22:P70, 1981.
2%
" _, Mannitol also may decrease the extractionfrac- Interfering drug(s): Aluminum-containing 2. McRae J, Sugar RM. Shipley 8 , et a1 Alterationsin
=
~-
~~

~~
I
ilf
=-
ai-
tion of 99mTc-DMSAthrough its effect on tran- REFERENCE antacids; sulfonamides; stannous ion-containing tissue disbibulion of Tc-99m pertechnetate in rats given
c
i
2
-i
~= ~~
~~

=.
sit time. I , Kremer Hovinga TK, Beukhof JR, van Luyk WHI, e l a[: drugs and radiopharmaceuticals. stannous tin. J Nuci Med 15:151-155, 1974.
c -=
2%
5% Management: Discontinue drug therapy and Reversible diminished renal wmTc-DMSAuptake during 3. Khenligan A, Garrelt M, Lum D, et al: Effects of prior
Nuclear medicine study affected: Brain scin- administration of Sn(1I) complexes on in vivo distribu-
L :-
assure
that
patient
the is adequalely hydraled converting-enzyme inhibition in a patient with renal ar-
~~

~~
%c_
-~ tigraphy; thyroid scintigraphy; Meckel's diver- tion of Tc-99m perlechnetate. J Nrtcl Med 17:380-384.
~

tery stenosis. E w J I V IMed

~ 9: 144-146, 1984.
:
=-z<
~.
%?
prior
to perfonning renal
scintigraphy. ticulum scintigraphy. 1976.
1
"
__
=~

- How documented: Study in rats (1). Effect on image: The noted drugsmay result in 4. Ancri D, Lonchampt M, Basset I: The effect of tin on
_,-, -=- the tissue distribution of Tc-99m sodium perlechnctale.
""Tc-LABELED MACROAGGREGATED a failure of [99mTc]pertechnetatetoleavethe
REFERENCE
"

_. Radiology 124144-450. 1977.

._:"
::-
~~~

~= - ALBUMIN AND ALBUMIN vascular space;i.e.,increased bIood pool ac-

1. Yee CA, Lee HB. BIaufox MD: Tc-99m DMSA renal 5. Chandler WM, Shuck L D Abnormaltechnctiurn-99111
> ,=
z
i.
-

~- uptake:
influence of blochemical and physiologic
fac- MICROSPHERES tivity isseenon the image. For example, in- pertechnetate imaging following slannous pyrophos-
-_
..
.~
x >.
I~

tors. J Nrrcl Med 22:1054-1058, 1981. Interfering drug(s): Heparin. creased activity has been observed duringbrain phate boneimaging. J A'ncl Med I6:518-519. 1975.
n =

i
-?=
z.
l i
Nuclearmedicinestudyaffected: Pulmonary scintigraphy in the superior sagittal sinus,the 6. Wang TST, Fawwaz RA, Esser PD, el at: Altered body
zs
-
transverse sinuses, and Lhe region of the choroid distribution of Tc-99m pertechnetate in iatrogenic hyper-
"
5 _
i _
Interfering
drug(s): Captopril. perfusion scintigraphy.
z
I c--
: aluminemia. JA'uclMed 19381-383, 1978.
=~~
I:
-
~~ ~

Nuclearmedicinestudy
affected: Renal scinti- Effect on image: Appearance of perfusion im- plexus (when scintigraphy has been performed 7. Montelibano EB, Ford DR, Sayle BA: Altered Tc-99m
$5

--
"
~~

zc1
.~ ~~ graphy. age is that typically observed with pulmonary following bone scintigraphy). perlcchnetate distribution in a thyroid scan after Tc-99m
s=-
_ -
- x_
~~
1 Effect on image: In paiients
with hypertension emboli. Significance: Decreased or absentuptake of Snpyrophosphateadministration. Clirl Nucl Med
l i
i=

s;- and unilateral renal arterystenosis, there may Significance: Since thromboembolic disease [99n'Tc]pertechnetateintonormal tissue (e.g., 4277-278,1979.
" -
sz:
- ~= be a decreased renal
uptake of 99mTc-DMSA by associatedwithheparin-inducedthrom- thyroid) or diseased tissue (e.g.,brain disorders
__-~
ci

=.
bocytopenia is a relatively rare occurrence, the or Meckel's diverticulum) may result in missed 9mT~-LABELEDRED BLOOD CELLS
Ti.
~:-
the affected
kidney
(reversibIe following
dis-
.~
,
,= _
E _
I
7 -
~~

continuance of captopril). paradoxical deterioration on perfusion scans in diagnoses in theseorgans.Thereis, however, Interferingdrug(s): @-Adrenergicblockers
conflictingdata concerning the efrect of prior
~~

;"?
= -
+ >~.~<
~~
Significance: This pattern of distribution may patients receiving heparin therapy may come as (e.g.,propranolol);calciumchannel blockers
-~
I

i-
indicate a deterioration of glomerular filtralion a surprise to the clinician. slannous ion administration on the distribution (e.g., verapamil); nitrates (e.g., nitroglycerin).
=
~.<
"
~

.~
~.
?*-
- ,
~
~~

as a result of drug therapy, ratherthana worsen- Mechanism: The presence of a heparin-depen- of [9ymmTc]per~cchnetate into the thyroid and Nuclear medicine study affected: Radionu-
i
-_
*?a
i

i
~ -~
"
=.e ing of theunderlying diseaseprocess;thus,con- dent IgG antibody in patients with delayed- stomach, i.e., whether il causes an increasedor clide ventriculography.
,_
j

l i_
.=
decreased uptake into these organs.
I $' fusion may arise as lo the cause of the dimin- onset, heparin-induced thrombocytopeniahas Effect on image: Therapy with @-adrenergic
. ~~~

.1-
1;i. ished radiotracer uptake. beenreportedtopredispose these patientsto Mechanism: It is not known how excess alumi- blockers, calciulu channel blockers, or nitrates
.
~jl
Is
i
LC
=-
~

a
.
*
~~

200 t Esseniials of NuclearMedicilreScience
may result in normal exercise radionuclide ven-
triculograms even in the presence of significant
coronary artery disease (CAD).
Significance: The presence or severityof CAD
may be missed andlor underestimated.
Mechanism: Two possible mechanisms may be
responsiblefortheeffectsofP-adrenergic
blockingagents.First, the effectsmayresult
from dmg-induced changes in the exercise per-
formance of patients. The administrationof a p-
blocker blunts the normal rise in heart rate and
systolic blood pressure which occurs with exer-
cise, resulting in a reduction in myocardial oxy-
gen consumption. In addition, P-blockers may
increase rnvocardial oxvren extraction and aug-
tientswith CAD and impairedleft ventricuhr
function typically show a greater and more con-
sistent increase in exercise performance than do
individuals without CAD. The net effect of P-
blockade therapy on exercise radionuclide ven-
triculography is to postpone the point at which
myocardialischemiaoccursbeyondthat at
which exhaustion limits the exercise test. As a
result, exercise may need to be stopped before
perceptible wall motion abnormalities (or a de-
crease in ejection fraction) can be induced.
Calcium channel blockers predominately act
byimprovingthe ratio of myocardial oxygen
supply to demand, butadditional mechanisms
such as changes in perfusion or myocardial me-
tabolism may be involved.
With nitrates four different actions may be
pressure resulting in reduced oxygen demand,
(cl relaxalion of smoothmuscletone in the
Discontinue calcium channel blockers and ni-
trate therapy prior to radionuclide ventriculog-
raphy in patients beingevaluated for CAD. The
recommendedtimeintervalsbetweenwith-
drawal of medications and the nuclear medicine
study is 48-72~hours for the calcium channel
blockers and 12 hours for the nitrates (2).
How documented: Letter to editor (1); review
(2); clinical studies (3- 11).
REFERENCES
1 . Ponto JA, Holmes KA: Discontinuarion of beta block-
ersbefore exercise radionuclidcventriculograms. J
Nucl Med 23~456-457, 1982.
2. Rabinovitch MA: Pharmacologicintervenlions in nu-
clearcardiology. InThrall JH, Swanson DP (eds):
j t u r d i d 44:i18-324,1979.
4. Marshall RC, Wisenberg G , Schelberl HR, et al: Effect
of oral propranolol on rest, exercise and postexercise
left ventricularperformance in normal subjects and
patients wmith coronaryartery disease. Circularion
63572-583, 1981.
5 . Rainwater J, Steele P, Kirch D, el aI: Effect ofpro-
pranoloI on myocardial perfusion images and exercise
ejection fractions in men with coronary artery dtsease.
Circulafioll 65:77-81, i982.
6. Borer IS, Bxharech SL, Green MV, el al: Effect of
niltoglycerine on exercise-induced abnormalitiesof lell
ventricularregionalfunctionand ejection fraction in
coronaryartery disease: assessmen1 by radionuclide
cineangiography in symptomaticand asymplomatic pa-
tients. Circularion 57314-320, 1978.
7 , Pem MA, Crawford MH,Sorensen SG, et a1 Short-
and long-term ellicacy of high-dose oral dillianem for
anginadue to coronary artery disease: a placebo-con-
trolled, randomized, double-blind crossover study.Cir-
Am J Cardio/49:425-430, 1982.
9. Pfislerer M,Glans L, Burkart F Comparative effecls of
D'rug-inducedAlterdonstReportedInstarsces 1 201
tion, regionalwall molion, lactate metabolism, and vivo, thus decreasing the reductive capacity of
hemodynamics. Am J Cardiol48:536-544, 1981. tin.
Quinidine and methyldopa are medications
Interfering drug(s): Heparin; methyldopa; which have been associated with RBC antibody
hydralazine; quinidine; digoxin; prazocin; pro- formation; the presenceof these RBC antibodies
pranolol;doxorubicin;iodinatedconlrastme- may be responsible, in part, for poor labeling of
dia. RBC in vivo with wmTc.
Nuclear medicine study affected: Radionu- Conflicting data are available on whether di-
clideventriculography;gastrointestinal (GI) goxin has an effect on labelingyield; the mech-
blood loss scintigraphy. anism is unknown.Likewise,themechanism
Effect on image: Poorradiolabeling of red for the effects of prazocin and propranolol is
blood cells(RBC) with 9 9 m T ~ opostlabeling
r
unknown. Apparently propranoiol causes an in-
dissociation of 9 9 m Tfrom
~ the RBC can cause a creased rate of release of 9 9 m Tfrom
~ the RBC
deterioration in the distinctness of the cardiac back intotheplasma but does not inhibitthe
chamber border on ventriculograms and can in- initial radiolabeling process
crease the likelihood that free [g9mTc]pertechne- Although it is not clear how doxorubicin
tate will appear as gastric or bowel aclivity on causes a decrease in labeling efficiency, it ap-
GI bleed studies. pears that the effect of the drug is dependent on
Significance: The diminution in ability to vis- its concentration in the blood at the timc that the
ualize the cardiac chamber border can compli- study is performed.
cate the diagnosis of wall motion abnormalities
The mechanism for interaction of iodinated
and the calculation of ejection fraction. Further- contrast media with RBC labeling by 9 9 m Thas
~
more, progressive loss of 99mTc from the RBC not yet been determined. Possibilities include:
can particularly affect stress tests which usually (a) alterationofredoxpotential of eitherthe
are performed toward the end of the scanning stannous ion or technetium species present,
period. If by this time the counting rate over the (b) a change in stannous ion distribution, e.g.,
heart chambers has faIlen considerably, a useful an alteration intheintracellularstannous ion
scan can be obtained only by keeping the patient concentration, (c) a competition for RBC-bind-
under stress for a long period of time. ing sitesbetween 99mTcand iodide, or (d) an
Additionally, thegastricand boweI activity alteration of RBC-binding sites by iodide.
seen on GI bleed studies may be confused with Management: Whenever it is possibk, avoid
sites of bleeding. injection of Sn-pyrophosphate and [99mTc]per-
Mechanism: Although therapywiththe drugs technetate through a heparin lock. Do not per-
listed above may produce the same net result form radionuclide ventricuIography or GI bleed
(reducedlabelingefficiency of 99mTc-labeled studies on thesameday that doxorubicin is
RBC or dissociationof the label from theRBC), administered. Schedule procedures requiring
the proposed mechanisms are widely varying. RBClabelingpriortostudiesrequiring iodi-
With heparin, a 99mTc-IabeIed heparin com- nated contrast media. If it is clinically feasible,
plex may be formed as 9 9 m T is ~injected through discontinue use of potentially interfering drugs
a heparinizedcatheter(which waspreviously prior to performing RBC labeling.
used for injection of pyrophosphate containing How documented: Studies with in vitro models
stannous ion). It is not positively known at this (1-4); study in rats ( 5 ) ; study in dogs (6); pro-
time whether therapeutic levels of heparin can spectiveclinical studies (1,7,8);case reports
be radiolabeled in a similar manner in vivo if 19).
slannousion is present.Onestudyindogs
showed that red cell labeling may be marginally
affected bythe previous injection of a single REFERENCES
lherapeutic dose of heparin. I . h i t 1 GP, Drew HMN. Kelly ME, et al: Interference with
It is proposed that methyldopaandhydra- Tc-99111 labeling of red bloodcells(RBCs) by RRC
antibodies. J N w l Med 21:P44, 1980.
lazinemayaffectthelabelingefficiency of 2. Zimmer AM, Spies SM, Majewski W: Eirect of drugs
99mTc-l;~bcled KBC by oxidizing stannous ion in onin vivo RDC labeling: a proposed rnechanisn~of
202 t Esselgtinls of Nrrcleor Medicirle Science
inhibition. Presented at the SecondInternationalSym-
posium on Radiopharmacology, Chicago,September
1981,
3. Zanelli GD: Effect of certain drugs used in the treatment
of cardiovascular diseaseon the 'In vitro' labeling of red
bloodcellswithTc-99m. N u c l M e d Cornrnurf
3155-161, 1982.
4. Pauwels EKJ, Feitsma RIJ, Blom I: Influence of
adriamycin on red blood cell labeling: a pitfall in scinli-
graphic blood poolimaging. Nucl M e d Comnfzm
4:290-295,1983.
5. Lee KB, WexlerJP, Scharf SC, et al: Pharmacologic
alterations in%-99m binding by red blood cells: concise
communication. J A'ucl Med 24:397-401, 1983.
6. Rao SA. Knobcl J, Coflier BD: Effect of therapeutic
dose of heparin on the i l l vivo labeling of red blood cells
with technetium99m for blood poolimaglng:impor-
tance of slannous ion concentralion. J NuclMed
26:P95-P96, 1985.
7. Hegge FN, Hamillon GW, Larson SM, etal: Cardiac
chamber imaging: a comparison of redblood cells la-
beled with Tc-99m in vitro and in vivo. J Nncl Med
19:129-134.1978.
8. Seawright SJ. Maton PI. Greenall I, et a[: hctors affect-
ing in vivo labeling ol redblood cells. J Nncl Med
Tcch?!ol 11:95,1983.
9. Talum JL, Burke TS, Hirsch 11, et al: Pitfall lo modified
in V I V O method of technetium-99m rcd blood cell label-
mp-iodinatedcontrastmedia. Clin ~Vfrcl M e d 8:
585-587,1983.
lnterfering drug(s): Doxorubicin.
Nuclear medicine study affected: Radionu-
clide Ventriculography.
Effectonimage: Abnormalejectionfraclion,
reduced left ventricular function.
Significance: RadionucIide ventriculography
often is used to monitor doxorubin-induced car-
diactoxicity. Thiseffect, however, may inter-
fere with the differential diagnosis of abnormal
cardiac function.
Mechanism: Doxorubicin causes a dose-related
cardiotoxicity (cardiomyopathy).
Managemenk None; a baselineradionuclide
ventriculogram should be performedprior to
initiation of doxorubicin therapy to identify un-
diagnosed heart disease.
How documented: Study in rabbits (1); clinical
studies (2-8).
REFERENCES
1. Gorton SI, Wilson GA, Sutherland R, el al: The predic-
Live value of myocardial radioisotopescanning in ani-
mals [reatcd with doxorubicin. J N d Med 21:518-522,
1980.
2. Singer JW, Narahara KA. Ritchie JL, el al: Time- and
dose-dependent changes in ejection fraction determined
by radionuclide angiography after anlhracyclinetherapy.
C m c r r Treat Rep 62945-948, 1978.
3. Feiglan DH. Gulenchyn KY, McLaughlinPR, etal:
Adriamycin cardiotoxicity:correlation of radionuclide
angiography and pathology. J Nucl Med 215'74, 1980.
4. Alexander I,Dainiak N, Berger HJ. et al: Serial assess-
ment of doxorubicin cardiotoxicity with quanlitative ra-
dionuclideangiocardiography. N Engl J M e d
300278-283, 1979.
5 . Dmck M, Bar-Shlomo 5 , Gutenchyn K. et al: Radionu-
clideangiography and endompcardlal biopsy in the
assessmenl o i doxorubicin cardiotoxicity. Am J Cardiol
47:401, 198I .
6. Morgan CW. Mcllvecn BM. Freedman A. et al: Radio-
nuclide ejection fraction in doxorubtcio cardiotoxicity.
Cancer Trear Rep 65629-638, 1981.
7 . McKillop IH, Bristow MR, Goris ML. et a]: Sensitivity
and specificily of radionuclide ejection fractions in dox-
orubicincardiotoxicity. Am Hem/ J 106:1048-1056,
1983.
8. Berger HJ, Choi W. Alexander J, et al: Serial radionu-
clide evaluation of doxorubicin cardiotoxicity in cancer
patients with abnormal baselme resting left ventricular
ejeclion fraction. J Nucl Med 22:P40: 1981.
llll~-DTPAAND 169Y~-DTPA
Interfering drug(s): Acelazolamide
Nuclear medicine study affected:Cistemogra-
PhY.
Effect on image: Delayed parasagittal migra-
tion of radiotracer with reflux of tracer into the
ventricles (in the absence of disease).
Significance: This pattern of dislribution mim-
ics that typically observed in patients with nor-
mal pressure hydrocephalus.
Mechanism: Acetazolamide induces a vaso-
contriction of thechoroid plexusarteriesand
inhibitsthe enzymecarbonicanhydrase.Both
of these phenomenon tend to decrease the pro-
duction of cerebral spinal fluid (CSF) which, in
turn, alters CSF kinetics. The reduced outflow
of CSF from the ventricles results in net reflux
of radiotracer into the ventricles.
Management: D i s c o n h u e therapy with acela-
zolamide several days prior to performing the
cistemography study.
How documented: Case report,beforeand
after discontinuation of acetazolamide ( I ) .
REFERENCE
1. hpanicolaou N, McNeil BJ, Funkenstein HH,el al:
Abnormalcislemogramassociated with Diamox [her-
apy, J Nucl Med 19:501-503, 1978.
"'IN-LABELED LEUKOCYTES
Interferingdrug(s): Antibiotics;cortico-
steroids; hyperalimentation; lidocaine; pro-
cainamide.
Nuclearmedicinestudyaffected: Inflam-
matory process scintigraphy.
Effect on image: Reduced or absenl uptake of
radiotracer into abscess.
Significance: Interferencefromantibioticand
corLicosteroid drugs as well as hyperalimenta-
tion may result in fake negative studies. It is
obvious, however, that drugtherapy does not
always alter the distributionof radiolabeled leu-
kocytes, since many positive scans are obtained
in patients receiving antibiotics or steroids.
With respect to lidocaine and procainamide,
a clinical study reported that a number of nega-
tive imagingprocedureswereobtained in pa-
tients, all of whom had received antiarrhythmic
drugs. A subsequent in vitro study, however,
demonstrated no effecton leukocyte. function at
normal therapeutic drug concentrations.
Mechanism: Drugtherapywithantibiotics,
corticosteroids, or hyperalimentation mayresult
in a reducedchemoattractantstimuliforthe
radiolabeledleukocytes.Additionally,cationic
antiarrhythmic drugs in higher-than-therapeutic
concentrations have been shown toinhibita
number of granulocyte functions including
chemotaxis (1).
Management: None.
How documented: Observations made in clini-
cal studies and in vitroexperiments (1-6); a
re\)iew editorial (7).
REFERENCES
I . MacGregor RR, Thomer RE, Wright D M Lidocaine
inhibils granulocyte adherence and prevents granulocyle
detiveryto inflammalorysites. Blood 56:203-209,
1980.
2. Loken MK, Forstram LA, Cook A, er al: 111-111 labeled
leukocytes for diagnosing inflamrnatorp diseases of the
abdomenand retroperitoneum. In Wahner HW, Good-
win DA (eds): I I I-lndirm Lobeled Plarelefsond Lertko-
c p s , Crystal Lake, 11, Society of NuclearMedicine,
1981, pp 145-159.
3 Daker WJ-Beighlol RW, Datz FL, et al: 1 I I-Indium
oxinc labcled leukocytes: a discussion orthe preparation
and use at Ihe Univcrsily of Ulah. Presented at Ihe 128th
Annual Meeting ol' the American Phnrmaceulical Asso-
cialionAcademy of Pharmacy PrdCliCe, SI. Louis,
March 198I .
Drug-induced Alterations: Reported Instances I 203
4. Thompson L, Ouzounian TJ, Wcbber MM,el al: In-1 1 I
WBC imaging in rnuscuIosLcleta1 sepsis. J Nucl Med
25:PS2, 1984.
5 . Aschner NL. Ahrenholz DH, Simmons RL, et al: In-1 11
autologous tagged leukocytes i n the diagnosis of intra-
peritoneal sepsis. Arch Surg 114:386-392, 1979.
6. Thakur ML, WaIsh W,Zaet BL, et al: Effect of antiar-
rhythmic drugs on In-1 1 I-labeled leukocytes: chern-
otaxisandadherence to nylon wool. J Nucl Med
23:131-135,1982.
7. Goodwin DA: Clinical use of in-1 11 leukocyte imaging.
Clin Nucl Med 8:36-38. 1983.
Interfering drug(s): Antibiotics ( e . g . , pen-
icillin).
Nuclearmedicinestudyaffected: Inflam-
matory process scintigraphy.
Effect on image: Visualization of colon.
Significance: Drug-induced accumulation of
lllIn-labeledleukocytesinthecoloncould
mimic a pattern of distribution observed in pa-
tients with inflammatory bowel disease not re-
lated to drug therapy.
Mechanism: Certainantibiotics are known to
cause pseudomembranous colitis, an inflam-
matory disease that may attract lllln-labeIed
leukocytes.
Management: None; however, the drug respon-
sible for inducing the colitis should be discon-
tinued and replaced w)ith alternative therapy.
How documented: Case report (1).
REFERENCE
1. Bushnell DL: Deteclion of pseudomembranouscolitis
with indium-1 I 1 labeledleukocytescintigraphy. Clirr
Nucl Med 9994-295, 1984.
"'IN-LABELED PLATELETS
Interfering drug(s): Heparin.
Nuclear medicine study affected: Pulmonary
embolus scintigraphy.
Effect onimage: Full-dose heparin therapy may
result in the failure of il'ln-labeled platelets 10
identify sites of pulmonary emboli.
Significance: Theability of heparin to cause
false negative studies decreases the usefulness
of lllIn platelels for the deteclion of pul~nonary
emboli.
Mechanism: Heparin inhibits the adherence of
platelels to experimental pulmonary emboli,
possibly due to interference with the thrombin-
platelel interaction (I).

204 I Essentials of N d e a r Medicine Science
Management: Perform scintigraphy prior toin- circulating body pool. Iodinated contrast media
itial anticoagulation or in conjunction with in- release iodide over a period of time, resulting in
terruption of heparin therapy. the same type of effect.
How documented: Study in dogs (2); observa- Chronic salicylate administrationcauses a de-
pression of thyroid function, presumablyvia the
tions made in dinical studies (2,3).
pituitary or higher centers.
REFERENCES
Sodium nitroprusside lowers uptake of radi-
1 . Thomas DP, Gurewich V, Ashford TP: Platelet ad-
oiodine because of the action of its metabolic
herence to Ihromboemboli in relalion to the pathogenesis
and treatment of pulmonary emboiism. N En#/ J M e d by-product, thiocyanate, to inhibit the thyroidal
274953-956, 1966. iodide-trapping mechanism.
2. Sostman HD. Neumann RD, Zoghbi S S , el al: Clinical Steroidsmayaffectthethyroiduptake by
and experimental studies of pulmonary embolism using suppressing TSH formation,through
a direct
Illindium labeled platelels. Inwsl Radio1 16392, 1981.
inhibitory effect on the thyroid itself or by in-
3 . Davis HH 11, Siege1 BA, Sherman LA, et al: Scinligra-
phywith "'In labeled autologous platelets in venous creasing renal radioiodine clearance.
thromboembolism. Rodiolugy 136203-207, 1980. Benzodiazepines may depress thyroid uptake
of iodine through some direct antithyroid effect
SODIUM [ 1231]IODIDEAND SODIUM
which has not been clearly elucidated.
[131i]IODIDE Management: A drug history should be taken
Interfering drug(s): See list below in "man- before the uptake studyis perfonned. If interfer-
agement" section. ing drugs are part of the patient's currenl thera-
Nuclear medicine study affected: Radioiodine peutic regimen, these drugs must be
withheld
thyroid uptake study. for an appropriate time period (Table 14.1) be-
Effect on image: Decreased uptake of radi- fore the uptake procedure is attempted.
oiodine.
Significance: In hyperthyroid patienls, certain Table 14.1.
drugs may decrease thyroid uptake into the nor-
Time to Withhold Therapy Prior to Initiation of
mal uptakerange, thus givingfalsenegative UptakeStudy
results. In normothyroid patients, a drug-in-
Time
' l y p 01 Medication
duced reduction in thyroid uptake may result in
a diagnosis of hypothyroidism (false positive). Anlithyroid (propylthiouracil, 1 week
In addition, a rebound increased uptake is con- Tapazole)
ceivable following the discontinuation of some Natural or synthetic thyroid 2-3 weeks
of these drugs. preparalions (Synthroid,
Cytomel, Thyrolar)
Mechanism: Antithyroid drugs inhibit the met- Expectorants,vitamins 2 weeks
abolic synthesis of thyroid hormones, resulting Phenyibutazone 1-2 weeks
in decreased iodide transport, Specifically, they Salicylates 1 week
interfere with the incorporation of iodide into Steroids 1 week
1 week
tyrosyl residues of thyroglobulin and inhibit the Sodium nitroprusside 1 week
Miscellaneous agents:
coupling of the iodotyrosylresidues to form Anticoagulants
iodothyronine. Moreover, these drugs may inter- Antihistamines
ferewiththeoxidation of iodideionand Antiparasitics
iodotyrosyl groups. Penicillins
Sulfonamides
Natural or synthetic thyroid preparations act
Tolbutamide
bysuppressingthesecretion of thyrotropin Thiopental
(TSH). Phenylbutazonealsomay inhibit TSH Benzodiazepines 4 weeks
release. iodides Topical 1-9 months
Intravenous contrast agenls 1-2 months
Vitamins,antitussives,expectorants,and
topical medications that contain various iodide Oral cholecystographic agents 6-9 months
Oil-based iodinated contrast agenls:
salts can decrease thyroid uptake by diluting the 6- 12 months
Bronchographic
vascular pool of radioiodide,thusdecreasing Myelographic 2-10 years
thespecificactivity of theradioiodine in the
Drrtg-induced Aliera!ions: Reported instances I 205
How documented: Various animal and clinical 18. Kohn LA, Nichols EB: Interference wilh uptake of
studies {l-27); review articles and chapters radioiodine tracer during administration of vitamin-
mineral mixlures. N Engl J Med 253:286-287, 1955.
(28-30).
19 Clark RE, Shipley Iw: Thyroidal uplake of '311 after
iopanoic acid (Telepaque) in 74 subjects. J CIirl Endo-
REFERENCES crinol 17:1008, 1957.
Thomas ID, Oddie TH, Myhill J: A diagnoslicradi-
20.
1 . Greer MA: The eIfect on endogenous thyroid activity
of feeding desiccaled thyroid to normal human sub-
oiodine uplake test in patients receivingantithyroid
drugs. J ClfnErfdocrrnol Merab 20:1601-1607, 1960.
jects. N Ens1 J Med 244:385-390, 1951.
Stanley MM. Astwood EB: The accumulation oiradio-
21.
2. Ceccarelli C, Grasso L, Martmo E: Re: rcduction of
thyroid uptake by iodine absorbed with eye-drop {her-
actwe icdide by the thyroid gland In noma1 thyrotoxic
subjects and the effect of thiocyanate on its discharge.
apy. J Nucl Med 23:364-365, 1982.
Elzdocrinolugv 42:107. 1948.
3. Pochin EE, Bamaby C F The effecl of pharmacological
Levy RP. Marsha11 JS: Short-term drug effects on thy-
22.
doses of non-radioactive iodide on the course of radi-
roid functlon tests. Arch Ilnerrl Med I14:413-416,
oiodine uptake by the thyroid. Healrh Phys 7: 125- 126,
1961.
1962.
4 . Slingerland DW: Influence of various factors on uplake
23. JVmd DE. GiIday DL, Eng B , el al: ShbIe lodine
of iodine by thyroid. I Clin Erzducrirrol 15:131-141, requiremenls for thyroidgIand blockage of iodinated
radiopharmaceuticals. J C a n A s s o c R a d i o l
1955.
5 . Austen FK, Rubini MEI Meroney WH, et al: Salicy-
25:295-296, 1974.
24.Magalotli MF, et al: Effect of disease and drugs on
lates and thyroid function. I. Depression of the thyroid
twenty-four hour '"I thyroid uptake. AJR 81 :47, 1959.
function. J Clininvesr 37:1131-1143. 1958.
6 . Coel N, Talner B , Lang H: Mechanism of radioaclive
25. Stemlhal E, Lipworth L, Stanley 8 ,et ai. Suppression
of thyroid radioiodine uptake by various doses or stable
iodine uptake following intravenousurography. Br J
iodide. N Engl J Med 303:1083-I088, 1980.
Radiol 48:146-147, 1975.
26. Oguoleye OT, Ejiwunmi AB: Influence of dlazeparn on
7. Hurley JR, Becker DV: Thyroid supprcsslon and stlm-
thyroid function tests in normal Nigerians. IN J ~Vucl
ulation tesllng: the place of scanning in the evaluation
Med B i d I 1 :203-204, 1984.
o f nodularthyroiddisease. S e n z ~ nNucl ]Wed
II:149-160, 1981.
27. Hankins JH, Heise CM, Cowan RJ: Iatrogenlc hyper-
thyroidism secondary to dextrothyroxine adrninistra-
8. Hannigren A: Determination of the anlithyroid action of
tion. Cli!~A ' r d Med 9:17-19, 1984.
para-am~nosalicylicacid using radioactive iodine. L a n -
28. Grayson RR: Faclorswhich influencetheradioactivc
ce/ 2117, 1952.
iodine thyroidal uptake test. Am J Med 28:397-415,
9.Linsk J, Paton DC, Persky M. et al:Theeffect 01
1960.
phenylbutazone and related analogueIG25671) upon
thyroid function. I Clirr Enducrinol 17:4 16-423. 1957.
29. Haden HT: Thyroid functlon lests, physiolog~cbasis
and clinical interpretation. PosrgradMed 40:129-137,
10. Scott KG, Frerichs J 3 , RieIIy WA: Effect of
1966.
butaLolidin upon the fate of 1-131 in the rat. Pruc Sur
30. Metller FA, Guibertcau MJ (eds): Essenrials uJNuclmr
E , I ~Bioi Aged 82:150-152, 1953.
Medfcine Irmgirzg. ed 2. New York, Grune & Smatton,
11. Friedell M T EKect of tranquilizing agents on radtoac-
1986.
tweiodmeuptake i n thethyroidgland. JAIAMA
167:983-985, 1958,
12. Same1 M : Blocking effecl of morphine on the secretion [ '311]IODOMETHYLNORCHOLESTEROL
of thyroid-stimulatinghormone in rals. ~ V a r u r e Interfering drug(s): Spironolactone; other di-
181:845-846, 1958.
uretics.
13. Yohalem SB: Use of meprobramate (Equanil) in hyper-
thyroidism. NY Stare J Med 57:2518, 1957. Nuclear medicine study affected:Adrenal cor-
14. Nourok DS, Glassock RJ. Solomon DH, et al: Hypo- tex scintigraphy.
thyroidism Iollowing prolonged sodium n~troprusside Effect on image: Bilateral adrenaluptake of
therapy. Am J Meed Sci 248:129-136, 1964. radiotracer (in patients with unilateral disease).
15. Wyngaarden JB, Wright BM, Ways R: Theeffect of
certain anions upon the accumulation and retention of
Significance: Bilateral uptake of radiotracer
iodidebythethyroidgland. E n d o c r i n o l o g y frequently occurs in patients with aldostero-
50537-549, 1952. noma who are receiving chronic spironolaclone
16. Godley AF, Stanbury JB: Preliminary expericnce in thc or other diurelic therapy. Therefore, administra-
trcalment of hyperthyroidism with potassium perchlor-
lion of thesedrugs may result in anincorrect
ate, J Clin Endocrirrol 14:70, 1954.
differentiation between unilateral adenoma and
17. Kelsey FO, Gullock AH, Kelsey FE: Thyroid activity in
bilateral hyperplasia with use of adrenal scinti-
hospilalized psychialric patients-relation of dietary
graphy, even when dexarnethasome suppression
iodinc to 1-13]uptake. Arch A'ewol Psychia:
77:543-548, 1957. is utilized.
206 I Esserdriais of Nuclear Medicine Science
Mechanism: Diuretics decrease serum sodium
and plasma volume, resulting in increased ac-
tivity of the renin-angiotensin system. A spe-
cialized diuretic, spironolactone, competitively
inhibits the sodium and chloride reabsorplion
action of aldosteroneontherenaltubules,
which also results in increasedactivity of the
renin-angiolensinsystem.Thisincreasein
plasmareninactivitystimulatesthezona
glomerulosa to synhesizeandsecreteal-
dosterone which results in an increased localiza-
tion of radiotracer in the normal adrenal gland.
In thepresence of an aldosteronoma,the in-
crease in uptake induced by diurelics would be
in the contralateral gland, resulting in bilateral
uptake of the radiotracer and, therefore, a false
negative scan.(Spironolactonealso a d s as a
directadrenal glomerulosaantagonist. If the
drug isgivenover along enoughperiod, it
would suppress aldosteronebiosynthesis and se-
cretion and, lherefore, probably suppress uptake
of 113111iodomethvlnorcholesterol into the adre-
continuediuretic therapy prior to, performing
adrenal scintieraDhv.
U I ,
H , , ~ documente& ~ospective clinical
(I); observations reported in review article (2).
REFERENCES
1. Fischer M. Vettern', Winkrg B , et ai: Adrenai scinligra-
phy in primary aldosleronism. Spironolactoneas a cause
01 incorrccl classification betweenadenoma snd hyptr-
plasia. Eur J N I Mcd ~ 7222-224, 1982.
2. Gross MD. Valk TW, Swanson DP, etal: Therole of
phamdcologic manipulation in adrenal cortical scinli-
graphy. Sernirz Hucl Med 11:128-148, 1981.
Interfering drug(s): Oral contraceptives.
Nuclear medicine study affected: Adrenal cor-
tex scintigraphy.
Effect on image: Early bilateral visualization of
the adrenals is observed in individuals with no
adrenal disease or with unilateral disease only,
despite dexamethasone suppression.
Significance: This interaction must particularly
be considered in the evaluation of women with
hyperandrogenism, since oral contraceptives
are often incorporated into their therapeutic reg-
imen. If the site of abnormal androgen produc-
tion is, indeed, outside of the adrenals, the early
bilateral visualization of radioactivity in the
adrenalglands may be falsely interpretedas
bilateraladrenalhyperplasia. Thispattern of
distribution could also maskanadrenal ade-
noma, which could be a source of excess an-
drogen production.
Mechanism:Oral contraceptives increasethe
adrenaluptake of ['3'I]iodome~hylnorcho-
lesterol by producinganelevation of plasma
reninactivitywhichresults in adrenal cortical
stimulation, increased cortisol secretion, and a
"functional hyperplasia. 'I
Management:Discontinue oral contraceptive
therapy if i t isnecessary to use [i3'I]iodo-
methylnorcholesterol for determining the con-
tribution of theadrenal glands to excessan-
drogen output,
How documented: Clinical observations re-
ported in review arlicles (1,2).
REFERENCES
Press, 1980, pp 127-175.
2. Gross MD, Valk TW, Swanson DP, el al: The r0k of
pharmacologic manipulaLion in adrenal cortical
scinli-
graphy. Sernin Nzrcl Med 11:128-148, 1981.
m-['3'I]IODOBENZYLGUANIDINE
(mIBG)
Interfering drug(s): Tricyclic antidepressants;
reserpine; sympalhomimetics.
Nuclearmedicinestudy affected: Adrenal
medullary scintigraphy.
Effect on image: An absence of uptake by the
salivary glands and the hear1 has been observed
in a few patients taking either imipramine, dox-
epin, or Entex, a nasal decongestant containing
both phenylephrine and phenylpropanoiamine.
For the most part, however, patients taking tri-
cyclic antidepressants (or reserpine) have been
inlentionallyexcludedfromscintigraphic pro-
tocols during clinical trials with 1311-mIBG.
Therefore, the effectof these drugs on uptake of
1311-dBGinto human pheochromocytomas has
no1 been established.
In animal models, reserpine consistently re-
ducestheadrenomedullaryuptakeof l3'l-
Drrrg-induced Alterations: Reporled Insionces
mIBG. There are, however, conflicting animal
data concerningtheeffect of desrnethylirnip-
rarnine. In dogs, the uptake of 1311-mlBGwas
markedly affected by desmethylimipramine.
but in rats, an effect was not observed. Pretreat-
ment of ratswith sympathomimeticdrugs re-
sults in large decreases in radiotracer concentra-
tion in adrenergic-richtissues such as the left
atrium,leflventricle,spleen,andparotid
glands.
Significance: The diagnosis of pheochromo-
cytoma with use of 1311-dBGscintigraphy may
be adversely affected if these drugs do inhibit
uptake of the radiotracer into the tumor; more
dalaare necessary, however, lo determine lhe
true significance. Moreover, the effects of these
drugs on 1311-mlBGscintigraphy of the heart
must be considered.
Mechanism: Sludies indicatethat 13'I-mIBG
enters adrenergic tissue and is stored in granules
of the adrenal medulla by mechanisms similar
to thosefor the neurotransmitternorepineph-
rine. Reserpine and tricyclic antidepressants in-
terferewithuptake of norepinephrine(and
mIBG) by adrenergic tissues and, theoretically,
may reduce the detectability of pheochomocy-
tomas.Sympathomimeticagents may act by
causing a release of norepinephrine (and d B G )
fromstoragesites,thusdecreasingtheac-
cumulation of mIBG in adrenergic neurons.
Management: I f it is clinicallyappropriate,
discontinuedrugspriortoperformingadrenal
medullary scintigraphy.
How documented: Study in rats (1,2); study in
mice (2); studies in dogs(2-5); case reports ( 5 ) ;
observations from clinical sludy (6).
REFERENCES
Shcrman PS, Fisher SJ, Wieland DM, el al: Over the
counter drugs block heartaccumulattono l MIBG . J Nucl
Med 26:P35,1985.
Guilloleau D, Baulieu JL, Huguel F, el a l : Meta-
iodobenzplpanidine adrenal mcdullalocalizalion: Au-
Lomdiographicand pharmacologicstudies. Eur J Nrd
Med 9:278-281, 1984.
Wleland DM, Brown LE, Tobes MC, et al: Imaging the
primateadrenal medullawith1-123 and 1-131 mela-
iodobcnzylguanidine: concise communication. J Mrcl
Mer1 22358-364, 1981.
M'ieland DM, Brown LE, Marsh DD,et al: The mecha-
nism of MIBG in localization: drug intervention sludies.
J Nfrcl Mer1 22:P20, 198 1 ,
f 207
5. Shapiro R , Wieland DM, Brown LE, el al: "'I-nlcla-
iodobenzylguanidine (MIBG) adrenal medullary scinti-
graphy: interventional studies. In Spencer R (ed): ilzwr-
verz~ionalNlfclear Medicirle. New York. Grune 6r
Slratton, 1984. pp 451-481.
6. Sisson JC, Frager MS, Valk TW. et al: Scintigraphic
localization of pheochromocytoma. N Engl J Mcd
305:12-17. 1981.
[zolT~]THALLOUS CHLORIDE
Interfering drug(s): P-Adrenergicblockers
( e . g . , propranolol); nitrates (isosorbide dini-
trate).
Nuclear medicine study affected: Myocardial
perfusion scinligraphy.
Effect on image: Clinically, these drugs tend to
decrease the number and size of exercise-in-
duced [201Tl]thallous chloride perfusion defects.
(?O'TI studies performed in resting dogs indicate
h a t propranololfavors a redistribution of
['alTl]thallous chloride in ischemic myocardial
regions toward the subendocardial layers, which
is beneficial, since myocardial ischemia always
originates in the subendocardial layers and sub-
sequently spreads ouI 10 the epicardium (1). I f
propranolol has the same effect at exercise, il
may help to explain the phenomenon observed
clinicaliy.)
S i g n i f i c a n c e :F a l s en e g a t i v ee x e r c i s e
[20'Tl]thallouschloridescanscan occur in pa-
tientsreceivingp-blocker or nitraleIherapy
who arebeingevaIuatedforCAD. Under-
estimation of the severity of CAD can result in
inadequate or inappropriate therapeuticmeas-
ures.
Mechanism: Two possible mechanisms may be
responsible for the effecls of P-blocking agents.
First, the effects may result from drug-induced
changes in the exercise performance of patients.
The administration of a P-blocker blunis [he
normal rise in heart rate and systolicblood
pressure which occurs with exercise, resulting
in a reduction in myocardial oxygen c o n s u n p
tion. In addition, @-blockers may increase m y -
cardial oxygen extractionand augmentstroke
volume despite a tendency for [he cardiac nu-
putto decrease. The overalleflect 01' Ihcsc
changes on exercise ability depends on h c 1111-
derlying function of the left ventricle. hlicnts
with CAD and impaired leftventricular lunctirm
typically show agrealerandmore consistcnt
208 I EssentiaIs of Nrrclear MedicineScience
increase in exercise performance than do indi-
vidualswithout CAD. The net effect of P-
blockadetherapy on exercise[m'Tl]thallous
chloride scintigraphy is to postpone the poinl at
which myocardial ischemia occurs beyond that
at which exhaustion limits the exercise test. As a
result, exercise may need to be slopped before
perceptibleperfusiondefects can be induced.
Nitrates may cause a beneficial redistribution
of coronary blood flow, resulting in decreased
myocardialischemia.Nitroglycerin, for in-
stance, has been shown to preferentially in-
creasesubendocardialblood flow. Redistribu-
tion of coronary blood flow may occur because
the nitrates preferenlially dilate the large con-
ductance vesselsrather than b e arteriolar re-
sistancevessels, which results in shunting of
blood to the ischemic myocardium. In addition,
collaleralvesselswhich developsecondary to
myocardia ischemia may be dilaled bythese
drugs.
Management: Discontinue P-blockertherapy
48 hours prior to performance of study (by ta-
pering dosage); also discontinue nitrate therapy
prior to study.
How documented: A sludy in dogs investigated
the distribution of [m'Tl]thalIous chloride in
normaland ischemic myocardium(1). Several
researchers have used various animal models to
study the effect of propranololonuptakeof
[201Tl]thaIlous chlorideinto the normal myocar-
dium; results rangefrom a slight decrease in
uptake to no significant change caused by the
drug (1 -6). One retrospeclive clinical study
showed that propranolol apparently did not alter
the myocardial-lo-background ratio of zOITl (7).
Otherclinicalstudies, however, havedocu-
mentedthatthesensitivityofexercise
[2D1Tl]thallouschlorideimagingisreduced in
patients taking propranoloI (8-12). At least one
clinical studyhas reported a similar loss of
sensitivity followingisosorbide dinitrate ther-
apy (13).
REFERENCES
van dcr Wall EE, JVeslera G , van Eenige MJ, el al:
Influence of propranolol on uplake of radioiodinated
hepadecanoic acid and lhallium-201 in the dog heart.
Eur J Nucl Med 8:454-457, 1983.
Hamilloik GW,Narahara KA, Yee H, et a1 Mpcardial
imaging with Iha1liun1-201: effect of cardiac drugs on
myocardial images and absolute tissue dishbution. J
Nucl Med 19:lO-16, 1978.
3. Z m t B L Radionuclide imaging of myocardial ische-
mia and Infarction. Circularion 53(Suppl): 1126-1 128.
1976.
4. Shclberl H, Ingwall J, Watson R, et al: Factors influenc-
ing the myocardial uptake of thallium-201, J Nucl Med
18598, 1977.
5. Costin JC, Zaret B L Effect of propranolol and digitalis
upon radioactivethalliumandpotassium uptake in
myocardialand skeletal muscle. J Nucl Med 17:535,
1976.
6. Weich HE, StraussHW, Pit1 B: The extraction of
thallium-201bythemyocardium. Circularion
56:188-191,1977.
7. Waschek J, Hinkle G, Basmadjian G. et aI: Effect of
cardiac drugs on imaging studies with thallous chloride
T1 201. Am 3Hosp Pharm 3831726-1728. 1981.
8. Hockings B, Saltissi S, Croft DN, et al: Effect of beta
adrenergic blockade on thallium-201 myocardial perfu-
sion imaging. Br Hearr 34953-89, 1983.
9 Henkin RE, Chang W. Provus R: The effecl of beta
blockers on thallium scans. J Nrtcl Med 23:P63. 1982.
10 Pohosl GM, AIpert NM. Ingwall IS. el al: Thallium
redistribution:mechanismsandciinicalulility. Semin
NucI Med 10:70-93, 1980.
11 Albro PC. Gould KL, Weslcott RJ, et al: Noninvasive
assessmenl of coronary stenoses by mqocardial imag-
ing duriog pharmacologiccoronaryvasodilation: LII
Clinical trial. Am J Cardid 42:751-760, 1978.
12 Osbakken MD. Okada RD, Boucher CA, et al: The
effect of Inderal, exercise level, and subcritical disease
on the specificity of exercise thallium-201 imaging. J
Nucl Med 22P41, 1981.
13 Wolf R, Pretschner P, Engel HI, et al: Errect ol isosor-
bide dinilrale on 201-thallium myocardial imaging in
coronary hearl disease. Am J Curdid 43:432. 1979.
Interfering drug(s): Vasopressin.
Nuclear medicine study affected: Myocardial
perfusion scintigraphy.
Effectonimage: Appearance of myocardial
perfusion defects (reversible on discontinuation
of drug) in patients without coronary artery dis-
ease.
Significance: Interactionisprobably of mini-
malclinicalsignificance,since[201Tl]thallous
chloride imaging rarely is performed in patients
on vasopressin therapy. In those instances when
this may occur, however, the ciinician should b e
aware of the polential for false positive results.
Mechanism: This phenomenon most likely re-
flectsthecapacity of vasopressinto increase
coronary vascular resistance.
Management: Disconlinuedrug therapysev-
eral hoursprior to performingf20'Tl]thallous
chloridescintigraphy, when it is clinically ap-
propriate.
How documented: Prospective clinical study
(1).
REFERENCE
1 . Davison R, Kaplan K, Bines A , etal:Abnormal
thallium-201scinligraphydunnglow-dosevasopressin
infusions. Presented at theAmericanCollege of Car-
diology Meeting. Atlanta. April 1982.
Interfering drug(s): Propranolol; cardiac gly-
cosides; procainamide; lidocaine; phenytoin;
doxorubicin.
Nuclear medicine study affected: Myocardial 6. Costin IC, Zaret B L Effect of propranolol and digilalis
perfusion scintigraphy.
Effect on image: These drugs tend to slightly I. Hamilton GW, Narahara K A , Yee H, et a1 Myocardial
decreasemyocardial localizationandincrease
liverlocalization of zOIT1.Thus, evaluation of
images that already have a relatively poor tar-
get-to-background ratio may be further compro- 8. Waschek J, H i d e G , Basmadjian G , et al:Effecl or
mised.
Significance: The effectof these drugsin possi-
bly decreasing myocardial uptake of 201Tlis not
likely to be clinicaIly relevant, since it is global
and would not be expected to resultin a change
in regional ,OIT1 concentration. Moreover, the
magnitude of the effect often is so small that it
is not significant. In some cases, e.g., pheny-
toin,heart-lo-blood and heart-to-muscle ratios
are changedonlyslightlybydrugtherapy,
which further minimizes the cIinical signifi-
cance. It has been noted, however, that decreas-
ing myocardial uptake can be associated with
increasing numbers of medications used in com-
bination.
Mechanism: The cardiac drugs probably exert
their effects (if any) by aItering coronary blood
flow and delivery of 20'T1 to themyocardial
cells.
Phenytoin and doxorubicin exert their effects
by direct actions on the sodium-potassium acti-
vated ATPase pump and the active transport of
20'TIinto the myocardial cells.
Management: None.
How documented: Studies in mice (1 ,Z), rats
(31, rabbits (4), and dogs (5-7); retrospectivc
clinical study (8).
REFERENCES
I , Bossuyt A, Jonckheer MH: Noninvasive dclerminalion
of the reglonal disiribulion of cardiac output: e l k t of
Drug-induced Alterations: Reporred Insranees I 209
pharmacological agents on the dishbution of T1-201. J
Nuci Med 19:973, 1978.
2. Schelberi H,Ingwalls J, Watson R, el al: Factors intlu-
encing the mpcardial uptake of TI-201. J NMCI Metl
18:598. 1977.
3. Schachner ER, Osier ZH, Cicale h%, et al: The effect or
diphenylhydantoin(Dilantin) on thallium-201chloride
uplake. Eur J Nucl Med 6585-586, 1981.
4. Forsl D, Sorensen S, O'Rourkc R, et a1: Reversibility ol
adriamycininducedreductioninmyocardial
thallium-201 uplake by intravenousdigoxin. Clirr Res
27:727A,1979.
5 . Weich HF, Strauss JW4, Pitt B: The extraction of
thallium-201 by themyocardium. Circirlrrrrurr
56:188-191,1977.
upon radioactive lhaliium and potassium uptake in myo-
cardial and skeletal muscle. J Nucl Med 17535, 1976.
imaging with thallium-201. Effect of cardiac drugs on
mpcardial imagesandabsolutetissue dishbution. J
Nucl Med 19:lO-16, 1978.
cardiac drugs on imaging smdies with thallous chloride
TI-201. Am d Hosp P h r m 38: 1726-1728, 1981,
RADIOCYANOCOBALAMIN
Interfering drug(s): Parenteralvitamin B12;
colchicine;neomycin;p-aminosalicyclicacid;
calcium chelating agents; biguanides; anlicon-
vulsants (phenobarbital, phenytoin, primidone);
potassium;cholestyramine;cyclohexamide;
daclinomycin; oral contraceptives.
Nuclear medicine study affected: Schiliing
test.
Effect on study:Decreased absorption of radio-
cyanocobalamin.
Significance: Reduced absorption results in de-
creasedexcretion of theradiotracer. In some
instances, the study result may still be within
normal limits; however, abnormal study results
may be misinterpreted as pernicious anemia or
other causes of malabsorption.
Mechanism: Drugs variably interfere with the
absorption of the radiotracer.
Parenteral vitamin BIZ:this effect is thought
to be related to high concentrations of B,, in the
bile diluting the radioactive B,, and salurahg
ileal-binding sites.
Aminosalicylic acid, biguanides, colchicinc,
ethanol,anticonvulsants,cyclohexamide: his
effect is thoughtto be a direct action on the ilcal
transportof BIZ, possibly by disturbing some
folate-dependent enzyme system.

Antibiotics: this effect is thought to be related
to decreased ilia1 mucosal binding of 3,? sec-
ondary to inflammatory reactions (enteritis).
Other possible mechanisms include gastritis
(decreased inirinsicfactorproduction and re-
Iease), increased intestinal motility, chelation of
calcium ions, and bacterial superinfection.
Calcium chelating agents:this effect is due to
sequeslration of ionic calcium, an ion required
in the absorptive mechanism for BIZ.
Potassium:slowreleasepotassiumtablets
cause acidification of intestinal contents to a pH
lower than [hat required in the absorptive mech-
anism for B,?.
Cholestyramine: effect caused by drug bind-
ing IO B,,-binding sites on intrinsic factor and
preventing the formation of the intrinsic factor-
B,? complex needed for absorption.
Management: Discontinuedrug therapy sev-
eral days prior to iniliation of Schilling test. In
somecases, reversal of malabsorptioncanbe
achieved by the administration of folic acid.
How documented: Studies in rats (1-4); case
reports (5-7); clinical studies(3,6,8-33); re-
views (34-36).
REFERENCES
1. Yell SDJ, Shils ME: Effect of actinomycin D and col-
chicine on intestmal absorption in rats. Fed Proc
25(21:322. 1966.
2 . Findlay J. Sellers E, Forslner G: Lack of eUect of
alcohol on small intesrinal blnding of the vitamm 8,?-
intrinsicfactorcomplex. Can J Phy.~iolPlra~macul
54469-476. 1976
3. Okuda K , Sasayama K : EfIects of ethylenedlam-
inelelradcetale and metal ions in inteshnal absorption of
vitamin B,,in man and rats. Proc Sur € - ~ pB i d Med
12017-20, 1965.
4 . Yeh SDJ.Shils ME: Cycloheximideefrecl on vitamin
B,?absorption and intrinsic [actor production in the rat.
Proc Soc Elrp Biol bled 130:1260-1264. 1969.
5 . Halsted CH, McIntyre PA: Intestinalmalabsorption
caused by aminosalicylic acid therapy.Arch Inrenr Med
130935-939, 1972.
6. Heinivaara 0. Palva I P Malabsorption of vitamin Blz
duringtreatmentwithpara-aminosalicyllc acid. Acta
Med S c a d 175:469-471, 1964.
7. Rcynolds EH, Hallpike JR. Phillips EM. et al: Revers-
lble absorplwe defects in anticonvulsant megaloblastic
ancmia. J C l i ~Parlrol 18:593-598, 1965.
8. Jacobson ED, Chodos RB, Falcon JWV Experimental
malabsorptioninduced by neomycin. Am J Meri
28524-533, 1960.
9. Gasbcck R, Nyberg W: Inhibition of radiovitamin B I Z
absorption by e~hylenediam~netetraaceta~e (EDTA) and
iks reversal by calcium ions. Scalld J Clin Lab I~rvesr
10:448, 1958
10. Webb Dl, Chodos RB, Mahar CO. el al: Mechanism of
vitamin B,? malabsorption in patientsreceivingcol-
chlclne. N Engl J Med 2792745-850. 1968.
11. Lindenbaum l, Lieber CS: Alcohol Induced malabsorp-
tion of vitamm B I 2in man. Narrrre 22.1306, 1969.
12 Mailloux LE, Street0 JM: The effecl of prior vitamin
BII admlnlstration on the Schilling test. Am J Med Sci
250:697-699.1965.
13 Chow B E Okuda K: Urinary excrellon test for vitamin
B,?.Fed Proc 14:430, 1955.
14. Ellenbogen L, V " m s WL, Rabiner SF, etal: An
improved urinary excretion test as an assay for intnnsic
factor. Proc Sue Exp Biol M e d 89:357-362. 1955.
15. Breuel HI', Fischer P: Theinfluenceofvltamin BL2
premedication on theresult of the Schilling test (au-
thor's Uanslalton). Ntrkleumledizih 18:186- 188, 1979.
16. Gmrnes GM, Reiswig R. Jansen C, et al: Feasibility or
consecutive-daySchilllnp tests. J Nfrcl M e d
15:949-952.1974.
17. Heinivaara 0, Palva lP Malabsorption and deliciency
of vitamtn B,? caused by treatment with para-ami-
nosalicylic acid. Acta Med Scnrtd 177:337-341, 1965.
18. Paaby P, Norvin E: The absorption of vitamin B I I
duringtreatmentwithpara-aminosalicylicacid. Acta
Med Scand 180:561-564, 1966.
19. PalvaIP, Rytkonen V , Alatulkila M, et al: DIU&-
induced malabsorption of vitamin BIZ.V. lnlestinal pH
and absorption of vitamin B I I dunng treatmentwith
para-aminosalicylic acid. Scand J Haernalol 9:5-7,
1972.
20. Toskes PP, Deren J J Seleclive inhibition of vitamin B12
malabsorption by para-aminosalicylicacid. Gaslroew
rerology 62:1232-1237, 1972.
21. M'illrns B,Creutzfeldi W: Contribution to the intestinal
resorptlon ol vttamin BII (SchilIingtest) and of D -
xylose in bigudnide treatment. Diaberdogia 6:652,
1970.
22. Berchtold P, Dahlqvist A , Gustafson A, et al: Erfects of
a biguanide (metformin) on vitamin B,? and iolic acid
absorptionandintestinal enzyme activities. Scand .l
Gasrroer~rerolh:751-754, 1971.
23. Tomkin GH, Hadden DR, Weaver JA, et al: Vitamin
B I I slatus or patients on long-term metformin therapy.
B r Med J 2(5763):685-687, 1971.
24. Tomkin G H Malabsorplion of vilamin BIZin diabetic
patientstreated with phenronnin: a comparisonwith
metformin. Br Med J 3(5882):673-675, 1973.
25. lounela AI, Pirtliaho H, Palva I P Drug-induced malab-
sorption or vitamin B I 2during Lrcatment with phenror-
min. Acta Med Scarad 196267-269, 1974.
26. rjloon WW. Chodos RB: Vitamin B,?absorption stud-
ies using colchicine, neomycin and continuous T o B,!
administration. Gasrruerrk=roloRy56:1251,1969.
27. Rdce TF, h e s IC, Moon WW: Inteslinalmalabsorp-
tion induced by oral colchicinc. Comparison with neo-
mycin and cathartic agents. Anr I Mer1 Sci 259:32-41,
1970.
28. Salokannel SI. Pdlvn IF, Takltunen J T Malebsrlrplion of
vitamin B,, duringtreatment with slowrelease po-
tassium chloride. Acta MedScurfd 187:431-432. 1970.
29 PalvaIP. Salokannel SI, Timonen T. et al: Drug-in-
duced malabsorption of vitamin B,?.IV. Malabsorption
and dehciency of B , 2 duringtreatmentwithslow-re-
l e a s ep o t a s s i u mc h l o r i d e . A c t a M e d Scund
19135-357, 1972.
30 PalvaIP, Salokannel SJ, Palva HLA, et al:Dmg-in-
duced malabsorptlon of vitamin B I Z .VU. Malabsorp-
tion of B 1 2 during treatmen1withpolassrumcitrate.
Acta Med Scarld 196525-524, 1974.
31 Lees F Radioactwevitamin E,, absorption in mcga-
loblastic anemia caused by anticonvukant drugs. Q J
Med 30231-248. 1961.
32. Coronalo A. Glass GBI: Depression ol theIntestinal
uptake of radio-vitamin B,: by cholestyramine. Prur
Soc E r p BiolMed 142:1341-1344. 1973.
33. ReisnerEH Jr, Rosenblum C, MorganMC: Urinary
excretion of orally administered Co-60 labeled vitamin
B12 in normalsubjects and patients with pernicious
anemia and sprue. Clin Res Proc 256, 1954.
34. Herbert B: Detecrion of malabsorption of vihmin B,!
due to gastric or intestinal dysfunction. Senzin Nucl
Med 2220-234. 1972.
35. Cohcn MF. Vilamin B I Zdeficiency. Semin Nrrcl Med
I 1 :226-227, 198 1 ,
313 Silberstein EB: Causes of abnormalities reponed in
nuclearmedicine tesung. J Nlncl Med 17:229-232,
1976.
RADIOXENON
Interfering drug(s): Total parenteralnutrition
(TPN) therapy; clofibrate.
Nuclear medicine study affected: Pulmonary
ventilation scintigraphy.
Effect on image: Appearance of radioactivity
in liver during washout phase of ventilation
study.
Significance: Manydisorders associatedwith
fatty liver infiltration, such as hyperlipidemias,
obesity, and diabetes mellitus, can promote ac-
cumulation of radioxenon in the liver. There-
fore, some confusion may arise with regard to
thereason for the hepatic activity noted on a
ventilation study.
Mechanism: Xenon is quite lipid soluble; he-
patic retention of 133Xe hasbeen correlated wilh
the fat and trigIyceride content of the liver (1).
Moreover, TPN therapy is known to cause he-
patic dysfunction, including fatty liver disease,
in some patients (2). In addition, ceriain authors
havespeculated that drugssuch as clofibrate,
which prevent hepaticbreakdown of triglycer-
ides, could be responsibIe for hepatic retention
of radioxenon (3).
Drug-ind1rced Alrerarions:Reported Insiances I 211
Management: None.
How documented: There are no known reports
of drug-induced hepatic uptake of radioxenon,
bul theoretical considerations strongly supporl
this concept (1-3).
REFERENCES
I . Kitant K . Winkler K: I n vitro determination of solubility
of "'xenonand855krypton inhumanlivertissuewith
varyingtriglyceride content. ScaJld J Clin Lab ilnwsr
291173-176. 1972.
2 . Brown R O Total parenteral nutrition-induced liver dys-
function: a review. Nurr Sup Sew 2:14-16, 1982.
3. Sharer RB, Bianco JA: Implications of hepaticxenon
activity in ventilation scans. J Nucl hied 20450-452.
1979,
Interferingdrug(s): Diazepaminsedalive
doses; general anesthetic agents.
Nuclear medicine study affected: Pulmonary
ventilation scintigraphy.
Effectonimage: Thenormaldistribution of
radioxenon in the lung (top to bottom) is shifted
slightly, wilh more activity in the top of the
lungs and less in the bottom as a result of the
drug therapy.
Significance: Postoperativepatients may pre-
sent with changes described above,
Mechanism: Sedativeandanestheticdrugs
cause a reduclion in the gradient of ventilation
from nondependent to dependent lung.
Management: None.
How documented: Clinical studies ( 1 , 2).
REFERENCES
I . Pralo FS, Knill RL: Diazepamsedationreducesfunc-
tionalresidual capacityand altersthedistribution of
venhlation in man. Anesrh Analg 61:209-210,1982.
2. Rchder K, Sessler AD, Marsh HM: General anesthesia
and [he lung. Am Rev Respir Dis 112:541-562, 1975.
[67G~]GALLIUMCITRATE
Interfering drug(s): Phenytoin.
Nuclear medicine study aEected: Tumor and
abscess localization scintigraphy.
Effect on image: Localization of radiogallium
in the mediastinum and pulmonary hilar struc-
tures(inpatientswithoutclinicalevidence of
lymphadenopathy).
Significance: The induction of pseudolym-
phoma by phenyloin may infrequently cause
false positive [67Ga]galliurn citrate scans mim-

212 f Esseniiuls of Nucleor Medicille Science
icking a pattern of distribution sometimes ob-
served in patients with true lymphoma. If con-
s i d e r e df r o m a d i f f e r e n tp e r s p e c t i v e ,
[6’Ga]gallium citrate imaging may be useful in
identifying patients at risk from the serious side
effects of phenytoin.
Mechanism: The administration of phenytoin
has beenassociatedwiththe development of
local or generalized lymphadenopathy including
benign lymph node hyperplasia, pseudolym-
phomaand,sometimes,evenlymphomaand
Hodgkin’s disease.
Management: None; if this patlem of distribu-
tion (indicating lymphadenopathy) is noted on a
[67Ga]galliurn citrate scan, however, the condi-
tion should be differentiated from other lypes
lymph node pathology and the patient observed
for an extended period. Whenever possible, al-
ternative lherapy should be used.
How documented: Case report and prospectil7e
clinical study (1).
REFERENCE
1. Lentle BC. Slarreveld E. Catz 2 , et al: Abnormal bio-
distribmion of radiogallium in persons treated with phe-
nytoin. J Curl Assoc Radio1 34: 1 14- 1 15, 1983,
Intcrfering drug(s): Amiodarone; bleornycin;
busulfan;nitrofurantoin; Baciilus Cairnetle-
Guirirr; multiple cycles of combinalion chemo-
therapy; lymphangiographic contrast media; ad-
dictive drugs of abuse.
Nuclear medicine study affected: Tumor and
abscess localization scintigraphy.
Effect on image: Diffuse pulmonary localiza-
tion (and sometimes local pulmonary uptake).
Significance: This pattern of distribution mirn-
ics [hat observed with other diffuse pulmonary
diseases not relatedto drug therapy, e.g., sar-
coidosis. If the examiner is not familiar with
toxic effects of drugs, this uptake of radiotracer
in the lungs may cause some slight confusion in
determining the cause of the pulmonary disor-
der. This is especially true considering the non-
specificity of [67Ga]galliumcitrate for diagnos-
ing any particular pulmonary disease. At limes,
there has been poor correlation between radio-
graphicfindingsand results of [67Ga]galliurn
citrate studies, which complicates matters fur-
ther.
Mechanism: These drugs are known to induce
nulmonarv interstitial Dneumonitis andlor fibro-
sis. Long-termintravenous injection of addic-
tive drugs of abuse is associated with vascular’
talc granulomatosis.
Management: Discontinue therapy when drug-
i n d u c e dd i s e a s ei sd e t e c t e d .S c h e d u l e
[67Ga]gallium citratestudiesprior to contrast
lymphangiography.
How documented: Studies in mice (1-3j; case
reports (4-10); prospective clinical study (1 1);
relrospective clinical studies {12,13).
REFERENCES
1. Shpsh A, M a l l e t - k t S , Lentle BC, elabAltered
biodistribulion of radiogalhum folImvin_eBCG treat-
ment in mice. Int J Nucl Med B i d 8:349-356, 1981.
2. Shysh A, Mallet-Paret S, Lentle BC, el al: lnflucnce of
of intrademal BCG on tbe biodistribution of radiogallium
in mice. 6 1 I Nucl Med Bioi 7333-336, 1980.
3. Sasaki T, Kojima S,Kubodera A: Uptake of %a in the
lung of mice during bleomycin lrealmenl. Eur J lVrrc1
Med 457-61. 1984.
4 van Rooij W J , van der Meer SC, van Royen EA, et al:
Pulmonary gallium-67 uptake in amiodarone pneumo-
nitis. J NuciMed 25:211-213, 1984.
5. Joelson I,Klugcr J, Cole SI et al: Possible recurrenceof
amiodarone pulmonary toxicity following cor-
ticosferoid therapy. C h a r 85:284-286, 1984.
6. Crook MJ, Kaplan PD, Adatepe MH: Gallium-67 scan-
ning in nitrofurantoin-induced pulmonaryreaction. J
Nucl Med 23690-692, 1982.
7. Richman SD, Levenson SM, Bunn PA, etal: W a
accumulationiopulmonarylesionsassociatedwith
bleomycintoxicity. Cuncer 36:1965-1972. 1975.
8. Manning DM, Strimlan CV. Tbrbiner EH: Early detec-
tion of busulfan lung: report of a case. Urn Nfrcl Med
5:412-414,1980.
9. MacMahon H. Bekerman C: The diagnosticsignifi-
cance ot gallium lung uptake in palients with normal
chesl radiographs. Radiology 127:189-193, 1978.
10. Bekerman C, Hoffcr PB, Bitran JD, et ai: GaIlium-67
citrate imaging studies of the lung. Scrnin Nncl Med
10286-301, 1980.
11. Bilgi C, Brown NE, McPherson TA, et al: Pulmonary
manifestations in patientswithmalignantmelanoma
during BCG immunotherapy. Chest75:685-687, 1979.
12. Lenlle BC, Castor WR, Khaliq A, et al: The effect of
contrast lymphangiography on localization of %a-cit-
rate. J Nucl Med 16374-376, 1975.
13. Gupta SM. Sziklas JJ, Spencer RP, et al: Significance
of dillusepulmonaryuptake in radiogalliumscans:
concise communication. J Hucl Mcd 2l:328-332,
1980.
Interfering drug(s): Metoclopromide; reser-
pine; phenothiazines; oral contraceptives; di-
ethylstilbestrol.
Nuclear medicine study affected: Tumor and
abscess localization scintim-aphy.
Dmg-bzduced Alterations:ReportedInstances f 213
Effect on image: Localization of [67Ga]gallium same plasma protein-binding sites in a manner
citrate in breasts (men and women). similar to thatof carrier gallium, resulting in
Significance: Probably of little clinical signifi- moreunbound67Ga.Otherantimetabolite
cance, aIthough this type of distribution is more drugs, such as 5-fluorouracil, cytarabine, and 6-
commonly observed in postpartum or pregnant thioguanine, may haveaneffectlike that of
women. methotrexate on the kinetics of iron.
Mechanism: These drugs induce gynecomastia Mechlorethamine and vincristinemay also
andhyperprolactinemiawhichmayaltract decrease plasma protein binding of [67Ga]gd-
[67Ga]gaIliurn citrate. lium citrate, although the exact mechanismis
Management: None. not known.
How documented: Case reports ( 1 , 2); retro- Themechanismtoexplaintheeffect of
spective clinical study (3). cisplatinurn has not been elucidated. In vitro
studiesindicate, however, that reducedtumor
uptake of [67Ga]gallium citrate may be a result
REFERENCES
1. Stepanas, AV, Maisey MN: Hyperprolactinaemia as a of intracellular biochemical changes inducedby
cause of gallium-67 uptake in the breast. Br d Radio1 prolonged exposure to cisplatinum rather than
49379-380,1976. by any affect on protein binding. This concept
2. Ajmani SK, Pircher FJ: Cia-67 ciuate in gynecomastia. J
may b e applicable to other drugs. For instance,
Nucl Med 19560-561, 1978.
certainantineoplaslicdrugsmaydamage the
3. Kim YC. Brown ML, Thrall JH: Scintigraphic patterns
of gallium-67uplake i n thebreast. Radiology specific cellular organelles that accumulate gal-
124:169- 175, 1977. lium.Another possibility is that chemothera-
peuticagentsmayinhibittheuplakeof
Interfering drug(s): Methotrexate;cisplati- [67Ga]galliumcitratethrough a competitive
num; gallium nitrate; mechlorethamine; vincris- blockade of specific receptors forgallium in
certain organs and tumors.
tinesulfate;othercancerchemotherapeutic
agents; iron. Management: Whenever it is possible, do not
Nuclear medicine study affected: Tumor and administer [67Ga]gallium citrate within 1 week
of the last dose of a cancer chemotherapeutic
abscess localization scintigraphy.
of iron. It may
Effect on image: Althougheachreport of al- agent or pharmacologic doses
also be helpful to measure the patient’s serum
tered biodislribution in thiscategoryvaries
iron and iron-binding capacity before injecting
slightly,the following items seem to be com-
mon factors observed in most instances: (a) in- [67Ga]galliurncitrate when potential problems
creased skeletal uptake of [67Ga]gallium citrate, are suspected.
(b) increased renal elimination of [67Ga]gallium How documented: In vitro study (1); study in
cilrate,(c)reducedhepaticaccumulation of rats (2); studies in mice (3,4); study in rabbits
[67GaJgallium citrate,and (d) reduced tumor or (5); case reports (6,7); clinical studies (8-10);
review (1 1).
abscess uptake of [67Ga]gaIljum citrate.
Significance: If tumoror abscess localizationof
the radiotracer is, indeed, decreased as a result REFERENCES
of cerlain antineoplastic drugs or iron, the de- Noujaim AA, Tcmer UK, Turner CJ, el al: Alterations
tectability of theselesions with [67Ga]gallium of gallium-67 uptake in tumors by cispIalinum. I w J
Nucl Med Bioi 8289-293, 1981.
citrate will b e diminished.
Fletcher JW, Herbig FK, Donali R M 6’Ga citrale dis-
Mechanism: Galliumnitrateaffectsthe
tribution foilowing whole-body irradiation or chemo-
[67Ga]galliurn citrate localization through a car-
therapy. Radiology 117709-712, 1975.
rier effect, i.e., competition for plasma protein- Nickel R, Levine G: A study of the effects of melho-
bindingsites, resulting in the distributionde- lrexnfc and iron dextran on the distribution of GR-67
citrate in mice. Monthly Scan June 1981.
scribed.
Chillon, HM, Witcofski RL, Watson NE. et al: Altera-
Methotrexate temporarily inhibits the incor-
tion or gallium-67 distribution in tumor-bearing mice
poralion of iron into erythrocytes, which results
foIlowing lreatmenl with methotrexate:concise com-
in anelevation of serumiron.Theiron then munication. J Nucl Med 22: 1064- 1068, 198 1 .
competeswith[67Ga]galliumcitrateforthe 5 . Osler ZH,Larson SM , Wagner H N Possible enhance-
214 I Essentiols oJNucleor Medicine Science
men1of "Ga-citrate imaging by iron dextran. 3 ~Vrtcl
Med 17.356-358.1976.
6 . Lentle BC. Scott IR. Noujaim AA, et al: Iatrogcnic
alterations in radionucIide biodisbibutions. Semin Nrrcl
Med 9:131-143. 1979.
7. Blei CL. Born ML, Rollo FD: Galliumbonescan in
myelofibrosis: case report. J Nucl Med 18:445-447,
1977.
8. Bekernan C. Pave1 DG, 3itran J, et al: Inadverlenl
administration of antineoplastic agents to patients pnor
to Ga-67 injection:recognition of a specific radionu-
clidedisrribution pattern and its diagnostic signifi-
cance, J Nucl Med 24P.50, 1983.
9. Bekernan C , h v e l DG. Bitran J, et al: The eflects or
inadvertentadministration or antineoplasticagents
pnor LO Ga-67 injection: concisecommunication. J
N d Med 25430-43.5, 1984.
IO. Sephton R, Martin JJ: Modification of distribution of
galiium67 inmanby administration of iron. Br J
Radio1 53572-575. 1980.
11.Hoffer P: Gallium:mechanisms: J NuclMed
2 I:282-285. 1980.
Interfering drug(s): Anlibiotics (e.g., clin-
damycin).
Nuclear medicine study affected: Tumor and
abscess localization scinligraphy.
Effect on image: Localization of [67Ga]gallium
citrate in the bowel.
Significance: Drug-induced accumulation of
[67Ga]gallium citrate could mimic other causes
of inflammatory bowel diseaseoreven intra-
luminal [67Gajgallium citrate activity which is
being eliminated from the body via the bowel.
Mechanism: Certainantibioticsare known to
cause pseudomembranous coltis, an inflam-
matory disease that may accumulate [67Ga]gal-
lium citrate.
Management: None; the drug responsible for
inducing the colitis, however, should be discon-
tinued and replaced with alternative therapy.
How documented: Case reports (1,2).
REFERENCES
1. F'echman R, Tetalman M , Antonmamei S , et al: Diag-
nostic significance of persistent colonic gallium activity:
scinligraphicpatterns. Radiology 128691-695, 1978.
2.Tcdesco FJ. Coleman RE, Siege1 BA: Gallium citratc
Ga-67acculnuIation in pseudomembranous colilis.
JAMA 235:59-60. 1976.
Interfering drug(s): Calcium gluconate; intra-
muscular injections.
Nuclear medicine study affected: Tumor and
abscess localization scintigraphy.
Effect on image: Soft tissue accumulalion of
[67Gajgallium citrate.
Significance: Extravasation of intravenous cal-
ciumgluconatesometimescanresult in a
[67Ga]gallium citrate scan that is indistinguisha-
ble from osteomyelitis unless the region of ab-
normal uptake can be clearlyseparated from
bone.
In addition, a patient with unexplained radio-
nuclideaccumulation in large musclemasses
should be examined to rule out local complica-
tions from intramuscular injections.
Mechanism: Pattern of radiogallium distribu-
tioncaused bylocalcomplications associated
with injection of drugs.
Management: None.
How documented: Case reports (1-3).
REFERENCES
1 . Sty JR, Starshk RJ, HubbardAM:Ga-67scinligra-
phy-calciumgluconateextravasation. Clin Nucl Med
7:377, 1982.
2. Carler JE, Joo KG: Gallium accumulalion in intra-
muscularinjectionsites. Clin Nlrcl Med 4:304,1979.
3. Bekeman C , Hoffer PB. Bitran JD. etal:Gallium-67
citrateimagingstudies of the lung. Semin Nucl Med
10:286-30 1, 1980.
Interfering drug(@: Ampicillin; sulfonamides;
sulfinpyrazone; ibuprofen; cephalexin and other
cephalosporins; hydrochlorothiazide; meth-
icillin, erythromycin; rifampin; pentamidine;
phenylbutazone; gold salts; allopurinol; furose-
mide;phenazone;phenobarbital;phenytoin;
phenindione.
Nuclear medicine study affected: Tumor and
abscess localization scintigraphy.
Effect on image:Increasedaccumulation of
[67Ga]gallium citrate in kidneys.
Significance: Drug-induced renal radiogailium
uptake could possibly be mistakenfor glomeru-
Ionephritis,pyelonephritis, or the nephrotic
syndrome. On the other hand, it has been sug-
gested that [67Ga]gallium citrate imaging actu-
ally may be useful in separating patients with
drug-induced interstitial nephritis from those
with acute tubular necrosis due to shockor
trauma (1). To c.omplicate matters, however, re-
sults of studies have shown that short-term ther-
apy with aminoglycosides or amphoterecin 3,
both known to be nephrotoxic agents, does not
induce [67Ga]gallium citrate uptake in rats (2).
Drug-inducedAlterations: Reporied instances
Furthermore, renal [67Ga]galliumcitrate activity
has been reported to occur relatively often even
in palientswithnorenaldisease ( 3 ) , and
[67Ga]gallium citrate does not reliably identify
cases of noninfectious interstitial nephritis (4).
Therefore, the clinica1 significance of drug-in-
duced [67Ga]gallium citrate renal uptake is un-
certain.
Mechanism: Apparently,[67Ga]galliurncitrate
uptake in the kidney is due to acute interstitial
nephritis induced by drug Iherapy.
Management: None; the drug responsible for
inducing the nephritis, however, should be dis-
conlinued and replaced with allernative therapy.
How documented: Case reports (1,5-9); study
in rats in which a nonassociation of [67Ga]gal-
hum citrateuptake is reportedwith antibiotic
therapy (2).
REFERENCES
Linlon AL, Clark WF. Driedger AA. et al: Acute inter-
stitialnephritisduetodrugs. A n n inrern Med
93735-741, 1980.
Taylor A. Nelson H , Vasquez M. el al: Renalgallium
accumulation III ratswithantibiotic-induced nephritis:
clinicalimphcations.Concise communicalion. J N'rd
Med 21:646-649,1980.
Garcia JE, NostrandDV,Howard WH 111, etal: The
spectrum of gallium-67 renal activity in patlents with no
evidence of renaldisease. J Nncl Med 25575-580.
1984.
Graham GD, Lundy MM, Moreno AJ: Failure of gal-
lium-67scintigraphy to Identifyreliablynoninfectious
interstitial neptuitis: conclse communication. J N r d
Med 24568-570, 1983.
Kurner D, Coleman RE: Significance of delayed 67-Ga
localization in thekidneys. 3 N d Med 17372-875,
1976.
Frankel RS, Richman SDI Levenson SM. et al: Renal
localization of gallium-67citrate. R o d i o l o g g
114:393-397,1975.
Sherman !+A, Byun KJ: Nuclear medicine in acute and
chronic renal failure. Semin ~ V u c Med
l 12:265-279,
1982.
8. Lin DS. Sanders JA. h t e l BR: Delayed renal localiza-
lion of Ga-67: concise communication. J Nucl Med
24394-897,1983.
9. Kleinknecht D, Kanfer A , Morel-Maroger L, et al: Im-
nmnologicallymediateddrug-inducedacuterenal
failure. Corrrrib A'ephrol 1042-52, 1978.
Interrering drug(s): Chemotherapeulic agents;
antibiotics.
Nuclear medicine study affected: Tumor and
abscess localization scintigraphy.
/ 215
Effect on image: Localization of [67Ga]galliurn
citrate in the thymus.
Significance: This pattern of distribution is of
minimal clinical significance, since it has been
reportedto be a normal variant in children. It
may, however, mimic an image similar to that
observed in patients with direct tumor invasion
of the thymus.
Mechanism: Depletion of thymic elementsmay
occur, in part, as a result of therapy with chemo-
therapeuticagentsorantibiotics.Ithas been
theorized lhatfollowingtheadministration of
these drugs, a period of thymic recovery occurs
with rapid proliferation of thymic lymphocytes
andincreasedmedullaryepithelial activity. It
maybeduringthisreparativephasethat
[67Ga]galliurn ciwate accumulates in the thy-
mus.
Management: None.
How documented: Case report (1) and retro-
spective clinical study (2).
REFERENCES
1. Spencer F W , Suresh PL, Karimeddini MK: Acquisition
of thymic uptake of radiogallium in a child after therapy
for inrection. Clin Nucl Med 7:407-408, 1982.
2. Donahue DM, Leonard JC, Basmadjian GP, et al: Thy-
mic gallium47 localization in pediatricpatients on
chcrnotherapy: concisecommunication, 3 N'ucl Med
22:1043-1048, 1981.
Interfering drug(s): High-doseheparin ther-
apy.
Nuclear medicine study affected: Renal Lrans-
plan1 rejection.
E f f e c t on image: Failuretoaccumulate
[67Ga]galliurn citrate in transplantedkidney dur-
ing acute rejection.
Significance:[67Ga]galliurncitrateisrarely
used in the evaIuation of renal transplant rejec-
lion. If it is used, however, a normal study in a
patientwith acute rejection wouldresultin a
missed diagnosis of rejection and potentially
severe consequences.
Mechanism: It is suggested that heparin inter-
rupls the inlravascularcoagulationcycle that
results in fibrin thrombosis, and may exerl an
anti-inflammatory effect, thus inhibiting the
formation of assumedaccumulationsitesfor
67Ga in rejecting kidneys.

216 I Essentials of NuclearMedicineScience
Management: If it is possible,interrupt
heparin therapy for the imaging study.
How documented: Observationsinclinical
studies (1,2).
REFERENCES
1. George EA. Codd JE. Newton WT, et al: Ga-67 citrate
in rena1 allograftrejection. Radiolog!' I17:731-733,
1975,
2. George EA, Codd JE, Newton WT, e! al: Comparative
evaluation of renal transplant relect~onwith radioiodi-
nated fibrinogen, 99m-Tc-sulfur colloid, and 67Ga-cit-
rate. f Nucl Med 17:175-180. 1976.
MISCELLANEOUS
RADIOPHARMACEUTICALS USED TO
ASSESS GASTRIC EMPTYING
Interferingdrug(s): Atropine; propantheline;
levodopa; albuterol; isoproterenol; morphine
and other narcotic analgesics; Librax; TPN ther-
apy.
Nuclear medicine study affected: Radionu-
clide gastric emptying studies.
Effect on image: Delayed gastric emptying.
Significance: The effect of these drugs to delay
gastric emptying must be taken into considera-
tion in the diagnostic work-up of gastroparesis.
Mechanism: Anticholinergics slow gastric
emptying by inhibiting cholinergic stimulatory
effects on the stomach. Dopamine is presumed
to be an inhibitory neurotransmitter in the ali-
menlarytract. The mechanism through which
P-adrenergic agonists prolong gastric emptying
is not clear, but it may be due lo an elevation of
gastrin levels caused by these drugs. The gaslric
stasis produced by narcotic analgesics is associ-
ated withanincrease in antral and duodenal
smooth muscle toneresulting from the action of
these drugs on cholinergic, tryptaminergic, and
enkephalinergic receptors in the gastrointestinal
tract.Slowing of gastric emptyingwhile the
patient is on parenteral nutrition probably is due
!o the increase in blood glucose induced by the
intravenousnutrient load.Aluminumion has
been shown to inhibit acetylcholine-induced
contractions of gastric smooth muscle.
Management: When it is clinically appropri-
ate, discontinue therapy with interfering drugs
before performing baseline radionuclide gastric
emptying studies.
How documented: CIinical studies (1 - 11); re-
view article (12).
REFERENCES
1. Humitz A , Robinson RG, Herrin WF: Prolongation of
gastric emptying by oral propantheline. Clin Pharm
Ther 22:206-210, 1977.
2 . Nimmo J. HeadingRC, Tothill P, et al:Phar-
macological modification of gastric emptying: effects
of propanlheline and metoclopromide on paracelamol
absorption. B r M e d f 1:587-589, 1973.
3 . Berkowilz D M , McCallum RW: Interaction of
levodopa and meloclopromide on gastricemptying.
Clin Pharm Ther 27:414-420, 1980.
4. Rees WR, Clark RA, Holdsworth CD: The effect of p-
adrenocepor agonists and antagonists on gastric emp-
tying in man. B r J C l i n Pharmacoi 10551-554, 1980.
5. Nimmo JVS, Heading RC, Wilson J, et al: Inhibition of
gastric emptying and drug absorption by narcotic anal-
gesics. Br f CIin Phnrmacol 2509-513, 1975.
6. Prokop EK, Caridc VJ. Winchenbach K, el al: The
effect or metoclopramide and morphine on small inles-
linaltransitlime in normalsubjects. J N d Med
24:P57, 1983.
7.Frank EB. Lange R, Pbdnkey M, el al: Elfecl of mor-
phine and naloxone on gastnc emplyingin man. J NucI
hled 23:P21. 1982.
8. Chaudhuri TK, HudginsMH: Effect of Librium,
Quarzan and Librax on gastric emptying lime. J Nucl
Med 23P21, 1982.
9. MacGregor IL. Wiley ZD. Lavigne ME, et al: Slowed
rate of gastric emptying of solid food inmanby high
caloric parenteral nutrition. Am f Surg 138652-654,
1979.
10. Bandinl P, Malmud L, Applega!e G , e l al: Dual radio-
nuclide studies of gastric emptyingusing a physiologic
meal. J Nucl Med 21:P66-P67, 1980.
11. Hunvitn A, Robinson RG, Vab TS, el al: Effecrs ol
antacidsongastricemptying. Gastroenterology
71:268-273,1976.
12. Malmud LS, Fisher lis, Knight L, el al: Scintigraphic
evaluation of gastricemptying. Semin Nucl Med
12116-125. 1982.
MISCELLANEOUS BRAIN-IMAGING
RADIOPHARMACEUTICALS
Interfering drug(s): Cancer chemotherapeutic
agents;specifically reported werecyclophos-
phamide, doxorubicin, vincristine, actinomycin
D and methotrexate.
Nuclear medicine study affected: Brain scinti-
graphy.
Effect on image: Patchy inchaseduptake of
radiotracer on brain images as a result of chem-
otherapeutic neurotoxicity has been noted in at
Drug-inducedAl?era!ions:Reported
least one report. Brain imaging in cases of ven-
kiculitisandmeningitis resulting from intra-
thecalmethotrexate therapy may demonstrate
ventricular and meningeal localization, respec-
tively.
Significance: This pattern of distribution may
be confused with other brain disorders.
Mechanism: Neurotoxicity of cancerchemo-
therapeutic drugs.
Management: None.
How documented: Case reports (1-3).
REFERENCES
1. Sherkow LH: Chemotherapeutic neurotoxicity on brain
scintigraphy. C l i ~Nncl Med 4:439-440, 1979.
2. Conway JJ, Seibert JJ, Kuhn GP, et al:The role of
radionuclides in evaluating cenual nervous system com-
plications from chemotherapeuticagents. I N'ucl Med
16:522.1975.
3. Ivlakler FT Jr, Gu~owiczMF, Kuhl DE: Methotrexale-
induced ventricuIitls: appearance on routine radionuclide
scan and emlssion computed tomography. Clirr Nucl
Med 322-23, 1978.
Interfering drug(s): Corticosteroids (e.g., dex-
amethasone).
Nuclear medicine study affected: Brain scinti-
graphy with various radiopharmaceuticals used.
Effect on image: Diminished uptake of radio-
tracer into brain lesions.
Significance: Steroid therapy decreases the sen-
sitivity of brain scintigraphy forthe detection of
brain neoplasms.Sincesteroids are used for
symptomatic treatmentof theselesions,itis
particulxly imporlant to beaware of their phar-
macologic effects on brain scans.
Mechanism: Accumulation of tracer is reduced
as a result of a reduction in peritumor edema
which is mediated through an improvement in
capillary integrity within the cerebral tumor.
Management: Preferably perform brain scinti-
graphy prior to starting or following the removal
of steroid medicalion for several daysin order to
avoid false negative results secondary to steroid
effects. The effectsof steroid therapy appear to
be less profound on imaging with 99mTc-glucep-
tate than on imaging with other brain imaging
agenls .
How documented: Case report (1); clinical
studies (2-7).
Inslmces I 217
REFERENCES
1. Stebner FC: Sleroid eFTect on the brain i n a patient with
cerebral metastases. J Hucl Med 16320-321. 1975.
2. Marty R, Cain ML: Effecls of corticosteroid (dex-
amethasone)administration onthe brain scan. Rad;.
ology 107:117-121, 1973.
3. Waxman, AD, 3eldon JR, Richli WR, etal: Steroid
induced suppression of gallium uptake in humor of the
central nervous system. J A'ucl Med 18:617, 1977.
4. Warman, AD. Beldon JR, Richli W , et ai:Steroid-
induced suppression of galhum uplake in lumors of the
cenlral nervous system: concise communlcation. J Nucl
Med 19:480-482, 1978.
5 . FIelcher JW, George EA, Henry RE, et al: Brain scans,
dexamethasone Iherapy, and brain tumors. JAhfA
232:1261-1263, 1975.
6. Crocker EF, Zimmerman R A , Phelps ME, el al: Thc
eflect of dexamethasoneupontheaccumulation of
meglumine iothalamate and technetium pertechnetate in
cerebral tumors as delemined by computed lomogrdphy.
J Nucl Meed 17528, 1976.
7. Crocker EF, Zimmeman RA, Phelps ME, el al: The
effecl of steroids onthe exlravascular distribution of
radiographic contrast material and lechnetium pertech-
nelatt in brain tumors as determined by computed I(]-
mography. Radiology 119:471-474, 1976.
Interfering drug(s): Psychotropic drugs.
NucIear medicine study affected: Cerebral ra-
dionuclide angiography.
Effectonimage: Rapidaccumulation of ac-
tivity in thenasopharyngealareaduringthe
arterialorcapillaryphase(termed the "hot
nose" phenomenon).
Significance: This patlern of distributionhas
been noted to occur also wilhinternalcarolid
arterial occlusion or increased intracranial pres-
sure; thus, drug-induced changes in radio(rxcr
distribution may sometimes bernisiztkcn for tlis-
ease.
Mechanism: Psychotropic drugs cause the hol
nose phenomenon by increasing blood flow in-
the external carotid circulation.
Management: Confirm diagnosis with other di-
agnostic modalities.
How documented: Retrospective cIinical study
(1).
REFERENCE
1. Watts G, Mena 1, Joe SH: Cerebral radioisolopc angio-
gram: ihc significance of increased external camlid cir-
culation. J Nucl Med 17:527. 1976.
218 I Enenrials of Nudear Medicine Science
MISCELLANEOUS
RADIOPHARMACEUTICALS USED TU
ASSESS RENAL FUNCTION
Interfering drug(s): Iodinated contrast agenls;
aminoglycosides(e.g.,gentamicin,tobra-
mycin).
Nuclear medicine study affected: Radionu-
clide renal function studies {[1231] or [1311]i~do-
hippurate;[1251jiothalamate).
Effect on image: Reduction in effective renar
plasma flow (ERPF) values. The degree of re-
duction dependson the degree of preexisting
renal disease,theamount of contrast material
administered, andlhe route of administration.
Aminoglycosides may also cause a decreased
glomerular filtration rate.
Significance: Renogramsperformedimmedi-
ately following arteriography or contrasl-en-
hanced CT scans should not be used as baseline
studies forcomparison with futureexamina-
tions. Aminoglycoside-induced decrease in
glomerular filtration rate may inlerfere with the
differential diagnosis of rend dysfunction.
Mechanism: Direct effect of contrast agents on
renal function; aminoglycoside nephrotoxicity.
Management: The effect of the contrast mate-
rial usually persists no longer than 2 weeks, at
which timethere is a return to baseline renal
function;therefore, if baselineradionuclide
study is needed, it should be performed 1-2
weeks following any study in which iodinated
contrast material is used.
A baselineglomerular fillration ratestudy
should be obtained priortoinitiationof ami-
noglycoside therapy, when clinically appropri-
ate.
How documented: Clinical studies (1,2)
REFERENCES
1 , Gales GF, Green GS: Transientreduction in renal func-
lion following arteriography and contrast enhanced CT
scanning. Scientific exhibitpresenied a[ the 28th Annual
Meeting of the Sociely of Nuclear Medicine, Las Vegas,
lune 1981.
2. Keys TF, K u m SB, Jones JD, e[al: Renal tonicity
during therapy with gentamicin or tobramycin. M a w
CIirr Proc 56556-559, 1981 I
Interfering drugls): Cyclosporine;cisplatin.
Nuclear medicine study affected: Renal func-
tion scintigraphy ([1231]or [13'I]iodohippurate
and 94mTc-DTPA for renal graft evaluation).
Effect on image: With cyclosporine, there typ-
ically is good perfusion of transplanted kidney
with 99"Tc-DTPA butreducedrenaltubular
functionwith [1231] or[1311]iodohippurate.
Cisplatin is reported to decrease urinary excre-
tion.
Significance: Thepattern of dislribution ob-
served in patientson cyclosporine therapy mim-
ics that observed in patients with acute tubular
necrosis (ATN); therefore, the differenliation of
ischemic ATN from cyclosporine nephrotox-
icity often is difficult in renal transplant recip-
ientstreatedwithcyclosporine.Similarly,
cisplatin may interfere in the differential diag-
nosis of renal tubular dysfunction.
Mechanism: Nephrotoxiceffects of cyclo-
sporine may become apparent early in the post-
operative course as acute renal failure or, later,
as a gradualdecrease in glomemlar filtration
rate; these nephrotoxic effectsalter scinligraphy
as described above.
Nephrotoxicity, which is dose related and can
be severe,mayoccur in patientsreceiving
cisplatinand is associated with renal lubular
damage.
Management: Nephrotoxicity usually isrevers-
ible on discontinuation or dosage reduction of
cyclosporine. Clinical findings, timing with re-
spect to transplantation, patient history, e k .
mustbeclosely correlatedwith radionuclide
study results in order to help make a distinction
between ATN and drug-induced disease. In ad-
dition,hyperbilirubinemia invariably is a sign
of high blood cyclosporine levels and, thus, is a
reasonable indicatorof nephrotoxicity in light of
worsening graft function. Graft biopsy may be
usefui in distinguishing drugtoxicity from other
transplant complications.
How documented: Clinical studies in small
numbers of renaland h e r uansplant patients
(1,2); study in rats (3).
REFERENCES
1. Kim EE, Guticrrez C, Sandler CM, el al: Radionuclide
deteclion of cyclosporin A nephrotoxicity in renal trans-
plant patients. I Nucl Aged 24:P129, 1983.
2. Klintmalm GBG, Klingensmith WC 111, Iwalsuki S, et
al: Tc-99m DTPA and 1-131 hippurdn findings i n cyclo-
sporin A nephroloxicity in liver transplanl rccipicnts. J
Nucl Med 22PY-P38, 1981.
1
3. McAree JG. Subramanian G , Schneider RF, et al: Tech- REFERENCE
netium-99m DADS complexes as renal function and
1 . Clorius JH, Dreikom K , &It J, et at: Renal graft evalua-
imaging agents:TI. Biologic comparison with 1.131 hip-
tion with pertechnetate and 1-131 hippuran. A compara-
puran. J Nucl ,Wed 26:275-286, 1985.
tiveclinicalstudy. I Nucl Med 201029-1037. 1979.
Interfering drug(s): Furosemide.
Nuclear medicine study affected: Renal func-
Interfering drug(s): Probenecid.
tion scintigraphy (['231] or[[3'I]iodohippurate Nuclear medicine study affected: Renal func-
and [99mTc]pertechnetate for renal grafi evalua- tion scintigraphy ([[231] or [ 13'l]iodohjppurate,
Effect
tion). on image: Relatively large increasesin 99mTc-gluceptate).
Effect on image: Decreased renal accumulation
dosage of furosemide can improve renal func- and excretion.
tion to the extent that misleadinglygood re- Significance: May give the false impression 01
nogram and flow curves are obtained, resulting renal tubular dysfunction.
in false negative studies; relatively largede- Mechanism: Probenecid is an inhibitor of renal
creases in dosage may have [he opposite effect, tubular transport mechanism for organic acids.
resulting in flow patterns suggesting slighl graft
Management: Discontinue probenecid prior to
deterioration. How documented: Rat study(11, rabbit study
study.
Significance: It is important to account for the
effects of furosemide on renal funclion studies, (2), mouse study ( 3 ) .
since it is a commonly used diuretic in the
management of patientswhohaveundergone
renal transplantatim. REFERENCES
Mechanism: Furosemide increases renal blood 1. Lee HB, Blaufox MD: Tc-99m glucoheplonale (GHA)
renal uptake: influence of biochemical and physiologic
flow by reducing renal vascular resistance
factors. I N u d hied 25:P75-P76, 1984.
through vascular dilationresultingfrom stirn- 2. Antar MA. Jones AN: Effect or probenecid on renal
dation of the prostaglandin syslem. extraction of three renal radiopbarmaceulicalsat 15 and
Management: Avoid large changes in furose- 30 minutes. J Nucl Med 26PI31, 1985.
mide dosage within 24 hours of performing ra- 3 . Frilzberg AR, Whitney WP, Kuini CC, et al: Bio-
distribution andrenal excretion of Tc-99m N. N'-
dionuclide renal function studies.
bts(mercaptoacetamido)ethplenediamine. Effect of renal
How documented: Retrospective clinical study tubular lransporr inhibitors. I r ~ r J Nucl ,Wed B i d
(1). 9:79-a2. 1982,

15
Iatrogenic Alterations in the Biodistribution of
Radiotracers as a Result of Radiation Therapy,
Surgery, and Other lnvasive Medical
In this chapter, we describe those changes in
radiopharmaceutical biodistributions which re-
sult from physical insults to the body. It would
be gratuitousto refer, for example, to the lackof
uptake of radiocolloid by the spleen after splen-
ectomy, however. Thus it is only those effects
which are unexpected or incidental that will be
described.
Much of the experiencethat is being accumu-
lated in this context is, of necessity, anecdotal
and the subject only of case reports. From the
number and diversity of reports, however, the
clinician should be alerted to the potential for
scan findings to reflect not only the disease bul
also his or her investigation and treatment.
Although chemicals oftenarepotentmodi-
fiers or thebiologicaldistributions of radio-
tracers (1, 2), changes in such distributions can
result from a variety of other causes. An under-
standing of these causes is essential before diag-
nostic inferencescanbemade From ascinti-
graph. MoEover, the observations documented
in this chapter reemphasize the importance of
understanding the whole patient rather than of
approaching a scintigraph as an existential exer-
cise in detecting disease.
No description of our understanding of the
effects of physical insults on radiophamaceuti-
cal biodistributions is, however, likely to remain
exhaustive for long.
220
THERAPEUTIC IRRADIATION
The changes occurring in an organ following
therapeuticirradiationcanbesummarized as
follows:
1. Cell death and damage
2. An acute inflammatory response
3. Latevascularchangeswith obliteration of
the vascular bed
4. Healing, including fibrosisand cell death
These effects are dependenton radiation dose
and fractionation, type of radiation, volume of
tissue irradiated,mitotic activity of cells ex-
posed, and degree of specialization of cells (3).
All of these variables influence the impactof
such irradiationonradionuclide scintigraphy.
This impact may be demonstrated in differing
ways with different radiopharmaceuticals. It
may be important not only in the avoidance of
erroneousscaninterpretations but also in the
assessment of organ damage by radiation.
The effectsof radiation, being complex, can-
not always be readily predicted. Thus, in this
review the effects on each organ are considered
separately.
Heart
Uptake of 99mTc-pyrophosphate has been ob-
served in the hearts of a group of patients with-
out obvious cardiac disease who had received
AItered Biodistrihution: R a d i a i i o ~ l i l l ~ ~ aTherapies
~i~~e I 221
leftchestwallirradiationin a d o s e of Liver
1800-5000 rad ontheaverage of 32 months
earlier. Such uptake was attributed to the myo-
cardium, pericardium, or both (4).
Inreviewingtheevaluation of Iiverand
spleen injury with radionuclides, Usselman (10)
andGilday and Alderson (11) have described
Lungs the geometricdefects in colloidliverimages
due io irradiation in amounts in excess of 3500
Korsower et al. (5) studied the effectsof 3000
radapplied to the hemithoraces of a group of
rad. This finding is so characteristic as to allow
a “spot diagnosis” and was described as early
rabbits. Two hours folIowing irradiation, 5 2 8
as 1965 (12). The same authors noted that liver
of the experimental group had a moderate de-
recovery may occur following as much as 5500
crease in pulmonary perfusion as studied with
rad. Radiation has been reported to have a more
L311-labeledmacroaggregated albumin (MAA).
markedeffectonthe liver Kupffercells, as
After 24 hours,pulmonaryperfusionbecame imaged with radiocolloids, than on the hepato-
normal, but 2 months later the animals demon- cytes, as imaged with 99mTc-iminodiaceticacid
stratedabnormallungperfusion. The early
(IDA) analogs or ‘j7Ga-citrate* (13). The chang-
changes were attributed to either edema or vas-
ing patternof uptake of liver imagingradiophar-
ospasm, whereasthelatechangeswereat- maceuticals has been described by Herbstet al.
tributed to vascular occlusion and fibrosis.
(14). The hepatocytes, being more acutely radi-
Bateman and Croft (6) have reported on the osensitive, may show deficient function earlier
effects of 3000-3400 rad on the human lung as after irradiation, while the Kupffer cell effects
observed with 133Xe gasventilation and 9 9 m T ~ -
have a different temporal evolution.
MAA perfusion scans. The patients had been
Thisdissociationbetween the Kupffer cell
irradiated between 6 months and 12 years pre-
and the hepatocyte may also be noted in imag-
viously. Ventilation to perfusion mismatches in
ing with 99mTc-labeled sulfur colloid and 67Ga-
patientsnotbelievedtohave hadpulmonary
citrate (Fig. 15.1, A and B). Otherwise, the
thromboembolism were attributed to irradiation.
various patternsdetectedbycolloid scintigra-
Sarrecketal. (7) reportedonapatientwith
phy that follow irradiation of the Iiver have been
histologically confirmed radiation pneumonitis
reported in several publications but tend to be
(6000 rad I year earlier) who demonstraled ab-
predictable if the radiation beam dimensions are
sent perfusion on a 99mTc-MAA perfusionlung
known (15-17).
scan of the irradiated area. Increased activity in
this area was also noted on a 99mTc-pyrophos- Kidneys
phale bone scan, an observation we also made Radiation in amounts in excess of 3000 rad in
(1). A probable explanation for these changes typicaltreatment schedules has been found to
may be thelatevascular changesinducedby cause an increase in the renal uptake of both
radiation while the airways remain patent. The 99mTc-labeIedpyrophosphate and methylene rli-
uptake of 99mTc-pyrophosphateislessreadily phosphonate (MDP) (18, 19). In one of the
explained. reports, this increased uptake, found berween 5
Freeman et al. (8) studiedtheuptake of and 6 monthsafter renalirradiation, did nor
[67Ga]gallium citrate in irradiated lungs to de- persist at 10 monthsafter treatmentandwas
termine whether this tracer might contribute to presumed to reflect radiation-induced renal tu-
thediagnosis of radiation pneumonitis. AI- bular damage (18).
lhough uptake of radiogallium in the lungs of
Bone
some of their 12 patients was noted, there was
The effects of radiation on the distribution of
no overall consistentcorrelation between the
bone-seeking radiopharmaceuticals has been
clinical and radiographic manifestations of radi-
ation pneumonitis and the gallium scan. Siem-
* Although [“Galgallium citrate is preferred by IWPAC.
sen et aI. (9) have alsoobservedoccasional 6’Ga-cirrate is standard, and both are used throughout [his
uptake of radiogallium in irradiated lung. chapter.
 Alrered Biodistributim:Rndiariorrllnvnsive Thernpies I 223
222 I Essentinls of Nuclear Medicine Scier7ce

studied in rabbits (20-22). In conkolled experi- changes. Radiation changeswerefound to

ments, the effects of a single dose of 756 rad be more marked in lrabecular bone than in
were compared with the effects of a fractionated cortical bone.
dose of 4650 rad given over 3 weeks. In both
Lund andNathanson (22)foundnewbone
groups of rabbits,within the first 24 hours,
formation in rabbitmandiblesirradiated with
there was an increase in blood volume in the
.. 2000 rad but not in mandibles irradiated with
bone marrow as measured with 5'Cr-Iabeled rab-
.e' 1000 rad in a single exposure. Abnormalities in
bit red bloodcells.Histologically, thiscorre-
such bonewere not detected,however, on
lated with marrow sinusoidal dilation. The bone
gammacameraimagesobtained with 49mTc-
marrow blood volume decreased below normal
MDP.
1 month afterirradiation and decreasedeven
Clinicalobservations usually identifythis
more 12 months after irradiation. In the longer
third phase of clearIy demarcated,decreased
term, tibial corlicalandepiphyseal blood vol-
uptake of 99mTc-labeledphosphates ( 1 , 2 3 ) .
umes fell below normal. Bone blood flow meas-
Clinicalstudieshave shown areduction in the
ured by an injection of 84RbC1 1 minute before
uplake of 99mTc-pyrophosphatein normal bone
the animal was killed showed progressive falls
irradiatedwith 2000-5400 radbetween 6
in blood flow to both bone marrow and cortical
months and 7 years before imaging (24). In this
bonewhich werenot obvious I month after
reporl, Cox also identified the uncertainty that
irradiation.
results from a decrease in uptake at a site of
Bone remodeling was studied by tetracycline
tumor that is irradiated. It is not clear whether,
labeling.Maximalremodeling was evident 3
for any given patient, this represents tumor re-
months after irradialion and persisted up to 12
sponse or merely the suppression of uptake of
months, at which timevascularpatency was
the radiotracer.
reduced.
Further case reports (25, 26) have noted not
These findings were related to bone imaging
only the suppressed uptake of wmTc-labeled
wilh 99mTc-pyrophosphale in irradiated animals.
phosphates in irradiated bone but also the in-
Both early images and images obtained 3 hours
creased uptake of those tracers in adjacent sofl
after injection of the radiotracer were obtained.
tissues.
Three phases of bone responsetoirradiation
At the Cross Cancer Institute in Edmonton,
were idenlified:
Alberta, Canada, we, like Cox (24), have noted
Up to 1 monthafterirradiation, increased a "flare" of activity onbonescansafterthe
[racer concentration was noted in the images palliativeirradiationof bonemetastases.The
of bone,particularly in the earlyimages increasedactivity of the "flare,"comparable
where it was presumed to largely reflect in- withthat observedfollowing chcInothcrapy
creased bonevascularityand altered capil- (27), usually decreases lo less Ihan normal a1
lary permeability. about 6 months after treatment (Fig. 15.2).
Between 3 and 6 monthsafterirradiation, We frequently see, although we are not aware
the early images were found to be normal or that it has been reported elsewhere, suppressed
to show reduced activity. Delayedimages uptake of 67Ga-citrate in irradiated bone which
demonstrated increased tracer concentrations is consistent with decreased uptake of 9 9 m T ~ -
believed to representincreasedbone re- MDP when both investigations are carried out.
modeling, a conceptsupportedbyauto- This finding merely reflects the known distribu-
radiographic data obtained with 99mTc-pyro- tion of 67Ga-citrate into bone and bone marrow
phosphate. This phase was accompanied by (28) and is consistentwithother observalions
increasedsoft-tissueactivity in some ani- made earlier.
mals.
Six to 12 months after irradiation, delayed Bone Marrow
images showed decreased bone tracer uptake Nelp et a]. (29) have studied irradiated bone
corresponding to radiation-induced vascular marrow in the lower limbs of rabbits by using
224 ! Esserltiols of Nuclear Medicine Science
Figure 15.2.Sequential scans (BmTc-labeled poIyphosphate) in a patient with metastatic breast cancer.
first scan reveals the initial evidence of metastatic disease in the atlas, confirmed radiographically. After local
palliative irradiation, the lesion first shows increased uptake of [he lracer and then shows less marked uptake,
although by the time of this last scan in June 1973 the patient had demonstrated evidence of disseminated
metastatic disease.
one limbas a controland both 99mTc-labeled
sulfur colloid and S9FeCl, to evaluate differing
marrow components. A fractionated dose of
200-5000 rad was administered. With doses in
excess of 1000 rad, there was an acute drop in
erythropoietic activity, with maximal drop OC-
cumng 7 days after irradiation and with partial
recovery occurring in 2 weeks. This finding was
not paralleledbythe reticuloendothelial (RE)
component of bone marrow activity, a dissocia-'
tion similar to that described previously for the
liver. The RE activitydecreased more slowly
after 2 weeks, to parallel that of the erythropoi-
etic cells.Thereafter,theextractionefficiency
of both cell lines continued to fall for 2 months,
and [hen, depending on dose, varying degrees
of return to normalcy were observed. It may be
that recovery is due to stem cell repopuIation of
erythropoietic marrow in irradialed marrow.
Clinically, Knospe et al. (30) sludied the dis-
trihlltinn nf 52Fp-tmncfprrin in nntientshaving
The
received belween 4000 and 4400 rad to varying
fields in the treatment of lymphoma. Some de-
gree of marrow expansion,depending on the
volume of bone marrow irradiated, was noted 3
monthsaftertreatment.Suppression of irradi-
ated marrow activity, with incomplete recovery
1 year after such irradiation, was evidenl; such
recovery does occur, however (31).
Rubin and Scarantino (32)have reviewed the
subject of radiation-induced bone marrow
damage and reported on theirexperience.In
patients with lymphoma treated with between
4000 and 4500rad,the RE marrow activity
examined with 99L1'Tc-labeled sulfur colloid did
not recover in the 6-12 months after treatment.
Thereafter, there was a gradual return to approx-
imately 66% of normalactivityafter 2 or 3
years and to 75% of normal activity after 4 or 5
years. Bone marrow expansion took 1 year to
developaftertreatment. In other experiments,
Rubin and Scarantino(32) found some evidence
Altered Biodistriblrfiol?:Radiarionll~wasiveTherapies t 225
fur colloid) 6 months after irradiation of bone
marrow with 3000 rad.
Bell et al.(34)found that in patients with
testicular tumors, doses of 3000 rad in 3 weeks
caused a decrease in the skeletal uptake of both
I8F and ""Tc-labeled sulfurcolloid,without
there beingradiographic abnormalities in the
bone. The depression of activity in the RE sys-
tem tendedto be more persistent than that in
.* *
- bone. Thus marrow imaging does have limited
- I . application in evaluating hematopoiesis after ra-
1
diation treatment (35).
Although it has not been systematically in-
vestigated, we have noted the expected changes
from therapeutic irradiaLion in bone marrow im-
ages obtained with ["IIn]indium chloride (Fig.
15.3, A and B).
Thyroid Gland
Scintigraphic abnormalities of the thyroid
after irradiation of the gland have been reported
(36) but are due to nonpalpablenodules and
merely reflect the known incidence of radiation-
associated nodular thyroid disease.
Salivary Glands
The clinical manifestations of radiation sial-
adenitis, namely tenderness progressingto a dry
mouth, are well known. Salivaryglands that
have been irradiated show an often-intense up-
take of 67Ga-citrate ( 3 7 , 38); this finding may
persist for at Ieast 3 years (39).
In our experience, salivary glands subjecled
tither to external beam irradiation or to sodium
[1311]iodide givenin doses intended to be thera-
peutic €or thyroidcancer will showimpaired
uptake of [""Tclpertechnetate.
Figure 15.3. A [ ll'ln]indium chloride bone marrow Gallium Biodistribution and 'hmor
scan, posterior view, in a patient who received axil- Imaging
laryandmediastinalirradiationinthetreatment of
The effects of whole-body irradiation on the
lefl breast cancer. The sharply demarcated defective
uptake o€ the lracerinirradiated biodistributionandexcretion
parts is clearly of 67Ga-citrate
evident. havebeenstudied in rats andmice (40-42).
Fletcher et al. (40) irradiated rats with a whole-
to suggest that marrow repopulation derives body dose of 720 rad before giving injections of
fromlocallysiluatedundifferentiatedmes- %a-citrate.Theynotedreduced whole-body
enchymal cells. retention of the radiotracer but increased uptake
In a study of a smallnumber of children, in the bone in these rats compared with a control
Siddiqui et al. (33) found recovery of marrow group of ani~nals.It was suggested that irradia-
RE aclivity (as detected with 99mTc-labeIedSUI- tion interfered with the binding of 67Gato trans-
226 I Essentials ofNucIenr Medicine Science

portplasmaproteins. Similarexperiments wereported as a cause of 67Ga uptake and hence Delayed Consequences of Surgery and Foreign substances introduced into the body
carried out by Bradleyetal. (41) OR rats with "falsepositive"imagesin tumor diagnosis Prostheses at surgery may predictably cause local inflam-
Walker-256 cervicosarcomas. In addition to the(56). The effectsof surgery are not limited to those mation and, apart from the use of radionuclides
- noted previously,they observed that
findings related to local tissue damage only. E k m a n et 10 diagnose the complications of such pros-
therapeutic irradiation reduced the tumor uptake IATROGENIC TRAUMA al. (70) have reported 67Ga-ciirate uptake in the theses as those which replace joints, have been
of radiogallium. Bradley et al. also reported on stomach of patienls with postoperative gastritis, found to cause uptake of both phosphate deriva-
Biopsy and Open Surgery
evidence thal they thought might be explained and we have suspected a similar explanation for tivesand'j'Ga-citrate (71-76). Thus radi-
by the saturation of transferrin with iron avail- It is well recognized that surgical incisions, the samefinding in patients withnausea and ogaIIiumhasbeen found to localize in tissues
able as a result of marrow suppression by radia- before [hey are healed, cause a local uptake of a vomiting following chemotherapy. involved with starch-peritonitis (71, 72) as well
tion. Interestingly, Sephton et ai. (.43,44) have variety of tracers such as 99mTc-labeled phos-
found that the detectability of tumors by galljurn phates and 67Ga-citrate, which presumably re-
is enhanced by theintramuscularinjection of flects the local increase in the extravascular ex-
iron 3 hours following the intravenous injection tracelldar space as wellasincreasedblood
of 67Ga-citrate. supply (1, 57-59). Silberstein et al. (60) have
Results of clinical studies have compie- shown that i n postlarninectomy patients,
mented these observations by demonstrating the changesinradiotraceruptakedueto surgical
limitations of the use of Wa-cilrate in deter- trauma occur less frequentlywith 94mTc-diphos-
mining theresponse of lumors to therapeutic phonate than with 67Ga-citrate.
irradiation (45, 46). Kondoetal. (46) have Relativelytrivialinsults such as biopsy and
found that irradiation of esophageal tumors with injeclionsitesmayalsocauserecognizable
more than 2000 rad significantlyreduced lhe changeson a scanmadewithsuchagents
uptake of radiogallium. (61-63) (Fig. 15.4). The localization of 9 9 m T ~ -
In animalexperiments,similar results have MDP at, for example, sites of injection of iron
been reported for 203BgC1,with both radiation dextran (64, 65) may occur for some time fol-
. . .
and cyclophosphamide(47),although this tu- lowingthe injection and may involvea local
mor-seeking radiotracer has no1 come into gen- chemical reaction between the injectate and the
eralusebecause of the radiation dose to the radiopharmaceutical, as described by Van Ant-
kidneys (48). werp et ai. (64). Extravasated calcium gluconate
from atlempled intravenous injection is associ-
Spleen ated with soft-tissue localization of 67Ga-citrate 67Ga-cit.
Bolh iherapeutic irradiation of the spleen for (66).
Hodgkin'sdisease (49) andirradiationfrom Nevertheless, in a prospectivestudy Tyler
Thorotrast adrninislered long before has resulted and Powers (67) did not find evidence, on sub-
in functional hyposplenia or asplenia as diag- sequent bonescansmade with %"Tc-hydrox-
nosed by imaging with 99mTc-labeled sulfur col- ymelhylene disphosphonate, o€ reaction to bone
loid (50-53). marrow biopsies performed with Jam Shidi 11-
gaugeneedles.Similarly, Alazraki et al. (68)
Lymph Nodes have suggested, through extrapolation from ani-
In keeping with the effects of irradiation on mal data, that needling or drilling metaphyseal
RE cell activity documented previously, Eng et regions in chiIdren probably will not affect the
al. (54) have found that radiation compromises results of later bone scans. This information
the uptake of 99mTc-labeIedanlimony sulfur col- may be of particular importance in the clinical
loid by lymph nodes. setting where an abnormal bone scan performed
following needle aspiration to help in the diag-
Gastrointestinal Tract nosis of osteomyelitis may be (falsely) assumed
Irradiation, when combined with chemother- to be the result of aspiration trauma.
apeutic drugs, in parlicular with adriamycin, Abnormal findings in the skull on both brain
Figure 15.4. A 67Ga&trete scan obtained 48 hours after injection of the radiotracer. The patient had a splenic
has been reporled to cause an esophagitis (55). (with[99mTc]pertechnetate or BmTc-labeled abscessdiagnosed bythistechnique and accounting for the intcnseactivity in the left upper a b d o ~ n i ~ ~ a l
Indeed, other mucosalsurfaces may respond chelates) and bonescanswillbefoundlong q u a h n l . Note, however, the smaller foci of increased uptakc in the left iliac crest at a biopsy site and in the
similarly,and thispolymucositishasbeen re- after a craniotonly (69). lerl deltoid at il site of uncomplicated injection of the pain-relicving drug "Talwin."
 Altered BiodistributioH: Radiationllnvasive Therapies / 229
228 I EaselltialsoJNuclearMedicine Science

as in a capsularcontracturearound a breast
implant. Presumablysuch findingsreflect no
more than a chronic low-grade inflammatory
response (73). wmTc-pyrophosphateand its ana-
logs have been found adjacent to both breast and
cardiac valve prostheses (74, 75) as well as a
paraffin pack used in relation lo a thoracoplasty
affected limb (77). The finding is not different analogs labeled with 9 9 m Tin~ the myocardium
(76). Such reports will almost cerlainly prolif-
erate.
from those due to sympathetic denervation of (82).
whatever origin (78). Ege (79) hasdescribed
Theeffects of surgery neednot a h a y s be External Cardiac Massage
how surgery may impair lymph node visualiza-
proximate to the surgical site. We havenoted
tion in h e corresponding draining Iyrnph nodes, Rib trauma commonly accompanies this pro-
that retroperitoneal dissections may result in a
presumably by blockade rvilh surgical debris. cedure such that the fortunate survivor, if then
surgical sympathectomy, with resultant in-
subjected to a bone scan, demonstrates findings
creased uptake of radiotracer in the bones of the
thatare obviously iatrogenic although a small
Cardioversion price to pay for survival (Fig. 15.6).
Defibrillation has been found to result in in-
creased uptake of bone imaging agents in the Intubation
tissues of the chest wall at the site of application Tissues subjected to trauma by the passage of
of the electrode (80, 81) (Fig. 15.5), and direct anasogastrictubehave been found to show
current transthoracic countershock has likewise increased uptake of a wmTc-labeled phosphate
been reported to cause localization of phosphate derivative (83).

Figurc 15.6. A 99mTc-MDP bone scan in a patient who had received cardiac massage after an arrest. The
Figure 15.5. A wlllTc-pyrophosphatescan of the thorax in a palient who hadbeensubjectedtocardiac uptake at bilateral anterior riband sternal fractures, although thesewere not inilially detected radiographic:ally,
defibrillation. The supcrflcial and, hence, noncardiac locnlizalion of the abnormal uptake is clearly evident in is typical of this form of iatrogenic trauma.
the tangential view ( f o p righr). The uplake was in a defibrillation bum.
230 I Esseurials of NuclearMedicineScience
BLOODTRANSFUSION
Blood transfusion, inasmuch as it may cause
iron overload, has been found to influence the
stability of 99mTc-MDP and,to a lesser extent,
99mTc-pyrophosphate.The result is poor bone
visualizationandmarkedrenal uptake of the
4 9 m T which
~ , possibly reflects the formation of
such a chelate as 99mTc-labeIediron ascorbate
(84).
CHEMOPERFUSION
Chemoperfusion has been observed to cause
marked uptake of a bone scanning agent in the
perfused limb (85).
IMMUNOTHERAPY
Imlnunolherapy has been employed in the
"
treatment of cancers. We have noted that pa-
tients treated with Bacillus Cnlmelte-GLr6rin
(BCG) may develop a systemic granulomatosis
(86). In both patients and experimental animals,
this granulomatosis is associated with changes
in thebiodistribution of radiogallium LhaL are
particuiarly evident as abnormal lung uplake of
that tracer (87,88). Local sites of injection of an
immune stimulanl such as Carynebncleriunl
panurn havealsobeenreported to result in
uptake of radiogallium (63).
RENAL DIALYSIS
On the basis of a series of images made with
"Ga-ci~rate in patients on renaldialysis and
showing little liver uptake and marked uptake in
bone, we had suspected that dialysis might in-
terfere with the biodislribution of radiogallium
(I). Detailedstudies have not confirmedthis
(89, go), and the finding may haverelatedto
renal bone disease.
Transientabnormalities found on the brain
scans of patients on dialysis have been reported
(91).
DeGraaf et al. (92), in a study made to deter-
mine [he sensitivily of 99mTc-hydroxyethylidene
diphosphonate (HEDP) in detecling gastric cal-
cification complicating chronic renal failure,
found that the radiochemical interacted with sa-
line and the dialysate fluid to form free pertech-
nelale. This resulted in the predictable uptake of
the pertechnetate by stomach, thyroid, and sali-
vary glands (92).
INADVERTENTLYALTERED ROUTES
OF ADMINISTRATION OF
RADIOPHARMACEUTICALS
Occasionally, a radiotracer is injected intraar-
terially which may resuIt in an abnormal scinti-
graph (1, 93). The nature of theabnormality
will be influenced by [he physical form of the
tracer; e . g . , 99mTc-MAAwill be virtually en-
tirely extracted in the periphery, whereas 9 9 m T ~ -
labeledphosphatesmerelyshow unusualcon-
centrations in tissues to which they are delivered
in high concentrations.
An interstitial injection has recently been re-
ported (94) to result in lymph node visualization
presumably due to a volume effect, as the tracer
(BmTc-MDP) was not one that might have been
expected to be extracted by the cells in such a
IIUUG I
Radiotracers[hatare rapidlyoreffectively
extracted are more prone to provide bizarre ra-
djotracer biodislributions. An example resulting
from the injeclion of 99mTc-MAA intoa pulmo-
nary artery catheter has been reporled (95).
A lrivial example but one with considerable
practical impiicationsis the development of a
cerebrospinal fluid leak afler lumbar puncture
which can both result from and be imaged by
tracerstudies (96). Thisleakcanresultin
chronic anddistressing headaches (97) and is
readily treaied by a "blood patch" (98).
CONCLUSION
A variety of iatrogenicphysical and other
insults causing changes identifiableon radionu-
clide images are described. The nature of these
abnormalities and the profusion of isolated re-
ports concerning them may, at first, be intim-
idating. Most, if not all, of these abnormalities,
however, might be anticipated from an under-
standing of disease processes, from aknowl-
edge of the particular patient, and from insighl
into the mechanisms of radiopharmaceutical lo-
calization.Therefore,this review merely em-
phasizes the importanceof undersianding radio-
nuclide scans as an aspect of patient care and
not asabstractexercisesdivorcedfromthe
human beings with whom we work.
ACKNOWLEDGMENTS
Weareindebted to Dr. P. G. Heslip of the
University of Alberta Hospital, Edmonton, for
Alteyerl Biodistriburion: Rndiarioldlrwmive Thernpies
Figure 15.5; to Mr. Karl Liesner for preparing
the illustrations, andto Mrs. M. Laschowski
and Mrs. E. Dolina for typing the manuscript.
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J N d Med 20:1142-1149, 1979.
21. King M A , Weber DA, Casaretl GW, et al: A study o l
irradiated bone: 11. Changes in Tc-99m-pyrophosphate
bone Imaging. JNucl Med 2122-30, 1980.
22. Lind MG, Nathansoo A: qqmTc-DPaccumulationin
rabbit skull bones after T o gamma irradiation. Acra
Radiol (Tlzer) 16489-496, 1977.
23. Sorkin SI, Horii S C , Passalaqua A. et al: Decreased
activity on a bone scan rollowtng therapeutic radiation:
a source of possible error. C h Nucl Med 3 6 7 , 1978.
24. Cox PH: Abnormalities in skeletal uptake of RmTc
polyphosphatecomplexes in areas of boneassociated
withtissueswhichhavebeensubjected Lo radiation
therapy. Er J Rodiol47:851-856. 1974.
2 5 , Vieras F: RadiationInducedskeletalandsofttissue
bone scan changes. C h Nrtcl &fed 2:93-94, 1977.
26. Bekier A: Extraosseousaccumulation of PPmTc-ovo- ..
phosphate in soft tissue after radiation therapy. J Hfrcl
Med 19:225-226,1978.
27. Gillespie PI, Alexander JL, Edelstyn GA: Changes in
*'mSr concentrations in skeletal metastases in patients
respondins lo cydical combinationchemotherapy for
advanced breast cancer.J Nucl Med 16: 191- 193, 1975.
28. Nelson 3, Hayes RL, Edwards CL, el al: Distribution
of gallium in human tissues after intravenous adminis-
[ration. J N r d Med 13:92- 100. 1972.
29. Nelp WB. Gohil MN. Larson SM: Loris-tern ellecls of
local irradition of the marrow on erythron and rcd cell
function. Blood 36:617-622, 1970.
30. Knospe WH, Rapudu VM, Cardello M, et at: Bone
marrow scanning with %on (5'Fe): Regeneration and
exlension of marrow afterablativedoses of radi-
olherapy. Cmcer 37:1432-1442, 1976.
31. Steere HA, Lillicrap SC. Clink HM, et al: The recovery
of iron uptake in erythropoietic bone marrow following
large lieid radlotherapy. Br J Rodiol52:61-66, 1979.
32. Rubin P, Scarantino CW: The bone marrow organ: the
criticalstructureinradiation-drug interaclion. lrff J
Radial O~ICOI Biol Phys 4:3-23, 1978.
33.Siddiqui AR, Oseas RS, Wellman HN. el al: Evalua-
tion o l bone-marroN,scanning w t h technetium-99m
sulfurcolloid in pediatriconcology. J I V d Med
20379-386, 1979.
34. Bell EG, McAfee JG, Constable WC: Local radiation
damage [o bone and marrow demonslraled by radi-
oisotopicimaging.Radiology 921083- 1088. 1969.
35, DeGowin RL, Chaudhuri TK. Christie JH, et al: Mnr-
row scanning in evaluation o l hemopoiesis arter radi-
otherapy. Arch hrerrf Med 134:297-303, 1974.
36. Gonzalen-Villalpando C, Frohman LA, Bekerman C,
et al: Scintigraphicthyroidabnormalities alter rddin-
Lion. An11 brlern Med 4755-58, 1982.
37. Bckerman C.Hoffer PB: Salivary gland uptake ofT h -
citralciollowing radialiontherapy. J HucI Mer1
17:685-687,1976.
38. Lentle BC. hcckson F1. McCowan DG: Localization or
g a l h n - 6 7 citralc in salivary glands following radialion
Il~crapy.J Crw h s o c Radiol 2739-91, 1976.
39. Rose I: Increased salivary gland uplake of 67Ga-c~tratc
230 / Essenrinls of Nuclear Medicine Science
BLOOD TRANSFUSION INADVERTENTLY ALTERED
ROUTES
Blood transfusion, inasmuch as it may cause OF ADMINISTRATION OF
RADIOPHARMACEUTICALS
iron overload. has been found to influence the
stability of 99mTc-MDPand, to a lesser extent, Occasionally, a radiotracer is injected intraar-
99mTc-pyrophosphate.The result is poor bone terially which may result in an abnormal scinti-
visualization andmarked renal uptake of the graph (1, 93). The nature of theabnormality
~ , possibly reflects the formation of will be influenced by the physical form of the
9 9 m Twhich
such a chelate as wmTc-IabeIed iron ascorbate tracer; e.g., 99mTc-MAAwilibe virtuallyen-
(84). tirely extracted in the periphery, whereas 9 9 m T ~ -
labeled phosphates merelyshow unusualcon-
CHEMOPERFUSION centrations in tissues lo which they are delivered
in high concentrations.
Chemoperfusion has been observed to cause
marked uptake of a bone scanning agenl in the An interstitial injection has recently been re-
perfused limb ( 8 5 ) . ported (94) to result in lymph nodevisualization
presumably due to a volume effect, as the tracer
IMMUNOTHERAPY (94mTc-MDP)was not one that might have been
expected to be extracted by the cells in such a
Immunotherapy has been
employed in the nnrl~
LLVUL.
lrealrnent of cancers. We have noted thal pa-
Radiotracersthatare rapidly or effectively
tients treated with Bacillus Calmette-Grr6rin
extracted are more prone to provide bizarre ra-
(BCG) may develop a systemic granulornalosis
diotracer biodistribufions. An example resulting
(86). In both patients and experimental animals,
from the injection of 99mTc-MAAinto a pulmo-
this granulomatosis is associatedwith changes
nary artery catheter has been reported (95).
in thebiodistribution of radiogallium that are
A trivial example but one with considerable
particularly evident as abnormal lung uptake of
praclical implicalions is the development of a
that tracer (87, 88). Local sites of injection of an cerebrospinalfluid leakafterlumbarpuncture
immune stimulant such as Colynebacrerium
which can both result from and be imaged by
pnrvml havealsobeenreportedto resull in
tracerstudies (96). Thisleakcanresultin
uptake of radiogallium (63).
chronic and distressingheadaches (97) and is
readily treated by a "blood patch" (9s).
RENALDIALYSIS
On lhe basis of a series of images made wilh CONCLUSION
67Ga-citrate in patients on renal dialysisand
A variety of iatrogenicphysical and other
showing liltle liver uptake and marked uptake in insults causing changes identifiable on radionu-
bone, we had suspected that dialysis might in- clide images are described. The nature of these
terfere with the biodistribution of radiogallium abnormalities and (he profusion of isolated re-
(1). Detailedsludies have not confirmedthis ports concerning them may, at first, be intim-
(89, 90), and the finding may have relatedto idating. Most, if not all, of these abnormalities,
renal bone disease. however, might be anticipated from anunder-
Transientabnormalities found onthe brain standing of disease processes, from aknowl-
scans of patients on dialysis have been reported edge of the particular patient, and from insight
1911. into the mechanisms of radiopharmaceutical lo-
DeGraaf et al. (92), in a study made to deter- calization.Therefore,this reviewmerely em-
mine the sensilivity of 99mTc-hydroxyethplidene phasizes the importance of understanding radio-
diphosphonate (HEDP) in detecting gastric cal- nuclide scans as an aspect of patient care and
cification complicating chronic renal failure, not as abslractexercisesdivorcedfromthe
found that the radiochemical interacted with sa- human beings with whom we work.
line and the dialysate fluid to form free pertech-
ACKNOWLEDGMENTS
netate. This resuhed in the predictable uptake of
the pertechnelale by slo~nach, thyroid,and sali- We are indebted to Dr. P. G. Heslip of the
vary glands (92). University of Alberta Hospital, Edmonton, for
AlleredBiorlistribution:RadiorionlinvasiveTherapies
Figure 15.5, to Mr. Karl Liesner for preparing
theillustrations, and lo Mrs. M . Laschowski
and Mrs. E. Dolina for typing the manuscript.
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16
Norma2 Clinical Variation in Anatomic
Structure and Physiologic Function and Its
Eflect on Radiopharmaceutical Biodistribution
J0h.n J. Coupal and E,Edmund Kim
The diagnos;ician nlust be familiar. with normal variation
if Ire
is not to give his patients diseases which they do not have.
Biologicalvariationinhumansimplies a ward to thelevel of theumbilicus or below,
range of normal variants in slmcture and func-
tion. Thus, alimited s p e c m m of organ ana-
tomicconfigurations is denoted as “normal”
and consonant withhealth or, at least, with
nondisease. Likewise, a limited range of phys-
iologic norms(e.g., flow rate, excretoryand
secretory routes) characterizes organ or system
function. Information on the most common nor-
malvariants in anatomic structureandphys-
iologic function that are evident in nuclzar med-
icine imagingstudiesareprovidedinthis
chapter.
LIVER AND SPLEEN
The liver is more proneto normal variation in
structure than is any other organ in the human
body (Fig.16.1).Thisoccurs, in part. due to
the large size of the liver (the largest organ in
thebody), its location(hence,proximity to
many other organs), its pliable nature, and its
ability lo regenerate itself (Fig. 16.2). Liver size
usually is directly related to body surface area
(2). Many anatomic characteristics of the liver
and juxtahepalic structures can lead to a false
positiveradiocolloidliver
listed in Table 16.1.
scan, and these are
Riedel’s lobe is a downward tongue-like ex-
tension of the righi lobe of liver along the right
end of thc inferior margin (3). It extends down-
234
E j j h of Clinicd V‘rjnrion OII Biodistribrrrion I 235
n
John Caffey (I)
possibly reaching the iliac crest. Although it is
found more often in women than in men, it can “You’re nkhr. hisliver& rhapedlihe Ihrfiffhgreerr a1 RlrrrIinR Trce.”
occur in infants and children. Riedel’s lobe was
seen in 4% of 66 subjects whose hepatic scans Figure 16.1. Reproduced courlesy of BilI Hoest and Porade magazine. 0 1983.
were normal (4) and in 3.3% of another group of
patients (86 of 2604; 60 females, 26 males) who
had undergone hepatic imaging (5).
Normal spleen weight in a 20-year-old man is
146 2 37 (mean 2 SD) gm (8). Spleen size in
men decreases progressively until age 29 and
then remains essentially constant until age 59,
from which point i t again progressively de-
clines.Normalspleen weight in a 20-yea-old
woman is 120 % 30 gm; spleen size in women
follows a course that parallels that of the man.
The configuration and the position of the nor-
malspleen are extremelyvariable.Notching,
septation,and oneormoreaccessoryspleens
also can be found. Notching occurs superiorly
(80-loo%), inferiorly (30-60%), andante-
riorly (3-15%) but rarely posteriorly or on the
diaphragmatic surface (9). Notching, in and of
itself, does not result in change of the normal
orientation of the splenic hilus which is directed
inframedially. Simpson et al. (10)reported on a
man whose 99Tc-labeled sulfur colloid (wmTc- ANT L LAT
SC) scan revealed a defect in rhe upper pole of Figure 16.2. Ankrior (ANT)and left latcral ( L L )slatjc images of liver and ipleen madewith Bmfc-labeled
the spleen (10). Suspicion of an “upside-down” sulfur colloid show unusually prominent left Iobc and abnormal focal activily (rrrrows) in the left lower lung
spleen led to performance of a combined radio- poskriorly. Liver hunction lests and chest radiographs were n o m d
236 i Essentids of Nwlear Medicine Science Effecr of ClinicalVnriation on Biodismribvtion i 237

Table 16.1. readily seen in the brain scan made of a young Table 16.2. The quality of the 99mTc-phosphateor phos-
Anatomic Causes of False Positive Radiocolloid child. They may not beseen in skullroent- Anatomic or Physiologic Causes of False Positive phonate bone scan is partially dependent on the
Liver Scan* genograms made of the same child. The normal Brain Scan* age of the patient:the older the patient, the
torcular angle formed by the transverse sinuses lower the quality of the scan (1 8-20).
Intrinsic anatomical variatior,
Enlargedhepaticfossa for porta hepatis, hepatic
and seen onthe posteriorviewis 162 * 8".
Coronal or lambdoidal suture
Middle meningeal veins anlerior to the sella
Accumulation of Done-seeking radiophanna-
vein,inferiorvenacava,ligamentumteres Holmes and Golle (12) havereportedthat the Asymmetry in [he lateralsinuses(therightusually ceuticals innormalosseous or extraosseous
hepatis, and gallbladder transverse sinuses in normal patients were sym- shows greater radioactivity than does the left) structures may show as false positive scans
Thin lefl hepalic lobe metrical in only 32 of 212 patients (15%). The Draining surface veins (Table 16.4). For example, hepatobiliary excre-
Large left hepatic lobe right was larger than the left in 56%, and the Choroid plexus if perchlorate is no1 given tion of bone-imaging radiopharmaceutical may
Riedel's lobe of liver SaIivary glands
left was larger than the right in 30%. occur as an alternate route to urinary excretion
Liebermeister's grooves on liver Large occipital sinus
Juxtahepatic structures attenuating liver radioactivity Normal separation of sutures or the presence (Fig. 16.3).
Prominent rib cage of an open fontanelle in an infant does not yield * Adapted from Reference 16. Radioactivity concentration in the anterior
Pendulous breast an abnormal brain image (13). lower neckon a 99mTc-phosphatebone scan
Rightkidney Noninvasiveregionalcerebral blood flow BONE sometimes is attributedto pertechnetate from
Lordotic spine
Prominen1 right psoas muscle
(nrCBF) was measured in 15 normal humans by Each of 150 female patients with breast carci- the radiopharmaceutical in the thyroid gland. In
Dilaled or displaced stomach Meyer et al. with use of 133Xe(14). The subjects noma receiveda whole-bodybonescan with reality, such uptake can be due to the presence
included 9 men and 6 women who rangedin age 99mTc-etidronate(HEDP) (17). The bone scan of radiopharmaceutical in thyroidcartilage
* Adapted from References 3-7. from 23 LO 62 years (mean, 36 years). Flow in was negative for all patients,and this group (22-23) or cricoid cartilage (23-24). A deter-
graymatter was 85.4 mll100 gm braidmin at comprisedthecontrol. A region of inlerest mination of the actual site requires consideration
age23 anddeclinedlinearly thereafter at the around the second lumbar vertebra (bone) and of shape of uptake, location of uptake (revealed
nuclide imaging study of the stomach (oral so- rate of 0.53 mlllO0 gm brainlminlyr of age (r = in an area just below the kidney and clear of the by comparison of scan with roentgenogram of
dium[""'Tc]pertechnetate) andspleen(intra- -0.59, p < ,051. Flow in white matter al age spine andpelvis (soft tissue) were isolatedon the neck), and presenceof ancillary uptake char-
venous y9n1Tc-SC).It was thereby shown that the 23years was approximately 19 mlllOO gm the CRT display of the lun~bosacral spine, The acteristic of pertechnelatebiodistribution.The
spleen was invertedand that theV-shaped brainlminand did not change with advancing ratio of bone to soft tissue (BIST) was computed reason for variablility in incidence of carlilagi-
splenic defect was filled in by q9mTc-pertechne- age ( r = -0.42, p 5. .OS). The relative weigh1 with use of relative counts in the respective nous radioactivity is unclear.
tate* located in the horizontal fundus of the of gray matter was 46.3% at age 23 years, and regions of interest.TheaverageBIST ratios
stomach. progressively declined at the rate of 0.32Wyr THYROID
partitioned by age of patients are shown in Table
thereafter (r = -0.62, p < .02). Cerebral 16.3. The normal thyroid gland has a butterfly ap-
CENTRAL NERVOUS SYSTEM vascular resistance increased progressively after pearance on a radionuclide scan.Sometimes,
When theratios from the age decades were
The normal brain scan in older children and age 23 years, although none of the subjects (a)
compared, the only statistically significant dif- the isthmus connecting thetwo lobes may not
preadolescents does not differmarkedlyfrom was hypertensive, (b) had evidence of arterio- ferences were between the 51-60-yeargroup be seen. A pyramidal lobe exlending from the
[he norn~albrain scan in adults (1 I). In infants sclerosis, or (c)had any arteriosclerosis risk and each of the 61-70- andthe 71-SO-year medial aspect of one of the upper poles is seen
and very young children, however, the skull is faclors. This study shows that gray matter blood groups (p < .01). The authors stale that a lower occasionally.Infrequently,onelobemay be
thin with few osseousirregularities,and the flow and the weight of gray matler progressively BlST ratio in patients over 60 years of age is substantially larger than the other and may dom-
scan has a delicate appearance. The small di- decline with advancing age. Such observations understandable in light of reduced bone mass inate thescanpattern(25). Rarely, anentire
mensions and relatively low mass of y-photon- agree weil with the progressive loss of cortical and of histologic evidence of reduced osteo- thyroid lobe may be missing as a m u l l of agen-
attenuating tissue in the infant's skull make neurones noted in normal individuals of advanc- blastic activity as one grows older.
"shinethrough" of distantorcontralateral ing age who came to autopsy (15). A venous
structures more pronounced, especially when a reflux of radioactivity is oftenelicitedbythe Table 16.4.
Table 16.3.
rectilinear scanner is used. Since the infant skull Valsalva maneuver. Anatomic and Physiologic Causes of False Positive
Ratio of Bonc to Soft Tissue by Age of Patient* BoneScan*
mayhave a triangularappearance in vertex Certainanatomic or physioIogicvariants
view, difficulties in diagnosis may arise.A thick cause false posilive brain scans. Examples of Ratio ai Bone to So€[ Tissue
skull may yield symmetricalwidening of the these variants are shown in Table 16.2. No. or epiphysis
Growing apophysis and
Age Range (yr) Palienrs Median Observed RaoW Cartilage
uptake
marginal rim of radioactivity. ShouIder uptake increased on side of dominant
The torcular herophili (evolved from the an- PANCREAS 30-40 I5 3.90 2.08-5.40 handedncss
teriorduralplexus) and [he lateral sinuses are Cerlain nonpathologic structures cause 41 -50 51 4.10 2.70-5.80 Mulliple
slernal
ossification
centers
51 -60 43 4.30 3.20-6.00 uptake
Breast
€alsely abnormalpancreaticscans (16). These 61 -70 34 3.90 2.40-5.90 Deltoid
lubcrosjty .
* AlthoughI"n~Tc]pertechnelate is preferred by are (a)thinning of theareawherepancreas 71-80 7 3.70 Hyperostosis
3.10-4.00
frontalis
IUPAC, wml'c-pertechnetate is standard, and both are passes over [he spine and (b) obscuring of the
used throughout this chapter. pancreas by overlying organs. * Adaptcd from Rcference 17. + Adapted
Keferences
from21-24.
 Eflecr of CZiuicul Vnriarion OII Biodismribution f 239
ANT
Figure 16.4. Anterior (ANT) and left lateral ( L LAT) views of the neck made with 99mTc-pertechnetateshow a
single lobe of the thyroid in the midline of middle neck.
probably would be normal.If there is any exten-
sion of radioactivity on the 99mTcO;image be-
low or above the thyroid gland (especially along
the left lobe),oneshouldsuspect tracer ac-
cumulation in the esophagus (28). Verification
of this phenomenon could be achieved by ante-
rior scintigraphyperformedwhile thepatient
swallows a dilute pertechnetate solution (Figs.
16.5 and 16.6).
Analogous to this situation, three false posi-
tive 13'1 total-body scans have been reported
(29). Radioiodide in salivary secretions within
the esophagus has the potential to indicate meta-
staticdisease.Havingthe patientdrinkwater
removes the esophageal radioactivity.
Figure 16.3. Anterior ( A N T ) and posterior (POST) whole-body bone images with99mTc-pyrophosphate show
unusual activities in the liver and probably the large bowel. Note that there is no activity in the stomach but BREAST
significant activity in the genital organ. There was no history of previous radionuclide study. No liver or Breast radioactivity on images resulls from
intestinal disease was found. concentration of radionuclides by mammary
tissue.Thisphenomenon is most pronounced
during lactation. There is considerable variation
esis; agenesis of theleft lobe is morecommon. vary secretion of pertechnetate may yieldan between women, .however, in excretion of a ra-
A sublingual or single lobe in the midline canarlifactthat could suggest a substernal thyroid. dionuclide in the milk. This has been shown for
be idenlified occasionally(Fig. 16.4). In contrast,
since
salivary
secretion of iodide w'nTc-pertechnetate (30, 31) and [67Gajgallium
Since 99nlTcO; is taken up andsecretedbyoccurs to a lesserdegree than doessalivary citrate (32, 33).
the salivary glands, esophageal retention ofsali- secretion of pertechnetate (26-27), an I3lI scan
L LAT
Absolute levels of radioactivity in milk and
resultant breast radioactivity on image vary
from person to person,depending on (a) the
efficiency of the concentrating mechanism for
the radionuclide (which is possibly under hor-
monal influence): (b) the stageof lactation (i.e.,
during theperinatal period or a laterperiod),
and (c) the resulting volume of milk flow.
For example, in two lactating women receiv-
ing sodium[99mTcjpertechnetate intravenously
for thyroid imaging, the concentration of WmTc
in milk reached a peak at 2-3 hours postinjec-
Lion and thereafter displayed biologic half-lives
of 7.6 and 9.1 hours,respectively (34). The
biologic half-life for 67Ga in human milk is
reported to be 9 days (33). Therefore, in lactat-
ing women receiving [67Ga]gallium citrate it is
especially prudent to periodicaIly withdraw and
discardmilk from the breasts by breast pump
before total-body imaging.
KIDNEY
In the human fetus, the number of nephrons
increases steadily from the sixth to thirty-sixth
week of gestation. From 36 weeks until 12 years
240 I Esserzfials of Nzrclenr MedicineScicrrce

of age, growth of the kidney resuits from matu-
ration of existing nephrons (35). By 22 weeks
gestation,all renal glomeruliarenearto or
adjoiningthe medulla (36). As timeelapses,
development of glomeruli procedes toward the
capsule. During development, there are always
more mature nephrons near the medulla than in
the outer cortex.
Functionally, thereisdecreased renal blood
flow in the perinatal kidney. This decrease may
be associatedwithlower arterial pressures as
well as with enhanced renal vascular resistance.
Measurement of effective renal plasma flow
(ERPF) with use ofp-aminohippuric acid (PAH)
reveals normal values of2O-40% of those found
in the adult. The resulting filtration fraction is
about 0.4 in the neonate (37). Other investiga- theapex of themedullarypyramids.Since queslioned whether such altered blood flow
tors report thal extraction of PAH during pas- bloodpassesthroughtheglomerulibefore would affectparameters of standardradionu-
sage through the kidneys is 60% and 91%, re- reachingthe medulla, renal radiopharmaceuti- clide renal function tests.
speclively, in infants 3 months old and in older cals must reach the medulla after transversing A renalnormalvariantwillaccumulate
children (38). The revealed filtration fraction of the cortex. Such [ransit pattern is altered in the 99n1Tc-gluceptate after a shortvascularphase
0.23 remains slightly higherthan that in the neonate due to the greater medullary blood flow (Fig. 16.7). A true masswilldemonstrate no
adult.Although maximal tubular transport of during that stage of life. Bell et al. (39) have radioactivityandwillbeconsidered a “cold
PAH is much lower in the newborn infant than
in [he adult, adult values are reached by approx-
imately 7.5 monlhs of age (39).
In the older child and adult, the renal cortex
(representing 70% of renal mass) receives
75-95% of total renal blood flow (39). Medul-
lary blood flow is one-third to one-sixth that of
cortical blood flow and diminishes progres-
sively from thejuxtarnedullary region toward

Figure 16.5. Anterior image o€99mTc thyroid scan ( A ) with thc patient in supine position shows a focal oval-
shaped activity simulating a hot nodule just below the isthmus ( o p d arrow). Subsequent ‘311 thyroid scan ( E )
fails lo show any abnormaIity. Anterior neck image(C) o€ the palient aftcr swallowing some Cream of Wheat
cerealmixedwithmmTc-pertechnetate shows focal activity retained in the esophageal scgmenl. Repeated Figure 16.6. Oblique (ieft) and frontal (righr) views of the barjum swallow for the same patient as in Figure
SmTc thyroidscan (D) with the patient in the uprightposition shows less activi!y accumulatedinthe 16.5 show slight exirinsic indentation of the esophageal segrncnt duc to an anomalous aortic arch. No evidence
esophagcal scgment (ope11 arrow). of Zenker’s diverticulum is noted.

Figure 16.7. Poslerior stalic renal image made with 99mTc-glucoheptonate (gluceplate)(Tc-GH)shows local
areas of relatively increased activities in the upper portion of both kidneys. Mass lesions without obs(ructive
uropathy were suggested. on intravenous pyelogram, but a renal sonogram was negative.
area.” With use of 99n‘Tc-gluceptatescintigra-
phy,a true normalvariant (true negative)was
found in 17 of 40 patientswithexcretory
urographic findings indicaiing a possible mass
lesion and was confirmed with use of another
modality (surgery,autopsy, orotherimaging
procedure) (40). A prominent column of Bertini
was one of thesetrue negative scintigraphic
studies. Of the 4 false positives (comprising
10% of the group), 2 were interpreted with sub-
optimal techniques (1in which a scar defect was
misinterpreted as a possible mass). In the third,
there was merelybilalerallydiminishedpe-
ripelvic radioactivity. In the fourth, reduced
tracer radioactivity in the lower pole was associ-
ated only with a separate (accessory) lower pole
renal artery on arleriography. Peripelvic lesions
are difficull to evaluate by scintigraphy because
of the normal defects produced by renal hilar fat
and other hilar structures. Computed tomogra-
phy is recommended for lesion detectionin that
area. With peripheralparenchymal bulges and
the more central “masses” that distort the cal-
yces and could be either true masses or promi-
nent columns of Bertini,scintigraphy is best.
Horseshoe kidney and crossed renal ectopia
are variants seen fairly often. Kidneys in aber-
rant locations such as the pelvis arereadily seen
on renal scintigrams.Congenitalabsence of a
kidney is a rare condition. A uniformly small
renal artery suggests a congenital s n d l kidney.
Raoelal.(41) reported that with use of
9~mTc-dimercap~osuccina~e, a false positive im-
age with the patient in the prone position was
seen clue to anterior displacement of the upper
pole of the left kidney. The abnormality can be
Effeci of Clinicnl Variufion on Biodistribution / 243
avoided by routinely obtaining all renal images LUNG
with the patient in the supine position and the Lung radioactivity seen on99mTc-Iabeledsul-
detector behind the patient I
fur colloid liver and spleen scansin children has
ADRENAL GLAND been reported by Winter et al. (44). These au-
thors perfonned 68 Iiver and spleen scans on 64
In approximatelytwo thirds of a group of children (36 males, 28 females) aged 4 days to
normal subjects receiving NP-59, the radioac- 14 years (mean, 5.5 years). Faint radioactivity
tivity of the right adrenal gland appears greater concentration was seen on scans of the lungs of
than that of the Ieft adrenal gland on the pos- 16 of the 36 children (8 males and 8 females)
terior view. This difference is probably associ- found to be normal, for a 44% incidence; il was
ated with a slightly posterior right adrenal gland not seen on scans of 20 of the 36 children (13
and superimposed radioactivity of the liver due malesand 7 females).Lung radioactivitywas
to higher right adrenal gland. A variation of up seenin 16 of theremaining 28 children (8
to 43% was seen in the percent uptakes between males, X females) (57%). Radioactivity locali-
the right and theleft adrenal gland, respectively. zation in thelungs wasnot seen in a normal
HEART child older than 11 years of age. No confirmed
mechanismaccountingforsuchlungradioac-
Innormalsubjects,anabnormality of
tivityisknown.According to Winter et al.,
[201Tljthallous chloride distributionat the apex
therefore,visible radioactivity in thelungs of
of theheart may be associatedwithnormal
childrenduringliverandspleenscanning
muscle thinning, not an abnormality of myocar-
should not be considered abnormal.
dial perfusion. The diaphragm has been shown
Holland el al. (45) evaluatedregional dis-
toattenuate photons originating fromthe in-
tribution of pulmonary ventilation and perfusion
ferior myocardial segment when thepatient is in
with 133Xein 6 normal men aged 65-75. Blood
lhe supine position for the left lateral view, with
flow per unit of lung volume in the upper lung
a resultant apparent defect (42).
zone was increased in older subjects compared
99mTc-pyrophosphate scintigraphy for detect-
with that in younger subjects. Overall distribu-
ing myocardial infarction is a very sensitive but
tion of perfusion increased from the apex to the
not a highly specific procedure. Fetz et al. (43)
base of the lung. Distribution of ventilation de-
reported on the relative incidence of positive
pended critically on the lung volume maintained
scintigraphic results in the absence of acute cor-
during the study. In tests performed in the rest-
onaryartery-mediatedmyocardialnecrosis.
ingtidalvoIumerange,ventilationwasdis-
This incidence is shown in Table 16.5.
tributed primarily to theupperzones of the
lung, whereas during avital capacity inspira-
tion,thenormaldistribution of ventilation
Table 16.5,
favored the lom8er zones.Thateffect of lung
Anatomic and Physiologic Causes of Wlse Positive volume is attributedto airwayclosure in the
BmTc-Pyrophosphale Mpcardial Images
lower zonesoccurring at relativelyhigh lung
volumes in their elderly subjects. Such airway
Common
Persistent apparent blood pool radioactivity closure may be due to the combined effect of
RadioactivityadherencetovesselendotheIium loss of elastic recoil and a decreased resistance
Less common
to airway collapse associated with normal
Dystrophic cardiac caicificalion
Valvular aging.
Coronaryartery Lung perfusion defects can be encountered in
Pericardial a “normal” population.Tetalman et al. (46)
Left ventricular dyssynergy reported that 10 of 61 clinically asymplomalic
Normal breast tissue adultswithnormal chestroentgenogramsand
Rare
._ cartilage
Calcified
costal with no history of pulmonary disease exhibited
.. some type ofperfusion defect after receiving
1~
r -~-
244 I Esssenriais of NuclearMedicineScience

Table 16.6. esses.

Repeated
imaging
procedures of this type
~~~~~l variantcauses hlse positive L~~~
Perfusion revealed
Scan'
ably
right
in a13-year-oldgirlwith cysticfibrosis invari-
lower quadrant radioactivity
R
in [he absence of any abdominal or Delvic ab-
Obesity normality (52). Marked I In uptake in the lung
Large breasts
Deformed chest cage was seen and was believed to represent leuko-
Arm-scapula internosition cytes in pooled secretions within bronchiectatic
~ z y g o iobe
s areas. (A similar finding in a
patient of ours is
shown in Figure 16.8.) Since sputum and stool
samples revealed significant "'In radioactivity,
"mTc-labeledhumanalbuminmicrospheres. it was concluded that the abdominal activity was
Six of the 10 subjects exhibited subtle perfusion apparently due to swallowed sputum containing
defects on the anterior view only: 5 with defect radiolabeled leukocytes.
in the right subapical region and 1 with defect in TM~O anatomicvarianlscansimulate a
the left. Such ill-defined minor defects are con- Meckel's diverticulum duringevaluationwith
sidered to be of no clinical significance and to 99mTc-pertechnetate.First, a ureteral or duod-
constitute normal variants. They should not be enaldiverticulumcan holdradioactivity in a
confused with embolic disease.Although the "pocket." Second, an extrarenal pelvis on the
cause of such subtle defects is unknown, they rightkidneycan b e mistakenfor aMeckel's
may represenlminorsegmentalperfusion de- diverticulum.Theuse of lateralviews during
fects. the imaging study can elucidate such potentially
Onperfusion lung images, 1he posterior im- false positive results.
Figure 16.8. Anterior image of chest and upper abdomen at 48 hours following the injection of 1"In-Iabeled
age may reveal decreased perfusion at both cos- A bone-imaging radiopharmaceutical showed autologousleukocytes shows signifcan1 activities retained in both lungs. Cheslradiographs were normal.
tophrenic angles (i.e., "rounded" costophrenic marked uptake in the region of the head of the
angles). This is a normal variant caused by hy- penis (53). The degree and pattern of activity
povenrilalionand is seen most often.in obese suggested that long-standingphimosis andre- [67Ga]gallium citrate rarely may be secreled REFERENCES
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IS. Hosain P: Technelium-99111 labelledpyrophosphate:a
slmple and reproducible bone scanningagent. B r J
Radio1 46724-728, 1973.
19. Wilson MA: The effect or age on the quality of bone
scans using techne1ium-99m pyrophosphate. Radiology
139:703-705, 1981.
20. Coupal IJ, DomstadPA,DeLand FH: Influence of
patient age upon Tc-99m-oxidronate (Tc-HMDP) bone
image (abstract). Clirl A ' d Med 6:P158,1981.
21. Alazraki N: Boneimaging by radionuclide technique.
In Resnlck D. Niwaya~na G: Diugnosis o/ Bore and
Jurul Disorders with Ewphasis O I I Arliczrlar A b ~ o r -
tndities. Philadclphia, WB Saunders, 1981, vol 1, pp
639-678
22. Silberslcin EB, Francis MD. Tofe AJ,et al: Distribu-
tion of 991nTc-Sn diphosphonate and free 99mTc-per-
rechnetate in selected soft and hard tissues. J Nfrcl >Wed
16:58-61, 1975.
23.Oppenheim BE. Cantez S: What causes lowerneck
uptake in bone scans? Radiology 124:749-752, 1977.
24. Heck LL: Extra-osseous lwalization of phosphate bone
agents. Semin N I Med ~ 1031 1-313, 1980.
25. DeLand FH: Wagner HN Jr: Atlas of Nuclear Me&
cine, VOI 3: Rericfrloermd~tlfeliul Sysfern. Liver. Spleen
U J I Thyroid.
~ Philadelphia, W B Saunders,1972,pp
246-247.
26. Lunia S . Chodos RB, Heravi M , et a1 False-positive
pertechnetate thyroid scintigram. Clin N d Med 3:48.
1978,
27. Rajgum HL, Poolose KP, Reba RC: Esophageal tracer
retentionsimulatingsubslernalgoiler(lettertothe
editor). J N'rrcl M e d l8:404, 1977.
28. Wells LD, Bcmicr DR: Radionrrclide Imaging Arri-
41crs. Chicago, Ycar Book Medical Publishers, 1980, p
100.
Effecr of Clinical Variarion otj Biodisrribrrriorr / 247
29. Tyson J W , Wilkinson RH Jr, Witherspoon LR, et a ] : ders, 1970, pp 34-35. labeled leukocyte scan in cystic fibrosis.Clin NuclMed
False-positive 1311 total-bodyscans.Caserepotl. J 48. Felson B: The lobes and interlobar pleura: fundamental 4:291-293,1979.
Nucl Med 15:1052-1053, 1974. roentgen considerattons. Am J Med Sci 230572-584, 53. Glassman A B , Selby JB: Another bone Imaging agent
30. Rumble WF, Aamodt RL, Jones AE. et al: Accidental 1555. false-positive:phimosis. Clin Nucl Med 5 3 4 . 1980.
ingestion of RmTc inbreast milkby a 10-week-old 49. Pendley WO: The azygos lobe inphotofluorography. 54. Rao BK, LiebermanLhl:Bilelayering: a causefor
child. Case report. J Nrrcl M e d 19933-915, 1578. U S N m d MedBalI 46:1920-1927, 1946. false-positivecholescintiscans. AJR 134:1251-1253,
31. Vagenakis AG, Abreau CMI Braverman LE: Duration 50. Anson BJ, Siekert RG, Richmond E, et al: The ac- 1980.
of radioactivity in lhe milk of a nursing mother follow- cessorypulmonarylobe of the azygosvein. Q Bull 55. Wahner HW, Brown ML, DicksonER:Galliumac-
ing %Tc administration. J NKCI Med 12:188,1971. Norrhwesrern Chi!, Med School 24:285-290,1950. cumulalion in the stomach: a false-positive scan sug-
32. Larson SM, Schall G L Gallium-67concentration in 51. Polga JP. Drum DE: Abnormal perfusion and ventila- geslingabscess,(lettertotheeditor). J Nucl Med
human breast milk. M M A 218:257, 1971. tion scintigrams in patients with azygos fissures. Case 20577-578. 1979.
33. Tobin RE, Schneider PB: Uptake of 67Ga in the lactal- report. I N d Med 13:633-636, 1972. 56. Lutzker LG: Sequestrational inspiration. J N I Med ~
ing breast and its pcrsislence in milk. Case report. J 52. Crass JR, L'Heureux P, Loken M: False-positive "lln- I7:944,1976.
Nucl Med 17:1055-1056, 1976.
34. Ogunleye CTT: Assessment of radiation dose ro infants
from breast milk following the administrationof P9rnTc-
pertechnetate to nursingmothers. HeaIIh P h y s
45149-151. 1983.
35. MacDonald MS,Emery JL: The lateintrauterine and
postnataldevelopment of humanrenal glomeruli. J
Anar 93331-311, 1959.
36. Potter E L Development of the humanglomerulus.
Arch Pathol 80:241-255, 1965.
37.West IR, Smith HW. Chasis H: Glomerularfiltration
rate, dfecrive renal blood flow, and maximal lubular
excreLory capacityininrancy. J Pediutr 3210-18,
1948.
38. Calcagno PL, Rubin MI: Renalextraction of para-
amino-hippurate in infanls and children. J Clill Irzvesr
42:1632-1639, 1963.
39. Bell EG, McAfee JG, Subramanian G: Radiopharma-
ceuticals in pediatrics. In James AE Jr. Wagner HN Jr,
Cooke RE (eds): Pediarric NuclearMedicine. Phila-
delphia, WB Saunders, 1974, pp 84-94.
40. Older RA. Korobkin M. Workman J, et al: Accuracy of
radionuclidelmagrngindistinguishing renalmasses
from normal variants. Rndiology 136:443-448, 1980.
41.Rao GM, Nagesh KG, Gumpraksh GH: Position-re-
latedfalse-positiverenalimaging. C h Nucl Med
5:318-319,1980.
42. Botvinick EH, Dunn RF, Hattner RS, et a1 A consid-
eration of faclors affecting the diagnostic accuracy of
thallium-201 myocardial perfusion scintigraphy detect-
ingcoronaryarterydisease. Semin N r d Med
10:157-167,1980.
43.Fetz RC, Stadalnik RC, Matin P: Mymardial"false
positive" 99mTc-pyrophosphate scintigrams. Semin
Nucl Med 1154-65, 1981.
44. Winter PF, Per1 U,Johnson PM: Lung uptake of colloid
during liver-spleen scanning: a normal finding In chil-
drcn. Nfrklearmedizin 15:294-296,1976.
45. Holland 1. Milic-Emili J, Macklem P r , et al: Regional
distribution of pulmonary ventilation and perfusion in
elderly subjects. J Clin Ilzvesr 4 7 3 - 9 2 , 1968.
16. Tetalman MR, Hoffer PB, Heck LL. et al:Perfusion
lungscan i n nornlalvolunteers. Rodiologg
106593-594, 1973.
47. DeLand M, Wagner H N Jr: Allas of Ntrclear Mcdi-
the, vol 2: I m t g ntJ Hean. Phihdelphia, WB Saun-

17
Unusual or Unanticipated Alterdons in the
Biodistribution of Radiuphurmuceuticuls as a
Result of Pathologic Mechanisms
E. Edmund Kiln and John J, Coupal
RADIOPHARMACEUTICALS FOR ing wilh 99mTc-pyrophosphateshowed increased
CENTRAL NERVOUS SYSTEM activity inthesamearea in one patienl and
IMAGING decreased activity in theother (4). Metastatic
Radionuclide Brain Imaging intracranial neuroblastoma was detected in a
child undergoing bone scintigraphy with 9 9 m T ~ -
In imaging of the normal brain with sodium
methylene diphosphonate (MDP) (5).
[g9mTc]pertechnetate,99n‘Tc-diethylenetriarn-
The most common intracranial cysts, poren-
inepentaacetic acid(DTPA). or 99mTc-gluceptate
cephaly, generally produce no abnormalilies on
(GH),* thecerebral hemispheres appear sym-
the staticbrainimages.Leptomeningealcysts
metrical and nearly free of radioactivity. These
may, however, produce increased peripheral ac-
radionuclides concentrate within and around
tivity thal simulates a chronic subdural hema-
brain lesionsbecause of local tissue and vas-
toma. The “ring or doughnui” sign on the brain
cular alterations. Leveille et al. (I) have sug-
image is commonlyassociatedwith cerebral
gesled tha! the accumulalion of 99mTc-GH in
tumor, hemaloma,infarction,andabscess. It
brain tumor (Fig. 17.1) may occur by active
has, however, rarely been seen in adrenoleuko-
transport in the form of a glucoseanalog in
dystrophy,sebaceouscyst, and metastatic
metabolically active neoplastic cells. Very well
Wilms’ tumor (6-8).
differenlialed aslrocytomas, grades 1 and 11,
The static brain images do not become posi-
may give negative brain images, possibly due to
live before 7-10 days following the stroke. Oc-
little or no breakdown of the blood-brain barrier
casionally, increased perfusion about some in-
(2). farclionduringtheearlyphasesofthe
Brain imagingwith99mTc-GHoccasionally
radionuclide angiogram is observed in the “hol
demonstratesmultifocalcerebrallesions of
stroke” (9). Focal radionuclidebrainimaging
acute lymphocytic leukemia (3). There has been
abnormalities may rarely appear after seizure in
a reporr of multiple myeloma involvingthe skull
patientswithprolongedidiopathicepilepsy
that demonstratedincreased activity on brain
(10). Visualization of cerebral ventricles during
imaging with 99mTc-perlechnetate.i Bone imag-
brain imaginghas been unusually associated
with intraventricularhemorrhage,anoxia, and
chemotherapeutic neurotoxicity (1 1-13).
* Gluccp1;ltc is the orficial (USAN) name for what was
previously known as glucohcplondte; the commonly used
abbrcviarion “GH” comes froom this laller l e m . Radionuclide Cisternogram
t Allhough [~mTcjpcrtcchnelateand [~~Ga]galliumcil-
Thechanges in thecisternographic pattern
rate are preferred by IUPAC, WmTc-pertechnetale and 6’Ga-
cilrate are staudard, and buth arc used throughout this chap- oblainedwithuse of “Iln- or I6YYb-labeled
ter. DTPA in palients with hydrocephalus are asso-
Alrered Biodi,rtriburimas a Resulr of Pathologic Meckmisnls I 249
Figure 17.1. Selective anterior ( A N T ) and right lateral ( R U T ) views of the static brain images obtained with
use of SmTc-GH show two melaslatic melanomas in the right frontal lobe which were developed 6 months
later.
ciated with [he presence or the absence of ven- also interfere with the trapping of perlechnetate
lricularrefluxandtherelalive rate of cerebra1
which is not organified. Thereported discrepant
spinal fluid (CSF) clearance. If the mechanical
images obtained with the use of radioiodine and
block is higher over the convexity of the CSF
sodium [ 99mTc]pertechnetatewere from certain
space, a combinalion pattern is seen, i.e., ven-
patients with chronic thyroiditis, benignnod-
tricularrefluxandvariably delayed flow over
ules,or malignantnodules (16). There was a
the convexities (14), depending on the degreeof
report of an unusual selective accumulation of
compensation. With normal pressure hydro-
WmTcin the thyroid during in vivo labeling of
cephalus (Fig. 17.2), there is usually persistent redblood cells (RBC) for gated blood pool
activity refluxed into the lateral ventricles. The
imaging;thisaccumulation could not be satis-
most commonpattern of cerebral atrophy is factorily explained (17).
delayedmigration of the radioactivity with or
A cold nodule (Fig. 17.3) on thyroid imaging
without various convexityblocks and wilhoul
is commonly associated with adenoma, colloid
ventricular reflux.Oftenthepattern may be
cyst, and carcinoma. Rare causes of a cold thy-
normal, however, and transientventricular re-
roid nodule include lymphoma, paraganglioma-
flux usually does not persist at 24 hours (15). tosis,andarteriovenous fistula (18-20). Most
malignanl thyroid nodules are photopenic due to
RADIOYHARMACEUTlCALS FOR poor radioactive uptake relative to normal thy-
THYROlU IMAGING
roid tissue, but there has been a report of imag-
The perlechnetate ion is trapped by the same ing of primary thyroid carcinoma with 13’1 (21).
mechanisms thal trapthe iodideion,andall
Ryo el al. (22) recentlynoted areas of extra-
conditions that interferewith iodidetrapping lhyroidal uptake on thyroid scans obtained with
250 t Esserrriafs of Nuclear Medicine Science
Alrered Biodistribufiorl as a ResuIr of Parhologic Mechanisms
use of 9 9 m Tand ~ 1231in four patients with fol-
licularthyroidcarcinoma,andallpalpable
nodes containing metastatic carcinoma showed
radionuclide uptake. A patient with medullary
carcinoma of the thyroid and lymph node me-
tastases was noted to show uptake of radioper-
technetate, radioiodine, and radiothallium. A
perchloratetest was positive which indicated
that the uptake was largely due to trapping (23).
There has been a report also of the rare occur-
rence of a carcinoma within autonomous hyper-
active (hot) Ihyroid nodules (24). We observed
l 3 I I uptake in a proven ovarian cyst (Fig. 17.4).
Breasl uptake of 1231has been reported in a
young primipara with postpartum lransient thp-
roloxicosis (25). Follow-up imaging with l Z 3 l
after treatment with propyIthiouraci1 showed no
further breast uptake. In two cases of subacute
Ihyroiditis,increasedactivity in the affected
areas, shown as cold areas on the 99mTc scans,
was observed on 201T1scans (26).
R
Figure 17.2. Anterior (ANT),left laleral (L LAT), and vertex ( K T ) views of the head at 24 and 48 hours
following [he injection of IIIIn-DTPA show persistent activity refluxed into lateral ventricles, consistent with
normal pressure hydrocephalus.
Tc-99m TI-201 ' I - 131
Figure 17.4. Anlcrior abdominal image at 24 hours following Ihe administralion of
Figure 17.3. Anlcrior thyroid image with SmTc-pertcchnetalc shows cold nodules in right and left lobes
.*,h;-h ,-nnPcntr?f,= 201TI A t <alruPrv thvroid ndmnmns we.m fnllnd. uptake in surgically proven ovarian cyst. S, stomach; 5,bladder.
f 251
RADIOPHARMACEUTICALS FOR
CARDIOVASCULAR IMAGING
Radionuclide Cardiac Imaging
Studies in which a focal defect on *O1T1im-
ages canbeseenina patient at rest are sug-
gestive of myocardial infarction. Hypertrophy
of the papillary muscle of the left ventricle
rarely was visualized as a defect on 201T1images
as well as ongated blood pool images (27).
Right atrial enlargement on 99mTc-labeledRBC
or human serum albumin (HSA) cardiac imag-
ing has, uncommonly, resulted from right ven-
tricular infarction, pulmonary stenosis, and tri-
cuspid or milral stenosis or regurgilation (28).
Paradoxical motion of the interventricular
septum onradionuclideventriculogramocca-
sionally has been seen in right ventricular tu-
mor, pulmonary stenosis, and constrictive peri-
carditis (29-3 l). A left-to-right shun1 delected
from Ihe curve analysis of pulmonary time-ac-
1311 s h o w radioiodine
252 I Esserltinls uf NuclearMedicifseScience AlleredBiodisrribuliun as a Resuli of Pa!hologic Mechanisms f 253

tivity has been less commonly associated with gregated albumin (MAA) often shows collateral was acase of pulmonary venousobstruction lary phase in that lobe and late opacification of
cerebral arteriovenous fistuIa and rarely associ- venous pathways alongthe chestwalland is producing V/Q mismatchdue to stagnating thecorrespondingdrainingvein (45). V/Q
ated with a right pulmonaryarteryoriginated commonly associatedwith lung cancer and lym- blood flow reflected by a delayed intense capil- mismatch was also reported to be due to aber-
from the aorta (32-33). phoma. It hasbeenrarelyassociatedwith
Documented transmural infarctions appear to t h r o m b o p h l e b i t i s ,a t r i a lm y x o m a ,n e u - _.
result in abnormaluptake of 99mTc-pyrophos- roblastoma,andleukemia (41). Infusion of
phate, gluceptale, or tetracycline in more than 99mTc-MAAinto the hepatic artery catheter has
90% of the patients (34). A false positive myo- been utilized for monitoring of catheter position
cardial scintigram obtained with use of 9 9 m T ~ - and tumor perfusion. Lung uptake of the MAA
pyrophosphatehasbeenuncommonlyassoci- due to arteriovenous (AV) shunt at the tumor
ated with cardiomyopathy and rarely observed bed (Fig. 17.5) may be useful in prediction of
in patients with secondaryhyperparathy- the therapeutic response of hepatic tumor. ....
roidism, pericarditis, chronic myocarditis (Cha-
gas' disease), metastatic tumor to the heart, and ANT POST R LAT L LAT
calcifiedcostalcartilages (34-38). Intense RADIOPHARMACEUTICALS FOR LUNG
lMAGING
myocardial uptake on a ggmTc-MDP bone scan
also was demonstrated in a p a k n t with hyper- 133Xeventilation and 99mTc-labeled human
calcemia or amyloidosis of unknownmecha- albumin microsphere (HAM) perfusion VlQ
nism (39, 40). mismatch unassociated with pulmonary embo-
lisnl has beenrarelyfoundinintrathoracic
Xadionuclide Vascular Imaging stomach (Fig. 17.6, A and B), pulmonary artery
Superior vena cava obstruction imaged with sarcoma, hemangioendotheliomalosis, and
99mTc-labeled sulf~wcolloid (SC) or macroag- lymphangitiscarcinomatosa (42-44). There A
L

R L

i
Figure 17.6. A , Multiple lung images with BmTc-HAM show sharply outlined perfusion defect in [he right
lowcr lobe preuperatively (upper row) due lo herniated stomach. Posloperative images are in the lower row
Figure 17.5, Antcrior image of the chesr and upper abdomen after infusion of Y9nlTc-MAA shows significant B . Prcoperalive venlilation study after l33Xe gas inhalalion shows markedly elevaied Iefl hemidiaphragm and
artivitien i n both lunes due to AV shunt a[ the tumor bed (T).
X denotes marker on xiphoid process. rnininlal dilfuse obstructive airway disease.
254 f Essentiols of ATuclear Medicine Science
rantarterialsupply from a systemicvessel
ratherthan frompulmonary circulation (45).
The presence of 99mTc-HAMin areas other than
lung suggests the presence of a right-to-left
shunt. Eisenmenger physiology may be shown
with reversal of a left-to-right shunt following
the development of severe pulmonary hyperten-
sion.
Myocardial activity was visualized on a per-
fusion lung scan in a patien1 with primary pul-
monary hypertension and a right-to-left shunt
through a foramen ovale (47). There was a re-
port of marked retenlion of 133Xeby the skeletal
structure (largely in the intraosseous fat), proba-
bly associatedwiththepatient’sprolonged
steroid therapy that alters systemic lipid metab-
olism by increasing the quantity of intracellular
lipidsynthesizingenzyme (48). Pulmonary
hydatid cyst evidenced by a [67Ga]galliurn cil-
rate scan that showed an oval area of homoge-
nous uptake has been reported (49).
L R
Figure 17.7. Postcrior image of theupperabdomen
melanoma shuws 110 focal defect but a hot spleen.
RADIOPHARMACEUTlCALS FOR
GASTROINTESTINAL IMAGING
Focal increased radioactive uptake in the sali-
vary gland is commonly associatedwith War-
thin’s tumor, probably due to secreting 99mTc-
pertechnetate not being excreted as quickly as
the saliva. An oxyphilic adenoma has been re-
ported to show these same findings (50). Focal
“hoi” spots on the colloidal liver scan usually
have been associated withsuperior vena caval or
hepatic vein obstruction.There have been re-
ports, however, of hot spots on the liver scan due
to inferior vena caval obstruction, isolatedin-
nominate vein obstruction, and tricuspid insuf-
ficiency (51-53). Hemangioma, hamartoma.
and abscess have been reported to cause a focal
area of increaseduplake of radiolabeled SC,
probablydue to increasedlocalvascularity
(54-56). There was a case of primary hepato-
cellular carcinoma appearing as adefect on a
with ~9mTc-labeled sulfur colloid in a patient with
Altered Biodis/ributio!z n Resuli oJPofhologic Mechonistns f 255
SC liver scan and visualized on a hepatobiliary Focal splenic defect oftenhas been associated
scan obtained with use of 99n1T~-pyridoxylidenewith infarctionsand rarelyhasresulted from
glutamate (57). Absence of hepatic uptake of splenicarteriovenousmalformationand
99n1Tc-labeledSC in aninfantwith Coxsackie amyloidosis (62). Functional asplenia (anatomic
B, viral infection has been described and may presence of the spleen but without the ability to
be associatedwithmarkedimpairment of accumulate intravenously administered radio-
Kupffer cell function in the liver (58). colloid) has been unexpectedly noted in SCzary
UsualIy, nonvisualization of thegallbladder syndrome(alymphoma of cutaneous origin)
on cholescintigraphy is due to obstructive cho- (63) andchronicaggressive hepatitis (64).
lecystitis, but an adenocarcinoma of the cystic There was a report that the spleen in a patient
duct has been reported to show these same find- with Sezary syndrome could not be visualized
ings (59). There has been a report of a palient with use of a 99mTc-labeledtin colloid (SnC) but
who hadclinicalandpathologicfindings of was visualized with useof a 9mTc-SC, although
acute cholecystitis but normal visualization. the samereticuloendo~helialsystem (RES) is
This situation may occur in patients with recent involved in the phagocytosis of both radiophar-
relief of cystic duct obstruction but persistence maceuticals (65). A “hot” spleen on the 9Yn1T~-
of the acute inflammatory response (60). Metas- SC scan (Fig. 17.7) has been described in pa-
tatic pulmonary nodules from a well-differenti- tientswith melanomaandmay be associated
ated hepatoma were demonstrated by 9 9 m T ~ - with increasedphagocytosissecondary to the
paraisopropyl iminodiacetic acid (PIPIDA) with unique antigenicity of the tumor (66).
unknown mechanism (61). Diffuselunguptake of 99mTc-SChas been
R L
S.C.
Figure 17.8. Antcrior image of the chest during the liver-spleen scan shows marked uptake of sulfur colloid
(S.C.) in the left lung. ‘I‘here were pleural effusions bilaterally. Liver and spleen images were negative.
 Altered Biodisrributiorr as a Resulr o j Parhologic h f e c l m l i s m s ! 257
256 I EsserItials of NuclearMedicineScience

uncommonly seen in patients with histiocytosis inflammatory response, or delayed clearance of

L R
A X , organ transplantation, and amyloidosis (67,
68). 99mTc-SC was accumulated in one lung
(Fig. 17.8) following blunt trauma to the chest,
although the lung remained clear radiographi-
callp. The cause of this phenomenon is unclear
and may be associated with fibrin deposition,
SC due to ipsilateral hypoventilation (69). There
was a report of lung and kidney uptakeof 99mTc-
SC following treatment for disseminated intra-
vascularcoagulation (70). Renaluptake of
wmTc-SC(Fig. 17.9) was observed in patients
with congestive heart failure (71).

.= L LAT
Figure 17.9.Posterior (POST) and leftlateral ( L)". images of the upper abdomen with 99mTc-labeled sulfur
colloid show markedrenaluptake of radioactivity in a patientwithcongestiveheartfailure.Note (he
significant reduction of renal activity after 10 days or treatment.

B B P
m Figure 17.11. Anterior and posterior whole-body images with 9P111Tc-diphosphonate show markedly increased
activities diffusely in [he long bones due to active osteoporosis.
 Altered Biodisrriburim as a ResuIt ofPofhoiogic Mechanisms I 259
258 I Esserlrinls of Nuclear Medicine Science

nal allograft function in spite of clinical, scinti- 67Ga-cilrate,andlllln-labeledleukocytes in

99"Tc-DTPA wasfound to localize in seg-
graphic, and histologiccriteria suggestive of some kidneys with chronic rejeclion (79). Graft
ments of bowel wilh inflammation due to ul-
hyperacute rejection (78). There have been re- scintigraphy with ll'ln-labeled platelets seems
cerative colitis, regional enteritis, and other
ports of significant uptake of 99mTc-labeled SC, to be useful for the diagnosis of rejection, al-
forms of entercolitis (72). Scintigraphy with
"'In-labeled leukocyles is a sensitive and rela-
tively specific clinical test for detecting lo-
calizedinfection.Leukocytes are reportedto
have accumulated in an area of small-bowel is-
chemia or infarction and mimicked a paracolic
abscess (73).

RADIOPHARMACEUTICALS FOR
GENITOURINARY IMAGING

Radionuclide Renal Imaging

Splenic uptake of ""Tc-DTPA was unexpect-
edly observed during the performance of a diu-
retic renogram (74). It was postulated thal this

MDP
Figure 17.13. Anterior images of the upper leg with use of99mTc-MDP and I11In-labeled leukocytes show a
focal lesion in the right femoral shaft. At surgery, sclerosing osteomyelitis was found.
 Altered Biodistributioft as a Result of Pathologic Mechmisms I 261
260 I Essentials o{Nuclear Medicine Science

Increasedaccumulation of 99mT~-phosphate Lutrin and Goris havereported intense renal

though a false positive image due lo hematoma
has been described (SO).
Radionuclide Adrenal
Imaging
Unilateral visualization of theadrenal gland
on a scan usually is due to adrenal cortical ade-
nomawithsuppressedcontralateralgland and
unilateral metastatic breast or lung carcinoma.
Rare causes of nonvisualization of unilaleral
adrenal gland have included aldosterone-pro-
ducing carcinoma with destruction of the uni-
kaleral gland and congenital adrenal cyst (XI).
Radionuclide Testicular Imaging
Increased scrotal radioaclivity usually is sug-
gestive of epididymoorchitis or seminoma, but
ararepheochromocytomaalsoshowedin-
creased aclivity of the scrotal contents (82). A
focal defect on the scrolal image (Fig. 17.10)
can be due to testiculartorsion,hydrocele,
hematoma, and tumor.
adjacent soft-tissue and bony structure. Cases of in pleural effusion (Fig. 17.15) or ascitic fluid uptake of 99mTc-pyrophosphate (Fig. 17.16) fol-
widespread thyroid
metastatic
bone,
disease
lo associated with various neoplasms has been ob- lowing chemotherapy or irradiation (99). Also
in which there is avid accumulation of I3’I and
served (92, 93). Unexpecteduptake of 9 9 m T ~ -reported are splenic uptake in patientswith thal-
no increased
uptake of the 99mTc-labeled phos-
labeled phosphate compounds hasbeen reported assemiamajor (loo), lunguptake in patients
phateComPiexes, have beendemonstrated. without precise mechanism in certain carci- with uremia (lOl), and uptake in patients with
nomas of breast, lung, rectum, and ovary, pan- amyloid nodules (102). Uptake of PgmTc-pyr~-
creaticisletcelltumor,neuroblastoma, phosphate in the necrotic liver, probably due to
Hodgkin’s disease, lipoma, liposarcoma, cere- calcium accumulation on mitochondria after
bral, myocardial, and intestinal infarctions, and disruption of the cell membrane, has been re-
dermatomyositis (94-96). ported (103). Splenic accumulation of 99mTc-
Severalpatientswithnormalintravenous diphosphonate in the bone scanof a patient with
pyelogram showed focal increased renal uptake, sicklecellanemiamaybeassociated with
usuallyunilateral, of 99mTc-labeled polyphos- splenic infarction and subsequent calcium depo-
phate, and all of them had documented metas- sition (104). Diffuselunguptake of thebone
tatic lung carcinoma (97). Abnormally in- scanning agent appears toreflect metastatic pul-
creased accumulation of 99mTc-MDPin uni- monarycalcification (105). There was an un-
lateral kidney subsequently was found to result usual report of 99mTc-pyrophosphate uptakein a
fromstenosis of ipsilateral renal artery (98). muscle hernia of the thigh (106). Diffuse soft-

RADIOPHARMACEUTICALS FOR
MUSCULOSKELETAL IMAGING
Radionuclide Bone Imaging
Increased activity of bone-imaging agenls
(Figs.17.11,17.12,and 17.13) isassociated
with bone blood flow and osteoblastic activity.
Myelofibrosis usually has been presented as a
hypermetabolicbonediseaseshowingsym-
metrically increased activity, especially around
the knee joints, possibly due to increased bone
blood flow orperiostitisobserved on myelo-
fibrosis ( 8 3 , 84). Decreasedboneuptake of
99mTc-labeled polyphosphatewas seen in a pa-
tient with thalassemia major (85). In rare cases
in which thebonehas beenreplaced by ag-
gressive malignant disease, the bone scan may
be negative. “Cold” Iesions (Fig. 17.14) have
been reported in palients with metaslatic carci-
nomas,osleomyelitis (X@, myeloma (87), fi-
brosarcoma (88),and Ewing’s sarcoma (89). An
abdominalaorticaneurysm was demonstrated
on static bone images as a photon-deficient re-
gion (90). A “cold spot” was noted in all three
phases Of bone Scan in a patient with gas gan- Figure 17.15. Anterior whole-body image obtained
grene Of the foot (91) and may result from de- with use of 9YmTC”Dp shoxv diffuse abnormal ac-
Figure 17.16. Posterior image of the iumbar spine which was obtained with use of SmTc-MDP shows intense
StruCtiOn of blood Vessels in the=ea Of myo- tivilies in the left chesl. A malignan1 pleural effusion
was found. uplake of radioactivity i n both kidneys. The patient received multiple courses of chemotherapy.
necrosis, with resultanl absent perfusion of the
.~
262 I Essenrials of NuclearMedicineScience
tissue uptake of WmTc-pyrophosphate was noted
in a patient with calcinosis universalis (107) and
electric burn (Fig. 17.17), and 99mTc-MDPwas
localized in the skin lesions of a patientwith
pseudoxanthoma elasticum (108). Accumula-
tion of 99mTc-MDP in the muscle of a patient
withmyophosphorylasedeficiencyand of
99mTc-MDP uptake in the diaphragm of a pa-
lien1 after severe ischemia have been described
(109, 110).
Radionuclide Bone Marrow Imaging
Nonvisualization of the femora1head in a
99mTc-labeled SC marrowscaniscommonly
due to aspect necrosis and traumaticfracture
anddislocation,but it has beenuncommonIy
seen in patients with Paget's disease, amyloido-
sis, pheochromocytoma, Gaucher's disease, pri-
mary liver disease, and pancreatitis (1 11-1 15).
Altered Biudisrriburim as n Result o j P d ~ o l o g i cMechonisnrs I 263
"GA-CITRATE
There have been a few reports to %a-citrate
uptakeinfracturesincludingstressfracture
(1 16), although Deysine et al. (117) reported no
alteration in 67Ga uptakein acute fractures. Dif-
fuse pulmonary concentration of 67Ga-citrate
(Fig.17.18)usuallyisassociatedwith active
pneumoconiosis,interstitialpneumonitis,and
chemotherapy. It rarely has been seen in diffuse
carcinomatosis,leukemia,disseminatedlupus
erythematosus, and idiopathic pulmonary fibro-
sis (118). There have been reports of 'j7Ga up-
take in a benign noninfected thymic cyst (119)
and without evidence of bacterial endocarditis
(120). Marked accumulation of 67Ga-citrate has
been noted in neurogenic arthropathy (121) or
tuberous sclerosis (122). Giant lymph node hy-
perplasia resembling abdominal abscess was
visualized on agalliumscan (123). Persistent
Figure 17.18. Anterior whole-body images at 48 hours following the ingeslion of Wa-citrate show marked
abnormal activities diffusely in both lungs, associated with bleomycin toxicity.
renal accumulation of 67Gaat 48 or 72 hours in of the rightilium(125).Themechanism of
patients with severe hepatocellular disease with- decreased gallium uptake is unknown bu1 may
out renal pathology has been described and may be associated with decreased blood flow.
be associated with less gallium in their livers,
which
allows
more
to available
be for renal ACKNOWLEDGMENTS
excretion (124). Decreased radioactivity uptake The authors thank Bill Hladik for his advice
was notcd on both bone and gallium scans in a and Ms. Linda Watts for the typing of this
patient with acute hematogenous osteomyelitis manuscript.
 264 I Essellrinls of Nuclear. Medicine Science
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18
Clinical Manifestations of
Radiopharmaceutical Formulation Problems
James A, Ponto, Demis R Swarzson, and John E , Freitas
Unexpectedpatterns of radiopharmaceutical
biodistributionusually provoke a flurry of in-
quiries regarding (he quality of the administered
agent. Although this unexpected biodistribution
may be relaled to nonradiopharmaceutical fac-
tors (discussed in other chapters of this book),
past experience hasshown that an improperly
formulaled radiopharmaceulical may be to
blame.
The clinical manifestations of most w m Tra- ~ radiopharmaceuticals are presented. These clin-
diopharmaceuticalformulationproblems are
generally associated with increased amounts of
[9yn1Tcjpertechnetate,99mTc-labeledcolloid,
andlorwmTcparticulateimpurities in the de-
siredY9'11T~ agent. Free pertechnetate is dis-
tributed throughoutthe vasculalure and inter-
slitial fluid and is concentrated in the stomach,
intestinaltract,thyroidgland,andsalivary
glands; the presence of free 99mTc-pertechne-
tale* impuritieswill,therefore,resultinin-
creased activity in theseorgans(Fig. 18.1).
Colloid particles are phagocytized by cells of
the reticuloendothelial system (RES) which are
Iocated primarily in the h e r and spleen;lhe
presence of y9mTc-labeIed colloid impurities
will, therefore, result in increased activity in the
liverand spleen(Fig. 18.2). Large (>lo p)
particles administered inlravenously become
physically lodged in the pulmonary capillaries;
* Although [%mTc]pcrtechnetate is preferred by
IUPAC, 99"lTc-perlecbnetate is slandard, and both are
used throughout this chapter.
2 68
Clinicd Mmifesrations of FormilationProblems 1 269
thepresence of largey9mTcparticulate im-
P
purities will, therefore,result in increased ac-
livity in the lungs (Fig. 18.3).
In this chapter, common formulation factors
whichaffectthelevel of theseimpuritiesio
wmTc-labeledradiopharmaceuticalsaredis-
cussed. In addition, formulation factors that
mayproducealternateeffects on thebio-
distribution of 99mTc-labeled tracers and other
ical manifestations of common radiopharmaceu-
ticalformulation problems are summarized in
Table 18.1.
CARRIER 99Tc
99mTcundergoesisomerictransition Lo the
very long lived isotope 99Tc (half-life, 200,OoD
years),whichcan, for practical purposes,be
considered stable in comparison to its metasta-
ble isomer. The decay of 9 9 m T therefore,
~, re-
sults in a rapid buildup of carrier technetium
with corresponding depressionof 99mTc-specific
activity. Excessivecarrier 99Tc is commonly
present in the eluate of a generator which has
not been eluted for several days. Expressed as a
percentage of total technetium atoms (99mTc
plus%Tc)obtainedin the generatoreluate,
wmTccomprises 28% of the total at 24 hours,
13% at 48 hours, and only 8% at 72 hours after
prior elution ( I , 2).
9 9 T ~which
, is chemicallyidenticaltoall
other technetiumisotopes,cancompete with
9 9 m Tfor
~ the reductive capacity and the ligand-
270 I EssehalsojNuclear Medicine Science Clinicol Mnruj!esfarioluof Forrnularion Problems I 271

Table 18.1.
Clinical Manifestations of Common Radiopharmaceutical Formulation Problems
Formulation Clinical
Radiophannaceulical Problem Manifcslation Reierrence

Pertechnetate ~ 1 4 3 Sustained blood pool focali- 25, 26

zation
Stannous ion f liver and spleen uptake 32, 44
Preparation with bacterio- 1 blood pool, liver,and 153
static saline spleenactivity
49mTc-labeled sulfur Carrier WTc i free pertechnetate 3
colIoidand Sn ~ 1 + 3 Lung uptake 12-14, 17-21
colloid Alkaline pH 1 free pertechnetate 41, 42
Incorrect order of mixing 1 free pertechnetate 17, 58
Radiolyticdecomposition f free pertechnetale 41
and/or oxidation
Sterilization with iodi- t free pertechnetate 116
nated anliseptics
Particleclumping Lunguptake 41, 190
Parlicle settling and/or J aclivity per volume with- 41, 96, 97
absorption to vial drawn
Lowheatingtemperature 1 freepertechnetate 61
Inadequate boiling time t free pertechnetate 14, 17, 61.
41,65
1 spleen uptake 14, 41
I Excessive boiling time Lung uptake 14, 41
Heating large volume 1 free pertechnetate 17
Commercia1source f free pertechnetate 3, 98
Low specificactivity 1 liver uplake; t bone mar- 82
rowuptake
Variable incubation time Variable particle size 74
99mTc-labeled phos- Carrier ' T c Slower blood pool clearance 10
phates and diphos- AI + 3 f liver and kidney uptake 22-24
phonales Aikaline pH 1 liver and kidney uptake 24, 32, 45-47
lnadequate stannous ? freepertechnetate 31, 34, 56, 191
binding sites of fixed concentrations of stannous ALUMINUM ION Excess slannous t liver and soft tissue uptake 32, 34, 128
Preparation with bacterio- I free pertechnetate I53
ion and chelating reagents, respeclively. Hence, slatic saline
it is not surprising that anunacceptably high The distribution of a number of 99mTc-labeled Improper mixing order f bloodpoolactivity; 1 liver 56
concentration of unreduced, free 99mTc-pertech- radiopharmaceuticals may be altered by the alu- uptake
nelate impurity has been found in many 9 9 m T ~ - minum ion (Al'3). The most common source of Low ligand concenlration J bone uptake; 1 soft tissue 46, 60
labeled radiopharmaceuticals prepared with use excessive A F 3 is breakthrough from the alumi- and kidney uptake
of low-specific-activity Monday morning gener- numoxideanionexchangecolumninthe Radiolytic decomposition I free pertechnetate 31-34, 56, 119,
and/or oxidalion 122, 125, 126,
ator eluates. This effect has been reported with 99MoP9mTcgenerator. If the breakthrough
128-131
the preparation of 99mTc-labeled sulfur colloid ispresent, it generally occurs withthefirst Inadequate or prolonged J bone: soft tissue uptake 73, 76-79
(3), gluconate (4),human serum albumin (HSA) generator elution (11, 121,although Al*3 con- incubation cime
(5), red blood cells (RBC) (6-8), and diethyl- centrations may vary from day to day and from Commercialsource 1 soft tissue uptake; liver, 79, 99, 105-107
enetriaminepentaaceticacid (DTPA) (9) and manufacturer to manufacturer (13). A F 3 break- gallbladder, and/or inles-
through was much more of a problem with the tinallocalization
may occur with many other 9 9 m Tpreparations
~ Carrier 95Tc f free pertechnetale 5
(2,6), Even if the reductive capacily of the kit is older,large-column,neutron-activated 99Mo Improper pH 1 free pertechnetate; t liver 39
not exceeded, high levels of 99Tcor 9 9 m Tmay ~ generators than it is with thepresent,small- uptake
affect the biodistributionof the labeled producl. column, fission 99Mogenerators (14, 15). Lim- lmproper mixing order t liveruplake 39
Radiolytic decomposition t free perlechnetate 33
For example,blood clearance rales of 9qmTc- its for the amount of permissible AIt3 break- and/or oxidation
hydroxymethylenediphosphonate (HDP) pre- through have beenestablished in the Unifed Commercialsource I free pcrtechnetate; *dif- 98, 100, 192
pared with high Icvels of either 99Tcor 9 9 m Tare
~ Srnres Pharmrcupeia (U.S.P.), whereby Al+3 ferences in blood clear-
significantlyslower than those preparedwith concentrations cannotexceed IO pglml gener- ance rales and liver uptake
less total technelium (10). ator eluale (16).
 Table 18.1"conti~tued Table 18.1-continued
Formulation Clinical Formulation Clinical
Radiopharmaceutical Problem Manifcsratron Reierencc Problem Manifestation Reference

99mTc-labeledmacro- Soluble protein t blood pool activity 80, 81 Improper pH T free pertechnetate 40
aggregaledaIbu- Smallparlicles t liveruptake 80, 90 Impropermixingorder t free pertechnetate or 1 40
min and albumin Clumping of particles Focal hot spots in lungs 90, 93 liver uptake
hadequate number of Perfusion defects, especially 94, 95 Radiolylicdecomposition T free pertechnetate 40, 127,133, 135
microspheres
parlicles peripheral patchiness and/or oxidation
Excessive number of par- f risk of toxicity 94, 95 AlkalinepH Rapid urinary excretion 5 1-54
ticles Radiolyticdecomposition 1 free pertechnetate; 1 kidney 53, 104,123,197
Radiolyticdecomposition 7 free pertechnetate 80 and/or oxidation uptake; T liver uptake
and/or oxidation Low ligand concentration I kidney uptake; 1 bone up- 53
Seltling of parlicles Inadequate number of parti- take
cles in suspension Inadequaleincubation 1 kidney uptake; ? bone up- 53
BmTc-labeled
RBC
Carrier 99T~ t free pertechnelate 6-8 time lake
~1+3 RBC agglutination 27 Commercialsource Differences in adsorption 111
Very acidic pH RBChemolysis 27 onto walls and stoppers of
hadequate stannous 1 free pertechnetate 7, 36,192 glassvials
Excessivestannous t piasmaactivity 7, 35-38,193 Carrier 99Tc t free pertechnetate 4
1 spleenuptake 194 Impropermixingorder t liver uplake 4
Improper mixing order f liveruptake 7 Radiolyticdecomposition f free pertechnetale 33
Low cell concentration 1 rate and extent of labeling 37 and/or oxidation
Radiolyticdecomposition T freepertechnetate 36, 193 ['3lI]iodohippurate Radiolyticdecomposition I thyroid uptake; 1 urinary 118, 134, 198
and/or oxidation andlor oxidation excretionrate
Inadequateincubation f free pertechnetate 36, 37, 71,72, Sodium['3lI]iodide AcidicpH t thyroid uplake in person- 168-170,172,
time 193 nel 174,175
InCubalion at lower than 1 rate of iabeling; f free 37, 72 Radiolyticdecomposition f thyroid uptake in person- 171, 173, 174
37" c perlechnetate andior oxidation nel
Heparinversus ACD 1 labeling efficiency; 1 exlra- 8 Metalions f thyroid uptake in person- 168, 175
vascular activity; f urinary nel
excrelion Chlorinated tap water for t thyroid uptake in person- 171
Excess ACD Sequeslation in spleen 155 dilution nel
99mTc-labeled Low heating lemperature 1 spleen uptake; t blood pool 62, 64 Storage above room tem- t thyroid uptake in person- 174,176
damaged RBC activity perature nel
Highheatingtemperature I spleen uptake; 1 liver up- 62, 64 Carrier iodide 1 thyroid uptake 137. 138
lake Encapsulation 1 thyroid uptake; retention of 156, 157
Inadequate heating time 1 spleen uptake; t blood pool 62-64, 69 abdominalactivity
activity Radionuclidiccontamina- 7 radiationdose;errorsin 178,180-186
Excessive heating lime i spleen uptake; f liver up- 62-64 tion dose calibration; image
lake degradation
Heating large volume 1 spleen uplake; t blood pool 68 201T1-chIoride Radionuclidiccontamina- lmage degradation 187-189
activily tion
Low specificactivity 1 spleen uptake; 1 blood pool 68 To-labeled Carrier cyanocobalamin 1 absorption and urinary ex- I40
activity cyanocobalamin and cretion
SmTc-IDAderivatives pH > 5.5 1rate of labelin@ 43 intrinsic factor Encapsulation J absorption and urinary ex- 159-161
Radiolyticdecomposition 1 free pertechnetate 43, 124, 195 cretion
andlor oxidation Isotope exchange Spurious resulls 163- 165
Inadequateincubation f free perlechnelate; 1 blood 43, 70 Commercialsource Uptake vs. no uptake in ce- 1 OS
time p o l aclivity rebralinfarct
L o w ligand concentration L rate of labeling 43 Carrier gallium f bone uptake; J uplake in 141, 142
99mTc-DTPA Carrier ' T c 1 free pertechnetate 9 usualorgans
lnadequate stannous f free Dertcchnetate 9, 113, 115 133Xe solution benzyl alcohol preser- Spurjous regional blood flow 154
Impropermixingorder f free pertechnetate 57 vative measurements
Radiolytic decomposition 1 free pertechnctate 59, 115, 117, 121, Iodinated cholesterd ? t liver,spleen,andbone 199
andlor oxidation 196 derivatives '
marrowuptake ,

Commercialsource Iifferences in renal cxcw 101-103 Limited solubility in Lung uptake 148
tion rates vehicle
274 I Essednls of Nudeor Medicine Science

as,over a period of hours.aluminum ion is ical form of 49mTc-labeled radiopharmaceuli- formed under acidic conditions with relatively
As early as the 1960s, it had been reported
hydrolyzed (26). cals. With regard to the effects of pH on radi- high Sn+Z concentrationswasretained in the
that Al+j interacts with smTc-labeledsulfur col-
also acts as an erythrocyte-agglutinating ochemicalpurily, it hasbeen shownthal (a) renal cortex, while another distinct complex
loid to form a flocculent precipitate (12: 14). In
decreased labeling of 99mTc(Sn)-HSA and elec- formed at an alkaline pH withrelativelylow
later studies, it was shown that this flocculation agent. Results of in vitro studies indicate a criti-
cal concentration of about 5 pg Al+3/mlat a pH trolyticallyprepared99mTc-gluceptateoccur Sn+2 concentrations exhibiled rapid urinaryex-
could result with concenirations
as lowas
range between 4 and 5 . Since necessary condi- above or below the optimal pH ranges between cretion and moderate uptake in tumor and bone
1 pg(ml(17). Although h e precipitate was orig-
tions for red cell agglutination by Al+3 do not 2 and 3 and 6.7 and 7.2, respectively (39, 40), (5 1-54). Several factors may be involved in the
Inally thought to be aluminum hydroxide (13),
occur in vivo, intravascular agglutination with (b) 99mTc-labeled sulfur colloidbreaksdown formation of these diffenmr complexes. For ex-
it waslaterdetermined thal combineswith
administration of generator eluate containing and liberates free 94mTc-pertechnetateat a neu- ample, the ratio of DMSA to Snt2 at pH 4 is
thephosphatebuffer to form insoluble dumi-
tral or alkaline pH (41, 42): and (c) decreased 2 : l ~whilethe ratio at pH 8 is 1 : I (51, 52).
num phosphate (18, 19).A flocculent aluminum AIi3 appears highly improbable (27).
labeling rates of 99mTc-iminodiaceticacid (IDA) Furthermore,thekidneylocalizingcomplex
phosphateprecipitate may beformed in vivo
STANNOUS ION derivatives are observed at pH valueshigher formed at acidicpH is probably Tc(II1)-DMSA,
when 99mTc-labeled sulfur colloid is adrnin-
The importanceof an optimal amount of stan- than the optimal pH of 5.5 (43). while that formed at alkalinepH is probably
islered to palients exhibitingelevated plasma
levels of AY3 (20). In both cases, the 9 9 m T ~ -nous ion (Sn+?) as a reducing agent in the prep- Stannous ion solutions become insoluble and Tc(V)-DMSA (54). Tc(V) maythendissociale
aration of *"Tc-labeled radiopharmaceuticals is form colloidalprecipilates at neuual and al- from the DMSA complex as TcO,-~ and, as a
labeled sulfur colloid is coprecipitaled with the
widelyrecognized. Too little Sn+2 limits the kaline pH. If 99mTc-pertechnetateis present, the structuralanalog to PO,-3, maylocalize in
aluminumphosphateprecipitateandresults in
lung localization, since these flocculated parti- reductive capacity, whichleads to decreased 9 9 m Tcan~ coprecipitate andlor complex with the some tumors and bones (54).
cles become lodged in the pulmonary capillaries labeling efficiency and increasedfree 9 9 m T ~ - tin colloid, which would result in a radiocolloid Different complexes of 99mTc-IDA com-
(13, 17,20,21). Avoidance of this problem may pertechnetate impurity; too much Sni2 may re- impurity that would localize in the RES ( 3 2 , pounds have also been observed at different pH
be achieved with theaddition of EDTA, a sult in the formalion of 99mTc-labeledcolloid 44). values. Rapid conversion in vivo to a common
chelatingagent for to the sulfur colloid impurities andlor decreased labeling efficiency. Good bone uptake and urinary excretion re- form probably occurs, however, since the bio-
formulacion (17, 19). Additionally,it has been Most 99mTc"kits"star1with sufficient, and sult from use of acidic formulations of 9 9 m T ~ - distributionpatiems are essentially the same
shown that sulfur colloid preparations formu- usually excess, amounts of Sn+2. This reducing pyrophosphate,whereasnegligibleboneaf- (55).
lated with an acetate buffer instead of a phos- capacity may be drastically decreased, however, finityand concentrations in the kidney result
phate buffer do not flocculate in the presence of by avariety of factors including loss of Sn'2 from use of neutral and alkaline formulations
during manufacture, deterioration andlor oxida- (45, 46). Imaging with alkaline99mTc-pyro- MIXING ORDER
(18, 19).
A second radiopharmaceutical affected by lion duringstorage, and oxidationduring kit phosphate formulations rather than with slightly The order of mixing components in the for-
is g9mTc-diphosphonate.Visualization of preparation (28-32). Furlhermore, excessive acidic formulalionsdemonstratessignificantly nlulation of 99mTc-labeled radiopharmaceuticals
liver and spleen backgroundactivity have re- amounts of carrier 99Tc decrease theapparent inferior bone scan quality (47). High liver and can have dramatic effects on the resulting bio-
sulledfromphagocytosis of a radiocolloid reducing capacity by cornpeiing with *"'Tc. kidney uptake have been demonstrated when distribution. In general, the reducing agent and
formed by the interaction of 9gmTc-diphospho- (See also seclions entilled "Carrier "Tc" and 9 9 m T c - h y d r o x y e t h y l i d e n e d i p h o s p h o n a t e ihe chelating agent should be mixed priorto the
nate in the presence of elevated Al+3 concentra- "OxidalionandlorRadiolyticDecomposi- (HEDPj is prepared at alkaline pH (24). It is not addition of 99mTc-pertechnetate in order lo ob-
tions (22-24). Thiseffect was not seen with tion.") clear,however,whetherthese pH effects on lainhighlabelingefficiencies.If Sn+i and
AI+' concentrations of <10 p@d,but liver Addition of excessiveamounts of Sn+2 to 99mTc-labeled phosphates are solely associaled "mTc-pertechnelate are combinedfirst, an in-
localizationand bonescanimagedegradation 99mTckits is a common practice for counteract- with the formation of radiocolloid or free 99mTc- soluble99mTc-labeledtincolloidmaybe
progressed with increasing A P 3 concentrations ing the effects of oxidants and inhibiting radia- pertechnetate impurities, since thereis evidence formed, withresullant increased liveractivity
tion-induced decomposition (29, 33). Although that suggests that the alteration in biodistribu- (4, 7, 56).
above this level (22).
tion may b e a result of differing chemical com- lmprovedlabeling of several 99mTc-labeled
The biodistribution of pertechnetate may b e this practice does effectively inhibit the €orma-
plexes formed at different pH values. For exam- radiopharmaceuticalscanbe achieved with a
altered by excessive Al+3.Failure of 99mTc-per- tion of free "'"Tc-pertechnetate impurities, hy-
ple, Tc(IV)-HEDP has been identified in acidic simple alteration in the mixing order during kit
technetate to leave the vascular space was ob- drolysis of theexcessSn+2can result inthe
solution, whereas Tc(V)-HEDP was formed in formulation.Instead of reconstituting thekit
served in apatientwithaplasma aluminum formation of wmTc-labeled siannous colloids
with resultant RES and other soft-tissue localiz- neutral or alkaline solutions (48). Similarly, with the required volume of 99"Tc-pertechnetate
level of 65 @g/l (25). Moreover, 99"Tc-pertech-
several components showing markedly different diluted previously with normal saline, themodi-
netate
injections containing in concentra- ation (32, 34). On the other hand, some 9 9 m T ~ -
bone uptakes and soft-tissue localizations have fied procedure calls for reconstitution with con-
tions of 4 pglml or more may result in reduced labeledradiopharmaceuticals may display de-
been separatedfrom99mTc-methylene diphos- centrated 99n'Tc-pertechnetate, incubation for
thyroidal uptake of pertechnetate (26). Al'3 in creased labeling in the presence of excess Sn+'
(35-38). phonate (MDPj mixtures prepared at different 3-5 minutes, and then dilution with an appro-
these higher concentrations apparently interacts
with pertechnetate to form neutral andionic
pH ranges (49, 50). priate volume of normal saline (57).
PH A number of different complexes of 99mTc- The radiopharmaceuticalmost affecled by the
pertechnebto-aluminumcomplexeswhich re-
Alteralions in pH can have marked effects on dinlercaptosuccinic acid (DMSA) have been ob- mixing order is 99mTc-labeled sulfurcolloid.
main in soft tissues. These complexes are rela-
served at different pII values.Thecomplex 99mTc-pertechnelate,hydrochloricacid,and
tively unstable and slowly release pertechnetate the radiochemical purity andlor the final chem-
276 I Exsenrials oJNuclear MedicineScience

thiosulfatesolutions must be combinedbefore HEATING biodistribution. Optimal duration of healing is measurable deterioration in bonescanquality
beingheated in order to ensure a high yield. The distribution of radiopharmaceuticals that variable, depending on the type ofapparatus. (withandwithoutgastricvisualization)has
Addition of 99mTc-pertechnetateor the acid so- require heating as part of their preparation may volume,andsuspendingmedia (62, 66-69), been reported to occur sporadically with use of
lution after heating andlor addition of the buffer be influenced by a number of factors involved in The optimal lenglh of heating time with use of incubated 99mTc-MDP(77). In thesecases, a
solution before heating results in negligible la- the healing process. These factors include tem- the Brookhaven National Laboratory procedure chemical form of 99mTc-MDP with analtered
beling and alterations in biodistribution reflect- perature, duration of heating: and volume appears to be 10-15 minutes (63, 66). affinity for bone isapparenllyformedduring
ing free 99mTc-pertechnetate(17, 58). heated. The third heating-related factor is the volume incubalion.Similarly, abnormalsoft-[issue lo-
Temperature plays an important role in the to be heated. Heating of small volumes is more calizalion of -"Tc-HDP and 99mTc-MDP has
formation and labeling of 99mTc-labeledsulfur uniform than is heating of large volumes. Sulfur beenassociated with long makeup-to-injection
LIGAND CONCENTRATION colloid. Because the reactionbetweenthiosul- colloidpreparationsconlaining > l o ml show limes (78, 79).
The ligand concenwadon is inversely propor- fate and acid is slow at room temperature, the inconsistentlabelingefficiencies,whencom-
tional to the final preparation volume. Low sulfur colloid reagents are heated in a boiling pared with smaller volume preparations boiled
ligand concentrations may necessitate longer in- water bath.Forconsistentlyhighlabeling for the same length of time (17). Similarly, Iage PARTICULATE SIZE AND NUMBER
cubation times andlor result in complexes hav- yields, the temperature of this water bath should volumes of radiolabeled RBC may demonstrale The biodistribu1ion of particulate radiophar-
ing different biodistribution patterns.Therefore, be 95-100" C. Heating at temperatures of less insufficienl damageforsplenicsequestration, maceutical~occurs as a function of their size.
preparationvolumesshouldnotbeun- than 95" C may result in poor labeling of the when compared with small volumes heated for Particles so small as io be consideredsoluble
necessarily large. colloidand increasedfree99mTc-pertechnetale the same length of time (68). (e.g., 99mTc-labeledHSA and some other pro-
Use of a DMSA kit prepared with 2 ml of impurity (61). teins) remain in the blood pool and soft tissue
perlechnetate yields about 90% of the kidney- The temperature used to damage 9 9 m T ~ or- INCUBATION and may degrade image quality (EO, 81). Parti-
localizingcomplex in 15minutes, whereasa 51Cr-IabeledRBC for splenic sequestrationstud- AIthoughmost99mTcchelalesareformed cles in the colloid size range demonstrate RES
preparation volume of 10 mi yields only about ies is critical. Too low of a temperature results in very rapidly, some complexation reactions re- localization;maximal bonemarrowuptakeis
70% in 15 minutes. In both cases, [he remainder insufficient RBC damagewithsignificant ac- quirea substantialincubationtime. In these conelaled withsmallercolloid size (82-86),
of the preparation consists of a different com- risity remaining in the blood pool; toohigh of a latter reactions, labeling usually follows an ex- with progressive splenic localization occurring
plex which is moderately localized in the bone temperatureresults in excessive RBC damage ponential curve, with plateauing achieved after as the colloid size increases (87-89). Particles
and rapidly excreted in the urine (53). Similarly, anddecreasedspleenuptakewithincreased severalminutes.lncubationtimes of approx- of even larger size ( > l o p) become physically
94mTc-IDA derivatives prepared in a volume of liver uptake (62). The recommended tem- imately 10-15 minutes arerequired to reach trapped in capillaries and precapillary arlerioles
10 ml compared wilh those prepared in a vol- perature for optimal red cell damage is 49-50" plateaulabelingforwmTc-DMSA(53)and (90).
ume of 2 ml show a decreased rate of labeling C (7, 62-64). 99mT~-IDA derivatives (43, 70), anda IO-min- The particle size of 99mTc-labeled sulfur col-
(43). Moreover, it has beenfound that in a A second imporlant factor is the duration of Ute incubation time is needed for both in vitro loid can be influenced by a number of factors
number of commercially available kits, diluied heating.When99mTc-labeledsulfur colloid is and in vivolabeling of RBC with 99mTc(36, (discussed hereandelsewhere in this chapter)
99mTc-DTPA injection becomes unstable and heated at 90-100" C, its labelingefficiency 71 -73). Use of the agenls before maximal Iabel- including aluminum ion concentration, healing
produces unacceptably high levelsof free 9 9 m T ~ -initially increasesrapidly andthenplateaus at ing may result in increased levels of free 99mTc- time and temperature, and aggregation.After
perlechnetate (59). 3-10 minutes (14, 17, 61, 65). Heating for an pertechnetate impurities. preparationand duringstorage,99mTc-labeled
In addition, the rate and extent of labeling of insufficientlength of timemaydecrease the The in vitro particle size of 99mTc-labeled(in sulfur colloid particles may aggregate over time
RBC with 9 9 m Tare ~ affected by cell concentra- labeling efficiency and increase free 99mTc-per- colloid preparation increases with the lenglh of toform clumpslargeenough to lodge in the
tion. The incorporalion of 9 9 m Tinto ~ RBC is technetate impurities. The lengthof heating also incubation time after reconstitution and affects pulmonary capillaries and to produce lung vis-
directly related tohematocrit, not to cell number affects the colloid particle size, with the mean Ihe relative organ uptakes (74) (also discussed ualization (41, 91). Theuse of stabilizing or
(37). colloid particle diameter increasing as a func- elsewhere in this chapter). protecting agents, such as gelatin, in the sulfur
Solutions of 99mTc-pyrophosphate diluted in tion of heatingtime(14, 41). If the 9 9 m T ~ - The chemical form andlor nature of a radio- colloid formulation markedly improves particle
viwo and, lo a lesser extent, in vivo demonstrate labeled sulfur colloid is heated for an insuffi- pharmaceutical may change during the incuba- size stability (91, 92). In contrast, small radio-
decreased bone uptake and increased soft-tissue cient period of time, poor splenic upiake can tion period, with resultant alterations in the bio- colloids may underestimate splenic function and
andkidneylocalizalion (46). Similarly, 9 9 m T ~ -result,whereas if it is heated for an exlended distribution. With 99mTc-MDP,ratios of bone to possibly result in a misdiagnosis of functional
HEDP diluted in vitro demonstrates decreased period of time, lung uplake of large "colloidal" soft tissue are reportedly higher after a 31-60- hyposplenia. This problem has been observed
bone uplake and increased soft-tissue and per- particles may result. minute incubation period than after shorter in- with 99'nTc-labeled phytate colloid, which fre-
technetale localization (60). The altered bio- The degree of radiolabeled RBC damage var- cubation times, even though the percent label- quenlly demonstrates insufficient splenic uptake
distribution of these two radiopharmaceuticals ies directly withthelengthof heatingtime. ing efficiency remains unchanged (75, 76). Ap- lo provide images of diagnostic quality (87,89).
with dilution has been ascribed to the formalion lnadequate or extended healing of RBC results parently, a chemical form of 99n1Tc-MDPwith a The splcnic uplake of 99mTc-phytate can beim-
of different complexes andliberation of free in insufficient or excessive damage, respec- different renal clearance is slowly formed from proved by the addition of ionic calcium to in-
pertechnetate (46, 60). tively, with resullant alteration in the expected the initial labeled producl. On the other hand, duce colloid aggregation (89).
278 i Essenlials oIA'wlear Medicine Science
The particle size of perfusion lung imaging
agents may have undesirable effects on pulmo-
nary localization. High blood pool activity has
beenreported following the administration of
99mTc-labeledmacroaggregated albumin prepa-
rations containing significant amounts of soh-
ble protein (80, 8 1). Small particles and particle
fragments < I O p may pass lhrough Ihe pulmo-
narycapillariesandbephagocytizedbythe
liver and spleen (80, 90). Macroaggregated al-
bumin andalbumin microspherepreparations
may demonstrateclumping of theparticles at
storage, Injectedintravenously, large particles
or particulate clumps > 100 p lodge in pulmo-
nary arleries and result in focal hot spots on the
lung image (90, 93).
The number of injected particles of macroag-
gregaled albumin and microsphere preparations
is important in lerms of both image quality and
toxicity. Too few injected particles may result in
degradalion of lung images, with definite perfu-
sion abnorlnalities. especially peripheral patchi-
ness,demonstraled (94, 95). Theminimum
number of particles that should be administered
for a lung scan is 60 particleslgm of lung tissue
or 60,000 particles for an adult patient (94, 95).
Injection o€ >250,000 parlides improves image
quality little (95), while it increases the risk of
Ioxiciiy (see Chapter 20).
Particulate radiopharmaceuticals tend to set-
tle or sediment withtime. Therefore, beforea
dose is withdrawn, the vial shouldbe gently
invertedseveral limes toresuspend (heparti-
cles. Failure to resuspend particles may result in
withdrawal of a larger-than-expected volume, a
somewhat higher percentage of soluble free
99mTc-pertechnetate in the withdrawn dose, and/
or an inadequale number of particles for lung
imaging. wmTc-labeled sulfur colloid has a ten-
dency to adsorb over time on the surfaces of the
glass vial, which thus necessilates withdrawal of
a larger-than-expected volume for the required
radioactivity dose (41, 91, 96, 97).
COMMERCIAL SOURCE
The com~nercial source of reagent kits and
the compalibility of generator elualeswith these
kits may affect the final radiochemical purity of
9y11'Tc-labeledradiopharmaceuticals. A specific
kit that yields a highly labeled product when it
is prepared with 9 9 m Tfrom~ one generator sup-
plier may demonstratedecreasedlabelingand
increasedfree99mTc-pertechnetateimpurity
when it is prepared with 9 9 m Tfrom~ an alternate
supplier. This phenomenon has been reported in
the preparation of various 99mTc-Iabeled sulfur
colloid ( 3 , 98), 99mTc-HSA (.98), and
99mTc-DTPAproducts (59). The biodistribution
of labeled kits may be affected by the source of
9 9 m TFor~ . example, abnormal soft-tissue local-
izationisseenmuchmorefrequenllywhen
99"Tc-MDP and 99mTc-HDPare prepared with
instant (melhyl ethylketoneextraction)tech-
netium than withtechnetium fromgenerators
(79, 99).
Even with comparable labeling, reagent kits
from different commercial sources may resultin
significant differences i n biodistribution and
eliminalion kinetics. Various w"Tc-HSA kils
have showndifferences in plasmaclearance
rates of up to fivetimes (loo), andvarious
preparations of 99mTc-DTPAexhibitsignifi-
cantlydifferentglomerularfiltrationrates
(101-103). Similarly, although lhe renal con-
centrations of two 99mTc-DMSApreparations
are equivalent,values for liveruptakesare
markedly different (1 04). Moreover, hepatic,
gallbladder, and/or intestinal localization is re-
portedly more frequenl with unstabilized 9 9 m T ~ -
MDP products than with 99mTc-MDP products
conlaining antioxidants (105).
At least four different complexes of 9 9 m T ~ -
MDP havebeen demonstraled by eleclropho-
retic analysis of MDP kiis from different manu-
facturers (106). One of these complexes results
in accumulation of activity in the liver. Results
of in vitroand in vivostudies have suggested
that this liverlocalization is associatedwith
methylphosphate, a degradation producl formed
from the hydrolysis of MDP (106). The results
of further studies have suggested thal variations
in image quality obtained with differenl prepa-
ralions of MDP may be associatedwith dif-
ferences in kit formulalion such as the MDP salt
form, the ratio of stannous to MDP,andthe
presence of an antioxidant (107).
Alleralions in biodistribution also occur with
non-99mTc-labeledradiopharmaceuticalsob-
tained from different sources. [67Ga]galliumcit-
rate obtained from one manufacturer readily lo-
calizesincerebralinfarctions bul does not
localize when obtained from another manufac-
turer (108). This phenomenon may be reIated 10
differingcitrate concentrations in the prepara-
tions ( I 09).
Incompatibilities between radiopharmaceuli-
cal solutions andrubber-stoppered glassvials
have also been reported. For example, signifi-
cantdifferences in thestability of stannous
chloride solutions havebeen observed in vials
stopperedwith differenttypes of elastomeric
closures (1 10).Similarly, significant differences
in the adsorption of 99mTc-DMSAon the walls
and stoppers of glass vials from different manu-
faclurers have been observed with siorage (1 I 1 j.
OXIDATION AND/OR RADIOLYTIC
DECOMPOSITION
In theformulation of 99mTc-labeledradio-
pharmaceuticak, avariety of factors may pro-
duce delrimental effects on the inilia1 labeling
process and subsequent stability. Many of these
factors are related to oxidationandradiolytic
decomposition which lead to increased levels of
free 99mTc-perlechnetale andlor 99mTc-labeled
colloid impurities and subsequent image degra-
dation.
In order for 9 9 m Tlo~bind to most chelaling
reagents, it must be reduced from the + 7 val-
ence state of perlechnetate to a lower valence
stale. This reduction usually is accomplished by
the stannous ion (SnY2) in the reagent kit.Sn+2
is readilyoxidized byatmosphericoxygen to
stannic ion (SII+~) which is no longer capable of
reducing pertechnetate. Therefore, reagent solu-
tions and lyophilized kilsusually are purged
wilh nilrogen andlor have nitrogen atmospheres
in order to remove the atmospheric oxygen re-
sponsible for this oxidation (7, 2 8 , 2 9 , 32, 112).
Furthermore,siorage at refrigerator or freezer
temperatures has been shown lo inhibit the rale
of oxidation (28). Trace amounts of oxygen may
continue to produce this oxidation during man-
ufaclureandlorstorage of reagentkits, es-
pecially if faully vial seals allow the entrance of
air ( 1 13). For~nulationof such a producl usually
results i n decreased labeling efficiency with in-
creased free 99mTc-pertechnelate impurity.
Oxidizing agents present in 99Mo/99mTc gen-
erator eluates aIso may interfere with the tech-
netium labeling process. Ionization of water in
the generator column produces hydrogenperox-
ide (H20Z) and, in the presence of oxygen,
hydroperoxy free radicals (.HO?) (9, 114). Both
of these compounds are strong oxidizing agents
and react with S ~ Ito+produce
~ Sn+4. In some
cases, the number of peroxide molecules added
toa reagent kit may b e of the same order of
magnitude as the number of Sn+2 ions (9). Re-
ports of decreased labeling efficiencies and in-
creased free 99mTc-per~echnetate impuritiesare
cornrnonly associated with these larger-than-ex-
pected concentrations of peroxides and hydro-
peroxy radicals (9, 39, 115).
Of a similar natureis the reporl of poor label-
ing and rapid unbinding of 99mTc by iodinated
antiseptics, with resullant 99mTc-pertechnetate
impurity. Iodinated antiseptics are good oxidiz-
ing agents and, if inadvertently introduced into
the vial afier sterilizationof [he septum, may
inhibit labeling with or may release previously
bound 9 9 m T(116).~ With theuse of alcohol
ralher than iodinated compoundsfor steriliza-
lion procedures, this effect can be avoided.
Oxidation of reduced and chelated 99mTcmay
also be associatedwithphysical factors.For
example, ultrasonic nebulization of 99mT~-
DTPA for radioaerosol lung studies reportedly
results in the liberation of >50% free pertechne-
(ale (117). Thus, since 99mTc-pertechnetateand
-"Tc-DTPA have different clearance rates from
the lung, ultrasonicnebulization may result in
variable, inconsistent lung studies.
Decomposition of radiopharmaceuticals is
characterized by four mechanisms: internal ra-
diation effects, direct radiation effects, indirect
radiation effects, and nonradiolytic chemical e[-
fects ( 1 18). Of significance in radiopharmaceu-
tical solutions are the indirect radiation effects
resulting from theionization of waterwhich
produces the strong oxidants, hydrogen perox-
ide and, in the presence of dissolved oxygen,
hydroperoxy radicals (114, 119). Radiolytic de-
composition is a function of total radioaclivity
c o ~ ~ t e nsince
t, it is dose rate dependent rather
than total dose dependent (33, 1 18). Decom-
position of virtuajly all radiopharmaceuticals
will occur if sufficienl time is allowed;however,
the rate of decompositionvaries widely froom
one radiopharmaceuticalto another and from
280 I Essenfinls ojNuclear Medicine Science Clinicol Manijeaoiions uf Furmulalion Problem f 281

one formulation and/or storage factor10 another SPECIFIC ACTIVITY ratios and inferior image quality. It should be be traced to reactions with benzyl alcohol, the
(59, 120,121). All radiopharmaceuticals noted, however, that in the presence of circulat- most commonly used active agent in bacterio-
should, therefore, be used as soon after prepara- The specific activity of radiopharmaceuticals ing antigen, a lower specific activity of radiola- static saline.
tion as possible to avoid radiolytic decomposi- may have important effects on their biodistribu- beled antibodies is desired. If high specific ac- When bacteriostatic saline is used to elute a
tion problems. lion. The effects of lowered specific activity on tivity and small amounts of total antibody are 99MoP9mTcgenerator, up to 99% of the 9 9 m T ~
The stability of radiopharmaceuticals can be radiopharmaceutical biodistribution are most administered in this case, most of the radioac- activity may be retained on the generator col-
prolonged by a number of tacticsthatinhibit pronounced when the localization of the agent tivity will be complexed to circulating anligen umn (153). It is theorized that the benzyl alco-
oxidation andlor radiolytic decomposition. demonstrates saturation pharmacokinetics. Sat- and cleared into the liver (147). hol in the bacteriostatic salinemay be trans-
Since dissolved oxygen promotes formation of uration may occurwheneverthere are only a The distributionof some radiopharmaceuti- formed by radiolytic oxidationto benzaldehyde,
hydroperoxy radicals, then minimizing the ex- limited number of receptor sites,carriers,en- cals is relatively unaffecled by specific activity. a weak reducingagent.One or both of these
posure of aradiopharmaceutical to the atmo- zymes, or otherinteractivebiologicalsub- Carrier macroaggregated albumin does no[ af- species may thenreducethe gPmTc-pertechne-
sphere, limiting introduction of air (especially stances responsible for the localization (136). In fect the quality of lung perfusion images ( 9 3 , a tate in situ to an insolubleformwhich is re-
bubbling) into the vial, and purging the solution these circumstances, carrier will compete with 106-fold excess of carrierghconatedoes not tained on the column.
wilh nitrogen helpminimizeoxidationand/or the specific radiopharmaceutical for these influencedistribulion of 99mTc-gluconate(4). Baclerioslatic saline used in (he preparaLion
decomposilion ( 3 1 , 33, 34, 51, 56, 5 9 , limited sites, and if saturation occurs, target-to- and a 105-fold excess of carrier HEDP does not of 99mTc-Iabeled radiopharmaceuticalsmay ad-
122- 125). Commercially available physiologic backgroundradioactivityratios will decrease. significantly change99mTc-HEDPdistribution verselyeffecttheradiochemicalpurily,sta-
saline containing low dissolved oxygen is being A classic example of this phenomenon is the (4). bility, and biodistribution. 99mTc-pertechnelate
promoted as offering beneficial effecls on radio- thyroid uptake of radioiodide. As little as 1 mg dissolved in bacteriostatic saline demonstrates a
pharmaceuticalIabeling and slability. Routine of carrier iodide may produce notable decreases SOLUBILITY significant increase in the percentage of wmTc-
use of low dissolved oxygen saline remainscon- in the 24-hour I3ll uptake (137), and doses ol The solubility of Y9mTc-labeled radiopharma- labeled colloid impurities. 99mTc-MDP prepared
troversial, however, in light of recent data show- sodiumiodide > I O mg suppressthe24-hour ceuticals in a suitablemediaforintravenous withbacteriostatic saline exhibits significantly
ing that the labeling efficiency and stability of radioiodine uptake by 98% (138). adminislration usually does not present a severe morefree99mTc-perlechnetate impurity, faster
99mTc-gl~~ceptate andtheclinical performance For the Schilling test, the amount of non- problem, because of the polar hydrophilic rate of decomposition, and higher blood, mus-
of *mTc-MDP were only minimally affected by radioactive cyanocobalamin in the ~ y a n o [ ~ ~ C o ] - nalure of most of these agents. Some radiophar- cle, and liver backgroundactivity than does
the oxygen content of the saline used (126, cobalamin capsules has been shown to be criti- maceuticals (e.g., radiolabeled cholesterols. Y9mTc-MDPprepared with preservative-free sa-
127). Excess stannous ion is effective for pro- cal. Amounts >2 p g appear to exceed the satu- amino acids, fatly acids), however, are insoluble line (153). Because of thesepotential de-
longing stability but may result in colloid for- ration level for intrinsic factor and may result in in water at physiological pH values, and their leteriouseffects,only preservative-free saline
mation if [here is an overabundance of this ion falselylow valuesforabsorption and urinary formulation is problemalic. A common problem shouldbe used in the preparation of 9 9 m T ~ -
(31-34).Perhapsmoreeffectiveistherecent excretion(139,140).Increasingamounts of encounteredwith use of lheselatteragents is labeled radiopharmaceuticals.
use of antioxidanls (viz., ascorbic acid and gen- 9mTc-labeled sulfur colloid particlesaffect pha- incomplete or unstable solubilizalion leading IO Benzyl alcohol is of limited applicability for
tisicacid) in g9mTc-labeledboneimaging gocytic localization, which results in a gradual increased RES andlor lung localization as a re- two additional reasons. First, it is a vasodilator
agents, which have dramatically improved sta- decrease in liver uptake and an increase in bone sult of colloidandlorparticulateformation and, therefore, cannot be usedwitha reagent
bility and image quality with storage over sev- marrow uptake (82). Likewise, the number of (148). Based on toxicity consideralions (see suchaslJJXe in saline solution intendedfor
eral hours (32, 34, 125, 128-132). It should be damaged radiolabeled RBC adminislered for a Chapter20), therequirement for intravenous regional bIood flow measurements.Second, it
noled, however, that preparations stabilized with splenic sequestration study may be important in administration of most radiopharmaceuticals undergoesradiationdecompositionwith the
antioxidants may demonstrate higher levels of certain clinical situations in which overloading limitsthe choice of sur€actants availablefor production of a precipitate (presumably benzoic
reduced-hydrolyzedtechnetiumthan do non- the sequestering ability of the spleen is possible solubilization of agents (149, 150). Recent evi- acid) in certainsolutions of high radioactive
slabilized preparations (133). Oxidation and/or (68). The presence of carrier markedly affects dence supports the use of hydroalcohol human concentrations (154).
radiolytic decomposition proceeds at faster rates the biodistribution of 67Ga-citraie by inhibiting serumalbuminsolutions(151)and the rela-
with increased temperatures; therefore, reducing localization in allusual(expected) organs ex- tively nontoxic poly(oxypropylene)poly(oxy- ANTICOAGULANTS
the temperature by refrigeration may noticeably cept bone (141, 142). ethylene)condensates (Pluronics)forthis pur- The in vitro labeling of RBC for subsequent
prolong the stability of most radiopharmaceuti- Many of the newer and investigational radio- pose (152). reinjectionrequires that the bloodsample be
cals (53, 118, 134, 135). The addition of car- pharmaceuticalsarelocalized bymechanisms fullyanticoagulated. Unfortunately,thepres-
rier, although seldom desired, may improve the wilh limited capacities. Examples include car-
PRESERVATIVES ence of an anticoagulant, usuallyheparin or
stability of manyradiopharmaceuiicals (40, rier-mediated uptake of hepatobiliary agents Since sterility of products for parenteral ad- acid-citrate-dextrose (ACD), may affect the la-
118). Finally, because radiolylic decomposition (136),anlibody-antigeninteractions involving minislration is essential, one might surmisethat belingandlorbiodistribution of thelabeled
is a function ol total radioactivity content, more radiolabeled specific antibodies (143, 144), and baclerioslatic saline would be used in [he prepa- RBC. For example, RBC labeled with 9 9 m Tin~
stability is achieved from formulation with the hormone-receptor localization ol radiolabeled ration of injectableradiopharmaceuticals.Un- lhe presence of heparin show a lower labeling
minimu~ndesired radioactivity than is achieved hormone analogs (145, 146). In each of these fortunately,bacteriostalic salincmay havese- efficiency,moreextravascularactivity,and
froom formulation with larger amounts of radi- cases, lowered specific activityresults in de- rious deleterious effects on many 99mTc-labeIed more urinary excretion than do those labeled in
---A:..:*.. (7') 1 1 n 114 1 1 7 1151 m m s d tarpet-to-backgroundradioactivity radiophannaceulicals. Most of these eflects can ACD (8). Excess ACD, however, causes damage
282 I Esselniols of Nuclenr MedicineScience
lo RBC,withresultantsequestration in the
spleen ( 155).
ENCAPSULATION
Encapsulation of radiopharmaceuticaldoses
for oral administration has gained widespread
acceptance as a convenient method for the han-
dling, dispensing, and administering of certain
radioaclive compounds.The use of encapsu-
lated radiopharmaceuticals presupposes thal Ihe
capsule will rapidly disintegrate and its contents
dissolve in the stomach fluids and that the radio-
pharmaceutical will no1 interactwith the cap-
sular ma~erials.Some evidencehassuggested
that the aforementioned assumptions are not
valid and that this oral dosage form may alter
the biodistribution of the radiopharmaceutical.
The possibility of residual I 3 ' I contained in
some undissolved capsule was sugpesled as the
cause of right-lo~ver-quadran1activity reported
in a patientadminisleredencapsulated sodium
[I3'I]iodide (156). Subsequenl studiesof the ef-
fect of encapsulation on thethyroid uptake of
I3]I demonslratedsubstantially lower uptakes
with I 3 l 1 capsules thanwith 13'1 oral solulion
(156). Proposed mechanisms for this effect in-
clude delayed dissolution and absorption of the
radioiodine, formalion of nonabsorbable iodine
complex with capsular material, and(or absorp-
tion of radioiodinated gelatin. A situalionhas
also been reporled in which the presence of p-
naphthol, a bacterioslatic agent in the I3lI cap-
sule, resulted in the formalion of iodinated p-
naphthol (157). This effect is most serious when
it may alter [he inlerprelation of a radioactive
iodine uptake study or produce visualization of
abdominalactivity. With the recent develop-
ment of a new I3'I capsuleformulation, how-
ever, it is reported that [he aqueous radioiodina-
tion of gelatin can be prevented by suspending
theradioiodinewithina polyelhylcneglycol
base (158). Furthermore, rapid dissolution of
(hepolyethyleneglycolbase in gastricfluid
allows bioavailability equalto that fromoral
solutions (158).
Encapsula~ed cyano[s7Co]cobalamin, com-
pared with cyano[5~Co]cobalamin solution, has
been shown to result in significantly decreased
absorplionandurinaryexcretion when admin-
ical tMurl$esrarions of Formulation Problems t 283
islered for Schilling tests (159). The difference orderto obviatetheeffect of exchange reac- reduces the vapor pressure of volatileiodine
in drug availability between the capsule and [he tions, it may be desirable to perform the tradi- (176).
solution is probably due lo both the speed of tional Schilling test in most cases (165). One last formulation method for reducing
capsule dissolution and the passage of the cap- volatility of I3'I is encapsulation of theradi-
IODINEVOLATILITY oiodide. I 3 l 1 diagnostic and therapeutic capsules
sule mass from the stomach to the duodenum.
Inhalation of volatilized radioiodine is a ma- have been s h o w to produce negligible airborne
Since falsely low urinary excretion values ob-
jorproblem associatedwiththe handlingand radioactivity, probably because many oxidation
tained with the encapsulated material may resull
administration of sodium [I3[I]iodide oral solu- factors are eliminaled andlor the iodine may be
in a false interpretalion of pernicious anemia, a
tions. Airborne I3lI activity in excess of max- absorbedby the capsular malerial (158, 167).
liquid dosage form is recommended (159).
imumpermissibleconcentrationshas beenre-
The interpretation of second-stage Schilling RADIONUCLIDICCONTAMINATION
ported with the handling of lherapeutic amounts
tests may be altered bytheadministration of
of 1311 andthe administration of suchdoses Several radiopharmaceuticals contain radi-
encapsulated doses. The coadministrationol en-
(167, 168). Furthermore, the thyroid glands of onuclidic impurities in large enough quanlities
capsulatedintrinsicfactor, comparedwiththe
the personnel handling these doses may be ex- to be of concern. Especially susceptible to the
administration of a solution of intrinsic faclor
posed to substantial radiation by the accumula- production 01radionuclidic contaminants are
premixed with ~yano[~~Co]cobalamin, has been
tion of I3lI (167-172). those radioisoiopesproduced in a cyclotron.
shown to result in significantly decreased urin-
Theiodide ion in sodium[13'I]iodidesolu- Anotherpossiblecause of significantradi-
ary excrelion ( I 60). The difference in urinary
tions is easily oxidized to iodine by dissolved onuclidic Contamination is parent breakthrough
excretion between the two forms of administra-
oxygen in anacidic solution(173, 174). The in a generatoreluate. 9 9 M contanlination
~ of
tion may be due to prolonged capsule dissolu-
presence of oxygen can occur from exposure to 9 9 m Tproducts
~ is negligible, however, since it is
tion, biological inactivity of some commercial
air (174) andlor oxygen generalion by [he radi- limited lo 0.015% for administration 10 patients
intrinsic-factor preparations, andlor the binding
olysis of water (171). Hydrogen ionscan be ( 177).
of intrinsic factor to blocking antibodies in the
presentfrom acid formulation of the solution One of themost imporlantconcernsisthe
gastric juice ( 1 60- 162). Since falselylow urin-
(16s) and/or lrom reactions accompanying the increase in radiation-absorbed dose from the
ary excretion values obtained with encapsulated
dissolutien of carbon dioxide in water (174). radionuclidic impurities. For example, the radi-
intrinsic faclor map result in a false interpreta-
The iodine thus formed is not very soluble in ation-absorbeddosestothethyroidandthe
tion of intestinal malabsorption, inlrinsic factor
waterand rapidly volatilizes out of solution whole body from radioiodide impurities, e.g.,
and ~yano[~~Co]cobalamin should be mixed to-
( 174). 124J in some 1231 products, approach, and may
getherinwaterpriortoadministration
The rale of volatility is influenced by a vari- even exceed, the doses from the principal radio-
( 1 60- 162).
ety of factors. anda number of methods that isotope (178).
ISOTOPE EXCHANGE diminish this rate hsve been developed. The Anotherconcern is the potential errors in
most imporlant faclor is that of pH. The use of dosecalibration.Since an ionization chamber
The dual-isotope (Dicopac) Schilling test al-
buffers to maintain an alkaline pH has resulted does nothaveintrinsic energydiscrimination
lows simultaneous performance of first- and
in significanlly lowered volatility rates and de- capability, the presence of radionuclidic im-
second-stage Schilling lests for the diagnosis of
creased thyroid accumulation, as comparedwith purities will affecl the reading of the instrument
pernicious anemia or inteslinal malabsorption
acidic formulations (168-170, 172, 175). (179). For example, the presence of radioiodide
syndrome. Unlike [he traditional Schilling test,
Several olher formulation methods also focus impurities in some 1231 products has been shown
thedual-isotopeprocedureemploys 1he coad-
on the oxidation reaction. Addition of an antiox- 10 significantly increase dose calibrator readings
ministration of cyano[~*Co]cobalarninand
idant such as sodium bisulfite or thiosulfate to (180, 181).Similarly,thepresence of radi-
cyan~[~~Co]cobalamin bound to human intrin-
the forn~ulationhelps to inhibit the oxidation of oiodideimpurities in some ]l3I products can
sic factor. Experience, however, has indicated a
iodide tovolatile forms of iodine (158, 168, introduce substantial errorsin radioactive iodine
disturbingly high frequency (17-46%) of spu-
174, 175). Inclusion of a chelating agent such as uptake (RAIU) measurements, especially if the
rious results with use of the dual-isotope method
disodium edelate prevenls catalytic oxidative re- probecounter is usedintheintegralmode
(163-165). These misleading results are proba-
aclions by melal ions ( 1 68, 175), and the use of (181-183).
bly due to rapid or variable rates of exchange of
distilledwateras a diluentcircumventsthe Of paramount concern clinically is image
bound and free cyanocobalamin on the intrinsic
problem of iodide oxidation by chlorine in tap degradalion caused by Compton scatterand sep-
faclor molecule (165, 166).Theexchange is
1: waler ( I 7 1). Sloriag and handling the solulionat tal penetration of high-energy photons emitted
especially striking at anacidic pH at which
room temperature or below helpsinhibitthe by radionuclidicimpurities.Significantimage
equimolar equilibrium may be achieved within
heat catalysis of [he oxidation reaction (174) and degradation has been observed with the use of
10 minutes in simulated gaslric juice (165). In
284 I Esser1riuls of Nuclear MedicineScience
lZ3Iproductscontaining 1241andotherradi-
oiodide contaminants (178, 184-186) and with
the use of 20'Tlproducts containing ZmTland/or
202T1contaminants (187, 188). For example,
Ricciardone et al. (189) haveobserved prob-
lems in cases in which [201Tl]thallous chloride
was used more than 3 days prior to the date of
calibration. Specificaily, at 4 daysprecalibra-
tion, the radionuclidiccontaminant 200T1
(which has a shorter physical half-life than does
201T1)may be present at levels that cause image
degradation.
Radionuclidicimpuritiesoftenhavelonger
half-livesthan do the principal radionuclide
(e.g., 12J1,*02T1).Thus, the percentage of radi-
onuclidic contanlination continuously increases
with time. lncreases in radiation dose, errors in
dose calibration and activity measurement, and
imagedegradalion,therefore,becomemore
pronounced as the time of use approaches the
expiration time.
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enclosed in capsules. A m I/nena M e d 83:827-829,
1975.
161. Jacobson BE, Onstad OR: Misleadingsecond-slage
Schilling tests due to inaclive mlrinsic factor concen-
Irate. A m /m/errz Med 91579-580, 1979.
162. Ponto JA: Queslionnblc bioactivity of inlrinslc factor
lorsecond-slageSchillingtest. Am J Hosp Plfnmf
37:1294-1296. 1980.
163. Pathy MS. Kirkman S , lvlolloy IMI: An evaluation or
s~rnullaneously administered free and intrinsic [actor
bound radioactive cyanocobalamin in the diagnosis or
perniciousanemia intheeIderly. J Chra Parlfol
32:244-250,1979.
164. Choy YC, Kim EE, Domslad PA, et al: Reliabilily of
dual isotopeSchillinglest for Iht diagnosis ol per-
niciousanemia or malabsorptionsyndrome. J A'ucl
Med 21:P26,1980.
165. Fairbanks VF?Wahner HW, Valley TB, el al: Spurious
results fromdual-isotope(Dicopac)vilamin BE ab-
sorption test due IO rapid or variable rates of exchange
of 5*Co-Bl2Tor "Co-B,, bound to intrinsicfactor. Nucl
Mcd Curnrfawr 4: 17-23, 1983.
166. Donaldson RM, Katz JH: Exchange between free and
gastric juice-bound cyanocobalamin. J Clilr Invesl
42334-545, 1963.
167,Browning El, Banerjee K, Reisinger W E Airborne
conccnlration of 1-131 in a nuclear medicitlc Iabora-
lory. J Nucl Mcd I9:1078-1081, 1978.
168. tuckett LW, SlotIer RE: Radiolodine volat~l~zation
from relomulaled sodium iodide I3'l oral solution. J
Nrrcl Med 21:477-479, 1980.
169. Carey JE, Swanson DP: Thyroid contamination lrom
airborne '311.J Nut( Med 20:362, 1979.
170. Jackson GL, MacInlyre F Accumulation of radi-
oiodine in stall members. J Nucl Med 20:995, 1979.
171.MaguireWJ: A precaulionforminimizingradialion
exposure from iodine vaporization. J Nucl Med Tech- 188. Hines HH, Lagunassolar MC: The effeect of different
~rol8:90-93, 1980.
172. Nishiyama H , Lukes SI, hlayfield G. el al. Internal
contamination of laboratory personnel by 1311. Radr-
dogy I36~767-771, 1980.
173. Howard BY: Safehandling of radioiodinated solu-
tlons. J A ' d Med Techol 4:28-30, 1976.
174. Croh BY: Safe handling of radioiodine. J NIV,,C/ Med
20:362-363,1979.
175. Wollangel RG: Accumulation of radloiodine in staff
members. Reply. J NuclMed 20:995, 1979.
176.Grossman LW. WilliamsCC: Chilling-an ellectlve
way of reducing volalilily ol therapeutic iodine soh-
tions. J h c t Med 21:P93. 1980.
177. Ponlo JA: Expirationlimeslor ""'Tc. J Nrd Mpd
Techrzul 9:40-4 1, I98 1 .
178. Baker GA. LumDJ. Smith EM, et a1 Slgnificance or
radioconlaminants In Iz31lor dosimetry and scintilla-
tion camera imaging. J N w t Med 17:740-743, 1976.
179. Suzuki A , Suzuki MN, Weis A M : Analysis of a radio-
isotope calibrator. J N'ucl Med Teclrml 4:193-198,
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180. Johnson AS, Baker SI. Arnold JE, e l al: Radionuclide
impurilies in commercial 1231 andtheir influence on
ihe dose calibrator assay or 1231. J N I K / Med 16:540, 195. hlajewski R', Zimmer AM, Spies SM: Radiochern~cal
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181
errors caused by vanable radionuclidic purityol 1231, J
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182 Chervu S. Chervu LR, Goodwin PN, et al: Thyroid
uptake measurements with 1231: problems and pitfaIls:
concise communication. J Nrrcl Med 23:667-670,
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183
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Nucl Mcd 20:803-805, 1979.

19
lnstrumentation and Procedural Problems in
Nuclear Medicine
In thischapter,thenuclear instrumentation
problems, procedural errors, and resultant scin-
tiphoto artifacts that might be encounlered be-
fore, during, and after a nuclear medicine scan
are discussed. In practice, whenevera scin-
tiphoto is of unacceptable quality or contains an
evidentartifact, it generallyisdiscarded, cor-
rective actions aretaken and, if possibie, the
study is repeated. Instead of discarding the un-
acceptable scan, however, a notebook of all of
these imaging artifacts could be compiled and
made accessible to all personnel in the depart-
ment.Thisartifact identificationnolebook is
especially useful in a teachinginstitution in
whichtechnologislsorresidentsarcbeing
trained. There is no better learning axiom than
that “you learn by your mislakes. ” It is much
easier on a department for rookies to learn from
the mistakes of others, as cited in the artifact
notebook, than for each individual Io repeat all
the common mislakes made bythose who came
before.It also becomeseasier to identifyor
recognize the cause of many artifacts by refer-
encing the manual or notebook.
The following should beplaced in the artifact
notebook:
1. A copy of thescancontaining the artifact
2. A brief description of theprocedure per-
formed
3 . Identification of the inslrumentalion used
(i.e., camera, collimator, etc.)
4. Corrective action taken to remedy the situa-
tion
5. A description of (he condition(s) causing the
artifacl
Inmwenrarion and Procedural Problems I 291
1 , During quality control (QC) procedures ment of the functional statusof our instrumenta-
2. lmmediately prior lo patient imaging (during tion and can, in fact, be a source of artifacts or
setup) pseudoabnormalities on subsequent patient
3. During patient imaging scans. Much time, effort, and patient inconve-
4. Afterimaging
In additiontothese temporally related catego-
nience can usualIy be saved by performance of
adequate QC tests prior to patient imaging.
ries, instrumentation problems are classified Manyproblemscanoccur with use of bar
into (a) those associatedwith planarimaging phantoms for linearity and resolution measure-
and (b) those associated with ECT. Those issues ment and with use of field flood phantoms and
or parameters common to both are discussed in sheetsourcesforenergy
this first section on planarimagingproblems;
calibration and field
uniformity tests. As is evident on the field uni-
those unique to ECT are discussed in the section formity image (Fig. 19.1), valuable information
on ECT imaging problems. is gathered concerning the functional slatus of
the gamma camera. In Figure 19.1, an obvious
PLANAR IMAGING PROBLEMS area of no activity is seen; this is highly indica-
6. Recommendations to preventtheproblem tive of a “burnt-out” photomultiplier tube.
from occurring again During QC Procedures
Forassessment of linearity,operatorsin
Problems associated with QC procedures are many nuclear medicine laboratories visually
An article by Johnson and Damm stresses the probably the most important to study. When QC judge the slraightness of the pattern produced
importance of maintaining anartifact manual testsareproperly performed, [hey provide a by a parallelbar phantom. Lee ( 5 ) hassug-
andgivesdetailedinformationfororganizing measurement of the functional status of our in- gested that determination of the straightness of
one (1). The artifact notebook or manual can be strumentation.When they are improperly per- the bar phantom often depends on the subjeclive
a valuable resource to those who are new to the formed, lheyprovide an inaccurale measure- opinion of Ihe individual. In his articIe, Lee has
field of nuclearmedicine, new to thedepart-
ment,orunfamiliar with a particulartype of
instrumentation in the department.
In this chapter, many of the instrumentation-
related artifactsandproceduralerrors that are
most likely to occur in a “standard”nuclear
medicine imaging laboratory equipped with
planarandemissioncomputed Lomography
(ECT) imaginginstrumentation are discussed,
A quality control checklist thal, if followed rig-
orously, should prevent the majority of artifacts
from everoccurring is presented.Whenthe
checklist and artifact nokbook are used in con-
junction, they becomevaluabletools for the
prevention, diagnosis, and treatment of imaging
illnesses.
The actual techniques and methods for per-
formingnuclearmedicinequalitycontrol and
imaging procedures arebeyond the scope of this
chapter; many excellent textbooks are available
for this type of information (2-4). In this chap-
ter, problems in nuclear medicine imaging and
the means ol rectifying these problems are the
primary focus.
lnstrumentationandproceduralproblems
Figure 19.1. Burnt-oul photomuItiplier lube on field flood image.
may occur in any one or more of the following
time frames:
292 I Essenriuls o j N~rrclearMedicitze Science

described a quantitative method of measuring bacteriostat such as bleach, periodically placed

intrinsic linearity wilh use of a Smith orthogo- in thephantom, will preventbacterial sludge
nal hole (SOH) phantom. from building up in the phantom and will lessen
Field uniformity quite frequently is assessed the messy task of emptying and filling the phan-
with use of afieldflood phanlom or a sheettom.Improperpositioning of thephantom, its
source at only one energy. A 57C0sheet source sources, or other sources into the camera field
rather than a 99n'T~ field flood phantom often is of view during bar phantom imaging can also
used, since its main pholon energy is near that produce unusual artifacts (9).
of 99mTc.Lewis et al. (6) have suggested that Recordingmedia,be it floppydisk or film,
patient studies not perfomed with 9 9 m Tmay ~ must be acceptance lested periodically toinsure
display different field uniformity and thal data proper type and function. In a study conducted
systemsproviding fielduniformity correclion by Grossman et al. (IO), substantialchanges in
(from T o source) can, on occasion,produce filmresponse as a function of imaging time or
clinically significant artifacls. QC studies on all dot focus were noted. The phenomenon respon-
scintillation cameras in the departmentshouldsible for thisvariation in filmresponse was
be conducted to assure that field response does referred to as a "film reciprocity law failure"
not change with photon energy. and is inherent
an feature of the
image-forming
Lukes et al. (7) havestatedthat *O'TI imagingprocess. Routine QC measures can be struc-
artifacts werenotdetectedon 9 9 m Tor~ 57C0 tured not only to veriEy instrumentoperation but
field uniformityimages. On 'O'TI scans of a also to slandardizephotographicresponse(i.e.,
patient, hot spots were noted; on 9 9 m Tand ~ 57Co an f-slop adjustment to account for various film Figure 19.2. Double exposure of thyroid scan on liver scan.
fieldflood images,these hotspots were not speeds).
seen.When a *OIT1 lieldflood image anda The acceptance test forincomingshipments
I3?Xe field flood imagewere obtained, each of film might be avisual inspection of film type
displayed the same hot spols as werenotedon and expiration date. Floppies would be accepl-
the ZolT#scan of apatient. Thisphenomenonance tesledto insure they would be the correct
occurred, according to the authors, bec,ause the type for your computer's disk drives (dual, sin-
crystal in thecamera was in theearlystages of gle density,single- or double-sided). This in-
hydration. Early stages of hydration produce a spectson should be performed immediately prior
variety of reflective changes at the front surface to inilializing each disk or on receipt of a large
of thecrystal,where 90% of 2*1T1and j3'Xe shipment of disks.
pholon absorptionoccurs (only 38% of 9 9 n 1 is T The
~ film cassetteisanother ilem that should
absorbed in the first2 mm of the NaIcrystal). be periodically inspected for light leaks. After
This crystal hydration was responsible for the continueduseandabuse,cassetteslidesand
energy-dependent nonuniformity. frames
become
can
loosened,
which
allows
Many problems can be caused by the simple light leaks to occur.
filling and handling of a field flood phantom. Figure 19.2 shows what might occur if film
Adding 99mTc-labeledparticulates or colloids to from apreviousstudy is left in the camera; a
a field floodphantomshouldbeavoided,as double exposure results. This can be prevented
they sometimes do not mix homogeneously by developing film immediately after cornple-
throughoutthe phantom (8). Imaging such a tion of a patient's scan. This practicewill help to .
phantom would givetheappearance of non- prevent patient-scan mix-ups.
uniform camera response. [99'nTc]pertechnetate, Anolher oversight that can result in a double-
due to its ionic nature, is the best radiopharma- exposureisobservingtheenergyspectrum
.
I
c

ceutical to add to a phantom. Another common while the film slide is pulled and then perform-
problemisleaving a large air bubble in the ing ascanwithout advancing the film(Fig.
phantomwhich shows up on lhe imageas a 19.3).
paucicy of pholons in thearea of thebubble. Many items on the preimaging checklist (Ap-
This problem is easily circumvented by displac- pendix 19.1, page 302) may be inspected during
ing the air with tap water. A few lnilliliters of a QC testing of the instrumentation. Items such as Figure 19.3. Double exposure of energy speclrum on liver scan.
 Imrumerziaiiord and Procedural Problems I 295

severely damage the crystal or actually bend or obese patient) optimizes PHA acceptance of
filmintensity settings, CKT focus, CRT lens collimator was used for thescan which ob-
close the lead septa of the coIlimator. Extreme scattered photons and not primary imaging pho-
cleanliness, and radiocontaminalion in the cam- viously is not thick enough to adequately colli-
caution must be exercised when coIIimators are tons, which results in image degradation. The
era field of view can be checked before or dur- mate the 364-keV I3lI photons. The mechanical
act of mounting and removing collimators can, changed, to protect not only the camerabut also energy spectrum switch should be placed back
ing QC testing. Another useful and often-over- the technologist and patient. Improperly tight- into the imaging mode if this has notalready
looked QC lest is that of t h es c a n n i n g of itself,lead to inslrumenlartifacts.Inadver-
tently crushing the collimatorbolts or olher arti- ened collimator bolts might be disastrous if a been done automatically.
mechanism. The scanningmechanismshouid patient is on the receiving end of a falling col- Thecameraor patient orientationswitches
always have a totally unobstructed path in order cles in between the collimator and crystal may
limator. should be considerednext. In somesystems,
to insure free and precise tracking. Therefore, a One of the most commonly overlooked set- this orientation switch is located on the console,
brief visual inspection of the pathway prior to tings on the gamma camera consoleis the radio- while in others, orientation switches are located
scanning should always be performed. A strale- nuclide selection switch or energy potentiome- on the back of the detector. Proper orientation,
gically misplaced paper clip can bring [he entire ter. Many new cameras feature automatic energy if questionable, may be checked by placement
scan to a hall. Additionally, a scanner linearity calibration, while most of the older ones require of a radioactive source in one quadrant of the
lest should be periodically performed. A scan- manualcalibration by visualization of theen- camera field of view and then by observation of
nerlinearity image will insure that successive ergy spectrum. The necessity for “peaking” the its relative position on the CRT; orienlation set-
passes for a dual- or a lriple-pass scan are prop- camera with a source other than the patient has tingsthen may be changed to getthe“heads
erly and precisely aligned on the resultant scin- been substantiated in many studies. Calibration up”orientation to which all of usareac-
tiphoto.Scanlinearity may be readily accom- of thecameraover thepatient (especially an customed. Nothing can be more aggravating for
plished by placement of a field flood phantom
(or sheet source) on the scanning table so that it
overlaps the adjacentscanning paths. The bar
phantom is then placed above or below the field
flood (depending on where the camera head is)
so that a bar phantom transmission scan may be
obtained. The bar phantom is then scanned on
dual or triple passes (syslem dependent), and an
image is obtained. The resultant.image of the
bar phantom should display straight bars all the
way across the width of the scan. If a parallel-
line equal-spacing (PLES) phantom is used, it
must be placed on thetable in anorientalion
such that the lead bars are askew from the scan-
ning direction. This orientation will make non-
linear alignment on the scintiphoto more appar-
ent to the observer.
lmmediately Prior to Imaging
After all necessary QC tests and inspections
are performed, setup fora specific study should
begin. Several things usually should be accom-
plished immediately prior to patient arrival.
The proper collimator must be selected for
the upcomingexaminations.Collimator selec-
tion criteria include: energy, resolution, sensi-
tivity, convergent, divergent, pinhole, and to-
mographic. Improper collimator selection at
this poinl may result in an unacceptable scan,
which is why it is included in the QC checklist.
Figures19.4 and 19.5 are sodium [1311]iodide
whole-bodyscans. The star patlern in thesc Figurc! 19.4. Septal penetration. 1311 whole-bc
scans is due Lo septal penetration. A 300-keV scan obtained with use of a 300-keV collimator.
. .:..
296 I Easenrials of Nuclear Mediciue Science
a diagnosticianthanto have lo flip-flopand
rotate one piece of film with multiple views
several times in order to get the proper perspec-
tive. On most computer systems, proper orien-
tation needs to be selected also.
Some sorl of patient identification should be
entered into the computer so that the film will
be identifiedaccordingly. Thecomputerand
camera shouldthen be placed into the proper
acquisition mode. The acquistion mode should
signal the computer as to what type of study is
to be performed and whether there is enough
storage left for that shdy; the cornpuler should
indicate when there is not enough storage left.
Somesystemsor proceduresrequirethat the
operatordetermine whether there is adequate
storage space for an examination. Information
giventothe compuler andlor camera may in-
clude preset count or preset time, dynamic or
staticimage. time per frame, lime delay be-
tween frames, number of images Iota1 and per
film, gated or nongaled sludy, and information
density.
Other items on the preimaging checklist (Ap-
pendix 19.1) are of a procedural nature, not an
instrumentalnature.Firstandforemoston the
procedural portion of the list is: “Did the patient
receive the correct radiopharmaceutical for the
examination. and did thepalientreceivethe
proper amounl of the radioactivity for his size
and age?” Misadrninistrations of a diagnoslic
radiopharmaceutical, although not generally of
a life-threatening nature due totheir lack of
pharmacological activity,do, in fact,result in
patient inconvenience, unnecessary radialion
dose. waste of time, and unwarranted expense.
Too much or too little radiation flux from [he
patient may resull in an image of unacceptable
quality. Alterations in the biodistribution of ra-
diopharmaceuticals may be anticipated from the
patient’s medical history. These alterations may
be due to iatrogenic or pathologic causes and
necessitate a change in the normal injection or
imagingprocedurefor that particular palient
(seethe approprialechapters in this book for
details). The patient’s char1 should be checked to
insure that the patient was adequately“prepped”
for the nuclear medicine procedure. The chart
shouldalso be examined, or thepatient ques-
tioned, to ascertainwhether thatpatient may
have receivedany radiodiagnostic,radiothera-
menlally. Place 2-5 mCi of ”mTc-pertechnetate often results in an appearance of asymmetic
peutic, or pharmaceutical agent thal might inter-
into a field flood phantom and then image this uptake in the shoulder joints, knee joints, and
fere with the upcoming nuclear medicine exam-
phantom by using the 13jXe window. All imag- feet, where this asymmetry is most often noted
ination.
ing parameters including film intensity settings (16). Physiological curvatures o€ the skeleton,
Afler the proper routeof administration of [he
and time should be identical to the 133Xe ven- eilher normal or pathologic, may be responsible
radiopharmaceutical is determined, recheck the
tilation imaging procedure. Fluid-filled scatter- for what appears to be nonsymmetrical uptake
patient’s identity and the label on the radiophar-
ingmedia may be interposed around the field of the tracer. The most common observance of
maceutical in order to insure that the right pa-
flood to simulate more closely the human torso. this is on a posterior bone scan when the normal
tient is receiving the right radiopharmaceutical.
The percent contribution can be easily calcu- curvature of the spine is away from the gamma
Injection technique is of paramount importance
lated by dividing the average number of 99mTc camera; therefore, the uptake of the bone scan-
in many studies. A single discrete bolus injec-
counts obtained in this experimental image (at ning agent appears to be less in this area than in
tion is required in many dynamic radionuclide
133Xesettings) by the average number of counts [he rest of the spine that is equidistanl from the
examinalions.Problemsarisingfromfrag-
obiained from several 13jXe ventilation images camera along its course. Improper positioning
mented bolus injeclions during quantitative ra-
of the patient. Inferences can then be made asto of the patient can result in various other imaging
dionuclideangiocardiography are discussed in
whether this percent conmibution of y9mTc into anomalies, such as pooling effects in the lungs
an article by Brendel et al. (11). If there is a
the 133Xewindow is statistically significant or or false positive renal images (17).
suggested lime delayfrominjection to scan-
not. Sometimes,simple visual observation of If a mental or even a documenled preimaging
ning, double-check to insure that this amount of
theexperimentalimage will indicatetheOUI- check is made of all of h e aforementioned in-
time has, indeed, elapsed before using the scan.
come. Window size is a parameter that may be strument and patient parameters, an acceplable
Procedural errors frequently occur from mis-
varied to minimize [he percent contribution. scan most likely will result. Once a nuclear
scheduling two nuclear medicine examinations
Femandez-Ulloa et aI. (14) have reported on medicine scan is underway, however, in-process
eithersequentially out of orderortemporally
spectral overlap. They found two cases in which problemsmayoccur,regardless of the thor-
too close together. Artifacts may occur on a
the l[lIn-labeled leukocyte images weredeter- oughness of the preimaging preparation.
subsequent scan if there is enough residual ac-
mined tocontainarlifacts due to 9 4 m Tcross
~
tivity leflfrom a previously inlroducedradi-
talk within the 173-keV photopeak of Ijlln. In During Imaging
odiagnostic or radiotherapeutic agent (12).
thesepatients,49mTc-hydroxymethylene di- In Table 19.1 are listed severalfactors that
Harris et al, (13) have described artifacts in
phosphonate (HDP) hadbeenadministered need to be evaluated during imaging of the pa-
l 3 I l renal images. Renal image arti€acts due to
within 24 hours prior to the administered I I In- tient. The patient is the primary contributor to
residual ggrnTcactivity from a previous injection
labeledleukocytes.Theartifactdisappeared in-processscanningprobIems.Patientscan
of 99mTc-gluceptate were visualizedduring a
when the II In window was decreased from 20% move during the scan, they can gel sick, they
[1311]iodohippuratestudy (a1 a photopeaken-
to 10%. A 24-hour waiting period after a 55mTc can lose bladder or bowel control, or they can
ergy setting of 364 keV). The cause of these
nudear medicine examination does not always becomeanxiousduring the scanand actually
arlifacts was explained by the authors as coinci-
insure background levels of radioactivily.De- panic. Rule 1 is to be attentive to your patient
dence summing at 281 keV due to a high 9 9 m T ~
pendingonbiologicalexcretion ratefor [hat before,during,andaftertheexamination.
counting rate. This problem hasbeen alleviated
patientand the duration of thefollowingim-
in newer cameras with pileup rejection circuits. Table 19.1,
ages, there could be enough activity to show up
The controversy continues over what should
as artifacts. Planar In-process Imaging Checklist
come first: the ventilation study or the perfusion
Too Iong a delay from injection lo scanning
sludy. Traditionalists perform the ventilation - Has patientmovement been minimized
can be just as detrimental as too short a delay.
study with 133Xefirst, while other investigators throughout scan?
Several sources of technical error in ”IT1 perfu- - Are there atlenuatingobjects over the
perform the wmTc perfusion study first. Tradi-
sion stress tests, including too long a delay in patient?
tionalists argue that if the 9 9 m T ~
perfusion study
obtaining the initialpoststress images, are de- __ Wereany noticeablepatientexcretafound
is performed first, there will be 9 9 m Tscattered
~ on the collimator, table, or sheets?
scribed in abook byMettler and Guiberleau
photons in the 133Xewindow on the subsequent Have all radioactivesources and radiocon-
133Xeventilationsiudy. Theyargue that there (15). ~
taminants been removed from the camera
Proper positioning of the patient against the fieId of view?
might even be enough scattered 99”1Tc photons
gam~uacamera is a very important criterion to __ Is thescanningdevicetracking and in-
accepted that could fill in areas of decreased
r consider in preparation of apatientto be im- dcxing properly?
ventilalion on the 133Xe scan. The percenl con- __ Are thecameraand table tracks clear?
aged. Malpositioning and rotation of the patient
tribution of scattered 9 9 m Tpholons
~ into the - Is the patientreceiving reassurances and
is the most common cause for diffuse asymme-
133Xe window may be easily determined experi- progress reporls on the scan?
tries of 9mTc-phosphonale uptake in bone and
298 I Easentiais o j Nrrclear MedicineScience Irurnrmeulnrion and Proceduml Problutns I 299

At this time, theresult of all the preparations, Table 19.3. small COR errors can result in hot or cold spots
Many patient-associated imaging artifacts may
be eliminated by keeping the patient informed checks,anddouble-checksshouldmanifest Additional Checklist for ECT-only lmaging on a 20'T1image. Pixel size is subject to drift,
as to what to expect from the examination and themselves as a completelyadequate,diag- and SPECTcamerasshouldbe calibrated Cor
- Is thecamera in the E f f mode? pixel size along with the COR. Pixel or voxel
the slatus of the scan as it is in progress. In a nostically accurate, quality nuclear medicine
__ Is the computer set for ECT acquisition?
book by Wells and Bernier(18),manyactual examination that is carried out correctly lhe first __ Has the patientbeenpositioned at the
(volume element) size must be known for accu-
patient-associated imaging artifacts (movement, time. center of rotation? rate size and volume determinations.A calibra-
contamination,attenuatingobjecls)arede- ECT IMAGING PROBLEMS - Doesthecameraclearthepatientthrough- tion set consisting of pixel size, COR, and field
out manual rotation? uniformity should be stored for each set of ac-
scribed. Several authors have reported photon- Single photon emissioncomputedtomogra- - Doestheorgan of interestremain in the
deficient areas occurring on bone and renal im- quisition conditions. Field uniformity, COR,
phy (SPECT) imaging (Fig. 19.6) is subject to field of view throughout manual rotation?
ages which resulted from h e patient having too - Is the up-to-dateflood correction image and pixel size vary with the c o l I i ~ ~ ~ and
~ ! o mag-
r
all of the problems of planarimagingplus a
heavy a lunch(19, 20). Otheritems listed in stored in the computer for the colIimator, nificationmodes.Fielduniformitycanalso
unique set of its own. To obtain clinically useful
Table 19.1includeassuring that thescanning and is the magnification mode in use? vary with camera orientation; thus i t is impor-
images requiressirictattention to quality con- - Areproperprojection filters beingused
device has a clear unobstructed path in which to tant to acquire the field floods used for corrcc-
trol procedures (Table 19.3) and a knowledge of for the examination?
operate and that it is tracking and indexing prop- tion in the same orientation as will be used [or
SPECTimagingartifactsandtheircauses. __ Is theattenuationcoefficient correct?
erly, as well as determining whether or not the __ What are the angular range and number of
patient acquisition. Routine imaging of an ECT
Threesources of artifacts in lornographic im-
film slide has been pulled. angles? phantom, such as the Jaszczak phantom shown
ages havebeenidentified byHarkness et al.
- What is the starting angle? in Figure 19.7, is the best way to detect changes
(21): (a) errors in camera setup and calibration, __ What is the direction of rotation?
After Imaging in camera performance.
(b) errors in patient preparation and the setup of __ Is the time per image correct?
If the examination has gone well up to this the camera in relation to the patient,and (c)
point, there are only a few more i t e m left that improper choice of reconstruction filter param- Problems Associated with Patient
can go wrong. The postimaging checklist (Table eters. Of these three, errors in camera setup and Preparation and the Setup of the Camera
and field uniformity. Of these, field uniformity in Relation to the Patient
19.2) contains items dealing mainly wilh verify- calibrationare the most significantsource of has the most effect on tomographic image quaI-
ing that the film is processed properly (and is of image arlifacts. ity. Field flood nonuniformities of more than Tomographicreconstructionsmagniry prob-
acceptable quality) andthat thecomputer has ? 1 % will result in bull's-eye artifacts in recon-
lems due topreparation of thepatient.Sincc
Problems Associated with Calibration of
acquired all the necessary data. One item not on structed tornographic images. COR errors result SPECTimages arereconstructedfrom many
SPECT Cameras Prior to Imaging images acquired around the patient, care must
thepostimagingchecklist is thepatient. Al- in loss of resolution or the introduction of ar-
though the patient's behavior at this time cannot SPECT cameras must routinely be calibrated betaken in patientpositioning.Thepatient
tificial structures. A point source imaged over
affectthe quality of thefinished scan, it is for centerof rotation (COR), pixel or voxel size, 180" with a COR error will result in atuning should beparallel with the axis of rotation of the
importantto make surethat the patient is re- camera, andthe detector head should be as
fork- or doughnut-shaped reconstruction. Even
laxed,Manytechnologists(including myself), cIose as possible to the patient for better resolu-
after completion of the examination, have tion. Prior to every acquisition, cale should be
walked away to process the film and have left taken lo (a) levef thedetector head and (b)
the patient in the scan position. This negligent assure [hat the detectorcan rotatearoundthe
practice can affect the quality of any unantici- patient withouthitting the patient. I t is ;11so
pated or repeat scans that may be deemed neces- necessary to check that the organ ol' intcrcsl
saryafter the standard viewsare taken. A pa- remains in the field of view throughout thc roia-
tient who has spent an unnecessary amount of tion. Patients arms should be abovc their he;ltl
time in an unrelaxed position is more irritable, when organs of the thorax or abdomen are im-
is moreuncooperative,will move more, and aged. If the arms are left at the patient's side,
may refuse lo undergo any more imaging. It is they create uneven atlenuation and will result in
important to be as empatheticwith the patient as a patchy appearance on images of organs sllch
possible. asthe liver. In transaxial images, a starburs1
artifact will result if a hot source (such a s injcc-
Table 19.2.
tion site with,extravasation)is in the field of'
Planar Postimaging Checklist view for some of the projection imngcs. Olhcr
- Hasthe filmslidebeenreturnedpriorto factors dcgrading the reconstructed irmgcs ;ITC
cassette removal? patient motion and the presence of ;ittcnu;ltion
- Hasthe filmbeenproperlyprocessed? sources inside or oulside of the patiem. Rcccnt
- Have imagesuitability and qualitybeen barium studies can cause artifacts to appear on
checked prior to patient dismissal? Figure 19.7. Jaszczak QC phantom. reconstructed images of the liver.
Figure 19.6. ECT camera.
300 I Essentinls o j Nuclear Medicine Science
Problems Associated with Improper
ReconstructionParameters
Imageartifactscan also beintroduced
through improper reconstruction parameters.
These artifacts are the easiesl to correct, how-
ever, as they do not require reimaging of the
patienl. Reconsltvction artifacts include: image
blurring,image noise, and an intensering
around the ouler edge of an organ due to im-
proper attentuation correction. The choiceof [he
proper reconstruction filter isrelated to the clin-
ical imaging situation and is dependent on the
information density of the images. A filter that
is too smooth can blur or remove normal struc-
tures as well as lesions. At the other end of the
spectrum, a filter that is too sharp can intensify
image noise and cause the appearance of struc-
tured noise in the organ of interest and hack-
ground (Fig. 19.8), The properfilter can be
selected by (a) imaging of phantoms simulating
actual clinicalsituations or (b) acquisition of
known normalpatient data andreconstruction
with use of various fillers in order to select the
one yielding the best representation (Fig. 19.9).
Figure 19.8. Normal liver scan reconstrucled with too sharp of a filler.
Insirumentarion and Procedwol Problems t 301
CONCLUSION L
The vast majority of instrumentation and pro-
cedural problems in nuclearmedicinecanbe
r
prevenled.Usually,these result from human
error, poor judgment, or human uncooperative-
E
ness which produces imaging artifacls. Rare is R
the spontaneous malfunclion of imaging equip-
ment. Most problems can be tracedback lo a
breech of procedure. Nuclear medicine imaging
is becoming less of an art and more of a science.
lnstrumentation is becomingmoresophisti-
cated, reliable, and ''foolproof,'' Following the
basic principIes outlined in this chapter, such as
selling up a nuclear medicine imaging "bloop-
ers" notebook andusing either amental or a
documented imaging checklist, will reduce to a
bare minimum camera downtime, repeat scans,
radiation exposure to self and palient, frustra-
tion, stress, and poor-qualiLy images.
REFERENCES
1. Johnson CK. Damm DW: Programmed learning man-
ualfor ;mifact identification. J N d Med Techrtol Figure 19.9. Normal liver scan.
4 : 3 - 3 3 , 1976.
12, LaRocque LR: Case of the quarter. J Mrcl Med Terl~rlo!
5~163-165, 1977.
13.Hamis CC, Wilkinsun RH. Schuler FR: Artifacts in
iodine-I31 rend images due lo coincidence summrng
of technerlum-99mphotons. Radiology 146505-507.
1983.
cobalt-57qualitycon[rottesting. Radiology
146:237-239, 1983.
302 I Essentials ofN’ucleor Medicine Science

Is the camera peaked for the proper radionuclide?

Has the proper collimator (energy, resolution) been selected lor the study?
Is the film intensity set correclly?
Is the cathode ray tube (CFT) in focus?
Is the CHT lens clean?
Has the appropriate time per image been selected?
20
Is the orientalion of the camera and computer appropriate?
Has the proper camera and computer acquisition mode been selected for the sludy?
Is lhere enough computer storage for the examination?
Adverse Reactions Associuted with
Are the floppy disks initialized?
Are floppy disks the correct type?
Has parient idenlification been enlered into the computer?
Radiopharmaceuticals
Are magnification settings on the camera and computer correct?
Is the film type correcl, and is the film loaded properly?
M , Annette Cordow, William B, Hladik 111, Buck A, Rhodes,
Is the CRT selection switch sel Tor imaging?
Has the correct radiopharmaceutical and proper dose been sclecled lor the patient?
and Harold L, Atkins
Has the proper injection site been selected?
Is the patient adequately prepped?
Is the time delay from injection to scanning adequate? Because the term “adverse reaction” is mosl maceulicals are subject to the same regulatory
Has the patient received any pharmaceutical, radiodiagnostic, or radiotherapeutic
agents which might inlerfcre with the exam?
comnlonly associatedwilh compounds known requirements that are in effect for all new drugs,
Is the palient properly positioned? as “drugs,” it is important to understand why including the reporting of adverse reactions
radiopharmaceuticals are considered to be drugs which are attributableto theseagents. Even
Appendix 19.1. ECT and planar preimaging quaiity control checklist. and which radioactive substances are classified after the approval and introduction of these
as radiopharmaceuticals. agentsinto the marketplace, it is important to
According to the United States Food, Drug, have an eslablished process for monitoring their
andCosmetic (FD & C)Act (l), drugs are safe use.
defined as “articles inlended for use in the diag-
nosis, cure, mitigation, treatment, or prevention DEFINITION OF ADVERSE REACTION
of diseaseinmanor other animals; . . . but In h e United States Code of Federal Regula-
does not include devices or their components, tions (2), an adverse reaction is defined as “any
parts, or accessories.” In general terms, a ra- adverseexperience associatedwith theuse of
diopharmaceutical is a compound labeled with the drug,whetheror not considered drug re-
eilher an intrinsic or a “foreign” radionuclide lated, and includes any side effect, injury, tox-
for use in the diagnosis or therapy of disease icity,orsensitivityreaction,orsignificant
and, as such, qualifies as a drug. faiIure of expected pharmacologic action.” This
Nearly all radioactive substances that are ad- definiiion does no1 entirely apply LO radiophar-
ministeredparenterally,orally, or topically for maceutical~because they are not generally ex-
diagnosis or therapy are consideredto be radio- pected to elicit a pharmacologic response (3).
pharmaceutical~.Thisincludesreagentkits Furthermore, although some of the ingredients
used in the preparation of radioactive drugs as incorporatedintocertainradiopharmaceuticals
well as generator systems which produce radio- may beconsidered to bechemically or phar-
nuclidesfor clinical use.Notableexceptions macologically toxic, for diagnostic purposes
include sealed sources of radionuclides used as they are given in minute quantities well below
therapeuticimplants and radiotracers that are the toxic range (3-5). The chemical toxicity of
components of in vitro diagnostic kits. These clinicallyusedradiotracers should present no
Iast two items areclassified as devicesrather problems as long as acceptable limitsof specific
than drugs. activity are not exceeded (4).
i’
i
In 1975, the United States Food and Drug RadiopharmaceuticaIs, unlike other drugs,
Administration (FDA) “officiallyrecognized” emit radiation.Anyacuteadverseeffects at-
radiopharmaceuticals as drugs by terminating a tributed to the radiation itself, especially with
then-existing exemption forradioactive pharma- regard lo diagnostic radiophmaceuticals, are
ceuticals from the investigational new drug re- mostlikely due toan overdoseand are more
n l l i + P m r n ~nf $ho E n % P A n t ‘I%,..-
-,,A;--I.-- ”“”I-. “l..”..:$:-.J” -L”.l”:-:-L”*:”. 7
302 I Essentials ofN’ucleor Medicine Science

Is the camera peaked for the proper radionuclide?

Has the proper collimator (energy, resolution) been selected lor the study?
Is the film intensity set correclly?
Is the cathode ray tube (CFT) in focus?
Is the CHT lens clean?
Has the appropriate time per image been selected?
20
Is the orientalion of the camera and computer appropriate?
Has the proper camera and computer acquisition mode been selected for the sludy?
Is lhere enough computer storage for the examination?
Adverse Reactions Associuted with
Are the floppy disks initialized?
Are floppy disks the correct type?
Has parient idenlification been enlered into the computer?
Radiopharmaceuticals
Are magnification settings on the camera and computer correct?
Is the film type correcl, and is the film loaded properly?
M , Annette Cordow, William B, Hladik 111, Buck A, Rhodes,
Is the CRT selection switch sel Tor imaging?
Has the correct radiopharmaceutical and proper dose been sclecled lor the patient?
and Harold L, Atkins
Has the proper injection site been selected?
Is the patient adequately prepped?
Is the time delay from injection to scanning adequate? Because the term “adverse reaction” is mosl maceulicals are subject to the same regulatory
Has the patient received any pharmaceutical, radiodiagnostic, or radiotherapeutic
agents which might inlerfcre with the exam?
comnlonly associatedwilh compounds known requirements that are in effect for all new drugs,
Is the palient properly positioned? as “drugs,” it is important to understand why including the reporting of adverse reactions
radiopharmaceuticals are considered to be drugs which are attributableto theseagents. Even
Appendix 19.1. ECT and planar preimaging quaiity control checklist. and which radioactive substances are classified after the approval and introduction of these
as radiopharmaceuticals. agentsinto the marketplace, it is important to
According to the United States Food, Drug, have an eslablished process for monitoring their
andCosmetic (FD & C)Act (l), drugs are safe use.
defined as “articles inlended for use in the diag-
nosis, cure, mitigation, treatment, or prevention DEFINITION OF ADVERSE REACTION
of diseaseinmanor other animals; . . . but In h e United States Code of Federal Regula-
does not include devices or their components, tions (2), an adverse reaction is defined as “any
parts, or accessories.” In general terms, a ra- adverseexperience associatedwith theuse of
diopharmaceutical is a compound labeled with the drug,whetheror not considered drug re-
eilher an intrinsic or a “foreign” radionuclide lated, and includes any side effect, injury, tox-
for use in the diagnosis or therapy of disease icity,orsensitivityreaction,orsignificant
and, as such, qualifies as a drug. faiIure of expected pharmacologic action.” This
Nearly all radioactive substances that are ad- definiiion does no1 entirely apply LO radiophar-
ministeredparenterally,orally, or topically for maceutical~because they are not generally ex-
diagnosis or therapy are consideredto be radio- pected to elicit a pharmacologic response (3).
pharmaceutical~.Thisincludesreagentkits Furthermore, although some of the ingredients
used in the preparation of radioactive drugs as incorporatedintocertainradiopharmaceuticals
well as generator systems which produce radio- may beconsidered to bechemically or phar-
nuclidesfor clinical use.Notableexceptions macologically toxic, for diagnostic purposes
include sealed sources of radionuclides used as they are given in minute quantities well below
therapeuticimplants and radiotracers that are the toxic range (3-5). The chemical toxicity of
components of in vitro diagnostic kits. These clinicallyusedradiotracers should present no
Iast two items areclassified as devicesrather problems as long as acceptable limitsof specific
than drugs. activity are not exceeded (4).
i’
i
In 1975, the United States Food and Drug RadiopharmaceuticaIs, unlike other drugs,
Administration (FDA) “officiallyrecognized” emit radiation.Anyacuteadverseeffects at-
radiopharmaceuticals as drugs by terminating a tributed to the radiation itself, especially with
then-existing exemption forradioactive pharma- regard lo diagnostic radiophmaceuticals, are
ceuticals from the investigational new drug re- mostlikely due toan overdoseand are more
n l l i + P m r n ~nf $ho E n % P A n t ‘I%,..-
-,,A;--I.-- ”“”I-. “l..”..:$:-.J” -L”.l”:-:-L”*:”. 7
 Adwrse Rencriorrs Associated with Radiophannace~rficnls t 305
304 I Essenrials of N u c l e w Mcdicil1e Scielsce

term adverse effects due to the radiation, such
as genetic effects or the induction of cancer, are
difficult to monitor and document because they
generally occur so late and with such low the-
oreticalincidence (3); somehavebeenat-
tributed 10 the use of lherapeutic r a d i o p h m a -
ceuticals, however (6, 7).
Rawlins and Thompson (8) have divided ad-
verse reactions to therapeutic drugsinto two
types. Type A reactionsare due to the phar-
macologicaction of a drug, arerelativelyfre-
quent, and areoftendose dependent. Type B
Therefore, to compile a large amount of data at
a single hospital or even from a small group of
related institutions is extremely difficult. In ad- ADVERSE REACTIC
dition, the reported incidence of adverse reac-
tions is quite low; thus, it is unlikely that any
one practitioner would be able to note trends or
problems associated with a particular radiophar-
maceutical.Unfortunately,manyreactions
probably go unnoticed, because nuclear medi-
TREATED WITH Rk DRUG
cine personnel see the patient for only a short
period and the patient may then be lost to fol- 0 RESULTED IN,OR
PROCONGED , I N P A T I E N T
low-up once he orshe has left the nuclear medi- HOSPITALIZATION

reactions.whichare unexpected andunrelated cine deparlment (10). Moreover, new radiophar- RESULTED IN SEVERE
13. AELEVANT TESTS1LAEORATORY DATA
tothenormalpharmacology of the drug, best maceuticals often replaceolder ones in the same OR PERMANENT
DISABILITY
describe the majority of reactions to radiophar- organ imaging calegory within the span of only
a few years,which thus limitsthe collective 0 NONE OF THE ABOVE
maceuticals.
I
Several authors have further defined what is experience with any one agent (10).
and what is 1101 an adverse reaclion to radiophar- Dataconcerningadverse reactionstoradio-
maceuticals. The following is a composite defi- pharmaceuticalshavebeensolicited in the
nition incorporating major discriminatingele- United States by the Sociely of Nuclear Medi-
ments of these definitions: cine (SNM) since 1967. The established report- I AFTER STOPPING DRUG? I
OYES UP40 D N A
ing system was modified in 1976 and for many
1. The reaclion is an unexpecled or unusual and 6. DAtLY DOSE 16. ROUTE OF ADMIMISTRATION
years was a cooperative effort of the SNM, the 21 DIDREACTION
undesirableclinicalmanifestalionresulting REAPPEAA AFTER
United States Pharmacopeia1 Convention 7, INDICATIONISI FOR USE REINTRODUCTION?
from the administralion of a radiopharma-
(USPC), and theFDA. Adverse reactionsand
ceutical (3, 4). 8. THERAPY
DATES fROrnJToJ 19. THEAAPY
DURATION DYES CD
tNNO
A
product defecls were reported on a SNM Drug
2. The reaction is associatedwilhthe vehicle
Problem Reportform (FDA 2822). These re-
carrying the radiation and not with the radia-
ports were mailed to the USPC who sent a copy
tion itself (4, 9). to the SNM headquarters, the manufacturer, and
3 . The reaction does not result from an over-
the FDA for follow-up (13). A second modifica-
dose, which is moreproperlyclassified as
tion o€ the reportingsystemoccurred in lale
misadnlinislration (3, 9).
1985 when the FDA discontinuedthe use of
4. The reaclion is not a result of injury caused
fonn FDA 2822. Instead, it was recommended
by poor injection technique (IO),
h a t nuclearmedicine practitioners should re- L
#. ONLY FOR A E W R T E S U B M I T r E D BY MANUFACTURER
It should be noted that not all authors agree port adversereactions associatedwithradio- 1. N A M EA N D ADDRESS OF MANUFACTURER fhclvdr zip Code) :
withthisentire definition. In Europe, parlicu- pharmaceuticals on form FDA 1639, the Ad-
larly in the United Kingdom,acute radiation verse Reaction Report for Drugs and Biologics
effects resulting frommiscalibration,radionu- (Figure 20.1). This form for the voluntary re-
clidic impurities, or maldistribution (including porting of reactions to radiopharmaceuticals and [I.INDINDA. NO. FOR SUSPECT ?4b. MFR CONTROL NO.
26b. TELEPHONE NO. (Include m a code)
DRUG
slow biologic clearance) of theradiotracerare nonradioactive drugs is used not only by practi-
I
also considered to be adverse reactions (1 1, 12). tionersbut also by drug manufacturers, as re- :. DATE 24d. REPORTSOURCE (Check
2 6 c . H A V E YOU ALSO REPORTED THIS REACTION TO THE
quired by Title 21 of [he Code of Federal Regu- 0 FOREIGN 0 STUDY 0 L~TERATURE
MANUFACTURER7
0 HEALTH
PROFESSIONAL 0 CONSUMER 0 YES 0 NO
lations(21CFR314.80).Thesereports are i. 15 D A Y AEPORT
REPORTING SYSTEMS reviewed,evaluated, and computerized by the DYES ON0
76% REPORT TYPE 26d. ARE YOU A H E A L T H PROFESSIONAL?
0 INITIAL 0 FOLLOWUP OYES U N O
An efrective, large-scale, adverse reaction re- FDA Division of Drug and Biological Product I I
NOTE: Rmulr.d o i rnanuiaumn.,t 21 CFA 314110.
porting system for radiopharmaceuticals is Experience. Inlormation collected by these re-
FORM FDA 1- (61.6) ,
importanl and necessary for severalreasons. porting systems hasbeen used (a) lo alert the P R E V I O U S EDlTION I S OBSOLETE.

First, compared with most nonradioactive thera- profession to potential or actual problems before
Figurc 20.1. Front of Adverse Reaction Report form used in thc Unitcd States for reporting adverse reactions
peutic drugs, radiopharmaceuticals are admin- they becomc widespread and (b) to define the associatctl with radiophann;~ceu~icals,
nonradioactive drugs, and biologics.
istered infrcquently and usually in single doses. types, characleristics, and incidence of adverse
 Adverse Reocrions Associared with Radiopharr~lacelrricnls I 307
306 I Essentials of h'ucleor Mediciue Science

CONFIDENTIAL
INSTRUCTIONS FOR COMPLETING FORM FDA. 1639
Results will n o t be made known t o anypersonwithouttheexpresspermissiori of the
person s u b m i t t i n g t h i s r e p o r t but are 'banked'withtheEuropeanReportingScheme,
and thegeneral DHSS Adverse Report Scheme.
REPORT OF fiN ADVERSE REACTION ATTRIBUTED TO A RADIOPHARMACEUTICAL
inadeouate.
1. Patient..................I n i t i a l s ............ Hospital No. .................
Age............ Sex ...........
Date of Test .................... Nature of Test ...........................
C l i n i c a lD i a g n o s i s ............................................................
2. Radiopharmaceutical : Radionuclide ......... Chemical Form ....................
B r i e f d e t a i l s of m a t e r i a l s , s o u r c e , method of preparation & s t o r a g e - r e f s . i f a n y
...............................................................................
...............................................................................
...............................................................................
Has a commercial
manufacturer, i f involved,
been
informed? YES / NO
3. NatureofReaction: Any c l i n i c a lo b s e r v a t i o n s and treatment, i f required ......
...............................................................................
...............................................................................
...............................................................................
Has t h ep a t i e n tr e c e i v e dt h i s or a relatedradiopharmaceuticalbefore?
...............................................................................
4. Approximate number of times t h i s preparation has beenuseduneventfully.
...............................................................................
Otherdrugsetc.currentlybeinggiven: ......................................
...............................................................................
5. Any o t h e r comments ............................................................
............................................................ c o n t i n u eo v e r l e a f .
Signed ......................... Name .......................................
Address ............................................................................

Return t o : The Medical Assessor, RadiopharmaceuticalAdverseReaction Reports,

B r i t i s h Ins ti t u t e of Radiology, 36 Portland Place, London W1N 3DG marked CONFIDENTIAL

Figure 20.1"codnued. Back of Adverse Reaction Reporl form used in the Uniled States for reporling
adverse reactions associated with radiopharmaceulicals, nonradioactive drugs, and biologics.
 308 t Essentials of Nuclear MedicineScience Arheue ReactionsAssockfed with Radiopharmacerrricals I 309

JOINT COMMllTEE ON RADIOPHARMACEUTICALS

THE dOiNT C O M M i l l E E o nRADIOPHARMACEUTICALS OF
EUROPEAN
NUCLEAR
MEDiClNE
SOCIETY SOCIETY OF NUCLEAR
MEDICINE - EUROPE the EUROPEAN NUCLEAR MEDICINE SOCIETY and the
ADVERSE REACTiON SEND TO: National
delegate SOCIETY of NUCLEAR MEDICINE - EUROPE
DRUG DEFECT or direcl to: EuropeanJointCommittee on Radiopharmaceuticals
REPORTING SYSTEM addr.: THE ISOTOPE-PHARMACY Aeporting 01 adverse reactions and drug defects.
378 Frederiksaundsvei. DK.2700 BrQnshoj.
Denmark. The monitoring of defects in radiopharmaceuticais and of adverse reactions associated wilh the use of
radiopharmaceuticais is consideredto be an important mean of maintaining and Improving the quality and
Radiopharmaceulical (namecode) Manufacturer Lot.no. safety of nuclear medicine.

The Joint Cornmiltee on Radiopharmaceuticals of the European Nuclear Medicine Sociely and the Society of
Nuclear Medicme - Europe (Gesellschafl fur Nukiear Median -
Europa) have therefore decided to sel u p a
system whereby such informalion can be collected on an European basis and made available to all parties
41 relevant: Radlonuclide generator Icode) Manulacfurer iot.no.
concerned.

The number of defects and adverse reactlons is most probably small. Collectionof data from a large area is
IherefOre important in order, thal problems can be indentified as early as possible. The Committee lherelore urges
index
Key - Please mark. I Date 01 Incidenl: everyone involved in work with radiopharmaceuticals lo parlicipate by repotting as soon as possible any
ADVERSEREACTION:
Type
1 Detailed descrlptlon: (see alsoquestions in the text)
observed defect or reaction.

II is nol. 01 course, intended to interlere with any national system or to act as an extra stage between the user
t and the manufaclurer.
0 Allergic Therefore: Report to
0 Pyrogenic
0 Drug elfect a. nalional aulhorities or society, i f required
b. Ihe manulaclurer of the radiopharmaceutlcal
i7 Olher: . . . . . . . . .
c. Ihe European Joint Cornmiltee on this lorm.
~ .. - ..................
Reaction: When a report has been received by lhe Joint Committee a receiptand a new report form will be sent. By conlacl
0 Moderate lo the secrelarial: Knvd Kristensen, The isotope-Pharmacy, Frederikssundsvej 378, OK-2700 Brqnshgj, Oenmark.
0 Severe Phone: (02)94 37 73. Telex: 35333 (Ipharm dk). informalion can be obtained aboul any similar reaclion, lhal may
Falal have been reporled earlier. The data submitted wlli be treated as confidential and the originator wiii nol be
identified in any reporl without writlen permission.
Probability 01 connectlon to
R.Ph. Admrnlstration: The Joinl Commiltee will issue an annual report, thal will include ail data in an anonymous form. If justified by
c. LOW the nalure of Ihe dala received an urgent publication willbe made. The annual reporl will be made public by the
Medium two societies and a copy of the report will be sent directly l o ail those who participated.
0 High
Adverse reaction is here laken to include ail unexpecled patient reactions. Such reactions should be reported
0 RADIOPHARMACEUTICALDEFECT: even if the probabilily of a relationship belween administration of the radiopharmaceulicai and the reaction
0 Transportdamage seems Small. if other causes seem more likely {e.g. administration of other pharnaceulicals) these should be
mentioned in the description.
0 Label
0 Package insert
The lerm 'Drug Delects' is used here to define ail variations from product specifications, from normal
Appearance appearance 01 packaging or from the expected biological behaviour of the radiopharmaceulicai.
13 Rad.surlace conlaminalion
m Radioaclive concentration it is 01 great imporlance that as many details as possible are reported.
Totalradioactivity
0 Radiochemical purily if the radiopharmaceutical was 'home-made' Ihe reporling department should be given as the manufacturer and
0 Radlonuclidic purity details provided with regards to specificatrons, preparalion methods, quality control elc.
pH Please contmue i l needed
0 Elutionefficiency in order l o be able to identily as far as possible a causal relationship the fol[owing details should always be
0 Particulateconlamination Report sent by: covered in the reporl:
0 Biodislribution Purpose 01 the investigation or trealmenl
Name:
0 Sterility Patient condition when the producl was administered
Occupation: Volume administered, roule a l administration etc.
0 brogens Inslilution:
0 Olher ............. ......... Delaiiled description of the reaction including clinical findings, physiological
......._ . . . . . . . . . . . . . . . . . . . . . . .
Address: .- measurements and laboratory results

I Telephone:
Time course of the incident
Trealment given to overcome Ihe reaclion
Consequences of the reaction to the patient
Reactions of other patients given Ihe same product

Figurc 20.3. Form (front, page 308; back, this page) distributed by h c Join1 Committee on Radiophannaceu-
licals for rcporling adverse reactions and defects associated with radiopharmaceulicals; this form is used by
scvcrnl European countries, and the dala are pooled.
310 t Essentials of Nuclear MedicheScience Adverse Reuctiorls Associared wilhRadiopharr?~aceuricuis 1 311

reactionstoradiopharmaceuticals (13). The measures have all but eliminated the problems
Table 20.1,
United States data have been published in the that were previously encountered with pyro-
Reported Adverse Reactions to Radiopharmaceuticals in the United States. from 1976 throuph 1984*
Journal of Nuclear Medicine or other appropri- gens. As a result of these and other factors, the
ate journals from time to time (10, 13-15). mix of adverse reactions have changed some- No. of Reports by Year
Reportingsystems have beendeveloped in what over the years and, depending on radio- Radiophmaoeulical
1980 1979 1978 1977 1976 1981 1982 1983 1984 Total
other countries also. Japan,forexample, has pharmaceutical usage patterns and current man-
had an ongoingsystemfor several years. Eu- ufacluring practices, continues to change (21). BmTc-labeled
suIfur
colloid 11 (7)t 19 (10) 13 (12) 11 13 5 7 2 3 84
It is worth notingthat, routinely, more ad- BmTc-labeled human albumin
rope has syslems in the United Kingdom, West microspheres (HAM) 19 14 16 6 4 14 4 68
Germany, and Denmark. In addition, the Joint verse reactions are reported directly to theFDA wmTc-medronate(MDP) 3 1 6 7 5 4 2 7 35
Committee on Radiopharmaceuticals of the Eu- by the manufacturers of radiopharmaceutical citrate [67Ga]gallium 1 A 5 4 2 16
ropean Nuclear Medicine Society and the Soci- drugproducts than by individualpractitioners BmTc-pyrophosphate(PYP) 10 ( 9 ) 2 2 1 1 16
ely of Nuclear Medicine-Europe set upa system using the volunteer syskm endorsed by SNM. BmTc-gluceptate 2 2 (1) 2 1 2 1 4 1 1 16
in 1979 LO monitor defects in radiopharmaceuti- This is partly because when a clinician notes a BmTc-labeled macroaggre-
gated albumin (MAA) 2 1 1 2 3 3 3 15
cals and adverse reactions associated with their suspected adverse effect, he or she often turns 2
[ ~~~1]iodomethylnorcholesterol 3 1 2 5 1 14
use in Europe (16). Reports from Ihe Joint Com- to the manufacturer lo inquire whether the effect BmTc-pentetate(DTPA) 1 3 3 2 1 1 3 14
mitteehave been published in the Europenn has been previously observed. Because of legal [131l]iodide
2 Sodium 1 2 1 1 1 8
Jourrmi oJNuclenr Medicineas well as NukIear- requirementsthemanufacturer must subse- Nonradioactive pyrophosphate
kil 1 4 1 1 7
nredizk (17-20). quently report the suspected reaction to the
SmTc-oxidronate (HDP) 4 2 1 7
Forms used in the United States, the United FDA, whereas under the volunteerreporling ~-[13'1]iodohippura~e 1 3 2 1 7
Kingdom,andEurope 10 documen1 suspecled system theclinician may or may not further BmTc-labeledhuman serum
adverse reactions associated with radiopharma- document the reaction. All of the United Siares albumin (HSA) 1 1 2 1 1 6
ceuticals have been reproduced as Figures 20.1, (lain given in this chapel are obrnined from lllIn-pentetate (DTPA) 2 1 1 1 1 6
20.2, and 20.3. In the European system (Figure practitioners' reporrs to fhe SNM and not j r o ~ n BmTc-ferpentetate
3 1 (1) 1 5
[2O~Tl]thaIlouschIoride 1 2 2 5
20.3), the form can be used to reportdrug ma?lufactwers' reports I O the FDA. [99mTc]pertechnetate
Sodium 1 1 1 1 4
defects as well as adverse reactions andthus Table 20.1 is a compilation of adverse reac- 131I-labeled rose bengal 2 1 1 4
serves two purposes. In the United States, drug lions that werereported to the SNM for each BmTc-disofenin ( D I S D A ) 2 2 4
product problems are now reported on a form radiopharmaceuticalduringtheyears1976 BmTc-succimer (DMSA) 2 1 1 4
separate from adverse reactions (form FDA through the end of 1984. There were 356 ad- BmTc-etidronate (HEDP) 1 1 2
169Yb-pentetate (DTPA) 2 2
33 1X). verse reactionsreported by use of the SNM Sodium [32P]phosphale 1 1
Drug Problem Report form over this 9-year pe- WmTc-lidofenin (HIDA) 1 1
riod. Of Ihese, 24% were atuibuted to 99mTc- 9mTc-butilfenin (BIDA) 1 1
STATISTICS ON REPORTED labeledsulfur colloid,19% to 99mTc-labeled 9gmTc-iprofenin (PIPIDA) 1 1
REACTJONS human albumin microspheres [1*3I]iodide
(HAM), and 10% Sodium 1 1
Wr-labeled human serum al-
Severalreviewarticlesandchaptershave to 99mTc-methplene diphosphonate (MDP). bumin (HSA) I I
summarized eariy data on adverse reactions at- 99mTc-IabeIed m a c r o a g g r e g a t e d a l b u m i n Red blood cells labeled in
tributedto the administralion of radiopharma- (MAA), 99mTc-gluceptate,99mTc-pyrophos- with vitro BmTc 1 1
ceuticals (4, 9). The presentchapter, on the phate, 99mTc-diethylenetriaminepentaaceticacid Total 60 52 47 35 45 39 36 20 22 356
other hand, deals almost exclusively with data (DTPA),[67Ga]gallium citrate,and ['311]iodo-
from the post-I976 years. This time period was methylnorcholesterol, accounted for another
* The probability that a reported adverse reaction was associated with administration of the radiopharlna-
ceutical has been evaluated for the years 1976 through 1981 (see Ref. 10).
selected partly because it coincideswiththe 4-5% each of the reported reactions. t Numbers in parentheses indicate number of reports. Sometimes more than one case per repori is cited.
establishment of the new SNM adverse reaction Theproportion of reactionsreportedfor
registry (first modification) and partly because 99mTc-labeledsulfurcolloiddecreasedfrom
of the many changes in nuclear medicine that 28%, for the years 1976 through 1979,to 19%, increase is doubtless partially due to a higher incidence of reactionsor an increasedapathy
haveoccurred over thepast 10 years.For in- for the years 1980 through 1984. Conversely, utilization of this agent. toward thereporting of theseadverseeffects.
stance, a high percentage of the current arma- the relative percentage of reactions attributable
InIerestingly,thenumber of reactionsre- In theUnitedKingdom, 61 reactions were
mentarium of radiophamlaceuticals has been in- to phosphate and phosphonate agents increased ported in the United Statesduring1983and reportedduringthe 7 yearsspanning1977
troduced (or come into widespread use) only from 14% in the earlier period (1976-1979) to 1984 is approximately one third (37%) of the through1983Isee-Table 20.2) (21). ColIoids
since 1976, and a few of the older radioactive 20% in the more recent period (1980-1984). number of reactions reported in 1976 and 1977. (33%), phosphonates (28%), and albumin par-
drugs have fadedfromuseduringthistime. '~"TC-MDP, in parlicular, rose from 5 % to 15%
Unfortunately, i t is impossible to determine ticulates (13%) were the most frequently cited
Moreover,improvements in qualilycontrol of the total between the two time periods; the
whether this drop reflects a true reduction in the offenders. The numberof colloid- and phospho-
312 I Esserlrinls o J h W e a rM e d i c i mS c i e n c e

Table 20.2.
Adverse Reactions to Radiopharmaceuticals Reported to the European Joint Committee on
Major Groupings of Adverse Reactions to Radiopharmaceuticals in the United Kingdom, 1977-1983
Radiopharmaceuticals, 1980-1983
Albumin
Colloids Phosphonatcr Parliculalcs Othcrs Subtotals No. of Repor~sby Ycar
Badiophamaceulicals 1980 1981 1982 1983 Tulal
January1977-mid-1980 12 (12) 4890 2 (2) 88 5 (4) 167~ 8 (7) 28% 27 (25) 100%
Mid-1980-December 1983 8 (6) 21 % 15 ( 1 3 3 45% 3 (3) 10% 8 (7) 24% 34 (29) 100% 99mTc-labeled SbS colloid 1 1 2 1 5
Total 20 (18) 3 3 8 17 (15) 28% X (7) 13% 16 (14) 2 6 8 61 (54) 100% 99mTc-labeledRhS colloid 1 1
99mTc-labeledsulfur colloid 1 1
* Numbers in parenthesesaretotals (ess thoseconsidered as "unlikely" to be associatedwiththe 9gmTc-labeled tin colloid 1 1
radiopharmaceutical. (Adapled from D. H. Keeling and C. B. Sampson: Adverse reactions to radiopharmaceu- 9mTc-labeled human serum albumin 1 2 3
ticals.UnitedKingdom1977-1983. Br. J. Radiol. 57:1091-1096, 1984, with permission.) "mTc-labeled microspheres 1 1 1 3
"mTc-labeled millimicrospheres 2 2
BmTc-DTPA 1 1
nate-associated reaclions showed wends quali- patient may expireduringtheprocedure or SmTc-MDP 4 3 3 3 13
tatively similar to, although quantitatively more shortly after the procedure is completed. Some- SmTc-HDP 1 1
dramatic than, those found in the United States times, it is very difficult to determine the exact WmTc-MAA 1 1 2
series. Colloids accounted for 48% of the total role that the radiopharmaceutical may have had 99mTc-MAAand 99mTc-perlechnecate 1 1
99mTc-pertechnelate 1 1
reactions reported from 1977 through mid-1980 in the patient's death. 99mTc-labeledplasmin
Three deaths have been reported through the
I 1
but for only 2170 of thesereactionsfrom [51Cr]chromate and 1251-HSA 1
mid-1980 through 1983. Fhosphonates, on the United Kingdom reporting system ( 1 1 , 21). "Cr-EDTA 1 2
other hand, made up only 8% of the reports for One death was associatedwitha hypotensive 67Ga-citrate 2 4
1977-80but 45% of the reports in the more reactionfollowing theinjection of a colloidal 75Se-choleslerol 3 3
Sodium [ 1231liadide 1
recent period (21). radiotracer in aseverely iil patient.Another 1231-labeledfatty acid 1 1
Over the 4-year period from 1980 through patien1 apparently died from a subarachnoid 123l-isopropylamphetamine 1 1
1983, 75 adverse reactions were reported to the hemorrhage shortly after the intravenous injec- ['23I)iodohippurate 1 1
European Joint Committee on Radiophamaceu- tion of [99mTc]pertechnetate. Thethird fatality [1251]iodohippurale and [1311]iodohippurate I I 2
ticals (see Table 20.3) (17-20). Phosphonates was reported to have occurred 3 days fo~lowing Sodium113'IIiodide 1 1
I3lI-labeledcboIesterol 9 1 10
and(various) colloids ranked asthe top two the injection of 99mTc-laheled human serum al- [131I]iodohippurate I 1
radioactive drug categories for which reactions bumin millimicrospheres; although a higher- '98Au-labeiedcolloid 1 2 3
had been reporled, with radioiodinated choles- than-normal amount of the drug was retained in 1311-labeledHSAcislernography 1 1 2
terol a close third. It is not surprising that these the lung field, no immediate problem was ob- 169Yb-DTPA cistemography 3 3
statistics agree with the United Kingdom series, served. In the first of these events, the hypoten- IlIln-DPA cistemography 1 1
~~IIn-Iabeled colloid 1 1
because 44% of all the European data is from sive episode may be associated with the admin- 1"ln-Iabeled platelets 1 1
the United Kingdom alone. Collectively, these istrationofradiocolloid,sincethistype of Total 25 16 22 12 75
three radiopharmaceuticals(colloid,phospho- reaction has been observed previously following
nates, cholesterol) account for 52% (39 of 75) intravenous dosing of radiopharmaceuticals. On
of all the reactions reported 10 the Joint Com- theotherhand, it is verydifficultto find a
mittee. The remaining 36 reactions involved 23 logical connection belween the othertwo deaths
there is a cause-effect relationship between the Severalpublicationshave listed some of the
different radiophamaceuticak (17-20). and the radiopharmaceuticals administered.
deaths and the use of the radiopharmaceuticals. clinical manifestations that are commonly ob-
According to the United States literature (14), The European Joint Committee has reported
ontwo deaths (17-20). One patient died after served with adverse reactions to specific radio-
the majority of adverse reactions occurring dur-
cardiac arrest which occurred 1 hour after the pharmaceuticals (10-12, 14). For thoseradio-
ing the years 1976-1979 were nlinor (resolved CHARACTERISTICS OF ADVERSE
injection of 67Ga-citrate,* and the other patient pharmaceuticals on whichenoughdata are
withnotherapy)orintermediate(requiring REACTIONS TO SPECIFIC
diedwithinhoursafter the administration of available, it is noleworthy that in reported cases,
someform of therapyfor r e k f hutnotlife- RADIOPHARMACEUTICALS
%"Tc-MAA and 99mTc-pertechnetate.In neither single clinical manifestations or, sometimes, a
lhreatening). Severe reactions involving anaphy- Most reported adversereactions havebeen
instance is there a strong reason to believe that pattern of symptomsoccurs againand again.
lactic shock or cardiac arrest were reported in allergic in nature (10, 14,17-20). Vasovagal Even so, with the exception of only a very few
only 3% of cases. In 52% (39 of 75) of the cases rcactions account,formuch of theremainder, radioactive drugs (e.g., possibly 99mTc-labeled
reported to theEuropeanJointCommittee,
* Although I~%a]palIiurn cifrate and IgY'llTc]pcrtechne- along with a few miscellaneous adverse effects human albumin miirospheres or [13'l]iodometh-
treatment was required (17-20). tale are prelcrred by IUPAC, 4"Ga-citrateand "Wqertech- such as pyrogen reactions,aches and pains, ylnurcholesterol,there is nosuch thing as a
Nuclear medicine studies often are performed nelalc arc standard, and botb are used throughour this chap- vomiting, and headache unrelated to pyrogens.
ler. "typical" adverse reaction.
on crilically ill patients; thus,occasionally a
314 f EssentinIs of h’uclear MedicineScience Adverse Reocriom Associored with Radiophalunaceurical~ f 315

The relationship between the reactions re- to prepare the reagent kit and the reported reac- Table 20.4-continued
porledfor a specificradiopharmaceutical and tions.Specifically, with 99mTc-MDP,four kit Tune of Trzalment
the source of that radiopharmaceutical was ex- sources and threesources of 99mTc-pertechne- Radiopharmaceutical Maniieslations
Clinical of Reaction Reaclion Onrct Required?

amined with use of the SNM reports for 49mTc- tate (six different combinations of kit-pertech-
human9gmTc-labeled 1. Itching 3 min Yes
MDP ( 13 reports) and 99mTc-labeledsulfur col- netale) were cited; with 99”Tc-labeled sulfur albumin
microspheres 2 . Flushing;
decreased
blood
pressure immediately
No
loid (12 reports)fortheyears1982through colloid, four kitsources,threegenerator 3 . Flushing of face; epigaslric discomforl 2 min No
1984. Even with this limited amount of data, it sources, and seven combinations of kit-perlech- 4 . Facial “burning”; nausea; tightness in chest;
is apparent that no single company is citedin all netatewere cited. Data collectedduringthese abdominal
pain
lower
severe 1 min No
same years for other multisource products are 5 . Flushing immediately; chills and fever within
adverse reaction reports for either of these ra- ~~

30 min
too scant to be credibly analyzed.
1 min No
diopharmaceulical products, nor can any manu- 6 . Flushing; urticaria; diaphoresis 3 min No
facturer be blamedfor a special typeof reaction. Table 20.4 liststheclinicalmanifestations 7. Flushing of face; shortness of breath; right-
Likewise,there is no correlationbetweenthe encountered with suspected reactions to the six upper-quadrant pain 3 min NO

source of 99n1Tc-perlechnetate (generator)used most frequently cited radiopharmaceuticals, as 8. Circumoral cyanosis; lethargy; spasms of ex-
tremities 5 min No
1. Pupil dilatation; general ionic convulsions;
bradycardia (probably all related lo very recent
Table 20.4. excessive alcohol and drug abuse) ?”shortly” No
Description or Adverse Reaclions to Six Radiopharmaceulicals Reported to the Sociely of Nuclear 2. Flushing of face, trunk and arms; weakness immediately No
Medicine,January1982-December1984 3. Numbness; palpitation; difficul~y in breathing 1 rnin NO
4. Urticaria on face, chest, and back 10 mill Yes
Tlme ol Trcatmenl
5. Urticaria 1 hr No
Radiaphnnnaccu1ical Manifesfations
Clinical of Reaction Reaction Onset Required?
6. Allergic reaclion (no details given) 15 min Yes
99mTc-MDP 1. Rash;
itching 40 min Yes
2, Rash;itching 36 hr ? Nonradioactive
pyrophos- 1 . Diaphoresis;
bronchospasm 1 min Yes
3. Rash; itching 10 hr Yes phak
reagent kit 2. Decreased
blood
pressure;
dizziness;
blurred
4. Ilching 4hr Yes vision; tightness in chest; nausea 10 min Yes
5 . Ikhing 2 hr Yes 3 . Generalized prurilis; hives on upper thighs 7 hr Yes
6 . Upper body flushing; single pelechial area two 4 . Wheezing; decreased PO, 10 min Ye S
inches from injection site 30 min No 5. Rash;itching 30 min Yes
7. Pyrexia; edema in extremities; red blotchy skin 4-8 hr No 6 . Chills; joint pain; nausea; dizziness; fever
8, Sore throat; rash; ?Stevens Johnson syndrome 48 hr Yes (which may be due to bacteremia from in-
9 . Vomiting 3 times within a 3-hr period 40 min No dwelIing intravenous line, but cultures were not
10. Generalizedpruriris;
wells and itching “bumps”
11. Cardiac arrhythmia; died (details are skelchy)
8-10
48 hr hr
2 br
I Yes
Died 67Ga-cilrate
perlormed)

1. Morbilliform rash on trunk and flexor surfaces

2 0 min Yes

12. Rash; chilk 1 hr Yes of extremilies;

itching 24 hr NO

13. Dizziness; nausea 5 min No 2.forearm

right
Hives
shoulder
on
and 10 min Yes
3. Inflammation at site of injeclion; rash around
99mTc-labeledsulfur 1, Maculopapular rash on upper trunk and ex- and on neck
mouthimmediately Yes
colloid tremities; itching 30 min Yes 4 . Erythematous, maculopapular rash on entire
2. AlIergic reaction (no details given) 15 min Yes body 15 min No
3. Urticaria; swelling of extremities 8 hr Yes 5 . Tachycardia; hives 3hr Yes
4. Rash; tightness in throat 10 min Yes 6 . Rash and pruritis on left f o r e m 12 hr Yes
5. Flushing; shortness of breath; coughing; itching
in palms, antecubital spaces and throat 10 min Yes
6 . Rash of neck; abdominal discomfort 6hr Yes
7. Urticaria 30 min Yes
8. Laryngospasm or laryngeal edema 2 min Yes
Colloids
24 hr
reported lo the SNM adverse reactionregistry
9. Whole-body rash NO
10. Tingling of extremities; tightness in chest and during the years 1982 through 1984. In devel- As mentioned previously, wmTc-labeled sul-
throat; increased blood pressure; tachycardia; opment of this table, there was no attempt lo fur colloid has been responsible for the largesl
maculopapular rash 15 rnin Yes delerminetheprobability of whether the ob- number of adverse reactions reported to the
11. Ikhing; swelling of lace and exlremilies; served reaction was actually caused by the ad- SNM. Even though the total number is high,
blisters on face 4-6 hr Yes
ministered radiopharmaceutical. Characterislics however, the incidence of reactions is not much
12. Chills; fever; felt “shaky”; incmascd blood
pressure, 4-6 hr No of reactions to individual radiopharmaceuticals greater than the average for all radiopharnlaceu-
are briefly discussed below. ticals combined, since *“Tc-labeled sulfur col-
316 I Essentials of Nuclear Medicine Science Adverse Reactions Associared wirh Radiopharrnaceuricais I 31 7

loidisadministered so frequently (14, 15). pulmonary function, only 0.2-0.3% of the ves-
Since 1976, the majority of adverse reactions to sels are blocked with a 1-mg dose of protein
wmTc-la'oeledsulfurcolloidreported in the consisting of particles ranging from approx- sea, and bronchospasm.
other reporting systems isto obtain current inci-
United States have been allergic in nature, wilh imately 20 to 90 pm (22, 23). This small frac- dence data for adversereactionsto radiophar-
rash, urticaria, pruritis,dyspnea, and nausea tion normallywill not cause a problem clini- [1311]I~domethglnorchoIesterol maceuticals in ordertohelpassesswhether
and vomiting being themost frequent symptoms cally. In apatientwith diminishedfunclional [I3'IJiodomethylnorcholesterol, which is there is a problem with a specific dmg. These
(10, 14). From 1976to 1981, anaphylactic or capacity of the pulmonary vasculature, however, used for adrenal cortex imaging, has been asso- data are generated by first multiplying the esti-
anaphylactoid reactions accounted for S7u of the the added insult could be significant (12). ciatedwith adversereactionscharacterized by mated number of total radiopharmaceuticar ad-
total (10). In the Uniled Kingdom, reactions Iron hydroxide precipitates were used for shortness of breath, tightness in the chest, pal- ministrations in a given time period by the rela-
involvingvasomotor changes, alongwith lo- lungimaginguntil 1973. Atthattime,the pitations, vasodilatation, nausea, and dizziness Live frequency of use for a particular radiophar-
calized discomfort, headache, and backache, United Slates Atomic Energy Commission and
were common, andreactions such as dyspnea the British Institute of Radiology (BIR) advised
persisting for 5-20 minutes postinjection. Th
4 maceuticalinthatsametimeperiod.The
manufacturer has attributed the reaction to the number of adverse reactions to the radiopharma-
and bronchospasm occurred in a small number discontinuing theiruse due to numerous adverse Tween-SO surfactant used in the product for-' ceutical is then divided by this figure to derive
of palients (21). reactions, including three dealhs, associaled mulation (25). Specifically, it has been reported incidence data. Because it is estimated that only
Before 1976, colloids of lssAu and 113mIn with the administration of theseagents.The thal polyoxyethylenesorbitanfatty acid esters one tenth to one half of the observed reactions
were also used for liver andlor spleen imaging. reactions may have beencaused by free ferric (i.e., Tweens) have been shown to release his- are actuallyreported, a range is estimatedby
Allergicreactions occasionally were reported hydroxideion which has anindirectvasocon- tamine from endogenous sources following in- use of the following equation (14):
for these agents, although a more serious prob- stricting effect (4,9). travenous administration (26,27). The reactions
lem with use of the 198Au was the poiential for Estimated range of adverse reactions
Phosphates and Phosphonates experiencedwith [1311]iodomethylnorcholes-
an accidental radiation overdose. terol are consistent with the effects of histamine
Althoughvirtuallyall of the 99mTc-labeled on thecardiovascular and pulmonarysystems 1I
Albumin Particulates phosphateandphosphonateagents havebeen (25). i
Macroaggregates or microspheres of albumin implicated in reports of adversereactions, \ \/
/
where A, equals the number of reported reac-
~ the two most conxnonly 99mTc-MDP has received the most noloriety. A
labeled with 9 9 m Tare tions,fequals the relative frecluencv of use of an
Cisternographic Agents
used agents in the United States for pulmonary reaction that is repeatedly observed with 99mT~- individuairadiopharmaceutical,and A equals
and arterialperfusionstudies. In 1978and MDP involves a late-onset rash andlor itching Historically, intrathecal radionuclide cistem- the total number of administrations of all radio-
1979, the only years for which data on the which appears 2-24 hours or longer after injec- ographic preparations were once oneof the mos~ pharmaceuticals.
incidence in the United States are available, tion and persists for several days (IO, 11). This frequentcauses of adverseeffectsdue to the Reportsby the SNM subcommittee on ad-
99111Tc-labeled human albumin microspheres had phenomenon has beenmentioned in 15 of 35 incidence of aseptic meningitis associated with verse reactions indicatedthat theincidence in
h e highest incidence of adverse reactions of any reports of reactions to 99mTc-MDPin the United theiruse.Theseradiopharmaceuticals, L311-1a- theUnitedStates is between 11100,000 and
radiopharmaceutical (14, 15). The clinical man- Statesseries.Thistype of reaction has been beled human serum albumin and, laler. "'In- 6/100,000 administrations.Theestimatesfor
ifestations reported most frequently were flush- carefully documented i n onereporl in the DTPA, wereoriginallytestedwith use of the the United States ranged from 8.S/100,000 ad-
ing associated with dyspnea and/or shortness of United States literalure (24), and in the United standard United States Pharmacopeia rabbit test ministrationsfor 99mTc-Iabeled human serum
breath, with or without olher allergic symptoms Kingdom series, British authors have noted sev- for pyrogens. Not until the introduction of the albumin to 0.12/100,000 for 99mTc-MDP in
(10,14). Anaphylactic or anaphylactoid reac- eralinstances of a similar reaction (1 1 , 21). limulus amebocyte lysate (LAL) test for endo- 1978 and from 5.41100,OOO for ""Tc-labeled
tions occurred in 10.1% of the reported cases Other adverse reactions to wmTc-MDP include toxins, however, did it becomeapparent that human albuminmicrospheres to 0.25/100,000
from 1976 through 1981 (10). misceHaneous symptoms such as flushing, these radiopharmaceuticals were, in fact, con- for 99mTc-gluceptate in 1979 (14, 15).
By comparison, the incidence of adverse re- headache, swelling of the extremities, and nau- taminated with pyrogens at a level not detected This estimate is lower than that reported by
actions to the more commonly used 99mTc-la- sea and vomiting (lo). There were two reporls by the rabbit test (9, 12). It was found that the Sampson and Keeling (28) in 1982 for 32 nu-
beledmacroaggregatedalbuminwasabout of broken bloodvessels in theeye following source of the endotoxin, in the case of the radi- clear medicine centers in the United Kingdom;
15-20-fold less than that observed for 99n1T~- administration of %mTc-MDP (10). The proba- oiodinated compounds, was the anion exchange thefiguresrangedfrom 1 reaction i n 400
labeledalbuminmicrospheres(14,15).Re- bility that this occurrence was caused by 99mTc- column used 10 remove unbound iodine. In the (250/100,000) for 99mTc-labeled macroaggre-
ported symptoms included flushing, tachycar- MDP is low (IO), but it is unusual that a patient DTPA preparations, the phosphatebuffer was g a t e da l b u m i nt o 1 r e a c t i o ni n4 , 2 5 0
dia, syncope, and rash (IO, 14), in the United Kingdom also developed a severe the component that contained the endotoxin (24/100,000) for 99mTc-pertechnetate(28). This
Adversereactions to albuminparticulates visual disturbance shortly after the injection of ( 1 2). Once the problem was identified and the was a reduction in incidence froma preliminary
may be attributed lo either antigenic reactions or this same radiophannaceutical (21). source of the pyrogens ascertained,the inci- survey report of United Kingdom data by
vascular obslruction in the lungs. These parli- Pyrophosphate injected both with and with- dence of asepticmeningilisassociatedwith Williams (29)in1974 who estimatedfrom 1
cles are trapped by the precapillary arterioles out the WmTc label has been associated with a these products was drastically reduced (9), and reaciionl36 administrations (2,7S8/100,000) for
and capillaries d the lungs where they are es- significantnumber of reactions in the United theincidence hasremained extremely low in 99mTc-labeledmacroaggregatedalbuminto
senlially ~nicroe~nboli. In a person with normal States. Clinical manifestations were similar re- recent years. 113,000 (331100,000) €or99mTc-DTPA.
318 i Essentinls of NuclearMedicine Scierzce
Williams (29), however, used a questionnaire to
obtain data based on the recent and retrospective
experience of 40 individuals, whereas Sampson
and Keeling (28) used data based only on recent
experience. Therefore, the incidence data from
the earlier survey may no1 be as reliable as that
from the follow-up reporl.
Extrapolating from data obtained in their re-
spectivedistricts,KeelingandSampson(21)
haveevenmorerecently estimated anoverall
incidence in theUnitedKingdom of approx-
imately 10-40 reactions1100,OOO tests.Results
from a series of reports from Japan indicate that
reactions to radiopharmaceuticals occur at a rate
of 6-20/100,000 administrations, with the ex-
ception of [l3’Ijiodocho1estero1whichhasan
adverse reaction rate of approximately 3-
511,000 (17, 18).
Regardless of thesource,incidencefigures
for radiopharmaceulicals appear to be, in gen-
eral, much less than those given for therapeutic
drugs or contrast media (30-33). That adverse
reactions occur much less often with radiophar-
maceuticalsthanwithcontrastagentsmay
sometimes influence the seleclion of the diag-
nostic imaging procedure of choice for a criti-
cally ill patient.
VALIDATION OF ADVERSE
REACTlONS
In most systems, it is recommended that any
adverseexperience associatedwiththe drug,
even if that association is not certain, should be
reported. Therefore, the validity of these anec-
dotalreports is sometimes questioned by both
professionals and manufacturers. Venning (34)
hassuggestedthat“anyregulatoryagency
using anecdotal reports of suspected reactions as
a basis for an early warning system will need to
develop criteriaforassessing thevalidityof
such reports.” Therefore, reports submitted lo
the SNM for the years 1976 through 1981 were
evaluated (10) with use of a modified algorithm
based on one developed by Kramer et al. (35)
for the assessment of adversedrugreactions.
The algorithm was used to analyze each case in
an accurate and reproducible fashion by system-
atically and objectively deriving a score for the
probability of an adverse reaclion occurring.
Criteria for evaluating adverse reactions to ra-
diopharmaceuticals included (a) previous expe-
rience with theradiopharmaceuticalincluding
the frequency with which a specific reaction to
theradiopharmaceutical was reporled,(b) Ihe
possibility (probability) of other etiologic can-
didates for the reaction or of an exacerbation or
recurrence of theunderlyingdisease,(c)the
timing of the adverse reaction in relation to the
administration of theradiopharmaceulical,(d)
whetheror not there was improvementafter
dechallenge, and {3 whether or not there was a
recurrence of the reaction following re^
with the radiopharmaceutical. Adverse reactions
were then classified,depending onthe score
derived from the algorithm, as definite, proba-
ble, possibIe, or unlikely.Withuse of this
method, adverse reaclions to radiopharnlaceuti-
cals were determined to be definite in 47 of 277
cases (17%), probable in 11 I cases (40%), pos-
sible in 100 cases(36%), andunlikely in 19
cases (7%) (10). Keeling (11) and Keeling and
Sampson (21) havesubjecteddatafromthe
United Kingdom to a similar analysis and found
that 7 of the 61 reporled reactions were unlikely
to be directly related to the administrationof the
radiopharmaceutical.
It is obvious from the SNM experience that
there are some inherent problems in evalualing
anecdotal information. One of the major draw-
backsisthal in somecases,thereports are
incomplete, either because the reporter did not
fill in all of the infonnation on the form (or did
not give enoughdetail) or becausethereare
inherent limitations with the reporling form it-
self. For instance, not until 1985 did the report
formusedforradiopharmaceuticals (FDA
1639) ask the reporter to lis1 the patient’s current
medicationsand allergichistory. This type of
informationwouldhavebeen(andwill be)
useful in helping to determinewhetherthere
was an alternative etiology for the reaction. In
defense of theoriginal reporting form (FDA
2822), it is only fair tomention that the form
was intentionally designed in a relatively simple
fonnat so that a majority of people would be
willingtotakethelimetocomplete it after
witnessing an adverse reaction. Reporters were
(and still are) encouraged, however, to give ad-
ditional information (not specifically requested
on the form) and to elaborate on specific cir-
Adverse Rencrions Associated w i d 8 Radiophormnceuricrrls
z-. a
cumstances or events [hat may be relevant to the
reaction. Some of the procedures that should be
g followed in the investigation and reporting of a
e-
j suspected adverse reaction have been described
’L 3 by Rhodes and Wagner (36). Complete and ac-
curate data always make the task of determining
the validity of the reaction much easier.
It should be notedthatthe most definitive
way to determinewhether a type 3 adverse
reaction to a drug has occurred is by rechalleng-
ing the patient with the suspected offender. Re-
F
challenge may occureitherbychanceorby
direcl intervention when this is ethically justi-
fied. In most cases, rechallenge with radiophar-
maceutical~is not attempted. There have been a
few cases reported tothe SNM, however, in
which a person who had experienced an allergic
responseto a radiopharmaceutical wassubse-
quently injected with the same radiopharmaceu-
ticalandexperiencedthesameallergic re-
sponse. This was reported in twoseparate
instances of adverse reactions to 99mTc-labeled
sulfur colloid. In a case involving 99mTc-MDP,
“
(he -tical reactions 1 month apart
(24). A similar,but moresevere,reactio5Xc-
curred in one patient following a repeat admin-
islraiion of wn2Tc-labeledhumanalbuminmi-
< crospheres 2 daysafterthe first injection. In
$ Chapler I1 (Definitions), Sec 201 [321] (g) (1).
19x2, the SNM received a report of rechallenge
by direct intervention wilh pyrophosphate re-
agentkit, in whicha lopica1 patchtest was
performed on a patient whohad experienced
generalized pruritis and urticaria following ad-
ministration of 6 mg of pyrophosphate (reagent
kit)inpreparalionfor a radionuclideven-
ticulographystudy. Thereporter in this case
2 first performed a patch test for stannous chlo-
ride, which was negative. This was followed by
I a patch test for the reagent kit contents (pyro-
; phosphate plus stannous chloride), which elic-
t ited a positive response.
$I
SUMMARY
The overall incidence rate for radiopharma-
ceulicals is estimaled to be less than 40/100,000
t adnlinistrations. Reactions are most commonly
: licalions, 1981.
associated with particulate carriers such as de-
f 9. Shani J, Arkins HL, Wolf W: Adverse reaclions to
natured albumin or colloidal material, as well as
the soluble carriers containing phosphonates or
fz iodon~ethyInorcholesterol.Attimes,the reac-
$+=
/ 3i9
tions may be caused by the pharmaceutical ad-
ditives (e.g., surfactants) found in these radio-
pharmaceutical preparations rather than by the
primary carrier itself.
Most reactions appearto be allergicin nature.
In addition, the majority occur within minutes
following theadministration of the radiophar-
maceutical, withthe notableexception of the
late rashes observed with the phosphonate bone
imaging agents.
Adverse reaction reporting systems in which
anecdotal informationis ulilizedto document
adverseeffectstoradiopharmaceuticalssuffer
generallyfrom poor participationandin-
complete reporting. If the adverse reaction reg-
istriesare going to be of utmost value to the
nuclearmedicine“community,”thecoopera-
tion of all professionals in the field is needed.
Suspectedreactionsshould be promptly re-
ported, andcare should be takento provide
complete and pertinent facts on each case. Only
then canthe objectives of the eslablished sys-
tems, i.e., to alert practitioners to potenlial
problems as early as possible and to determine
accurate incidence data, be met.
REFERENCES
1 . UnitedStaresFederalFood Drug and Cosmetic Act,
2 . United Stales Code ofFederal Regulations, Titlc 21,
Par1 310,301 (b).
3 . Atkins HL: Adverse reactions. In Rhodes BA ( e d ) :
Quality Control in Nuclear Medicine. S I Louis, CV
Mosby, 1977. pp 263-267.
4. Bleha V. Colombetti LG: Adverse Reactions to radio-
tracers. In Colombetti LG (ea): Princzjhs o/ Radi-
uplfnmfnco1og.s.Boca Raton, FL, CRC Press, 1977, pp
165-177.
5 . Shani J. Sard 0,Rogel S, et al:Comparativecardiac
eKecls of thee hepatobiliary radiophamaceulicdls in
the dog: concisecommunicalion. J Nrrcl Merl
23337-341,1982.
6. Ahmed SR, Shale1 SM: Radioactive iodine and teslicu-
Iar damage. N Engl J Med 31 1:1576, 1984.
7 . Ahmed SR,Shalet SM: Gonadal damage due to radio-
active ”‘1 Irealmenl for thyroid carcinoma. Postgrad
Med J 61:361-362, 1985.
8 . Rawlins MD, Thompson J W : Pathogenesis of adverse
drug reactions. In Davies DM (ed): Texrbook oJAdverse
Drug Rencriorls. ed 2 . Oxford, Oxford Medical Pub-
rarliupllarmaceuticals. Semin Nuci Meed 6305-328,
1976.
10. Cordova MA, Hladik W B 111, Rhodes BA: Validation
320 I Essentials of Nuclear Medicine Science

and characterization of adverse reactions 10 radiopha- pharmaceuticals.United Kingdom1977-1963. Br J

maceuticaks. NonirlvasiveMed lmagirzg 1:17-24, Radiol 57:1091-1096, 1984.
1984, 22. Harding LK, Horsfield K, SinghaI SS, et al: Theprepa-
11. Keeling DH: Adversereactions to radiopharmaceutl- ration of lungvesselsblockedbyalbumin mac-
cals. In Kristensen K , Norbypaad E (edsl: Sdefery and
Eflcacy of Radiopharmacerrticals. The Hague,The
rospheres. J N d Med 14579-562, 1973.
23. Davis M: Particulateradiopharmaceuticals for pulmo-
21
nary studies. In Subramanian G , Rhodes BA, Cooper
Netherlands, Martinus Nijhoff, 1983, pp 240-250.
12. Keeling DH: Side effects associatedwiththeuse
radiopharmaccukicals. I n Gorrod J\I‘ led): Dnrg TOX-
Of JF, Sodd VJ (eds): Radiupharmocefrrical. New York.
Society of Nuclear Medicine, 1975, pp 267-261,
Regulutory Problems in Nuclear Medicine
icily. London. Taylor & FrancisLtd..1979, PP 24. Spicer JA, Preston DF, Stephens RL: Adverse allergic
285-295, reaction to technetium-99m methylene diphosphonate. James F, Vandergrift
13. Ford L, Shrofi A, Benson W, et al: SNM drug problem J N r d Med 2 6 3 3 - 3 7 4 , 1985.
reporting system. J Nucl Med 19116-117, 1978. 25. Swanson DP: Adversereactions lo NP-59(personal
14. Cordova MA, Rhodes BA: Adverse reactions to radio- communication to all investigators of [“’l]iodomethyl-
pharmaceuticals:incidence In 1978, andassociated norcholesterol, May 8 , 1980.) Governmental involvement in the practice of (NCRP). In practice,theseagencies andtheir
symptoms. Reporttheadversereactions subcommit- 26. Marks LS, KolmenSN:Tween 20 shock in dogs and medicine has increased sharply within [he past standards are not so well defined. The NRC is a
tee of the Society of Nuclear Medicine. J NrrcI Med relatedfibrinogen changes. Am J Plzvsiol 220:216- fewyears. The impact on health care has, for regulatoryagencybutdoes,attimes,issue
21:1107-1110, 1960. 221, 1971.
the most part, been in termsof financial interac- guidelines and even voluntary standards. Also,
15. Cordova MA, Rhodes BA, Atkins HL, et al: Adverse 27. BurnellRH, Maxwell GM: General andcoronary
reactions to radiopharmaceuticals. J N m l Med haemodynamic effects of Tween 20. Ansr J Exp B i d tions between heahh care facilities and federally therecommendations of the NCRP are, at
23550-551, 1982. Med Sci 52:151-156, 1974. funded health services programs. One might say times, issued by a regulatory agency as regula-
16. Roundtable discussion on radiophmaceuticals: re- 28, Sampson CB,Keeling DH: Adverse reactions to radio- that this type of governmental involvement has lions, or they are made a part of regulations by
porting of adverse reactions and drug defects. Nidklear- pharmaceuticals-a follow-up survey in the U.K. Re- indirect impac~on the medical and/or technica1 specific reference.
rnedizirl 20:10- 12, 196 1 . port presented at the Annual Scientific Meetlng, British
NuclearMedicineSociety, London, 1982.
decisions in the practiceof nuclear medicine. In As we proceed through this chapter, I do not
17. The Joint Committee on Radiopharmaceuticals of the
European Nuclear Medicine Society and the Society Of 29. Williams ES: Adversereactions to radiopharmaceuti-
other areas, however, governmental policies and attemptto distinguishbetween regulation and
Nuclear Medicine-Europe: The system for “reprtlng cals: a preliminary survey in the United Kingdom. B r J regulationshave had a more direct and funda- recommenda!ior~.This is relalively simple at the
of adverse reaclions and drug defects” (1980- 1982)- Radiol 4754-59, 1974. mental impact on nuclear medicine than on any federal level, but there may be significant dif-
first reporl. Nuklenrmedizin 21:274-277, 1982. 30. Ansell G , TWeedy MCK, West CR:Contrastmedia other medical specialty. Without an understand- ferences at state and local levels. in a specific
16. TheJoint Committee on Radiopharmaceuticals Of the toxicology. Br J Rodiol 57548, 1984.
ing and acceptance of this situation, the practice nucIear medicine facility, one must first estab-
European Nuclear Medicine Society andthe SOClety Of 31. Shehadi Vi%, Toniolo G : Adverse reactions to contrast
Nuclear Medicine-Europe: First report on the SySlenl media. Radiology 137:299-302, 1980. of nuclearmedicinecan be very frustrating. lish who is themost proximal authority and then
for “reporting of adverse reactions and drug defects” 32. Stewart RB: Adverse drug reactions in hospitalized Thischapter is thuswritten in thehope that ascertain what practicesare a matter ofreg-
1980- 1982. Em- J N~rclMed 9:45-49, 1984. patients. Plzarm Inr 1:77-79, 1980. polential fruslrationcan be reducedor eIimi- ulatory compliance andwhat practices area
19. The Join1 Committee on Radiophamaceulicals or the 33. Miller RR. Greenblatt DJ (eds): Drug Effecrs in Hospi- nated. matter of practical circumstances and personal
European Nuciear Medicine Society and the Society Of talized Purienrs. New York, John Wiley & Sons. 1976.
judgmenl.
NuclearMedicine-Europe:Europeansystem tor re- 34. Vennmg GR: Validity ol anecdotal reports of suspected REGULATION VERSUS
porting of adverse reactions and drug delects-second adverse drug reactions-the problem of false alarms.
Er Med J 284:249-252, 1982.
RECOMMENDATION
report 1982- 1983, Nuklearmedirin 23: 107-108, 1984. SPECIFIC STAGES OF INTERACTIONS
20. The Joint Committee on Radiophamaceulicals of the 35. Kramer MS, Leventhal JM, Hutchinson TA. et al: An There are authorities at the federal, state, and BETWEEN THE NUCLEAR MEDICINE
European Nuclear Medicine Society and the Society Of algorithm for theoperationalassessment of adverse local levels who set standards,writepolicies,
NuclearMedicine-Europe:Europeansystem for re- drug reactions I. Background, description. and instruc- FACILITY AND ITS REGULATORY
andlor defineresponsibilities which may have
porting of adverse reactions and drug defects: second tions for use. JAMA 242623-632, 1979. AGENCIES
[he force of law (regulations) or may simply be
reporl 1982-1983. Eur J NuciMed 9:386-389, 1984. 36. Rhodes BA, Wagner HN Jr: Adverse reactions lo radio- Licensing
21 . Keeling DH, Sampson CB: Adverse reaclions to radio- pharmaceuticals. J Nuci Med 15:213-214, 1974. “standards of good practice” (recommenda-
tions). Agencies that promulgate regulations are Obtaining a nuclear medicine radioactivema-
themselves given authority by, and limited to, terials (RAM)license for a new facility or the
specific legislation which defines their jurisdic- renewal of a license for an established facility is
tion.Scientificand/orprofessionalgroups, al- a critical step in the regulatoryprocess.The
though lhey may be highly respectedand immi- licensingprocesscan be timeconsuming and
nentlyqualified,provideonly a consensus tedious; therefore knowledge of the processis of
opinion in the form of recommendations. These help.
recommendations may be accepted or rejected First, the type of licensediffers from one
without specific penally. operation 10 another. For example, when only
An example of the first category of aulhority “exempt” quantities for in vitro procedures are
is the Nuclear Regulatory Commission (NRC) to be used, one obtains a registration number by
and the second type is the National Council on submittinga very simpleapplication. At the
R a d i a t i o nP r o t e c t i o na n dM e a s u r e m e n t olher extreme, if onerequires a broadscope
 Regularory Problems in Nuclear Medicine 1 323
322 1 Essentials of Nuclear Medicine Scieuce

license to cover medical diagnosis, therapy, and ment but maybe an autonomousagency or Table 21.1 “continued
research, thelicensingprocess may be quite some other part of state government. In Table
-
Slate Agency Address
long and involved. 21.1 are listed the agreement states and the
The licensing authority is eilher the NRC or a licensing agency asof March 1984. The mailing Nebraska Division of Radiological Health State Department of Health
state agency. If the nuclear medicine facility is address of the NRC for nonagreement states is 301 Centennial Mal1South
in a “nonagreement” state or is a federal facility included. P.O. Box 95007
A first step in licensing is to contactthe Lincoln, Nebraska 68509
(VeteransAdministration hospital, military in- Nevada RadiologicalHealth Consumer Health Protection Services
slallation, etc.), the licensing authority is the appropriateauthorityandobtain (a) a copy of Room 103, KinkeadBuiIding
NRC. In “agreement” states, the licensing au- applicableregulations, (b) a copy of that CapitolComplex
thority often is a part of a stale health deparl- agency’s “licensing guide,” and (c) the forms CarsonCity,Nevada 89710
New Hampshire Radiological Health Program Division of Health Services
Table 21.1. Bureau of EnvironmentalHealth Health & Q‘eIfare Building
Hazen Drive
Concord, New Hampshire 03301
New Mexico RadiationProreclionSection Environmental Improvement Division
P.O. Box968
Alabama Division of Radiological Health Environmental Health Administration CrownBuilding
Room 314 Sanle Fe, New Mexico 87503
State Office Building New York TechnicalDevelopmentPrograms NewYork State Energy Office
Montgomery, Alabama 361 30 AgencyBuilding 2
Arizona Arizona Radiation Regulalory Suite 2 2 Rockefeller Plaza
Agency 925 South 52nd Streel Albany,New York 12223
Tempe,Arizona 85281 NorthCarolina Radialion Protection Section Division of Facility Service
Arkansas Division of Environmental Health Arkansas Department of Health Box12200
Protection 4815 West Markham Street Raleigh, North Carolina 27605
Liltle Rock, Arkansas 72205 NorthDakota Division of Environmental En- Slate Deparrmenl of Health
California Radiologic Health Section Department of Health gineering 1200 Missouri Avenue
Room 498 RadiologicalHealthProgram Bismarck,NorthDakota58501
714 P Streel Oregon Radialion Control Service Department of Human Resources
Sacramento, California 95814 Division of Health 1400 South West 5th Avenue
Colorado Radialion & Hazardous Waste Con. Department of F’ublic Health Portland, Oregon 97201
trolDivision 4210 Easl 11th Avenue RhodeIsland Division of Occupational HeaIth Rhode Island Deparlment of Health
G€ficeof Health Protection Denver.Colorado 80220 CannonBuilding
Florida RadioIogjcal Health Program Department of Health and Rehabilitation Service 75 Davis Street
Health Program Office 1323 Winewood Bouievard Providence. Rhode Island
Tallahassee, Florida 32301 SouthCarolina Bureau of Radiological Health Stale Deparlmenl of Heallh and Environmental
Georgia Emergency Medicine and Radi- Department of Human Resources Control
ological/Occupationa1Health 47 Trinity Avenue J. Marion Sims Building
Section Allanta,Georgia30334 2600 Bull Streel
Idaho RadiationControlSection Idaho Deparlment of Health & Welfare Colombia, South Carolina 29201
State House Tennessee Division of Radiological Health Department of Public Health
Boise, Idaho 83720 Cordell Hull State Office Building
Kansas Bureau of Radiation Control Departmenl of Health and Environment Nashville, Tennessee 372 19
Division of Environmenl Building 740 Texas Division of Occupational Heallh Texas Department of Health
Forbes Field and Radiation Control 1 100 West 49th Street
Topeka, Kansas 66620 Auslin, Texas 78756
Kentucky RadialionControlBranch Deparlment of Human Resources Utah Bureau of Radiation Control State Department of Health
275 E. Main Streel 150 West North Temple
Frankfort,Kentucky40601 Box 2500
Louisiana Nuclear Energy Division Olfice of Environmental Affairs Salt Lake City, Utah 84110
P.O. Box 14690 Washington Radioactive Materials Deparlment of Social & Health Services
Baton Rouge, Louisiana 70898 Mail Stop LD-11
Maryland Division oE Radialion Control Department of Heallh & Mental Hygiene Olympia, Washington 98504
201 West Preston Street All Nonagreement .United States Nuclear Regulatory Material Licensing Branch
Baltimore, Maryland 20201 Commission Stntcs Division of Fuel Cycle & Material Safely
Mississippi Division of RadioiogicaI Health State Board of Health Office of Nuclear Material Safety & Safcguards
Jackson,Mississippi39205 Washington, D.C. 20555
324 / Essenlids of Nuclear Medicine Science
appropriale for the type of licensebeing re-
quested.
Whenmakingapplicaiion, one should b e
aware that stalements, procedures, records, etc.
that are part of the application will, on approval,
become part of the licensing document by refer-
ence. 11 is, therefore, important thal the applica-
tion represent honest intent and not an exercise
in saying what “they” want to hear. Unrealistic
or insincere statements at this time will almosl
certainly create problems at a Ialer time.
The NRC and many agreement states have, in
recent years, developed categories of use which
helpto simplifylicensingapplications some-
what,
One of h e major components of an applica-
tion is informalion regarding the physician’s
and/or user’s qualiFications. Specialty Board
Certificalion is usually accepted as evidence of
adequate [raining and experience. Certification
in a professional specialty such as radiology or
pathology, however, normally will not be con-
sidered adequale for all radiopharmaceutical
procedures or for any therapy procedures. Cer-
tification by theAmericanBoard of Nuclear
Medicine is generally accepted as adequate for
all categories of routinediagnosticand thera-
peutic procedures involving radiopharmaceuti-
cal sources. This cerlification does not include
teletherapyorbrachytherapywithuse ol
“sealed” sources, however.
License Amendments
The license, depending on how it is written,
may not allow for innovations, new procedures,
or even increased patient load. When this is the
case and changes are desired, an amendment to
the license is necessary. An amendmen1 consists
of a request lo change a specific part or to add a
new partalong with justification in terms of
safety andlor efficacy of the new procedure.
When these changes involve experimental (non-
routine) radiopharmaceuticals oran unapproved
use of an established radiopharmaceutical, one
mustobtainFoodandDrugAdministration
(FDA) approval or become accepted as an in-
vestigator under a manufacturer’sInvestiga-
tional New Drug (IND) submission. (Refer to
Chapter 23 for detailed discussion of IND pro-
“,I ..”,. \ mosl inspections, tend to rely heavily on records
License Renewal
A license is issued for a specified period of
time, usually 3 or 5 years. Three or 4 months
prior to its expiration, renewal procedures
should begin. If there are no changesto be made
and a simple continuation of the present license
is all that is needed, a requesttoextendthe
expiration date may suffice. Some agencies re-
quirethat one“amend in entirety,” however.
When an amendment in entirety is required,
theamendment in effect consists of complete
reapplication. In this case, the original applica-
lion, with all changes and addilionsincorpo-
rated into a single up-to-date document, is sub-
mitted. Over a period of years, one may find il
difficult lo keep track of the separateamend-
ments and the parts of [he original license af-
fected. An amendment in entirety can be very
helpful in remedying this situation.
Radiopharmaceutical Purchases
Radiopharmaceuticalsuppliers are licensed
and regulated in the same manner asare nuclear
medicine facilities. One of the requirements is
that suppliers do not transfer (sell) any radioac-
tive malerial to anyone unlessthe recipient is
aulhorizedto receive the specific material re-
quested,Radiopharmaceuticalsuppliers, there-
fore, will require that each Facility provide doc-
umentation as proof of authorization. A copy of
the license or other documentalion should show
theexpirationdate,radionuclides,chemical
forms,maximumpossessionlimitsand, in
many cases, the patient dosage range and clini-
cal usage.Supplier records should be updated
each time the license is amended and renewed if
there are changes affecting any of these data.
On-site Inspections
The licensing agency normally conducts on-
site inspections to assurethat (a) general reg-
ulatory safety standards, (b) specific licensing
conditions,and(c)record-keepingpractices
comply with the regulations. Inspection fre-
quency varies from stateto stale. Facilitiesli-
censed by agreement stales tend to be inspected
morefrequently than arefacilitics licensedby
the NRC. In both cases,inspeclionscan be
either announced or unannounced.
Radioactive material license inspections, like
as the primaryevidence of compliance. Sur-
veys, interviews, and measurements by inspec-
tors are not uncommon, however.
There is one source of encouragement rela-
tive to these inspections. The RAM license in-
spection is so thorough and comprehensive [hat
inspections by other agencies often consist of a
simple review of the findings of the RAM li-
censeinspection. For example:hospitals are
inspected by theJointCommission on Ac-
creditation of Hospitals (JCAH) as well as other
licensingand/or accreditation agencies.When
lhese inspections occur, JCAH inspectors very
oflen simply ask to see the report of the lasl
RAM license inspeclion.
Of course, the firsl priorityof the JCAH is to
assure that their standards for quality of patient
care are met, whereas the first priority of the
NRC (or agreement state agency) is to assure
safe use of radioaclive materials.Because of
this difference in priorities, the two inspections
may not be identical.
The following list contains items commonly
reviewed during RAM license inspections:
1. Inventory. Are the amount and the type of
material in agreement with those indicated in
the license? Are records of receipt, use, and
disposal complete and up to date?
2. Survey and monitoring records. Are surveys
conducted as required, and are they recorded
properly? Are high exposure and/or contami-
nation levels investigated, and is corrective
action taken? If an ALARA (as low as rea-
sonably achievable) program is required,
what studies, results,and conclusions are
available as evidence [hat doses are as low as
reasonably achievable?
3. Instrumenlcalibralion.Areclinicaland
safetyinslrumenlschecked on a regular
schedule for reproducibility,linearity, and/
or accuracy?
4. Quality assurance. What are thetestsand
results of tesls for radiopharmaceutical qual-
ity? What tests are performed and what are
the resulls wilh regard to image quality and/
or the diagnostic quality of patient data?
Low-levcl Radioactive Waste (LLW)
Disposal
Radioactive waste disposal has always beena
orobiem in nuclear medicine, but becauseof the
RegulatoryProblem in Nuclear Medicine I 325
enormous increases in cost over the past few
years andmore strict requirements on gener-
ators in gaining access to commercial disposal
sites, this aspecl of nuclear medicine is becom-
ing a more significant problem. The relatively
short half-life of most radiopharmaceuticals in
clinical use is the only reason that this problem
has been kept from becoming insurmountable.
Only five options are available for LLW dis-
posal. In Table 21.2 are listed the methods of
LLW disposal, therelative cost of LLW dis-
posal, and themajorlimitationsimposed by
each use.
Within the clinical nuclear medicine facility
(disregardingvendors), LLW disposalvery
oftencanbehandledby a combinalion of
(a) relurningexpired or used sources tothe
supplier or (b) radioactive decayand disposal
of “cold” residue.
Theradiopharmaceuticalaspects of nuclear
medicine consist of an “in-house” operation or
an outside supplier who provides radiopharma-
ceuticals in “unitdose”quantities on a daily
basis, and this will directly impact on LLW
disposal.
In-house Radiopharmacy: LLW Disposal
Aspects
For the in-house radiopharmacy, h e follow-
ing steps are of help in the management of LLW
disposal:
1. Include return and disposal of nuclide gener-
ators as part of the purchasingagreement.
2. Avoid practices that produce a large volume
of waste.
3. Segregate waste according to half-life, i.e.,
t ~1 < 24 hours, 24 hours < f M < 1 week,
etc.
4. Compact dry waste to reduce volume.
5 . Set up practices to label, store, anddiscard
“decayed” waste.
Unit nose Radiopharmaceutical Supplier:
LLW Disposal Aspects
For those facilities with a unitdose radiophar-
maceutical supplier, the following steps are of
help in the management of LLW disposal:
1. Include return and disposaI of LLW as part
of nurchasingvcontract.
 326 I Essenrids of Nuclear Medicirw Science Regulnrory Problems in Nuclenr Medicim t 327

Table 21.2. used for medical purposes is subject to controls scribe or administer radiopharmaceuticals. This
by one or both of these agencies. authority is grantedonlyby the NRC orthe
Comparison of Melhods for Low-level Radioaclive Waste Disposal
Figure 2 1.1 provides a simplified descriplion appropriateagency of an “agreementstate.’’
Disposal Uerhod Rclativc cos1 Lirnitalions of the relationships between a nuclear medicine Furthermore, a RAM license issued to a medical
operation and the various federal and stale reg- facility or physician is limitedtothe phpsi-
Very
system
Sewage Iow 1. Very difficult to conirol and document
disposal compliance ulatory agencies. As is indicated, [he NRC and cian(s) specifically stated in the license and the
2. Gross limitis 1 Cityrllacility the state licensing agency have fundamentaland clinical procedures covered by a license are to
Incinerator Low to moderate,
depending on 1. Very diffjcuit to prove compliance wilh generalauthority,whereas the FDA, Environ- be carried outby theseindividuals or under
availability of existing facility and stack concentrationrequirements, and mentalProtection Agency (EPA), Department their direct supervision.
physical control requirements [his is compounded when a mixture of
nuclidesisinvolved of Transporlation (DOT), and Occupalional As stated earlier, there are training and expe-
2. Mayproduceradioactiveashrequiring Safety and Health Administration (OSHA) have rience requirements for licensure in nuclear
secondary disposal methods authority over limited aspects of operation. All medicinebeyondthe“normal”medical train-
3. Specificlicensingapproval is required of lheseagencieshaveresponsibilitiesbeyond ing.Also, aphysicianmaymeettherequire-
Siorage decay Moderately expensive because a se- 1. Spacerequircmenls Tor long-term s1or- those relating lo nuclear medicine. ments for group I procedures involving uptake
curedspaceisrequiredand.spe- age may be prohibitive
2. Requires careful segregalion of wasle al The EPA, for example, is generally responsi- ordilutionstudies and not meetrequirements
cia1 shielding may be requlred
the time of generation ble for establishing and enforcing slandards LO for group I11 proceduresinvolvingtheuse of
3. Means and methods for assaying wasle protect people andthe environmentfrom the generatorsandreagentkits (1). Inalmostall
or suflicienlrecords IO assure“com- disposal andlor release of all hazardous mate- states,therestrictions on themedical use of
plete” decay rials.Thedisposal of radioactivematerials is ionizing radiation from radioactive malerials
Venlingto ahnosphereCostwilldepend on the means avail- 1. %sle musibe in gaseousorvolatile only a smallpart of thisresponsibility.Like-
able plus provision for an isolaled form does no1 restrictthemedical use of ionizing
ventilation
system 2. Strict
limitalions
concenlralion
on at wise, the NRC is responsible for regulation of radiation from x-ray generators.
point of release industrial use of by-producl materials as we11 as
(IandfilI)
Burial Very low cost 1, In many juriadiclions [his is prohibited fissionablematerials used inelectricalpower
’2 May resuI[ in legal problems at a later SPECIAL COMPLIANCE PROBLEMS IN
generation.
time NUCLEAR MEDICINE
3. May require specific licensed authoriza- LIMITS IMPOSED ON CLINICAL Radioactive Patient
tion
PRACTICE AS A RESULT OF The patient in nuclear medicine is listed as a
(colnrnercial)
Burial Most expensive
method 1. cost
2. Access IO disposal site isdifficult al REGULATIONS specialcomplianceproblembecause(a) the
present and,depending on present Withrespect to thephysician, a license lo regulations that can be applied (radiation dose
efforts to eslablish“regionalcom- practice medicinewhichauthorizes the holder
pacls.” may become Inore difficult levels, release of radioactive materials, etc.) do
to prescribeandadminister“prescriplion” no1 specificaily address the patient and (b) the
drugs does no( authorize the physician to pre- slandards that are available are no1 published by
2. Steps 2, 3, 4, and 5 aboveapply, bul the impossible to define in a general or comprehen-
problem of volumereduction is muchless sive way. Regulationsatthefederallevelare
significant,sincevials,syringes,etc.are generally applicable 10 all subdivisions, but
returnedfordisposalandgloves,cotton state or locd regulations can be more strict or OSHA
cover sources of radiation not included in fed- Occupational
Safety
swabs,etc.shouldbetheonlyremaining
source of LLW. Paper towels, plastic bags, eral regulaiions .
etc. may, of course,becomecontaminated The NRC is authorizedtoregulatethe pur- N RC
fromaccidentalspills andresultingdecon- chase, receipt, use, and disposal of by-product StateRegulotory Agency
tamination. materials used in nuclear medicine. This author- Medical U s e Of.
Radiooctwe Maternal
ity does nor include regulation of other radionu-
clidesources,such as acceleralor-produced or
FEDERAL, STATE, AND LOCAL naturally occurringsources. Ailradiopharma- DOT EPA
REGULATORY AGENCIES RadioactiveMateriol Low Level Waste
ceuticals, however, areregulated by the FDA. Transport Disposal
The difference and the relationship between The FDA is authorized to regulatetheentire (Suppties ti Waste1
regulatory agencies at different levelsof govern- process, from radiophamlaceutical research and
ment as weIl as the relationship between differ- development to marketing, distribulion, and Figure 21.1. Diagram showing the relationship bctwcen a nuclear medicine facility and various regulalory
ent agencics at the same governmental level are clinical use. Therefore, any radioactive ~naterial agencies.
328 I EsserlfioIs of Nuclear Medicine Science
a regulatory agency and do not appIy mainly to Report No. 37 (2) are listed. Very often a “con-
hospitalized patients. dition”stating how to handle radioactivepa-
An exemption is generally assumed with re- tients willbe a par1 of the RAM license sf
spect to monitoring, permissible concentrations therapeutic procedures are permitted by the li-
and body burdens, sewage waste disposal, etc. cense.
for radioactivity administered to a human being In addition to, oras a part of, a licensing
€or diagnosticpurposes.Therapeutic levels of “condition,”specificprovisions andinstruc-
radioactivityare only slightly moreregulated. lionsmust b e developedformembers of the
Currently, the NRC generally requires (as a li- hospital siaff outside the nuclear medicineserv-
cense “condition,” not by regulation)thata ice. Addressed in these instructions should be:
patient be hospitalized if he receives more than
30 mCi of a radionuclide and that he not be I . Patient room assignment policies.
released until the radionuclide burden falls be- 2. Instructions to nursing care personnel.
low 30 mCi. A revision of par1 35 of Title 10. 3. lnstructionsregardingdietaryservices and
Code of FederalRegulalions (10 CFR 35), conlaminated food dishes and utensils.
whichmayofficiallychange,amongother 4. Instructions regardingpotentiallycontami-
things, the criteria used to determinewhen a naled waste,linens,andfurnishings for
patient can be released following therapy with housekeeping and laundry services.
radiopharmaceuticals, is being considered. Al- 5 . Instructions for clinicallaboratory services
though not yet finalized (as of May 1986), the and personnel.
revised document will likely slate that a palient 6. Policies regarding surveysand room reas-
cannot be released from the hospital untilthe signment following patient discharge.
exposwe rate from the patient is <6 mWhr at a 7. Instructionsregardingchild care, pregnant
distance of 1 m. In contrast, the NCRP recom- family members, food handling, etc. €or the
mends that a patient b e hospitalized if [he initial patient and the patient’s family.
activity exceeds a certainspecifiedlevel,de- 8 , Provisions and inshwlions must also be pro-
pending on the radionuclide involved andthe vided in the event of death of the patient
age of household members who will be in con- during a specified period following a thera-
[act with the treated individual. In Table 21.3, peutic administration. These policies should
themore coInnlon therapy sourcesand their be addressedto [he palhologistand funeral
minimum “oulpatient“ levels as given in NCRP service personnel.
Table 21 -3.
Radioactivity Levels lor Discharge of Radioactive Palients from Hospital*
Some Rcs~ricl~ons
Required
All Household Some Household
Radlonuclide No Rcsrriclions Members >45 YOAt Members <45 YOAi
350 mCi 100 mCi
5lCr 35 mCi
198Au 23 mCi 230 mCi 70 mCi
1251 0.2 f l h r at 1 m 2 m W h r a t 1 rn 0.5 mWhr at 1 m
1311 8 mCi 80 mCi 50 mCi
1921r 0.4 mCi 4 mCi 1.2 mCi
222R n 4.6 mCi 46 mCi 18 InCi
* Adqtcd from Table 4 , NCRP Report No. 37, National Council on Radiation I’rotcclion and Measure-
ments, 1970 (2).
t YOA, years of a g c .
Control of Radioactive Gases
The containmenl, detection, control, and dis-
posal of radioactive solids and liquids are lech-
nicallysimple,comparedwiththose of
radioactive gases. When radioaclive gases such
as 133Xeare used,specialattentionmustbe
given for their licensing, use, and disposal.
Ventilation syslerns that meelrequirements
for temperature and comfort control may not be
adequate in terms of flow rate and the relative
supply andlor exhaust rates withinan imaging
room.
Licensing of radiogases requires that the air
flow rale be adequate to dilute the gas released
into the room bejow the permissible concenlra-
tion ( 1 X pCilm1) averaged over year.
a lower MPD, nor do they seem to imply that
In additionto average dilution volumes, the
exhaust rate should exceed the supply air rate so
thal air movement is alwaysinto the contami-
nated air. In other words, a room in which 133Xe
is handled should be at ”negative pressure.”
Accidental “spills” of radioactive gases and
associatedprocedures also must be addressed.
Unlike liquid spills, the only appropriate action
for gas release is to evacuate the area and allow
sufficient time IO passfor dilution andlor re-
moval lo occur. The time required for exchange
of IO room volumes of air is an accepted “rule
of thumb.”
Ventilation sys~emisolation is a basic require-
ment for meeting the flow rate specifications in
each of these situations.
ALAR A
The ALARA conceptis as oldasnuclear
medicine; within recent years, however, it has
taken on a moreformalized,systematic, and
regulatorymeaning.The NRC Regulatory
Guide 10.8 includes Appendix 0,“Model Pro-
gramforMaintainingOccupationalRadiation
Exposures at Medical Institutions ALARA” ( 3 ) .
The title and source of this publication imply
that (a) it is subject to alterations and modifica-
tion and (b) it specificallyapplies to NRC li-
censes.
Atthepresent.time,themajorimpact of
ALARA is on occupational radiation exposure
as demonstrated by “whole body” monitoring
(dosimeter records). Maximum permissible
Regrrlnfov Problems i n Nuclear Medicine I 329
dose(MPD)limitshave no1 beenchanged.
Whathaschangedisthedose level at which
investigation and correctiveactions areiniti-
ated.Thischange(asstated i n Regulatory
Guide 10.8) requires that any occupational radi-
ation dose above the MPD for the occasionally
exposed worker (i,e., 10% of MPD for the oc-
cupationally exposed worker) must be investi-
gated bytheRadiationSafetyOfficer (RSO)
andreviewedbytheinstitutionalRadiation
SafetyCommittee(RSC).When occupational
doses exceed 30% of MPD, corrective actions
are required or the institution must specifically
justify a higher dose level.
As stated earlier,ALARA policies do not
these dose levels are unsafe.
There is a noteworthy inconsistency between
this ALARA policy stalemenl and the regulation
requiring personnel monitoring. Investigational
level I is 10% of the occupational MPD. The
level of occupational exposurewhichrequires
[ha1a dosimeter be issued is 25% of the applica-
ble MPD. An attempt to change the regulation
to set the dosimeter requirement at 10% MPD is
being made, however. At the present time, this
ALARA policycanonly be achieved if each
employee’slikelihood of receiving a quarterly
dose of 125 mrem to the Lola1 body is reevalu-
ated. Areevaluation of hospitaloperations is
likely to result in an increase in the number of
people n~oniloredif the 10% level instead of the
traditional 25% level is used. The invesligation,
tabulation, and explanation of personnel doses
above 10% by the RSO will certainly increase
the time, effort, and cost required. In the past,
manyinstitutionshaveused a 75% “action
level” for investigatingindividualexposures.
SUMMARY
Compliance with government regulations is
as much a par1 of the practice of nuclear medi-
cine as is equipment purchasing, lechnical pro-
cedures, patient selection, or any other part of
the total operation. Unfortunately, it is viewed
by many as the most undesirable, unpleasant,
and unproductive aspect of this medicalspe-
cially. An objectiveanalysis,however,will
show that the vast majority of regulatory re-
330 t Essentials of Nrtckar MedicineScience
quirernents arenecessary in orderthatem-
ployee,patient, and community safety not be
jeopardized or ignored. I1 is in the interest of
every person not only that we tolerate regulation
but also that we become actively involved with
the development,implementation, evaluation,
and modification of these regulations. Only in
this way can safety be maintained, cost be con-
trolled, and the community's medical needs be
mel.
REFERENCES
I . Title 10, Code of Federal Regulations, PdTl 35: Human
uses of by-producr material. Uniled States NuclearReg-
ulatory Commission.
2. National Council on Radiation Protection and Measure-
ments, Report No 37: Precunfiatrsit1 [he Matlagetnolr OJ
Patiem Who Have Received Therapeutic Amounrs of
Ill
Radimuclides. NCRP hblicalions, October 1970.
3. United SlatesNuclear Regulatory Commission, Off~ce
of Standards Development, RegulatoryGuide 10.8:
Grride l o r ?he Prepararion o,f Applicalions for. Medical
Considerutiuns
Programs. October 1980.
for the Preclinical
and the Clinical Investigation
of New Radiopharmaceuticals
 22
Animal Models of Human Disease
Prantika Som and Zvi H , Oster
WHAT IS AN ANIMAL MODEL?
A model, as defined in theOxfordEnglish
Diclionary, is “something that accurately re-
semblessomethingelse.” No diclionary de-
scribes an animal model or animalmodel of
disease. Wessler (1) has defined animal model
of disease as “a living organism with an inher-
ited, naturally acquired or induced pathological
process that in one or morerespectsclosely
resembles the same phenomenon occurring in
[the] human.” No single animal model can ever
duplicate a human disease; it can provide only
similarity to thediseaseprocess.Theterm
“model” implies an identical replica of the dis-
ease in humans, which never happens. For lack
of a better word, il is used commonly in refer-
ence tothe similarpathophysiological occur-
rence in humans. For a model to be useful it
does not necessarily have to be identical to the
human conditions (2). Sometimes, mice are bet-
ter models for some human diseases than are
primates. Moreover, cost and availability allow
many more mice to be tested. Animals that are
phylogeneticallycloser to humans(viz., non-
human primates) are often, however, better indi-
cators of human pathophysiology.
The evalualion of radiopharmaceuticals in an-
imal models prior to their use in humans is well
established and required by law. This evaluation
serves several purposes: to investigate thekinet-
ics and localization of the compounds, to deter-
mine toxicity, and to calcuiate the radiation
dose. Most studies are performed on animals in
a normal physiological state, while some stud-
ies must be performed in conditions simula~ing
humanpathophysiology. Although at the pre-
sent time no animal model mimics exactly the
333
normal human physiological stateand reproduc-
tion of human disease entities in animals is even
harder to obtain, the data acquired from animal
models have been of great help in understanding
normalandpathoIogica1 conditions as well as
developing diagnostic and therapeutic agents
for use in humans.
The selection of an animal model for a spe-
cific study is most important in order to assure
that theoutcome of the study is not compro-
mised. One must consider not only the appro-
priateness of the model but also the availability,
the ease of handling and disposal, and the cost
of the animal.
Furthermore, in working with radiolabeled
compounds,theamountandspecific activity
needed to obtain adequatecounting statistics
should be balanced with the need to minimize
radiation exposure to personnel.
Exlrapolation of data from animal experi-
ments to humansmust lake intoaccount the
differences in overall size,differences in rela-
tive organ size, differencesin life-span, species
variations in proteinand enzyme patlerns and
the metabolic rate, and variations in the number
of functional cells per gram of tissue.
Moreover, the clinical expression of an etio-
logical agent may differ in humans and animals,
although various etiological agents may produce
similarclinicalexpressions.Nonetheless,the
growing awareness of the important contribu-
tions that animal models can make to the ad-
vancement of medical science has led to the
discovery of many animal models that can serve
as replicas of human disease. It is impossibleto
list all the models available; therefore, we dis-
cuss lhc most commonly used models in nuclear
medicine science and the need and possibililics
334 I Essentials of N d e m Medicine Science
of using some newer modeis. The Registry of
CornparalivePathology of the ArmedForces
Institute of Pathology has published a handbook
that describes 150 models of animaldisease
relevant to the study of human disease and that
is mainly based on comparative pathology (3).
SKELETAL SYSTEM
The pathophysiology of theskeletal system
not only involves its static supportive function
butalso affects the dynamic(metabolic and
homeostatic) functions. Bone serves not only as
a mineral reservoir bul also as the primary site
of hemalopoiesis. Since ancient time the skel-
etal disorder and the process of fracture healing
have been of interest to mankind. Almost every
mammalian species (bats lo primales) has been
used as animal models for bonemetabolism.
Rodents (smaller animals)are cheap to buy, and
therefore, more extensive studies can be carried
out with use of rodents than, for example, with
use of primates. The skeleton of small animals
such as rodentsresponds diflerenlly 10 altera-
tions in hormone, vitamin, and mineral levels,
and therefore, use of these animals presents a
problem. Homeostatic regulation of vitamin D
levels is known to occur in various laboratory
animals and in rals; parathyroid hormone has a
differentend-organeffecton animals than on
humans. Moreover, rat and mouse bone lack an
Haversian system, and therefore, rats and mice
demonstrate continuedepiphysealgrowthfor
their enlire life-span. The bone structure innon-
human primates is similar 10 the bone structure
in humans and responds to hormones, vitamins,
and minerals in an identical manner. Horses also
show such similarities. Nevertheless, large ani-
mals such as monkeys and horses are very sel-
dom used as disease models primarily because
of their high cost, Many small animal models
have been studied to measure the blood flow in
normal bone (4- 1 1). The animal models of dis-
ease most frequently studied include those asso-
ciated with fracture, inflammatory lesions, and
metabolicdisorders.Thereis no idealanimal
model to study the metabolic derangements of
bone, primarily because bone metabolism is a
complex phenomenon involving the interaction
of vitamins, minerals, and hormones, which are
still very poorly understood in human bone me-
tabolism. Osteoporosis, the mosl common met-
abolic disorder in humans, is brought about by
various types of immobilization. These include
neurogenic immobilization, immobilization fol-
viability arthritis,trauma, head
lowing fractures,rheumatoid
and bed rest. Several animal modelsof immobi-
lizationosteoporosisareavailable. In Table
22.1 are summarized the commonly used ani-
mal models of bonediseaseandappropriate
references (12-31).
CARDIOVASCULAR SYSTEM
Animal models of myocardial infarction (MI)
have been used extensively for the study of the
hemodynamic, metabolic, histologic, and elec-
lrocardiographicdeviationsfrom the n o m as
well as for the study of the acute and late se-
quelae of MI. Five animal modelshave evolved:
rats,rabbits,dogs,pigs, and primates. In the
rat, focal myocardial necrosis, but not true myo-
cardial infarction,has been produced by the
injection of epinephrine (32) or of isoproterenol
(33) or by electrical bums over the epicardial
surface (34, 35). Some of these models served
for the evaluation of infarct-avid imaging agents
(34, 35). The advantages of the rat model are (a)
availability at low cost and (b) ease of handling;
therefore, it is possible to perform studies on a
large number of animals. Because of [he rat's
small size, however, this model does not allow
forimagingwith(hegammacamera.In
slightlylargeranimal, e.g., the rabbit,local
myocardial necrosis can be produced by intra-
cardiac injection of vasopressin in oil (36).
In the dog, myocardial infarction can be pro-
duced by permanent or temporary ligation of a
coronary artery (37-39). The study of collateral
development after coronary occlusionwas stud-
ied with the 133Xewashout method (40), and the
early metabolic changes after coronary occlu-
sion, including 99mTc-pyrophosphate accumula-
tion, could also be observed (41). Since open-
chestmodels in the anesthetized dog are not
comparable to MI in the human, variations of
the technique have been developed in the intact
conscious dog. The transcatheter placement of
d i p s on the coronaries (42) is one such example
of permanent coronary artery constriction. Al-
Animal Models os Hrttnan Disease / 335
Table 22.1.
Animal Models of Bone Disease
Disease Animal Reference
Blood flow:
Femoral Dogs 12
Fracture:
Healing process, osteogenesis Rabbits, Dogs 13-15
Osteomyelitis:
Pathologic and radiographic appearance similar IO human Rabbits, Dogs 14, 16
Arthritis:
Degenerative, similar to human osteoarthritis Rabbits 17
Polyarthritis, acute self-limiting Rats 18, 19
Metabolic bone disease:
Rickets Rats 20
Hypervitaminosis A , cessation of bone formation, destruction of Rats 14
cartilage
Osteoporosis:
Immobilization (local disuse) Rabbits, Dogs, Rats
21-24
ImmobiIization (systemic, whole body) Monkeys 25-27
Ammonium chIoride induced: simiiar to calcium deficiency Rats 28
osteoporosis
Low-calcium diet Rats 29-30
Osteomalacia Young rats 71
tematively, devices that constrict a coronary ar- with anesthesia and arrhythmias (51-53).
terycan beplacedsurgically, andlhedevice A basic deficiency of these previously men-
may be activated to constrict lhe artery after the tioned models is lhat only one vessel in these
recovery of theanimal (43, 44). A simpler animaIs is affected by the intervention, whereas
method isthe transcatheter insertion of plugs many vessels in the human suffering from MI
that expand on contact with blood (45, 46) or may be affected.Atherosclerosiscanbe in-
the transcatheterintroduclion of a copper coil duced in animals by various interventions of
around which thrombus forms rapidly (47). Sit- longduration. Repeated intravenousadrenalin
uations that simulate strenuousexercise have injections and a milk and egg diet were reported
a been described also (4s). to induce atherosclerosis inrabbits (54, 55);
Although the dog is a very convenient model overdosage of vitamin D induced calcinosis of
for study of thefunction of the human heart, the majorarteries (56); and variouscornbina-
two differences distinguish the function of the tions of high-cholesterol, high-fat diets with or
heart of a dog from that of a human. The dog withoutthiouracylwere found to induce athe-
hasa predominantly left coronary circulation, romatosis in the rat (57), rabbit ( 5 8 ) , swine (59),
whereasthehumanhasa predominantlyright and rhesus monkey (60).
coronary circulation, and the dog develops pro- Hypertension hasbeen studied with the Gold-
fuse collaterals in response to coronary artery blalt model (61), bilateral nephrectomy, and di-
occlusion. Primates which have a coronary cir- alysis in the dog (62); with unilateral nephrec-
culation and physiology similar 10 that in hu- tomy, high-salt diet, and desoxycorticosterone
mans have been used for the study of the heart in the rat (63); andwith cellophane wrapping
(49, 501, although their widespread use has for compression of one kidney in the mouse,
been restricted by high costand by handling rat, rabbit, and dog (64,65). The breeding of
difficulties. The coronary circulalionin swine is salt-dependent hypertensive rats enables the
very similar tothat inhumans,and although study of genetically identical animals with and
swine are available and not very expensive, they without hypertension (66).
are harder to manage, and there are difficulties A dog model of hemorrhagic(67)and car-
336 f Enenrials of Nuclear Medicine Scietm

diogenicshock (68) hasbeen describedalso. nonhuman primales (85, 86). Down’s syndrome Table 22.2.
Myocarditis can be induced in the rat (69) and in humans is associatedwithAlzheimer’s dis- Animal Models of Cardiovascular Disease
rabbit (70) by epinephrine; endocarditis has ease.Althoughsenileplaques that are associ-
Disease Animal Reference
been induced by mechanical damage and bac- aied with Alzheimer’sdisease have been re-
terial inoculation (7 1-73). In the dog, spontane- ported in aged dogs and monkeys (87-89), they Myocardialnecrosis:
lack the twisted neurotubules invariably present Epinephrine Rats
ous chronic valvularfibrosis occurs withhigh Isoproterenol
32
frequency (74). Uremic pericarditis causedby in human lesions. Many of the microscopic Rats 33
Electrical burns Rats
bilateral ligation of the ureters in the rabbit (75) changes characteristic of the aged human brain 34, 3.5
Vasopressin,intracardiac Rabbits 36
andcobalt-inducedmyocardiopathyinthe are alsoseen in the brain of old animals, but Myocardialinfarction:
guinea pighave been reported (76). In Table they are less extensive than those in humans Permanent or temporary ligation of coronary arlery Dogs 37-39
22.2 are listed the commonly used animal mod- (90). Alzheimer’s disease is the most common Study of collateral development, 133Xe Dogs 40
Early metabolic changes, PYP accumulation Dogs 41
els of cardiovascular disease (32-76). degenerative disease of the human nervous sys- Transcatheter clip placemen1
tem, and there is a lack of an appropriate animal Dogs 42
Perivascular baIloon snare Dogs 43, 44
CENTRAL NERVOUS SYSTEM model with similar clinicopathologic manifesta- Expandingsponge plug Dogs 4.5, 46
Many animal species, particularly rats, cats, tions. Although many neurophysiological mod- Copper coil inducing lhrornbus fornlalion Dogs 47
elshavebeen studied inanimals,models of Exercisemodel Dogs 48
and nonhuman primates, have been used to
study neurophysiology as well as neuropathol- human diseaseare not as varied.Asepticand Baboons and rhesus 49, 50
septic meningitis and the clearance of chelates monkeys
ogy. A select few are discussed here. In a recent Pigs 51 -53
report, the neurological diseases of animals have been studied in the dog (9 1, 92). Encepha- Atherosclerosis:
were discussed in relation to those in humans litis can be produced in hamstersby inoculation Repeal intravenous adrenalin Rabbjrs 54
of the Edmonston strain of measles virus (93), Milk and egg diet Rabbits
(77). Some models are close replicas of human Vitamin D overdosage, cafcinosis
55
pathology, others merely mimic certain patho- and hydrocephalus can be induced in the dog by Rats 56
Thiouracil, cholic acid, cholesterol andfat Rats 57
logic processes, while others are quite variable. the injection of Silastjc inlo thebasal cisterns Internitten1 choleslerol feeding of mature animals Rabbits 58
The more prevalent diseases of the human ner- (94). Hydrocephaluscan also beinduced in High-fat and high-cl~olesLerol dict pius propyllhjouracyl and Swine 59
vous system are less well represented by good smalleranimals.Theadministration of 6 - irradiation
aminonicotinamide to pregnantratsresults in Five difkrent diels Rhesusmonkeys 60
animal models. There is no other good model of Hypertension:
stroke due to cerebral infarction than that of old hydrocephalus in the offspring (95), andvi- Goldbla~tkidney
tamin A deficiency in the pregnant rabbit results Dogs 61
pigs (78). Due to thenatural susceptibility of Bilaleral nephrectomy plus dialysis Dogs 62
their cerebral vasculature to atherosclerosis, in congenital hydrocephalus in 70% of the off- Unilateral nephrectomy plus DOC plus NaCl Rats 63
however, pigs are more commonlyused to study spring (96). Cerebral microembolisms induced UnilateraI cellophane wrapping Rats 64
by the injeclion of carbon microspheres in the Figure-of-eighl Iipturc of one kidney Mice, rats, rabbits, 65
vascular disorders (79-81). At 10-12 years of
age, pigs develop spontaneous atheromatous rathavebeensludiedwithuse of multiple anddogs
Dah1 salt-dependent hyperlensive rats Rats 66
plaques of significant severity and frequency on tracers (97), and a model of subdural hematoma Shock:
the intracranial portions of the internal carotid can be produced in dogs by injection of a mix- Hemorrhagic Dogs 67
arteries, basilar artery, and middle and anterior ture of autologous blood and cerebrospinal fluid Cardiogenic Dogs
Myocarditis: 68
cerebral arteries, a pattern similar to that which (98). In conscious squirrel monkeys, epilepsy of
Epinephrine induced Rats 69
occurs in humans.Pigs,more thananyother short duration can be induced by cobalt powder
(99). Thestudy of centralnervoussyslem Rabbits 70
mammals, are also susceptible to various infec- Endocarditis, arteritis, valvular damage:
tions of the nervous system. Recently, a stroke- (CNS) tumors in large animals has been limited Mechanicaldamage Rabbits 71
pronehypertensive rat strainhas been deveI- to spontaneouslyoccurringcases,andmost Puncture of aortic valve pIus enlerococci Dogs 72
studies in which transplantable tumors were Placement of catheter plus staphylococcus Rabbits 73
oped which appears to be auseful model for Spontaneous chronic valvular Iibrosis
studying strokes resulting from hypertensive used were conducted in smallrodents (100, Dogs 74
Pericarditis:
cardiovascular disease in humans (82). Several 101). Animal models of induced diseases of the Bilateral ligature of ureters, uremia Rabbits 75
demyelinatingdisorderssimilartomultiple CNS are shown in Table 22.3 (91-101). Myocardiopathy:
sclerosishavebeen studied in animals; none, Chronic coball feeding Guinea pigs 76
however, are a counterpart of multiple sclerosis RESPIRATORY SYSTEM
in humans ( 8 3 , 84). Ananimalmodel of For extrapolation of data from animal models
amyotrophiclateralsclerosis has not yet been of lung pathology10 human diseases, considera- (104, 105).Despitetheinherentdrawbacks, respimory system and about therapeutic modal-
reportcd. Down’s syndrome has been observed tionshould be given to anatomical (102, 103) much hasbeenlearned fromanimalmodels ities.
andfunctionaldifferencesbetweenspecies aboul mechanisms of human diseases of the The sludy of pulmonaryemboli in the dog
as a nalural phenomenon in aging mice and in
338 I Esserlrials ojh'uclear Mediche Science Atrind Models of Hwnan Disease I 339

Table 22.4.
Anima1 ModeIs of Lung Disease
Disease Charactenstics Animal Model Relemncs Model Animal Reiercnce
-
Aseptic and septic meningitis uogs "1,
Y 92 Pulmonary embolus:
Encephalitis,viral Hamsters 93 Thrombin injected into vein segment, cIot released Dogs I06
Communicating hydrocephalus: Venous thrombus:
Silastic injection in basal cisterns Dogs 94 EIectricalstimulation Dogs 107
6-Aminonicotinamide to mothers Rats 95 Pulmonary hypertension:
Vitamin A deficiency in pregnant animals Rabbits 96 Hypoxia Rats 1 09
Cerebralmicroembolism: Croralarin specmbilis Rats 110
Carbon particles Dogs 97 HyaIine membrane disease:
Chronic subdural hematoma: Spontaneous FoaIs,piglets Ill
Injection of autologous blood plus CSF Dogs 98 0, induced Rhesusmonkeys 112
Epilepsy induced by cobalt powder Monkeys 99 Carcinoma of lung:
Braintumors: InIrabronchial polycyclic hydrocarbons Rats, mice, hamsters 113
Intravenous melhyl nitrosourea Rats 100 Asthma:
lmplanted intracerebrally Mice 101 Spontaneous Dogs 114
Bronchoconstriclion Guineapigs I15
Acute respiratory distress syndrome: phorbol myristate acetate Rabbits 122
(PMA)
and the uptake of labeled streptokinase (106), physema models have resulted from bronchial Chronic bronchitis:
the effect of clot age on the fibrinogen uptake instillation of elastase in sheep (120) or papain Mycoplasma pulmorris Mice 117
(107), and the accumulation of platelets on de- in dogs (121). The sheep model is worlh men- Spontaneous Dogs 118
nudedendothelialsites (108) are well docu- tioning because it pennits simultaneous meas- Idiopathic pulmonary fibrosis: Cattle 119
urements of various parameters. Animal models Emphysema:
mented. A model of pulmonaryhyperlension Elaslase Sheep
of lungdiseasearelistedinTable22.4 120
can be produced in the rat by hypoxia (109) or Papain Dogs
(106-123). 121
Crofalaria specrabilis feeding (110). Hyaline Pulmonary fibrosis Mice 1 23
membrane disease of the lung has been studied Review of animal models of respiratory diseases Various 116
in foals and piglets in which it occurs spontane- GASTROINTESTINAL SYSTEM AND
ously ( 1 11) or in prematurerhesus monkeys PANCREAS
exposed to high oxygen levels (1 12). Lung car- diseases that occur in the dog and have potential viruses (128). A comparison of alcoholic pan-
Digestive System as models. If a caninemodelisused,one crealitis in humans and rats has shown that the
cinoma models in mice, rats, and hamsters have
been studied intensively (1 13), bul experimental The criteria for a suitable animal model for should be aware that [he canine small intestine rodentmodelexhibitssimilarhistological
studies in larger animalshavebeen conducted gastrointestinaltractdiseaseare:(a) a host is an active amylase-secreting organand that the changes (129). Animal models of gastrointesti-
only on sponlaneously occurring cancers of the whosegaslrointestinal tract resembles that of canine liver degrades amylase more slowly than nal tract diseasesarelistedand referenced in
lung. the human in structureandfunction, (b) the does the human liver; as a result, normal serum Table 22.5 (130-141).
Only certain dogs are suitable as modelsof an disease that closelymimicsthehumancondi- amylase levelsare higher in dogs than in hu-
exhnsic IgE-mediated or anintrinsic type of tion, and (c) the availability of either large num- mans. A monograph on experimental acute pan- Hepatobiliary System
asthma (1 14). Studies on bronchoconstriction in bers of animals with spontaneousdisease or creatitis discusses comparative studies and the Many models of norma1 animals have been
guinea pigs (115) as well as in other animals reproducible experimental models (124). Dogs applications of experimental results tocondi- used for evaluation of hepatobiliary radiophar-
with asthmatic conditions have been carried (and to a lesser extent cats) havebeenexten- tions in humans and emphasizes that the differ- maceuticais (142-146). Observationsmade in
out, however (116). Chronic bronchitis in the rat sivelystudied to understand the inflammatory ent enzyme patterns in related species and spe- animals cannot always be translated to humans.
occurs spontaneously and mostly is due to M y - neoplastic and inherited abnormalities that af- cies-specific anatomical features are important Certain genera1 ideason the uptake,storage,
coplasma pulrnonis infection.Itsoutstanding flict the alimentary tract o€ humans. (127). and clearance of a radiopharmaceutical, how-
featuresinclude,however,inflammatory The major human digestive tract diseases for Rodentmodelshavealsobeenusedfre- ever, can be obtained, and the effects of phar-
changes in theparenchymawhichresult in which an appropriate animal model is important quently for the studyof pancreatitis. It has been n~acologicaland physical interventions can be
bronchiectasis (1 17). Somebreeds of small dogs are: peptic ulcer, ulcerative colitis, Reye's syn- suggested that infecliouspancreatitis resulting observed. There are significant interspecies dif-
are more suitable models of human chronic drome,cirrhosis,hepatitis,gallstones, biliary from use of coxsackievirus B 1 in mice provides ferences in both hepaticanatomyand phys-
bronchitis which is characterized by increased airesia,andCrohn'sdisease. Dogs have been agood modelforsludying pancreatic disease iology as well as ig the hepaticandbiliary
mucous secretion (1 18). used for most of the studiesonpancreatitis. due to viruses and for elucidating the relation- storage and excretion capacity of various sub-
Idiopathic pulmonary fibrosis occurs sponta- Pancreatitis, acinar cell carcinoma (125), and ship between diabetes mellitus in humans and stances (147-151). Bromosulfophthalein (BSP)
neously in cattle (1 19), and experimental em- juvenile atrophy (126) are exocrine pancreatic viral infection with coxsackievirus B and other has been widely used to study hepatic physiopa-
340 t Esserltinls of NrtcleflrMedicineScience A n i m l Models of Human Disease / 341

Table 22.5. lestinal motility (pentobarbital in dogs, ket- and experimental groups for tissue radioactivity
Animal Models of Gastrointestinal Tract Diseases amineandlorsparine in rabbits). Of ailthe assessment, scintigraphy, and autoradiography.
available animal models, dogs (and, to a lesser In the evaluation of renal radiopharmaceuticals,
Disease Anlnlals Reference extent,rats) havebeenused morefrequently young rats are used because of the increasing
than otheranimals to studyhepatobiliary dis- frequency with age of spontaneous glomerular
Esophagitis:
Acid-pepsininduced Cats 130 ease, due to ease of handling and the large size sclerosis (181). The use of rabbits is restricted
Chronic duodenal or gastric ulcers: of their hepatobiliary system which permits because their renal system differs from that in
Acetic acid induced, resembles human peplic ulcer Rats, cats 131, 132 catheterization. Animal models of hepatobilixy humans, in that the glomerular activity is inter-
Catecholamineinduced 133
134
pathophysiology are summarized in Table 22.6 mittent, even in the adult rabbit. Increased water
Iodoacetamide-induced ulcer of glandular stomach, with many features similar
to human disease
(164-180). and salt intake induces activation of glomeruli,
propionitrile or cysteamine induced, with morphological aspects similar Rats 135, 136 which results in copiousdiuresis (182, 183).
to human disease The dog has been studied in the normal physio-
Gastrointestinalbleeding Dogs 137-139 GENITOURINARY SYSTEM logical state as well as in situations mimicking
Gastroenteritis: Various species have been used for the study human disease. The dog is convenient for sur-
Virus induced, model of acute inrantile diarrhea Pigs I40
Inlestinal blood flow Dogs 141 of kidney physiology and for the evaluation of gical experiments or forstudies requiring the
radiopharmaceuticals.Althoughthemouseis administration of fluid and the collection of
available in most researchlaboralories,il has urine from both or from each kidney separately
thology. The hepatic storage capacity of BSP and physiology in the pig resemble that in the never been used as extensively as has the rat. In (1 84).
and its biliary transport have been quantified in human more closely than it resembles that in the addition to the wealth of physiological data Various models of human disease have been
several animal species with normal as well as dog.Thebilecompositioninthepigis very availableon therat,many rat modelsclosely studied in rars. Renal failure has been produced
abnormal hepaticfunction. Both spontaneous similar tothat in the human, buthepatic Tm and mimic diseases found in the human. Their low by resection of 80% of the renal tissue or by
bile flow and biliary transport maximum (Tm) storage capacity of 3 S P are about one half and cost and availability enable [he study of control bilateral ureteral ligation (1x51, but this proce-
for BSP per kg of bodyweightare 10 times two times higher, respectively, and bile flow is
higher in ratsandrabbitsthan in humans, about three times higher in the pig than in the
whereas hepalic storage capacity is only about human (149, 156). Sponlaneous bile flow and
Table 22.6.
two-thirds that of humans (148, 149). There is a Trn of BSP are four times higher in sheep than
Animal Models of Hepalobiliary Disease
quantitative difference in bile composilion be- in humans, but due to their large size and ease
tween rodents (rats, rabbits) and humans, and of manipulation,sheepmodelscanbeused Disease Animals Rclcrcncc

althoughrats lack a gallbladder,their hepatic when Catheterization studies withoul the use of biliary
obstruclion Complete Dogs I64
anatomy is quite similar to that in humans. The anesthesiaare needed. In both anatomy and Acute hepalic coma Dogs 165
absence of gallbladdershould not affectthe physiology,nonhuman DogsprimatesmimicJaundice
condi- (hemolytic) Prehepatic I66
liver uptake and clearance of compounds: how- tions similar to those in humans, but these mod- Hepatocellular jaundice:
els areused very seldom for physiological or Acute hepatic necrosis 167-169
ever, since the gallbladder represents only a part
Hepatic cirrhosis
of theextrahepatic biliary pathway. Spontane- pathophysiologicalstudies (157, 158). When Dimethylnitrosamine (DMNA) induced 169 167- Dogs
ous bile flow andcomposition in the dog are choosing a model for hepatobiliary studies, one AlcohoIinduced Rats, dogs 170, I71
similar to those in the human (152), bul T m and shouldtakeintoconsiderationfactorssuchas lronoverload Dogs 172
storage capacity of BSP is three times higher in the age of the animal, its body temperature, and Hepatitis
types of anesthesia, any of which induced
may affect the Alcohol Dogs 170, 171
the dog than in the human (149, 153, 154), and Virus induced
the liver anatomy of the dog differs consider- hepatobiliary function. It has been shown that Marmosets, dogs 173, 174
Galactosamine induced Mice 175
ably from that of the human. The dog, because with increasing age thereis a decrease in hepatic k t t y liver, lobar necrosis
of its largesize, however, couldbeused in transporl and bile flow in rats (159). Certain Carbon tetrachloride induced Rats I76
studies inwhich percutaneous catheterization of anesthetics affect hepalobiliary function mainly Hepatic fibrosis Rats 177
bylowering body temperature (160) or by Hereditary and congenital defects:
hepatic vein, hepatic artery, and portal vein are Crigler-Najjar
syndrome
(unconjugaled
hyperbilirubincrnia) Rats (Gunn rats, 178
necessary with use of a technique similar to that altering hepaticbloodflow(161),gallbladder
genetically in-
used in the human; moreover, studiescanbe motility, bile flow, enzyme activity, and biliru- bred jaundiced
carried out in anonanesthetizedstate (155). binand bile salt excretion (162, 163). In rats, rats)
Guinea pigs are not good models for hepatobil- ether and halothane causeda significantde- Dubin-Johnson syndrome (congenilal hypcrbilirubinemia) 179
(mutant
Sheep
iary studies because their hepatic physiology is crease in hepatobiliary excretion, but pentobar- Gilbert’s
syndrome
(impaired
hepatic uplake of unconjugated
Corriedale)
quite difrerent from that of humans as well as a dose of 40 rnglkg did not show
bital 10(Southdown) any
Sheel bilirubin) 180
from that of rats and rabbits. Hepatic anatomy effect. Some typesof anesthesia affect gaslroin-
342 I Ease~~ricrls
of Ahclear Medicirle Science
dure results in a relatively high mortality rate.
Chemically induced renal failure (186) and tu-
bular necrosis from the administration of gen-
tamicin have been reported in rats (187).
Chronic glomerulonephrilis with nephrotic
syndrome has been produced in rats (188). In
another rat model, a condition mimicking post-
streptococcal glomerulonephritis was described
(189). Models of pyelonephritis have been de-
scribed in the rat (190) and the monkey (191),
and experimental ureteral colic was induced in
(he dog in order to evaluate lhe significance of
hydrostatic pressure, ureteral dilatation, mu-
cosalresponse, andperistalsis (192). Changes
in the hydrostatic pressure can be controlled and
monitored, which thus mimics the severity of
obstruction (193). Autoimmune nephritis in the
rat can be induced by injection of renal tubular
preparation i n completeFreund'sadjuvant
(194). Hyperacute renal transplant rejection can
be studied in a dog model (195). Papillary ne-
crosis and cystic disease can be induced in h e
Table 22.7.
Animal Models of Genitourinary Disease
Disease
Normal physiology:
Evaluation of radiopharmaceuticals
Water and saIt loading
Renal failure
Tubular necrosis
Glomerulonephritis:
Chronic type, N,N-diacetylbenzidine
Poststreptococcalglomerulonephritis
Pyelonephritis
Pyelonephritis
Ureteral colic
Obstructive uropathy
Autoimmunenephritis
Hyperacute renal rejection
Papillary necrosis
Cystic disease by diphenyiamine feeding
Acute oliguric renal failure by norepinephrine
Rend artery stcnosis, clamp
Renalartery stenosis, cuff
R e n d artery stenosis, Swan-Ganz catheter
Renal artery stenosis, embolization
Hypertension, genctic
Animal Models of Hlman Disease I 343
rat (196, 197). Acute oliguric renal failure in the NUTRITIONAL-METABOLIC Celebes apes (214),and keeshond dogs (215).
dog may be induced experimentally by infusion DISORDERS AND ENDOCRINE Many experimental techniques are available for
of norepinephrine into the renal artery(198), FUNCTIONS re-creation of the diabetes syndromein animals.
and renal arterystenosiscan be producedby TheobservationbyMinkowskiand Von-
surgical placement of constricting clamps (199, Diabetes
Mehring in 1889 that pancreatomy in dogs re-
200), byuse of inflatablecuffs (201), or by Spontaneousdiabetesis a common occur- sults inpolyuria,polydipsia, and glycosurea
variations of these techniques. A percutaneous rence in many animal species, and experimental similar to those seen in human diabetes was,
approach produces similar results. Thus a diabetes can be induced in animaIs by chem- indeed, a milesloneintheuse of animalsas
Swan-Ganz catheter placed in the renal artery icals,hormones,injection of viruses, and sur- models for thestudy of humandisease.Di-
can be used to produce various degrees of ste- gery. Although hyperglycemia is a common abetes can be induced experimentally by:
nosis, with simultaneous monitoring of the pres- feature of diabetes in animals, no syndrome in
sure distal to the balloon (202). For the study of animals corresponds exactly to anyof the forms 1 . Contrainsulin hormones, viz ., epinephrine,
chronic stenosis, embolization of the renal ar- of diabetes occurring in humans, which feature glucagon, glucocorticoids, growth hormone,
teryhasbeenproduced experimentally(203). other abnormalities. The most commondiabelic and ACTH (216).
Experimental hypertension can be studiedin the syndromes in obese .animals are hyperinsulin- 2. Virus (217).
S-strain of rats developed by Dah1 (66). When emia and insulin resistance. The diabetes in lean 3 . Hypothalamic lesions: electrolytic or chem-
these rats are fed a high-salt diet, they develop animals is most frequently characterized by hy- ical (218, 219).
hypertension, but rats fed asalt-poor diet re- poinsulinemia, ketosis, and insulin depen- 4. Toxic chemicals (207-210, 216, 220, 221).
main normotensive and thus serve as genetically dence. Despite these differences, diabetic ani- In Table 22.8 are summarizedspontaneously
identical controls. In Table 22.7 are surnma- mals may b e considered as models of disease in occurring and experimentally induced diabetes
rizedthe models of genitourinarydiseases in humansandmayservetoadvanceresearch models (204-21 1, 216, 218-227). In Table
large and small animals (66, 181-203). leading to the evaluation of tracer kinetics and 22.9 are summarized various diabetogenic
metabolism in diabetic animals which will add chemical agents (207, 216, 220, 221).
to our knowledge and understanding of the pa-
thophysiology of diabetes in humans. In addi- Amgloidosis
tion, animal models (especially rodents) allow Amyloidosis is a disease of unknown etiology
the study of many generations in a short period characterized by the deposition of an abnormal
of time. These animal models permit study of protein-mucopolysaccharidecomplexwithin
Animal Rclcrence
theinteractionbetweenheredityand environ- tissue parenchyma andaround bloodvessels.
mental factorssuchasdiet,drugs,infectious Although amyloidosis has been recognized as a
agents, and {oxins. Many obesity and diabetic pathological andclinicalentity for over 100
Rats 181
models are available with use of rodents. Most years, only recently have detailed studies been
Rabbits 182, 183
Dogs 184 of these animals, such as the Chinese hamster, carried out tounderstandtheetiology,patho-
Rats 185, 186 mimic closely the nutrition-related and obesity- genesis, and possible clinical importance of
Rats 1 87 related maturity-onset type of diabetes seen in amyloid deposition. Amyloidosis usually in-
humans (204-206). The BB/W rat model and volves multiple organ systems (particularly the
Rats 188
streptozotocin mouse model mimicthe juvenile- kidneys,hearl, liver, spleen,andbrain). AI-
Rats 189
Rats 190 onset insulin-dependent type of diabetes usually though the etiologyof amyloidosis in humans is
Monkcys 191 seeninadolescenthumans(207-212).Al- not known, it is regarded as a disorder of protein
Dogs 1 92 though spontaneous diabetes is quite common m e t a b o l i s m ;t h i si n c l u d e s (a) hyper-
Dogs 193 in animals, only a few models have beenused to globulinemia, (b) an abnormalily of there-
Rats 194
characterize the diseaseprocess.Amongthe ticuloendothelialsystem,probabIy caused by
Dogs 195
Rats 196 animal models available, the rodent model has chronic immunological stimulation resulting in
Rats 197 been studied most thoroughly, mainly because the deposition of amyloid, (c) precipitation of
Dogs 198 (a)rodents havea shortgenerationlime and antibody or antibody-antigen complexes, or (d)
Dogs 199, 200 life-span, (b) their hyperglycemia and obesity all of these. The disease exhibits several clinical
Dogs 20 1 are inherited, and .(c) theyarerelatively inex- types.Someshowgeneticpredisposition,
Dogs 202
Dogs 203 pensive. Spontaneous diabetes in lean animals whereas others are associated with chronic in-
Kats 66 has been sludied in BB rats, a spontaneous flammatory diseases, neoplasms, and the aging
mutation of' Wistar rats (21l),guinea pigs(21 3), processes. Amyloidosis can occur spontane-
344 I EJsenrials of Nuclear Medicine Science Animal Models of H m a n Diseuse / 345

ous amyloidosishasbeensuggested to be a a useful model for evaluating end-organ re-

Table 22.8.
useful model for the study of the relationship of sistance to vitamin D in uremia (250).
Some Common Animal Models of Diabetes amyloidosis, aging, and immune processes, es-
Animal Characrerisdcs Disease Modd Reierencc pecially to renalfunction(244).Spontaneous HEMATOLOGIC DISORDERS
andinducedamyloidosismodelsarelisted in Experimentalanimalmodels of thehema-
Spontaneous: Table 22.10 (228-237, 244, 245). topoietic system are limited mostly to the my-
Metabolicallysimilar to humanjuvenile-onsetdiabetes, very BB rats(Bio-Breed- 21 1, 222, 223
low plasma
insulin,
high
ketosis, insulitis; etioIogy:
ing Lab, Canada) eloid line and to the coagulation system. Other
?infection Table 22.10. disordershavebeenstudied in animalswith
Close
resemblance to nuthion-related and obesity-related
Chinesehamsters 204-206, 224, inheritedhematopoieticdiseases,which have
diabetes inlermitienl
maturity-onset age;
of middle 225 Animal Models of Amyloidosis
been perpetuated by breeding the affected ani-
glycosuria to ketosis, no insulitis etiology: genetic Disease
Characlerisiics Animal hlodcl
Reference mals.
High
plasma
insulin
earIy,
followed by low or normal later,
Obesemice
225-227
no ketosis; etiology: genetic Myelofibrosiswithmyeloidmetaplasia can
SpontaneousamyloidosisMice 229. 230. 244
Experimentally induced: Induced
amyloidosis
Mice 235-237, 245 be induced in rabbits by the intravenous injec-
Hypothalamicdiabetes:similar 10 obesitycaused by hypo- Rals mice, monkeys 218, 219 Rabbits 232, 236 tion of saponin. The lesions produced resemble
thaimic (ventromedial nuclei) lesion in human; obese, Guinea pigs 233 those found in humans with agnogenic rnyelofi-
hyperglycemic, hyperinsulinemia; induction: eleclrolytic or Cattle 228 brosis and metaplasia (251). Hemolytic anemia
chemical(goldthioglucose) Horses 231
Toxic diabetes: canbeinduced inrabbits by theinjection of
Hamsters 234
Irreversible P-cell-specific toxins, insulinemia; induction: see Dogs, mice 207-210, 216, humananti-1coldagglutinins(252).Chem-
Table 22.9 220, 221 icallyinducedchronicmyelogenousleukemia
Reversible P-cell-specific toxins can be produced inrats by feeding 2,7-diacetyl-
Increased endogenous insulin requirement; induction: see Other Metabolic Diseases arninofluorene(253).Cyclicalneutropeniacan
Table 22.9 There are very few animal models that have be induced in dogs by injecting cyclophospha-
beenutilized to studythyroidandparathyroid mide (254). Warfarin-resistant rats are bred for
ously in dogs (228) and in aged mice of certain mouse has been a favorite model for the study of abnormalities.Congenitalgoiterhasbeenre- thestudyofvitamin K (255),whileintra-
strains (229, 230). amyloidosis (229, 230, 235-237, 239-241). In ported in sheep, goats, and cattle (246-248). A vascular coagulation can be induced experimen-
A variety of animals,whensubjected to addition, laboratory mice frequently deveIop model of diet-inducedhyperparathyroidism in tally in the dog by endotoxin (256), which is
properstimuli, have been shown to develop spontaneous amyloidosis which increases in fre- ratshas beenreported to be of valueforthe very similar to the Shwartzman phenomenonin
amyloidosis (23 1-237). Although the inoculat- quency with age (229, 230, 242, 243), and this study of neonatal tetany (249). A rat model for the rabbit (257). Blood pool agents canbe stud-
ingmaterialusually is proleininnature,non- modelhasbeensuggestedasbeing a valid the study of the skeletal resistance to vilamin D ied more effectively in anesthetized dogs after
niirogenoussubstances(viz., silicateandse- modelforhumansenireamyloidosis (242). in renal failure has been developed by partial or splenectomy. Animal models of hematopoietic
lenium) sometimes havebeenused, to induce Amyloidosisinduced by repeatedinjection Of iota1 nephrectomy and has been suggested to be diseasesarelisted inTable 22.11(251-257).
amyloidosis (238). Since 1897, when Davidson casein in rabbits is histologically similar to the
reported finding a higher incidence of induced disorder in humans (236). A hybrid of the SIJ Table 22.11.
amyloidosis in mice than in other animals, the and A strains of mice which develop spontane- Animal Models of Hemalopoietic System Disorders
Reference Animal Model
Table 22.9.
Diabetogenic Chemical Agents Myelofibrosis:
25 Rabbits saponin Intravenous I
Irreversible p-Cytotoxic
Agents
Revcrsiblc
p-Cyloloxic Agenu Other Agenls Refcrcnce Hemolytic anemia:
Rabbits
agglutinjns
cold anti-l
Injection of human 252
Alloxan 6-Aminonicotinamide Anti-insulin
antibodies
207, 216,
220, Chronicmyelogenousleukemia:
Slreptozotocin L-Asparaginase Somatoslatin 22 1 Oral 2,7-diacetyIaminofluorene 253 Rats
Diphenylthiocarbazine Azide Catecholamines CycIic neutropenia:
254
Oxine-9-hydroxyquinolone Cyanide Glucocor~icoids Dogs Cyclophosphamide
Vacor Cyproheptadine Glucagon Warfxin resistance:
Dehydroascorbic acid Hereditary
Fluoride R als 255
Intravascularcoagulopathy: Dogs 256
Iodoacetate endotoxin Rabbits 257
Malonate Blood pool agent evaluation:
Thiazides Splenectomy Dogs*
2-Deoxyglucose
Mannoheptulose * Personal experience.
 346 f Essentials oJNrrclear Medicine Scierrce
ONCOLOGY
Both in vitro and in vivo oncologic models
have been used extensively for diagnostic and/
or therapeutic studies. Mice and rats have been
used most commonly as in vivo models, and
hamsters, rabbits, and dogs have been used to a
lesserextent (258). Induced,transplanted, or
transmittedtumormodelsare used morefre-
quentlythan arespontaneous tumor models,
mainly because of availability. Transplanted or
induced tumor models have certain definite ad-
vantages,e.g.,thenumber of hostsis not
limited, and the histological type of tumor to be
studied as weII as the anatomical location, tu-
morsize, andhost age can be selected. Gal-
lagher et al. (259) hasrecently pointed out,
however,thatthecommonlystudied sub-
cutaneous tumors are not realisticmodelsfor
imaging studies, since the large tumor burden
on thesurface of the body does no1 occur in
humans and therefore is not relevant to external
detection by scintigraphy of regional and distant
melastases and smail primary tumors. Sponta-
neous tumor models, although rarely used, are
closer to the actual tumors occurring in humans
because of their type of blood supply, organ of
origin, and syslemjc responseto the presenceof
lumors. The most commonly used tumor mod-
els for studies of monoclonalantitumoranti-
bodiesare limited to murine or rat tumorsas
well as humantumorxenograftsgrowing in
Table 22.12
Commonly Used Induced and Transplanted Tumor Models
lhmor Type
Mice, Adenocarcinoma
Sarcoma
Melanoma
Glioma
Ehrlich ascites
Leukemia
Epcndymoblastoma
Hepatoma
Squamous cell carcinoma
Himan ruIn0r~s.s:
NeuroblnsLomn, lymphoma,
adenocarcinoma,
schwannoma
micc
Nude
Ostcogenic sarconm
nude(athymic) or immunosuppressed mice.
Human xenografts have been implanted at dif-
ferent sites in the body of mice (subcutaneous,
intravascular, footpad, intrapineal, intracranial,
intrasplenic). Bogden et al. (260, 261)devel-
oped a subrenal capsulemodel for rapid screen-
ing of new chemotherapeutic agents. More re-
cently, this model has been used to investigate
the radiolabeled monoclonal antibodies in solid
lymphoma growing under the subrenal capsule
of immunocompetent mice (259). This model
shows promise inthat the renal capsule provides
a rich vascular supply which results in rapidly
growing tumor andmimicsmorecloselythe
deep-seated tumors in humans. A similar model
has been developed in mice, with use of a sub-
splenic capsule as the site of tumor cell trans-
plant (262,263). With the advantageof a highly
vascular bed and easy accessibility, the hamsier
cheek pouch model hasalsobeenused quite
often (264) to follow up the rate of growlh and
effect of therapeutic interventions (264).
Theradiation-induced rat mammarytumor
model perhaps best simulates radiation-induced
breast cancer in the human female (265, 266).
This model is based on demonslration that radi-
ation exposure of the human female increases
the risk of breast cancer development (267,
268). This technique similarly increasesmam-
mary carcinogenesis in the female rat. Further-
more, radiation-induced mammary carcinogen-
esis occurs by a scopal mechanism in both the
Animal Model Relercnce
269, rats 265,
275-278
Mice 279-286
Mice,hamsters 277, 287-292
Mice, rats 293, 294
Mice 295-297
Mice 298-300
Mice 298
Rats 297, 301, 302
Hamster cheek pouch 264
303
Thymectomized mice 304
human Female andthefemale rat (269-271).
There is no evidence for a scopal mechanismin
mice, dogs, and guinea pigs (272, 273). More
recently, the hereditary asplenic mouse hetero-
zygous for the nu gene has been shown to be a
useful and relevant model of human breast can-
cer. A high percentage of these mice, startingal
the ageof 5 months, develop spontaneous breast
carcinoma, with maximum incidence at the age
of 10 months (available from the Armed Forces
Inslitute of Pathology in Washington, D.C.)
(274).Somemodels of inducedandtrans-
planted tumors are shown in Table 22.12 (264,
265, 269, 275-304).
SUMMARY
Animal models are used for the study of the
normal metabolism and physiological processes
as well as for the study of disease processes in
humans. It is taken for granted that results ob-
tained from experiments on animals which, in
the phylogenetic scale, are close to humans, are
more applicable than are results obtained from
species [hat are more remote phylogenetically.
Manyconditions can be studiedinrodentsor
othersmallanimals, however,and the results
obtained can still be validfor human conditions.
It is the thorough knom)ledge of the anatomical
and physiological variations of species that en-
ablesthechoice of theappropriateanimal
model which will yield information that is sla-
tistically significant, is economical, and can be
applied to the human in health and disease.
ACKNOWLEDGMENTS
Research was supported under the United
States Department of Energy Contract No. DE-
AC02-76CH00016.
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279. Hall JN. Chcn JD. Woolfenders JM, el a1 Com-
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356
299.
300.
23
301.
Considerations in the Assembly and
Submission of the Physician-sponsored
Investigational New Drug Application*
Geoffrey Levilze mzd Neil Abel
Any attempl to write a chapter dealing with
theInvestigational NewDrug(IND)process
and the design of a clinical h a 1 for a radiophar-
maceutical drug, in order for it to move success-
fullythroughthe IND processwithoutundue
delay, cannot be undertaken without the direct
acknowledgmentand acceptance of the Food
andDrugAdministration (FDA) guidelines on
thesubject (1). Becausetheseguidelines
(Grridelines for ihe Clinical Evaluation of Ra-
diopharmaceutical Drugs) are so fundamental
to the long-lerm welfare of the nuclear medicine
community as well as of the patients it serves, it
is highly recommended thal al1 individuals in-
volved wilh the clinical evaluation of radiophar-
maceuticalsfamiliarizethemselveswiththe
contents of this document. The guidelines are
clear and relatively comprehensive in delineat-
ing expectations; it is the interpretation of these
guidelines in specificcircumstances, however,
which needsclarification,and it is to these
specificCircumstancesthatweaddressour-
selves later in this chapter.
There are those who would argue that radio-
pharmaceuticalsare,indeed,differentthan
other classes of drugsand that this has gone
unrecognized by the FDA. Examinalion of the
guidelines for the clinical evaluation of radio-
phannaceuticals (1) compared to guidelines for
Ihe clinical evalua~ionof nonradioactive drugs
(Z), however, will quickly reveal that this “dif-
* This work does no[ necessarily represent Ihc opinion of
Ihe I 9 A .
357
ference” has been acknowledged, although the
degree of acknowledgment is subject to contro-
versy (1 -4).
The ability to inleract successfully with the
FDA and other govemmenl agencies depends,
to a largeextent, on understanding both the
philosophy andthe flow of paper within the
process, particularly as these relare LO the laws,
statutes,andregulationswhichultimately
govern both the context and content ol the proc-
ess. Dr. Siegel (3,4),past chairman of the FDA
RadiopharmaceuticalDrug Advisory Commit-
tee, hasrecently reviewed the process of new
drug approval(for radiopharmaceuticals) from
theclinician’s perspeclive.He noted that the
slow approval of newradiopharmaceuticals
arises fromdeficiencies in theactions of the
FDA, radiopharmaceuticalmanufacturers, and
nuclearmedicinepractitionersalike. In the
same article, Dr. Siegel reviewed the historical
considerations leadingup to FDA jurisdiction in
the area of radiopharmaceuticals, noting [hat the
[ransition from Atomic Energy Commission
(AEC) (Nuclear Regulatory Commission
(NRC)) control has progressed through the [ran-
sition phase but has not fully matured. Others
have cornmenled on the difficulty in meeting
literal compliance with guidelines that seem to
“become frozen into regulations” (5).
PARTICIPANTS IN THE PROCESS
TWO groups canfire an IND application: man-
ufacturersand health practitioners.Thecom-
mercialmanufacturer should haveIitlle diffi-

358 I Esseurials of Nuclear Medicirle Science
culty in knowing when or if it should file an
IND. The health practitioner, on the other hand,
doeshave some difficulty in deciding if the
study he or she has planned (a) requires anIND,
(b) falls under the practice of medicine andlor
pharmacy, or (c)can be handled by internal
(instilutionai) committees. Thischapter, then,
focuses on clarifyingthe role of the sponsor
and/or investigator with regard to the IND pro-
cess.The need for abetter understanding is
underscored by the observationthat new ad-
vances in nuclear medicinehave,toa large
extenl, come from hospital- and university-
based health practitioners. This is in sharp con-
trast to traditional pharmaceuticals (3, 4) which
have been developed predominantly by pharma-
ceutical manufacturers. In addition, it should be
noted that movingthe new agentsthroughthe
process to commercialization (wide dislribu-
tion) does not come without significant cost (6,
7).
The filing of an IND application can be com-
pared tothesituation in whichastudent is
takinga long subjective type of examination.
The student wants to please the teacher by say-
ing what the teacher wants lo hear; although the
teacher is determined to be flexible but correct
and fair. The student, however, must be aware of
(byeither experience, maturity, know-how, or
brilliance) the hidden agenda for thecontext and
conlenl of reasonable flexibility. During the
classic exchange betweensludentand teacher
over the scoring of an essay question, the stu-
dent often states, “You know that 1 am aware of
this information already.” The teacher replies,
“1 can only grade what you say; I cannot read
between the lines.” In reality, theperspective
that the teacher obtains having read a hundred
essay examinations is quite different from that
of the student. Indeed, having read hundreds of
IND applicalions the reviewer can approach a
particular applicationwith a broaderbase of
knowledge andlor experience, albeit a sense of
conservatism.
Each group (the practitioner-investigators and
the FDA reviewers) views the other as the ex-
pert. The clinician looks to the FDA, with its
massive aggregate of financial resources, its
large talent pool todraw on, its infinite non-
urgent sense of time, and ullimate veto power,
i
as the expert. The agency looks to the investiga-
tors as the experts. After all, the FDA doesn’t
have patients, nor does it design the studies. If
he FDA personnel designed and developed the
drugs, they would then become the experts, but
they don’t,FDApersonnel, to somedegree,
necessarily view themselves as generalists eval-
uating the protocols of the specialists, thus acl-
ing as editors rather than authors.
CLINICAL TESTING FOR SAFE AND
EFFECTIVE DRUGS: AN OVERVIEW
OF THE PROCESS
Before 1962, there wasno requirement thal
the FDA be notified that drugs were being tested
on humans. The 1962 Kefauver-Harris Amend-
ments to the Federal Food,Drug, and Cosmetic
Act greatly strengthened the Government’s au-
thority over clinical (human) testing of new
drugs. With this new regulatoryauthority,the
FDA has laken steps to:
1. Provide added safeguards for those on whom
drugs are tested.
2. Improve reports by drug investigators.
3. Establish investigative procedures to supply
substantial scientific evidence that a drug is
safe and effective.
First Step
Before a new drug may be tested on humans,
the sponsor (usually a pharmaceutical firm,
sometimes a physician) must give the FDA the
informalion specified as a “Notice of Claimed
Invesligalional Exemption for a New Drug”
(Fomls FDA 1571, 1572, and 1573) known as
an “IND.” Copies of these IND forms may be
obtained from
Forms Warehouse
Food and Drug Administralion
12100 Park Lawn Dr.
Rockville, Maryland 20852
(These forms are included with this chapter as
Appendices 23.1, 23.2, and 23.3.)
The IND should include lhc following infor-
mation:
(a)Conlpletecomposition of thedrug,its
source,andmanufacturingdata, toshow
that there are appropriatestandards to in-
sure its safe use.
(b) Results of all preclinical investigations in-
cluding animal studies. Initially, these
shouldbedirectedtowarddefiningthe
drug’s safetyrather thanitsefficacy. The
data must demonstrate that there wiII not be
unreasonable hazard in initiating studies in
humans.Furtheranimalstudiesmaybe
conducted concurrently with clinical stud-
ies. The Bureau of Drugs (now the Center
for Drugs and Biologics) will, on request,
comment on the adequacy of the proposed
FDA generally re-
animalstudies.The
quires, as a minimum, that (i) there be a
pharmacoIogica1 profile, (ii) acute toxicity
be determined in several species of animals
and theroute of administrationbethat
which will be used in the animal trials, (iii)
there be short-term sludies ranging from 2
weeks to 3 months, depending on the pro-
posed use, to evaluale Loxicity. Addiiional
animal studies frequently are necessary.
(c) A detailed outline (protocol) of the planned
investigation.
(d) Information regarding the training andex-
perience of the investigators. Investigators
are responsible for, and required to submit
to the sponsor (not the FDA), eilher Form
FDA 1572forclinicalpharmacology or
Form FDA 1573 for clinical trials,
(e) Copies of all informationalmaterialsup-
plied to each investigalor. (The lype of in-
formation is listed in Form FDA 1571 .)
(f) An agreementfromthe sponsor tonolify
the FDA and all investigators if any adverse
effects arise during either animal or human
tests.
(g) The investigator’s agreement to obtain the
consent of the person on whom the drug is
to be tested before the tesl is carried out.
(h) Agreemenlto submitannualprogressre-
ports and commiiments regarding disposal
of the drug when studies are discontinued.
Physician-sponsored IND
When an invesligator wishes to acl as sponsor these circumstances. It remains
for the use of a drug solely as a research tool or sponsibility, however, to see that the ilems in (he
for early clinical investigation of a drug of ther- DMF meet the requirements.
apeulic or diagnostic potential (clinical phar-
macology Phases I and II). a simpler abbrevi-
atedform of submission is acceptable.An
example would be the study of a drug that no
manufacturer is interested in sponsoring. An
outline of such a study should provide the fol-
lowing infomlation:
I . The identity of the compound or compounds
together with facts that satisfy the investiga-
tor that the agent may be justifiably admin-
istered to a human as intended.
2. The purpose of the use and the general pro-
tocol.
3. Appropriate background information includ-
ingabriefslatenlent of theinvestigalor’s
scientific trainingand experienceandthe
nature of the facilities available to him. The
physician sponsoring this type of IND deals
directly with the FDA. The FDA has no
authority over the practice of medicine and
cannot require a physician to prescribe or not
lo prescribe a drug for a particular illness.
Physicians are encouraged to submitan
IND, however. when they use a drugfor
purposesother than those approved bythe
FDA. This enables the FDA to accumulate
data on the safety and efficacy of the drug
for that kind of treatment and to share this
information with other physicians (8).
If the sponsor does no1 perform the manufac-
turing and control operations for the new dlvg
substance or finaldosage form himself, this
information(whichisrequiredbyparts 1
through 5 of the Notice as found on Form FDA
1571) can be furnishedon behalf of the sponsor
by the supplier who performs lhese operations.
Similarly, a supplier may provide the preclinical
or clinical study data. The sponsor mayforward
such supporling information or arrange to have
it lransmitted directly to the FDA.’ In practice,
the manufacturer usually maintainsa Drug Mas-
ter File (DMF) containing manufacturing infor-
mation with the FDA and, on the requesl of an
investigator or sponsor, appends thisinforma-
lion to the 1ND application. The sponsorrarely,
if ever, reviews the contents of the DMF under
his or her re-
 360 I Essentials of NrrcIenr MedicineScience Considerations in Phvsicion-sp0lrsol.d IhW AppIicnfiurr ! 361

Clinical Investigation Phase I11

PRECtlNlCAL PHASE I PHASE II PHASE 111
Proposals for Phase UI of the clinical investi- I POST-MARKETING
The kind and the extent of the investigational 1
gation, which involves extensive clinical trials,

!
drug tests are crucial for producing the substan- TESTNG lh ‘EARLYTESTING *COKIROLLED TRIALS .TRIALS TO ACQUIRI EPIDEMIOLOGICAL
are in order if the information obtained in the ANIMALS: IN HUMANS: FOR EFFECTIVENESS INFORMATION SURVEILLANCE
tial scientific evidence of safety and effective- NECESSARYFOR
ness needed to approve the drug for marketing. firsttwophases demonstratesreasonable as- -RATIONALE 8 -PHARMACOKINETICSEVALUATION OF RISKS FULL LABELING REPORTING OF
surance of safety and effectiveness or suggests MECHANISM FOR PHYSICIANS ADVERSE EFFECTS
This evidence is obtained in three phases. -TOXICTP(
that the drug may havea potential value Out- -POTENTIAL
EVALUATION OF
Phase I weighing possible hazards. The Phase LII stud- EFECTlVENESf -EFFECTIVENESS I NEW USES

Pharmacology studies are used to determine ies are intended to assess the drug’s safety, ef- -TOXICOLOGY

loxicity, metabolism,absorplionandelimina- fectiveness,andmostdesirabledosage in h e

tion, andother pharmacologicalactions, pre-
ferred route of administration, and safe dosage
range. These studies involve a small number of
persons and are conducted under carefully con-
trolled circumstances by persons trained in clin-
ical pharmacology.
Phase 11
Initial trials are conducted on a limiled num-
ueatment of a specific disease in a large group
of subjects. The studies, no matter how exten-
sive, should be carefully monitored. INVESTIGATIONAL NEW DRUG APPLICATION IIND)
The FDA continually receives reports on the
REVIEW BY FOA FOR:
progress of each phase, If the conlinuation Of -SCIENnFIC OBJECTlVES AND SAFETY IN HUMANS
-TOXICOLOGY DATA
the studiesappears to presentan unwarranted -CHEMISTRY DATA AND FORMULATlON
hazard to the patients, the sponsor may be re-
REVIEW OF HUMAN STUDIES BY INSTITLITIONAL
quested to modify or discontinue clinical testing REVtEW BOARDS. FOR ETHICAL CONSIDERATIONS IOVAL FOR
until further preclinicalwork has been com- AND INFORMED CONSENT

ber of patients for a specific diseasetreatment or pleted (8).

prevention. Additional pharmacological studies
performed concurrently on animals may be nec-
essary to indicate safety
In Figure 23.1, one can schematically exam-
NEW DRUG APPLICATION (NDA)
ine the overall new drug developmenl process. REVIEW a y FDA FOR:
In Figure 23.2, the development and regulation -DATA TO SUF6ORT SAFEFY AND EFFECTIVENESS
-APPROPRIATE LABELING OF DRUG
-EVIDENCE OF PROPER MANFACTURE

Figure 23.2. Schematic showing regulatory monitoring of drug development and evaluation.

30-DAY
t_ MARKETING
PRELIMINARY
DEVELOPMENT
of drugs? including radiopharmaceuticals, are hesitate to believethat the preparation of an IND
IDEA FOR
further described. is an exercise in “word engineering.”
NEW DRUG
CHEMICAL INSTRUCTIONS FOR SUBMITTING AN FRAMEWORK AND CRITERIA FOR
DEVELOPMENT IND APPLICATION (FORM FDA 1571) REVIEW OF AN IND APPLICATION
ANIMAL
The submission of an IND application by an Knowledge of theframeworkandcrileria
SHORT-
STUDIES
individual heahhcare practitioner can be a rela- used bythe reviewer can be of help in the
tively painless exercise or can be one froughr successfulcompletion of the application. A
IND with futility. It should come as no surprise thal reading of the IND portion of the Bureau of
SUBMISSIONS
the task would be reiatively more difficultif one DrugsGuide BD 4831.1, INDlNDA Medical
HUMAN tried to fill out the application without a set of Review Guidelines (10) (Appendix 23.4), offers
STUDlES instructions. Instructions for the submission o€ a rare insight into theposition which will be
PHASES 1-11! Form FDA 1571 by an individualphysician taken bythe reviewer in evaluating the IND
investigator are, in fact, available from the FDA application. In answering the individual ques-
on writlen request (9). Yet, we have reviewed or tions of the Form FDA 1571, referring to the
NDA assisled in the preparation of IND applications
1 I I J I IND Medical Review Guidelines willgivethe
SUBMISSION
on numerous occasions in whichtheinstruc- investigator the opportunity to discover the type
USE OF DRUG tions were never consulted. The most difficult of response which, is appropriate. Additionally,
BY CONSUMERS task in the preparation of an IND application is answeringthequestions in a way which both
to make sure [ha1 it is complete and understand- parties {investigator and reviewer) deem appro-
Figure 23.1. Schematic of new dnlg dcvclopment process. able to allparties concerned;oneshould not priate will forestall unnecessary time delaysand
thus could lead to more rapid approvals. This is data must meet the same requirements as data result, the drug languishes and doesn’t get ap- anydosereceived from other modalities or
no1 to say (hat there might not be differences of oblained in the United States. proved. It is far easierto demonstrate that a drug agents which are part of the study protocol as
opinionand/or of interpretation.Also,the 3. The criteria for patient selection must be images a particular organ than it is to prove [hat well.
guidelinesarejus1 that, and [he reviewer will explicitly stated. The criteria for patient selec- adrug can be used for the detection of some Often omitted are the changes in radiophar-
often choose olher criteria in addition to those tion depend on what one is trying to prove. For disease. Often, with regard to thecompany- maceutical distribution that result in subsequenl
staled based on his or her experiencein review- example,supposeone is trying to showthe sponsored IND, toobroad of an objective is changes in dosimetry (e.g., due to differences
ing a specific type of agent. effectiveness of lllIn-labeledleukocytes in a sought(thereis difficulty in findingadequate that arise in specific subpopulalions or changes
patientwithan abscess.Theexistence of the controls). In this situation, “coming in” with an that occur in patients receiving adjunct therapy.
abscess must be shown byanothermodality, objective that can be easily measured and then For example, if 99n1Tc-labeledsulfur colloid is
AREAS OF THE INDIVIDUAL i.e.,biopsy,ultrasound,etc.Thus, if you amending the objectives €or use at a later date lo be administered to patients suspected of hav-
(PHYSICIAN)-SPONSORED IND WHICH haven’t shown the existence of Ihe disease, you shouId be considered. ingliver metastases, it can be reasoned(and
.FREQUEKTLY CAUSE PROBLEMS haven’t proved anything. 8. Thesamplesizemustbesufficient to shown) that there would be an expected shift of
One of the major difficulties with individual show a difference between two studygroups. theradiolabeledsulfur colloid to thespleen.
Certain portions of the individual-sponsored What size i s this? There is no numerical answer
(physician)-sponsored clinical trials is that drug Likewise, if the thyroid is blocked with Lugol’s
IND applicalion forradiopharmaceuticals are thal applies in every case, because a sufficient
regimens and assumptions are not always listed. solution prior to the administration of an1311-
repeatedly found to be inadequate or incomplete sample size depends on what you are studying,
One would like to minimize the interfering fac- labeled monoclonal antibody, one could antici-
in their coverage of thespecifictopic.These tors that tend to cloud the endpoint of a study. the frequency with which it occurs, [he popula- pate a shift of free iodide in the agent from the
areasarelistedbelow,occasionallywith Two examples, in terms of patient selection, tion size, resources, etc. The “bottom line” is thyroid to other organs.
editorial comment. might be pregnancy and children. that a statisdcally valid number of patients must 10. The sponsor of an IND can be anyone
1. Theobjectiveandduration of the stud?; 4. The populations of the patients must be of be used so thal enough good values remain afler (e.g.,physician,scientist,pharmacist,corpo-
should be staled as explicitlyand concisely as equal quality. For example, if ”‘In-labeled leu- thestudy iscompleled.Forexample, in the rale executive, etc.). In any study or phase of a
possible, It must b e remembered that the re- kocyles are being tested on two groups of pa- study of an arthritis drug on gerialric patienls, study involvingpalients, although anyonecan
viewer may not have the same technical or med- tienls with abscess and one of thegroups i s 30 normally would not be an unreasonable num- be an investigalor, a physician must be, at least,
ical background as the investigator and that the predominantly on antibiolic therapy, Ihe groups ber, whereas in the study of cyclosporine [her- co-investigator, since in the event of an adverse
reviewer’s reasoning will be inductive rather are no1 equal. In another example, first-year. apy foIlowing heart-lung transplantation in chil- reaction or similar circumstance a physician is
lhan deduclive. Thus, it would probably serve healthy medical students earning a few dollars dren, 3 might be an unreasonable number at one best qualified to treat the patient. If a particular
both parties better if the investigator leaned to- whileundergoingesophagealtransitstudies institution. The imporlant considerationis a sta- study involves only lrials in animals, however,
ward ”spoonfeeding”his or her information wilh 99mTc-labeledscrambled eggs may not be tistically valid samplesize for the statistical the investigatormaybe a clinicalphar-
rather than overwhelming the reviewer with his representative of the general population. design chosen. macologist, nuclear pharmacist, or other
or her medical or technical brilliance and ver- 5. Whenfiling an INDapplication,the in- There are scores of study designs to be fol- qualified individual.
nacular, vesligator or sponsor must be in compliance lowed, although the determinalion of sensitivity Other than the evalualion of new radiophar-
2. Acuteandsubacute toxicilylestingmust with his or her own local or state regulations in and specificity i s used quite often. Furthermore, maceuticals, a number of areas of clinical inves-
be carried out on animals before the drug can be addition to the federal regulations. Each state or +
the use of a scale ( I to +4j. compared with a tigation could be examined by nuclear medicine
used in humans. For example, consider 99mTc- distric1 has its own Board of Medicine or Phar- carefully chosen standard, is quile common professionals. These include investigations that
telracycline. If ilhasbeenshown(hatthe macy. Each investigator or sponsor must insure (e.g., for comparing radiotracer uptake in organ (a) prove new indications for exisling radiophar-
tetracycline issafe and effective, it must be thal he orshe i s complying with thoseregu- syslems or areas of pathology). The criteria for maceuticals, even if by citizen petition, (b) de-
shown that the presence of the technetium does lations. A state may or may not have regulations eachdesignalionmust be clearly identified so fine new routes of administrationfor existing
no1 alter the ~etracyclineso that it will adversely dealing with investigational drugs, however, and [hat the clinician andreviewer can understand radiopharmaceulical agents,(c)describe new
aflect the study or be a molecule of sufficient will defer to the FDA for responsibility. Califor- one anolher. dosage forms, and (d) evaluale new salts of
difference tohavean adverse toxicity of its nia is an example of a statehavingits own 9. Thecalculation of radiationdose(e.g., existing active agents.
own.The pointto bemadehereis that one regulations that deal with investigational drugs. radlmCi, mGylMBq) is of equal value whether 1 I . The design of a study with a diagnostic
cannot simply reason it out; the experiments to 6. Sufficient medical and occupational histo- calculated by the investigator, the Radiopharma- radiopharmaceuticalcantake on numerous
demonstrate what you are trying lo prove musl riesshould be obtained so [hat adequate inler- ceutical Internal Dose Information Center at forms. For instance,a crossoverstudyis not
have been carried out. pretation of the study can be made. Would not Oak Ridge, or by reference to a journal article always required in order toobtain an IND. What
Additionally, one musl choose an appropriate the interprelation of a slress fracture sludy with or package insert. The investigator must show is required, however, is a cleariy defined objec-
animal model. Testing of the iminodiacelic acid 99”1Tc-n~ethylene diphosphonate(MDP) vary that he understands the meaningof these values. tive, a clearlydefined rationale, and a clearly
agents in an animal that does not have a gall- betweenaballerina, college football lineman, The lolalradiation dose that eachclinical defined endpoint. For example, an appropriate
bladder would be useless. The FDA will review marathon runner, secretary, and chemist? study volunteer will receive must be includedin double-blindcrossoverstudymightinclude
data obtained from other countries in evaluating 7. Oftenthe poinl that the invesligator is the submission; this takes into account not only ]”In-Iabeled leukocytes and [67Ga]gallium cil-
the safety and effectiveness of a drug. Foreign tryingtoprove is too difficulttoprove. As a lhe dose froom the investigational drug but also rate ror abscess localization. Nonetheless, one
 Cmlsiderarioos i n PiI~sician-sponsoredIND Applicaiion t 365
364 t Esserrfinls of Nuclear Medicine Scierlce

category). The IND is then reviewed by three rate and is confirmed by a chest x-ray, the chest
can obtain valuable information in a study with studies that can reasonably be expected; nev-
disciplines(phamlacology,chemistry,clinical x-ray becomes part of the total doseforthe
either II’In-labeled leukocytes or 67Ga-citrate’ ertheless, it seems possible that more of the
medicine) and others as required. purpose of the proposed sludy.
when the same palient has been scanned off and pertinenl questions can be answered without
3. On receipt, the FDA has 30 days to evalu- 8. The curriculum vitae (CV) of the primary
on (or on and off) antibiotics. any increase in the total number of patients
atethe IND for safety (safety only, not effec- investigalor and co-investigators (if any) is used
With a therapeutic radiopharmaceutical, it exposed to clinical trials.”
tiveness). It is valuable to sendthe IND by toascertain whether their training in the han-
may be inappropriate, unethical,or legally risky One example, of the many he discussed, in- certified or regislered mail so that you have dling and administration of radioaclive drugs is
lo denya patient the benefit of a worthwhile volves the comparison of a new dmg to a posi- proof that theIND was received in orderto adequate. The CV of the person(s) preparing the
treatment. Thus, prior knowledge obtained from tive control(not a placebo)byshowingitis validate the 30-day safety period. An acknowl- radiopharmaceutical is also important (phar-
earlystudiesbecomesmoreimportantwith similar to a positive control. The logic isreveal- edgmenl lelter of receipt should be sent by the macist,technologist).The IND application
lime. One can compare the findings from the ing if not often unrecognized. FDA. The sponsor will be notified of a “hold” must state whether the preparation of the radio-
new drug, retrospectively, with findings from a Suppose one is comparing lllIn-Iabeled leu- and the reason for it if the INDis held up pharmaceutical will be under the supervision of
similarpreviouspopulation of patients(e.g., kocyteswith67Ga-citrate in apatientwith a because of a question concerning safety. Any of a physician (practice of medicine or pharmacy)
oncologypatienls). Attempting to carry ou1 a parlicular infection.Showing thatbolh drugs thedisciplinescan recommend a “hold,” but or be prepared by a drugmanufacturingfirm
double-blind sludy witha drug such as cyclo- producesimilarscans or areequivalent in a theDirector of [he Division of Oncology and (and thus be regulated by Good Manufacturing
sporine,whichisused to inhibittransplan1 study does not demonstrate that either is effec- Radiopharmaceuticals makes the final decision Practices).
organ rejection, could prove legally and thera- tive, sincethepresence of infection must be to initiate a “holding” action. 9 . Title 21 Code of FederalRegulations
peutically embarrassing while denying a patient demonstrated by some other modalily. It does It is an interesting marriage in that radiophar- (CFR) 50.25 requires that informed consent be
the benefit of treatment. show, however, thatbothare effective or that maceutical~,perhaps the most benign category oblained. The sponsorof the IND need only say
12. Any attempt to discuss the importance of neilher were effective. Because the posilive of “drugs,” arelumped logether (in the same [hat informed consent will be obtained. A copy
the appropriale design of a clinical trial in this control is known to beeffective, we usually reviewing division of lhe FDA) with chemother- of the informed consent need not be submitled
chapter, other than in a consciousness-raising conclude thal both agents are effective if equiv- apeutic drugs, perhaps the most toxic of drugs with the application. However, reviewers can be
format, would fallterribly short. Robert Tem- alence is shown. A crucial assumption underlies (Fig. 23.3). quite helpful in pointing oul deficiencies in the
ple, M.D., Director of the FDA Office of Drug the conclusion, however, viz.: that the effective 4. Be sure lo answer each question and do so investigalor-prepared informed consent forms-
Research and Evaluation (formerly the Officeof drug was effective in theparticularsludy in in the propersequence. It is atedious job to this beingclearly to the investigator’s advan-
New Drug Evaluation), has brilliantly reviewed question; this conclusion may no1 be valid. The search lhrough piles of paper to find the answer tage. The lnstitulional Review Board (IRB) is
the commonmistakes,errorsin.design,and error in reasoning would be just as appropriate to a question. the body thal officially approves the informed
misinterpretations frequently made in the design in comparingtwoboneagents or twoliver 5 . If theINDdocumentcontainsmany consent document and/or statement.
of clinical trials (1 1). In this article, he hascited agents , etc . pages, paginate. 10. The IRB is not theRadiationSafety
several problem areas in designandproposed 6. Recognize that INDapplicalions are of Committee(RSC) and is nor the Radioactive
design solutions and has suggesled a number of INSURANCE AGAINST UNNECESSARY two majortypes:(a) con~merciallysponsored Drug Research Committee (RDRC) and should
aspects of designevaluation that could be im- DELAYS: TIPS FOR SPONSORS OF 1ND INDs, in which a Iarge populalion will be put at not beconfused with these other committees
proved with little or no increase in development APPLICATIONS risk, and (b) individuallysponsored INDs, in (12).
time or cost. Temple describes the difficulties as A number of simplistic, common sense, ad- which a small population will be placed at risk. 1 I . The 30-day safety period can be waived
falling into two broad categories ( I 1): ministrative problemsimmediately evidentto The IND will address two primary situations: on requesl, Le., on an IND appIication for an
“ 1 . Individualstudiesmaybedesigned the reviewer can, if not handled properly, resuil (a)one in which the drughas already been already-approveddrug(becausethere would
without careful consideration to the questions in unnecessary delays. Paying close attention to approved,perhapsfor another indication,and probably be no safety problem).
they really are capable of answering. The detail and to instructions for filling out the IND (b) one in which there is a new clinical entity, When an IND is filed for what is really the
result is either a) a useless trial that answers applicalion is important.Theseobvious over- i.e., a new drug. In the former situation,the practice of medicineandpharmacy,the FDA
no questions at all, or b) a trial that answers sighls are mentioned here becausethey occur s~ safety may havealreadybeen established and doesn’treally find it necessary to review the
some other question, not lhe one intended, or often. Information about how the IND is pro- the literature can be cited. A photocopy of a few study, nor does it want to. It will do so as a
only part of the intended question. cessed inside the FDA is presented to aid the articles attached lo the back of the IND as an courtesy at the present time, however.
2. The total package of sludies may b e de- sponsor andlor investigator. appendixaidsthe process. If nothingelse, it 12. TheINDprocessisconlinually under
signed without lhoughtful consideration of all 1. The IND application (Form FDA 1571) saves duplicate trips to the library. review. A rewrite of IND regulations, which
the questions that are pertinent. There are, of must be signed. 7. Whencalculations of dosimetry are in- will applymostly to commercial sponsors, is
course, practical limitations on the number of 2. The application must be submitted in trip- cluded, (a) “walk” the reviewer throughthe currently in progress.
licate. Many of the applications are held up for calculations, since he or she cannol make as- 13. TherearenoFDA-requiredlimitson
this reason. INDs are initially sent to a Central sumptions, and (b) includethe total radiation dosage. Each case is examined on its own merit,
Although [6’Ga)galliorn citratc is preferred by IUPAC, Record Koom where they are given a number as
+
dose lo the patient from all modalities. Thus, if but consider the following when submitting an
“Cia-citrate is standard. and both arc used throughout this
they are received (1NDs arenot numbered by a pulmonary infection is detected by 67Ga-cit- IND: Is the risk to be taken worthwhile for the
chapter.
366 / Esserlrinls of Nuclear Medicine Scierrce
information to be gained? Does the patient ben-
efit or willthe information more likely be of
benefit to mankind?
EXAMPLES OF WHEN AN IND IS (AND
IS NOT) REQUIRED
Under what circumstances is it necessary to
submit an IND, and under what circumslances
is the careof the patient (or a patient population)
considered to be the practice of medicine and
pharmacy? The following examples should help dioactive Drug Research Comnitiee (RDRC), if
toclarify theseoflen-asked, albeit confusing, there is one?
questions.
I Example 1. A university hospilal-based investi-
I '
I I I
gator (physician) wishes to use "Cu as cupric
chloridetoevaluate whether or notapatient
who is scheduled to undergo a liver transplant
c.
e has Wilson's disease.
c
+- Comment. The United Statesliteralure reports
E
s the use of 64Cu.11is not on the NRC Section 10
CFR Part 35 list of approvedradionuclides,
however. The study has not been used for years
-
1 -
I
(at least since the 196Os), except in a relatively
I small number of patients, because of the rela-
tively smallnumber of individuals withthis
disease. [MCu]cupric chlorideis purchased as a
nonsterileradiochemical.There is no Drug
Masler File (DMF).
L
Is the preparation and use of this isotope cow
sidered the practice of nledicinc and pharmacy?
Answer: Yes
Whal if the patient is at anorher hospiral and is
covered by the same NRC liceme, the same
Radiation Safety Committee, but a different
IRB?
Answer: This falls under the practice of medi-
cine and pharmacy.
Szrppuse the parient is a child?
Answer: This falls under the practice of medi-
cine and pharmacy. In each of these situations,
the individual care or lrealment of thepatient
may be determincd by the resulls of the test, and
the patient will have a choice as to whether or
not lo receive a treatment plan.
Is an IND required in any of the above situa-
tions?
Answer: Probably not.
Is an informed coment required?
Answer:Not from the federal (FDA) point of
viem8. If an IND is no1 required, an informed
consent is not required. An individual hospital
or individual IRB, however, may have more
stringent requirements.
Is i f necessary to have the approval of the Ra-
Answer: No
What if one is evaluating the effect ( i . e . , the
degree of improvement) of a liver transplant on
patients wilh \Wilson's disease, compared wi/h
thecfSect of Brirish antilewisite (BAL) on pa-
tients not undergoing transplant.? is an IND
required prior to the administration of "Cu?
Answer: Yes, an IND application would have to
be filed.
This apparently is a bona fide research study
in which the findings from two groups are com-
pared. The patienthas no choice as to which
group he or she is entered into.
Example 2. A university hospital-based physi-
cian who had submitted Form FDA 1571 for the
use of 9911'Tc-labeledantimonysulfidecolloid
(ASC) in themanagement of patientswith
melanomahasreceived FDA approval.He
moves to anotheruniversityhospitalwhere
99mTc-ASCis requested for use in the manage-
ment of patients with melanoma undergoing
three Ueatment protocols. Other investigators at
the new hospital alreadyhaveapprovalto use
99mTc-ASCfor internal mammarychain lym-
phoscintigraphy.
Can !he n e d y anivedphysiciatl be called 011 io
pelfort31 ire p9"Tc-ASC study?If he cannot, h o ~
can use of 991'1Tc-ASCfor patientswith
rnehrwma be arranged?
Answer: No, he cannot. The IND may or may
no1 move with the intestigator. It would, how-
ever, be more advantageous for the invesligator
who moved 10 fiIe a new IND and make refer-
368 t Esserlrials 01Nucleur Medicine Science Corlsidernriorn irr Pj~~~~icinn-sporrsored
IND Applicarion / 369

ence to his previous IND withregardto the theevent of error a criminal penalty can be ity of thesolute-solventrelationship (e.g., oil “OnFebruary 4, 1983, the NRCpromul-
technical and medical content. The IRB at the avoided with such a mechanism, errors of mal- versuswater). Try, forexample,toelute a gated a final rule granting the first exemption
new institutionwould be requiredtogrant its practice would stillbe applicable under civil law 99mMo/”mTcgenerator with water or 0.45% sa- to the ‘route of administration’restriction.
approval for use. on behalf of the patients involved. line instead of 0.9% saline. What would happen Thisexemptionpermitstheuse of 9 9 m T ~ -
It would also beappropriate for the investiga- to the insolubility of 32PcolIoidal chromic phos- DTPA as an aerosol for pulmonary imaging.
tors in residence to modify or amend their IND Would a Radioactive Drug Research Commiiiee phate if [he pHwas out of specifications? Would Moreover, this rule establishes a mechanism
for internal mammarychainlymphoscintigra- (RDRC) (12) have an)’ role in this process? soluble 32Pdiffuse through the cavity wall and whereby similar exemptions might be ap-
phy to include melanoma. Answer:TheRDRC hasno rolewhatsoever result in ahered biodistribution and significantly proved by the NRC. . . [(4)].”
A third option is for all of the investigators to regarding the use of a radioactive pharmaceuti- differenl radiation dosimetry?
file Form FDA 1573 (Statement of Investigator) cal for patient management. If one was simply Example 9 givesadditional informationon
and become clinical investigators for a sponsor looking at the kinetics of a radiolabeled drug for unapproved uses of approved radiopharmaceuti-
researchpurposes,the RDRC couldconceiv-
Example 5. The nuclear medicine department cals.
wilh an active Form FDA 1571 (IND).
of a children’s hospital wishes to prepare a lung
ably have a role. Nonetheless, an IND would
scan dose of 99mTc-labeIed macroaggregated al-
Would the diagnostic test wiih P9”Tc-ASCstill not be required in this situation. Example 7. A physician working in coopera-
bumin for a 6-month-old infant. Examination of
j as a result of the evaluation
be invesfigational i
the package insert directions provides no guid- tion with an immunology laboratoryai a univer-
of a patient with 99mTc-ASC,the degree of dis- Example 4, A nuclear pharmacist in a depart- sity-based health center is a leader in the deve1-
ance in terms of how to prepare the product for
ease became known and the rreatmenl plan was ment of nuclear medicine wishesto dilute a vial opment of hybridoma technology. A labeled
of 32P colloida1 chromic phosphate so that the an infant under these circumstances.
alrered? monoclonalantibodywhichhas been thor-
Answer: No, the use of %*Tc-ASC would no1 dose can be more accurately measured and dis- oughly tested as a diagnosticagent in normal
Is an IND needed?
be investigational but would fall under the prac- pensed in a larger volume. 32Pcolloid is pre- mice, [urnor-bearing mice, and human tumor-
Answer: Obviously one does not request a lung
tice of medicine and pharmacy. pared in 30% dextrose solution as the diiuent. bearing nude mice is considered for testing in
scan for a n infant without a clear and justifiable
The dose willbe used within 2 hours of dispens- a patient for the first time. The inlent is to de-
need to obtain certain specific information. Not
Example 3. Theadministration of tritiated ing. terminewhethertheagent will localize in a
to perform thisstudycould be viewed as an
water and [ I4C]urea are requested as an indicator specific patient’s tumorandperhapseven lo-
omission by some. Moreover, h e FDA has rec-
aide in evaluating pulmonary edema and capil- Is an IND needed? calizeinmetastases.Theuniversity hospital
ognized that many limes the literature ( 3 , 4 ) and
Iary pemleability in patients undergoing hearl- Answer: The use of an approved drug for the has a Radioactive Drug ResearchCommittee
clinical practice ( 3 , 4) are farahead ofthe
lung transplants. diagnosis or ueatment of a specific patient for (RDRC).
package insert materials (e.g., approved indica-
anapproved use (in thiscase anintracavity
tions). This example falls under the practice of
Both agents are purchased ns radiochemicals. administration) falls under the practice of rnedi- Con the RDRC at this wriversity-based health
medicine and is not contrary to existingregu-
Is there an Ih‘D requirement? cine andpharmacy. Thus, an IND is not re- center arcrhorize testing in humans in this case?
lations.
Answer: There is no IND requirement for the quired. Answer: On May 6, 1983, the FDA Radiophar-
use of tritiated water or [I4C]urea either as part maceutical Drug Advisory Committee reviewed
of a research study or in the practice of medicine Can this dilutionbe prepared by a nuclear med- Example 6. A hospital-based physician wishes Section 21 CFR 361.1, regulationsthat had
andpharmacy. icine technologist or radiopharmaceutical sci- to administer the renal agent wmTc-diethylene- been promulgated 8 years earlier and in which
The term radioactive drug as defined in Title entist rtnder a physician’s supervision? triarninepentaacetic acid (DTPA) by a different the responsibilities of the RDRC had been set
21 CFR310.311 (1 3) specifically excludes Answer: Yes, it can. route of administration, i.e., as anaerosol for forth.Onetopic of discussioncentered about
“ . . . drugssuch as carboncontainingcom- pulmonary imaging. the question of new chemical entities as drug
pounds or potassium containing salts which Does one need to conduct stability silrdies prior products for human use, with approval handled
containtracequantities of naturally occurring to modifying a specific radiopllarmacentical Is this unapproved use of a mdiopharmaceuti- by the RDRC. The currentregulations state thal
radionuclides. . . . ” There are IND require- preparation? cal allowable? if the radiopharmaceutical drug productis a
ments for other than radioactive drugs, and Answer: In general, if the opportunity is pres- Answer: On August31, 1981, the NRC Ad- radionuclide attached to an established drug for
these requirements should be metif the product ent, it is to one’s advantage toconductsuch visory Committee on the Medical Use of Iso- which the physiological usein humans is known
is not endogenous. studies.Whether or not suchstudies are re- topes discussed the problemof unapproved uses and the dose administered in the tracer study is
A second question that is raised deals with quired falls within the judgment of pharmacists of approved radiopharmaceuticals in whicha below the physiologic dose, the Committee has
the conversion of a radiochemical toa radio- and pharmaceutical chemists. When there is un- variance fromthelabeling with regardtothe the authority to approve of its use.
pharmaceuticalwith the drug’s subsequent re- certainty, references in the literature cannot be route of administration is involved. NRC staff If, however, the radiopharmaceutical is a new
moval from FDA jurisdiction. found, andlor expert advice cannot be satisfac- members indicated their willingness to review chemicalentityfor phich thepharmacologic
A radiopharmaceutical may beprepared from torily gained, it is prudent not to take a chance. requests forsuchuses andto approvethose dose in humans is not known, animal data can-
radiochemicals on a prescription basis under the Just the changing of a solvent can often alter the judged to result in acceptable radiation exposure not be used to establish the fact that [here is no
practice of medicine and pharmacy. Although in dissolution rate of a drug by changingthe polar- to patients (3, 4, 14). human pharmacological effect.
370 I E J S C I I of
? ~Nltclenr
~~ Medicine Science

Thusundercurrentregulations,since a the diversity of interests between clinicians and tioned that there are many varieties of fibrino- radiopharmaceuticals. The agencyapproved the
monoclonalantibody is a new chemica1 or a the FDA. gen, however, and that only the approved type of u s e of s o d i u m [ 9 9 m T c ] p e r t e c h n e t a t e f o r
biological entity, the RDRC would not be able Human naturedictatesthatthe members of fibrinogen from an approved lot will be accept- dacryocystography, 99mTc-labeled sulfurcolloid
organizations (the FDA or the “organization of able.The“bottomline” is that if the FDA for oral administration (e.g., gastrointestinal
to authorizetestinginhumansandanIND
individual practitioners”) defend the vested in- learned of the use of I3’1-fibrinogen as an imag- studies), and ‘33Xe for intraderma1 injection.
would have to be filed.In practice, however, the
terests of that organization or society. Each ing agent in a research study, it would notify the Previously, the FDA had approved NDA sup-
RDRC can play a valuable oversight role.
grouphas a mission to accomplish.Because investigator that an IND was necessary. plementswhichadddirectradionuclide
Cat1 itformation oblairled in an RDRC study be neither (protection of the public health nor care cystography to theIist of indicationsfor
of the individual patienl) is mutually exclusive, Who makes the decision regarding the need for [99mTc)-pertechnetate.
lrsed IO provide itzjiirnratiotr that will be used 10
thereusually is room andflexibilityto find a OII IhID? Another example which is appropriate for this
irenf a patient?
mutuallyacceptablesolution.Thecontinuous Answer:Atmostinstitutions,theRadiation process is the use of 99mTc-MAAto verify he-
Answer: Yes, it can.
striving for mutually acceptable solutions, how- SafetyCommittee authorizes possession of a patic catheter placement for chemotherapyinfu-
ever, willrequire tenacityand goodwill if the radioactively labeled drug in a specific chemical sion by pump. More than a dozen articles in the
Suppose that irr this firsf patient to be studied
!he findings worrld Itme an impact on the cowse development of safeandeffective radioactive fom, usually through itshuman use subcom- literaluresuggest thesafety,efficacy, andap-
agents are to reach patients in the shortest possi- mitteewhenthe material will be used in hu- propriateness of this indication. The approval of
of treatment. Would this be consideredthe prac-
ble time. mans. Additionally, the IRB, also known as the this indication will, however, depend onthe
tice of Inedicine.7
human experimentation committee or a similar design of the studies and whether ornot the data
Answer: This process would, in effect, be skip-
Example 8 . A university-basedphysician name, reviews the project for design and for the support the conclusions which are reached. Two
ping over the intent of a Phase I IND study
wishes to begin studies on the possible forma- establishrnent of an informed consent docu- other radiopharmaceuticals which are appropri-
which is carried out, in part, to demonstrate
lion of deep vein thrombosis (DVT) following ment. If the institution has an RDRC, this com- ate for this process and need to be evaluated are
safety. Phases 11 and HI of the IND process
the use of a surgical cuff. For this purpose the mittee couldhelpmakethedecisionaswell. 99mTc-DTPAforcisternographyand l1l1n-
representtheclinica1trial. The RDRC cannot
controls will be the contralaterallegforone Usually, the nuclear medicine physician makes DTPA for gastrointestinal tract studies.
approve the use of anydrug that is partof a
group of patients,and,for the secondgroup, the initial decision, however.
clinical trial. The clinical trial is approved by
the IRB. randomized surgical patients with and without Example 10. A university-based hospitalhas
the cuff. The patients will not benefit from the Could t3ii-labeledfibrinogen be prepared and filed an IND for the use of ]In-Iabeled Ieuko-
Comment. There has been talk that should the
study unless the presence of DVT is discovered used to image DVT i n a single patient? cytes to detectsites of infection. One patient
role of the RDRC be expanded to approve new
and found to be necessary to treat. Since Answer: Yes, and without filing an IND. presents with a lymphoma in the cheek whichis
entities,thecomposition of theCommittee
likelywouldbechangedtoincludephar- labeled fibrinogen is unsuitable for imaging, the thought to b e a site for the trapping of lympho-
agent of choice might be 1311-labeledfibrinogen Example 9. cytes, since the patient is lymphocyte depleted.
macologists and toxicologists (14). Advantages
of such a change migh! include (a) the prelimi- or ”’ln-labeled platelets. Assume thatI3’I-la-
beled fibrinogen is selected as the agent for this Can a??approved I-adiophart~lnceuricai admin- How is ihis siruatiorr best handled?
nary testing of the new drugentity in a very
study. isiered via one roolire be administered by another Answer:There are over 400 INDs for leuko-
small number of humans prior to the submission
of an IND, (b) speeding up theresearch pro- ruufefor an unapproved indication? cytes, and to date, it appears to be safe. Because
Is rhe s t d y investigafional? Afler d l , slrrgical Answer: Yes, undercertaincircumstances. By lymphocytes are part of the leukocyte popula-
cess,sincein-house communication could be
cuffs are used roufinely anyway. law, indicationscanbeadded to thepackage tion, in this case,safety would not be anex-
faster than communication with the FDA, and
Answer: Yes, this is a bona fide study in which inserts when the safe and effective use of that pected problem.
(c)possiblyIessinformationrequired bythe
pat~entsare randomly entered. indication has been proven by datasubmitted Since the IND application has been filed, one
RDRC than would be submitted in an IND.
for evaluation. If the holder of a radiopharma- can simply submit an amendment to the present
A subcommittee of the FDA Radiopharma-
Does otle need to file an IND, since ’3ii-labeled ceutical NDA does not submit a request for a IND, i.e., a new study protocol for one of the
ceutical Drug Advisory Committee chaired by
fibrinogen has been reported to be used fur this new indication,the FDA cannotarbitrarily active agents in a previously filed IND. Since
H. William Strauss has been appointed to exam-
purpose in the literature? Use of 131i is merely placea new indication inlo the package insert this is a drug entity which appears to be safe, is
ine whether or not the role of the RDRC should
&e sdxritufiutt of one radioacfivesrrbsfmtcefor withoutadequate data tosupportthespecific suspected of being effective, and is for the man-
beexpanded to include theresponsibility of
another ( i . e . , for 1251}. indication. agement of a particularpatient, however,the
permitting theinvestigation of new chemical
Answer: Fibrinogen (labeled with Iz5I) has been An independent group or even an individual nuclearmedicinediagnosticstudyreallyfalls
entities (14). This subcommittee could recom-
found to be sale and effective for detection (but citizen may act to amendthe indication of a under the practice of medicine and pharmacy
mend that the RadiopharmaceuticalDrug Ad-
not imaging, per se)of DVT. I f the radionuclide drug by petition after a thorough search of the such that an IND wouid not be required. None-
visory Committee proposea change in the regu-
is used in trace quantity, any of several radionu- literature. The Radippharmaceutical Drug Ad- theless, had one nor already had an IND filed
lations which would allow fortheexpanded
role. Nonetheless, it is up to the FDAto ap- clidescouldpotentiallybe substituted asthe visoryCommitteeusually is involved inthe for]l1ln-oxine, one would haveconsiderable
tracer, and the resulting compoundcouldbe process (3, 4, 14). During1984, the FDA ap- difficulty in obtaining L1lln-oxine from any of
prove of the expandedrole. It is exactly this
investigated as an imaging agent. One is cau- proved new indicationsforthreewidely used the manufacturers in order to label the lympho-
particular impasse which represents the crux of
372 I Esserriials of Nuclear MedicineScierlce Considerairons in Physician-sponsored IND Application I 373

cytes. (Note: lllIn-oxine forlabeling autologous ( f ) Secretarialcharge for typingpatient re- 2. Department of HealthandHuman Services: General ring Form FDA 1571. A Notice of Claimed Inwstiga-
leukocytes is now approved by the FDA.) ports. Comiderations fur rhe Ciirlicul Evaluation of Drugs, lions! Exemption for a New Drug, by an Irldividual
This brings up the subjecl of the emergency (g) Review and analysis of the entire projecl by HHS (FDA) 77-3040. WashingLon DC, UnitedStales Plzysician Investigntor (Investigational New Drug Ap-
(compassionate) IND. In those circumstancesin the investigators and the collaborative per- GovernmentPrinting Office. 1977 plication), FDA, Document Control Section HFD-106,
3. Siege1 BA: Radiopharmaceuticals and F D A a clini- New DrugEvaluation. Rockville,MD. Bureau of
which a specific patient requires diagnosis and/ sonnel.
clan's perspective. Medlrlsrrnmenr 15:355-360, 1981. Drugs, 1982.
or treatment, the 30-day evaluation period can (11)Ordering,receipt,wipetesting,and other 4 . Siege1 EA: Radiopharmaceuticals and FDA a clini- 10. Department oTHealth and Human Services: TND Medi-
be waived by direct contact (telephone) between radiation control practices. cian's perspective. J Nucl Med Techno1 1 I:177-186, cal Review Guidelines, Guide BD 4831 . I AtLachmenl
the physician and the medical director (or his or (i) Preparation and review of the informed con- 1983, A. Washington DC. FDA Internal Document, 1980.
her representative) of the FDA. Specific clinical sentstatement.(Howdo you chargefor 5 . News and Comment: Indusmyairs grievances over 1 1 . Temple R: Govemmenlviewpoint of clinical trials.
FDA's NDA review process. Am Pharm NS23:8, 1983. Drfrg Inform J 16:lO-17, 1982.
circumstances and justification for the investi- committee time?)
6. Bennett LR: Where are the costs of radiopharmaceuti- 12. Food andDrug Administration: P a r t 3hl"hescription
gational study are required. The compassionate (j) Preparation and submission of the IND ap- cals leading us? Editorial. Appf Rndio! 12:73, 1983. drugs human use generally recognized as safe and ef-
IND process might be appropriate (if the proc- plication, if required, 7. Lipton J: The State of Nuclear Medicine: AnIndustry fective and no1 misbranded: drugs used in research.Fed
ess is not abused) when recognizingthe large (k) Service contracts on the equipment used- Perspective. An address given to Amencan College ol Reg 21:155-160, April 1982.
commirment of time and manpower in the proc- Ibrinator,dosecalibrator,Geiger-Miilier Nuclear Physicians.September 24, 1983. 13. FoodandDrug Administration: 21 CFR Part 310.3.
8 . Department of Health and Human Services: Clinical definition and interpretation. Fed Reg, 1983.
ess of preparing the IND application. Certainly, counters.
Tesring for Safe and Effective Drugs (revised), HHS 14. Callahan RI: Reporc of the Government RelatlonsCom-
there are many occasions in which thephysician (L) Indirect costs-heat, light,electricity, ad- (FDA) 74-3015. Washington DC, UnitedStates Gov- mittee. Radiophorm Sci Council Newslerr 9-10, Fall
investigalorsimply lacks theforebearancere- ministrative staff (accounting, etc.). ernmen!Printing Office, 1981. 1983.
quired to go throughthe lengthyprocess and (m)Supplies(syringes,needles,gloves, pad- 9 . h o dand D N Administration:
~ lnsrrucrionsfor Snbmir-
seltles for what may or may not be a less spe- ding, markers, etc.).
cific or less sensitive form of diagnosis or treat- (n)Conlracteddecontamination(radiation
ment. safety) services, in the event of a spill.
Answer: With regard to irein a , the charge €or
Example 11. A community-based hospital's de- thedrug, the sponsor wouldhave toobtain
partments of nuclear medicine and surgery are permission from the FDA in order to charge the
conducting a cooperative study to evaluale the investigatorfortheinvestigationaldrug. In
effect of a surgical cuff on cIot formation in the practice, it is unlikely that such permission
mated leg, with the contralateral leg used as a would be forthcoming, since it does not appear
control. Patients are randomly placed into to be proper to charge an investigalorfor an
groupsreceivingthesurgicalcuff,drugs, experimental drug. Thesame is true for the
placebo, or nothing. shippinganddeliverycharges (ifem b), since
these are generally considered par1 of the radio-
Which of Ihe followirzg con~ponentsrepresents a pharmaceulicaldrugcost. However, lhe FDA
r e c o w v of actrtal costs imlohvd ill conducting hasno regulalions that preventthephysician
this study? investigator from chargingthe patient for the
(a) Purchase of 1251-labeledfibrinogen (with a investigational drug or any related services.
cost of X dollars per kit of five doses). Likewise, the pharmacist who is compounding
Note: Whatwouldhappen if only four or preparing the pharmaceutical can charge the
doses are used prior to expiration of patient forservicesrendered. In olherwords,
thekit? Do fourpeopledividethe with respect to items a-11, the FDA takes no
charge for five doses? official position as to what the investigator can
(b)Shippinganddeliverychargesfromthe charge the patient in a clinical study. Since the
manufacturer. FDA takes no position in these areas, the bot-
(c) Radiopharmacy time for preparation of the tom line for a charge to a patient is a matter of
dose, including assay, quality conlrol, and conscience and appropriateness.
dispensing.
HEFERENCES
(d) Tcchnologist and hospilal fee for conduct-
1 , Departmen1 of Health and Human Services: Grridelirlrs
ing the study.
foor rhe Clruicnl E t d u a t i o n of Radio~~harrr~acerrtical
(e) Physician's component for interpreting the Drugs (revised), HHS (FDA) 81-3120. Washington
study. DC, United States Government Prinling Office. 1981,
 Form Approved: 0,WB No, 091 0.0014 lakc lhc phase 01 the Ins'esllgalion oullined in section 10 of [he "Nollce review and approval u i the proposed clinical study. The sponsor must
DEPAATMENT OF H E A L T H AND HUMAN SERVICES of ClaimedInvcrligallonaiExemption lor a New Drug." (In cruciat
PUBLIC HEALTH SERVICE Expworion Dore: Febmory 29, 1984. also pronde assuritnce thal t h e inrestlgalors will report l o thc IRB all
F O O D A N 0 D R U G ADMINISTRATION
sltualions,phase 3 investigators may be addedand thls iorm supple. cllanges in lhe research adiwt? and all unanticipated problenls mvotv-
~nentcdbyrapidcommunicationmethods, and thesigned Form FD- Ins risks 10 human subjects or olhers. and that the investigators LviU not
1573 shall bc abtaincd promptly lhereaflcr.) make ani' changes in the rescarcll without IRB approval, ehcepl u,llcrc
10. An uuthne o i any phase or phases of the planned mverllgalions necessaw to elimmalcapparcntimrncdlale hazard l o thc bumansub-
and 2 descripllan 01 the mstit~t~onal rwlew commillcc. as follows jects. FDA will regzrd lhe r i v i n g o i l h e Form FDA 1571 ar providing
a. Cllnical pharmacology. Thls 15 ordmarily dlmded Into two phases: the necessary ~ P S U I ~ C Cabovc.
E
Phasc 1 startswhen fhe new drug is i i i s t introduccd Inlo man - only (The n o l m or claimedinvesligallonalckernptlon may be llmlted
I an~maland In virro data a e available - with thc purpose of delermining lo any one or more phases.provrdcd the outline o i the additional
human toxicity, metabohsm, absorption, ellmination. and other phar- phase or phases is submilled bclorc such addltianalpl~asesbegm A
macological action, prcicncd mule o i admmistratlon. and safc dosage limitalion on anewmpliondocs no1 preclude conlinuing a sublccl
Date Name of Sponsor rdngc; phasc 2 covers [he initlal trials on a limited number o i patlenrs o n lhe drug irom pliarc 2 to phase 3 wthout mlcnuption while the
ior specific diseasc control or propllylaxls purposes A generaloutltne plan ior pthase 3 LS being dere1oped.l
Telephone ( ) of lhese phases shall be subrnltled, rdentiiying the Investigator 01 Invest-
Address Ordmarliy. a plan l o r clinical mal wlll no1 be regarded as rcasonable
rgalors, l h e hospilds 01 mcarch lacililies where the clln~calp11~~n1d- unless, among other things. i t prorldeh lor more than one mdependenl
cology ~ w l lbe undertaken.any elplrt commlllels or panels lo be compelen1 inresllgalor l o m a i n t a r adequate case hislorm o i a n >de
Name of Investigational Drug utilizcd, the mavlrnurn number of subjects lo be involvzd. and the esti- quatc number o i sub~ccls. desgned lo record observations and prrmli
maled duration oi thcse earl) phases of invcst~gatlon. hlodifical~on or eYaluation o i any and aU disccrnlble clTcr.1~ allrlbulablcto lhc drug in
FOR A DRUG: FOR A BIOLOGIC: the erpcrimcnii design onthe basls o i enperlence gamed need be wch indiridual trcatcd, and comparable records on any mdirulualr
Jeporled only in lhe propers reports on time early phases, 01 In lhc employed ar conl~ols.These records shall be mdkv#duhl rccords lor car11
Food And Administration
Drug
andFood Drug Administration development a i the plan Tor lhe chn~caltrial, phase 3. Thc l i n t two subject maintained l o Include adcquate inio11natio11llerlainlnp 10 coch.
Office of New Drug Evaluation (HEW-106) Office of BioIogics(HF-823/ pharcr ma? overlap and, \when indicaled, ma). requuc addlllonalanhmal lncludrng a p . sek. condlrmnr m a t e d , doragc. ircqucncy o f atlnlinprtra
8800 Rockville Pike d a b befoorc rhesc phases can be completed or phase can bc undcrtaken. lmn 01 Ibe drug, resulls 01 all relcmnl clniical obrerrallonr and labora
5600 Fishers Lane Such anlmaltests shall be dcslgned l o lakc Into accmnl Ihc expected tory exdmmatlonsmade, adequateiniormarlon concernan? a n ? o l l ~ c r
Rockville,Maryland 20857 BeLhesda,Maryland 30205 durarlllon o i admmirtrallon 01 the drug l o human beings, the age groupa lrcatmecll g n e n and a full slalernent 01 any advcrse eirecls and ureiul
and physical slatus, as lor example,Incants,pregnant women, pre- resulls observed, together wlth an oplnion ar lo whcther ~ u c hc i i c c l s
menopausal twomen, o i those human beings to whom Ihe drug may be or IcsuIls a r e attributable to lhe drug undcr mvestigailon.
Dear Sir: adminislcred. unless thrs h x alrcadl; bscn done ~n thc orimnal animal 11. A stalemen1 lhat the sponsor w i l l noliiythc Food and Vrug
sludies. If a drug 1s a radioactive drug, the clln~calpharnlacology phase Adminlsualion ~f the inrestlgallon IS d~sconlinued.and t l ~ c reason
must mcludc rlrrdies which WIU obtam sulficientdala io! dosimerry rlwcior
calculal~ons.l h c s c sludies should cvaIualc lhe excretion. whole bod? 12. A slalenwnl lllal IIlc rponmr 11111 notlfy each investigator !r
relelltlon, and organ distribullon o f l h c radloactivc malerial. B ncwdrug applicarhon 1s approved, ur if the Invesliprwn is dmoll-
b. Clinical trial. This phasc 3 provider the a s ~ e s r n r n l01 the drug's lmued
A Ltached herelo in triplicate are: saicty and eflcct~rencssand optilnum dosagc rchedules in l h e dmgnosis. is 10 be sold. a fuU chplrnation why sale II rtqulrcd
13. l l l t l r u r u ~
bcatmcnl. or prophylaxis oigroups oisubJeclr mi*olvmg a givcn dlsease and should no1 be regarded as the comnlercralization o i a new orug lor
or condillon. A reasonable protocol IS developed on lhe basis 01 llle whicll an appilcallon is nol approved.
1. The bcsl available descrlpllue name oi rhc drug, including l o the b . I i the drug has been markeled commerclally or Invesllgalcd (e.: iactsaccuniulaled in thcearherphases, mcludmg completed and sub 14 A stalclncnttl>al thc sponsor assurer that cilnlcal 5lud1cr I"
exlent known lhe chem~cal name and slructum o i any newdrug rub. outside Ihe Urutcd Slalcr), complete iniormalaon about such drstrzbu rnbttedanimal studiesThls plmc IS conducted b y reparatc groups io1 humans will not bc initlaled pr!or In 30 days after t l ~ cd a w o i recclpl
S~IIICE. and a stalcmcnl 01h o w i t is l o be adminirtcred. (lithe drug has Lion or investigatlon shall bc submllled, along with a conlplrtc b ~ b l ~ louving tliesame prorocol (nllh rcaronablelarlillions and allcmatlves o l the nuliw by l h c 1-ood and Drug Admmlrlratlon and lhal Ihc \vi[[
only a coda nanlc,enough Intormallon should be supphed to Idenlily ogIaphy o i a n y publicar~ons aboulthc drug. perrn~tledby the plan) l o produce weU-con1rolled clinical d a h Far IhLr continue 10 wllhhold or IO reslrlct clinical rtudles [I rcqucrlcd 10 do 1"
thc drug.) c . 11 t h e drug is a cornblnallon oi prevlourly mwthgaltd 01 m a r
phase. the following dam shall be submltred: by [ha r o o d and Drug Admmirtrallon prlor 10 Ill? cxpralion o l such
2. Complete iisl of componenlr oi the drug, mcluding any reason- keteddrugs, an adequalc rummar? o i preexLrling mformalion 110111 I. The names and addresses oi the invcrlgalorr. (Addlt!onal mvati 30 days. I1 such requesl IS made. lhcsponsor ail1 be providd rpccillc
abic allcrnatcs for inactivc componcntr. preclinical and clmcal lnvesugationsand cxper~cncc\vi111 ~ t scompo galors may bc added.) rniormatlon ar IO Ihe deliclcncler and will be allorded a conrcrcncc on
3 Complete statement of quantitative composillon oldrug, includ- nents,includmg all reports arallablc to thc sponsor ruggcrting rid? Mi. Thc spccific nature or the mvesliptlonP l o be conduclcd. t o rcquert. Thc 30 daydclar maybc waned by lhc Food and Urug
mg rearonable rariallonsthat may be expectedduIing the illucstiga- en'ecrs. conlralndications,andineifecl~vcncss In us? 01 such compo gclher rvilh inlormallon or caw ICIIOII forms 10 shew thc scope and Adrnmistratron upon a stlowng of good reason loor such w a ~ v c r :aud
tional s l q e nsnts. Such summary should includc an adequale bibliography 01 detail o i the planned clinical obscnarlons and tllc c l m ~ c dlaboratory lor lnvcatgallons SubJecl 10 Inrulutional rerxw commlllecapproual
4. Dcrcription o i sourceandprcparalion oi. any ncu'.drug sub publications aboul the cornponenls and may incorporate by relcrencr tests l o be made and reporlcZ as described 111 ~lemtOc abovc, andaddilionnl s t a l e n m l assuring lhal
stances used as components.including rhe name and address o i each anyinlorrnatlonooncernmgsuchcornponcnrr previously rubrnured ili The approximarc number ui rubjcctr l a reanonable range o i Ita? Inrcstigallon >vilL nol bc Inulalcd prior lo apprura oi llw rtudy by
suppl~er01 ~ I O C C S S O ~other
. lhan the sponsor, 01 cach newdrug sub. by rhe sponsor t o the I'ood and Drug Administrauon. lnclude a rM1c subjccls 1s pcmiissrble and addillons map bc mad?). and c n l e n 3 pro such con~n11tlct
slance men1 of lhe expcctcd pharmacological e i k c t s 01 Lhc combinallon. posed l o r sub~mlrelectlon by agc. sex. and coltdzlmn 15 W ~ o nrcqucblcd b y the agcnry, a l l eI1vmwncntaI 11111111'1
5 , A slatcrnent o f lhc methods. lacililics. and cont10lr used ioor the d. If the drug is a radioacuw drug, sulrjclent d a b must be availablr 1%'. The estimatedduraflon of lhc clmicill l r i d 2nd themtcnak. anatvrlr rcporl pursuant 10 5 2 5 . 1 olrh~5chap1cr
manulailurmg, proccrsmg. and packing o i lhc new drug l o cslablirh h o r n srumd studies or prcwous human sludes 10 alio\v a reasonabl! m t chcccdulg 1 year. a1 w h l h propess reports rhoumg the results of 16. A s i a l c m c n l l h d t all ~nun~lrnlcallaboratory rludlcr h a m b r r n
and maintaln approprlalc standards oi idcnllty, strcngth qualily, and calculation a i radiation absorbed dose upon admmislral~on to a humm the lnvcsll~rllonss r U be submitted t o lhe Food and Drug Admmlstrd- or \will be, canduclcd In complinncc will1 the good Inboraton pracl~cc
punty as nccdcd lor saiety and to give sipilicance l o clinlcal invcsliga- being. tion regulahons re1 iortll hn Part 5 8 oi 1111s chaplcr, 01, ~ i s u c hqtudirh h n w
tlons niodc w t h the drug. 7 . A t o t a l (one ~n each o i lhelhrcecopies o i thenollcel 01 ail c. lnstilulional review board (IKB). The sponsor must g ~ v ea s w r 1101 becn conducted 111 complraoce with such i c p u l a b o ~ ~ sa. stalu111~'nt
6 A slatcrnenl covermg all inlormathon available t o thc SponsoI inlormatlonalmaterial,includinglabel and labeling. whlch LS to bk ancc thal an IKH that cornpl~esrwth lhe rcquvemcnts sel iorlh in Part l l ~ dercribcs
l indetail all dillerenccs brlsvccn 1 1 1 ~pracr~ccr UICLI 111
dcrwcd irom preclinical uwestlgalionr and any clinical studies and supplicd 10 each mvesligator: T h ~ shalls mcludc an a c c u ~ a t edercnptron 56 of thls chapter will be responsrblc ior thc mltlal and c o n t ~ ~ ~ u h ~ g conducting lhc;ludy and 1110~ requmd111 the rcpulalmn~.
e q x r l c n c e u,ith lhe drug ar follows. 01 the p r ~ o rInvesligatlonsand evper~enccand ttmr m u l l s perllnenl
a . ndcquateinformat~onaboul thc preclinical invcsllgations, in- lo Lhc saiety and Qosslblc urclulncss oi lhr drug undcr lhe cdndiliow \'cry truly yourr.
cludmg sludies made on Laboratory animals, a n the basis of n,hich the o i the inucsrlgalion. 11 shall not reprcsent lhal the salety or uselulnes
sponsor has concluded lhal it is reasonablysafe Io lnillatc clinical o l the drughas been eslablirhed lor the purposes to be mvesllgaled
investipalionrwilhthedrug:Suchinlormallonshouldmcludeidenti I1 shall describe a l l relevant hazards,conlraindicatlons, side-eUecla.
fication o i lhe person who conducled each inrcstigallon;idcnti~calion and precaulions suggested by prhor mvcstiglionr and cxpcnence wit11
andqualifications of the~ndividualswhocvalualedthe rcsuIls and the drugunder lnvestigalron and related drugs lor thciniormallon
concluded lhatit is reasonably saic 10 mitiale clinical invesllgatlons oiclmcal mvertigalors.
with Ihc drugandaslaternen1 of u-here the investigations were con- 8. The scientific tralnlng and ehpenence consideredapproprlarr
ducted and where the records are available lor mspectlon: and enough by !he sponsor to qualify thc mvcstigalors as sulrable experls l o invesll
detailsaboutthc invesligatgonr to perm,( sclenliiic ILYICW. Thc pre- gate the saiety of lhe drug. bearing in mmd what is known about thr
clinical lnvesllgalions shall no1 bc considered adequale 10 justiiy pharmacologi~al aclion 01' the drug and thc pharc 01 lllc mvcrligational
chnical lcsung U ~ I C S I thcy pre proper altcntlon lo Ihe condillons of propam that is l o be undcrlaken
thc proposcd clinical testing. When lhgs iniormatmn, the outlineo l the 9,The names and a summary of lhe trainlng and cxprrwncc o i
plan o i clinicd pharrnocologl'. 01 anyprogrssrreport on the clinical cach inverllgalor and oi lhe indlvudual charged withmonilor~ngthr
pharmacolugy,indicatcsanecd lor full rcweu' of lhc preclinrcal dala propess or the ~nvcstlgal~on and evaluating the evidencc 01 saicly ancl SPONSOR PEA
l x l o r e a clmical trial is underlaken, Ihe Departmcnl will nolily the eiieclweness oi Ihedrug as i f is receivedfromthe investiptors, 10
sponsor 10 submil l h c cotnplele preclinical data and t o withhold clintcal gclhcru,ilh 3 strlemcnllhal Ihe sponso1 has obtained irom each
INDICATE AUTHORITY
klrls until lhe I ~ Y I C W is conllllcred and lhc sponsor noulred. Thc Uood invesligator a complcled and signed iorm. as provided in subparagrapll
and Urug hdminislratron will bc prcparcd to conier w t h the sponsor (121 or (111 o i this paragraph,andthal the mvestigalor is qualificrl
concerr~ingthis action. by scientific trailung and expcrucncc as an approprlatc experl l o lrndcr (This notice may be amcnrled or r u ] ~ p I c m c ~Troll1
~ ~ e dlime to lime on tlie basis 01 Ihc chlwrlcncc rdincd w ~ t the
h new drug. I'TOPLCSI rcpurrs ~mavI I P l l w i
1 0 updalc ttm noricc.)
ALL NOTICES AND CORRESPONDENCE SHOULD BE SUBMITTED IN TRIPLICATE.

Appendix 23.1-cot11i1zricd
 Considerotions n IND Applicarion I 377
i P~t~~sicinll-spollsor.ed
376 I Essentiols uf NuclearMedicirleScience

5. GENERAL OUTLINE OF T H E PROJECT T O BE U N D E R T A K E N (Modification hpcrmirtcd o n rhc basis of experienccp.in.d wirhovtsdvaocs

DEPARTMENT OF H E A L T H A N 0 H U M A N S E R V I C E S Form Approved: OMB No. 09;0.0015 submission o f 8meodmeofs to the genemi outline, but with Ihe approvai of the r e v i m cornmiflee and upon notificarion of rhs sponsor.)
PUBLlC HEALTH SERVICE
FOOD AND O R U G AOMINISTRATION E x p i r o n o n Dole: December 31. 1984.

STATEMENT OF INVESTIGATOR
(Clinical Pharmacology)

ITE: No drug may be shipped or study initiated unless a completed statement has been received (21 C F R 3 1 2 . I ( a ) ( 1 2 ) )
N A M E OF INVESTIGATOR IPllnrOr T w e )
I: SUPPLIER OF T H E D R U G (Name andaddress. include ZIP Code)

OATE

N A M E OF ORUG

;.THE UNDERSLGNED UNDERSTANDSTHAT THE F O L L O W l N G C O N D I T I O N S G E N E R A L L Y A P P L I C A B L E T O N E W D R U G SFOR

I N V E S T I G A T I O N A L USE G O V E R N H I S R E C E I P T A N 0 USE O F THIS I N V E S T I G A T I O N A L D R U G

a. The sponsor is required to supply the investigator with lull nolified.Upontherequestofascientificallytrainedand

informationconcerningthepreclinicalinvestigationthat specificallyauthorizedemployee of t h eD e p a r t m e n t s. l
justifies clinical pharmacotogy. reasonabletimes,theinvestigator will madesuchrecordr
available lor inspectionandcopying.Thenames o t the
6. The investigator is required to maintain adequate records of subjectsneednothedivulgedunlesstherecords of the
the disposition 01a l l receipts of the drug, including dates, particularsubjectsrequirea more d e t a i l e ds t u d y of the
quantity,andusebysubjects,and il theclinicalpharma. cues. or unless there is reason to believe that the records
cology is suspended,terminated,discontinued, or c o m - do not represent actual studies or do not represent actual
pleted, to return to the sponsor any unused suppty of t h e resultsobtained.
drug. If the investigational drug is s u b j e c t t o l h e C o m p r e -
hensive Drug Abuse Prevention and Control Act or 1970 1. The investigator certifies that the drug will be administered
adequate precautions must be taken, including storage of only to subjects under his personal supervision or u n d e r t h e
the investigational drug in a securely locked, substantially supervision oi thefollowinginvestigatorsresponsibleto
constructed cabinet. or other securely locked, substantia~~y him,
c o n s t r u c t e d e n c l o s u r e a c c e s t o w h i c h is limited, to prevent
theft or diversion of the subslance into illegal channels of
distribution.

c. Theinvestigator is requiredtoprepareandmaintainade-
quate case histories designed lo record all observations and
other data pertinent to the clinical pharmacology.
The investigator assureb that an IRB that complies with the requirements set forth in Part6 6 of this chapter will be res onsible
for the initial and continuing review and approvd 01 the proposed clinical study. The investigator also assures Chat helr!e will d.Theinvestigator is required to furnishhis reports t o t h e
r e p o r i t o t h e IRB all changes in the research activity and all unantici ated problems involving risks to human subjects or others. s p o m r who is responsible lor collecting and evduating the
and that helshe will not make any changes in the research that woulfincrease the risks to human subjects without I R B approval. results,andpresentingpropressreportstotheFoodand
FDA will regard the signingo t t h e F o r m FD 1 5 7 2 as providing the necesary assurances stated above. DrugAdminislrationatappropriateintervals, not exceed-
T H E E S T I M A T E D D U R A T I O N OF THE PROJECT AND THE MAXIMUM NUMBER OF SUBJECTS T H A T W I L L BE I N V O L V E 0
ing 1 year.Anyadverse effe.:t whichmayreasonablyhe
regarded as caused by, or is probabIy caused by, the new-
drug shall be reported to the sponsor promptly: and if lhe
adverse effect is alarming it shall be reported immediately.
An adequate report of the clinical pharmacology should be
furnished to the sponsor shorily after completion.
e. The investigahr shall maintain the records of disposition of
the drug and the case reports dercribed above for a period
of 2 gears following the date the new-drug application is
approved l o r the drug; or if no applicalion is to be filed
or is approveduntil 2 years after the investigation is dis.
continuedand
the
Food and
DrugAdministration so
and that the drug will not be supplied to any other investi-
gator or to any clinic for administration to subjects.
g. T h e investigator certifies that he will inform any patients or
any persons used as controls, or their representatives, that
drugs are being used ior investigational purposes. and will
obtain the consent of the subjeck, or their representatives.
exceptwherethis is notfeasible or> in theinvestigator's
professional judgment, k c o n t r a r y to the best interests of
the subjects.
h. The investigator is r e q u i r e d t o m u r e t h e s p o n s o r t h a l for
investigations suhjcck to an institulional review requirement
under Part 56 of Chis chapter the studies will not be initi-
ated until the institutional review board has reviewed and
approved thestudy.
(Theorganization andprocedure
requirementsforsuchaboardassetforthinPart 56
shouId be explained Lo the investigator by the sponsor.)

Very truly yours,

Name of Invesligator

Address Telephone ( )

DAM FDA 1572 [lo1831 PREVIOUS EDITIONSAREOBSOLETE,

Appendix 23.2-conti11tred
Appcudix 23.2. For F D A 1572: Stalernent of Invesligalor (Clinical Pharmacology).
 378 I Easerzriala of Nuclear Medicine Scierrcr

DEPARTMENT OF H E A L T H A N D H U M A N S E R V I C E S
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
I Form opprovrd;OJIiBNo. 0910-0013
Expirotion Dote: December J I . 1984.
2a. TheinvestlEatorassuresthatan 1RB thatcomplieswith
the requirements scl iorth in Part 56 o i thischapterwillhe
responsible for the initial and continuing review and approval
c.Theinvestigatorisrcquired to prepareandmaintainade-
quate and accuratc case histories designed to rccord
vations and other data pertinent to the invesligalion
all obser-
on each
~

01 theproposed clinical study.Theinvestigator also assures
STATEMENT OF INVESTIGATOR Note: KO drug may be shipped or study mitiatcd unless that hefshe will report to the IRB all changes in the research
a Completed statement has been received activityand all unanticipatedproblemsinvolving risks to
( 2 1 CFR 3 1 2 . 1 ( a ) ( i Z ) ) ~ human sublects or others, and that hclshe will not make any
NAME O F INVESTIGATOR p i n 1 01 Type1 changes in the research that would increase the risks t o h u m a n
TO: SUPPLIER OF DRUG p m e . oddre=, and Zip Code)
subjects wbthout IRB approual. FDA will regardthesigning
o l the Form FDA IS73 as providing the necessary assurances
DATE
stated above.
b. A descriptlon o i any clinrcallaboratoryfacilitiesthat will
be used. (If lhis informatton has been submitted to thc spon-
I sor and reported by him on Form FDA 1571, refercnce to the
Dear S i r : prenous submission will be adequate).
3. The~nvesligaIianr1drug will be lrsed by !he undersigned
or under hls superrision in accordance with rhe plan of invesri-
grtian described as follows. (Ourline the plan ofmvestigalion
including approxifnarion o/ lhe number of subjects 10 be
treated with the drug arzd Ilze number Io be emplayed as COW
trols. if any; clmlcal uses to be inuesrigared: character~~lrcs oj
s ~ b j e c l rby age, sex and condirioll; the kind of clrnical abser-
~ , a r i o ~and
t s laborglary tesls Io be underraken prior fa. durmg,
and o f f e r admznislrarian of the drug: the esrrmated duration
of the inrcst~galian:and a descriptionorcopies a( reporr
[ornls fa be used Io lnoinlain an adequsle record a j rlfe abser-
ua~ronxm d testresulrr obtained. This plan may Include rea.
sonoble alternotes ojrd variatrons and should be supplem~nred
ar arneflded when any sigllificant change in direction orscopc
aJ the #nvesrigotmn IS underrakelz.)
4 . THE UNDERSIGNED UNDERSTANDS THAT THE FOL-
b, POSTGRADUATE MEDICAL OR O T H E R P R O F E S S I O N A L T R A I N I N O . G I V E D A T E S , N A M E S O F I N S T I T U T I O N S , A N D N A T U R E O F T R A I N I N G . LOWING CONDITIONS.
GENERALLY APPLICABLE TO
NEW DRUGS FOR INVESTIGATIONAL USE, GOVERN
HIS RECEIPTSAND USE O F THIS INVESTIGATIONAL
DRUG:
individual Ireated with the drug or employed as a control in
the investigatlon.
d. Theinvestigator is required to furnish tus rcporlstothe
sponsor of the drug who is responsible for collecting and eval-
uating the results obtained by various investigators. The spon-
sor is rcquiredtoprescntprogressreports to theFoodand
DrugAdministrationalappropriateintervalsno1exceedmg
I yearAnyadverseelicct thatmay reasonablybe regarded
as causedby, or probably causedby, the new drug shall be
reportedtothesponsorpromptly, and if theadveneelfecl
is alarming,itshallbereportedImmediately. An adequale
reparl o i the investlgatlon shouId be iurnished to the sponsor
shortly alter completionof the investigation.
e. The investigatorshallmamtaintherecords o l disposltlon
o i the drug and the case histories described above lor a period
of 2yearsfollowingthedateanew-drugapplication IS ap-
provediarthedrug; or if the apptication IS notapproved,
until 2 years after the investigation is dlscontmued. Upon the
requestofasclentlficallytrainedandproperlyaulhorlrcd
employee o i the Department, at reasonable times, the investi-
gator will makesuchrecordsavailableforinspectionand
copying. The subjects’ names need not be divulged unless the
records of particular indivlduals require a more detailed study
a i the cases, or unless therc is reason to beiieve that the rec-
ords do not reprcscnl actual cases studied, or d o not represent
actual results obtamed.
i. The invesligalor certilies that the dmg will be administered
only Lo subjectsunderhispersonalsupervision or under the
supervision 01 thefollowinginvestigatorsresponsibletohim,

a. The sponsor IS required Lo supply the investigator with full

informatlon concerning
the
preclinical
investigations
thal
lustily clinical trials. together w t h iully informatwe matcriat andthatthedrug wlll notbesupplied to anyotherinvesti-
describinganypriorinvestigationsandexperienceandany gator or l a any clinic for administration to subjects.
possiblehazards,cantraindlcations,side-etfects,andprecau-
c. TEACHING O A RESEARCH EXPERIENCE. GIVE DATES, INSTITUTIONS, AND BRIEF DESCRIPTiON OF EXPERIENCE. g. The investigator cerlllies that he will iniorm any sublecrs
tlons to be taken inio account In the course oi the mvestlga-
tion, includingsublectsused a s controls, at theirrepresentatives,
thatdrugs are beingused ior investigationalpurposes,and
b. Thelnvesllgalor 15 requiredtomamtainadequaterecords xm111 obtain the consent oithe sublects. or thcu represcnlauver,
o i the disposltlon o i all receipls oi the drug, mcludmg dates, exceptwherethis IS not feasible or, I n themvestlgator’s pro-
quantitlcs,andusebysubjects,andif the mvcstigatlonis fessionaljudgment,iscontrarytothebeslinterests o i Ihe
termmated, suspended. discontinued, or completed, to return subjects.
la the sponsor any unused supply o i the drug. If the invesli-
galionaldrug is subjecttotheComprehensbveDrugAbuse h.Theinvestigalorisrequired t o assurethesponsorthat lor
frcvenllon and Control Act o i 1970,adequateprecaullons investigatlonssubject t o anmslitutionalreviewrequ~remenr
d. EXPERIENCE IN MEDICAL PRACTICE O R OTHER PROFESSIONAL EXPERIENCE. GIVE OATES, INSTITUTIONAL AFFILIATIONS. NATURE must be takenindudingstorage oi theinvestigatlonaldrug under Part 56 a i thks chapter the studies wdl not be mtiated
OF PRACTICE. O R OTHER PROFESSIONAL EXPERIENCE
In a securetylocked,substantiallyconslructedcabmet, or until the institutional renew board has reviewed and approved
other securely lockedsubstantlallyconstructedenclosure. the study. (The organization and procedure rcquuemcntr tor
access to which is limtled, to prevent thefl or divers~an of the suchaboardas set iorthinPart 5 6 should be explainedto
subslancc into illegal channels o i dirlribution. the investigator by the sponsor.)

Very truly yours,

Name o i Investigam
L REPRESENTATIVE LlST OF P E R T I N E N T M E D I C A L O R OTHER SCIENTIFIC PUBLICATIONS. GlVETITLES O f ARTICLES, NAME OF
PUBLICATIONS AND VOLUME, PAGE NUMBER.A.ND DATE.

Addresr Tclmhone I

Appendix 23.3. Form FDA 1573: Statenlenl of lnvcsligator (Clinical Trials). Appendix 23.3-co1riinued
 380 i Essenrials of Nuclear Medicine Science Considerations in Physicialr-sponsoredIND Applicalion / 381

STAFF MANUAL GUIDE

FOOD AND DRUG ADMINISTRATION i

i
BUREAU OF DRUGS GUIDE BD 4831.1

NEW DRUG EVALUATION

INDlNDA MEDICAL REVIEW GUIDELINES
1. Purpose
2 . Background
3. Objective
4. Responsibility
Attachment A IND Medical Review Guidelines
Atlachmcnt B NDA Medical Review Guidelines

1 , PURPOSE. This guide providesdirection to themedicalofficer for the preparatlon of written review of INDs and NDAs. i

2. BACKGROUND. Before a new drug can be approved lor markeling, it must be established through adequate and well-
controlled clinical trials thal the drug is safe and effective lor its labeled indications lor use. An IND 01 NDA is reviewed by :
at leastthreescientificdisciplines (medicine, pharmacology, andchemistry),and in someinstancesstatisticaland/or ~

microbiologicalreviewsmay also beneeded. The reviewersconstitute a team. and eachdisciplineprovidesitscontribution i

to [he ultimate ins[itul~onaldecision.
1!
Each proposed clinical study presents a medical question of whether the study is “reasonably safe” from what is known
aboutthe drug. Similarly3eachproposal LO market a new drug is a medicalquestion olwhether the safetyandeffectiveness 1i
datadenlonstratethat[hepotentialbenefitsoutwelgh the potentialrisks.Becausetheseultimatedecisions are medical
questions. the medical ofhcer is designated as the leader of the review team.

Each IND and NDA is assigned 10 a rev~ewdivision for review and 8dmin:strative control, The INDs and NDAs in each
division are divided between two to four therapeutic drug groups. Med~calofficers are assigned to a specific therapeutic
drug group (usually on the basis o l expertise). For each drug group a senior medical officer is designated a5 group leader. I
I
Thegroupleaderassigns new lNDs and NDAs to themedicalofficersworking In that group, sets priorities, follows up on I
pendingwork,reviewsandendorsesmedicalreviews for scientific adequacyandconsistencywithbureauandagency
policy.Differences in opinion beween the medicalrewewerand the group leader are discussed.Shouldthedifference in i
~

opinion remain unresolved, the group leader records the basis for his dirference of opmion and recommendation in the file I
for the Division Director’s aclion.

sponsored INDs and NDAs.

GT No. BD 80-23 (8/14180)

oRIGINAToR: New Drug Evaluation
. . . .. Appendix 23.4”continued
 382 I Essenriola o l N l ~ l e a Medicine

BUREAU OF DRUGS
r Science

GUIDE
- BD 4831 .I ATTACHMENT A

a.Pharmacodynamics

sponsor Completed Dale Review

1. (3) Results of human sfudies, if any.

This should be a one page summary of the proposed study analogous to lhe abstracl of a scientific paper. The summary b. Pharmacokinelics
should be inlroduccd by a sentence or LWO classifying the drug, ils intended use, its potenlial clinical advantages, and the
general objective of the study. Thc indication or disease under the study, the type and number of patients, the principal ( 1 ) B l o d leveldatainanimals and humans:
clinical endpoinb being utilized, the typc of controls and other irnporlant characleristicsof the study should be included as
soace and [heir importance p e r m i t s . If the design is complete, a flow c h m or schema of allemalive paths of Ireatment should (a1 Half-life, ifknown(speciesvarialions).
be considered for this summary presentation.

This one page abstract should be suilable to stand alone as a summary of the proposed study and should be on a page by
itself appropriately identified with provisions for !he sponsor's name, date of submission and 1ND number.

An illustration example (places to be filled in are underlined) follows.

This IND proposes LO study the use of (generichrade), a (drug category)), in (symptom. disease, etc.). One (the) submitted
proloco] is for an (e), (controlled. double-blind. single-blind, etc.) study in ( # patients) with (patient characteristics)
10 (specific obicctive of the studv). The principal investigator (appearsldocs not appear 10 be) qualified. (Brief slalemenf
about rationale for study; where it [its in overall investigation. why it is k i n g done, if not obvious).

(a) Generaltoxicotogy;

(b) ReproductionandIoxicology:
etc., as important).
(c) Carcinogenicity

d . Conclusions rafter conference with pharmacologist).

(The secondprotocol . . , .) (1) Special obscrvations needed during clinical studies on Ihc basis olpreclinical findings;

2. GeneralInformation (2) Maximum duration and dosage of dmg administration supponed by preclinical dam

a. Name of drug (3) Funher data or srudies needed (and implications. Le,, may studies proceed while they arebcing oblalrrcri'! Miry
(1) Generic; clinical studies go beyond Phases I or 11 or 111, elc.?).
(2) Proposed tradename;
(3) Chemical (structure optional); 5 . ClinicalBackground

b. Pha~macologicCategory; a. Previous similar human studies and [heir results [including foreign studies).

c.Proposedindicationb); b. Literalure references that are especially appropriate (summarize the dafa lrom each of thcse published reporis)

d . Dosage fomls) and route(s) of administration; c. hportanl Informationfromrelated INDs and NDAs. Thissectionshould he perfinent to sfudy desip,. prc.c;luliolls
necded. elc. II may fhus be very long or very shnrf, depending on the availability of useful data.
e. Relateddrugs.
6. ProposedCllnicalStudies
3. Manuf"cturing Controls ( d e r [o Chemistry Revicw), Lis! any problems with clinicai implications, afkr conkrence with
reviewingchemist.

Appcndix 23.4-co11iinued
 Considerafions in Physician-sponsored IND Application t 385
384 I E s s e d a i s of Nzcciear Medicine Science

i . routine;
(1) 1s the monitor qualified? of animal
ii. special studies performed bccauseor the nature of the drug, the patient population involved, results
studies. etc.;
(2) Is the investigalor qualified?
(c) Indications for removing a patient from study (e.g.,worsening of symptoms, adverse reactions).

(4) Efficacyconsiderations

(a) Clinical and laboratory measurements used to characterize efficacy or comparability;

(b) What degree of difference will be (or was) defined as significant?

(c) Are Ihc proposed endpoints appropriatc?

( 5 ) Results of statistical consultalion. If none was obtained, indicatcat what point in the overall investigationa statistical
consultation wouId be most appropriale.

7 . Summary Statements Regarding the Adequacy of the Protocol

All six should be included. Any may bc elaborated or^ as indicated.

a. The risks of the proposed study (arclare not) acceptable inview of its objectives

b. The risks (arelare not) adequately appreciated.

E. Adequateprecaulions ( d a r e no[)beingtaken

d. PaLients (arelare not) adequately informed through thc informed consent form (Note [hat the regulations do not require
[he investigatoror sponsor to submit an inform4 consent form. If the reviewing division hada particular concern about
a drug for safely reasons, then a copy of the consent form should be requesled).

e. The study objcctives (arelare not) clear and (are/are not) based on a sound rationale.

1. The study protocol (idis not) adequate to provide data that will achieve the study objectives

8. Recommended Regulatory Achon. Oneofthe following should be included. Anymay be elaborated on if the M.O.so
desires. In those cases in which othcr Lhan a standard regulatory action is recommended the rationale should be presented:
records);
iii. others. a. Study may proceedwithoutmcdiiication

b. Study may proceed but would suggest considering the modifications suggested in the deficiency list

c. Study may proceed if deficiencies , . . . are correctcd

(b) Type of exprimenla1 controls (placebo, aclive drug, historical), study design (crossover, randomization), and d. Study maynot proceeduntiltheactiontaken LO correctdeficiencies
measures to eliminate bias (single-blind, double-blind); comment on appropriateness andadequacy Of these
, . . , arereviewedbytheAgency.
procedures;
e. Study may not proceed because repeated attemptsto demonwatc it scientific rationale(or phmacologic effect) have no!
(c) Dosage schedule, durationof use, and route of administration forsludy drug (and placebo,if any): also describe succeeded.
dosage schedule and routc for any othcr drugs thal are admmistered as part of the protocol. Descrik Special
f. Study may not proceed because the serious potential toxicity of the drug outweighs any possible bcncfit.

9. DcfciencylFmblem List. A listing of deficiencics or problems in t h t submitted proloco1 or in the IND itself. They may
indicate a need for required changes in, or additions to, the protocol or for additional studies, clinical or preclinical, that
-
the be carried
mustIND lhat doout.
not On the other
represent hand. problemsldeficiencies
requirements, may lead
al least at the present to suggestions for modifications in the protocol or
lime.
(a) Clinical studies, i.c., history and physical examinations;
Dcficiencieslproblemsshould be clearly,conciselystated and approprialelyreferenced to a particular p i n t in the
(b) Laboratory studies

Appendix 23.4-contirtued Appendix 23.4-continued

 submission. The recommended solution (an additional measurement, a new study, etc.) should be staled if i l is not clearly
implied. Def~crencieslproblems will.be listed verbatim m the letter lo the sponsor. A clear statement Or the implications Ol
the problemtdeficiency should also be included and will also go into the letter to the sponsor. The nine choices below will
cover mosr situations. (Letters are lor in-house use.)

a. This is a suggestion for improving the study burnot a requirement. IV

b. This is a deficlency rhar musl be corrected before an NDA can be approved

c.This IS adeficiencythat must be corrected before Phase Ill studles are started.
Intemctiurts among
d. This is a deficiency lharmusr be corrected before Phase 11 s!udies are started Nuclear Medicine Health
e. This is a deficiency !hat must be correcled before Phase I studies are stmed. Cure Professionals and PQtients
f. This is a deficiency [hat should be correcled during the present study if possiblc but the study may proceed.

p, This is a deficlency that must be corrected during the present srudy (withln- days) or the sludy musl be terminated
(or, alternatively, no new parients may be added, etc.).

h. This is a dericiency that musr be corrected hforc Ihc propobed sludy is slarled but the correction need not be revierccd by
(he Agency before startmg [he study.

i . This is a deficiency that must be corrected and the corrective action reviewed and approved by the Agency before thc
srudy is started.

10. 1ND Review of a Completed Sludy. This revlew would begin with a description of theprotocoland Ihe study objective
(similar to the Resume of the protocol review, above). The srudy would then be rewewedas outlined under the NDA Medical
Revlew Guideline, Seclion 5 a (41 (a) (b) (c) and (d) and 5 b.

GT NO BD 80-23 (8/14/80)
ORIGINATOR:
New Drug Evaluation
Appendix 23.4"coniiaued
 24
Radiopharmaceutical information and
Consultation Services
William B , Hladik 111, Ned Gregorio, Terry L, Braun,
Victor J, Sfathis, arzd James A. Ponto
The need fortraditional drug information has
been evidenced by the growth of drug informa-
tion centers throughout the United States over
the past two decades (1, 2). It generally is ac-
cepted that the provision of druginformalion
services to medical professionals has improved
thequality of patient careas this growth has
occurred (1-4).
Thesuccess of druginformationcentersis
based on the fact that they are prepared to an-
swer a wide range of complex questions from a
variety of medicalspecialities.Generally,the
answers to the questions asked are beyond the
immediate capabilities or resources of the indi-
viduals requesting the informalion. The obvious
advantage of employing the services of a drug
information centeristhatthesefacilities have
access to a large pool of information resources
andare staffedbyindividualswho are we11
trained in retrieving and analyzing literature for
solving clinical problems.
1t certainly would b e convenient for nuclear
medicine professionals to have access to an in-
formation center to which they could refer for
detailed, sophisticated, or perplexing questions.
Unfortunately, tradiiional drug information cen-
ters presently are poorly equipped and ill pre-
paredto deaI with theinformationneeds of
nuclear medicine practitioners. If this is true,
the logical quesiion is: “Why doesn’t someone
in nuclear medicine establish one ormore infor-
mation centers designed to meet the specialized
needs of the field?”
In this chapter, (herefore, we focus our dis-
cussion on:
7 on
1. The nature, scope, anddepth of typical
“drug” or “radiopharmaceutical”informa-
tion questions that arise in nuclear medicine
facilities and
2. Possible approaches for handling andlor pro-
cessing “radiopharmaceutical”information
questions for nuclear medicine, along with
exploration of the feasibility of establishing
a radiopharmaceutical information center.
TYPE OF INFORMATION NEEDED BY
NUCLEAR MEDICINE PROFESSIONALS
For the past several years, the University of
New Mexico (UNM) Radiopharmacyhas of-
feredan informalconsultingservicewhich is
utilized primarily (aIthough not exclusively} by
local nuclear medicine physicians and tech-
nologists as well as by graduates of the UNM
radiopharmacy training program (5). Many in-
dividuals in this latter group work in the cen-
tralized nuclear pharmacy setting and thus rep-
resentmultiplehospitalsnationwide.The
experience of the UNM groupindicates that
information requested by nuclear medicine pro-
fessionals can generally be categorized into the
following nine subject areas:
I. Unusual or rmarrticipaled nuclear medicine
study results
Examples: A . If a patient is placed on hemo-
dialysisafteradministration ol
[67Ga]gaHium citrate, will there be
any effect on the biodistribution of
the radiotracer when the patient is
imaged 6 hours later?
390 t Esssenrials of Nuclear Medicine Science
B . Do hyperthyroidpatientsfre-
quently demonstrate thyroid uptake
of radiotracer on bone scans?
C. Under what circumstances could
apatienthavea normal hepatobil-
iary study with 99mTc-labeleddiiso-
propyI iminodiacetic acid (DISIDA)
and yet on the next day have non-
visualization of rhe Iiver following
administration of 99mTc-Iabeled sul-
fur colloid?
2 . lnrernal radiation dosimetv
Examples: A . What is the radiation dose to the
fetus from 10 mCi of sodium [l3l1]-
iodide administeredtoa woman 2
months pregnant?
B . How soon afterreceiving a 4
mCidose of 99mTc-labeledmac-
roaggragated albumin (MAA) is it
safe to breastfeed?
3. Use of interventional drugs and procedures
in nuclear medicine studies
Exarnpies: A . Whatguidelinesshouldbe fol-
lowed when intravenous dipyrida-
mole is administered in conjunction
with[201Tl]thallousc.hloridefor
myocardial perfusion imaging?
B . Whatdosageregimen of phe-
nobarbital should b e administered to
aninfanlprior to hepatobiliary
imaging in order to assist in the dif-
ferential diagnosis of neonatal jaun-
dice?
4 . Pediatric doses of radiophart~laceuticals
Examples: A . How manyparticles of 99mTc-
MAA should be administered to an
infant 3 months old?
B . Whatdose of sodium [Iz31]-
iodideisappropriatefor a6-year-
old, 23-kg euthyroidpatient in order
to obtaingoodimagequality and
yet keep the radiation dose reasona-
bly low?
5 . Adwrse reactions associated with radio-
pharmaceuticals
Examples: A . AI what point following Ihe ad-
ministration of 99n‘Tc-methylene di-
phosphonate (MDP) is theap-
pearance of a skin rash most likely
to occur?
B . Arealladversereactionsre-
ported for 99mTc-labeled sulfur col-
loid associated with only one manu-
facturer’s product?
6. Reports of clinical studies documenting the
safety and efjicacy of a radiophartnaceutical
for a new indication
Examples: A . To date,hastheinformation
gainedfromlymphoscintigraphy
studies in melanomapatients sig-
nificantly assisted the surgeon?
B . How sensitive and specific is
lhe combination of [201Tl]thallous
chlorideandsodium[”“Tclper-
technetate for the detection of para-
thyroid adenomas?
7. SpeciJc physicochemical,pharmaceutical,
or kine~icproperlies of radioaclive drugs
Examples: A . How quickly is 99mTc-dimercap-
tosuccinic acid (DMSA) cleared
from the blood in apatientwith a
creatinine clearance of 40 mllmin?
B . Havetherebeenanyreported
problems with administralion of so-
dium[1311]iodide in capsularform
rather than in solution?
8 . Formdatiotr,preparation, and quality as-
surance of radiopharmaceuticals
Examples: A . What is the besl thin-layer chro-
matography system for performance
of radiochemicalpuritytesting of
99“T~-DISIDA?
B . From a radionuclidicpurity
standpoint, is it safe to administer
[20’Tl]thallouschloride at 4 days
precalibration?
9. Regulotoq requirements associated with rhe
clinical use of approved and invesiigational
radiopharmaceuticals
Examples: A . Is it necessary to submit an IND
in order to routinely use *Tc-la-
beled suIfur colloid in scrambled
eggs for gastric emptying studies?
B . Does the local Radioactive Drug
Research Committee (RDRC) have
authority to approve research de-
signed to study the biodislribution
of 99mTc-genlamicin in 10 nonnal
volunteers?
Because each of the nine categories is associ-
ated in some way with the preparation or clin-
ical use of radiotracer drugs, inquiries associ-
ated with these topics could logically be called
“radiopharmaceuticalinformation”questions,
which is analogous to the more conventional
term,i.e.,“druginformation”questions.The
former. however, is obviously more appropriate
for [he specialty area of clinical nuclear medi-
cine. Hereafter,the term “radiopharmaceutical
informadon” is used to represent the concept of
information needs in nuclear medicine.
Although challenging, if not puzzling, ques-
lions do arise in each of the nine subject areas,
inquiries perlaining lo unusual or unanticipated
nuclearmedicinestudyresults are, by far, [he
most common.Therefore,exploration
particular area in more detail. so [hat the com-
plexity of the subject can be better appreciakd,
may be worthwhile.
Two principal phenomena may cause unusual
or unanticipaled nuclear medicine study results:
(a) altered biodistribution or biorouting of radio-
p l ~ ~ r n ~ n c e u t i cand
a l s ( b ) miscellaneous tech-
nical artifacts. Multiple underlying factors may
be responsible for these phenomena; some
themorefrequentlyencounteredfactorsare
found in Tables 24.1 and 24.2.
The most difficult part of dealing withun-
usual or unexpectedstudyresults is sorting
Ihrough all the factors that may be responsible
for the occurrence and then pinpointing the
one(s) applicable in a particular case. In other
words, the challenge is to determine the cause
of the observed results in a specific patient. with
the many possibilities kept in mind. Consider
Table 24.1.
Causes of Altered Biodistribution or Biorouting of
Radiopharmaceuticals
Nonradioactive drug therapy
latrogenic trauma (surgery)
Renal dialysis
Radiation therapy
Blood transfusiops
Unexpccted palhophysiologic inlerference
Innppropriatcinjectiontechniques
Radiopl~ar~nnceutical formulation problems
TabIe 24.2.
MiscellaneousTechnical Artifacts
Inappropriate sequencing of studies
Instrumenta~ionfaiiure
Operator error
Patient-induced errors
Other imaging artifacts
the following typical radiopharmaceutical infor-
malionrequests:
1. Radioactivily is visualized in the lungs of a
patient injected with 99mTc-labeled sulfur
colloid.
2.Theliver is clearly observedon a 9 9 n 1 T ~ -
of this
MDP bone scan.
What could have caused the altered radiophar-
maceutical biodislribution paltern in each of
thesecases?The first step in answering this
question is tosearchtheliteramre by utiIizing
variousinformationretrievalsystems (or by
using a database specific for nuclear medicine)
in order to locate those factors that are associ-
of ated with puln~onary accumulation of 99mTc-
labeledsulfurcolloid (Table 24.3) andliver
uptake of 99n‘Tc-labeled boneimagingagents
(Table 24.4). Next,patient dala,technical pa-
rameters, and other case-related information can
be integrakd into the problem-solving process
in order to determine thereason for thelung
uptake of radiocolloid (or liver uptake of 9 9 m T ~ -
MDP) in the case in question. Alternatively,a
compuler program couid be developed Lo di-
rectly interfacelileraturereferences (dalabase)
with case-specific data, thus meshing the pre-
vious two sleps into one.
The provision of radiopharmaceutical infor-
mation should be individualized,i.e., made
specific to the patient, whenever possible. The
feasibility of providing patient-specific
re-
sponses (“output” information) dependslargely
on the quantity and quality of case “input” data
that is received from the caller. This concept is
discussed in more detail later in the chapter.
One should keep-in mind that theliterature
may not be of help in suggesting, identifying, or
subslanlialingthecause of thealtered bio-
distribution in a specific case. If thissituation
392 I Essentials of Nuclear Medici>ge Science Radiopharmaceutical Inforn~arionandConsulration Services I 393

Table 24.4.
Factors Associated with Liver Uptake of Bone Imaging Agents
Factors Refcrenmes

Al+) (aluminum antacids) 33, 58 Cholangiocarcinoma 76

Bacterialendotoxin 19, 24, 45 Liver metastases from:
Malignantlymphoma 20 colon of Adenocarcinoma 62, 70,74,76-78,
Spleen and/or bone marrow transplant 20, 31, 58 98
Intra-abdominalabscesses 19, 58 Adenocarcinoma ol pancreas 65
Advanced breast carcinoma 28 Stomach carcinoma 73
Mucopolysaccharidosis type 11 (Hunter) 30, 58 carcinoma cell Breast carcinoma
Squamous of esophagus 84, 98
Wlciparum malaria 27 adenocarcinomaMucinous of rectum 81
Histiocytosis X 37, 58 79
Liver transplant 31 Malignant melanoma
Variation in colloid preparations (e.g., macroaggregation of the radiopharmaceutical 19, 21, 30, 32, carcinoma
Oat cell of lung 75, 93,
64, 68 97
and other technical factors) 34, 35, 3 9 , 40. Ovariancarcinoma 66, 71
42, 46, 50, 51, 58 Lymphoma 94, 95
Hepatocellular disease, hepatic failure, and/or intrahepatic cholestasis 19, 21, 34, 48, Hepaticnecrosis 62, 67, 86, 88,
49, 58 Amyloidosis 103
Liverangiosarcoma 16
calcification Hypercalcemia, 72
Acule infection superimposed on alcoholic hepalitis 16 68, 69, 71, 79,
Children (? normal finding) 36, 58 81, 87, 96, 99,
Disseminated intravascular coagulation 17, 61 100
Neoplasia(various) 19, 58 Increased quantities of iron in liver: thalassemia major 63
Systemicamyloidosis 18, 43, 5 8 Positioning artifact: spinal “shine through” 62
Intravascular clot 39 Apparent
(due uptake due
Artifaclual to abdominal
to prior waIlcolloid
BmTc-labeled or rib uptakestudy)
sulfur 77
Exogenous reticulaendolhelial syslem stimulants 19, 4 4 , 49 76
Atelectasis(focaluptake) 52 material contrast Elevated serum A1+3
radiographic
Following 82, 89
Trauma 57 85
Hepatoma 58 Specific drug therapy 90, 9 2
Hypercoagulability 58 Probable colloid formation due to:
Infectiousmononucleosis 59 Preparation of kit at alkaline pH
Lassa lever 60 generator
and pH kit
Incompatibility
of of kit
Preparation presence
in of elevatedpH
Al+3 (from generator
eluate) 83 82, 91
77,
Miscellaneous supportive data 22, 23, 25, 26; 80, 82, 102
29, 38, 41, 47, Leukemia IO1
53-56

that by 1985 the volume of information would excellent effort of institutions to provide needed
occurs, important facts or concepts gained from ADVANTAGES OF ESTABLISHING A be between 4 and 7 times what it was ir, 1980 information, it shouldbe realized that these
the case should b e submitted for publication to RADIOPHARMACEUTICAL (6). These statements describe an uncontrolled endeavors are exlremely time consuming. Addi-
afford a broaderbase of information to indi- INFORMATION CENTER and, probably, an unorganized information ex- tionally, as stated at the beginning of the chap-
viduals subsequently searching for data on the plosion and could, logically, lead those who try ter, the answer to the questions are often beyond
same, or a closely related, topic. In his book, Megarrends, author John Nais- to locate or utilize the informationto the conclu- the immediale capabilities or resources of the
Selected radiopharmaceutical information re- bitt states that 6000 to 7000 scienlific articles sion that this resource is more of a hindrance institution itself. One very practical medium to
sources for each of the nine subject areas dis- are written each day (6). This translates into an than a help. Use of this resource will become so effectively andefficientlycontrol information
cussed previously are given in Appendix 24.1. overail increase in scientific and technicalinfor- cumbersome that users will, in increasing num- needs is acentralizedinformationcenter. Ob-
In addition, journals that often include articles mation of 13%/year; at thisrate,thebase of bers, pay to locate the specific information they viously, one person for each nuclear medicine
pertaining to radiopharmaceuticalsandlor nu- infom1ation doubles every 5.5 years. The rate need. facility or oneperson for each metropolitanarea
clear medicine are listed in Appendix 24.2. This soon will jump to perhaps40%/yearbecause Nuclear medicine is a growing medical pro- is no longer a viable approach to processing the
list does not include journals from other medicalnew, more powerful information systems and an fession with a scientificandtechnicalbase information needs of the nuclear medicine com-
specialties (e.g., cardiology,gastroenterology, increasingnumber of scientislswillbe avail- about which physicjam, technologists, phar- munity. One solution,to this situation might be
orthopedics) that occasionally may include arti- able. The base of information wilI then double macists, and allied health professionals all have to establish anationwide center or several re-
cles relevant to nuclear medicine. every 20 months. In 1982, Naisbittpredicted questions andinformation needs.Despitethe gional, but strategically located, infomation
394 f Essmrirrls of N,rrcleor Arlcdirirre Science
centers to serve all nuclear medicine facilities.
Another solulion might be IO form a network of
information centers, each of which specializes
in one or more of the nine information subjecl
areas previously described. A logical name for
thesefacilitiesmight be“radiopharmaceutical
information centers” (RPlC).
During the following discussion of the advan-
tages of establishing an RPIC, many paral-
lelisms between the traditional drug information
cenler and the proposed RPlC are evident.
1. Qunl$ed Staff
The staff of h e RPIC should be familiarwith
traditional sources of medical informalion aboul
nonradioactive drugs as we11 as diagnostic and
therapeutic radiopharmaceuticals. In addilion,
the staff members should be experts on the
conknl and use of exisling dalabasesandre-
trieval systems.
2 . RapidAccess tu Cur-renr Literature and
Other Resources
A completelibrary of books and access to
majorjournals in nuclear medicineshouldbe
available. Reference material such as [hat listed
in Appendices 24.1 and 24.2 shouldbecon-
tinuallyexpandedandupdatedto enable the
staff to efficiently locate and retrieve inforrna-
tion,
3 . Quality Assurallce of Radiuphal-lllnceutical
I~~$orm~~iior~
Thecenler couldrespondto questionsby
verbal andlor written responses as deemed ap-
propriate. The responses thal the center would
give lo callers could be critically evaluated by
use of melhods commonly employed by tradi-
tional drug information centers to ensure qual-
ily, accuracy, and timeliness.
4 . Clearillglrouse fur INDs
The RPIC could coordinate the establishment
of a bank of investigational protocols accessible
to all facilities. Many nuclear medicine depart-
mentsbecomeinvolvedwithinvestigational
procedures and INDs much in advance of subse-
quent Food and Drug AdminisIration (FDA) ap-
proval. The most recenl example is ”’In-labeled
leukocyles. As a specialservice:the RPlC
could bank all INDs voluntarily submitled to the
cenler and arrangc for distribulion to interested
partics.
5. Cowulring Experfise in Troubleshooting U I Z -
~~slral Scan Resrtlrs
As discussed previously, nuclear medicine
personnel quite frequently inquire about the cir-
cumslances responsible for unexpectedstudy
results,i.e., unusual radiotracerlocalization.
The center should be uniquely qualified 10 lo-
cate the specific information needed in order to
systematically determine the camels) of unan-
ticipated or unusual radiopharmaceutical bio-
routing.
6. Capability of Expanding into Ofher Areas os
Radiology
Withonlyslightmodification.[he RPIC
could be equipped to provide information on all
drugs and related medicinals used in radiology.
including not only radiopharmaceuticals for nu-
clear medicine but also contrast agents for diag-
nostic radiology, new compounds in ultrasound,
and magnelophamaceuticals for magnetic reso-
nance imaging studies.
7. Copabiiiy of Developing R Database Spe-
cific to Nuclear Medicitte ( o r Diagnostic
Imaging)
Over a period of time, the logical goal of the
RPIC staff might be to coordinate the establish-
ment of a searchable, on-line database, to in-
clude literature that is specific for nuclear medi-
cineand/or the enliregamut of diagnostic
imaging modalities. The significance of this
proposed projecr stems from the fact thal the
existingdatabases, e . g . , MEDLINE, do no1
index articles from all of the journals thal pub-
l i s hi n f o r m a t i o no nn u c l e a rm e d i c i n e .
MEDLINE,forinstance,indexesonlyaboul
half of the journals listed in Appendix 24.2 (7).
The feasibility of developing this database de-
pends largely on the size and workload of the
RPlC slaff and/or onthe amount of oulside
reviewers that could contribule to the indexing
of informationcontained in the database. This
database,which mighl becalled NUCL-
MEDLINE or RADIOLINE, could be accessi-
ble to users nationwideon a subscription basis,
in a manner similar to other databases.
8 . Commierli Access to the Itfortnotiorl Center
The center should be accessible by a toll free
telephonenumberduringnormalbusiness
hours. During nonbusiness hours and week-
ends, a messageserviceshouldbe available.
Radiopharrnaceuricai IrIformatiorl
EVOLVING CONCEPTS IN NUCLEAR
MEDICINE RELEVANT TO
ESTABLISHMENT OF AN RPIC
Hospitals have been perceived by the general
public, as well as by the government, as being
profit motivated. This perception is no illusion,
as hospilals have consistently shown profit and
revenue increases year after year. Moreover, be-
cause hospitals generallywere no1 held account-
able for their expenses, here was no motivation
for them to becostefficientundertheold
method of governmental reimbursement (8). It
became apparent lhal the third party reimburse-
ment method was obsolete; as a result, the pov-
ernment decided to make a radical change. Pro-
spective payment, the method currently used by
[he govemmenl, is a flat rate set in advance of
care based on a diagnosis-related group (DRG)
(X, 9). The prospeclive payment method will be
expanded in the fulure to include all payors and
providers. Obviously, the era of prospective
payment will be an ever-present reality for hos-
piialsto cope with in their efforl to remain
profitable.
A majoractivityevident in all hospital de-
parlmenls is the task of defining strategies that
can be employed in order lo economically func-
lion below the flat rate provided undereach
DRG. Controlling COSIS, increasing productiv-
ity, and utilizing resources effectively are three
main methods used (10).Thefollowingcon-
cepls, which could have a large impacl on sup-
plementing these activities or methods, deserve
to be considered by nuclearmedicine practi-
tioners.
The firstconcept is thereemphasis of the
diagnostic imager as a true consultant (9, 1 I).
Undemanding the role that nuclearmedicine
plays in a patient’s therapeuticand diagnostic
management, coupled with the abiIity to com-
municatethisinformation to referringphysi-
cians, will enhance the proper utilization of this
diagnosticimaging modality. Eventually, peer
review organizations will be established to look
explicilly aithe utilization of various imaging
procedures. In addition, they will also review
the validity of patient diagnosis and monitor the
quality of care received ( I 0). The decisions that
the diagnostic imager will make, based on the
and Consultation Services / 395
nuclear medicine study, may alter, confirm, or
further clarify the patient’s managemenl. In
compiex clinical situations, information pro-
vided by the RPIC may significanlly add to the
overall data required by the physician in orderto
make appropriate diagnostic decisions.
Thesecondconcept i s concerned with im-
proving the efficiency of performing a nuclear
medicinestudy (9). Efficiency, in this sense,
can be defined as the fastesl progression of the
patientthrough thediagnosticprocedure.One
approach to increase efficiency is through the
prospective screening of patient data in order to
identify any problems that mayinterfere with
the procedure, thus causingmisdiagnosesor
unnecessary delays, costs, or exposure to radia-
tion.Computerization of patienl medicaldata
should allow professionals to rapidly search for
factors that may (a) indicate inappropriate use or
sequencing of diagnostic tests, (b) preclude a
patient from undergoing a particularnuclear
medicine procedure, or (c) interfere with inter-
pretation of study results (12).
Certaindiseases,medications,or invasive
medical procedures are known to alter biorout-
ing of radiopharmaceuticals, thus causing con-
fusion for the nuclear medicine physician. For
example,propranolol, a drug commonly used
in patients with cardiac disease, improves myo-
cardial blood flow to ischemic areas. By virtue
of this hemodynamiceffect, propanol01 has
beenreported to reduce the sensitivity of
[201Tl]thallous chloride imaging by masking un-
derlyingcoronaryartery
disease (13, 14).
Therefore, it is obvious that the diagnostician
should be aware of all medications(and other
faclors) thal may interfere with, or complicate,
the outcome of the study. In thisregard, the
RPIC could distributeinformation to be used in
writing or updatingcomputerprogramsde-
signed to scanthe patient’smedicaldalabase
andflag factors that maychangetheentire
course of the procedure or alter the study re-
sults.
These two concepts are provided to show how
nuclearmedicinecanslrengthen its financial
position under prospective payment through the
establishment of an RPIC. Ideally, each facility
would have the motivalion and qualified person-
nel IO aid the physician in solving problematic
396 t Essenrials of Nuclear Medicine Science
patient cases before, during, and after the pro-
cedure; presently, this very often does not occur.
The RPIC could bean ideal mechanism through
which these evolving concepts, discussed pre-
viously, could materialize.
OPERATIONAL ASPECTS OF THE
RPIC: IMPORTANCE OF QUALITY
ASSURANCE
On a daily basis, the RPIC would undoubt-
edly receive numerous inquiries from a variety
of callers. The operation of the W I C would be
dependent on the acquisition of complete input
data and the provision of accurate and thorough
output data. Therefore, the quality of both input
information and oulput infomation would have
to be continually evaluated by the RPIC. Input
information is the data extracted from the caller
that is required in order to formulate a patient-
specific answer to the inquiry. To retrieve appro-
priateliteratureresources by use of the estab-
lished computer database, it is necessary lo
know [he enlire set of circumstances associated
withthe case in question. It would be the re-
sponsibility of the RPIC staff to, ensure that all
pertinent facts are obtained before its members
attemptto formulate aresponse. A computer
program that prompts RPIC staff members to
ask the caller questions that will facilitate the
gathering of all essentia1 factscould be em-
ployed to assure the qualityand conlpleteness of
input data. This type of interaction with use of
both open-ended and directed questions would
enable the caller to reflect on factors concerning
[he patieni andanytechnical information not
immediately obvious to him.
The RPICshould be able to provide objective
evalualion of the responses (outpul data) given
to callers.Some key poinls to consider with
respect lo theinformationto beprovidedin-
clude the following:
1 . In most cases, [he RPIC should be able to
answer patient-specific questions adequately
by cornpuler-assisted retrieval of archived
literature citings and previous consullations
or through logical deduction.
2 . The RPIC should be abIe to evaluate quickly
the verbal and written responses with regard
LO completeness, accuracy, appropriateness,
and caller satisfaction. Within a reasonable
lime, the responses could also be evaluated
for timeliness as well as clinical and finan-
cial impact through a feedback mechanism
arranged with the caller.
A review of the quality assurancemethods
used by traditional drug information centers
provides useful information fordeveloping a
similar quality assurance program for theRPIC
(15). As expected,theseprograms are estab-
lished lo ensure quality radiopharmaceutical in-
formationand to identify andsolveproblems
associated with provision of this information.
Onepossiblemeanstoaccomplishthis task
would be through the formation of a committee
consisting of various nuclear medicine profes-
sionals who would review information provided
by the RPIC on a regularly scheduled basis.
SUMMARY
In this chapter, the information needs of the
nuclear medicine communityare discussed, and
a workable and efficient approach io handling
these informalion needs is suggested. Specifi-
cally, the establishment of an RPIC andlor the
development of an on-line database might pro-
vide nuclear medicine professionals with infor-
mation needed to answer important clinical or
research questions. Providing radiopharmaceu-
tical information by use of the same methods as
lradilional drug information centers should have
a positive impacton nuclearmedicine, both
clinically and financially.
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Med 5:299-301. 1980.
65. Ghaed N, Marsden RI: Accurntrlaiion of Tc-99m di-
phosphonare i n hepatlcneoplasm. R a d i o l o g y
126:192, 1978.
66. Debois J M : Uptake of Tc-99111 diphosphonate in liver
metastasis of an ovarian carcinoma. Eur J Nucl Med
4273-275. 1981.
67. LyonsKP,Kuperus J. Green HW: Locallzalion of
Tc-99mpyrophosphate in !he liverdue Lo massive
liver necrosis: case report. J Nucl M e d 18:550-552.
1977
68. Oren VO, Uszler JM: Livermetastases of oat cell
carcmoma of lung dclected on the Tc-99m diphospho-
nate bone scan, Clir~A ' d Med 3:355-358. 1978.
09. Dudezak R . Anfelberger P, Kletter K , el al: Translent
accumulation of Tc-99m MDP in the liver.Efrr J Nrrd
Med 5:189-191, 1980.
70. Garcia AC.Yeh SDJ, Benua RS: Accumuladon of
bone-seekingradionuclides in h e r metastasis h m
colon carcinoma. Clirz Nrrcl Med 2:265-269, 1977
71.Gates G F Ovariancarcinomaimapedby Tc-99m-
pyrophosphate: case report. J NIfcl Med 1?:29-30,
1976.
72. Vanek JA, Cook SA, BukowsklRM:Hepatic uptake
of Tc-99m-labeled diphosphonale in amyloidosls:
case report. J N m l &fed 18:1086-1088. 1977.
73. Toonam1 N . hlaeda T. Aburano T, el al:Marginal
accumulation of Tc-99m methylene dlphosphonaie In
liver melastasis Tram stomach carcinoma. Euf J N r r d
Mer/ 6:43-45, 1981.
74. Stevens IS. Clark EE. Liver metastasis of colon ade-
nocarcmoma demonstrated on Tc-99m pyrophospllate
bone scan, Clirz Nucl Med 2:270-27 1. 1977.
75.Delong JF. Leonard JC, Allen EW: Casereport:
Tc-99m diphosphonale concentration in a malignant
melanomametastatic to liver. Tram Eqrrilib 6:l,
1977.
cumulation of Tc-99m diphosphonale i n four patients
wilhhepdlic neoplasm: case reporls. J Nncl Med
17:1060-l061.1976.
77.Poulose KP. Reba RC, Eckelman WC, et al: Extra-
osseous locallmiion of Tc-99m-Sn pyrophosphate. Br
J Radio1 48:724-726, 1975.
78. BalachandranS:Localization of Tc-99m-Sn pyro-
phosphate in liver melastasis from carcinoma of
colon. Clirr #vue1 Med 1:165, 1976.
79. Kirby JC, Barlow 3H. DresserTP, et al: Accumulation
or MDP in hepeticmetaslasesfrommucinous ade-
nocarcinoma of the colon, Clin Nucl Med 7:25-27,
1982.
80. Chaudhurl TK: Liveruptake of Tc-99n1diphosphu-
nate. Radiolug 119:485-486,1976.
8 I . Wilklnson R H Jr. Gaedc JT: Concenlration of Tc-99m
melhylene diphosphonate in hepatic melaslases iron)
squamous cell carcinoma. J N d Aged 20303-305,
82. Chaudhuri
1974. TK: The effecl of alummum and pH on
allered body dislribution of Tc-99m EHDP. i r n J ~Vucl 95
Med Biol 3:37-38. 1976.
83. Aldridge RE: Case of the quarter. J NrrclMed Techno1
4:89-90,1976.
84. Baumert IE. Lantieri RL. Homing S . et al: Llver
metastases of breast camnuma detected on Tc-99m
m e t h y l e n ed i p h o s p h o n a t eb o n es c a n .
134:389-391,1980.
85. Cmwford JA. Gumerman LW: Alteralion of body dla-
tributlon of Tc-94mpyrophosphaicbyrddiographlc
conirastmaterial. Clin h ' f d Med 3:305-307. 1978
86. Echevarria RA, Bonanno C. Davrs DK: Uptake of
Tc-9911)pyroplmsphate in livernecrosis. C h A k l
Med 2:322-323. 1977.
87. Fralkin MJ: Hepaticuptake of boneImagingradio-
phammceuticals. ClinNfrcl Med 2286-287. 1977.
88. Hansen S , StadalnikRC: Lwer uptake of Tc-99m
pyrophosphate. Smmh N u d M e d 12:89-91, 1982.
89.Zimmer AM, Pdvel DG: ExperimentalInvestigations
of the possible cause of liver appearance during bone
scanning. Rndiologl I26:813-816,1978.
90. LenLle BC. Scott JR. Noujaim AA, ei XI: ialrugenic
altelations in radionuclide biodislributions. Senrilr
N U C /hfed 9~131-143. 1979.
91. Eckehnan WC, Reba RC, Kubota H. et al:Tc99m
pyrophosphateforboneimaging.
15:279-283,1974.
92.Hladik WB, N i g g K K , Rhodes BA: Dmg induced
changes in thebiologicdistribution of radiopharma-
ceuticals. SeftfiffN r d Med 12:184-218. 1982
93. Powers CI. Lin DS, Lin CM: Liver localizat~onof
Y P m T ~ M D Pin a case of metastaticmalignant
melanoma. lnr J N I hfed ~ Biol 1 1 3 - 7 6 , 1984.
94 . Stone CK, SissonJC:Whatcausesupiake of tech-
netium-99m methylene diphosphonate by tumors? A
cdscwhere the tumors appeared to secrete a hyper-
calcemia-causing substance. J Mrc/ Med 26:250-253,
1985.Carey RM, Innes DJ Jr. el al: Poorly
Williamson BRJ,
differentiared lymphocytic lymp1101nawith ectopic
parafhormone production:visualization of metastatic
calcillcalion by bone scan. Clu?f l ~ ~ c l M3:3)32-384,
ed
. Rosenfield
197s. N . Treves S : Osseous and extraosseous
96
AJR uplake of fluorine-I 8 and technet~um-94n1polyphos-
Venkatesh N, Polcyn RE. Norback DH Mc~;~st;lric
calcification: therole of hone scannmg. Rnrtiolofi?
129:755-758. 1978.
Williamson BRJ. Teates CD, Bray ST. Bone scanning
i n delecting soft tissue abnormalities. Somh Med J
73853-862. 1980
Seid K, Lin D, Flowers WM lr: lntense myocardial
uptake of Tc991n MDP in a case of hypercalcemia.
CILr Nrrcl Med 6:565-567. 1981
Chaudl~ri TK: Increased hepalic predilectlon of bone
seeking rddiopham~aceuticals in palientswlthhyper-
calcemia. Z n f J N r d Med B i d 3199-200, 1976.
4 m a s R, Neumann R, Goldsmith SJ: Differential
skeletal uptake of Tc-99m tagged pyrophosphate and
methylenediphosphonare In leukemia. J Nrrcl Med
24:799-802,1983.
J Nrrcl M e d 102. Zilnmer AM. Pave1 DG: Experimental Investigations
of the possible cause or liver appearance during bone
scannmg. Rfdiologv 126:813-816, 1978,
103. tkdkim S , Joo KG. Baeumler GR:Visualizarlon of
acutehepatic necmsls wilh a boneImagingagent.
Clifr Nrtcl Med 10597-698. 1985.
400 I Essentials o j Nuclear Medicim Science

5 . Treves ST:Pediatric Nuclear Medicine. New York, Springer-Verlag, 1985.

CATEGORY A: Unusual Nuclear Medicine Study Results, e.g., Altered Biodistribution and Artifacts 6 . Levine G , Mazzetti C, IvlahliB: A methodology for preparingpediatricdoses of Tc-99m MAA for pulmonw
perfusion studies. J Nuci Med Technoi 8:94-96, 1980.
1 , Hladik W B , Ponko JA, Stathis VJ: Drug-radiopharmaceutical interactions.In Thrall JH, Swanson DP (eds): Dfugnusric
7 . Subcolnmiltee on Pediatric Dosing, FDA Radiopharmaceutical Drug Advisorp Committee.
Interventions in Nuclear Medicine. Chicago, Year Book Medical Publishers, 1985, pp 226-246.
8. Shore RM,Hendee WR:Radiopharmaceuticaldosage seleckion for pediatricnuclearmedicine. f Nucl Med
2. Welells LD, Bernier DR: Radionuclide Imaging Arrfacts. Chicago, Year Book Medical Publishers, 1980. 27287-298,1986.
3. Rw, UY. Bekeman C, Pinsky SM: Atlas uf Nuclear Medicine Ar~faclsand Variunrs. Chicago, Year Book Medical
CATEGORY E: Adverse Reactions to Radiophmaceuticals
1. Cordova MA, Hladk W B , Rhodes BA, Atkins HL:Adverse reactions associated with radiophmaceuticals, In Hladik
W B , Saha GB, Study KT (eds): Essemials oJNuclearMedicine Science. Baltimore, Williams & Wilkins, 1987, pp
Procedures. St Louis, Maliinckrodl. 1981,
303-320.
6 , Hladik WB, Saha GB, Study KT (eds): Essentials u f h ’ d e a r Medicine Science. Baltimore. Williams & Wilkins, 1987.
2 . Swanson DP, Thrall JM. Chilton HM (eds): Pharmacoradiolugy. New York, Macmillan, 1987,
7. Swanson DP, Thrall JH, Chilton H M : Pharmucorudiolugy. New York. Macmillan, 1967.
3. Cordova MA, Hladik W B ,Rhodes BA: Validation and characlerization of adverse reactions to radiopharmaceuticals.
8. Iowa Drug InIormation Service, University of Iowa
Nonirwasive Med Imaging 1:17-24, 1984.
CATEGORY B: Internal Radiation Dosimetry 4. Food and Dmg Administration, Division of Drug and BiologicaI Product Experience.
5. Volunteer Reporling System sponsoredby SNM, USP, FDA (Form FDA 1639): Contacr the chairman of the Sociely of
1. Radiopharmaceutical lntemal Dose Information Center, Oak Ridge National Laboratories, Oak Ridge, T N . Phone Nuclear Medicine Subcommitlee on Adverse Reactions.
(615)576-3449. 6. Mandatory Reporting System required of drug sponsor (Form FDA 1639): Conract regulatory affairs division of drug
2 . Coffey JL, Watson EE, Hubner KF, Stabin MG: Radiopharmaceutical absorbed dose considerations. In Hladik WB, manufacturer.
Saha GP, Study KT (eds): Essenrials OjNuclearhfedicine Science. Baltimore, Williams & Wilkins, 1987, pp 51-74.
3. Section 7800 (Radiophannaceuticals). In McEvoy GK, McQuame GM (eds): American ~ o s ~ i r u Z ~ o r m ~ { ~ u ~ ~ e ~ i c e - CATEGORY F Clinical Studies Documenting Safety and Efficacy
Drug InJorormalion. Bethesda, MD, American Society ol Hospital Pharmacists (monographs will appear beginning in
1 Computer searches of prjmary literarure.
I

1987).
2. lowa Drug Information Service, University of Iowa.
4. Swanson DP, Thrall J H , Chillon H M : Phurmucoradiulogy. New York, Macmillan, 1987.
5 . Medical Internal Radiation Dose(MIRD) Pamphlets andMlRD Dose Estimate Reports.New York, Sociely of Nuclear CATEGORY G: SpecificPhysiochemical,Pharmaceutical, or KineticProperties of RadiopharmaceuticaIs
Medicine (published at unspecified lime intervals).
1 . Spencer RP (ed): Radiopkarniacer{/icu~s~ Swurrure-Acrivity Re/orionskips. New York, Grune & Slratton, 1981.
6. Cloulier RI, Watson EE, Coffey JL: Radiopharmaceutical dose calculation. In Harbert J, Da Rocha AFG (eds): Texlbuok
2 . Colombetti LG (ed-in-chief): CRC series on Radiotracers in Biology and Medicine (9 titles). Boca Raton, E, CRC
ofNuclear Medicine, cd 2, vol I: Basic Science. Philadelphia, Lea & Febiger, 1984, pp 267-282.
Press, 1982.
7 . Watson EE, Schlafke-Slelson AT, Coffey JL. Cloutier RJ (eds): Tllird InrernarionaI Radiopharrnacefrrical Dosinrerr):
Symposium, HBS Publication FDA 81-8166. Rockvillc, MD, National Center for Devices and Radiological Health, 3 . Freeman LM (ed): Freeman and Joohrfson’sClinical Radionrrclide Imaging. ed 3. New York. Gmne & StratLon. 1984.
4. Seclion 78:OO (Radiopharmaceutlcals): In McEvoy GK, McQuarrie GM (eds):American Hospild Formuiaq Jew&-
1981,
8. Robeflson 1s: Radiation dosimetry foi internally d i s ~ b u t e dradionuclides. In Wahner H W (ed): Nuclear Medicine: Drug I&nnafiou. Bethesda, MD, American Society of HospitaI Pharmacists (monographs will appear beginning in
1967).
Quarlrirarive Procedures. Boston, Little, Brown, 1983, pp 31-42.
5 . Swanson DP, Thrall JH, Chilton HM (eds): Pharmacoradiology. New York, Macmillan, 1987.
9. Product package inserts
6. Saha GB: Fwfdarne>fraIsof A’rtclear Pharmacy. ed 2. New York,Springer-Verlag, 1984.
10. Fullerlon GD, et a1 (eds): Medical Physics Monograph No. 5: Biological Risks of Medical Irradiations. American
7. Phan T,Wasnich R: Practical Nuclear Pharrmcy, ed 2. Honolulu, Banyan Enterprizes, 1981.
InslituLe of Physics, 1980.
8 . Deutsch E, Nicolini M.Wagner HN Jr (eds): Teclznerium ill Chemisrv andh’frcleurMedicine.New York, Raven Ress.
11. Walson EE Schlafke-Stelson AT (eds): Forrrrh Interrfational Radiopl~arn~aceulical
I Dosimerry Symposium. Oak Ridge,
1983.
TN, Oak Ridge Associated Universilies, 1986.
9. Eckelmon WC, Coursey BIM (eds): Technerium-99m: generators, chemistry, and preparation ofradiophmaceuticals.
CATEGORY C: Use of Inlerventional Drugs in Nuclear Medicine I r f f J Appl Radiar Isor 33(IO): October 1982 (entire issue).
10.HeindeI ND, Burns HD, Honda T, Brady LW (eds): The Chemisrv u~Radiuphurmacenrical,NewYork, Masson
1 , Thrall JH, SwansonDP (eds): DiagrlosticInten~enrionsin Nuclear Medicine.Chicago, Year Book Medical Publishers,
Publishing,1978.
1985.
2. Spencer RP (ed): Inrewenrional A’ucIear Medicine. New York, Grune & Slratton, 1984.
11. Billinghurst MW. Fritzberg .4F: CkenislryJoor N d e a r Medicine. Chicago, Year Book Medical Publishers, 1981.
12. Eckelman W C Radlophamaceutical chemislry. In Harbert J, Da Rocha AFG (eds): Tenbook ofNucleur Medicirre, ed
3, Ponto JA , Hladik WB: Common uses of nonradioactive drugs in nuclear medicine.Am J Husp Pharm 4 1:1189- 1 193,
2, vol I: Basic Science. Philadelphia, Lea & Fcbiger, 1984, pp 212-266.
1984.
13. Rhodes BA (ed): Qualify Control in Nudear Medicine. St Louis, CV Mosby, 1977.
4. Thrall JH. Swanson DP lntervenlional aspects of nuclear medicine. In Freeman LM, Weissman HS (eds): Nuclear
14. Workshop Manudfor Radionuclide Handling and Radiuphormucef~~ical Q ~ d i Assurafrce.
p H H S Publicarions FDA
Medicine Annual. New York, Raven Press, 1963, pp 1-49.
82-810I , Rockville, MD, National Center for Devices and Radiological Health, 1982.
5 . Saha GB, Swanson DP, Hladik WB: Inlerventional studies in nuclear medicine. In Hladik WB, Saha GB, Study KT
15. Robbins PJ: Chrornarogrphy of Techneril~n-99mRadiupkarrnacellricals-A Pracricul Guide. New York, Society of
(eds): EsseFlrjals of Nuclear Medicine Science. Baltimore, Williams & Wilkins, 1987, pp 115-132.
h’uclear Medicine, 1984.
CATEGORY D: Pediatric Radiopharmaceutical Doses 16. H a m i h n DR, Hemera NE, Paras P, Rollo FD, Maclntyre WJ (eds): Qua/+ Assuraltre irr NucIear Medicine.
Proceedings of an International Symposium and Workshop. HHS Publication FDA 84-8224. Rockville, MD,National
1, Bekernan c , Conway JJ, Pinsky SM, Weiss SC (eds):Manual oft‘ediurric and Urnrsual Nuclear Medicine Procedures.
Center for Devices and Radiological Heallh, 1984.
Crystal Lake, lL, Central Chapter, Society o l Nuclear Medicine, 1979. 17. Krislensen K:Preporalion and Cunwol ofRadiophormaceuricals in Ho,rpirals. Vienna, International Atomic Energy
2. Dav KE: Melhod for calculating pediatric radioactive doses. In: Transienf Eqrrilibrinm. ER Squibb 8; Sons, Hospital Agency,1979.
Division, January 1977, pp 1-2.
3. Sly JR, Starshak RJ, Miller JH: Pediurric h’uclear Medicifle. Norwalk, CT, Appleton-Century-Crofts. 1983. CATEGORY H: Formulation, Preparation, and Quality Assurance ol‘Radiopharmaceuticals (See Category G)
4. Siddiqui AR: Nuclear imaging in Pediarrics. Chicago, Ycar Book Medical Publishers, 1985.

Appendix 24.1. Radiopharmaceuticalinformation:sclcctedresourcesandreferences other than primary Appendix 24.1-continued

literature
 1. Acra Radiologicn: Diagnosis
2. Acra Rodiologica: Oncology, Radiarion, Physics, Biology
3 . Acta Radiologica Supplemenrum
4. AJR. American J o u r r d of Roerrrgerlologv
5. Annoles de Radiologie
6. Applied Radiology
7. Brirish Journal of Radiology
8. Cardiovascular and Intenwuional Radiology
9. Clinical Nuclear Medicine
10. Clinical Radiology
11, CRC Critical Reb,iea*s in Diagnostic Ifnuging
12. Diagrfosricimaging irl Clinical Medicine
13. European Journal of Nuclear Medicirle
14. Gasrruinresrinal Rodio!ogy
15. Health Physics
16. Inrerrlariorzal Jourrlal of Applied Radiation and Isotopes
17. Inrerraational Jozrrrml o f h h l e a r Medicine and Biology
Appendix 24.1-confinued 18. Imerrzational Jorrrnal of Radiotlon Biology arzd Relured Srudies in Physics, Chemisrr); and Medicine
,19. international Journal of Radialion Oncology BiologypPhysics
20. fnvestignfive Radiolog):
21. Jorrrnal Belge de Rodiologie
22. Journal of Labelled Compounds and Radiopharfnaceuricah
23. Joonrr~alof Laborafog and Clinical Medicine
24. Journal of Nuclear Medicrne
25. Journal of Nnclear Medicine and Allied Scfences
26. Journal of Nuclear Medicine Techlology
27, Joar~~al of Radiarion Research
28. Joonrrm de Radtologie
29. Kaku Igaku
30. Nr1clear Medicine Communicarions
31, Nzrklearmedizin
32. Pediarric Radiology
33. Polski Prieglud Radiologii i Medycyn? Nuklearnej
34, Progress in Nuclear Medicifre
35. Radiation and Enviro?zmenral Biophysics
36, Rfldiatior?Medicine
37. Radiorion Research
38. Radioacriw Isotopes ill ClirficulMedicilre
39. Radiobiologia, Radrorherapia
40. Radiobiologiia
41. Radioisotopes
42. Radiologe
43. Radiologio Diognosrica
44. Radiologia Medica
45. Radiologic Clinics of North America
46. Radiology
47. ROEFE: Forrsclrrirre arrf dem Gebiere der Roenrgensrrahlen und der Nuklearmedizirl
48. Recenr Advarzces in Clinical R'rrclear Medicine
49. Recerrr Adwarms in Nuc,clear Medicine
50. Seminars in Nuclear Medicine
5 1. Urologic Radiology
5 2 . Vesrnik Rentgenologii Radiologii

Appendix 24.2. Selected journaIs that may include arlicles perlaining to the topics of nuclear medicine and
radiopharmaceuticals.

25
Issues of Patient Education
Patient education is not a new field in heallh
care, Today, however, greater emphasis is being
placed on delivering organized, systematic pa-
tient education as an integral entity within the
health care system rather than as a haphazard,
episodic, fragmented occurrence ( 1 , 2). Health
care organizationsand thevarioushealth care
disciplines are examining their role in educating
the many clients h e y serve. This self-examina-
tion may be initiated by consumer demands, by
new or more stringent standards of care, or by
attempts to market health care services lo the
public.
Patient education can be defined as a “sys-
tematic, planned, learning experience, based on
an individual’s needs[,] that results in a change
of behaviorwith the goal of promotionand
maintenance of optimal health” (3). One is hard
pressed IO find, however, a model patient educa-
tion program. A review of the lilerature reveals
that many articles have been published describ-
ingvarious aspects of patienteducation as an
integral component of comprehensive health
care. In thenuclearmedicineliterature, how-
ever, only a few scattered articles on the topic of
patient education are availabie (4, 5).
Results of interviews with physicians and
technicians in several nuclear medicine depart-
ments indicate that there is no model forpatient
education but that patienl education stems di-
rectly from questions and answers between the
technician and the patient. Thus patient educa-
tion stems from the individual department and
is not a systematically planned activity.
PATIENT’S RIGHT TO KNOW
Humanbeings in theUnitedStates are en-
dowed with the“right to self-determination.”
This basic right, when applied to patient care,
cedures. It would be wise practice, however, for
the physician and technician performing thenu-
clear medicine procedure to determine the ex-
tent of the patient’s understanding prior to ini-
tiatingtheprocedure.Failure to informthe
patient properly could result in litigation, and all
health care personnel associated wirh that pa-
tient’s care must share in the responsibility to
obtain an informed consent.
Since most hospitals hold membership in the
American HospitalAssociation,the“Bill of
Rights” may be seen as a standard of care to be
achieved in member institutions. Nevertheless,
some physicians fear that patient education will
make malpracticeliligation worse (7): “ ‘The
more patients know, the more likely they are to
find something to sueabout.’Actually, mal-
practice experts state that lack of rapport is a
major cause of malpractice. Making the effort
to help the palient understand his or her illness
should decrease theincidence of malpractice
suits.”
Professionalorganizations,then,havere-
sponded to the patient’s right to informed con-
sent by bureaucratically addressing the issue of
patient education.Thesesameorganizations,
however, have done little to assist health care
professionals in identifying properapproaches
to patient education.
THEORETICAL APPROACHES TO
PATIENT EDUCATION
Principles of teaching and learning have been
known €or many years. Currenl research, how-
ever, indicates that a pedagogical approach may
not be appropriate for adults, especially when
that adult is faced with the stressors of illness
and/or hospitalization. Within the past decade,
research on the patient as a learnerhas been
carried out (8-10). Results of this research indi-
cate the need to incorporate several principlesof
adult education into the process of patient edu-
cation, which inchde: (a) teach the patient what
he or she wants to learn, (b) buiId on a knowl-
edge base,(c)achievephysicalreadiness to
learn, (d) allow the patient to participate in the
teaching-learning process, (e) obtainfeedback
on learning outcomes, (f) adjust presentation of
information to the patient’s level, and (g) pro-
mote a warm interpersonal relationship.
Issues of Patienf Edrrcafion I 405
Teach What the Patient Wants to Learn
The ideal place to begin the patient’s teach-
ing-learning process is in the identification of
questions that the patient may have concerning
the nuclear medicine procedure. Once a basic
explanation of the procedure and the reason the
patient needs that procedure have been provided
by the attending physician, the patient should be
asked, “What questions do you have concerning
this procedure?” Once the patient has identified
anyquestionshe or she may have aboutthe
procedure, explanations to answer these ques-
tionscanbeprovided.Furtherinformation
about the procedure should be withheld until all
of the patient’sown questions havebeen an-
swered,sincethepatientmay not beable to
concentrate on any other information until the
questionsuppermost in his or hermindhave
been answered. When these questions havebeen
answered, the technologist can provide a clear
explanation of exactly what will happen lo the
patient during the procedure. Once this explana-
tion hasbeen provided,the patient should be
askedagainwhetherhe or she has any ques-
tions, and any questions thal surface should be
answeredhonestly andin a simplelanguage.
Build on a Knowledge Base
Adults learn best when content to be learned
is presented in relationtowhat they already
know. Most adults have undergone an x-ray
examination at somelime in their Iife.Thus,
most patients alreadyknow that pictures are
being taken during the procedure and that a
certain amount of radiation wiII be used. As the
result of themedia (especiallytelevisionand
newspapers) and knowledge of such events as
“ThreeMileIsland,” however, patientsoften
associate the word “nuclear” with harmful radi-
ation and even cancer. The exact nature of the
patient’s knowledgeaboutradiation andtheir
feelings about it need to b e determined. Patients
often ask such questions as “How long will the
radioactivematerial stay in me?”, “Will radi-
oactivityharmme?”,and“Can I be around
other people after I have been injected with the
radioactive materia!?”
Patients are often already aware of how little
time is involved in taking an x-ray. Thus, infor-
mation needs to be provided to help the patient
406 I Enenrials of N d e o r MedicineScience
understand how nuclear medicine procedures
differ from x-rays, including the fact thatnu-
clear medicine procedures involve injection of a
radioactive substance, thal time is required to
allow theinjectedmaterial to reach the target
organ, and that the total time involved in the
procedure will be about an hour.
Achieve Physical Readiness to Learn
Humans learn mosl effectively and efficiently
when they arephysically healthy, well rested,
and physically comfortable. This may presenl a
dilemma for palient education, since the exact
opposite conditions often are the norm. Patients
may be in pain, andthustheirattenlion span
will be shortened and the levelat which they can
understandmaterialbeingpresentedwill be
lowered,Electrolyteimbalances may interfere
with the ability to understand clearly, and cer-
lain medications being given to the patient (es-
peciallythosewithneurologicallyrelated ef-
fects) may interfere with his or herabilityto
learn.
Before beginning a teaching-learning interac-
tion withthepatient,thetechnologist should
ascerlain the patient’s level of com€orl. Whether
the patient is seated or is lying in bed, his or her
position should be relaxed and comfortable. At-
tenlion to room temperature is important, since
a lack of comfort from being chilled or too
warm may inlerlere with the patient’s ability to
pay altentionto [he material being presented.
The room in which teaching occurs should be
well lighted, and distractions (such as noise and
the movemen1 of patients or personnel through
the area) should be minimized if not eliminated.
Allow the Patient to Participate in the
Teaching-Learning Process
Use of the traditional pedagogical approach,
in which the learner is subjected to passively
listening to a lecture, seldom achieves optimal
results in patient education. The adult learner
needs to be actively involved in both determin-
ing what is to be learned and in the presenlation
of that material.
Patient education oflen is less effective than is
intended because hcallh care professionals leach
what they think is imporlant, not what the pa-
lient thinks is important. Thus, one of the first
steps in the teaching-learning process should be
to allow the patient to determine what he or she
needs to learn. This requires that each patient-
leachinginteraction beindividualized, which
oflen places someburdenonthe busyhealth
care professional.Standardizedteaching pro-
grams, wilh established objectives and content,
may not be as effective in patjenireaching as
they are in colleges or universities. Thus, if the
nuclear medicine department is trying to sys-
tematize its patient education activities, guide-
lines for information lo be given patients can bc
helpful in organizingthetechnoiogist’sap-
proach lo patient education, but these guidelines
should not be seen as being engraved in stone.
The patient’s own concerns should b e dealt with
first,andindividuallearningneedsshould be
determined prior to launching into a presenla-
tion of standardized content.
Parlicipation in Ihe teaching-learning process
is also achieved through the involvement of the
patient’svarious senses. Hearing is the body’s
most passive sense.Thus, ateaching-learning
interaction which is primarily a lecture will no1
achieve the most efficient learning outcomes for
the patient. Verbal information being presenled
lo the patient should be emphasized by visual
stimulation. This can be accomplished through
the use of photographs, simple drawings or il-
lustrations. and even a demonstration of whal it
is that is being discussed. Allowing the patient a
chance to touchtheequipmentbeforebeing
subjected to theprocedureisoftenhelpful in
gaining their understanding as well as in allay-
ing their fears and anxieties.
Obtain Feedback on Learning Outcomes
Each teaching-learning interaction should be
evaluated to determine the level of the patienl’s
understanding. It is not enough to ask the pa-
tient, “Do you understand?”; many patients
will be too embarrassed to admit thal they do
not .
Feedback may be obtained by asking the pa-
tient a specific question that is prefaced with an
explanation, such as “I want to besure you
understand what it is that we are going to do.
Please tell me what your lungscan will in-
volve?”, or “Tellmewhat you understand
about theradioactive substance thal 1 will be
injecting?” Although this may see111redundanr
to the busy technologist, it is the only way that
true feedback on learning can be obtained.
Once thepatient has provided feedback on
what he or she had learned, the technologist can
fill in the gaps in understandingby repealing
information that thepatient hasmissed or by
correcting infomlation that the patient has mis-
understood.Feedback is then againoblained,
and the process repeated. until Ihe patient under-
stands enough information about the procedure
togive “informed” consent.
Adjust the Presentation l o the Faticnt’s
Level
Since the ability of patients to learn varies,
the technologist teaching paiients about nuclear
medicine procedures must approach [he patient
at an appropriate Ievel, and present material al:
anappropriate rate, IO insure optimal learning
outcomes.
Health care professionals should not fall inlo
[he [rap of assuming that thelevel of fomal
education ol‘ a patient is related to the patient’s
ability to learnthemalerial beingpresented.
Fear, anxiety, less-than-optimal physicaf condi-
tion, and other circumstances limit the patient’s
ability lo learn. Thus, even the patient who has
a college education may not be able tolearn
what is being taught if [he material is presented
too technically or too quickly.
Patient education often makes use of printed
materials lo supplement whal is beingtaught.
For instance, several booklets for patient educa-
tion are available fromMallinckrodtNuclear
(11-15) and the Society of Nuclear Medicine
(16, 17). Thesebookletscontain textand car-
toons designed lo provide ‘‘answers to the ques-
tions mosl commonly asked by patients.” The
nuclear medicine technologist should be aware
of two facts prior to using Lhese booldets or any
other printed media for patient education. Firs[,
a large segment of [he population doesnot know
how to read. Even in the United States where
there is relatively easy access to education,
many people are functionally illiterate. Patients
often are too embarassed Lo admit that they do
not know how to read, and therefore, Ihe lech-
nologist may be lulled into a falsesense of
security once a booklet is given to the patient.
This author uses the following approach when it
is unknown whether or not the patient is able to
read: The booklet or brochure is handed to the
patient upside down; if the patient looks at the
malerialwhilecontinuing lo hold i t upside
down, he or she does not know how to read.
Second, even if a patient knows how lo read,
the level of understanding of what is being read
may no1 be very high.The average reading
ability of people in the UniLed Slates is the sixth
grade level (this is the level at which the average
daily newspaper is written). A survey done by
this author indicates that many patient education
malerials are written at a much higher levcl 111ar1
can be understood by patients. FoI Insmcc. l:hc
“avcrage” consent for surgical procedures form
i s writien at about the sevenleenth grade level
(first year of graduale school) or at about (he
level of the h’ew E ~ ~ g l a Jownni
r~d of Mcdicilw.
A recommendation that makes a great deal of
sense Pol thetechnologistwho wishes lo use
printed media is to have the material read by a
grade school studen1 (especially a sixth or sev-
enth grader). If that student can understand the
material,the ”average” patient should be able
to understand i t ,
Promote a Warm lnlcrpersonal Relationship
Goodrapporlwilhpatients,ashasbeen
pointed out, is a n~eansl o decreasethe inci-
dence of malpractice suits. A warm rapport with
the patient also enhances the learning outcome.
The palient who isanxiousor fearful will
respond to warmth and understanding by relax-
ing and by exploring those fears and anxicties.
The technologist shouldnot give the impression
of being in a hurry to explain the nuclear medi-
cine procedure. The comfort the patient re-
ceives through thewarmth and rapport of the
technologistwill not only help the palient
achieve a greater level of understanding but will
also help the technologist achieve better patien1
cooperation throughout the procedure. With this
cooperation, more than the amount of time it
look to provide a careful explanation of the
procedure can often be gained.
Patient educationcan be a lime-consuming
activily that adds ’a burden to the already-busy
nuclear medicine technologist. If thesepre-
viously discussedprinciples of patient educalion
408 I Essenfials of NucIear Medicine Science
arefollowed, however, learningoutcomescan
be achieved, resulting in a more satisfiedpa-
tient, a moreeffective proceduralresult,and
less likelihood of an unpleasant experience for
the patient and the technologist.
PATIENT EDUCATION: A TEAM
EFFORT
It is the patient who initiates the entry into the
health care system, This initiative occurs in the
form of choosing a personal physician and then
visiting that physician when the patient be-
comes aware of theneed.From then on, I h e 4.
patienl is subjected to contact with many other
health care professionals. When a nuclear medi-
cine procedure is required, the patient may be
lreated as an outpatient (in which case the nu-
clear medicine health care team has sole respon-
sibility for teaching and caring for Ihe patient)
or as an inpatient (in which casemanyother
health careteammemberscomeinto contact
with the patient). In each situation, the patient
requires information and receives that informa-
tion from many sources.
The team approach topatient educationre-
quires coordination and communicationin order
to assure continuity, not only in the care of the
patient but also in the teaching-learning pro-
cess. All members of the health care team need
lo coordinate their activities,especially the con- ing their success. The staff‘s perception of their
ten1 that they teach the patient,in order to elimi-
nate unnecessary duplication.This same coordi-
nation willeliminatecontradictionsandcon-
flicting information. One person may teach one
thingtothe patient, and someone e k e may
teacha differentpiece of informationwhich
may seem contradictory to the patient.
Communication centered around the indj-
vidual patient and patient education, in general,
need to be ongoing. Many health care profes-
sionals(suchas staff physicians,professional
nurses, etc.) have no awareness of what actually
takes place during a nuclearmedicineproce-
dure. Therefore, it behooves every health care
institution that performs nuclear medicine pro-
cedures to provide in-service education pro-
grams for all personnel who have conlact with
the patient. These in-service presentations
should include at least the following infoma-
tion:
1. Specific nuclear medicine procedures:
Whatactuallyhappensinthenuclear
medicine department. Information con-
cerning theinjection of radioactivesub-
stances, Patient care measures that may be
necessary before, during, and after a nu-
clear medicine procedure.
2.Interviewing skills-to assist in determining
the patient’s level of knowledge and under-
standing.
3.Roles and responsibilities of various nuclear
medicine health care team members.
Teaching-leaming principles:
How to teach.
What to teach.
5.Communicationskills.
6.Evaluation skills-to determine the extentof
learning.
Once an in-service presentation has been
made, it will be important for the staff (in both
the nuclear medicine department and the rest of
the institution)toreceive positive reinforce-
ment. When a patient who is undergoing a nu-
clear medicine procedure appears for the sched-
uled examination and is well prepared for that
examination (informed consent already exists),
the staff who provided this informalion should
be given feedback and reinforcement concem-
role in patient educationwilltherebybeen-
hanced.
Thesuccess of patient educationactivities
can be insured by involvement of all staff mem-
bers in planning for, implementing, and evalua-
ing patient education outcomes. Successful pa-
tient education cannot be accomplished by only
one of ihe disciplines working on the nuclear
medicine health care team. Therefore, each dis-
cipline must be represented when patient educa-
tion is being discussed.
Patient education must be seen as an expecta-
tion of everyperson’s job performance.The
manager or administrator of the nuclear medi-
cine department must hold each member of the
staff accountablefortheir part in the patient
educationprocess.Onceagain,reinforcement
should be given when positive results are ob-
tained, thereby increasing the stafl‘s awareness
of the importance of patient education activities.
DIRECTIONS FOR THE FUTURE
Research has shown that patients want to
learn about, and understand, not only their con-
ditions but also those procedures that they have
lo undergo. Research has also shown thatpa-
tients learn differently than do healthy people,
because of fears, anxieties, or other factors as-
sociated with their illness.
The future for patient education has infinite
possibilities. Nuclear medicine professionals
should consider conducting researchon patients
who are undegoingnuclearmedicineproce-
dures. This research could serve to identify
what type of and how much informalion these
patients want or need to learn. Research could
identify factors present in hospitalization (or in
being an outpatient) that limit patients’ abilities
to understand what is being taught.
Quality assurance will takeon more impor-
tance not only as third-parly reimbursers look to
the quality of care they can or will pay for but
also as consumers of health care become more
aware of their rights as patienls. The Joint Corn-
mission on Accreditation of Hospitals (JCAH),
in their latest slandards for quality assurance,
recommend that quality assurance be organized
as a hospital-wideactivity.Suchimportant
components of quality assurance as safety and
risk management, education, and clinical moni-
toring are associated with patient education ac-
tivities. Issuesconcerninginformedconsent,
theactual procedures carried out, and the pa-
tient’sunderstanding of theprocedures and
healthcaremust be examined in the light of
assuring delivery of quality care.
Educational preparation of the heaIth care
professionals also has implications for the fu-
ture. As technology and the body of scientific
knowledgeincrease withinmedicine(and all
health care professions), these health care prac-
titioners must remain up-to-date in their knowl-
edge and skills. Continuing education is seenas
a way to prevent professional obsolescence and
to assure quality care. It would be ideal if every
health care professionaI’s basic (or continuing)
education included experiencing “one of every-
thing” that a patient has to undergo. This, how-
ever, would not bepraclical or feasible. It
shouId suffice to try to increase the health care
professional’sawareness of what it is that the
patient experiencesduringillness,whether or
not it requires hospitalization.
SUMMARY
Patient education isanimportant,integral
component of comprehensive patient care. Re-
gardless of whether a patienl is acutely ill or is
merelyundergoinga nuclearmedicineproce-
dureas a health mainlenance activity,patient
education aclivities will help that patient under-
stand what is about to happen as well as what
thepalientcan do to cooperate and make the
procedure more effeciive.
Illness as well asfactors inheren1 in hospj-
talization may hinder the patient’s ability to
learn. By paying attention to cerlain adult edu-
calionprinciples, thenuclearmedicine health
care leam member can do much to insure the
quality of the nuclearmedicine procedw-
quality results from the procedure as well as a
well-informed satisfied patient.
ACKNOWLEDGMENTS
The author gratefully acknowledges the input
of Michael Shannon, M.D., in development of
this manuscript.
REFERENCES
1 . Breckon DJ: Highlightsin the evolution of hospital-
based patlent education programs, J Allied Heolth
5:35, 1976.
2 . Lee EA, Garvey J L How is inpatient education being
managed? Hospitals 51:75, 1977.
3. Fylling CP: A comprehensive system of patienl educa-
lion: guidelines fur developmenl. In BjlJe DA (ed):
Practical Approaches to Parienr Teaching. Boston, Lil-
[le, Brown, 1981, p 16.
4. Bassett CE: Care of the patient in the x-ray deparlment.
Con J Radio8 Radiurher Nucl Med 10343-44, 1979.
5 . Bubb D: Teachingpatients about ultrasound and CAT
brain scans. AmJNurs 44(12):64-65, December 198 I .
6 . American Hospital Association: “A Patient’sBilI of
Rights.”Chicago, American Hospml Associalion,
7. Thompson
1972, R E Obtaining physician support In Dille
DA (ed): Practical Appruaches tu Patient Tenchfi.
B o s h , Litlle, Brown, 1981, p 222.
8 . Dille DA: F’atients’ knowiedpe and compliancc with
posthospitalizationprescriptions as related IO body i n -
age and teaching format. Ph.D. disserlation. University
of Wisconsin-Madison, 1975.
9. Knowles M:The Adult Learner: A A’eglecrcd Species.
ed 2. Houston, Gulf Publishing, 1973.

12. Brucer M:W I U / You Con ExperfJrom Your Lfmg Scan.
St LOUIS.Mallinckrodl Nuclear, 1972. 1977."
13. Brucer M: W z m YOIICan E.rpec/frofnYofrr Brnirl S c m .
14.
St Louis, Mallinckrodt Nudear, 1972.'
Bmcer hi: Whnr You Carl Expect from Yo'olr?'Belle . k f l r f .
St Louis. Mallinckrodl Nuclear, 1976.'
15. Brucer M: Wznr You CONE.y?ecrfiom Y o w Liwr S C f l l l ,
St Louis. MallinckrvdrNuclear, 1972, 1978.*
16. A W r i e n r ' s Guide ID Mrclear Medicine. New YOrk,
Society of Nuclear hledicine (no year given).
17. Gllidditfe.F for Pc~rienrsReceivirlg Radioiodlde Zeal-
'Available through the h.lallir~ckrod~Nuclearrepresen- mw. New York, Socicly oiNuclcar Medicine (no year
tatives or from Mallincbodt Nuclear. Sr Louis, hI0 63134. given).
P
+
*
5
4
26
Patient Preparation for Nuclear Medicine
Studies *
- Victor Stathis, Doyle K Cantrell, and Teresa J, Canhdl
JI
In order to optimizethe useful information
derived from a nuclear medicine study, the po-
tential difficultiesassociatedwith eachproce-
dure must be addressed. The patient, when con-
sidered as one of several variable parameters in
the study, represents a possible source of com-
plications. A patient's anatomical and phys-
iologic characteristics and his or her mental and
emotional condition at the time of the study can
be reflected in theprocedure's results. Addi-
tionally, limitations and peculiarities of the ra-
diotracerutilized in thestudycan affect the
outcome.
Drugand patient influences,when not di-
rectly associated with the organ system or dis-
ease process being evaluated, can diminish the
validity and usefulness of theinfomlationde-
rived from a nuclear medicine study. Therefore,
each patienl should be prepared for their pariic-
ular procedure so that inherent potential inter-
ferences are minimized.
Thereareseveralpreparatoryprocedures
which can be useful in mosl situations. One of
the simplest forms of preparation, and perhaps
one of the most important, is explaining to the
patient whattype of procedurehe or she is
having, why it isnecessary, andexactlywhat
will beinvolved in the process.Enhancing a
patient's understanding of the procedure helps to
developrapport betweenthe patient and the
*Although [99mTclpertechnctatc, [6"Ga]palIium citrate,
and [~O~Tl]thalluus chloride are prckerrcd by IUPAC, %mTc-
pertechnetale, "Cia-cilrate,and "'TI-chloride are standard, used to derive additiona1 or more specific infor-
and all are used throughout this chapter.
411
professional. This rapport will encourage pa-
tient cooperation,whichisnecessaryfor the
successfulcompletion of thestudy(refer lo
Chapter 25).
To obiain thepatient'sdrughistory, when
possible, is useful. Manypharmaceutical-radio-
pharmaceutical interactions have been described
in the literature ( I -4). Drug effects caninterfere
with interpretation of the scan, especially when
the nuclear medicine staff is not aware of the
patient's medication regimen (refer to Chapters
13 and 14).
Patient counseling and the obtainingof a drug
history are two examples of preparation which
can be applied to most patients and will be of
benefit in almost every typeof nuclear medicine
procedure. In order to maximize the amount of
useful information derived from astudy, how-
ever, ii maybenecessary to take additional
preparatory steps that are specific to the patient
group or tothe study being performed. This
chapter focuseson these additional patient prep-
aralion procedures.
With regard lo purposeful pharmacologic in-
tervention in nuclear medicine studies, it is
noteworthy that only those practices which fa-
cilitate performance of the procedure or mini-
mize interfering influences are described. That
is, pharmaceuticals are discussed only with re-
gard to how they are used in patient preparation
to overcome inherent radiopharmaceutical dis-
tribution problemsor patient limitations.The
reader is referred to,Chapter 10 for a description
of procedures in whichpharmaceuticals are
mation from nuclear medicine studies.
 412 I Essentials of Nucieor MedicineScience
PEDIATRIC STUDIES
The pediatric patien1 oftenrequiresspecial
preparation. Cooperation may be difficult to ob- Ingestion), the quantity of radioiodinated lracer
tain but can be maximized through the applica-
tion of concertedinterestandinlerpersonal
communication skills. Theseeffortsmustbe
directed toward patien1 and parent alike. Paren-
tal supporl can contribute greatly to the success
of the procedure.
In pediatric nuclear medicine, patient Ammo- [he following types of producis:
bilization is usually a significant practical chal-
lenge. One approach is the use of sandbags to
maintain the patient in position (5). If the bags
are only partiallyfilled, they may be molded
somewhal to the desired shape and are no1 as
likely to roll off thetable top. Restraintwith
sheets or towels and simple manual irnmobiliza-
tion have been used also (6).
Restraint methods may be inadequate when
[he pediatric patient is very active or agitated.
Sedation may be necessary. Any one of several
sedative-hypnotic agents can be used (6-8).
Chloral hydrate (50 mglkg;maximumsingle
dose is 1 g) appears to work well in most pa-
tients and can be administered as an oral liquid
or in suppository form ( 5 ) .
Before any type of sedative is administered,
consulcation with the referring physician is nec- and specific reviews (1-4, 10- 18) and in Chap-
essary. The patient may be receiving sedative
medication or drugs with sedative effecls.Also,
some children exhibit idiosyncratic reactions to
sedatives, ranging from excessivecentral ner-
vous system depression to extreme agitation (9).
Occasionally, stronger sedatives or larger doses
may be needed. The referring physician must be Adrenal (and gonadal) steroids
consulted.
THYROID UPTAKE AND IMAGING
Obtaining a patient's drughistorypriorto
nuclearmedicinestudies that elevatethyroid
function or structure is especiallyimportant,
since many pharmacologic agents can interfere
with the thyroidal uptake of radioactive kacers.
For example, drugs lhal contain large amounts
of iodine inhibil thyroidal concentrationof radi-
oiodinated pharmaceuticals (10). It is postulated as those that alter hormone synthesis (e.g.,pro-
that this effect is dueto radiotracer dilution.
When the amount of nonradioactive iodide in
thevascular pool is elevated (e.&., byiodine
presentrepresents a smallerfraction of the
body's iodide pool. Consequently, the greater
portion of iodide concenlrated by the thyroid
gland will be of nonradioactivetype. Tracer
uptake will be minimal (1).
The patient should be questioned regarding
Lugol's solution, saturated solution of potas-
sium iodide(SSKI), and other iodineprepara-
tions
Viramin and mineral supplements
Topical iodides (e.g., Betadine)
Radiological contrast media
Iodide-containinganfitussives or expectorants
Otherpharmacoiogicagentscan alsoinflu-
ence radiotracer uptake. Any drug that alters the
thyroid gland's uptake, organification, de-
iodination, or secretion mechanisms can inter-
fere with nuclearmedicine thyroid studies or
therapeutic procedures.There is an enormous
amount of data regarding drug-induced altera-
tions in the biodistribution of thyroid imaging
agents. The subject is addressed in both general
ter 14. The patient should be screened by lhe
nuclear medicine staff as IO the following types
of medications:
Natural or synthetic thyroid hormones
Antilhyroid medications
Salicylates
Sulfonamides, sulfonylureas
PhenyIbutazone
Nitroprusside
[99mTc]perlechnetalethyroid scanscan also
be influenced by pharmacologic agents. Unlike
radioiodides, pertechnetate is not organified by
the thyroid. Technetium is transported from the
bloodstream into the thyroid but is not used by
the gland in (he productionof thyroid hormones
(19, 20). Therefore, drugs that influence uptake
will affect pertechnetate biodistribution, where-
pylthiouracil) will not.
NONTHYROID STUDIES WITH The excreted radioactivity which accumdaLesin
RADIOIODINATED the urinary bladder can hinder visualization of
PHARMACEUTICALS bonystructures in thepelvic region (32, 33).
In orderforinterference resulting from the
Radioiodinatedpharmaceuticals are utilized
presence of radioactivity in the bladder to be
in several nonthyroidal nuclear medicine proce-
minimized, the patient should void prior to the
dures. In these studies, it often is advantageous
scanning procedure. Ingestion of fluids during
to inhibit uptake of unbound radioiodide by the
the time between radionuclide injection and
thyroid gland, Thyroid blockade, with 30-130
imagingwillstimulatethemicturition reflex
mg of potassium iodide per day(usuallyas
Lugol'ssolution or SSKI) prior to theproce-
(34, 35). This procedure should also minimize
dure, encourages excretion of unbound radioac- theradiation dose lo theurinarybladder by
tive iodide (21-23). This decreases background decreasing the residence timeof radioactivity in
radioactivity and, especially when 1311 is used: the bladder.
reduces the radiation dose to the patient (24).
Thyroidalradioiodineuptakesuppressioncan
be initiated 24-48 hours prior to the study and
BRAIN AND CEREBRAL
maybecontinuedfor several daysafterward PERFUSION STUDIES
(25, 26). (99mT~-PERTECHNETATE, 99mT~-
Thyroidblockade immedialelyprior to the DIETHYLENETRIAMINEPENTAACETIC
study usually is the most practical method and ACID (DTPA), 99"T~-GLUCEPTATE)
generally is effeclive. It is not necessary to
When 99mTc-pertechnetateis used for brain
begin blockade earlier. In fact, iodideadmin-
imaging or cerebral perfusion studies, the pa-
islered as late as 6 hours after radioiodine intake
lien1 should receive 200-400 mg of potassium
has been shown to suppress in excess of 90% of
perchlorate prior to the study. This drug inhibits
normal thyroid uplake function (22, 23).
uptake of radiopertechnetate by the choroid
Asanalternative 10 iodide,anionssuchas
plexus. Radioactivity present in the choroid
perchlorate or thiocyanate can be used 10 inhibit
thyroid concentration of radioiodine or pertech-plexus can interferewith interpretation of the
scan (36-37). Perchlorateusually is admin-
netate. Potassium perchlorate usually is admin-
istered in oral liquid or capsule form 10-30
istered for this purpose. These ions act as com-
minutes before perlechnelate administration.
petetiveinhibitors of thethyroidgland's
transportmechanism (27-28). Thyroid block- Thereisevidence, however,that the choroid
adeusuallyisincludedinthepreparation plexus will be blocked evenwlhen oral perchlor-
of
patients for: ateand inlravenouslyadministered 99mTc-per-
technetate are givensimullaneously (38). If a
'251-labeled fibrinogen uptake studies liquid preparation of perchlorateisused,the
lZsl or 1311 in R E A plasma studies patient should be advised that the taste may be
f 1311]iodomethylnorcholesterol (NP-59) adrenal slightly objectionable. The taste has somelimes
imaging been described as stale or salty.
rn-[1311]iodobenzylguanidine(mIBG) imaging Because pertechnetate is also concentrated by
1311-oleicacid or triolein absorption studies Ihe salivary glands, it may be advisable to pre-
medicatethepatientwith 0.4 rng of atropine
sulfate to inhibit saliva production (19, 20,39).
BONE STUDIES (99mT~-LABELED If the patient is not premedicated, vertex views
PHOSPHATES AND PHOSPHONATES) of the brain may be difficultto interpret because
Approximately 50% of an injected 9 9 m T ~of the presence of radioactive saliva in the facial
area.
bone-localizing agent normally depositsonto
Perchlorate and atropine are not required
osseous tissue. The olher 50% of theadmin-
when "mTc-DTPA or 99mTc-gluceptate are used
istered dose undcrgoes renal excretion (29-31).
 414 / Esserltials oJNuclear- Medicble Sciefzce
for scintigraphic brain studies. These two radio-
tracers are not noticeably concentrated by the
choroidplexus or salivary glandsand, there-
fore, are an alternative to radiopertechnetate in
patients who may have difficulty ingesting per-
chlorate (38).
TUMOR AND ABSCESS LOCALIZATION
([ %AIGALLIUM CITRATE)
The excretion of 67Ga-citrate is arelatively
slow process.On the average, 65% of an in-
jected dose remains within the body after 7 days
(40). Thekidneysaretheprincipalroute of
elimination during the first 24 hours. Following
thisphase,galliumisexcretedprimarily
through [he bowel, possiblyas intestinal mu-
cosal secretions (4 1-43).
Radioactivity in theintestine will interrere
withtheinterpretation of abdominalgallium
scans. For this reason, it is helpful to cleanse
the b o w l priorto imaging, which is initiated
48-72 hours afterradiotracerinjection, Lw-
atives or enemas may be utilized and usually are
starled on the dayof gallium administration (44,
45). The following is an example of a bowel
preparation regimen:
1. The patient is administeredtwobisacodyl
tablets ( 5 rng) 48 hours before scanning.
2 . On theday before imaging, thepatient is
given three bisacodyl tablets in the morning.
At noon, a normal meal may be eaten. At 2
P.M. the patient will drink one bottle (12 oz)
of magnesium citratefollowed by X oz of
water.
3. The patient is administeredone bisacodyl
suppositoryinthemorning on the day of
scanning.
Morevigorous measures includingenemas
may benecessaryif bowel radioactivity per-
sists.
The e.fficacy of orally administered cathartics
as a means of removing gut radioactivityhas
been questioned by some investigators (46,47).
Thc ineffectiveness noted by these authors may,
in part, be due IO palient noncompliance (48).
It has been suggested that confusion related
to intestinal radiogallium may be minimized by
imaging before the fecal elimination phase has
be,gun. Perkins (49), however, has shown that in
addition to excessive background radioactivity
due to incomplete blood clearance, some gal-
lium is alreadypresent in the gastrointestinal
tract at this time. Consequently, scan interpreta-
tion maybeimpededwhenearlyimagingis
attempted without bowel cleansing.
PANCREAS IMAGING
([75S~)SELENOMETHJONINE)
The following is an example of the type of
preparation whichshould be ingested by the
patient prior to a pancreas scintigraphic imaging
procedure:
Six egg whites
50 gm of Meritene
Artificial sweetener
100 ml whole milk
The preparation used shouldconlain large
quantities of fatsandproteins.Thesesub-
stances, when in the duodenum, stimulate the
release of cholecystokinin (CCK) into the cir-
culation. Pancreatic production of digestive en-
zymes increases in response to elevated con-
centralions of CCK in the plasma (50). There-
fore, i t is be1ieve.d that injectedradioactive
methionine, which will be utilized in digestive
enzymesynthesis,ismore readily transported
intothe pancreaswhen plasma CCK is high
( 5 1 ).
Other proposed methods of encouraging
[75Se]selenomethionine uptake include direct
CCK administration or indirect stimulation by
means of pharmacologically induced modifica-
tions of the parasympathetic or hypothalamic
control over enzyme production (52-54). It has
been suggested that pancreatic images may be
further enhanced by inhibiting lhe accumulated
radiotracer's discharge from the pancreas (55).
All of these methods require further investiga-
tlon.
THROMBUS LOCALIZATION
('z5I-LABELEDFIDRINOGEN)
As discussed previously, in order to prevent
accumulalion of L2s1 by the thyroid gland, ap-
proximalely 100 mg of potassium iodide should
be administered to the patient 24 hours before
radioiodineinjection.Potassiumperchlorate
may be used in patienls who aresensitive IO
iodine. Thyroid blockage should be maintained
for at leas( 20 days following 12s1-labeledribrin-
ogen administralion (25, 56, 57).
With a waterproof marker, marks are made on
h e patient's legsoverthe greater saphenous
veins. This i s necessary in order to insure that
probe posi~ioningwill be consistent from day to
day during the course of the monitoring proce-
dure. The marks must be close enoughtogerher
so that thc detector, when guided by thesemark-
ings. will evaluate every segment of the veins.
Generally, Ihe markings are made at 2-inch in-
tervals (58). Counts recorded over the palient's
hear1 are used as a 100% reference lo which the
radioactivity assayed in h e legs is compared
(54, 60).
PARATHYROID IMAGlNG
(7'S~~SELENOMETHIONINE
Under nornlal conditions, both the para-
thyroids and the thyroid gland concentrate ap-
preciable amounts of sele~~omelhionine(61).
Therefore, parathyroid imaging should be pre-
ceded by thyroid blockade. The administration
of thyroid hormone (e.g., Cytomel, 25 pg
daily) will suppress thyroid
function and
thereby
inhibit thyroidal
uptake of radi-
omethionine. This permits better visualization
of the parathyroid glands (62-643. Cylomel ad-
ministration shouldbegin 4 days before the
study.A99n1Tc-pertechnetatethyroid study, if
indicated, should performed
be prior to
Cytomel suppression in order to achieve max-
imum pertechnetate uptake.
MECKEL'S DIVERTICULUM IMAGING
(9Y"'T~-PERTECHNETATE)
The identification or ectopic gastric mucosa
by wmTc-pertechnetacescintiscanningcan be
aided by pharmacologic intervenlion (see also
Chapter IO). Several drugs have been shown to
enhance thepotenlial for lesiondetection in
rhese studies. Pl,emcdicaliotl of the patient with
300 mg of cimetidilie will increase gastric mu-
cosal rckntion of diopcrtechnetale (65-66). 11
is theorizctl lhal cimelidine, a histamine €3,re-
ceptor antagonist, inhibitsparietal or superhci;~!
mucosal cell secretion of the radiotracer. There-
fore, more radioactivity remains within the gas-
tric mucosal tissue, and detection of these a r e a
is enhanced (66).
Another pharmaceutical that shows promise
in Meckel's djverticululn imaging studiesis glu-
cagon. This druginhibitsperistalsis,which
therebydelersthetransrer of pertechnetate
through the stomach and small bowel (67). The
radiotracer is. therefore, more likely to remain
at the site of secretion, marking rhe lesion area.
The combination of glucagon with pentagas-
trin, a parietal cell agonist, appears to be even
more effective than either glucagon or pentagas-
lrin alone. Pentagaskin stimulates the uptake of
pertechnetate by parietal cells. In a study by
Khettery el al. (68), a 65% increase in murine
gastricconcentration of radioperlechnetate OC-
curred following pentagastrin administration.
When both glucagon and pentagastrinaread-
ministeredprior to a Meckel'sdiverticulum
imagingprocedure, thevisual quality of the
resultant scan can be greatly improved (6.5).
Utilization or these or similarpharmaceu-
ticals in Mec.kel's diverticulumscanshas not
gained widespread acceptance. There is evi-
dence that pharmacologic intervention may not
necessarilyimprovethe procedure's potential
for lesion detection (69) and that parietal cells
may not be involved in gastric uptake and secre-
tion of perlechnetate. In a study by Schwei-
singer et al. (69), the stomach concentration of
radiotracer in patients receivingcimetidine or
pentagastrin was not significantly different from
thal in conlrol subjects. Furlher studies are indi-
cated.
RENAL FUNCTION STljDlES
([12~I]IODOHIPPUR.4TE OR
[13'I]IODOHIPPURATE)
Orallyadministered fluidscan be used in
('231]iodohippurate or ['3LI]iodohippurate renal
functionstudies in orderto assure adequate
urine flow, if hey are not contraindicated by the
presence of edema or congestive heart 1'1'1 I ure.
Approximately 10 m l of water or tea pcr kg
body weight should be administered to the pa-
tient l hour prior to [he procedure (70).

For a reliable study, it is recommended that
the urine flow rate be at least 2 mllmin (71).
Severalinvestigators (72-75) haveshown that
in radioiodohippurate renograms, the time to
peak and the slope of the descending curve are
highly dependent on urine flow rate when urine
excretion is SIOW. When the flow rate exceeds 2
mllmin, however, renal functioncurves in the
normal patient remainfairIy constant.Conse-
quently, low urine flow rates can distort re-
nogram curves, whereas more rapid urine out-
flow helps to assure that renograms will more
consistently describe kidney function (7 1).
M1'OCARDIAL PERFUSION STUDIES
({201T~]THALLOUS CHLORIDE)
'OIT1-chloride nuclear medicine studies often
include an evaluation of myocardial perfusion
under physiologic stress (see also Chapler 10).
In this procedure, the patient is exercised, usu-
ally on a treadmill, until at least 90% of pre-
dicted maximal heart rate is attained. An elec-
lrocardiogram is recorded throughout the study.
The Bruce protocol (Table26.1) is one example
of a treadmill stress regimenthat may be utilized
in this procedure (76).
Table 26.1.
Bruce Multistage Exercise Protocol
~~
Duration Treadmill Speed
Stage (Mm) (mph)
1 3 I .7
2 3 2.5
3 3 3.4
4 3 4.2
5 3 5.0
6 3 5.5
7 3 6.0 22
The patient should receive nothing by mouth ischemic myocardium (84-85). In redistribution
(NPO) for approximately 4 hours priorto this or studies, however, the results following exercise
any similar rigorous exercise regimen. A zorTl- and dipyridamole may be dissimilar (86).
chloridedoscisthenadminisleredquickly
through a conlinuously running inlravenousline
(TKO) or other preestablished intravenous line, imately 4 minutes) or orally. An oral dose of
andexercise is continued for an additional 200-300 mghas been usedwithsatisfactory
30-60 seconds, The imaging procedure should
commence within 3 -10 minutes after exercise
has been stopped (77, 78). Because of the pos-
sibility of arrythmias or olher cardiac complica-
tions, Zo'T1stress studies should be supervised
by a cardiologist or otherqualified physician. A
defibrillatorandallnecessarymedication
should be available for immediate use.
Exercise-induced stress prior to imaging in
201T1 studiesserves ~ W Opurposes.First, when
the myocardial demand for oxygen is elevated
by stress,perfusion of thecardiactissue in-
creases and myocardial uptake of the radiotracer
will be more rapid andcomplete. In studies
during exercise-induced slress, compared with
those during rest, the concentration of thallium
in the myocardium will be greater and there will
be less activity in the liver, spleen, kidneys, and
gastrointestinal tract (79-80). Second, areas of
ischemic, yet no1 infarcted, myocardium which
may not be detected in a thallium study during
rest can often be demonstrated by a stress proce-
dure. This is because stenolic myocardial blood
vessels, which are capable of accommodating
normal perfusion. are not able to dilate in re-
sponse to more rapid blood flow during stress.
Consequently, thallium distribution in the myo-
cardium can be irregular (demonstrating ische-
mia) during exercise but appear uniform or nor-
mal duringrest. Usually, both procedures are
performed; i.e., a thallium scan during stress is
followed approximately 4 hours later by a study
or redistribulion
during rest(81-82).
Trcadmlll Grade to exercise in201 T1 myocardial
1%)
imaging is the induction of coronary vasodila-
10 tion by pharmacologic agents such as dipyrida-
12
14 mole(seealsoChapter10). In a study by Ham-
ilton et al. (83), dipyridamole
16 administration in
dogs produced a 60% increase in the uptake of
18
thallium by myocardial
20 tissue. clinical
Several
investigators describe
dipyridamole
as being as
effective as exercise in the production of non-
uniform thallium distribution in the regionally
Dipyridamole can be administered by intra-
venous infusion (0.14 mglkglminforapprox-
rcsults (84).
HEPATOBILIARY IMAGING the tracer's movement toward the gallbIaddeI.
(99"T~-IMINODIACETICACID (IDA) Freeman et a]. (93) believethat premedica-
DERIVATIVES) tion with CCK or sincalide may not be adv;m-
It may be helpful to have patients fasl, when tageous in cholescintigraphic studies, since s e w
possible, for 2-6 hours prior to hepatobiliary sitivity for the detection of chronic cholecyslitis
scintigraphic procedures. In postprandial stud- is markedly reduced. When gaIlbladder visuali-
ies, visualization of the gallbladder is often ap- zation is artificiallystimulated,detection OF
preciably delayed, a finding which may be er- chronic cholecystitis (usually associated with
roneously interpreted as cystic duct obstruclion delayedgallbladderappearance)will not be
or chronic cholecystitis (87-89). The radio- possible. These investigators suggest that con-
tracer hepalocyte clearance and parenchyn~al traction should be induced only when the gall-
transit time have also been shown lo be affected bladder has not been visualized after 2 hours ol
by the ingestion of food prior to the study (87). imaging. In his way, cystic duct patency can hc
In this case, there may be no interference with evaluated withouttheability to deteclchIonlc
diagnosis. The ingestion of food can, however, disease being lost.
inlerfere with the empirica1 determination of
normalvaluesfortheinvolvedcholescinti- VARIOUS PROCEDURES (ORALLY
graphic parameters. ADMINISTERED
Theoretically, radiopharmaceutical passage RADIOPHARMACEUTICALS)
intothe gallbladderis inhibited in nonfasting IC is recommended thal oralIy administered
patients by the outward flow of bile Prom the radioactive pharmaceuticals, Iike many other
gallbladder toward the common bile duct. This drugs, be takenonan emptystomach.The
movement of biIe away from the gallbladder is patient should not eat for several hours before
established by gallbIadder contraction and the radiotraceringeslion.Thepresence of food in
relaxation of the sphincter of Oddi. These two the stomach may delay gastric emptying. which
actions are stimulated by CCK released into the thereby decreasesthe rate of drug absorptiorl
bloodstream when food is present in theduo- from the duodenum (94-96). Furthermore, gas-
denum (90). It is believed that because CCK tric contents can impede [he drug's enteral dis-
stimulation is not occuring in thefasting pa- integralionand dissolutionnecessary for ab-
tient, the flow of bile will be toward thegall- sorptioninlothebloodstream (97). Nuclear
bladder, encouraging radionuclide movement in medicine procedures which involve the use of
that direction (87).
oral radioactive dosage forms include thyroid
Another lechnique for promoling gallbladder uptakeand imagingstudies, thyroid therap):
visualization is lo adminisrer CCK or sincalide Schilfingtests, andother gastrointesrinal ab-
(a synthetic CCK analog) before the scanning sorption evaluations.
procedure (91, 92) (see also Chapter 10). This
practice is effective as long as &he radiophamla- CONCLUSION
ceuticd is administered after the acute contrac-
In this chapler are described methods of pa-
tile effects of CCK have dissipated.
tient preparation that canfavorably affectthe
The rationale for CCK premedicationisas outcome of nuclear medicine studies in specific
follows. If thecysticduct is patent, CCK-in- Filuations. Some of these practices may be con-
duced gallbladder contraction is believed to re- sidered essential to the success of the nucle;ir
move viscous bile from the gallbIadder and medicine procedure, whereas others
may be
cystic duct, which thereby minimizes resistance thought of simply as a means of obtaining Inore
to subsequent radiotracer flow (91). If this is the valid or reIiable information. Regardless of rcla-
case, lhe contraction obviouslymustbe corn- live importance, each of the preparatory merh-
pletedbeforetheradiopharmaceuticalhas ods discussed can'contribute tothe qualily of
finisheditstransitthroughthchepaticpar-
thc respeclive study and can serve asa mca~lsof'
enchymal tissue and into the bile collectingsys- maximizing the value of nuclear medicine pro-
ten]. Otherwise, outflowing bile would impede cedures.
418 f Essmriols oJ-Nucfem'Medicine Srieme
Thespecific patientpreparation techniques
discussed in thischapter may not be readily
applicable to every practice setting or situation.
Theseorsimilarprocedures can be used or
modified as necessary. It is important, however,
that when new protocols are developed, the ra-
tionale and theoretical basis of each lechnique
be considered.
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withthallium-201. A1n J Cardiol 37:118-126, 1976.
79. Alkins HL, Budinger TF, Lebowitz E, etal: T h a l -
lium-201 for medical use 111. Human distribution and
physical imaging properties. J NrtclMed 18:133-138.
I977.
80. Strauss I-IW, Hamisonk. Langan J K , et al: Thal-
lium-201 for myocardialimaging.Relation of thal-
lium-201 to regional myocardial perfusion. Circulario~~
51:641-660.1975.
81. Pohost GM. Zin LM, McKusslck KA. et al: Difrer-
entiation of transiently ischemic irom infarcted myocar-
diumbyserialimagingafter a singledose ol
thallium-201. Circdorion 55:294-299,1977.
82. Ritchle IL, Trobaugh GB, Hamillon GW. et al: Myocar-
dial imaging with thaIlium-201 at rest and during exer-
cise: compwison with coronary arteriography and rest-
Ing and stresselectrocardiography. Circrtloriort
56:66-81, 1977.
83 Hamilton GW. Narahara KA, Yee H. et al: MyocardlaI
imaging with thallium-201: elfect of cardiac drugs on
myocardial images and absolute tissue distribulion. J
Nfrcl )Wed 19:10- 16, 1978,
84 Albro PC. Could KL. Westcott RJ: et a]:Noninvasive
assessment of coronary stenoses by mpcardlal imag-
ing during pharmacologiccoronaryvasodilation HI.
Clinical trial. Am J Cardiol42:751-760. 1978.
85. Albro PC, Gould KL, Westcotr RJ, et al: Noninvasive
assessment or coronary disease in man by myocardial
imaging durmg pharmacologic vasodilation. J Nlrcl
Med 19~743,1978.
86. S k l x J, Kirch D , Eouth J, et al: Diflcrences in thallium
redislribution after exercise and dipyridamole infusion.
J A'ud Med 2241, 198 1.
87. Klingensmith WC, Spitzer VN, Fritzberg AR, et al:
Index
The normal fasting and post-prandial diisopropyl IDA
Tc-99m hepatobiliary study Rodiolugy 141:771-776, Page numbers in irolics indicate illustrations; I following a page number indicates tabular material.
1981.
88. Weissmann HS, Frank MS, Bernstein LH. et al: Rapid
and accurate diagnosis of acute cholecystitis with 99m-
Abdomen, clinicalvariations in, radiopharmaceuticalbio- hyperplasia of, versus adenoma, 1 16- 117
Tc-HIDA cholescintigraphp AJR 132523-528, 1979.
89. Baker RJ. Marion MA: Biliary scanning with Tc-99m distribution and, 244. 245 imaging of
p~rjdoxylidellplutamate:the efiects of food in normal Abdominalimaging,gastrointcslinalbleedingand, NP-59, 12
subjects. J N~rclAged 18:793-795, 1977. 123-124 pathologic mechanisms altering. 260
90. Hendryx TR: The absorptive function or the alimentary AbscessIocalizaIion interventionalstudies.of, 116-117, 117
canal. In Mountcastle VB (ed): MediculPhysiofogy. Sf drup-radiopharlfiaceulical interactionsaffectmg Adrenalmedulla imaging, drug-radiopharmaceuticalinter-
Louis, CV Mosby, 1980, vo1 2, pp 1305-1307. [6iGa]galIium citrate in, 21 1-215 aclions affecting, mIBG in, 206-207
91. Eikman EA, Cameron JL, Colman M, et al: Radioac- 1"In-labeled leukocytes in, 203 P-Adrenergic blockers
tivetracertechnlques in the diagnosis of acute cho- (67Ga]galliumcitrate for. 14-15 SmTc-labeled red blood cell interactions with, 199-201
lecystitis. J N'rrcl Med 14392. 1973. '1%-labeledleukocytes lor, 15, 94-95 [1*lTl]thallouschlorideinteraclionswith, 207-208, 209
92. Eikman EA, Cameron JL. Colman M. el al. Test lor [6"Ga]gallium cilrate versus. 79 Adverse reactions, 303-319
patency or the cystic duct in acutecholecysLilis. A m patlent preparation lor. 414 characteristics of, 313-317. 3141-31%
Jnrenl Med 82:318-322, 1975. Absorbed dose (see a h Dose) definition of, 303-304
93. Freeman LM,Sugarman LA. Weissman HS: Role or altered biodmribution and, 69-71 incidence of, 317-318
cholecystokinetic agents ~n RmTc-IDAcholescintigra- general principles of, 5 1-53 reporting .system for, 304-310, 305-309
phy. SenIiJlN d Med 11: 186-193, 1981 invesligationalnew drugs, 53-55, 363 statistics on, 3 10-3 13. 3 1 1 r-3 13r
94. Toothaker RD, Welling PG: The e f k t of food on lactationand.59-64 type A versus type B. 304
drug biolavailability. A m Rev Pharmocol Toxicol 20: pediatric (see Pediatricpatient) type B , validation of. 319
173-199, 1980. pregnancy and, 64-69 validation or, 318-319
95. Levine RR: Factors affectinggastrointestinalabsorp- radionuclidicimpurities and, 283 Aerosol (see Radioaerosols)
tion of drugs. Am J Dig Dis 15:171-188, 1970. regulatoryagencies and, 53-56 Age (see also Pediatric patient)
96. Nammo WS. Drugs. dlsedses and altered gastric empty- Acalculous cholecystitis, 127 biokinetics and, 57, 58, 5%
ing. Clirl Plronf~acukirler1:189-203, 1976. Accuracyq test,135, 135, 137r bone scan and, 237. 2371
97. Mayer SE, Mclmon KL, Gilman AG: Introduction: the ACD (see Acid-citrate-dextrose) radiation risks and, 58-59
dynamics of dmg absorption. distribution and elimina- Acelanunophen. 99mTc-gluceptate interaction with, 197 therapeuticeffectand,112-113, 1121, 113
(ions In Gilman AG, Goodman LS, Gilman A (eds): Acetazolamide, II'ln-DTPAand '"Yb-DTPA interactions Agreemenl states, 53, 3221-3231
The Plmr~nocologicolBnsiJ OJ Tllerapezrrics. New with, 202 ALARA,329
Acid-citrate-dextrose(ACD).281-282 Albumin
York. Macmillan, 1980, pp 5-6.
Acidosis. (*7GrgalIlum citrate and. 179 iodinated serum, fetal dose of, 66
Acqulsition, mode of. 146, 148 macroaggregated (see YP"Tc-labeledalbumin, macroag-
Actinomycin D (see Daclinomycin) gregated)
Addictive drugs of abuse, {67Ga]galliu~ncitrate interaction WmTc-labeled (see BmTc-labeled albumin)
with, 212 Albumin microspheres (see olso WmTc-labeled albumin), 5
Adenocarcinoma, animal model of, 3461 Albulerol, gastricemptyingradiopharmaceuticalinterac-
Adenoma, adrenal, 1 16-1 17 tions with, 216
Adminismation Alcohol (see Benzyl alcohol; Ethanol)
errors in, absorbed dose and, 70-71 Aldosteronoma, 117
route of Alkylating agents, side effects of, 55
inadveflcntly altered, 230 Allergic reactions, 313
selection of radiopharmaceutical and, 79 albuminparticulates and, 316
Adrenalcortex imaging, drug-radiopharmaceuticalinterac- colloids and, 316
tions affectillg, [~"Ijiodomethylnorcholesterol in, Allograftrejection,258-260
205-20G Allopurinol.[6iGa]galliumcitrateinleractionswith,
Adrenal gland 214-215
clinical variations in. radiopharmaceutical biodistribudon Aluminum (see olso Hyperaluminemia), liveruptake of
and, 243 radiotracers and,177
42J
422 I lndex Irzdes i 423

Aluminun~ion, formulation problems caused by, 270, 274 Antibiotics (see d s o specific agent; specific class of antibi- BIDA (see Butyl iminodiacetic acid) patient preparation for. 4 13
Aluminum-containingantacids otics! Biguanldes,radiocyanocobalamininteraclions wifh selection of radiopharmaceutical Tor, 80. 81
'9mTc-labeled phosphateandphosphonate interactions cell membrane efiects of, I6? 209-2 1 0 strucrure-distributionrelationshrps of *IIITc-I;I~cIc~I
with,194-195 [6'Gajgatliurn citrate interactions with, 214-215 Biliary atresia, oeonaial hepatitis versus, I26 agenlsfor, 41 41
W'lTc-pertcchnctate interactions with. 199 L'lln-labeled leukocyte interactions wilh, 203 Blliaryobstruction *"Tc-phosphonate compounds in, 7-8
AmericanHospitalAssociation,"Patient'sBill of Rights" thyroid-scanning effects of, 184 animal models of, 341f Bone infarct, "IIn-labeledleukocytes for diagnosis of. 95
and, 404-405 Antibodies. labekd. radiodlagnostics based on, 36 diagnosis of, with irninodiacetic acid compounds. 26 Bonenlarmw.therapeuticirradialioo of. radiotraccl d~strl-
€-Aminocaprobc acid. gy'"T'Tc-labeledphosphate and phos- Anticoagulants, formulation problems related lo, 281-282 extrahepatic, 126 burionaffecled by. 223-225. 723
phonateinteractionswlth, 196 Antlconvulsanls. radiocyanocobalanlin inleractions with, Biodistriburion Bonemarrom Imaging
Am~noglycosides,renal funcllon radiopharmaceutical inler- 209-2 10 altered drug-radiopharmaceutlcal inlcmcmw aflccring. Uq"lTc-
actions with, 21 8 Antidepressanfs.~ricyclic. mIBG interactions with absorbeddoseand.69-71 labeledcolloids in, 190-191
p-Amlnoaalicylic acid. radiocyanocobd~arnm interactions 206-207 drug-induced pathologic mechanisms allering. 2h?
with, 209-210 Anrihistamines.thyroid-scannlng effects of. 183 reportedinstances oi, 189-219 Bone pain, sodium I~'PJphospl1;rtc h r . 8 5 . xb
Amiodaronc,[6'Ga]galliumcitrateinteractions with,212 Antimonysulfidecolloid.9kT~-labelcd,normal bio- theoretical considerations, 165- 184 Bowel preparation regimen, abdor~>in;tlirn:Iprl< p r c ~ c d c t ~
Ammoniumchloride,AmTc-DMSAinteractionswifh. dlstributlon of. 6-7 frequenr causes of. 391; by, 4 14
197-198 Antioxidants. Wqc-labeled radiopharnlacellricals and. 8 l , invasive therapy causing. 220-230 Braln Imaging
h~phorericln8.""Tc-labeled phosphate and phosphonate 81. 280 paihotogic mechanisnls causing. 248-2633 d r u e - r a d i o p h a r n ~ a c e u t i c n l i n l c r a c ~ l ~ l r;11fcr1111r.
l>
lnlcractlons w l h . 194 Antllhyroidagents drugeifecrs on 216-217
Alupicillin, 16'Ga]gallium citrarcinleraclions with, effects on thyrodscanning agents, 183 blood components and, 169 wmTc-pertechnetatc in, 169- I7 1 . l 99
214-215 iodidcinteractionswith;204. 2041 cellrnembrancand.166-169 nornlal clinical varlations affecting. 236. 237r
Amyloidosis, animal models of, 343-345, 3 4 3 Arteriovenou~.shuut,252, 252 enzymesand, 164 pathologic meclmisms altering,248, 2#Y
Analog-lo-digital converters,146.147, 147 Arteritis. anlmal lnodels or, 3371 factors defennining, 156 pahenr preparation Tor, 413-414
Analomic structure, normal varmiions in. radlopharmaceuli- Arlhriris,animalmodels of, 3351 rum1111afiot1 problemsand, 268-284 q"flTc-DTPA.4-5
ca1 blodistriburionand. 234-245 Arrifactnjanual. 290 normal, 3- 1 G wmTc-gluceptale,5
Androgens."y~Tc-labelcdcolloidlnteraclions w r h . Artifacrs, 290 clinical varialions of. 69. 234-245 9PmTc-pertechnetate, 4
190-19f colllrnalor selectlon and, 294 SIrucIurc md. 33-42 Brain lumor (see also Cenfral nervous sysrem. d l s e a m (11'
Auel~~ia. helnolylic, animal model 6 . 345. 3451 freqtlent causes of. 391r Diokir~clics,age and. 57 animal models of, 336, 33x1
Anesthctics qualily control procedures and, 291 Biopsy. radio1r:lcer disrrtbutiun affccted by, 226, 227 Breasr
ccll tnembranc effects of, 167.168. 178 renal imaging, 296 BlCeding. gaslloin~cstina~ (see Gaslrornteslinal bleeding) cancer of. animal models of. 346-347
radloxcnon interactions with. 21 1 single photon emission computed tomography, 300 Bleolnycirl cllnicai varlatims in, radiopham~aceulicalbiottislr1hurit)ll
reliculoendothehalsystemarfecied by. 174 Ascpric meninpltis. animal models of, 336, 33% 16'Galgallium citrale mteraclmns with. 212 and, 239
q"Tc-labeledcolloidinteractions with, 191 Asialoproteins. 166 toxicity. 263 Breast milk (see also Lactation), 54
Angiocardiography,119 Asplenia, 226 Blood-brain barrier. per\echneiate uptake and, 4 , 169, 170. radioactivity in. 59-61, 6O!, 239
A11&rdp11y, cerebral, psychotropicdrugcFfects on. 217 Asthma+ anima[ models of, 338, 339r 171 "InTc ingested in, 62-63. 62t-631
Aninlal models,333-347 Atherosclerosis Blood components Srornosulrophthalein ( E S P ) , hepatobiliary animal model5
;~n~yIoidosis, 343-345. 3451 animal models of, 335. 337r drug erfects on. radiotracer distribution and. 169 and, 339-340
cardiovescular sysrerns. 334-336. 3371 caotid allerg. "lln-labeled platelets in diagnosis of. 96 radiolabeled,preparauonand chnical utility or, 90-96 3-Bromo-2.4.6-trimethylphenylcarbamoyln~ethyliminodia-
cenlralnervous system, 336. 3381 Atresia.biliary.neonatalhepatlrisversus. 126 Blood flow cetic acid (mebrofenin), structure or. 38, 39
clinical testing preceded by, 362 Atropinc bone, animal models of measurement oi. 334, 3 3 5 ~ Bronchitis. chronic, animal models of, 338, 339r
defined. 333-334 brain Imaging preceded by. 41 3 cerebral. scintigraphic compurcr anafysis of. 157 Bruce mul~is~agc exercise protocol, 4161
diabetes. 343. 344r gastrlc enlplyinp radiophnrn~;lcc~~tica[
interactions w i t h . intestinal. animal models of, 340r BSP (see Bromosulfophthalein)
digestive system. 338-339. 340r 216 Blood pool imaging. 119, 151-154, 151-152, 155 Busulfan, [6'GaJpalIium citrate inreractions wlrh, 212
genitourinary system, 341-342. 3421 Altenualion correction. I59 animalmodels or. 345, 3451 Bulyl iminodiacetic acid (BIDA), ""Tc-Iabcled. norlnal
hematologic disorders. 345, 3451 IqBAu colloid, 86, 316 W"'Tc-labeled red blood cells in, I I blodistribution of, 9
hepambiliary system, 339-341. 341r Azygos fissure,244 "mTc-pcrteclmetalein, 4 By-produeis, 53
investigational drug, 54-55, 362 Azygos lobc. 244 Blood transrusion, rediotracer biodisrribution and, 229
nlelabolic disorders. 345 Bone (see nlso enlries beginning with SkcleiaI) I4C-DTPA, metabolism of. 48
oncologic. 346-347, 3461 BocillfrsCalmefle-Glrhifr,[b7Ga]galliu~n citrate iflleraclions animal models of disease in, 334. 3351 114C]glucose.sperm metabolismassessed by, 107- 1 0 3 ,
rcspir;ltory system. 336-338. 339r with, 212 Clinical variations In, radiopharmaceuiical biodistnbu[ion 1031
skeletal system, 334, 3351 Bacleriostatic sallne. W"kTc-[abelerlradiopharmacellricals and.237, 2371, 238 Caffeine, effecrs on sperm, 102-103, 103r
Anions, radiopharlllncclllical. n~etabolisn~of. 45-46 and. 281 cold lesions of. 260 Calcitonin, effecrs on radiophannaceuticals, 176
Annihilntioli,r;lrlialion,tomography al~d,160 Bar phantoms. problems with use of. 291, 292. 294 tllcrapeutic irradialion or, radiotracer distriburion affected Calciuni channel bleckers
Antacids Bayes' theorem. 105, 137-139. 138 by,22 I 223, 224 cell membrane effects of, 168
alulllinllm-col~t;lininp Bcnzodiazctincs. iodltleintcractions with, 204. 204r Bone imaging 'n'l'Tc-labeled red blood ceil interactions w i ~ j I~Y, - 2 0 0
.1 colloidal inlpurities In. 268, 269
qJ"~Tc-labeletI phosphate and phospbon;lle interactions Calciumchelating agems, radiocyanocoballlrlliIl infcl;lr-
with. 194-195 drug erfects on agenfs Tor, 175-178 lions with,'209-210
*'nTc-pcrtcchnclatc ir~lernclio~~~ with, 189 evalualiou or therapy with, 102 Calcim gluconate
gaslroesophaycal rcllux ; m I > t22 free pcrlechnctetc in, 268. 269 16'Gnlpallium citrate inleractions wilh. 214
w"'Tc-lebclcd colloid interacllnns with. 190- 191 l i w r uprake in itgcnrs for, racrorsassociated with, 393, W"'l'c-labeIed phosphate and phosphonate in!cr:wtirlllh
cardiotoxic c~fccrsor, 181- 182
A~~tl~racycli~~cs, pnthdogic mCCtl;ll~isl~ls :Ilkring, 257-262, 260-26: with, 195
 424 I Idex

Calclurn ion clinicnl variations in. radiopharmaceutical biodistribution

Cistcrnography Corticosteroids
cell membrane erfccts of, 168 and. 236, 2371
agnls for, adverse reactions to, 317 brain-Imaging radiotracer InteracLions with. 217
digitalis and, 181 diseases of. animal models of. 336. 3381 drug-radiopharmaccut~calinleractlons alfectmg. "'In-
radiopharmaceuticals for. pathologicalalterationinbio- "'In-labeled leukocyte inleraclions with, 203
eifecls on radiolracerdistribution. 176. 177 DTPAand'GgYb-DTPA In. 202
distributlon of. 248-249. 249-250 ""Tc-lahcledphosphate andphosphonateintcrxc11~1113
Camera pathologic mechanisms altering. 248. 250
Cenrral processing unil (CPU).349-150 with, 196
gamma (see Gamma camera) Clinical t e s h g , new drug (see also Inveskiga!ionalnew Cos1
single photon emission computed tomography3 298, 298 Cephalexin, [6'Ga]gallium citfateinteractionswith:
drugs), 358-361, 360-361 monitoring. I OS- 109. I091
calibration problems with, 299. 299 214-215 Clofibrate.radioxenoninteracllons with, 211
Cephalosporins. [6'Ga]gallium citrateintcraclions with. selection of radiopharmaccut~caland, 82
relation to patlent. 299-300 Codeine, hepatobiliary imag~ngand, I84 CPU (see Ccntral processing unit)
CAMP (see Cyclic adenoslne monophospllale) 214-215 Colchlcine CPZ (see Chlorpromazine)
Cancer (see Q / S U Carcinoma; specific site) Cercbralblood Flow analysis.sclntigraphic computer i n , phapocytoslsand.174 51Cr-labeIedplatelets.15
anlmal models of. 346-347. 3461 157 radiocyanocobalamin interactlons with, 209-210 5'Cr-labeled red blood cells
chemotherapeutic agents for (see Chemotherapeutic Cerebral infarlion. anilnalmodels of, 336 CoHagendegradation, 176
Cerebral nucroembollsm. animal models of. 336, 3381 clinicalutilily of, 91
agents) Collimator select~on.294-295, 295-295
Cerebral perfusion studies, patient positioning lor. 413-414 preparationof, 90-91, 91r
radiation-Induced, age and.58-59 Colloids Crystal hydratlon, field uniformity and. 291
Captopril. ''pmTc-DMSA interactlonswith.198 Cerebral spinal fluid clearance. rate of. 248-249 'YsAu. 86 CycI~cadenosine n~onophosphate(CAMP)
Carcinoma (see also Cancer) Cemlctide,126. 128 heparin elfects on uptake of. 172 cardlac function and. 181
lung. animal models of,338.3391 Chemoperiusion in~puriliesin. 268, 269
radiotracer biodislribution and, 229 ethanol and benzyl alcohol effects on. 180
sodium ["ll]iodide for. 88 ""Tc-labcled (see "'"Tc-labeled colloids) pinocylosis and. 170
thyroid, 25 1 regional, "mTc-labeled phosphate and phosphonate inter-
Coma. hepatic, animal models or, 3411 rcticuloendothelialsystem-imagingagentsand.173
Cardiac function. multiple-gated Imaging of, 153-154, I S 3 actions wl!h. 195
Commercialsourcc.formulationproblcmsrelated IO. Cyclic nucleotide. intr;cellular concentration of, 168
C;lrdiac glycosides. [?DlTllthallous chloride interxt!ons Cl~ernorhcra~xu~~c agents 278-279
brain-imaging radiotracer interactions with. 216-217 Cyclohexamide, rad~ocyanocobala~nir~ interactions w r r l ~ .
w t h . 209 CompartmenIal analysis (see Radiopharmacolilnetics)
combination. [Walgalliun~citrate i~~teracl~ons with. 212 209-210
, .
Cardiac imaglnp Conlplen~entsystem, 172-173 Cyclophosphamide
moniloring with, 102 "cytotoxic." 9PmTc-labelcd phosphateandphosphonate Compliance problcms. 328-329. 3281
interactions wmith. 194 brain-imaging radiotracer interactions with, 216-217
pathologicmechanismsaiterrng,251-252 Computedtomography (,we Emisslon compulcd tomogra-
[b'Ga]galliumcitratelnleraclions with, 213,215 49"'Tc-labeled phosphateandphosphonate inferaction3
physiologicInterventionin,119 phy: Single photon em~ssioncomputed tomopla- with. 194
"mTc-labcled albumin. 1 1 VmTc-Iabcledcolloidinteractions w i t h . 190
PhYl Cyclosporine. renalfunctionradiotracerinteractions wth.
gPmTc-labetcd phosphate. 8 Children (see Pediatricpatlent) Computerk)
Chloral hydratc.pediatricparienlsedationwlth, 412 218
99mTc-labeledredblood cell. 1 1 . 91 apphcations of, 145-160 Cyst(s)
[~~Tl]thallous chloride,13 Chloroqurne, [~~Ga]galliun~ citrateaffecled by, 179 basics of, 145-150. 1466148, 1491 inlracranial,248
Cardiacmassage.external,radiopharmaceuticalbio- Chlorpromazine (CPZ), IzP and, 168 central processing unit of. I49-150 ovarian, 251, 251
distributionand. 228-229, 22Y Cholecystitis , 126, 127, 255 datastorage. 149 Cytochalasin E, 178-179
Cardiac perfusion abnormalilles (see rrlso Myocardial perfu- Cholecystographicagents, iodideinteractions with. 2041 displaydevlces. 147. 149 Cytochrome P-450, 44
sion Imaging). 118. 118 Cholecystokinericagents.126-127.128 inputs to, 145-147, 146-148
Cardiacradlolracers.drug crfects on. 180-18? Cholecystokinin (CCK).126 laboratoryusesof. 160 Dachomycin
Cdiwactive drugs.cycllcadenosinemonophosphateand. hepatobiliary imaging and, 417 memory In. 146, 149r, 150
stimulation of, pancreas imaging preceded by. 414 brain-imaging radiotracer inleracLions wilh, 216-217
181 outputdevices, 147-150, 146 radiocyanocobalamininleractionswith, 209-210
Cardiology, 180- 183 Cholescint~graphy scintigraphlc. clinical uses for. 150-160 Decay mode, selection of radiopharmaceutical and. 75-76.
scintigraphic computer in. 150- 157 dmg-radiopharmaceuticalinteractlons alfecling. 9PmTc- syslcm bus, 146, 149. 150 761
Cardioloxlcily.anrhracycline.181-182 iminodiacetlcacid derivatives in. 191-182 con A (see Concanavalin A ) Decision analysis, 139-142, 140-142
Cardiovascular system sincalidewith.126-127 Concanavalin A (con A): 176- 179 Declsion making. 133-134
diseases or, anirnal rnodets of; 334-336,337r Cholestyramine, radiocyanocobalamin interacllons with, Condit!onalprobabilities,133-134 Bayes' theorem in, 137-139, 138
imaging of. pathologicmechanisms affecting, 251-252 209-210 Congestive heart faiIure, 256 probabilitiesin.133-134, 134r
interventionat studies of.117-119 Chromatography,high-performanceliquid(HPLC), Consul~ant,concept of diagnosllc imager as. 395 Decisionnlatrix,134-137, 1341, 135-136
WmTc-labelcdred blocd cell, 91 ~~T~-~,hl'-bis(mcrcaptoacetyI)-2,3-dian~inopro- Consullalionservice,389-396 Decision tree, 139- 142, 140-142
Cardioversion. 262 panoate,37 Contamination Decomposition, radiolytic, formulation problems relaled t o .
radiolraccr biodislribution and, 228, 228 Chromic['?P]phosphale computer analysis or, 160 279-280
Carotid artery, radiolabeled platelet examination of, 96 dcscripion of, 86 formulation problems rclaled to, 283-284 Defibrillation,gP'nTc-pyrophosphaleuptakeand,228, 228
Carrier T c , formulation problems vith, 268, 270 dose of, 86-87 Continuing education, 409 Department of Transportation (DOT), regulatory autll(>rily
Cation permeability of membranes, immunologic reactions indicelionsfor, 86 Contraceptives, oral (see Ora[ contraceptives) or, 327
and, 167 mechanisms of action of. 86 Conlrastagents Dexamethasonesuppression,116-117, 117
Cations. radiopharmaceutical, metabohsm ol, 45 mctaboiism of, 46 iodideinteractionswith, 204r Dextran, 14'Gajgalliu~n citrate affected by. 179
CCK (see ChoIecysrokinin) monitoring parameters for, 87 iudinatcd Diabeles, aninla1 models of, 343, 344r
Cellmcmbranc pharmacodynamics or. 87 renal function radlomcer inleraclions wlth, 218 Diagnosis, radiopharmacokinetics and. 26
dmg effectson. radiotracerdistribution and. 166- 169 toxicity uf, 87 p'n'Tc-labeled rcd blood cell interactions with. 201 Dialysis
permcability, 166-167 Cimctidinc, Meckel's tliverticululn detection and. 125. 415 Iym~'ha~lgiogral)t~ic,[Wa]gallium citrale interactions complcmentactivity and, 173
Ccltoptvane.dialyzer.complelnent activation and.173 Cisplnti~l wilh. 212 r:~tliopl~arn~accuLical
biodislribution and, 230
Cellular cffccts of radiation, 110-1 I 1 I~~Ga]yallium chloridc interactions with, 213 Con~naryartery discase, myocardial perfusion imaging and. wn'Tc-pertechnetate, 170- 171
Ccntral ncrb'ous syhtcru (sw olso Brain irnaglng) renal functionradiotracerinleractions with. 218 151, 156-157, 156. 158 Diazepam, radioxenon interactions with, 21 I
 426 i Iltdex

Dicopac Schilling test. 182-283 r9Fc.feral dose of. 65-66 Gastmntestinal bleeding
Dicthylcnetrianlinepentaaceticacid (DTPA) (see "lIn-dieth- Fetus, radiation risks to, 64-69, 68r animal models, of, 340r
ylenetriaminepentaacelic acld: yqnTc-dlethylene- Fibrmogen (see '?Tfibrinogen) diagnosis of
trialllincpentaacetic acid) Field flood phanloms,problems with use of, 291,291, 292, lLIIn-labeledplatelets in, 96
2.6-Dietl1ylin~inod1acetic acid. normal b~odislribulion of. 294 ggmTc-labeledredblood cells in. 91-92
8-9 Fielduniformity, 292 inlerventional studies of.123-124
Diethylstilbestrol Follicular carcinoma, sodium ["'lliodide for. 88 radiopharmaceutical efficacy and, I 1 1
["Ga\ylliunl citrnte interactionswith. 212-2[3 Food and Drug Administration (FDA) Gastrointestinal disease. animal models of, 338-339, 340r
YY"'Tc-labeled phosphate and pllosphonate inlcraclions adverse reactions and. 303-310 Gastroinlestinal imaging
with. I96 investlgationalnew drugs and "'In-labeledleukocytes in. 95
Dlgcstive system (see enlries bepnning wilh Gastrolntesti- Ecu~>omics or monitoring, 108-109. 1091. I I I I application processing and. 55-56. 364-367, 366 pathologic mechanisms altering. 254-258. 254-256
nal) ECT (Jet Emisslon computed loll1opraphy) gu~del~nes for.54-55.357 y5'nTc-labeled red blood cells in. drug interactlons w i t h ,
Diglvnl imaging (.reg Co~nputer(s);specific site1 Education (see also htlcnt education). conlinulng. 409 regulatory authority of. 53, 326-327. 327 20 1
Digitalis. calcium ion and. 18 I Elreclivethyroid ratlo ( E m , probdbililies of. 1 3 4 clinical testing ofnew drugs and, 358-360 Gnstrointestinal lrdct, therapeutic irradiatlon or. radiotracer
Digox in Erficiency or nuclcdr medlcine stt~dy~ 395 Formulation, select1011 o~rddiophannaceuticals and.
81-82, distribufion affected by, 226
Ehrlich ascites, anilnal models of. 3461 81 Gated blood pool imaging (see Blood pooI imaging)
"K and. 181
Ejection fraction. 151 Fomwlalion errors. absorbed dose and. 70 Gated ventr~culography(see also Blood pool Imaging).
radloassay. 101-102. 103
'FJn'Tc-labeled redblood cell mteractions with, 101 Embolism.pulmunary (see Pulmona~y enlbolisn~) Formula!ion problems. clinical manireswtlons of. 268-284. 151-154. 151-153, 155
Dihydrolachysterol, radiolrdceruptakeand. 176 Emission computed tomopraphy (see dso Single photon 2711-2731 Gaviscon, gastroesophageal renux and, I22
Diiodotyrosine. 12 emission computed tomography). imapng prob- Fourieranalysis. cardiac contraclionand. I54 Genirourinarydisease.animal models of. 341-342.3421
Diphosphonate. qVmTc-labeled phosphateand phosphol~dle lems in. 298-300, 299, Fraclure. animal nlodcls of, 334, 3351 Gcnitourinary imaging, palllologic mechanisms altering,
Interactionswith. 193. 197 Emphysema. animal models of. 338. 3391 Frame mode acquisition. 146. I48 258-260
DipllosphonnteIlgand."""Tc-labeled bone-imaging xfc11t. Encapsulation. forn~ula~iun problems rcl;wd tu. 282 Freepertcchnetalc Genlamicin. yymTc-labeledphosphateandphosphoniltcIn-
stluclurr or. 4 I 41 Enccphatitis, animal lnodels of. 336. 3381 absorbed dose-and. 70 tcractions with, 194
Dipyridamole.cardiacimagingand. 117-1 19, 1 1 8 . Endocarditis. animal models 01. 336. 337f distriburion of, ?68. 269 Gcnlisicacid,effects on YgmTc-labeledradiopharmaccuti-
182-183. 416 Environmental Protection Agency (EPA). regulatory author- hrosernidc (Laaix) cals or, 8 1 . 81
Dlsease ity of, 32?. 327 I"'GaJpal1ium citralc interactions \ A h . 214-215 GFR ( w e Glomerular fillration rate)
animal modcls of3 333-347 Enzymc substrate. 34-35 renal ('unction r;diotracer interaction with. 21 9 GI4 (see Gluceptatc (glucoheptonate))
biodistributron and absorbed dose and. 69-70 Enzymes (sce ~ l r ospec~licenzyme) renal imaging and. 119-120, 121 Glioma. animal models of,346r
chronlc. slages in. 99. IIM drug efrects on. radiotracer biodislribulion and. 169 Glumcrular filtralion rate (GFR)
monitoring of. 1041 nonmicrosomal versus microsomal. 44 [6"Ga]gallium citrate computer asscsm~entof, 159. I60
radiotraceruptakc and. 166 EPA (see El~vironn~e~~ral Protection Agency1 advcrse reaclions to. 3 1 5 DTPA and, 4
DISIIIA (see '~mTc-diisopropyI-substitllledimlnodlilcclic Ependymoblaslonxl, annnal mudcls of. 346/ dose lo breastfeedine newborn. 63, 631 Glomerulonephritis. animal models of3 342, 3421
acid) Epilepsy. anirual modcls of. 336. 338r drug inleractions with. 178-180, 21 1-216 Glucagon
Diuretics (see u h u Renal imaging: spcclricdiurctic). Epincphrinc, splccn ~maping and. 12'7, 129 Ictal dose or, 65, 67 gastrointestinalbleeding studies with.123-124
(~'~I]~odorncthylnoIrhole~teml interactions ~ 1 1 1 1 . Erythrocylrb Iser Red blood cellsl "IIn-labeled Ieukocytcs versus. abscess imaglng and. 79 Meckel'sdiverticulum detection and, 125, 415
205-206 Erythromycin.["Gojgall~urncitrate interactlullS with. lactation and 59. 601 Glucep~ate(glucoheptonate) (GH) (ser ""Tc-gluceptate)
Diverliculum. bkcliel's (ser Mcckcl's rli!rcrliculum) 214-21s mchbolism or, 45 Gluconate,agents containing, 177
.i.
DMSA (ser 9y.Tc-dimercnprosuccirlic ac~dl Esophagitis norma1biodistributlon of, 14-15. 14 Glucose
Dogs. cardiovascular models w t h . 334-336 m m a l models of, 3401 pediatric use of, 57 IJC-labeIed. sperm metabolism assessed by, 103. 1031
Dose (see d s u Absorbed dose) illduced by irradiation. 226 lumor and abscess localization with. patien1 preparation cardiac. effects on radiotraceruptake or, 183
calibration of. impuritiesaffecting. 283 Estrogens lor. 4 14 Glucose tolerance factor (GTF). 45-46
pediatric (see Pediatric patient) plasmaprotelns sri~nulatcdby. 178 uptake or Glycoenzymes, 167
reliculoendothelial syslem aA'ectedby.174 normal varialions in, 244-245 Glycogenolysis. ischemia and, 181
Dosimetry
cakulations. 23-24, 24. 241. 5 1-72 "mTc-labe[ed phosphareand phoaphonak Inler;lcliuns pathologlc mechanisms altering. 262-263. 263 Glycols, effects on radiotracer dlstribution, 176-177
p r c p n c y and, 64 with, 196 Gallbladder (see entries beginning with Hepatobiliary) Glycopyrrolare, pertechnetate uptake and, 169
DOT Isre Departmcnt of Transporlalion) Ethanol, [6'Ga]gallium citrate and. 180 Gallium nitrate. [6'Ga]gallium cllrate interactlons with, 213 Goiter. toxic multinoduIar. sodium [l'lIJiodide for. 88
ETR (see Effective thyroid ratio1 G a m m a camera, 146, 147 Gold salts, [6"Ga]pdliom citrate interactions with. 214-215
Double exposure, 292. 293
Europe imaging with. exercise tolerance rest and. 154, 156, 156 Government (see Regulations; entries beginning withRepu-
Doxontblcin
brain-imagingradiotracerinteractions wich,216-217 adverse reaction reporling in, 308-309, 310 proper sctling of. 295-296 latory)
adverse reaction statistics in. 3 12-3 13. 3 13f ton~ographicreconstruction of images from, 159- 160 Granuloma~osis.radiogalliumand. 229-230
cardioroxicily of. 181-182
""'Tc-labeled phosphate and pt1ospllonole interactions Excretion Gamma emission. principal, selection of radiopharn~aceuti- Graves' disease. 116
rate of. seleclion oi' radiopl~a~nloccutical and.80 cal and. 75-76, 761 sodium [I3'IJiodide Cor, 88
with, 194. 197
uoule or. sclcclion of rnrliopl~;~~macc~l~ical79and, Gases. radiophormacc~~tical Groin.clinlcal variations i n , radiopharmaceuticalblo-
'~'~"Tc-lnbcledred blood cell inIcrac4ions with, 20?
[~U~Tl]~hatlous chloride IIiIcractionb with. 209 Excrcisc IolcI.:uux tcbt [ s w SIrcsa testing) ~netnbolisn~ or, 45 distribution and, 244
Drug history (,weo h hticnt prqw:ltio11), lhyrtlirl sludics Ijxpected ~ ~ ~ i l i140-143.
ty, 141-14.1 regulatory control of. 329 GTF (,Tee Glucose loler,ance factor)
Expcclormts. iodideinteractlolls with, 204. 2 0 4 Gnslric enlptying studics, 122- I23
and, 4 I?
radiop~~nr~~~;~ceuticals for, drug interactions with, 216 Half-life. selcclion of radiopharnlaceutical and, 75,761
D N inleractions,
~ absorbcrl (hhe i n ~ l .71
Elsling. hepalohilinry inloglng and, 417 G:lstroenteritis. ;~rlin~al nwdels of, 340r Hansch hypothesis, 33, 37
Drug intervention, 115-129
FDA (see Fuorl and Drug Administration) Gastroesophageal r e f l u x . intcrventional studies of, 120, 122 Hashilnolu's thyroiditis, 116
ahsorbcrl dose and. 7 t
Hazards (see Radiation hazards) Human albumin (see WmTc-labeled albumin) adrenalimagingwllh. 116, 117, I17 Instrumenlalion, probIemswith,290-300
HDP (see qqmTC-hydroxymethylene diphosphona~ej Humanexperimentalion,checklisr [or, 1081 adversereaclions to, 317 losul~n.cardlac radiotracer effects ol, 183
Heart (see oho entries beginning wlth Cardiac: entries be- Hyalinemembrane disease, animalmodels of. 338, 33% drugioterac:ionswith,205-206 Inlerveotional sludies. 115- 129
ginning with Myocardial] Hydralazine, SmTc-labeled red blood cell inlerdclions wllh. metabolism of, 48 Interventricular syslem, paradoxical motion of, 25 1
clinical variatlons in, radiopharmaceulical distribution 201 normal biodistributionof,12 Intestinal tract (.Tee also entrles beginnlng wirh Gastmintcs-
and, 243, 2431 Hydrocephalus. 248-249, 250 Ibuprofen. [67Galgallium citrateinteraclions with, 214-215 tinal). free pertechnetale in, 268, 269
dog versus human, 335 animalmodels ol, 336.338r IDA derivatives (see lminodiacetic acid derivatives) Inlracranial cysls, 248
rherapeutic Irradiation of, radiotracer distribution affected Hydrochlorothiazide, [6iGa]gallium citrale interactions lmage degradation. radionuclidic impurities and, 283-284 Intramuscutar injeclion. [6'Ga]gal[iun~citrate interacmw
by, 220, 221 with, 214-215 lminodiacelic acid (IDA) derivalives (see qg'mTc-Iabeled iml- with. 214
Heartbear. multiple-gated imaging of, 153-154, 153 Hydroxyapalile.pyrophosphate and, 175 nodiacelicacid derwatives; specificderivative) Inlravascularcoagulopathy. mtn:ll modch ol: 345.345r
Hear1 wall. motion of, 154 Hydroxyethylidene diphosphonate (HEDPj (see also 99mTc- InrubatLon, radiotracer biod!slribuliml and. 320
Heating.lormulationproblems caused by. facrors in. hydroxyethylidene diphosphonale). ~nalrixvesicle Invasive procedures, absorbed duac : I I I ~ 7 I
276-277 functioning and, 175-176 In silu preparation, ease of, selection oCradiopharmaceutica1 lnvestigalional new drugs [INDs)
Heavymetals. thyroid-imaging efiecls of. 184 Hyperaldosteronism, 116, I I7 and.82 apphcationior. 53, 54. 55
HEDP (see Hydroxyclhylidene diphosphonate) Hyperalimenlalion (see Nutrilion, Iota1 parenteral) Io utero exposure. 64-69 avoiding delays In processing 0 1 , ?h4-30?. .i(lo
Hemarological disease, animal models or, 345, 3451 Hypcralumincmia.170-171 "'In-dielhylcnetriaminepentaacelic acid (DTFA) considerations in. 357-372. 374- L S 5
Hematological efiecls. sodium ['?P]phospha~e, 85 Hyperbilirubinemia, neona~al. 125 adverse reaclions to, 317 examples of situarions requmng. 367-372
Hemalolna. subdural, anlmnlmodels of, 336. 3381 Hyperlipidemia.[6'Ga]gaIlium citrate and, 179 drug inleractions with. 202 forms lor. 374-379
Hcn~od~alysis Hyperprolactmemla, [6i'Ga]galliurn cmate accumularion rnelabolism of, 45 -X,:
framework and criteria for review 111. 30 1
complement:Icliwtionand.173 and.179-180 I%-labeled leukocytes participants in process of, 357-358
pertechnetatedistributionand.170-171 Hypcrtension,animalmodels of. 335, 337f clinical ulilily of. 94-95 submissionInstructions lor, 361
Hcmolyt~canemla. animal models or, 345, 3 4 3 pulmonary. 338, 339r drug i n l e r d o n s n,ith, 203 clinicaltrialsof. 5 5 , 358-3151, 360-361
Hemorlhage,gastIoin~estinal (see Gastroinrestinal bleed- Hyperthyroidism. 116 I"'Ga]g:dliun~cilralcversus.absceasnnagingand. 79 three phases of, 360-361. 360-361
ing) soddurn {IJlIjiodlde for.88 normalbiodistribution of, IS Medical Review Guidelines for. 361. 3RO-.;SS
Heparin, 28 I thyrolropln-releasing hormoncInfusion test and. I16 prcparatlon or. 92-94, 931 physician-sponsored
[6'Ga]galliumcitrateinteracrionswitll.215-216 Hyposplenia,226 "'In-labeled platclels clinicallrialsof, 359
"lIn-labeted platelel inleractions wilh. 203-204 Hypothesis. research, 106 clinical urility of. 95-96 problemareaswith.362-364
rclicolocndolhclralsyslcmaffcctedby.172 I-lypolhyroidism, primary versus secondal y, 1 I 6 drug internclions with. 203-204 requirements for. S4-55
"Ym'l'c-labeledmacrwggrepted albumin and albumin mi- normal biodislribulion of. 15 sampicsize and. 363
crosphere lnteraclions with. 198- 199 preparation of. 95, 96r studydesignfor,363-364
YymTc-labcledphosphateandphosphonule inlcraclions lltIn-oxine,metabolism 01; 45 Invesligational slud~es, 105-107,108r
with, 195 12II-fibrinogen 'llIn-oxine-labeled red blood cells, preparation of, 90 hypolhesis in, 106
gPmTc-labeledredbloodccllinlcractinns with, 201 lachtion and. 60-61, 60r lllIn-tropolone-Iabeledleukocyles.prcparalionof, 94, 941 prognostic efkcliveness of, 107
Hepatic artery infusionchemotherapy,inrcractions wlth normalbiodislriburion of. 13 ["'InJind~umchloride rcporling of, 107-108
""'Tc-labeled iminodlacct~cacid derivatives, thrombuslocalizalron W I I ~ I .paticnl preparalion lor, ~netabolismor. 45 research design of, 106- 107
192- 193 414-415 nuclear propcrtles of. 761 lod~des(see also Radioiodides; Sodium Il"I]iodidej. d r u p
Hcpalic coma. an~lnalmodcls ol. 3411 "!I-hippuran [see o-["'l]iodohippurare) [ll'ln]~ndiumchloride cunraming. thyroid-imapng eriecls of. I83
HepaticIuncIion, measu~enlent01, charactrrislics of ideal 1311-labeledagents(see d s o Radiuiodides;Sodium feral dose of. 66-67 Iodinated contrast agcnls, renal lunchon radiotracer inlcwc-
breath Lest substrare for. 112. 112t [13'lliod~de) merabolism of, 45 lions wilh , 2 1 8
Hepatitis,neonatal,biliary alresia versus.126 indotricarbncyanine, SLnlcture of, 40-4 1, 40-41 Incubation. rornlulation problenu rcla~edto. 277 Iodinated semnl album~n,feral dose of, 66
Hepalobiliarydisease.anilnalmodelsof. 339-341. 341r nl-["llliodobenzylguanidine (mlCBl IND (set Invest~ga~ronal new drugs) lodmalion, 12
Hcpalobiliary imaging drug intcraclions with, 206-207 Indotricarbocyanlnes.1311-labelcd, slmcture of, 40-41, lod~nemetabolism, 46
drug-radiopharmaceuticalinteractlons allccting. I S 4 rnelabolism of. 48-49 40-4 I p-lodo-iminodiacetic acid, 8
"'"1Tc-Iabeled lminodlacelic acid derivalivcs In, smclure or, 34-35, 34 Infants (see also Newborn) Iron (see a l . 59Fe)
~
192-193 p-['~I]iodobenzylgua~~idine (pIBG). mcmboIism of, 48-49 brain imaging or. 236 erfccls on radiotracer distribution, 176, 177
patientprcparntion for. 417 19-[~3'l]iodocholeslerol,adrenalimagingwith, 116 brrdsrfeeding, radialion dose to. 62-64 ["Gelgallium cilrate interactions with. 213
re~iculoendolhelialsystem imaging versus, 77 o-l'~~I]iodo~ippura~e lung perfusion imaging in. 82 wmTc-labeledphosphateandphosphonalc in~cr~timh
selection of radiopharmaceulical lor, 80. 801 normalbiodistribution of. 12 Infarcrlon wilh, 193-194
slructure-dislribulion relalionshlps of agents for, 38-41. renal function studies with,patientpreparation lor. cerebral, animalmodelsof, 336 Irondextran
39-41 415-416 myocardial (see Myocardial infarction) ["Gdlgalliumcitrate and, 180
WmTc-labelediminodiacericacidderivative, 8- 10, I O , o-l1J'I]iodohippurate (hippuran) InCcclion, bone and joint, lllln-labeledleukocyles for diag- radiolracerdistribution and, 177
26, 27-28 lnelabollsm of, 48 nosis of. 95 w4'"Tc-labeled phosphate and phosphunate I I I I C I :ICIIC)IIS
Flepalobiliary syatem, ~nterventional studies or, 125- 127, normalbiodislribulion of, 12 Inflammatory process imaging, I%-labeled leukocyles in, with, 195
I28 renal funclion studieswith, palien1 prcpmtion Cor. 15 Iron hydroxide preciplmes, adverse reactions 111. ? 1 h
Hepatocyres. 77 415-416 tlrug-radiopharmaceulical interaclions and, 203 Irradialion ( s e e d s o enlries beginnlng with R:~dia~ion].ttwr-
Hepatoma.animalmodels of, 346r renogram wilh. 26 Intornlalion ccntcrs, 389-396 apeutic, radiotracerbiodislrlbution ~ d ~ c r chy. d
Hippumn. 'Wlabcled (see o-l"lI]iodohip~)ura~c) abnorlnal, 30 Injection 220-226
Hodgkin's dlseasc, 127 furosemide and, 120 e r r m in, absorbcd dose altd. 70-71 Ischenlla,myocardial. 118, 119, 154
Horrnonc reccptors, ccll Inclnbr:lnc erlccls or, I68 normal, 29 inlramus~ular~ [Wa]g:~lliun> citraleinteractions with. cyclicadenosinemonophosphare and, 181
HPLC (see Chronlatopphy. high-performance liquid) 6~-[~~~I]iodomethylnorcha~es1crol iNP-59) 214 nycardial infamion versus, 157
430 1 I d e x

lsopro[erenol Licensing states, 53. 3321-3231

effects on sperm, 103, 1031 Lidocaine
gastric emptying radioiracer interactions with. 216 IIIln-labeled leukocyte interactions with, 203
Isolope exchange, iormulatlonproblem5related io. [2n1Tl]tha~lous chloride inieraclions with. 209
282-283 Ligand concentration. formulation problems and, 276
Isotopicallysubstiluted b~ochcmicals,34 Limited-angletomography, 159-160
Lipid permeability, drug effects on radiotracer dislribution
Jaszczak phantom. 299, 299 and. 167
Jdundlce, an~malmodels 01, 3411 Lipophiliclly
JCAIl (see hint Commission on Accreditallon ofHospitals1 Hansch equation and. 33
loin1 Commission on Accrediralion or Hospirnla (JCAHI. structure-dis~ributionrelationships and. 37. 38
license ~nspectionby3 325 Liposome-cellinteractions. cell menlbrane eflects oi.
Joint Infections. "'In-labeled leukocytes in delection of,95 168-169
LISImode acquisition. 146, 148
rjK. digoxin ellecrs on. 181 Lwer (see also entries beginning with Hepaiic)
Ketosis,[b'Ga]g;dlluru c~lrate and. 179 clinical variations In. radmpharmoceutical blodistribulioll
Kldney (see nlso cntries beglnnlnp with Renal) md, 234, 235, 236r
clinical variarlons In. r;~diopt~armaceutical
biodistribulion collo~dalimpuritiesin. 268, 269
and, 239-243, 242 rherapeutic irradialion of, radiotracer disrribuLion aiieclcd
intcrventional s t ~ ~ hin,
e r 119-120, I21 by. 221, 222
scintigraphic computers in, 157. 159 Liver imaging
therapeutic irwdlalion of. radiorraccr distlibullnn :lnd, druf-radiopt~arn~aceut~cal intcractions afrecling. y""ITc-
22 1 labeledcolloids i n , 190-191
Kinetlcs (sce Radiopharmacokinctics) parliculale ~nlpurit~es in. 268. 270
Kincvac (.we Sincalide) selection of radiopllarnlacelltical Tor, 77
8'mKr Y'"1Tc-labeled iminodiaceiic acid derivaitves in. 9- 10
in cllildren. 57 PV'L'Tc-labeled sulfur colloid in. 7
met;rbulis~nol. 45 Liver uplake. bonc nnagln: agcnl. Iactors associilted wiltl.
Kupffer celtb. 77 3931
LLW disposal (see Low-levelradioactive wasle disposal)
Labeling Low-level radioactwe waste (LLW) disposal
com~ncrcialsource and, 278 in-house radlopharmacy and. 325
oxid;ltion and, 279 regulation of. 325, 3261
Laclation unit dose radiopharmaceutical supplier and. 325-326
duse estimation during. 61-64 Lung (ser also entries bcglnnlng %,ith Pulmonary)
radlalioll hazards during. 59-64. 239 chronic obstrucrivc disease of. 76
Lactol'crrin, [ T j a j g a l l ~ u ellrate
n~ and. 178 c1inIcal varialions I n . radlopharmaceutical biodistrlbulion
Lasix (see Furosemide) and, 243-244. 2441
Lesions (see also 'rumor), peripelvic. 242 particulate impurilies In. 268, 270
Leukemia: anima1 models of. 3361 pathology, animalmodels of, 336-338. 33%
chronic myelogenous. 345, 3451 therapeutic irradiatlonof. radiotracer distributlon affectcd
Leukocyles by, 221
damage lo, monllormg causing, 1 I O Lung imaging
function of, [6'Ga]galIiurn citrak distribution and. 178 pathologic mechanisms altering, 252-254, 253
'1%-labeled selcclion of radiopharmaceutical [or, 78. 81-82
clinical utility of. 94-95 49n'Tc-labeled macroaggregated albumin, 5. 6
drug mteraclions with, 203 Lung veniilaiion and perfusion studies
normal biodistribution of. 15 radioaersol, 78
preparation of. 92-94, 931 sciniigmphlc computer in, 157
"1In-tropolonc-labeled. preparation of. 94, 941 133Xe. 15-16, 16. 78
Lcukopenia, ["Gajgallium citrate and. 178 Lymph nodes, therapeutic irradiation ol. radiuiracer bio-
Leukotoxine, 15 distributionaffectcd by, 226
Levodopa. g:rstrlc emptying radiolracerinlcracrions willl. Lynlphangiography, contrast media for, [6'Gn]galliunl cil-
216 rate interactions with, 180. 212
Librax, gastric emptying radiotracer inlcractions with3 216 Lymphocytes, [6'Ga]galliu~n cilrate and. 178
License anlendmcnls, 324 Lymphoma, [6'Ga]palliurncitrate in. 176
License inspections. 324-325 Lymp~loscintigraphy.~'"Tc-labclcd aruilnony sullidc col-
License renewal. 324 loid, 6-7
Licensing. radioactive m:ltcrials, 32 1-324, 3241-3251, 329 Lysosomal cnzymes. collagen degradaiion and, 176
Licensing agencies. 3221-323 Lysosnnlca. I("Ciajpalllun1 citrate in.179

Neutropenia, cyclic, animal models of, 345. 3 4 3
New drug application (NDA) (see also lnvestipational new
drugs), 55-56
approvaltime of, 46
Newbom (see a h Infants)
breastfeeding. radiation dose to. 62-64
hepatitis versus biliary atresia in, 126
hyperbilirubinemia in. 125
lung perfusionImagingin. 82
h'icotinicacld,"mTc-labeledlminodiacelicacidderivative
interactions w ~ t h . 192
Nltrares
SmTc-labeled red blocdcellinteractionswith,
[1~'Tl]thallouschloride mteractions with, 207-208
Nitrofuranloin, [6'Ga].gallinn1 citrate interactions with, 212
Nitroglycerin: cardiac imaging and, 119
Nitrosoureas."'nTc-labeledcolloidinreractionswith,
Noncompliance, nuclex medicinemonitoring in assess-
ment of, 100
NP-59 (see 6~-~~"I]iodomethylnorcholesterol)
Nuclear medicine profcssionals, information
389-392, 391r-393r
Nuclear Regulatory Commission (NRC), 321
ALARA and. 329
authority of, 326-327, 327
licensing and, 322-324
radjoactivepatientand. 328
responsibilities of, 53-54
Nutritrnn (see also Totalparenteral nutrlllon). retlculoen-
dothelialsystemaffected by, 174
Objectiveprobabilities. 133
Occupationalexposure, 329
Occu~~atior~al SafetyandHealthAdministrallon
regulatoryauthorlly of, 327
01H (see o-['3'I]iodohippurate: o-["'l]iodohlppurare)
Oncology (see also Cancer), anmal models of. 346-347.
3461
Opsonin. 172
Opsonization. 172, 173
Oral contraceptives
["Ga]galliurn citrate mleractions with. 212-213
['~~I]iodometl~ylnorcholcsterol inieractions with, 206
radiocyanocobala~nininteractions with, 209-210
Organification, 12
Organogenesis. 6%
OSHA (see Occupational Safety and FIedllh Administration)
Osleolnalacia. animal models of, 333
Ostcomyelitis, 259
ani~nalmodels of, 3 3 3
Osteoporosis, 257
animal models of, 334, 3351
Ovarian cyst, 251, 251
Oxidases.mixedfunction. 44
OxIdation
formulation problems relatcd to, 279-280
Iodine volatility and, 283
Oxyquinoline (see I"ln-oxinc)
(see also Chromic[32P]phosphate;Sodium['?P]phos-
parental preparation for procedures with. 412 ceutical biodislribution and, 234-245
preparation of. 4 12
phate),chlorpromazine and. 168 plgs, central nervous system models with, 336
Penicillin.""Tc-gluceptateinteractionswith. 197
Packageinsert. 56 Pinocytosis. 170
Pentagastrin,h.leckel'sdiveniculunlimaging and. 124-1 25,
Paget's disease. 176 PIPIDA (see wmT~-p-ispr~pyliminodiacetic acid)
415
Pancrcas PlacentalImaging,"mTc-labeled albumin, 1 1
Pentamdine, Ib'Gal_ealliurn cltrateinreractionswifh. PlacentalIransfer, 69
clinical variations in, radiopharmaceutical biodistribution
214-215 {67Ga]gaIliumcitrate, 65
and, 236
Pcrchlorate [l"ln]ind~urn chloride. 66-67
disease 01: animal models oI, 338-339
brain imaging preceded by- 413 Iodine, 64. 641
imaging ol
pertechnetarc uptake and, 169- I70 nn'Tc-labeled agents. 65
patienl preparation for, 4 I4
Perfusion (see specdk type) Planar imaging. problems involving, 291-298
~'~Se]seler~omethion~ne, 15
Perfusion defects , 5, 253 afrer Imaging, 298, 298r
Papillary carcinoma, sodium ['J'l]iodide for. 88
Perfusion imaging, 78. 78r during imaging, 297-298, 2971
199-200 Pdratlel-line equal-spacing (PLES) phantom. 294
kits for, 81-82 prior to imaging, 294-297. 294-295
Parathyroid hormone (PTH). radiorracer excretion and, 176
Pericarditis. animal models of. 336. 337r Platelets (see also "lln-labeledplatelets).aggregation of,
Parathyroid Imaging. patienl preparation lor, 415
Peripelvic lesions. 242 reticuloendothelialsystemaffected by, 175
Pxticulale size and number, formulation problems related 10
kritmeai effusion. chromlc ["Plphospllate I'or. 86. 87
190 277-278 PLESphantom (see Parallel-line equal-spacing phantolll)
PCrlechnetate (See a h o Free pertechnetate; qP'nTc-perlecllne- Pleural effusion, 260. 261
Partttion coefficienl, in Hansch equation, 33
tale), agentsinflucncingbiodislribution of. 165 chromic {"Pjphosphatefor, 86. 87
hthologic mechanisms,alleredbiodlstributioncaused by.
aluminumion. 274
248-263 Plummer'sdisease. 116
p H . alleratiOllS in,formulationproblemscaused by3 Polarity
nccdedby. Palicnt.radioactivec. compliance problems with, 327-328,
274-275 drug en'ecls and, 33
3281
Pllagocytosis.intramuscular.reticuIoendothe[ial aystem dmg cxcrelion and, 37
Wtlent cducation, 404-409. 41 1
and. 171-172 slnfcture-distribution relat~onships and, 37
delinition ol. 404
Phantolns (see spcc~fictype)
future of. 409 Polycythemiavera,sodium["Plphosphate for, 85, 86
Pharmacodynanncs, radlonuclidc[racers of, 105-IO6
team approach to, 408 ~olym~cosiris. 167GaJgalliumcitrale uplake and, 226
Pll;~rmacokinctics(see Radiopharmacokinetics)
theoretical approaches to, 405-408 Positioning. patient (see nho Patient preparation), 297
Pharmacologic inlelventions, 115-129 Positroncmissiontomography, 160
Patlent pos~llon~ng, 297
Phenazone.[6'GalgaItiumclrrateinteraciionswilh. Posilron-emittingradioisoropes. 102
M e n 1 preparation, 4 1 1-4 16
214-215 Poslerior probabilities, 134
bonc imaging, 413
Phenindionc.[67Ga]palIiumcitrateinteraclionsnqth, Postimagingprocedures, 298. 2981
bram and cerebral perfusion imaging. 413-414
214-215 Potassium
heparobiby imaging, 4 17
Phenobarbjtal lolK versus, 182
Meckel's diverticulum imaging. 415
[47Ga]cilrdteinteraclionswith, 214-215
(OSHA). myocardial perfusion imaginp , 4 16, 4 16f radiocyanocobalamininieractions witI1. 209-210
hcpatobiliarysludies with, 125-126
nonlhyroid imaging with radloiodinc. 413 ~?olTl]thallous chloride and, 45
radiocyanocobalamininreraclions with. 209-210
orally admin~s~ered radlopharmaceuticalsand. 417 Porassium ion. [6'Ga]gallium cltrale and. 179
Phenothiazines, L6'Ga]ga[liom citraleinteractionswith,
pancreas Imaging, 4 I4 Polasium perchlorate. 9WcTc-pertechnetatepreceded by, 4
212-213 POlaSSium perchlorate tesl, 116
parathyroid imapnp. 4 15
Fheoylbulazone
pediatric, 412 Predidve value.test, 135
16'GaJgallium citrate inleractions wuth. 214-215
renalimaging. 415-416 Pregnancy
iodideinleraclions with, 204, 204r
requirementsfor,selectlon of rad~opt~armaceuticaI
and. cautions during. 56
thyroid Imaging elfects of, 183
82 radiation hazards during, 64-69
Phenytoin
single photon emission computed [omography. problems Preimagingprocedures (see olso Patientpreparation).
16'GalgaIlium citrateinteracrionswith, 211-212- 294-297
with, 299-300
214-215 Preservatives. Ionnulation problems related [ o , 281
[hrombus localization, 414-4 15
radiocyanocobalamininleractionswith, 209-210
thyroidimaging. 412 Primidone,radiocyanocobalanlininteracrlons
[~o~Tl]thalious chloridc interactions with, 209
tunlor and abscess localization, 414 209-21 0
Phosphate, radiotracer distriburion and, I77 Prior probability- 133
huent selection, crlteria for, investigational new drug ap-
Ptlosphdlidylinositol content, cellular, 168 Probability
plication and, 362
Phospho-Soda
Patient's right to know, 404-405 Bayes'lheorcm and, 137-139, 138
boneimaging and, 177
Pediatric paticnl (see also Infants) decision making, 133-134,1341
yymTc-IabeIedphosphateandphosphonateinteractions
absorbed dose estimation in, 56-59 hobenecid
with. 193
absorbeddose to renal runction radiotracer interactions with. 219
Phospholipids, calcium andacidic. I68
biologic paramcters and, 57-58, 58f qy""l'c-peniciIIanlincand, 184
Phospllorus melabolisln. 46
calculation of. 5 2 Procainanlide
Photopeakefficlcncy, 74, 761
eslimation of, 56-59 '"in-hbelcd leukocyte interactions with. 203
Physical hslr-hfc, scleclion or phamlaceulical and, 75
physicalparameters and, 56-57 ImlTlllhalluus chlorideinteractionswith, 209
PhpiOlOgiCfUIlclion,normalvariationsin. radiophama.
brainimaging in, 236 hoccdural problems. 290-300
 Index t 435

Product formularion. selection of radiopharrnaceutica! and. occupational exposure as. 329 passive analysis of. 21-22. 22 pat lent preparation for, 4 15-4 16
81-82, 81 Radiarion lherapy, aliered radiopharmaceutical biodistribu- radiopharmaceutical design and. 24-25 selection of radiopharmaceu~icalfor. 77-78
Prolactin. ["Gajgallium citrate accumulation and. 179- 180 tion as resulr of. 220-226, 222. 224, 225 single compartmental analysls or, 20-21, 21 95mTc-Dh.ISA in, 10- 1 1
Propantheline,gastricemptyingradiotracerinteraclions RadioactiveDrugResearchCommltrec (RDRC), 55. 365. Radiopharmacy, in-house, low-levecl radioactivewaste dis- PPmTc-gluceptate versus, 79-80
with. 2 16 368-370 posal concepts of. 325 qPmTc-gluceptatc In,5
Propranolol Radioactive waste disposal (see Low-lewi radioactive waste Radiopolasslum,normalbiodislribution of, 13 Renal lranspianl evaluation, dmg-radiopharmaceutical inter-
cardiacradioiracer efkcls of, 182, 183 disposal) Radioiracers (see a130 speciflc agent) actionsaffecting,[6'Ga]galliumcitrateIn,
contraceptive efiectives of. 103 Radioaerosols. mmTc-DTPA,78 biodistribution of 215-216
effects on sperm. 103, 103 Radiocyanocobalamin, drug inrcracrions with, 209-210 allered by invasivetherapy.220-230 Renografin. 60, 171
I?OITl]thatlouschlorideinrcractions with, 207-208. 209 Radiogases. controlandlicenslng of, 329 drugeffects on RES (see Reiculnendothelial system)
Propytthiourac~l(PTU), 82 Radiohalogenation. strcturc-distrlbutlon relarionshlps and. bloodcomponents and. 169 Research,106-108, 108r
cardiac radiorracer effects of, 183 36, 40-41, 4&41 cellmembrane and, 166-169 designs for, 106-107
Radioiodides (see also Sodium ['3'l]iodide;specific
Prospecrive p a p e n t , radlopharmaceurical information cen- iso- enzymes and,169 Reserpine
ler and, 395 tope) factors deternlining, 166 {b7Gajgalliunl cilrate interactions with. 212-213
Prostaglandin E. cyciic adenosine monophosphale and, 174 fetal dose or. 66, 68-69 lalrogenic alterations i n , 165- I84 mIBG interactions wirh. 206-207
Proslhcses, radiotracer biodistribulion and, 227-228 metabolism of, 48-49 reportedinslances of drug-Inducedaltcrations in. Restrainl. pediatric patient. 412
Pro!eins. plasma cs~rogensand, 178 nonrhyroid skudies with, patient preparaiion for, 413 189-219 ReticuloendothehaI system (RES)
nonnal biodistribution of, 1 I - 12 cardiac, drug elkcts on. 180-183 heparin effects on. 112
Psychotropicdrugs
brain-imaging radiotracer interactions with, 217 pediatric use. 57, 58, 58? concepts of moniloring wilh 100-104 hepatobiliary imaging versus imaging of, 77
membrane transport alterations and, 177- 178 RadiolabeledmetabolicsubslrmesIRMS). sperm moiility pharmacodynamicstudies wilh, 105-106 imaging agents for, I7 1 - 175
and.102-103, 103 Radioxenon (see "'Xe) Rifalnpin, ["Ca)gallium citrate inleractions with. 214-215
FTH (sep Pdrarhyroid hormone)
Rndiolylic decomposition. formulation problems related lo, RDRC (see Radioaclive Drug Research Committee) Right to know. patient's. 104-405
! T U (see Propythiouracil)
Pulmonaryabnormalities,complementactwationand. 173 279-280 Reagent Lis, commercial source of. 278-279 Risks (see Radlatlon hazards)
Pulmonary embolism, 78 Radionuclidlcconlamination.283-284 Rccewccr operatlngCharacteristic (ROC) C U I V C . 136. I37 RMS (see Radiolabeledmetabolicsubstrates)
Radiopertcchnctale (sec wmTc-pertechnetale) Receptor-bindlngbiochemicals.35-37 ROCcurve (see Receiveroperalingcharacteristiccurve)
ani~nalrriodeh of, 337-338, 339r
Radiophnrn~aceuticalinformationcenter (RPICj, 389-396
imaglnp of, drug-radiopharmaceutical interactions affecr- Reco~nmendarionsversus rcgularions. 321 Rolating slant hole tomography
ing. Itlln-labeled plateleis in, 203-204 advisability of cstablishing. 392-391 Recowtruction paramclers. single phoron emusia[l corn- Inmted-angle. 159- 160
Pulmonary ilbrosis, idiopalhic, animal modcls of, 338. 339r cvolvlng lluctear medicine concepts relevant to, 395-396 puled lomography. 300. 3011-3113 myocardial. 157. I58
Pulmonary hyperie~~sion, animal models or, 338. 33% operationalaspectsof,396 Recording media, qualiiy cuntrul ou, 292 RPIC 1 . w RadiopI~armaceuricaIinformation center)
qualityassuranceand,396 Red blood cells (see n/su 99mTc-labeled red blood cells)
Pulmonaryperfusion imaglng, 5 , 78. 81-82
dnpradiophermaceutical inleraclions aireclinf. q 5 T c -Radiopllarmaceutlcal mformation resources, 400-403 agglutination or, aluminum ion and, 274 S value. cnlculdlion 111, 56-57
labeledalbumin i n , 198-199 Rad~opharmaceuticals (see also Radiotracers; specific radiolabeled "S-tabeled sulfur colloid, biodistribulion of. 47
ventilation imaging versus. 78, 781 agent) clinicd utility or. 91-92 Salicylates, iodldeinleraclionswith. 204, 204r
Pulmonary uptakc. 5q"1Tc-labelcdcotluid, factors associated absorbed dose considerations. 51-72 heating i[l formulation of. 276-277 Salinc, bactcrioslatic. 9~nLTc-labeled radiopharmaceutlcals
with. 3921 adverse reaciions to. 303- 3 19 preparatlon of. 90-91. 911 and, X I
bicdisiribotlon and sIrucIure in, 33-42 Reierence Man, absorbed dose in. 54 Salbwry glands
Pulmonary ventilation imaging
drue-radiophnrmaccuti~~l classes of, 34-38, 3 4 , 35t, 38. 44-45
inreraclions aifecting. radio- Repistratlonstates. 53 iree perlcchnetate in, 268, 269
design of Regulations increascd radialracer uptake in, 254
xenon in. 21 1
phamucological approach lo. 34 limitsImposed by.327 lhe~apcuticirradialion or. radiotracer distribution affccted
perfusion imaging versus, 78, 78r
radiopharmacokinetics in. 24-25 versus rccommendalions, 32 I by,225
PYP (.Tee Pyrophosphate)
drug effects on biodistribution of, 165-184. 189-219 Rcgularory agencies (see also Investiga!ionalnew drup: SAR h e e Slnrclure-activiry relationsh~pj
Pyridoxylaminatcs, simcture of, 40, 40
Pyridoxylidenephenylalanine.struclure or, 40, 40 efficacy of, 11 1-1 12 specific agency) Sarcoma. animal models of, 3461
inadvertently altered routes of administration of, 230 kdelal. slate. and local, 326-327, 327 Sarcoplasmicreliculunl.cyclicadenosinemonophospllate
Pyrophosphate (PYP)
inverltoryof,compllter, 160 illleractionswith, 321-326 and. I81
drug effects on, 175
reagent kit, nonradioactive,adversereactions melabolism of. 44-49
to. 31%
responslbilirles and views or. 53-54 Schilling tesr, 280
normal biodistributionof, 3-16 Regulatory problems,321-330 drug-ratllopharmaceulical interactions affecting. radlo-
patient preparation for, 4 1 1-41 8 Reidel'slobe, 234 cyanocobalaminin,209-210
Qualirycontrolprocedures
purchases of, regulalions and, 324 Renal dialysis (see Dialysis: Hemodialysis) dual-isolope (Dicopacj, 282-283
patlent education and, 409
selection of, 75-82 RenalFailure,animalmodels or, 341-342.342r encapsulated doses and, 282
planar imaging problems during, 291-294, 291-293
subslrate-nonspecific, 35r, 37-38, 38 Renalimaging. 26. 77-78 Scicnlllic method, process or, I06
Quinidine, WmTc-labeledred blood cell interaclions with,
substrate-specific, 34-37, 34, 351 abnormal , 30 Scroial ima@ing.256, 260
20 1
rherapeutic applicaiions of, 84-88 artlfaclsin, 296 SDR ( w e Structure-dislributionrelationship)
unitdose suppliers of, lowlevel radioactivewaste dis- diurclics in. 1 19-120. 121 ["Se]setenorncthioninc
Radialion, nonpenetraling versus penelrating, 56 posal and, 325-326 drug-radlopharlnaceutical intcracrions in, 218-219 norrlral biodislrihulion or. 15
Radiation cxposr~re(see nlsu Absorbed dose). general con- RadiopharmacokInctics ''~J""LTc-DMSA in, 197-198 pancreas ilnaging with. parient preparation for. 414
sideralions in 51 active or nonlinear analysis of> 22-23, 23 'F'nlTc-gluceptatein. 197 paralltyroidirnngingwith,patien1preparationfor. 4 15
Radiationhazards basics of, 20-23 o - [ lJIIlir)dohippuratci [ l . I2 Sedalion. lsdiatric paticit. 412
age and, 58-59 diagnosis and, 26 kinetics and. 26, 29-30 Selectron of mdiopt~arnlaceutical,75-82
lactation and, 59-64 rlosimctrycalculations a114 23-24 1iorma3, 29 Selnen, drug cffcccts on. 102-103, 103r
monitoring and. 110-1 1 I n ~ u ~ t i c o ~ ~ ~ p ;a~dry~s ins~of,
c ~21-22,
~ r ~ l 22 palhalogiclnechallistusallcring:258-260 Scnsilivily. tcsl Tor, defined. 134-135. 1351. 137r
 436 I Index Inde?r t 437

toxicity of, 85 nuclear medicine monitoring of. 1041 clinicalmanifestations of problems with,268-270,
Sensltivilyanalysis,142-143, 143
Sortware, 150 open, radiotracer biodistribution allecled by, 226 269-270
Septal penetration, collimator selection and, 294, 294-295
SOH phantom (see Smith orthogonal hole phantom! Sympathomimetics, mIBG interactions with, 206-207 commercial source and, 278-279
Septic meningitis, animal models of, 336, 3381
Shmk, animal models of, 335-336, 3371 Solubility ligand concentralion aKecting, 276
"Shock lung," 173 formulation problems related to, 281 T: (see Triiodothyronine) mixing order in, 275-276
relative, lor lipid or biood phases, 33 T4 radioimmunoassay, probabilities of, 134, 1341 pirliculate size and numlxr in, 277-278
Sialadenitis, radiation, 225
Sincalide (Kincvac) Source malerial. 53 Target uptake rate, selection of radiopharmaceutical and: 79 oxidation and, 279-280
Special nuclear material, 53 T c (see Carrier ~ " ' T c ) pH and, 274-275
dose of. 127
Specialty Board Certilication. licensing and, 324 ""'Tc radiolytic decomposition and, 279-280
hepatobiliary imaging with, 126- 121, 4 17
Specific activity, formulation problems related to, 280-281 nuclear properties ol. 76, 761 specific activity and, 280-281
Single photon emission computed tomography (SPECT).
Specificity.test, 135 particulate Impurities in, 268, 2 70 stannous ion arlectlng, 274
159
SPECT (see Single photon emission computed tomography) gmTc chelates lactation and, 59-60, 6 0 1
problems with, 298-300, 2941
Spectral overlap, 297 biodislribution and struclure of, 37-38, 38 metabolism of, 46-48
Skeletal imaging (see olso Bone)
Sperm, drug effects on. 102- 103, 1031 Incubationof, 277 preservatives and, 281
anterior, "Tc-HDP, 9
Spironolactone, ~~~~l)iodomethylnorcholeslerol interaclions ~~Tc-~",A~'-bis(mercaploacelyl)-2,3-dian1ino~ropanoa~e, solubility of, 281
drug-radiopharmaceutical interactions affecting, RmTC-
labeledphosphates a n d phosphonates ~ n , wilh. 205-206 structure of, 37, 38 g9mTc-labeledalbumin
197-196
_,_ _,- Spleen wmTc-diethylene~riarninepcntaaceticacid (DTPA) macroaggregated
Skeletal metaslases, sodlum [12P]phosphatcforpain from. clinical variations in, radiopharmaceutical biodislribution brain imaging with. palient preparation for, 413-414 drug interactions with. 198-199
and, 234-236, 235 diurelic renogram with. 120. 121 metabolism of, 47
85, 86
Skeletal system. pathophysiology of, animal models Of, intervenlionalstudies of, 127. 129 furosemide and, rcnal imaging with, 120, f 2 I nomlal biodislribution of, 5 . 6
334, 3351 therapeulic irradiationof, radiotracer distribution affected metabolism or, 48 pediatric use, 51
Smith orthogonal hole (SOH) phantom. 292 by, 226 normal biodistribution or, 4-5 metabolism of. 47
Society of Nuclear Medicine, adverse reaction reporting Spleen imaging pediatric use, 57 lnicrospheres
and, 304 drug-radiopharmaceuticalinteractionsaffecting, wmTC- radioaerosol. 78 adverse rcactlons to, 3I5r, 316
Sodium ascorbate,effects on SmTc-labeled radiophama- labeled colloids in. 190- 191 P"n~c-diisopropyI-substituted iminodiacetic acid (DISIDA) drug interactions with, 198-199
wmTc-labeledred blood cells in. 11 heputobiliary imaging with pediamic use, 57
ceuticals, 8 1
Sodium bicarbonate Splenic sequestration. Tr-labcled red blood cell studies Of, abnormal.28 normal biodistribution of. 1 1
91 normal. 27 WmTc-labeledcolloids
cardiac radiotracer effects of. 183
Squamous cell carcinoma, animal models of, 346r normal biodislribution of. 8- 10. 10 anlimooy trisulfide, 67
99mTc-Dh.iSA interactionswith, 197-198
Sodium [rlCr]chromale, metabolism of, 45-46 Stannous ion 99mTc-dimercaplosuccinicacid IDMSA) drug interaclionswilh, 190-191
Sodium diatrizoate. RmTc-labeled phosphate and phospho- drugs containing. 9YmTc-pertechnetate Interactions with, drug interactions wlth, 197-198 irnpurilies in. 268, 269
nate interactions with, 195 199 incubation time and. 277 normal biodistribution or, 4-7, 7
Sodium [l~'I]iodide, normal biodistribution of, 11-12 formulation problems caused by, 274 normal biodistribution of, 10- 1 1 pulmonary uptake of, factors associated with. 392r
Stateradiologicalhealthdepartments,53-54,322. pediatric use. 57 sulfur
Sodium IYIiodide
3221-3231 pH, effcct on biodistribution. 275 adverse reactions to. 3 141. 3 15-3 16
descriplion of. 87
Steroids (see a h Corticosteroids). iodide interactions with. "'"Tc-gluceptate versus, renal imaging and, 79-80 aluminum ion affecting formulation of. 274
dose or. 88
204, 2041 99mTc-diphosphonate,a t u m ~ n u mion arfecling Iormulakion efficacy of, 1 I 1
breastleeding newborn. 63. 631
Stomach (see also Gastric emptying studies) of, 274 liver and spleen Imaging with, 234-236. 235
- fetal. 64, 64r. 65,66-67. 68-69
-
$7
drug interacrions with, 204-205 free pertechnetate in. 268. 269 gPmTc-disofenin(see ""Tc-diisopropylimrnodiacetic acid) metabolism of, 46-47
9"Tc-gluceptate (glucoheplonate) normal distribution 6 . 5-7, 7
F

encapsularion of, problems causedby, 282 intrathoracic, 252, 253

5

g indications for. 8s Stresstesting, 119, 154,156-157, 156, 416. 4161 adverse reactions to, 3 151 pediatric use. 57
E Stroke. 248 brain imaging with. patient preparation lor, 413-414 renal accumulatlon of, 174
i? lactation and. 601, 61 drug interactions with, 197
mechanism of action or, 67-86 animal models of, 336 "Vc-labeled iminodiacetic acid (IDA) derivatives
Strucrure-activity relationship (SARI, 33 normal biodislribution of. 5 drug interactions with, 191-193
metabolism of, 48-49
radiotracersand, 166 pedialric use, 57 hepatobiliary imaging with, patient preparation for,417
monitoring parameters of, 88
Structure-distribution relationship (SDR), 33-34 9P"Tc-DMSA versus, renal imaging and, 79-80 metabolism of, 48
normal biodislribution of. 11-12
quantihtive examples of. 38-41. 3 9 4 1 gYnlTc-hydroxyethylidine diphosphonare (HEDP) normal biodistribution or, 8- 10, IO
5 nuclear
properties 761 of. nletabolism of. 47-48
pharmacodynamics of, 88 Subdural hematoma, animal models of, 336, 338r phenobarbital and, hcpatobiliary imaging with, 325- 126
normal biodistribution or, 7-8
pregnancy and, 64. 641 Subjectiveprobabilities, 133
pH effect on biodislribution, 274-275
quantitative structure-distribution relationships of.
toxicity of, 88 Substrate-nonspecific agents, 37-38, 351, 38 38-40, 39
Substrare-specific agents, 34-37, 34, 35r WmTc-hydroxymethylene disphosphonate(HDP) rddiopharmacokinetics of, 24-25, 2 4 , 241
uplake of, 24-hour, probability of, 1341
Sulflnpyrazone, I6"GaIgalliurn citrate interactions w i h . comparison wilh MDP, SO seleclion of, hepalobiliary imaging and, 80: 801
volatility of, formulation problen~srelated to, 283
Sodium nitroprusside, iodide inleractions W i t h . 204, 2041 214-215 metabolism of, 47-48 P"mTc-ldbeledkits, 81-82
r' Sodiunl [3zP)phosphare Sulfonamides normal biudistribulioo of. 7-8, 9 slannous ion and, 274
["'Ga]gallium citrate interaclions with, 214-215 9R"Tc-p-isopropyliminodlacelicacid (PIPIDA), noma1 bio- wn'Tc-labeledphosphate and phosphonate (see also spccjfic
description of, 84
gql"Tc-pcrtechnetate interactions wilh. 199 distribution d,8 , 9 ageno .
dose of, 85
Sulfur colloid (see WmTc-labeled colloids, SUlfUr) wmTc-ldbeled agents(see nlso specific agent) adverse reactions LO, 3 16-3 17
indications for, 85
Surgery bone imaging with, SO, 102 bone studies with, patient prepration for- 413
mcchanism of actlon of, 84-85
delayed conscqucnccs of. radiotracer biodistribudon and. ktal dose or, 65, 66-67 drug interactions with, 193-197
monitoring parameters for, 86
221-228 lormulation of nlerdbolism of, 47
pharmacodynamics ol, 85-86
438 I 1Igde.x Il&r I -1.w

WmTc-labeled phosphate and phosphonatc--onrifIlred carcinoma or. sodiunl ["lllrodide for, 88 radiolmmunoassay.probabilities of. 1 3 4 patient prcpararion for localization of. 414-4 t5
normal biodistribution 6 , 7-8. 9 clinical variatlons In. radiopharmaceutical biodlslribution resin test. probabil1t:es of, 1341 Ventilationirnaging. 78. 78r
pedialric use. 57 and. 237-239. 239-241 suppr?ssion test. 115- I16 Ventilation systems. radiogasesand. 329
WmTc-labeled red blood cells. 4 cold nodule of. 249. 250. 251 Trimethoprlln-sulin~ethoxazole. gq"Tc-gluceptaleintcrac- Venlricular reflux. 248-249
anticoagulants affcctlng. 26 1-282 free pertechnetatein. 268. 2tjY lions with.197 Venlriculography (see also Blood pool imaging)
clinical utility oh 91-92 interventional studies involving. 115- 110 Trupolone. 94 drug-mdiopharmaceulicalinreractlonsnll'ecling. *'""IC-

drug interactions with. 199-202 organificatlon defectsin. 116 TSH (see Thyroid-stimulating hormone) labeled red blood cells in.199-202
efficacy of. 1 11 therapeu~lcirradiation of. radiotracer dlstribulion affected Tubular necrosis, mimal Inodek of. 3 4 3 galed. 151-154, 151-153, 155
normal biodistribulion of. 11 by. 225 Tumor (see also Cancer) Vinblaslinc.phagocytosis and.I74
pedlatric use, 57 Thyroid hormone manipulat~on,115-1 16 animal models 01, 346-347. 3461 Vlncristine
preparation of. 90-91. 921 Thyrold Imaging brain. 248. 249 brain-imagingradiopharmaceutical i n t e x t ~ c ~hbrh.
h
9y'"Tc-melhylene dlphosphonate (MDP) drug-radiopharmaceuticat Internctlonsafiecllng. central ncr\'ous aysrem, animal models of. 336, 3381 216-217
adverse reactions lo. 3141, 316 163-184 localization [67Ga)gdliumchlo: irle mkmctions with, 2 13
comparison wilh HDP. 80 sodium ['l'l]iodide and sodium ["Illiodide. 204-205 paticntpreparation lor. 414 ~JmTc-labclcd phosphate and phosphonarc inwrxliwn
hydrolysis of. 278 ""Tc-pertechnetate. 199 drup-radiupharllIaceutical inferactions afrecling. with. 194
nornxd biodistribulion of. 7-6 patholopc mechanlsms allerlnp. 249-251. 250 [67Ga]galli~~n~cmate in. 111-215 Vitamin BI,. radiocyanocobalaminintelactw[l\ wLltl.

WmTc-penic~llamn~e. 164 patlenl preparntion lor. 412 Tyrosine.iodlnatlon 01. 12 209-2 I O

qq'"Tc-perlcchnetalc selectlon of radiopllarmaccutical for. 19 Vitamin Dl, radiotracer uptake and.176
al~~minum ion arfectlng formulal~onof, 274 WmTc-perlechnetate in,4 , 4 . 239 ?"U. 53 Vitamins, iodide interactions with, 240. 204r
brain imagrng with. patienl preparatlon Cor. 413 Thyroid preparations. iodide interactions with.204. 2041 ? W . 53 Volatility. iodine. formulation problems lchted IO.3 7
dose to breastfeeding ncwborll. 62-63. 62f-63r Thyroid uptake rest. 102 Ulcer. duodenal or gnsrrlc. animal models of. 340r
drug interacbons with, 169-171.199 probabilities of. 134r United Kingdom Warlarinresislance. anma1 models of. 345. 3451
Mcckcl'a diverticulum imaglng w t h sodium Il'llliodide. I15 adversc rcaclion rcporhng in. 3117 Waste (see Low-levelradioactive waste)
patlcn~prcparation for. 4 I5 Thyroid-slimulatlng hormone (TSH). 116 adverse leaction alat~st~cs
on. I:. 1-31?, 3121 Whole-body irradiation [b'Ga]gallium cltlate b i u d ~ ~ l ~ ~ l w w ~
pentagastrin and. 124-125. 415 test, I 16 Unitcd States and. 225-226
met;rbolism of, 46 Thyroiditls,Hashilnolo's, I16 adwrse reaclion reportlllp in, 304, 305-306, 310
nortnnl biodistribution of. 3-4. 4 Thyrotoxlcosls, 251 adwrsc reachon s~at~stics on. 31 1-31?, 31 11 "'XC
variations of. 237-239, 239 Tllyrotropin-rcleasinf hormone (TRH), infusion lcsl. 116 U r a n ~ u m ,5 3 in ctnldren, 57
pediamc use. 57 Time compression. scintigraphic computer for. 159 drug interactlons with. 21 I
thyroid imagine w i t h . 4 Tin complex, pertechnetate dlstrlbulion and. 17 1 Valvular damage. animal models of, 3371 field floodimaging with. 292
paticnt prcparation Tor, 4 ! 2 [~nlTl]thatlous chloride Vascularimaging, pathologic ~ncchanisn~s
altering, 2 5 2 : mctabolisnl of. 45
U I I U S U ~pathologic
~ \?ariations. 249-250 coronaryarterydisease and. 154, 156-157. 156, 158 252 normalbiodiatribution of, 15-16, 16
wmTc-~lypl~osphnte drug interactions with, 207-209 Vasoconstriction,vasopressmfor. 124 problenls in imagingafter W"Tc perfusionsludics.
n011na1 biodistribulion ol. 7-8 fleld flood imaging, 292 Vasodllaion. dipyridamole. 117-1 19 296-297
strmttre oi. 41. 41 melabollsm of, 45 Vasopressin regulalory control of. 329
'~J~"'Tc-pylopll~~s]~llate (PYP) myocardial imaging wilh. I 16- 1 19. 118 gastrointestinal blerdmg studiesand, 124
bollc imagine w l h . therapeutic irradiation cffccls on. 223 patlent preparation for. 4 16. 4 161 I~UITl]tl~allouschloride inrer;lctions w i t h . 208-209 formulatm errors involving, abhorbed dose and. 711
metabolism or, 47-48 normal biodistribulion of. 13 Vasovagal reactions. 3 13 acld(DTPA). rlrup in-
l~yVYb-dicthylcnc~ri;ln~inepentaacetic
normal biodismibution of. 7-8 nuclear properties or, 76. 76r Vena cava obstruction, 252, 254 telactionswith,202
Tcmpcralurc. "mTc-lnbeled snlli~rcolloid rorlnulation and, polassium versus, 182 Vcnou:. thrombus
276 Tomography (,wenlso specific type). 158. 159-160 animal models or. 3391 Zona glornemlosa. aldosterone producrron In. 117
Teratogcnlcity,64-69.68r annihilationradiation and, 160 l?51-i~br~nogcn rtcmtion of. 13 Zymosan. phagocytosis and. 174
Test reaulls. distribution. 135-136. 135-136 Total parenteral nutrllion (TPN) "lln-lobeled plnlelet detection of. 95-46
Testicularimaging. pathologic mechanisms alterina, 256. gastric cmplying radiolracer interactlons wlth. 216
260 "'In-labeled leukocyte interactions with. 203
Thalassemia major. 260, 261 radioxenon inreractions with, 21 1
Tk;rllium, normal biodislribution of, 13 "mTc-labelcd iminodiacetlc acidderivativeinteractions
Therapeutic applicatlons. 84-88 with. 192
Therapcutic irradiation ( w e Radiation therapy) TPN (SFP Total parenteral nutrition)
Thorium,53 Tranquilizcrs (see also specific agent)
Thorium dioxidc, Y'>"Tc-labeled colloid interactions willl. cell nlembranc cfrects of. 167, 178
191 Trdnsferrin. [67Ga]galliumcitrate and, 178
Tt~rcsl~uld ~alucs, optimal. 135-136,1371 Transfusion. radiotracer biodistribution and. 229
Tlmnlbos Trat1splanl rejection
Iocahzaion of. pnricnt preparatlon fur, 414-4 I5 drug-radio~~han~~accu~ical intcractionsaffecting.215-216
vcnous "Iln-lnbeled lettkocyte deteclion of, 95
anllnal models or. 339r limnla, ialrogenic. radiotracer biodistribution and.
115I-fibrinogen detection or. I3 226-229, 227-229
~11In-Inbelcdplatelct detection of, 95-96 TRli ( w e Thyrotropin-releasing hom~one)
l'hyroid htockade. 413. 415 Trilodothyronine (T& 115-1 16
Thvmirl nllnrl cardiac effects of. 116