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The Plot Against Asthma and Allergy Patients
The Plot Against Asthma and Allergy Patients
The Plot Against Asthma and Allergy Patients
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Page i
THE PLOT
AGAINST ASTHMA
AND ALLERGY
PATIENTS
Asthma, Allergies, Migraine, and Chronic
Fatigue Syndrome are Curable,
KOS
Publishing
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ACKNOWLEDGMENTS
This book is my first and only literary child. It took nine long years to carry
it, and I would not have been able to deliver it without the support of several
people.
I want to pay tribute to the late Drs. Bayard Horton and Kenneth Melmon
for their fascination with histamine, their devotion to it, their research and
their belief that one day histamine will serve patients.
This book would not be possible without my wife Galina who is, actually,
my co-author. She conceived the idea and for two years, while I was fighting
in the courts, she worked on it alone, researched the medical sources collected
by me and began to put my ideas on paper. When I joined her, she became my
sounding board, the only knowledgeable person with whom I could share my
astonishing, at times dramatic discoveries made during my detective search of
medical literature. The situation forced her to immerse herself so deeply into
some of the most serious fields of medicine and science that by the end, she
became, albeit unofficially, the equivalent of a professional in clinical
immunology. Her background as a university professor enabled her to work
out how to present the most complicated material in the way digestible not
only for those who have a medical or biological education, but also for intellectuals with little or no such experience.
I express my love to my son Alex who was a comforting friend, whose
advice I sought in many critical situations during the process, and who
patiently corrected my imperfect English.
I would like to express my special thanks to Klemmens Fass, my unofficial
lawyer, who remained faithful to me when my other lawyers betrayed me. He
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Acknowledgments
refused outright to be paid for the long hours of discussions during the years
of my prosecution by the College. He also became my behind-the-stages law
teacher, and his advice helped me to go through all the stages of the legal
proceedings as well as the writing of this book.
I am grateful to Denise Crawford for her willingness to help with the
numerous technical and linguistic problems that I encountered through the
years of writing.
I appreciate the enormous work done by Isidor Zelinkovsky at the early
stages of my prosecution by the College of Physicians and Surgeons of
Ontario. He managed to get the Canadian Broadcasting Corporation interested in the histamine affair and persuaded them to give the opportunity to
my patients to tell their stories of their almost miraculous improvement and
outright recoveries with histamine therapy and the despair over losing it. The
program aired in Canada and in parts of U.S. created the necessary publicity,
which, in my opinion, contributed to my having not lost my license outright;
I was given a reprimand and forbidden to use histamine.
I am thankful to Ed Sprague, a patient who has become a close friend and
as such accompanied me to all of my meetings with the lawyers and through
the many stages of my trial as a silent witness. The numerous improprieties
he saw have changed his views on our justice system forever. Later on, he was
the most active organizer of press releases sent to the medical institutions,
media and government bodies of Ontario.
I cannot overestimate the tremendous support of Elizabeth and Daniel
Gamper that enabled me to go on with my work and book writing.
My gratitude goes to Tom Hirsch, my first literary agent, who became a
passionate advocate of histamine therapy and was willing to give up his fees
just to see this book published.
Last, but not the least, I thank Helke Ferrie who has dared to publish this
book. The people of Ontario should be grateful to her for the courage to fight
the medical regulatory authorities and for regularly publishing the facts about
the crimes committed by them against patients and doctors.
I am thankful to those of my patients who organized PRET (Patients
Rights for Effective Treatment), a group that arranged the meeting at CBCs fifth
estate television studio, demonstrated in front of the building which houses
the College of Physicians and Surgeons of Ontario, published and distributed
information on histamine therapy, attended the legal proceedings and kept
writing letters of support.
iii
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616.97'06
C2003-906757-2
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TABLE OF CONTENTS
Acknowledgements
ii
Introduction by Helke Ferrie
vii
PART 1
Immune Mechanisms
1
PART 2
Causes and Triggers in Allergy
69
PART 3
Allergic Inflammation
98
PART 4
Histaminegate
106
PART 5
Medications
173
PART 6
Allergy Skin Testing and Immunotherapy
203
PART 7
Bronchial Asthma
238
PART 8
Diseases of Hypersensitivity
318
A. Chronic Rhinitis
B. Skin Allergies
C. Hay Fever
PART 9
Functional Encephalopathies
344
A. Vascular Headache
B. Chronic Fatigue and Immune Dysfunction
Syndrome
C. Depression
D. Attention Deficit and Hyperactivity Disorder
E. Irritable Bowel Syndrome
F. Other Histamine-Related Encephalopathies
Epilogue
Eppur Si Mouve!
387
Bibliography 390
Appendix
396
Abstracts presented by Dr. F. Ravikovich at
international conferences and his article
Letter by Dr. K. Melmon to Dr. F. Ravikovich
Press release by the patients committee, PRET
Notice to the reader
Index
408
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Introduction:
Renovating Medicine
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Introduction
happen now. It is my fervent hope that this outstanding book will start the
same process of revival for asthma and allergy.
Today, the sell-out of medical practice to agendas that have nothing to do
with curing the sick, is nearly total. Patients are now referred to as
consumers who are encouraged to believe that they have choices of treatment offered in that enormous market of modern medicine run as a business.
It is as if illness has become an accepted life-style choiceright after the car
industry. After all, Pfizer is not only the worlds largest pharmaceutical corporation, but also the worlds second largest corporation. The representatives of
the drug companies are accepted as stake-holders in medicine to the point
where they are part of determining standards of practice, sit on the councils
of the medical licensing authorities, virtually control all medical research in
the absence of publicly funded research (but not in most of continental
Europe), and act as policy and fundraising staff for our political leaders.2
As for the business mantra of consumer choice, for the asthma and
allergy patient its basically steroids or steroids or steroids: mint flavored
syrups for kids, or laced with antibiotics (to cover all bases), or as shots, as
creams, and usually as the ever present puffer shaped as a toy for kids, handy
and pretty like a lipstick for the ladies. As for the cure, profits can only be
harvested from chronic disease a CEO of a pharmaceutical giant observed in
a recent shareholders meeting.3
But whose responsibility is it to fix this situation? Consider this then: The
worlds most prestigious science journal, Nature (March 28, 2002), ran an
article entitled Can you believe what you read? showing how the editors of
the most respected medical journals have begun to do some radical housecleaning when it became overwhelmingly apparent that published research
too often reflects corporate interests to the point of distorting the observed
facts. On June 27th 2002 Nature reported that even medical bio-ethicists are
now being offered stock board positions, consulting contracts, research grants,
and even stock options by pharmaceutical companiesand they accept
these goodies! Two international conferences were held in 2002 on conflicts
of interest in medicine (Atlanta and Warsaw). The former editor of the New
England Journal of Medicine, Marcia Angell, justly famous for her fearless
scrutiny of corruption in medicine, now works closely with the Center for
Science in the Public Interest (www.csip.org), a watchdog exposing unethical
behavior of doctors selling out to industry and industrys false or self-servingly
incomplete product claims.
ix
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Just how bad things have become can be measured by the fact that on
February 5 2002 the prestigious journal, Annals of Internal Medicine (vol. 136,
no. 3) and the UKs famous Lancet simultaneously published the Physicians
Charter as a new manifesto to guide medicine (www.professionalism.org).
The charter asserts that it is time doctors get back to the basics. The Charter
reads like the Hippocratic Oath of 2,500 years ago translated in modern
English. The message is simple and blunt: dont abuse your patients financially or sexually, dont hurt them, let them chose among available treatments,
and treat them properly even if they are black, Jews, poor, retarded, dying, just
plain old, or dont have any money, and dont blab about them to others
without their consent. Central among all these ancient basics of medical
ethics was the admonishment that a doctor must not lie when you do research
because somebody offers to pay you for it. (The immunologists whose work is
discussed in this book would do well to read this Charter.) Wow! This document was prepared by an international team of medical ethicists for the international effort called the Medical Professionalism Project. It states at the
outset: We share the view that medicines commitment to the patient is being
challenged by external forces of change which tempt physicians to forsake their
traditional commitment to the primacy of patients interests.
So, that is what the international medical community admits, Dr. Ravikovich provides in this book evidence in support of this urgent need for a major
renovation of the House of Medicine and why that renovation must start with
doctors, after which the pharmaceutical industry is easily tamed.
This book is not simple. But neither is living with asthma, hives, irritable
bowel syndrome, chronic fatigue, constantly itchy skin, the annual round of
hay fever, or potentially fatal food allergies. The information in it is not alternativethe research is entirely mainstream. Here you will learn why you are
sick, why your standard treatments dont work very well and make you sicker
through so-called side effects, how you could become healthy, or at the very
least greatly improved and get off drugs, and what you can do to help make
this healing treatment available.
This is no ordinary self-help bookindeed I wish it was. This book is a
crash course in asthma and allergy medicine designed to empower you with
knowledge and hopefully inspire you with a holy rage and the determination
to help bring out these facts so they become generally known to doctors and
patients alike.
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Introduction
A good book like this does not need my recommendation, but a quick
guided tour might help the reader who is new to this material. Thus, Part 1
provides the technical detail of how the immune system works, as is generally
agreed upon by scientists in this field. For the beginner Part 2 may serve as a
useful beginning; Part 5 will help patients understand why they are not
improving and what is known in mainstream pharmacology about these
drugs and their serious limitations and dangers. Part 4 has the provocative
title Histaminegate which refers intentionally to the Watergate scandal of
the 1970s. This chapter deserves the readers closest attention and is worth
reading with the greatest attention to detail. The remaining chapters provide
information on the various allergic diseases which will be of special interest
to different readers.
The Epilogue is something of a bombshell because it describes the most
recent publication on allergy research that came out only two weeks before
this book was submitted in its manuscript form to me. This research paper
fully validates everything you read in this book and returns to the research
that was more and more successfully hidden over the past two decades. The
politically significant fact of this development is that this was published by
the Swiss governments research institution funded by tax money, not drug
companies. The equally important medical historical facts are that now the
truth which was denied entrance through the door has forced its way in by the
windowas the Russian proverb puts it and as Dr. Ravikovich is fond of
reminding us.
The Appendix contains documentation on the terrible struggle Dr.
Ravikovich became involved in when his life-saving treatment was attacked
by the medical licensing authorities, and suggestions are included on what
you, as the reader or friend of an asthma and allergy patient, can do to change
the current situation.
Treating asthma, allergy and related diseases successfully, at a fraction of
the current cost of mere limited symptom control, is an art and a science easily
learned by any interested doctor. There is currently a great deal of interest in
therapies that cure and are not merely symptom control methods generally
employed by the majority of physicians. What suffering patients often dont
realize is how terrible the frustration of doctors is who wish to help but often
are prevented by the regulatory systems from employing new methods.
xi
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1. Michael Bliss, William Osler: A Life in Medicine, University of Toronto Press 1999
2. See The Olivieri Report, published by the Canadian Association of University
teachers, Lorimer, 2002. For cancer see S. Epstein, The Politics of Cancer Revisited,
1998, East Ridge Press. Epstein is one of the worlds leading oncologists known especially for his success in getting DDT banned and refocusing cancer research onto the
science of carcinogens. He is responsible for laws protecting workers from asbestos,
pesticides, radiation etc. throughout North America and the European Union. For
psychiatry see the new book by the world-renowned pharmacology scientists and
corporate whistleblower David Healey, Let Them Eat Prozac, Lorimer 2003,
published by the Canadian Association of University Teachers.
3. J. Robinson, Prescription Games: Money, Ego and Power Inside the Global
Pharmaceutical Industry, McClelland & Stewart, 2001.
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Page 1
PART ONE
IMMUNE MECHANISMS
CELLS
Almost a century and a half ago, a German scientist, Rudolf Virchow, made a
revolutionary discovery: the body is actually a state consisting of citizenslive cells, each of which is a perfectly balanced unit. A deviation from
the cellular balance is a disease, that is, lack of ease. Cells are our invisible
natural workforce and best health guardians. Therefore it is important to
understand what can go wrong with their complicated functioning, how to
help them restore their rhythmical work, and how to achieve this with
minimal introduction of suppressive medications.
What is a cell? It is a tiny basic operative unit of a live body. If we accept
Virchows view of our body as a state, then it is populated with over 100 trillion citizens working in coordination with each other. Our health and quality
of life depend totally on how our cells function. Cells have different colours,
sizes, and shapes and can be stationary or in motion. Under the membrane of
each cell, there is a chemical lab, and the chemicals it generates determine the
cellular function. Similar cells unite in teams to form tissues and organs.
Cellular teams work in unison, no matter where in the body they reside, and
produce the same chemicals at any given moment. A cell contains over a billion
molecules, and each carries specific chemical messages. Cells communicate
with each other in a cell-to-cell talk through these chemicals, just as we
communicate with words, spoken or written. The more chemicals a cell is able
to manufacture, the more verbal it is. Some cells perform limited local functions only, and their inner labs are fairly simple. Others are complex pharma-
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ur body consists of
cells, which are tiny
chemical labs of various
complexities. The chemicals released by cells
are the language of
their communication.
They listen attentively
to each others talk, and
therefore, the work of
different groups of cells
is interrelated. This
makes the functioning
of the organs comprised
of these cells also
interrelated.
GENES
All cells comprise the same set of over 30,000 minuscule particles within its
nucleus. They are called genes. A gene is a biological unit of heredity that
passes certain physical characteristics from parents to their children. Genes
determine everything from such evident things as the eye colour, the voice
timbre or the height, to such imperceptible minutiae as actual operations of a
cellular lab. Every cellular chemical has its gene that governs its function.
Genes are behind each cellular operation and secretion. In their chemical
language, they instruct the cells what proteins and in what amount to produce
in particular situations. A cells performance depends on the performance of
the genes. The same genes work synchronically in all cells and send the
messages from within, and the genetic instructions influence the labs activity
qualitatively and quantitatively. If there is no genetic error or mutation
affecting the functioning of our cells, our health is good.
Nature is not faultless. Our dissatisfaction with something in our appearance is actually a reflection of how we perceive our visible genetic imperfec-
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Immune Mechanisms
tions. Health problems often reveal genetic imperfections hidden from the
eye. We may be born with genetic errors or may acquire them inexplicably in
the course of life or through exposure to a harmful factorsuch as radiation,
toxic environment, etc. The term for genetic changesmutationcomes
from the Latin mutareto change. Defective genes send flawed messages to
the cellular lab, leading to the inappropriate production of the corresponding
chemicals. The resulting imbalanced chemistry means a disease in the organ
or system comprised of cells that produce this substance. Several genes or
even a group of them may be responsible for each
disease. Changes in DNA, the nucleic acid which is the
iny particles inside
carrier or genetic code, can be structural and funccells called genes are
tional. The latter means that the genes are, in princarriers of our heredity.
ciple, structurally normal, but have some variations
The genes govern
in their activity. This is of key importance for clinical
cellular functioning, and
medicine, since if only the genes functioning is
hence, chronic diseases
impaired, attempts to correct it can be successful. Not
are mainly the result of
by deleting and replacing them, as is planned in the
incorrect messages sent
current trend towards potentially dangerous genetic
to the cellular lab by
engineering, but by tuning them up instead.
faulty genes. Genetic
Once initiated, a genetic change is potentially
changes occur spontatransmissible, and may be passed by parents to their
neously or through the
children, grandchildren, etc. Genetic errors leading to
impact of external
health problems may be so subtle that their existence
factors and may be
remains unnoticed for years until time and/or strong
passed to future
effect deepen the hidden flaw. Doctors often see
generations. If the
parents that are taken aback when their child is diaggenetic faults are of a
nosed with asthma or other allergic disease that
functional, rather than
neither of them seems to have; it is the combination of
structural nature, mediparents genes that has amplified their own noncine has a chance to
apparent genetic errors in their offspring.
attempt a correction.
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it may seem. It is not simply a matter of the genes governing and the lab
obeying. Genes need fuel or feedback for their functioning, and certain
chemicals generated by the cellular lab itself play this role as do some chemicals coming from outside. Some activate the genes functioning, others inhibit
it. Genes can give proper instructions to the cells only when they get an
adequate fuel supply. Indeed, as Dr. Craig Venter, one of the two leaders of the
Genome Project, said on April 23, 2002 at the Gairdner Foundation International
Awards event, proteins are the building structure of life, not genes.
The understanding of the reciprocity in the functioning of the genes and
cells may turn the dream of medicinesafe and efficient genetic engineering
into reality. Use of proper substances may gently correct the functioning of
the genes and hence, rectify their messages to the cells. These substances would
be genomodulators, and their effect upon the genes
he activity of the
would be genomodulation. To modulate means to adjust.
cellular lab and the
The Latin root modulare means to bring out characterisfunctioning of the genes
tics peculiar to a definite region; thus, genomodulation
are interdependent.
would mean a repair of genetic functioning to the
Moreover, cellular
normal level. Such type of genetic engineering would
production at large can
be non-invasive and safe. Since medicine does not use
affect the genes
this sort of genomodulation, one would think that such
activity. Medicine can
proteins-modulators are not known or are commeruse this fact as the key
cially unavailable. Wrong. This book will discuss later
to access the genes if
two powerful genomodulators that work in harmony
their defects are only
with each other like a unit.
functional, not struc1. One is a chemical generated by the cells and
tural, and thus realize
released into extracellular space, also existing
safe genetic engiin a form of a drug.
neering. The use of a
2. The other is an intracellular enzyme.
well known synthetic
Both have been known for decades as messengers
version of a bodys
informing the cellular lab. If their harmonious work is
chemical triggers the
impaired, we may use a synthetic version of the first in
response of an intracelinjections, and it will naturally engage the other.
lular enzyme and
Numerous chronic conditions can improve or be cured
enables the latter to
by this. The improvement means that the genetic funcrestore the functioning
tioning in the patients treated this way was corrected
of impaired genes.
temporarily or for good.
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Immune Mechanisms
IMMUNITY
ur immunity consists
Everybody knows that immunity is the bodys defence
of highly complex
against disease, but, among laymen, few are aware that groups of cells called
it is, actually, a defence realized by cells called immuno- immunocompetent cells.
competent. These cells are competent in recognizing the They work in coordinaenemy and producing the chemistry that protects the tion with each other and
host. We are born only with the seeds of immunity. The specialise to fight
fighting ability of immunocompetent cells is dormant different diseases. These
for the first several months of life. Exposure to an cells start to malfuncenemy wakes them up. Each exposure provides a chal- tion if the genes
lenge for them to specializeto become competent in governing the immune
fighting a particular enemy. Some cells neutralize viruses response are mutated.
and bacteria, some fight cancer, others react to allergens
in those who are prone to allergic reactions. Each category of the specialized
cells performs its specific function. Thus, many groups of cells are united under
the concept of immunocompetence. Their coordinated work can be compared
to a well-rehearsed orchestra, and the released chemistry is the music.
Immunocompetent cells are located throughout the body. Certain genes
govern all aspects of their functioning. As was recognized a century ago,
immune diseases are the result of changes of the genes that govern all the
activity of the immune cells. The instructions of defective genes are, naturally,
defective, so are the kinds and the amounts of the chemicals liberated by these
cells. An error may turn the cellular music into a cacophony the way a poorly
tuned piano key can turn a concerto into a disaster. The uncoordinated music
of the immunocompetent orchestra means a poor defence against diseases,
no defence at all, or a distorted defence/reaction.
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what amounts to deliver them. For example, the longer life span among
women compared to men is considered to be due to the frequent hormonal
challenges that strengthen their immune system.
However, our society has created numerous challenges that exceed the ability
of our immune system to resist them with success. Our food is full of colorants
and preservatives, some indicated on labels, others hidden. We breathe toxic
fumes and drink contaminated water. We feed the cattle and chicken with
antibiotics and hormones that speed their growth. We
enes malfunction
even legalize the hazardous effects of these drugs by
due to inborn errors
allowing their permissible amount in meat and
or those acquired in the
poultry. Cattle are fed grass and grain treated with fertilprocesses of life. Their
izers, and we allow a certain amount of these poisons in
functioning may also
canned goods that use dairy and meat products. To
change under the influcompound our problems, we often take medications
ence of extreme envibecause we do not want to tolerate a slight discomfort,
ronmental factors.
even for a short period of time, and easily find a doctor
Genetic changes are
willing to write out a prescription. The respect of the
called mutations.
society to drugs is so high that we write them with capital
Mutations create a
letters. We are forced into vaccinating our children
predisposition to cellular
although the generally accepted hygiene theory by S.
malfunctioning, since
Romagnani recognizes that the increased exposure to
flawed genes send
vaccinations is among the factors contributing to the
wrong signals to the
spread of allergies and asthma.1
cells they govern.
Social pressures in our competitive society are also
important health hazards. Our biological evolution has
not caught up with the fast pace of civilization and its stressful and
sustained emotional factors that contribute to the destruction of our great
defenderthe immune system. This destruction starts with the genes that
govern the pharmaceutical lab of immunocompetent cells. Apart from
accumulating unfavourable external conditions that affect our genes, their
malfunctioning and/or mutation may occur spontaneously in the course of
life, without any obvious reason.
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Immune Mechanisms
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reactions without any trigger are also left unexplained. This deflects attention
from primary errors to secondary events.
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Immune Mechanisms
HOMEOSTASIS
To understand how medicine can tune up the body and help it to reverse
allergies on its own, we must understand a basic law of naturehomeostasis.
The word consists of two roots: home(o)sameness and stasisstanding, and
thus, the term denotes the tendency to preserve a balance. Nature strives for
harmony and endowed us with delicate self-regulatory systems. Whenever
unfavourable forces affect our body, these systems are challenged and, without our
awareness, adjust to the changes, thus protecting us. For
example, exposure to cold causes shivering, which is
he body functions
the bodys way of warming up, while exposure to hot
normally when all the
weather automatically causes profuse sweating that
cellular substances are
prevents overheating. Both the warming and the
produced in balanced
cooling are achieved through spontaneous changes in
amounts. A healthy body
the cellular chemistry.
possesses regulatory
Look how clever the body deals with dieting: after
tools through which it
an initial weight loss, the metabolism slows down to
corrects imbalances.
make better use of the smaller amount of food the
The main condition
dieter consumes. In fact, weight loss may practically
under which the immune
stop despite the reduced food intake. While this may
system functions
upset dieters, our metabolism is computerized to
normally is a homeohelp the body to survive during food-deficient times.
static production of all
Another example: if you eat a lot of sweets, the
chemicals by the
high level of blood sugar mimics the condition of
immunocompetent cells.
diabetes and may lead to metabolic changes. To
prevent complications, the body has a mechanism to cope with the dangerous
excess: the insulin-producing gland gets the instruction to increase its output
to metabolize the sugar.
Any deviation from the norm, be it a deficit or a surplus, may be equally
harmful, and these examples show that a healthy body self-rectifies such
changes through its protective autoregulatory switches governing all functions. The tendency towards maintaining equilibrium, no matter whether it is
body temperature, blood pressure or hormone production or, in fact, production of any chemical, is an inborn feature that keeps the body alive and is a part
of the universal law of homeostasis.
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CELLULAR RECEPTORS
What are the tools through which a healthy body regulates the production of all of its substances? Knowing
them in general, we could probably find the ailing regulatory tools in allergy patients, repair them and help
these people. The instruments through which the body
establishes homeostatic amounts of cellular secretions
are cellular receptors, which all cells have either on the
surface of the cell membrane, or inside the cell itself.
Receptors are molecules of protein that work like
antenna, each very selective in their response to the
surrounding environment. Each type of receptor is
tuned to a certain signal. Some discern a signal of pain,
others of temperature, sound, color, a specific chemical
substance, etc. Signals come in the form of chemicals,
the language of the cells. Each receptor selectively binds
to a specific substance, or picks up the information
contained in a physical stimulus, and then dispatches
the obtained information to the cellular lab. The received signals affect the
manufacturing process in the inner cellular lab. The information travels with
a lightning-like speed. The more complex the cellular lab, the more varied its
receptors are. Different groups of cells may have the same type of receptors
and hence, respond to the same signal by changing their chemistry in tandem.
Intracellular signaling followed by chemical effects is called signal transduction, while cell-to-cell talk is signal transmission. The development and
activity of all cellular receptors are determined by genes.
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Immune Mechanisms
A cell with its receptors can be compared to an insect whose antenna detect
signals from its peers or the environment. In response to a stimulus, a signal,
the insects body produces certain chemicals, and that changed chemistry
conveys a message for action. The signal may prompt the insects body to
exude venom to repel/kill an enemy or to secrete pheromones specific to the
situation: to alert its peers of a danger, to attract an insect of the opposite sex,
to call for help. Similarly, receptors are conductors of such cellular messages.
Imagine an insect with its antennas severed: all its communication with the peer
community and the environment are is cut off, and the insect is doomed to die.
Similarly, the cells ability to synthesize and release chemicals depends on its
receptor functioning and our health depends on proper receptor functioning.
RECEPTORS AS SWITCHES
A cell is a generator of chemicals, and like any generator, it is supposed to have switches to turn the
he body corrects any
processes on or off. An immunocompetent cell
unbalanced cellular
synthesizes numerous chemicals and has switches for
production through
each of the chemicals it generates. Cellular receptors
receptors that work like
play the roles of switches that intensify or temper the
turn-on and turn-off
cellular production process. To make sure that the
switches. Every cellular
cell produces just the right amount of a particular
chemical is regulated by
substance, there are receptors that switch on its
its specific receptors,
release and other receptors that switch it off. Each
and like switches, they
cellular switch works within a range. The regulation
adjust production to
is implemented the same way the temperature of an
cellular norm. Only propiron is increased or reduced by turning the lever,
erly working on/off
depending on the type of the fabric being pressed.
switches provide the
Proper control over the synthesis and release of
correct release of each
chemicals is vital because both excess and deficit can
cellular chemical.
lead to disease, as is, for instance, the case of a coma
resulting from blood sugar excess or its shortage.
Each receptor type is tuned to a certain chemical. Cells measure the
amount of this chemical in the surrounding space with their receptors in the
same way that an insects antenna senses the environment for specific signals
and then passes its message to the inner lab. The lab responds accordingly
either with intensification or inhibition of the release. This receptor-mediated
process goes on incessantly.
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If a certain receptor type, say an off switch, is inefficient, its counterpart, the on switch, works unopposed. This can make the cell generate so much of a
chemical that it inundates the tissues and leads to
disease. Only efficient on/off receptors can provide
balanced output.
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T-CELLS
Any discussion of a self-regulatory disease should start
with the commanders of the immune cells. They are
the T-cells or T-lymphocytes. These cells are a natures
masterpiece. The verbs used to define the T-cells role
in immune response and function affirm that they
initiate, propagate and orchestrate all immune reactions. T-cells mainly direct the battles by telling other
immunocompetent cells what chemicals to generate
and in what amounts. They also most actively participate in all processes where their subordinates are
involved, and immediately respond to the messages
coming from other cells. Various chemicals signal these
commands and responses.
T-cells possess a unique ability to learn how to
participate in immune reactions and govern them. At
first, these cells are nave. In a medical context this
word is used to describe the fact that an immune cell
has not yet been exposed to invaders and, therefore, has not yet had a chance
to express its fighting potential. Exposure to a virus, microbe, or any other
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Immune Mechanisms
intruder provides the cell with information that causes it to become educated.
This activation signifies the beginning of their specialization in the corresponding field. The process continues with repeated exposure to the trigger
in a way similar to muscle training when exercise results in a corresponding
muscle development.
Allergy is a deviation from the norm. T-cells are supposed to be our
protectors, but in the allergic patient they lack their regulatory ability. This
creates the background for an exaggerated activity of
-cells are central to
the subordinate immune cells, now promoting disease.
immunity. They
In allergy-prone people, any foreign substance or any
specialize
in fighting
unspecified event may become a trigger of a diseasepromoting immune response. T-cells called different diseases. After
T-helpers (TH1 and TH2) now unfortunately help to an encounter with an
invader, which they
produce chemicals promoting the allergic response.
The only other subdivision of T-cells that never perceive as an enemy,
fails us and stays in the disease fighting mode are the they retain memory of
T-suppressors. T-suppressors get activated simulta- what chemicals to
neously and in response to the activity of all other produce for any future
helper cells. In the 70s, the term was introduced that fight. In allergy, there
labeled suppressors as T-suppressor regulatory cells are two natural opposing
denoting that they regulate all responses, especially in subdivisions of T-cells
allergies.2 Suppressors moderate not only the host- helpers that are mainly
hostile activity of helpers, but also the disease- on the diseasepromoting activity of other immunocompetent cells. promoting side, and
In the process of maturation, all T-cells, T-suppressors suppressors that funcand both kinds of T helpers, become memory T-cells. tion to promote health
This means, that like the brain, they remember how to and also control the
participate in the fight by releasing certain chemicals work of T-helpers. Both
characteristic for their and activities in promoting or kinds of cells, once
specialised, become
suppressing disease.
memory cells and
remember how to fight
T-SUPPRESSORS
T-suppressors are our protectors in the immune for or against the
systems war we call allergy. Their overall activity disease.
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-suppressors are
controllers of all
allergy-related immune
responses, and their
activity and memory are
the keys to the normal
functioning of all participating cells. Inability of
T-suppressors to control
T-helpers and organize
the defence against
them explains allergy
symptoms. Inexplicably,
during the 90s, these
cells have practically
disappeared from all
allergy-related scientific
publications, which
creates the false view
of our immunity as a
system ruled and operated totally by negative
forces.
MAST CELLS
Among the closest subordinates of T-cells, two kinds play a special part in
allergic reactions. They are sister cellsstationary mast cells and mobile
basophils. Mast cells reside in tissues, while basophils flow with blood. Due
to the similarity of their functions, when speaking about mast cells, we imply
basophils as well, even though they enter an allergic reaction at different
stages.
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DENDRITIC CELLS
The third type of cells important in allergies is the
dendritic cell. The name dendritic comes from the Greek
tree. Indeed, threadlike extensions of dendritic cells
resemble a branched treethe image that inspired their
name. These cells secretory products are more diverse
than those known for any other cells of the immune system, states the leading
medical textbook on internal medicine.4 There are several types of dendritic
cells, and they densely populate the skin, the lungs, the lymph nodes, and the
nasal mucosa. One kind is of particular interest for us because of its regulatory
activity in immune processes, its ability to affect the performance of T-cells, and
its cardinal role in skin allergies and related skin conditions. These are Langer-
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hans cells, or simply LCs. These cells are a repository of numerous chemicals,
histamine among them. They bind to the intruder and present it to T-cells for
identification and action. LCs also possess the unique migratory ability of traveling from the skin to the regional lymph nodes and inform T-cells of the presence of intruders encountered on the skin or in the air passages. In addition, the
changing chemistry of LCs following their encounter
mong immunocomwith an intruder, can directly involve other immunopetent cells, there is
competent cells. LCs have another unique feature
affinity with nerve cells, which also belong to the family the family of dendritic
of dendrites. The extensions from LCs stretch to the cells. One type,
dendrites of nerve cells, thus forming their continua- Langerhans cell or LCs,
tion. These connections, as well as the cells reciprocal are especially important
chemistry, become the bridges for their communica- in allergy. They densely
tion. The involvement of LCs on the skin inevitably populate the skin, while
leads to the involvement of the nerve cells and vice versa. other members of the
Skin diseases of neurological origin, such as psoriasis or dendrite family reside
neurodermatitis, are the best examples of the ties and all over the body. Upon
interdependent functioning of the immune and an encounter with an
enemy, LCs bind to it
nervous systems in the body.
and present it to T-cells,
thus activating them.
HISTAMINE
Since all allergic reactions start and continue with a Dendritic cells have a
histamine spill, histamine will become central to this special affinity to nerve
book. Practically speaking, allergies and asthma are cells, which are also
diseases of one substancehistamine. When a person dendrites, hence the
does not have allergies, histamine release in that easy involvement of
persons immunocompetent cells is balanced. That is both in each others
activities.
why it is so important to clarify what histamine is.
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HISTAMINE IS AN AUTACOID
The word autacoid comes from the Greek autosself and akosremedy or
medicine. There are several autacoids, such as adrenalin, a powerful hormone
that increases blood pressure, accelerates the heart rate, etc. Then there is
serotonin, familiar to migraine and depression sufferers, since its imbalance
leads to these conditions. Too much adrenalin can be fatal; at the same time,
synthetic adrenalin saves lives in critical situations. Autacoids are substances
of bifocal activity: too much can be harmful, as can be too little. Not all
medical dictionaries list the word autacoid, but if you are lucky to find it, you
will read that histamine is an autacoid as well. Strangely, in the same dictionaries, the entry for the word histamine will not mention its remedial properties.
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23
istamine is a
substance of dual
activity. It does cause
allergy as well as some
other disorders, but only
when it is released
excessively. More
important is the fact
that histamine is
responsible for
messages of health
among the cells. By
originally including
histamine into the group
of autacoids, science
recognized its healing
properties. By excluding
it now, the medical
profession has distorted
scientific fact. Silence
about the vital role of
histamine for the functioning of the whole
body and its curative
ability is of special
concern in clinical
immunology and allergy
where histamine is
of overwhelming
importance.
HISTAMINE RECEPTORS
Histamine-synthesizing cells have not one but several
kinds of histamine receptors that regulate its synthesis
and release. They are marked by the letter H that stands
for histamine and numbers that denote their type. We
will speak mostly about three kinds of histamine receptors and just mention the forth, although science has
identified more. All four receptorsH1, H2, H3, H4
are important in passing numerous histamine
messages. Since H receptors operate with the substance that participates and
regulates numerous immune and neurological functions, these functions
depend on the efficiency of these receptors. In allergy, H1 receptors are turn-on
switches for histamine synthesis and release. H2 and H3 receptors are off
switches. Only when H2/3 receptors are deficient, the normal H1 receptors
become disease-promoting tools because they contribute to the histamine
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Immune Mechanisms
25
istamine production
and activity are
regulated by stimulatory
and inhibitory receptors
marked with the letter
H. By now, several kinds
of H receptors have
been discovered and
their mode of action
established as different
in different organs. The
fact is that clinical textbooks tend only to
contain information that
leads to the production
of medications that
block stimulatory H1
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Immune Mechanisms
27
genetically defective
and/or scarce, there is
little or no opposition to
the normal H1 receptors,
and histamine release
turns into a flood.
Histamine excess causes
the production of prodisease chemistry by
the participating cells.
The tissues full of
histamine-induced
chemistry respond with
corresponding allergy
symptoms. The two ways
to treat patients are:
1) temporarily control
histamine release by
blocking H1 receptors
and provide symptomatic relief; 2) activate
H2 and H3 receptors and
fix the problem.
Continual blocking
disrupts normal functioning of the tissues
with H1-receptor-bearing
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is too overwhelming for them. However, they discern the isolated mild signal of
the injected histamine amid the frenzy of the pro-disease signals and respond to
it by getting more active. A signal enables them to turn off the H1-tap. We may
compare the weak H2/3 receptors with a child who passes by a huge rock that
looks like a mountain for him, but picks up a small stone. The healthy H1 receptors feel comfortable within the milieu full of histamine and histaminetriggered pro-inflammatory mediators; a small dose of the injected histamine
will not be strong enough to incite them to adverse activity. This is why we
achieve the H2/3 effect by injecting small doses of histamine.
To see how both kinds of histamine work, let us take asthma as an example.
The lung tissue, if spread out, would occupy an area the size of a tennis court.
The lungs have the largest number of mast cells and basophils, the main
producers of histamine. Add to this the disease-promoting chemistry induced
by the initial spill. Now, compare this ocean with a small amount of histamine
in a syringe. Not only the small dose of diluted synthetic histamine is too mild
to activate H1 receptors, but its half-life is only a few minutestime not sufficient to unleash, not to say sustain, a disease process. However, the time and the
dose are enough to activate H2/3 receptors and hence, lead to the production of
pro-health chemistry by all participating cells. The protective H2/3 effect
opposes the H1 effect exactly in the way a healthy body does. Even though
medicine operates mostly by measuring and crunching numbers to establish
what is less than normal, and what is beyond the range of the normal, qualitative effects may be more important in regulatory diseases than mere measured
quantities. In allergy, it is not so much the amount of the opposing chemistry that
reverses the disease process, but the regulatory potency of the newly introduced
mediators. For an asthma patient, it means relief of the symptoms.
The degree of the improvement varies and depends on the functional
resilience of these receptors and the degree of their original deficiency. The
exact concentrations of histamine which activate only H2 receptors and
control H1-receptor activation (from 109 M to l04M) have been scientifically established.9 The H2/3 receptors react synergistically, which means they
are more effective when working together, and the H3 receptors are sensitive
to even lower doses of synthetic histamine.
Within a few minutes, the injected histamine starts breaking down and leaves
behind only its stimulatory effect. Like a pendulum that swings for some time
after it is released, the weak receptors temporarily continue their natural function
of turning off histamine leakage. The length and degree of their activation
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ontinuous and
excessive histamine
spillage from the cells
that have inefficient
H2/3 receptors (off
switches) produces
mostly unopposed H1
effect, and this maintains histamine leakage
and the disease state.
Synthetic histamine,
with its short half-life,
much lower concentrations and independence
of the pro-disease
chemistry, produces
only a mild signal, which
leaves H1 receptors
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knowledge. The H3-receptor effect is also kept in the theoretical domain even
though both animal testing and trials on humans are very promising.
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Through the thirties and fifties, Bayard Horton, a world-renowned American neurologist, employed histamine in diseases such as vascular headaches,
multiple sclerosis, Alzheimers, Menieres disease. Hortons name is assigned
to two medical conditions. One of them, Hortons syndrome, has another
namehistamine cephalgia (headache). So great were the achievements of
this scientist that in 1988, seminars were held by American neurologists in
honour of his work. Although the doses of histamine used by Horton were
not homeopathic, he abided by the principal of homeopathylike treats like.
He fought the excessive histamine release by injections of synthetic histamine:
big fire is best extinguished by another big fire. As often happens with
geniuses, Horton received posthumous acknowledgement, while during his
life, he had often been ridiculed for his obsession with histamine and his
belief that nature heals but histamine cures. Patients were coming to him
from Texas, from Oregon and Washington, and from the mid-west to mobile
home sites near the hospital, and were rolling in with their campers to
receive histamine treatment.12 Yet, his 1,402 medical charts have not yet been
evaluated.
Hortons treatment was later revived by S. Diamond who is now world
leader in vascular headaches and director of the Diamond Headache Clinic in
Chicago. In the past, his team used histamine for cluster headaches in addition to other therapeutic measures and had a 40% success rate.13 Around 1989
or 1990, I saw a documentary on TV that showed the use of histamine in that
clinic and wrote a letter to Dr. Diamond. Responding on August 10, 1990 Dr.
Diamond and his colleague Dr. F. Freitag stated that, like myself, they had
achieved excellent results in selected patients with intractable cluster
headache and regretted that in the past this excellent technique was inappropriately used, which led to its falling into disfavor in the medical community. The professors wrote that they were interested in my research and would
want more information on my own method of selecting patients for histamine therapy. I wrote to them that the method was described in my published
article that had accompanied my first letter, and that clinical implementation
of my method would require meeting personally. I received no further reply.
From the flyers now advertising annual seminars conducted by the Diamond
Headache Clinic for practitioners, I know that these no longer include histamine therapy.
As a more recent example of the never-dying interest in histamine is the
Web site of the American Council for Headache Education that in Headache
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Immune Mechanisms
change sometimes in the interpretation of the events, but rarely on the events
repeatedly seen under the microscope or even with just the naked eye.
Furthermore, documented clinical trials have repeatedly confirmed theory. Still,
since the early 90s, allergy medicine has continuously ignored this immense
body of knowledge by disregarding, silencing and actively distorting the facts
that could lead to the restoration of health in millions of people. This fact is
observed so frequently (as we discussed above), appears to be so well orchestrated, and is so clearly visible in the works of different authors that it is hard not
to suspect what I would call a plot against histamine.
The finishing touch, as it were, of this obvious conspiracy is the silent and
inexplicable removal of all the material on histamines immunomodulatory
properties from the recent editions of several textbooks on allergy and clinical
immunology. This removal did not occur because of new findings which discredit
everything known so far about histamine, but was undertaken without scientific
debatequietly. Here are several examples:
In 1985, the chapter written by R. Rocklin in the textbook Allergy spelled
out all histamine-centered and related mechanisms of allergy. The 1997
edition of this same textbook, still used in universities, is now updated:
this specific chapter has been eliminated; no revision of the discarded
scientific data is reported.
The 1982 textbook Immunopharmacology contained a chapter with a
detailed analysis of histamine and its role in immunity; the textbook has
not been reprinted.
The second edition of Therapeutic Immunology excluded the only chapter
contained in its first edition on the immunomodulatory effects of histamine in chronic immune diseases, including rheumatoid arthritis.
In 1990, S. Hill, a renowned immunopharmacologist who specialized in
histamine research, wrote the chapter Classification of Histamine
Receptors in the 1990 edition of Pharmacological Reviews. In the 1997
edition, this chapter became 12 pages shorter and much less informative.
The vital fact that histamine works as a modulator of the immune
response, as Hill had called it in 1990, was taken out seven years later.
Also gone is the idea of the possibility to use H2 agonists as immune
suppressant agents, as is the fact that a number of histamine congeners
(agonists) have now been produced.
Stephen Holgate is one of the worlds most respected contemporary
immunopharmacologists and one of the most prolific authors in this field.
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CYTOKINES
Histamine is the primary mediator of allergic reactions. Among other participants, there are also cytokines. This term has recently become an inherent part
of immunology. The word comes from the Greek, where cyto means cell, and
kinesismovement. Cytokines are products of the immune system; they are
proteins released by immunocompetent cells. They provide kinesis, the
dynamics in the cells and among cellular mediators. In a broad sense, the
words mediators and cytokines are interchangeable: both denote cellular chemicals taking part in immune reactions. The difference is that cytokines are
regulatory chemicals, choreographers rather than the actual dancers in the
ballet called allergy. In different immune diseases, there are different choreographers, but they always preserve their guiding role.
Cytokines can be roughly divided into two groups: disease-promoting and
disease-inhibiting, or, as science calls them, pro-inflammatory and anti-
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Immune Mechanisms
inflammatory. When they are released into the extracellular space, their presence works as a command telling cells what to doto carry on with the state
of illness or to undo that process. The amount, kind and activity of cytokines
determine which way the course of the disease will turn.
ellular products
HISTAMINE-INDUCED CYTOKINES
carry certain
Cellular production of chemicals is an interdependent
process. Profuse histamine release announces the messages and are called
beginning of an allergic reaction and induces various mediators. Those
chemical events. Like all mediators, pro- and anti- mediators that direct
inflammatory cytokines are brought to life by the reactions are called
original excessive histamine spill. Allergy medicine cytokines. The origin
even named the two central groups of cytokines hista- of chronic immune
mine-induced suppressor (or inhibiting) factors (HSF) diseases lies in the defiand histamine releasing factors (HRF), with the word ciency of antiinflammafactor as the substitute for cytokine. These two groups tory cytokines. The
provide opposite effects during allergic reactions. An course of the disease
allergic reaction is maintained through the prevalence depends on how
of histamine releasing factors. As the term indicates, prevalent the prothey increase histamine release and hence, the cascade inflammatory cytokines
of disease-promoting chemistry. Histamine releasing are over the anticytokines are produced by various immunocompetent inflammatory ones.
cells when their H1 receptors are activated by histamine.
Histamine-induced suppression works in the opposite direction: it
reverses the disease process by inhibiting the liberation of histamine and
histamine-related pro-disease chemistry. By calling these cytokines histamine-induced factors, science acknowledges that their formation is secondary
to the histamine effect. Regrettably, the word induced is mostly omitted,
which changes the meaning and correspondingly, the understanding of the
notion. The use of the word induced indicates that those factors activated by
histamine cause the suppression of histamine in its harmful function. By not
using this terminology, one hides the original induction and also subsequent
remedial role of histamine. The production of suppressing factors is induced
when histamine activates the H2 receptors. The prime generators of
suppressor factors are, as the name tells us, T-suppressors. T-suppressors
possess a major regulatory influence in allergy, wrote R. Rocklin who discovered the first suppressor factor in 1977.29,31 His chapter in Allergy 1985 indi-
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cated on page 176 the overwhelming importance of these cells as well as their
product, the suppressor factors, for controlling allergic processes. On page
182, the author emphasized the fact that histamine is the originator and regulator of both pro- and anti-inflammatory effects. I referred to this chapter as
being central to understanding allergies, and speculated that its elimination
from the 1997 edition of the textbook was probably intentional for reasons
totally unrelated to good medicine.
As the law of homeostasis dictates, the ratio of histamine-induced proinflammatory to anti-inflammatory cytokines determines health. The universally known medical textbook, Harrisons Principles of Internal Medicine,
which is published in new and updated editions every two years, stated the
following already back in the 1987 edition: complex cellular interactions involve a delicate balance among positive and negative influences and
ultimately result in expression of an appropriate immune response. The
slightest imbalance in these immunoregulatory circuits may result in aberrant
immune function leading to clinically apparent immune-mediated disease
(p. 334). If the consequences of the slightest imbalance are that serious, the
damage caused by disregarding a major imbalance of the pro- and antiinflammatory cytokines can hardly be overestimated. Once the topic was
considered so important that an award-winning work covering the cytokines
as the missing link in understanding allergies was presented at the AAAIsponsored lectures for post-graduate courses.30 We do not hear about this
anymore.
The interrelationship of histamine and the cytokines is further proof of
natures wholeness: not only does the histamine spill lead to their release, but,
in turn, the release of cytokines affects the further leakage of histamine. Thus,
pro-inflammatory cytokines contribute to further histamine release, while
anti-inflammatory ones inhibit it. A simplistic comparison of the interdependence would be a can of sardines in oil: sardines acquire the taste of the oil,
while the liquid tastes of the fish.
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Immune Mechanisms
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T-suppressors, proves the protective role of these cells in allergy. The central
role of the histamine-induced cytokines in reversing allergic disease and bronchial
asthma was confirmed by a number of eminent authors, and Dr. A. Kaplan, the
editor of the two editions of the textbook Allergy and the 2003 President of World
Allergy Organization, is one of them.
In 1991, Dr. Kaplan was a member of the team that
istamine, being a
made a presentation at the 47th annual meeting of the
substance of dual
American Academy of Allergy and Immunology on activity, produces both
histamine-induced cytokines. In that presentation it pro-inflammatory and
was observed that: an imbalance of these factors may anti-inflammatory chemplay a role in the pathogenesis (mechanisms) of istry. The proportion
disease in which histamine is an important mediator, of histamine-induced
and these factors are an important regulatory mecha- protective and histanism in the releasability of histamine.32 Four years mine-induced diseaselater, this same team of authors again covered hista- promoting chemistry
mine-induced cytokines as important participants in determines control or
the chemical war in allergy. The views expressed in progression of allergic
that article are consistent with the views on any war: reactions. The producvictory is achieved only when the less powerful party tion of histamine and
succumbs to the more powerful one. The article histamine-induced
admits that the ratio of histamine releasing factors to cytokines is interdesuppressor factors may be critical to pathogenesis of pendent.
a wide variety of allergic and rheumatic diseases,
and that it may determine the level of inflammation observed in allergic
disease.32,33 Since histamine induces the production of both the pro-and
anti-inflammatory chemistry, it controls the border between health and
disease. This puts histamine into the very centre of allergic reactions. Equally
important is also the fact that histamine plays a critical role in another
group of immune-related diseases, namely the rheumatoid kind.
Logically speaking, allergy should look at the two viable ways of preventing
or aborting an allergic reaction, namely curb the activity of the disease mediators or increase the production of the protective factors. But it seems that the
logic of allergy has become the servant of the drug manufacturers. At present,
the protective regulatory cytokines that inhibit the pro-inflammatory activity
without medications are hardly ever mentioned even in theoretical textbooks.
Clinical allergy focuses totally on restraining the pro-disease chemistry,
choosing to develop suppressors to each mediator and cytokine. As there are
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one which is most critical for recovery. Thus, recent textbooks and periodicals avoid the word histamine, and only occasionally, one may find out that
there is a mediator called histamine. The fact that it is an autacoid, or a
healing substance, can only be discovered if one is curious enough to undertake a purposeful, detective-style investigation through
ince clinical
the older literature on allergy. The protective function
immunology (or
of histamine H2 receptors in allergy is found in sources
allergology)
conceals
on molecular biology or genetics. On the contrary, the
negative effect of H2 receptors on the production of the anti-inflammatory
gastric secretions is emphasized in textbooks, periodi- properties of histamine,
cals and pharmaceutical compendia, obviously to it is only natural that it
support the need for the overwhelmingly popular would also conceal the
receptor-suppressive medications (zantac and pepcid). existence of histamineThis development is taking place in spite of the induced anti-inflammafact that medical science has shown that the tory cytokines and their
T-suppressor cell is a unique cell with a unique func- primary producers, Ttion; that these cells are the key clues to the regula- suppressors. Thus allertion of function in the immune system, and provide gists totally disregard
a functional cadre of T cells that act to downregulate the bodys own ability
the immune response.36 In the past, allergists also to produce regulatory
admitted that The suppressor cells abnormalities disease-fighting
observed in allergic subjects may reflect a primary cytokines and never
defect inherent to the atopic diathesis (allergy) seem to even think of
(Allergy ed. by A. Kaplan 1985: 190). As was said, the activating their producchapter that stated this is gone from the second edition tion. Instead, they work
of this textbook. With the disappearance of all these on the development of
histamine-connected phenomena, gone is the under- numerous medications
standing of what allergies and asthma are, and what that could suppress the
should become the target for therapy. This explains why multitude of pro-disease
cytokines.
the conventional therapies are not successful.
Interestingly, all allergy-related articles that simply
cannot avoid references to T-suppressors usually call them CD8+ cells, but
never identify them as suppressors. Calling them CD8+ effectively hides their
protective role, since this term comprises two kinds of T-cells, not just
T-suppressors. The abolishment of suppressors urgently needs a scientific justificationespecially so because on the cellular level, the regulatory
role of T-suppressors can be compared to that of the heart or brain.
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47
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H1-receptor blocking
H2/3-receptor stimulation
Just looking at the table, one can clearly see the advantage of the stimulatory effect over suppression. Why is it that modern medicine does not introduce the simple, biologically preferable approach of H2/3-receptor activation
into clinical practice? Why, instead, would medicine insist on suppressing the
activity of the H1 receptors and disrupt their needed messages throughout the
body? The reason is simple: the slightest possibility of permanent or lasting
correction of the functional genetic error endangers the profits of the drug
market.
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49
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rotein molecules
called enzymes form
the intracellular fuel
that transmits messages
relayed by different
substances via their
receptors. One such
enzyme, cyclic AMP,
is vital for the normal
functioning of the cells
in numerous organs and
systems, and especially
for the immune system.
Science recognizes
histamine as the primary
activator of cAMP in
immunocompetent cells.
Histamine uses H2
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51
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include the genes responsible for the function of the immune system, the
brain, the lungs, the skin, the skeletal muscles, the heart, the endocrine glands,
etc.
Mother Nature never fails to surprise us, and cAMP is one of her greatest
surprises. Not only does this enzyme always protect the body, but it is also
flexible in its performance; therefore, depending upon the bodys need, cAMP
may suppress the disease-promoting activity or activate the production of the
disease-suppressing chemistry. Activity of this enzyme determines the fighting
ability of the immune system.
Nature combined the two miraclescAMP and histamineinto one unit
to work for us. It really is a marvellously simple scheme: histamine, via H2
receptor generates cAMP, which in turn regulates the performance of the
genes, and that results in a wide range of anti-inflammatory chemistry and
disease-fighting effects. Working together as a pump that provides genetic
fuel, histamine and cAMP form the backbone for signal transduction, cellular
production and the subsequent cell-to-cell talk. The fact that histamine can
change the functioning of immunocompetent cells and neurons permitted
science to call histamine an immuno- and neur-omodulator. However, there
is more to histamines miraculous features.
All operations in the body are genetically driven, and this gene activity
together with its subsequent effects has a name: gene expression. Histamine is
capable of reaching the heart of the cell, and influence genetic functioning. In
order to do its healing work, histamine needs as a prerequisite functionally
adequate H2 receptors which provide the natural pathway for histamine
messages to reach the genetic material. As we know, allergy symptoms are the
result of the weakness of this very receptor.
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53
All the defects are of GENETIC originmalfunctioning of the genes affects the protective aspects of
istamine messages
immunity, such as the allergy-participating cells, their
via the H2 receptors
receptors and products. In the absence of genetic activate the enzyme
flaws, most of the effects of the environment on the cAMP. This enzyme
production of symptoms are brief. This fact makes the ignites a chain of intrainner causes that require correction primary in impor- cellular chemical events
tance, and the outer triggers secondary.
that reach the genetic
The first level is BIOCHEMICALpre-existing low
material and change the
levels of the enzyme cAMP, which provides fuel
functioning of the genes
for the operation of the defensive forces of our
known as gene expresimmune system. Without this enzymes induction,
sion. Successful correcthe balance shifts, and the overreacting immune
tion of gene expression
forces prevail.
results in those
The second level is MOLECULARhere we may
corrected messages to
find deficient, synergistically working molecules
be transmitted to the
called H2 and H3 receptors. This may cause an
cellular lab. This brings
inactivation of the enzyme cAMP, because this
about normalized
enzyme becomes activated only by healthy histacellular production, and
mine messages via the H2 receptor.
the end of allergy symp The third level is CELLULARhere a defect manifests,
toms. To be able to
first of all, in the mast cells/basophile high histadeliver stimulatory
mine releasability and T-suppressor inefficiency,
messages, these recepboth resulting from the H2/3-receptor inefficiency.
tors must be efficient
To correct the defects at all the levels, one should acti- and functional.
vate H2 and H3 receptors with injections of histamine. Their synergistic operation will raise the levels
of cAMP, inhibit histamine release from mast cells and basophils, and
generate and activate T-suppressors. The understanding of the prime defects
in allergy and asthma can then lead to a proper management of these diseases.
Treating allergy and asthma is relatively easy when these principles are applied.
This is not useful to the pharmaceutical corporations.
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he lasting correction of
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deaf hear, and the blind see. I know. I have seen it happen. More miracles in
my experience have been wrought with histamine than with all other therapeutic procedures combined.44
Gene modulation in allergies and related diseases could be standard practice
if only clinical immunologists employed the findings of their own research.
However, they withhold the theoretical knowledge of all curative properties of
histamine to prevent the use of its synthetic analogues in a clinical setting.
Allergy medicine bears full responsibility for sabotaging the main task its
professional status requireshelp its patients.
Serotonin
55
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Imitrex been universally accepted and has also received the highest pharmaceutical award as the best medication of the year. By contrast, histamine,
even though it has many similar properties, has been resisted by the highest.
This attitude to medications has deep social roots.
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57
DUALITY IN NATURE
An observation that may be worth exploring at this point is the logic of natures
laws and the logic of histamine therapy that goes along with it. Let us speculate
on duality. Everything in life is dual: life and death, love and hatred, health and
disease. This has been depicted through the centuries in the two-faced god
Janus, or Yin /Yang symbols, and in the eternal fight of Good and Evil.
Opposing chemical processes co-exist in the body at any given moment,
and the state of health vs. disease is determined by the prevalence of one over
the other. For example, as long as the formation of new cells exceeds their
degeneration, the body grows and develops. When degeneration takes over,
ageing starts. Take another example. If the bodys consumption of food is well
regulated by metabolism, we keep our weight under control. As we age, we
become prone to gaining weight even with the same food intake. This
happens because age wears out the mechanisms that regulate our metabolism, and it slows down. To stay in good shape, we should either reduce our
food consumption, or boost the bodys chemical processes by exercise, or,
better, do both. Balance is the answer to all problems.
In a healthy body, balance is achieved through its innate autoregulatory
mechanisms and systems. However, whenever damage does occur, relief
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should come from fixing the processes, rather than using artificial, unreliable,
or collateral means. Therefore a change in exercise level and diet is a better
response to weight gain than the consumption of appetite-suppressing pills
or radical stomach stapling.
However, anything bad that does not exceed the bodys ability to overcome it, presents a challenge to the protective forces and keeps them active.
For instance, the fight against a virus teaches the immune system how to
defend the host if the virus repeats its attack. The virus expands the protective memory of the immunocompetent cells. In the same manner, any good
possesses seeds of the bad. The bodys processes are never unilateral, moreover, bad and good ones go on simultaneously. Here is an example of a
natural duality: a small sliver gets under the skin. To destroy it, immunocompetent cells specialised in fighting foreign bodies rush to the site, gobble
it up and turn it into pus in the process. On the one hand, pus is the product
of this protective activity, on the other, its potential release into the blood
and lymph flow harbours danger such as a secondary generalized infection
or sepsis.
With the genes, this pattern of duality is also found in the actions of effectors and repressors. While the first kind gives instructions to the cells what
chemicals to produce, the second type moderates the effectors activity. In
many chronic illnesses, genetic changes are functional and therefore potentially correctable. The effector gene messages depend on the messages of the
repressor. The H1-receptor effect implemented by T-helpers becomes overwhelming only if the counterbalancing H2 effect is inefficient. The duality of
allergic reactions can be easily proven: allergy patients suffer but rarely die
because the power of the pro-disease forces in the body is not absolute, and
the defensive forces, though weakened tends to carry the day.
The inborn ability of cellular histamine to stimulate both positive and
negative forces is yet another confirmation of duality in allergy. Some effects
of histamine are pro-inflammatory whereas others are anti-inflammatory,
said a pioneer of histamine research, R. Rocklin.45 Thus, although histamine
spill from mast cells initiates an allergic reaction, histamine release from
mast cells may paradoxically limit the extent of inflammatory and immune
reactions, and reduce the levels of pro-inflammatory cytokines.46
Duality is a law of nature especially applicable to such self-regulatory
systems as the immune system. To ignore this is to defy nature itself. By
presenting immune mechanisms in allergy as a unilateral process, allergy justi-
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receptors, and they establish lasting, balanced production of the good mediators. This approach helps avoid creation of additional health problems, so
common in patients on daily drugs.
Allergology medicine does not generally acknowledge the duality of
allergic processes; therefore it cannot recognize the legitimacy of two
opposing approaches in the management of allergic diseases. Allergy employs
only the one that suits itsuppression of natural chemistry. Its creed isthe
more suppression, the better.
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provided prolific data, including the discovery of the H1 receptor in the early
thirties. Medicine universally embraced histamine as the central allergy mediator that initiates and maintains allergic reactions. The development of H1receptor blockers known as antihistamines was consistent with the theoretical
data existing at that time, and more than satisfactory from the standpoint of
profit. Antihistamines met all the requirements needed by the drug manufacturers: they did not cure, were considered (at that stage) safe, and were to be
taken on a daily basis (up to several times a day). On todays drug market,
there are no drugs that can compete with H1-antihistamines for profitability.
From the moment of its discovery, fascination with histamine prompted
worldwide research, and new findings of its role in the body accrued through
the years. The discovery of the H2 receptor signified another phase, during
which outstanding discoveries were made. The first extensive descriptions
were made in the sixties, and in the early seventies. L. Lichtenstein and M.
Melmon found that the H2 receptor possessed an opposite function to the H1
type, allowing it to play the protective role in allergies. Moreover, H2 receptor
possessed the unique ability to transform histamine messages into accumulation of the intracellular enzyme cAMP. H2-receptor stimulation enabled the
body to reverse immune inflammations and allergic reactions, by turning off
the histamine flood. This permitted science to classify histamine as an autacoid, a self-remedy of unprecedented importance in immunology. The curative properties of histamine and its synthetic analogues were thoroughly
studied. In the 50s, Parrot developed histaglobulin, and in the 70s, K.
Melmon and his team synthesized histamine congeners. Both proved to be
safe and effective in allergic diseases and could thus become successful rivals
to antihistamines and other conventional therapies.
Up until now, histaglobulin is quietly employed here and there, while the
congeners have remained unknown to clinical medicine. Also remaining
concealed is the theoretical substantiation of the potential benefits of histamine therapy in other chronic immune disorders. The efficiency of histamine
in allergy would be in inverse proportion to their marketability. Along with
the stimulatory effect of the H2 receptor, the possibility of blocking it was also
researched, and here, the results were different: a new drug categorythe H2receptor antagonists or H2 antihistamineswere developed to be used for
excessive stomach acidity. They were welcomed by the drug industry, and
together with H1 antihistamines, have become one of the most profitable
pharmaceutical products.
65
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In the early eighties, H3 receptors were found in nerve cells, and their
histamine-inhibiting effect, which is similar to H2 effect, was described. Some
time later, this receptor was found on immunocompetent cells as well.
Further research showed that H3-receptor stimulation could regulate not only
histamine release but also the release of other neurotransmitters, mediators of
nerve cells. H3-receptor agonists were created and proved effective for neurological symptoms as well as certain immune-related conditions. Actually, H3
receptor could become the key to the new therapyneuromodulation. It
could correct the imbalance of neurotransmitters and rid patients of a wide
number of neurological symptoms, including such common ones as vascular
headaches. Moreover, the synergism of the H3-receptor and H2-receptor
functioning steps up the remedial effect in allergies as well. But, the improvement would be lasting or permanent, and this appears to have doomed H3receptor agonists.
Still, nothing exposes the close ties between allergists and the drug industry
more than developing a certain drug group for asthma, which I mentioned
earlier. They target the enzyme cAMP, the levels of which are lower than
normal in allergy patients. The simplest solution would be imitation of
Nature which would mean H2-receptor stimulation. However, this avenue is
closed, since it would lead to the unwelcome revelations about the demoted
histamine. The drug developers choose a circuitous approach: through
another enzyme, they try to inhibit the natural degradation of cAMP. This
method is doomed from the start because with the pre-existent low level of
this enzyme, the effect of the new medications will be limited. The inhibition
may, at best, maintain the existing levels. This is contrary to the potentially
successful straightforward increase through histamine.
These allegedly novel drugs are, in fact, very old as they mimic the effect
of the half-a-century-old theophyllines. The best illustration of the efficiency
of theophyllines is given in the work supported by a research grant from the
Agency for Healthcare Research and Quality. It says that theophyllines,
which once dominated asthma therapy (63% of visits in 1978), were used in
only 2% of visits in 2002.49
By looking towards the increase of the enzyme cAMP in the development
of an asthma medication, allergists acknowledge its prime role in allergic
inflammation. Of most peculiar interest is that the development of these
drugs is headed by L. Lichtenstein, who had described in the late 60s and in
the 70s the pathway that leads to cAMP activationH2-receptor activation.
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The logical conclusion is: the choice of less efficient ways of asthma management is intentional.
Somebody thoroughly calculated the potential fiscal loss from the use of
histamine and its synthetic versions. The theoretical data on histamines
possessing immune-, neuro- and gene modulation properties had imprudently been entered in theoretical sources through the unsuspecting 60s,
70s and 80s. It provided the solid basis for the clinical employment of histamine in chronic immune and neurological diseases. Open and double-blind
clinical trials confirmed histamines efficiency in patients with allergy,
asthma, and certain neurological disorders. Perversely, these trials spelled out
histamines potential negative effect on the drug market. By the nineties, this
blunder and its possible financial repercussions were fully realized. This
explains how the information on histamine has been kept virtually out of the
reach of doctors and patients.
ENDNOTES
1.
2.
3.
4.
5.
67
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22. E. Vannier et al. Histamine Suppresses Gene Expression and Synthesis. J.Exp.Med.
1991;174:281-284.
23. D. Takeuchi et al. Histamine alters gene expression JACI 2001;107:310-4
24. JACI, 1990;86:589-686
25. R. Leurs et al. Molecular pharmacological aspects of Pharmacology & Therapeutics
1995;66:413-463
26. S. Holgate. The epidemic of allergy and asthma. Nature 1999;402:Suppl:B2-B4
27. B. Zweiman, M. Rothenberg. Beyond Our Pages. JACI 2002;109:728
28. J Clin Invest 2001;108:1865-73
29. Allergy 1985, p. 184
30. J.A.Grant et al. Histamine-releasing factors and inhibitors: historical perspectives and possible
implications in human illness. JACI 1991;88:683-93
31. R. E. Rocklin, D. K. Greineder, K. L. Melmon. Histamine-induced suppressor factor Cell
Immunol 1979;44:404
32. P. Kuna et al. IL-8 inhibits histamine release induced by histamine releasing factorsJACI
1991;87:207
33. P.Kuna et al. Chemokines of the alfa, beta-subclass inhibit human basophils responsiveness to
MCAF/ MCP. JACI 1995;95:574-8
34. JACI 2001:108:S147-336
35. Allergy 1985 p.183-5
36. E. Sercarz, & U. Krzych. The distinctive specificity of antigen-specific suppressor T cells.
Immunology Today 1991;12:110-117
37. R. Rocklin et al. Generation of antigen-specific suppressor cells N.Engl.J. Med,1980;302:1213.
38. M. White The role of histamine in allergic diseases, JACI 1990;86:605.
39. JACI 2001;108:S178
40. I. Elenkov et al. Histamine potently suppresses human IL-12 and stimulates IL-10 production
via H2 receptors. The Journal of Immunology, 1998, 161:2586-2593
41. R. Leurs et al. Molecular pharmacological aspects of histamine receptors. Pharmacology and
Therapeutics. 1995;66:41342. E. Vanier et al. Histamine suppresses gene expression and synthesis of tumor necrosis factor via
histamine H2 receptors. J.Exp. Med. 1991;174:281-4
43. H. Bourne, L. Lichtenstein, K. Melmon et al. Modulation of inflammation and immunity by
cyclic AMP. Science 1974;19-28
44. B. Horton. Chronic progressive retrobulbar neuritis Boswell Hosp Proc 1979;5:4-20
45. Allergy 1985:188
46. E. Vannier et al.. Histamine Suppresses Gene Expression and J.Exp.Med 1991;174:281-284
47. A. Kaplan, ed. Allergy 1985. p. 679.
48. Focus On The Literature 1996;15:9
49. R. Stafford et al. National trends in asthma visits and asthma pharmacotherapy, 1978-2002. JACI
2003;111:729-35
50. The Editors Choice. JACI 2002;109:580
51. A Mazzoni et al. Histamine regulates cytokine production J Clin Invest 2001;108:1865-73
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PART TWO
CAUSES AND
TRIGGERS IN ALLERGY
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were not in any way scientifically disproved, there was no factual reason to
ignore this information and no new findings that rendered the known causes
obsoletethe most important information for a student of allergy was
simply left out of the new textbooks, and excluded from all publications and
gatherings of allergists.
In the absence of true knowledge false claims become inevitable. Todays
allergy medicine exclusively connects allergic diseases to allergens, that is, the
triggers, whereas the cellular defects, without which no allergen could provoke a
chronic allergic condition, are never named as the key
factors. Textbooks present allergies as reactions to
he true cause of
harmless substances, or a hypersensitive state acquired
allergy is the genetithrough exposure to a particular allergen, or a disorder
cally preconditioned
in which the body becomes hypersensitive to particular
hypoactive functioning
allergens. Such descriptions distort the fact known to
of the protective part of
the majority of allergy sufferers: allergy symptoms may
the immune system.
arise in the absence of allergens. As a result of the
Environmental factors
distortion, medicine fights triggers and tries to control
are triggers that may
the secondary hypersensitivity processes provoked by
only provoke or accelthem. It never considers re-activation of the originally
erate the pre-existing
hypoactive immune mechanisms in order to correct
cellular malfunctioning.
the condition.
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71
ntigen is a substance
able to trigger an
immune response. A healthy
body defends itself from
dangerous antigens by
forming two major categories of specific proteins
cytokines and antibodies.
Cytokines are chemical
instructions of T-cells to
other cells: what chemicals
to produce and in what
amount. An instruction to
produce antibodies is one of
the many messages of
T-helpers to the antibodyproducing B-cells.
Antibodies need 314 days
to develop after the first
encounter of the host with
the antigen, after which
they are ready to inactivate
those antigens in subsequent encounters. Proteins
acting as antibodies are
called immunoglobulins, and
the sign for them is Ig. The
chemistry of each antibody
is compatible with the
chemistry of the challenging
antigen. Antibody formation
is a protective act of a
healthy immune system, and
like any immune process, it
is supervised by T-cells.
T-helpers help in cytokine
and antibody production,
while T-suppressors implement control over the whole
process. Antibody formation
is a process secondary to
the original T-cell activation.
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how to organize a defence, also explains why certain infections do not occur
twice.
In the normally functioning immune system, during the course of antibody formation, different T-cells perform different functions, but all of them
are protective. Thus, the role of T-helpers is to render help in the production of antibodies and cytokines, while T-suppressors implement the qualitative and quantitative control of the whole process, mainly by secreting their
own cytokines.
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gone, the allergic reaction unleashed by it would abate after 23 days. This is
exactly what happens, for instance, with hay fever patients: the end of the
pollen season means the end of their allergy symptoms. This, however, is not
so in too many instances. A reaction ignited by a certain trigger continues and
may even intensify in its absence. In other words, the
llergens only trigger
antigen plays the role of the car starter, and after that,
symptoms in those
the motor runs on its own. What keeps the motor
who have cellular
running becomes most important in view of the fact
defects related to H2that allergy medicine focuses on allergens and IgE antireceptor deficiency and
bodies. The explanation is found in the excessive
T-suppressor weakness.
leakage of the disease-promoting chemistry orchesThese inner immune
trated by T-cells. In chronically ill allergy patients,
defects allow the disease
liberation of histamine is continual because the weak
to continue even when
H2/3 receptors are unable to control it. It is accurate to
the triggering antigens
say that histamine is the central event that opens
are no longer present,
Pandoras box containing numerous diseaseand the IgE antibodies
promoting chemicals. This chemistry is the biological
have degraded. This
marker of immune dysfunction, while IgE antibodies
supports the view that
are merely a part of this chemistry and the consecellular malfunctioning
quence of the dysfunction. The severity of the symptoms
is primary, and that
depends not on the IgE count but on the degree of the
IgE antibodies are
H2/3-receptor weakness and the resultant pro-disease
secondary in allergies.
chemistry. This explains why the disease may continue
even when the IgE antibodies have degraded.
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cells provides a clear explanation of reactions that are not related to specific
allergens. This is what happens during nonspecific reactions.
It so happens, that the immune and nervous systems are interrelated.
Nothing in the body acts in total isolation. T-cells, mast cells, dendritic cells,
and neurons all live and work in tissues close to one another. They are washed
by each others secretions and often have similar receptors responding to the
same stimuli. All four groups of cells possess histamine receptors and, therefore, respond to its overspill. Any of the four may unleash that reaction.
For instance, something as simple and common as an environmental
change from warm to cold may affect sensory nerve endings in the skin,
causing their chemistry to change, and in doing so involves mast cells that
start to leak with histamine. The reactions that follow are similar to the ones
provoked by allergens like ragweed. A local skin exposure to a low temperature may increase a systemic reaction, especially in the areas of the highest
histamine spill. So, the patient may have a skin itch or get the hives, have a
stuffy nose, or an asthmatic attack, with no allergen in the picture. Cold may
directly activate mast cells, which are in abundance in the skin and airways,
and their profuse spill of histamine will start a reaction. Dendritic cells in the
skin may also react to cold, and their changing chemistry will also activate Tcells, followed by the engagement of the main histamine producers, mast
cells. Finally, T-cells may become directly activated, as they are also found in
large numbers in the skin and respiratory tract. The compromised T-helpers
respond by producing disease-promoting cytokines and mediators similar to
those observed in classical, allergen-provoked reactions. Histamine produced
de novo by the participating cells, amplifies the disease process started by the
leaking mast cells and basophils. The participating cells become the source of
numerous diseases-promoting cytokines and mediators, which, in turn,
contribute to further liberation of histamine and histamine-induced chemistry. This all leads to allergic symptoms characteristic of that organ or tissue,
in which the reaction takes place. Thus, an asthma attack or a stuffy nose,
upon exposure to low temperatures, is rather common even though often
misdiagnosed as a cold.
Also analogous are the processes that underlie allergy symptoms
provoked by the bodys physiological changes. Here is an example. Awakening
in the morning is accompanied by the activation of certain departments of
the central nervous system dormant at night. That involves those brain areas
that regulate the production of hormones needed by the body for its adapta-
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tion to the working day after a nights sleep. The variety of hormones involved,
as well as their levels in the blood, change according to those demands. The
T- and mast cells found in large numbers are able to respond because they
accept communications coming from this changing chemistry. If, however,
these cells are faulty by nature, they overreact to the chemical messages with
a histamine overspill and make matters worse by transmitting their alarm
reaction to the peripheral structures via the histaminergic system. This
explains why some patients have early-morning sneezing attacks or difficulty
breathing upon awakening. These changes are, by the way, unpredictable in
each individual.
The T-cells, mast cells, dendritic cells and nerve cells, all become engaged in
the same reaction, regardless of which one of the group initiated it. They work
together as a well-trained army. Their activation by any non-specific stimulus,
be it external or internal, provokes a histamine overspill. Its continuous leakage
maintains the process and chemically involves all of them. While a nonspecific
reaction bypasses the stage of specific IgE antibody formation, the final
outcome of events remains very similar to a reaction triggered by an allergen.
Although reactions to nonspecific trigger show that the presence of IgE antibodies is not a reliable indicator of allergies in a person, contemporary allergy
medicine insists on focusing on IgE antibodies and, therefore, fails to explain all
those commonly observed deviations from the standard. Sometimes these are
even fatal reactions to peanuts, for example, in babies who have never been
exposed to peanuts and, therefore, cannot have IgE antibodies to these nuts. The
immune system supposedly only responds to a repeated exposure, once
specific IgE antibodies have formed. The fact that babies may die during such
a very first exposure does not fit the accepted concept, and leads to the
unfounded search for the mothers consumption of peanuts during her pregnancy or breastfeeding, even though we know that IgE antibodies do not pass
through the umbilical cord and have not been found in breast milk.
There is an even more impressive example: the very first bee sting received
in life can be fatal. The IgE-based concept cannot explain this phenomenon.
Also vague are the explanations of the processes that underlie reactions due
to such nonspecific factors as cold, sun light, physical exertion, etc., although
the ability of these phenomena to provoke symptoms has forced allergists to
recognize their existence and they even have a name for them, namely physical allergy. In all such cases, the cause is genetically predetermined-readiness of mast cells/basophils to release histamine.
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onspecific triggers
stemming from body
chemistry or an environmental physical factor
may cause a response of
hypersensitive immunity
similar to the one
caused by specific triggers. The response
always starts with an
excessive histamine
release from mast cells.
The similarity of receptors, the cellular ability
to produce and respond
to the same chemicals
histamine in particular
and the shared
chemical-electric
language of communication explain the simultaneous engagement of
nerve cells and immunocompetent cells in
allergic processes. No
matter what triggers
these reactions, and
what cells get activated
first, the reactions are
immunologic, since
major immune cells and
their products take part
in them.
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cigarette smoke used to belong to the group of nonspecific irritants. Then IgE
antibodies were identified, and this permitted re-classification of smoke into
an allergen. Another example is latex. Opinions about latex as an allergen
have recently been challenged. Latex allergy used to be limited to latex gloves,
and medical professionals who wore them were considered to be a risk group.
Not long ago, it was found that hypersensitivity to latex was also common in
other groups of the population that never wore latex gloves. Toys, pacifiers,
tires and other products of rubber are among the many sources of latex. Latex
particles are found everywhere, and lately, latex has been relabeled by allergists as a pollutant. Has there been an observed physical change of the routes
through which latex causes an allergic reaction? No. Will it change anything
in the treatment? Absolutely not, since it has always been limited to avoidance. So, why is the strict classification so badly needed? This game-playing
with real, biological events merely served to conceal the allergists inability to
explain and treat allergies in general, specially when it comes to irritants.
The cellular processes that lead to symptoms are never clarified in textbooks and only occasionally touched upon in periodicals. The focus is on
triggers. Moreover, true science is further distorted when the symptoms to
nonspecific triggers or irritants are presented as nonimmunologic even though
allergy symptoms are the result of the involvement of immunocompetent
cells. Strangely, allergists fiercely fight to keep patients with such nonimmunologic diseases in their purely immunologic practice.
The truth is that in allergy, irritants or pollutants work through the same
mechanisms as specific and nonspecific triggers. Upon inhalation or touch,
irritants may:
produce a direct effect upon T-cells, and these start to generate diseasepromoting chemistry;
directly affect dendritic or mast cells and make them leak with histamine
and histamine-induced disease-maintaining mediators;
affect sensory nerve endings, and the changing chemistry of nerve cells may
involve immune cells.
The subsequent reactions are more or less similar: activation of mast cells/
basophils with their exaggerated release of histamine and histamine-induced
chemistry. This is exactly what a combined team of scientists from England and
Turkey said in an article on asthma: air pollutants... may modulate airway
disease, such as asthma, by increasing the release of pro-inflammatory mediators.1
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mmunocompetent
cells and nerve cells
share certain receptors
and respond to and
release the same chemicals. They become
inevitably involved in
the reactions started by
either kind. This explains
why allergy symptoms
are often accompanied
by neurological symptoms. Histamine, as the
central mediator in
allergy and a governing
neurotransmitter, can
become the cause of
both allergy and neurological symptoms if
produced in exaggerated
amount.
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unusual specific antibodies, IgE, were found in the hosts body and declared to
be the hallmark of allergic diseases. Following this discovery, medicine
proclaimed that only the presence of IgE antibodies confirms allergies.
At that time, the scarcity of knowledge in this field justified such a declaration. Since then, accumulating information made it clear that the notion of
allergy was much wider than the original, solely allergen-dependent theory,
and that non-specific factors could also provoke allergy symptoms. This
simply meant recognizing that patients might have allergy symptoms without
showing the antigen/IgE antibody complex on mast cells. Their symptoms
could equally well be the result of activation of their hyper-responsive
immune mechanisms. At this point, allergy should have embraced the new
data and reconsidered the stance that only IgE antibodies can be the single
indicator of allergies. It did not happen. As history teaches us, the moral and
ethical standards of those who have already come to power often become
entrenched, and the bearers of new knowledge always seem to endanger those
in power. To preserve their positions of authority, the supporters of the
allergen/IgE antibody-based concept turned it into a cult, they started to
conceal the existing findings and created a new hypotheses, which are not in
agreement with observed facts.
Proof that this concealment and distortion are intentional can be found in
the entries on the word allergy in medical dictionaries: the original meaning,
now obsolete, includes all states of altered immunological reactivity, immunity
as well as hypersensitivity, allergic reactions to cold, heat, light, etc. are named
physical allergy.2 Occasionally, the most renowned scientists dare publicly to
recognize that the term allergy has become corrupted and is now frequently
used synonymously with IgE-mediated allergic disease, whereas some
allergic diseases develop through Ig-E-independent mechanisms3
However, these very scientists still continue to disseminate the IgE-based
doctrine. Today, this dogma has become the Procrustean bed that all mechanisms of allergy must fit into, and the true causes are simply cut off because
they do not fitas the legs were cut off from people who did not fit the bed
created by the ogre Procrustos in the Greek myth. The best proof of the power
of the allergen-based concept is the universal acceptance that allergies are
caused by cats, mites, pollens, etc., and that by eliminating, avoiding or
destroying these, one gets rid of the disease.
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normal part of the environment do not affect us but can be fatal only to the
people with no previous exposure to them.
Although allergy medicine has not been able to solve its version of
Hamlets dilemma: to eliminate or not to eliminate, allergen elimination
remains central in the management of allergies.
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responded best.6 Of course, the higher percentage of the removed mites upon
repeated washing with the given detergents is likely to expand the market for
Clorox, but will it help allergy patients? The article does not provide the answer.
In March 1996, the participants of the 52nd annual meeting of the AAAAI
heard a report later published by the flagship journal on allergy.7 The study
was designed to assess the clinical efficacy of special bedding covers in house
dust mite respiratory allergy and was staged in a highly scientific setting with
the use of placebo mattresses as opposed to mattresses with Intervent
covers. The conclusion sounds like a scientific joke: allergen avoidance by
Intervent covers is effective. However, in this group of moderate asthmatic
patients, it did not improve allergic asthma. The question is what WAS effective, if the patients did not improve?
It is not uncommon to read articles written by allergists on what types of
air filters and vacuum cleaners to buy, how many minutes are needed to
achieve the best results, what water temperature to use for washing the
bedding to destroy the mites, and what sort of mattress pads to purchase so
that body moisture does not contribute to the spread of the mites. Are these
measures more effective than the effective Intervent mattresses that supposedly control the mites but do not relieve asthma?
Many pseudoscientific arguments regarding dust mites can be easily
rebuffed. For instance, nocturnal asthmatic attacks may well be related not to
the spooky mites but to the low levels of activity of our hormones during the
night, especially, natural corticosteroids and adrenalin. During the day, they
are produced in higher amounts, and this diminishes the number and severity
of the attacks. This explains the lesser need of medications in the day time by
the majority of asthmatics. Additional proof of the insignificance or absence
of an external effect is that there are those who soundly sleep in the same
bedrooms full of mites. Yet further proof is that an allergy patient whose asthmatic attacks occur only at night can sleep in a tent with no mites around and
still cough and wheeze. Should he look for these tiny culprits hiding in or
behind the tent?
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some articles also speak in favor of pets. For instance: Does early exposure to
cat or dog protect against later allergy development?8 So, before parting with
your favorite pet, wait until science makes a final decision on whether they are
dangerous or curative.
An amazing study was once conducted at the Henry Ford Hospital in
Detroit. It revealed that despite weekly bathing of cats with distilled water or
their spraying with a preparation, which could reduce shedding, there was little
improvement in the allergic patients. Although cats are not exactly animals that
love bathing, distilled water cannot harm them. As for the spray, as a person
who loves cats, I only hope the cats survived the chemical exposure.
Water temperatures for washing pets and the frequency of the washing
procedure are among highly debatable topics professionals carry out on the
pages of their periodicals, at symposia and share with the lay sources. Will dry
cleaning be the next issue for scientific research? Pets are so notorious among
allergists that the 2000 issue Canadian guidelines on asthma specifically point
to them: Have a non-allergic person bathe the pet weekly.9
Here, I want to refer to the official statistics on allergies. Although, they
vary in different sources, I am inclined to believe those provided by the
worlds leading immunologist, the editor of the European journal Clinical
and Experimental Allergy, professor S. Holgate who said that 50% of the
population suffer from allergies and asthma.10 In this connection, I feel sorry
for pet owners: try to find a non-allergic nanny to bathe a cat in the society
where every second person has some hypersensitivity! A formidable task.
Despite the conflicting results of numerous studies, the guidelines worked
out by the American allergists, and published in the March 2001 supplementary issue of The Journal of Allergy and Clinical Immunology have, among
cockroaches and dust mites, a picture of a kitten as the most common indoor
threat to be avoided or eliminated. Unexplained remains the fact that pets, as
a part of the human household for hundreds of thousands of years, have never
been considered so notorious in the production of diseases, even though exposure
to animals must have been even higher in the past. Also unexplained is the fact
that many pet owners remain symptom-free.
In life, tragedy and farce often go hand in hand. The tragedy is that allergy
has made the intentional decision to go off the right road and thus, leaves
patients in a lurch. The farce is that phony science has been substituted and
silly arguments about dogs and cats have been elevated to the level of the
cause of the most common diseases of the century. The readily available unre-
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FOOD ALLERGY
Allergists agree that allergy skin testing is unreliable for diagnostics, and this
will be discussed in detail in the section on this topic. Still, despite their general
agreement, skin testing for foods is often performed, and to the surprise of
many, they are diagnosed with allergies to the foods they were consuming all
their life without any reaction. These patients often end up with giving up on
a productnaturally, without any relief in their allergy symptoms.
Dieticians or doctors specializing in alternative medicine often suggest
elimination diets to pinpoint the allergenic products. As a rule, patients know
what foods cause severe reactions, and therefore those do not need analysis
and challenge. Elimination of less allergenic products starts with keeping a
journal on reactions that may occur when eating regular foods. The analysis
of the notes may help to eliminate one or several foods that trigger mild to
moderate reactions. Few comply with this lengthy and tiresome procedure.
Besides, it is too often unsuccessful because allergy is mostly not limited to
one or two food products; besides, traces of the allergenic substance may turn
up in unexpected products, sometimes, even in allergy medications.
According to the existing regulations, manufacturers must indicate on labels
only those ingredients that exceed a specified amount, whereas a patient with
a hypersensitive disease may overreact to a substance in minute quantities.
Moreover, by excluding one or two allergenic foods, the patient may still
develop allergic reactions to something he cannot pinpoint. These people are
doomed to eating only at home and cooking from absolutely known ingredientsquite a difficult task.
Misdiagnosis of lactose intolerance is especially common. Many patients
came to me with such a diagnosis, but almost none of them had had the test
necessary to establish that the particular hypoactive enzyme was missing. The
diagnosis had been made solely on the basis of the medical history, or simply
because dairy products, milk in particular, are among no-no products in the
opinion of their doctor. They had given up on all dairy products, often with
minimal or no success at all. A no-milk diet is especially difficult for children
who are tempted with ice cream, milk chocolate and pastry, which their peers
consume in their presence. Unable to resist temptation, these kids often eat
the forbidden product and pay the pricesuffer from an itchy rash, a
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unspoiled New Zealand. Paradoxically, the official statistics say that the countries without proper regulations on hygienic standards and, therefore, I assume,
with the highest cockroach counts, such as India, have the lowest rates of allergies and asthma. Something must be wrong with the suggested concept, as
there is evident discrepancy between the scientific declarations on allergy
causes and the statistical figures existing in allergy theory.
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immunologist repeated the same advice about cats and fathers, this time, in a
medical periodical. A sense of humor is a commendable quality in a doctor,
but in a medical publication, one would also expect a serious recommendation. There was none.
Bernard Shaw once compared good advice to castor oil, which is easier to
give than to take. Allergy patients are too often given castor-oil-advice.
Moreover, if all these recommendations were given solely to patients, this could
be considered part of their education on elimination of the offenders. Whether
the patients followed the advice or not would be a matter of their choosing,
savings in the bank and love for their pets and fathers. However, these astonishing masterpieces of medical thought are delivered by the experts in the field
to an audience of fellow immunologists and become a part of established
science. Look at the covers of Journal of Allergy and Clinical Immunology, and
you will mostly see pictures of cats, mites and cockroaches. Although the work
of allergists often incorporates things that do not exactly belong to immunology,
they do such investigations as their professional (well-paid) mission.
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WHATS IN A NAME?
If allergies can start without an allergen, or, being started by one, can
continue in the absence of this allergen, what is the legitimacy of the term
allergic diseases? The conventional term allergy narrows and distorts the meaning
of the diseases and unjustifiably pins them to allergens and thus, to IgE antibodies. It permits the medical profession to continue costly allergy testing to
allegedly identify the offensive allergens but, strangely, almost never adjusts the
treatment. It makes the search for triggers the centre of diagnostics and turns
trigger elimination into the main, though ineffective, treatment method.
Current concept of allergic diseases is confusing not only for laymen but for
doctors as well. Furthermore, the absence of detectable allergens may be
harmful to patients when a necessary medical certificate is denied because of
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the prevailing orthodoxy and humiliates them by denying the reality of their
physical disease, dismissing it as the condition of an unstable mind. This situation leads to absurdities such as the one in April 1998 when chronic fatigue
syndrome was recognized as a physical disease by a Canadian court. Since
when does medicine need judges to establish a diagnosis in medicine?
In the majority of cases, symptoms are provoked by both identifiable
specific and less easily identifiable nonspecific triggers; therefore strict categorization in this field of medicine only confuses the understanding of the
immune processes; a change is urgently required. The idea of revising the
term allergy is not new in science. In 1999, I came across an article unusual in
its criticism.12 There I read that: There is probably no term more misused in
medicine, both by physicians and medicine, than the term allergy.
According to the author, restricting the disease to the IgE/mast cell mechanism is anachronistic, and there is a need to redefine all those terms
invented decades ago. Will it be done? The change in terminology requires a
change in understanding what underlies diseases of hypersensitivity.
Expunging the word allergy from the medical vernacular would be a good
start to better understand the pathophysiology of diseases, states the same
source. In my opinion, expunging of the term now is difficult because it has
become deeply rooted. Of course, the term hypersensitivity would be more
appropriate as it points to the true cause of the symptoms, but then, what do
you call the specialists that treat diseases of hypersensitivity? The more practical decision would be to leave the term as it is, but agree upon the real nature
and meaning of hypersensitivity and to tell the truth about what is currently
concealed. Namely that there is this duality of histamine and its chemistry,
which lie at the heart of allergies. It is not the change of the term that is
needed, but the change of these admittedly anachronistic views.
Allergists do not consider it urgent, despite their every-day failure in the
treatment. Allergen/IgE-based religion has become even stronger in the new
millennium. Thus, in 2001, Harvard Medical School reaffirmed, in a study
supported by a National Institutes of Health the concept that IgE plays a critical role in asthma pathogenesis (underlying mechanisms)13 The cover of
the journal that published this article depicted the usual, most notorious
allergensdust mites, pets, cockroaches, while nonspecific triggers have
completely been excluded from the contents of this supplementary issue.
Interestingly, just a decade ago, the data presented at the XIV Congress of the
European Academy of Allergy and Clinical Immunology stated that only 15%
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of asthma had allergic origin, 41% are non-allergic, and 44% were mixed.14
Have the diseases of hypersensitivity changed their origin, or has allergy
medicine inexplicably changed its views within the decade that separates
these works?
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Unlike the outdated IgE-based concept that fails to clarify the scope of the
disease and appearance or escalation of symptoms in the absence of any
evident allergen, this simple classification would remedy the situation. It
would also save the often useless and painstaking efforts to find the offender
and eliminate it. Such classification unites all five categories in the similarity
of the underlying cellular processes, all of which are obviously immunologic
and differ in details only. The main point, however, is that the re-classification
would focus on the cause of the diseaseimproperly functioning cells and
initial histamine hyperreleasabilityand thus lead to the potential for their
repair.
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PART THREE
ALLERGIC INFLAMMATION
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Allergic Inflammation
99
llergic inflammation
is a chemical,
inflammation-like local
and/or systemic reaction, secondary to
dysregulated functioning
of the immune cells.
Unlike the external
cause in other inflammations, immune-related
inflammations arise
from the internal cause
deficient immunoregulatory forces responsible
for excessive release of
pro-disease mediators,
of which histamine is
the most important.
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Allergic Inflammation
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Allergic Inflammation
antibiotics and steroids strengthens the false impression of the analogy between
infectious and allergic inflammations, and creates a sense of safetyalso false.
With less and less hesitation, under the pressure of increasingly treatmentresistant allergies and asthma, and under the even worse pressure brought to
bear upon doctors by those who formulate therapeutic guidelines, doctors
prescribe and patients take steroids. What doctors rarely, if ever, reveal, and their
patients are not informed of is that steroids belong to immunosuppressive remedies. The consequences? Read the word again. Can the already dysfunctional
immune system of an allergy/asthma patient improve with a drug given to
suppress the functioning of the immune system in general? Besides, all too
often, consumption of steroids becomes as chronic as is the disease itself.
Continuous suppression of the already weakened immunitynot a very
encouraging prospect. Suppressed is the ability of the cells to produce not
only the targeted bad mediators and cytokines , but the good ones as well,
and in time, steroids disable the cellular lab. Not that doctors do this intentionally. Their textbooks keep them blissfully unaware of the origin of allergic
inflammation, and the leaders in the field, as well as the manufacturers, assure
them of the safety of steroids. With the primary cellular defects remaining
unattended, the chances to arrest the resulting events are slim. The aggravating fact is that these immunosuppressive medications do not have any effective alternativeat least not as generally taught in medical schooland this
justifies their aggressive prescription.
The height of misunderstanding of what an allergic inflammation is, can
be gauged by the fact that the notion of asthma being a chronic injury and
repair response, with classic wound-repair factors participating in the
disease is gaining popularity.3 There is an obvious conflict here. First, the
nature of a wound is inapplicable to allergic processes. Second, a wound is a
lasting condition incompatible with the reversibility of processes in allergies
and asthma. Third, steroids impede wound healing, and therefore their
imperative prescription for wound repair in allergies and asthma is more
than contradictory; it is false.
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processes that occur in its development. The etiology of allergies has never been
spelled out, and as a result, their pathogenesis is inconsistent. Inflammation is
a nonspecific term of wide scope. Allergists have proclaimed inflammation as
the cause of asthma and allergic diseases, therefore speaking of their etiology,
we speak about the etiology of allergic inflammation.
The etiology of allergies is the primary deficiency of the genes responsible
for the protective regulatory immune tools, with the resulting low performance of the protective arm of the immune system that comprises T-suppressors, the histamine H2 receptors and cyclic AMP system. These etiological
factors logically determine the pathogenesis of allergic inflammation.
The Pathogenesis of allergies stems from the inability of the immune
system to perform its autoregulatory role as nature designed it, namely to
temper any negative response of the immune cells through their own energetic
positive counteraction. The pathogenetic mechanisms include the primary
excessive release of histamine and histamine-induced pro-inflammation
cytokines and mediators, that is, prevalence of H1 negative effect over H2/3 positive effect. The response of the surrounding tissues mediated by this predominantly inflammatory chemistry is what science calls allergic inflammation.
These definitions of the etiology and pathogenesis correlate with the textbook description of those in chronic diseases in general. As we have already
quoted from the main medical textbook, the cell/mediator interactions
involve a delicate balance among positive and negative influences and ultimately result in expression of an appropriate immune response. The slightest
imbalance in these immunoregulatory circuits may result in aberrant
immune function leading to clinically apparent immune-mediated disease.4
This is exactly what we see in allergies.
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Allergic Inflammation
its most powerful weapons. The main reason why allergists present allergic
inflammation as the cause of allergies is to support the intention to expand the
use of anti-inflammatory steroids. The unfortunate fact that physiological
dependence develops over the time is also handy, for consumption grows with it.
Although allergists insistently propagate the concept of allergic inflammation, they are evasive as to what causes it. Ask a doctor the same question
about other inflammations, and you will get a clear answer: viruses, bacteria
or injury. In relation to allergic inflammation, you will, most probably, hear
about dogs, cats, dust mites and pollens as causes. Only medically uneducated
patient can accept this idea, and a doctor must be equally illiterate to believe
it. If you are lucky to find a doctor who mentions an exaggerated histamine
release as the cause of your symptoms, ask him what makes you different
from your neighbor who does not have this defect. Then, with the knowledge
you have by now about histamine, ask this doctor what prevents medicine from
using its self-remedial qualities. I doubt you will find a physician who will know
what you are talking about. Do not blame him. Illiteracy in the field of allergy
is a carefully nurtured fact, true knowledge is rejected, and research is
supported in any area but the one that could help resolve the problemhistamine and related events and mechanisms. Instead of rejoicing in the
reversibility that distinguishes allergy from other immune areas dealing with
more resistant or therapeutically irreversible diseases, the leading allergists
stonewall the spread of the existing true and relevant knowledge.
The drug market has become the main source of medical information. It
determines the value of drugs not from the standpoint of patients wellbeing
but from the economic perspective. The drug market has become the underlying mechanism in the promotion of the secondary eventallergic inflammationas the origin of allergies. The etiology of this process is the sickness of our
society in general and the sickness of medicine as its inseparable and the most
lucrative field. These forces maintain the marriage of poor medicine and the
rich drug industry.
ENDNOTES
1.
2.
3.
4.
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PART FOUR
HISTAMINEGATE
If liberty means anything at all, it means the right to tell people what
they do not want to hear.
George Orwell
Read not to contradict, nor to believe, but to weigh and consider
Francis Bacon, The Essays
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Histaminegate
First of all, although the researchers knew the mechanisms that underlie
allergies in detail, they failed as clinicians because they were unable to observe
clinical findings in patients and interpret them on the basis of their own theoretical discoveries. Second, when allergists realized how damaging these
discoveries could be for the drug market, they used this lack of clinical
substantiation to silence the well-researched theoretical findings many of
which came from the labs of these allergy gurus. At present, this fundamentally significant material is virtually unknown, and the researchers themselves
never mention their discoveries that form the foundation of allergy as a
science. Astonishingly, some pioneers of histamine research have never actually declared a change in their position, they have gradually disappeared from
public view during the 90s. Others, strangely propagate their newly acquired
views on the immune processes in allergy and avoid the very name of the
substance that launched their careershistamine.
You may be curious to know if I believe that the scientists, whose works I
am going to discuss and quote, are among the participants of the plot against
histamine. My answer is: I do not know whether they have changed their
stand voluntarily or under duressbut it is highly improbable that they are
unaware of the vacuum that started to form around histamine in the early
90s, and which is now virtually complete. Their high status in medicine and
their profound knowledge make it improbable for them not to have noticed
the concealment of all the data pertaining to histamine, including their own
earlier research. Conspicuous is also the absence of explanations of what
necessitated the dramatic shift in their scientific views. Only time will reveal
who was an involuntary witness, and who became a complicit participant in
the plot.
This chapter is a critical review of certain textbooks and numerous papers
published in peer-reviewed journals. The authors are often the editors or
board members of these journals, chairs of international conferences, writers
and editors of textbooks, and they are thus, trend-setters in clinical
immunology. By definition, a critical review is scholarship performed with
the purpose to correct or improve. The concept of a critical review suggests
analysis of the material with exposure of errors, misstatements and contradictions within a given text as well as comparison with other existing views.
As any critical review, mine is not directed at the scientists, but at their works.
Its purpose is to improve the existing bleak situation with regard to allergies
and asthma. The emphasis is on the inexplicable turn in contemporary
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allergology, on the active effort to silence and misinterpret those wellresearched notions and ideas that could preserve allergy as a science. Unlike
most critical statements, books, and articles in the area of allergic diseases,
this book offers a fairly easy concrete solution. I realize I am inviting the rage
of allergists and hope that at least some of them will have the courage to
admit publicly what they already acknowledge behind closed doors: their
failure to manage patients with allergic diseases and asthma and to recognize
the urgent need for a change.
Experts are never right or wrong; they win or lose. Right and wrong are
decided by proof; winning and losing are decided by who is doing the talking
or talks the loudest, has the last, latest or only word, and is quoted by
reporters, says a quote from The Globe & Mail. I understand, that my voice
is a whisper compared to the loud chorus emanating from the central periodicals, huge textbooks and monumental monographs. To make myself
heard, I choose to speak with their words taken from the same journals, textbooks and volumes and only point to the obvious discrepancies. Not merely
in the details, but in the most essential material.
For those who may say that being a general practitioner, I am unable to
access and scrutinize the scientific work of the allergy moguls, I can say that
my medical background does permit me to do this. I have a residency in
internal medicine and specialization in allergology. For 8 years, I worked as
an allergist in a republic of the former Soviet Union. The fact that in Canada,
I did not acquire a local certification was due to the fact that I simply could
not financially afford 4 or 5 years of residency here. For the 4 years of my
internship and preparation for exams in Canada, my wife carried the heavy
burden of being the only breadwinner in the family, and I felt I had a responsibility to start working as soon as possible. I am permitted to work as an
allergist in Canada and nothing deprives me of my previous knowledge, or
diminishes my interest and ability in this field. For 30 years, I have studied
everything I could on histamine. In Canada alone, I have successfully treated
about 2,500 patients with histamine, and many more back in Russia. In 1989
and 1992, I made presentations at international conferences about my own
clinical experience and presented the supportive scientific data. These presentations covered the role of H2/3-receptor effects and the stimulation of cyclic
AMP by histamine as the central regulatory mechanisms and therapeutic means.
In the late 80s, I wanted to share my experience with others and
suggested to the Ontario allergists having a discussion on histamine
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and its title is again forthright about the role of histamine in the immune
system; it reads: Modulation of cellular-immunity by histamine. The article
says: Once released, histamine presumably activates the suppressor limb of the
immune reaction and dampens the response by decreasing production or
release of inflammation-promoting lymphokines (cytokines). The
suppressor limb involves mainly H2-receptor activation of T-suppressors that
inhibit allergic reaction. It is of special importance that for support, Rocklins
article sent the reader to an earlier work by L. Lichtenstein who is another
pioneer in the research into the modulatory properties of histamine. His works
will be discussed below.
Rocklin devoted another lecture of his to immunotherapy.4 On page 332,
the author names the therapeutic targets for immunotherapyinduction of
suppressor cells/factors and decreased reactivity of mediator-releasing
cells. This simply means that activation by histamine enables T-suppressors to
inhibit all inflammation-promoting factors in allergy and also dampens the
hyperreleasability of the immunocompetent cells. Rocklin reinforced these
ideas two years later in the 1985 textbook Allergy by adding that not only are
T suppressors activated by histamine, but also their very existence depends on
it. On page 185, he talks about the generation of histamine-induced
suppressor T cells and histamine activation of human suppressor T cells.
There was no conspiracy around histamine at that time, and Rocklin could
easily call a spade a spade. So could others. Through the 70s and 80s, the
content of many articles and their titles were crystal-clear about the
immunoregulatory role of histamine. For instance, some of the titles were:
Histamine-induced suppressor factors or autacoids as modulators of the
inflammatory and immune response; or Modulation of cellular-immune
responses in vitro and in vivo by histamine receptor-bearing lymphocytes;
or H2 receptor and the immune system, etc. All of this was before the era
that started in the 90s when histamine became mysteriously taboo.
Textbook have stringent requirements to present either the established
information or explain that the given findings are being questioned or reconsidered. The requirements should be especially strict, if the presented material
is based on morphology, physiology and molecular biologybasic sciences
that do not usually change in essence but expand through new research. There
is no doubt that A. Kaplan, the editor of both editions of the textbook Allergy,
would have abided by these rules, or his position among his colleagues would
have been untenable.
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Now imagine my surprise when in October 1997, at the university bookstore, I unsealed a fresh copy of the second edition of Allergy.103 My first intention was to see if there was new information on histamine, therefore I looked
up Rocklins name in the table of contents. By then, I had already noticed the
growing tendency to omit all histamine-related immune-modulating tools
and events. I had an inkling that, for medically unrelated reasons, the direction
of the new textbook might shift. What I saw exceeded my worst fears. The only
image I can think of here is that of a beheading. Allergy as a clinical science was
beheaded: Rocklins chapter, the only one on the primary underlying mechanisms in allergy, had disappeared from this new edition.
The strangest thing, however, had happened to T-suppressors. The very
term T-suppressor was mentioned only in an allergy-unrelated chapter which
on page 783 questioned the very existence of these cells by asserting, without
any reasons given, that these cells had supposedly become one of the major
controversies in immunology. A material cell disappeared.
This raises a number of very basic and disturbing questions. How can one
explain the existence of their marker, T8 or CD8+, evidenced by the most
reputable medical textbooks and dictionaries? Are we suddenly to believe that
Gershon and his colleagues had in 1972 discovered some sort of phantom
cells, which they had capriciously named suppressors? Was this discovery a
hoax or a fantasy? Furthermore, how can one explain the discovery of the Is
(immune suppressor) genes that govern the functioning of the non-existing
T-suppressors? How can counter-suppressor cells exist if there are no
suppressors? How could the Clinical Immunology Committee of the
International Union of Immunological Societies at the World Health
Organization point to expanded suppressor cells as their target in the
improvement of immunotherapy if all of this was fantasy? By whom, how and
when were these cells abolished?
Mind you: T-suppressor is not just another cell. It is (was?) the key figure
in the regulation of all allergic processes of the immunity. If it was lost,
banned or re-classified, this unique fact had to be registered in all medical
sources and, above all, be explained! It had not.
With the disappearance of T-suppressors from all the chapters of Allergy
1997, H2 receptors, which are the distinctive feature of these cells, also went
missing. It is as if they were not discovered in the sixties by the Nobel
Laureate James Blackwith the Nobel Prize seemingly being the only record
left of this discovery. If one was cynical, one might now expect, that the next
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step will be the exclusion from the genome all of those already detected genes
responsible for the functioning of both T-suppressors and H2 receptors.
With Rocklins chapter excised, the facts and details, which substantiate
the mechanisms that underly allergy and prove the inseparability of these
mechanisms from histamine, we have a situation now in which there is no
real explanation in the current textbook, Allergy 1997, for what allergy actually is. This disappearance of histamine cannot be accidental: all mechanisms of allergy, disease-promoting as well as protective, have an innate
dependence on histamine, and hiding its central role has led to a fundamental
misrepresentation.
The burying of this knowledge was done cautiously, so that it wouldnt be
too obvious. On the surface, everything appeared proper: the chapters in the
revised textbook written by other authors listed all the cells (except Tsuppressors!) and their mediators and cytokines participating in allergic reactions (except, of course, the histamine-induced suppressor factors). However,
listing of the cells is not enough to explain their effects, significance and interrelationship or show what to correct in the case of cellular malfunctioning.
Now, with everything related to histamine being omitted, the events in
allergic reactions have become hopelessly distorted. Thus, while the chapter
on mast cells and basophils provides a general description of their functions,
it does not specify that their release of histamine is the cardinal event both in
the early and late phases of allergy. Nor is there an indication that the cause
of these cells hyperreleasability is their deficient H2-receptors which are
unable to turn off the leakage.
Allergy 1997 is not so much a textbook, but a collection of puzzles with all
the needed clues gone. It does not answer the main questions: what cells and
what receptors control the balanced production of all cellular chemicals in
healthy people, and what goes wrong and leads to the disease. The new textbook has created the impression that the immune system of an allergy patient
consists of cells whose chemicals work solely against the host. Naturally, only
the helping hand of the drug industry can correct this situation. Not surprisingly, therefore, the second edition of Allergy 1997 has increased in the
number of pages now devoted to medicationthe antihistamines.
You might object that as science develops, even some of the most solid
findings of the past may become obsolete, and this could be the reason for
changing the material in the textbook. That is a reasonable objection.
However, if this had been the case during the 12 years that separate the two
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Melmons works reveal that he never changed his opinion about the curative properties of histamine. The 1996 textbook Therapeutic Immunology (ed.
by K. Austen et al.), with Melmon as an author, stated on page 192: Histamine
appears to play an important role in limiting the inflammation processes
unlike any mechanism known for classic immune-suppressive therapeutic
agents. The authors believe in histamines potential as a therapeutic
immune-suppressive agent.10 But, no matter how safe and good histamine
congeners may be, one should have strong reasons to doubt that they will be
used in medical offices in the near future, and this is why.
From the above-cited article, we know that agents now are available that
stimulate one or the other receptor on selected lymphocytes, which means
that for, at least 20 years, safe and effective drugs have existed that could selectively activate the needed H2 receptor without activating its counterpartthe
H1 receptor. Allergy sufferers are definitely interested in knowing where these
agents are. So are doctors who deal with resistant allergies every day. Still, the
congeners have not been tried even for those patients with immune-related
inflammation who are not helped by any other medications. My opinion is
that Melmons research reached that stage in clinical medicine where even the
best minds are not free to choose the direction of their work. For example,
research grants are almost entirely controlled by the pharmaceutical industry,
and every contract contains a gag clause which provides the sponsor with the
power to disband the research effort when its results begin to contradict the
sponsors financial interests. These gag clauses are illegal in Canada, but they
continue to control research anyway.12 This is equivalent to a Do not trespass! sign blocking practical application of all medical research. It seems that
Melmons findings were so compelling that they had to be buried. Not surprisingly, the second (2001) edition of Therapeutic Immunology no longer contains
that chapter written by this great scientist and his team.
The process of research censorship appears to be systematic, because the
earlier 1997 edition of this same source, the Pharmacological Reviews, already
then excluded those parts contained in its even earlier 1990 edition, namely
the information that stressed the anti-inflammatory features of histamine
and the possibility of using histamine congeners developed by Melmon. For
example, the following passage was dropped: These data suggest that histamine-inducible suppressor cells may be important for normal immune regulation and raise the possibility for the use of H2-selective and lymphocyte-selective
agonists as immunosuppressant agents. An exciting advance in this area of
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research has been provided by the development of lymphocyte-specific histamine derivatives. A number of histamine congeners have now been
produced. Two references to Melmon are given at this point.13 The curative
properties of histamine did not change with time, and only the editors know
why the key elements needed for therapeutic purposes suddenly needed to be
hidden and were deemed so irrelevant as to be removed from the text. This
elimination makes even less sense in view of the regret the editor Dr. Hill
expresses over the neglect of histamine in the report made by his team at the
International Union of Pharmacology. This report was later included into the
1997 edition of Pharmacological Reviews.14
I can only imagine the disappointment Melmon must have felt when in
the last years of his life he realized that all his gigantic work was unclaimed
for clinical application and would not be used to help patients.
I have read all the works by Melmon on histamine I could find. Within
our correspondence, I was also privileged to view his not yet published work
on a newly discovered histamine receptor. His extensive knowledge of histamine activity, and especially his desire to find a practical solution to the
problem of immune inflammations through histamine and its derivatives,
impressed me most. In 1991, I wrote Melmon a letter about my use of histamine for asthma and allergies and enclosed the following abstract, already
accepted for the presentation at an international congress.
H2/3 Effect in Allergy
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receptor-bearing cells, while IgE level changes are inconsistent. This adds to the
classical theory based on antigen-antibody mechanism unable to explain certain
events in pathogenesis and suggests that the basis for allergy might be an inherited or acquired receptor/enzyme deficiency to be corrected by stimulatory H2/3
effect of exogenous histamine and/or conventional hypo sensitization. The
hypothesis uniting non-specific and specific factors is supported by works of few
authors successfully using histamine and by my experience with about 2,000
patients with various allergies, over 75% of whom were treated with histamine.
The original technique for the method is described elsewhere. The preliminary
results, especially in cases of hay fever in season and bronchial asthma, are superior to those by any other treatment 15
I asked Melmon if he was interested in the effect his research could have in
clinical practice and if he did, I would send him additional information. In
response to my letter and abstract, to prove the seriousness of his interest,
Melmon supplemented his letter of August 28, 1991 with his impressive 30page curriculum vitae and his articles on the (crucially significant) dual role
of histamine. He even sent me his yet then unpublished paper in which a
hand-written sign confidential crossed each page. In his letter (see Appendix)
the scientist wrote: I am substantially interested in knowing how you came
to the conclusion, which I share, that H2/3 activity is likely to be immunosuppressive (suppresses allergic inflammation through activation of protective immunocompetent cells). Encouraged by his interest and support, I sent
Melmon my recently published article, which had references to his work.
Melmons second letter of December 3, 1991 ended with I do look
forward to further opportunities to reviewing and sharing your excellent
work. I was happy that the great researcher was supportive of my work, but
our communication was interrupted for reasons of a nonmedical nature. In
1993, the journalists of the Canadian Broadcasting Corporation, who were
sympathetic to the plight of allergy/asthma sufferers, were preparing a
national TV program of the CPSOs actions against my histamine therapy. In
a telephone conversation, they asked Melmon to comment on my work.
Melmon refused to do so. By that time, I had already become a medical dissident. Melmon had been contacted by the prosecutor, as the latter admitted
later during my discipline hearings, and, most probably, he had been told that
it would be wiser to sever our communication!16
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I have the highest respect for the work done by Rocklin and Melmon. I
believe that for their contribution to allergy research, they deserve much more
credit than allergists have given them. But the very reasons for which they
should be revered are the reasons for concealing the essence of their work
the histamine connection.
LAWRENCE LICHTENSTEIN is a former president of the AAAI and
Director of Johns Hopkins Asthma and Allergy Center, one of the worlds
most prestigious medical schools. He is a recipient of the Research Career
Development Award of the National Institute of Allergy and Infectious
disease of the US Public Health Service given for his research on the underlying immune mechanisms of allergy. Lichtenstein is a prolific author and
editor of papers and textbooks, key-note lecturer at international forums and
committees, and a board member of leading medical periodicals.
Lichtenstein and Melmon teamed up at the time of their most outstanding
discoveries related to histamine and produced a number of articles of such
basic importance to allergology that they continued to be referred to, even at
the peak of the censorship of works on histamine. Curiously, at the time his
own presentations began to show a dramatic change in his views on histamine.
None of his works or oral presentations has provided any scientific explanation
for these changes.
Lichtenstein started to study the H2-receptor functions soon after their
discovery by James Black and he was actually the first to show that this
receptor is an instrument through which histamine realizes its immune
modulating function. Together with Melmon, Lichtenstein specified the
concentrations at which histamine self-inhibition actually takes place, namely
at 106M (i.e. ten to the power of minus 6).17 Two years later, in another
article with the self-explanatory title Inhibition of histamine release by histamine controlled by H2 receptor, they say: exogenous histamine could stop
the release of endogenous [histamine]. In another article, he again pointed
to mast cells and basophils as the major histamine-releasing cells and specified the concentrations at which the leakage stops.18 The article develops the
idea that the H2 receptor located on the histamine-releasing cells, possibly
mediates an inhibitory effect on the inflammatory responses. It is of interest
that the authors compare the histamine effect to that of antihistamines and
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favor the first: no clear effect of antihistamines on the inhibition of histamine release was observed. Moreover, they add that in high concentrations,
antihistamines were cytotoxic, that is, their toxicity disrupts cellular functioning. (It should be of great interest to patients that today, allergists are
suspiciously silent about the self-inhibitory effect of histamine as well as
about the toxic side effects of antihistamines, but instead are very vocal about
their supposed benefits).
Four years later, Lichtenstein was still researching the H2-receptor effect and
wrote: Our results suggest that differentiation of T-cells is accompanied by
appearance of histamine (H2) receptors; and again the authors specify the
protective role of these receptors in allergy.19 In another paper written with
Melmon, Lichtenstein expresses the idea of the exclusive anti-inflammatory
role of the H2 receptors in the functioning of T-cells, mast cells and basophils.
At this time of the most intensive research into histamine, the authors theorize
about the possibility of transferring the histamine H2-receptor effect into clinical practice and so they wrote: understanding of such a regulatory mechanisms may open the way to new therapeutic approaches to treatment of
immunologic and inflammatory disorders in man.20 In other words, activate
the H2-receptors, and the differentiated T-regulator-suppressor cells will
mediate an inhibitory effect on the inflammatory responses. Only the scientists themselves can tell why they stopped short of employing histamine clinically. Was it their insufficient clinical expertise?
In the early 90s, Lichtensteins stand inexplicably changed. In 1994,
Toronto allergist Dr. Allan Knight, was appointed as an expert witness by the
CPSO during my disciplinary trial in order to disprove the benefits of the therapeutic use of histamine. The official transcripts contain his admission during
cross-examination that he was unfamiliar with the H2-receptor immune
modulating function described in depth by Lichtenstein 20 years before.
Knights lack of expertise and knowledge in histamine properties and treatment prevented him from providing scientific arguments and/or sources
against the histamine immunotherapy or desensitization I was using, and so
the expert decided to come to the hearings with a better weapona personal
letter from Lichtenstein. Judge for yourself whether this letter of January 19,
1994 can be recognized as providing a scientific basis for disproving histamine
therapy:
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inefficient type (H2) with histamine or its congeners? Especially so, because
Lichtenstein knows and reported repeatedly that a bronchial spasm is an event
secondary to the histamine-induced pro-inflammatory chemistry in the
airways. His own role in establishing this scientific fact becomes evident in
Chapter 10, written by Rocklin in Allergy 1985.
When Rocklin wrote that deficient histamine H2 receptors are the primary
cause of any allergy, he referred to Lichtenstein (references 55, 56).11 With this
knowledge, the stimulatory effect of histamine should look more attractive
than the use of beta-adrenergic drugs for several reasons.
First, the effect of bronchial inhalers on beta-receptors is short-lived since it
is applied to the secondary event;
Second, it is a recognized fact that bronchodilator use is dangerous in the
long run.
Histamine, on the contrary, produces an immune modulating effect via the
H2 receptors, and the effect can be lasting because it goes to the core of the
problem.
Being a physiologic autacoid, histamine is safe, as Lichtenstein once
declared.
Why, when and for what real reasons did these advantages turn into disadvantages in the opinion of the learned scientist?
Anti-inflammatory immunosuppressive medications may serve as
another example of the scientists positionnow biased towards drugs in
spite of his own research. Compounds more commonly prescribed to alleviate the chronic inflammation of asthma are often helpful, writes
Lichtenstein on inhaled steroids in 1993.30 By saying that, he encourages the
use of these drugs, immunosuppressive in the generally accepted pharmacological classification, but immune modulating in the vocabulary of allergists. What could possibly be wrong then with the use of histamine, whose
activity Lichtenstein had also called immunomodulatory ? Lichtenstein
evidently saw the therapeutic use of histamine back in 1974, when he said:
histaminemight limit the extent or severity of an inflammatory reaction31 and also three years later when he repeated the idea: histamine has
marked modulatory effects on immunity32 Isnt modulating an inflammatory reaction the goal of any therapy in allergies? If so, why was histamine
excluded from the list of the core allergy mediators taught at the AAAI-sponsored training program for allergists and immunologists in 1994 when
Lichtenstein was its president?33
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develops drugs for asthma that are supposed to target this enzyme cAMP. The
drugs are phosphodiesterase inhibitors, or PDE inhibitors. Strangely,
Lichtenstein, who described how exactly to reach this enzyme, chose a different,
twisted approach. The drugs he is working on will have an effect similar to the
one of theophylline. The Canadian Compendium of Pharmaceuticals and
Specialties writes in the entry on Theo-Dur: The actions of theophylline may be
mediated through inhibition of phosphodiesterase and a resultant increase in
intracellular cyclic AMP. The above quoted article co-authored by Lichtenstein
described as far back as 1974 the target of this drug group, and on page 20 of
that 1974 Science article, we learn that it is inhibition of histamine.
Thus, it is a case of all roads leading to Rome: control over histamine release
is the unspoken but ever-desirable aim of allergy/asthma medications, and the
novel PDE inhibitors are not an exception. Now that asthma has reached
epidemic proportions, the idea of reinventing theophylline-like medications
must be very attractive for drug producers. It kills two birds with one stone.
First, by concentrating on retarding the metabolism of the enzyme cAMP
with PDE inhibitors, allergy diverts attention from the possibility of raising
it with histamine.
Second, the development of theophylline-like medications will provide
numerous scientists with work, and their gratitude will come back to the
sponsors in the form of high profits.
Will the newly synthesized inhibitors be more effective than their antiquated,
not-so-effective older cousins? I doubt it, and, indeed, the first trials of the
novel drugs are admittedly not very promising.
There is nothing wrong with improving antihistamines, perfecting allergen
extracts or creating new inhibitors. Allergy is a troubled field in clinical medicine today, and anything should be researched to put the best into practice.
However, Lichtenstein who studied in depth the biochemical mechanisms that
underlie allergies and knows the most efficient ways to treat these diseases, is
now doomed to settle for ineffective ways based on false targets. He works on
antihistamines once recognized by himself as cytotoxic. He tries to make
allergen extracts safer, although at the time of his ground-breaking research on
cAMP, he thought that understanding of such a regulatory mechanisms may
open the way to new therapeutic approaches to treatment of immunologic
and inflammatory disorders in man. He knows how to activate H2 receptor in
order to increase the much-needed enzyme, but instead, he develops impotent
inhibitors that may, at best, maintain its levels as they are.
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The first histamine-induced suppressor factors brought to life by H2receptor activation were described by Rocklin in 1977.41 Discovery of other
histamine-induced suppressor factors soon followed. Along with that, the
pro-disease histamine releasing factors, HRF, or pro-inflammatory cytokines,
were discovered. In 1989, J. Grant and R. Alam (the latter received an award
for this research) gave lectures at the annual meeting of the AAAI. These
lectures formed the basis for their article published two years later.42 The
authors called histamine-induced factors a missing link in the understanding of the underlying mechanisms of allergy. On page 690, one reads:
Histamine, a major mediator of allergic injury, may have an additional effect
by increasing synthesis of HRIF, a specific inhibitor of HRF, which may restore
local homeostasis. [HRIFhistamine release-inhibitory factors, synonym of
histamine-induced suppressor factors] Moreover, the clinical relevance of
cytokine-dependent mediator release from mast cells/basophils extends
beyond the boundary of the atopic (allergic) disease, and that similar effect is
observed in many chronic inflammatory disorders. These include rheumatoid
arthritis, ulcerative colitis and the rejection process of some tumors. Not
only does this all point to the common roots of these chronic diseases, but
also puts histamine into the center of various immune-related inflammations. Allergic inflammation is just one of them, but it is most closely related
to histamine activity. This also means that the state of disease or health is
determined by what histamine-induced factors prevailpro- or anti-disease.
Naturally and unavoidably, the article has references to the works by L.
Lichtensteinand also by A. Kaplan.
At the time of this report, AAAI obviously did not realize how explosive
this missing link could be in understanding allergies. The very mention of
histamine-induced suppressor factors leads inevitably to considering
T-suppressors that generate them. In turn, T-suppressors lead to H2 receptors
because there are no active suppressor cells, or their protective factors without
efficient H2 receptors because: differentiation of T-cells is accompanied by
appearance of histamine H2 receptors, as Lichtenstein wrote.43
The chain logically ends with the final linkhistamine, as the best natural
activator of H2 receptors. Melmons team described, and we earlier quoted,
the reciprocal relationship of histamine and histamine-induced chemistry:
Histamine regulates the release of lymphokines. Release of histamine is
influenced and regulated by lymphokines.44 All this knowledge involuntarily
leads to the seditious idea of using histamine with the purpose of counter-
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diseases as well as other chronic immune diseases. The authors also wrote
that this ratio may play a role in the pathogenesis of disease in which histamine is an important mediator and recognize that histamine induces the
production of bifocal chemistry, which, in turn, is an important regulatory
mechanism in the releasability of histamine. This echoes the above-quoted
idea expressed by Melmon the same year in Agents and Actions: Histamine
regulates the release of lymphokines. Release of histamine is influenced and
regulated by lymphokines. Thus, in the interpretation of Kaplan and his
team, histamine release becomes the determining factor in the development
of immune-related inflammatory diseases.
In 1995, as a co-author of another article, Kaplan still preserves the same
views on allergic reactions: a balance between molecules of HRF or HRIF
activities exists which may determine the level of inflammation observed in
allergic diseases.46,47
Only two years separate this article from the second edition of the textbook Allergy edited by Kaplan (discussed above in some detail), but the
revised edition inexplicably omits these determining factors, as does the
chapter by A. Kaplan himself on cytokines. Only one sentence on page 78
reveals that the author does know that immune processes are a two way street:
Some initial studies of asthma have examined the possibility that HRF, as
inflammatory agonist, and HRIF, as control mechanisms, are important
contributors to symptoms, and that the relative ratio of the two might determine the clinical course. For a reader not privy to this secretive information,
the off-hand use of HRIF looks not as the determining event that could
reverse allergic reactions but as an insignificant detail undeserving of clarification. There is no explanation that HRIF stands for histamine-induced
release-inhibitory factors, which is, actually, a synonym of HSFhistamineinduced suppressor factors. With the absence of the required explanation, only
those who have studied these factors since this research began will understand
the meaning of the abbreviation HRIF.
However, the author does more than just hide the protective chemistry.
The pro-inflammatory factors described by Dr. Kaplan in the textbook make
allergic reaction appear as if it was a unilaterally disease-oriented phenomenon. One can only wonder about the reasons for his preference for such an
incorrect description of allergic reactions in the textbook, which, as Dr.
Kaplans website states, is utilized in training programs throughout the
world (www.alergycenters.salu.net/stuff/html).
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effects. Thus, on page 704 in the Index we find under histamine that there
is the rubric immune response modulation by (histamine). The reference at
this point sends the readers to pages 179189 on which Rocklins chapter
convincingly, and in detail, covers immunomodulation with histamine. Pages
58 and 60 of this textbook are not included in the Index under histamine,
which they should have been for their relevance. Page 58 says: cells with
histamine receptors can also generate immunoregulatory substance upon
activation with histamine. This immunoregulatory substance cannot be
anything but histamine-induced suppressor factors studied by Kaplan. The
table on page 60 names the H2-receptor function as immunomodulatory,
and the very term points to the presence of a living body with its regulatory
immune system. With all this being in the textbook, one can only wonder why
the editor insisted that I had misinterpreted the data, as I simply implemented
into practice the statements, data and ideas that A. Kaplan had accepted for
publication. I conducted successful immunomodulation with the best natural
activator of H2-receptors. Dr. Kaplans letter was misleading in not providing
the true facts.
The big flaw in Dr. Kaplans note is that it defies to the very foundation of
medicine when it says that the theories I relied on have nothing to do with
clinical disease. Theory and practice are inseparable in any area. As a saying
goes: theory without practice is dead, practice without theory is blind.
Theories in medicine must lead to therapies and cures, serve the sick and not be
entertained in scientific labs simply to get more funding. Regrettably, Dr. Kaplan
did not connect his own work with practice. Thus, when he stated that a
balance between molecules of HRF or HRIF activities exists, which may
determine the level of inflammation observed in allergic diseases,49 it was
only natural to conclude that histamine-induced inhibiting factors materialize immunomodulation. This points to the duality of histamine. It was also
natural to speculate how this duality could be used to balance the chemistry
in disease and help allergy patients. Even though Dr. Kaplans text implies
this, he never expanded on the material.
Dr. Kaplans note surprised me because of the lack of concern it displayed
for the plight of my allergy patients. When he condemned histamine therapy,
which, in his opinion, has no validity whatsoever, he did not pay attention
to the fact that about 2,500 of my patients, the majority of whom had failed
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cells: The bottom line is that the mast cells initiate the process. If you inhibit
mast cells reactions, you inhibit both the immediate and late reactions.53 Let us
trace Kays position on this who is who in allergic reactions at different
times.
Mast cells/basophils
The 1984 volume Asthma: Physiology, Immunopharmacology and Treatment is
edited by A. Kay and L. Lichtenstein. It covers the Third International
Symposium on Asthma and includes the informal discussions that take place
at this gathering. Dr. Kay is one of the participants of these discussions, and
we read on page 426: many of the features of asthma such as bronchial
hyperactivity, and bronchial inflammation might be secondary to the primary
mast cells defect. Kay explains what this primary defect in mast cells is: in
asthma, mast cells are intermittently leaky, and the leakiness can be intermittent (episodic asthma) or continuous (chronic asthma) reflecting the
severity of the disease. For support, Dr. Kay refers to his own earlier work
published in the Lancet.54 Then he goes even further when on page 427, he
points how to control asthma: To define the triggers and drugs that inhibit
release it may be necessary to work with asthmatic mediator/mast cells.
Another participant of the discussion, Dr. A. Kaplan, sees abnormal histamine release as the main cause of stimuli that trigger asthma (p.425).
Dr. Kay, present at the discussion, does not argue against this fact. The position of science did not change in 1995, if we believe Dr. Kays co-editor, Dr. L.
Lichtenstein, who still considered mast cells and basophils as the central
mediator-containing cells at all stages of allergic reaction.55
In 1997, Dr. Kays views changed mysteriously. That year, he authored the
5-page chapter titled Late Allergic Responses in the second edition of the
textbook Allergy. Those five pages are, actually, the replacement of Rocklins
20-page chapter entitled Role of Cell-Mediated Immunity, which was part
of the first edition of the textbook Allergy, and which was excluded from its
1997 edition. An allergic reaction consists of two stagesimmediate response
that lasts 24 hours and the subsequent late-response phase that may be
short, but may last much longer and even become chronic. Allergy accepts
that this late-response phase is actually ongoing allergic inflammation that,
no matter what ignites it, continues due to the malfunctioning of the participating cells. Therefore, the knowledge of what cells are primary, what makes
them malfunction, and how to correct their production becomes so essential,
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both for understanding the pathogenesis, and for selecting the treatment
target. The very name of the Rocklins chapter says that any immune allergic
reaction depends on what cells are involved in the reaction. Rocklin did what
he was supposed to do: he named all the participating cells, indicated their
ranks in the process and specified the particular defects responsible for their
malfunctioning. His meticulous description helps one understand the
common origin of various allergic diseases and could help one find methods
of correcting the failing immune tools, irrespective of the end organ in which
the disease develops. Dr. Kay was supposed to do the same.
The drastic reduction in the number of pages compared to Rocklin
from 20 to 5would be irrelevant, if the problem had been presented
concisely. As the editor, A. Kaplan was to ensure that the author, A. Kay,
included this basic material into the replacement chapter. Have the author
and the editor fulfilled their obligations?
Both editions of Allergy are, actually, clinical textbooks grounded in basic
sciences, since they present the processes on the cellular and molecular levels.
Textbooks usually include those data from basic sciences that have been
accepted by medicine and specify the phenomena that require more research.
Kaplan included both Kay and Rocklin into the textbook Allergy 1985. The
inclusion meant that the material presented by both authors was verified and
solid, and that their views were compatible with the views of the editor.
Speaking about the roles of the cells in the late-phase allergic reaction,
Rocklin says on page 179: It has been recognized that many, if not all, delayed
hypersensitivity reactions contain sizeable infiltrates of basophils. In fact,
any definition of mast cells and basophils, be it in a textbook or a medical
dictionary, starts with this most distinguished characteristic of theirs.
Moreover, if mast cells can release other mediators apart from histamine,
basophils release primarily histamine. Therefore the presence of a large
number of basophils at the site of allergic reaction is unequivocal in its
meaning, namely exaggerated spill of histamine.
In 1987, just two years later, Dr. Kay also recognizes the well-documented
association between mast-cell-derived products and late-phase reactions56
This means that covering the late phase in Allergy 1997, Dr. Kay was
supposed to emphasize the well-documented histamine leakage from
basophils. He was also expected at least to name the first stage launched by
histamine overspill from mast cells. He did neither of this. Kay simply
reduced mast cells and basophils to ordinary participants, but he did it skil-
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fully. Nobody can rebuke him for excluding mast cells: he focused on the late
stage of reaction, and this allowed him to cut off the initial stage based solely
on histamine as an initiator.
However, even basophils that take over mast cells functioning in the late
stage of allergic reaction now lost their importance as did the amount of
crucial mediators and cytokines they produce, and this in spite of the uncontested fact that they release more than 90% of all the secreted histamine. As
none of the works by this scientist had indicated that he started to have
doubts about the well-established scientific data, we may only speculate
what prompted him to turn basic immunology upside down by attaching the
central role in allergy to another group of cells, namely the eosinophils that
were never considered central. The fact that he did it in a textbook, and not
in an article, makes all this especially hard to comprehend.
Eosinophils
In 1985, in the first edition of Allergy, Kay wrote the chapter entitled
Eosinophils nothing in it indicated that these cells were central players, in
allergy. On the contrary, at that time, Dr. Kay described eosinophils as
dependent on mast cells and T-cells: eosinophils appear to be recruited and
activated as a result of T-lymphocyte-derived mediators and at least in
part, their activation is a result of factors derived from mast cells. When in
1997, Kay assigns to the eosinophils a greater importance than to other
participating cells, he comes into conflict not only with science in general, but
also with logic. Given this fact Dr. Kay up to now remains a fervent supporter
of the IgE antibody hypothesis as the origin of all allergies, he should have
given the priority to mast cells and basophils, since they are the prime residence of IgE antibodies and the place for antigen/antibody reaction. This fact
alone makes eosinophils inferior, at the very least, to mast cells that ignite and
maintain the reaction.
Another change in the views of Dr. Kay concerns the protective role of
eosinophils for the immunity. In 1985, he recognized this by saying that the
eosinophils dampen mast cell activity, that is, slow down histamine release.
Thus, he wrote on page 96: A role for the eosinophil in deactivating histamine has been proposed by a number of workers, and the author does not
argue this position. How could argue this, since the fact that eosinophils
possess protective functions is common knowledge? In allergy, their activity
is implemented in the same way as with the other cellsvia activation of
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Regrettably, numerous authors have picked up the idea put forward by Dr.
Kay, namely that remodeling takes place through eosinophils, and that this is
the core event in asthma. This is now shaping up to become a new trend in
the perception of this disease. This is happening even though the author of
the concept has again changed his views.
In 2001, Drs. Kay and Kaplan were among the group of authors writing on
the late-phase reaction, and once again the self-contradiction is amazing.60
On page 400, the text says that eosinophils are actually only bystanders in
allergic reaction, which may go on without their active involvement: Taken
together, these observations support the view that airways eosinophilia is not
a prerequisite to the airway narrowing associated with late asthmatic reactions. This statement coincides with Kays (and Kaplans) views of 1987 but
contradicts his (their) 1997 views.
As a specialist in eosinophils, Dr. Kay undoubtedly knows the unique
function of the recently-discovered histamine H4 receptor. Especially so,
because an article that answers the question why there are numerous
eosinophils at the site of allergic inflammation is published in the journal
edited by him. This receptor passes histamine messages to bone marrow and
stimulates production of immune cells. Therefore H4 receptor may make it
a therapeutic target for the regulation of immune function, particularly with
respect to allergy and asthma.61 Another authoritative pharmacological
source also states that H4 receptor gives rise to numerous immunocompetent
cells, including eosinophils, and the authors see a potential new role for
histamine in allergy and asthma.62
Intensified production of immune cells is a natural defensive reaction of
the body, and the fact that histamine induces such a production emphasizes its protective role in the functioning of the immune system. The
increased production of eosinophils indicates their protective role, not
a disease-promoting role, as ascribed to them by Dr. Kay. The specifics of
the reparative role of eosinophils are not part of this review. However,
the arguments whether their role in the production of asthma is nil or
most important should not distract from the main fact, namely that a
continuous profuse mast cell/basophile histamine release is the principal
underlying event in allergy and asthma. Histamine, any reference to
which Dr. Kay avoided, hit him unexpectedly: eosinophils, seemingly
independent of histamine, turned out to be generated and activated only
by it!
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T-cells
T-cells are another element fluctuating in significance in the works of Dr. Kay.
They are universally recognized to be the leaders among the immunocompetent cells participating in allergic reactions, although in a different sense than
mast cells and basophils. It has become common to describe them as the
conductors of the immune orchestra. Even if we limit the functions of
T-helper cells to their facilitation of antibody formation (negative in allergy),
an increased IgE antibody formation is an indication of excessive activity of
these cells. The only force able to restrain their disease-promoting effect is
that of the regulatory T-suppressors. They control the number and the
activity of all T-cells, IgE antibody levels, and also the chemical activity of all
immunocompetent cells engaged in the allergic reaction.
When Rocklin wrote in his now censored chapter in Allergy 1985: The
suppressor cell abnormalities observed in allergic subjects may reflect a primary
defect inherent to the atopic diathesis (pp. 190191), Dr. Kay had a similar
position that found its way into his article written two years later. In this paper,
he is even clearer about his knowledge of the true leading cells in allergic reactions.63 Here is a sentence from the introduction: successful immunotherapy has been associated with both an increase in the relative number of
suppressor (OKT8) T-cells as well as an abrogation of allergen-induced latephase responses. Again, for support of the idea that suppressors are central in
abrogating the reaction, Dr. Kay gives in reference 11 the article by Rocklin64
which forms the basis of Rocklins chapter in Allergy 1985, Role of Cell-Mediated
Immunity, that centers on T-suppressors. Dr. Kay also writes: the possibility
exists that OKT8 cells control these inflammatory events by preventing the
release of helper T-cell-derived mediators. For instance, OKT8 cells produce a
histamine-induced suppressor factor that inhibits lymphocyte proliferation
and lymphokine production.
At this point, there is reference 27 that leads us to the 1979 paper by
Rocklin and Melmon entitled Histamine-induced suppressor factor (HSF):
further studies on the nature of the stimulus and the cells which produce it.
Dr. Kays article even specifies the underlying defect in asthma, namely a
defect in suppressor cell function, and he also recognizes histamineinduced suppressor factor produced by T-suppressors as the vehicle of
controlling allergic reactions.
In 1997, the textbook Allergy does not mention of T-suppressors in Dr.
Kays chapter on late-phase allergic reactions. The prime defender in allergy
has inexplicably vanished.
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In 2001, Kay and Kaplan are among the group of scientists writing on the
late-phase reaction. This article60 recognizes T-suppressors as the target for
therapy. On page 401, when speaking of downregulation of late response in
asthma, the authors say: CD8+ cells have been shown to be increased after
successful immunotherapy. As CD8 is the marker of suppressors, this phrase
is a repetition of the Rocklins statement in Allergy 1985: suppressor T cells
bearing histamine receptors were generated during antigen desensitization. Rocklin was very precise in the description of allergic processes, and
saying this, pointed out that failure to detect these cells in untreated patients
may be a reflection of the underlying defect leading to the atopic diathesis,
that is, allergy. In other words, the prime defect of allergy, according to
Rocklin, is that the number of suppressors is too small. Now, after a decade
and a half of hesitations, Dr. Kay (and Kaplan) once again share Rocklins
position. Can we expect that they will publicly recognize their erred stand in
Allergy 1997 and correct it in the next edition of the textbook?
Finally, in 2003, Dr. Kay makes another indirect admission of his 1997 delusion regarding the position of the cells in the late-phase allergic response when,
in co-authorship with a team of scientists, he proudly described the development of peptides as compounds that could be used for immunotherapy in
asthma.65 And what does he now indicate is the concrete underlying mechanisms in allergy and the target for immunotherapy? Regulatory/suppressor Tcell! These cells, absent in his chapter on the main stage of allergic reaction, now
suddenly rise from the ashesjust when Dr. Kay is involved in the creation of
new drugs and cannot avoid showing the target for their pharmacological effect!
Histamine
As was demonstrated in the 80s, Dr. Kay agreed with the position that it is
histamine leaking from mast cells that launches allergic reactions; that reactions are over as soon as the leakage is stopped; that the defensive power of
T-suppressors determines the course of allergic reactions; that this power is
histamine-determined. The textbook Allergy 1997 mentions histamine only
in passing. This makes an article published just a year later in the journal Clinical
and Experimental Allergy, where Dr. Kay is a co-editor, especially striking.66
The very titleHistaminea major role in allergy?is amazing, and now
the approach is presented affirmatively, even though the title has a question
mark. This is what it says:
Since its discovery in 1911, histamine has been recognized as a major
mediator in allergic reactions and diseases Thus, findings indicate that
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This is the natural result of the substitution of the key phenomena with
numerous inferior minutia. Added to that is intermittent professional
amnesia regarding some of the events and players and their reappearance
under different names, without any clarification of their identity. The earlier
described disappearance of histamine-induced suppressor factors for a whole
decade, and then the frequent use of the term interleukin-10, without stating
that it is a histamine-induced suppressor factor, is an example.70
However, allergy research, such as it is, cannot prevent other medical areas
from publishing the data prohibited in its field, and indeed the compelling
material coming from the National Institutes of Health and the Cancer
Institute in the USA serves to expose the plot. The authors name histamine as
the best activator of the enzyme cAMP and state that none of the other
mediatorshas any effect on the production of Il-10. They also indicate the
H2 receptor as the pathway for the induction of this interleukin.71
Another example of the determination of allergists never to call a spade a
spade is the complete removal of T-suppressors from all allergy sources and
the use of CD8+ or OKT8 cells. Without identifying these in allergy, both
terms have the same meaning, namely T-suppressors. The concealment is
such that today, the T-suppressors regulatory role has been attributed to
other kinds of T-cells that possess innate defensive qualities, but whose
activity is nonspecific in allergy. They have become the substitution to the
abolished specific T-suppressors, and now immunologists seriously discuss
their allegedly immunomodulatory activity in allergy.
Funny, some authors, who are most probably not informed of the plot,
inadvertently, at times, reveal the truth and declare that the newly
proposed defenders are not really controllers of allergic reactions.71 Even
the most fervent proponents of the new trend have not completely hidden
those T-suppressors under their new name, and so they write: It is difficult
to dismiss, however, the fact that CD8+ T cells may have some function in the
control of immune response to inhaled proteins, and that independent
studies have identified a potential role for CD8+ cells.72 One gets lost in this
field of medicine, even as a specialist practicing in it; it is now so full of disassociated, misinterpreted, silenced or twisted theoretical events and notions,
all of which are not applicable to clinical practice. Sadly, it is ultimately the
patients who become the victims.
The tacit ban on exploring histamine and histamine-dependent immune
tools forces allergy to resort to disguising or avoiding T-suppressors and their
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which shows how very important it was to the CPSO to stop this therapy from
being permitted. Interestingly, I was not permitted to see Holgates letter
(another legally abusive turn of events), and learned about its existence only
at the hearings themselves from the prosecutor, Bob Armstrong. Holgate
allegedly wrote that his 1989 letter to me had not been the response of an
editor to an author but a personal one, and that he had never approved of
histamine therapy.
His response is very strange indeed. First, my relationship with him was
one of a purely professional kind, and such a letter of an editor to a writer
cannot be anything but his official response. Second, it is highly improbable
that this renowned scientist would suggest such a senseless project as scientific trials based on an invalid idea. Third, if Holgate did not believe that
histamine therapy could be efficacious, why did he volunteer the information
about its successful application in China. Moreover, at our meeting, Holgate
suggested to me personally that should I talk to Dr. Busse whose research was
related to the histamine-related mechanisms of allergies and asthma. Why
would he needlessly burden his high profile colleague with an insignificant
topic offered by an unknown doctor? (By the way, I met with Dr. Busse during
that conference only to hear that his work was in another area. In fact, Dr.
Busse, who later became the president of AAAAI, researched and continues to
research underlying mechanisms of asthma.)
In the nineties, the protective properties of histamine and histaminerelated elements were becoming more and more obscure. However, Holgate
went further than obscurity. He, who had described T-suppressors as the key
defense tools, inexplicably turned them into hostile cells. Thus, among
immunocompetent cells that produce pro-allergic cytokines, he named
CD8+ T cells, the other name for suppressors. He has never given an explanation as to what caused the transformation of this savoir into an evil force
within a mere decade that separates this work from the above-discussed
article, The Role of Histamine in Asthma.
Holgates later articles now became full of the word antihistamines and
reference to histamine is almost completely omitted. The 962-page volume
Inflammatory Mechanisms in Asthma 1998, co-edited by him goes so far as to
completely exclude all protective activities of the allergy-related immune
system, histamine included. Nature and science has been edited and is
presented in a fashion so biased as to be beyond recognition. Only once did
the editors overlook a detail that exposed their knowledge of the true mech-
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matory processes.81 By presenting asthma as an interplay between Tlymphocyte-mediated airway inflammation, tissue destruction, and remodeling, he plants such confusion that means his dream is not likely to come
true.
Over three decades ago, cyclic AMP was recognized as an effective mechanism to control allergic reactions, and the drug industry knows this very well.
To help patients radically, one should follow natures way: use histamine H2
receptor as the pathway to increase that enzyme with the effect of activating
the entire anti-inflammatory chemistry. An important article in basic science
written by a group from the National Institutes of Health in Bethesda recognizes that cAMP provides the central mechanism for activating the immune
system. This article also emphasizes that none of the agents stimulating cAMP
is able to induce IL-10 (the key allergy-protective histamine-induced factor)
and regulate the expression and secretion of a wide variety of cytokines
released by immunocompetent cells.82 This article provides the proof that
allergies are diseases of one predominant mediator, and recovery depends on its
proper release and activity. The way for rectification lies in the cAMP activation
via the H2 receptor. A well-read clinician can easily draw the logical conclusion
on how to transfer this knowledge into practice. Likely success, as I have
demonstrated in my practice, would be a serious problem for the pharmaceutical industry. It pays the best minds to search for other less efficient ways to
reach cAMP. Such new drugs must, of course, never cure but only improve the
condition of the sufferers when taken regularly.
Like Lichtenstein, Holgate works on the development of phosphodiesterase inhibitors, drugs with a theophylline-like mode of action, and an
article he co-authored expresses a hope that these drugs may emerge as a
new anti-inflammatory therapy in the treatment of allergic diseases such as
asthma.83 While acknowledging the prime role of cAMP in cellular regulation, by stating that increases in cellular cAMP are associated with a generalized downregulation of inflammatory cell activity, the references
(especially nos 10 and 11) lead the reader to two articles that name histamine
as one of the best activators of cAMP and Lichtenstein is the author of
both! The leaders in the field know how to treat asthma in the most effective
way. Both choose not to do it.
PETER BARNES is another leading immunopharmacologist. Like A. Kay and
S. Holgate, he presides at international gatherings, writes in prestigious
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With explicit reference to Barnes, Arrang and his co-authors state that in
the respiratory field, one observes the inhibition of inflammatory process
upon H3-receptor stimulation in guinea pigs in vivo or in human airway
preparations in vitro. They conclude: These observations suggest that H3receptor agonists may constitute a novel approach in the treatment of asthma.
The article also brings us the happy news that finally not only guinea pigs but
people have been found deserving of the attention of medicine: Initial clinical studies (with histamine agonists) have shown to be well tolerated in asthmatic patients receiving the drug either via aerosols or the oral route, even in
very high dosage. One would think that more than a decade after this initial
success in the management of such a potentially fatal disease as asthma, science
would seize upon histamine therapy and start helping asthmatics. Not at all!
Even Dr. Barnes, the chief worlds strategist of asthma therapies, disregards the
research on the theoretical aspects of asthma, successful trials on animals and
man, and his own above-quoted pro-histamine ideas.
Similarly to learned colleagues, Barnes, made an inexplicable turn in his
views. In 2000, he wrote an article in the new JACI publication called New
millennium: The conquest of allergy. There, he wrote that steroids, which are
now first-line treatment for persistent asthma in all patients, often do not
control the disease, produce side effects and are not curative, and inflammation recurs when they are discontinued.86 This would be the best time to
suggest exogenous histamine, previously studied by himself after all, at least
on those patients whose asthma is resistant to steroids. But he chose another
way. Weighing the pros and cons of various treatments, including
immunomodulation, which, as you know, in the language of allergists is not
immunotherapy but the euphemism for immunosuppression, he considered
the possibility of using a potent immunosuppressant as an immunomodulator. He used this oxymoron although, as an immunopharmacologist, he
knows the difference between the two better than anybody. His article on the
directions of how to treat asthma ends with the pessimistic: The possibility
of developing a cure for atopy is remote, and the only feasible way, in his
mind, is to inhibit or suppress components of the allergic inflammatory
response. This of course, amounts to giving the drug industry a free hand,
for which he works, to produce countless suppressantsimmune modulators
in the ambiguous vocabulary of allergy medicine.
The very word histamine is not used in the text and only once, does Barnes
reveal his true knowledge of what the precise target of asthma therapy should
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be. On page 11, speaking about immunomodulation (by immunosuppressors) the author writes that steroids also inhibit suppressor T cells that may
modulate the inflammatory response. Thus, we learn in passing that
immunomodulatory T-suppressors still exist despite the fact that clinical
allergy has done its best to ignore their existence, that steroids disable the
activity of these central protectors in allergy, and that the real meaning of the
word modulate is change to the desirable, that is, normal active level, not
to suppress below the norm.
The only hope is found in the fact that true science breaks through, no
matter how thoroughly quashed. For example, speaking about certain
cytokines (that) have anti-inflammatory or immunomodulatory effects,
Barnes assumes that their secretion may be defective in patients with
asthma, and understanding these processes may give a better understanding
of disease. This, he suggests, may also lead to novel therapeutic approaches,
such as drugs that increase the release of endogenous inhibitors or mimic
their effects.88 Not only does he admit that such therapeutic approaches are
attractive since they may restore anti-inflammatory mechanisms to normal,
but tells us that such drugs carry a lower risk of adverse effects.
Although histamine and histamine-induced factors are not named in the
text, the defective secretion in asthma means that the balance is favoring inflammation, and the degree of the imbalance explains the severity of the disease.
While he mentions endogenous inhibitors or products that mimic their effect,
it is strange that he does not name histamine, which, as a physiologic autacoid,
carries a lower risk of adverse effects compared to conventional therapies.
Histamine, its agonists and congeners are doomed to remain in the
domain of experiments. We understand this when we read in the Arrangs
article cited above from Agents and Actions that Ongoing studies are exploring
the activity of the drug on various models of experimentally-induced bronchoconstriction in asthmatic volunteers. Why do we need to induce bronchial
spasm in volunteers with so many asthmatics suffering from spontaneous
bronchial spasms? The answer is simple: the use of histamine on real asthma
patients could undermine the huge research into lucrative medications for
asthma. The Real Drug Pushers by Joel Lexchin published in 1984 states on
page 86 that the drug industrys focus is to develop major drugs for major
markets. The key influence on the direction or misdirection of pharmaceutical research is whether or not the product can be patented. New uses of
already existing chemicals cannot be patented, and therefore industry research
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tends to ignore these substances. Histamine is one such century old substance,
not just ignored but viciously fought by allergists because it cannot be
patented. It carries the potential for cure but not the potential favoring
industry growth.
The intention to conceal the self-regulatory forces in allergy is reflected in
an ARIA document which states that it is intended to be state-of-the-art for
the specialist as well as for the general practitioner.101 ARIA (see JACI 2001,
108) is the abbreviation for Allergic Rhinitis and its Impact on Asthma. This
workshop took place at an international conference that drew the leaders of
allergy medicine and was conducted under the auspices of the World Health
Organization. As the document states on page S182, For didactic reasons,
only pro-inflammatory chemistry is covered. For example, although the document is on allergies, the H2 receptor is presented solely as one responsible for
gastric acid secretion, while its curative stimulation of the enzyme cAMP and
its therapeutic negative feedback effect are not even mentioned. What are
these didactic reasons that force one to conceal the defensive tools of the
immunity.
Somebody must take responsibility for the plot against histamine. The
virtual disappearance of the central chemical involved in all allergic reactions,
a major mediator and biological marker of all immune processes and a
central regulatory neurotransmitter requires an explanation. It takes great
effort to hide this immense body of research from visibility. Burning libraries
has ever been the work of those who want total control over minds, states,
people. These volumes of research are very much needed and most precious.
History teaches us what happens when pages are torn out of books, or books
are thrown into a fire. Usually authors follow, and obscurantism sets in.
My histamine story can be reduced to a sentence: a doctor, who used a
well-researched, inexpensive medication, helped or cured hundreds of
patients with undiagnosed and/or resistant diseases, and was able to explain
the underlying routes of their recovery, was not only prohibited from using
his therapy, but prosecuted and punished.99
The situation is not new in society: What judgment shall I dread, doing
no wrong?, asks Shakespeare in The Merchant of Venice. Medicine is just a
part of society and lives by the same rules. I should have expected the judgment. Thinking, especially thinking differently, has always been considered
as an occupational hazard. I just happened to study basic science and theoretical allergy research that described the biochemical immune mechanisms
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lying at the roots of my histamine therapy as central and regulatory. I investigated the chaos of fragmented details, arranged the key elements into a
logical system, introduced it into clinical practice and offered this to the
medical world without any personal gain in mind. The very scientists who
had researched and developed these fragments rejected them in their clinically
implemented form. They have never given an explanation for their rejection,
even though they have been unable to offer any alternative. This is because the
truth must have scared them and threatened other, incompatible priorities.
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gerated histamine release by the hypersensitive mast cells, and not with allergens, and that in allergy, it is histamine hyperreleasability that is a link
between non-IgE immune responses and mast cell activation.89
Actually, this concept leaves beheaded conventional allergy, which
remains wedded to the IgE antibody dogma. The fact that histamine overspill
may ignite allergic reaction without any IgE participation renders senseless
the chase after mites, cats and cockroaches as causes. Ironically, in the new
millennium, IgE and allergen elimination are still the core management of
allergies and asthma. The presently propagated ideas imply that histamine is
just one of many mediators of allergy and therefore does not deserve preferential consideration. Moreover, if other mediators are still named, histamine
is often not even mentioned as an ordinary player.
Such views can easily be refuted, first of all, by the very name of this international conference that concentrated solely on histamine and the possibility
of its use in the management of patients. Secondly, even though histamine is
only one of many mediators of allergic disease, it should be strongly considered when analyzing the cause and treatment of any mast cell-related disease,
observed Dr. White, M. Kaliners co-author of the chapter Histamine in the
authoritative volume Inflammation.90 She continues in the same article: The
presence of the H3 or H2 receptor might alter susceptibility to H1 effects and
also: H3 receptor is primarily responsible for turning off histamine secretion.
This receptor is found in the brain, but some data suggest that it may also be
present in the lungs and other tissues. Furthermore, the ability of the H2
receptor to turn off histamine secretion in the basophile may be mediated by
the H3 receptor. In other words, efficient H2/3 effect wins over H1 effect (Later
research proved the existence of H3 receptors in the lungs and other tissues).
Like the discoverer of H3 receptors, J. Arrang, Dr. White emphasized the
synchronized functioning of H2 and H3 receptors. Paradoxically, the author
makes a statement that contradicts all she said before: she suggests H1 and H2
blockers be used together. Her informative report fails in its conclusions
because blocking H2 receptors would make them even less effective. One can
only ponder the logic of this suggestion.
Along with the widely used statements that histamine is important in
provoking asthma symptoms, some ideas that would today be considered
outright seditious were expressed at the symposium. For instance: Mediators,
perhaps including histamine, are important in immunomodulation. Or:
Therapy directed at cells that produce these (histamine-releasing) factors
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The Ten Commandments are more than just religious laws. Their essence is the
code of civil and social morality on which culture is founded. Not only the
Bible, but also the collective morality of civilization demands that Thou shalt
not give false testimony against thy neighbor. Those who know the truth, but
give false testimony at their symposia or in their publications, reveal their lack
of morals, a quality unacceptable in a medical doctor. Again, not only the Bible,
but also the collective consciousness insists that Thou shalt not kill. They kill,
although not directly. Allergists admit that their ability of controlling
morbidity from asthma has been rather limited, and we all know that
mortality from asthma is on the rise. At the same time, profound research has
found ways of natural immunomodulation, and medications for this exist,
namely synthetic histamine and its congeners. They may open the way to the
creation of other modulators that will be preferable to immunosuppressive
drugs. However, Animal models became preferred because of ease of implementing experiments in animal models of human immune-based diseases, and
an unfortunate separation soon developed between human clinical immunologists and mouse immunologists, say two allergists of the highest stature.97
Allergists regret that research is all organ-based diseases, whereas it should
concentrate on immune cells and their functioning, study immune regulation, immunotherapy, immunogenetics, and immunodiagnostics, and look
for a cross-disciplinary approach to understanding of what allergic diseases
are. What the authors do not say is that the existing mouse immunology is
purposeful, and that any introduction of knowledge that may lead to efficient
management of patients is routinely sabotaged. Furthermore, not only
animals have undergone trials with histamine and its agonists. Double-blind
studies on humans have also been successfully conducted in Switzerland and
Japan, but they have been successfully hidden. Open clinical studies that took
place in France and Poland were published in small periodicals, and their
success has remained unknown. Only a general lack of interest and critical
opposition permits such grossly unethical concealment of vital knowledge, its
substitution with invalid contradictory hypotheses, and the diversion of
allergy medicine into the wrong direction, all to the detriment of patients.
The recently updated Hippocratic Oath and Charter on Medical Professionalism introduced in 1999 define such activity as professional and scientific misconduct.98 Indeed, one begins to believe that the fewer doctors there
are, the healthier the world might be. Far from being dedicated professionals,
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WHAT NEXT?
Allergology should honestly admit that at present, genetic engineering, for
example, is a hypothetical possibility not feasible in the near future. Logically,
the next step should be to deal with these diseases on the level of their major
productscytokines and mediators. The aim of the therapies should be the
restoration of balanced chemical production through the restoration of those
immune tools that are deficient. This would lead to the development of therapeutic agents capable of activating these tools, namely immuno- and neuromodulators. The repaired tools will acquire the ability to fight effectively on
their own, and their restored functioning may even correct the functioning of
the relevant genes. Since in many chronic diseases, the inefficient tools are
certain polysystemic cellular receptors and enzymes, their activation
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should become the prime goal. Such interdisciplinary approach would lead to
the introduction of psychoneuroendocrineimmunology in clinical medicine,
whereas now, it exists mostly as a theoretical discipline.
Simply put, clinical allergy ought to recognize the vast basic knowledge
available to its field, and then properly consider and incorporate it. There are
many weighty reasons why asthma, allergy and other histamine-induced
diseases should and can be tackled right away:
They affect a large percentage of the population.
They are the fastest growing afflictions, now reaching epidemic proportions.
They are functional, at least at the beginning, and are therefore much more
reversible than other chronic diseases with organic changes.
Effective medications in the form of synthetic histamine and its congeners
exist.
Targeting one allergic condition may and, in most cases does, cover related
neurological symptoms.
Indeed, every aspect of the origin of allergic and related diseases and their
interdependence and therapy has solid support from basic science.
Only one thing is lackingthe desire of those in power to implement all
of this. Doctor, cure thyself first. Clinical allergy is in urgent need of curing
itself by reconsidering all missing links and focusing on how to help its
patients.
Revolutions have never succeeded unless the establishment does threequarters of the work (Peter Ustinov). Does the allergy establishment feel the
need of a revolution? Does it want to revolutionize its field? Or is it satisfied
with its own impotence and the suffering of its patients?99
ENDNOTES
1. I.R. McWhinney. Why are we doing so little clinical research? Editorial. Canadian Family
Physician 2001;47:1944
2. K. Melmon, R. Rocklin, R. Rosenkranz. American Journal of Medicine1981; 71:100-6
3. D. Beer, R. Rocklin, JACI 1984;73:439-52.
4. R. Rocklin. Clinical and immunologic aspects JACI, 1983;72:323-334
5. S. Hill. Pharmacological Reviews 1990;42
6. I. Elenkov et al. Histamne potently suppresses human Il-12 and stimulates Il-10 production via
H2 receptors. The Journal of Immunology, 1998;161:2586-2593
7. H.R.Bourne, L.M. Lichtenstein, K.L. Melmon, et al. Modulation Of Inflammation & Immunity
by Cyclic AMP, Science 1974;184:19-28
8. M.Bourne, K. Melmon, L. Lichtenstein, Science 1971;173:743
169
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9. M. Khan and K. Melmon, Are Autacoids More Than Theoretic Modulators of Immunity?
Clinical Immunology Reviews 1985;4(1):1-30
10. K. Austen, ed. Therapeutic Immunology 1996:192,198
11. A. Kaplan ed. Allergy, Churchill Livingstone Inc. 1985
12. For a detailed analysis of this system see The Olivieri Report published by the Canadian
Association of University Teachers in 2001
13. S. Hill. Pharmacol Rev. 1990;42:69
14. S. Hill et al. Classification of Histamine Receptors. Pharmac Rev 1997;49:253-278
15. F. Ravikovich. H2/3 Effect in allergy. Allergie & Immunologogie 1992;24:72
16. The transcripts of my trial are in the public domain and can be checked by interested persons.
17. M.Bourne, K. Melmon, L. Lichtenstein, Science 1971; 173:743
18. L. Lichtenstein, E. Gillespie Nature 1973;24:287-8
19. L. Lichtenstein et. al. Selective Display of Histamine Receptors on Lymphocytes,
Science1977;195: 683-5
20. R. Bourne, L.M. Lichtenstein, K.L. Melmon, et al. Modulation Of Inflammation & Immunity by
Cyclic AMP, Science 1974;184:19-28
21. M. Ichinose, P. Barnes. Histamine H3 receptors modulate antigen-induced bronchoconstriction
in guinea pigs. JACI 1990;86:491-5
22. S. Hill. Pharmacological Reviews,1990;42:69
23. R. Leurs et al. Molecular pharmacological aspects of histamine receptors. Pharmac. Ther.
1995;66:413-463
24. R.G. Andersson et al. Studies of the mechanism of desensitization of anti-IgE-mediated
histamine release from human basophils. Agents and Actions; 1989;27, :25-28
25. M. Jutel, et al. Nature 2001,413:420-25.
26. W. Roszkowski, M. Plaut, L. Lichtenstein. Science 1977, 195:683-5
27. Allergy And The Immune System, Scientific American, Sept.1993:117-124.
28. Presidential address. JACI 1995;95:783-796
29. B. Zweiman, M. Rothenberg. Articles of Note. JACI 2002;109:375
30. Allergy and the immune system. Scientific American September 1993:117-124
31. Science 1974;184:19-28
32. Science 1977;195:683-5
33. AAAI Training Program Directors Committee: W. T. Shearer et al. Committee report. Core
content outline for clinical and laboratory immunology. JACI 1994;94:933-41
34. L. Lichtenstein et al. Inhibition of histamine release by histamine controlled by H2 receptor.
Nature 1973;244:287-8
35. Science 1974;184:19-28
36. S. Hill. New Perspective in histamine research. AAS 1991;33:145-159
37. G. Chrousos. Stress, chronic inflammation, and emotional and physical wellbeing: concurrent
effects and chronic sequelae. JACI 2000;106S275-91
38. JACI 2003; Volume 111 No 2
39. JACI 2000;106 No5 Suppl. and 2002;110 No 6 Suppl.
40. For worldwide efforts being made to change this situation see www.doctorsforresearchintegrity.com;
address: 81 Wychwood Park, Toronto, Ontario, M6G 2V5.
41. J. Imunol 1977;118:1734
42. J.A.Grant et al. Histamine-releasing factors and inhibitors: historical perspectives and possible
implications in human illness, JACI 1991;88:683-693
43. L. Lichtenstein et al. Selective Display of Histamine Receptors on Lymphocytes. Science
1977;195:683-5
44. Agents and Actions 1991;33Supl.:376
45. M. Clerici et al. An immunoendocrinological hypothesis of HIV.Lancet 1994:343:1552-3
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46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
JACI 1991;87:207
P. Kuna et al. Chemokines JACI 1995;95:574-86
D. Beer, R. Rocklin, Histamine-induced suppressor-cell activity. JACI. 1984;73:439-452
JACI 1995; 95:574-86
For an overview of all these abusive prosecutions see www.collegeofphysicianswatchdog.com
MC Lilu et al. Immediate and late inflammatory responses Am Rev Respr Dis 1991;144:51-8
Hebert et al. The regulatory effect of histamine on the immune response: characterization of
the cells involved. Cellular Immunology 1980;54:49-57
M. Kaliner. A Hierarchy of mediators of the allergic reactions. JACI 1992;90:727-8
Lancet 1983;1:520
L. Lichtenstein. Presidential Address JACI 1995;95:783
M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and
suppressor (OKT8) T-cells in asthma. Am Rev Respir Dis 1987;136:600-604
Ed. by J.I. Gallin et al. 1988
B. Kay. Allergic diseases and their treatment. New England J Med 2001;344:109-113
JACI 2003;111:S261
I. Hasaelden et al. Late asthmatic reactions provoked by intradermal injections JACI
2001;108:394-401
M. Church. H1-antihistamines and inflammation. Clinical and Experimental Allergy.
2001;31:1341-43)
I. Liu et al. Cloning and pharmacological characterization of a fourth histamine receptor (H4)
expressed in bone marrow. Molecular Pharmacology 2001;59:420-6
M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and
suppressor (OKT8) T-cells in asthma Am.Rev.Respr. Dis. 1987;136:600-604
New.England J Med. 1980;302:1212
K. Shirley et al. T-cells peptide epitopes in man may be associated with the induction/
expression of a population of regulatory/suppressor T cells. JACI 2001;1007(2):S67
I. Bachert. a major role in allergy? Clin Exper Allergy Histamine 1998;28,S6:15-19
A. B. Kay. Allergy and Allergic Diseases. The New Eng J of Med 2001; 344:30-7) (A. B. Kay
Allergic diseases and their treatment. New Engl J Med 2001;344:109-113
M. C. Gonzalez et al. Allergen-induced recruitment of bronchoalveolar helper (OKT4) and
suppressor (OKT8) T-cells in asthma Am Rev Respri Dis 1987;136:600-604
ARIA: Global guidelines and new forms of allergen immunotherapy. JACI 2001:108:497-9
J. Elenkov et al. Histamine potently suppressesJ. of Immunol 1998;161:25-86-93
A. Mazzoni et al. Histamine regulates cytokine production in maturing dendritic cells, resulting
in altered T-cell polarization. J. Clin. Invest. 2001;108:1865-73
H. Tiemessen et al. CD4+ CD25+ regulatory T cells are not functionally impaired in adult
patients with IgE-mediated cows milk allergy. JACI 2002;110:934-6
G.Hoyne et al. Immunological tolerance to inhaled allergen. Am J Resp. Crit Care Med
2000;162:S169-S174
M. Jutel et al Differential Histamine H1 and H2-Receptor Expression Determines Up-regulation
of Th1 and Down-regulation of Th2 Responses Following Histamine Stimulation. JACI
2000;105(II):157
S. Holgate. The epidemic of allergy and asthma, Nature 1999;402:SB2-B4
C. Brightling et al. Mast-cell infiltration of airway smooth muscle in asthma. N. England J Med.
2002;346:1699-1705
J. Black. The role of mast cells in the pathophysiology of asthma. N Engl J Med. 2002;346:1742-3
S. Holgate. The cellular and mediator basis of asthma in relation to natural history. The Lancet
1997;350 SII:5-9
S. Holgate. Role of systemic leukotrienesJACI 2003;111:S18-36.
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PART FIVE
MEDICATIONS
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and this attitude forms their policy and influence on doctors who do the
prescribing.
Drugs are usually more toxic than is indicated on the labels, and the
reasons for that are clearly outlined in the 1990 medical publication Drug
Protocol by J. Rovers:
1. Groups of patients who undergo testing are rather small.
2 Those who may potentially mar the drug efficacy coefficient are excluded
from the trials, such as old patients and patients with concurrent medical
conditions requiring medicationsin short, most prescription-needy
clients.
3. The period of testing is too short to enable anybody to notice a delayed
adverse reaction, which may manifest years later.
4. The reports given by the doctors involved in trials have poor validity (the
author assesses it as mediocre).
Always keep in mind that the scientists and doctors who provide the information on the clinical drug use are often sponsored by drug manufacturers
and thus have a conflict of interest.
Given the fact that the principal approach in allergy treatment, elimination of allergy triggers, does not solve the problem, an allergy sufferer is
forced into accepting occasional or daily allergy symptoms. Lucky are those
whose symptoms are mild, and they can manage without taking drugs. For
those whose symptoms become an obstacle to normal life, daily medications
are the only answer. I am going to discuss allergy medications. Medications
for asthma will be covered separately in the part entitled Bronchial Asthma.
ANTIHISTAMINES
The largest group of allergy medications is antihistamines, which act on H1
receptors. The fact that they are the worlds most commonly used medications is not surprising in view of the increasing number of allergy patients.
The name, antihistamines, indicates that medicine knows that histamine is at
the heart of the problem, and to control its activity is to control the symptoms. As we know, the H1-receptor messages become exaggerated if H2/3
receptors are inefficient. Antihistamines block H1 receptors to prevent the
negative effects of histamine. The blocking effect lasts only while the level of
the drug in the body is high enough. Following the drugs natural excretion,
its concentration falls, so does the potency, and another pill is needed.
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to block the histamine (H1) receptor while also inhibiting at the same time
the major pathway for the metabolic inactivation of histamine in bronchial
epithelium.1 Paradoxically, this means that antihistamines interfere with the
work of the gene that protects us from allergies and asthma. As a result, there
may be worsening of the allergies, occurrence of asthma in those allergy
patients who did not yet have it, or aggravation in those who had it along with
allergies. This makes the authors dream of developing new kinds of antihistamines which do not inhibit HNMT.
IMMUNOSUPPRESSION BY ANTIHISTAMINES
The findings of the suppressive effect of antihistamines on the adrenals were
registered in trials on rats, and the description goes back to 1982. In 1992, an
article covering this drug effect said: The antihistaminic activity is well
documented in vitro (in a tube) but has not been investigated as thoroughly
in vivo (in a live body).2 Quite naturally, over time, the low level of the
adrenals. Vital hormones diminishes the fighting ability of the immune
system. If we logically extend the idea, the long-term use of antihistamines
will, in turn, necessitate later on the consumption of corticosteroid drugs,
which, being immunosuppressive by definition, weaken the immune system
even further. Now, twenty years after the first alarm sounded, it still remains
unknown to clinicians if there have been similar investigations in people.
Those rat trials were done by several major medical schools and clinics in the
U.S. and supported by National Institutes of Health grants, but something
must have prevented studies on humans from being done.
ANTIHISTAMINES AND CANCER?
As all chronic diseases, allergies tend to intensify over time, and so a patient
may become a regular antihistamine user. In a series of articles, oncologists
from the Manitoba Institute of Cell Biology, expressed their concern over
tumor promotion, melanoma in particular, in those who took Seldane and
Hismanal. The researchers compared the tumor-contributing effect of
Tamoxifen (breast cancer drug) for which a 300% increase in uterine cancer
has been documented,3 with the effects of antihistamines: given the similarities in the pharmacological profiles of the antidepressants4 and antihistamines (with Tamoxifen), we have real concerns.5
Most of the evidence comes from studies on mice, but some, from investigations on humans. The first data on these serious possible connections
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were published in the early eighties, but allergists, the most passionate advocates of antihistamines, remained silent. In 1994, the information started to
leak into lay magazines. To comfort the public, televised interviews with the
producers of Seldane and Hismanal followed. They reassured the public by
stating that mice could not serve as a model for making decisions regarding
humans, and only epidemiological studies could prove or disprove similar
side effects in humans. Besides, the defenders said, antihistamines did not
cause new tumor formation but just accelerated the development of already
existing cancers, and even then, not in all kinds of cancer.5,6
One can only ponder such declarations in silent amazement. First, due to
the great similarity of the immune systems of mice and man, mice are used as
the model to study the basic immune mechanisms. In the past, the tobacco
industry created exactly the same defence, and it took half a century to arrive
at the evident conclusion that the effect of tobacco on mice was the same as
on people. Second, in many cases, it takes years for a cancer tumor to develop
out of a few existing cancer cells. Any of us may have cancer cells, but they are
regularly destroyed by our immune systems with the assistance of our H1
receptors. What if H1 antihistamines really speed up tumor growth? Seldane
and Hismanal are the oldest medications of the non-sedating group, and, by
the way, were taken off the shelves for side effects unrelated to cancer. Can the
manufacturers of antihistamines guarantee that their newer products will not
show similar carcinogenic effects over time? Is this possibility being tested
elsewhere? After all, there are definite similarities in the effect of all H1 antihistamines despite some of the differences in their ingredients.
Since you know how cells and their receptors work, it is easy to understand why H1 antihistamines may contribute to cancer. T-cells cannot efficiently function as cancer fighters, when they are deprived of histamine, as
cytotoxic or T-killer cells become efficient when activated with histamine.
Therefore blocking H1 receptors leads to a histamine deficit and thus undermines the efficiency of cancer-fighting T-cells. If an occasional disruption of
immune functions in this area cannot harm severely, a regular blocking can.
The individual potency of each antihistamine may only influence the speed of the
cancer-contributing effect, and we should not be surprised if with time, other
drugs of this group join Seldane and Hismanal in their probable carcinogenic
effect. Do we have the luxury of postponing a decision for two or three
decades, pending epidemiological studies, if chances of tumor growth in antihistamine consumers exist today? Will a belated sorry be enough if this
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turns out to be true? So far, the US Food and Drug Administration doubts the
need of epidemiological studies, since it considers the drugs safe.7 Have there
been additional studies to prove or disprove the findings of the Manitoba
researchers? I personally failed to find any such data.
The initial shock and interest in the cancer connection with antihistamines
soon subsided. Considering the few choices for allergy sufferers, antihistamines will continue to enjoy a wide market. New kinds will be synthesized,
and only future generations may realize the full extent of the problem.
One more thought to consider: epidemiological studies last decades, not
years, since they have to cover different health-related events and their causes
in order to determine the significance in the development of the given
disease. Since the creed of medicine is to weigh the pros against the cons, the
dilemma of whether to take or not to take antihistamines does not exist. This
is because concerns for the few of those who may get tumors are superseded
by the multitude of consumers wishing to get at least some relief from their
allergy symptoms. An indirect confirmation of the possible tumorpromoting effect of antihistamines comes from two articles on tumor regression due to the histamine therapy.8 Quite logical: if histamine deprivation
contributes to tumor growth, histamine stimulation shrinks tumors.
H2-ANTIHISTAMINES?
Although, from the scientific standpoint, activation of the inefficient regulatory tools is the only logical solution, allergy has predominantly pursued the
path of suppressing those bodys immune tools, which become overactive as
a result of the inefficiency of their counterparts. Such is the case with H1 antihistamines, such has become the case with H2 antihistamines that target the
already inefficient H2 receptors. H2-receptor blockers already exist as medications for stomach problems, such as Zantac and Pepcid.
The main idea behind the suggested use of H2 antihistamines in allergy is
that they prolong the clearance time of the conventional H1-antihistamines by
acting through liver enzymes. Basically, it means that H2 antihistamines
should be taken together with the conventional H1 antihistamines, and with
that, the latter will be more effective. The drug industry will definitely find the
idea most attractive: two drugs instead of one! For patients, H2 antihistamines
will be a disaster as they will further paralyze the already deficient receptors
and thus inhibit the self-remedial action of histamine. This will deprive the
body of the major means of defense against allergy.
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The knowledge of the danger of H2 blockers in allergy has been around for
over 2 decades. Look what the highest ranking allergist, R. Rocklin, says in a
textbook: Their administration to patients in vivo might. potentiate histamine release and worsen allergic symptoms. In fact, this seems to be the case.9
An article by world-renowned immunopharmacologists informs us that
H2-receptor antagonists might increase the bronchoconstrictor response
by facilitating the release of histamine...10 Simply speaking, it means asthma
gets worse.
With the knowledge of the protective effect of H2-receptors in allergy,
their blockers should be contraindicated, and allergists should know that. Do
they? It seems unbelievable, but is true that an article was published by
leading Canadian allergists at the same time as the two above-quoted sources,
in which they actually recommended (!) H2 blockers for those who develop
anaphylactic reactions.11 Anaphylactic reactions are the extreme stage of
allergy, at times fatal due to an explosion of histamine and histamine-induced
pro-disease chemistry. It may happen upon eating a highly allergenic food,
taking a drug or being stung by an insect. By excluding H2 receptors from the
game, the body is left helpless at the mercy of the disease.
DECONGESTANTS
Decongestants form another very popular group of short-term relief allergy
medications, although their primary indication is for a stuffy nose in colds.
Among them are Sudafed, Dristan, Otrivin. They constrict nasal vessels, and
the resultant shrinkage of the swollen mucous membrane allows air to pass.
These drugs should be taken in moderation in view of their well-known
rebound action, that is, paradoxical aggravation, that may set in shortly after
one starts using them. It is all right to take a decongestant for a cold that
usually lasts a few days only. Allergies, however, have a lasting course, and
after some period of using a decongestant, an allergy sufferer can never be
sure whether the symptoms persist due to allergy, or they are the ricochet
action of the drug. At times, just by discontinuing the drug, the patient may
have a symptomatic improvement.
The best known decongestant is ephedrine, a synthetic version of a plant
ephedra used since ancient times. It also stimulates cardiovascular tone and
the central nervous system, and for that reason, is sometimes used by athletes
as an upper. By the way, Maradona, a world famous soccer star, and Laumann,
a Canadian gold medalist in rowing, were both disqualified for using ephedrine.
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Medicine does not put decongestants into the category of harmful drugs
although, as adverse reactions to the stimulatory effect of ephedrine, its users
may experience hyperactivity, anxiety, palpitation, tightness in the chest,
general weakness, vomiting and fainting.
As with Seldane and Hismanal revelations that came years after the drugs
had virtually flooded the market, certain side effects of decongestants, undisclosed for decades, drew attention. The 1997 annual meeting of the American
Academy of Neurology heard a report by Dr. L. Vives-Castro from the
University of Pennsylvania on the risk of medications that contribute to
vascular constriction. Among the high risk group are migraine sufferers and
postmenopausal women on replacement estrogens. Instability of the vascular
tone in migraineurs and the medications they take, as well as the predisposition to various vascular problems in estrogens users, put these patients at risk
even if they do not abuse decongestants. The researchers suggested retroactive studies of patients with brain hemorrhage to see if there was a
contributing factor from decongestants. They also considered the possibility
of tightening the regulations covering this drug group, since, like antihistamines, decongestants are among the most common over-the-counter
medications and can, thus, be easily abused.
Within the five years that followed, those who suffered from migraine
headaches or took synthetic estrogens had a choice: nasal congestion or a
possibility of brain damage by a stroke. In May 2001, the FDA and Health
Canada banned 63 cold remedies that contained a certain decongestant.
Among them, there were the familiar Dimetap Cold and Sinus, Contac Cold
and Alka-Seltzer Plus. American authorities documented about 200 to 500
strokes a year in young people who took these medications, the population
group normally not known for such accidents. Numerous bleeding strokes
were registered in adults under 50, women in particular. My suspicion is
that the number of cases is higher. Many deaths could have been attributed
to a different medical condition, since hardly any doctor would blame
innocent decongestants for fatalities.
As is to be expected, manufacturers will reformulate their cough and sinus
medications and will replace the decongestant. Only time will show how safe
the new ones are. Do not forget that the banned drugs had a long history of
use and had originally been recognized as safe.
Naturopaths and herbalists often suggest taking ephedra instead of
synthesized decongestants. In essence, the net results are similar. Ephedra has
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recently been banned in this country. So has pure ephedrine. Strangely, the
legions of ephedrine-containing drugs continue to be widely used.
COMBINATION DRUGS
It has become fashionable to design drugs that combine several into one, thus
creating an allegedly new breakthrough product for diverse purposes. For
instance, ephedrine and ephedrine-like drugs are often added to painkillers
and antihistamines. You may recognize these compound drugs through the
letter D for decongestant or word Extra on the label, for example, Claritin
Extra, Tylenol D(econgestant). The only benefit of such medications is in taking
one compound drug instead of taking two pills separately. Do not forget that
although the combination drug offers all the benefits of the ingredients, their
side effects are also preserved.
Antitussives are drugs that suppress a cough, and codeine, a narcotic, is the
most common cough-suppressive ingredient. Decongestants and antitussives are
a popular combination. Cough-suppressing syrups, so often offered to your kids,
are nothing more than a sweetened dose of codeine added to something else.
One of the combo-drugs for allergy is Actifed. I chose it not because it is
more dangerous than others, but due to the heated discussions it produced a
decade ago. The experimental mice who were fed it showed a higher incidence
of liver tumors. It may be that liver tumors do not develop in humans,
although, even a low probability of having such a side effect makes a stuffy
nose preferable. My purpose here is different: Actifed is a combination of an
antihistamine, decongestant, antitussive and sometimes a painkiller. It is a
typical pharmacological amalgam with the benefits and side effects similar to
other combinations.
The entry in the Canadian Compendium of Pharmaceuticals on Actifed,
spells out under Precautions who should not take the drug: children under six
years of age, people with persistent or chronic cough such as occurs with
smoking, asthma or emphysema, patients with high blood pressure, heart or
thyroid disease, diabetes or difficulty in urination, pregnant women and
nursing mothers, patients on antidepressants. Also cautioned are those who
may drive a motor vehicle or operate machinery requiring mental alertness.
From this list one very important point is missingthe instruction as to who
can take the medication that has so many contraindications. A healthy, nonpregnant adult who uses public transportation and can afford to be mentally
relaxed at work? Are there many such people among allergy patients?
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CORTICOSTEROIDS
Corticosteroids, or simply steroids, are the most potent drugs generally prescribed
for asthma and becoming more and more common as the treatment of choice
in other allergies. The name corticosteroids is used to denote, first, natural
hormones produced by our body and, second, the drugs, which are synthetic
versions of these hormones. The general public often knows about a different
kind of steroids (anabolics) that also exist in the form of drugs and are illegally
taken by some athletes to build up muscles and increase performance. However,
our topic is corticosteroids, and the short form steroids will be substituted.
Synthetic steroids have been on the market for half a century. They are the
first-line medications in such life-threatening conditions as shock, coma,
poisoning, severe asthmatic attacks or allergic reactions. They are an integral
part of the medical regimen of organ transplant recipients: by suppressing the
immune system that tries to rid itself of a foreign organ, doctors suppress the
rejection and prolong the patients life. Modern medicine extensively
prescribes them in a lot of chronic diseases such as rheumatoid arthritis, ulcerative colitis, Crohns disease, cancer, etc.
Steroid drugs are produced in various forms depending on their intended
use: in pills; in injections that can be administered intramuscularly, directly
into an inflamed joint or lesion, or are infused intravenously; in creams,
lotions and ointments for skin application; in eye and ear drops; in sprays for
nasal and chest allergies; as a rectal suppository. Should todays dentists fall
under the charms of the steroid manufacturers, we will find steroid tooth paste
on the shelves tomorrow.
What is there about steroids that allows their wide-spectrum use and calls for
manufacturing them in so many forms? Steroids are one of the greatest discov-
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eries of medicine. This group of drugs is a miracle, for it saves lives in emergency situations and in severe debilitating illnesses. The picture changes when
steroids are taken regularly. Any drug taken on a long-term basis may be
harmful, still, few drugs can compete with steroids in the seriousness of their
complications. All textbooks, articles and lectures on steroids urge dose reductions as soon as the patients condition allows. However, in view of their
growing market share, transparency regarding steroid-related side effects is very
limited. Moreover, the legend of their safety has been recently created in allergy,
and this has skyrocketed their use. But I want to tell you what you will rarely
hear from your doctors, but what you, as an allergy patient, should know.
I intend to unravel the facts about one of the main causes of the growing
severity of all allergic diseases and rising mortality from the most serious of
them, bronchial asthma. The truth is thoroughly concealed from the public
although, I admit, an inquisitive steroid consumer can find it in the drug insert
or a pharmaceutical compendium. But who reads a terminologically complicated scientific text, especially if written in tiny letters? It is similar to the former
microscopic warning against cigarette smoking on an attractive package with
the brand name in capital letters. Generally, patients rely on the information
they get from their doctors. Doctors, in turn, are expected to obey the practice
guidelines which dictate the wide use of steroids. These are formulated by their
own associations, usually with strong input from the pharmaceutical companies whose representatives sit on the medical councils; the doctors on these
councils and professional associations are often themselves in conflict of
interest due to the fact that their research grants are funded by pharmaceutical
companies.12 Besides, very few doctors will tell you that, in the long run,
steroids aggravate the very condition they are prescribed for. Some conceal this,
others simply do not know.
ADRENALS
Since corticosteroid drugs are a synthesized equivalent of the bodys
hormones, we should know about the organ that produces the natural version
of the chemical. We should also know what role steroids play in the functioning of the body, and what happens to their natural producer when
synthetic hormones flow in the blood.
The steroid producer is the adrenals, pea-size, paired endocrine glands
situated above the kidneys. In Latin, ad means near, and ren stands for kidney.
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The adrenals are vital for the body. This tiny gland has a wide spectrum of
action: through its hormones, it regulates and maintains the metabolism of
proteins, carbohydrates, fats and minerals, controls water balance and is also
a source of sex hormones. Knowing this, it is easy to understand that
malfunctioning of the gland may impact all of these processes. Steroids
produced by the outer layer of the adrenals, its cortex (bark, shell, rind in
Latin), correspondingly got their full name, namely corticosteroids. They are
our power sourcehormones give us strength and resistance and life itself.
Along with steroids, our body draws these powers from another hormone
produced by the inner layer of adrenalsepinephrine. Its synthetic version,
adrenalin, is also given to patients in emergency situations. The well-known
Epipen carried by those prone to anaphylactic reactions is, actually, a syringe
filled with adrenalin.
We know that in critical situations, a man can lift a weight he is normally
not able to lift, run away from danger at a speed inconceivable under normal
circumstances and withstand the most extreme conditions for a certain
period of time. This is possible because of the adrenals that start to work
instantaneously at a high capacity in demanding situations and supply us
with their wonder hormones.
The adrenals hormones also protect us from stress. If in lay language,
stress is usually associated with a psychological strain, as a medical term,
stress has a much wider notion. It is defined as a bodys reaction to any
adverse stimulus that may disturb its homeostasis. This includes hard physical effort and severe emotional pressure, intense pain and an infectionall
extreme situations which put an extra load on the body and require adaptation to the situation. The adrenals are directly involved in the required adaptation process by increasing the production of corticosteroids and
epinephrine, which mobilize the bodys resources.
Immune diseases put great demands on the adrenals, and without corticosteroids and epinephrine, the body may perish. Severe allergy, and especially
asthma, create a situation of stress, and for these patients, activity of the adrenals
is of prime importance. In short, the hormones of the adrenals are the fuel,
which this endocrine gland supplies for the proper functioning of all organs.
The body cannot work without this organ, just as an engine cannot work
without fuel. Therefore this gland should always be in good shape, not only to
meet the every day demands of its hormones but also to be ready for any unexpected emergency.
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HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
To understand the vital importance of the adrenals to the functioning of the
whole body, we must know the glands connection with the two other superior organs situated in the brainthe pituitary and the hypothalamus. Their
functioning is inseparable. Different endocrine glands join the pituitary and
the hypothalamus to form an axis, and each axis regulates the production of
the hormones specific for the given gland. The adrenals team up with the
pituitary and hypothalamus to form the hypothalamic-pituitary-adrenal
axis, for short, HPA. The axis controls the production of steroids generated
by the adrenals. It is a three-story structure: the adrenals are subordinate to
the pituitary gland which, in turn, is subordinate to the hypothalamus.
THE PITUITARY
From the lower story, the adrenals, we can move up to the pituitary. Medicine
calls it the master gland because it regulates the work of almost all endocrine
glands. Hormones affect everythinggrowth, maturation, reproduction,
behavior. The pituitary plays the role of a meter that determines the appropriate
levels of hormones released by other glands into the blood and adjusts them
to the required level. It communicates with other glands such as to intensify
or slow down the production of their hormones. The bodys need of different
hormones at any given moment depends on the time of the day, period of life,
emotions, etc. For example, the need of adrenalin and steroids during sleep is
lower than during daily activity. This, by the way, explains why asthmatics
often feel worse at night or early in the morning: less defensive hormones are
produced, and so allergic processes run against less resistance.
The pituitary is multilingual: it uses its own special stimulatory hormones
as a language of communication, different for each subordinate gland. Thus,
the language it uses to communicate with the adrenals is the hormone called
corticotropin. The pituitary assesses the amount of steroids in the blood that
reaches it, decides if their production should be reduced or increased and correspondingly adjusts the amount of corticotropin that stimulates the adrenals.
The master gland is not interested in whether the hormones are generated by
the body itself or taken as medications. Its decisions are made purely on the
quantitative measurements of their levels in the blood.
THE HYPOTHALAMUS
The hypothalamus is on the upper level of the HPA axis. This miniature regulatory center is a complex, supremely important structure of the brain, which,
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similar to the pituitary, is the bridge between the nervous and endocrine
systems. Although a tiny organ, the hypothalamus activates, controls and integrates the work of the major endocrine glands, some parts of the nervous
system and the cardiovascular system. It supervises our behavior, sleep,
appetite, body temperature, emotions, libido, etc. Hardly anything is left
beyond its supervision. The pituitary is attached to the hypothalamus and
receives all important directions from its superior, also in the form of special
hormones. These hormones help the pituitary to properly regulate the
endocrine glands at the periphery. Both the pituitary and the hypothalamus
are a part of the brain, therefore in addition to hormones, they use another
language of communication used by nerve cellsneurotransmitters.
SUPPRESSION OF ADRENALS
The human body is a clever structure. For survival, it is programmed by
nature to sacrifice less important substances or parts to preserve its most vital
organs. Thus, in severe frost, the circulation to the extremities is shut off to
keep enough blood supply for the internal organs. From the biological point
of view, extremities are a small loss compared to life itself. Reasoning by
analogy, the ultimate level of blood hormones is more important for the
functioning of various organs than the normal performance of just one
glandadrenals. An excess or a deficit of hormones equally impair the
steady, homeostatic level needed by the body to function normally.
A doctors prescription of steroids in immune-related inflammation has a
logical basis: the body needs these power hormones to cope with a stressful
situation. When steroid medication reaches the pituitary with the blood flow,
it is perceived by the meter in the same way as would the natural hormones.
The addition of the synthetic hormone to the natural hormones produced by
the adrenals creates a surplus. The pituitary, indifferent to the source of the
hormones, tries to correct the impaired imbalance by ordering the adrenals to
diminish their steroid output and does this by reducing the amount of its
corticotropin. Less stimulation by corticotropin means less active adrenals.
Deactivation of the adrenals lasts as long as the steroid medications are
taken. During periods of prolonged drug use, the adrenals, similar to muscles
weakened by inactivity, also weaken. Their ability to generate steroids steadily
reduces. The longer the drug is taken, the longer it takes the gland to restore
its functioning when the medication is stopped. Therefore, when the patients
condition improves, and the drug is discontinued, the long-suppressed adrenals
are often unable to meet the bodys demand. During their regeneration
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period, the patient is forced to rely on the synthetic steroids that make up for
the deficit of the natural hormones. This physiological dependence is the
reason why, unlike other medications, steroids cannot be stopped abruptly
but should be weaned slowly, even if the disease for which they were
prescribed, is controlled. In such situations, steroids are taken because of
dependency and not because of the original symptoms.
What happens if steroid tapering is done too suddenly? This was a question from an interview given by Dr. Teik Chye Ooi, and Associate Professor of
Medicine at the University of Ottawa.13 His answer was that a number of
problems may arise, and in the most extreme situation, sudden death can
occur. This happens due to the adrenals shut-down and hence, sudden
systemic shortage of their vital hormones. With sustained steroid consumption,
the adrenals may atrophy, and such patients are doomed to take synthetic
steroids for the rest of their life.
The body possesses an amazing ability to keep the balanced production of
its chemicals. Therefore, when synthetic hormones become a daily interference, the adrenals become redundant, and the body sacrifices them. Their
atrophy is the price for the relative balance of the level of steroids in the
blood. The result is the bodys dependence on the steroid drugs.
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COMPLICATIONS OF STEROIDS
Given the critical need of adrenal steroids for the normal functioning of all
organs, we should not be surprised that many organs and systems suffer in
cases of inadequate supply with a synthetic version. Complications arising
from steroid use can be divided into:
a) temporary adverse reactions which usually go away when the drug is
discontinued;
b) lasting complications which may subside with drug discontinuation,
but may turn into a chronic condition due to the sustained drug use;
c) development of new chronic diseases.
Most drugs are known to have unwanted side effects, but few are as notorious as
steroids. Among the temporary adverse reactions listed by pharmaceutical
compendia are nausea and vomiting, indigestion, headaches, dizziness, fainting,
irregular heartbeat, elevated blood pressure, nose bleeds, frequent urination,
moon-like face, weight gain, unusual tiredness, weakness, mood swings, insomnia,
muscular cramps, joint pains, unusual bruising, etc.
Allergology is full of paradoxes, and steroids prescribed in allergy is one of
them: they may result in allergic reactions of various degreesfrom skin
rashes and hives to systemic reactions. As was reported at a semi-annual
meeting of the American Contact Dermatitis Society by the chairman of the
department of dermatology in a New Orleans hospital, Dr. R. Rietschel,
corticosteroid allergy is real and more common than expected. This doctor
referred to systemic reactions and reported the findings in five comprehensive studies conducted in Europe and North America.14
Steroids produce numerous serious side effects that may not go away when
the drug is discontinued after protracted use. They include hypertension, water
retention, growth retardation in children, fragile skeletons in older people and
menopausal women due to calcium loss (i.e osteoporosis), obesity and suscepti-
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there is only one receptor that mediates the action of the steroid drugs. This
makes it impossible to achieve only the desired positive effects and avoid the
undesired negative effects of steroids, and the easy access of the corticosteroid
receptor to the genetic material makes synthetic steroids especially
dangerous.16 Compare this with the flexibility of histamine: different receptors implement stimulatory and inhibitory effects, which enables physicians
to achieve the desired effect by targeting the ones needed. There is a huge
difference between playing a one-key musical instrument and an instrument
with several keys.
Genes are interdependent in their work. Mutation of one gene may affect
numerous characteristics and lead to complex abnormalities in the immune
functioning. Therefore, any organ and even system of organs may suffer as a
result of gene mutation. Genetic mistakes have a tendency to repeat in future
generations, and the offspring of steroid consumers may inherit undermined
health.
Bernard Shaw once remarked, Science is always wrong: it never solves a
problem without creating ten more. His remark is fully applicable to the use
of steroids in allergies.
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as a constant flow of water wears away a stone, chronic use of steroids wears
away the immunity.
Here is one of the most recent confirmations coming from an annual
meeting of the AAAAI.17 The authors write about steroid-containing nasal
spray: data using more sensitive parameters suggest that low doses of
inhaled fluticasone propionate (flonase) are associated with a significant
degree of detectable systemic bio-activity, including HPA axis suppression.
The article gives many references and concludes that doctors should use
caution in terms of assessing the effects of therapeutic low doses of flonase on
HPA axis.
To say that there is no side effect at a lower dose also suggests that patients
respond equally to that same dose, while certain groups, such as children,
pregnant women, older people, patients on concurrent drugs, or those who
have an innate exaggerated sensitivity to medications, can hardly be categorised as an average group. It is peculiar that with steroids having been
around for half a century,well-controlled studies relating the safety of inhaled
corticosteroids in pregnant women are not available, there are limited clinical data on the use of inhalers in children, and it is not clearly established
whether inhaled corticosteroids are excreted in breast milk, etc. The quotations are from the Canadian Compendium of Pharmaceuticals 2000.
But one does not even need trials on these groups. A thorough retrospective
analysis of those kids, pregnant and lactating women who were forced, due
to their asthma, arthritis or ulcerative colitis, to take steroids would be
enough to draw appropriate conclusions. Most probably, this has been done,
and not just once. Most probably, the results turned out to be unpleasant for
the producers, and, most probably, a gag clause in the contract prevents the
researchers from disclosing the results.
All this indicates that the dose shown to be safe during the drug testing on
healthy young males cannot be automatically applied as such to other categories. The history of Seldane is a classic example of how an extensively tested
and supposedly safe medication turned out to be fatal in certain patients
years later. The same is true for decongestants that have been on the market
for well over a century, and only today, we learn that a recommended dose,
meant to unplug a stuffy nose, may lead to a stroke in a migraine sufferer.
This means that these medications were known to have side effects before, but
only when these reached numbers too high to conceal, the truth came out.
There is no such thing as a safe dose, especially if this dose is repeated daily.
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system by recommending the daily use of the drugs which, as they claim, are
supposed to bring allergies under control.
The alleged safety of steroids is evident from the earlier-cited interview
with Dr. Teik Chye Ooi published in The Parkhurst Exchange, April 1994:
Patients should wear a Medic Alert bracelet to show that they are on steroid
therapy, and they should carry a prepackaged syringe with 4 mg of dexamethasone phosphate (also a steroid) for emergency use.
Look around: more and more people suffer from severe allergies and
asthma. Ask them what medications they have been taking and for how long.
The majority are on steroids. At times, this becomes evident from the names
of their medications that contain cort, which stands for corticosteroidspulmicort, nasocort, rhinocort, etc. Still, many steroid preparations are unrecognizable because they have been given decorous names. Consumers seldom read
the inserts in the drug packaging, they are often convinced that their medications have nothing to do with the dangerous hormonal preparations they may
have heard about. Should we be surprised by the growing severity of allergies
and the rising curve of asthma mortality if we, doctors, help create this situation day by day?
An alert should sound in every medical office and at every doctors
conference. Allergy patients should also be informed of this drugs danger, no
matter in what form it is taken, and behind what name it is hidden. Do not
expect that to happen soon, though. The reason is simple: there is no drug in
conventional allergy can use to replace steroids. We started with Moliere and
will finish with D. Jerrold, the English humorist who said: In this world,
truth can wait, shes used to it.
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case, and inflammation is indeed at the core of the problem, why do steroids
never cure? Why are they needed again and again? Moreover, why does the
course of allergies/asthma often get worse, and the dose of steroids rises
accordingly? Because inflammation itself is not the origin of the problem.
To sort out what is primary, and what is secondary in allergy, let us
imagine an allergic disease as a tree. Its branches are the symptoms, its trunk
is an allergic inflammation that gives rise to the branches. The roots that
feed the trunk are the malfunctioning cells that produce predominantly
inflammation-promoting chemistry. If the roots are rotten, no matter how
thoroughly the gardener trims the branches or props up the trunk, the tree
sickens and dies. Therefore, to keep the tree growing, he must be sure that the
roots are healthy.
Basic sciences provided us with the knowledge how to access the faulty
genes, the seed from which this tree started: through the receptors of the cells
that deliver messages to the genetic material. The main carrier of the protective immune messages, H2 receptor, if active, delivers the histamine/cAMP
messages to the genes and corrects (yes, corrects!) their functioning. This
process of accessing is called immunotherapy or immunomodulation. It can
also be called geneomodulation. A term I have not come across, but suitable in
this situation. This approach would be the best therapeutic modality for
allergy sufferers. But the gardeners neglect the roots and start with the
branches. They try to rid allergy patients of their cough, itch and sneeze by
identifying and eliminating the allergens which, in their opinion, provoke the
symptoms. As a rule, elimination fails, and doctors turn to antihistamines,
decongestants and bronchodilators that relieve those symptoms for a period
of time dependent on the drug clearance time and with a different degree of
efficacy. In too many cases, such tending does not work at all or works
insufficiently, and the failure shifts the attention from the branches
to the trunkallergic inflammation.
The notorious side effects of steroid drugs prompt some authors to
caution in prescribing them for allergic disease. But some suggest even more
potent immunosuppressive medications, which, although they ruin the
immune system, can, at least, be discontinued at once since they do not
produce physiological dependence. Indirectly, allergists admit that the
essence of the problem is malfunctioning immunocompetent cells: allergic
rhinitis and asthma need to be understood as inflammatory diseases arising
from mediator release cytokine secretion. This statement comes from L.
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allergists are undoubtedly the first to get paid by the pharmaceutical industry
for their research, development and testing.
In support of the allegedly wide spectrum of allergology, Dr. M. Kaliner,
Chief Allergist in the National Health Institute, said at a round-table discussion24 that allergists provide certain aspects of care that may not be given by
other physicians, including an emphasis on the environmental control of allergens and other triggers. Indeed, during patients visits to their offices, allergists may conduct individual educational classes on the makes of appliances,
breeds of non-allergenic pets, delivery devices of medications and techniques
of inhalers use. Of course, their time has a high price tag, although these
aspects are hardly in the department of immunology. But if leading specialists
say so
Medicine and the areas servicing it should be grateful to allergists for job
creation. Due to the success of allergists in breaking up the medical problem
into a myriad of irrelevant issues, they keep themselves in the business, and
also let many other medical professionals do so as well.
A NARROW FIELD
Somebody once said that if you have one instrument only, and this instrument
is a hammer, everything around will look like a nail. Allergy has one instrument, steroids, and they are as powerful as a hammer hitting all body cells at
once. It may look as though histamine, I suggest using for all allergies and
related diseases, is also a hammer in my hands, but this is wrong. I suggest
medicine should accept the stimulatory approach. This would facilitate
creation of various agents able to activate its immunomodulatory receptors.
The advantage of histamine is that it and its congeners are already available
and have undergone clinical and double-blind studies. All of them could be used
right away for the sake of those who cannot find relief with conventional
medications. Immunomodulation with histamine would be the natural way of
restoring the functioning of the immune system. But allergology ignores and
prohibits this approach.
A quoted high profile allergist declared at the above-referred roundtable
discussion that allergists are a small specialty with a narrow focus25 Is this
so? Is immunology a narrow field isolated from other medical areas? I personally disagree. The narrower the specialization of a doctor, the broader his general
knowledge of the bodys processes should be. For example, before performing
complex operations, top heart surgeons do not just wield their scalpels, but
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Medications
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ENDNOTES
1. Lan Yan et al. Histamine N-methyltransferase pharmacogenetic. Pharmacogenetics 2000;10:261-6
2. M. Reilly, E. Sigg Suppression of histamine-induced adrenocorticotropic hormone release by
antihistamines and antidepressants, J Pharmacol Exp Ther 1992;222(3):583-588
3. This is not a typographical error: Tamoxifen increases the risk of cancer especially in the liver,
while slightly reducing cancer risk in the breast. See oncologist S. Epstein, M D, The Breast
Cancer Prevention Program, 1999
4. For the adverse effects, including the 7-fold increase in cancer risk associated with antidepressants see Harvard Universitys J. Glenmullen, Prozac Backlash, 2001, and D. Healey, Let The Eat
Prozac, Lorimer, 2003
5. Brandes L.J. et al: Results of a clinical trial in humans with refractory cancer of the intracellular
histamine antagonist in combination with various single antineoplastic agents, J.Clin Oncol
1994; 12:1281-90
6. Note: according to the regulations governing safety standards in Canada and the USA (not
always followed, of course), the reason studies are conducted on mice, is because they largely
share the same enzyme system with humans; extrapolating from mice to people regarding toxicity and carcinogicity has proven to be totally reliable.
7. FDA reviews antihistamine mouse study. FDA Talk Paper 1994; May 17:2
8. C.Brutin et al To the editor, The New England Journal of Medicine, 1983;308:591-2, S. Borgstrom
et al To the Editor, The New England Journal of Medicine, 1983; 308:592
9. Immunopharmacology 1982:52
10. M.Ichinase, P. Barnes. Histamine H3 receptors modulate antigen-induced bronchioconstriction
in guinea pigs. JACI 1990; 86:491-5
11. G. Sussman., J. Dolovich. Seminars in Dermatology 1989;8:158
12. According to the Journal of the American Medical Association, 87% of doctors who get clinical
practice financially tied to the pharmaceutical industry. JAMA 2002;287;612-7
13. Parkhurst Exchange, April, 1994:76-9
14. Dermatology Times of Canada, Sept. 1996, p. 1
15. R. Sapolksy, et al Pulsender Wa Science, 1985;229(4720):1397-1400
16. P. Halloran. Four decades of glucocorticosteroid immunusuppression. Can Med Assoc J
1992;147(5):613-4
17. B.Lipworth, C. Jacson Effects of oral and inhaled corticosteroids on the hypothalamic-pituitaryadrenal axis, JACI 1999;104:13
18. R. Geha. Regulation of IgE synthesis in humans. JACI 1992;90:143-5
19. P. Creticos. Immunology and Allergy Clinics of North America, 1992; 12:26
20. JACI 1995; 97:870
21. Frew et al. Sublingual immunotherapy. JACI 2001;107:441
22. M. Kaliner. Presidential address. JACI 1997:99:729-34
23. Kaplan ed. Allergy 1985, p.679
24. JACI, 1995;97
25. Visions in Allergy: Impact on Health Care Reform. JACI 1995;97:864
26. Justifying a mechanism-based specialty. N. F. Adkinson et al. JACI 1995;97:868-71
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PART SIX
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The situation with asthma, the most serious allergic disease, is a reflection
of the situation in allergy medicine as a medical field. The only treatment that
could repair the ailing immune system is immunotherapy, but, as the same
textbook wrote back then, with little evidence of efficacy for the technique as
commonly practised, immunotherapy fell into disrepute in the scientific
community at large (p. 679).3 Allergists blame the quality of the allergen
extracts for this failure and produce guidelines to improve their standardisation and storage conditions. They also modify the production of the extracts
to prevent aggravations and even deaths from them. Still, within the past two
decades, nothing has changed the low efficacy and potential danger of allergy
shots, as laymen call immunotherapy. It is required to last from 2 to 5 years
and the first results (if any) manifest not earlier than 6 months after the start.
It is not uncommon that immunotherapy is discontinued because of the
various adverse reactions, both local and generalized, while the disease is still
not controlled.
For safety reasons, this treatment, meant to repair the ailing immunity,
may be prescribed along with immunosuppressive steroids. It is mostly
limited to allergic rhinitis and hay fever and is never recommended for skin
allergies. All guidelines caution against using it in asthma even though it is
asthmatics that need it most in view of the gravity of their disease.
Immunotherapy is not even considered as a possibility for the related neurological and non-specific symptoms because their common roots with allergies are unknown to clinicians. All this has assigned a Cinderella role to
immunotherapy among allergy/asthma therapies.
So hopeless for patients and compromising for doctors is immunotherapy
that an ex-president of AAAI, M. Kaliner acknowledged at a prestigious gathering of American allergists: immunotherapy is easy and lucrative. If we
didnt have it, we would have a better specialty. Having said that, I think we
are going to go where immunotherapy is going to be restricted.2 Something
must be terribly wrong with this most logical and scientifically founded
procedure if a top allergist thinks of restricting this already unpopular
therapy. Actually, for patients, this means being condemned to medicalization
for life. Dr. Kaliner is right in one respect though: any therapy based on its
profitability for doctors instead of its benefit for patients ought to be
restricted or even banned.
Before suggesting changes, we should thoroughly scrutinise immunotherapy in its present performance. The scrutiny should start with allergy skin
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the epidermis at that spot. Usually, an itchy wheal forms at the prick site often
surrounded by redness or a flare, as it is called. A few minutes later, drops of
allergen extracts (pollen, mould, house dust mite, animal dander, etc.) are put
on the skin followed by a series of pricks at each spot. The size of the wheal
and flare formed by each allergen is compared to that formed by the histamine prick, which is thus used as sort of the yard stick in the evaluation of the
local reaction. As a rule, allergists also use a negative control, which is a drop
of saline, to see if the patients sensitivity is so exaggerated that his skin reacts
even to a neutral substance. The use of saline is not mandatory according to
the FDA recommendations. Each allergen extract, to which no skin reaction
occurs, becomes a negative control due to its neutrality in the hosts body.
A localized reaction developing upon a prick is a typical appearance of what
allergy calls allergic inflammation. Doctors explain it this way: Do you see the
hives where I put mould (mites, pollens, etc.) extracts? It means you are allergic
to them. In the majority of cases, at this stage, the patient is given a prescription for a conventional drug and told to avoid the offenders. In rare cases,
when immunotherapy becomes the treatment of choice, the mixture prescribed
for injections almost invariably contains those allergens that showed the most
marked skin reactions. The doctor says: I will prescribe you the mixture of
these allergens. By getting them in gradually increasing doses, you will be
desensitized to the triggers and hopefully will get rid of your allergies. The
explanation sounds logical. The patients are impressed by the solemn procedure and by the knowledge of the specialist who can do it and become optimistic of a successful outcome. Through this lengthy course of immunotherapy,
the patients usually continue to use their previous medications.
On the surface, the explanation given by specialists is faultless, but then,
why do top specialists state that they would have a better specialty without
immunotherapy?
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First, the name of the outer skin layer where testing is performed is
epidermis, and the epidermis does not contain mast cells! No mast cells
no complexesno reaction!
Second, there is almost always a skin reaction to the initial prick with
histamine which is not an allergen. So, what is this reaction in the absence
of antibodies?
Third, textbooks teach that in response to various stimuli, IgE-mediated
histamine release with human mast cells requires 1540 minutes. In other
words, skin reaction upon a prick with an allergen can not be observed
right away. Then, why do doctors often see it within minutes?
Conventional allergy does not provide answers to these questions. The deficiencies of AST do not end here. According to statistics, only 20% of urticaria
(hives) and less than 50% of asthma are allergen-related, and therefore skin
testing is not applicable for the remaining majority. Such non-IgE-mediated
factors as, for instance, temperature or weather changes, touch to skin, stress,
sun light or exercise cannot be verified in skin testing. Neither can be the vast
group of pollutants, for example perfumes, as they do not exist in the form of
standard allergen extracts.
An additional complicating factor is that allergy patients overwhelmingly
have symptoms in response to mixed triggers, i.e. specific and non-specific. In
such patients, even if the offensive allergen is detected and eliminated, nonspecific factors remain still unidentifiable by pricks, and pinpointing specific
triggers will not significantly change these patients management. Only those
few lucky patients whose symptoms are solely allergen-produced may hope
that skin testing will reveal their triggers. Ironically, it is in these cases that
skin testing may often prove to be redundant. For example, if your symptoms
always come in the same season when the radio stations remind us every hour
of the rising ragweed count, and ingratiating TV ads incessantly promote
medications for the pollen-triggered allergies, do you still doubt you have hay
fever due to exposure to ragweed? Nevertheless, patients with obvious triggers
are skin-tested.
All these flaws make the procedure of AST useless even in reaching its
narrow goaldetect the offensive allergens. Paradoxically, allergy patients
leave specialists offices with the assurance that they can depend on the conclusions regarding the causative allergens. They are promised either to be desensitized against those or to get instructions on how to control the offenders.
Doctors are also satisfied with the impression they produce by this procedure.
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robber is. The vagueness of the scream (the wheal and flare) in identifying
the culprit (allergen), is confirmation of the diagnostic imprecision of the
todays AST.
The true knowledge that the local reactions are mostly non-indicative is
at best presented in a piecemeal way in professional papers. It is doubtful that
practical physicians ever read them because the demands of daily practice
leave little time for keeping up with the literature, while the work of finding
the needed material, and especially interpreting it, is time-consuming. It is
also highly undesirable to reveal the fact that LCs activity is not limited to the
skin but echoes all over the body. Langerhans cells relatives, other dendritic
cells, exist not just in the skin but in the lungs, nasal mucosa and conjunctiva.
The chemical signals sent by LCs from the skin surface involve the whole
network of immune and nerve cells. The involvement requires, histamine
spill from mast cells and basophils followed by other chemical events. Thus,
a local process started and spread by LCs turns into a cause for the whole
body reaction. In other words, by touching the skin we touch other organs.
This leads to a most important revelation: by treating the skin, we treat the
whole body! However, what the drug industry can do, clinical medicine is
prohibited from doing. And the best minds are used to help skilfully hide the
fact that histamine can engage the whole body into recovery, and that LCs can
help do the main job.
You may think that I am splitting hairs, that this is a purely theoretical
exposition, which is irrelevant to practical allergy medicine and not needed
by allergy patients whose central concern is improvement. Wrong. This seemingly theoretical issue has a very practical outcome for patients. At present,
the judgment regarding what you are allergic to, what components of the
surrounding environment you should avoid or eliminate, and what allergen
extracts must be used in your shots depends totally on what allergens form
skin hives. You may be forced to spend money on irrelevant and impractical
elimination measures, make an emotionally difficult decision to part with
your pet, or turn your otherwise happy life upside down by deciding to move
to a place where the offender does not exist.
My prediction is: in either case, you will remain a consumer of allergy
medications because mostly, the measures will not work. An incorrect judgment also dooms any subsequent immunotherapy because the therapeutic
cocktail contains invariably irrelevant or therapeutically useless allergen
extract(s).
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pricks and engage the network of related cells into a reaction. The immune and
nerve cells work in unison and respond to a histamine spill in different parts of
the body because they possess histamine receptors, and it does not really matter
what cells start the reaction. The histamine-induced shift of the cellular chemistry is bound to bring about symptomatic bifocal changesimprovement or
worseningbasically depending on the prevalence of anti- or pro-inflammatory
cytokines. The more mediator-releasing cells a diseased organ contains, the
more potential it has to be involved in the reaction, and the more pronounced
the changes are in the corresponding symptoms.
All this explains why it is only natural to expect that allergy skin testing
may lead to systemic reactions. If the doctor who conducts skin testing does
not detect systemic changes, it is because he does not anticipate and therefore
does not observe them. In medical school, he was taught only how to assess
the wheal and flare occurring on the skin surface and to view them only as an
IgE antibody-mediated event pointing to a trigger. Doctors are never told that
they should expect a histamine spill regardless of IgE existence. They also
remain unaware of the involvement of other organs and systems through
chemical changes started by skin pricks. Strangely, they do know about
systemic reactions, up to anaphylactic shock, that may result from skin
testing. They also know about whole-body reactions to topical medications,
steroids in particular. Still, at AST, they limit their observations to the local
skin signs and never ask patients about their baseline symptoms right before
the testing and the symptomatic change afterwards. And this is the biggest
diagnostic flaw of the procedure.
Like a mirror, our skin reflects the chemical processes occurring in the
tissues and organs stricken by immune and related diseases.9 A localized skin
reaction at a prick site is the manifestation, first of all, of a local histamine spill.
However, it is followed by a systemic reactiongeneral effects elsewhere due
to the histamine-initiated changes all over the body.
Doctors cannot see the organs inside the body, but monitoring of the
symptoms before and after the pricks would help determine how the allergyinvolved organs respond to the bodys chemical changes. Just a few questions
asked directly before the pricks could elicit all the needed information: Is your
nose stuffy (runny)? Are your eyes watery (itchy)? Do you feel the urge to
cough? Are you short of breath? etc. As histamine is a major neurotransmitter,
the doctor should also ask about neurological or related symptoms such as a
headache, fatigue, bloating, muscular pains, etc. The same questions asked
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1015 minutes after the procedure may reveal changes and thus the relevance
of these symptoms to allergies. Among the relevant symptoms, there may be
those of migraine, depression, chronic fatigue syndrome, irritable bowel
syndrome, etc. Some of these diseases are poorly interpreted, therefore undiagnosed and mostly unattended.
Conventional interpretation of skin tests sees the tip of the iceberg only,
but presents it as the whole iceberg. Allergists measure the size of the wheal
without measuring the more essential partthe hidden immune mechanisms which are inevitably engaged in the process when histamine or allergens encounter the immune cells through skin pricks. The changing body
chemistry reflected in such systemic reactions is not in the picture.
If you have had allergy skin testing, try to remember whether the doctor who
did it asked you questions about possible symptomatic changes. I bet he did not,
although this is a must for a physician performing any diagnostic procedure.
Apart from lack of proper theoretical knowledge, there are two banal
reasons why no attention is given at AST to the accompanying systemic reactions. First, clinical observation is not a subject taught well enough at medical
schools, hence, the inability of doctors to observe. Second, the Time is
money slogan has become the creed of our life, and doctors simply do not
want to invest time and effort to observe, analyze or make decisions. They
prefer to follow standard guidelines.
Lack of understanding what underlies local skin manifestations during
allergy skin testing prevents clinicians from noticing systemic immune reactions and making the right judgment regarding the response of the numerous
body organs.
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for a liability suit. Still, if the reactions do occur, obeying the technical rules
of the procedure removes all liability from the doctor even in event of a
patients death.
It is of interest that theoretical sources have noticed that anaphylactic
reactions after skin pricks may occur with minimal to no skin reactivity.12
In other words, a severe systemic reaction may occur to a prick that reveals
few or no IgE antibodies. This, more than anything else, should tell allergists
that systemic reactions are more important than the notoriously imprecise
wheals and flares, since the chemical changes produced in the whole body are
more important than the superficial, often non-indicative skin signs.
An important point not taken into account by doctors, but suggested by
common sense, is that reactions with aggravations do not necessarily lead to
the death of a patient. The scope of worsening can be wide, ranging from a
minor worsening to anaphylaxis, depending on the individual sensitivity.
While the most sensitive patients respond with a severe reaction, in the rest,
it is easy to detect minor changes only by comparing the symptoms before
and after the pricks. Only a doctor who understands that the whole body
becomes involved in the reactions following skin pricks expects a change and
asks about the symptoms.
It is natural that if at the testing, the patients attention is not drawn to the
symptoms, he will not inform the doctor about symptomatic changes unless
there is a dramatic worsening. Since ups and downs are normal in any allergic
disease, the patient will accept a mild or moderate aggravation as such. As was
said, selection of the therapeutic mixture for allergy shots is made solely on the
basis of wheals and flares, and the cocktail of allergens may contain the aggravating ones. Unlike homeopathy that employs the method of administering
tiny doses of offensive substances, conventional allergy starts with much
higher doses and drastically raises them. Thus, if a mild dizziness or a more
congested nose escapes the doctors attention, the situation may worsen during
the subsequent immunotherapy.
The lack of attention to the symptoms at allergy skin testing continues
during immunotherapy and accounts for the fact that the worsening may be
noticed only when it reaches a serious level. This is not so uncommon: a lot
of patients experience acute systemic reactions. Besides, there is a general
(unfounded) belief that it gets worse before it gets better, and the patients
may still go on with their injections assuming that side effects are an
inevitable part of the treatment. The expectations set during allergy skin
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testing were so high! The situation is complicated by the fact that often,
weekly injections are given by nurses according to a standard schedule of dose
increment, and the doctors are unaware of the transitory aggravations until
they strike severely.
Unrecognized systemic reactions with aggravation during skin testing are
the reason why conventional immunotherapy may be dangerous.
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As was cited before, even fatalities may occur in the absence of local skin
reactions. Similarly, symptomatic relief does not always correlate with the
degree of the localized reaction. This is an important fact, since the cocktail
prescribed for immunotherapy is based on those allergens that produce the
most impressive wheals at the testing. If among the allergen extracts, one is a
good match for a particular patient, even the prick with this extract may
result in improvement. Thus, the potentially effective allergen may be excluded
from the cocktail only because it does not produce a wheal, whereas systemic
reactions with improvement, which could help finding the specific allergen
suitable for immunotherapy, go unnoticed. This makes the judgment
regarding allergy shots even more flawed.
There is another factor that is not helpful in detecting positive systemic
reactions. For fear of causing an aggravation, allergy and especially asthma
patients are tested mostly in remission or under the protection of strong
medications. However, to reveal an improvement, testing should be conducted
in symptomatic patients, with the exception of those with life-threatening
asthma or who are in a severe allergic episode, and the patients should
certainly not take allergy medications at that time.
Unrecognized systemic reactions with improvement make immunotherapy ineffective because the potentially effective allergen(s) may not be
selected for the treatment.
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both pro- and anti-inflammatory effects, theoretically speaking, an aggravation is as possible as an improvement. The scope of either reaction can be
wide, and again, the degree depends on the individuals sensitivity. Knowing
all this, can we be sure that the fatalities described in scientific journals are
due to an allergen and not to the prick with histamine? Of course we cannot.
Today, the role of histamine at skin testing is reduced to comparison with
localized reactions: the wheal and flare formed by each allergen extract are
measured against the wheal and flare produced by the histamine prick. Since
systemic reactions are disregarded, allergists do not measure the systemic
response to allergen extracts against the systemic response to histamine in the
same manner they measure localized manifestations. Grave consequences can
arise from this method of testing in highly sensitive patients. A histamine
prick may overstimulate the H 1 receptors and call to life allergy proinflammatory mediators and cytokines. This will drastically aggravate the
patients condition. If it is asthma, an attack may occur. Those who are prone
to anaphylaxis may now have that reaction.
Histamine is not in the picture in any article warning of possible complication and even fatalities at AST. If doctors knew about the phenomenon of
systemic reactions in general and to histamine in particular, diluted histamine
would be used for the first prick. A mild adverse reaction to a histamine prick
such as a headache or increasing tightness in the chest, would warn the doctor
not to proceed with another prick at an increased dose and thus prevent a more
serious aggravation. Doctors are not taught this, moreover, the use of histamine
as a placebo in double-blind trials of allergen extracts illustrates how little allergists know about this substance. As a result, a standard testing kit contains only
concentrated histamine for a control prick. Unaware of the potential danger of
this full-strength histamine, allergists use it in their every day practice.
Dont be surprised that a small prick can result in a tragedy: a sting by a
bee may kill, and histamine is the main active ingredient in bees venoms, up
to 36%. Treating patients with histamine in my practice I observed that, in
highly sensitive patients, the slightest dose elevation could lead to transient
side effectsflushing, dizziness, a headache or tightness in the chest.
Therefore one cannot exclude the possibility that the fatal reactions described
in medical sources were the result of a prick with undiluted histamine.
If even the well documented pro-inflammatory properties of histamine
are not taken into account at skin testing, it is only natural that systemic
improvement upon a prick with histamine escapes doctors attention. Doctors
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release locally and all over the body. Documented are anaphylactic reactions
occurring within seconds or minutes after pricks in the absence of any skin reactivity. They are the best examples that even the most severe allergic symptoms
may not have anything to do with IgE antibodies. The most powerful example
instantaneous death due to a bee sting in a person never exposed to bees
before and thus not having IgE antibodies to the venom. Histamine gushing
from the mast cells of the bee sting victim is the cause. This proves that it is
senseless to conduct skin testing solely for the purpose of finding IgE antibodies that allegedly point to the trigger(s). It is similarly improper to start
immunotherapy based on such an unreliable diagnostic procedure and hope
it will be successful.
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field whose names are on the lists of the Editorial Boards and Boards of
Directors of all central journals. The majority, openly or in a hidden way, are
connected with the drug manufacturers.
Information about a symptomatic improvement in response to a prick
with histamine would prove its systemic response, hence its curative properties. This could become hard evidence in favor of its beneficial employment in
therapy. Histamine would become a strong competitor of the medications
advertised in these very journals, and therefore information related to its
neuro- and immunomodulatory properties will never pass censorship. The
best proof that histamine must be considered a dangerous competitor for over
two decades is found in the following fact: its successful use in double-blind
trials conducted on asthma and allergy patients in the medically advanced
Japan have not been published in English, the main language of science. I
started to thoroughly study bibliographic sources after I had found that occasionally such information slips through inadvertently. Here are several of such
papers published in the December 1997 issue of JACI:17
1. K. Ito. Clinical evaluation of histaglobin for bronchial asthma
a double-blind study using human gammaglobulin as control.
(in Japanese). Rinshoutokenkyuu 1979;56:3085-69.
2. A. Ito et al. Clinical effect of histaglobin on nasal allergy double-blind
study (in Japanese). Jibiinkokatenbo 1979:22:38-49.
3. J. Kukita. A double-blind study of histaglobin on allergic dermatitis.
(in Japanese) Nishinipponhifuka 1980;42:470-7.
It is peculiar that the references warn you not to try to find the material in
English by writing in brackets In Japanese. By pure luck, I was able to read
the English translation of these articles done by a patient of mine. My
personal experience also shows how undesirable for clinical immunology
effective methods are. In the early 1990s, in Toronto, an international conference on chest diseases took place, and asthma was one of the topics. I
submitted an abstract on my successful use of histamine on about 2,000
patients. The conference organizers rejected the abstract due to logistics
problems: a noncompetitive problem, the answer stated. A new practical,
and successful approach was of no interest to those who were organizing a
conference on that disease. All this at the time when the mouthpiece of allergists, their central journal admits: Despite advances in the understanding and
management of asthma, it remains the only treatable (!?) condition in the
western world with increasing morbidity.13
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ANTI-CHALLENGE TEST
There is a notion in medicine called a challenge test. To confirm the diagnosis,
doctors create a situation in which the patient is exposed to a major trigger, and
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the symptoms are bound to occur. In other words, the purpose of a challenge test
is to provoke an aggravation. For instance, to confirm the diagnosis of asthma, a
patient inhales a substance that causes an asthma attack. If there is a recorded
aggravation, doctors conclude that this asthma challenge test is diagnostically
valuable. However, if a diagnostic test leads to an improvement, it stops being a
challenge test and requires a different name. The fact that doctors are warned
regarding possible adverse reactions and even fatalities means that allergology
sees (at least subconsciously) AST as a variant of a challenge test to the skin.
After having monitored hundreds of cases, the idea came to me that skin
testing should also be viewed as a potential anti-challenge test, a non-existing
notion in medicine. An anti-challenge test should be done with the purpose
opposite to the challenge testto provoke symptomatic relief and use it as a
guide in choosing the therapy. One prerequisite is needed for that: the doctor
must know that skin testing is a procedure not only with a potential systemic
reaction with aggravation, but one with possible improvement as well. Any
physician who conducts the test must know the duality of the immune systems
functioning. Only then, will he expect symptomatic relief as a possibility both
upon a histamine prick and at the next session with allergen extracts. Having
done both, he should compare the degree of the relief that occurs with each test.
Before skin testing, the examiner obviously does not have a clue as to the
possible reaction: will there be an aggravation? an improvement? no symptomatic change? The doctor will be able to find what to use in the subsequent
immunotherapy only if the purpose of testing is to find what will improve
the symptoms, and not what produces the biggest wheal. Already at the
testing stage, the patients should be taught to observe their symptoms. Before
testing, a thorough questioning about the symptoms experienced at the given
moment and their changes afterwards clarifies the common origin of allergic
symptoms and the ones that initially do not seem to be allergy-related.
Among them, there may be an abdominal discomfort, muscular pains,
headaches, irritability, fatigue, etc. Because AST can improve a number of
symptoms and conditions, often nonspecific, it should be considered an antichallenge test worthy of conducting.
During the course of immunotherapy, the observation continues. In fact,
every allergy shot should be looked at as an anti-challenge test, since its purpose
should be improvement. Do patients continue to improve? What symptoms go
away and for how long? If the symptoms reappear, are they as strong as they
were before the last injection or milder? Does the patients requirement for
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drugs continue at the same level, or does he needs less drugs? Patients learn to
inform the doctor about all the changes as well as the mildest side effects, so
that further adverse effects are prevented by dose adjustment. Their feedback
will also allow the doctor to speed up the recovery by accelerated dose increases,
if the recovery is slow. The treatment based on the patients observations makes
the patient responsible for providing the needed details. He becomes an active
participant in the treatment process, and my experience shows patients love it.
Reactions to allergen extracts or histamine are a pendulum that may sway
in both directionspro-disease or anti-disease. Following the abovesuggested separation of histamine and allergens, use of diluted histamine and
monitoring systemic reactions will inevitably lead to a safe test and later, to an
effective immunotherapy. The use of a test which will reverse the symptoms is
a dream come true in any field of medicine, and this dream is easier to realize
in allergy than in other less reversible chronic conditions. Allergy can use skin
testing and subsequent allergy shots as a tool to substantially improve the
patients condition, or often even cure them.
Recently, I found the information that gives legitimacy to my idea of antichallenge testing. The biological mechanism that underlies this test is explained
by hormesis, the phenomenon especially common for the immune system
functioning. Hormesis is the stimulatory effect produced by small concentrations of any offensive substance or any harmful effect on the organism, the
immune system in particular. Mild stimulus cannot cause a significant aggravation; on the contrary, it challenges the protective forces. Even radiation in
small doses can be beneficial for the health, as Japanese sources inform us. In a
similar way, psychological stress, when short-lived and/or not too overwhelming,
is helpful in making us stronger in withstanding stress in general. Introduction
of sub-toxic amounts of offensive substances or influences teaches the cells
to defend us.
Defensive performance of the immune system is its production of protective chemistry. The symptomatic relief at AST is the result of the chemistry
implemented, first of all, by the local units made up of T-suppressors, LCs,
mast cells and then further involvement of other related cells. This proves the
logic of conducting this diagnostic procedure with the expectation of relief,
that is, as an anti-challenge test. Actually, homeopathy is based on the premises of hormesis; ironically, so is immunotherapy employed by allergists
themselves. Mechanisms underlying immunotherapy remain obscure. Thus,
it is difficult to develop a logical strategy for improving the treatment, states
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An allergen protein consists of peptides (a group of amino acids). Nonstimulatory peptides are only fragments of the protein. If the whole protein can
provoke symptoms when used in shots, a peptide, with its allergenic part
removed, cannot. This almost completely eradicates the side effects of allergen
extracts. Conventional allergy recognizes only specific immunotherapy, the one
that eliminates hypersensitivity to the injected allergen. Injections of peptides
are this, a nonspecific immunotherapy, since their specific, allergenic part is not
there. Nonspecific peptides may invoke an immunomodulatory effect
depending on what receptors they activate.
For example, it is possible to develop peptides that will be able to stimulate only our protective H2/3 receptors and thus contribute to allergy-protective
cytokine production. A peptide vaccine was shown to inhibit histamine
release(it) reduced IgE antibody formation and serum histamine concentration, and abolished systemic anaphylactic reactions in response to allergen
challenge. This peptide may form the basis of a vaccine in a new approach to
the immunotherapy of atopic (allergic) disease. This comes from the most
prestigious British medical journal The Lancet.15 Note the year of the publication1990.
A Canadian source written five years later agrees that a peptide based on
house dust mite extract has the potential for controlling and eliminating the
patients specific allergy while providing a glimpse of the future.16 In fact,
house dust mite extract, even if not reduced to its safe part, may play the role
of a non-stimulatory peptide when it is administered to a patient who is NOT
specifically allergic to it. When skin-testing with dust mite, I always watched
for improvement. If there was one, I employed the dust mite extract for
therapy, no matter what size of wheal it formed.
The use of a nonspecific, so to say, irrelevant, substance for treatment is
not new in medicine. It is done to stimulate defensive forces. Thus,
substance P is the number one pro-inflammatory neuropeptide among
sensory nerve mediators (like histamine among allergy mediators). However,
substance P also possesses modulatory features (also like histamine), and its
positive effect manifests in the pharmacological agent Capsaicin. This plantderived product provides relief when used in an ointment for arthritis
(zostrix) and intranasally in chronic rhinitis (another proof of common roots
of immune and some neurological symptoms). Although neither pharmaceutical compendia, nor researchers clearly explain the mode of action, the
stimulatory effect of this seemingly irrelevant chemical is, actually, rather
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Something of this sort happened to me. My understanding of reactions characterized by systemic improvement go back to my work in the Soviet Union.
When I was in residency in internal medicine, allergic diseases were not
taught. Allergy as a branch of science was only emerging in the world. IgE
antibodies were discovered in 1966, and they were soon proclaimed to be
the foundation for this new field which gained its general recognition as
allergy medicine because of this discovery. I was among the first doctors in
the former Soviet Union to specialize in allergy at the Moscow Allergy
Institute that had opened in the early seventies. The knowledge I gained
during my specialization adhered to the traditional scheme: allergic diseases
and asthma are always allergen-triggered and therefore IgE-mediated; skin
testing should focus on the signs produced on the skin which reveal the
specific offenders; these offenders should be eliminated and/or used in
extracts for desensitization.
After specialization, I continued my work in the central teaching hospital
in Petrozavodsk, the capital of Russias Northwest republic of Karelia. This
hospital was the basis for teaching medical students and also the consulting
centre for local hospitals. Complicated cases were referred here from all over
the republic for diagnosis and initiation of the treatment, which was then to
be continued by the referring doctors where the patients lived. Allergies and
asthma were common but often remained undiagnosed and were treated as
recurrent pneumonia and/or infectious bronchitis with antibiotics (as they
are still now, by the way). An important difference between medicine in the
Soviet Union and the West was the fact that drug pushing did not exist where
I worked because of the absence of a market economy, the lack of influence
by drug companies, and the resulting unavailability of many drugs. This
explains why medicine in the Soviet Union, although technologically inferior
to the West, placed a much higher value on the needs of the patient and
doctors were trained to be far more attentive in their clinical approach.
Doctors there were reluctant to prescribe steroids as frequently as their
Western colleagues did, even when they became available. Experience had
taught us that the immune system, not suppressed by steroids, is more
resilient, and properly selected immunotherapy is more efficient in this
setting than in cases of a steroid-scorched immune systems. This simple fact
accounted for my success with immunotherapy which, from the very start, I
perceived as the most logical treatment.
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Medical service was free for everybody in the Soviet Union. The hospital
where I worked provided free accommodation to the referred patients for a
week or two. Within that short period, I had to be ready with the diagnosis
and was expected to start the treatment. I did not have the luxury of
rejecting severe asthmatics as candidates for immunotherapy, since the very
fact of their being referred to his hospital meant that they had exhausted all
other means at their local hospitals. Nor could I wait until they were in
remission to skin-test them, even though, according to the accepted standards, symptomatic asthma patients were not suitable for testing. I was the
last hope for those asthmatics. Under those conditions, necessity became
the mother of invention.
A thorough medical history was the first step in the decision whether to do
skin testing. I was taught that in severe asthmatics, pricks with allergens could
aggravate the condition. To prevent any adverse reaction to histamine, uniformly
described in allergy medical literature as Evil Number One, I separated histamine
pricks from the pricks with allergens and started to use diluted histamine. This
enabled me to determine, in the case of aggravation, which of the two was the
real cause of the reaction. In order to monitor the patients condition, I asked
them about their symptoms right before giving the first pricks. My actions were
dictated by professional prudence. Knowing the dangerous side of histamine, I
repeated my questions regarding the symptoms after the pricks. To my surprise,
time after time, I heard about systemic improvement, a fact I had not been taught
and hence, had not expected. Testing with allergens the next day showed that
they too could render an improvement. I learned that both histamine and allergens could sway the pendulum for the better, and this was not accidental. I
started to compare when relief was more pronounced: with histamine or with
allergens. The logic guiding me was that if a prick improved the symptoms, injections with the same substance could improve the condition still further.
Naturally, this would apply the other way aroundthe substance that produced
side effects during the tests should not be used for therapy, as it might worsen the
symptoms. I worked intuitively, and my intuition was base on my initial observations and eleven-year clinical experience.
In Russia, like in many European countries, along with allergen extracts,
histaglobin (histaglobulin) was available as a conventional means of treating
allergies, while histamine was used in testing only. The combination drug
histamine plus gammaglobulinowed its effectiveness to histamine, since the
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specific approach. First, I precluded the occurrence of aggravation by separating the pricks with allegedly dangerous histamine from the allergen
extracts and also by using diluted histamine. Secondly, trying to avoid aggravation, I introduced detailed questioning and observation before and after
the pricks. I did not conduct uniform skin pricking, but tailored it to each
individual. Similarly, my immunotherapy was customized and not a one-sizefits-all approach. To my mind, this is a more scientifically rigorous approach.
My thorough questioning and observations had one more benefit.
Although I was treating allergies and asthma, I noticed that certain symptoms
disappeared along with the targeted ones. Sometimes, it happened right after
the skin testing. A question, What other symptoms are you having now?
asked before the testing and, Are you still having (headache, stomach discomfort, fatigue, etc.) now? asked after the testing would often reveal that many
non-allergic symptoms were, in fact, allergy-associated. Twice a year, when
the patients would come for a follow-up consultation, they told me about the
disappearance or improvement of unrelated medical problems in the course
of their immunotherapy. Well matched therapy, be it histamine or an allergen
extract, worked broadly and systemically.
I published my observations regarding systemic reactions and how to
handle the transition to immunotherapy in the most prestigious Russian
medical journals, Therapeutic Archive and Clinical Medicine. My observations
and conclusions about systemic reactions with improvement at allergy skin
testing were the first, and as far as I know, the last of this kind in the worlds
medical literature. In 1978, I spoke about my asthma treatment based on the
evaluation of systemic reactions at the fourth International Symposium on
Circumpolar Medicine in Novosibirsk, the scientific centre in Siberia. There, I
reported that certain neurological symptoms, hypothalamic (or, as it was
called in Russia, diencephalic) syndrome disappeared in a patient who was
successfully treated for asthma.
For several years, apart from a pediatrician who specialized in allergy, I
was the only allergist in the republic and thus did not have any one else to
consult with. Great personal responsibility for each case dictated that I should
be on the lookout for even the slightest symptomatic changes. By nature, I
attend painstakingly to details, and I am always inclined to analyze, assimilate
and co-ordinate the numerous details I observe. All the while, I tried to relate
my observations to what textbooks taught and found there were gaps in
theory, which affected clinical application.
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PART SEVEN
BRONCHIAL ASTHMA
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standing of asthma, can we help the patients. The price asthma patients pay
is too high, and society must do its utmost to save them.
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Bronchial Asthma
Dr. M. Sears, a leading Canadian asthma specialist, states that an allencompassing definition remains difficult to construct. He assumes that
genetic studies may help but looks for the causes outside the body, and
again, we hear about house-dust mites, indoor pollutants, passive smoking,
childhood infections and their treatments. It is not surprising that the superficial, triggering events replace the inner predisposing factors, and his speculations over the definition of asthma relate it to the time of the first wheeze,
sensitisation with cigarette smoke, risk of mothers smoking, etc.9 The
leaders in allergy have recently started to present asthma as a disease characterized by degenerative structural changes in the bronchial tree and the lungs.
The term invented for this is remodelling. In this interpretation, asthma is
no longer the most reversible disease driven by the abnormal regulatory
processes in the immune system, but an affliction characterized by tissue
degeneration and scarring. Organic changes in the bronchi and lungs cannot
occur without underlying pathological processes, but allergists do not
provide clarification as to what these processes are. This new concept of
remodelling is dangerous in several aspects.
First, it dissociates the structural changes from the cause, without which
they cannot occur, and which by definition cannot be reversed/ corrected.
Second, it changes the perception of asthma as an immune disease and
turns it into a disease of tissue degeneration.
Third, it changes the general perception of asthma as being a reversible
condition, into an irreversible one whereas organic tissue changes are
observed in very advanced stages of the illness.
If this concept is accepted, we will see the statistics in asthma getting
grimmer day by day, because the treatment, should be applied to the core of
the disease, not just the organ in which it develops. Otherwise, doctors will just
manage the illness and wait and see if structural damage will occur.
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ASTHMA SYMPTOMS
Asthma is not an age-related disease, although most cases develop in early
childhood. It hits men and women alike. It is marked by recurrent bouts of
shortness of breath, wheezing, and cough. In the majority of cases, the disease
is characterized by spontaneous attacks, and the length of symptom-free
periods differs from patient to patient. The severity of the disease may fluctuate over the course of time. Some patients remain symptom-free for years.
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This makes them believe they are disease-free, which is not the case for most
asthmatics. Very few children outgrow asthma, but even in the lucky ones who
experience a lasting remission, asthma may reoccur when it is least expected.
An asthmatic attack is characterized by a spastic narrowing of air passages
and/or swelling of the mucous membranes that may start to secrete phlegm.
The constriction of the bronchi and/or their obstruction with phlegm result
in shortness of breath. The spasm and/or phlegm moving with respiration in
the narrow canal produces an effect of a whistlea wheezing sound. Cough
occurs due to the need to overcome the spasm and/or evacuate the excessive
accumulation of phlegm. Classic cases present all of these symptoms, while
others are limited to one or another only. This leads to diagnostic mistakes:
too often a resistant dry cough is diagnosed as a cold, while a cough with
expectoration (coughed up phlegm) is taken for infectious bronchitis. A
wrong diagnosis leads to the wrong therapy.
The lungs function is to enrich the incoming blood with oxygen. Oxygen
enters the lungs during inspiration. There, it gets into the blood vessels, and
the oxygenated blood delivers it to other organs. When the bronchi are
constricted in attacks, the lungs become hyper-inflated because the obstruction prevents the air from being exhaled. The trapped air cannot get out, and
at the same time, the patient gasps for more and more airall this worsens
ventilation and blood oxygenation. The functioning of the organs becomes
impaired if not enough oxygen reaches them. The lack of oxygen supply to the
tissues is called hypoxia. Hypoxia alone may lead to death in the worst cases.
This clearly indicates that although asthma is a disease developing in the
airways, it is a systemic disease and may affect the whole body when it strikes.
In severe cases, attacks may follow one another with practically no break.
This condition is called status asthmaticus. It requires urgent measures, at
times, resuscitation. Over the years, protracted asthmatic attacks, with
constant lung over-inflation, may result in degeneration of the lung tissue
leading to an incurable disease called emphysema. In emphysema, lung tissue
loses its elasticity, and live tissues are replaced by non-functional ones, and
eventually, the lungs functional ability gets irreversibly reduced.
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encounter with the same agent, the memory of the T- and B-cells, previously
excluded from the fighting process, is blank, and we need another prescription for antibiotics. Therefore, their use must be limited to cases of confirmed
bacterial infection.
If the causative agent is a virus, antibiotics are irrelevant since they are
unable to fight viruses. A virus, like any live organism, has a limited life span.
Therefore a viral infection is a self-limited condition that, as a rule, resolves
spontaneously with as little effort as bed rest and drinking a lot of fluids.
Asthma patients are often convinced by the appearance of the phlegm that
they have infectious bronchitis. This is an unreliable sign because the colour
and thickness of the phlegm depend on the ease of its removal from the
airways. An airway obstruction may delay mucus evacuation, and its colour
may change to green or dark yellow and resemble pus; it may even acquire a
stale smell. To confirm pneumonia, a chest x-ray should be taken. Helpful for
diagnosing pneumonia are the accompanying fever and distress, which usually
increase in severity very rapidly.
Antibiotic users should abide by the rule of completing the therapy course
as prescribed. However, these drugs are toxicity, and various symptoms such as
weakness, dizziness, various abdominal distress, etc. may develop during a
treatment course. This forces patients to discontinue the medication as soon
as the symptoms disappear. If not all bacteria are killed, they become resistant
to the drug, and the next time, a new, stronger antibiotic may be needed to
combat the same infection. Frequent and unnecessary courses of antibiotics
may lead to unpleasant and even dangerous toxic and immune reactions.
Some of these drugs are allergenic and may, thus, intensify allergy and asthma
symptoms. Most important is that when they are prescribed to an asthmatic,
antibiotics do not deal with the cause, and the patients asthma may continue
to progress while the patient consumes irrelevant medications.
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absolutely different nature of their action and hence, different pharmacological meaning and classification. Still, with the overwhelming number of asthmatics who visit doctors offices, it is inexcusable for a physician to
misdiagnose the disease even if it is not the classical form as described by textbooks. No less a reason for the ease with which antibiotics are prescribed is
that the social status of doctors is such that he or she gets away with it. A
doctor is a figure put on a pedestal by our society and maintained there due
to the efforts of the medical profession itself. In this position of grandeur it is
easy to forgo additional learning about ones field of expertise, and this leads
to ignorance. Only in purely medical publications, can one read such admissions as: It is paradoxical that the past decades have provided the introduction of new and more potent anti-asthma medications, especially inhaled
corticosteroids, but the success of controlling morbidity from asthma has
been rather limited.15 The patients are never informed about the weaknesses
of the profession, and are often prescribed antibiotics for an alleged infection, often along with a bronchodilator to breathe easier, and not infrequently, along with a steroid puffer as well. Asthmatics are assured that they
are prone to bacterial bronchitis and remain unaware that a prescription for
an inhaled bronchodilator is an unspoken confirmation of asthma.
Dr. S. Wolfe, the author of Worst Pills Best Pills writes in the chapter on
antibiotics: After congressional hearings and numerous academic studies..., it
has become the general consensus that 40 to 60% of all antibiotics in this
country are misprescribed. We know very well the tendency to downplay unresolved medical problems, therefore, the actual figures are assuredly higher.
Canadians should be especially wary, for according to statistics in this
country, we have one of the worlds highest figures of asthma incidence. This
may explain the fact that physicians here prescribe antibiotics twice as often
as in US and five times the rate of European countries. It is due to the indiscriminate prescription of antibiotics that we face problems with antibioticresistant tuberculosis, flesh-eating infection resistant to all antibiotics, as well
as the more common condition of resistant strep throat which can lead to
permanent heart damage. The problem of antibiotic abuse has become so
overwhelming that it has become known through the mainstream media.
Regrettably, journalists write about the over-prescription of antibiotics in
case of plain colds and totally miss the fact that these drugs are grossly abused
in asthma.
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under the age of 6, and only recently, the trend has changed towards
prescribing them to children of 34 years old and even younger. Thus, children may cough for months, take courses of antibiotics without any effect or
with only temporary relief and still be diagnosed as having colds or bronchitis
instead of asthma. Finally, they reach the steroid-permissive age, asthma is
diagnosed, and a prescription for a steroid inhaler is made. Not being able to
relieve asthma symptoms effectively without steroids, doctors, actually, delay
the diagnosis until they can prescribe them.
The percentages of undiagnosed asthmatics vary in different sources, and
some report up to 2540% undiagnosed cases. This significantly raises the
official asthma figures. How the situation is downplayed can also be seen
through a strange but fashionable trend to split asthma into several different
conditions. Here are examples. Co-existence of a postnasal drip (back drip)
and asthmatic cough is common, since their origin lies with the same
immunologic imbalance. Recently, several sources presented postnasal drip as
one of most common causes of chronic cough. No textbook has diseases called
postnasal drip or chronic cough because they do not exist. This misinterpretation elevates postnasal drip to the level of a new and separate medical condition that allegedly provokes a chronic cough. Moreover, the very term chronic
cough is diagnostically incorrect, since it is a symptom and not a disease.
Although of no help to the patient, this helps the asthma figures look better.
Another semantic innovation may also serve as an example of the continuous trend of belittling the asthma drama. Thus, a Canadian doctor, recognized in 1999 as Number One allergist, proudly announced her invention of
a new term and therefore new medical diseaserhinobronchitis. Her explanation, however, did not differ from the postnasal drip/chronic cough
phenomenon. In both cases, the first part, chronic rhinitis, is presented as the
cause of the second, chronic bronchitis. Time will show whether the new term
and the underlying meaning will be accepted, but I doubt it will be easier to
cope with allergic rhinobronchitis than with asthma.
Among other euphemisms for asthma I found in the works of specialists
are wheeze and rattle given not as symptoms but as medical conditions,
and these, allegedly, go away with time. There is also a disease called hyperresponsive airways strangely treated as asthma. Not uncommon is the diagnosis of alveolitis, although it is a totally different immunological
degenerative disease of the lungs, mostly found in an occupational setting
and caused by repeated inspiration of organic particles (such as pigeon
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Bronchial Asthma
breeders lung). One thing is definite though: the innovative terminology that
creates new diseases improves the asthma statistics.
Some allergists and respirologists try to explain the statistical rise in
asthma as being over-diagnosed. There is now a trend towards over-diagnosis, say two authors, one of whom is director of the Toronto Asthma
Centre and president of Canadian Network for Asthma Care, Dr. K.
Chapman.17 In these authors opinion, another disease must always be
considered when treatment fails. If it is not asthma, what could it be? asks
the article rhetorically and answers: emphysema, left ventricular failure,
angina, cystic fibrosis, localized obstruction, vocal cord dysfunction, etc.
How plausible is it? First, the common frequency of asthma compared to
the rarity of the other named diseases increases the probability of asthma
being the correct diagnosis. Secondly, emphysema is a disease that results
from lasting and severe asthma or long-time smoking. This excludes emphysema as the diagnosis in young children, the fastest growing group of asthmatics. Similarly, angina should also be very low on the list of possibilities in
those who are under 40. Ironically, the authors do give an involuntary explanation as to what lies in the origin of these symptoms at the beginning of
their article: Despite an improved understanding of asthma and the many
new treatments available for its control, a surprising number of patients
appear refractory or unresponsive to the best management. Evidently, impotence in the management of the most prevalent chronic disease of our time
prompts the medical profession to conveniently break it down into several
allegedly different conditions, and by that remove the responsibility of recognizing the ineffectiveness of treatments.
The internationally known authors of the book Asthma Epidemiology
write on page 9: Virtually all reviewers have concluded that the increases (in
asthma mortality) are real and are not solely due to changes in the diagnosis
or classification of asthma.18
The non-wheezing form of asthma, or the one without shortness of breath,
may present some diagnostic difficulty. Still, with the officially recognized 10%
among adults and 1520% among children, every general practitioner has a
fair number of patients with similar symptoms and must therefore detect the
disease even in its non-classical form. A patient of mine treated for asthma
immediately understood that her six month old son was also asthmatic when
doctors in ER diagnosed croup and gave him a ventolin mask. Croup is an
acute obstruction of the larynx due to infection (the child did not run a high
251
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fever), new growth or a foreign body. The boys mother understood that it was
asthma simply because he was prescribed a bronchodilatoras usual, to
breathe better. One may only ponder why a medically illiterate woman could
use her previous personal experience and diagnose the illness better than those
who had studied the subject for years, and whose practice included a high
percentage of asthmatics. Most probably the explanation is simple: if you diagnose a disease, you have to treat it effectively. As physicians fail with asthma,
they, consciously or subconsciously, avoid the diagnosis. In other words, when
they hear trotting, they think of zebras instead of horses.
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processes, and the learning patterns, that is, how the system adapts and
changes in order to restore its ability to self-regulate. The orientation of
connectionism is that causality forms the basis for scientific understanding.
Although this general science does not provide the answer to what causes
asthma, it correctly points that: asthma is a fault in the activation pattern of
the bodys self-regulatory network, and this fault is causally prior to the known
inflammatory mediators. Asthma is a breakdown in the efficiency of that
part of the network controlling inflammatory self-regulation in the lung that
gives rise to the inflammatory mediators, while triggers are exacerbating or
risk factors only. Correct understanding of the causative mechanisms, enables
connectionist theory of asthma to name the regulation of the internal environment as the treatment target, and it predicts that if asthma is, in essence,
a form of faulty learning within a network, then asthma can, in principle, be
cured.23 If a general science looks at asthma as the disease with internal
causes, why do those who specialize in asthma look for external causes?
The title of the article written by the worlds leading experts in asthma
epidemiology cited earlierHow much asthma is really attributable to
atopy?is proof that allergy concentrates on the wrong aspects of the disease.24
This article, as well as a number of others are written primarily by the same
group of researchers from New Zealand, who also wrote Asthma Epidemiology.25
The book summarizes hypotheses of asthma origin. The search concentrates on
triggers and risk factors that remain speculative. Both the book, and the article
that refers to the statistical investigation among 1314 year old asthmatic children from 42 countries,26 reveal that the most striking figures are especially
characteristic for English-speaking countries. Reading that, one inevitably starts
to wonder what evil role the English language plays in the course of asthma.
Does it mean that French-speaking Canada should have lower rates than the rest
of the country? Are asthma statistics lower in New Mexico and California where
a large part of the population speaks Spanish? Why does India, with English as
an official language, have one of the lowest asthma mortality figures of all countries included in the study? What is the mysterious link between the English
language and asthma in such geographically, climatically, culturally and otherwise different countries such as New Zealand and United States? Indeed, one of
the worlds cleanest countries, New Zealand, with its mild climate differs greatly
from the United States, with its wide range of climatic zones and various degrees
of pollution in different areas. How to explain the fact that China, Algeria and
India, countries where there is hardly any law enforcement with respect to envi-
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consumers and even the medical profession. These improvements are desired
by the governments and industries as revenue-generating factors, and they are
highly advertised and supported by government policies.
Among the powerful consumer goods proclaimed to improve our lives,
medications are of immense importance. They inundate the market in all industrialized countries. The high living standard there allows every person to resort
to these drugs even if the discomfort is mild. A painkiller? Here it is. An antibiotic? No problem. You are going through a family problem and having trouble
sleeping? The best remedy is a sleeping pill and/or a tranquillizer. Vaccination is
now available even for the non-life-threatening chickenpox. Our immunity no
longer has to develop naturally. The drugs will do the work instead. Side effects
may show up in the future, moreover, the cause and the effect may be stretched
over time for years or decades and will be hard to trace and prove. The pharmaceutical industrys main role is to please the consumer and temporarily relieve
the symptoms, not to heal, as it falsely claims. To capture a customer, it uses
seductive advertisement. Just listen to the TV ad offering a medication that
allows one to get rid of toe-nail fungus. The sweet voice encouraging you to buy
the medication inspires such a strong desire to have beautiful nails that liver or
kidney damage listed at the end as possible complications sound almost like a
reward. In other words, drugs have become a commodity and, paradoxically, one
of the most potent health-aggravating factors.
The birth country of the drug industry is Germany. However, being defeated
during the war, it lost its priority in this area, and England and the US took over.
It is only natural that the companies opened their branches in developed
English-speaking countries. The largest of them made the US neighbor, Canada,
their stronghold, and also stretched their tentacles to other industrial colonies,
dominions and territories of the Commonwealth. And here comes the feature
common to all countries with the highest asthma figuresEngland, US, New
Zealand, Australia, Canada, Ireland: they are connected to the pharmaceuticals
industry like a child to its mother by the umbilical cord. All these countries are
industrially advanced and their well-off citizens are able either to pay for the
drugs out of their own pocket or through the generous insurance plans. The
populations in those countries abuse drugs from an early age. Medications are
prescribed at the slightest sign of any discomfort, and an asthmatic can resort to
the best remedies the moment he produces his first cough. In contrast, in
India, although English-speaking, the percentage of the poor population is too
large, and the social system of the country is unable to distribute these remedies
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for free. Ironically, Indias poverty saves its people from the overwhelming
morbidity and mortality caused by asthma in developed countries.
Drug production in European countries lagged behind that in the rich
North America, and the opposition to the foreign intrusiondrug
importsdelayed the consumption there. The highly unsafe medications for
asthma were therefore introduced in Europe later and at a slower pace, and
this positively affected the asthma morbidity and mortality rates. The asthma
figures in the former East Germany and West Germany may serve as a
comparative example: in the heavily industry-polluted East Germany, asthma
rates were paradoxically much lower than in its cleaner neighbor but have
inexplicably started to rise lately.
In my opinion, the aggressive medicalization of the population is the
central factor uniting the countries with the highest figures of asthma
morbidity and mortality. My assumptions are supported by a leading professional, Dr. W. Busse, the 2001 president of AAAAI. He blames conventional
medications for the morbidity: It is estimated that about 5% to 10% of
patients with asthma have severe disease that is recalcitrant to typical treatment modalities, including administration of systemic corticosteroids. This
may occur as a result of chronic exposure to beta-agonists or corticosteroids.27 A recent report from the Centers for Disease Control and
Prevention stated that the prevalence of and mortality due to asthma continue
the upward trajectory that was begun more than 15 years ago, says another
article from the same issue of the leading immunological periodical.28
We are witnessing a dramatically growing morbidity of asthma accompanied by the development of chronic conditions. The process is in parallel with
the use of bronchodilators in the past, and now continues in parallel with the
growing abuse of immunosuppressive corticosteroids that started to be aggressively advertised in the mid eighties. This is confirmed by the first-class source,
an article written by researches from the National Institutes of Health,
Bethesda.29 The authors investigated what factors make immune-related
inflammatory diseases resistant, and say that corticosteroids modify the clinical phenotype and worsen the course of these diseases. Under phenotype,
science understands the entire physical, biochemical and physiological
makeup of an individual as determined both genetically and environmentally.
In other words, a person formerly responsive to medications becomes resistant
due to the consumption of the most common asthma medications. Is this not
a direct recognition of the danger of these medications?
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Admissions of this kind are done rarely and mainly in purely theoretical
articles, with no proper conclusions (such as: lets give up on such medications), with no solution (which the authors mostly do not know). The public,
including the medical profession, must not be disturbed. No high profile
specialist has ever raised (or will raise) the question why, despite the fact that
these drugs have been available for the treatment of asthma for almost 50
years and are still the most effective medication for this condition, information about their effects in vivo is limited.30
The lack of data on the complications of these highly prescribed medications for the most prevalent chronic disease cannot be accidental. Moreover,
since no other drug is as effective in asthma as steroids, even such occasional
admissions of their harm disappear in the ocean of steroid-supporting literature. Thus, the editor-in-chief of the Canadian Respiratory Journal started
his editorial by saying that the most common topic in papers so far
submitted to the Journal concerns the high rate of mortality from asthma in
young people. After having consulted with specialists, one of whom was the
world-famous Dr. M. Sears, the editor concludes that poverty and inadequate
use of steroids are the central reasons.31 Strangely, neither the editor nor
his consultant notices the obvious contradiction with the statistical data: the
polluted India and China where steroid medications are unknown to and/or
inaccessible for the majority of asthma patients lag behind the steroidadvanced New Zealand and Australia in asthma mortality.
The 1993 president of AAAI, L. Lichtenstein, was once confident that the
pharmaceutical and biotechnology industries and academia will help resolve
these issues (effective and safe drugs for asthma) to a significant extent within
the next few years.32 We do not see it happening now, a decade later. Judging
by the almost universal switch to steroids and the massive inappropriate use of
antibiotics for asthma during the last two decades, the drug industry only serves
itself, and academia faithfully serves the industry. The industrially advanced
English-speaking countries lead the trend and the rising statistics.
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Nostalgia for the good old times when parasites and real infections, as
counterbalance to IgE antibodies, were accessible to everybody still enjoys
overwhelming recognition among scientists. The Cambridge University
pathology professor, Anne Cooke, suggests developing an extract that would
play a trick on the body: it will chemically imitate a worm and thus cause
positive immune responses. In the Canadian newspaper The Globe & Mail on
May 17, 2001, I read about another believer in such ideas, professor Koichiro
Fujita of Tokyo Medical and Dental University who had implemented this
idea in real life. He had suffered from hay fever and, encouraged by the
worm/no-allergy hypothesis, had consumed three kinds of worm eggs to find
relief. The inference one can draw from all this is that, being unable to
perform immunomodulation, allergists should hand their jobs over to parasites. Surprisingly, the conclusion that exposure to infections, dirt and worms
is allergy-protective, co-exists with the generally accepted and heavily disseminated ideas of the need to eliminate/avoid all potential environmental triggers. The contradictions are overwhelming.
Numerous articles discuss hypotheses forwarded by different researchers
but leave them as speculations. One idea is that large head circumference at
birth is a risk factor for subsequent development of asthma.39 The conclusion here is that this intriguing finding may be associated with mothers
higher nutritional habits that affect programming of the developing
immune or respiratory system, predisposing to the subsequent development
of asthma. So, better and more abundant maternal nutrition is supposedly
the cause of asthma.
Another article assumes that a small family size (is) associated with an
increased risk of development of asthma. According to the researchers, large
families have a chance to avoid asthma because natural infections, some of
which may protect against asthma, are transmitted among the siblings,
whereas an only child is protected from contamination through low contact
with other children. Asthma Epidemiology refers to researches that name
several infections allegedly incompatible with asthma. For instance, positive
tuberculin responses have been found to protect against atopy (allergy) in
Japan, and hepatitis A infections were found to protect against atopy in Italy.
It simply means that those who have tuberculosis and hepatitis A do not
develop asthma. The author refers to another team of scientists who
concluded that measles infections have been found to protect against atopy
in Guinea-Bisseau, and therefore it is also possible that immunization may
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responses, and that mast cells histamine releasability supposedly lies in the
origin of allergic reactions. Although the author knows very well what
compromised immune mechanisms make these cells leaky, he does not say so.
Instead, in the very same article he points to environmental allergens as the
central factor and names supposedly new (?) allergens such as nuts, soya and
latex.43 If latex can rightly be considered as a recent industrial product, nuts
and soya seem to have existed from time immemorial. We can only speculate
why they have suddenly turned into potent allergens, and what made the
immune system react viciously to them.
Here is another example of looking for the causes of asthma outside the
body. With bewilderment, one reads in a leading periodical in the section The
New Millennium: Conquest of Allergy, that lifestyle factors relating to the
socio-economic status of a population or a family, its size, and the number of
siblings of a given individual, early childhood infections with viruses and
bacteria, and a subjects dietary habits account for the high incidence of
allergies, while genetic factors are unlikely to explain the prevalence of allergies.44 Medicine has come to the point when genetic predisposition to
chronic diseases, well established a century ago, is almost completely
discarded. Strangely, it is genetics and not the environment that is highly
recognized in the breeds of our pets. Allergy tries to create picture that will
more easily fit into the frame it has created. This position is dangerous and
has its precedents. In Stalins Russia, genetics was also officially disregarded,
which led to the degradation of science and perishing of its supporters in the
Gulag. Shouldnt we learn from the past?
The article, to which we referred earlier, contains more surprises. One of
them is that out-door pollution of sulphur dioxide, diesel exhaust are not
causally related with allergies. In other words, there is no need to fight for
clean air. The other surprise is that passive smoking has convincingly been
shown to increase the risk for asthma and bronchial hyperresponsiveness
among exposed children. This does not correlate with the findings presented
in Epidemiology of Asthma, written by the same author, that the lowest prevalence of asthma was observed in the community living in mainland China,
despite the highest level of cigarette consumption. Now that tobacco companies are forced by the courts to pay for the casualties they have caused with
their products, they have the unexpected support from allergists and may
suggest that eliminating second hand smoking is unnecessary, so everyone
should be an active smoker. Will this reduce asthma incidence in the first-
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world countries to the officially recognized low level in China? The paradoxes
of allergy in the new millennium!
Along with the growing number of articles on the advantage of early-life
exposure to common inhaled allergens, the popular dogma still reigns that dust
mites, pet dander and cockroaches remain the key factors in asthma. Thus, the
already cited article states that early-life cockroach allergen exposure at 3
months of age predicts activation of pro-inflammatory T-cells (helpers) and
hence, asthma. The word cockroach is even given as a key word to the article.45
In general, the allergen/IgE-based theory became a citation classic, as is
still believed by a world renowned North American allergist and respirologist Dr.
D. Cockroft. In a recent article, the author claims that asthma is caused (not triggered) by allergens: IgE-mediated airway inflammation is, perhaps, the most
important cause of airway hyperresponsiveness in asthma.46 Dr. Cockroft calculated that a classic paper written 23 years before by himself and three other
Canadian specialists had been cited almost 800 times proving by that that this
hypothesis on the origin of allergies and asthma is immortal. All of this despite
the epidemiological evidence that the population-based proportion of asthma
cases that are attributable to atopy (allergy) is usually less than one half, that
there is a component to the asthma syndrome which is not related to atopy.47
I would suggest, however, that if more than half of asthma cases are allergen/IgEunrelated, it is high time to reconsider the classical but unfounded concepts.
An American critic Eric Bentley once said: Ours is the age of substitutes:
instead of language we have jargon; instead of principles, slogans; and instead
of genuine ideas, bright ideas. Allergy is full of bright ideas on the origin of
asthma. Contradictory and confusing, they peacefully co-exist, and nobody has
made a critical review that would select the ones, which are scientifically sound.
This creates real chaos, and in such a situation, the conquest of allergies is
unlikely. The truththe genetically mediated malfunctioning of immune
cellsdrowns in the ocean of inconsistent hypotheses, controversial data and
collateral events. Instead of studying the faulted immune mechanisms and
attempting their correction, immunologists look for numerous triggers of
symptoms. Millions of dollars are wasted on investigations, at times laughable
in their essence, on the role of unsubstantiated factors upon the occurrence of
allergies and asthma. Research that distracts from the core of the problem
receives unrestricted grants from the drug industry, and the results are
published in most prestigious journals. Drug developers nurture pseudoscientific hypotheses because without a concrete therapeutic target, the asthma
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problem will never be solved, and meanwhile, they can continue with their socalled pharmacologic advances aimed always and invariably at the secondary
events.
The bleakness of the asthma reality is confirmed in the very first article
that covers the 2000 annual meeting of American allergists: In many ways,
the epidemiology of asthma is in a situation similar to that of cancer
epidemiology or cardiovascular disease epidemiology before major advances
in understanding of the causes of these diseases in the 1960s.48 This is recognition that the knowledge of asthma lags behind even cancer.
Time has come to differentiate science from pseudoscience. It is normal
that in the course of scientific development, 8090% of all hypotheses turn out
to be erroneous, but errors are not pseudoscience. Pseudoscience in clinical
immunology is born out of purposeful lack of access to the true information
and the resultant overwhelming illiteracy in the field. If the reasons for this
illiteracy are not exposed, we will chase cockroaches and pets in futile attempts
to curb asthma and see its ever-rising trajectory.
Asthma medications provide the best proof that allergy is operating in the
dark. Allergists make it look as if there are numerous asthma medications,
while in fact, there are actually only two groups. One, categorized as relievers
or rescue drugs, cannot be avoided by any asthmatic. The real name of these
drugs are bronchodilatorsthey dilate the constricted windpipe. They are
the oldest anti-asthma medications. One such agent, ephedrine, was
employed as a herbal preparation for asthma as far back as 5000 years ago in
China and is still recommended for use by herbalists, though restricted by
conventional medicine. Strangely, it is incorporated into various unrestricted
decongestants and combo medications such as Claritin Extra. In the past,
different tinctures, plant extracts, and even inhalation of morphine and marijuana were used for that same bronchodilating purpose.
At the end of the nineteenth century, another fast-acting agent, adrenalin,
came into practice. It is a synthetic analogue of a hormone produced by adrenals.
Adrenalin is similar in action to ephedrine but has a much stronger effect. Both
substances are still in use, although with the advent of the drug industry, other
remedies have appeared on the market. At present, different types of bronchodilatorsinhaled, injectable and oralexist. Some provide immediate relief,
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some delayed, the effect of others starts only with sustained consumption. There
are bronchodilators taken in the event of an attack, others are taken on a daily
basis. All of are similar in their purposeto open up the air passages.
Take notice: The mode of action of all bronchodilators is their activation of
the enzyme cAMP and subsequent inhibition of the release of histamine and
histamine induced inflammation promoting chemistry.49 This is proof that
the best activator of cAMP, histamine, is intentionally substituted by less
effective stimulants.
INHALED BRONCHODILATORS
Inhaled bronchodilators, although younger than their oral relatives, are the most
commonly used relievers. They belong in the group of Beta-adrenergic
agonists, that is, activators of Beta-adrenergic receptors that open the bronchi.
Beta-agonists are the most widely prescribed bronchodilator drugs for the
symptomatic treatment of reversible airways disease. They alone generated
revenues estimated at US $194 million in 1988, and represent a class of drug
where the number of prescriptions is growing annually.50 The effect of shortacting bronchodilators starts within few minutes and may last up to 6 hours.
The spontaneity and unpredictability of asthma dictate that these rescue drugs
be carried in a pocket or purse even by patients with a mild form of the disease.
An attackan inhalation of the magic stuff, and the patient can go on in the
majority of cases. In the past, the fast symptomatic relief created the impression
of the drugs safety. For decades, inhalers were recommended for use not only
during attacks but also as a preventive measureto keep the bronchi free at all
times. Certain adversities of bronchodilators were accepted as inevitable:
dryness in the mouth and throat, trouble sleeping, restlessness, hyperness
(especially in children), rapid heart beats, shakiness, dizziness, headaches and
elevated blood pressure. However, weighing the cons against the pros was in
favor of the inhalers. They gave the ability to breathe and literally saved lives.
Not a common but possible consequence of their use is a paradoxical
bronchoconstrictionwhen instead of opening the bronchial tube, the
bronchi constrict. This was described in occasional cases but did not get any
publicity, although pharmaceutical compendia do warn about this possible
side effect. Like many other drugs, bronchodilators have a rebound effect:
with long-term use, they start to worsen the condition instead of improving
it. This rebound effect as a consequence of their frequent use became known
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receptors may completely atrophy, that is, lose their natural ability to dilate
the bronchi. One day, they may not respond to the inhaler, or respond paradoxically by constricting. This is fatal for the patient. It is worth mentioning
that all this knowledge had occasionally appeared in periodical literature
within the two decades before the catastrophe became official, but the specialists had been too busy with prescribing bronchodilators to read and seriously
consider the material. Those who set guidelines usually have close ties with
the drug industry and have personal reasons to keep silent.52
A further well known side effect of the sustained use of bronchodilators is that
they affect the cardiovascular system, and this may account for cardiac arrest.
Another potential grave complication is that the patients body may start
to produce antibodies to the receptors, and the immune system rejects them.
Finally, one complication is the finding that bronchodilators shift the
underlying chemistry in favor of allergy promoting inflammation. This
explains the paradoxical increase in asthma morbidity and mortality associated with the chronic use of Beta-adrenergic agonists.53 Thus, not only do
inhalers make the body defenseless locally by paralyzing the work of the vital
receptors, but they also promote the underlying immune inflammatory
process and by that, accelerate the progress of asthma on the whole. This,
however, increases their consumption, and thereby their profitability.
Up until now, most professionals, not to mention the public, remained
unaware of all of this information. However, the declared facts were a blow to
the inhaler manufacturers. They needed to save face (and revenues) and started
to defend their products. Thus, in 1992, Glaxo Canada (i.e.GlaxoSmithKline),
the worlds largest producer of the most frequently prescribed bronchodilator,
ventolin (salbutamol sulphate), distributed a flyer thanking doctors for
prescribing it. The flyer claimed that the drug had over 18 years of safety and
efficacy behind it. It stated that by prescribing ventolin, doctors helped the
company to sponsor special programs, in particular, respiratory fellowships, a
career counseling program for medical students, support for symposia and the
distribution of reference materials. The flyer said, So the next time you write a
Ventolin-no-substitution prescription, do it with confidence and pride! Both
your patients and your profession will benefit. To tell the truth, I dont think
that Glaxo needed to worry. Considering the current state of asthma management, no patient can escape.
At the time of the numerous epidemiological studies in the eighties,
asthma rates in the North America, though on the rise, did not reach the
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same high level as in other English-speaking countries for two main reasons.
First, Australia and New Zealand, for better efficiency, used stronger
concentrations of the aerosols than North America. Second, North America
was ahead in the aggressive introduction of steroids, the use of which
temporarily reduced the need for bronchodilators. The shocking statistics
on the link between bronchodilators and mortality necessitated changes,
i.e. cut the drug use. The conclusion was that doctors over-treated
patients with these symptomatic medications and disregarded the underlying inflammation. This gave the green light to anti-inflammatory steroids
whose casualties we have already started to count.
Ironically, despite the universal caution concerning frequent use of
inhaled bronchodilators, they have remained the most commonly (ab)used
medications. In fact, we witness the rising resistance of asthma to all conventional medications, including steroids, and the need for air necessitates that
asthmatics use bronchodilators more and more regardless of their risk.
LONG-ACTING BRONCHODILATORS
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CONCLUSION ON BRONCHODILATORS
Textbooks do not disclose the scientifically recognized mechanism of
bronchial obstruction in asthma, which is the enzyme cAMP-dependent
histamine-induced pro-inflammatory chemistry. This fact, however, has been
known since 1968, when it was first described by L. Lichtenstein.74 Neither do
pharmaceutical compendia disclose the cAMP-related mode of action of
bronchodilators. Silent about this is the entry for ventolin, the most common
short-acting bronchodilator. Still, the year 2000 entry on its cousin serevent,
a long-acting inhaler, spills the beans: the medication offers more effective
protection against histamine-induced bronchoconstriction. The side effects
of this are well known: While such pharmacological effects are welcomed by
patients, the practice of continually inhibiting mast-cell degranulation may
not be as beneficial as originally believed. The text of this already-quoted
article explains what makes the use of bronchodilators undesirable: Betaagonists can upregulate IgE production and induce a reduction in suppressor/
cytotoxic T-cells.58
You will recall that IgE antibodies are a pro-disease element, and that a low
number of T-suppressors allows allergies to progress. As for cytotoxic cells,
they help destroy viruses, bacteria and cancer cells. Now make your own judgment as to what is good for you. The effect of these drugs is known as being
wide spectrum. By suppressing mast cells, they not only suppress their production of pro-inflammatory mediators and cytokines, but also of the ones that
may be broadly considered anti-allergic or anti-inflammatory. The suppression could result in chronic tissue damage and increased scar tissue formation. Such changes are certainly consistent with the observed deleterious
effects of regular treatment of asthmatics with beta-agonists, the article
informs us. And so the wisdom of allowing this to occur on a chronic basis
is questionable; the author thinks it is time to begin to clearly identify the
underlying mechanisms. These mechanisms are known, but now, 10 years
later, they still out of reach.
If beta-agonists are deleterious, what about other drugs of this group?
Since information on histamine is usually hidden, only an educated reader
will understand that theophylline also aims at its inhibition. The 2002
Canadian Compendium of Pharmaceuticals writes on page 1683 that The
actions of theophylline may be mediated through a resultant increase in
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intracellular cAMP. Although the compendium states that the exact mechanisms(s) has not been determined, this is not true. As we know, the mechanism of increasing cAMP by different agents (theophylline included) was
studied by L. Lichtenstein who said that histamine, like no other agent is
effective in increasing cAMP, which, in turn, results in the inhibition of the
cellular histamine release. Oh, this omnipresent histamine!
For now, bronchodilators are a compulsory medication for all asthmatics.
Their high use under the circumstances of growing asthma morbidity
remains a cause of concern. Two authors, a medical doctor from the
Washington Institute for Asthma and Allergy and a mother of an asthmatic
child, who made the fight for better asthma treatment her lifes mission,
grieve that the published literature is lacking in data on the frequency and
severity of medication side effects in the general asthma population.59 They
say that up to 79% of the surveyed 1834 asthmatics had unwanted sideeffects from their bronchodilators. When those patients complained to their
doctors, the advice was either to change the brand (which helped little if at
all) or put up with the complications. The authors conclude that there is a
need for new, rapid-acting bronchodilators with fewer side effects.
Given the current situation of complete secrecy surrounding histamine,
asthmatics do not stand a chance of getting such medications. The knowledge
that could lead to the reduction in the use of bronchodilators will not get
through the barriers established by the drug producers who are readily
supported by the medical Establishment.
Solid proof of this claim is that Dr. M. White, one of the two authors of the
article, had previously written the chapter Histamine in the extensive book
Inflammation in co-authorship with M. Kaliner, Head of Allergic Diseases
Section in the National Institutes of Health in Bethesda. Dr. M. White is also
the author of the article The Role of Histamine in Allergic Diseases.60 Her works
as well as her (earlier quoted) presentation at the symposium Histamine and
Disease in 1989 on the cardinal role of the H2/3-receptor reveal that she is
knowledgeable in the underlying mechanisms of allergy. There must be reason
that prevents Dr. White from informing her co-author, Mrs. N. Sander, of that
substance that has self-inhibiting and self-remedial propertieshistamine.
This substance, if used in therapy, would probably help Mrs. Sanders daughter
to avoid the dangerous bronchodilators.
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Modern medicine dictates that relievers be taken only with the protective background created by another group of medications, taken daily and allegedly
targeting the underlying allergic inflammation. These drugs are called
controllers and represent the second largest group of common asthma medications. The group is subdivided into corticosteroids and non-steroidal remedies.
Among the non-steroidal anti-inflammatory, there are Intal and Tilade
used as inhalers. Intal has been in regular use for decades, and mostly in children. Tilade is much younger. Both are intended for regular daily usage and
should not be used as an alternative to bronchodilators, state pharmaceutical
compendia. This simply means that they are adjunct drugs, and bronchodilators are their imperative companions. Consequently, not only bronchodilators are needed but, too often, steroid therapy is used as well.
The pharmacological action of Tilade is inhibition of the release of mediators from mast cells, both pre-formed and generated, during an allergic reaction, as pharmaceutical compendia inform us. Since there is only one pre-formed
mediator in mast cells, histamine, and the rest are induced by its initial spill,
we can arrive at the only one logical conclusion: the anti-inflammatory
action ascribed to Intal and Tilade is accomplished essentially through their
inhibition of histamine release.
ZADITEN
Zaditen is a product of the early nineties. Its primary consumers are children,
therefore the medication is sold mainly as a syrup. Our success is childs
play, assures a picture advertising Zaditen. Let us see if it is so.
The prescribing information classifies the medication as a paediatric
asthma prophylactic and anti-allergic agent, as an add-on-medication in the
chronic treatment of mild asthmatic children. Furthermore, several weeks
of Zaditen therapy may be necessary before the therapeutic effect becomes
clinically evident. Zaditen is recommended for children over three years of
age, twice daily for six to twelve weeks, the objective being to achieve the
greatest effect and to reduce the use of other concurrent medications, steroids
in particular. The adverse effects are mentioned as being of a relatively low
incidence. Among them are sedation, weight gain, rash, respiratory infections, headache, sleep disturbance, abdominal pain, rashes, ear infections,
nose bleeds, puffy eyes. The text warns about amplification of the sedative
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through the same mechanism via H2-receptor stimulation and that it acts in a
sustained and profound manner. It is obvious that attempts to achieve the desired
effect by using less efficient tools cannot be accidental.
A popular ad in medical periodicals shows a pretty young asthmatic woman
who is able to extinguish candles on her birthday cake with such force that the
cake itself flies away. This colourful ad assures that Advair, the first of such
combo drugs, is more beneficial than bronchodilators and inhaled steroids
taken separately. Besides, as the text on the ad indicates, the patients taking this
combo drug must use short-acting bronchodilators for acute symptoms. The
asthma candle is being burnt from both ends by the hazardous agents.
Would you trust a technician who came to your house to repair your TV
with a hammer and saw? Do you think our body is any less complex than a
TV set? An immunosuppressive drug has become the main instrument in
repairing the sophisticated ailing machineryour immune system!
The book has been with the publisher, in October 2003, when the news came
that the Canadian provice of Quebec was removing the combo medications,
Advair by Glaxo and Symbicort by Astra-Zeneca from the drug plan formulary
to prevent physicans from using them as first-line therapy. Other provinces will
follow. This is the beginning of the end: the best asthma medication turned out
to be so hazardous that caution is advised when they are prescribed. Now, the
internationally accepted guidelines that had supported their priority among
other drugs have to be reconsidered. Had the situation with asthma not been so
grim, the conclusions of the medical elite could have been considered laughable:
as a replacement of the combination of steroids and bronchodilators, these
drugs ae suggested separately, steroids as the first and bronchodilators as the
second line of therapy! Another embarrassment of choices!
OLD GUIDELINES
Two periods can easily be traced in the management of asthma. They become
obvious through the history of steroids. When steroids were first introduced
in pills and injections, their powerful effect and the feeling of being able to
move mountains, was so great that doctors started to prescribe them not only
for rheumatoid arthritis and more rarely, in asthma, but also as a life style
drug. The fact that steroids were a synthetically produced body chemical
created the illusion of their safety. The realization of danger came soon when
withdrawal symptoms and numerous side effects were noted, and this forced
the medical profession to became cautious prescribing in the drug.
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We must remember, however, a simple axiom: the worse our health, the
higher the industrys profits. The natural chain of events fits this axiom: a
chronic medical conditionchronic use of a medicationthe bodys adjustment to the drug and the need for a higher dosemore and more pronounced side effectsdrugs to relieve the side effects, etc. In asthma, even if
a patient starts with inhaled steroids, the finale is dependence on them due to
the failing or atrophied adrenals and decreasing ability of the stifled
T-suppressors to defend the host. Even if the side effects of steroids do not
appear at once and are minor for some time, the patient inevitably ends up
with a cascade of them hitting different organs and eventually undermining
the whole body. You say you take steroids in innocent small doses? For how
many months? Years? Decades? Doesnt it remind you of smoking safe cigarettes with filters?
DOUBLETHINKING
The universal acceptance of steroids was unable to exclude a hesitation: to
give or not to give these drugs? What to use as a substitute if they produced
significant side effects? Are there treatments with proven efficacy, as Dr. S.
Holgate called them? At their meetings in the early nineties, allergists argued
with each other, and at times, even with their own views. The inconsistency
in the opinions of professionals on asthma is well demonstrated in the 1996
report Canadian Asthma Consensus.75 Here are some examples:
Theophylline remains an effective anti-asthma drug. (p. 95)
Theophyllines should not be used as first-line therapy in asthma (p. 96)
(Why not, if the drug is effective?)
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Eighty percent of the systemic effect of these agents is via this route.78 Potential
liability for not disclosing a drugs adverse effects forces drug companies to
reveal them. At the same time, their desire to downplay side effects results in
the kind of paradoxical entries as the one on Vanceril (Beclomethasone), a
product of Schering. One sentence states that the drug has a strong local effect
and minimal systemic effect. The next sentence reveals that only 1025% of
a dose reaches the respiratory tract; the remainder is swallowed and absorbed
from the gastrointestinal tract, and orally absorbed drug is metabolized by
the liver. The drug producer does not explain how the drug, 7590% of which
goes from the lungs into the liver, has a minimal systemic effect. If most of
the inhaled steroids are absorbed by the gut, (which is systemic), they are akin
to oral steroids, and this should stop all talk about the negligible adverse effects
of inhalers. Moreover, steroids are by no means a cure, as symptoms recur
soon after discontinuation in most patients.79 A recurrence means a return to
the drug, and repeated drug courses lead to permanent complications.
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SYSTEMIC STEROIDS
Oral and injectable steroids are called systemic for their ability to affect the
whole body. The published entries on oral steroids are carbon copies of the
ones on inhaled steroids only in darker colours. They say that systemic steroids
are prescribed for incapacitating allergic conditions and to steroid-responsive patients. The latter is admission that not every asthmatic responds to
steroids in any form. These entries cautiously warn that drugs are able to affect
any organ or system of organs. When taken for long periods of time, they are
difficult or impossible to wean, even when the asthma, for which they are
prescribed, comes under control.
The compendium lists both the immediate and the long-term effects of
oral steroids:
a. cardiovascular systemprogressive development of atherosclerosis, cardiac
arrhythmia, increased mortality after a recent myocardial infarction; elevation of blood pressure, excessive bleeding, stroke;
b. metabolic complicationssalt and water retention (that is, weight gain
and/or oedema); increased protein and bone loss as well as calcium excretion (osteoporosis) leading to spontaneous fractures and suppression of
growth in children; increased appetite (weight gain); development of
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c.
d.
e.
f.
g.
h.
i.
diabetes mellitus and poor metabolism of the injected insulin in the existing
diabetes; increased fat deposition.
eye complicationscataracts, glaucoma, possible damage of the optic nerves;
immunologic complicationshigh susceptibility to infections, development
of severe resistant infections; poor healing or recovery process;
psychoneurologic complicationsfrom insomnia and mood swings to
personality changes, severe depression, seizures, psychic derangement;
skin manifestationsthinning of the skin to atrophy, allergic dermatitis,
fungal infections;
hormonal changesmenstrual irregularities, miscarriages, infertility;
reduced libido, impotence, hirsutism (facial hair growth), adrenal suppression to fatality; growth hormone suppression and hence, poor wound
healing and stunt linear growth in children;
muscular system complicationsmuscle weakness, loss of muscle mass;
gastrointestinal complicationspeptic ulcer with possible perforation and
haemorrhage, perforation of the small and large bowel, particularly in
patients with inflammatory bowel disease.
UNANSWERED QUESTIONS
A lot of legitimate questions are left unanswered by pharmaceutical
compendia and the allergy elite:
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The inhalers have been on the market long enough to enable access to such
data. Were asthma a short-term disease, we would not have to worry about
the side effects. However, in Greek, Chronos means time, and thus, chronic
denotes a disease persisting over a long period. Chronic use of steroids, even
in the inhaled form, must be re-evaluated by the medical profession rather
than imposed more and more aggressively. As the number of asthmatics
grows, with it grows the chance of having a huge percentage of the population
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with undermined immune systems and numerous serious conditions (worsening asthma among them). The most effective and safe medications
create the setting for this immense potential epidemic.
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This all means that among the numerous unknowns that surround
inhaled steroids, one thing is unquestionabletheir serious side effects at any
dose. They are just a matter of time. The fact that in children, the side effects
manifest earlier is not surprising, since they are the most sensitive group of
the steroid consumers. Similarly, the deaths of canaries in coal mines warn of
the dangers that are yet unknown.
A safe dose does not exist. What is proclaimed safe by some authors may
be found by others to be dangerous. A dose, safely inhaled for few weeks may
necessitate a drastic increase over a longer period of time, since asthma has a
relentless tendency to relapse with time and/or dose reduction. In fact, any
suggestion of a dose cut-back, be it in a textbook, periodical or pharmaceutical
compendium, is accompanied by a warning of a possible worsening of the
symptoms that can often be only by a high dosage. Steroid defenders assure us
that side effects are usually reversible upon dose reduction or discontinuation
of the drug. Can they guarantee the reversibility after repeated relapses and
hence, repeated courses of steroids? Is a few months period, in which trials are
conducted, long enough to come to conclusions about a safe dose if asthma, a
life-time disease, may necessitate indefinite doses? With the phrase the clinical
significance of these changes in the long-term treatment is not known, authors
and drug developers free themselves from liability as well as the responsibility
of answering these questions with yes or no.
As a rule, conclusions are made on the basis of small groups studied for a
short time, several months at most, although within the 30 years of inhaled
steroids being on the market, it is logical to expect that data on their long-term
complications be made available. More than a decade after the wide use of inhaled
steroids, the chapter in the textbook Allergy 1985 (page 658) says: The effects, if
any, of IS (inhaled steroid) drugs have not been adequately studied to date.
Another decade later, in 1996, a world-renowned scientist warns that the longterm risks of their use are still a concern to many, patients and physicians
alike.82 A textbook published in the new millennium again states: As with oral
GC (glucocorticoid) therapy, high-dose inhaled GC therapy has been associated
with adverse systemic effects, and it is still unclear whether long-term administration of inhaled GC will result in growth suppression and osteoporosis.83 The
laments of the medical profession about inadequate information have not initiated an investigation into the thirty year use of inhaled steroids. Will steroid
consumers sue the manufacturer and/or doctors years later when they realize that
sustained drug use did produce irreversible side effects? We have examples of
physicians admitting their wrongful support of smoking. We know the tobacco
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Once Dr. L. Fraher from the Lawson Research Institute said, in his speech
at an annual meeting of the American Society of Bone and Mineral Research
in Minneapolis, that steroid users may end up with translucent skeletons full
of holes that you can see through. We can add to this that for older patients,
disabled by fractures occurring due to steroid consumption, these drugs may,
actually, be fatal.
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Meeting of the AAAI in San Francisco, the choir sang in unison that allergic
inflammation was the only proper dress to wear. All other styles were
proclaimed as illegitimate. Asthma has become solely an inflammatory
disease. Steroids, formerly prescribed with caution, flooded the drug market.
Paradoxically, despite their proclaimed effectiveness, asthma morbidity and
mortality have increased dramatically in the United States during the last 20
years necessitating still wider use of bronchodilators.89
The adverse effects of steroids are so obvious that even Peter Barnes, a
consultant to the producers of asthma medications, admits that there is a
need for the development of new treatments that would avoid the side
effects that may be associated with anti-inflammatory drugs such as corticosteroids.90 He is pessimistic though: the possibility of developing a cure
for atopy is remote. One may only wonder as to what destroyed his optimism
expressed a year before in another article of his that was assuring us of the
opposite: in the future there are real possibilities for the development of
preventative and even curative treatments.91
Asthma patients cannot be overly optimistic either: according to the
February 14, 2002 issue of the New England Journal of Medicine, drug makers
spent $2.5 billion U.S. dollars in 2000 for advertising (for educational
purposes) mostly anti-inflammatories and antihistamines. The revenues
received from this investment by the manufacturers are impressive: In 1998,
the annual cost of asthma was estimated at $12.7 billion, with medications
the single largest cost component.92 Drug markets have no interest in a cure.
Despite the numerous side effects of steroids and despite the dramatically
rising mortality among their users, many authors see the problem of asthma
in doctors prescribing too little steroids and too late in the disease course.
They accuse parents of asthmatic children of noncompliance with the
management based on steroids. They even invented a new term for this
parental prednisone phobia. As usual, the ends do not meet: as was reported by
a group of scientists from Iceland at the 58th annual meeting of AAAAI,
inhaled glucocorticoids are widely and successfully used in over 90% of
patients with moderate to severe asthma.93 This is almost universal successful
coverage of asthmatics, and it is doubtful that American doctors are lagging
behind their Iceland colleagues in their prescription patterns.
However, even a figure as high as 90% does not satisfy the Chicago team
whose report in the same issue (page S183) declares: There are a large
number of persistent asthmatics who are not prescribed these medicines by
301
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their primary physicians. This time, not parents, but physicians are supposedly reluctant to prescribe. What are the reasons for not prescribing steroids
to every single asthma patient? Who dares not follow the steroid-enforcing
guidelines? The article reveals that A significant percentage of pediatricians
surveyed have discontinued inhaled corticosteroids due to perceived (!?) side
effects. It is of interest that urban pediatricians and pediatricians who graduated from medical school after 1989 were more likely to use inhaled corticosteroids for all classes of persistent asthma. It means that in small towns
and villages, where doctors know each person, they seem to discontinue
medications when their young patients experience adverse effects. However,
when the older doctors retire and urbanization reaches these small communities, steroids will reign in that obedient and impersonal world.
So, now, we have an asthma epidemic. Soon, with the rising number of
prescriptions for steroids, we may have an epidemic of deaths among asthma
patients, but wait: the scientists will find new explanation for this too.
IS ASTHMA AN INFLAMMATION?
It is important to understand why steroids should never have become first-line
asthma remedies. We have already spoken about the phenomenon of allergic
inflammation, immunogenic in nature. Unlike in other inflammations, the
tissues may long remain physically intact even with the changing chemistry.
For years, the integrity of the bronchi and lungs in asthma may be preserved,
and their dysfunction may remain reversible. Tissue scarring appears only in
advanced stages of the disease. Calling asthma an inflammatory disease
without specification as to what causes this inflammation is wrong, in the
sense that the inflammation in the respiratory tract is the process resultant
from the histamine-induced cascade of mediators and cytokines.
There is a parallel with migraine that occurs due to histamine- and
serotonin-induced chemical changes in the neurovascular tissues, but is only
occasionally labeled as a neurogenic inflammation. It is also unscientific to
omit the specific causative chemicals when speaking about inflammation in
asthma, because anti-inflammatory medications should have specific targets,
concrete inflammatory mediators or cytokines. The generally accepted term
inflammatory regarding asthma is dangerous because it justifies an early
introduction of steroids as potent anti-inflammatory drugs allegedly
targeting the cause of the symptoms, while in reality, targeting the
secondary events. Contemporary allergy supports this term and, correspondingly, the aggressive use of steroids.
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The dangerous signs of the suppressive approach are seen everywhere but
are silenced, downplayed or distorted. Maybe one day, a daring journalist or
a scientist will share with us the figures of steroid-dependent asthmatics who
are crippled by frequent fractures (osteoporosis), suffer from diabetes, die of
strokes (hypertension), undergo cardiac surgery or surgery for peptic ulcers,
suffer vision loss because of cataracts, become infertile or have miscarriages .
Will there be a journal that will publish this medical information and these
statistics? Will there be a daring lawyer who files a class action suit similar to
those against tobacco and asbestos industries? Will there be a court that will
grant a judgment in favor of the victims, as were the judgments in those cases?
Peer pressure forces even apparently independent leading experts to
change their position (probably, not really their views) in favor of steroids. We
have already quoted Dr. OByrne, a leading Canadian respirologist, who said in
1996 that the long-term risks of (steroid) use are still a concern to many,
patients and physicians alike.82 In April 2000, the same scientist told the 200
professionals at the annual Allergy Update symposium in Toronto that inhaled
steroids were free of unwanted effects in proper doses, and that they provided
optimal control in most cases. Unfortunately, Dr. OByrne did not share with
the audience what those encouraging data might be, and when and from
where he had received them within the 4 year period between his declarations.
The 1997 president of the Canadian Society of Allergy and Clinical
Immunology, Dr. Z. Chad, proudly said in his interview with Family Practice
that Canada was a world leader in treating asthma with higher doses of
inhaled steroids, and even the U.S. was lagging a little behind in their early
introduction. The Canadian updated guidelines recommend steroids at a very
early stage, and this dubious practice makes the country the frontrunner. The
guidelines start and end with steroids. This, certainly, has not helped to
improve the asthma situation, and Asthma remains the only preventable
disease where the morbidity and mortality are still increasing in most parts of
the world.94
Of certain interest is that usually, guidelines recommend what to use and
do not indicate what NOT to use, especially in resistant asthma, when
anything that relieves the plight of the patients should be encouraged. So, the
Canadian allergists became the frontrunners in advising against the use of
histamine in their guidelines! I guess I should be flattered that my case has
created a precedent in the century-old history of histamine. Regrettably, this
is a dirty history, and the document produced by the Guideline Advisory
Committee in February 2002 is the best illustration of this miserable situation.95
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It indicates the areas of high need and the identification of future topics, in
other words, what medical areas require most of the attention. Asthma is not
even among them; in comparison, nonfatal, rather infrequent bronchitis has
found its place there. This can be explained either by the reluctance of specialists once again to reveal their impotence with asthma, or because the effect of
the efforts to conceal helpful knowledge has been so effective that even the
guideline creators mix up asthma with trivial bronchitis.
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drug sales, and this explains why subsidies for research that prevents revealing
dangerous true facts are especially lavish.
If lawyers impress the audience by their court attire, doctors use their
titles to impress. The opposing and even contradictory data look like professional dialogues, while the judge called Big Pharma (Big Brother?) allows this
verbiage to continue and knows the decision in advance. The audience in the
medical courts is the patients. They are misguided about the validity of new
hypotheses through the medically uneducated and, therefore, easily misinformed media who are also usually misguided by the spokespersons for the
drug companies. The public trusts journalists more than drug companies and
does not suspect the behind-the-scene brainwashing of those who write the
stories on the new discoveries. These stories cause enthusiasm through their
terminology and the titles of the researchers. Patients try to fit their symptoms into the framework of every newly theory to find the explanation for
their symptoms. The choice is so wide that there is always a suitable theory.
While the deception of lawyers has become proverbial, patients still cannot
believe that doctors may be corrupt as a profession.
Three different provincial governments of Ontario knew about my
Histaminegate. None interfered despite the letters they received from the
patients deprived of histamine that had allowed them to live drug-free, despite
major media coverage most sympathetic to my patients, and despite emergency
rooms full of asthmatics. Governments lament the lack of money in the public
health system, and with the quadrupling of asthma figures within the last two
decades in Canada that necessitate over 600 million dollars annually, there
was no intervention. All the courts, including the Supreme Court of Canada,
disregarded the exhibits proving the great public interest in the asthma solution. They overlooked the forged and misrepresented the key evidence
submitted by the CPSO in their court documents. They even turned a blind
eye to the Colleges violation of its own bylaw as well as its violation of the
federal law. The courts protected Verbatim, the court reporters, in their
production of two versions of transcripts, one with a forged signature of a
court reporter, and disallowed the cross-examination of the manager and/or
the court reporter.
The interests of the medical and legislative bodies merged somewhere. This
was probably easy to do, since, like all legislative bodies, the College, is headed by
lawyers. No appeal was ever granted. No explanation was ever given. This despite
the fact that the tape produced by the Canadian Broadcast Corporation showed
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Canada with the purpose to change patient behavior such that they would be
able to control their asthma rather than be controlled by their asthma.
Sponsored by Health Canada and GlaxoSmithKlein, a new milieu for asthma
carethe community pharmacy has been created, with pharmacists taking
responsibility for outcomes, assessment of a patients readiness to change and
tailoring education to that readiness and physician consultation to achieve
asthma prescribing guidelines. Some 27 pharmacies and 33 pharmacists took
part in the study, which showed the approach was cost-effective, as it reduced
the number of visits to doctors offices as well as ER admission. There is no
mention of the medications used that allegedly improved the situation;
instead, the article emphasizes educational value of the enterprise.
However, with no other means than steroids, we can be sure that the education included the proper use of puffers and the intensified use of steroids, most
probably, the combination drugs, as is the fashion now. If this approach96
becomes accepted, the specialty of allergy as a medical discipline will be wiped
out: the proper use of immunosuppressive medications will replace the need to
study the immune mechanisms and repair them. Even by a wide stretch of the
imagination, one cannot call these measures educational, since what they teach
is skill, while education would mean the knowledge on what underlies asthma.
But then, the doctors involved are not knowledgeable themselves.
Doctors have actually removed themselves from the grim asthma statistics,
and it is now the patients that shoulder the burden of the problem. Asthmatics
should take care of themselves in every day life and inhale, swallow and sip
steroids, while specialists operate in their medical courts, and save their
patients in emergency rooms.
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and the individual. We thus compare the degree of the weakening of the
immune system by steroids vs. the degree of its restoration by histamine. This
is a huge difference.
With daily suppressive steroids, the defensive part of the whole immune
system slowly dies, and due to the shriveling adrenals and the growing resistance
of asthma, the body starts to rely on the drugs more and more. Never forget that
side effects of daily steroids are a reality at any dose. Many of the adverse effects
are diseases, and some are more debilitating than asthma itself. At the same time,
side effects of histamine are limited to temporarily intensified allergic and
related symptoms: dizziness, a headache, a more congested or runny nose, more
pronounced skin itch or heavier breathing. Even these manifestations are transitory, lasting only minutes and rarely a few hours. An observant doctor can
reduce the adverse effects to minimum and provide a smooth recovery from the
very start by asking the relevant questions before and after the skin testing and
during treatment, before and after each therapeutic injection.
The key difference between steroids and histamine lies in the fact that the
degree of the (temporary) improvement due to steroids is proportional to the
general suppression of the immunocompetent cells on the whole, including
their production of the protective chemistry, whereas the strengthening of the
targeted H2/3 receptors leads to the restoration of the normal cellular functioning of all receptor-bearing cells and hence, normalized production of
histamine and numerous anti-disease mediators. Another fact in favor of the
histamine immunotherapy is that one can stop it at any time, whereas
steroids often require tapering because of the physiological dependence on
them.
Unlike steroids that are not recommended for kids under 4 or 6, histamine
is especially effective in children and babies. As I said in my presentation at the
international symposium in 1989 in West Berlin, the younger the child, the
better the results. It can be due to a more resilient immune system of a young
body. A lot of people, especially children, whom I treated with histamine
remained symptomless and drug-free for years.
Is there interaction of histamine with other medications? Yes. Histamine is
incompatible with steroids since it tries to restore the functioning of the same
cells the steroids extinguish. If steroids were taken before therapy with histamine, such immunotherapy may be less successful and require a longer treatment period, because to revive the suppressed cells is more difficult than to
activate the ones that are untouched. Cells suppressed by steroids, T-cells first
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of all, may never be able to regain their functioning. This explains why the
immunotherapy conducted concurrently with steroids cannot thus be effective.
Histamine therapy is also less effective in those patients who take H2receptor suppressors such as Zantac and Pepcid, prescribed for gastrointestinal problems. This is because histamine injections activate H2 receptors,
and their simultaneous activation and suppression are impossible.
Histamine injections are the therapy that repairs the flawed receptors and
increases the efficiency of T-suppressor cells. In the majority of cases, the effect
may even last months or years. Only in those with the most inflexible immune
system, the treatment may continue throughout the patients life. Chances are
high that the patients become independent from daily medications. Histamine
may also eliminate the accompanying symptoms, seemingly allergy-unrelated,
often nonspecific and therefore undiagnosed. Suffice to say that the normalized function of T-cells in general not only rids patients of allergies, but also
strengthens the whole immune system and by that, rids them of superimposed
infections. T-cell strengthening may also be beneficial in another respect.
Recent studies in San Diego and Goteborg, Sweden, showed that the combination of histamine and inflammation-promoting mediators in melanoma
increased the number of killer cells by 62 times, whereas the mediators alone
provided only 5-fold increase. Since any defense against cancer is based on
killer cells ability to destroy tumor cells, it is logical to assume that histamine
can be beneficial in cancer. This subject was thoroughly studied in the 80s and
early 90s and discussed in the publications of the Histamine Research Society
Agents and Actions.
The revived cellular talk of the immunocompetent cells with the nerve cells
and the cells of endocrine glands positively affects the functioning of the nervous
and endocrine systems. Most remarkable is the bolstering effect of histamine on
the adrenals (via corticotropin) that synthesize corticosteroids. Their activation
diminishes the need of the outside help with the synthetic version.
Almost always, the improvement starts at the very beginning of the histamine treatment, actually, at the skin testing. By restoring the efficiency of
T-suppressors and allowing them to fight allergic inflammation, histamine
injections reduce the bodys need for crutchesother medications, including
histamine itself. It is different with all other drugs when, due to the bodys
adjustment to their regular use, the need of increasing dosages continues.
Last but not the least I need to emphasize the cost of histamine therapy. It
is very low compared to daily drugs and thus, saves personal and public
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money. It is this advantage, however, that is viewed as a huge threat by the drug
industry, and this outweighs all the beneficial properties of histamine therapy.
The purpose of any treatment should be to rid patients of the disease,
whenever possible, or at least control the rate of decline and symptoms for the
longest period possible and by the safest means possible. Histamine injections
reach the goal other medications are meant to reach, but does it with an
immeasurably higher effect and lesser degree of complications. I saw that in
asthma, histamine worked better than in any other allergic disease. This can
probably be explained by several factors.
Compared to other tissues, the lungs possess the highest concentrations of
mast cells and basophils. The number of these cells exceeds those in other
organs also due to the large lung surface and to the permeation with blood
vessels for oxygenation. Thus, when histamine injections inhibit the leakage of
histamine from these cells, the magnitude of the effect is most apparent in the
lungs. The positive aspect of this is that the very same facts make asthma a very
dynamic and reversible disease, in the absence of organic tissue changes
common for advanced or neglected cases.
AN UNFAILING DRUG
You may wonder if histamine works in all cases. Nothing is absolute in nature.
There are, after all, asthmatics who do not respond to steroids. Basic sciences
explain this phenomenon as the result of an irreversible defect of steroid
receptors. One learns whether one is a responder or not only after trying a
treatment. If steroids do not work, they should be stopped because they may
only harm. The high doses prescribed in the hope of improvement may lead
to serious consequences, particularly unreasonable because their consumers
get no relief from their asthma. Unfortunately, in view of the lack of any
substitute, steroids are still prescribed in escalating doses with the accompaniment of add-on drugs. These patients, in addition to having resistant asthma,
acquire dependence on steroids plus numerous side effects.
Histamine may not produce any effect when there is a genetically predetermined irreversible defect and/or irresponsiveness of the H2/3 receptors.
However, a trial with histamine can do no harm. A potential temporary
aggravation can be reduced to a minimum through a slow dose increment,
and the attempts can be stopped at any moment. Practice proves overwhelmingly that the majority of patients who are not steroid-dependent, respond to
histamine injections.
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Would you want to try histamine therapy? Even if you would, you cant.
Even if steroids fail in your case. Even if your condition forces you to abuse the
condemned bronchodilators. Histamine therapy is not in the guidelines. In
Canada, it was even banned when the medical Establishment realized that
patients with allergies and asthma, whom I treated, recovered in large numbers.
Regrettably, doctors all over the world who conduct histamine therapy are
forced to do this empirically, since the theoretical knowledge that could support
their therapy is hidden. They grope in the dark trying to select the dose. Having
been taught that histamine is allergy-conducive only, they are afraid of aggravations, unable to explain them and may give up on the therapy that could save
their patients. They cannot speed up the improvement because a higher dose
does not necessarily mean a faster recovery. They often combine histamine
therapy with different irrelevant substances and do not understand that the
effect is due to histamine. The flaws in conducting histamine therapy belittle
its wonderful properties and accentuate its negative role in allergy. The vital
information disappeared even from those few textbooks that had once
contained it. Medicine dictates you swallow or inhale daily steroids and bronchodilators and be happy if you are a responder.
TO USE A DRUG
The US Food and Drug Act is based on the general premise that once a
drug is approved to be marketed for any one indication, physicians are legally
free to use it for any other indication without any additional evidence.99 This
quotation is from an article published in one of the most prestigious medical
periodicals, the Journal of American Medical Association. It is written by Dr. D.
Eddy, Professor of Medicine and Mathematics, consultant to the U.S.
Government on drug use and author of the monthly column Clinical Decision
Making. Histamine therapy, described in the remote past in detail even in
textbooks100 and later substantiated theoretically101 should be available and
free to be employed by a trained doctor. As Eddy describes, hundreds of
diagnostic tests, devices, procedures and services are currently used and paid
for without any evidence of effectiveness for any indication.
By contrast, the efficacy and safety of histamine are confirmed by
numerous open clinical and double-blind studies. The recognition of its
safety comes from the fact that histamine is a non-prescription drug. The
most astounding fact exposing the deplorable lack of knowledge by immu-
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nologists of the dual action and potency of histamine is its common use as a
placebo (?!) in controlled trials for allergen extracts.
Basic sciences know more about histamine than about most medications.
It belongs to the group of autacoids due to its natural remedial effect. The
regulations of the central legislative body of the drug industry do not prohibit
the use of histamine since it fits into the framework of hundreds of other
drugs referred to by D. Eddy as those once approved to be marketed. The
1988 Helsinki Accord on Human Rights, signed by the governments of all the
participating countries, including US and Canada, states that a practitioner
can use any remedy at his discretion if it is not more dangerous than the
conventional means. So far, there has never been a report on the danger of
histamine in clinical practice. On the contrary, clinical trials proved its
success. But the august medical authorities will not allow it. Any pretext is
good. Some say it is dangerousthen, why is it used as a placebo in trials?
Others say it gives a psychological effect onlythen, why is it the standard of
the biological activity of allergen extracts? Logic and scientific facts become
redundant when the decision makers violate the very laws they created.
Ultimately, you are just an asthma sufferer without medical knowledge,
power or the right to make a decision for yourself or your child. You are
doomed to succumb to the management imposed on you by the medicopharmaceutical conglomerate conveniently supported by governments and
legal bodies, but not by law.
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lists inhaled steroids under the heading Asthma Prophylactics (p. 1642).
Manufacturers of inhaled steroids are multinational companies, therefore the
entries in the compendia in other parts of the world are the same or similar.
The hands of those who offer an effective resolution to chronic medical
problems are tied, and the recent strict guidelines are the manacles. Legally
is a robust adverbit justifies many ill-gotten gains, said Honore de Balzac.
Guidelines that should never be legislative, have become legal restrictions in
allergy practice. The reasons for the restrictions are simple. Grants and funds
for research are the central elements that drive the developments in medicine.
The high costs of funding can more readily be turned into continuous profit
streams by drugs that only offer temporary relief instead of an actual cure.
Therapies that may provide full or lasting independence from daily drugs are
unacceptable as loan repayments. Asthma patients from all over the world are
paying the pharmaceutical industry for research into the drugs that may
cripple or even kill them.
As an extreme mockery, our democratic society gives asthma sufferers
freedom of choice: 1) a bronchodilator of any kind with any imaginable
delivery system; 2) a steroid drug in any form: oral, injectable, inhaled; 3) the
recently developed (and already restricted) combo drugs consisting of a bronchodilator and a steroid; 4) a number of ineffective adjunct medications to be
taken along with the main two. All the choices are compulsory. Asthmatics
can also choose to wait until medicine sorts out all the genes, studies their
interrelationship, develops methods of genetic engineering in asthma and
starts using them on a wide scale. How soon will it happen? Gene therapies
currently show little promise for treating this prevalent and generally nonmorbid disease, states another speaker of the conference.103 Paradoxically, we
can be grateful for the fact that it is not going to happen soon, since, as
legends say, the ancient Atlantis perished because its medical professionals got
the false idea of their grand abilities and created genetic monsters such as
mermaids and centaurs.
It is evident that the status quo satisfies all parties involved in asthma but
the patients. Drug developers get back what they invest into the new research,
plus a little more (a little?), researchers get their grants and bonuses, doctors
have an unceasing stream of asthmatics in their offices, engineers develop
devices for asthmatics, hospitals enlarge the areas to accommodate all those
who gasp for air, nurses get special training in teaching asthma patients how
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to avoid environmental triggers and how to use their inhalers properly and
become experts in reduction of steroid doses. And finally, pharmacists have
joined the party and now not just dispense the medications, but consult
patients and their doctors (!) on how to intensify the use of steroids.
You may ask where the governments are that spend millions on health
services? Governments corruption is an open secret, and their protection of
the most lucrative industry is not a secret either. In the case of asthma, the
annual direct casualties provided by the official statistics (definitely below the
real figures) are only (!) 60,000 deaths annually among the 130 million
sufferers in western countries.104 Death from asthma is rare, informs us a
flyer sponsored by The Lung Association of Ontario. Is it? Are the figures of
5,000 plus and growing for the US and over 500 for Canada still too low for
the governments to be bothered about? What figure will be good enough to
start an inquiry?
ENDNOTES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
315
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69.
70.
71.
72.
73.
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PART EIGHT
ALLERGIC DISEASES
CHRONIC RHINITIS,
SKIN ALLERGIES,
HAY FEVER
All allergic diseases have, in principle, the same immune roots, but as they
affect different organs, the manifestations are different.
INTRODUCTION
A. CHRONIC RHINITIS
We know its root rhino from the familiar rhinoceros, and both words come
from the Latinnose. This chapter covers chronic rhinitis, which is a protracted, often life-long non-infectious, allergic inflammation of the nasal
mucous membrane.
The nose is a protective filter against physical, chemical and infectious
agents. Its sieve-like structure with its narrow passages prevents particles from
getting inside. The secretions of its mucous membrane are designed to
neutralize those chemicals and disease-causing bacteria that do get in. Both
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CLASSIFICATION
Chronic rhinitis exists in several forms. One is allergic rhinitis, which can be
divided further into two kinds. A seasonal form provoked by pollen is a part
of hay fever. The other group includes patients with perennial symptoms triggered by other allergens, for instance, dust mites.
There is yet another form of chronic rhinitis, in which the symptoms are
triggered not by allergens but by nonspecific factors such as changes of environmental temperature, air impurities, emotions, change of posture, awakening, biological cycles, etc. Nonspecific triggers are innumerable, and therefore
these people may suffer all year round or have spontaneous relapses. Their
rhinitis is called vasomotor and its Latin roots indicate that the condition is
related to the fluctuations of blood flow in the vessels: vasusvessel and
motormovement. In fact, the term is not very precise, as similar vascular
changes are present in all forms of rhinitis. Allergen-related seasonal and/or
perennial forms of rhinitis often coexist with nonallergic or vasomotor rhinitis
in one and the same patient.
Although conventional medicine labels these forms as allergic and nonallergic, the underlying mechanisms of all forms of chronic rhinitis are basically the same: they are all caused by malfunctioning immunocompetent
cells, which are responsible for the allergy-controlling part of the immune
system. Change in the body chemistry provoked by a histamine spill leads to
two events which then lead to the symptoms of rhinitis:
1. an engorgement of the vessels and thus, an increase of the blood flow in the
nasal mucosa;
2. excessive secretions, i.e. nasal discharge and/or obstruction.
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THE SYMPTOMS
It is fairly easy to differentiate chronic rhinitis from an infection, as it is often
accompanied by other allergic or related symptoms. These may vary from
patient to patient and include a chronic cough as a sign of the accompanying
asthma, or various ear discomfort, or allergic dermatitis. The fluctuating nature
of the symptoms is another clear indication of the allergic origin of chronic
rhinitis. Family history often elicits allergies, asthma or related diseases in close
relatives, and thus provides another proof of the allergic nature of the illness.
Chronic rhinitis is a trivial disease when compared to the numerous
debilitating conditions also found in this area of medicine. However, its
persistent course and the accompanying allergic inflammation spreading to
the surrounding areas create a dismal picture. Inflammation of the nasal
membranes may produce local swelling and irritation leading to a prolonged
itchy, drippy, plugged or runny nose and sneezing attacks. The obstruction,
due to the swelling, can make simple breathing a difficult or even painful act.
Nasal drippings become a nuisance and force the sufferers to carry boxes of
tissue with them. Non-stop sneezing attacks are exhausting also. The symptoms, benign at first sight, can make a persons life miserable. At times, they
are similar to a severe cold or flu without a high temperature. Indeed, in hay
fever season, it looks as if there is a flu epidemic going around. The inability
to breathe through the nose wakes the patients up at night. They often snore
and thus may affect the sleep of others as well. The broken sleep pattern may
lead to irritability, depression and insomnia. Thus, a simple conditiona
stuffy noseoften turns into a devastating medical problem.
Allergic inflammation of the nasal mucous membrane is seldom a spacelimited disease. It often spreads beyond the nasal area into the sinusesair
cavities on the sides and above the nose. This creates a feeling of heaviness in
the area, and patients with rhinitis often have sinus headaches. The term for
this combined condition is allergic rhinosinusitis. As with other diseases of
hypersensitivity, the term allergic is not accurate in relation to chronic
rhinitis, since allergens may have nothing to do with the symptoms. Just how
common this condition is becomes evident from the repeated TV advertising
of drugs for the relief not only nasal symptoms but also of sinus headaches
as well. These combo drugs contain antihistamines, decongestants and
painkillers in different proportions.
Postnasal drip is another unpleasant accompanying symptom. The
phlegm formed by the secretions from the nasal lining gets into the throat
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and causes discomfort, soreness and a throaty cough (not to be mixed up with
the chesty cough in asthma). Unfortunately, doctors do not routinely differentiate between a viral and bacterial throat infection and an allergic pharyngitis. Even worse, some allergy patients are diagnosed as having chronic
tonsillitis and enlarged adenoids. As a result, many, especially children, end up
having unwarranted tonsillectomy and/or adenoidectomy, and adults go
through nasal surgery. It always reminds me of the saying that the best
remedy for dandruff is a guillotine. Just how unnecessary and harmful such
surgery tends to be is well described by a well-known American pediatrician
R. Mendelssohn in his book Confessions Of A Medical Heretic.
Lately, there is a strong tendency to single out postnasal drip as a separate
condition leading to asthmatic-like cough instead of recognizing it as a
symptom that may accompany chronic rhinitis and/or asthma.
RECURRENT OTITIS?
Ear, nose and throat form one apparatus, hence the name of physicians who
treat the diseases in this areaENT specialists. The spread of allergic inflammation to the eustachian tube that connects nasal passages with the eardrum
area is accompanied by poor drainage and thus, accumulation of non-infectious fluid in the middle ear. The condition is called otitis. This term implies
any inflammation in the ear, infectious or non-infectious, which naturally
leads to confusion. As a result, recurrent allergic otitis, which usually appears
in parallel with allergic rhinitis, is almost always misdiagnosed. When allergic
inflammation spreads to ear passages, it may produce signs similar to infectious otitis, such as fluid accumulation behind the eardrum, plugged ears and
poor hearing, itch, discomfort or even pain.
The absence of a fever and/or pus points to an allergic nature of the
condition and, therefore, does not call for antibiotic treatment. Besides, like
any disease of hypersensitivity, allergic otitis has a characteristic course of
frequent recurrence and fluctuations and is accompanied by other allergy
symptoms; pre-existing chronic rhinitis is most common among them.
Regrettably, a proper differential diagnosis seems to be a challenge for a lot of
doctors. Furthermore, even though allergic otitis is so common, its discussion
is virtually absent from medical textbooks as a disease in its own right or as a
companion to chronic rhinitis.
Allergic otitis often becomes the reason for numerous troubles in schoolchildren. Due to plugged ears, these young patients may not hear well and are
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ashamed to admit that to their teachers. They may not even be aware of the
problem. Poor hearing affects their concentration and comprehension of the
material. Add to that the constant symptomatic discomfort from the other
accompanying allergy symptoms, and you will understand why such a child
is in trouble. The symptoms may be mild, and therefore the child disregards
them. However, they distract from studies, and such a child is often labeled by
the teachers as a poor learner. The child may carry the label through his entire
school years. It may become a lasting psychological wound especially for
sensitive children who, in reality, may be quite bright. The situation may traumatize the whole family. The number of kids having allergic rhinitis grows in
proportion to the rising incidence of all allergies that are hitting the younger
generation more and more frequently. This basically harmless illness (it
doesnt kill one) does, however, continue to create various chronic medical
and social problems.
Mothers, not familiar with the medical subtleties, sometimes overreact to
their childs symptoms, and with the very first complaint, take their kid to a
doctor. Unfortunately, very few doctors take a swab, to confirm or disprove an
ear infection, if they see redness in the external canal, which they interpret as
inflammation. Hence, antibiotics are routinely over-prescribed. It is almost as
if a prescription seems to be ready and waiting for the patients. In fact, even
if the ear passages do look red and inflamed, these signs are nonspecific and
common for allergic condition as well. Antibiotics may temporarily improve
the condition due to their collateral non-specific action, although it is
possible that a remission is spontaneous and reflects the fluctuating course of
any allergy. The frequency of these prescribed courses of antibiotic drugs
contributes to the evolution of antibiotic-resistant strains of bacteria, now
one of the worst problems in world medicine.
However, the real reason for prescribing antibiotics so liberally and unnecessary is the growing incidence of respiratory allergies and the inefficiency of
allergy drugs. Antibiotics are, in fact, prescribed to camouflage the impotence
of allergy therapy. Their danger to society prompted a series of articles in
professional sources and in the media. Special medical committees started to
warn doctors against over-prescription of antibiotics, and pamphlets addressed
to patients began to explain the harm of the drugs. But the harm has already
been done and is continuing: fatal, antibiotic-resistant infections threaten our
civilization. As it often happens in medicine, it counts its losses decades later. It
is of more than passing interest that Alexander Fleming, the discoverer in 1928
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of the first antibiotic, penicillin, warned in his 1945 Nobel Prize acceptance
speech against bacterial antibiotic resistance as a very real danger that could
make this great drug discovery helpless against infectious disease.
Another way of treating chronic otitis is insertion of tubes into ears for
better drainage even though it is a fact that many of the otitis cases are an
allergic condition. Indirect confirmation of this comes from the skyrocketing
incidence of allergies, chronic rhinitis in particular, and the correspondingly
rising frequency of infectious otitis.
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immunotherapy, with all its side effects and limitations, still looks like a
worthy treatment, and this contradicts the humble role it plays in todays
practical allergy therapies.
B. SKIN ALLERGIES
GENERAL DESCRIPTION
The general idea of skin allergies covers several types of diseases. As with other
allergies, the term allergic is fundamentally wrong in the usual sense, since in
the majority of cases, the symptoms are allergen-unrelated or only partially
related. Like asthma and chronic rhinitis, skin allergies are diseases of hypersensitivity. To simplify the overview, I will still abide by the accepted terminology and use the term allergic.
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Although the skin is a cover for our internal organs, it is not just a passive
enclosure of the organs, but a large, living and very sensitive organ. The skin is
the first physical barrier that protects the body as walls protect the inside of a
house. It is also a chemical barrier due to the presence of blood vessels, nerve
endings, and various cells with their several million kinds of receptors. These
receptors respond to chemicals, environmental and body temperature changes,
pain, pressure, light, vibration, etc., and the cellular chemistry induced by their
signals protects us by neutralizing the enemies that contact the skin or try to
penetrate it.
The presence of immunocompetent cells makes the skin an immune
organ, while the extensive spread of nerve cells indicates its close relation with
the nervous system. The skins involvement in allergic reaction does not differ
from the involvement of the bronchi or the nose. It may occur upon contact
with an allergen, an assault of a nonspecific factor such as exposure to an
environmental or physical factor, as a result of the hosts own changing chemistry, or it may arise spontaneously, without any apparent trigger. Usually,
immune cells adjust both to outer attacks and to inner changes, and only if
the impact is too strong, there may be a temporary symptomatic reaction. If
the cells are generally healthy and, most importantly, able to restore their
normal functioning, a spontaneous relief sets in after a while. In a patient
with malfunctioning immune cells, various triggers may lead to the initial
histamine overspill from the sensitive mast cells followed by an exaggerated
response to that by other cells in the surrounding tissues. The inability of the
cells to adjust to the insult protracts the reaction. The nerve cells in the
vicinity become engaged too. The receptors disseminate the signal all over the
body, and the reaction may spread to other tissues and organs in the same way
as a fire that starts in a small area may engulf the whole house.
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finding of one fifth of all cases being unrelated to IgE mediation, is a high figure
because that means that this is an allergic disease in which allergens may play no
role! However, unfortunately allergists do not explain this phenomenon.
Chapter 10 written by R. Rocklin in the 1985 textbook Allergy thoroughly
spells out all the mechanisms of allergy. This description is applicable to any
allergic condition, and atopic dermatitis is no exception. (Strange as it is,
another author writes on page 417 that the etiology and pathogenesis of atopic
dermatitis remain enigmatic, whereas, all the author had to do was to read
Chapter 10 in the same book.) In fact, the most essential component in atopic
dermatitis is a skin reaction to a local histamine overspill followed by a cascade
of the allergy mediators joining in. Like in any allergy, the genetic defect manifests in weak T-suppressors unable to counterbalance the pro-allergy chemistry
produced by mast cells, basophils, Langerhans cells and T-helpers.
THE SYMPTOMS
An allergic skin inflammation in dermatitis manifests in an intensely itchy
rash. The skin also becomes scaly, crusty and cracks. Patches of affected areas
usually cover the arms and legs, especially behind the knees and the inside of
the elbows, the neck and face but may easily spread all over the body. At times,
the itch is merciless. The constantly scratched surface becomes damaged, and
this may cause a superimposed infectious inflammation.
Children are more common sufferers of allergic dermatitis than adults, and
another name for the disease is infantile eczema. Their eczematous skin may
become infected because children are often unable to observe hygienic measures as well as refrain from scratching. With age, their dermatitis may disappear,
but the skin may remain damaged with numerous scars. Disappearance of the
dermatitis does not mean that the pathological immune process is over. It is
known that often, it transforms and manifests years later in another allergic
condition. Many asthmatics had atopic dermatitis in childhood, and it is gone
by the time the first asthma symptoms appeared. This should prompt doctors
to view allergic skin problems in a child as an early sign of potential allergic
rhinitis and/or asthma in the future. All three diseases are known to medicine
as the atopic triad.
Allergic dermatitis may be a traumatizing disease not only because of its
itchy cracking skin but also psychologically. The sight of the skin lesions may
put off and scare those who are unfamiliar with the non-contagious nature of
the disease. Parents may forbid their youngsters to play with a child who
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suffers from allergic dermatitis. The situation may turn dramatic when peers
mock or tease the child. Even adults suffer psychologically when lesions are
on the face, but the emotional impact of this on a child is especially severe.
One can only hope that the child outgrows the disease, and his emotions will
stabilize as well. Both can be wishful thinking, though.
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dosage of steroids, which determines the degree of their effect, both positive
and adverse. The 1999 CPS writes on page 590 in the entry on Elocom that
comes in a cream, ointment and lotion: (it) has been shown to have topical
and systemic pharmacologic and metabolic effects characteristic of this class
of drugs. And further: Any of the side effects that have been reported
following systemic use of corticosteroids, including adrenal suppression, may
also occur with topical corticosteroids, especially in infants and children. All
this is not surprising, since the skin is an excellent absorbent of the drug.
Children, as the most frequent victims of allergic dermatitis, become the
main consumers of the steroid-based topical remedies. The producers warn
of the increased danger of applying topical steroids over a large surface and
for a long time. The disease is, however, chronic, and in many, the lesions
cover large areas. All this means no escape from the drugs side effects.
Paradoxically, one of the listed complications is skin thinning or even
atrophy. Just think: the skin may get irreparably damaged due to the medications meant for its treatment!
Steroids are frequently combined with antibiotics. Such topical centaurs
are supposed to act like the stone that kills two birds: steroids aim directly at
allergic dermatitis, while antibiotics treat secondary infections, which may
develop due to the damaged skin. Infections may also be the result of the
adverse affect of the steroids that make the skin more susceptible to infections. In such a case, one medication in the combo drug relieves the adverse
effect of anothera common phenomenon in medicine.
The paradoxes of allergy treatments continue: there is a possibility of an
allergic reaction to antibiotics, the penicillin group in particular. The reaction
may be skin-limited, which means appearance of rashes or lesions in response
to the drug; it may also be systemicemergence of new allergic symptoms
and/or worsening of the existing ones. And we know all too well what the
most effective drug for all allergic reactions issteroids! This time, patients
take them in inhaled, oral or injectable form.
Oral steroids are prescribed in allergic dermatitis when topical ones fail,
and the itchy rash becomes intolerable. Even in those patients who improve,
the itchy rash may and often does come back as soon as the drug is discontinued. It is the same vicious circle that we saw in asthma treated with steroids.
To avoid serious side effects of and dependence on steroids, medicine occasionally offers another group of miracle drugsCyclosporin, Tacrolimus and
the most recent Pimecralimus. The CPS classifies them as highly potent
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in the skin are engaged directly and invite the neighboring immunocompetent
cells into the process by sharing their chemistry. It may also be the other way
around: Langerhans cells and T-cells get activated by touch and involve others
by their chemicals. In any case, both groups become participants in the reaction. A gentle massage does not over-activate H1 receptors. At the same time,
the signals from the tender touching activate the inefficient H2/3 receptors, the
cells start to produce more anti-disease mediators and cytokines, and this
arrests the allergic reaction. Massage, acupressure and acupuncture work similarly in this respect. Highly qualified specialists in massage therapy and acupressure empirically know that pressure to the skin should not be too light but
should not exceed a certain level. Only through experience, they acquire the feel
of how much is too much or too little.
It is also possible that the involved nerve cells send the message of the
physical pleasure of the touch to the brain. The involvement of the brain is
important for any immune process. In this case, the brain cells start to
produce the inner morphine (endorphins) and anti-inflammatory
cytokines. The favorably changing chemistry reverses the aftermath of the
local histamine overspill, which initiated the disease.
Is acupuncture helpful in atopic dermatitis? My answer: it is justifiable on
theoretical grounds, although these are unknown or vaguely known to the
practitioners who conduct the procedure, and, of course, it is safer than
steroids or Tacrolimus. The efficacy of acupuncture is probably limited. I have
seen very few cases when it had, at best, produced a slight, temporary relief,
and never a case of substantial relief or a cure. Besides, those parents whose
children have allergic dermatitis should welcome a chance to avoid or reduce
the amount of steroid creams by resorting to daily skin massaging.
Concluding thoughts on atopic dermatitis: I have treated many patients
with atopic dermatitis. The majority improved to different degreesfrom
diminished itch to complete recovery. In young children, the success was
especially notable.
URTICARIA
GENERAL DESCRIPTION
Another kind of skin allergy is itchy hives, the scientific name for which is
urticaria. The Latin word urtica means stinging nettlean herb armed with
pricking, stinging hairs. This gives you an idea of the symptoms.
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process not only on the skin but also processes hidden inside the body. When
examining patients with urticaria, one can literally see their hives fade and
disappear. Some authors write on similarities in the pattern of response
observed in the lungs as being also observable on the skin. Allergy knows that:
As a superficial part of the immune system, the skin makes a perfect object
for a visual observation of how allergic inflammation goes on elsewhere
during a disease and correlates with the processes in other immune organs.5
Thus, the simplicity of urticaria, which is purely a phenomenon of histamine-induced proinflammatory chemistry, allows one to observe with the
naked eye the course of this disease and at the same time understand that
similar ups and downs take place in other diseases of hypersensitivity.
Other allergies are more complex than urticaria. They cannot be seen and
are mostly judged on the basis of the information given by the patient and are
rarely amenable to conventional testing. This makes their understanding and
treatment more difficult. Even atopic dermatitis, which is also a skin disease,
cannot provide precise information in this regard due its multifactorial
nature. It is a blend of two medical fieldsallergy and dermatology, and has
lower reversibility than most allergic conditions and asthma because of the
potential of severe lesions and possible scarring. All this allows one to
conclude that understanding of the true immune mechanisms involved in the
simplest allergic disease, urticaria, helps us understand allergies in general.
There is general lack of understanding of the similarity of the underlying
mechanisms in urticaria and the phenomena observed during skin testing.
Because for allergists, superficial signs are more important than the essence of
the immune reactions, doctors conducting allergy skin testing do not monitor
systemic reactions. Thus, they miss the reactions with improvement, which
could form the basis for immunotherapy, or allergy shots. This, in turn, makes
it clear why immunotherapy is never conducted in skin allergies. If allergists
fail with the management of urticaria, how can they be expected to properly
manage the more complex asthma, chronic rhinitis or atopic dermatitis?
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Angioedema is usually classified into four major types. First, the hereditary type which is mostly the familial form, resulting from the bodys failure
to synthesize certain enzymes and/or proteins, does not belong in diseases of
hypersensitivity. Among the three other forms, there is an allergen-specific
kind. Another type is nonspecific or physical allergy. The third is
angioedema of unknown origin or idiopathic, as it is called in medicine.
Idiopathic angioedema is, actually, a susceptibility to react in a hypersensitive
way, a chronic form of the disease. Only one kind, allergen-specific, is potentially fatal. These patients develop reactions through exposure to certain triggers, among which peanuts are considered to be especially dangerous. At
times, even the smell or touch of a peanut-containing product may cause a
severe response. Reactions to penicillin, especially in injections, are another
example. Such hypersensitivity is incurable, and the triggers, once identified,
should be absolutely avoided. This type should not be confused with food
allergies, which may be curable.
C. HAY FEVER
This section on hay fever will be short despite the high incidence of this
disorder. The reason is that hay fever is like a bouquet of the diseases already
described earlier, only in this case, they are seasonal and are triggered by pollen.
Allergic rhinitis is the central manifestation although occasionally, it may not
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Does it help? Judging by the number of people who dread the coming of
warm days, not a lot. Of course, the best choice would be to leave the
country (province, or state) for the season. Do not forget to take your children with you because, most probably, they have inherited your allergies.
You think such trips are expensive? Never mind, to be in debt is better than
to suffer physically.
There are several additional tips patients with hay fever can use on top of
the Three As Program. Drive your car carefully in hay fever season. The roads
are full of drowsy people either due to the drugs they take or to the sleepless
nights they have had because of cough, congested nose and itchy skin. Driving
may also be dangerous in another sense: spontaneous sneezing attacks are
fraught with accidents. In 1989, while being in London, England, I read an
article about a car accident, in which the drivers mother was killed. He was
acquitted because he suffered from hay fever, and a severe sneezing attack had
been the cause of a car crash. On August 16, 1997, a lucky Canadian driver got
away with just few minor injuries after his car had turned upside down
during a similar sneezing fit. As you see, hay fever is not an innocent condition to sneeze at.
No matter how severe your cough is, do not rush to take antibiotics
prescribed by your doctor for alleged bronchitis. First, the weather is getting
warmer and warmer, second, you do not have a high fever. Even if your
family got infected from you or the other way around, it may not be due to
a viral epidemic, but simply because your children, siblings, parents and
grandparents probably suffer from the same medical problemhay fever. Be
positive: suffering together may unite your family still more. If antihistamines, decongestants and inhalers do not work, try to put up with the
temporary inconvenience, for even the longest season is over with the first
frost. You live in a place where pollens are in the air all year round? I am sorry
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for you, but either you change your location or keep hoping that you will
outgrow hay fever. Of course, it may take quite a few years or decades, but
you still have a chance.
In case the agony is intolerable or becomes dangerous due to your worsening asthma, you have one choice onlysteroids in nasal sprays, eye drops,
inhalers, and pills. Their consumption during the pollen season goes up drastically, and lucky are those consumers who have hay fever limited to only a
specific pollen and can restore their health from the steroid aftermath during
the rest of the year.
Pre-seasonal or year-round allergy shots are not very effective for the
majority, at least judging by the seasonal demand of daily medications. The
medical articles, though, often say the opposite. As soon as you start experiencing minor side effects from your shots, inform your doctor about that, and
consider discontinuing them if the side effects become more and more
pronounced. Remember: UK doctors prefer to have resuscitation facilities
around when they provide allergy shots, and medical papers warn doctors
about possible liability in administrating immunotherapy in their offices. Is
your doctors office close to a hospital?
My mockery is directed at the specialists proclaiming the high efficacy of
allergy medications and the efficiency of their Three As Program and similar
programs. Besides, laughter is the best cure, and smiling at this nonsense may
help an allergy sufferer feel better at least while reading.
Real help may come from histamine injections. Hundreds of my
patients started to live a normal life due to histamine injections. Many hay
fever patients came to me in a symptomatic stage. Within minutes of
allergy skin testing, the eyes would stop itching, congested noses would
open, headaches lift, shortness of breath or cough would disappear. The
main change, however, was disbelief that it was so simple to feel better. It
was still harder for them to believe that they would not be able to have this
therapy anywhere else. Some of them traveled a long distance to get the
treatment. Thanks to histamine, the majority of my patients became able
to enjoy summer camping, do the unthinkable such as mow grass, keep
their windows open, and drive without a fear that a sneezing attack could
turn fatal.
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PART NINE
FUNCTIONAL
ENCEPHALOPATHIES
WHAT IS ENCEPHALOPATHY?
This word consists of two Greek roots: Cephalic meaning pertaining to the
head, and pathosrelated to disease. Medical textbooks refer to encephalopathy only as a degenerative, organic disease of the brain often resulting from
a systemic disease elsewhere in the body. Such are, for instance, advanced
hepatic diseases, kidney failure resulting in dialysis, or lead poisoning. This
interpretation of encephalopathies is incomplete, since many people have
neurological symptoms in the absence of organic disorders. Their symptoms
are solely due to the imbalance of neurotransmitters in the brain, a condition
that should be classified as functional encephalopathy. Although very
common, these diseases have never been described before as one group, and
the classification functional encephalopathy does not exist in medicine. In this
sense, mental and neurological diseases such as headaches, attention deficit and
hyperactivity syndrome, depression and anxiety, chronic fatigue syndrome,
autism, many seizure disorders, schizophrenia, etc. are functional encephalopathies. The general notion of functional encephalopathy does not have any
place in nosology, the science that classifies diseases according to their origin
and body mechanisms involved in disease causation. The explanation lies in
the lack of understanding what mechanisms underlie the disorders united
under this name.
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Our nervous system consists of the centerthe brain and spinal cord,
and peripheral neurons and neural elements. Their distribution all over the
body explains why chemical changes in the center may involve any tissue or
organ in the disease. The central mediator in allergies, histamine, is also a
major neurotransmitter in the central nervous system. It does bothmediates neurological processes and regulates many. The pathways through which
neurons in the brain and elsewhere conduct histamine messages form a histaminergic neuron system. This section deals with those common
encephalopathies that result from the chemical disturbances in neurotransmission and assesses to what extent histamine imbalance contributes to functional encephalopathies.
HISTAMINE AS A NEUROTRANSMITTER
Histamine is an omnipresent cellular substance of a high physiological
potency and multifaceted effects. Its messages are distributed by the receptors
marked by the letter H. Each type of H receptor has its own function, that
may differ depending on the organ in which this receptor is situated.
Launched by a local trigger in any part of the body, histamine reaction can
invoke not only local but also systemic effects. Therefore, inefficient performance of any of the histamine receptors may alter the normal signals in the whole
histaminergic system and create a chemical imbalance both of histamine itself
and also of other numerous chemicals whose activity and release depend on its
regulatory messages.
Like histamine, many of these chemicals are both allergy mediators and
neurotransmitters. The role of histamine is magnified due to the fact that the
main histamine producers, mast cells and basophils, are highly disseminated
in various tissues including the brain. The degree of the involvement of the
nerve cells determines the severity of neurological symptoms. They may
accompany allergies but, if pronounced, can be isolated as a functional
neurological disease.
Long ago, observant clinicians noticed the co-existence of neurological
and allergic symptoms. Indeed, immune and neurological diseases seem to
cluster in families, although the predominance of certain symptoms over
others may differ among the members of the same family. The earlier-quoted
article by L. Mansfield1 gives historic references that go as far back as 1921,
when the relationship between the occurrence of asthma and rhinitis (the
immune system) and migraine (the brain) was noticed. Mansfield also refers
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to the works of the 70s and 80s that confirm an increased histamine output
in allergic dermatitis, food allergies as well as during migraine attacks. In
many aspects, pathological processes in these functional encephalopathies are
similar to the ones in allergies. This allows us to view these neurological
manifestations as allergic conditions of the nervous system or rather, hypersensitivity of the nervous system.
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part, depend on histamine messages and are relieved if the histamine pathways re-acquire their normal regulatory functioning.
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A. VASCULAR HEADACHES
HEADACHES ARE A HEADACHE FOR ALL MANKIND
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ancies of the official statistics. Besides, those having mild headaches may not
consult doctors, and neither do the patients who, after having unsuccessfully
tried numerous medications, realized the impotence of medicine in this area
and are resigned to putting up with the pain.
About 85% of male and 70% of female sufferers do not consult doctors
after initially unsuccessful visits. Even if we assume that these figures from a
lay magazine are exaggerated, they are still demonstrative, and with the
unrecorded cases, the cost of headaches to the health system and the economy
in all countries is enormous. The same U.S. survey in 1989 found that lost
productivity due to headaches was estimated to be $1.4 billion annually. In
1999, the costs of migraine headaches to the Canadian economy were estimated at $592 million a year. The population of Canada is about one tenth
the size of the U.S. Make your own calculation as to what this costs our
neighbor.
Conventional medicine offers only symptomatic relief for headaches,
hence, there is no hope that in the near future, the medical, social and fiscal
aspects of the problem will improve.
THE ROLE OF HISTAMINE IN VASCULAR HEADACHES
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Migraine headaches take a special place due to their high prevalence, severity
and, as a result, their grave monetary impact on society and the health system.
They do not spare even small children. Although different studies give
different figures on the percentage of children under 12, the latest estimates
say that the headache frequency among them does not really differ from that
in adults. In the early years, girls and boys suffer in equal proportions, but this
changes by the age of puberty. Women are hit by migraine two-three times
more often than men. Thus, the more frequent migraine attacks during
menses are related to the fluctuations in the estrogen levels, while the change
in hormones during pregnancy usually reduces their occurrence. Once again,
the relationship of hormones and neurotransmitters leads us to the hypothalamus with its regulatory histaminergic neurons.
Migraine is a temporal, mostly unilateral, throbbing headache, often
accompanied by nausea, vomiting, and extreme sensitivity to light and sound.
Complicated migraine may have wide-spectrum symptoms up to a transient
hemiplegia or blindness. The sufferers usually sense an approaching attack
through various bizarre signs, especially eye symptoms, but are powerless to
prevent it. This makes them irritable and anxious in advance of the attack.
To arrive at the diagnosis of migraine headache should not present great
difficulty in the majority of cases. Despite that, the fuss about inaccurate diagnostics goes on in periodicals and at conferences. A proverb teaches that when
you hear trotting, first think of horses, then of zebras. Medicine often looks
for the zebras first. As a result, patients with obvious symptoms and a family
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These headaches are usually bilateral, often throbbing, lasting from hours to
months. They are usually explained by the tension of neck muscles.
Electromyographic investigations deny the neck muscle tone as their origin,
and the fact that muscle relaxants do not really work for tension headaches is
also proof. Tension headaches are secondary to the disorganized cerebral
vascular tone, and as in migraine and cluster headaches, the pain is due to
swollen dilated vessels that press on the brain structures. Since the vascular
wall is lined with nerve cells, which are closely connected with mast cells, and
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migraine attacks as well as with other vascular headaches, and this makes
them analogous to allergies. Mansfield, quoted earlier, made a statement that
migraine is probably atopic (allergic) disease7 He also established a bridge
between therapies of neurological and allergic symptoms by saying: A
productive approach to migraine treatment and prophylactics will require the
same type of integrated analysis that is leading to better therapy of such
disorders as asthma. His article points out that the histaminergic neuron
system regulates serotonergic and noradrenergic activity via activation of H3
receptors and suggests H3-agonists as prophylactic agents for people who
suffer from vascular headaches. This attributes to histamine far greater
importance than to serotonin, at least in the production of vascular headaches. Clinical medicine ignores this scientific fact.
The pioneering ventures of some doctors to correct histamine imbalance
with histamine injections are discouraged quickly. Horton, being so famous,
could at least publish his articles, whereas attempts by practitioners of a lower
rank are doomed.
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and kidneys. Forbes Magazine, in the December 1997 issue, states there were
hundreds of fatalities of Tylenol overdose that year. Patients with headaches
must be the prime drug consumers. The amount of dollars paid for liabilities
is easily absorbed by the profits from the general drug sales, and the number
of casualties remains unknown to the general public under the terms of the
agreements between the manufacturer and the beneficiaries.
Tylenol #2 contains 15 mg of codeine, while Tylenol #3 has 30 mg of the
narcotic. Naturally, the more narcotic content, the better the pain relief. With
time, headaches become refractory to medications, the transitory relief
shortens, and correspondingly, the need of medications escalates. Narcotics
taken for a long time and/or in large doses form a habit. Simply put, headache
sufferers may involuntarily become drug addicts. Sadly, even upon the realization of the drug dependency, they may not be able to stop the medication
because of withdrawal symptoms. In fact, a lot of headache sufferers are
hidden drug addicts, and addiction is the price paid for the relief of every
attack. Considering the amount of the narcotic ingredient consumed by the
patients with headaches, one should not be surprised to find referrals to rehabilitation facilities among the treatments offered by Pain Management
Clinics. The word rehabilitation is a substitution for detoxification. Narcoticcontaining painkillers are especially dangerous for pregnant women, as their
babies may suffer withdrawal symptoms upon birth. Luckily, nature took care
of the potential disaster created by medicine, and the hormonal changes are
often favorable in that they rid pregnant women of headaches.
Whether another painkiller, Advil, is better or worse than aspirin or
Tylenol in relieving a headache, depends on the individual. Most patients
with headaches experiment with all of them at some stage.
Since headaches are common in allergy patients, Tylenol, Aspirin and
Advil are often combined with other medicationsdecongestants, antihistamines, antitussives (cough suppressants), and expectorants. These all claim to
relieve headaches, the accompanying cough, nasal congestion, and cold. The
latter is mostly misinterpreted allergic rhinitis. Each of the ingredients has its
side effects. I do not dare speculate about their interactions and cumulative
effect, which is highly probable because the chronic nature of headaches and
allergies forces a lot of patients to abuse the combo drugs.
For fear of liability, the producers list complications of their products, and
the responsibility lies entirely with the prescribers. Depending on the ingredients, the combination drugs may be contraindicated for patients with a
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and that prolonged remission of chronic cluster may be achieved by this type
of treatment, thus confirming the results of Horton. In spite of this information, the editor of Headache, Dr. Edmeads, states on page 62 in Conclusions that
no biochemical or imaging markers have been observed in headaches, and
the nature of the central nervous system dysfunction is unknown.11
Ironically, this very article exposes the nature of the dysfunction. It has
abstracts in English and in French. In the English version, the title is Cluster
headache, in French, it is La cephalee vaculaire de Horton, that is Hortons
headache. Before a cluster headache was renamed as Hortons vascular headache, it had been called histamine cephalgia. Although Hortons name has
been omitted in the main medical textbook, it still exists unchanged in
medical dictionaries and clearly points to the cause of headaches.
An interesting situation is created:
theoretically, the more significant role of histamine (compared to serotonin)
is well established;
one kind of vascular headacheclusteris directly called histamine
headache, and the central role of histamine in the two others is recognized;
a prominent scientist (Mansfield) speculates about histamine agonists in
headaches in his work based on 32 references;
histamine congeners exist in the Stanford laboratory;
histamine agonists are reported to be effective (by J. Arrang);
oral histamine derivative (Serc) and injectable histaglobin underwent
double-blind and open clinical studies, which are reported to be successful;
a world-famous neurologist (Horton) leaves 1402 medical charts of the
patients with neurological conditions, mainly headaches, whom, in the
majority of instances, he successfully treated with histamine. The 1985 neurological symposium, where he was given awards posthumously, recognized him
as an outstanding scientist whose belief that nature heals, but histamine
cures was based on his considerable knowledge of pathophysiology;
a group of contemporary professors of medicine (Diamond et al.) used
histamine with a rather high degree of success in clusters that had not
responded to other medications.
We have the solid grounds to employ histamine or its congeners at least on
those headache sufferers who are failures to any other therapy. Inexplicably,
in the same article, Mansfield turns 180o from being a proponent of histamine to becoming a promoter of its antagonists. The knowledge of histamine
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The word syndrome is of Greek origin and means a set of symptoms which
occur together. The abbreviated form for the disease is CFIDS orCFS. Look
attentively at the name of the disease. It sends the message that immunerelated and neurological events coexist, which is compatible with the
morphology (structure) and physiology (functioning) of our body. Another
message is that dysregulation in one of these systems finds, as a rule, finds its
way to the other. In fact, CFS is the best illustration of the coordinated functioning of various regulatory mechanisms, their unity and interdependence
in health and disease. The affliction of the two regulatory systems, nervous
and immune, may manifest in such an assortment of symptoms that there has
hardly ever been another disease causing so much discussion on its very existence. For doctors to master the concept of disease in principle and to understand the pathogenesis of this complex syndrome in particular, the
knowledge of psychoneuroimmunology, PNI, becomes a must. PNI is the
only science that studies the total body. Failure of the medical profession with
CFS both diagnostically and treatment-wise is a perfect illustration of what
happens when medicine excludes this science from its agenda.
Since the end of the seventies, an unexplained epidemic has been
spreading all over the world, especially in the developed countries. The main
complaint was an unusual tiredness unrelated to the load of work performed
or stress endured. It often affected young, otherwise healthy people, especially so-called yuppies. The question of why CFS has been initially registered among the younger and more educated people is of great interest, and
does not have one answer. Definitely, ambition and psychological stress
among the yuppies are higher than in the average population, and this
contributes to the development of diseases. Another thing is that educated
people care more about their health and hence, notice their ailments earlier.
There is also a high professional demand to be fit, which explains their
interest in medical achievements and desire to turn those into their service.
Thus, yuppies consult doctors and start taking medications earlier than
other groups of people, and the disease in this case had more to do with the
awareness than with environment or genetics. The reasons are mainly of
social, not medical nature.
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transmitters. Like many chronic diseases, CFS may not have any identifiable
trigger. Therefore, the understanding of the genetically predetermined regulatory defects in the functioning of the immune and nervous systems becomes of
utmost importance, while what triggers the process is of lesser significance.
Nevertheless, the attention of clinical medicine is focused solely on the
secondary events, and the fight is going on to eliminate those potential triggers, which are the products of our abusive attitude towards nature. The fight
for cleaner air and water is justified. However, this fight for an improved environment would in no way be less justified if doctors started to focus on
tuning up the immune and nervous systems of those who are now paying the
high price for the progress of our civilization. Trigger elimination and environmental purification can hardly help them at their most immediate level.
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action. CFS patients are not given even this illusion of hope. Their disease does
not have a specific season to make them aware of its approach. They do not
know what to avoid, as there are no certain identifiable stimuli. They cannot
act because not only are they physically unable, but they do not know what to
do. The doctors are helpless, and the most sincere of them admit the fact.
A lot of self-help groups have appeared. Probably, psychologically it is
easier to know that you are not alone, and that many others suffer from the
same mysterious general malaise that is often difficult to describe. A lot of
patients see their families falling apart because other members are unable to
cope with a permanently sick (pretending?) person or to comprehend that a
severe illness may exist and not show in tests. Financial difficulties add up due
to the inability of the sufferer to work. The combination of the untreatable
physical symptoms and the resulting social problems takes its toll, and the
number of suicides among CFS patients is rising.
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of these therapeutic means. I am merely stating the sad fact of their failure to
produce any significant positive effect.
The list of medications prescribed by doctors includes antidepressants
such as Prozac and Elavil, symptomatic drugs for intestinal disturbances,
painkillers for aches, muscle relaxants for tense muscles, anti-inflammatory
drugs for aching joints, antihistamines for allergic symptoms, and antibiotics
for recurrent sore throat (despite the absence of any bacterial proof of such
infections). As is the case with all chronic diseases, the drugs target the
organs affected at a given moment. What if a patient has numerous symptoms at once? Imagine starting the morning with a pile of pills in front of you!
To know how ineffective the medications are, one only needs to open any
book on CFS or read patients pleas on the Internet.
The panacea for all chronic conditionssteroidshas already put its foot
in the door. Steroids are not yet the main drug in CFS, as they are in asthma,
but wait, it is only the beginning. The idea of using them was born when a lab
testing revealed that patients with CFS often have a decreased level of adrenal
corticosteroids. A prescription for their replenishment with oral or injectable
steroids was ready at once, with all the possible consequences. And again we
hear assurances about the harmlessness of the low doses in which steroids are
prescribed. Such is, for instance, the conclusion of one of the initiators of
steroids in CFSthe research team at the National Institute of Health in
Bethesda, Maryland, that has studied the illness since 1979. This idea has
supporters. We have steroids as the first-line therapy in asthma and know
their effect on the immune system. In case of CFS, steroids will inhibit the
hosts already weakened immune system and also adrenals and thus deprive
the sufferers of their central natural defense. For these patients, steroids may
prove even more harmful, as depression is a common symptom of CFS, and
it is also a typical side effect of steroids. The drugs may deepen the existing
depression and increase the need of antidepressants later. The logic of medicine never fails to amaze me.
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involve the whole body in disease. Similarly, correction of the defect can
rectify numerous problems. The following is what should be widely known
about the functioning of the central regulatory systems and histamines
involvement in it:
the total body is not a mechanical construction made up of different
isolated parts but an artful indivisible design of nature;
the functioning of the nervous, immune and endocrine systems is reciprocal;
the crossroads of these systems is the hypothalamus and pituitary unitthe
brain structures controlling neuro-endocrine and immune mechanisms;
histaminergic neurons are abundant in the hypothalamus and only relatively less in the peripheral nervous system;
histamine is an inherent chemical in all body tissues and a major product
of immunocompetent cells;
all cells possessing histamine receptors form the histaminergic system that
conducts and realizes its messages;
histamine messages are central in allergy, asthma and are very important
in other chronic immune inflammatory diseases; they also carry regulatory
instructions to neurotransmitters in neurological disorders;
histamine messages work through the CRH/mast-cell/histamine axis and
thus involve the HPA axis (CRH stands for corticotropin-releasing hormone)
histamine regulates CRHthe pituitary hormone-messenger, which activates the work of the adrenals, our main organ in adapting to all situations
stressful to the body.
histamine imbalance can affect the functioning of the whole body due to the
spread of histamine-generating cells and histamine receptors.
Since any functional encephalopathy arises as a result of a chemical imbalance
in the brain, histamines ability to modulate the release of other important
mediators and neurotransmitters may become crucial. Histamine governs
serotonin, which is central to the origin of vascular headaches, depression,
chronic fatigue syndrome, irritable bowel syndrome;
norepinephrine, whose imbalanced release leads to depression, anxiety,
chronic fatigue syndrome;
dopamine, whose release is central in schizophrenia and Parkinsonism, and
endorphins that affect mood and control any pain, including headaches.
The impaired regulatory activity of histamine becomes the cause for functional
encephalopathies, including CFS. You might say that dysregulation of any other
major mediator or neurotransmitter can be equally responsible for the symptoms, and thus, histamine is not unique. That is correct, but partially only.
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are either depressed or agitated, or their mood inexplicably swings. Often, this
is perceived as bad manners or an evil disposition. These people present a
huge economic burden to society due to the treatment expenses, the low
performance level at work, the high absenteeism and the disruptive effects on
co-workers, family and friends.
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consumption. An abrupt discontinuation may bring on withdrawal symptoms such as anxiety, sweating, and hallucinations. Therefore, tranquilizers
should be tapered down rather than abruptly discontinued.
It is not the intention of this book to suggest which of the existing tranquilizers and depressants are more effective, less hazardous, and what interactions may occur in those who concurrently take other medications, etc. A
patient may receive this information from his doctor, read in the
Compendium of Pharmaceuticals and Specialties or the inserts put into the
drug packaging, or find it in books such as The Worst Pills, The Best Pills.
Instead, I want to point to the inexpensive, safe and effective therapy, which
is not accepted by the medical profession ironically, due to the fact that it is
inexpensive, safe and highly effective. You guessed it, I am referring to histamine injections. I treated allergy patients who had accompanying anxiety and
depression, and the majority greatly improved or recovered with histamine
therapy. For them, histamine was both effective and devoid of the side effects
of the drugs used in the treatment of depression and anxiety.
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RITALIN
Every doctor agrees that the diagnosis of ADHD is of prime importance both
from the medical and social points of view. Let us assume the doctor arrived
at the diagnosis of ADHD. Can the disease be controlled? Yes, says mainstream
medicine and prescribes Ritalin on a daily basis. At present, Ritalin is the
principal medication for ADHD and, therefore, necessitates a special review.
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I usually explained to the parents the concurrence of neurological symptoms with allergies and suggested they monitor the childs behaviour during
the therapy. It worked. Not a single parent complained that his child suffered
from Ritalin deprivation.
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Functional Encephalopathies
more and more frequently, it is diagnosed in children. One can easily see the
similarity in the growing prevalence of IBS along with the increase of other
functional disorders such as allergies, asthma, chronic fatigue syndrome and
attention deficit disorder.
As all syndromes, IBS consists of a number of typical symptoms, which
occur in various combinations. Among them, there is abdominal pain of varying
intensity, at times so severe that the patients are rushed to ER. Abdominal
discomfort, loose bowel movements or diarrhoea with mucus in the stool,
constipation, bloating, gas, nausea, etc. are common. As a rule, patients with
IBS undergo numerous tests in the offices of gastroenterologists to exclude
peptic ulcer disease, inflammatory bowel disorders, lactase intolerance, etc.
They learn, finally, that the tests do not show any organic cause. Lucky are those
whose doctor at least diagnoses IBS and assures them that it is not a malignancy.
The majority remain without any definite diagnosis, or are misdiagnosed.
The textbook Harrisons Principles of Internal Medicine (1987) starts the
description of the disease on page 179 with the following paragraph: The irritable bowel syndrome is the most common gastrointestinal disease in clinical
practice, and although not a life-threatening illness, it causes great distress to
those afflicted and a feeling of helplessness and frustration for the physician
attempting to treat it. The textbook also explains the reasons for the frustration: Unfortunately, no specific drug or dietary regimen affords good relief in19
all patients, and thus a number of therapeutic manoeuvres need to be tried.
The 2000 statistical data given by Dr. G. Kandel from the University of
Toronto state that the symptoms of IBS are present in about 30% of the
general population.16 This leads us to the inevitable conclusion that this is the
single most prevalent disease in medicine. Since the disease has no treatment,
it is especially interesting to see what medicine does for the people with IBS.
Quite naturally, a poorly understood and generally misdiagnosed disease
cannot be treated properly. Doctors do not treat the condition as a neuroregulatory disorder but as a gastrointestinal disease. It is not different from
the treatment of allergies and asthma that are also dealt with in the end organ.
Antacids and painkillers are common medications for abdominal cramps;
opiates are given for diarrhoea and soluble fibre for constipation.
Only a patient with IBS can understand how embarrassing it is to have a
severe bloating or to feel an urge to defecate in the middle of a serious
meeting. The few doctors who understand that its roots are in the brain
chemistry, may prescribe antidepressants. This, however, does not resolve the
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problem either. The chronic nature of the disease can make antidepressants
regular medications and thus lead to a number of complications. The need to
deal with additional symptoms intensifies the patients dissatisfaction and
depression and by that, aggravates the course of IBS. Antidepressants may
also be prescribed to patients with IBS because many of them become deeply
frustrated with their never-ending bowel symptoms and do develop depression and/or anxiety.
Some doctors may suspect an infection and prescribe antibiotics, medications completely inappropriate for IBS. This often creates paradoxical situations. Thus, one of the adverse effects of antibiotics is constipationthe
symptoms the patient may already have. Other adverse reactions include
headaches and muscle aches or pains; and again, the patients may already have
those, as these symptoms commonly accompany encephalopathies.
Modern medicine recognizes the presence of numerous symptoms that
point to the central role of the brain in IBS. Dr. Kandel, for instance, discusses
a constellation of them: mood swings, panic attacks, anxiety and depression
as well as non-specific brain-related symptoms such as headaches, backache,
fibromyalgia and urinary tract symptoms. Saying that, one would think
science should seek the roots of all these manifestations in the chemistry of
the brain as uniting regulatory arm. However, as with allergies and other
encephalopathies, medicine points to the more evident superficial connections. This author, for instance, says that 40% of the patients with IBS have a
history of sexual or physical abuse and pronounces these factors as central in
the origin of the disorder. No argument, a severe stress, no matter of what
nature, may contribute to the development of any chronic disorder, but such
factors are not specific to IBS per se.
This Canadian gastroenterologist makes another assumption that may
even insult many syndrome sufferers: IBS is a disease of physician-seeking
behaviour. In other words, patients see a physician in order to attract his
attention or out of fear that their symptoms are the result of cancer or
another dreadful disease. No wonder the author suggests that reassurance
should become the pivotal point of management. Other specialists also
support psychological encouragement, which in some cases is better than
medications, at least from the standpoint of side effects thereby avoided.
The answer to IBS, its cause and treatment is similar to that in all
encephalopathies. The underlying cause lies in imbalanced neurotransmission in the brain-gut pathways. This inevitably indicates the involvement of
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381
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tive product, as they will also deal with the effects secondary to histamine
imbalance. Patients should be happy if these medications provide at least
short-lived improvements. The drug industry, with support of the medical
academia, successfully fights nature in all that involves histamine.
Almost half of the patients with allergies present with various degree of
IBS, and it is most typical of patients with chronic fatigue syndrome. This is a
direct indication that in their origin, these three most common chronic
diseases merge.
The majority of my patients came for the treatment of their allergies or
asthma. I invariably asked them about their gastrointestinal symptoms, which,
as a rule, they neglected to mention, not knowing the connection. It usually
took a long time to explain what IBS was, and how it related to their other
symptoms. To the patients surprise, my prediction that relief of their bowel
symptoms might be a bonus often came true. Similar to other encephalopathies, the improvement was often obvious at the allergy skin testing: those
who were experiencing symptoms at the time of the testing felt relief.
Histamine therapy worked in almost all cases.
The sad conclusion is: IBS, a disease of the highest incidence, is poorly
understood, mostly misdiagnosed and does not have any treatment. Any
manoeuvre, as the main medical textbook says, is worth trying in order to
relieve the plight of these patients. Histamine could render that help. Still, it
may never be allowed despite the available theoretical substantiation from
basic sciences of its modulatory capacity, and despite its availability in several
forms. The problem with histamine is that in all relevant areas, it turns out
to be too effective and would thus shrink the drug market.
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I had four patients with autism. The degree of improvement ranged. The
best results were achieved in a boy with advanced autism, a savant, who stayed
on the treatment for over two years. He was brought initially for food allergies,
without the slightest expectation of improvement in his main problem. In the
end, his performance at school improved dramatically, he started to make eye
contact and logically answer questions. In fact, only a very close observation
could find some minor deviations from the norm in his behavior. Prior to the
histamine treatment, the boy had received a vast variety of unconventional
treatments from North American and European specialists that his well-off
parents could pursue. Another four-year old autistic child, for the first time in
his life started to pronounce words after just four or five injections.
Regrettably, the family could not travel the long distance and stopped the
treatment. The third patient was a small girl with an advanced form of autism.
She was treated for her allergies but showed better behavior, became calmer
and stopped gritting her teeth. Her treatment was stopped because of the ban
of histamine therapy imposed upon me by the CPSO, and this probably
deprived her of further improvement. The forth was a young adult who
became calm and compliant after a few injections. His elderly parents were
unable to bring him on a regular basis, and the treatment stopped.
Considering that no treatment exists for autism, histamine could at least be
used on a trial basis.
I also treated several children with uncontrolled urgency to urinate or with
bedwetting. As it is common in medicine, if an organic cause is not found, the
symptoms are considered to be of psychological origin. Therefore, parents of
these children planned a visit to a psychiatrist on the advice of their family
physician. I suspected the allergy-associated chemical imbalance in the area of
the brain that regulated the bladder functioning. On my advice, the parents
postponed the visit to a psychiatrist for the few weeks that I was treating their
children for allergies and asthma. In all these cases, the symptoms of incontinence disappeared, often faster than the allergy symptoms.
Of interest is a case of a nonspecific condition. The patient, a 7 year-old boy,
suffered from nightmares. He would get up at night and walk around the house.
His mother called my office several days after the initial prick test with histamine. The boy stopped his night wandering, and she decided to postpone the
next visit, to see whether this was coincidental. She brought her son back half a
year later when the symptoms resumed. A short treatment was successful.
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There was another peculiar casean elderly man with ALS, amyotrophic
lateral sclerosis, a fatal disease due to progressive degeneration of the neurons.
The patient could not swallow and suffered from severe pains in his jaw. The
neurologist who had seen him before and after my histamine treatment stated
in his report, Interestingly, his pain was relieved by histamine injections.
The menopausal hot flushes related to hypothalamic/pituitary dysfunction are treated by gynecologists and family physicians generally by synthetic
hormonal replacement therapyHRT. The studies on HRT are contradictory
in their findings, but lately, in view of dangerous complications, this treatment is recommended only in cases of severe symptoms. Histamine therapy
almost completely eliminated or greatly relieved these symptoms as well as
some others that often accompany menopause, such as insomnia, perspiration, dizziness, depression and anxiety. In these cases, the patients needed
maintenance shots for a lasting period in view of the continuing hormonal
changes. None reported any side effect but only positive changes.
Blood vessels do not exactly belong in the area of neurology. However,
vascular tone is regulated by neuro-endocrine processes and is thus affected
by the hypothalamus. The abundant presence of histamine in the hypothalamus and histamine receptors in the vascular wall is the reason why hypertension may respond to histamine. The normal activity of histamine
receptors improves the tone of the vessels, and blood pressure normalizes.
There is another important point in the treatment of hypertension. Betablockers often prescribed for high blood pressure may become a trigger for asthma
patients who have inefficient beta-adrenergic receptors. These receptors need
stimulation, not suppression. Thus, not only does histamine therapy normalizes the vascular tone by activating H2/3 receptors in the vascular wall, but it
also eliminates the need of beta-blockers and the resulting worsening in
current asthma or the possibility of inciting a latent form.
You may say that no drug is a panacea, and histamine cannot be one either.
Right. However, human beings are whole entities. Our central regulatory
systems function in coordination, and successful immuno- or neuromodulation resonates through the whole body by restoring numerous functions. The
word holistic is defined in dictionaries as relating to the conception of man as
a functioning whole. This is in perfect harmony with the most comprehensive
field of medicinepsychoneuroimmunology, which remains primarily in the
domain of theoretical sciences. Our market-focused medicine has lost the
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holistic approach of ancient medicine. This is when other sciences are parting
with the old hard-nosed materialism of the XIX century and switching to integrative holism of the XX century.
Medicine has reached that shocking state where it cannot exist without its
sponsorthe drug industry. If in the remote past, the industry was supposed
to serve medicine, it is the opposite today. This has made medicine an exception among sciences and, as a result, it has become hostile not only to everything new but also to everything old that can be useful and healing. This is
especially obvious in the most reversible diseasesallergies, asthma and functional encephalopathies.
ENDNOTES
1. JACI 1990;86:673-76
2. Is the histaminergic neurone system a regulatory centre for whole-brain activity? Trends on
Neuroscience 1991;14:415-8
3. G. Chrousos. Stress, chronic inflammationJACI 2000;106:S275-91
4. U. Knigge, J. Warberg, The Role of Histamine in the Neuroendocrine Regulation of Pituitary
Hormone Secretion, Acta Endocrinologica, Copenhagen 1991;124:609-19
5. U. Knigge, J. Warberg, The Role of Histamine in the Neuroendocrine Regulation of Pituitary
Hormone Secretion, Acta Endocrinologica, Copenhagen 1991;124:609-19
6. H. Wada et al. Trends on Neuroscience 1991;14:415-8
7. L. Mansfield. The role of antihistamine theraphy in vascular headaches. JACI 1990;86:673-76
8. J. Edmeads. Cluster headache and its cousins: A family of pain management problems. Pain Res
Manage 2000;5:58-63
9. JACI 1990:673-76
10. S. Diamond et al., Treatment of Intractable Cluster. Headache, Jan.1986:44-45
11. Pain Res Manage 2000;5(1):58-63
12. For a full discussion of the medical politics of this condition see the investigative report by
H. Johnson, Oslers Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic,
Penguin, 1996
13. Pollard Publishing 1990
14. Brandes L.J.et al. Stimuilation of malignant growth in rodents by antidepressant drugs at
clinically relevant doses. Cancer Res 1992;52:3796-3800
15. For full understanding of the known danger of antidepressants, I refer you to the study by
David Healey, Let Them Eat Prozac, 2003
16. G. Kandel. Irritable Bowel Syndrome. The Canadian J of Diagnosis, December 2000: 82-91
17. G. Chrousos. Stress, chronic inflammation and emotional and physical wellbeing: concurrent
effects and chronic sequalae. JACI 200;106:S275-91)
18. Parkhurst Exchange Nov. 1999, p. p. 76-9
19. Harrisons Principles of Internal Medicine, 1987
20. Harrisons Principles of Internal Medicine, 2001
21. Thome J. et al. Cyclic AMP response element-binding protein and depression. Expert Reviews in
Neurotherapeutics 2002; 2:347-54
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EPILOGUE OR:
EPPUR SI MOUVE! 1
Exactly one week before the submission of this manuscript to the publisher,
the saga on histamine took an unexpected turn when I opened the latest issue
of The Journal of Allergy and Clinical Immunology. To say that I was stunned
is an understatement: there was a review article with the content-revealing
title of Histamine in the Immune Regulation of Allergic Inflammation.2 The
rubric under which the article was published was no less remarkable:
Rostrumthis in Roman times, was the platform a person stepped onto in
order to gain the publics ear. I do not have an explanation of how such an
exotic fish could slip through the thick net that had solidly protected the
steroid-saturated journals for more than a decade. However, the very appearance of this publication gives me a slight hope that the truth and medical
ethics will one day be victorious in allergy.
The authors are clinical immunologists from the Swiss Institute of Allergy
and Asthma Research, and their work was sponsored by grants form the Swiss
National Foundation (not a pharmaceutical company, but a tax-payer-funded
national body). The paper is the most comprehensive and accurate overview
of histamine and its functions since the times of R. Rocklin. It is based on 73
references and covers the histaminergic system and the four known histamine
receptors on which its functioning depends. The theoretical work revives
almost all the buried information on the histamine-related mechanisms of
allergy with the emphasis on those that participate in the reversal of allergic
inflammation. The authors
unearth the immune- and neuromodulatory role of histamine;
suggest a novel therapeutic approach in man: using H3-receptor agonists
and implementing through them the negative feedback loop enables one
to control excessive inflammatory responses;
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Epilogue 389
practice in order to help those millions who suffer needlessly only because
somebody, obviously for personal reasons, decided to conceal the truth.3
Clinical allergy can break away from the drug industry and significantly
reduce its dependence on it if, instead of medicating its patients with immunosuppressive steroids, it will start to revive the bodys sick regulatory tools with
well-researched, safe, effective and inexpensive histamine. This would allow
the national health systems to save billions of dollars that could be channeled
into different problems. The statements coming from the rostrum should not
fall on deaf ear. In this sense, this book is a litmus paper for the Medical
Establishment: the way they treat the material presented here will be indicative
of whether the patients interests are truly above their own interests.
ENDNOTES
1. This statement is attributed to Copernicus who is said to have muttered it as he left a trial
before the Inquisition where he was forced to recant his mathematical proof showing that
the sun, not the earth, is at the centre of our solar system.
2. C. Akdis, K. Blaser. Histamine in the immune regulation of allergic inflammation. JACI
2003;112:15-22
3. K. Melmons letter of August 28, 1991, to Dr. Ravikovich, that recognizes therapeutic
H2/3 activity: See Appendix. p. 404.
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1995 September 1;153:569-71
Schwartz L. The Mast Cell. In: Allergy, ed. Kaplan A. 1985:58
Sears M. Descriptive epidemiology of asthma. Lancet 1997;350 SII:104
Sercarz E. The distinctive specificity of antigen-specific suppressor T cells. Immunology Today
1991;12:110-7
Sharma J. et al. Chronic urticaria. Journal of Cutaneous Medicine and Surgery 2000;4:89-93
Shearer W. et al. AAAI Training Program Directors Committee: Committee report. Core
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Shearer W. et al. Defining the spectrum of clinical immunology. JACI 2003;111:S766-73
Shirley K. et al. Attenuation of cutaneous and bronchial late allergic reactions JACI
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Sirois P. et al., eds. Immunopharmacology. Elseveir Biomedical Press 1982
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Szefler S. The changing face of asthma. JACI 2000;106:S139-43
Takeuchi D. et al. Histamine alters gene expression JACI 2001;107:310-4
Tattersfield A. Foreword. Lancet 1997;350:S11
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Von Mutius E. Editorial. Clinical and Experimental Allergy 2001;31:1651-2
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401
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SAMPLE
To The Premier of Ontario
Your area MPP
The media (TV, newspapers, radio)
(Adjust the text to include your own story as a patient or physician.)
Dear . . .
I have read The Plot Against Asthma and Allergy Patients by Dr. Felix Ravikovich
(KOS Publishing Inc. 2003) and learned that effective treatment for asthma and allergy
exists and that it has been actively suppressed by the College of Physicians and Surgeons
of Ontario (CPSO). I urge you to read this book and examine the documented facts
regarding the highly effective and scientifically supported histamine therapy.
The CPSO has indefinitely and arbitrarily forbidden its use in the absence of patient
complaint or harm, despite scientific support and public protest by hundreds of patients
helped by this treatment and denied access to it since 1992. One request that you:
1. order the CPSO to lift its ban on Dr. Ravikovichs use of histamine therapy and
2. take steps to allow Dr. Ravikovich to teach doctors willing to learn his technique.
I base my demand on the Helsinki Accord on Human Rights, an international treaty to
which Canada signed in 1988. Among its clauses you will find one by the World Medical
Association, which in 2000 became part of Ontarios Medicine Act in 2000, but has been
effectively ignored by the CPSO. It states the following:
In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgment, it offers hope of saving life,
reestablishing health, or alleviating suffering.
I am looking forward to your reply.
Signed
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Page 408
Index
A
ADHD . . . . . . . . . . . . . . . . . . . 372, 376
adrenals . . . . . . . . . . . . . . . . . . . . . . 185
suppression of. . . . . . . . . . . . . 187 ff
allergens . . . . . . . . . . . . . . . . . . . . . . 82
allergic inflammation . . . . . . . . . . . . 99
allergy . . . . . . . . . . . . . . . . . . . . . 71, 93
borderline diseases, and. . . . . . . . 81
causes vs. triggers in . . . . . . . . . 69 f
angioedema . . . . . . . . . . . . . . . . . 338 ff
animal dander . . . . . . . . . . . . . . . . . . 86
antibiotics . . . . . . . . . . . . . . . . . . . . 101
and asthma. . . . . . . . . . . . . . . . . 245
anti-challenge test . . . . . . . . . . . . . . 226
antigen. . . . . . . . . . . . . . . . . . . . . 70, 72
antihistamines
and cancer . . . . . . . . . . . . . . 36, 177
and FDA. . . . . . . . . . . . . . . . . . . . 36
and genetic interference of . . . . 176
and immunosuppression . . . . . . 177
and side effects . . . . . . . . . . . . 176 ff
anti-inflammatory drugs . . . . . . . . 102
anti-IgE agents . . . . . . . . . . . . . . . . 280
antileukotrines . . . . . . . . . . . . . . . . 279
asthma
antibiotics. . . . . . . . . . . . . . . . . . 101
as chronic inflammatory
disease . . . . . . . . . . . . . 156, 302
as a growing problem . . . . . . . . 238
causes of . . . . . . . . . . . . . . . . . . . 256
conventional treatment for . . . . . 12
current definition. . . . . . . . . . . . 240
diagnosis of . . . . . . . . . . . . . . . . 249
historic understanding of . . . . . 300
B
B-cells . . . . . . . . . . . . . . . . . . . . . . . . 71
Barnes . . . . . . . . . . . . . . . . . . . . . 156 ff
basic science . . . . . . . . . . . . . . . . . . . 63
bronchiodilators
long-acting . . . . . . . . . . . . . 269, 275
C
cAMP. . . . . . . . . . . . . . . . . . . . . . 37, 50
cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
immunocompetent . . . . . . . . . . . . 5
Chronic Fatigue Syndrome. . . . . . . 361
social problem . . . . . . . . . . . . . . 364
therapies for . . . . . . . . . . . . . . . . 365
psychoneuroimmunology and . 367f
cluster headaches . . . . . . . . . . . . . . 351
combination drugs . . . . . . . . . . . . . 182
conventional classification of allergy 80
corticosteroids. . . . . . . . . . . . . . . . 183 f
cytokines . . . . . . . . . . . . . . . . . . . . . 40 f
D
decongestants . . . . . . . . . . . . . . . . 180 f
dendritic cells . . . . . . . . . . . . . . . . . . 18
depression . . . . . . . . . . . . . . . . . . . . 370
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Page 409
Index 409
Diamond Headache Clinic . . . . . . . . 33
Dristan . . . . . . . . . . . . . . . . . . . . . . 180
drugs for headaches . . . . . . . . . . . . 354
duality in allergy . . . . . . . . . . . . . . . . 59
in medicine . . . . . . . . . . . . . . . . . . . . 60
in patients . . . . . . . . . . . . . . . . . . . . . 62
E
economics in medicine . . . . . . . . . . . 56
encephalopathy . . . . . . . . . . . . . . . . 343
and histamine . . . . . . . . . . . . . . 347
eosinophils . . . . . . . . . . . . . . . . . . . 141
European Histamine Research
Society . . . . . . . . . . . . . . . . . . . . 125
F
FDA bans. . . . . . . . . . . . . . . . . . . . . 181
food allergy . . . . . . . . . . . . . . . . . . . . 89
I
G
gene mutations . . . . . . . . . . . . . . . . . . 3
genetic functions (histamine). . . . . . 51
genomodulation . . . . . . . . . . . . . . . . . 4
H
hay fever . . . . . . . . . . . . . . . . . . . . 339 f
headaches . . . . . . . . . . . . . . . . . . . 349 f
histaglobin . . . . . . . . . . . . . . . . . . . 32 f
histaglobulin . . . . . . . . . . . . . . . . . . 32 f
histamine. . . . . . . . . . . . . . . . . . . . . . 17
as a cure . . . . . . . . . . . . . . . . . . . . 33
as neurotransmitter . . . . . . . . . . 344
asthma, and . . . . . . . . . . . . . . . . . 29
bias against. . . . . . . . . . . . . . . . . . 30
cellular vs synthetic . . . . . . . . . . . 23
congeners of . . . . . . . . . . . . . . . . 120
corrects genetic defect . . . . . . . . . 51
degranulation and . . . . . . . . . . . . 17
derivatives of . . . . . . . . . . . . . . . 120
disease and . . . . . . . . . . . . . . . . . 162
drug industry and. . . . . . . . . . . . 65f
dual activity of . . . . . . . . . . . . . . . 43
encephalopathies and . . . . . . . 345 f
homeostasis and. . . . . . . . . . . . . . 22
induced cytokines . . . . . . . . . . . 41 f
K
Kaplan. . . . . . . . . . . . . . . . . . 131, 133 ff
Kay . . . . . . . . . . . . . . . . . . . . . . . . 138 ff
L
Langerhans cells . . . . . . . . . . . 18, 210 f
Lichtenstein . . . . . . . . . . . . . . . . . 122 ff
M
mast cells. . . . . . . . . . . . . . . . 16ff, 139 f
as protective . . . . . . . . . . . . . . . . 163
medications. . . . . . . . . . . . . . . . . . . 173
side effects of . . . . . . . . . . . . . . 173 f
skin reactions and . . . . . . . . . . . 209
Melmon . . . . . . . . . . . . . . . . . . . . 117 ff
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Page 410
migraines. . . . . . . . . . . . . . . . . . . . . 351
N
negative feedback . . . . . . . . . . . . . . 158
neurotransmitters . . . . . . . . . . . . . . . 20
non-steroidal anti-inflammatory
drugs (NSAID) . . . . . . . . . . . . 277 ff
P
Peptides . . . . . . . . . . . . . . . . . . . . . . 229
R
rhinitis . . . . . . . . . . . . . . . . . . . 318, 323
and immunotherapy . . . . . . . . . 326
Ritalin . . . . . . . . . . . . . . . . . . . . . . . 375
Rocklin. . . . . . . . . . . . . . . . . 421, 110 ff
S
science and freedom . . . . . . . . . . . . 313
Seladane . . . . . . . . . . . . . . . . . . . . . 181
serotonin . . . . . . . . . . . . . . . . . . . 358 ff
skin allergies . . . . . . . . . . . . . . . . . . . . .
signal transduction . . . . . . . . . . . . . . 10
signal transmission . . . . . . . . . . . . . . 10
skin testing . . . . . . . . . . . . . . . 203, 253
and immunotherapy . . . . . . . . . 223
delayed systemic reaction . . . . . 220
false positive/negative . . . . . . . . 208
potential dangers of . . . . . . . . . . 219
reactions to as improvement . . . 216
systemic reaction to . . . . . . 212, 214
T
T-cells. . . . . . . . . . . . . . . . . . 14, 70, 144
T-suppressors . . . . . . . . . . . . . . . . . 15 f
as defence against allergy . . . . . 44 ff
tension headaches . . . . . . . . . . . . . . 352
Tilade. . . . . . . . . . . . . . . . . . . . . . . . 277
Theophylline . . . . . . . . . . . . . . . . . . 274
treatments
elimination as. . . . . . . . . . . . 84, 255
antibiotic. . . . . . . . . . . . . . . . . . 99 ff
triggers vs causes. . . . . . . . . . . . . . . . 92
nonspecific . . . . . . . . . . . . . . . . . . 74
U
urticaria . . . . . . . . . . . . . . . . . . . . 334 ff
V
vascular headaches . . . . . . . . . . . . . 350
histamine in . . . . . . . . . . . . . . 351 ff
Z
Zaditen . . . . . . . . . . . . . . . . . . . . . . 278