Professional Documents
Culture Documents
Cox 2 Document
Cox 2 Document
Cox 2 Document
1/9/00
4:56 PM
Page 1
COX-2-selective NSAIDs:
New wonder drugs?
COX-2-selective NSAIDs:
New wonder drugs?
1. Introduction
Aspirin and other non-steroidal antiinflammatory drugs (NSAIDs) are one of the most widely used
classes of drugs, with both prescription and over the counter sales of the agents contributing to
total usage. NSAIDs are believed to act through inhibition of prostaglandin (PG) synthesis
secondary to their inhibition of the enzyme cyclooxygenase (COX). This results in suppression of
inflammation, and effective analgesia. Most NSAIDs not only inhibit PGs at sites of inflammation,
but also PGs which serve important functions in other parts of the body, a factor which accounts
for some of the toxicity of these agents. The most frequent complications associated with NSAID
usage are those involving the gastrointestinal tract (GIT). GI bleeding, ulceration and perforation
are a significant cause of morbidity and mortality in patients who are treated with these agents.
A new approach to avoiding NSAID-induced complications became feasible with the discovery
that there are 2 isoforms of COX, COX-1 and COX-2. These enzymes are under distinct
regulatory control mechanisms. COX-1 is constitutively expressed in most tissues, and plays a
major role in normal functioning of the GIT, kidneys and platelets. In contrast, COX-2 is
expressed primarily in response to inflammation, but to some extent in other tissues including
kidneys and brain. Traditional NSAIDs are non-selective and inhibit both COX-1 and COX-2,
providing benefits in inflammation, but at the cost of potential adverse effects. Recently, two
COX-2-selective NSAIDs have been approved by the TGA, celecoxib (Celebrex) and rofecoxib
(Vioxx). Celecoxib, the first of these drugs to become available, is one of the best selling new
drugs to be marketed in the USA. It is likely that these agents will be covered by the PBS in the
year 2000. Both drugs are being aggressively marketed by the pharmaceutical industry, however
there is limited clinical experience, and monitoring adverse events in patients is a priority for
clinicians who prescribe these agents.
This document provides a review of the physiology and pharmacology of the COX system, and
published studies and clinical trials which have investigated the COX-2-selective NSAIDs.
Prostaglandin(s) Involved
PGE2, PGF2, PGI2
TXA2
PGI2
PGE2, PGI2
PGF2
PGE2, PGI2
PGE2, PGI2
PGE2, PGF2
PGI2
PGD2
Differences
Regulation
Tissue Expression
COX-1
COX-2
Chromosome 9; 22kB
Chromosome 1; 8.3kB
2.8kB
4.5kB
72kDa; 599 amino acids
72kDa; 604 amino acids
Amino acids: 90% between species for both isoforms;
similar Vmax and Km values for arachidonic acid
Glucocorticoids inhibit expression of COX-2, not COX-1;
the active site of COX-2 is larger than that of COX-1
Predominantly constitutive.
Predominantly inducible
Increased 2- to 4-fold
(10- to 20-fold).
by inflammatory stimuli
Constitutive in certain tissues
Most tissues,
Induced by inflammatory stimuli
but particularly platelets,
and mitogens in macrophages/
stomach, kidney
monocytes, synoviocyes. chondrocytes,
fibroblasts, endothelial cells. Induced
by hormones in the ovaries and foetal
membranes. Constitutive expression
in the CNS, kidney, testes, tracheal
epithelial cells.
Generic Name
Aspirin*
Diflunisal
Indomethacin
Dolobid
Arthrexin, Hicin, Indocid, Indomed
Sulindac
Heteroaryl acetic acids
Toradol
ACT-3, Actiprofen, Brufen,
Nurofen Rafen
Ketoprofen
Naproxen/
Napoxen sodium
Tiaprofenic acid
Mefenamic acid
Surgam, Tiafen
Mefic, Ponstan
Piroxicam
Tenoxicam
Tilcotil
Phenylbutazone
Butazolidin
Pyrazolidinediones
* low dose analgesic, antipyretic and antiplatelet preparations of aspirin have been excluded from this list.
Celecoxib
Celebrex
Rofecoxib
Vioxx
Although these data may be used to suggest advantages of one drug over another. their
significance is not clear. For example, the results are based on concentrations of drug in plasma,
which may not reflect the steady state concentration in the synovial fluid. Furthermore, if these
log IC80 ratios of traditional and widely utilised non-selective NSAIDs are compared with the
risk of serious GI toxicity of these agents as determined by a large meta-analysis,26 there is a
correlation, but it is not strong. This suggests that the clinical significance of these data for
predicting adverse GI events is of uncertain importance, and the safety profile of one drug over
another will only be determined by wide use in a clinical setting.
(particularly GI side effects), but it is possible that the COX-2-selective NSAIDs will cause
unwanted effects independent of their selective actions on COX-2.
Drug adverse effects can be classified as being type A or type B reactions. Type A reactions are
common reactions which are dose-dependent and in line with the pharmacology of the drug.
Type B reactions are idiosyncratic, rare and more likely to be serious. Most clinical trials are
powered to detect drug efficacy, not safety. Therefore, although type A reactions will often
emerge in the clinical trial process, this is not always the case. For example, it was some years
after marketing that the ACE inhibitor cough emerged as one of the most common adverse
effects of this class of drug. Since type B reactions are infrequent, they are rarely detected by
clinical trials. These reactions emerge as a consequence of vigilant reporting of adverse
reactions.
This section reviews some of the physiological roles of COX and PGs, in addition to describing
some of the adverse effects commonly associated with COX inhibition by non-selective
NSAIDs. The adverse effects of the COX-2-selective NSAIDs which have emerged in clinical
trials are discussed below in section 5.2.
increases linearly with age 40, and remains constant over time.41, 42 Other risk factors for GI
damage are higher doses of NSAIDs (including the use of two or more NSAIDs), a history of
gastroduodenal ulcer or gastrointestinal bleeding, concomitant use of corticosteroids, serious
coexisting conditions, and concomitant use of anticoagulants.40
Within a six month period of treatment, between 5 and 15% of patients can be expected to
discontinue therapy because of dyspepsia 43, and it has been estimated that approximately 0.42% of patients who take an NSAID for a year are at risk of developing a serious ulcer
complication.38, 39 The mortality rate amongst patients who are hospitalised for NSAID-induced
upper GI bleeding is approximately 10%. In the USA, the number of deaths per year attributed
to NSAID gastropathy is estimated to be 7600 and the number of hospitalisations is
76000/year.39 In the UK, it has been estimated that 12 000 ulcer complications and 1200
deaths/year are attributable to NSAID usage.44 There are no recent figures which document the
incidence of serious NSAID-induced GI complications in Australia, although it has been
estimated that in 1988 there were approximately 1200 hospital admissions for ulcer
complications attributable to NSAID usage, in people aged 65 years and over.45
Surveys in Australia in the late 1980s showed that approximately 20% of the elderly
population were taking NSAIDs, and that 43% of community use of NSAIDs was in patients
over 60 years of age.45, 46 Since this time there has been a significant reduction in prescription
sales of NSAIDs in Australia (Figure 4a) as a consequence of educational and regulatory
interventions.45 In 1996 Henry and coworkers published a meta-analysis of clinical trials which
highlighted differences in GI risk associated with specific NSAIDs.26 This study reported the
lowest pooled risk was associated with diclofenac and ibuprofen at doses of less than
1600mg/day. The highest pooled relative risk was with piroxicam and ketoprofen (See Figure
5). It is important to note that the relative risk for ibuprofen increases at doses greater than
1600mg/day, and for all NSAIDs, the antiinflammatory effects and the incidence of adverse
effects are both dose related.47
Figure 4b.
The National Prescribing Service (NPS) conducted an educational campaign early in 1999 to
alert to differences in relative risk associated with NSAIDs. Although statistics for the latter half
of 1999 are not yet available, data obtained from the PBS show that in the first half of 1999,
prescribing of longer acting (higher risk) agents fell. There has been a corresponding increase in
the number of prescriptions of shorter acting (lower risk) agents (Figure 4b).
Although prescribers are generally aware of the potential for adverse effects with NSAID
therapy, public perceptions and understanding about side effects and drug usage may not
always reflect that of health care professionals. For example, a recent survey of 4799 people
conducted in the USA reported that 45% of the group took NSAIDs for five or more
consecutive days/month, and 40% of these took both OTC and prescribed NSAIDs. Many of
the group were unaware or unconcerned about the possibility of adverse GI effects, and
incorrectly believed that warning signs would precede a serious GI episode.42 There are
currently no data available on OTC consumption of naproxen sodium, ibuprofen, mefenamic
acid, topical diclofenac or aspirin in Australia.
In a study assessing the influence of COX inhibition on renal function in young, healthy and
salt-depleted males, celecoxib was found to cause Na+ and K+ retention. These are early clinical
features of renal dysfunction induced by NSAIDs in hypovolaemic patients. Conversely
rofecoxib had minimal effects on renal function in healthy, elderly patients with normal renal
function (defined as creatinine clearance > 50mL/min or serum creatinine < 2mg/dL) and a high
intake of dietary sodium (200mEq/day). These data support the findings in animals which
suggest that COX-2 expression may be important in the physiological response to a low sodium
diet.
An important role of COX-2 in kidney function and development is suggested by studies
utilising COX knockout mice. COX-2 homozygous knockout (-/-) mice show severe renal
pathology which progressively deteriorates with age 79, 80, but the kidneys of COX-1
homozygous (-/-) knockouts show only minor abnormalities even at 5 months of age.81
4. Drug interactions
Celecoxib is metabolised to inactive metabolites via CYP2C9. Drugs known to inhibit this
isoenzyme should be coadministered with caution due to the potential risk of increasing the
plasma concentration of celecoxib.
Although not involved in its metabolism, celecoxib is an inhibitor of CYP2D6, and hence has
the potential to cause an interaction resulting in the elevation of plasma concentrations of any
drugs metabolised via this isoenzyme.
5, 87, 88
Inhibitors of CYP2C9:
amiodarone, cimetidine,
fluoxetine, zafirlukast,
fluconazole, fluvastatin,
fluvoxamine, metronidazole
ACE inhibitors, angiotensin II
receptor antagonists
Warfarin
Cytochrome P450 enzymes play a minor role in metabolism of rofecoxib, which is mainly
metabolised in the liver by reduction and then excreted in the urine. There are a number of
drug interactions when rofecoxib is coadministered with other agents. Concomitant
administration of antacids led to a 20% decrease in serum concentrations of rofecoxib.
Concomitant administration of rifampicin decreases rofecoxib plasma concentrations by 50%.
Plasma concentrations of methotrexate are increased by a mean of 23% when administered
with rofecoxib, and plasma concentrations of lithium are also increased by rofecoxib.
Rofecoxib taken with warfarin resulted in a 10% increase in prothrombin time. The mechanism
of these interactions is unknown, but therapy with these agents should be carefully monitored
in patients who are taking rofecoxib. Rofecoxib also may decrease the anti-hypertensive effect
of ACE inhibitors.5, 90, 91
5. Published trials of efficacy and adverse effects with celecoxib and rofecoxib.
This section reviews published efficacy studies and adverse event studies for celecoxib and rofecoxib, and makes recommendations on dosage in RA
and OA. Both celecoxib and rofecoxib were approved for use by TGA when full details of studies comparing the active drug to placebo or other
NSAIDs were available only in abstract form, making critical appraisal and assessment by independent reviewers extremely difficult. The experience
in other countries has been similar (see http://www.ti.ubc.ca/pages/letter31/htm). Several studies have now appeared in the literature, and in this
section, efficacy studies with celecoxib and rofecoxib are reviewed. When the details of phase III studies are available, data from phase 2 studies is
not presented. Some additional data is also presented from the approved product information for both drugs.
Design/Age
Exclusions
Dur-ation
OA, knee
Multicentre,
randomised,
double-blind
placebo &
active
controlled
trial
Patients with
NSAID or
sulphonamide
sensitivity
excluded
malignancy
active renal GI
hepatic or
coagulation
disorders;
oesophageal or
gastroduodenal
ulceration in
previous 30 days
12 weeks
Mean 62-3 yo
(assessed
wks 2,6
& 12)
Drug &
Dose
50mg bd
100mg bd
200mg bd
n
203
197
202
Better
than
n
204
placebo
placebo
Comp-arable
to
Naproxen
500mg bd
n
198
Significant
Adverse Effects*
Most common
events were GIT
symptoms , and
these were
similar amongst
all groups
One patient in
naproxen group
had a bleeding
ulcer, one
patient in
celecoxib 50mg
group had an
ulcer
OA, knee
RA
Notes
Reference
50mg celecoxib
minimally
effective
compared to
higher
celecoxib doses
or naproxen
Higher doses
were of
comparable
efficacy to each
other and to
naproxen
Identical to
previous study
Multicentre,
randomised,
double-blind
placebo &
active
controlled
trial
Mean 54-5 yo
active renal GI
hepatic or
coagulation
disorders;
malignancy,
oesophageal or
gastroduodenal
ulceration in
prev. 30 days or
if baseline
endoscopy
showed ulcers or
> 10 erosions
12 weeks
(assessed
wks 2,6 &
12)
100mg bd
200mg bd
400mg bd
240
235
218
placebo
*
placebo
placebo
*
patient
but not
physician
global
assessment
231
Naproxen
500mg bd
225
all celecoxib
doses were
similarly
efficacious
Supported in part by
Searle
randomised,
double-blind
parallel
activecontrolled
trial
Mean 54-55yo
OA, knee
and hip
RA
Placebo and
active
controlled
clinical trials
up to 12
weeks
duration.
Approx. 4200
patients
Placebo and
active
controlled
clinical trials
up to 24
weeks
duration.
any concomitant
rheumatic
condition, active
or suspected
peptic ulceration
or GI bleeding,
coagulation
defect or any
other disorder
precluding
NSAID use,
malignancy,
renal or hepatic
disorder,
inflammatory
bowel disease,
diclofenac
intolerance,
hypersensitivity
to NSAIDs, COX2-selective
NSAIDs or
sulphonamide,
any abnormal
clinical or
laboratory values
pretreatment
+others (see
study)
24 weeks
(assessed
wks 4, 8,
12, 16,20
& 24)
326
Diclofenac
SR
75mg bd
329
continued
See table 2.1 for
GI side effects -
Celecoxib and
diclofenac were
similarly
effective in
managing RA
pain and
inflammation
200mg bd
100mg bd
200mg od
200mg bd
Placebo
Naproxen
500mg bd
Celecoxib
comparable to
naproxen.
Total daily dose
of 200mg
maximally
effective.
Celebrex product
information. (Some
details have not been
published, although
summaries may be
available in abstract
form)
100mg bd
200mg bd
Placebo
Naproxen
500mg bd
Celecoxib doses
similar in
effectiveness
and
comparable to
naproxen
Celebrex product
information. (Some
details have not been
published, although
summaries may be
available in abstract
form)
Supported by Searle
Approx. 2100
patients
*
Studies in efficacy section - were included again in the Side effects section if the title of the article made a specific reference to side effect profile
WOMAC - Western Ontario and McMaster Universities Osteoarthritis Index (Composite of pain, stiffness and functional measures)
VAS -Visual analog scale ACR-20 - American College of Rheumatology responder index (Composite of clinical, laboratory and functional measures)
Additional Study
92
- Four Phase 2 trials: 2 week OA efficacy trial; 4 week RA efficacy trial; 1 week endoscopic study of GI mucosal effects and a 1 week study of effects on platelet function.
Design/Age
Exclusions
Dur-ation
OA,
knee
Randomised
placebo
controlled trial
Previous
gastric/duodenal
ulceration; history of
GI bleeding; renal
impairment,
diabetes, history of
cardiovascular,
hepatic, neurological
neoplastic or
coagulation disorder
6 weeks
1) WOMAC
2) patient assessment of OA
pain on a VAS
3) physician and patient
global assessment of
response to Tx
4) physician global
assessment of disease status
(Likert scale)
5) patient global assessment
of disease status
6) % of patients who
discontinued due to lack of
efficacy
Mean 63.5yo
RA
Phase II
Randomised,
double-blind
placebo
controlled trial
Mean 54-55yo
OA,
knee or
hip
Six randomised
clinical trials of
rofecoxib
lasting from 6
to 86 weeks.
4035 patients
including
approx. 400 pts
>80yo
other inflammatory
arthropathies,
uncontrolled
diabetes, active GI
bleeding or
ulceration,
positive stool guaiac
screen, malignancy,
recent serious
cardiovascular
disease, hepatic or
renal impairment,
NSAID or
paracetamol
sensitivity
(assessed
1,2,4 & 6
wks)
8 weeks
(assessed
2,4 & 8
weeks)
Drug &
Dose
25mg od
125mg od
5mg od
25mg od
50mg/od
1.25mg od
25mg od
n
73
74
158
171
161
Better
than
Placebo
Placebo
Comparable
to
72
Significant
Adverse Effects
1 gastric bleed
in association
with gastric
and duodenal
ulcers in
rofecoxib
125mg
treatment
group
Dose-related
peripheral
oedema 2.7%
and 6.8% in 25
and 125mg
treatment
groups
respectively
No clinically
significant
oedema or
hypertension.
No serious GI
effects
168
Notes
Reference
Both doses of
rofecoxib were
superior to
placebo from
1wk (1st
assessment) for
duration of study
125mg is 5 times
the maximum
recommended
dose for
treatment of OA
25 and 50mg
rofecoxib
significantly
better than
placebo. 5mg
not significantly
different to
placebo.
Rofecoxib Groups
well matched for
age and sex
Placebo
Diclofenac
50mg tid
Ibuprofen
800mg tid
Rofecoxib
comparable to
diclofenac or
ibuprofen
Study Design
Treatment
Measures
Placebo
Celecoxib 100mg bd
Celecoxib 200mg bd
Celecoxib 400mg bd
Naproxen 500mg bd
231
240
235
217
225
Supported by Searle
Rossat, J. et al. (1999).
Renal effects of selective
cyclooxygenase-2 inhibition
in normotensive saltdepleted subjects. Clinical
Pharmacology and
Therapeutics. 66:76-84
Sponsored by Searle
Placebo
Celecoxib 200mg bd
Celecoxib 400mg bd
Naproxen 500mg bd
10
10
10
10
Celecoxib 200mg bd
212
Diclofenac SR
75mg bd
218
Placebo
Single dose of:
Celecoxib 100mg
Celecoxib 400mg
Celecoxib 800mg
Ibuprofen 800mg
7
7
7
7
7
Study Design
Treatment
Measures
Placebo
Rofecoxib (12.5, 25 and 50mg
od)
NSAID (ibuprofen 800mg tds,
diclofenac 50mg tds or
nambumetone 1500mg od)
514
3357
177
1564
195
186
184
Placebo
Rofecoxib 250mg od
Ibuprofen 800mg tds
Aspirin 650mg qid
51
51
51
17
Placebo
Rofecoxib 50mg od
Indomethacin
50mg tid
12
12
12
6. Conclusions.
Celebrex and Vioxx are not more effective as antiinflammatory agents than existing NSAIDs,
although they have a slightly different adverse event profile. Randomised, double-blind,
controlled trials have demonstrated a decreased incidence of gastric and duodenal ulceration
compared to non selective NSAIDs. Patients with existing ulcers have largely been excluded
from these published trials, but some trials have allowed enrolment of patients with a history of
peptic or duodenal ulcers, and amongst these patients there did not appear to be an increased
incidence of GI injury. As such, COX-2-selective NSAIDs appear to be drugs of choice for
patients with gastric sensitivity to non-selective NSAIDs, and provide new options for patients
who could not tolerate non-selective NSAIDs. COX-2-selective NSAIDs seem also to be an
appropriate option for elderly patients (over the age of 65 years) with RA or OA who at high
risk for adverse GI events with non-selective NSAIDs. Further trials are required to investigate
the impact of H. pylori infection in patients who are treated with COX-2-selective NSAIDs, as
is investigation into the role and efficacy of gastroprotective agents in combination with COX2-selective NSAIDs.
COX-2-selective NSAIDs can lead to other problems in certain groups of patients, but it seems
as though the same cautions apply as for traditional NSAIDs. For example, care should be
exercised in prescribing COX-2-selective NSAIDs for patients with renal insufficiency, cardiac
disease and thromboembolic disease. The drugs are contraindicated in pregnancy and in
patients with aspirin-sensitive asthma.
Because of the improved GI safety profile of these agents, there seems to be an assumption that
these agents will be safer drugs. In support of this, ADRAC has more than 300 reports
describing adverse reactions to celecoxib in the first 3 months after marketing, and most of
these events have been documented in clinical trials and described in the product information.
The improved GI safety profile of celecoxib has formed the basis of the advertising campaign in
this country, and this seems to have impacted on public and prescriber perceptions of the
adverse event profile. (For a discussion of the issues involved in the promotion of drugs see
http://www.camtech.net.au/malam and for a specific discussion of the advertising of celecoxib
see http://www.camtech.net.au/malam/Inter.htm.) It is almost certain that adverse effects other
than those reported in clinical trials will emerge as more people take these drugs. Prescribers
who use these agents need to aware of the potential for adverse effects which may be new and
rare events, and report these events to ADRAC.
7. References
1.
Smith, W. L., L. J. Marnett. 1991. Prostaglandin endoperoxide synthase: Structure and catalysis. Biochem Biophys Acta. 1083: 1-17
Campbell, W. B., P. V. Halushka. 1996. Lipid-derived autacoids: eicosanoids and Platelet-activating factor. In Goodman and Gilmans
The Pharmacological Basis of Therapeutics, 601-616.
Foegh, M. L., M. Hecker, P. W. Ramwell. 1998. The eicosanoids: Prostaglandins, thromboxanes, leukotrienes and related compounds.
Seventh Edition ed. In Basic and Clinical Pharmacology, ed. B. G. Katzung, 304-318. Stamford, Connecticut, USA: Appleton & Lange
Mitchell, J. A., T. D. Warner. 1999. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br J
Pharmacol. 128: 1121-1132
Kaplan-Machlis, B., B. S. Klostermeyer. 1999. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann. Pharmacotherapy. 33:
979-88
Fu, J. Y., J. L. Masferrer, K. Seibert, A. Raz, P. Needleman. 1990. The induction and suppression of prostaglandin H2 synthase
(cyclooxygenase) in human monocytes. J Biol Chem. 265: 16737-40
Masferrer, J. L., B. S. Zweifel, K. Seibert, P. Needleman. 1990. Selective regulation of cellular cyclooxygenase by dexamethasone and
endotoxin in mice. J Clin Invest. 86: 1375-9
Lee, S., E. Soyoola, P. Chanmugam, S. Hart, W. Sun, H. Zhong, S. Liou, D. Simmons, D. Hwang. 1992. Selective expression of
mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem. 267: 25934-25938
Jones, D., D. Carlton, T. McIntyre, G. Zimmerman, S. Prescott. 1993. Molecular cloning of human prostaglandin endoperoxide
synthase type II and demonstration of expression in response to cytokines. J Biol Chem. 268: 9049-9054
10
OSullivan, M., F. Chilton, E. Huggins, Jr, C. McCall. 1992. Lipopolysaccharide priming of alveolar macrophages for enhanced
synthesis of prostanoids involves induction of a novel prostaglandin H synthase. J Biol Chem. 267: 14547-14550
11
Komhoff, M., H.-J. Grone, T. Klein, H. W. Seyberth, R. M. Nusing. 1997. Localization of cyclooxygenase-1 and -2 in adult and fetal
human kidney: implications for renal function. Am J Physiol. 272: F460-8
12
Topper, J. N., J. Cai, D. Falb, M. A. J. Gimbrone. 1996. Identification of vascular endothelial genes differentially responsive to fluid
mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively
up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA. 93: 10417-22
13
Kaufmann, W. E., P. F. Worley, J. Pegg, M. Bremer, P. Isakson. 1996. COX-2, a synaptically induced enzyme, is expressed by excitatory
neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci USA. 93: 2317-21
14
Cao, C., K. Matsumura, K. Yamagata, Y. Watanabe. 1996. Endothelial cells of the rat brain vasculature express cyclooxygenase-2
mRNA in response to systemic interleukin-1 beta: a possible site of prostaglandin synthesis responsible for fever. Brain Res. 733:
263-72
15
Dubois, R. N., S. B. Abramson, L. Crofford, R. A. Gupta, L. S. Simon, L. B. Van De Putte, P. E. Lipsky. 1998. Cyclooxygenase in biology
and disease. Faseb J. 12: 1063-73
16
Gierse, J. K., J. J. McDonald, S. D. Hauser, S. H. Rangwala, C. M. Koboldt, K. Seibert. 1996. A single amino acid difference between
cyclooxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem. 271: 15810-4
17
Kurumbail, R. G., A. M. Stevens, J. K. Gierse, J. J. McDonald, R. A. Stegeman, J. Y. Pak, D. Gildehaus, J. M. Miyashiro, T. D. Penning,
K. Seibert, P. C. Isakson, W. C. Stallings. 1996. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory
agents [published erratum appears in Nature 1997 Feb 6;385(6616):555]. Nature. 384: 644-8
18
19
Brooks, P., P. Emery, J. F. Evans, H. Fenner, C. J. Hawkey, C. Patrono, J. Smolen, F. Breedveld, R. Day, M. Dougados, E. W. Ehrich, J.
Gijon-Banos, T. K. Kvien, M. H. Van Rijswijk, T. Warner, H. Zeidler. 1999. Interpreting the clinical significance of the differential
inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology. 38: 779-788
20
Smith, J. B., A. L. Willis. 1971. Aspirin selectivity inhibits prostaglandin production in human platelets. Chest. 59: 12S
21
Vane, J. R. 1971. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature. 1083: 1-17
22
Patrignani, P., M. R. Panara, A. Greco, O. Fusco, C. Natoli, S. Iacobelli, F. Cipollone, A. Ganci, C. Crminon, J. Maclouf, e. al. 1994.
Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide
synthases. J Pharmacol Exp Ther. 271: 1705-12
23
Warner, T. D., F. Giuliano, I. Vojnovic, A. Bukasa, J. A. Mitchell, J. R. Vane. 1999. Nonsteroid drug selectivities for cyclo-oxygenase-1
rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA.
96: 7563-8
24
Mitchell, J. A., M. Saunders, P. J. Barnes, R. Newton, M. G. Belvisi. 1997. Sodium salicylate inhibits cyclo-oxygenase-2 activity
independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. Mol Pharmacol. 51: 907-12
25
Hamilton, L. C., J. A. Mitchell, A. M. Tomlinson, T. D. Warner. 1999. Synergy between cyclo-oxygenase-2 induction and arachidonic
acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy. Faseb J. 13: 245-51
26
Henry, D., L. L. Lim, L. A. Garcia Rodriguez, S. Perez Gutthann, J. L. Carson, M. Griffin, R. Savage, R. Logan, Y. Moride, C. Hawkey, S.
Hill, J. T. Fries. 1996. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs:
results of a collaborative meta-analysis [see comments]. Br Med J. 312: 1563-6
27
1997. Therapeutic Guidelines: Analgesic. 3rd Edition ed. North Melbourne, VIC, Australia: Therapeutic Guidelines Ltd
28
Anderson, G. D., S. D. Hauser, K. L. McGarity, M. E. Bremer, P. C. Isakson, S. A. Gregory. 1996. Selective inhibition of cyclooxygenase
(COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis. J Clin Invest. 97: 2672-9
29
Crofford, L. J., R. L. Wilder, A. P. Ristimki, H. Sano, E. F. Remmers, H. R. Epps, T. Hla. 1994. Cyclooxygenase-1 and -2 expression in
rheumatoid synovial tissues. Effects of interleukin-1 beta, phorbol ester, and corticosteroids J Clin Invest. 93: 1095-101
30
Siegle, I., T. Klein, J. T. Backman, J. G. Saal, R. M. Nsing, P. Fritz. 1998. Expression of cyclooxygenase 1 and cyclooxygenase 2 in
human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory joint diseases. Arthritis Rheum. 41: 122-9
31
Hishinuma, T., H. Nakamura, T. Sawai, M. Uzuki, Y. Itabash, M. Mizugaki. 1999. Microdetermination of prostaglandin E2 in joint
fluid in rheumatoid arthritis patients using gas chromatography/selected ion monitoring. Prostaglandins Other Lipid Mediat. 58:
179-186
32
Amin, A. R., M. Attur, R. N. Patel, G. D. Thakker, P. J. Marshall, J. Rediske, S. A. Stuchin, I. R. Patel, S. B. Abramson. 1997.
Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest.99:
1231-7
33
Davies, P., P. J. Bailey, M. M. Goldenberg, A. W. Ford-Hutchinson. 1994. The role of arachidonic acid oxygenation products in pain
and inflammation. Annu Rev Immunol. 2: 335-57
34
Williams, T. J., M. J. Peck. 1977. Role of prostaglandin-mediated vasodilatation in inflammation. Nature. 270: 530-532
35
Yamamoto, T., N. Nozaki-Taguchi. 1996. Analysis of the effects of cyclooxygenase (COX)-1 and COX-2 in spinal nociceptive
transmission using indomethacin, a non-selective COX inhibitor, and NS-398, a COX-2 selective inhibitor. Brain Res. 739: 104-10
36
Coceani, F., E. S. Akarsu. 1998. Prostaglandin E2 in the pathogenesis of fever. An update. Ann NY Acad Sci. 856: 76-82
37
Zimmermann, K. C., M. Sarbia, K. Schror, A. A. Weber. 1998. Constitutive cyclooxygenase-2 expression in healthy human and rabbit
gastric mucosa. Mol Pharmacol. 54: 536-40
38
Silverstein, F. E., D. Y. Graham, J. R. Senior, H. W. Davies, B. J. Struthers, e. al. 1995. Misoprostol reduces serious gastrointestinal
complications in patients iwht rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs. A randomized, double-blind,
placebo-controlled trial. Ann Intern Med. 123: 241-9
39
Fries, J. F. 1991. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol
Suppl. 28: 6-10
40
Wolfe, M. M., D. R. Lichtenstein, G. Singh. 1999. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med.
340: 1888-1899
41
MacDonald, T. M., S. V. Morant, G. C. Robinson, M. J. Shield, M. M. McGilchrist, F. E. Murray, D. G. McDevitt. 1997. Association of
upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. Br Med J. 315:
1333-7
42
Singh, G., G. Triadafilopoulus. 1999. Epidemiology of NSAID-induced GI complications. J Rheumatol. 26 Suppl 56: 18-24
43
Singh, G., D. R. Ramey, D. Morfeld, H. Shi, H. T. Hatoum, J. F. Fries. 1996. Gastrointestinal tract complications of nonsteroidal antiinflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med. 156: 1530-6
44
Hawkey, C. J. 1996. Non-steroidal anti-inflammatory drug gastropathy: causes and treatment. Scand J Gastroenterol. Suppl. 220:
124-7
45
McManus, P., J. G. Primrose, D. A. Henry, D. J. Birkett, J. Lindner, R. O. Day. 1996. Pattern of non-steroidal anti-inflammatory drug
use in Australia 1990-1994. A report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee
[see comments]. Med J Aust. 164: 589-92
46
Henry, D., A. Dobson, C. Turner. 1993. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal
anti-inflammatory drugs. Gastroenterology. 105: 1078-88
47
Graham, D. Y. 1996. Nonsteroidal anti-inflammatory drugs, helocobacter pylori, and ulcers: where we stand. Am J Gastroenterol.
91: 2080-2086
48
Schoen, R. T., R. J. Vender. 1989. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med. 86: 44958
49
Whittle, B. J. R., G. A. Higgs, K. E. Eakins, S. Moncada, J. R. Vane. 1980. Selective inhibition of prostaglandin production in
inflammatory exudates and gastric mucosa. Nature. 284: 271-3
50
Levi, S., C. Shaw-Smith. 1994. Non-steroidal anti-inflammatory drugs: how do they damage the gut? Br J Rheumatol. 33: 605-612
51
Bamba, H., S. Ota, A. Kato, F. Matsuzaki. 1998. Nonsteroidal anti-inflammatory drugs may delay the repair of gastric mucosa by
suppressing prostaglandin-mediated increase of hepatocyte growth factor production. BiochemBiophys Res Commun. 245: 567-71
52
Maliekal, J., C. M. Elboim. 1995. Gastrointestinal complications associated with intramuscular ketorolac tromethamine therapy in
the elderly. Ann Pharmacother. 29: 698-701
53
Lanza, F. L., G. L. J. Royer, R. S. Nelson. 1980. Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric-coated
aspirin on gastric and duodenal mucosa. N Engl J Med. 303: 136-8
54
Lichtenstein, D. R., S. Syngal, M. M. Wolfe. 1995. Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. The doubleedged sword. Arthritis Rheum. 38: 5-18
55
Graham, D. Y. 1997. High dose famotidine for prevention of NSAID ulcers? (Editorial). Gastroenterology. 112: 2143-5
56
Graham, D. Y., P. D. Klein, A. R. Opekun, T. W. Boutton. 1988. Effect of age on the frequency of active Campylobacter pylori
infection diagnosed by the [13C]urea breath test in normal subjects and patients with peptic ulcer disease. J Infect Dis. 157: 777-80
57
Chan, F. K., J. J. Sung, S. C. Chung, K. F. To, M. Y. Yung, V. K. Leung, Y. T. Lee, C. S. Chan, E. K. Li, J. Woo. 1997. Randomised trial of
eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers [see comments].
Lancet. 350: 975-9
58
Hawkey, C. J., Z. Tulassay, L. Szczepanski, C. J. van Rensburg, A. Filipowicz-Sosnowska, A. Lanas, C. M. Wason, R. A. Peacock, K. R.
Gillon. 1998. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs:
HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention [see comments]. Lancet. 352: 1016-21
59
Sawaoka, H., S. Kawano, S. Tsuji, M. Tsuji, W. Sun, E. S. Gunawan, M. Hori. 1998. Helicobacter pylori infection induces
cyclooxygenase-2 expression in human gastric mucosa. Prostaglandins Leukot Essent Fatty Acids. 59: 313-6
60
McCarthy, C. J., L. J. Crofford, J. Greenson, J. M. Scheiman. 1999. Cyclooxygenase-2 expression in gastric antral mucosa before and
after eradication of Helicobacter pylori infection. Am J Gastroenterol. 94: 1218-23
61
Mizuno, H., C. Sakamoto, K. Matsuda, K. Wada, T. Uchida, H. Noguchi, T. Akamatsu, M. Kasuga. 1997. Induction of cyclooxygenase
2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice [see comments]. Gastroenterology.
112: 387-97
62
Jones, M. K., H. Wang, B. M. Peskar, E. Levin, R. M. Itani, I. J. Sarfeh, A. S. Tarnawski. 1999. Inhibition of angiogenesis by
nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med. 5:
1418-23
63
Sheng, H., J. Shao, S. C. Kirkland, P. Isakson, R. J. Coffey, J. Morrow, R. D. Beauchamp, R. N. DuBois. 1997. Inhibition of human colon
cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest. 99: 2254-9
64
Murata, H., S. Kawano, S. Tsuji, M. Tsuji, H. Sawaoka, Y. Kimura, H. Shiozaki, M. Hori. 1999. Cyclooxygenase-2 overexpression
enhances lymphatic invasion and metastasis in human gastric carcinoma. Am J Gastroenterol. 94: 451-5
65
Kawamori, T., C. V. Rao, K. Seibert, B. S. Reddy. 1998. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor,
against colon carcinogenesis. Cancer Res. 58: 409-12
66
Dimberg, J., A. Samuelsson, A. Hugander, P. Soderkvist. 1999. Differential expression of cyclooxygenase 2 in human colorectal
cancer. Gut. 45: 730-732
67
Eberhart, C. E., R. J. Coffey, A. Radhika, F. M. Giardiello, S. Ferrenbach, R. N. DuBois. 1994. Up-regulation of cyclooxygenase 2 gene
expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 107: 1183-8
68
Schlondorff, D. 1986. Renal prostaglandin synthesis. Sites of production and specific actions of prostaglandins. Am J Med. 81: 1-11
69
Kaojarern, S., P. Chennavasin, S. Anderson, D. C. Brater. 1983. Nephron site of effect of nonsteroidal anti-inflammatory drugs on
solute excretion in humans. Am J Physiol. 244: F134-9
70
Clive, D. M., J. S. Stoff. 1984. Clinical syndromes associated with nonsteroidal antiinflammatory drugs. I Med. 310: 563-572
71
Patrono, C., M. J. Dunn. 1987. The clinical significance of inhibition of renal prostaglandin synthesis. Kidney Int. 32: 1-12
72
Henry, D., J. Page, I. Whyte, R. Nanra, C. Hall. 1997. Consumption of non-steroidal anti-inflammatory drugs and the development of
functional renal impairment in elderly subjects. Results of a case-control study. Br J Clin Pharmacol. 44: 85-90
73
Murray, M. D., D. C. Brater. 1993. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Ann Rev Pharmacol Toxicol. 33: 43565
74
Whelton, A. 1999. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J
Med. 106: 13S-24S
75
DeFronzo, R. A. 1980. Hyperkalemia and hyporeninemic hypoaldosteronism [clinical conference]. Kidney Int. 17: 118-34
76
Harris, R. C., J. A. McKanna, Y. Akai, H. R. Jacobson, R. N. Dubois, M. D. Breyer. 1994. Cyclooxygenase-2 is associated with the
macula densa of rat kidney and increases with salt restriction. J Clin Invest. 94: 2504-10
77
Harding, P., D. H. Sigmon, M. E. Alfie, P. L. Huang, M. C. Fishman, W. H. Beierwaltes, O. A. Carretero. 1997. Cyclooxygenase-2
mediates increased renal renin content induced by low-sodium diet. Hypertension. 29: 297-302
78
Cheng, H. F., J. L. Wang, M. Z. Zhang, Y. Miyazaki, I. Ichikawa, J. A. McKanna, R. C. Harris. 1999. Angiotensin II attenuates renal
cortical cyclooxygenase-2 expression. J Clin Invest.103: 953-61
79
Morham, S. C., R. Langenbach, L. C.D., e. al. 1995. Prostaglandin synthase-2 gene causes severe renal pathology in the mouse. Cell.
83: 473-82
80
Dinchuk, J. E., B. D. Car, R. J. Focht, J. J. Johnston, B. D. Jaffee, M. B. Covington, N. R. Contel, V. M. Eng, R. J. Collins, P. M. Czerniak,
e. al. 1995. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature. 378: 406-9
81
Langenbach, R., S. G. Morham, H. F. Tiano, C. D. Loftin, B. I. Ghanayem, P. C. Chulada, J. F. Mahler, C. A. Lee, E. H. Goulding, K. D.
Kluckman, e. al. 1995. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and
indomethacin-induced gastric ulceration. Cell. 83: 483-92
82
Schafer, A. I. 1999. Effects of nonsteroidal anti-inflammatory therapy on platelets. Am J Med. 106: 25S-36S
83
Murata, T., F. Ushikubi, T. Matsuoka, M. Hirata, A. Yamasaki, Y. Sugimoto, A. Ichikawa, Y. Aze, T. Tanaka, N. Yoshida, A. Ueno, S.
Oh-ishi, S. Narumiya. 1997. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature. 388:
678-682
84
McAdam, B. F., F. Catella-Lawson, I. A. Mardini, S. Kapoor, J. A. Lawson, G. A. FitzGerald. 1999. Systemic biosynthesis of prostacyclin
by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2 [published erratum appears in Proc Natl
Acad Sci U S A 1999 May 11;96(10):5890]. Proc Natl Acad Sci USA. 96: 272-7
85
Zuckerman, H., U. Reiss, I. Rubinstein. 1974. Inhibition of human premature labor by indomethacin. Obstet Gynecol. 44: 787-92
86
Hammerman, C. 1995. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA
pathophysiology and treatment. Clin Perinatol. 22: 457-79
87
1999. Celecoxib for arthritis. Med Lett Drugs Ther. 41: 11-2
88
89
1999. Potential interaction: Celebrex (celecoxib) and warfarin. FDA MedWatch Safety Information Summary. May
90
1999. Rofecoxib for osteoarthritis and pain. Med Lett Drugs Ther. 41: 59-61
91
Merck Sharp & Dohme (Aust.) Pty Ltd. 1999. Approved product information.
92
Simon, L. S., F. L. Lanza, P. E. Lipsky, R. C. Hubbard, S. Talwalker, B. D. Schwartz, P. C. Isakson, G. S. Geis. 1998. Preliminary study of
the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in
osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum. 41: 1591-602
93
Saag, K., C. Fisher, J. McKay, E. Erich, P. L. Zhao, J. Bolognese, B. Seidenberg, B. Daniels. 1998. MK-0966, a specific COX-2 inhibitor,
has clinical efficacy comparable to ibuprofen in the treatment of knee and hip osteoarthritis (OA) in a 6-week controlled clinical
trial. Arthritis Rheum. 41: S196
94
Cannon, G., J. Caldwell, P. Holt, B. McLean, Q. Zeng, E. Ehrich, B. Seidenberg, J. Bolognese, B. Daniels. 1998. MK-0966, a specific
COX-2 inhibitor, has clinical efficacy comparable to diclofenac in the treatment of knee and hip osteoarthritis (OA) in a 26-week
controlled clinical trial. Arthritis Rheum. 41: S196
Contributing authors
Reviewers
Dr Stephen Kerr
Decision Support Officer
National Prescribing Service
Level 1/31 Buckingham Street
Surry Hills. NSW. 2010.
Ms Joy Gailer
Clinical Pharmacist
Drug and Therapeutics Information Service
Repatriation General Hospital
Daws Rd
Daws Park. SA. 5041
Dr John Dowden
Editor
Australian Prescriber