COX-2 inhibitors - Australian Prescriber
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`Experimental and clinical pharmacology
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`COX-2 inhibitors
`Peter M. Brooks, Executive Dean, Health Sciences, University of Queensland, Brisbane
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`Summary
`There are two cyclo-oxygenase enzymes: COX-1 regulates physiological function in the gut and kidney, while COX-2
`is induced in inflammation and repair.Selective COX-2 inhibitors are now available. In early clinical trials their
`efficacy in arthritis was equivalent to that of less selective non-steroidal anti-inflammatory drugs and they had a
`significantly lower incidence of gastrointestinal adverse effects. Larger and longer outcome studies are awaited to
`address issues such as a possible delaying effect of COX-2 inhibitors on ulcer healing and the potential for adverse
`cardiovascular effects.
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`Key words: anti-inflammatory drugs, arthritis, adverse effects.
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`Aust Prescr 2000;23:30-2
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`Introduction
`The inhibition of prostaglandin synthesis by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) was
`first described over 20 years ago.1 The NSAIDs are now one of the most commonly used medications worldwide,
`with annual sales in the order of US$13 billion. These drugs are frequently used for the management of
`musculoskeletal diseases and for other causes of acute and chronic pain. Despite their clear efficacy in the
`management of inflammation, NSAIDs are a significant cause of adverse events, particularly gastrointestinal
`ulceration2 and altered renal function.
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`The enzyme responsible for prostaglandin synthesis is cyclo-oxygenase (COX). Following the observation that
`dexamethasone inhibits the increase in COX activity induced in macrophages, but has no effect on basal production
`of prostaglandins, it was proposed that there were two enzymes, COX-1 and COX-2.3 The COX-1 enzyme seems to
`have primarily a `housekeeping' role, subserving normal physiological function in the gut and kidney and being
`involved with platelet activation. The COX-2 enzyme is induced during inflammation and tissue repair and also has
`significant physiological roles to play in reproduction and in renal function (Fig. 1). The molecular function and
`protein structures of the COX isoforms were rapidly identified. This led to the development of a number of selective
`COX-2 inhibitors. These drugs should provide the same efficacy as the non-selective NSAIDs with fewer
`gastrointestinal adverse reactions.
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`There is a huge potential market for these drugs. In the first few months following its launch in the USA sales of one
`COX-2 inhibitor exceeded those of sildenafil.
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`Fig. 1
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`Cyclo-oxygenase enzymes.
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`COX-1 is involved in normal physiological functions including the production of protective
`prostaglandins in the stomach. COX-2 is induced by inflammation.
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`Both enzymes are inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). COX-2
`inhibitors have little effect on COX-1 activity and so do not inhibit prostaglandin
`synthesis.
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`Fig. 2
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`Selectivity of COX-2 inhibitors and non-steroidal anti-inflammatory drugs5 given as
`log inhibitory concentration (IC80) ratio. The `0' line indicates equipotency.
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`Log [IC80 ratio (William Harvey Human Modified Whole Blood Assay (WHMA)
`COX-2/COX-1)]
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`Assessment of COX-2 selectivity
`There is a wide variety of assays to assess COX-1 and COX-2 selectivity.4 This has led to confusion in the reporting
`of the relative effects of some of the new selective inhibitors depending on which assay system is used. The Human
`Whole Blood Assay is probably the best available currently to assess inhibition of COX-1 and COX-2.
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`This assay has recently been modified slightly as the William Harvey Human Modified Whole Blood Assay (WHMA). A
`wide range of COX-2/COX-1 ratios has been reported for currently available and experimental NSAIDs.5 These data
`are summarised in Fig. 2 with rofecoxib being greater than 50-fold COX-2 selective, and celecoxib being 5-to-50 fold
`COX-2 selective. Diclofenac, sulindac and piroxicam have less than 5-fold COX-2 selectivity.
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`Measuring COX inhibition in gastric mucosa by using gastric biopsies may also provide important additional
`information. Although these investigations may define COX selectivity, they do not necessarily imply that COX-2
`selective drugs will have improved safety profiles - this can only be shown by randomised controlled clinical trials.
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`Clinical studies
`When comparing the adverse effects of COX-2 inhibitors with those of NSAIDs appropriate doses must be used. It is
`essential to compare doses which have similar efficacy.
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`Although the new COX-2 inhibitors had significantly lower incidences of gastric injury in the short term, 12-month
`anti-inflammatory and gastrointestinal outcome studies against standard NSAIDs are required to fully assess their
`efficacy and adverse effects.
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`Celecoxib
`In single dose studies celecoxib (100 mg and 400 mg) was superior to placebo and as effective as aspirin (650 mg)
`in relieving the pain of dental extraction. Phase II and III studies of up to six months in doses of 100-400 mg/day for
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`osteoarthritis and 200-800 mg/day for rheumatoid arthritis showed equivalence to naproxen 1 g daily or diclofenac
`150 mg daily in terms of efficacy. In normal volunteers, endoscopic studies with celecoxib 100 mg or 200 mg twice
`daily for seven days revealed levels of gastric mucosal injury similar to those of placebo. Larger three-6 or six-month
`studies showed the incidence of ulcers was similar to placebo and significantly reduced compared to naproxen and
`diclofenac.
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`Rofecoxib
`Rofecoxib has a long half-life and is suitable for once-daily dosing in osteoarthritis and rheumatoid arthritis. A single
`dose of 50 mg is superior to placebo and equivalent to ibuprofen 400 mg or naproxen 550 mg for relieving acute
`pain after dental extraction. Gastric mucosal injury at seven days is similar to placebo, but less than ibuprofen 2.4 g
`daily or aspirin 2.6 g daily. A recent analysis of eight double-blind randomised controlled trials, including two one-
`year efficacy studies versus diclofenac 150 mg daily, in over 5000 osteoarthritis patients has reported a significantly
`lower 12-month cumulative incidence of perforations, ulcers and upper gastrointestinal tract bleeding with rofecoxib
`than with other NSAIDs (1.3% versus 1.8%).7
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`Future directions
`Significant interest has now been shown in the role that inflammation (driven by COX-2) plays in conditions such as
`Alzheimer's disease and colonic carcinoma.8 COX-2 is certainly induced around the inflammatory plaques seen widely
`throughout the central nervous system in Alzheimer's disease, and COX-2 expression is upregulated dramatically in
`colonic carcinoma. Epidemiological data support the argument that patients taking NSAIDs have a lower incidence
`and a slower rate of progression of Alzheimer's disease. NSAIDs also reduce the growth rate of colonic polyps in
`humans9 and the incidence of colonic tumours in animals.
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`The selective COX-2 inhibitors seem to have similar effects, increasing blood pressure and reducing renal function,
`as the non-selective COX inhibitors. Selective COX-2 inhibitors should not be given to people with aspirin sensitivity
`as there are no published studies to show that this is safe for these patients. Although there is some theoretical
`concern relating to the potential for an increased risk of thrombosis with COX-2 inhibitors this does not seem to have
`been borne out by studies to date. Larger and longer-term studies are however required to answer these and other
`issues such as whether or not ulcer healing might be impaired by a selective COX-2 inhibitor. Since these drugs have
`the potential for widespread use in the community it is important that cost-effectiveness studies are carried out,
`although it would seem that the selective COX-2 inhibitors may be cost-effective for those patients at high risk of
`ulcer complications.10
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`Conclusion
`The efficacy of the new drugs is not greater than that of the NSAIDs. However, if the current large outcome studies
`of celecoxib and rofecoxib confirm the reduced gastrointestinal toxicity then these drugs will increase the options for
`the treatment of arthritis.
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`References
`
`1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature
`1971;231:232-5.
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`2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. N Engl J
`Med 1999;340:1888-99.
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`3. Masferrer JC, Seibert K, Zweifel B, Needleman P. Endogenous glucocorticoids regulate an inducible
`cyclooxygenase enzyme. Proc Natl Acad Sci USA 1992;89:3917-21.
`
`4. Brooks P, Emery P, Evans JF, Fenner H, Hawkey CJ, Patrono C, et al. Interpreting the clinical significance of the
`differential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Br J Rheumatol 1999;38:779-88.
`
`5. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. 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 1999;96:7563-8.
`
`6. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC, et al. Anti-inflammatory and upper
`gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA 1999;282:1921-8.
`
`7. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao P-L, Quan H, et al. Adverse upper gastrointestinal effects
`of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
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`8. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and
`disease. FASEB J 1998;12:1063-73.
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`9. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal
`adenomas with sulindac in familial ademonatous polyposis. N Engl J Med 1993;328:1313-6.
`
`10. Peterson WL, Cryer B. COX-1-sparing NSAIDs - Is the enthusiasm justified? JAMA 1999;282:1961-3.
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`http://www.australianprescriber.com/magazine/23/2/30/2
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`FURTHER READING
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`Hawkey CJ. Cox-2 inhibitors. Lancet 1999;353:307-14
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`Professor Brooks has acted as a consultant to Searle and is on advisory boards for Merck Sharpe and Dohme.
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`(A summary of all clinical trials of the COX-2 inhibitors appears on the National Prescribing Service web site at
`www.nps.org.au under Topics)
`Self-test questions
`The following statements are either true or false (click here for the answers)
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`First published online: 1st of February 2000
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`http://www.australianprescriber.com/magazine/23/2/30/2
`
`5/9/2015
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