Elsevier

The Lancet

Volume 353, Issue 9149, 23 January 1999, Pages 307-314
The Lancet

New Drug Classes
COX-2 inhibitors

https://doi.org/10.1016/S0140-6736(98)12154-2Get rights and content

Summary

In the past 100 years aspirin has demonstrated its value as an analgesic, anti-inflammatory, and antithrombotic agent. However, by 1938, it was clear that aspirin was gastrotoxic. Non-steroidal anti-inflammatory drugs (NSAIDs), developed since the 1960s, failed to achieve the goal of “a safer aspirin”. The demonstration that inhibition of prostaglandin synthesis via a cyclo-oxygenase (COX) enzyme was central to both the therapeutic and toxic effects of aspirin and non-aspirin NSAIDs appeared to establish the principle of no gain without pain. This link may have been broken by drugs that selectively inhibit the inducible COX-2 enzyme. The COX enzyme is now a target of drug interventions against the inflammatory process. Might the “safe aspirin” be here at last?

Section snippets

Screening for COX-1 and COX-2 selectivity

Drugs have been tested for COX-2 selectivity in various systems, including purified recombinant enzyme, transfected cell, and whole-blood assays.9 In the wholeblood assay, synthesis of thromboxane from platelets during clotting is used as an index of COX-1 activity while synthesis of PGE2 (principally from monocytes) in whole blood exposed to lipopolysaccharide is an index of COX-2 activity. Each method gives somewhat different results, probably reflecting differences in protein binding and

COX-1 good, COX-2 bad?

The development of COX-2 inhibitors as potentially gastro-safe NSAIDs is based on the notion that COX-1 predominates in the stomach, yielding protective prostaglandins, while COX-2 is induced in inflammation giving rise to pain, swelling, and stiffness. This concept is flawed. Firstly, most NSAID use is for conditions not regarded as inflammatory; despite this, COX-2 inhibitors are analgesic in such conditions, although their potency is debated. Secondly, the human gastrointestinal tract

Existing drugs

Attempts to explain the toxicity of existing NSAIDs in terms of their COX-2 selectivity have not been successful, which is not surprising since nearly all existing NSAIDs tend to be predominantly COX-1 selective. Of the older NSAIDs, only dicloflenac even approaches equipotency in its effects on COX-1 and COX-2.9 Differences in overall potency of the doses of individual NSAIDs used in practice are more likely important in explaining differences between different NSAIDs in their association with

COX-2 agents

Designer drugs that have emerged from drug-development programmes based on an understanding of the differences between COX-1 and COX-2 are so much more selective than preferential inhibitors that the problem of loss of selectivity at higher doses is unlikely to occur. It has been proposed that the term COX-2 specific inhibitor should be used to describe agents which inhibit COX-2 but have no effect on COX-1 over the whole range of doses used and concentrations achieved in clinical usage.28 One

Alternatives to specific COX-2 inhibitors

It is already clear that COX-2 inhibitors are very likely to have major advantages although these may be counterbalanced to some extent by some limitations. Will other strategies prove better?

Conclusions

COX-2 inhibitors are likely to have a major impact on prescribing in inflammation and analgesia. As their strengths and weakness become clear with continuing use, non-selective NSAIDs with or without coprophylaxis of misoprostol or omeprazole may establish alternative niches. It is too soon to speculate about any possible role for NO-NSAIDs. Paradoxically, the imminent arrival of COX-2 inhibitors appears to have stimulated a move for non-selective NSAIDs from a prescription-only medication

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