Comments for:
Abstract
Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs — adverse effects attributed to suppression of COX-1–derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2–derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a “balance” between COX-2–derived PGI2 and COX-1–derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.
Authors
Tilo Grosser, Susanne Fries, Garret A. FitzGerald
Level of COX-2 inhibition in use does not discriminate COX-2-selective drugs from traditional NSAIDs
Submitter: Timothy D Warner | t.d.warner@qmul.ac.uk
William Harvey Research Institute, Barts & the London, Queen Mary University of London, EC1M 6BQ
Published January 17, 2006
Grosser et al. provide an excellent review of developments that followed the discovery of COX-2 and the rapid production of COX-2- selective drugs. We would contend, however, that in discussing the nonsteroid anti-inflammatory drugs (NSAIDs) attention is often, and erroneously, focused upon the relative selectivity towards COX-2 of the newer COX-2-selective NSAIDs (c2NSAIDs) versus traditional NSAIDs (tNSAIDs). This results in readers forming the belief that in clinical use it is the level of COX-2 inhibition that differentiates c2NSAIDs from tNSAIDs; i.e. that in inhibiting COX-2 c2NSAIDs do something that tNSAIDs do not. However, the standard clinical doses of tNSAIDs and c2NSAIDs are associated with very similar levels of COX-2 inhibition and very similar reductions in whole body prostacyclin production. At clinically effective doses tNSAIDs are anti-inflammatory, anti-pyretic and analgesic because they strongly inhibit COX-2 (by 80% or more). As, is obvious, no matter how selective a compound is towards COX-2 it cannot inhibit the activity of this enzyme by more than 100% (if a c2NSAID is 100-times more COX-2- selective than a tNSAID it cannot produce 100x80=8000% inhibition!). So in general clinical use c2NSAIDs and tNSAIDs inhibit COX-2 to a similar extent. At the same time c2NSAIDs inhibit COX-1 much less than tNSAIDs, and would actually have been better named COX-1-sparing drugs as this more accurately describes their key difference from tNSAIDs.
The single most marked difference between tNSAIDs and c2NSAIDs lies, therefore, at the level of COX-1 inhibition associated with standard clinical doses. This is proven in studies examining the whole body production of prostanoids, which show that c2NSAIDs, in direct contrast to tNSAIDs, have little effect upon thromboxane A2 production, taken as an index of platelet COX-1 activity; c2NSAIDs do however inhibit prostacyclin production in a very similar fashion to tNSAIDs. This pushes our consideration of c2NSAIDs and tNSAIDs in a different direction - the actual factor that varies enormously between tNSAIDs and c2NSAIDs is the level of COX-1 inhibition associated with application of these drugs at their standard clinical doses.
So the two simplest conclusions we can draw are: 1 – if it is solely inhibition of PGI2 production dependent upon the action of COX-2 that underlies cardiovascular side effects no differences in these side effects will be seen between c2NSAIDs and tNSAIDs (both produce similar inhibition of COX-2 in clinical use); 2 – any difference in cardiovascular side effects between NSAIDS and COX-2-selective drugs can not be explained solely on the basis of inhibition of COX-2-dependent PGI2 production (all NSAIDs are COX-2 inhibitors and all NSAIDs inhibit PGI2 production).
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