The Second Generation of COX-2 Inhibitors

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Abstract
The discovery of two cyclooxygenase (COX)-isoenzymes, a constitutive OX-1, serving homeostatic prostanoid synthesis, and an inducible COX-2, responsible for proinflammatory prostanoid production, led to the development of new non-steroidal anti-inflammatory drugs (NSAIDs), the selective COX-2 inhibitors, promising minimal NSAID-typical toxicity with full anti-inflammatory efficacy. So far, the strategy of selective COX-2 inhibition has been successful. Selective COX-2 inhibitors have significantly less gastrotoxicity and no effects on platelet aggregation. However, with regard to renal adverse events, selective COX-2 inhibitors do not offer a clinically relevant advantage over non-selective inhibitors. Moreover, concerns over the cardiovascular risk of selective COX-2 inhibitors have recently been raised. The second generation of COX-2 inhibitors with higher COX-2 selectivity was developed with the promise of further reduction of NSAID-typical adverse effects. The leading compounds are valdecoxib, parecoxib, etoricoxib and lumaricoxib. At the present time they have proven efficacy for the treatment of pain and inflammation. Parecoxib as a parenteral, highly selective COX-2 inhibitor has the potential to become the NSAID of choice for treatment of postoperative pain. In clinical trials, valdecoxib, parecoxib, etoricoxib and lumaricoxib have caused no more endoscopic ulcers than placebo. However, to date, no data on the clinically relevant endpoints perforation, symptomatic ulcer and bleeding are available. Furthermore, no definite conclusions on renal and cardiovascular safety are possible. Current evidence points to a marginal, if any, gain of safety compared with the first generation of COX-2 inhibitors. However, trials with the new COX-2 inhibitors offer the chance to address these open questions of highly selective COX-2 inhibition; that is, thrombogenic risk, sodium and water retention, and interference with tissue repair, in particular, healing of mucosal damage.