Scientific rationale for specific inhibition of COX-2.

Cyclooxygenase (COX) is the principal enzyme involved in the production of prostaglandins. Inhibition of COX is also the primary mechanism of action of aspirin and other nonsteroidal antiinflammatory drugs (NSAID). Since prostaglandins are important regulators of cellular function, inhibition of prostaglandin production may lead to adverse effects. Two isoforms of COX have been identified, sequenced, and cloned. COX-1 is constitutively produced and is believed to be involved in regulating normal cellular processes, such as gastrointestinal (GI) cytoprotection, vascular homeostasis, and renal function. In contrast, COX-2 -- the inducible form -- is undetectable in most tissues but is present in inflamed tissue. Evidence therefore suggests that the GI toxicity associated with NSAID use is primarily the result of inhibition of COX-1, and antiinflammatory effects are largely due to inhibition of COX-2. A drug that specifically inhibits COX-2 without affecting COX-1 would, theoretically, reduce inflammation without leading to GI side effects. A variety of biologic assays have been developed to characterize the relative activities of NSAID against COX-1 and COX-2. Such in vitro testing has demonstrated that individual NSAID possess different relative inhibitory effects in various tissues. Several NSAID have been reported to show more potent inhibition of COX-2 than of COX-1 in vitro; however, the clinical relevance of differential inhibition of COX isozymes is as yet unknown. Some clinical studies indicating reduced toxicity for these NSAID may, in fact, be attributable to use of these agents at subtherapeutic doses. As yet, no clinically available NSAID has been shown to have significant in vivo effects on COX-2 while sparing COX-1 activity in humans. However, compounds that may be 100 to 300-fold more effective inhibitors of COX-2 and that therefore may have lower risks for toxicity as well as more potent antiinflammatory effects have been developed, but are not yet available for clinical use.