SELECTIVE CYCLOOXYGENASE-2 INHIBITION BY NIMESULIDE IN MAN

Prostaglandins are generated through two isoforms of the enzyme cycloo xygenase, the constitutively expressed cyclooxygenase (Cox)-1 and Cox- 2, which is induced at sites of inflammation. Selective inhibition of Cox-ii is desirable as this may avoid the gastropathy and platelet inh ibition seen with nonselective agents. Moreover, these agents will all ow us to examine the relative contribution of the two isoforms to pros taglandin formation in man. We examined the activity of nimesulide, a Cox-2 selective nonsteroidal antiinflammatory drug, in vitro against p urified enzymes and in vivo in man. Nimesulide 100 mg twice daily or a spirin 300 mg three times daily were administered randomly for 14 days to 20 subjects complaining of musculoskeletal pain. Serum thromboxane B-2 was determined as an index of Cox-1 activity and endotoxin-induce d prostaglandin E-2 formation in whole blood as an index of Cox-2 acti vity. Urinary excretion of prostaglandin metabolites was determined by GC/MS. Nimesulide was highly selective against ovine Cox-2, so that a t concentrations attained in vivo, it had no effect on Cox-1 but compl etely suppressed Cox-2. Aspirin markedly inhibited serum thromboxane B -2 (181.92 +/- 19.77 to 2.83 +/- 0.96 ng/ml, P <.002), whereas nimesul ide had very little effect (207.53 +/- 47.30 to 181.15 +/- 54.59 ng/ml ). In contrast, nimesulide suppresses endotoxin-induced prostaglandin E-2 formation (35.03 +/- 8.73 to 2.62 +/- 0.95 ng/ml, P =.002). As exp ected, aspirin reduced TX metabolite excretion, whereas nimesulide had no significant effect. In contrast, both compounds suppressed PGI(2) formation to the same extent. The findings suggest that TX is largely Cox-1 derived. Moreover, Cox-2 is expressed in man and generates prost aglandin I-2.