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Vol. 287, Issue 2, 578-582, November 1998
Centre for Cardiovascular Science, Royal College of Surgeons in
Ireland, St. Stephens Green, Dublin 2, Ireland
Prostaglandins are generated through two isoforms of the enzyme
cyclooxygenase, the constitutively expressed cyclooxygenase (Cox)-1 and
Cox-2, which is induced at sites of inflammation. Selective inhibition
of Cox-2 is desirable as this may avoid the gastropathy and platelet
inhibition seen with nonselective agents. Moreover, these agents will
allow us to examine the relative contribution of the two isoforms to
prostaglandin formation in man. We examined the activity of nimesulide,
a Cox-2 selective nonsteroidal antiinflammatory drug, in
vitro against purified enzymes and in vivo in man.
Nimesulide 100 mg twice daily or aspirin 300 mg three times daily were
administered randomly for 14 days to 20 subjects complaining of
musculoskeletal pain. Serum thromboxane B2 was determined
as an index of Cox-1 activity and endotoxin-induced prostaglandin
E2 formation in whole blood as an index of Cox-2 activity.
Urinary excretion of prostaglandin metabolites was determined by GC/MS.
Nimesulide was highly selective against ovine Cox-2, so that at
concentrations attained in vivo, it had no effect on Cox-1
but completely suppressed Cox-2. Aspirin markedly inhibited serum
thromboxane B2 (181.92 ± 19.77 to 2.83 ± 0.96 ng/ml, P < .002), whereas nimesulide had very little effect (207.53 ± 47.30 to 181.15 ± 54.59 ng/ml). In contrast,
nimesulide suppresses endotoxin-induced prostaglandin E2
formation (35.03 ± 8.73 to 2.62 ± 0.95 ng/ml, P = .002). As expected, aspirin reduced TX metabolite excretion, whereas
nimesulide had no significant effect. In contrast, both compounds
suppressed PGI2 formation to the same extent. The findings
suggest that TX is largely Cox-1 derived. Moreover, Cox-2 is expressed
in man and generates prostaglandin I2.
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