BACKGROUND: The aim of this study was to test the hypothesis that nimesulide, a nonsteroidal antiinflammatory drug, or its principal metabolite 4-hydroxynimesulide, is a selective inhibitor of prostaglandin H synthase-2 in human beings. METHODS: Heparinized whole blood samples obtained from healthy subjects were incubated with lipopolysaccharide (10 micrograms/ml) for 24 hours at 37 degrees C and prostaglandin E2 was measured in plasma as an index of monocyte prostaglandin H synthase-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 minutes was assessed as an index of platelet prostaglandin H synthase-1 activity. We also measured the urinary excretion of 11-dehydrothromboxane B2, prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 as in vivo indexes of cyclooxygenase activity. All prostanoids were measured by previously validated radioimmunoassay techniques. RESULTS: In the whole blood assays in vitro, nimesulide was twentyfold more potent than 4-hydroxynimesulide toward the two isozymes and both compounds displayed a twentyfold preference for prostaglandin H synthase-2 versus prostaglandin H synthase-1. The administration of a single oral dose of 100 mg nimesulide to six healthy subjects significantly (p < 0.01) reduced monocyte prostaglandin H synthase-2 and prostaglandin H synthase-1 activity ex vivo by more than 90% and 50%, respectively, up to 6 hours. At 24 hours, prostaglandin H synthase-2 but not prostaglandin H synthase-1 activity was significantly reduced by 49% (p < 0.05). Nimesulide significantly (p < 0.05) reduced the urinary excretion of 11-dehydrothromboxane B2 and 6-ketoprostaglandin F1 alpha by approximately 30% and 25%, respectively, while not affecting that of prostaglandin E2 and thromboxane B2. CONCLUSIONS: Nimesulide is a potent inhibitor of human monocyte prostaglandin H synthase-2. However, despite a twentyfold selectivity ratio, therapeutic plasma levels of nimesulide are sufficiently high to cause detectable inhibition of platelet prostaglandin H synthase-1.
BACKGROUND: The aim of this study was to test the hypothesis that nimesulide, a nonsteroidal antiinflammatory drug, or its principal metabolite 4-hydroxynimesulide, is a selective inhibitor of prostaglandin H synthase-2 in human beings. METHODS: Heparinized whole blood samples obtained from healthy subjects were incubated with lipopolysaccharide (10 micrograms/ml) for 24 hours at 37 degrees C and prostaglandin E2 was measured in plasma as an index of monocyte prostaglandin H synthase-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 minutes was assessed as an index of platelet prostaglandin H synthase-1 activity. We also measured the urinary excretion of 11-dehydrothromboxane B2, prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 as in vivo indexes of cyclooxygenase activity. All prostanoids were measured by previously validated radioimmunoassay techniques. RESULTS: In the whole blood assays in vitro, nimesulide was twentyfold more potent than 4-hydroxynimesulide toward the two isozymes and both compounds displayed a twentyfold preference for prostaglandin H synthase-2 versus prostaglandin H synthase-1. The administration of a single oral dose of 100 mg nimesulide to six healthy subjects significantly (p < 0.01) reduced monocyte prostaglandin H synthase-2 and prostaglandin H synthase-1 activity ex vivo by more than 90% and 50%, respectively, up to 6 hours. At 24 hours, prostaglandin H synthase-2 but not prostaglandin H synthase-1 activity was significantly reduced by 49% (p < 0.05). Nimesulide significantly (p < 0.05) reduced the urinary excretion of 11-dehydrothromboxane B2 and 6-ketoprostaglandin F1 alpha by approximately 30% and 25%, respectively, while not affecting that of prostaglandin E2 and thromboxane B2. CONCLUSIONS:Nimesulide is a potent inhibitor of human monocyte prostaglandin H synthase-2. However, despite a twentyfold selectivity ratio, therapeutic plasma levels of nimesulide are sufficiently high to cause detectable inhibition of platelet prostaglandin H synthase-1.