Effects of nimesulide on constitutive and inducible prostanoid biosynthesis in human beings
MR Panara, R Padovano, MG Sciulli… - Clinical …, 1998 - Wiley Online Library
MR Panara, R Padovano, MG Sciulli, G Santini, G Renda, MT Rotondo, A Pace, C Patrono…
Clinical Pharmacology & Therapeutics, 1998•Wiley Online LibraryBackground 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 μg/ml)
for 24 hours at 37° 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 …
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 μg/ml)
for 24 hours at 37° 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 …
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 μg/ml) for 24 hours at 37° 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° 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 F1α, 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 nimeslude 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 prostglandin 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 F1α 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.
Clinical Pharmacology & Therapeutics (1998) 63, 672–681; doi:
Wiley Online Library