10381787|t|Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects.
10381787|a|We evaluated whether therapeutic blood levels of meloxicam are associated with selective inhibition of monocyte cyclooxygenase (COX)-2 in vitro and ex vivo. Concentration-response curves for the inhibition of monocyte COX-2 and platelet COX-1 were obtained in vitro after the incubation of meloxicam with whole blood samples. Moreover, 11 healthy volunteers received placebo or 7.5 or 15 mg/day meloxicam, each treatment for 7 consecutive days, according to a randomized, double-blind, crossover design. Before dosing and 24 h after the seventh dose of each regimen, heparinized whole blood samples were incubated with lipopolysaccharide (10 microgram/ml) for 24 h at 37 degrees C, and prostaglandin E2 was measured in plasma as an index of monocyte COX-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 min was assessed as an index of platelet COX-1 activity. The administration of placebo did not significantly affect plasma prostaglandin E2 (21. 3 +/- 7.5 versus 19.1 +/- 4 ng/ml, mean +/- S.D., n = 11) or serum thromboxane B2 (426 +/- 167 versus 425 +/- 150 ng/ml) levels. In contrast, the administration of 7.5 and 15 mg of meloxicam caused dose-dependent reductions in monocyte COX-2 activity by 51% and 70%, respectively, and in platelet COX-1 activity by 25% and 35%, respectively. Although the IC50 value of meloxicam for inhibition of COX-1 was 10-fold higher than the IC50 value of COX-2 in vitro, this biochemical selectivity was inadequate to clearly separate the effects of meloxicam on the two isozymes after oral dosing as a function of the daily dose and interindividual variation in steady-state plasma levels.
10381787	T10	CHEMICAL	1095	1111	prostaglandin E2
10381787	T11	CHEMICAL	88	97	meloxicam
10381787	T12	GENE-Y	231	253	cyclooxygenase (COX)-2
10381787	T13	GENE-Y	1353	1358	COX-2
10381787	T14	GENE-Y	1414	1419	COX-1
10381787	T15	GENE-Y	1514	1519	COX-1
10381787	T16	GENE-Y	1562	1567	COX-2
10381787	T17	GENE-Y	337	342	COX-2
10381787	T18	GENE-Y	356	361	COX-1
10381787	T19	GENE-Y	869	874	COX-2
10381787	T1	CHEMICAL	1184	1198	thromboxane B2
10381787	T20	GENE-Y	1013	1018	COX-1
10381787	T21	GENE-Y	38	54	cyclooxygenase-1
10381787	T22	GENE-Y	68	84	cyclooxygenase-2
10381787	T2	CHEMICAL	1298	1307	meloxicam
10381787	T3	CHEMICAL	1486	1495	meloxicam
10381787	T4	CHEMICAL	1657	1666	meloxicam
10381787	T5	CHEMICAL	409	418	meloxicam
10381787	T6	CHEMICAL	514	523	meloxicam
10381787	T7	CHEMICAL	168	177	meloxicam
10381787	T8	CHEMICAL	805	821	prostaglandin E2
10381787	T9	CHEMICAL	903	917	thromboxane B2
