The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.

Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A 2 and on systemic biosynthesis of prostacyclin in vivo . Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA 2 -dependent aggregation, induced ex vivo by arachidonic acid (83 ± 11% vs. 11.9 ± 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB 2 (−95 ± 2% vs. −6.9 ± 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB 2 (−70 ± 9.9% vs. −20.3 ± 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA 2 -dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB 2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE 2 in whole blood ex vivo ) to a comparable degree (−93.3 ± 2% vs. −83 ± 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF 1α . These data suggest that ( i ) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; ( ii ) comparable COX-2 inhibition is attained by celecoxib (100–800 mg) and ibuprofen (800 mg) after acute dosing; and ( iii ) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.

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have been approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal antiinflammatory drugs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients with CTD who developed ischemic complications after receiving celecoxib. All patients had a history of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite of thromboxane A 2 in 2 of the patients as an indicator of in vivo platelet activation, and this was markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated patients with diseases that predispose to thrombosis should be monitored carefully for this complication.Prostaglandins (PG) and thromboxane (TX) are regulators of platelet and endothelial cell function. Activated platelets synthesize TXA 2 , which is a potent platelet aggregant and vasoconstrictor. PGI 2 , which is synthesized primarily by endothelial cells, inhibits platelet activation by elevating platelet cyclic AMP and induces vasodilation. There is evidence that endogenous PGI 2 has antithrombotic properties. Infusion of PGI 2 and enhancement of endogenous PGI 2 also provide antiplatelet activity (1).A multienzyme pathway that includes the cyclooxygenase (COX)