Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.

Background: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies

Methods: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily)

Results: Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given.

Vascular biology of thrombosis: platelet-vessel wall interactions and aspirin effects.

The antithrombotic effect of aspirin has long been recognized, and administration of low doses (80-160 mg/day) for the prevention of ischemic events in patients with coronary artery disease (CAD) is now generally considered to be routine practice. The action of aspirin derives mostly from the selective inhibition of cyclo-oxygenases (Cox). These enzymes (Cox-1 and Cox-2) catalyze the synthesis of eicosanoids, which play an important part in platelet-vessel wall interactions.

Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease.

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies.

Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in platelets.

The polymorphism responsible for the Pl(A2) alloantigen on the beta(3)-component of beta(3)-containing integrins is reported to be a risk factor for coronary thrombosis. This study examined the effect of Pl(A2) on the function of beta(3)-integrins using platelets from subjects homozygous and heterozygous for Pl(A1) and Pl(A2). There was overlap in the distribution of the dissociation constant (K(d)) and maximum fibrinogen binding (B(max)) values for fibrinogen binding to alpha(IIb)beta(3) on platelets from Pl(A1) and Pl(A2) homozygotes and Pl(A1)/Pl(A2) heterozygotes.

Cyclooxygenase inhibition and thrombogenicity.

Cyclooxygenase (COX)-1 and COX-2 catalyze the formation of prothrombotic and antithrombotic eicosanoids, respectively. Aspirin, conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2-specific inhibitors exhibit different patterns of inhibition of COX-1-mediated thromboxane biosynthesis and COX-2-mediated prostacyclin biosynthesis. The relationship between the pharmacologic inhibition of these vasoactive eicosanoids and the thromboprophylaxis or thrombogenicity exhibited by different therapeutic agents is currently unclear.