PROTECTIVE EFFECT OF ORAL XEMILOFIBAN IN ARTERIAL THROMBOSIS IN DOGS - INCREASED ACTIVITY IN COMBINATION WITH ASPIRIN

Background-Inhibition of platelet aggregation by preventing the bindin g of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets r esults in antithrombotic activity. We report on the antithrombotic eff ect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, admini stered alone or with aspirin (ASA) in an acute thrombosis model. Metho ds and Results-Conscious dogs were treated with xemilofiban (1.25, 2.5 , 5.0, or 6 mg/kg, n=6); low-dose (LD, 81 mg) ASA, n=7; high-dose (HD, 162 mg) ASA, n=6; xemilofibran 1.25 mg/kg plus LD ASA, n=6; xemilofib ran 1.25 mg/kg plus HD ASA, n=6; or placebo, n=7. Dogs were anesthetiz ed 60 minutes later, and the effects of the treatments were evaluated after electrolytic injury (250 mu A for 180 minutes) in the left circu mflex coronary artery. Bleeding time (BT) was assessed in a separate s tudy. Incidence of thrombosis was reduced (P<0.05) by xemilofiban grea ter than or equal to 2.5 mg/kg, HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA compared with placebo. Xemilofiban greater than or equal to 2. 5 mg/kg or xemilofiban 1.25 mg/kg plus HD ASA significantly increased time to occlusion, inhibited ex vivo platelet aggregation to collagen >90%, and prevented or decreased (P<0.05) cyclic flow variations (CFVs ) compared with placebo. BT was increased (P<0.05) with xemilofiban gr eater than or equal to 2.5 mg/kg but not with xemilofiban 1.25 mg/kg p lus HD ASA. Conclusions-Xemilofiban greater than or equal to 2.5 mg/kg , HD ASA, or xemilofiban 1.25 mg/kg plus HD ASA significantly reduced the incidence of thrombosis. These doses of xemilofiban or xemilofiban 1.25 mg/kg plus HD ASA increased time to occlusion, inhibited ex vivo platelet aggregation by >90%, and prevented or reduced CFVs. Xemilofi ban greater than or equal to 2.5 mg/kg but not xemilofiban 1.25 mg/kg plus HD ASA significantly increased BT.