Antithrombotic Action of TA-993, a New 1,5-Benzothiazepine Derivative, in a Canine Model of Femoral Arterial Thrombosis

TA-993 is a novel 1,5-benzothiazepine derivative of l-cis configuration, having a potent antiplatelet action and an increasing action on femoral blood flow. We evaluated the antithrombotic effect of TA-993 in a canine model of femoral arterial thrombosis. Thrombus was induced by both application of direct anodal current to the femoral artery and partial occlusion of the artery. The partial occlusion by placing an adjustable occluder on the artery and the current application were carried out 40 and 60 min after the intraduodenal administration of drugs, respectively. In control dogs, complete sustained occlusion of the femoral artery due to thrombus occurred 55.4 +/- 9.2 min after the onset of current application. TA-993 (3 and 10 mg/kg) dose-dependently prolonged the time for occlusion. Aspirin (30 mg/kg) also prolonged it. TA-993, 10 mg/kg, significantly inhibited whole-blood aggregation 60 min after the administration with a weaker potency than that of aspirin (30 mg/kg), whereas 3 mg/kg of TA-993 did not. The inhibitory effect of TA-993 (10 mg/kg) on platelet aggregation was maintained for >7 h. Moreover, TA-993 (10 mg/kg) increased femoral blood flow in spite of the partially occluded condition. These results indicate that TA-993 has an antithrombotic effect on femoral arterial thrombosis and suggest that an increasing action on femoral blood flow of TA-993 is more relevant than its antiplatelet action to the antithrombotic effect in this model.