Antithrombotic Effect of TA-993, a Novel 1,5-Benzothiazepine Derivative, in Conscious Rats

Since reported experimental models of thrombosis are not suitable for comparison of several drugs by oral administration, we developed a convenient model for this purpose by applying direct current through an intravascular electrode. In conscious rats, which were implanted with anodal electrodes in the abdominal aorta on the day before the experiment, application of 200 microA of direct current induced the formation of a platelet-rich thrombus around the intravascular electrode. Using this model, we studied the antithrombotic effect of the novel antiplatelet agent TA-993, (-)-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-8-methyl-2-(4- methylphenyl)-1,5-benzothiazepin-4(5H)-one maleate, and compared its effect with other antiplatelet agents. TA-993 at doses of 30 mg/kg, p.o. or more by single administration or at doses of 10 mg/kg or more by repeated administration dose-dependently suppressed the thrombus formation. Aspirin (10 mg/kg, p.o. or more), cilostazol (100 mg/kg, p.o.) and ticlopidine (30 mg/kg, p.o. or more) also suppressed the thrombus formation by single administration. These results suggest that TA-993 has a comparable antithrombotic effect with other antiplatelet agents, and thus it is a possible remedy for thrombotic and embolic diseases.