Inhibition of thrombus formation in vivo by novel antiplatelet agent

The antithrombotic and antihemostatic effects of the novel antiplatelet compound, alpha, alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (GT-12), were investigated in a baboon model of platelet-dependent thrombosis under high flow conditions. In this model, segments of collagen-coated tubing and Dacron vascular graft were placed as thrombus-inducing extension devices in exteriorized femoral arteriovenous shunts. The deposition of 111In-labeled platelets was measured for each thrombogenic segment throughout 1 hour by using gamma camera imaging. In addition, the 125I-fibrin retained in the forming thrombus was measured. Intravenous infusion of GT-12 (100 mumol/kg, 63.3 mg/kg) over a 15-minute period before the insertion of the test segments prolonged the bleeding time from a baseline value of 4.4 +/- 0.4 min to 7.6 +/- 1.0 min (p = 0.036) and inhibited platelet aggregation ex vivo induced by adenosine diphosphate (ED50 4.7 +/- 0.9 to 10.3 +/- 2.2 microM; p less than 0.02) and collagen (ED50 2.0 +/- 0.4 to 8.0 +/- 2.4 micrograms/ml; p less than 0.05). Deposition of platelets and fibrin was decreased in concert by 30% (p less than 0.05) for vascular grafts and possibly collagen segments at the end of the 60-minute observation period. We conclude that GT-12 is antithrombotic for Dacron graft-induced thrombus formation in vivo.