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.
Marzec
U M
UM
Roon Research Center for Arteriosclerosis and Thrombosis, Scripps Clinic and Research Foundation, La Jolla, California.
Kelly
A B
AB
Hanson
S R
SR
Lasslo
A
A
Harker
L A
LA
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D001807:Blood Vessel Prosthesis; D003094:Collagen / Q000494:pharmacology; D005337:Fibrin / Q000378:metabolism; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010978:Platelet Factor 4 / Q000378:metabolism; D011093:Polyethylene Terephthalates; D013927:Thrombosis / Q000517:prevention & control*; D001620:beta-Thromboglobulin / Q000378:metabolism
D009557:Nipecotic Acids; D010975:Platelet Aggregation Inhibitors; D011093:Polyethylene Terephthalates; D001620:beta-Thromboglobulin; C043099:alpha, alpha'-bis(3-(N,N-diethylcarbamoyl)piperidino)-4-xylene; D010978:Platelet Factor 4; D000244:Adenosine Diphosphate; D005337:Fibrin; D003094:Collagen