PREVENTION OF CAROTID-ARTERY THROMBOSIS BY ORAL PLATELET GPIIB IIIA ANTAGONIST IN DOGS/

Background and Purpose Current antithrombotic therapy in acute ischemi c stroke and myocardial infarction in which a combination of antiplate let agents (aspirin) and anticoagulants (heparin) was used led to part ial reduction of acute thrombotic complications. Recent advances in an tiplatelet research led to the discovery of the platelet glycoprotein IIb-IIIa complex (GPIIb/IIIa), the final common pathway for platelet a ggregation. The present study was undertaken to determine the oral ant ithrombotic efficacy of a potent and specific platelet GPIIb/IIIa anta gonist, DMP728, in an electrically induced carotid artery thrombosis m odel in dogs. Based on the powerful antiplatelet efficacy of this mech anism in inhibiting all agonist-induced platelet aggregation as well a s in inhibiting platelet procoagulant activity (thrombin generation an d hence fibrin formation), an orally active antagonist for this integr in receptor might have potential benefits in stroke. Methods Anestheti zed dogs were Instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery how velocity. Animals were treated with saline or DMP728 (0.1 to 1.0 mg/kg PO). Thrombus formation (platelet- rich aggregate with fibrous coating and a few erythrocytes) by anodal electrolytic stimulation (300 mu A) to the Intimal surface of the righ t carotid artery was initiated 120 minutes after oral DMP728 administr ation and continued for 180 minutes, Whole blood cell counts, ex vivo platelet aggregation, and template bleeding rime were determined at di fferent time points throughout the study. Results DMP728 administered at 0.1 to 1.0 mg/kg PO exhibited dose-dependent antithrombotic efficac y in this model. DMP728 was shown to be significantly effective in inh ibiting ex vivo platelet aggregation and in inhibiting thrombosis at 0 .3 to 1.0 mg/kg PO, The antiplatelet, antithrombotic effects of DMP728 were demonstrated without any significant changes in the different he modynamic or coagulation parameters. These data demonstrated the oral antithrombotic efficacy of DMP728 in dogs. Conclusions Platelet GPIIb/ IIIa blockade with an orally active antagonist was shown to be safe an d effective in the prevention of carotid artery occlusive thrombosis.