ANTITHROMBOTIC EFFECTS OF DMP-728, A PLATELET GPIIB IIIA RECEPTOR ANTAGONIST, IN A CANINE MODEL OF ARTERIAL THROMBOSIS/

The platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa, fibrinogen re ceptor) represents the final common pathway for platelet aggregation. Inhibition of GPIIb/IIIa with antibodies or peptides containing the RG D sequence has been reported to prevent arterial thrombosis. We examin ed DMP 728 -arginyl-glycyl-L-aspartyl-3-(amino-methyl-benzoic acid], m ethanesulfonic acid salt], a cyclic peptidomimetic, GPIIb/IIIa recepto r antagonist, for prevention of thrombosis and rethrombosis in a canin e model of carotid artery thrombosis. Dogs were anesthetized, and both carotid arteries were instrumented with an electrode, a flow probe, a nd a stenosis. A 300-muA current was applied to the intimal surface in the right carotid artery (RCA, control) through the electrode; time t o occlusive thrombus formation and thrombus mass was noted. The RCA se rved as the control vessel; the left carotid artery (LCA) served as th e test vessel after DMP 728 administration (0.1 or 1.0 mg/kg, intraven ously, i.v.). As compared with controls, occlusive thrombus formation was reduced by both doses of DMP 728 (control 100% n = 12; 0.1 mg/kg i . v. 17%, p < 0.05, n = 6; 1.0 mg/kg i.v. 0%, p < 0.05, n = 6), time t o occlusion was increased (p < 0.05), and thrombus weight was reduced (p < 0.05). Ex vivo platelet aggregation was inhibited in all groups. In a second group of animals, a carotid artery thrombus was formed and lysed with anisoylated plasminogen activator complex (APSAC; 0.05 U/k g intraarterially, i.a.) with or without DMP 728. Dogs receiving salin e demonstrated a 100% rate of rethrombosis as compared with 25% of DMP 728-treated dogs reoccluding after recannalization (p < 0.05). Compet ition binding analysis showed that DMP 728 can prevent binding of 7E3 GPIIb/IIIa antibody to platelets in vitro. The data suggest that DMP 7 28 may have therapeutic potential as an effective antithrombotic agent by inhibiting the platelet-fibrinogen interaction representing the fi nal common pathway in platelet-dependent thrombus formation.