THE PROTECTIVE DOSE OF THE POTENT GPIIB IIIA ANTAGONIST SC-54701A IS REDUCED WHEN USED IN COMBINATION WITH ASPIRIN AND HEPARIN IN A CANINE MODEL OF CORONARY-ARTERY THROMBOSIS/

Fibrinogen receptor antagonists block the fibrinogen-platelet interact ion at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-547 01 is the active metabolite of SC-54684A, an orally active fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydro chloride salt) with that of aspirin (ASA) or heparin and with combinat ion therapy in a canine model of continuous current injury. Methods an d Results Sixty-six dogs were used (6 per treatment). SCa (15-minute l oading dose followed by [//] infusion [mu g/kg per minute]: (0.87//0.3 9 = 1 x SCa; 0.52//0.23 = 0.6 x SCa; and 0.425//0.20 = 0.5 x SCa), ASA (2.8 mg/kg), heparin (200 U/kg plus 1000 U/h), or saline (0.1 mL/kg) was administered intravenously. Experimental time was 180 minutes of c urrent. Time to occlusion was increased (P < .05) by SCa (T = incidenc e of thrombosis) (1 x SCa, > 180 minutes [T = 0]; 0.6 x SCa, 158 +/- 1 5 minutes [T = 2]; 0.5 x SCa, 130 +/- 22 minutes [T = 4]), heparin (11 4 +/- 16 minutes [T = 5]), and ASA plus heparin (130 +/- 11 minutes [T = 5]) relative to saline (58 +/- 7 minutes [T = 6]). Time to occlusio n for the SCa treatments was increased compared with ASA (64 +/- 7 min utes [T = 6]). When 0.5 x SCa was administered with ASA plus heparin, time to occlusion was > 180 minutes [T = 0]. SCa provided complete pro tection at greater than or equal to 90% inhibition of ex vivo collagen -induced platelet aggregation. Cyclic flow variations were minimal wit h SCa or any treatment involving 0.5 x SCa and ASA. Conclusions SCa ha s dose-dependent antithrombotic efficacy and inhibits ex vivo platelet aggregation. ASA, heparin, or saline was ineffective in this model. S Ca (0.5 x) plus ASA and heparin maximized the antithrombotic effect of this lower dose of SCa.