ANTITHROMBOTIC EFFECTS OF MK-0852, A PLATELET FIBRINOGEN RECEPTOR ANTAGONIST, IN CANINE MODELS OF THROMBOSIS

The antiaggregatory and antithrombotic actions of MK-0852, a cyclic he ptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 muM ADP in the presence of 1 muM epinephrine with an IC50 value of 0.10 muM. The i.v. infusion of 1.0 and 3.0 mug/kg/min MK-0852 to anesthetized dogs significantly inhibited ex vivo platelet aggregation responses to ADP and collagen, with the 3.0 mug/kg/min infusion completely inhibiting ex vivo aggrega tion responses to both agonists. The i.v. administrations of 100 and 3 00 mug/kg MK-0852 suppressed platelet-dependent cyclic flow reductions in stenosed canine left circumflex (LCX) coronary artery for periods of 24 +/- 3 and 64 +/- 4 min, respectively. In a canine model of coppe r coil-induced femoral arterial thrombosis, i.v. MK-0852 (100 mug/kg 1 mug/kg/min), initiated 15 min before coil placement, reduced the in cidence of occlusive thrombosis during the 45-min post-coil time perio d of continued therapy (1/5 MK-0852 vs. 7/7 saline; P < .01). MK-0852 was administered as an adjunctive therapy with tPA to evaluate its eff ects on thrombolysis after copper coil-induced femoral arterial thromb us formation. MK-0852 (i.v.; 100 mug/kg + 1 mug/kg/min), initiated 15 min before tPA, reduced the incidence of post-thrombolysis reocclusion . During the 60-min period of continued drug infusion after the termin ation of tPA, 0 of 5 animals receiving MK-0852 reoccluded vs. 7/8 sali ne (P < .01). In a canine model of electrically induced LCX coronary a rtery thrombosis, i. v. M K-0852 (100 mug/kg + 3 mug/kg/min), initiate d 15 min before the initiation of electrical injury, prevented occlusi ve thrombosis in 4 of 6 preparations despite the continued electrical stimulation of the vessel for 180 min. Thrombotic occlusion was delaye d in the remaining two preparations (99 and 100 min), compared with oc clusion in 4 of 4 saline-treated preparations (69.3 +/- 6.3 min). When administered as an adjunct to thrombolytic agents for lysis of electr ically induced LCX coronary artery thrombi, i.v. MK-0852 (300 mug/kg 3 ug/kg/min), initiated 15 min before tPA or streptokinase, both incr eased the incidence of reperfusion (tPA: 8/8 MK-0852 vs. 3/8 saline; s treptokinase: 5/8 MK-0852 vs. 2/8 saline) and accelerated reperfusion. The incidence of reocclusion during continued adjunctive therapy was reduced. These findings demonstrate antithrombotic efficacy for MK-085 2 in several diverse experimental thrombosis models, suggesting broad utility for MK-0852 in the treatment of vaso-occlusive disorders, alon e or as an adjunct to thrombolytic therapy.