NONPEPTIDE GLYCOPROTEIN IIB IIIA INHIBITORS .5. ANTITHROMBOTIC EFFECTS OF MK-0383/

The antiaggregatory and antithrombotic actions of MK-0383, a low molec ular weight, nonpeptide antagonist of the platelet glycoprotein IIb/II Ia, were evaluated in a variety of canine models. Inhibition of ex viv o platelet aggregation responses to ADP and collagen were observed aft er the acute sequential i.v. administrations of 10 to 500 mu g/kg or 3 60-min continuous i.v. infusions of 1 to 10 mu g/kg/min of MK-0383. He mostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, sugg esting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP w as abolished without significant extension of bleeding time. In a mode l of platelet-dependent cyclic flow reductions in injured, stenosed le ft circumflex coronary artery, the bolus i.v. administrations of 300 a nd 1000 mu g/kg of MK-0383 totally abolished cyclic flow reductions fo r periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of el ectrically induced left circumflex coronary artery occlusive thrombosi s, 10 mu g/kg/min i.v. of MK-0383 initiated 15 min before electrical i njury prevented occlusive thrombosis in three of six preparations desp ite continued electrical stimulation of the vessel for 300 min, delaye d occlusion in three of six preparations (160.3 +/- 5.5 min) and reduc ed thrombus mass(5.1 +/- 1.3 mg), compared to the development of occlu sive thrombosis in six of six saline-treated preparations (50.5 +/- 8. 7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolyt ic agents in the presence of background heparin for lysis of electrica lly induced left circumflex coronary artery occlusive thrombus, 10 mu g/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminog en activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline ; streptokinase: eight of eight MK-0383 vs. two of eight saline) and a ccelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjun ct to thrombolytic therapy in the treatment of coronary artery ischemi c syndromes.