NONPEPTIDE GLYCOPROTEIN IIB LIIA INHIBITORS .14. ORAL ANTITHROMBOTIC EFFICACY OF L-738,167 IN A CONSCIOUS CANINE MODEL OF CORONARY-ARTERY ELECTROLYTIC INJURY/

Background A conscious dog model of left circumflex coronary artery el ectrolytic injury was used to assess the oral antithrombotic efficacy of L-738,167, a potent nonpeptide antagonist of platelet GP IIb/IIIa. L-738,167 was administered either as a single oral pretreatment dose 2 hours before initiation of vessel injury or as two oral doses adminis tered 24 hours apart, 12 hours before and after initiation of vessel i njury. Methods and Results In untreated controls, electrolytic coronar y injury (50 mu A, 3 hours) resulted in thrombotic occlusion and myoca rdial ischemia in 15 of 16 dogs, with 4 developing lethal arrhythmias. Significant reductions in thrombus mass and complete prevention of my ocardial ischemia and infarction were achieved with a single 100- to 3 00-mu g/kg dose of L-738,167 pretreatment and with two 100-mu g/kg dos es administered 12 hours before and after initiation of vessel injury. Delays and/or reductions in incidence of ischemia, thrombus mass, and infarct sizes also were achieved with 10- to 30-mu g/kg pretreatment and with two 30-mu g/kg doses administered 12 hours before and after i nitiation of vessel injury. None of the L-738,167-treated animals deve loped lethal arrhythmias. A single oral 100-mu g/kg dose of L-738,167 achieved greater than or equal to 90% inhibitions of ADP (extent)- and collagen (rate)-induced ex vivo platelet aggregation and fivefold to sixfold or greater elevations in bleeding time; a single oral 30-mu g/ kg dose of L-738,167 achieved sustained 40% to 70% inhibitions of ADP- and collagen-induced ex vivo platelet aggregation and modest twofold to threefold elevations in bleeding time. At 12 to 24 hours after sing le oral 30- and 100-mu g/kg doses of L-738,167, a substantially greate r L-738,167 concentration was associated with platelets than free in p lasma. Conclusions These findings are indicative of potent and sustain ed oral antithrombotic efficacy and suggest that L-738,167 possesses p otential for the oral management of chronic thrombotic occlusive disor ders.