EFFECTS OF G4120, A ARG-GLY-ASP-CONTAINING SYNTHETIC PLATELET GLYCOPROTEIN IIB IIIA-RECEPTOR ANTAGONIST, ON ARTERIAL AND VENOUS THROMBOLYSIS WITH RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR IN DOGS/

The effects of G4120, L-cysteine, ginylglycyl-L-alpha-aspartyl-cyclic( 1->5)-sulfide, 5-oxide, a novel synthetic cyclic RGD-containing pentap eptide, on thrombolysis with rt-PA were investigated in a combined art erial and venous thrombosis model in the dog. In a blinded study, desi gn dogs were randomly assigned to 0.5 mg/kg rt-PA+0.1 mg/kg G4120 (gro up I, n=5), 0.5 mg/kg rt-PA+placebo (II, n=5), 0.25 mg/kg rt-PA+0.1 mg /kg G4120 (III, n=5) or 0.25 mg/kg rt-PA+placebo (IV, n=5). Cyclic ref low and reocclusion occurred in 8 out of 10 animals given rt-PA alone versus 2 out of 10 dogs given rt-PA+G4120 (p<0.05). The patency status , classified as persistent patency, cyclic reflow with final patency a nd final occlusion was 51010, 2/3/0,3/1/1 and 0/1/4 for groups I to IV , respectively (p=0.006). Venous clot lysis was not altered by G4120. ADP-induced ex vivo platelet aggregation was completely inhibited duri ng the infusion of G4120, and partially recovered 30 min (22+/-9% of b aseline) and 90 min (38+/-15%) later. Bleeding times increased from 2. 1+/-0.1 min at baseline to 26+/-2 min during G4120 infusion, and retur ned to 2.8+/-4 min within 90 min. Thus, G4120, a potent short-lived re versible platelet GPIIb/IIIa receptor antagonist, maintains arterial p atency following recanalization with rt-PA. It may be useful for the p revention of reocclusion following thrombolytic therapy in patients wi th acute myocardial infarction.