ANTITHROMBOTIC EFFECTS AND BLEEDING-TIME PROLONGATION WITH SYNTHETIC PLATELET GPIIB IIIA INHIBITORS IN ANIMAL-MODELS OF PLATELET-MEDIATED THROMBOSIS/

Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cyste ine, yl)-D-tyrosyl-L-arginylglycyl-Lalphaaspartylcyclic (1-5)-sulfide, 5-oxide (G4120) and partyl-[0-methyttyrosyl]-L-arginyl-L-cysteinamide , cyclic 1-9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, e x vivo platelet aggregation and bleeding time prolongation with both a gents was studied in hamsters with a standardized femoral vein endothe lial cell injury predisposing to platelet-rich mural thrombosis, and i n dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in v ivo thrombus formation with a 50% inhibitory bolus dose (ID50) of appr oximately 20 mug/kg, ex vivo ADP-induced platelet aggregation with ID5 0 of 10 mug/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +/- 9 to 1,100 +/- 330 s. Administration of TP9201 in ham sters inhibited in vivo thrombus formation with ID50 of 30 mug/kg, ex vivo platelet aggregation with an ID50 of 50 mug/kg and bolus injectio n of 1 mg/kg did not prolong the template bleeding time. In the dog ev ersion graft model, infusion of 100 mug/kg of G4120 over 60 min did no t fully inhibit platelet-mediated thrombotic occlusion but was associa ted with inhibition of ADP-induced ex vivo platelet aggregation and wi th prolongation of the template bleeding time from 1.3 +/- 0.4 to 12 /- 2 min. Infusion of 300 mug/kg Of TP9201 over 60 min completely prev ented thrombotic occlusion, inhibited ex vivo platelet aggregation, bu t was not associated with prolongation of the template bleeding time. TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus form ation without associated prolongation of the template bleeding time.