ANTIPLATELET AND ANTITHROMBOTIC EFFICACY OF DMP-728, A NOVEL PLATELETGPIIB IIIA RECEPTOR ANTAGONIST/

Background Currently used antiplatelet drugs, including aspirin, ticlo pidine, and others, are effective against certain but not all of the m any. endogenous platelet activators. Because of their limited efficacy , a significant number of serious thromboembolic complications still o ccur, highlighting the need for a more effective therapy. Thus, we hav e identified a systemically active peptide analogue (DMP 728) of the a rginine-glycine-aspartic acid (RGD) recognition sequence that mediates the binding of ligands such as fibrinogen to the platelet glycoprotei n (GP) IIb/IIIa receptors. The goals of the present study were to dete rmine the antiplatelet and antithrombotic efficacies of DMP 728 in var ious arterial thrombosis models. Methods and Results DMP 728 demonstra ted antiplatelet efficacy in vitro in inhibiting ADP-induced human pla telet aggregation (IC50, 46+/-2 mmol/L) and fibrinogen binding to huma n platelets (IC50, 2.3+/-0.8 nmol/L) or purified human GPIIb/IIIa rece ptors (IC50, 0.6+/-0.1 nmol/L). DMP 728 demonstrated high affinity and specificity for human platelet GPIIb/IIIa over other adhesion molecul es. In anesthetized mongrel dogs, DMP 728 at 0.001 to 1.0 mg/kg IV pro duced dose-dependent antiplatelet effects in inhibiting ex vivo platel et aggregation induced by ADP and in prolonging template bleeding time . DMP 728 effects on bleeding time prolongation were more rapidly reve rsible than those on platelet aggregation inhibition. A maximal antipl atelet effect for DMP 728 was demonstrated at 0.01 mg/kg IV bolus. The antithrombotic efficacy of DMP 728 was examined in vitro and in vivo after TV administration at different doses in various models of arteri al thrombosis. In the coronary artery Felts model in dogs, DMP 728 dem onstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED(50) of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions . Additionally, DMP 728 demonstrated 100% prevention of primary thromb osis and rethrombosis (P<.01) after treatment with different thromboly tics, including tissue plasminogen activator and streptokinase, in an electrolytically induced femoral artery thrombosis model in dogs. Conc lusions Acute intravenous DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in differen t arterial thrombosis models. These data suggest that DMP 728, a low-m olecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic p otential as an effective antithrombotic agent in coronary and peripher al artery thromboembolic disorders.