METHODS AND RESULTS:
DMP 728 demonstrated antiplatelet efficacy in vitro in inhibiting
ADP-induced human platelet aggregation (IC50, 46 +/- 2 nmol/L) and
fibrinogen binding to human platelets (IC50, 2.3 +/- 0.8 nmol/L) or purified human
GPIIb/IIIa receptors (IC50, 0.6 +/- 0.1 nmol/L).
DMP 728 demonstrated high affinity and specificity for human platelet GPIIb/IIIa over other adhesion molecules. In anesthetized mongrel dogs,
DMP 728 at 0.001 to 1.0 mg/kg IV produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by
ADP and in prolonging template bleeding time.
DMP 728 effects on bleeding time prolongation were more rapidly reversible than those on platelet aggregation inhibition. A maximal antiplatelet 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 IV administration at different doses in various models of arterial
thrombosis. In the coronary artery Folts model in dogs,
DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED50 of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions. Additionally,
DMP 728 demonstrated 100% prevention of primary
thrombosis and rethrombosis (P < .01)
after treatment with different thrombolytics, including
tissue plasminogen activator and
streptokinase, in an electrolytically induced femoral artery
thrombosis model in dogs.
CONCLUSIONS: Acute intravenous
DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in different arterial
thrombosis models. These data suggest that
DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective
antithrombotic agent in coronary and peripheral artery thromboembolic disorders.