Sa. Mousa et al., ANTIPLATELET AND ANTITHROMBOTIC EFFICACY OF DMP-728, A NOVEL PLATELETGPIIB IIIA RECEPTOR ANTAGONIST/, Circulation, 89(1), 1994, pp. 3-12
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.