Circulation, Vol 89, 3-12, Copyright © 1994 by American Heart Association
SA Mousa, JM Bozarth, MS Forsythe, SM Jackson, A Leamy, MM Diemer, RP Kapil, RM Knabb, MC Mayo and SK Pierce
BACKGROUND: Currently used antiplatelet drugs, including aspirin,
ticlopidine, and others, are effective against certain but not all of the
many endogenous platelet activators. Because of their limited efficacy, a
significant number of serious thromboembolic complications still occur,
highlighting the need for a more effective therapy. Thus, we have
identified a systemically active peptide analogue (DMP 728) of the
arginine-glycine-aspartic acid (RGD) recognition sequence that mediates the
binding of ligands such as fibrinogen to the platelet glycoprotein (GP)
IIb/IIIa receptors. The goals of the present study were to determine the
antiplatelet and antithrombotic efficacies of DMP 728 in various arterial
thrombosis models. 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.
ARTICLES
Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist
DuPont Merck Pharmaceutical Co, Cardiovascular Diseases Division, Wilmington, Del. 19880-0400.
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