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.
DMP754 (
roxifiban), a
prodrug of
XV459, is a recently discovered, potent
antiplatelet agent with high affinity and specificity for platelet
GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC(50)=0.030 to 0.05 micromol/L) or
anticoagulant used for blood collection.
DMP754 rapidly converts to its active free-
acid form,
XV459, which has a comparable high affinity for both resting and activated platelets (K(d)=1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determine intravenous and oral antithrombotic efficacies of
DMP754 and
XV459 and to compare them with those of other antiplatelet and
anticoagulant agents in canine models of arterial
thrombosis. In these models,
thrombosis was induced either electrolytically (200-microA anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with
stenosis, which resulted in either total occlusive
thrombus formation or cyclic flow reduction, respectively.
DMP754 and
XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of
DMP754,
aspirin,
heparin, and
ticlopidine in the canine carotid artery electrolytic injury model were compared.
DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED(90-100)=<0.1 mg/kg IV or PO). Additionally, both
DMP754 and
XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO) demonstrated maximal antithrombotic efficacy in preventing electrically induced carotid and coronary artery
thrombosis and significant antithrombotic efficacy (P<0.001) at relatively low doses in different settings of arterial
thrombosis in the canine model.
DMP754 resulted in a significant reduction in
thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive
thrombosis. In contrast, administration of
aspirin (10 mg/kg PO for 2 days),
heparin (10 IU/kg IV bolus followed by 90 IU/kg IV infusion over 3 hours), or
ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial
thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial
thrombosis. These studies demonstrated a distinct antithrombotic efficacy of
DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of
DMP754 in the prevention and treatment of thromboembolic disorders.