Administration of a small molecule tissue factor/factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time.

Introduction: Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation.

Materials And Methods: PHA inhibits the TF/VIIa complex with an IC(50) of 13.

Assessment of bleeding propensity in non-human primates by combination of selective tissue factor/VIIa inhibition and aspirin compared to warfarin and aspirin treatment.

This study in non-human primates was designed to evaluate the bleeding propensity of a selective, small molecule inhibitor of tissue factor (TF)/VIIa in combination with acetylsalicylic acid (ASA) in comparison to the combination of ASA and warfarin. Bleeding time was increased by ASA but was not prolonged further by the addition of the TF/VIIa inhibitor, PHA-927, at doses that elevated the prothrombin time to 8-fold. In contrast, bleeding time was prolonged by warfarin alone and further exacerbated by the presence of ASA.

Pharmacological interruption of acute thrombus formation with minimal hemorrhagic complications by a small molecule tissue factor/factor VIIa inhibitor: comparison to factor Xa and thrombin inhibition in a nonhuman primate thrombosis model.

This study was designed to evaluate the antithrombotic efficacy and bleeding propensity of a selective, small-molecule inhibitor of tissue factor/factor VIIa (TF/VIIa) in comparison to small-molecule, selective inhibitors of factor Xa and thrombin in a nonhuman primate model of thrombosis. Acute, spontaneous thrombus formation was induced by electrolytic injury to the intimal surface of a femoral blood vessel, which results in thrombus propagation at the injured site. The TF/FVIIa inhibitor 3-amino-5-[1-[2-([4-[amino(imino)methyl]benzyl]amino)-2-oxoethyl]-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoic acid dihydrochloride (PHA-927F) was fully effective in prevention of thrombosis-induced vessel occlusion at a dose of 400 microg/kg/min, i.

Orbofiban: an orally active GPIIb/IIIa platelet receptor antagonist.

A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban.

Protective effect of oral xemilofiban in arterial thrombosis in dogs: increased activity in combination with aspirin.

Background: Inhibition of platelet aggregation by preventing the binding of fibrinogen to glycoprotein (GP) IIb/IIIa on activated platelets results in antithrombotic activity. We report on the antithrombotic effect of xemilofiban (SC-54684A), an oral GP IIb/IIIa antagonist, administered alone or with aspirin (ASA) in an acute thrombosis model.

Methods And Results: Conscious dogs were treated with xemilofiban (1.

Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog.

We have previously reported on the basic pharmacologic properties of SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), a novel angiotensin (AII) receptor antagonist that binds potently to AT1 receptors in rat adrenal cortex and blocks AII-mediated contraction in isolated rabbit aorta. In the present study, the ability of SC-52458 to block AII pressor responses in conscious dogs was measured. In addition, we determined whether SC-52458 lowered mean arterial pressure in dogs with 2 kidney/1 clip renal hypertension when given daily for 4 days.

The protective dose of the potent GPIIb/IIIa antagonist SC-54701A is reduced when used in combination with aspirin and heparin in a canine model of coronary artery thrombosis.

Background: Fibrinogen receptor antagonists block the fibrinogen-platelet interaction at the GPIIb/IIIa receptors and inhibit thrombus formation. SC-54701 is the active metabolite of SC-54684A, an orally fibrinogen receptor antagonist. We compared the efficacy of SC-54701A (SCa, hydrochloride salt) with that of aspirin (ASA) or heparin and with combination therapy in a canine model of continuous current injury.

Effects of SC-56525, a potent, orally active renin inhibitor, in salt-depleted and renal hypertensive dogs.

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.

Cardiovascular effects of chronic high-dose atriopeptin III infusion in normotensive rats.

Seventy-eight Sprague-Dawley rats received continuous intravenous infusions of either atriopeptin III (APIII), 60 micrograms/kg/hr, or distilled water vehicle for a period of 7 days by means of osmotic minipumps. On Day 7 approximately one-half of the animals (20 vehicle-treated rats and 21 APIII-treated rats) were instrumented for evaluation of cardiac function and terminated for measurement of heart weight. The minipumps remained in place during the evaluation of cardiac function.

Mexrenoate potassium: a steroidal aldosterone antagonist and antihypertensive.

Mexrenoate potassium (SC-26714) is a water soluble salt of a steroidal hydroxy acid which has been shown to antagonize the sodium-retaining effects of aldosterone at oral dosages of 1 mg/kg and about 1.8 mg/kg in the dog and rat, respectively. Dose-related natriuretic responses, indexed as a reversal (increases) in the aldosterone-depressed urinary log Na/K ratio, indicated that mexrenoate was between 2.

Potassium prorenoate: a new steroidal aldosterone antagonist.

Potassium prorenoate (SC-23992) is a water-soluble steroidal compound with the ability to antagonize the sodium-retaining and, when apparent, the potassium-dissipating effects of mineralocorticoids. A significant natriuretic response was obtained at dosages of 1 mg/kg and approximately 1.8 mg/kg in the dog and rat, respectively.