1. Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban in rat and rabbit models of venous thrombosis.
- Author
-
Kaku S, Uemura T, Saitoh M, Suzuki K, Iwatsuki Y, Funatsu T, and Kawasaki T
- Subjects
- Animals, Anticoagulants administration & dosage, Anticoagulants toxicity, Antithrombins administration & dosage, Antithrombins pharmacology, Antithrombins toxicity, Azepines administration & dosage, Azepines toxicity, Benzamides administration & dosage, Benzamides toxicity, Blood Platelets drug effects, Blood Platelets metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Glucuronides pharmacology, Hemorrhage chemically induced, Humans, Male, Rabbits, Rats, Rats, Sprague-Dawley, Species Specificity, Venous Thrombosis pathology, Anticoagulants pharmacology, Azepines pharmacology, Benzamides pharmacology, Factor Xa Inhibitors, Venous Thrombosis drug therapy
- Abstract
The oral direct factor Xa inhibitor darexaban administered intraduodenally prevented venous thrombus formation in both rats and rabbits with no effect on bleeding. The indirect parenteral Factor Xa inhibitor fondaparinux exerted similar properties, only prolonging bleeding time at extremely high doses. In contrast, the thrombin inhibitor ximelagatran and low-molecular-weight heparin enoxaparin prolonged bleeding time at antithrombotic doses. Studies using human platelets showed darexaban glucuronide, a darexaban metabolite that predominantly determines darexaban antithrombotic effects in vivo, had no effect on platelet activation and aggregation, while heparin and enoxaparin activated platelets. Melagatran, heparin, and enoxaparin all inhibited thrombin-induced platelet aggregation at clinically relevant concentrations. Taken together, these results suggest that thrombin-inhibiting drugs may increase the risk of bleeding, while darexaban may have potential as an orally available antithrombotic agent with a wide therapeutic window., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF