Antithrombotic and anticoagulant effects of direct factor Xa inhibitor darexaban in rat and rabbit models of venous thrombosis.

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.
Authors	Seiji Kaku, Toshio Uemura, Minori Saitoh, Ken-ichi Suzuki, Yoshiyuki Iwatsuki, Toshiyuki Funatsu, Tomihisa Kawasaki
Journal	European journal of pharmacology (Eur J Pharmacol) Vol. 699 Issue 1-3 Pg. 40-7 (Jan 15 2013) ISSN: 1879-0712 [Electronic] Netherlands
PMID	23200896 (Publication Type: Comparative Study, Journal Article)
Copyright	Copyright © 2012 Elsevier B.V. All rights reserved.
Chemical References	Anticoagulants Antithrombins Azepines Benzamides Factor Xa Inhibitors Glucuronides darexaban glucuronide darexaban
Topics	Animals Anticoagulants (administration & dosage, pharmacology, toxicity) Antithrombins (administration & dosage, pharmacology, toxicity) Azepines (administration & dosage, pharmacology, toxicity) Benzamides (administration & dosage, pharmacology, toxicity) Blood Platelets (drug effects, metabolism) Disease Models, Animal Dose-Response Relationship, Drug Factor Xa Inhibitors Glucuronides (pharmacology) Hemorrhage (chemically induced) Humans Male Rabbits Rats Rats, Sprague-Dawley Species Specificity Venous Thrombosis (drug therapy, pathology)

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