title: Antithrombotic activity of the novel oral anticoagulant, Tecarfarin [Sodium 3-[4-((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yloxy) carbonyl) benzyl]-2-oxo-2H-chromen-4-olate] in animal models.
abstract: The antithrombotic activity of tecarfarin, a novel orally active vitamin K epoxide reductase inhibitor, was assessed in canine and rabbit thrombosis models. In dogs, once-daily oral doses of 0.5mg/kg tecarfarin selectively reduced the levels of the vitamin K-dependent coagulation factors (factors II, VII, IX, and X) and prolonged the prothrombin time (PT). A 4 to 7day course of oral tecarfarin (0.05 - 0.5mg/kg) prolonged the PT by 3 to 5-fold and reduced thrombus formation in arterial and venous segments subjected to a combination of electrical injury and flow-limiting constriction. To compare the effects of tecarfarin with those of warfarin, rabbits were given once-daily oral doses of 1mg/kg tecarfarin, 1.5mg/kg warfarin, or saline for 2days. After verifying increases in the PT with tecarfarin and warfarin, blood loss from standardized ear incisions was measured to assess hemorrhagic potential. Then, after intravenous injection of (125)I-labeled rabbit fibrinogen, thrombosis was induced in an isolated jugular vein segment by a combination of balloon catheter-induced endothelial denudation and venous occlusion. Compared with the saline control, both tecarfarin and warfarin prolonged the PT, increased blood loss from the ear incisions, and attenuated thrombus formation. Thus, like warfarin, tecarfarin attenuates venous and arterial thrombus formation in animal models by reducing the levels of the vitamin K-dependent coagulation factors.
authors.affiliation: ARYx Therapeutics, 6300 Dumbarton Circle, Fremont, CA 94555, USA. sbowersox@aryx.com
authors.forename: S Scott
authors.initials: SS
authors.lastname: Bowersox
authors.forename: Daniel
authors.initials: D
authors.lastname: Canafax
authors.forename: Pascal
authors.initials: P
authors.lastname: Druzgala
authors.forename: Peter
authors.initials: P
authors.lastname: Milner
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D011517:Prothrombin Time; D011817:Rabbits; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D014859:Warfarin / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000925:Anticoagulants; D001565:Benzoates; D003374:Coumarins; D014859:Warfarin; C547288:tecarfarin; D005466:Fluorocarbons