title: Antithrombotic actions of selective inhibitors of blood coagulation factor Xa in rat models of thrombosis.
abstract: The antithrombotic actions of selective factor Xa (FXa) inhibitors, recombinant tick anticoagulant peptide (rTAP) and DX-9065a, were evaluated in experimental thrombosis models in anesthetized rats. In the first model, thrombosis was induced by exposing flowing blood to a silk thread anchored in an arteriovenous (AV) shunt. rTAP, DX-9065a and heparin, given as an iv infusion 1 hr before blood was circulated in the AV shunt, had ID50s of 0.007, 0.6 mumol/kg/hr and 16 U/kg/hr, respectively. In the model of venous thrombosis which was induced by hypotonic saline (0.225%) followed by 15-min stasis of abdominal vena cava, rTAP and heparin had ID50s of 0.007 mumol/kg/hr and 3.5 U/kg/hr, respectively. In both models, full inhibition of thrombus formation was achieved with FXa inhibition at doses which only modestly increased ex vivo plasma clotting time APTT (1.26 to 1.82 over the baseline). By contrast, the maximum antithrombotic effect of heparin was associated with high and significant APTT prolongation (> 5 fold over the baseline). Therefore, our study suggests that FXa inhibitors are effective agents in preventing thrombosis in both rat thrombosis models and may have therapeutic antithrombotic potential.
authors.affiliation: DuPont Merck Pharmaceutical Co., Wilmington, DE 19880-0400, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: E J
authors.initials: EJ
authors.lastname: Crain
authors.forename: O
authors.initials: O
authors.lastname: Nguan
authors.forename: C A
authors.initials: CA
authors.lastname: Watson
authors.forename: A
authors.initials: A
authors.lastname: Racanelli
mesh_terms: D000818:Animals; D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; D011422:Propionates; D011994:Recombinant Proteins; C063967:tick anticoagulant peptide