Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants.
(+)-2S-2-[4-[[(3S)-1-Acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate (DX-9065a) is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DX-9065a with a direct thrombin inhibitor and AT III-dependent anticoagulants in rat models of thrombosis and bleeding. Rats were administered intravenously DX-9065a (0.1-1 mg/kg/h), argatroban (0.1-1 mg/k/h), low molecular weight heparin (25-100 anti-XaU/kg/h), unfractionated heparin (25-100 anti-XaU/kg/h) or Orgaran (30-300 anti-XaU/kg/h) for 1 h. DX-9065a dose-dependently inhibited both thrombus formation and elevation in plasma thrombin-AT III complex (TAT) level in a copper wire-inserted arteriovenous (AV) shunt model in rats. The dose required for 50% inhibition of thrombus formation was 0.27 mg/kg/h. DX-9065a did not prolong transection bleeding time up to 7.78 mg/kg/h. Argatroban and AT III-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose. These results suggest that direct and selective inhibition of factor Xa by DX-9065a is preferable for the treatment of thrombosis in the aspect of lack of compromising primary hemostasis.
Morishima
Y
Y
New Product Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Tanabe
K
K
Terada
Y
Y
Hara
T
T
Kunitada
S
S
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000990:Antithrombin III / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D001120:Arginine / Q000031:analogs & derivatives; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000032:analysis / Q000187:drug effects; D010875:Pipecolic Acids / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D009281:Naphthalenes; D010875:Pipecolic Acids; D011422:Propionates; D013449:Sulfonamides; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D001120:Arginine; D010447:Peptide Hydrolases; D013917:Thrombin; C031942:argatroban