Antithrombotic effect of YM-75466 is separated from its effect on bleeding time and coagulation time.
The antithrombotic effects of YM-75466 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid monomethane sulfonate), a novel orally-active factor Xa inhibitor, and its effects on bleeding time and coagulation time were studied in rats and compared with those of warfarin. Both agents were orally administered. In the venous thrombosis model, YM-75466 and warfarin inhibited thrombus formation dose-dependently, with ID50 values of 3.3 and 0.56 mg/kg, respectively. Ex vivo study showed that both YM-75466 and warfarin prolonged prothrombin time dose-dependently, with doses, causing a two-fold prolongation of prothrombin time in the control group, of 89 and 0.38 mg/kg, respectively. In bleeding time studies, YM-75466 and warfarin prolonged bleeding time dose-dependently, with doses, causing a two-fold prolongation of bleeding time in the control group, of > 100 and 0.43 mg/kg, respectively. These results show that the antithrombotic effects of YM-75466 are markedly separate from its effects on bleeding time and coagulation time compared with warfarin.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Tsukuba, Ibaraki, Japan. satoh_k@yamanouchi.co.jp
K
K
Sato
S
S
Kaku
F
F
Hirayama
H
H
Koshio
Y
Y
Matsumoto
T
T
Kawasaki
Y
Y
Iizumi
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013925:Thromboplastin / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010880:Piperidines; D013449:Sulfonamides; C114145:YM 75466; D014859:Warfarin; D013925:Thromboplastin