Antithrombotic effects of YM-60828, a newly synthesized factor Xa inhibitor, in rat thrombosis models and its effects on bleeding time.
1. The effects of YM-60828, a newly synthesized factor Xa inhibitor, were investigated to analyse the relationship between its antithrombotic effects and its prolongation of template bleeding time in rats. YM-60828 was compared with argatroban, heparin and dalteparin. All agents were intravenously administered as a bolus. 2. In ex vivo studies, YM-60828 and argatroban prolonged both prothrombin time and activated partial thromboplastin time in a dose-dependent manner, while heparin and dalteparin prolonged only activated partial thromboplastin time. 3. In a venous thrombosis model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0081 mg kg(-1), 0.011 mg kg(-1), 6.3 iu kg(-1) and 4.7 iu kg(-1), respectively. 4. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.010 mg kg(-1), 0.011 mg kg(-1), 10 iu kg(-1) and 4.2 iu kg(-1), respectively. 5. In bleeding time studies, all agents prolonged template bleeding time in a dose-dependent manner. ED2 values, the doses causing a 2 fold prolongation of bleeding time in the saline group, of YM-60828, argatroban, heparin and dalteparin were 0.76 mg kg(-1), 0.081 mg kg(-1), 18 iu kg(-1) and 25 iu kg(-1), respectively. 6. The ratio (ED2/ID50) of YM-60828 was more than 30 fold greater than that of heparin and more than 10 fold greater than those of argatroban and dalteparin. 7. These data show that YM-60828 can exert its antithrombotic effects with little prolongation of bleeding time compared with the other currently used anticoagulant agents.
Sato
K
K
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, Tsukuba, Ibaraki, Japan.
Kawasaki
T
T
Hisamichi
N
N
Taniuchi
Y
Y
Hirayama
F
F
Koshio
H
H
Matsumoto
Y
Y
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives; D001166:Arteriovenous Shunt, Surgical; D001760:Bleeding Time; D001798:Blood Proteins / Q000378:metabolism; D017985:Dalteparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013924:Thrombophlebitis / Q000097:blood / Q000188:drug therapy; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
D000925:Anticoagulants; D001798:Blood Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009281:Naphthalenes; D010875:Pipecolic Acids; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; C111032:YM 60828; D006493:Heparin; D001120:Arginine; C031942:argatroban; D017985:Dalteparin