Synergistic antithrombotic effects of argatroban and ticlopidine in the rat venous thrombosis model.
Argatroban, a synthetic thrombin inhibitor, and ticlopidine, an anti-platelet agent, are major antithrombotic agents. We investigated the antithrombotic effects of a combination of argatroban and ticlopidine in the rat venous thrombosis model. Argatroban or ticlopidine inhibited thrombus formation in a dose-dependent manner; 50% inhibition (ED50) is obtained with 1.0 mg/kg/h (infusion) argatroban or 30 mg/kg (p.o.) ticlopidine. The combination of argatroban and ticlopidine inhibited thrombus formation in a dose-dependent manner; ED50 is obtained with 0.25 mg/kg/h argatroban plus 10 mg/kg ticlopidine and 0.5 mg/kg/h argatroban plus 3 mg/kg ticlopidine, whereas 0.5 mg/kg/h argatroban alone or 10 mg/kg ticlopidine alone had negligible effect (<20% inhibition). Isobole analysis showed that the antithrombotic effects of the combination of argatroban and ticlopidine involved synergism with potentiation. In contrast, the combination of argatroban and ticlopidine did not prolong the bleeding time synergistically. These data showed that the combination therapy of argatroban and ticlopidine should be clinically beneficial, but the different administration route may restrict the clinical usage.
Morishita
K
K
New Product Research Laboratories 2, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. moriscjz@daiichipharm.co.jp
Iwamoto
M
M
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D000991:Antithrombins / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D004357:Drug Synergism; D008297:Male; D010875:Pipecolic Acids / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides; D013988:Ticlopidine / Q000008:administration & dosage*; D020246:Venous Thrombosis / Q000188:drug therapy*
D000925:Anticoagulants; D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban; D013988:Ticlopidine