Effects of inogatran, a new low-molecular-weight thrombin inhibitor, in rat models of venous and arterial thrombosis, thrombolysis and bleeding time.
Inogatran (MW 439 Da), a new, selective, active site inhibitor of thrombin, was evaluated in three rat models of thrombosis. In the venous thrombosis model, inogatran dose-dependently inhibited thrombus formation with a > 80% antithrombotic effect at a plasma concentration of 0.45 mumol l-1. In the arterial thrombosis model, inogatran dose-dependently inhibited thrombus formation, preserved vessel patency and the mean blood flow. Acetylsalicylic acid (ASA) potentiated the effects of low plasma concentrations of inogatran in the arterial thrombosis model. In the model of rt-PA-induced thrombolysis of a thrombus in the carotid artery, inogatran improved the patency time and the cumulative blood flow during the two hour thrombolysis period more than rt-PA alone. At high therapeutic plasma concentration of inogatran, there was only a moderate prolongation of bleeding time compared with the control value. It is concluded that inogatran is an effective antithrombotic agent both in the venous and arterial thrombosis models and also as adjuvant to rt-PA in the thrombolysis model.
Gustafsson
D
D
Department of Cardiovascular Pharmacology, Astra Hässle AB, Mölndal, Sweden.
Elg
M
M
Lenfors
S
S
Börjesson
I
I
Teger-Nilsson
A C
AC
D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D001241:Aspirin / Q000627:therapeutic use; D001760:Bleeding Time; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use; D008297:Male; D008970:Molecular Weight; D010875:Pipecolic Acids / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D015912:Thrombolytic Therapy; D013924:Thrombophlebitis / Q000188:drug therapy*; D013927:Thrombosis / Q000188:drug therapy*
D000991:Antithrombins; D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; C099871:inogatran; D006493:Heparin; D001120:Arginine; C031942:argatroban; D001241:Aspirin; D005998:Glycine