LB30057, an orally effective direct thrombin inhibitor, prevents arterial and venous thrombosis in rats and dogs.
The anti-thrombotic effects of LB30057, a direct thrombin inhibitor, were evaluated with in vivo rat and dog thrombosis models. In rats, 1 mg/kg of LB30057 inhibited half of the clot formations in the inferior vena cava at 5 minutes after intravenous application. When measured at 2 hours after oral application, 100 mg/kg prevented approximately half of the clot formations in the inferior vena cava and 50 mg/kg prolonged the mean occlusion time from 15.6 +/- 1.3 minutes to 47.2 +/- 8.3 minutes in the carotid artery. In dogs, the formation of thrombus in the jugular vein was reduced to half at a dose range of 20-30 mg/kg at 6 hours after oral application. In addition, the LB30057 dosage required to reduce venous clot formation by approximately 80-90% in dogs was only about 10% of that required for the same reduction in rats. This is probably due to the variation in its time-dependent blood concentration profiles in each species; for example, the plasma half-life of LB71350 in dogs was longer than that in rats (153.0 +/- 3.0 vs. 129.7 +/- 12.7 min at 30 mg/kg, i.v., respectively). AUC, T(max), C(max), and BA in dogs were 59, 8.9, 9.17, and 13.3 times higher than those in rats at oral 30 mg/kg, respectively. Taken together, these results suggest that LB30057 administered orally is effective in the prevention of arterial and venous thrombosis in rats and dogs. It therefore represents a good lead compound for investigations to discover a new, orally available, therapeutic agent for treating thrombotic diseases.
Park
Hee Dong
HD
LG Biotech Research Institute, LG Chem, Daejeon 305-380, Korea.
Kim
Hee Jin
HJ
Oh
Yeong Soo
YS
Kim
In Chull
IC
Kim
Yong Zu
YZ
Koh
Hyun Chul
HC
Shin
In Chul
IC
Lee
Yong Hee
YH
Lee
Chang Ho
CH
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000097:blood; D002341:Carotid Artery Thrombosis / Q000378:metabolism / Q000517:prevention & control*; D004285:Dogs; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020246:Venous Thrombosis / Q000378:metabolism / Q000517:prevention & control*
D001549:Benzamides; D005343:Fibrinolytic Agents; C116605:LB 30057