Deep venous thrombosis (DVT) is a common
cardiovascular disease, resulting in significant mortality each year in the United States.
Direct thrombin inhibitors represent a new class of drugs that could potentially be better than conventional antithrombotic
therapy based on indirect inhibition of
coagulation factors with
heparin and
warfarin.
BCH 2763 is a potent, selective bifunctional
thrombin inhibitor that blocks both the active catalytic site and the
anion binding exosite. The objective of this study is to test the antithrombotic efficacy of
BCH 2763 in a canine model of DVT induced through electrolytic injury to the femoral vein.
BCH 2763 was administered at three dose levels: 0.125 mg/kg bolus followed by 10 microg/kg/min IV infusion (low-dose; n = 5), 0.25 mg/kg bolus followed by 20 microg/kg/min infusion (mid-dose; n = 5), and 0.75 mg/kg bolus followed by 60 microg/kg/min (high-dose; n = 5). The control group (n = 5) received a 5-ml intravenous bolus of saline followed by a 1 mL/kg/h infusion. The parameters evaluated were changes in activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombin time (PT), time to formation of an occlusive
thrombus in the femoral vein, and the amount of venous blood flow delivered over the course of the experiment. There were significant dose-dependent increases in aPTT, TT, and PT in the BCH 2763-treated animals compared with the control group. The time to formation of an occlusive
thrombus in the control group averaged 69.6 +/- 9 minutes. Treatment with
BCH 2763 prolonged the time to occlusion to 126.4 +/- 13 minutes in the low-dose group, 155.4 +/- 17 minutes in the mid-dose group, and 229 +/- 7 minutes in the high-dose group (80% remained patent for the duration of the study), which were all significantly greater than the controls. Femoral venous blood flow was significantly greater in the mid-dose (51 +/- 8%) and the high-dose (70 +/- 6%) groups compared with the control vessels (22 +/- 3%). In conclusion, the results of this study indicate that
BCH 2763 is an effective intravenous
antithrombotic agent in the canine electrolytic injury model of
venous thrombosis.