Abstract 632: A Wide Safety Margin of a Factor Xa Inhibitor, DU-176b, Between Antithrombotic Effect and Exacerbation of Intracerebral Hemorrhage in Rats: Comparison with a Thrombin Inhibitor
Intracerebral hemorrhage (ICH) is a major clinical concern about anticoagulation. Oral anticoagulants like warfarin increase the risk of ICH. Recently new orally active anticoagulants, such as DU-176b, a factor Xa (FXa) inhibitor and melagatran, a thrombin inhibitor are evaluated in clinical studies as substitutes for warfarin. Objective: To compare the exacerbating effect between DU-176b and melagatran in an ICH model induced by collagenase in rats.
Methods: Male Wistar rats were anesthetized with thiopental. A 29-gauge needle was introduced into the striatum (3.0 mm left lateral to bregma, 5.5 mm in depth below the skull). ICH was induced by the administration of 2 μL solution containing 0.1 U collagenase (type VII) over 10 min. Immediately after ICH induction, DU-176b and melagatran were infused into the jugular vein for 5 hr. At the end of drug infusion, blood was collected for prothrombin time (PT) measurement and brain was removed for ICH size evaluation. To compare the safety margin, antithrombotic effects were evaluated in a rat venous thrombosis model. Thrombosis was induced in the inferior vena cava by insertion of a platinum wire for 1 hr and protein content of thrombus was assayed.
Results: DU-176b at 3 mg/kg/hr had no effect on ICH volume, while PT was prolonged 2-fold. Higher doses of DU-176b (6 and 18 mg/kg/hr) significantly increased ICH volume in a dose-dependent manner (180% and 230%, respectively). PT was prolonged 2.8 and 6.5-fold, respectively. No death was observed in DU-176b groups. Melagatran enlarged ICH volume at 1 mg/kg/hr (280%) with 6.1-fold PT prolongation. At a higher dose (3 mg/kg/hr), all rats died probably due to severe ICH damage (390%, PT prolongation >30-fold). Melagatran at 0.3 mg/kg/hr did not affect ICH. Both compounds at these doses had no effects on physiological parameters. The doses required for 50% inhibition of thrombosis of DU-176b and melagatran were 0.045 and 0.12 mg/kg/h, respectively. The safety margins of these drugs were 133 and 8.
Conclusion: The safety margin between antithrombotic and ICH exacerbation effects of DU-176b was wider than melagatran. Moreover, melagatran induced fatal ICH. These results suggest that the FXa inhibitor, DU-176b, is preferable than the thrombin inhibitor in the aspect of low risk of ICH.