Comparison of antithrombotic and haemorrhagic effects of edoxaban, an oral direct factor Xa inhibitor, with warfarin and enoxaparin in rats

Abstract Introduction Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban...

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Published in:Thrombosis research 2012-09, Vol.130 (3), p.514-519
Main Authors: Morishima, Yoshiyuki, Honda, Yuko, Kamisato, Chikako, Tsuji, Naoki, Kita, Akemi, Edo, Naoko, Shibano, Toshiro
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anticoagulants - administration & dosage
Biological and medical sciences
Bleeding time prolongation dose
Blood and lymphatic vessels
Cardiology. Vascular system
Cardiovascular system
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
ED50
Enoxaparin - administration & dosage
Factor Xa Inhibitors
Fibrinolytic Agents
Hematology, Oncology and Palliative Medicine
Hemorrhage - diagnosis
Hemorrhage - prevention & control
Hemostatics - administration & dosage
Male
Medical sciences
Oral anticoagulant
Pharmacology. Drug treatments
Pyridines - administration & dosage
Rats
Rats, Wistar
Thiazoles - administration & dosage
Treatment Outcome
Vasodilator agents. Cerebral vasodilators
Venous Thrombosis - diagnosis
Venous Thrombosis - prevention & control
Warfarin - administration & dosage
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Summary:Abstract Introduction Factor Xa (FXa) is a key serine protease in the coagulation cascade and a promising target for a new antithrombotic agent. Edoxaban is an oral, selective and direct FXa inhibitor. The objective of this study was to compare the antithrombotic and haemorrhagic effects of edoxaban with clinically available anticoagulants, warfarin and enoxaparin, in rat models of thrombosis and haemorrhage. Methods Rats were treated with single oral administration of edoxaban, repeated oral dosing of warfarin for 4 days and single subcutaneous administration of enoxaparin before thrombosis or haemorrhage induction. Thrombosis was induced by the insertion of a platinum wire into the inferior vena cava for 60 min. Tail template bleeding time was measured after making an incision on the tail. Results Edoxaban at 0.3, 1 and 3 mg/kg exerted dose-dependent and significant inhibition of venous thrombus formation. The 50% thrombus inhibition dose (ED50 ) was 1.9 mg/kg. At supra-therapeutic doses (10 and 20 mg/kg), edoxaban significantly but moderately (less than 2-fold) prolonged bleeding time. Warfarin and enoxaparin also dose-dependently inhibited venous thrombosis and prolonged bleeding time. The ED50 values of warfarin and enoxaparin were 0.12 mg/kg and 500 IU/kg, and the 2-fold bleeding time prolongation doses (BT2) were 0.16 mg/kg and 1700 IU/kg, respectively. The safety margin (ratio of BT2 to ED50 ) of edoxaban (> 10.5) was greater than those of warfarin (1.3) and enoxaparin (3.4). Conclusions Edoxaban inhibited venous thrombosis comparably to warfarin and enoxaparin, and the attendant bleeding risk of edoxaban was lower than that of warfarin and enoxaparin in rats.
ISSN:0049-3848
1879-2472
DOI:10.1016/j.thromres.2012.05.008