Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis.
BACKGROUND
Oral anticoagulant therapies targeted at thrombin are being developed to overcome limitations associated with current standard therapies.


OBJECTIVE
This study was undertaken to assess and compare the antithrombotic and anticoagulant effects of the novel, selective and reversible, direct thrombin inhibitor (DTI), dabigatran, and its oral prodrug dabigatran etexilate, to that of unfractionated heparin (UFH), hirudin and melagatran using a rabbit model of venous thrombosis.


METHODS
A rabbit model of venous thrombosis consisting of endothelial damage with blood flow reduction was used with minor modifications.


RESULTS
All compounds demonstrated a dose-dependent reduction in thrombus formation following i.v. administration with complete or almost complete inhibition at the highest doses. Dabigatran (in the dose range 0.03-0.5 mg kg(-1)) had a 50% effective dose of 0.066 mg kg(-1). By comparison, UFH (5-50 U kg(-1)), hirudin (0.01-0.05 mg kg(-1)) and melagatran (0.01-0.3 mg kg(-1)) had a 50% effective dose of 9.8 U kg(-1), 0.016 mg kg(-1) and 0.058 mg kg(-1), respectively. Similarly, oral dabigatran etexilate (1-20 mg kg(-1)) inhibited thrombus formation in a dose-dependent manner. Maximum inhibition was achieved within 1 h of administration, suggesting a rapid onset of action. For both routes of administration, inhibition of thrombus formation directly correlated with prolongation of the activated partial thromboplastin time.


CONCLUSIONS
These findings demonstrate the potent anticoagulant and antithrombotic activity of dabigatran as a selective thrombin inhibitor in a rabbit model of venous thrombosis. Notably, dose-dependent and long-lasting antithrombotic efficacy was observed after application of its oral form dabigatran etexilate, which is currently undergoing phase III clinical development.
Wienen
W
W
Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach, Germany. wolfgang.wienen@bc.boehringer-ingelheim.com
Stassen
J-M
JM
Priepke
H
H
Ries
U J
UJ
Hauel
N
N
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D001596:Benzylamines / Q000008:administration & dosage / Q000627:therapeutic use; D000069604:Dabigatran; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use; D024764:Hirudin Therapy; D007275:Injections, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy*
D000925:Anticoagulants; D001384:Azetidines; D001562:Benzimidazoles; D001596:Benzylamines; D005343:Fibrinolytic Agents; D011355:Prodrugs; D011725:Pyridines; C109573:melagatran; D006493:Heparin; D000069604:Dabigatran