Antithrombotic and anticoagulant effects of the direct thrombin inhibitor dabigatran, and its oral prodrug, dabigatran etexilate, in a rabbit model of venous thrombosis

Abstract

Summary. Background: Oral anticoagulant therapies targeted at thrombin are being developed to overcome limitations associated with current standard therapies. Objectives: 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 ) 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.

Dabigatran: An Oral Novel Potent Reversible Nonpeptide Inhibitor of Thrombin

“…9 Also, in this species, this compares favorably with melagatran (ED 50 of 0.058 mg/kg), unfractionated heparin (ED 50 of 9.84 U/kg), and hirudin (ED 50 of 0.016 mg/kg). Similarly, in rabbits, a dose-dependent increase in aPTT was observed in these studies.…”

The Discovery of Dabigatran Etexilate

“…In the same model, dabigatran etexilate administered orally between 0.5 and 7 h prior to thrombus induction resulted in a dose and timedependent inhibition of thrombus formation. In a rabbit arteriovenous shunt model of thrombosis, infusion and oral administration of dabigatran revealed a dose-dependent inhibition of clot formation (Wienen et al, 2007c). In both the rat and rabbit thrombosis models the observed antithrombotic effects were inversely correlated with a dose and time-dependent prolongation of the ex vivo aPTT.…”

Avaliação da tromboflebite jugular experimental em equinos tratados com heparina

“…Para aumentar sua biodisponibilidade e permitir administração oral, o dabigatran é produzido como etexilato de dabigatran [37]. Em um modelo de trombose em veia jugular de coelhos, o dabigatran mostrou-se altamente eficiente na redução da formação de trombos [39]. Em humanos, a administração de doses altas de etexilato de dabigatran mostrou-se mais efetiva do que a administração de enoxaparina para prevenção de eventos tromboembólicos em pacientes submetidos à cirurgia ortopédica.…”