Effects of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate, on thrombus formation and bleeding time in rats

 

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Summary

Dabigatran is a reversible direct, selective thrombin inhibitor, undergoing clinical development as its orally active prodrug, dabigatran etexilate. The objective of this trial was to assess the antithrombotic and anticoagulant effects of dabigatran and dabigatran etexilate in a rat model of venous thrombosis. In order to do this a modifiedWessler model was used to assess the antithrombotic and anticoagulant effects of intravenous (i.v.) dabigatran and oral dabigatran etexilate administration. In addition, a rat tail bleeding time model was used to investigate the antihemostatic effect of dabigatran.The study demonstrated that bolus administration of dabigatran (0.01–0.1 mg/kg) reduced thrombus formation dose-dependently,with an ED50 (50% of the effective dose) of 0.033 mg/kg and complete inhibition at 0.1 mg/kg. By comparison,ED50 values for heparin (0.03–0.3 mg/kg),hirudin (0.01–0.5 mg/kg) and melagatran (0.1–0.5 mg/kg) were 0.07, 0.15 and 0.12 mg/kg, respectively. Oral administration of dabigatran etexilate (5–30 mg/kg) inhibited thrombus formation in a dose- and time-dependent manner, with maximum inhibition within 30 min of pretreatment, suggesting a rapid onset of action. Following i.v. administration of dabigatran (0.1–1.0 mg/kg), a statistically significant prolongation of bleeding time was observed at doses at least 15- and 5-fold greater than ED50 and ED100 (100% of the effective dose) doses, respectively; there was no significant increase in bleeding tendency at the maximum therapeutically effective dose (0.1 mg/kg). It can be concluded that dabigatran and its oral prodrug, dabigatran etexilate, show promise in the management of thromboembolic disease.

• References

• 1 Becattini C, Agnelli G, Emmerich J. et al. Initial treatment of venous thromboembolism. Thromb Haemost 2006; 96: 242-250.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Hirsh J, Warkentin TE, Shaughnessy SG. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119 (Suppl. 01) 64S-94S.
  CrossrefPubMedGoogle Scholar
• 3 Hirsh J, Dalen J, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119 (Suppl. 01) 8S-21S.
  CrossrefPubMedGoogle Scholar
• 4 Weitz JI. Emerging anticoagulants for the treatment of venous thromboembolism. Thromb Haemost 2006; 96: 274-284.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Lind SE. The hemostatic system. In: Blood: Principles and practice of hematology. Philadelphia: Lippincott; 1995: 949-973.
  Google Scholar
• 6 Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: 1028-1040.
  CrossrefPubMedGoogle Scholar
• 7 Weitz JI, Hudoba M, Massel D. et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-391.
  CrossrefPubMedGoogle Scholar
• 8 Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544-552.
  CrossrefPubMedGoogle Scholar
• 9 Gustafsson D, Nystrom J, Carlsson S. et al. The direct thrombin inhibitor melagatran and its oral prodrug H376/95: intestinal absortion properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101: 171-181.
  CrossrefPubMedGoogle Scholar
• 10 Gustafsson D, Bylund R, Antonsson T. et al. A new oral anticoagulant: the 50-year challenge. Nature Rev Drug Discovery 2004; 3: 649-659.
  CrossrefPubMedGoogle Scholar
• 11 Boos CJ, Lip GYH. Ximelagatran: An eulogy. Thromb Res 2006; 118: 301-304.
  CrossrefPubMedGoogle Scholar
• 12 Hauel NH, Nar H, Priepke H. et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
  CrossrefPubMedGoogle Scholar
• 13 Ries UJ, Wienen W. Serine proteases as targets for antithrombotic therapy. Drugs Future 2003; 28: 355-370.
  CrossrefPubMedGoogle Scholar
• 14 Herbert JM, Bernat A, Maffrand JP. Importance of platelets in experimental venous thrombosis in the rat. Blood 1992; 80: 2281-2286.
  PubMedGoogle Scholar
• 15 Gustafsson D, Elg M, Lenfors S. et al. Effects of inogatran, a new low-molecular-weight thrombin inhibitor, in rat models of venous and arterial thrombosis, thrombolysis and bleeding time. Blood Coagul Fibrinolysis 1996; 7: 69-79.
  CrossrefPubMedGoogle Scholar
• 16 Leadley Jr RJ, Chi L, Rebello SS. et al. Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents. J Pharmacol Toxicol Methods 2000; 43: 101-116.
  CrossrefPubMedGoogle Scholar
• 17 Eriksson BI, Carlsson S, Halvarsson M. et al. Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 1997; 78: 1404-1407.
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Peternel L, Stegnan M, Drevensek G. et al. Antithrombotic potential of new direct thrombin inhibitors built on the azaphenylalanine scaffold in two rat venous thrombosis models. Thromb Haemost 2005; 93: 437-442.
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Just M, Tripier D, Seiffge D. Antithrombotic effects of recombinant hirudin in different animal models. Haemostasis 1991; 21 (Suppl. 01) 80-87.
  PubMedGoogle Scholar
• 20 Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999; 94: 187-197.
  CrossrefPubMedGoogle Scholar
• 21 Elg M, Gustafsson D, Deinum J. The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997; 78: 1286-1292.
  Article in Thieme ConnectPubMedGoogle Scholar
• 22 Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: Time for a fresh look. Thromb Haemost 2006; 96: 547-552.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Walenga JM, Hoppensteadt DA. Monitoring the new antithrombotic drugs. Sem Thromb Hemost 2004; 30: 683-695.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Carlsson SC, Mattsson C, Eriksson UG. et al. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays. Thromb Res 2005; 115: 9-18.
  CrossrefPubMedGoogle Scholar
• 25 Berry CN, Lassalle G, Lunven C. et al. SSR182289A, a novel, orally active thrombin inhibitor: In vitro profile and ex vivo anticoagulant activity. J Pharmacol Exp Ther 2002; 303: 1189-1198.
  CrossrefPubMedGoogle Scholar
• 26 Eriksson BI, Dahl OE, Ahnfelt L. et al. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004; 2: 1573-1580.
  CrossrefPubMedGoogle Scholar
• 27 Eriksson BI, Dahl OE, Büller HR. et al. for the BISTRO II Study Group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3: 103-111.
  CrossrefPubMedGoogle Scholar
• 28 Lorrain J, Millet L, Lechaire I. et al. Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor. J Pharmacol Exp Ther 2003; 304: 567-574.
  CrossrefPubMedGoogle Scholar
• 29 Sato K, Kawasaki T, Taniuchi Y. et al. YM-60828, a novel factor Xa inhibitor: Separation of its antithrombotic effects from its prolongation of bleeding time. Eur J Pharmacol 1997; 339: 141-146.
  CrossrefPubMedGoogle Scholar
• 30 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939 – an oral, direct factor Xa inhibitor. J Thromb Haemost 2005; 3: 514-521.
  CrossrefPubMedGoogle Scholar
• 31 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Sem Thromb Hemost 1990; 16: 1-20.
  Article in Thieme ConnectPubMedGoogle Scholar