Mechanism of action of the oral direct thrombin inhibitor ximelagatran

Seminars in Vascular Medicine

Volumn 5, Issue 3, 2005, Pages 235-244

  Mattsson, Christer ^a   Sarich, Troy C ^b   Carlsson, Stefan C ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b ASTRAZENECA   (United Kingdom)

Author keywords

Mechanism of action; Oral direct thrombin inhibitors; Ximelagatran

Indexed keywords

ANTICOAGULANT AGENT; ANTITHROMBIN; ANTIVITAMIN K; ARGATROBAN; BLOOD CLOTTING FACTOR 10A INHIBITOR; DALTEPARIN; EFEGATRAN; ENOXAPARIN; FIBRINOLYTIC AGENT; FONDAPARINUX; HEPARIN; HIRUDIN; HIRULOG; IDRAPARINUX; INOGATRAN; LOW MOLECULAR WEIGHT HEPARIN; MELAGATRAN; PLACEBO; RECOMBINANT HIRUDIN; THROMBIN; THROMBIN INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; WARFARIN; XIMELAGATRAN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICOAGULANT THERAPY; BLEEDING; BLOOD CLOTTING TIME; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CORONARY ARTERY THROMBOSIS; DOSE RESPONSE; DRUG EFFECT; DRUG MECHANISM; DRUG SELECTIVITY; HEART INFARCTION; HEMATOLOGICAL PARAMETERS; HUMAN; INFLAMMATION; META ANALYSIS; NONHUMAN; NORMAL HUMAN; PARTIAL THROMBOPLASTIN TIME; RAT; REVIEW; RISK BENEFIT ANALYSIS; SYSTEMATIC REVIEW; THROMBOCYTE ACTIVATION; THROMBOEMBOLISM; THROMBOSIS PREVENTION;

ADMINISTRATION, ORAL; ANTI-INFLAMMATORY AGENTS; ANTICOAGULANTS; AZETIDINES; BENZYLAMINES; BLOOD COAGULATION; HUMANS; INFLAMMATION; PLATELET ACTIVATION; THROMBIN; THROMBOEMBOLISM; THROMBOSIS;

EID: 24144482599     PISSN: 15289648     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2005-916162     Document Type: Review

References (56)

1. Van Aken H, Bode C, Darius H, et al. Anticoagulation: the present and future. Clin Appl Thromb Hemost 2001;7:195-204
2. Linkins LA, Weitz JI. New anticoagulants. Semin Thromb Hemost 2003;29:619-631
3. Narayanan S. Multifunctional roles of thrombin. Ann Clin Lab Sci 1999;29:275-280
4. Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997;78:386-391
5. Lorand L, Chenoweth D, Gray A. Titration of the acceptor cross-linking sites in fibrin. Ann NY Acad Sci 1972;202:155-171
6. Furie B, Furie BC, Flaumenhaft R. A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 2001;86:214-221
7. Hughes PE, Pfaff M. Integrin affinity modulation. Trends Cell Biol 1998;8:359-364
8. Dore M, Korthuis RJ, Granger DN, Entman ML, Smith CW. P-selectin mediates spontaneous leukocyte rolling in vivo. Blood 1993;82:1308-1316
9. Ueno A, Murakami K, Yamanouchi K, Watanabe M, Kondo T. Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. Immunology 1996;88:76-81
10. Colotta F, Sciacca FL, Sironi M, Luini W, Rabiet MJ, Mantovani A. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994;144:975-985
11. Mutch NJ, Robbie LA, Booth NA. Human thrombi contain an abundance of active thrombin. Thromb Haemost 2001;86:1028-1034
12. Granger CB, Miller JM, Bovill EG, et al. Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 1995;91:1929-1935
13. Direct Thrombin Inhibitor Trialists' Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Lancet 2002;359:294-302
14. Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003;31:294-305
15. Gustafsson D, Antonsson T, Bylund R, et al. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes. Thromb Haemost 1998;79:110-118
16. Nilsson T, Sjoling-Ericksson A, Deinum J. The mechanism of binding of low-molecular-weight active site inhibitors to human alpha-thrombin. J Enzyme Inhib 1998;13:11-29
17. 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
18. Sarich TC, Eriksson UG, Mattsson C, et al. Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects. Thromb Haemost 2002;87:300-305
19. Sarich TC, Wolzt M, Eriksson UG, et al. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. J Am Coll Cardiol 2003;41:557-564
20. Mattsson C, Björkman JA, Ulvinge JC. Melagatran, hirudin and heparin as adjuncts to tissue-type plasminogen activator in a canine model of coronary artery thrombolysis. Fibrinolysis Proteolysis 1997;11:121-128
21. Mattsson C, Björkman JA, Abrahamsson T, et al. Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran). Thromb Haemost 2002;87:557-562
22. Klement P, Carlsson S, Rak J, et al. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. J Thromb Haemost 2003;1:587-594
23. Mattsson C, Menschik-Lundin A, Nylander S, Gyzander E, Deinum J. Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro. Thromb Res 2001;104:475-486
24. Hemker HC, Wielders S, Kessels H, Beguin S. Continuous registration of thrombin generation in plasma, its use for the determination of the thrombin potential. Thromb Haemost 1993;70:617-624
25. Boström SL, Hansson GF, Kjaer M, Sarich TC. Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects. Blood Coagul Fibrinolysis 2003;14:457-462
26. Boström SL, Dagnelid E, Hansson GFH, Ulvinge JC. Inhibition of thrombin-induced feedback activation of factor V: a potential pathway for inhibition of thrombin generation by melagatran. Blood Coagul Fibrinolysis 2004;15:25-30
27. Lindhout T, Blezer R, Hemker HC. The anticoagulant mechanism of action of recombinant hirudin (CGP 39393) in plasma. Thromb Haemost 1990;64:464-468
28. Sandset PM, Bendz B, Hansen JB. Physiological function of tissue factor pathway inhibitor and interaction with heparins. Haemostasis 2000;30(Suppl 2):48-56
29. Boström SL, Hansson GF, Sarich TC, Wolzt M. The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma. Thromb Res 2004;113:85-91
30. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 1999;103:879-887
31. Hagberg IA, Lyberg T. Evaluation of circulating platelet-leukocyte conjugates: a sensitive flow cytometric assay well suited for clinical studies. Platelets 2000;11:151-160
32. Nylander S, Mattsson C. Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action. Blood Coagul Fibrinolysis 2003;14:159-167
33. Sarich TC, Osende JI, Eriksson UG, et al. Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis. J Thromb Haemost 2003;1:999-1004
34. Eriksson UG, Bredberg U, Gislén K, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59:35-43
35. 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
36. Eriksson BI, Arfwidsson AC, Frison L, et al. A dose-ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I MElagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002;87:231-237
37. Gustafsson D, Nystrom J, Carlsson S, et al. The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001;101:171-181
38. Eriksson BI, Carlsson S, Halvarsson M, Risberg B, Mattsson C. 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
39. Scherstén F, Wahlund G, Bjornheden T, Carlsson S, Mattsson C, Grip L. Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model. Blood Coagul Fibrinolysis 2003;14:235-241
40. Fuentes-Prior P, Iwanaga Y, Huber R, et al. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature 2000;404:518-525
41. 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
42. Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review. Thromb Res 2003;109(Suppl 1):9-15
43. Esmon CT. Crosstalk between inflammation and thrombosis. Maturitas 2004;47:305-314
44. Özmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes 2002;51:1779-1784
45. Malhotra OP, Nesheim ME, Mann KG. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins. J Biol Chem 1985;260:279-287
46. Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med 2004;116:651-656
47. Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999;81:396-399
48. Blanchard RA, Furie BC, Jorgensen M, Kruger SF, Furie B. Acquired vitamin K-dependent carboxylation deficiency in liver disease. N Engl J Med 1981;305:242-248
49. White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995;122:40-42
50. Cushman M, Booth SL, Possidente CJ, Davidson KW, Sadowski JA, Bovill EG. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol 2001;112:572-577
51. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000;87:266-272
52. Bendayan P, Boccalon H, Dupouy D, Boneu B. Dermatan sulfate is a more potent inhibitor of clot-bound thrombin than unfractionated and low molecular weight heparins. Thromb Haemost 1994;71:576-580
53. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. 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
54. Agnelli G, Pascucci C, Cosmi B, Nenci GG. The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits. Thromb Haemost 1990;63:204-207
55. Serruys PW, Herrman JP, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. Helvetica Investigators. N Engl J Med 1995;333:757-763
56. Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001;119:95S-107S