Old versus new anticoagulants: Focus on pharmacology

Recent Patents on Cardiovascular Drug Discovery

Volumn 5, Issue 2, 2010, Pages 120-137

  Benmira, Sihame ^a   Banda, Zuliana K ^a   Bhattacharya, Vish ^b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b QUEEN ELIZABETH HOSPITAL   (United Kingdom)

Author keywords

Anticoagulant; Apixaban; Fondaparinux; Heparin; Idraparinux; Low molecular weight heparin; Pharmacology; Rivaroxaban; Warfarin; Ximelagatran Thromboembolism

Indexed keywords

ACETYLSALICYLIC ACID; ANTITHROMBIN III; APIXABAN; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; BLOOD CLOTTING FACTOR 7; BLOOD CLOTTING FACTOR 9; CYTOCHROME P450 2C9; DABIGATRAN; DIGOXIN; ENOXAPARIN; FONDAPARINUX; HEPARIN; IDRAPARINUX; LOW MOLECULAR WEIGHT HEPARIN; MELAGATRAN; PIROXICAM; PROTAMINE SULFATE; RIVAROXABAN; THROMBIN; VITAMIN K GROUP; WARFARIN; XIMELAGATRAN; ANTICOAGULANT AGENT; AZETIDINE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; BENZYLAMINE DERIVATIVE; DABIGATRAN ETEXILATE; MORPHOLINE DERIVATIVE; OLIGOSACCHARIDE; POLYSACCHARIDE; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; PYRIDONE DERIVATIVE; THIOPHENE DERIVATIVE;

ALOPECIA; AMINOTRANSFERASE BLOOD LEVEL; ANAPHYLAXIS; ANGIONEUROTIC EDEMA; ANTICOAGULANT THERAPY; ANTICOAGULATION; ARTICLE; BLEEDING; CLINICAL TRIAL; DRUG ABSORPTION; DRUG CHOICE; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG MONITORING; DRUG SAFETY; HEPARIN INDUCED THROMBOCYTOPENIA; HUMAN; HYPERKALEMIA; HYPERLIPIDEMIA; INJECTION SITE REACTION; OSTEOPENIA; OSTEOPOROSIS; OUTCOME ASSESSMENT; PHARMACOGENETICS; PRIORITY JOURNAL; SIDE EFFECT; SKIN NECROSIS; THROMBOEMBOLISM; THROMBOSIS; THROMBOSIS PREVENTION; URTICARIA; ANIMAL; ANTAGONISTS AND INHIBITORS;

ANIMALS; ANTICOAGULANTS; AZETIDINES; BENZIMIDAZOLES; BENZYLAMINES; FACTOR XA; HEPARIN; HEPARIN, LOW-MOLECULAR-WEIGHT; HUMANS; MORPHOLINES; OLIGOSACCHARIDES; POLYSACCHARIDES; PYRAZOLES; PYRIDINES; PYRIDONES; THIOPHENES; THROMBIN; WARFARIN; FACTOR XA INHIBITORS;

EID: 77953750689     PISSN: 15748901     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489010791515269     Document Type: Article

References (164)

1. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin:The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl): 188S-203S.
2. McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41: 250-7.
3. Brinkhous KM, Smith HP, Warner ED, Seegers WH. The inhibition of blood clotting: An unidentified substance which acts in conjuction with heparin to prevent the conversion of prothrombin into thrombin. Am J Physiol 1939; 125(4): 683-7.
4. Abidgaard U. Highly purified antithrombin III with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest 1968; 21: 89-91.
5. Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res 1976; 9(6): 575-83.
6. Linhardt RJ. Award address in carbohydrate chemistry. Heparin: Structure and activity. J Med Chem 2003; 46(13): 2551-64.
7. Rosenberg RD, Bauer KA, Marcum JA. Protease inhibitors of human plasma. Antithrombin-III. The heparin-antithrombin system. J Med 1985; 16(1-3): 351-416.
8. Casu B, Oreste P, Torri G, Zoppetti G, Choay J, Lormeau JC, et al. The structure of heparin oligosaccharide fragments with high anti-(factor Xa) activity containing the minimal antithrombin III-binding sequence. Chemical and 13C nuclear-magnetic-resonance studies. Biochem J 1981; 197(3): 599-609.
9. Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984; 218(3): 725-32.
10. Lindahl U, Thunberg L, Backstrom G, Riesenfeld J, Nordling K, Bjork I. Extension and structural variability of the antithrombin-binding sequence in heparin. J Biol Chem 1984; 259(20): 12368-76.
11. Oosta GM, Gardner WT, Beeler DL, Rosenberg RD. Multiple functional domains of the heparin molecule. Proc Natl Acad Sci USA 1981; 78(2): 829-33.
12. Nesheim ME. A simple rate law that describes the kinetics of theheparin-catalyzed reaction between antithrombin III and thrombin. JBiol Chem 1983; 258(23): 14708-17.
13. Ofosu FA, Sie P, Modi GJ, Fernandez F, Buchanan MR, Blajchman MA, et al. The inhibition of thrombin-dependent positive-feed back reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243(2): 579-88.
14. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-veinthrombosis. N Engl J Med 1986; 315(18): 1109-14.
15. Samama MM, Bara L, Gouin-Thibault I. New data on thepharmacology of heparin and low molecular weight heparins. Drugs1996; 52 (Suppl 7): 8-14; discussion -5.
16. Zhou F, Hook T, Thompson JA, Hook M. Heparin protein interactions. Adv Exp Med Biol 1992; 313: 141-53.
17. Mahadoo J, Heibert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1978; 12(1): 79-90.
18. Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1978; 12(5): 773-82.
19. de Swart CA, Nijmeyer B, Roelofs JM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982;60(6): 1251-8.
20. Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. An experimental study on dogs and humans. Acta Med Scand 1963; 173: 619-30.
21. Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 1982;31(1): 104-13.
22. Oie CI, Olsen R, Smedsrod B, Hansen JB. Liver sinusoidal endothelial cells are the principal site for elimination of unfractionated heparin from the circulation. Am J Physiol Gastrointest Liver Physiol 2008; 294(2): G520-8.
23. Friedman Y, Arsenis C. Studies on the heparin sulphamidase activity from rat spleen. Intracellular distribution and characterization of the enzyme. Biochem J 1974; 139(3): 699-708.
24. Hirsh J. Heparin induced bleeding. Nouvelle Revue Francaise Hematol 1984; 26(4): 261-6.
25. Shantsila E, Lip GY, Chong BH. Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management. Chest 2009; 135(6): 1651-64.
26. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287(7): 324-7.
27. Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost 2008; 99(5): 807-18.
28. Harenberg J. Pharmacology of low molecular weight heparins. Semin Thromb Hemost 1990; 16 (Suppl): 12-8.
29. Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem 1980; 255(21): 10081-90.
30. Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis: A comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39(2): 107-12.
31. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79(1): 1-17.
32. Bhandari M, Hirsh J, Weitz JI, Young E, Venner TJ, Shaughnessy SG. The effects of standard and low molecular weight heparin on bone nodule formation in vitro. Thromb Haemost 1998; 80(3): 413-7.
33. Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169)and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39(5): 631-6.
34. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337(10): 688-98.
35. Boneu B, Caranobe C, Cadroy Y, Dol F, Gabaig AM, Dupouy D, et al. Pharmacokinetic studies of standard unfractionated heparin,and low molecular weight heparins in the rabbit. Semin Thromb Hemost 1988; 14(1): 18-27.
36. Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59(6):1239-45.
37. Horne M, Chao E. The effect of molecular weight on heparin binding to platelets. Br J Haematol 1990; 74(3): 306-12.
38. Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65(1): 64-73.
39. Blajchman MA, Young E, Ofosu FA. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann N Y Acad Sci 1989; 556:245-54.
40. de Romeuf C, Mazurier C. Heparin binding assay of vonWille brand factor (vWF) in plasma milieu-evidence of the importance of the multimerization degree of vWF. ThrombHaemost 1993; 69(5): 436-40.
41. Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, et al. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest 1991;87(5): 1787-93.
42. Dempfle CE, Zharkowa U, Elmas E, Ahmad-Nejad P, Neumaier M, Borggrefe M. Heptest-STAT, a new assay for monitoring of low-molecular-weight heparins, is not influenced by pregnancy-relatedchanges of blood plasma. Thromb Haemost 2009; 102(5): 1001-6.
43. Garon JE. Monitoring low molecular weight heparins. Clin Leadership Manage Rev 2003; 17(1): 47-50.
44. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332(20): 1330-5.
45. Lindblad B, Borgstrom A, Wakefield TW, Whitehouse WM Jr, Stanley JC. Protamine reversal of anticoagulation achieved with alow molecular weight heparin. The effects on eicosanoids, clotting and complement factors. Thromb Res 1987; 48(1): 31-40.
46. Racanelli A, Fareed J, Walenga JM, Coyne E. Biochemical and pharmacologic studies on the protamine interactions with heparin, its fractions and fragments. Semin Thromb Hemost 1985; 11(2):176-89.
47. Holst J, Lindblad B, Bergqvist D, Garre K, Nielsen H, Hedner U, et al. Protamine neutralization of intravenous and subcutaneous low-molecular-weight heparin (tinzaparin, Logiparin). An experimental investigation in healthy volunteers. Blood Coagul Fibrinolysis 1994; 5(5): 795-803.
48. Wardrop D, Keeling D. The story of the discovery of heparin and warfarin. Br J Haematol 2008; 141(6): 757-63.
49. th ed.British Medical Association and Royal Pharmaceutical Society of Great Britain: London 2009.
50. Kimmel SE. Warfarin therapy: In need of improvement after all these years. Expert Opin Pharmacother 2008; 9(5): 677-86.
51. Nutescu EA, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf 2006; 5(3): 433-51.
52. Hamberg AK, Dahl ML, Barban M, Scordo MG, Wadelius M, Pengo V, et al. A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther 2007; 81(4): 529-38.
53. Herman D, Peternel P, Stegnar M, Breskvar K, Dolzan V. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95(5): 782-7.
54. Kim MJ, Huang SM, Meyer UA, Rahman A, Lesko LJ. A regulatory science perspective on warfarin therapy: A pharmacogenetic opportunity. J Clin Pharmacol 2009; 49(2): 138-46.
55. Erban S. Initiation of warfarin therapy: recommendations andclinical pearls. J Thromb Thrombolysis 1999; 7(2): 145-8.
56. Garcia DA, Regan S, Crowther M, Hylek EM. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol 2006; 47(4): 804-8.
57. Hylek EM. Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors. Semin Vasc Med 2003;3(3): 271-8.
58. FDA US. Warfarin. Available at: http://www.fda.gov/ohrms/dockets/ac/cder05.html#PharmScience. Accessed on: September 1, 2009.
59. Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008; 25(1):45-51.
60. Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements - a systematic review and meta-analysis. Eur J Clin Pharmacol 2009; 65(4): 365-75.
61. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002; 72(6): 702-10.
62. Dias VC. Warfarin. Pharmacokinetics and use in the elderly. Minn Med 1983; 66(4): 235-6.
63. th ed. Churchill Livingstone Philadelphia 2007.
64. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood 2005;106(7): 2329-33.
65. Au N, Rettie AE. Pharmacogenomics of 4-hydroxycoumarin anticoagulants. Drug Metab Rev 2008; 40(2): 355-75.
66. Hirsh J, O'Donell M, Weitz J. New anticoagulants. Blood 2005;105: 453-63.
67. van Boeckel, Petitou M. The unique antithrombin III bindingdomain of heparin: A lead to new synthetic antithrombotics. Angew Chem Int Ed Engl 1993; 32: 1671-90.
68. Bauer KA, Hawkins DW, Peters PC, Petitou M, Herbert JM, van Boeckel CA, et al. Fondaparinux, a synthetic pentasaccharide: The first in a new class of antithrombotic agents - the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20: 37-52.
69. Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41(suppl 2): 1-9.
70. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: A meta-analysis of 4 randomized double-blind studies. Arch. Intern Med 2002; 162(16): 1833-40.
71. Coussement PK, Bassand JP, Convens C, Vrolix M, Boland J, Grollier G, et al. A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. Eur Heart J 2001; 22: 1716-24.
72. Vuillemenot A, Schiele F, Meneveau N, Claudel S, Donat F, Fontecave S, et al. Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent-a pilot study in the setting of coronary angioplasty. Thromb Haemost 1999; 81(2): 214-20.
73. Choay J, Petitou M, Lormeau JC, Sinay P, Casu B, Gatti G. Structure-activity relationship in heparin: A synthetic pentasaccharide with high affinity for antithrombin III and elicitnghigh anti-factor Xa activity. Biochem Biophys Res Commun 1983;116: 492-9.
74. Petitou M, Lormeau JC, Choay J. Interaction of heparin and antithrombin III. The role of O-sulfate groups. Eur J Biochem 1988;176(3): 637-40.
75. Petitou M, Duchaussoy P, Lederman I, Choay J, Jacquinet JC, Sinay P, et al. Synthesis of heparin fragments: A methyl alpha-pentaoside with high affinity for antithrombin III. Carbo hydr Res 1987 167: 67-75.
76. Herbert JM, Petitou M, Lormeau JC, Cariou R, Necciari J, Magnani HN, et al. SR 90107A/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovasc Drug Rev 1997; 15: 1-26.
77. Turpie AG. Fondaparinux: A Factor Xa inhibitor for antithrombotic therapy. Expert Opin Pharmacother 2004; 5(6): 1373-84.
78. Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux). Thromb Res 2003; 109(1): 1-11.
79. Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement. JBiol Chem 1992; 267(18): 12528-38.
80. Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA 1997; 94: 14683-8.
81. Walenga JM, Hoppensteadt D, Mayuga M. Functionality of pentasaccharide depends on endogenous antithrombin levels. Blood 2000; 96(11): 817a.
82. Boneu B, Necciari J, Cariou R, Sie P, Gabaig AM, Kieffer G, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III inman. Thromb Haemost 1995; 74: 1468-73.
83. Lieu C, Shi J, Donat F, van Horn R, Brian W, Newton J, et al. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs. Clin Pharmacokinet 2002;41(suppl): 19-26.
84. Paolucci F, Clavies MC, Donat F, Necciari J. Fondaparinux sodiummechanism of action: Identification of specific binding to purified and human plasma-derived proteins. Clin Pharmaco kinet 2002;41(suppl 2): 11-8.
85. Faaij RA, Burggraaf J, Schoemaker RC, Van Amsterdam RG, Cohen AF. Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin. Br J Clin Pharmacol 2002; 54(3): 304-8.
86. Mant T, Fournié P, Ollier C, Donat F, Necciari J. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clin Pharmacokinet 2002; 41(2): 39-45.
87. Ollier C, Faaij RA, Santoni A, Duvauchelle T, van Haard PM, Schoemaker RC, et al. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clin Pharmacokinet 2002; 41 (Suppl 2): 31-7.
88. Warkentin TE, Cook RJ, Marder VJ, Sheppard JA, Moore JC, Eriksson BI, et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106(12): 3791-6.
89. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-4.
90. Stein DM, Dutton RP, O'Connor J. Determinants of futility of administration of recombinant factor VIIa in trauma. J Trauma 2005; 59: 609-15.
91. Lagrange F. Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledonin vitro. Thromb Haemost 2002; 87(5): 831-5.
92. Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006; 108(5): 1569-70.
93. Herbert JM, Herault JP, Bernat A, Van Amsterdam RGM, Lormeau JC, Petitou M, et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91(11): 4197-205.
94. Weitz JI, Linkins LA. Beyond heparin and warfarin: The new generation of anticoagulants. Expert Opin Investigat Drug 2007;16(3): 271-82.
95. Hirsh J, O'Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: Current and future advances. Circulation 2007; 116(5): 552-60.
96. The PERSIST Investigators. A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemostas 2004; 2(3): 540.
97. The Amadeus Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism inpatients with atrial fibrillation: A randomised, open-label, non-inferiority trial. Lancet 2008; 371(9609): 315-21.
98. Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemostasis 2007; 5 (Suppl 1): 60-4.
99. Sinha U, Ku P, Malinowski J, Zhu BY, Scarborough RM, Marlowe CK, et al. Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis. Eur J Pharmacol 2000; 395(1): 51-9.
100. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PYS, Pinto DJ, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor:in vitro, antithrombotic and antihemostatic studies. J Thrombos Haemostas 2008; 6(5): 820-9.
101. Hermans C, Claeys D. Review of the rebound phenomenon in newanticoagulant treatments. Curr Med Res Opin 2006; 22(3): 471-81.
102. Harenberg J. Indirect and direct anticoagulants predominantly inhibiting factor Xa. Therapy 2008; 5(2): 177-92.
103. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban: An oral, direct Factor Xa inhibitor. Blood 2006; 108:Abstract 905.
104. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmaco kinetics, and pharmacodynamics or rivaroxaban (BAY 59-7939) in healthysubjects. J Clin Pharmacol 2007; 47: 218-26.
105. Kubitzaa D, Beckab M, Rotha A, Muecka W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24(10): 2757-65.
106. Zhao X, Sun P, Zhou Y, Liu Y, Zhang H, Mueck W, et al. Safety, pharmaco kinetics and pharmacodynamics of single/multiple dosesof the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br J Clin Pharmacol 2009; 68(1): 77-88.
107. Kubitza D, Becka M, Mueck W, Zuehlsdorf M. Safety, Tolerability, pharmacodynamics, and pharmacokinetics or rivaroxaban-an oral, direct Factor Xa inhibitor-are not affected by aspirin. J Clin Pharmacol 2006; 46: 981-90.
108. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Rivaroxaban (BAY59-7939) - an oral, direct Factor Xa Inhibitor- has no clinically relevant interaction with naproxen. Brit J Clin Pharmacol 2007; 63:469-76.
109. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effects of food, anantacid, and the H2 antagonist ranitidine on the absorption of BAY59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthysubjects. J Clin Pharmacol 2006; 46: 549-58.
110. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. No interaction between the novel, oral direct factor Xa inhibitor BAY 59-7379 and digoxin. J Clin Pharmacol 2006; 6: 702.
111. Kubitza D BM, Mueck W, Zuehlsdorf M. Co-administration of rivaroxaban - a novel, oral, direct Factor Xa inhibitor - and clopidogrel in healthy subjects. Eur Heart J 2007; 28(Suppl 1)Abstract 189.
112. Laux V, Perzborn E, Kubitza D, Misselwitz F. Preclinical and clinical characteristics of rivaroxaban: a novel, oral, direct factor Xainhibitor. Semin Thromb Hemost 2007; 33(5): 515-23.
113. Hirsh J, O'Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin: Current and future advances. Circulation 2007; 216: 552-60.
114. Bayer Healthcare AG. Xarelto Rivoroxaban. Available at: http://www.xarelto.com/scripts/pages/en/index.php. Accessed on:August 1, 2009.
115. Perzborn EHM. Recombinant Factor VII a partially reverses the effects of the Factor Xa inhibitor rivaroxaban on thrombin generation, but not the effects of thrombin inhibitors, in vitro. J Thromb Haemost 2007; 5(Suppl 2): Abstract P-W-640.
116. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thrombopro-phylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-75.
117. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thrombo embolism after total hiparthroplasty: A double-blind, randomised controlled trial. Lancet 2008; 372: 31-9.
118. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thrombo-prophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776-86.
119. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD 4): A randomised trial. Lancet 2009; 373: 1673-80.
120. NICE. Rivaroxaban for the prevention of venous thromboem-bolism after total hip or knee replacement in adults. Available at:www.nice.org.uk/TA170 (Accessed on: September 22, 2009).
121. Bayer Healthcare. Bayer Completes Enrollment into Major Phase III Study with Rivaroxaban (ROCKET AF). Available at:http://www.bayerscheringpharma.de. Accessed on: March 12, 2010.
122. Eriksson BI, Dahl OE, Lassen MR, Ward DP, Rothlein R, Davis G, et al. Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: An exploratory study. J Thromb Haemost 2008; 6(3): 457-63.
123. Roser-Jones C, Becker RC. Apixaban: an emerging oral factor Xainhibitor. J Thromb Thrombolysis 29(1): 141-6.
124. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metabol Dispos 2009; 37(1): 74-81.
125. Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, incombination with antiplatelet therapy after acute coronary syndrome: Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119(22): 2877-85.
126. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P, et al. Apixaban versus enoxaparin for thrombo prophylaxis after knee replacement (ADVANCE-2): A randomised double-blind trial. Lancet 375(9717): 807-15.
127. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after kneereplacement. [Erratum appears in N Engl J Med 2009 Oct 29;361(18): 1814]. New Engl J Med 2009; 361(6): 594-604.
128. Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353(10): 1028-40.
129. Hauel NH, Nar H, Priepke H, Ries U, Stassen J-M, Wienen W. Structure-based design of novel potent nonpeptide thrombininhibitors. J Med Chem 2002; 45(9): 1757-66.
130. Gustafsson D. Oral direct thrombin inhibitors in clinical development. J Intern Med 2003; 254(4): 322-34.
131. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy malesubjects. Br J Clin Pharmacol 2007; 64(3): 292-303.
132. Trocóniz IF, Tillmann C, Liesenfeld KH, Schäfer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombininhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. J Clin Pharmacol 2007; 47(3): 371-82.
133. Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G, et al. Dose escalating safety study of a new oral direct thrombinin hibitor, dabigatran etexilate, in patients undergoing total hipreplacement: BISTRO I. J Thromb Haemost 2004; 2(9): 1573-80.
134. Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. Themetabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metabol Dispos 2008; 36(2): 386-99.
135. Stangier J, Stahle H, Rathgen K, Reseski K, Kornicke T. No interaction of the oral direct thrombin inhibitor dabigatran etexilateand digoxin. J Thromb Haemost 2007; 5(suppl 2): abstract P-W.672.
136. Stangier J, Stahle H, Rathgen K, Reseski K, Kornicke T. Co administration of the oral direct thrombin inhibitor dabigatran etexilate and diclofenac has little impact on the pharmacokinetics of either drug. J Thromb Haemost 2007; 5(suppl 2): abstract P-T-677.
137. Wallentin L, Ezekowitz M, Simmers T. Safety and efficacy of anew oral direct thrombin inhibitor dabigatran in atrial fibrillation: Adose finding trial with comparison to warfarin. Eur Heart J 2005;26(suppl): 482.
138. Eriksson BI, Dahl OE, Buller HR, Hettiarachi R, Rosencher N, Bravo ML, et al. A new oral direct thrombin inhibitor, dabigatranetexilate, compared with enoxaparin for prevention of throm boem-bolic events following total hip or knee replacement: The BISTROII randomized trial. J Thromb Haemost 2005; 3(1): 103-11.
139. Eriksson UG, Bredberg U, Hoffmann K-J, Thuresson A, Gabrielsson M, Ericsson H, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metabol Dispos 2003;31(3): 294-305.
140. Gustafsson D, Antonsson T, Bylund R, Eriksson U, Gyzander E, Nilsson I, et al. Effects of melagatran, a new low-molecular-weightthrombin inhibitor, on thrombin and fibrinolytic enzymes. J Thromb Haemost 1998; 79(1): 110-8.
141. Eriksson UG, Bredberg U, Gislen K, Johansson LC, Frison L, Ahnoff M, et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003; 59(1): 35-43.
142. Eriksson UG, Johansson S, Attman P-O, Mulec H, Frison L, Fager G, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42(8): 743-53.
143. Halperin JL, Executive Steering Committee Sportif III, Investigators VS. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrialfibrillation: Rationale, objectives, and design of a pair of clinicalstudies and baseline patient characteristics (SPORTIF III and V). Am Heart J 2003; 146(3): 431-8.
144. Olsson SB, Executive Steering Committee of the SIIII. Strokeprevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): Randomised controlled trial. Lancet 2003; 362(9397): 1691-8.
145. Eriksson BI, Bergqvist D, Kalebo P, Dahl OE, Lindbratt S, Bylock A, et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: The METHRO II randomised trial. Lancet 2002;360(9344): 1441-7.
146. Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple J, et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: A phase 2 dose-finding study. Arch Intern Med 2001; 161(18): 2215-21.
147. Gustafsson D, Nystrom J, Carlsson S, Bredberg U, Eriksson U, Gyzander E, et al. The direct thrombin inhibitor melagatran and itsoral prodrug H 376/95: Intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001; 101(3): 171-81.
148. Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother 2003; 4(5): 653-66.
149. Sarich TC, Johansson S, Schutzer K-M, Wall U, Kessler E, Teng R, et al. The pharmacokinetics and pharmacodynamics ofximelagatran, an oral direct thrombin inhibitor, are unaffected by asingle dose of alcohol. J Clin Pharmacol 2004; 44(4): 388-93.
150. Bates SM, Weitz JI. New anticoagulants: Beyond heparin, low-molecular-weight heparin and warfarin. Br J Pharmacol 2005;144(8): 1017-28.
151. Hirsh J, Warkentin TE, Shaughnessy SG, Anand SS, Halperin JL, Raschke R, et al. Heparin and low-molecular-weight heparin:mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119(1 Suppl): 64S-94S.
152. Ameer, G.A., Zhang, Y. Method for removal or inactivation of heparin. WO2010011600 (2010).
153. Amiral, J., Vissac, A.M. Method and kit for the detection of heparin-dependent antibodies and the diagnosis of immune orautoimmune pathologies potentiated by heparin such as heparin-induced thrombocytopenia. WO2007147983 (2007).
154. Rusconi, C.P., Tonkens, R.M. Administration of the reg1 anticoagulation system. WO2007140000 (2007).
155. Wurster, M. Method and system for administering anticoagulation therapy. US20020116222 (2002).
156. Chen, Y.T., Shen, C.L., Chang, C.F., Lee, M.T.M., Hsu, J.C., Lu, L.S., Wen, M.S. Warfarin dosage prediction. US20070298426 (2007).
157. Misselwitz, F., Kubitza, D., Park, S.M., Wehling, K. Prevention and treatment of thromboembolic disorders. US20090004265 (2009).
158. Schror, K., Hohlfeld, T., Weber, A.-A. Method for the treatment of thromboembolic disorders in patients with aspirin resistance. EP1190714 (2001).
159. Karlheinz, P. Anticoagulation agent and uses thereof. WO2007003010 (2007).
160. Skjevold, P.O., Odegaard, R., Brosstad, F., Flensgsrud, R. Anticoagulant. US20040171579 (2004).
161. Branellec, J-F., Morello, C., Potier, P., Trouilleux, P., Batsiaansen, P.M.F.M., Claassen, H.C.J. Fondaparinux sodium composition of high purity, method for production of said composition and pharmaceutical compositions containing the same as active ingredient. WO2004078105 (2004).
162. Grunenberg, A., Lenz, J. New forms of specific substituted thiophene carboxamide (rivaroxaban), useful for prevention and treatment of thromboembolic disease, have higher solubility thanknown modifications. DE102005047564 (2005).
163. Masse, C.E. Substituted oxazolidinone derivatives. US20090137535 (2009).
164. Czarnik, A.W. Deuterium-enriched rivaroxaban. US2009076264(2009).