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Bosentan

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Abstract

▴ Bosentan is a nonpeptide, specific, competitive, dual antagonist at both endothelin receptor subtypes (ETA and ETB). Orally administered bosentan effectively prevents endothelin 1-induced vasoconstriction in pulmonary vessels in patients with pulmonary arterial hypertension.

▴ Improvement in exercise capacity from baseline was significantly greater with bosentan than with placebo in two phase III trials in patients with WHO functional class III or IV pulmonary arterial hypertension (primary or associated with connective tissue disease) despite treatment with vasodilators, diuretics, anticoagulants, cardiac glycosides, or supplemental oxygen. The beneficial effects of bosentan on exercise capacity were maintained for at least 20 weeks.

▴ Compared with placebo, bosentan led to a significantly greater improvement from pretreatment values in secondary efficacy end-points such as the Borg dyspnea index, WHO functional class, and cardiopulmonary hemodynamic parameters (cardiac index, pulmonary vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure).

▴ Bosentan significantly reduced the incidence, and delayed the onset, of clinical worsening of pulmonary arterial hypertension compared with placebo.

▴ In published clinical trials, adverse events that occurred with similar or greater frequency with bosentan 125mg twice daily than with placebo included headache, syncope, flushing and abnormal hepatic function. Those that occurred less frequently with bosentan 125mg twice daily than with placebo included dizziness, worsening of symptoms of pulmonary arterial hypertension, cough and dyspnea.

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References

  1. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987 Aug; 107 (2): 216–23

    PubMed  CAS  Google Scholar 

  2. Kim NH, Rubin LJ. Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther 2002 Jan; 7 (1): 9–19

    Article  PubMed  CAS  Google Scholar 

  3. De Backer TLM, Smedema J-P, Carlier SG. Current management of primary pulmonary hypertension. Biodrugs 2001; 15 (12): 801–17

    Article  PubMed  Google Scholar 

  4. Klings ES, Farber HW. Current management of primary pulmonary hypertension. Drugs 2001; 61 (13): 1945–56

    Article  PubMed  CAS  Google Scholar 

  5. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998 Aug 29; 352: 719–25

    Article  PubMed  CAS  Google Scholar 

  6. Rich S. Primary pulmonary hypertension. Fauci AS, Braunwald E, Isselbacher KJ, et al. In: Harrison’s principles of internal medicine. 14th ed. New York: McGraw Hill Companies, Inc., 1998: 1466–8

    Google Scholar 

  7. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol 1999; 61: 391–41

    Article  PubMed  CAS  Google Scholar 

  8. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Ann Rev Pharmacol Toxicol 2001; 41: 851–76

    Article  CAS  Google Scholar 

  9. Kaur S, Frishman WH, Singh I, et al. Endothelin as a therapeutic target in the treatment of cardiovascular disease. Heart Dis 2001; 3 (3): 176–88

    Article  PubMed  CAS  Google Scholar 

  10. Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension. Lancet 2001 Oct 6; 358 (9288): 1113–4

    Article  PubMed  CAS  Google Scholar 

  11. Lüscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation 2000; 102 (19 Suppl.): 2434–40

    Article  PubMed  Google Scholar 

  12. Holm P. Endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction. Scand Cardiovasc J 1997; 31 Suppl. 46: 1–40

    Google Scholar 

  13. Actelion Pharmaceuticals US Inc. Tracleer (bosentan) prescribing information [online]. Available from URL: http://www.tracleer.com/traclee_website/default.asp [Accessed 2001]

  14. Clozel M, Breu V, Gray GA, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 1994 Jul; 270: 228–35

    PubMed  CAS  Google Scholar 

  15. Wu-Wong JR, Dixon DB, Chiou WJ, et al. Endothelin receptor antagonists: effect of serum albumin on potency and comparison of pharmacological characteristics. J Pharmacol Exp Ther 1997 May; 281: 791–8

    PubMed  CAS  Google Scholar 

  16. Wanstall JC, Kay CS, O’ Donneil SR, et al. Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries. Fundam Clin Pharmacol 1997; 11 (No. 6): 584–91

    Article  PubMed  CAS  Google Scholar 

  17. Yang Z, Krasnici N, Liischer TF. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETAand ETB receptor blockade. Circulation 1999 Jul 6; 100: 5–8

    Article  PubMed  CAS  Google Scholar 

  18. Chen S-J, Chen Y-F, Meng QC, et al. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995 Dec; 79 (6): ™-31

    Google Scholar 

  19. Holm P, Liska J, Clozel M, et al. The endothelin antagonist bosentan: hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs. J Thorac Cardiovasc Surg 1996 Oct; 112 (4): 890–7

    Article  PubMed  CAS  Google Scholar 

  20. Kim H, Yung GL, Marsh JJ, et al. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000 Apr; 15 (4): 640–8

    Article  PubMed  CAS  Google Scholar 

  21. Weber C, Schmitt R, Birnboeck H, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996 Aug; 60: 124–37

    Article  PubMed  CAS  Google Scholar 

  22. Weber C, Schmitt R, Birnboeck H, et al. Multiple-dose pharmacokinetics, safety, and tolerability of bosentan, an endothelin receptor antagonist, in healthy male volunteers. J Clin Pharmacol 1999; 39: 703–14

    Article  PubMed  CAS  Google Scholar 

  23. Galie N, Hinderliter AL, Torbicki A, et al. Effects of oral endothelin receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary artery hypertension [abstract no. 1081-80]. J Am Coll Cardiol 2002 Mar 6; 39 (5 Suppl. A): 224A

    Article  Google Scholar 

  24. Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation 2000 Jul 25; 102 (4): 411–8

    Article  PubMed  CAS  Google Scholar 

  25. Weber C, Gasser R, Hopfgartner G. Absorption, excretion, and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab Dispos 1999 Jul; 27: 810–5

    PubMed  CAS  Google Scholar 

  26. Dingemanse J, Bodin F, Weidekamm E, et al. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol 2002 Mar; 42: 283–9

    Article  PubMed  CAS  Google Scholar 

  27. Dingemanse J, Schaarschmidt D, Van Giersbergen PLM. Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Br J Clin Pharmacol 2002 May; 53 (5): 547P

    Article  Google Scholar 

  28. van Giersbergen PLM, Halabi A, Dingemanse J. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 2002; 53: 589–95

    Google Scholar 

  29. Binet I, Wallnöfer A, Weber C, et al. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int 2000 Jan; 57 (1): 224–31

    Article  PubMed  CAS  Google Scholar 

  30. van Giersbergen PLM, Treiber A, Clozel M, et al. In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. Clin Pharmacol Ther 2002; 71: 253–62

    Article  PubMed  Google Scholar 

  31. Weber C, Banken L, Birnboeck H, et al. Effect of endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999 Aug; 39 (8): 847–54

    Article  PubMed  CAS  Google Scholar 

  32. Weber C, Banken L, Birnboeck H, et al. The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects. Br J Clin Pharmacol 1999 Jun; 47: 701–6

    Article  PubMed  CAS  Google Scholar 

  33. Badesch DB, Bodin F, Channick RN, et al. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr Thera Res 2002 Apr; 63 (4): 227–46

    Article  CAS  Google Scholar 

  34. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001 Oct 6; 358 (9288): 1119–23

    Article  PubMed  CAS  Google Scholar 

  35. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 Mar 21; 346 (12): 896–903

    Article  PubMed  CAS  Google Scholar 

  36. Rubin LJ, Galié N, Simonneau G. Bosentan for pulmonary hypertension [letter, reply]. N Engl J Med 2002 Jul 25; 347 (4): 293–4

    Google Scholar 

  37. Roux S, Kobrin I, Rainisio M, et al. Long-term open-label study in patients with pulmonary hypertension who participated in controlled clinical studies with bosentan (interim study report - protocol AC-052-354). Actelion Pharmaceuticals US, Inc., 2001 Oct 3

  38. Roux S, Kobrin I, Rainisio M, et al. Open-label, long-term study in patients with pulmonary hypertension who participated in controlled clinical studies with bosentan (second interim study report - protocol AC-052-053). Actelion Pharmaceuticals US, Inc., 2001 Oct 3

  39. Actelion Pharmaceuticals UK Ltd. Tracleer™; (bosentan) summary of product characteristics [online]. Available from URL: http://www.actelion.com [Accessed 2002 Sep 16]

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  1. Adis International Inc., 860 Town Center Drive, Langhorne, Pennsylvania, 19047, USA

    Amitabh Prakash & Caroline M. Perry

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  1. Amitabh Prakash
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  2. Caroline M. Perry
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Correspondence to Amitabh Prakash.

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Prakash, A., Perry, C.M. Bosentan. Am J Cordiovosc Drugs 2, 335–342 (2002). https://doi.org/10.2165/00129784-200202050-00006

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