Review on Bosentan, A Dual Endothelin Receptor Antagonist for the Treatment of Pulmonary Arterial Hypertension

Recent Patents on Cardiovascular Drug Discovery

Volumn 5, Issue 3, 2010, Pages 184-195

  Serasli, Eva ^a   Michaelidis, Vassilis ^a   Kosmas, Andreas ^a   Antoniadou, Maria ^a   Tsara, Venetia ^a  

^a GPapanikolaou Hospital   (Greece)

Author keywords

Bosentan; Clinical trials; Endothelin; Endothelin receptor antagonist; Pulmonary arterial hypertension; Treatment

Indexed keywords

ALPHA BETA INTERFERON RECEPTOR; AMBRISENTAN; ANGIOTENSIN II; BETA INTERFERON RECEPTOR; BOSENTAN; CONTRACEPTIVE AGENT; CYCLOSPORIN A; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; DIGOXIN; ENDOTHELIN; ENDOTHELIN 1; ENDOTHELIN 2; ENDOTHELIN 3; ENDOTHELIN RECEPTOR ANTAGONIST; GLIBENCLAMIDE; ILOPROST; KETOCONAZOLE; PHENYTOIN; PLACEBO; PROSTACYCLIN; SILDENAFIL; SIMVASTATIN; SITAXSENTAN; TADALAFIL; THROMBIN; UNINDEXED DRUG; VASOPRESSIN; WARFARIN;

ABDOMINAL PAIN; AMINOTRANSFERASE BLOOD LEVEL; AREA UNDER THE CURVE; BILIRUBIN BLOOD LEVEL; BIRTH DEFECT; BODY WEIGHT; CHRONIC OBSTRUCTIVE LUNG DISEASE; CONNECTIVE TISSUE DISEASE; DRUG DOSE REDUCTION; DRUG ELIMINATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EISENMENGER COMPLEX; ESCHERICHIA COLI; ESSENTIAL HYPERTENSION; FATIGUE; FEVER; FLUSHING; HEADACHE; HEART FAILURE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; IDIOPATHIC DISEASE; JAUNDICE; LETHARGY; LIVER FUNCTION; LIVER INJURY; LUNG ARTERY PRESSURE; METABOLISM; MONOTHERAPY; MORTALITY; MULTIPLE CYCLE TREATMENT; NAUSEA; PERIPHERAL EDEMA; PRIORITY JOURNAL; PROTEIN BINDING; PULMONARY HYPERTENSION; QUALITY OF LIFE; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SINGLE DRUG DOSE; VOMITING; WORLD HEALTH ORGANIZATION;

ANIMALS; ANTIHYPERTENSIVE AGENTS; DRUG INTERACTIONS; HUMANS; HYPERTENSION, PULMONARY; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RECEPTORS, ENDOTHELIN; SULFONAMIDES;

EID: 78650042893     PISSN: 15748901     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489010793351944     Document Type: Review

References (112)

1. Clozel M, Breu V, Gray GA, Kalina B, Loffler BM, Burri K, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther 1994; 270: 228-35.
2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in Collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009; 53(17): 1573-619.
3. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. The task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30: 2493-537.
4. Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother 2003; 37: 1055-62.
5. Dingemanse J, van Giersbergen P. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 2004; 43 (15): 1089-115.
6. Weber C, Gasser R, Hopfgartner G. Absorption, excretion and metabolism of the endothelin receptor antagonist bosentan in healthy male subjects. Drug Metab Disp 1999; 27: 810-5.
7. Dingemanse J, Bodin F, Weidekamm E, Kutz K, van Giersbergen P. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol 2002; 42: 283-9.
8. Weber C, Schmitt R, Birnboeck H, Hopfgartner G, van Marle SP, Peeters PA, et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther 1996; 60(2): 124-37.
9. Van Giersbergen PLM, Halabi A, Dingemance J. Single and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol 2002; 53: 589-95.
10. Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension Clin Pharmacol Ther 2003; 73(4): 372-82.
11. Treinen KA, Louden C, Dennis MJ, Wier PJ. Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits. Teratology 1999; 59(1): 51-9.
12. Sütsch G, Kiowski W, Yan XW, Hunziker P, Christen S, Strobel W, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998; 98(21): 2262-8.
13. Roux S, Breu V, Ertel SI, Clozel M. Endothelin antagonism with bosentan: A review of potential applications. J Mol Med 1999; 77: 364-76.
14. Kim H, Yung GL, Marsh JJ, Konopka RG, Pedersen CA, Chiles PG, et al. Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Eur Respir J 2000; 15: 640-8.
15. Holm P, Liska J, Clozel M, Franco-Cereceda A. The endothelin antagonist bosentan: Hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs. J Thorac Cardiovasc Surg 1996; 112: 890-7.
16. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 2001; 6; 358: 1119-23.
17. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903.
18. Williamson DJ, Wallman LL, Jones R, Keogh AM, Scroope F, Penny R, et al. Hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation 2000; 25; 102(4): 411-8.
19. Stresser D. Evaluation of the inhibitory potential of bosentan on the activities of the human cytochrome P450 isoforms 2A6, 2B6, 2C8 and 2E1 in vitro. Allschwil Actelion Pharmaceuticals Ltd. 2001.
20. Kim RB. Drugs as P-glycoprotein substrates, inhibitors and inducers. Drug Metab Rev 2002; 34: 47-54.
21. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008; 64: 43-50.
22. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Deliv Rev 1997; 15: 201-14.
23. Dingemanse J, Schaarschmidt D, van Gierbergen PLM. Bosentan, a dual endothelin receptor antagonist, is a mild inducer of the metabolism of simvastatin. Clin Pharmacol Ther 2002; 71: P45.
24. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol 2008; 48(5): 610-8.
25. Humbert M, Segal ES, Kiely DG, Carisen J, Schwierin B, Hoeper MM. Results of the European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30: 338-44.
26. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1998; 332: 411-5.
27. Takahashi M, Matshushita Y, Iijima K, Tanzawa K. Purification and characterization of endothelin-converting enzyme from rat lung. J Biol Chem 1993; 268: 21394-8.
28. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, et al. The human endothelin family: Three structurally and pharmacologically dinstinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 1989; 86: 2863-7.
29. Firth JD, Ratcliffe PJ. Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest 1992; 90: 1023-31.
30. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004; 61: 227-37.
31. Davie N, Hallen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, et al. ETA and ETB receptors modulate the proliferation of human smooth muscle cells. Am J Respir Crit Care Med 2002; 165: 398-405.
32. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou- Gharios G, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a RAC/phosphoinositide 3- kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 2004; 15: 2707-19.
33. Prefontaine A, Calderone A, Dupuis J. Role of endothelin receptors on basal and endothelin-1-stimulated lung myofibroblast proliferation. Can J Physiol Pharmacol 2008; 86: 337-42.
34. Shi-Wen X, Rodriguez-Pascual F, Lamas S, Holmes A, Howat S, Pearson JD, et al. Constitutive ALK5-independent c-Jun Nterminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: Evidence of an autocrine endothelin loop operating through the endothelin A and B receptors. Mol Cell Biol 2006; 26: 5518-27.
35. Eguchi S, Hirata Y, Imai T, Marumo F. Endothelin-1 as an autocrine growth factor for endothelial cells. J Cardiovasc Pharmacol 1995; 26: S279-83.
36. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 62S-7S.
37. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990; 85: 587-90.
38. Matsumoto H, Suzuki N, Onda H, Fujino M. Abundance of endothelin-3 in rat intestine, pituitary gland and brain. Biochem Biophys Res Commun 1989; 164: 74-80.
39. Dupuis J, Goresky CA, Stewart DJ. Pulmonary removal and production of endothelin in the anesthetized dog. J Appl Physiol 1994; 76: 694-700.
40. Dupuis J, Stewart DJ, Cernacek P, Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation 1996; 94: 1578-84.
41. Michel RP, Langleben D, Dupuis J. The endothelin system in pulmonary hypertension. Can J Physiol Pharmacol 2003; 81: 542-54.
42. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732-9.
43. Bressollette E, Dupuis J, Bonan R, Doucet S, Cernacek P, Tardif JC. Intravascular ultrasound assessment of pulmonary vascular disease in patients with pulmonary hypertension. Chest 2001; 120: 809-15.
44. Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001; 120: 1562-9.
45. Migneault A, Sauvageau S, Villeneuve L, Thorin E, Fournier A, Leblanc N, et al. Chronically elevated endothelin levels reduce pulmonary vascular reactivity to nitric oxide. Am J Respir Crit Care Med 2005; 171: 506-13.
46. Humbert M, Simonneau G. Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic disease. Nat Clin Pract Rheumatol 2005; 1: 93-101.
47. Hocher B, Schwarz A, Fagan KA, Thöne-Reineke C, El-Hag K, Kusserow H, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 2000; 23: 19-26.
48. Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a Cdna encoding an endothelin receptor. Nature 1990; 348: 730-2.
49. Sakurai T, Yanagisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, et al. Cloning of a CDNA encoding a non-isopeptideselective subtype of the endothelin receptor. Nature 1990; 348: 732-4.
50. Eguchi S, Kozuka M, Hirose S, Ito T, Hirata Y, Marumo F, et al. Identification of G protein-coupled endothelin receptors in cultured bovine endothelial cells. Biochem Biophys Res Commun 1991; 174: 1343-6.
51. Knott PG, D'Aprile AC, Henry PJ, Hay DW, Goldie RG. Receptors for endothelin-1 in asthmatic human peripheral lung. Br J Pharmacol 1995; 114: 1-3.
52. Sham JK, Crenshaw BR, Deng LH, Shimoda LA, Sylvester JT. Effects of hypoxia in porcine pulmonary arterial myocytes: Role of Kv channel and endothelin-1. Am J Physiol 2000; 279: 262-72.
53. Iwamuro Y, Miwa S, Zhang XF, Minowa T, Enoki T, Okamoto Y, et al. Activation of three types of voltage-independent Ca2+ channel in A7r5 cells by endothelin-1 as revealed by a novel Ca channel blocker, LOE 908. Br J Pharmacol 1999; 126: 1107-14.
54. Clarke JG, Benjamin N, Larkin SW, Webb DJ, Davies GJ, Maseri A. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989; 257: 2033-5.
55. Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993; 91: 1367-73.
56. de Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, et al. Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1988; 85: 9797-800.
57. Dupuis J, Hoeper M. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008; 31: 407-15.
58. Luengo, J.I., Elliott, J.D. Endothelin receptor antagonists. US10072614 (2002).
59. Michel RP, Langleben D, Dupuis J. The endothelin system in pulmonary hypertension. Can J Physiol Pharmacol 2003; 81: 542-54.
60. Prie S, Stewart DJ, Dupuis J. EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotalineinduced pulmonary hypertension. Circulation 1998; 97: 2169-74.
61. Dupuis J, Prie S. The ETA-receptor antagonist LU 135252 prevents the progression of established pulmonary hypertension induced by monocrotaline in rats. J Cardiovasc Pharmacol 1999; 4: 33-9.
62. Prie S, Leung TK, Cernacek P, Ryan JW, Dupuis J. The orally active ETA receptor antagonist (+)-(S)-2-(4,6- dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats. J Pharmacol Exp Ther 1997; 282: 1312-8.
63. Chen SJ, Chen YF, Meng QC, Durand J, Dicarlo VS, Oparil S. Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995; 79: 2122-31.
64. Muramatsu M, Rodman DM, Oka M, Mcmurtry IF. Endothelin-1 mediates nitro-8-L-arginine vasoconstriction of hypertensive rat lungs. Am J Physiol 1997; 272: 807-12.
65. Attina T, Camidge R, Newby D, Webb D. Endothelin antagonism in pulmonary hypertension, heart failure, and beyond. Heart 2005; 91: 825-31.
66. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ambrisentan in pulmonary arterial hypertension, randomized, double blind, Placebo Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2. Circulation 2008; 117(23): 3010-9.
67. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxentan. JACC 2006; 47: 2049-56.
68. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903.
69. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115: 343-9.
70. McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244-9.
71. Denton CP, Pope JE, Peter HH, Gabrielli A, Boonstra A, van den Hoogen FH, et al. TRacleer Use in PAH associated with Scleroderma and Connective Tissue Diseases (TRUST) Investigators. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis 2008; 67: 1222-8.
72. Williams MH, Das C, Handler CE, Akram MR, Davar J, Denton CP, et al. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006; 92: 926-32.
73. Sitbon O, Lascoux-Combe C, Delfraissy JF, Yeni PG, Raffi F, De Zuttere D, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008; 177: 108-13
74. Ehrenreich H, Rieckmann P, Sinowatz F, Weih KA, Arthur LO, Goebel FD, et al. Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120. J Immunol 1993; 150: 4601-9.
75. Petitpretz P, Brenot F, Azarian R, Parent F, Rain B, Herve P, et al. Pulmonary hypertension in patients with human immunodeficiency virus infection: Comparison with primary pulmonary hypertension. Circulation 1994; 89: 2722-7.
76. Sitbon O, Gressin V, Speich R, Macdonald PS, Opravil M, Cooper DA, et al. Bosentan for the treatment of Human Immunodeficiency Virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2004; 170: 1212-7.
77. Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993; 71: 448-50.
78. Galie N, Beghetti M, Gatzoulis M, Granton J, Berger R, Lauer A, et al. Bosentan therapy in patients with Eisenmeger Syndrome. A multicenter, double blind, Randomized, placebo-controlled study. Circulation 2006; 114: 48-54.
79. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000; 161: 487-92.
80. Fine N, Dias B, Shoemaker G, Mehta S. Endothelin receptor antagonist therapy in congenital heart disease with shunt-associated pulmonary arterial hypertension; a qualitative systematic review. Can J Cardiol 2009; 25 (3): 63-8.
81. Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, et al. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: The future-1 study. Br Clin Pharmacol 2009; 68(3): 948-55.
82. Holman, L., Trenktrog, T. Dispersible bosertan tablet. US200810193528 (2008).
83. Brenot F. Primary Pulmonary hypertension. Case series from France. Chest 1994; 105: 33S-6S.
84. Galiè N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (Early study): A double-blind, randomized controlled trial. Lancet 2008; 371: 2093-100.
85. Gruenig E, Michelakis E, Vachiéry JL, Vizza CD, Meyer FJ, Doelberg M, et al. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: Results of the COMPASS 1 Study. J Clin Pharmacol 2009; 49: 1343-52.
86. Hoeper MM, Faulenbach C, Golpon H, Winkler J, Welte T, Niedermeyer J. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004; 24(6): 1007-10.
87. Iversen K, Jensen AS, Jensen TV, Vejlstrup NG, Søndergaard L. Combination therapy with bosentan and sildenafil in Eisenmenger syndrome: A randomized, placebo-controlled, double-blinded trial. Eur Heart J 2010; 31: 1124-31.
88. Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Pulmonary arterial hypertension and response to tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119(22): 2894-903.
89. Frost AE, Langleben D, Oudiz R, Hill N, Horn E, McLaughlin V, et al. The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: Demonstration of a ceiling effect. Vascul Pharmacol 2005; 43(1): 36-9.
90. Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24: 353-9.
91. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 125763.
92. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159(1): 158-64.
93. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J, Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981; 36(10): 752-8.
94. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J 2008; 32(3): 619-28.
95. Chaouat A, Bugnet AS, Kadaoui N, Schott R, Enache I, Ducoloné A, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005 15; 172(2): 189-94.
96. Gray GA, Webb DJ. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther 1996; 72(2): 109-48.
97. Mylona P, Cleland JG. Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team. Eur J Heart Fail 1999; 1(2): 197-200.
98. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol 2002; 85(2-3): 195-7.
99. Jiang BH, Tardif JC, Shi Y, Dupuis J. Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure. Eur Respir J 2010 Jul 1 [Epub ahead of print].
100. Sata, K., Pandey, B. Process for preparation of bosentan. WO2010032261(2010).
101. Dixit, G., Gaikwad, N., Naidu, H.P., Pradhan, N.S., Valgeirsson, J. Novel polymorphs of bosentan. EP2205591 (2010).
102. Gaitonde, A., Manojkumar, B., Sonawane, S., Kokane, D., Mekde, S., Shinde, D, Bansode, P. Process for introduction of hydroxyethoxy side chain in bosentan. EP2170841 (2010).
103. Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D, Burns N, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007; 30; 100(6): 923-9.
104. Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007; 49(2): 85-9.
105. Mouchaers KT, Schalij I, de Boer MA, Postmus PE, van Hinsbergh VW, Van Nieuw Amerongen GP, et al. Effective reduction of MCT-PAH by Fasudil. Comparison with bosentan and sildenafil. Eur Respir J 2010 [Epub ahead of print].
106. Fong, B. Fasudil in combination with bosentan for the treatment of pulmonary arterial hypertension. EP2111863 (2009).
107. Fong, B. Fasudil en polytherapies pour traiter l' hypertension arterielle pulmonaire. EP1951253 (2010).
108. Bodin, F. Pharmaceutical composition for the treatment of Pulmonary arterial hypertension. US20040102361 (2004).
109. Bolli, M., Boss, C., Clozel, M., Fischli, W., Weller, T. Pyrimidinesulfamides and their use as endothelian receptor antagonist. US7452896 (2008).
110. Ashton, W.T., Chang, L.L., Greenlee, W.J. Endothelin antagonists bearing 5-membered heterocyclic amides. US5538991 (1996).
111. Bolli, M., Boss, C., Clozel, M., Fischli, W., Weller, T. Sulfamides and their use as endothelin receptor antagonists. US7094781 (2006).
112. Martin, B.M., Boss C., Fischli W., Clozel M., Weller T. Sulfamides and their use as endothelin receptor antagonists. US7285549 (2007).