Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

详细信息    查看全文

• 作者：Marie-Camille Chaumais (1) (2) (3)
  Christophe Guignabert (2)
  Laurent Savale (2) (5)
  Xavier Ja茂s (2) (5)
  Ath茅na茂s Boucly (5)
  David Montani (2) (4) (5)
  G茅rald Simonneau (2) (4) (5)
  Marc Humbert (2) (4) (5)
  Olivier Sitbon (2) (4) (5) (6)
  
  1. Facult茅 de Pharmacie ; Univ. Paris-Sud ; Ch芒tenay Malabry ; France
  2. INSERM UMR_S 999 ; LabEx LERMIT ; Centre Chirurgical Marie Lannelongue ; Le Plessis-Robinson ; France
  3. AP-HP ; Service de Pharmacie ; D茅partement Hospitalo-Universitaire (DHU) Thorax Innovation ; H么pital Antoine B茅cl猫re ; Clamart ; France
  5. AP-HP ; Centre de R茅f茅rence de l鈥橦ypertension Pumonaire S茅v猫re ; D茅partement Hospitalo-Universitaire (DHU) Thorax Innovation ; Service de Pneumologie et ; H么pital Bic锚tre ; Le Kremlin-Bic锚tre ; France
  4. Facult茅 de M茅decine ; Univ. Paris-Sud ; Le Kremlin-Bic锚tre ; France
  6. Service de Pneumologie et Soins Intensifs ; H么pital Universitaire de Bic锚tre ; 78 ; rue du G茅n茅ral Leclerc ; 94270 ; Le Kremlin-Bic锚tre ; France
  
• 刊名：American Journal of Cardiovascular Drugs
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：15
• 期：1
• 页码：13-26
• 全文大小：782 KB
• 参考文献：1. O鈥機allaghan DS, Savale L, Montani D, Jais X, Sitbon O, Simonneau G, Humbert M. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol. 2011;8:526鈥?8. CrossRef
  2. Stevens T. Functional and molecular heterogeneity of pulmonary endothelial cells. Proc Am Thorac Soc. 2011;8:453鈥?. 513/pats.201101-004MW" target="_blank" title="It opens in new window">CrossRef
  3. Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J. 1992;5:757鈥?2.
  4. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:13S鈥?4S. CrossRef
  5. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M. An antiproliferative bmp-2/ppargamma/apoe axis in human and murine smcs and its role in pulmonary hypertension. J Clin Investig. 2008;118:1846鈥?7. 503" target="_blank" title="It opens in new window">CrossRef
  6. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S20鈥?1. CrossRef
  7. Guignabert C, Tu L, Le Hiress M, Ricard N, Sattler C, Seferian A, Huertas A, Humbert M, Montani D. Pathogenesis of pulmonary arterial hypertension: lessons from cancer. Eur Respir Rev. 2013;22:543鈥?1. 59180.00007513" target="_blank" title="It opens in new window">CrossRef
  8. Tu L, Dewachter L, Gore B, Fadel E, Dartevelle P, Simonneau G, Humbert M, Eddahibi S, Guignabert C. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45:311鈥?2. 5/rcmb.2010-0317OC" target="_blank" title="It opens in new window">CrossRef
  9. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, Drazba J, Anand-Apte B, Erzurum SC. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2007;293:L548鈥?4. 52/ajplung.00428.2006" target="_blank" title="It opens in new window">CrossRef
  10. Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier-Mur AM, Simonneau G, Hamon M, Naeije R, Eddahibi S. Angiopoietin/tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1025鈥?3. CrossRef
  11. de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, Francois C, Schalij I, Dorfmuller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780鈥?. CrossRef
  12. de Man FS, Handoko ML, Guignabert C, Bogaard HJ, Vonk-Noordegraaf A. Neurohormonal axis in patients with pulmonary arterial hypertension: friend or foe? Am J Respir Crit Care Med. 2013;187:14鈥?. CrossRef
  13. Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S, Guignabert C, Humbert M. Leptin and regulatory t-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J. 2012;40:895鈥?04. 59911" target="_blank" title="It opens in new window">CrossRef
  14. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RM, Stuehr DJ, Erzurum SC. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Nat Acad Sci USA. 2007;104:1342鈥?. 5080104" target="_blank" title="It opens in new window">CrossRef
  15. Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Nat Acad Sci USA. 1989;86:2863鈥?. CrossRef
  16. Clozel M, Breu V, Gray GA, Kalina B, Loffler BM, Burri K, Cassal JM, Hirth G, Muller M, Neidhart W, et al. Pharmacological characterization of bosentan, a new potent orally active nonpeptide endothelin receptor antagonist. J Pharmacol Exp Ther. 1994;270:228鈥?5.
  17. Dingemanse J, van Giersbergen PL. Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet. 2004;43:1089鈥?15. 5/00003088-200443150-00003" target="_blank" title="It opens in new window">CrossRef
  18. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ. 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鈥?9. CrossRef
  19. Markewitz BA, Farrukh IS, Chen Y, Li Y, Michael JR. Regulation of endothelin-1 synthesis in human pulmonary arterial smooth muscle cells. Effects of transforming growth factor-beta and hypoxia. Cardiovasc Res. 2001;49:200鈥?. CrossRef
  20. Eguchi S, Hirata Y, Imai T, Marumo F. Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature. Endocrinology. 1993;132:524鈥?.
  21. Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF. Both eta and etb receptors mediate contraction to endothelin-1 in human blood vessels. Circulation. 1994;89:1203鈥?. CrossRef
  22. Masaki T. Possible role of endothelin in endothelial regulation of vascular tone. Annu Rev Pharmacol Toxicol. 1995;35:235鈥?5. 5.040195.001315" target="_blank" title="It opens in new window">CrossRef
  23. Hall SM, Davie N, Klein N, Haworth SG. Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment. Eur Respir J. 2011;38:851鈥?0. CrossRef
  24. Kim NH, Rubin LJ. Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther. 2002;7:9鈥?9. CrossRef
  25. Nagendran J, Sutendra G, Paterson I, Champion HC, Webster L, Chiu B, Haromy A, Rebeyka IM, Ross DB, Michelakis ED. Endothelin axis is upregulated in human and rat right ventricular hypertrophy. Circ Res. 2013;112:347鈥?4. CrossRef
  26. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732鈥?. 56/NEJM199306173282402" target="_blank" title="It opens in new window">CrossRef
  27. Cacoub P, Dorent R, Nataf P, Carayon A, Riquet M, Noe E, Piette JC, Godeau P, Gandjbakhch I. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res. 1997;33:196鈥?00. CrossRef
  28. Dupuis J, Cernacek P, Tardif JC, Stewart DJ, Gosselin G, Dyrda I, Bonan R, Crepeau J. Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension. Am Heart J. 1998;135:614鈥?0. 5" target="_blank" title="It opens in new window">CrossRef
  29. Silva Marques J, Martins SR, Calisto C, Goncalves S, Almeida AG, de Sousa JC, Pinto FJ, Diogo AN. An exploratory panel of biomarkers for risk prediction in pulmonary hypertension: emerging role of ct-proet-1. J Heart Lung Transplant. 2003;32:1214鈥?1. CrossRef
  30. Montani D, Souza R, Binkert C, Fischli W, Simonneau G, Clozel M, Humbert M. Endothelin-1/endothelin-3 ratio: A potential prognostic factor of pulmonary arterial hypertension. Chest. 2007;131:101鈥?. CrossRef
  31. Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, Hoeffken G. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest. 2001;120:1562鈥?. 5.1562" target="_blank" title="It opens in new window">CrossRef
  32. Frasch HF, Marshall C, Marshall BE. Endothelin-1 is elevated in monocrotaline pulmonary hypertension. Am J Physiol. 1999;276:L304鈥?0.
  33. Stelzner TJ, O鈥橞rien RF, Yanagisawa M, Sakurai T, Sato K, Webb S, Zamora M, McMurtry IF, Fisher JH. Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol. 1992;262:L614鈥?0.
  34. Miyauchi T, Yorikane R, Sakai S, Sakurai T, Okada M, Nishikibe M, Yano M, Yamaguchi I, Sugishita Y, Goto K. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res. 1993;73:887鈥?7. 5.887" target="_blank" title="It opens in new window">CrossRef
  35. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J. 2008;31:407鈥?5. CrossRef
  36. Barst RJ. Sitaxsentan: a selective endothelin-a receptor antagonist, for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2007;8:95鈥?09. 517/14656566.8.1.95" target="_blank" title="It opens in new window">CrossRef
  37. EMA. Thelin (sitaxentan) to be withdrawn due to cases of unpredictable serious liver injury. 2010. 500099707.pdf" class="a-plus-plus">http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/12/WC500099707.pdf.
  38. Lavelle A, Sugrue R, Lawler G, Mulligan N, Kelleher B, Murphy DM, Gaine SP. Sitaxentan-induced hepatic failure in two patients with pulmonary arterial hypertension. Eur Respir J. 2009;34:770鈥?. 58409" target="_blank" title="It opens in new window">CrossRef
  39. Lee WT, Kirkham N, Johnson MK, Lordan JL, Fisher AJ, Peacock AJ. Sitaxentan-related acute liver failure in a patient with pulmonary arterial hypertension. Eur Respir J. 2011;37:472鈥?. CrossRef
  40. Hoeper MM. Liver toxicity: the achilles鈥?heel of endothelin receptor antagonist therapy? Eur Respir J. 2009;34:529鈥?0. CrossRef
  41. Clozel M, Breu V, Burri K, Cassal JM, Fischli W, Gray GA, Hirth G, Loffler BM, Muller M, Neidhart W, et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature. 1993;365:759鈥?1. 5759a0" target="_blank" title="It opens in new window">CrossRef
  42. Wilkins MR. Selective or nonselective endothelin receptor blockade in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:433鈥?. CrossRef
  43. Riechers H, Albrecht HP, Amberg W, Baumann E, Bernard H, Bohm HJ, Klinge D, Kling A, Muller S, Raschack M, Unger L, Walker N, Wernet W. Discovery and optimization of a novel class of orally active nonpeptidic endothelin-a receptor antagonists. J Med Chem. 1996;39:2123鈥?. CrossRef
  44. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ. 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;117:3010鈥?. 510" target="_blank" title="It opens in new window">CrossRef
  45. Beghetti M, Haworth SG, Bonnet D, Barst RJ, Acar P, Fraisse A, Ivy DD, Jais X, Schulze-Neick I, Galie N, Morganti A, Dingemanse J, Kusic-Pajic A, Berger RM. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: The future-1 study. Br J Clin Pharmacol. 2009;68:948鈥?5. 5-2125.2009.03532.x" target="_blank" title="It opens in new window">CrossRef
  46. Gutierrez MM, Nicolas LB, Donazzolo Y, Dingemanse J. Relative bioavailability of a newly developed pediatric formulation of bosentan vs. The adult formulation. Int J Clin Pharmacol Ther. 2013;51:529鈥?6. 5414/CP201806" target="_blank" title="It opens in new window">CrossRef
  47. Casserly B, Klinger JR. Ambrisentan for the treatment of pulmonary arterial hypertension. Drug Design Dev Ther. 2009;2:265鈥?0.
  48. Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, Frost AE, Zwicke D, Naeije R, Shapiro S, Olschewski H, Rubin LJ. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:529鈥?5. 5.04.050" target="_blank" title="It opens in new window">CrossRef
  49. GSK. Volibris-Summary of product characteristics-WC500053065-pdf.
  50. Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, Weller T, Bolli MH, Boss C, Buchmann S, Capeleto B, Hess P, Qiu C, Clozel M. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327:736鈥?5. CrossRef
  51. Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67:977鈥?4. CrossRef
  52. Sidharta PN, van Giersbergen PL, Dingemanse J. Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol. 2013;53:1131鈥?.
  53. Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica Fate Foreign Compounds Biol Syst. 2012;42:901鈥?0. 54.2012.664665" target="_blank" title="It opens in new window">CrossRef
  54. Sidharta PN, Lindegger N, Ulc I, Dingemanse J. Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment. J Clin Pharmacol. Epub 3 Oct 2013.
  55. Dingemanse J, van Giersbergen PL, Patat A, Nilsson PN. Mutual pharmacokinetic interactions between bosentan and lopinavir/ritonavir in healthy participants. Antivir Ther. 2010;15:157鈥?3. 51/IMP1506" target="_blank" title="It opens in new window">CrossRef
  56. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64:43鈥?0. CrossRef
  57. Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C. Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol. 2012;52:1784鈥?05. CrossRef
  58. Frampton JE. Ambrisentan. Am J Cardiovasc Drugs. 2011;11:215鈥?6. 5/11207340-000000000-00000" target="_blank" title="It opens in new window">CrossRef
  59. D鈥橝lto M. An update on the use of ambrisentan in pulmonary arterial hypertension. Ther Adv Respir Dis. 2012;6:331鈥?3. 53465812458014" target="_blank" title="It opens in new window">CrossRef
  60. Spence R, Mandagere A, Walker G, Dufton C, Boinpally R. Effect of steady-state ambrisentan on the pharmacokinetics of a single dose of the oral contraceptive norethindrone (norethisterone) 1聽mg/ethinylestradiol 35 microg in healthy subjects: an open-label, single-sequence, single-centre study. Clin Drug Investig. 2010;30:313鈥?4. 5/11534940-000000000-00000" target="_blank" title="It opens in new window">CrossRef
  61. Atsmon J, Dingemanse J, Shaikevich D, Volokhov I, Sidharta PN. Investigation of the effects of ketoconazole on the pharmacokinetics of macitentan, a novel dual endothelin receptor antagonist, in healthy subjects. Clin Pharmacokinet. 2013;52:685鈥?2. CrossRef
  62. Weiss J, Theile D, Ruppell MA, Speck T, Spalwisz A, Haefeli WE. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013;701:168鈥?5. CrossRef
  63. Bruderer S, Aanismaa P, Homery MC, Hausler S, Landskroner K, Sidharta PN, Treiber A, Dingemanse J. Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14:68鈥?8. CrossRef
  64. Sidharta PN, Dietrich H, Dingemanse J. Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Clin Drug Investig. 2014;34:545鈥?2. CrossRef
  65. Sidharta PN, van Giersbergen PL, Wolzt M, Dingemanse J. Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects. Br J Clin Pharmacol. Epub 24 Jun 2014.
  66. 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鈥?1.
  67. Clozel M, Hess P, Rey M, Iglarz M, Binkert C, Qiu C. Bosentan, sildenafil, and their combination in the monocrotaline model of pulmonary hypertension in rats. Exp Biol Med. 2006;231:967鈥?3.
  68. Choudhary G, Troncales F, Martin D, Harrington EO, Klinger JR. Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension. J Heart Lung Transplant. 2011;30:827鈥?3. CrossRef
  69. Yigitaslan S, Sirmagul B. Relation of bosentan, iloprost, and sildenafil with growth factor levels in monocrotaline-induced pulmonary hypertension. Clin Exp Hypertens. 2012;34:222鈥?. 52" target="_blank" title="It opens in new window">CrossRef
  70. Clozel M. Roux S [the pharmacology of endothelin and its antagonist bosentan]. Annales d鈥檈ndocrinologie. 2000;61:75鈥?.
  71. Filep JG, Fournier A, Foldes-Filep E. Acute pro-inflammatory actions of endothelin-1 in the guinea-pig lung: involvement of eta and etb receptors. Br J Pharmacol. 1995;115:227鈥?6. 5381.1995.tb15868.x" target="_blank" title="It opens in new window">CrossRef
  72. Guimaraes CL, Da-Silva S, Couture R, Rae GA. Mixed endothelin et(a) and et(b) antagonist bosentan inhibits oleic acid-induced lung plasma extravasation in mouse. J Cardiovasc Pharmacol. 2000;36:S371鈥?. 5344-200036051-00107" target="_blank" title="It opens in new window">CrossRef
  73. Karavolias GK, Georgiadou P, Gkouziouta A, Kariofillis P, Karabela G, Tsiapras D, Sbarouni E, Chaidaroglou A, Degiannis D, Adamopoulos S, Voudris V. Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: Relation to clinical and hemodynamic responses. Expert Opin Ther Targets. 2010;14:1283鈥?. 517/14728222.2010.523421" target="_blank" title="It opens in new window">CrossRef
  74. Uhlmann D, Gabel G, Ludwig S, Armann B, Hess J, Pietsch UC, Tannapfel A, Fiedler M, Kratzsch J, Hass J, Witzigmann H. Effects of et(a) receptor antagonism on proinflammatory gene expression and microcirculation following hepatic ischemia/reperfusion. Microcirculation. 2005;12:405鈥?9. 590960322" target="_blank" title="It opens in new window">CrossRef
  75. Gatfield J. Mueller Grandjean C, Sasse T, Clozel M, Nayler O. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PLoS One. 2012;7:e47662. CrossRef
  76. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119鈥?3. 50-X" target="_blank" title="It opens in new window">CrossRef
  77. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896鈥?03. 56/NEJMoa012212" target="_blank" title="It opens in new window">CrossRef
  78. Keogh AM, McNeil KD, Wlodarczyk J, Gabbay E, Williams TJ. Quality of life in pulmonary arterial hypertension: improvement and maintenance with bosentan. J Heart Lung Transplant. 2007;26:181鈥?. CrossRef
  79. Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (early study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093鈥?00. CrossRef
  80. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M. Bosentan Randomized Trial of Endothelin Antagonist Therapy I. Bosentan therapy in patients with eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48鈥?4. 5" target="_blank" title="It opens in new window">CrossRef
  81. Sitbon O, Gressin V, Speich R, Macdonald PS, Opravil M, Cooper DA, Fourme T, Humbert M, Delfraissy JF, Simonneau G. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;170:1212鈥?. 5OC" target="_blank" title="It opens in new window">CrossRef
  82. Savale L, Magnier R, Le Pavec J, Jais X, Montani D, O鈥機allaghan DS, Humbert M, Dingemanse J, Simonneau G, Sitbon O. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur Respir J. 2013;41:96鈥?03. 511" target="_blank" title="It opens in new window">CrossRef
  83. Hislop AA, Moledina S, Foster H, Schulze-Neick I, Haworth SG. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38:70鈥?. 53510" target="_blank" title="It opens in new window">CrossRef
  84. Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697鈥?04. 5.01.066" target="_blank" title="It opens in new window">CrossRef
  85. Oudiz RJ, Galie N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ, Group AS. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:1971鈥?1. CrossRef
  86. Klinger JR, Oudiz RJ, Spence R, Despain D, Dufton C. Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. Am J Cardiol. 2011;108:302鈥?. CrossRef
  87. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809鈥?8. 56/NEJMoa1213917" target="_blank" title="It opens in new window">CrossRef
  88. Benedict N, Seybert A, Mathier MA. Evidence-based pharmacologic management of pulmonary arterial hypertension. Clin Ther. 2007;29:2134鈥?3. CrossRef
  89. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther. 2001;69:223鈥?1. CrossRef
  90. Hartman JC, Brouwer K, Mandagere A, Melvin L, Gorczynski R. Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes. Can J Physiol Pharmacol. 2010;88:682鈥?1. CrossRef
  91. Markova SM, De Marco T, Bendjilali N, Kobashigawa EA, Mefford J, Sodhi J, Le H, Zhang C, Halladay J, Rettie AE, Khojasteh C, McGlothlin D, Wu AH, Hsueh WC, Witte JS, Schwartz JB, Kroetz DL. Association of cyp2c9*2 with bosentan-induced liver injury. Clin Pharmacol Ther. 2013;94:678鈥?6. CrossRef
  92. Roustit M, Fonrose X, Montani D, Girerd B, Stanke-Labesque F, Gonnet N, Humbert M, Cracowski JL. Cyp2c9, slco1b1, slco1b3, and abcb11 polymorphisms in patients with bosentan-induced liver toxicity. Clin Pharmacol Ther. 2014;95:583鈥?. CrossRef
  93. Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of european post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007;30:338鈥?4. CrossRef
  94. McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin VV, Gerber MJ, Dufton C, Despain DJ, Rubin LJ. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009;135:122鈥?. CrossRef
  95. Ben-Yehuda O, Pizzuti D, Brown A, Littman M, Gillies H, Henig N, Peschel T. Long-term hepatic safety of ambrisentan in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2012;60:80鈥?. 5" target="_blank" title="It opens in new window">CrossRef
  96. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, Iglarz M, Meyer S, Rein J, Rey M, Treiber A, Clozel M, Fischli W, Weller T. The discovery of n-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-n鈥?p ropylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist. J Med Chem. 2012;55:7849鈥?1. CrossRef
  97. Trow TK, Taichman DB. Endothelin receptor blockade in the management of pulmonary arterial hypertension: Selective and dual antagonism. Respir Med. 2009;103:951鈥?2. CrossRef
  98. Schirger JA, Chen HH, Jougasaki M, Lisy O, Boerrigter G, Cataliotti A, Burnett JC Jr. Endothelin a receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention. Circulation. 2004;109:249鈥?4. 5.EB" target="_blank" title="It opens in new window">CrossRef
  99. Vercauteren M, Strasser D, Vezzali E, Stalder A, Iglarz M, Hess P, Clozel M. Vasopressin is involved in endothelin receptor antagonist-induced fluid retention in rat. Differential effect of selective eta and dual eta/etb receptor antagonists. Eur Respir J. 2012; 40 (Suppl 56): P3898.
  100. Maron BA, Waxman AB, Opotowsky AR, Gillies H, Blair C, Aghamohammadzadeh R, Loscalzo J, Leopold JA. Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension [from the (aries) study 1 and 2 trials. Am J Cardiol. 2013;112:720鈥?. 51" target="_blank" title="It opens in new window">CrossRef
  101. Dhillon S, Keating GM. Bosentan: A review of its use in the management of mildly symptomatic pulmonary arterial hypertension. Am J Cardiovasc Drugs. 2009;9:331鈥?0. 5/11202270-000000000-00000" target="_blank" title="It opens in new window">CrossRef
  102. GSK. First-line combination of ambrisentan and tadalafil reduces risk of clinical failure compared to monotherapy in pulmonary arterial hypertension outcomes study [press release]. Gilead Sciences, Inc.; 2014.
  
• 刊物主题：Cardiology; Pharmacotherapy; Pharmacology/Toxicology;
• 出版者：Springer International Publishing
• ISSN：1179-187X

文摘

Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH.