The molecular targets of approved treatments for pulmonary arterial hypertension

Thorax

Volumn 71, Issue 1, 2016, Pages 73-83

  Humbert, Marc ^a,b,c   Ghofrani, Hossein Ardeschir ^d,e  

^a BICÊTRE HOSPITAL   (France)

^b UNIVERSITÉ PARIS SACLAY   (France)

^c INSERM   (France)

^d JUSTUS LIEBIG UNIVERSITY GIESSEN   (Germany)

^e IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AMBRISENTAN; BERAPROST; BOSENTAN; ENDOTHELIN 1; ILOPROST; MACITENTAN; PHOSPHODIESTERASE V INHIBITOR; PROSTACYCLIN; PROSTANOID; RIOCIGUAT; SELEXIPAG; SILDENAFIL; TADALAFIL; TREPROSTINIL; ANTIHYPERTENSIVE AGENT; ENDOTHELIN RECEPTOR ANTAGONIST; PHOSPHODIESTERASE INHIBITOR; PROSTAGLANDIN; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE;

ANEMIA; CLINICAL TRIAL (TOPIC); COUGHING; DIARRHEA; DISEASE EXACERBATION; DIZZINESS; DRUG EFFICACY; DRUG INDICATION; DRUG RESPONSE; DRUG SAFETY; DRUG TARGETING; DYSPEPSIA; GASTROINTESTINAL HEMORRHAGE; HEADACHE; HOT FLUSH; HUMAN; INJECTION SITE BLEEDING; INJECTION SITE PAIN; INJECTION SITE REACTION; JAW PAIN; LEG EDEMA; LIVER DYSFUNCTION; MYALGIA; NAUSEA; NOSE OBSTRUCTION; PERIPHERAL EDEMA; PRIORITY JOURNAL; PULMONARY HYPERTENSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHINOPHARYNGITIS; SORE THROAT; THROAT IRRITATION; COMBINATION DRUG THERAPY; DRUG INTERACTION; HYPERTENSION, PULMONARY;

ANTIHYPERTENSIVE AGENTS; DRUG INTERACTIONS; DRUG THERAPY, COMBINATION; ENDOTHELIN RECEPTOR ANTAGONISTS; HUMANS; HYPERTENSION, PULMONARY; PHOSPHODIESTERASE INHIBITORS; PROSTAGLANDINS; PYRAZOLES; PYRIMIDINES;

EID: 84958103114     PISSN: 00406376     EISSN: 14683296     Source Type: Journal    
DOI: 10.1136/thoraxjnl-2015-207170     Document Type: Review

References (91)

1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.
2. Voelkel NF, Gomez-Arroyo J, Abbate A, et al. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J 2012;40:1555-65.
3. McLaughlin VV, Archer SL, Badesch DB, 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. Circulation 2009;119:2250-94.
4. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-65.
5. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl):S20-31.
6. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36.
7. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13S-24S.
8. Humbert M. Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology. Eur Respir Rev 2010;19:59-63.
9. Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014;130:2189-208.
10. Benza RL, Miller DP, Barst RJ, et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from REVEAL. Chest 2012;142:448-56.
11. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-63.
12. Humbert M, Sitbon O, Yaici A, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010;36:549-55.
13. Conole D, Scott LJ. Riociguat: first global approval. Drugs 2013;73:1967-75.
14. Adempas® US prescribing information. 2013. http://labelingbayerhealthcare.com/html/products/pi/Adempas-PI.pdf
15. Bayer Pharma AG. Adempas® Canadian prescribing information. 2013. http://www.bayer.ca/files/ADEMPAS-PM-EN-17Sep2013-162761.pdf
16. Bayer Pharma AG. Adempas® (riociguat tablets): EU summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR---Product-Information/human/002737/WC500165034.pdf
17. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62:D60-72.
18. Taichman DB, Ornelas J, Chung L, et al. Pharmacological therapy for pulmonary arterial hypertension in adults: CHEST guideline. Chest 2014;146:449-75.
19. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990;112:485-91.
20. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-4.
21. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010;55:1915-22.
22. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:624-33.
23. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9.
24. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496-502.
25. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.
26. Galiè N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093-100.
27. Galiè N, Olschewski H, Oudiz RJ, 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;117:3010-19.
28. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809-18.
29. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57.
30. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-903.
31. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330-40.
32. McGoon MD, Frost AE, Oudiz RJ, et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009;135:122-9.
33. Rubin LJ, Badesch DB, Fleming TR, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest 2011;140:1274-83.
34. Oudiz RJ, Brundage BH, Galie N, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol 2012;60:768-74.
35. Rubin LJ, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015;45:1303-13.
36. Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep 2008;60:3-11.
37. Blindt R, Bosserhoff AK, vom Dahl J, et al. Activation of IP and EP(3) receptors alters cAMP-dependent cell migration. Eur J Pharmacol 2002;444:31-7.
38. Wharton J, Davie N, Upton PD, et al. Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells. Circulation 2000;102:3130-6.
39. Wallerstedt SM, Bodelsson M. Endothelium-dependent relaxation by substance P in human isolated omental arteries and veins: relative contribution of prostanoids, nitric oxide and hyperpolarization. Br J Pharmacol 1997;120:25-30.
40. Vane J, Corin RE. Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg 2003;26:571-8.
41. Li RC, Cindrova-Davies T, Skepper JN, et al. Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of endothelin-1 or basic fibroblast growth factor. Circ Res 2004;94:759-67.
42. Kothapalli D, Stewart SA, Smyth EM, et al. Prostacylin receptor activation inhibits proliferation of aortic smooth muscle cells by regulating cAMP response element-binding protein- and pocket protein-dependent cyclin a gene expression. Mol Pharmacol 2003;64:249-58.
43. Christman BW, Mcpherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary-hypertension. N Engl J Med 1992;327:70-5.
44. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925-32.
45. Barst R. How has epoprostenol changed the outcome for patients with pulmonary arterial hypertension? Int J Clin Pract Suppl 2010;64:23-32.
46. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82.
47. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003;41:2119-25.
48. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012;40:874-80.
49. Actelion. Selexipag. 2014. http://www.1actelion.com/en/scientists/development-pipeline/phase-3/selexipagpage
50. McLaughlin VV, Channick R, Chin KM, et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the GRIPHON study. J Am Coll Cardiol 2015;65.
51. Davie N, Haleen SJ, Upton PD, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 2002;165:398-405.
52. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9.
53. Rubin LJ. Endothelin receptor antagonists for the treatment of pulmonary artery hypertension. Life Sci 2012;91:517-21.
54. Frumkin LR. The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev 2012;64:583-620.
55. Seo B, Oemar BS, Siebenmann R, et al. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994;89:1203-8.
56. Hirata Y, Emori T, Eguchi S, et al. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 1993;91:1367-73.
57. Eguchi S, Hirata Y, Marumo F. Endothelin subtype B receptors are coupled to adenylate cyclase via inhibitory G protein in cultured bovine endothelial cells. J Cardiovasc Pharmacol 1993;22(Suppl 8):S161-3.
58. Humbert M, Segal ES, Kiely DG, et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007;30:338-44.
59. Opitz CF, Ewert R, Kirch W, et al. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J 2008;29:1936-48.
60. Seferian A, Simonneau G. Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow? Eur Respir Rev 2013;22:217-26.
61. Cardillo C, Kilcoyne CM, Waclawiw M, et al. Role of endothelin in the increased vascular tone of patients with essential hypertension. Hypertension 1999;33:753-8.
62. Oudiz RJ, Galiè N, Olschewski H, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:1971-81.
63. Kass DA, Takimoto E, Nagayama T, et al. Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 2007;75:303-14.
64. Corbin JD, Beasley A, Blount MA, et al. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun 2005;334:930-8.
65. Murray F, MacLean MR, Pyne NJ. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002;137:1187-94.
66. Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 2007;116:238-48.
67. Corbin JD, Francis SH. Molecular biology and pharmacology of PDE-5-inhibitor therapy for erectile dysfunction. J Androl 2003;24:S38-41.
68. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the international society of heart and lung transplantation (ISHLT). Eur Heart J 2009;30:2493-537.
69. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123:2263-73.
70. Zhao L, Mason NA, Strange JW, et al. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic peptide activity. Circulation 2003;107:234-7.
71. Ignarro LJ, Buga GM, Wood KS, et al. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84:9265-9.
72. Arnold WP, Mittal CK, Katsuki S, et al. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 1977;74:3203-7.
73. Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol 2013;218:279-313.
74. Follmann M, Griebenow N, Hahn MG, et al. The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angew Chem Int Ed Engl 2013;52:9442-62.
75. Schermuly RT, Stasch JP, Pullamsetti SS, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:881-91.
76. Stasch JP, Hobbs AJ. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 2009;191:277-308.
77. Galie N, Muller K, Scalise AV, et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 2015;45:1314-22.
78. Coeytaux RR, Schmit KM, Kraft B, et al. Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Chest 2014;145:1055-63.
79. Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol 2011;108:1177-82.
80. Bai Y, Sun L, Hu S, et al. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology 2011;120:157-65.
81. Manes A, Palazzini M, Tremblay G, et al. Combination therapy for pulmonary arterial hypertension (PAH) reduces consistently clinical worsening as compared to monotherapy: an updated meta-analysis of randomized controlled trials. Eur Heart J 2014;35 (Abstract supplement).
82. Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-9.
83. Galiè N. The AMBITION study: design and results. Eur Respir J 2014;44.
84. GlaxoSmithKline. A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) (AMBITION). 2015. https://clinicaltrials.gov/ct2/show/NCT01178073
85. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30.
86. Actelion. Study of macitentan (ACT-064992) on morbidity and mortality in patients with symptomatic pulmonary arterial hypertension. 2015. https://clinicaltrials.gov/ct2/show/NCT00660179
87. McLaughlin V, Channick R, Ghofrani H-A, et al. Effect of bosentan and sildenafil combination therapy on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the COMPASS-2 study. Chest 2014;146:860A.
88. Pfizer. Assess the efficacy and safety of sildenafil when added to bosentan in the treatment of pulmonary arterial hypertension. 2014. https://clinicaltrials.gov/ct2/show/study/NCT00323297
89. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:1257-63.
90. Benza RL, Gupta H, Soto FJ, et al. Safety and efficacy of bosentan in combination with sildenafil in PAH patients who experience inadequate clinical response to monotherapy: the COMPASS-3 Study. Chest 2010;138.
91. Tapson VF, Torres F, Kermeen F, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest 2012;142:1383-90.