Novel Therapeutic Approaches of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is an uncommon disease characterized progressive remodeling of pulmonary vasculature. Although treatment for PAH have improved in last two decades but the outcome remains fatal. Currently, the therapies for PAH target three well-established pathways the nitric oxide (NO) pathway, endothelin receptors, and prostanoids. There are multiple potential targets for development of newer drugs in PAH which requires meticulous research and clinical trials.

Keywords

pulmonary arterial hypertension - therapeutic - novel - phosphodiesterase - nitric oxide - prostaglandins - endothelin receptor

• References

• 1 Hoeper MM, Humbert M, Souza R. , et al. A global view of pulmonary hypertension. Lancet Respir Med 2016; 4 (04) 306-322
• 2 McLaughlin VV, Archer SL, Badesch DB. , et al; ACCF/AHA. 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 (16) 2250-2294
• 3 Simonneau G, Montani D, Celermajer DS. , et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53 (01) 1801913 [ https://doi.org/10.1183/13993003.01913-2018 ]
• 4 Bishop JM, Cross KW. Physiological variables and mortality in patients with various categories of chronic respiratory disease. Bull Eur Physiopathol Respir 1984; 20 (06) 495-500
• 5 Pepke-Zaba J, Delcroix M, Lang I. , et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124 (18) 1973-1981
• 6 Coghlan JG, Wolf M, Distler O. , et al. Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis. Eur Respir J 2018; 51 (04) 1701197
• 7 Ghofrani HA, Galiè N, Grimminger F. , et al. PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330-340
• 8 Rubin LJ, Galiè 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 (05) 1303-1313
• 9 Galiè N, Ghofrani HA, Torbicki A. , et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
• 10 Galiè N, Brundage BH, Ghofrani HA. , et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119 (22) 2894-2903 Circulation 2011;124(10):e279
• 11 Granton J, Langleben D, Kutryk MB. , et al. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: the PHACeT trial. Circ Res 2015; 117 (07) 645-654
• 12 Falcetti E, Hall SM, Phillips PG. , et al. Smooth muscle proliferation and role of the prostacyclin (IP) receptor in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 182 (09) 1161-1170
• 13 Akagi S, Nakamura K, Matsubara H. , et al. Epoprostenol therapy for pulmonary arterial hypertension. Acta Med Okayama 2015; 69 (03) 129-136
• 14 Simonneau G, Barst RJ, Galie N. , et al; Treprostinil Study Group. 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 (06) 800-804
• 15 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 (18) 1915-1922
• 16 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 (05) 624-633
• 17 Barst RJ, McGoon M, McLaughlin V. , et al; Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2003; 41 (12) 2119-2125
• 18 Galiè N, Humbert M, Vachiéry JL. , et al; Arterial Pulmonary Hypertension and Beraprost European (ALPHABET) Study Group. 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 (09) 1496-1502
• 19 Olschewski H, Simonneau G, Galiè N. , et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347 (05) 322-329
• 20 Galiè N, Channick R, Chin K. , et al. Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the GRIPHON study. J Am Coll Cardiol 2015; 34 (4, Suppl.): S163
• 21 Sitbon O, Channick R, Chin KM. , et al; GRIPHON Investigators. Selexipag for the treatment of pulmonary artery hypertension. N Engl J Med 2015; 373 (26) 2522-2533
• 22 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 (07) 1578-1584
• 23 Clozel M, Breu V, Burri K. , et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365 (6448): 759-761
• 24 Galié N, Badesch D, Oudiz R. , et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46 (03) 529-535
• 25 Iglarz M, Binkert C, Morrison K. , et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther 2008; 327 (03) 736-745
• 26 Pulido T, Adzerikho I, Channick RN. , et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369 (09) 809-818
• 27 Benedict N, Seybert A, Mathier MA. Evidence-based pharmacologic management of pulmonary arterial hypertension. Clin Ther 2007; 29 (10) 2134-2153
• 28 Galiè N, Channick RN, Frantz RP. , et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019; 53 (01) 1801889
• 29 Spiekerkoetter E, Sung YK, Sudheendra D. , et al. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J 2017; 50 (03) 1602449
• 30 Komrokji R, Garcia-Manero G, Ades L. , et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol 2018; 5 (02) e63-e72
• 31 Boucherat O, Chabot S, Paulin R. , et al. HDAC6: a novel histone deacetylase implicated in pulmonary arterial hypertension. Sci Rep 2017; 7 (01) 4546
• 32 Chun HJ, Bonnet S, Chan SY. Translational advances in the field of pulmonary hypertension. Translating microRNA biology in pulmonary hypertension. It will take more than “miR” words. Am J Respir Crit Care Med 2017; 195 (02) 167-178
• 33 Meloche J, Pflieger A, Vaillancourt M. , et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 2014; 129 (07) 786-797
• 34 Budas GR, Boehm M, Kojonazarov B. , et al. ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. Am J Respir Crit Care Med 2018; 197 (03) 373-385
• 35 Lu HI, Huang TH, Sung PH. , et al. Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice. Acta Pharmacol Sin 2016; 37 (05) 589-603
• 36 Piao L, Fang YH, Cadete VJ. , et al. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl) 2010; 88 (01) 47-60
• 37 Hansmann G, de Jesus Perez VA, Alastalo TP. , et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 2008; 118 (05) 1846-1857
• 38 Viethen T, Gerhardt F, Dumitrescu D. , et al. Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: a pilot study. Int J Cardiol 2014; 175 (02) 233-239
• 39 Dahal BK, Cornitescu T, Tretyn A. , et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 2010; 181 (02) 158-167
• 40 Hoeper MM, Barst RJ, Bourge RC. , et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127 (10) 1128-1138
• 41 Mouchaers KT, Schalij I, de Boer MA. , et al. Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil. Eur Respir J 2010; 36 (04) 800-807
• 42 Benza RL, Miller DP, Gomberg-Maitland M. , et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122 (02) 164-172
• 43 Ghofrani HA, Al-Hiti H, Vonk-Noordegraaf A. , et al. Proof-of-concept study to investigate the efficacy, hemodynamics and tolerability of terguride vs. placebo in subjects with pulmonary arterial hypertension: results of a double blind, randomised, prospective phase IIa study. Am J Respir Crit Care Med 2012; 185: A2496
• 44 Said SI. Vasoactive intestinal peptide in pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 185 (07) 786 , author reply 786
• 45 van Campen JS, de Boer K, van de Veerdonk MC. , et al. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. Eur Respir J 2016; 48 (03) 787-796
• 46 Tamura Y, Phan C, Tu L. , et al. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest 2018; 128 (05) 1956-1970
• 47 Diller GP, van Eijl S, Okonko DO. , et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 2008; 117 (23) 3020-3030