Selexipag for the treatment of pulmonary arterial hypertension

References

• Galie N, Humbert M, Vachiery JL, et al. ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37:67–119.
   PubMed Web of Science ®Google Scholar
• Humbert M, Ghofrani HA. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71:73–83.
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319–329.
   PubMed Web of Science ®Google Scholar
• Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79:1193–1226.
   PubMed Web of Science ®Google Scholar
• Alfranca A, Iniguez MA, Fresno M, et al. Prostanoid signal transduction and gene expression in the endothelium: role in cardiovascular diseases. Cardiovasc Res. 2006;70:446–456.
   PubMed Web of Science ®Google Scholar
• Norel X. Prostanoid receptors in the human vascular wall. ScientificWorldJournal. 2007;7:1359–1374.
   PubMed Web of Science ®Google Scholar
• Benyahia C, Boukais K, Gomez I, et al. A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor. Prostaglandins Other Lipid Mediat. 2013;107:48–55.
   PubMed Web of Science ®Google Scholar
• Gryglewski RJ. Prostacyclin among prostanoids. Pharmacol Rep. 2008;60:3–11.
   PubMed Web of Science ®Google Scholar
• Woodward DF, Jones RL, Narumiya S. International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev. 2011;63:471–538.
   PubMed Web of Science ®Google Scholar
• Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev. 1994;46:205–229.
   PubMed Web of Science ®Google Scholar
• 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;102:3130–3136.
   PubMed Web of Science ®Google Scholar
• Vane J, Corin RE. Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg. 2003;26:571–578.
   PubMed Web of Science ®Google Scholar
• 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;94:759–767.
   PubMed Web of Science ®Google Scholar
• Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004;103:147–166.
   PubMed Web of Science ®Google Scholar
• DeWitt DL, Day JS, Sonnenburg WK, et al. Concentrations of prostaglandin endoperoxide synthase and prostaglandin I2 synthase in the endothelium and smooth muscle of bovine aorta. J Clin Invest. 1983;72:1882–1888.
   PubMed Web of Science ®Google Scholar
• 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;159:1925–1932.
   PubMed Web of Science ®Google Scholar
• 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;327:70–75.
   PubMed Web of Science ®Google Scholar
• Walch L, Labat C, Gascard JP, et al. Prostanoid receptors involved in the relaxation of human pulmonary vessels. Br J Pharmacol. 1999;126:859–866.
   PubMed Web of Science ®Google Scholar
• Walch L, De Montpreville V, Brink C, et al. Prostanoid EP(1)- and TP-receptors involved in the contraction of human pulmonary veins. Br J Pharmacol. 2001;134:1671–1678.
   PubMed Web of Science ®Google Scholar
• Clapp LH, Gurung R. The mechanistic basis of prostacyclin and its stable analogues in pulmonary arterial hypertension: role of membrane versus nuclear receptors. Prostaglandins Other Lipid Mediat. 2015;120:56–71.
   PubMed Web of Science ®Google Scholar
• Morrison K, Ernst R, Hess P, et al. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther. 2010;335:249–255.
   PubMed Web of Science ®Google Scholar
• Lang IM, Gaine SP. Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension. Eur Respir Rev. 2015;24:630–641.
   PubMedGoogle Scholar
• Dey I, Lejeune M, Chadee K. Prostaglandin E2 receptor distribution and function in the gastrointestinal tract. Br J Pharmacol. 2006;149:611–623.
   PubMed Web of Science ®Google Scholar
• Gryglewski RJ, Korbut R, Ocetkiewicz A. Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature. 1978;273:765–767.
   PubMed Web of Science ®Google Scholar
• Rubin LJ, Groves BM, Reeves JT, et al. Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation. 1982;66:334–338.
   PubMed Web of Science ®Google Scholar
• 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;112:485–491.
   PubMed Web of Science ®Google Scholar
• Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301.
   PubMed Web of Science ®Google Scholar
• Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest. 2006;129:683–688.
   PubMed Web of Science ®Google Scholar
• Hoeper MM, Gall H, Seyfarth HJ, et al. Long-term outcome with intravenous iloprost in pulmonary arterial hypertension. Eur Respir J. 2009;34:132–137.
   PubMed Web of Science ®Google Scholar
• Knudsen L, Schurawlew A, Nickel N, et al. Long-term effects of intravenous iloprost in patients with idiopathic pulmonary arterial hypertension deteriorating on non-parenteral therapy. BMC Pulm Med. 2011;11:56.
   PubMed Web of Science ®Google Scholar
• Ewert R, Halank M, Bruch L, et al. A case series of patients with severe pulmonary hypertension receiving an implantable pump for intravenous prostanoid therapy. Am J Respir Crit Care Med. 2012;186:1196–1198.
   PubMed Web of Science ®Google Scholar
• Bourge RC, Waxman AB, Gomberg-Maitland M, et al. Treprostinil administered to treat pulmonary arterial hypertension using a fully implantable programmable intravascular delivery system. Chest. 2016;150:27–34.
   PubMed Web of Science ®Google Scholar
• McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41:293–299.
   PubMed Web of Science ®Google Scholar
• Kitterman N, Poms A, Miller DP, et al. Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY(R). Mayo Clin Proc. 2012;87:825–834.
   PubMed Web of Science ®Google Scholar
• Rich JD, Glassner C, Wade M, et al. The effect of diluent pH on bloodstream infection rates in patients receiving IV treprostinil for pulmonary arterial hypertension. Chest. 2012;141:36–42.
   PubMed Web of Science ®Google Scholar
• Keusch S, Speich R, Treder U, et al. Central venous catheter infections in outpatients with pulmonary hypertension treated with continuous iloprost. Respiration. 2013;86:402–406.
   PubMed Web of Science ®Google Scholar
• Kingman MS, Tankersley MA, Lombardi S, et al. Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey. J Heart Lung Transplant. 2010;29:841–846.
   PubMed Web of Science ®Google Scholar
• Sammut D, Elliot CA, Kiely DG, et al. Central venous catheter-related blood stream infections in patients receiving intravenous iloprost for pulmonary hypertension. Eur J Clin Microbiol Infect Dis. 2013;32:883–889.
   PubMed Web of Science ®Google Scholar
• Farber HW, Miller DP, Meltzer LA, et al. Treatment of patients with pulmonary arterial hypertension at the time of death or deterioration to functional class IV: insights from the REVEAL registry. J Heart Lung Transplant. 2013;32:1114–1122.
   PubMed Web of Science ®Google Scholar
• Steffen RP, De La Mata M. The effects of I5AU8I, a chemically stable prostacyclin analog, on the cardiovascular and renin-angiotensin systems of anesthetized dogs [corrected]. Prostaglandins Leukot Essent Fatty Acids. 1991;43:277–286.
   PubMed Web of Science ®Google Scholar
• McNulty MJ, Sailstad JM, Steffen RP. The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog. Prostaglandins Leukot Essent Fatty Acids. 1993;48:159–166.
   PubMed Web of Science ®Google Scholar
• 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;165:800–804.
   PubMed Web of Science ®Google Scholar
• Greig SL, Scott LJ, Plosker GL. Epoprostenol (Veletri(R), Caripul(R)): a review of its use in patients with pulmonary arterial hypertension. Am J Cardiovasc Drugs. 2014;14:463–470.
   PubMed Web of Science ®Google Scholar
• Walmrath D, Schneider T, Pilch J, et al. Aerosolised prostacyclin in adult respiratory distress syndrome. Lancet. 1993;342:961–962.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–329.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Ghofrani HA, Walmrath D, et al. Recovery from circulatory shock in severe primary pulmonary hypertension (PPH) with aerosolization of iloprost. Intensive Care Med. 1998;24:631–634.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160:600–607.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Ghofrani HA, Schmehl T, et al. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med. 2000;132:435–443.
   PubMed Web of Science ®Google Scholar
• Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest. 2003;124:1294–1304.
   PubMed Web of Science ®Google Scholar
• 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;55:1915–1922.
   PubMed Web of Science ®Google Scholar
• Withdrawal report for Tyvaso (EMEA/CHMP/739698/2009). European Medicines Agency; 2009 [cited 2016 May 9]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/07/WC500095023.pdf
   Google Scholar
• Yuki H, Sato S, Arisaka Y, et al. Orally administered beraprost sodium inhibits pulmonary hypertension induced by monocrotaline in rats. Tohoku J Exp Med. 1994;173:371–375.
   PubMed Web of Science ®Google Scholar
• Okano Y, Yoshioka T, Shimouchi A, et al. Orally active prostacyclin analogue in primary pulmonary hypertension. Lancet. 1997;349:1365.
   PubMed Web of Science ®Google Scholar
• Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1188–1192.
   PubMed Web of Science ®Google Scholar
• Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2119–2125.
   PubMed Web of Science ®Google Scholar
• 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;39:1496–1502.
   PubMed Web of Science ®Google Scholar
• Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013;144:952–958.
   PubMed Web of Science ®Google Scholar
• 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;127:624–633.
   PubMed Web of Science ®Google Scholar
• 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;142:1383–1390.
   PubMed Web of Science ®Google Scholar
• Meanwell NA, Rosenfeld MJ, Trehan AK, et al. Nonprostanoid prostacyclin mimetics. 2. 4,5-Diphenyloxazole derivatives. J Med Chem. 1992;35:3483–3497.
   PubMed Web of Science ®Google Scholar
• Meanwell NA, Rosenfeld MJ, Trehan AK, et al. Nonprostanoid prostacyclin mimetics. 3. Structural variations of the diphenyl heterocycle moiety. J Med Chem. 1992;35:3498–3512.
   PubMed Web of Science ®Google Scholar
• Meanwell NA, Rosenfeld MJ, Wright JJ, et al. Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic. J Med Chem. 1992;35:389–397.
   PubMed Web of Science ®Google Scholar
• Skuballa W, Schillinger E, Sturzebecher CS, et al. Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity. J Med Chem. 1986;29:313–315.
   PubMed Web of Science ®Google Scholar
• Kuwano K, Hashino A, Asaki T, et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetam ide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther. 2007;322:1181–1188.
   PubMed Web of Science ®Google Scholar
• Whittle BJ, Silverstein AM, Mottola DM, et al. Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist. Biochem Pharmacol. 2012;84:68–75.
   PubMed Web of Science ®Google Scholar
• Asaki T, Kuwano K, Morrison K, et al. Selexipag: an oral and selective ip prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J Med Chem. 2015;58:7128–7137.
   PubMed Web of Science ®Google Scholar
• Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med. 2010;104:9–21.
   PubMed Web of Science ®Google Scholar
• Nakamura A, Yamada T, Asaki T. Synthesis and evaluation of N-acylsulfonamide and N-acylsulfonylurea prodrugs of a prostacyclin receptor agonist. Bioorg Med Chem. 2007;15:7720–7725.
   PubMed Web of Science ®Google Scholar
• Kuwano K, Hashino A, Noda K, et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetam ide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery. J Pharmacol Exp Ther. 2008;326:691–699.
   PubMed Web of Science ®Google Scholar
• Morrison K, Studer R, Ernst R, et al. Differential effects of selexipag [corrected] and prostacyclin analogs in rat pulmonary artery. J Pharmacol Exp Ther. 2012;343:547–555.
   PubMed Web of Science ®Google Scholar
• Benyahia C, Ozen G, Orie N, et al. Ex vivo relaxations of pulmonary arteries induced by prostacyclin mimetics are highly dependent of the precontractile agents. Prostaglandins Other Lipid Mediat. 2015;121:46–52.
   PubMed Web of Science ®Google Scholar
• Kaufmann P, Okubo K, Bruderer S, et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs. 2015;15:195–203.
   PubMed Web of Science ®Google Scholar
• Bruderer S, Hurst N, Kaufmann P, et al. Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. Pharmacology. 2014;94:148–156.
   PubMed Web of Science ®Google Scholar
• Baldoni D, Bruderer S, Muhsen N, et al. Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study. Int J Clin Pharmacol Ther. 2015;53:788–798.
   PubMed Web of Science ®Google Scholar
• Bruderer S, Okubo K, Mukai H, et al. Investigation of potential pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy male subjects. Clin Ther. 2016;38(5):1228–1236.e1.
   PubMed Web of Science ®Google Scholar
• 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;40:874–880.
   PubMed Web of Science ®Google Scholar
• Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med. 2015;373:2522–2533.
   PubMed Web of Science ®Google Scholar
• Hoch M, Darpo B, Remenova T, et al. A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug Des Devel Ther. 2015;9:175–185.
   PubMed Web of Science ®Google Scholar
• Uptravi®. Actelion; 2016 [cited 2016 Jul 9]. Available from: https://www1.actelion.com/en/healthcare-professionals/products/uptravi/index.page
   Google Scholar
• Drugs@FDA. [cited 2016 May 6]. Available from: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
   Google Scholar
• Uptravi. European Medicines Agency; 2016 [cited 2016 Jul 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003774/WC500207176.pdf
   Google Scholar
• Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–818.
   PubMed Web of Science ®Google Scholar
• Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373:834–844.
   PubMed Web of Science ®Google Scholar
• 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;182:1161–1170.
   PubMed Web of Science ®Google Scholar
• Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006;129:1636–1643.
   PubMed Web of Science ®Google Scholar
• Barst RJ, Galie N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195–1203.
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–340.
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Grimminger F, Grunig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016. Epub 2016 Apr 8. doi:10.1016/S2213-2600(16)30019-4.
   Web of Science ®Google Scholar
• The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON). Actelion; [cited 2016 May 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT02558231
   Google Scholar
• Beraprost-314d Added-on to Tyvaso® (BEAT). Lung Biotechnology PBC; [cited 2016 May 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT01908699
   Google Scholar
• Trial of the Early Combination of Oral Treprostinil With Background Oral Monotherapy in Subjects With Pulmonary Arterial Hypertension (FREEDOM-Ev). United Therapeutics; [cited 2016 May 6]. Available from: https://clinicaltrials.gov/ct2/show/NCT01560624
   Google Scholar
• Sitbon O, Sattler C, Bertoletti L, et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016. Epub 2016 Mar 17. doi:10.1183/13993003.02043-2015.
   Google Scholar
• Sitbon O, Jais X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43:1691–1697.
   PubMed Web of Science ®Google Scholar
• Coons JC, Miller T, Simon MA, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients transitioned from parenteral or inhaled prostacyclins: case series and treatment protocol. Pulm Circ. 2016;6:132–135.
   PubMed Web of Science ®Google Scholar