evrazkarЕвразийский Кардиологический ЖурналEurasian heart journal2225-16852305-0748Евразийская ассоциация кардиологов10.38109/2225-1685-2013-1-6-17evrazkar-5535Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSНОВЫЕ ВОЗМОЖНОСТИ ПАТОГЕНЕТИЧЕСКОЙ ТЕРАПИИ ЛЕГОЧНОЙ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИNEW OPPORTUNITIES PATHOGENETIC THERAPY OF PULMONARY ARTERIAL HYPERTENSIONМартынюкТамила ВитальевнаMartynukT. V.trukhiniv@mail.ruНаконечниковСергей НиколаевичNakonechnikovS. N.snn_cardio@mail.ruЧазоваИрина ЕвгеньевнаChazovaI. E.noemail@neicon.ruФГБУ Российский кардиологический научно-производственный комплекс МЗ РФ, институт клинической кардиологии им. А. Л. МясниковаРоссияRussian cardiology research complexRussian Federation20133003201301617Copyright © Мартынюк Т.В., Наконечников С.Н., Чазова И.Е., 20132013Мартынюк Т.В., Наконечников С.Н., Чазова И.Е.Martynuk T.V., Nakonechnikov S.N., Chazova I.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.heartj.asia/jour/article/view/5535

В обзоре представлены новые данные о возможностях лекарственной терапии легочной артериальной гипертензии (ЛАГ). Известно, что основной характеристикой патологического процесса является легочное сосудистое ремоделирование - комплексный процесс, включающий клеточную пролиферацию, гипертрофию, миграцию клеток, нарушение апоптоза, продукции и деградации межклеточного матрикса. Это определяет интерес к лекарственным препаратам, которые являются не только мощными вазодилататорами, но и имеют антипролиферативный и антиремоделирующий эффекты. Следует выделить два основных подхода для дальнейшего улучшения терапии ЛАГ: 1) новые, более эффективные или более удобные для применения лекарственные препараты, которые воздействуют на вышеуказанные установленные мишени; 2) лекарственные препараты, которые воздействуют на новые патогенетические мишени, выявленные в результате последних научных исследований в области ЛАГ. Они показали потенциальную эффективность в экспериментальных моделях, а также в ранних фазах клинических исследований и являются перспективными с точки зрения дальнейшего совершенствования патогенетической терапии ЛАГ.

The review summarizes new data on medical treatment of pulmonary arterial hypertension (PAH). Pulmonary arterial remodeling is known to be the main pathophysiological characteristic, involving cell proliferation, hypertrophy and migration, as well as apoptotic abnormalities and changes in extracellular matrix production and degradation. This makes promising the evaluation of drugs with not only vasodilatory, but also antiproliferative and anti-remodelling properties. There are two approaches to improvement of PAH therapy: 1) novel agents with higher efficacy or more convenience for use, acting on the above mentioned targets, and 2) agents aimed at new pathophysiological targets, discovered by the most recent research in PAH area. They have shown potential efficacy in experimental models as well as in early phase clinical trials and seem promising for further improvement of pathophysiologically oriented treatment of PAH.

легочная артериальная гипертензияэндотелин-1антагонисты рецепторов эндотелинаоксид азотаингибиторы фосфодиэстеразы типа 5простациклинpulmonary arterial hypertensionendothelin-1endothelin receptor antagonistsnitric oxidetype 5 phosphodiesterase inhibitorsprostacyclinReferencesGalie N., Manes A., Negro L. et al. A meta-analysis of randomized controlled trials pulmonary arterial hypertension. Eur Heart J 2009; 30: 394-403.Galie N., Manes A., Negro L. et al. A meta-analysis of randomized controlled trials pulmonary arterial hypertension. Eur Heart J 2009; 30: 394-403.Galie N., Hoeper M.M., 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 and the European Respiratory Society, endorsed by the International Society of Heart and Lung Transplantation. Eur Heart J 2009; 30 (20): 2 493-537.Galie N., Hoeper M.M., 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 and the European Respiratory Society, endorsed by the International Society of Heart and Lung Transplantation. Eur Heart J 2009; 30 (20): 2 493-537.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. Circulation2010; 122: 156-163.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. Circulation2010; 122: 156-163.Rubin L.J. Therapy of pulmonary hypertension: the evolution from vasodilators to antiproliferative agents. Am J Respir Crit Care Med 2002; 166: 13081309.Rubin L.J. Therapy of pulmonary hypertension: the evolution from vasodilators to antiproliferative agents. Am J Respir Crit Care Med 2002; 166: 13081309.Мартынюк Т.В., Чазова И.Е., Масенко В.П. и соавт. Эндотелиальная дисфункция у больных с легочной гипертензией. // Кардиология. 1997. № 10. С. 25-29.Мартынюк Т.В., Чазова И.Е., Масенко В.П. и соавт. Эндотелиальная дисфункция у больных с легочной гипертензией. // Кардиология. 1997. № 10. С. 25-29.Stewart D.J., Levy R.D., Cernacek P. Increased plasma endothelin-1 in primary pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 464-469.Stewart D.J., Levy R.D., Cernacek P. Increased plasma endothelin-1 in primary pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 464-469.Shi-Wen X., Denton C.P., Dashwood M.R., et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 2001; 116: 417-425.Shi-Wen X., Denton C.P., Dashwood M.R., et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol 2001; 116: 417-425.Yang Z., Krasnici N., Lüscher T.F. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation 1999; 100: 5-8.Yang Z., Krasnici N., Lüscher T.F. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation 1999; 100: 5-8.Wagner O.F., Christ G., Wojta J., et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066-16068.Wagner O.F., Christ G., Wojta J., et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066-16068.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: 736-745.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: 736-745.Raja S.G. Macitentan: a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. Curr Opin Investig Drugs 2010; 11: 1066-1073.Raja S.G. Macitentan: a tissue-targeting endothelin receptor antagonist for the potential oral treatment of pulmonary arterial hypertension and idiopathic pulmonary fibrosis. Curr Opin Investig Drugs 2010; 11: 1066-1073.Souza R. SERAPHIN: results from a landmark study. Abstracts from ERS Congress 2012. www. clinicaltrials.gov.NCT00660179.Souza R. SERAPHIN: results from a landmark study. Abstracts from ERS Congress 2012. www. clinicaltrials.gov.NCT00660179.McLaughlin V.V., Badesch D.B., Delcroix M., et al. End points and clinical trial design in pulmonary arterial hypertension. J Am CollCardiol 2009; 54: Suppl. 1, S97-S107.McLaughlin V.V., Badesch D.B., Delcroix M., et al. End points and clinical trial design in pulmonary arterial hypertension. J Am CollCardiol 2009; 54: Suppl. 1, S97-S107.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: 549-555.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: 549-555.Mubarak K.K. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010; 104: 9-21.Mubarak K.K. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010; 104: 9-21.Kuwano K., Hashino A., Asaki T., et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino] butoxy]-N-(methylsulfonyl) acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007; 322: 1181-1188.Kuwano K., Hashino A., Asaki T., et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino] butoxy]-N-(methylsulfonyl) acetamide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007; 322: 1181-1188.Kuwano K., Hashino A., Noda K., et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-[4-[(5,6-diphenyl pyrazin-2-yl) (isopropyl) amino] butoxy]-N-(methylsulfonyl) acetamide (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.Kuwano K., Hashino A., Noda K., et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, 2-[4-[(5,6-diphenyl pyrazin-2-yl) (isopropyl) amino] butoxy]-N-(methylsulfonyl) acetamide (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.Simonneau G., Lang I., Torbicki A., et al. Efficacy, safety and tolerability of ACT-293987, a novel oral, nonprostanoid, prostaglandin I2 (IP) receptor agonist: results from a phase IIa study in pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2010; 181: A2515.Simonneau G., Lang I., Torbicki A., et al. Efficacy, safety and tolerability of ACT-293987, a novel oral, nonprostanoid, prostaglandin I2 (IP) receptor agonist: results from a phase IIa study in pulmonary arterial hypertension (PAH). Am J Respir Crit Care Med 2010; 181: A2515.ClinicalTrials.gov. ACT-293987in pulmonary arterial hypertension.NCT01106014. http://clinicaltrials.gov/NCT01106014. July 27, 2011.ClinicalTrials.gov. ACT-293987in pulmonary arterial hypertension.NCT01106014. http://clinicaltrials.gov/NCT01106014. July 27, 2011.Tapson V.F., Torres F., Kermeen F., et al. Results of the FREEDOM-C Study: a pivotal study of oral treprostinil used adjunctively with an ERA and/or PDE5-inhibitor for the treatment of PAH. Am J Respir Crit Care Med 2009; 179: A1040.Tapson V.F., Torres F., Kermeen F., et al. Results of the FREEDOM-C Study: a pivotal study of oral treprostinil used adjunctively with an ERA and/or PDE5-inhibitor for the treatment of PAH. Am J Respir Crit Care Med 2009; 179: A1040.United Therapeutics. FREEDOM-M Trial of oral treprostinil in pulmonary arterial hypertension meets primary endpoint. http://ir.unither.com/releasedetail.cfm. ReleaseID5582786. May 5, 2011.United Therapeutics. FREEDOM-M Trial of oral treprostinil in pulmonary arterial hypertension meets primary endpoint. http://ir.unither.com/releasedetail.cfm. ReleaseID5582786. May 5, 2011.ClinicalTrials.gov. A 16-week, international, multicenter, double blind, randomized, placebocontrolled study of the efficacy and safety of oral UT-15C sustained release tablets in subjects with pulmonary arterial hypertension (FREEDOM-C2). NCT00887978. http://clinicaltrials.gov.NCT00887978 August 9, 2011.ClinicalTrials.gov. A 16-week, international, multicenter, double blind, randomized, placebocontrolled study of the efficacy and safety of oral UT-15C sustained release tablets in subjects with pulmonary arterial hypertension (FREEDOM-C2). NCT00887978. http://clinicaltrials.gov.NCT00887978 August 9, 2011.Crosswhite P., Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 2010; 28: 201-212.Crosswhite P., Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 2010; 28: 201-212.Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-221.Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-221.Sitbon O., Brenot F., Denjean A., et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension.A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151: 384-389.Sitbon O., Brenot F., Denjean A., et al. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension.A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151: 384-389.Schermuly R.T., Stasch J.P., Pullamsetti S.S., et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008; 32: 881-891.Schermuly R.T., Stasch J.P., Pullamsetti S.S., et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008; 32: 881-891.Mittendorf J., Weigand S., Alonso-Alija C., et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009; 4: 853-865.Mittendorf J., Weigand S., Alonso-Alija C., et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009; 4: 853-865.Evgenov O.V., Kohane D.S., Bloch K.D., et al. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med 2007; 176: 1138-1145.Evgenov O.V., Kohane D.S., Bloch K.D., et al. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med 2007; 176: 1138-1145.Grimminger F., Weimann G., Frey R., et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009; 33: 785-792.Grimminger F., Weimann G., Frey R., et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009; 33: 785-792.Ghofrani H.A., Voswinckel R., Gall H., et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6: 155-166.Ghofrani H.A., Voswinckel R., Gall H., et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6: 155-166.Ghofrani H.A., Hoeper M.M., Halank M., et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010; 36: 792-799.Ghofrani H.A., Hoeper M.M., Halank M., et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010; 36: 792-799.ClinicalTrials.gov. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with pulmonary arterial hypertension (PAH) (PATENT-1). NCT00810693. http://clinicaltrials.gov/ct2/show/NCT00810693 Date last updated: August 4, 2011. Date last accessed: August 4,2011.ClinicalTrials.gov. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with pulmonary arterial hypertension (PAH) (PATENT-1). NCT00810693. http://clinicaltrials.gov/ct2/show/NCT00810693 Date last updated: August 4, 2011. Date last accessed: August 4,2011.ClinicalTrials.gov. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with CTEPH (CHEST-1). NCT00855465. http://clinicaltrials.gov/ct2/show/NCT00855465. July 27,2011.ClinicalTrials.gov. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with CTEPH (CHEST-1). NCT00855465. http://clinicaltrials.gov/ct2/show/NCT00855465. July 27,2011.Sakao S., Tatsumi K. Vascular remodeling in pulmonary arterial hypertension: multiple cancerlike pathways and possible treatment modalities. Int J Cardiol 2011; 147: 4-12.Sakao S., Tatsumi K. Vascular remodeling in pulmonary arterial hypertension: multiple cancerlike pathways and possible treatment modalities. Int J Cardiol 2011; 147: 4-12.Grimminger F., Schermuly R.T. PDGF receptor and its antagonists: role in treatment of PAH. Adv Exp Med Biol 2010; 661: 435-446.Grimminger F., Schermuly R.T. PDGF receptor and its antagonists: role in treatment of PAH. Adv Exp Med Biol 2010; 661: 435-446.Steeghs N., Nortier J.W., Gelderblom H. Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol 2007; 14: 942-953.Steeghs N., Nortier J.W., Gelderblom H. Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol 2007; 14: 942-953.Kerkela R., Grazette L., Yacobi R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Med 2006; 12: 908-916.Kerkela R., Grazette L., Yacobi R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Med 2006; 12: 908-916.Barst R.J. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005; 115: 2691-264.Barst R.J. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005; 115: 2691-264.Klein M., Schermuly R.T., Ellinghaus P., et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008; 118: 2081-2090.Klein M., Schermuly R.T., Ellinghaus P., et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008; 118: 2081-2090.Schermuly R.T., Dony E., Ghofrani H.A., et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115: 2811-2821.Schermuly R.T., Dony E., Ghofrani H.A., et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005; 115: 2811-2821.Hatano M., Yao A., Shiga T., et al. Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int Heart J 2010; 51: 272-276.Hatano M., Yao A., Shiga T., et al. Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int Heart J 2010; 51: 272-276.Ghofrani H.A., Seeger W., Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353: 1412-1413.Ghofrani H.A., Seeger W., Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005; 353: 1412-1413.Ghofrani HA., Morrell NW., Hoeper MM., et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010; 182: 1171-1177.Ghofrani HA., Morrell NW., Hoeper MM., et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010; 182: 1171-1177.Souza R., Sitbon O., Parent F., et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006; 61: 736.Souza R., Sitbon O., Parent F., et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006; 61: 736.ClinicalTrials.gov. Imatinib in pulmonary arterial hypertension (IMPRES). NCT00902174. http://clinicaltrials.gov/NCT00902174 December 1,2010.ClinicalTrials.gov. Imatinib in pulmonary arterial hypertension (IMPRES). NCT00902174. http://clinicaltrials.gov/NCT00902174 December 1,2010.ClinicalTrials.gov. Extension to QTI571A2301 to evaluate the long-term safety, tolerability and efficacy of imatinib in severe pulmonary arterial hypertension (IMPRES Extn). NCT01117987. http://clinicaltrials.gov/ct2/show/NCT01117987. October 22,2011.ClinicalTrials.gov. Extension to QTI571A2301 to evaluate the long-term safety, tolerability and efficacy of imatinib in severe pulmonary arterial hypertension (IMPRES Extn). NCT01117987. http://clinicaltrials.gov/ct2/show/NCT01117987. October 22,2011.Kantarjian H., Giles F., Wunderle L., et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542-2551.Kantarjian H., Giles F., Wunderle L., et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542-2551.Duggan N., Bonneau O., Hussey M., et al. Comparison of effects of imatinib and nilotinib in a rodent model of pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 181: A6304.Duggan N., Bonneau O., Hussey M., et al. Comparison of effects of imatinib and nilotinib in a rodent model of pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 181: A6304.ClinicalTrials.gov. Efficacy, safety, tolerability and pharmacokinetics (PK) of nilotinib (AMN107) in pulmonary arterial hypertension (PAH). NCT01179737. http://clinicaltrials.gov// NCT01179737. August 10,2010.ClinicalTrials.gov. Efficacy, safety, tolerability and pharmacokinetics (PK) of nilotinib (AMN107) in pulmonary arterial hypertension (PAH). NCT01179737. http://clinicaltrials.gov// NCT01179737. August 10,2010.Abenhaim L., Moride Y., Brenot F., et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.N Engl J Med 1996; 335: 609-616.Abenhaim L., Moride Y., Brenot F., et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.N Engl J Med 1996; 335: 609-616.Dempsie Y., MacLean M.R. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 2008; 155: 455-462.Dempsie Y., MacLean M.R. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol 2008; 155: 455-462.Herve' P., Launay J.-M., Scrobohaci M.-L., et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-254.Herve' P., Launay J.-M., Scrobohaci M.-L., et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-254.Eddahibi S., Humbert M., Fadel E., et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001; 108: 1141-1150.Eddahibi S., Humbert M., Fadel E., et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001; 108: 1141-1150.Eddahibi S., Raffestin B., Pham I., et al. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol Heart Circ Physiol 1997; 41: H1173-H1181.Eddahibi S., Raffestin B., Pham I., et al. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol Heart Circ Physiol 1997; 41: H1173-H1181.Hironaka E., Hongo M., Sakai A., et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003; 60: 692-699.Hironaka E., Hongo M., Sakai A., et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003; 60: 692-699.Shah S.J., Gomberg-Maitland M., Thenappan T., et al. Selective serotonin reuptake inhibitors and the incidence and outcome of pulmonary hypertension. Chest 2009; 136: 694-700.Shah S.J., Gomberg-Maitland M., Thenappan T., et al. Selective serotonin reuptake inhibitors and the incidence and outcome of pulmonary hypertension. Chest 2009; 136: 694-700.Dumitrascu R., Kulcke C., Konigshoff M., et al. Terguride ameliorates monocrotaline induced pulmonary hypertension inrats. Eur Respir J 2011; 37: 1104-1118.Dumitrascu R., Kulcke C., Konigshoff M., et al. Terguride ameliorates monocrotaline induced pulmonary hypertension inrats. Eur Respir J 2011; 37: 1104-1118.Ergonex. Ergonex Pharma initiates Phase II clinical trial of terguride in pulmonary arterial hypertension. www.ergonex.om/attachments/news/: January 29, 2008. 92Ergonex. Ergonex Pharma initiates Phase II clinical trial of terguride in pulmonary arterial hypertension. www.ergonex.om/attachments/news/: January 29, 2008. 92

The authors declare that there are no conflicts of interest present.