Биохимический путь оксида азота в терапии легочной артериальной гипертензии и результаты исследования RESPITE
Биохимический путь оксида азота в терапии легочной артериальной гипертензии и результаты исследования RESPITE
Шмальц А.А., Горбачевский С.В. Биохимический путь оксида азота в терапии легочной артериальной гипертензии и результаты исследования RESPITE. Системные гипертензии. 2018; 15 (2): 72–76. DOI: 10.26442/2075-082X_2018.2.72-76
Биохимический путь оксида азота в терапии легочной артериальной гипертензии и результаты исследования RESPITE
Шмальц А.А., Горбачевский С.В. Биохимический путь оксида азота в терапии легочной артериальной гипертензии и результаты исследования RESPITE. Системные гипертензии. 2018; 15 (2): 72–76. DOI: 10.26442/2075-082X_2018.2.72-76
Недостаточное содержание эндогенного оксида азота и циклического гуанозинмонофосфата (цГМФ) в стенке легочных сосудов играет важную роль в патогенезе легочной артериальной гипертензии (ЛАГ). Стимулятор растворимой гуанилатциклазы риоцигуат и ингибитор фосфодиэстеразы-5 (иФДЭ-5) силденафил увеличивают содержание цГМФ и имеют доказанную клиническую эффективность при ЛАГ. Потенциально выгодными особенностями механизма действия риоцигуата являются независимость от эндогенного оксида азота при синтезе цГМФ и независимость от других (помимо ФДЭ-5) изоферментов фосфодиэстераз. Клиническая возможность, безопасность и эффективность замены иФДЭ-5 на риоцигуат у больных ЛАГ впервые показана в неконтролируемом исследовании RESPITE и продолжает оцениваться в рандомизированном плацебо-контролируемом исследовании REPLACE.
Endogen nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) deficiency in pulmonary vessels walls plays essential role in pulmonary arterial hypertension (PAH) pathogenesis. Soluble guanylate cyclase stimulator riociguat and phosphodiesterase-5 (PDE5) inhibitor sildenafil increase cGMP content and have proven clinical efficacy in PAH treatment. The potentially beneficial mechanisms of riociguat mechanism of action include endogen NO independence in cGMP synthesis and its independence from other phosphodiesterase isoferments (other than PDE5). Clinical options, safety and effectiveness of iPDE5 – riociguat transition in patients with PAH were for the first time shown in non-controlled study RESPITE and the assessment is continued in randomized placebo-controlled trial REPLACE.
1. Легочная гипертензия. Под ред. И.Е.Чазовой, Т.В.Мартынюк. М.: Практика, 2015. / Legochnaia gipertenziia. Pod red. I.E.Chazovoi, T.V.Martynyuk. M.: Praktika, 2015. [in Russian]
2. Легочная гипертензия. Российские клинические рекомендации, 2016. http://cr.rosminzdrav.ru/ schema.html?id=136#/text / Legochnaia gipertenziia. Rossiiskie klinicheskie rekomendatsii, 2016. http://cr.rosminzdrav.ru/schema.html?id=136#/text [in Russian]
3. Galiè N, Simonneau G. (eds). Updates in Pulmonary Hypertension Proceedings of the 5th World Symposium on Pulmonary Hypertension. J Am Coll Cardiol 2013; 62 (25; Suppl. D).
4. Galiè N, Humbert M, Vachiery JL et al. 2015ESC/ERSGuidelines 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 (1).
5. Galiè N, Humbert M, Vachiery JL и соавт. Рекомендации ESC/ERS по диагностике и лечению легочной гипертензии. Рос. кардиол. журн. 2016; 5 (133): 5–64. / Galiè N, Humbert M, Vachiery JL i soavt. Rekomendatsii ESC/ERS po diagnostike i lecheniiu legochnoi gipertenzii. Ros. kardiol. zhurn. 2016; 5 (133): 5–64. [in Russian]
6. Hoeper MM, Simonneau G, Corris PA et al. RESPITE: switching to riociguat in pulmonaryarterialhypertensionpatients with inadequateresponse to phosphodiesterase-5inhibitors. Eur Respir J 2017; 50 (3): 1602425.
7. Madigan M, Zuckerbraun B. Therapeutic Potential of the Nitrite-Generated NO Pathway in Vascular Dysfunction. Front Immunol 2013; 4: 174.
8. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev 2012; 21 (123): 19–26.
9. O’Callaghan DS, Savale L, Montari D et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 2011; 8: 526–38.
10. Ghofrani HA, Voswinckel R, Gall H et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6: 155–66.
11. Stasch JP, Pacher P, Evgenov OV. Solubleguanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011; 123: 2263–73.
12. Ignarro LJ. NO More Heart Disease: How Nitric Oxide Can Prevent – Even Reverse – Heart Disease and Strokes. New York: St. Martin's Press; 2005.
13. Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increasenitric oxidesignalling in cardiovascular disease. Nat Rev Drug Discov 2015; 14 (9): 623–41.
14. cGMP: Generators, Effectors and Therapeutic Implications. Ed. by: HH Schmidt, F Hofmann, JP Stasch. Handbook of Experimental Pharmacology 191. Springer-Verlag Berlin Heidelberg, 2009.
15. Stasch JP, Evgenov OV. Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension. In: Humbert et al. (eds.). Pharmacotherapy of Pulmonary Hypertension. Springer-Verlag Berlin Heidelberg, 2013; p. 279–313.
16. Cooper CJ, Landzberg MJ, Anderson TJ et al. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 1996; 93: 266 –71.
17. Koshland DE. The Molecule of the Year. Science 1992; 258: 1861.
18. Kielstein JT, Bode-Böger SM, Hesse G et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005; 25 (7): 1414–8.
19. Giaid A, Saleh D. Reducedexpression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333 (4): 214–21.
20. Hemnes AR, Champion HC. Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension. Exp Rev Cardiovasc Ther 2006; 4: 293–300.
21. Ревацио®. Инструкция по применению лекарственного препарата для медицинского применения. ЛП-000197-13052014. http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=59d051ad-f651-452e-acbd-aaae0b671b74&t=96e8cd08-f9fc-4471-a60b-303dc92f2b5a / Revatsio®. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia. LP-000197-13052014. http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=59d051ad-f651-452e-acbd-aaae0b671b74&am...
[in Russian]
22. Galiè N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. New Engl J Med 2005; 353: 2148–2157.
23. Simonneau G, Rubin LJ, Galiè N 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.
24. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43 (7): 1149–53.
25. Singh TP, Rohit M, Grover A et al. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oralsildenafiltherapy in severepulmonary artery hypertension. Am Heart J 2006; 151 (4): 851.e1-5.
26. Guha M. First-in-class guanylate cyclase stimulator approved for PAH. Nat Biotechnol 2013; 31: 1064.
27. Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortalityin pulmonary arterial hypertension. N Engl J Med 2013; 369: 809–18.
28. Evgenov OV, Pacher P, Schmidt PM et al. NO-independentstimulators and activators of soluble guanylate cyclase: discovery and therapeuticpotential. Nat Rev Drug Discov 2006; 5 (9): 755–68.
29. 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. Chem Med Chem 2009; 4: 853–65.
30. Ghofrani HA, Galiè N, Grimminger F, Grünig E et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330–40.
31. Таран И.Н., Мартынюк Т.В., Наконечников С.Н., Чазова И.Е. Инновация в медикаментозном лечении легочной артериальной гипертензии: стимулятор растворимой гуанилатциклазы – риоцигуат. Евразийский кардиол. журн. 2015; 4: 12–9. / Taran I.N., Martyniuk T.V., Nakonechnikov S.N., Chazova I.E. Innovatsiia v medikamentoznom lechenii legochnoi arterial'noi gipertenzii: stimuliator rastvorimoi guanilattsiklazy – riotsiguat. Evraziiskii kardiol. zhurn. 2015; 4: 12–9. [in Russian]
32. Адемпас. Инструкция по применению лекарственного препарата для медицинского применения. ЛП-002639-250914. http://grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath= \Vneseno_v_Grls\441575\IP&idReg=86125&isOld=1&fileType=jpg&pfolder=2 / Adempas. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia. LP-002639-250914. http://grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath=\Vneseno_v_Grls\441575...
[in Russian]
33. 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: 1303–13.
34. Galiè N, Muller K, Scalise AV, Grunig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in PAH. Eur Respir J 2015; 45: 1314–22.
35. Bayer AG. Adempas (riociguat tablets): EU summary of product characteristics. www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/002737/WC500165034.pdf Date last updated: March 27, 2014. Accessed: 2017.
36. Bayer AG. Adempas: US prescribing information. http://labeling.bayerhealthcare.com/html/products/pi/Adempas_ PI.pdf Date last updated: February 23, 2014. Accessed: 2017.
37. REPLACE. Riociguat replacing PDE-5i therapy evaluated against continued PDE-5i therapy. Сlinical Trials.gov Identifier: NCT02891850.
38. Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 2014; 146 (2): 449–75.
39. Politi M, Caruso N, Lescano J et al. Switch from bosentan to macitentan in adult outpatients with pulmonary arterial hypertension: a real-world study. J Heart Lung Transplant 2017; 36: 4 (Suppl.): S166.
40. Blok IM, van Riel ACMJ, van Dijk APJ et al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Int J Cardiol 2017; 227: 51–2.
41. Safdar Z, Thakur A, Frost A. Tolerability of switch to macitentan from bosentan in pulmonary arterial hypertension. South Med J 2017; 110: 223–8.
42. Sitbon O, Manes A, Jais X et al. Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension. J Cardiovasc Pharmacol 2007; 49: 1–5.
43. 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: 132–5.
44. Lichtblau M, Harzheim D, Ehlken N et al. Safety and long-term efficacy of transition from sildenafil to tadalafil due to side effects in patients with pulmonary arterial hypertension. Lung 2015; 193: 105–12.
45. Dos Santos Fernandes CJC, Humbert M, Souza R. Challenging the concept of adding more drugs in pulmonary arterial hypertension. Eur Respir J 2017; 50: 1701527 https://doi.org/10.1183/13993003.01527-2017.
________________________________________________
1. Legochnaia gipertenziia. Pod red. I.E.Chazovoi, T.V.Martynyuk. M.: Praktika, 2015. [in Russian]
2. Legochnaia gipertenziia. Rossiiskie klinicheskie rekomendatsii, 2016. http://cr.rosminzdrav.ru/schema.html?id=136#/text [in Russian]
3. Galiè N, Simonneau G. (eds). Updates in Pulmonary Hypertension Proceedings of the 5th World Symposium on Pulmonary Hypertension. J Am Coll Cardiol 2013; 62 (25; Suppl. D).
4. Galiè N, Humbert M, Vachiery JL et al. 2015ESC/ERSGuidelines 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 (1).
5. Galiè N, Humbert M, Vachiery JL и соавт. Рекомендации ESC/ERS по диагностике и лечению легочной гипертензии. Рос. кардиол. журн. 2016; 5 (133): 5–64. / Galiè N, Humbert M, Vachiery JL i soavt. Rekomendatsii ESC/ERS po diagnostike i lecheniiu legochnoi gipertenzii. Ros. kardiol. zhurn. 2016; 5 (133): 5–64. [in Russian]
6. Hoeper MM, Simonneau G, Corris PA et al. RESPITE: switching to riociguat in pulmonaryarterialhypertensionpatients with inadequateresponse to phosphodiesterase-5inhibitors. Eur Respir J 2017; 50 (3): 1602425.
7. Madigan M, Zuckerbraun B. Therapeutic Potential of the Nitrite-Generated NO Pathway in Vascular Dysfunction. Front Immunol 2013; 4: 174.
8. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev 2012; 21 (123): 19–26.
9. O’Callaghan DS, Savale L, Montari D et al. Treatment of pulmonary arterial hypertension with targeted therapies. Nat Rev Cardiol 2011; 8: 526–38.
10. Ghofrani HA, Voswinckel R, Gall H et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6: 155–66.
11. Stasch JP, Pacher P, Evgenov OV. Solubleguanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011; 123: 2263–73.
12. Ignarro LJ. NO More Heart Disease: How Nitric Oxide Can Prevent – Even Reverse – Heart Disease and Strokes. New York: St. Martin's Press; 2005.
13. Lundberg JO, Gladwin MT, Weitzberg E. Strategies to increasenitric oxidesignalling in cardiovascular disease. Nat Rev Drug Discov 2015; 14 (9): 623–41.
14. cGMP: Generators, Effectors and Therapeutic Implications. Ed. by: HH Schmidt, F Hofmann, JP Stasch. Handbook of Experimental Pharmacology 191. Springer-Verlag Berlin Heidelberg, 2009.
15. Stasch JP, Evgenov OV. Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension. In: Humbert et al. (eds.). Pharmacotherapy of Pulmonary Hypertension. Springer-Verlag Berlin Heidelberg, 2013; p. 279–313.
16. Cooper CJ, Landzberg MJ, Anderson TJ et al. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 1996; 93: 266 –71.
17. Koshland DE. The Molecule of the Year. Science 1992; 258: 1861.
18. Kielstein JT, Bode-Böger SM, Hesse G et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005; 25 (7): 1414–8.
19. Giaid A, Saleh D. Reducedexpression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333 (4): 214–21.
20. Hemnes AR, Champion HC. Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension. Exp Rev Cardiovasc Ther 2006; 4: 293–300.
21. Revatsio®. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia. LP-000197-13052014. http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=59d051ad-f651-452e-acbd-aaae0b671b74&am...
[in Russian]
22. Galiè N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. New Engl J Med 2005; 353: 2148–2157.
23. Simonneau G, Rubin LJ, Galiè N 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.
24. Sastry BK, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43 (7): 1149–53.
25. Singh TP, Rohit M, Grover A et al. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oralsildenafiltherapy in severepulmonary artery hypertension. Am Heart J 2006; 151 (4): 851.e1-5.
26. Guha M. First-in-class guanylate cyclase stimulator approved for PAH. Nat Biotechnol 2013; 31: 1064.
27. Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortalityin pulmonary arterial hypertension. N Engl J Med 2013; 369: 809–18.
28. Evgenov OV, Pacher P, Schmidt PM et al. NO-independentstimulators and activators of soluble guanylate cyclase: discovery and therapeuticpotential. Nat Rev Drug Discov 2006; 5 (9): 755–68.
29. 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. Chem Med Chem 2009; 4: 853–65.
30. Ghofrani HA, Galiè N, Grimminger F, Grünig E et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330–40.
31. Taran I.N., Martyniuk T.V., Nakonechnikov S.N., Chazova I.E. Innovatsiia v medikamentoznom lechenii legochnoi arterial'noi gipertenzii: stimuliator rastvorimoi guanilattsiklazy – riotsiguat. Evraziiskii kardiol. zhurn. 2015; 4: 12–9. [in Russian]
32. Adempas. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia. LP-002639-250914. http://grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath=\Vneseno_v_Grls\441575...
[in Russian]
33. 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: 1303–13.
34. Galiè N, Muller K, Scalise AV, Grunig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in PAH. Eur Respir J 2015; 45: 1314–22.
35. Bayer AG. Adempas (riociguat tablets): EU summary of product characteristics. www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/002737/WC500165034.pdf Date last updated: March 27, 2014. Accessed: 2017.
36. Bayer AG. Adempas: US prescribing information. http://labeling.bayerhealthcare.com/html/products/pi/Adempas_ PI.pdf Date last updated: February 23, 2014. Accessed: 2017.
37. REPLACE. Riociguat replacing PDE-5i therapy evaluated against continued PDE-5i therapy. Сlinical Trials.gov Identifier: NCT02891850.
38. Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 2014; 146 (2): 449–75.
39. Politi M, Caruso N, Lescano J et al. Switch from bosentan to macitentan in adult outpatients with pulmonary arterial hypertension: a real-world study. J Heart Lung Transplant 2017; 36: 4 (Suppl.): S166.
40. Blok IM, van Riel ACMJ, van Dijk APJ et al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Int J Cardiol 2017; 227: 51–2.
41. Safdar Z, Thakur A, Frost A. Tolerability of switch to macitentan from bosentan in pulmonary arterial hypertension. South Med J 2017; 110: 223–8.
42. Sitbon O, Manes A, Jais X et al. Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension. J Cardiovasc Pharmacol 2007; 49: 1–5.
43. 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: 132–5.
44. Lichtblau M, Harzheim D, Ehlken N et al. Safety and long-term efficacy of transition from sildenafil to tadalafil due to side effects in patients with pulmonary arterial hypertension. Lung 2015; 193: 105–12.
45. Dos Santos Fernandes CJC, Humbert M, Souza R. Challenging the concept of adding more drugs in pulmonary arterial hypertension. Eur Respir J 2017; 50: 1701527 https://doi.org/10.1183/13993003.01527-2017.
Авторы
А.А.Шмальц*, С.В.Горбачевский
ФГБУ «Национальный медицинский исследовательский центр сердечно-сосудистой хирургии имени А.Н.Бакулева» Минздрава России. 121552, Россия, Москва, Рублевское ш., д. 135;
ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2 *shmaltzanton@inbox.ru
________________________________________________
А.А.Shmalts*, S.V.Gorbachevsky
A.N.Bakulev National Medical Research Center of Cardiovascular Surgery of the Ministry of Health of the Russian Federation. 121552, Russian Federation, Moscow, Rublevskoe sh., d. 135;
Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125995, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1 *shmaltzanton@inbox.ru