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Выживаемость пациентов с легочной артериальной гипертензией на фоне терапии таблетированными ЛАГ-специфическими препаратами
Выживаемость пациентов с легочной артериальной гипертензией на фоне терапии таблетированными ЛАГ-специфическими препаратами
Платонов Д.Ю., Царева Н.А., Авдеев С.Н. Выживаемость пациентов с легочной артериальной гипертензией на фоне терапии таблетированными ЛАГ-специфическими препаратами. Системные гипертензии. 2017; 14 (3): 58–64. DOI: 10.26442/2075-082X_14.3.58-64
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Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Легочная артериальная гипертензия (ЛАГ) является жизнеугрожающим синдромом, который характеризуется прогрессивным повышением легочного сосудистого сопротивления (ЛСС), среднего давления в легочном артериальном русле, а также рядом функциональных нарушений и морфологическим изменением легочных артерий. Несмотря на относительное обилие ЛАГ-специфических препаратов, выбор подходящего агента для терапии конкретного пациента остается весьма сложной задачей. Вероятно, одним из самых важных параметров, оцениваемым в клинических исследованиях, является выживаемость пациентов или, в некоторых случаях, смертность. Выживаемость или смертность как вторичные или как составляющие первичных конечных точек так или иначе изучались в клинических исследованиях препаратов для лечения ЛАГ. Для таблетированных препаратов для лечения некоторых форм ЛАГ (силденафил, риоцигуат, бозентан, мацитентан, амбризентан) на сегодняшний день доступны данные ряда исследований, предметом изучения которых явилась, в том числе, выживаемость.
Ключевые слова: легочная гипертензия, ЛАГ-специфическая терапия, выживаемость, силденафил, риоцигуат, бозентан, мацитентан, амбризентан.
Key words: pulmonary hypertension, PAH-specific therapy, survival, sildenafil, riociguat, bosentan, macitentan, ambrisentan.
Ключевые слова: легочная гипертензия, ЛАГ-специфическая терапия, выживаемость, силденафил, риоцигуат, бозентан, мацитентан, амбризентан.
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Key words: pulmonary hypertension, PAH-specific therapy, survival, sildenafil, riociguat, bosentan, macitentan, ambrisentan.
Полный текст
Список литературы
1. Легочная гипертензия. Под ред. И.Е.Чазовой и Т.В.Мартынюк. М.: Практика, 2015. / Legochnaia gipertenziia. Pod red. I.E.Chazovoi i T.V.Martyniuk. M.: Praktika, 2015. [in Russian]
2. Государственный реестр лекарственных средств. https://grls.rosminzdrav.ru/ Gosudarstvennyi reestr lekarstvennykh sredstv. https://grls.rosminzdrav.ru/ [in Russian]
3. Galie N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
4. Alonzo G et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med 1991; 115: 343–9.
5. Farber HW et al. Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest 2015; 148 (4): 1043–54.
6. Инструкция по применению лекарственного препарата для медицинского применения Траклир. ЛС-002509-310812 / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Traklir. LS-002509-310812 [in Russian]
7. Channick RN et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet 2001; 358: 1119–23.
8. Rubin LJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903.
9. McLaughlin VV et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244–9.
10. Galiè N 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.
11. Simonneau G et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol 2014; 172: 332–39.
12. Инструкция по медицинскому применению лекарственного препарата Опсамит. ЛП-003310-010916. / Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Opsamit. LP-003310-010916. [in Russian]
13. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 809–18.
14. Souza R et al. Long-term survival and safety with macitentan in patients with pulmonary arterial hypertension: results from the seraphin study and its open-label extension. Am J Respir Crit Care Med 2017; 195: A2294 (Available at: http://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2294)
15. Инструкция по применению лекарственного препарата для медицинского применения Волибрис. ЛП001345 от 25.03.2016. / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Volibris. LP001345 ot 25.03.2016. [in Russian]
16. Galiè N 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: 3010–9.
17. Oudiz RJ et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: 1971–81.
18. Инструкция по применению лекарственного препарата для медицинского применения Ревацио. ЛП 000197-130514. / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Revatsio. LP 000197-130514. [in Russian]
19. Galiè N et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353: 2148–57.
20. Rubin LJ et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension. Chest 2011; 140 (5): 1274–83.
21. Инструкция по медицинскому применению лекарственного препарата Адемпас (от 05.10.2017). / Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Adempas (ot 05.10.2017). [in Russian]
22. Ghofrani H-A et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 330–40.
23. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45: 1211–3.
24. Ghofrani H-A 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; 4: 361–71 (http://dx.doi.org/10.1016/S2213-2600(16)30019-4)
25. Halank M et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study. Respiratory Medicine 2017; 128: 50–6.
26. Huan-long Liu et al. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension. A Meta-analysis of Randomized Controlled Trials. Chest 2016; 150 (2): 353–66.
2. Gosudarstvennyi reestr lekarstvennykh sredstv. https://grls.rosminzdrav.ru/ [in Russian]
3. Galie N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
4. Alonzo G et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med 1991; 115: 343–9.
5. Farber HW et al. Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest 2015; 148 (4): 1043–54.
6. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Traklir. LS-002509-310812 [in Russian]
7. Channick RN et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet 2001; 358: 1119–23.
8. Rubin LJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903.
9. McLaughlin VV et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244–9.
10. Galiè N 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.
11. Simonneau G et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol 2014; 172: 332–39.
12. Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Opsamit. LP-003310-010916. [in Russian]
13. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 809–18.
14. Souza R et al. Long-term survival and safety with macitentan in patients with pulmonary arterial hypertension: results from the seraphin study and its open-label extension. Am J Respir Crit Care Med 2017; 195: A2294 (Available at: http://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2294)
15. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Volibris. LP001345 ot 25.03.2016. [in Russian]
16. Galiè N 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: 3010–9.
17. Oudiz RJ et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: 1971–81.
18. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Revatsio. LP 000197-130514. [in Russian]
19. Galiè N et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353: 2148–57.
20. Rubin LJ et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension. Chest 2011; 140 (5): 1274–83.
21. Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Adempas (ot 05.10.2017). [in Russian]
22. Ghofrani H-A et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 330–40.
23. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45: 1211–3.
24. Ghofrani H-A 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; 4: 361–71 (http://dx.doi.org/10.1016/S2213-2600(16)30019-4)
25. Halank M et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study. Respiratory Medicine 2017; 128: 50–6.
26. Huan-long Liu et al. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension. A Meta-analysis of Randomized Controlled Trials. Chest 2016; 150 (2): 353–66.
2. Государственный реестр лекарственных средств. https://grls.rosminzdrav.ru/ Gosudarstvennyi reestr lekarstvennykh sredstv. https://grls.rosminzdrav.ru/ [in Russian]
3. Galie N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
4. Alonzo G et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med 1991; 115: 343–9.
5. Farber HW et al. Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest 2015; 148 (4): 1043–54.
6. Инструкция по применению лекарственного препарата для медицинского применения Траклир. ЛС-002509-310812 / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Traklir. LS-002509-310812 [in Russian]
7. Channick RN et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet 2001; 358: 1119–23.
8. Rubin LJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903.
9. McLaughlin VV et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244–9.
10. Galiè N 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.
11. Simonneau G et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol 2014; 172: 332–39.
12. Инструкция по медицинскому применению лекарственного препарата Опсамит. ЛП-003310-010916. / Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Opsamit. LP-003310-010916. [in Russian]
13. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 809–18.
14. Souza R et al. Long-term survival and safety with macitentan in patients with pulmonary arterial hypertension: results from the seraphin study and its open-label extension. Am J Respir Crit Care Med 2017; 195: A2294 (Available at: http://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2294)
15. Инструкция по применению лекарственного препарата для медицинского применения Волибрис. ЛП001345 от 25.03.2016. / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Volibris. LP001345 ot 25.03.2016. [in Russian]
16. Galiè N 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: 3010–9.
17. Oudiz RJ et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: 1971–81.
18. Инструкция по применению лекарственного препарата для медицинского применения Ревацио. ЛП 000197-130514. / Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Revatsio. LP 000197-130514. [in Russian]
19. Galiè N et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353: 2148–57.
20. Rubin LJ et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension. Chest 2011; 140 (5): 1274–83.
21. Инструкция по медицинскому применению лекарственного препарата Адемпас (от 05.10.2017). / Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Adempas (ot 05.10.2017). [in Russian]
22. Ghofrani H-A et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 330–40.
23. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45: 1211–3.
24. Ghofrani H-A 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; 4: 361–71 (http://dx.doi.org/10.1016/S2213-2600(16)30019-4)
25. Halank M et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study. Respiratory Medicine 2017; 128: 50–6.
26. Huan-long Liu et al. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension. A Meta-analysis of Randomized Controlled Trials. Chest 2016; 150 (2): 353–66.
________________________________________________
2. Gosudarstvennyi reestr lekarstvennykh sredstv. https://grls.rosminzdrav.ru/ [in Russian]
3. Galie N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67–119.
4. Alonzo G et al. Survival in Patients with Primary Pulmonary Hypertension. Results from a National Prospective Registry. Ann Intern Med 1991; 115: 343–9.
5. Farber HW et al. Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest 2015; 148 (4): 1043–54.
6. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Traklir. LS-002509-310812 [in Russian]
7. Channick RN et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet 2001; 358: 1119–23.
8. Rubin LJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896–903.
9. McLaughlin VV et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005; 25: 244–9.
10. Galiè N 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.
11. Simonneau G et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. Int J Cardiol 2014; 172: 332–39.
12. Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Opsamit. LP-003310-010916. [in Russian]
13. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 809–18.
14. Souza R et al. Long-term survival and safety with macitentan in patients with pulmonary arterial hypertension: results from the seraphin study and its open-label extension. Am J Respir Crit Care Med 2017; 195: A2294 (Available at: http://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2294)
15. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Volibris. LP001345 ot 25.03.2016. [in Russian]
16. Galiè N 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: 3010–9.
17. Oudiz RJ et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54: 1971–81.
18. Instruktsiia po primeneniiu lekarstvennogo preparata dlia meditsinskogo primeneniia Revatsio. LP 000197-130514. [in Russian]
19. Galiè N et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353: 2148–57.
20. Rubin LJ et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension. Chest 2011; 140 (5): 1274–83.
21. Instruktsiia po meditsinskomu primeneniiu lekarstvennogo preparata Adempas (ot 05.10.2017). [in Russian]
22. Ghofrani H-A et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 330–40.
23. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45: 1211–3.
24. Ghofrani H-A 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; 4: 361–71 (http://dx.doi.org/10.1016/S2213-2600(16)30019-4)
25. Halank M et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study. Respiratory Medicine 2017; 128: 50–6.
26. Huan-long Liu et al. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension. A Meta-analysis of Randomized Controlled Trials. Chest 2016; 150 (2): 353–66.
Авторы
Д.Ю.Платонов1,2, Н.А.Царева3,4, С.Н.Авдеев*3,4
1 ГБУЗ Тверской области «Областная клиническая больница». 170036, Россия, Тверь, Петербургское ш., д. 105;
2 ФГБОУ ВО «Тверской государственный медицинский университет» Минздрава России. 170100, Россия, Тверь, ул. Советская, д. 4;
3 ФГБУ «Научно-исследовательский институт пульмонологии» ФМБА России. 105077, Россия, Москва, ул. 11-я Парковая, д. 32;
4 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*serg_avdeev@list.ru
1 Regional Clinical Hospital. 170036, Russian Federation, Tver, Peterburgskoe sh., d. 105;
2 Tver State Medical University of the Ministry of Health of the Russian Federation. 170100, Russian Federation, Tver, ul. Sovetskaja, d. 4;
3 Research Institute of Pulmonology of FMBA of Russia. 105077, Russian Federation, Moscow, ul. 11-ia Parkovaia, d. 32;
4 I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*serg_avdeev@list.ru
1 ГБУЗ Тверской области «Областная клиническая больница». 170036, Россия, Тверь, Петербургское ш., д. 105;
2 ФГБОУ ВО «Тверской государственный медицинский университет» Минздрава России. 170100, Россия, Тверь, ул. Советская, д. 4;
3 ФГБУ «Научно-исследовательский институт пульмонологии» ФМБА России. 105077, Россия, Москва, ул. 11-я Парковая, д. 32;
4 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*serg_avdeev@list.ru
________________________________________________
1 Regional Clinical Hospital. 170036, Russian Federation, Tver, Peterburgskoe sh., d. 105;
2 Tver State Medical University of the Ministry of Health of the Russian Federation. 170100, Russian Federation, Tver, ul. Sovetskaja, d. 4;
3 Research Institute of Pulmonology of FMBA of Russia. 105077, Russian Federation, Moscow, ul. 11-ia Parkovaia, d. 32;
4 I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*serg_avdeev@list.ru
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