pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2021-31-1-75-87pulmo-2269Research ArticleКЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯCLINICAL PHARMACOLOGYСовременные возможности терапии ингаляционными глюкокортикостероидами пациентов с хронической обструктивной болезнью легкихCurrent opportunities of inhaled corticosteroid therapy in patients with chronic obstructive pulmonary diseasehttps://orcid.org/0000-0002-1620-7159ЛещенкоИ. В.LeshchenkoI. V.

Лещенко Игорь Викторович - доктор медицинских наук, профессор кафедры фтизиатрии и пульмонологии УГМУ МЗ РФ; главный научный сотрудник УНИИФ – филиал ФГБУ «НМИЦ ФПИ» Минздрава России.620028, Екатеринбург, ул. Репина, 3; 620039, Свердловская область, Екатеринбург, ул. 22-го Партсъезда, 50.тел.: (343) 246-44-75

Igor V. Leshchenko - Doctor of Medicine, Professor, Department of Phthisiology and Pulmonology, Ural State Medical University, Healthcare Ministry of Russia, Chief Researcher, Ural Research Institute of Phthisiopulmonology -a branch of National Medical Research Phthisiopulmonology and Infectious Diseases Center, Healthcare Ministry of Russia.ul. Repina 3, Ekaterinburg, 620028; ul. 22nd Parts'ezda 50, Sverdlovskaya obl., Ekaterinburg, 620039.tel.: (343) 246-44-75

leshchenkoiv@yandex.ruМещеряковаА. С.MeshcheryakovaA. S.

Мещерякова Анастасия Сергеевна - региональный медицинский советник по пульмонологии.123112, Москва, 1-й Красногвардейский пр. 21, стр. 1.тел.: (904) 985-26-44

Anastasiya S. Meshcheryakova - Medical Scientific Liaison, Respiratory & Immunology Ural, “AstraZeneca Pharmaceuticals” Limited Liability Company.1st Krasnogvardeyskiy pr. 21, build. 1, Moscow, 123112.tel.: (904) 985-26-44

kas_ekb@mail.ruУральский государственный медицинский университет Министерства здравоохранения Российской Федерации; Уральский научно-исследовательский институт фтизиопульмонологии - филиал федерального государственного бюджетного учреждения «Национальный медицинский исследовательский центр фтизиопульмонологии и инфекционных заболеваний» Министерства здравоохранения Российской ФедерацииРоссияUral Federal State Medical University, Healthcare Ministry of Russia; Ural Research Institute of Phthisiopulmonology - a branch of National Medical Research Phthisiopulmonology and Infectious Diseases Center, Healthcare Ministry of RussiaRussian FederationОбщество с ограниченной ответственностью «АстраЗенека Фармасьютикалз»Россия“AstraZeneca Pharmaceuticals” Limited Liability CompanyRussian Federation2021190220213117587Copyright © Лещенко И.В., Мещерякова А.С., 20212021Лещенко И.В., Мещерякова А.С.Leshchenko I.V., Meshcheryakova A.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/2269

Хроническая обструктивная болезнь легких (ХОБЛ) является лидирующей причиной смерти в структуре болезней органов дыхания. Проблема рациональной фармакотерапии ХОБЛ привлекает к себе внимание медицинской научной общественности в течение многих лет. С течением времени понимание патогенеза болезни меняется, корректируются и подходы к терапии. С целью профилактики обострений и снижения выраженности симптомов заболевания некоторые пациенты с ХОБЛ нуждаются в регулярной комбинированной терапии длительно действующими бронходилататорами (ДДБД) и ингаляционными глюкокортикостероидами (иГКС). При выборе регулярной терапии одним из критериев является уровень эозинофилов в периферической крови. С появлением фиксированных тройных комбинаций иГКС / ДДБД повышается эффективность лекарственной терапии у больных ХОБЛ, а новая ингаляционная форма доставки фиксированной комбинации будесонид / формотерол позволяет успешно применять иГКС у пациентов с наиболее тяжелой формой заболевания.

Chronic obstructive pulmonary disease (COPD) is the leading cause of death in the structure of respiratory diseases. The problem of rational pharmacotherapy of COPD have attracted attention of the medical scientific society for many years. The understanding of the pathogenesis of the disease has deepened and approaches to the therapy have changed. Some COPD patients need regular fixed-combination therapy: long-acting bronchodilators (LABD) and inhaled corticosteroids (ICS) in order to prevent exacerbations and reduce the severity of symptoms of the disease. Blood eosinophils count is one of criteria for choosing regular therapy. The appearance of fixed triple combinations of ICS/LABD increased the effectiveness of COPD therapy, and a new delivery device for fixed combination of budesonide/formoterol makes it possible to use ICS successfully in the most severe patients.

хроническая обструктивная болезнь легкихингаляционные глюкокортикостероидыдлительно действующие бронхо-дилататорыэффективностьингаляционное устройствоchronic obstructive pulmonary diseaseinhaled corticosteroidslong-acting bronchodilatorsefficacyinhalation deviceПубликация осуществлена при финансовой поддержке компании ООО «АстраЗенека Фармасьютикалз». Мнение авторов может не совпадать с позицией компании. Компания ООО «АстраЗенека Фармасьютикалз» не несет ответственности за возможные нарушения авторских прав и иных прав третьих лиц в результате публикации и распространения данной информации.ReferencesWorld Health Organization. The top 10 causes of death. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death [Accessed: July 21, 2020].World Health Organization. The top 10 causes of death. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death [Accessed: July 21, 2020].Global Initiative for Chronic Obstructive Lung Disease. 2021 Global Strategy for the Diagnosis, Management and Prevention of COPD. 2021 GOLD Reports. Available at: https://goldcopd.org/2021-gold-reports/ [Accessed: July 21, 2020].Global Initiative for Chronic Obstructive Lung Disease. 2021 Global Strategy for the Diagnosis, Management and Prevention of COPD. 2021 GOLD Reports. Available at: https://goldcopd.org/2021-gold-reports/ [Accessed: July 21, 2020].Arkhipov V., Arkhipova D., Miravitlles M. et al. Characteristics of COPD patients according to GOLD classification and clinical phenotypes in the Russian Federation: the SUPPORT trial. Int. J. Chron. Obstruct. Pulmon. Dis. 2017; 12: 3255-3262. DOI: 10.2147/COPD.S142997.Arkhipov V., Arkhipova D., Miravitlles M. et al. Characteristics of COPD patients according to GOLD classifica-tionand clinical phenotypes in the Russian Federation: the SUPPORT trial. Int. J. Chron. Obstruct. Pulmon. Dis. 2017; 12: 3255-3262. DOI: 10.2147/COPD.S142997.Лещенко И.В. Возможности и ограничения применения ингаляционных глюкокортикостероидов в терапии хронической обструктивной болезни легких. Пульмонология. 2018; 28 (5): 603-612. DOI: 10.18093/08690189-2018-28-5-602-612.Leshchenko I.V. [Possibilities and limitations of the use of inhaled glucocorticosteroids in the treatment of chronic obstructive pulmonary disease]. Pul'monologiya. 2018; 28 (5): 603-612. DOI: 10.18093/0869-0189-2018-28-5-602-612 (in Russian).Айсанов З.Р., Авдеев С.Н., Архипов В.В. и др. Национальные клинические рекомендации по диагностике и лечению хронической обструктивной болезни легких: алгоритмы принятия клинических решений. Пульмонология. 2017; 27 (1): 13-20. DOI: 10.18093/08690189-2017-27-1-13-20.Aisanov Z.R., Avdeev S.N., Arkhipov V.V. et al. [National clinical guidelines on diagnosis and treatment of chronic obstructive pulmonary disease: a clinical decision-making algorithm]. Pul'monologiya. 2017; 27 (1): 13-20. DOI: 10.18093/0869-0189-2017-27-1-13-20 (in Russian).Российское респираторное общество. ХОБЛ: Федеральные клинические рекомендации. 2018. Доступно на: https://spulmo.ru/upload/federal_klinicheskie_rekomendaciy_hobl.pdf [Дата обращения: 31.10.20].Russian Respiratory Society. [COPD: National clinical guidelines. 2018]. Accessed at: https://spulmo.ru/upload/federal_klinicheskie_rekomendaciy_hobl.pdf [Accessed: 31.10.20].Анаев Э.Х., Чучалин А.Г. Легочные эозинофилии: диагностика, подходы к терапии. Пульмонология. 2012; (4): 106-115. DOI: 10.18093/0869-0189-2012-0-4-106-115.Anaev E.H., Chuchalin A.G. [Pulmonary eosinophilia: diagnosis, approaches to therapy]. Pul'monologiya. 2012; (4): 106-115. DOI: 10.18093/0869-0189-2012-0-4-106-115 (in Russian).Cazzola M., Rogliani P., Calzetta L., Matera M.G. Triple therapy versus single and dual long-acting bronchodilator therapy in COPD: a systematic review and meta-analysis. Eur. Respir. J. 2018; 52 (6): 1801586. DOI: 10.1183/13993003.01586-2018.Cazzola M., Rogliani P., Calzetta L., Matera M.G. Triple therapy versus single and dual long-acting bronchodilator therapy in COPD: a systematic review and meta-analysis. Eur. Respir. J. 2018; 52 (6): 1801586. DOI: 10.1183/13993003.01586-2018.Yoon J.K., Lee J.K., Lee C.H. et al. The association between eosinophil variability patterns and the efficacy of inhaled corticosteroids in stable COPD patients. Int. J. Chron. Obstruct Pulmon. Dis. 2020; 15: 2061-2070. DOI: 10.2147/COPD.S258353.Yoon J.K., Lee J.K., Lee C.H. et al. The association between eosinophil variability patterns and the efficacy of inhaled corticosteroids in stable COPD patients. Int. J. Chron. Obstruct Pulmon. Dis. 2020; 15: 2061-2070. DOI: 10.2147/COPD.S258353.Lipson D.A., Barnhart F., Brealey N. et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N. Engl. J. Med. 2018; 378 (18): 1671-1680. DOI: 10.1056/NEJMoa1713901.Lipson D.A., Barnhart F., Brealey N. et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N. Engl. J. Med. 2018; 378 (18): 1671-1680. DOI: 10.1056/NEJMoa1713901.Лещенко И.В., Баранова И.И. Хроническая обструктивная болезнь легких: проблемные вопросы клинической эпидемиологии, факторов риска и базисной терапии (обзор литературы). Consilium Medicum. 2016; 18 (11): 8-18.Leshchenko I.V., Baranova I.I. [Chronic obstructive pulmonary disease: clinical issues, epidemiology, risk factors and the basic therapy (review)]. Consilium Medicum. 2016; 18 (11): 8-18 (in Russian).Burge P.S., Calverley P.M., Jones P.W. et al. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320 (7245): 1297-1303. DOI: 10.1136/bmj.320.7245.1297.Burge P.S., Calverley P.M., Jones P.W. et al. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br. Med. J. 2000; 320 (7245): 1297-1303. DOI: 10.1136/bmj.320.7245.1297.Pauwels R.A., Lofdahl C.G., Laitinen L.A. et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 1999; 340 (25): 1948-1953. DOI: 10.1056/NEJM199906243402503.Pauwels R.A., Lofdahl C.G., Laitinen L.A. et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N. Engl. J. Med.1999; 340 (25): 1948-1953. DOI: 10.1056/NEJM199906243402503.Vestbo J., S0rensen T., Lange P. et al. Long-term effect of inhaled budesomde in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 1999; 353 (9167): 1819-1823. DOI: 10.1016/s0140-6736(98)10019-3.Vestbo J., S0rensen T., Lange P. et al. Long-term effect of inhaled budesomde in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 1999; 353 (9167): 1819-1823. DOI: 10.1016/s0140-6736(98)10019-3.The Lung Health Study Research Group: (Wise R., Connett J., Weinmann G. et al.) Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343 (26): 19021909. DOI: 10.1056/NEJM200012283432601.The Lung Health Study Research Group: (Wise R., Connett J., Weinmann G. et al.) Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N. Engl. J. Med. 2000; 343 (26): 19021909. DOI: 10.1056/NEJM200012283432601.Calverley P., Pauwels R., Vestbo J. et al. Combined salme-terol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003; 361 (9356): 449-456. DOI: 10.1016/S0140-6736(03)12459-2.Calverley P., Pauwels R., Vestbo J. et al. Combined salme-terol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003; 361 (9356): 449-456. DOI: 10.1016/S0140-6736(03)12459-2.Szafranski W., Cukier A., Ramirez A. et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 21 (1): 74-81. DOI: 10.1183/09031936.03.00031402.Szafranski W., Cukier A., Ramirez A. et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur. Respir. J. 2003; 21 (1): 74-81. DOI: 10.1183/09031936.03.00031402.Gizycki M.J., Hattotuwa K.L., Barnes N., Jeffery P.K. Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue. Thorax. 2002; 57: 799-803. DOI: 10.1136/tho-rax.57.9.799.Gizycki M.J., Hattotuwa K.L., Barnes N., Jeffery P.K. Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue. Thorax. 2002; 57: 799-803. DOI: 10.1136/tho-rax.57.9.799.Hanania N.A., Darken P., Horstman D. et al. The efficacy and safety of fluticasone propionate (250 mcg)/salmeterol (50 mcg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003; 124 (3): 834-843. DOI: 10.1378/chest.124.3.834.Hanania N.A., Darken P., Horstman D. et al. The efficacy and safety of fluticasone propionate (250 mcg)/salmeterol (50 mcg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003; 124 (3): 834-843. DOI: 10.1378/chest.124.3.834.Hattotuwa K.L., Gizycki M.J., Ansari T.W. et al. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am. J. Respir. Crit. Care Med. 2002; 165 (12): 1592-1596. DOI: 10.1164/rccm.2105025.Hattotuwa K.L., Gizycki M.J., Ansari T.W. et al. The effects of inhaled fluticasone on airway inflammation in chronic obstructive pulmonary disease: a double-blind, placebo-controlled biopsy study. Am. J. Respir. Crit. Care Med. 2002; 165 (12): 1592-1596. DOI: 10.1164/rccm.2105025.Mahler D.A., Wire P., Horstman D. et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2002; 166 (8): 1084-1091. DOI: 10.1164/rccm.2112055.Mahler D.A., Wire P., Horstman D. et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2002; 166 (8): 1084-1091. DOI: 10.1164/rccm.2112055.Paggiaro L.P., Dahle R., Bakran I. et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with COPD. Lancet. 1998; 351 (9105): 773-780. DOI: 10.1016/s0140-6736(97)03471-5.Paggiaro L.P., Dahle R., Bakran I. et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with COPD. Lancet. 1998; 351 (9105): 773-780. DOI: 10.1016/s0140-6736(97)03471-5.Thompson W.H., Carvalho P., Souza J.P., Charan N.B. Controlled trial of inhaled fluticasone propionate in moderate to severe COPD. Lung. 2002; 180 (4): 191-201. DOI: 10.1007/s004080000093.Thompson W.H., Carvalho P., Souza J.P., Charan N.B. Controlled trial of inhaled fluticasone propionate in moderate to severe COPD. Lung. 2002; 180 (4): 191-201. DOI: 10.1007/s004080000093.Hurst J.R., Vestbo J., Anzueto A. et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N. Engl. J. Med. 2010; 363 (12): 1128-1138. DOI: 10.1056/NEJMoa0909883.Hurst J.R., Vestbo J., Anzueto A. et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N. Engl. J. Med. 2010; 363 (12): 1128-1138. DOI: 10.1056/NEJMoa0909883.Spencer S., Jones P.W. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax. 2003; 58 (7): 589-593. DOI: 10.1136/thorax.58.7.589.Spencer S., Jones P.W. Time course of recovery of health status following an infective exacerbation of chronic bronchitis. Thorax. 2003; 58 (7): 589-593. DOI: 10.1136/thorax.58.7.589.Celli B.R., Thomas N.E., Anderson J.A. et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am. J. Respir. Crit. Care Med. 2008; 178 (4): 332-338. DOI: 10.1164/rccm.200712-1869OC.Celli B.R., Thomas N.E., Anderson J.A. et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am. J. Respir. Crit. Care Med. 2008; 178 (4): 332-338. DOI: 10.1164/rccm.200712-1869OC.Donaldson G.C., Hurst J.R., Smith C.J. et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest. 2010; 137 (5): 1091-1097. DOI: 10.1378/chest.09-2029.Donaldson G.C., Hurst J.R., Smith C.J. et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest. 2010; 137 (5): 1091-1097. DOI: 10.1378/chest.09-2029.Rebordosa C., Plana E., Aguado J. et al. GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD). Pharmacoepidemiol. Drug Saf. 2019; 28 (2): 126-133. DOI: 10.1002/pds.4448.Rebordosa C., Plana E., Aguado J. et al. GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD). Pharmacoepidemiol. Drug Saf. 2019; 28 (2): 126-133. DOI: 10.1002/pds.4448.Mullerova H., Maselli D.J., Locantore N. et al. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015; 147 (4): 999-1007. DOI: 10.1378/chest.14-0655.Mullerova H., Maselli D.J., Locantore N. et al. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015; 147 (4): 999-1007. DOI: 10.1378/chest.14-0655.Ferguson G.T., Rabe K.F., Martinez F.J. et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir. Med. 2018; 6 (10): 747-758. DOI: 10.1016/S2213-2600(18)30327-8.Ferguson G.T., Rabe K.F., Martinez F.J. et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir. Med. 2018; 6 (10): 747-758. DOI: 10.1016/S2213-2600(18)30327-8.Papi A., Vestbo J., Fabbri L. et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018; 391 (10125): 1076-1084. DOI: 10.1016/S0140-6736(18)30206-X.Papi A., Vestbo J., Fabbri L. et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018; 391 (10125): 1076-1084. DOI: 10.1016/S0140-6736(18)30206-X.Singh D., Papi A., Corradi M. et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting e2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016; 388 (10048): 963-973. DOI: 10.1016/S0140-6736(16)31354-X.Singh D., Papi A., Corradi M. et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting e2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016; 388 (10048): 963-973. DOI: 10.1016/S0140-6736(16)31354-X.Sander N., Fusco-Walkert S.J., Harder J.M., Chipps B.E. Dose counting and the use of pressurized metered-dose inhalers: running on empty. Ann. Allergy Asthma Immunol. 2006; 97 (1): 34-38. DOI: 10.1016/s1081-1206(10)61366-x.Sander N., Fusco-Walkert S.J., Harder J.M., Chipps B.E. Dose counting and the use of pressurized metered-dose inhalers: running on empty. Ann. Allergy Asthma Immunol. 2006; 97 (1): 34-38. DOI: 10.1016/s1081-1206(10)61366-x.Rennard S.I., Tashkin D.P., McElhattan J. et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: Results from a 1-year randomized controlled clinical trial. Drugs. 2009; 69 (5): 549-565. DOI: 10.2165/00003495-200969050-00004.Rennard S.I., Tashkin D.P., McElhattan J. et al. Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: Results from a 1-year randomized controlled clinical trial. Drugs. 2009; 69 (5): 549-565. DOI: 10.2165/00003495-200969050-00004.Tashkin D.P., Rennard S.I., Martin P. et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: Results of a 6month randomized clinical trial. Drugs. 2008; 68 (14): 1975-2000. DOI: 10.2165/00003495-200868140-00004.Tashkin D.P., Rennard S.I., Martin P. et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: Results of a 6month randomized clinical trial. Drugs. 2008; 68 (14): 1975-2000. DOI: 10.2165/00003495-200868140-00004.Broeders M.E., Sanchis J., Levy M.L. et al. The ADMIT series - issues in inhalation therapy. 2. Improving technique and clinical effectiveness. Prim. Care Respir. J. 2009; 18 (2): 76-82. DOI: 10.4104/pcrj.2009.00025.Broeders M.E., Sanchis J., Levy M.L. et al. The ADMIT series - issues in inhalation therapy. 2. Improving technique and clinical effectiveness. Prim. Care Respir. J. 2009; 18 (2): 76-82. DOI: 10.4104/pcrj.2009.00025.Azouz W., Chrystyn H. Clarifying the dilemmas about inhalation techniques for dry powder inhalers: integrating science with clinical practice. Prim. Care Respir. J. 2012; 21 (2): 208-213. DOI: 10.4104/pcrj.2012.00010.Azouz W., Chrystyn H. Clarifying the dilemmas about inhalation techniques for dry powder inhalers: integrating science with clinical practice. Prim. Care Respir. J. 2012; 21 (2): 208-213. DOI: 10.4104/pcrj.2012.00010.

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