vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2025-734vedomostiregmed-734Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯCLINICAL STUDIESПрограмма клинических исследований лекарственных препаратов для лечения хронического запора: анализ руководства Европейского агентства по лекарственным средствамPlanning a clinical trial programme for medicinal products for chronic constipation: An analysis of the European Medicines Agency Guidelinehttps://orcid.org/0000-0003-0934-5067ПроскуринаИ. А.ProskurinaI. A.

Проскурина Ирина Анатольевна - канд. мед. наук.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Irina A. Proskurina - Cand. Sci. (Med.).

8/2 Petrovsky Blvd, Moscow 127051

https://orcid.org/0000-0002-5430-6975ГорскаяТ. Е.GorskayaT. E.

Горская Татьяна Евгеньевна

Петровский б-р, д. 8, стр. 2, Москва, 127051

Tatiana E. Gorskaya

8/2 Petrovsky Blvd, Moscow 127051

gorskayate@expmed.ruhttps://orcid.org/0009-0005-2105-7270ИльинР. С.IlinR. S.

Ильин Роман Святославович

Петровский б-р, д. 8, стр. 2, Москва, 127051

Roman S. Ilin

8/2 Petrovsky Blvd, Moscow 127051

https://orcid.org/0000-0001-8583-2372ГорячевД. В.GoryachevD. V.

Горячев Дмитрий Владимирович - д-р мед. наук.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Dmitriy V. Goryachev - Dr. Sci. (Med.).

8/2 Petrovsky Blvd, Moscow 127051

Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202501052025152229240Copyright © Проскурина И.А., Горская Т.Е., Ильин Р.С., Горячев Д.В., 20252025Проскурина И.А., Горская Т.Е., Ильин Р.С., Горячев Д.В.Proskurina I.A., Gorskaya T.E., Ilin R.S., Goryachev D.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.vedomostincesmp.ru/jour/article/view/734ВВЕДЕНИЕ

ВВЕДЕНИЕ. Хронический запор — широко распространенное заболевание, приводящее к существенному ухудшению качества жизни пациентов и требующее значительных прямых и косвенных расходов на диагностику и лечение. Ограниченное количество доступных эффективных лекарственных препаратов (ЛП) для лечения хронического запора, проблемы с их переносимостью и безо­пасностью при длительном применении обусловливают необходимость разработки и проведения клинических исследований (КИ) новых эффективных ЛП для лечения этого заболевания. В настоящее время в Российской Федерации и в других государствах — членах Евразийского экономического союза (ЕАЭС) отсутствуют рекомендации, регламентирующие вопросы планирования и проведения КИ новых ЛП для лечения хронического запора.

ЦЕЛЬ

ЦЕЛЬ. Оценка возможности использования зарубежных методических подходов для подготовки руководства по планированию программы КИ новых лекарственных препаратов для лечения хронического запора.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Проведен анализ основных положений руководства Европейского агентства по лекарственным средствам (European Medicines Agency, EMA) по КИ новых ЛП для лечения хронического запора. Определены особенности проведения фармакологических исследований и подтверждающих КИ (выбор популяции исследования, дизайна и длительности КИ, выбор первичных и вторичных конечных точек для оценки эффективности, оценка безопасности), а также особенности проведения подтверждающих КИ у детей и пациентов пожилого возраста.

ВЫВОДЫ

ВЫВОДЫ. Положения Руководства ЕМА соответствуют всем требованиям, необходимым при планировании программы КИ, и могут быть положены в основу руководства, разрабатываемого для проведения КИ в Российской Федерации и государствах — членах ЕАЭС.

INTRODUCTION

INTRODUCTION. Chronic constipation is a widespread condition associated with substantial direct and indirect costs for diagnosis and treatment and a significant reduction in the quality of life of patients. There is a need for the development and clinical studies of novel medicinal products for chronic constipation due to the limited availability of effective treatment options and concerns regarding the long-term safety and tolerability of these options. Currently, the Russian Federation and other Member States of the Eurasian Economic Union (EAEU) lack guidelines governing the design and conduct of clinical trials of new medicinal products for chronic constipation.

AIM

AIM. This study aimed to analyse the relevant international approaches and methods as a potential basis for drafting a regional guideline for planning clinical trial programmes for novel medicinal products for chronic constipation.

DISCUSSION

DISCUSSION. This study analysed the main provisions of the European Medicines Agency (EMA) outlined in the Guideline on the evaluation of medicinal products for the treatment of chronic constipation (including opioid-induced constipation) and for bowel cleansing. The authors identified special considerations for conducting pharmacology studies and confirmatory clinical trials (selection of the clinical trial population, design, and duration; selection of primary and secondary efficacy endpoints; and safety assessment). Additionally, the authors highlighted special considerations for confirmatory clinical trials in paediatric and geriatric populations.

CONCLUSIONS

CONCLUSIONS. The EMA guideline covers all the requirements that are necessary for designing a clinical trial programme for a novel medicinal product for chronic constipation. Therefore, the EMA guideline can inform the ongoing development of the corresponding guideline for the Russian Federation and other EAEU Member States.

хронический запорклиническое исследованиелекарственный препаратэффективностьбезопасностьруководствоЕвропейское агентство по лекарственным средствамЕМАслабительные средстваchronic constipationclinical trialmedicinal productefficacysafetyguidelinesEuropean Medicines AgencyEMAlaxativesРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00001-25-00 на проведение прикладных научных исследований (номер государственного учета НИР 124022300127-0)This study was conducted by the Scientific Centre for Expert Evaluation of Medicinal Products as part of the applied research funded under State Assignment No. 056-00001-25-00 (R&D Registry No. 124022300127-0)ReferencesRoque M, Bouras E. Epidemiology and management of chronic constipation in elderly patients. Clin Interv Aging. 2015;10:919–30. https://doi.org/10.2147/CIA.S54304Roque M, Bouras E. Epidemiology and management of chronic constipation in elderly patients. Clin Interv Aging. 2015;10:919–30. https://doi.org/10.2147/CIA.S54304Bharucha AE, Pemberton JH, Locke GR. American gastroenterological association technical review on constipation. Gastroenterology. 2013;144(1):218–38. https://doi.org/10.1053/j.gastro.2012.10.028Bharucha AE, Pemberton JH, Locke GR. American gastroenterological association technical review on constipation. Gastroenterology. 2013;144(1):218–38. https://doi.org/10.1053/j.gastro.2012.10.028Chu H, Zhong L, Li H, Zhang X, Zhang J, Hou X. Epidemiology characteristics of constipation for general population, pediatric population, and elderly population in China. Gastroenterol Res Pract. 2014;2014:532734. https://doi.org/10.1155/2014/532734Chu H, Zhong L, Li H, Zhang X, Zhang J, Hou X. Epidemiology characteristics of constipation for general population, pediatric population, and elderly population in China. Gastroenterol Res Pract. 2014;2014:532734. https://doi.org/10.1155/2014/532734Mugie SM, Benninga MA, Di Lorenzo C. Epidemiology of constipation in children and adults: A systematic review. Best Pract Res Clin Gastroenterol. 2011;25(1):3–18. https://doi.org/10.1016/j.bpg.2010.12.010Mugie SM, Benninga MA, Di Lorenzo C. Epidemiology of constipation in children and adults: A systematic review. Best Pract Res Clin Gastroenterol. 2011;25(1):3–18. https://doi.org/10.1016/j.bpg.2010.12.010Eoff JC. Optimal treatment of chronic constipation in managed care: Review and roundtable discussion. J Manag Care Pharm. 2008;14(9 Suppl A):1–15. https://doi.org/10.18553/jmcp.2008.14.s8-a.1Eoff JC. Optimal treatment of chronic constipation in managed care: Review and roundtable discussion. J Manag Care Pharm. 2008;14(9 Suppl A):1–15. https://doi.org/10.18553/jmcp.2008.14.s8-a.1Маевская ЕА. Хронический запор: тактика ведения на основе научных фактов. Фарматека. 2014;(14):17–23. EDN: SVQFTFMaevskaya EA. Chronic constipation: Management tactics based on scientific evidence. Farmateka. 2014;(14):17–23 (In Russ.). EDN: SVQFTFCamilleri M, Ford AC, Mawe GM, Dinning PG, Rao SS, Chey WD, et al. Chronic constipation. Nat Rev Dis Primers. 2017;3:17095. https://doi.org/10.1038/nrdp.2017.95Camilleri M, Ford AC, Mawe GM, Dinning PG, Rao SS, Chey WD, et al. Chronic constipation. Nat Rev Dis Primers. 2017;3:17095. https://doi.org/10.1038/nrdp.2017.95Forootan M, Bagheri N, Darvishi M. Chronic constipation: A review of literature. Medicine (Baltimore). 2018;97(20):e10631. https://doi.org/10.1097/md.0000000000010631Forootan M, Bagheri N, Darvishi M. Chronic constipation: A review of literature. Medicine (Baltimore). 2018;97(20):e10631. https://doi.org/10.1097/md.0000000000010631Lacy BE, Mearin F, Lin Chang, Chey WD, Lembo, AJ, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–407. https://doi.org/10.1053/j.gastro.2016.02.031Lacy BE, Mearin F, Lin Chang, Chey WD, Lembo, AJ, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–407. https://doi.org/10.1053/j.gastro.2016.02.031Андреев ДН, Заборовский АВ, Трухманов АС, Маев ИВ, Ивашкин ВТ. Эволюция представлений о функциональных заболеваниях желудочно-кишечного тракта в свете Римских критериев IV пересмотра (2016 г.). Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2017;27(1):4–11. https://doi.org/10.22416/1382-4376-2017-27-1-4-11Andreyev DN, Zaborovsky AV, Trukhmanov AS, Mayev IV, Ivashkin VT. Evaluation of the functional gastrointestinal diseases concept from standpoints of Rome IV (2016) diagnostic criteria (review). Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;27(1):4–11 (In Russ.). https://doi.org/10.22416/1382-4376-2017-27-1-4-11Tack J, Müller-Lissner S, Stanghellini V, Boeckxsta­ens G, Kamm MA, Simren M, et al. Diagnosis and treatment of chronic constipation — a European perspective. Neurogastroenterol Motil. 2011;23(8):697–710. https://doi.org/10.1111/j.1365-2982.2011.01709.xTack J, Müller-Lissner S, Stanghellini V, Boeckxsta­ens G, Kamm MA, Simren M, et al. Diagnosis and treatment of chronic constipation — a European perspective. Neurogastroenterol Motil. 2011;23(8):697–710. https://doi.org/10.1111/j.1365-2982.2011.01709.xDukas L, Willett WC, Giovannucci EL. Association between physical activity, fiber intake, and other lifestyle variables and constipation in a study of women. Am J Gastroenterol. 2003;98(8): 1790–6. https://doi.org/10.1111/j.1572-0241.2003.07591.xDukas L, Willett WC, Giovannucci EL. Association between physical activity, fiber intake, and other lifestyle variables and constipation in a study of women. Am J Gastroenterol. 2003;98(8): 1790–6. https://doi.org/10.1111/j.1572-0241.2003.07591.xHaug TT, Mykletun A, Dahl AA. Are anxiety and depression related to gastrointestinal symptoms in the general population? Scand J Gastroenterol. 2002;37(3):294–8. https://doi.org/10.1080/003655202317284192Haug TT, Mykletun A, Dahl AA. Are anxiety and depression related to gastrointestinal symptoms in the general population? Scand J Gastroenterol. 2002;37(3):294–8. https://doi.org/10.1080/003655202317284192Бордин ДС, Кучерявый ЮА, Андреев ДН. Хронический запор: актуальность проблемы и современные возможности терапии. Эффективная фармакотерапия. 2019;15(36):76–80. https://doi.org/10.33978/2307-3586-2019-15-36-76-80Bordin DS, Kucheryavy YuA, Andreyev DN. Chronic constipation: Urgency of the problem and modern possibilities of therapy. Effective Pharmacotherapy. 2019;15(36):76–80 (In Russ.). https://doi.org/10.33978/2307-3586-2019-15-36-76-80Tucker DM, Sandstead HH, Logan GM Jr, Klevay LM, Mahalko J, Johnson LK, et al. Dietary fiber and personality factors as determinants of stool output. Gastroenterology. 1981;81(5):879–83. PMID: 6269944Tucker DM, Sandstead HH, Logan GM Jr, Klevay LM, Mahalko J, Johnson LK, et al. Dietary fiber and personality factors as determinants of stool output. Gastroenterology. 1981;81(5):879–83. PMID: 6269944Остроумова ОД, Шахова ЕЮ, Кочетков АИ. Лекарственно-индуцированный запор. Доказательная гастроэнтерология. 2020;9(1):20–31. https://doi.org/10.17116/dokgastro2020901120Ostroumova OD, Shakhova EYu, Kochetkov AI. Drug-induced constipation. Russian Journal of Evidence-based Gastroenterology. 2020;9(1):20–31 (In Russ.). https://doi.org/10.17116/dokgastro2020901120Трухан ДИ, Деговцов ЕН, Дрокина ОВ. Пациент с синдромом запора на амбулаторнополиклиническом приеме: актуальные аспекты дифференциальной диагностики и лечения. Медицинский совет. 2021;(5):142–53. https://doi.org/10.21518/2079-701X-2021-5-142-153Trukhan DI, Degovtsov EN, Drokina OV. Patient with constipation syndrome at the ambulatory-polyclinic reception: Actual aspects of differential diagnosis and treatment. Medical Council. 2021;(5):142–53 (In Russ.). https://doi.org/10.21518/2079-701X-2021-5-142-153Sbahi H, Cash BD. Chronic constipation: A review of current literature. Curr Gastroenterol Rep. 2015;17(12):47. https://doi.org/10.1007/s11894-015-0471-zSbahi H, Cash BD. Chronic constipation: A review of current literature. Curr Gastroenterol Rep. 2015;17(12):47. https://doi.org/10.1007/s11894-015-0471-zNyam DC, Pemberton JH, Ilstrup DM, Rath DM. Long-term results of surgery for chronic constipation. Dis Colon Rectum. 1997;40(3):273–9. https://doi.org/10.1007/bf02050415Nyam DC, Pemberton JH, Ilstrup DM, Rath DM. Long-term results of surgery for chronic constipation. Dis Colon Rectum. 1997;40(3):273–9. https://doi.org/10.1007/bf02050415Rao SS. Constipation: evaluation and treatment of colonic and anorectal motility disorders. Gastroenterol Clin North Am. 2007;36(3):687–711. https://doi.org/10.1016/j.gtc.2007.07.013Rao SS. Constipation: evaluation and treatment of colonic and anorectal motility disorders. Gastroenterol Clin North Am. 2007;36(3):687–711. https://doi.org/10.1016/j.gtc.2007.07.013van der Schoot A, Drysdale C, Whelan K, Dimidi E. The effect of fiber supplementation on chronic constipation in adults: An updated systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(4):953–69. https://doi.org/10.1093/ajcn/nqac184van der Schoot A, Drysdale C, Whelan K, Dimidi E. The effect of fiber supplementation on chronic constipation in adults: An updated systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2022;116(4):953–69. https://doi.org/10.1093/ajcn/nqac184Basilisco G, Coletta M. Chronic constipation: A cri­tical review. Dig Liver Dis. 2013;45(11):886–93. https://doi.org/10.1016/j.dld.2013.03.016Basilisco G, Coletta M. Chronic constipation: A cri­tical review. Dig Liver Dis. 2013;45(11):886–93. https://doi.org/10.1016/j.dld.2013.03.016Davani-Davari D, Negahdaripour M, Karimzadeh M, Seifan M, Monkam M, Masoumi SJ, et al. Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods. 2019;8(3):92. https://doi.org/10.3390/foods8030092Davani-Davari D, Negahdaripour M, Karimzadeh M, Seifan M, Monkam M, Masoumi SJ, et al. Prebiotics: Definition, types, sources, mechanisms, and clinical applications. Foods. 2019;8(3):92. https://doi.org/10.3390/foods8030092Ивашкин ВТ, Маев ИВ, Абдулганиева ДИ, Алексеенко СА, Горелов АВ, Захарова ИН и др. Практические рекомендации Научного сообщества по содействию клиническому изучению микробиома человека (НСОИМ) и Российской гастроэнтерологической ассоциации (РГА) по применению пробиотиков, пребиотиков, синбиотиков и обогащенных ими функциональных пищевых продуктов для лечения и профилактики заболеваний гастроэнтерологического профиля у детей и взрослых. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2021;31(2):65–91. https://doi.org/10.22416/1382-4376-2021-31-2-65-91Ivashkin VT, Maev IV, Abdulganieva DI, Alekseenko SA, Gorelov AV, Zakharo­va IN, et al. Practical recommendations of scientific society for the study of human microbiome and the Russian gastroenterological association on use of probiotics, prebiotics, synbiotics and functional foods in treatment and prevention of gastroenterological diseases in children and adults. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(2):65–91 (In Russ.). https://doi.org/10.22416/1382-4376-2021-31-2-65-91Le Nevé B, de la Torre AM, Tap J, Derrien M, Cotillard A, Barba E, et al. A fermented milk product with B. Lactis CNCM I-2494 and lactic acid bacteria improves gastrointestinal comfort in response to a challenge diet rich in fermentable residues in healthy subjects. Nutrients. 2020;12(2):320. https://doi.org/10.3390/nu12020320Le Nevé B, de la Torre AM, Tap J, Derrien M, Cotillard A, Barba E, et al. A fermented milk product with B. Lactis CNCM I-2494 and lactic acid bacteria improves gastrointestinal comfort in response to a challenge diet rich in fermentable residues in healthy subjects. Nutrients. 2020;12(2):320. https://doi.org/10.3390/nu12020320Stanghellini V, Vandeplassche L, Kerstens R. Best response distribution of 12-week treatment with prucalopride (RESOLOR) in patients with chronic constipation: Combined results of three randomised, double-blind, placebo-controlled phase III trials. Gut. 2011;60:159–60. https://doi.org/10.1136/gut.2011.239301.338Stanghellini V, Vandeplassche L, Kerstens R. Best response distribution of 12-week treatment with prucalopride (RESOLOR) in patients with chronic constipation: Combined results of three randomised, double-blind, placebo-controlled phase III trials. Gut. 2011;60:159–60. https://doi.org/10.1136/gut.2011.239301.338Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(1):1–35. https://doi.org/10.1038/ajg.2008.122Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol. 2009;104(1):1–35. https://doi.org/10.1038/ajg.2008.122Лузина ЕВ. Безопасность использования слабительных средств. Российский медицинский журнал. 2014;20(5):41–4. EDN: SZVCUNLuzina EV. The safety of application of laxatives. Russian Medicine. 2014;20(5):41–4 (In Russ.). EDN: SZVCUNКарпухин ОЮ, Елеев АА, Кутырева МП, Юсупова АФ, Ханнанов АА. Использование оригинальных рентгеноконтрастных маркеров в диагностике хронического запора. Kолопроктология. 2016;(2):6–11. https://doi.org/10.33878/2073-7556-2016-0-2-6-11Karpukhin OYu, Eleev AA, Kutyreva MP, Yusupova AF, Khannanov AA. The use of original radiopaque markers in diagnosis of chronic constipation. Koloproktologia. 2016;(2):6–11 (In Russ.). https://doi.org/10.33878/2073-7556-2016-0-2-6-11Rao SS, Hatfield R, Soffer E, Rao S, Beaty J, Conkin JL. Manometric tests of anorectal function in healthy adults. Am J Gastroenterol. 1999;94(3):773–83. https://doi.org/10.1111/j.1572-0241.1999.00950.xRao SS, Hatfield R, Soffer E, Rao S, Beaty J, Conkin JL. Manometric tests of anorectal function in healthy adults. Am J Gastroenterol. 1999;94(3):773–83. https://doi.org/10.1111/j.1572-0241.1999.00950.xRasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. Childhood functional gastrointestinal disorders child/adolescent. Gastroenterology. 2006;130(5):1527–37. https://doi.org/10.1053/j.gastro.2005.08.063Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. Childhood functional gastrointestinal disorders child/adolescent. Gastroenterology. 2006;130(5):1527–37. https://doi.org/10.1053/j.gastro.2005.08.063Пахомовская НЛ, Татьянина ОФ, Лазарева ТЮ. Функциональные запоры у детей. Медицинский совет. 2022;(1):106–13. https://doi.org/10.21518/2079-701X-2022-16-1-106-113Pakhomovskaya NL, Tatianina OF, Lazareva TYu. Functional constipation in children. Medical Council. 2022;(1):106–13 (In Russ.). https://doi.org/10.21518/2079-701X-2022-16-1-106-113Koppen IJN, Lammers LA, Benninga MA, Tabbers MM. Management of functional constipation in children: Therapy in practice. Paediatr Drugs. 2015;17(5):349–60. https://doi.org/10.1007/s40272-015-0142-4Koppen IJN, Lammers LA, Benninga MA, Tabbers MM. Management of functional constipation in children: Therapy in practice. Paediatr Drugs. 2015;17(5):349–60. https://doi.org/10.1007/s40272-015-0142-4Gordon M, Naidoo K, Akobeng AK, Thomas AG. Cochrane Review: Osmotic and stimulant laxatives for the management of childhood constipation (review). Evid Based Child Health. 2013;8(1):57–109. https://doi.org/10.1002/ebch.1893Gordon M, Naidoo K, Akobeng AK, Thomas AG. Cochrane Review: Osmotic and stimulant laxatives for the management of childhood constipation (review). Evid Based Child Health. 2013;8(1):57–109. https://doi.org/10.1002/ebch.1893Kuizenga-Wessel S, Benninga MA, Tabbers MM. Reporting outcome measures of functional constipation in children from 0 to 4 years of age. J Pediatr Gastroenterol Nutr. 2015;60(4):446–56. https://doi.org/10.1097/MPG.0000000000000631Kuizenga-Wessel S, Benninga MA, Tabbers MM. Reporting outcome measures of functional constipation in children from 0 to 4 years of age. J Pediatr Gastroenterol Nutr. 2015;60(4):446–56. https://doi.org/10.1097/MPG.0000000000000631Kuizenga-Wessel S, Heckert SL, Tros W, van Etten-Jamaludin FS, Benninga MA, Tabbers MM. Reporting on outcome measures of functional constipation in children — a systematic review. J Pediatr Gastroenterol Nutr. 2016;62(6):840–6. https://doi.org/10.1097/mpg.0000000000001110Kuizenga-Wessel S, Heckert SL, Tros W, van Etten-Jamaludin FS, Benninga MA, Tabbers MM. Reporting on outcome measures of functional constipation in children — a systematic review. J Pediatr Gastroenterol Nutr. 2016;62(6):840–6. https://doi.org/10.1097/mpg.0000000000001110Koppen IJN, Saps M, Lavigne JV, Nurko S, Taminiau J, Di Lorenzo C, Benninga MA. Recommendations for pharmacological clinical trials in children with functional constipation: The Rome Foundation Pediatric Subcommittee on Clinical Trials. Neurogastroenterol Motil. 2018;30(4):e13294. https://doi.org/10.1111/nmo.13294Koppen IJN, Saps M, Lavigne JV, Nurko S, Taminiau J, Di Lorenzo C, Benninga MA. Recommendations for pharmacological clinical trials in children with functional constipation: The Rome Foundation Pediatric Subcommittee on Clinical Trials. Neurogastroenterol Motil. 2018;30(4):e13294. https://doi.org/10.1111/nmo.13294Маев ИВ, Самсонов АА, Дичева ДТ, Андреев ДН. Обстипационный синдром. Медицинский вестник МВД. 2012;(4):42–5. EDN: PAWRDHМаев ИВ, Самсонов АА, Дичева ДТ, Андреев ДН. Обстипационный синдром. Медицинский вестник МВД. 2012;(4):42–5. Mayev I, Samsonov A, Dicheva D, Andreyev D. Obstipation syndrome. MIA Medical Bulletin. 2012;(4):42–5 (In Russ.). EDN: PAWRDHFosnes GS, Lydersen S, Farup PG. Drugs and constipation in elderly in nursing homes: What is the relation? Gastroenterol Res Pract. 2012;2012:290231. https://doi.org/10.1155/2012/290231Fosnes GS, Lydersen S, Farup PG. Drugs and constipation in elderly in nursing homes: What is the relation? Gastroenterol Res Pract. 2012;2012:290231. https://doi.org/10.1155/2012/290231Fleming V, Wade WE. A review of laxative therapies for treatment of chronic constipation in older adults. Am J Geriatr Pharmacother. 2010;8(6):514–50. https://doi.org/10.1016/s1543-5946(10)80003-0Fleming V, Wade WE. A review of laxative therapies for treatment of chronic constipation in older adults. Am J Geriatr Pharmacother. 2010;8(6):514–50. https://doi.org/10.1016/s1543-5946(10)80003-0

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