Цель исследования. Определить подходы к терапии обострения хронического панкреатита с СРК-подобным синдромом. Материалы и методы. Под наблюдением находились 312 пациентов с обострением хронического панкреатита (ХП), получавшие стандартную терапию: спазмолитики, ферменты, ингибиторы протонной помпы. У 85 (27,2%) пациентов не отмечалось ответа на лечение. После исключения обструктивного варианта ХП, целиакии, декомпенсации сахарного диабета, ишемического и микроскопического колита, синдрома избыточного бактериального роста (СИБР) как причины абдоминальной боли и кишечной дисфункции выделена группа из 54 пациентов с обострением ХП и СРК-подобным синдромом. Они разделены на две группы: 1-я группа – лица, получающие, наряду со стандартным лечением ХП, ципрофлоксацин в дозе 500 мг 2 раза в сутки 10 дней (26 пациентов), 2-я группа – рифаксимин 400 мг 3 раза в сутки 10 дней (28 пациентов). Оценивали динамику клинической картины, показатели биоценоза, эндоскопические, морфологические особенности толстой кишки, концентрации интерлейкина-2 (ИЛ-2), ИЛ-6, ИЛ-8 в слизистой оболочке толстой кишки (СОТК). Результаты. У 54 (63,5%) пациентов с затяжным (более 4 нед) обострением ХП определен СРК-подобный синдром. С учетом результатов клинико-инструментального, лабораторного, бактериологического исследования предложена модификация терапии. У 68% пациентов с обострением ХП, получавших в дополнение к стандартной терапии рифаксимин, достигнуты клиническое улучшение, нормализация показателей кишечного биоценоза, снижение концентраций цитокинов в тканях, уменьшение признаков хронического воспаления в СОТК, а также концентрации ИЛ-2, ИЛ-6, ИЛ-8 в СОТК (p<0,05). Заключение. Обострение ХП, устойчивое к стандартной терапии, может быть связано с формированием СРК-подобного синдрома. Включение рифаксимина в комплексную терапию затяжного обострения ХП способствует купированию кишечной дисфункции, абдоминальной боли, связанной с кишечником, улучшает показатели биоценоза, способствует уменьшению воспалительных изменений, а также снижению концентрации цитокинов в СОТК.
Aim. To determine approaches of the exacerbation’s treatment of chronic pancreatitis (CP) with IBS (irritable bowel syndrome)-like syndrome.
Materials and methods. 312 patients with exacerbation of CP were observed and received standard therapy: antispasmodics, enzymes, proton pump inhibitors. 85 (27.2%) patients had no response to treatment. After excluding obstructive CP, celiac disease, decompensation of diabetes (DD), ischemic and microscopic colitis, small intestinal bacterial overgrowth (SIBO) as a cause of abdominal pain and intestinal dysfunction, a group of 54 patients with exacerbation of CP and IBS-like syndrome was isolated. They were divided into 2 groups: group 1 – persons receiving with standard treatment of CP ciprofloxacin in a dose of 500 mg 2 times a day for 10 days (26 patients), group 2 – rifaximin 400 mg 3 times a day for 10 days (28 patients). The dynamics of clinical picture, biocenosis indices, endoscopic, morphological features of the colon, interleukin-2 (IL-2), IL-6, IL-8 concentration in the colon mucosa (CA) were evaluated.
Results. IBS-like syndrome was determined in 54 (63.5%) patients with prolonged (more than 4 weeks) exacerbation of CP. A modification of therapy is proposed with the results of clinical and instrumental, laboratory, bacteriological studies. 68% of patients with exacerbation of CP, receiving in addition to the standard regimen rifaximin, achieved clinical improvement, normalization of intestinal biocenosis, reduced concentrations of cytokines in tissues, reducing signs of chronic inflammation in the colon mucosa with reducing concentrations of IL-2, IL-6, IL-8 in colon mucosa (p<0.05).
Conclusion. Exacerbation of CP, resistant to standard therapy, may be associated with the formation of IBS-like syndrome. The inclusion of rifaximin in the complex therapy of prolonged exacerbation of CP contributes to the relief of intestinal dysfunction, abdominal pain of intestine, improves biocenosis, reduces inflammatory modifications, and reduces the concentration of cytokines in the colon mucosa.
1. Ивашкин В.Т., Маев И.В., Охлобыстин А.В., Кучерявый Ю.А. и др. Рекомендации Российской гастроэнтерологической ассоциации по диагностике и лечению хронического панкреатита. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2014;(4):70-97 [Ivashkin VT, Maev IV, Okhlobystin AV, Kucheryavyy YuA, et al. Guidelines of the Russian gastroenterological association on diagnostics and treatment of a chronic pancreatitis. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2014;(4):70-97 (In Russ.)].
2. Быкова А.П., Козлова И.В. Механизмы развития и особенности патологии органов желудочно-кишечного тракта при хроническом панкреатите. Экспериментальная и клиническая гастроэнтерология. 2016;135(11):69-75 [Bykova AP, Kozlova IV. Mechanisms of development and characteristics the pathology of the gastrointestinal. Experimental & Clinical Gastroenterology. 2016;135(11):69-75 (In Russ.)].
3. Lariño-Noia J, de la Iglesia D, Iglesias-García J, Macías F, Nieto L, Bastón I, et al. Morphological and functional changes of chronic pancreatitis in patients with dyspepsia: A prospective, observational, cross-sectional study. Pancreatology. 2018;18(3):280-5. doi: 10.1016/j.pan.2018.02.003
4. Ивашкин В.Т., Ивашкин К.В., Охлобыстин А.В. Боль при хроническом панкреатите: происхождение и возможности коррекции (материалы авторской программы академика РАН, профессора В.Т. Ивашкина на портале internist.ru 6 марта 2015 г.). Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2015;25(3):4-11 [Ivashkin VT, Ivashkin KV, Okhlobystin AV. Pain at chronic pancreatitis: origin and treatment options (Data of author's program of professor V.T. Ivashkin at www.internist.ru portal on March, 6, 2015) Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2015;25(3):4-11 (In Russ.)].
5. Leeds JS, Hopper AD, Sidhu R, Simmonette A, Azadbakht N, Hoggard N, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol. 2010;8(5):433-8. doi: 10.1016/j.cgh.2009.09.032
6. Trespi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin. 1999;5;47-52. doi: 10.1185/03007999909115173
7. Talley NJ, Holtmann G, Nguyen QN, Gibson P, Bampton P, Veysey M, et al. Undiagnosed pancreatic exocrine insufficiency and chronic pancreatitis in functional GI disorder patients with diarrhea or abdominal pain. J Gastroenterol Hepatol. 2017 Nov;32(11):1813-7. doi: 10.1111/jgh.13791
8. Калягин А.Н., Решина И.В. Современные аспекты ведения больных с хроническими панкреатитами. Сибирский медицинский журнал. 2011;(4):143-5 [Kalyagin AN, Reshina IV. The modern aspects of conducting the patients with chronic pancreatitis. Sibirskii Meditsinskii Zhurnal. 2011;(4):143-5 (In Russ.)].
9. Anderson MA, Akshintala V, Albers KM, Amann ST, Belfer I, Brand R, et al. Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology. 2016;16(1):83-94. doi: 10.1016/j.pan.2015.10.015
10. Быкова А.П., Козлова И.В. Клинико-эндоскопические и морфологические особенности слизистой оболочки толстой кишки при хроническом панкреатите. Экспериментальная и клиническая гастроэнтерология. 2017;139(3):22-7 [Bykova AP, Kozlova IV. Clinical-endoscopic and morphological features of the colon in chronic pancreatitis. Experimental & Clinical Gastroenterology. 2017;139(3):22-7 (In Russ.)].
11. DiMagno MJ, Forsmark CE. Chronic pancreatitis and small intestinal bacterial overgrowth. Pancreatology. 2018;18(4):360-2. doi: 10.1016/j.pan.2018.04.011
12. Ní Chonchubhair HM, Bashir Y, Dobson M, Ryan BM, Duggan SN, Conlon KC. The prevalence of small intestinal bacterial overgrowth in non-surgical patients with chronic pancreatitis and pancreatic exocrine insufficiency (PEI). Pancreatology. 2018;18(4):379-85. doi: 10.1016/j.pan.2018.02.010
13. Приказ Министерства здравоохранения и социального развития Российской Федерации от 27 октября 2005 года № 651 «Об утверждении стандарта медицинской помощи больным с другими хроническими панкреатитами». Доступно по ссылке: http://docs.cntd.ru/document/901954702 (дата обращения 27.03.2019) [Order of the Ministry of Health and Social Development of the Russian Federation of October 27, 2005 No. 651 “On approval of the standard of medical care for patients with other chronic pancreatitis” (In Russ.)].
14. Hoffmeister A, Mayerle J, Beglinger C, Büchler MW, Bufler P, Dathe K, et al. English language version of the S3-consensus guidelines on chronic pancreatitis. Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis. Z Gastroenterol. 2015;53(12):1447-95. doi: 10.1055/s-0041-107379
15. Lohr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, Lerch MM, et al. United European Gastroenterology evidence–based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). UEG Working Group United Eur Gastroenterol J. 2017;5:153-99. doi: 10.1177/2050640616684695
16. Frulloni L, Falconi M, Gabbrielli A, Gaia E, Graziani R, Pezzilli R, et al. Italian consensus guidelines for chronic pancreatitis. Dig Liver Dis. 2010;42(6):381-406. doi: 10.1016/S1590-8658(10)60682-2
17. Dupont HL. Rifaximin: An antibiotic with important biologic effects. Mini Rev Med Chem. 2016;16(3):200-5.
18. Jiang ZD, DuPont HL. Rifaximin: in vitro and in vivo antibacterial activity – a review. Chemotherapy. 2005;51:67-72.
19. Hirota SA. Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders – a focus on the modulation of host tissue function. Mini Rev Med Chem. 2016;16(3):206-17.
20. Cianci R, Frosali S, Pagliari D, Cesaro P, Petruzziello L, Casciano F, et al. Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin. J Immunol Res. 2014;2014:696812. doi: 10.1155/2014/696812
21. Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun. 2018;70:61-75. doi: 10.1016/j.bbi.2018.02.013
22. Oppenheim JJ, Rosso JL, Gearing AJ. Clinical application of cytokines. Role in pathogenesis, diagnosis and therapy. Cary, NC: Oxford University Press, 1994. 379 p.
23. Melchior C, Aziz M, Aubry T, Gourcerol G, Quillard M, Zalar A, et al. Does calprotectin level identify a subgroup among patients suffering from irritable bowel syndrome? Results of a prospective study. Unit Eur Gastroenterol J. 2017 Mar;5(2):261-9. doi: 10.1177/2050640616650062
24. Labro MT. Anti-inflammatory activity of ansamycins. Expert Rev Anti Infect Ther. 2005;3(1):91-103.
25. Balzan S, de Almeida Quadros C, de Cleva R, et al. Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol. 2007;22(4):464-71. doi: 10.1111/j.1440-1746.2007.04933.x
26. Calanni F, Renzulli C, Barbanti M, et al. Rifaximin: beyond the traditional antibiotic activity. J Antibiot (Tokyo). 2014;67(9):667-70. doi: 10.1038/ja.2014.106
________________________________________________
1. Ivashkin VT, Maev IV, Okhlobystin AV, Kucheryavyy YuA, et al. Guidelines of the Russian gastroenterological association on diagnostics and treatment of a chronic pancreatitis. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2014;(4):70-97 (In Russ.)
2. Bykova AP, Kozlova IV. Mechanisms of development and characteristics the pathology of the gastrointestinal. Experimental & Clinical Gastroenterology. 2016;135(11):69-75 (In Russ.)
3. Lariño-Noia J, de la Iglesia D, Iglesias-García J, Macías F, Nieto L, Bastón I, et al. Morphological and functional changes of chronic pancreatitis in patients with dyspepsia: A prospective, observational, cross-sectional study. Pancreatology. 2018;18(3):280-5. doi: 10.1016/j.pan.2018.02.003
4. Ivashkin VT, Ivashkin KV, Okhlobystin AV. Pain at chronic pancreatitis: origin and treatment options (Data of author's program of professor V.T. Ivashkin at www.internist.ru portal on March, 6, 2015) Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2015;25(3):4-11 (In Russ.)
5. Leeds JS, Hopper AD, Sidhu R, Simmonette A, Azadbakht N, Hoggard N, et al. Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency. Clin Gastroenterol Hepatol. 2010;8(5):433-8. doi: 10.1016/j.cgh.2009.09.032
6. Trespi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin. 1999;5;47-52. doi: 10.1185/03007999909115173
7. Talley NJ, Holtmann G, Nguyen QN, Gibson P, Bampton P, Veysey M, et al. Undiagnosed pancreatic exocrine insufficiency and chronic pancreatitis in functional GI disorder patients with diarrhea or abdominal pain. J Gastroenterol Hepatol. 2017 Nov;32(11):1813-7. doi: 10.1111/jgh.13791
8. Kalyagin AN, Reshina IV. The modern aspects of conducting the patients with chronic pancreatitis. Sibirskii Meditsinskii Zhurnal. 2011;(4):143-5 (In Russ.)
9. Anderson MA, Akshintala V, Albers KM, Amann ST, Belfer I, Brand R, et al. Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology. 2016;16(1):83-94. doi: 10.1016/j.pan.2015.10.015
10. Bykova AP, Kozlova IV. Clinical-endoscopic and morphological features of the colon in chronic pancreatitis. Experimental & Clinical Gastroenterology. 2017;139(3):22-7 (In Russ.)
11. DiMagno MJ, Forsmark CE. Chronic pancreatitis and small intestinal bacterial overgrowth. Pancreatology. 2018;18(4):360-2. doi: 10.1016/j.pan.2018.04.011
12. Ní Chonchubhair HM, Bashir Y, Dobson M, Ryan BM, Duggan SN, Conlon KC. The prevalence of small intestinal bacterial overgrowth in non-surgical patients with chronic pancreatitis and pancreatic exocrine insufficiency (PEI). Pancreatology. 2018;18(4):379-85. doi: 10.1016/j.pan.2018.02.010
13. Order of the Ministry of Health and Social Development of the Russian Federation of October 27, 2005 No. 651 “On approval of the standard of medical care for patients with other chronic pancreatitis” (In Russ.)
14. Hoffmeister A, Mayerle J, Beglinger C, Büchler MW, Bufler P, Dathe K, et al. English language version of the S3-consensus guidelines on chronic pancreatitis. Definition, aetiology, diagnostic examinations, medical, endoscopic and surgical management of chronic pancreatitis. Z Gastroenterol. 2015;53(12):1447-95. doi: 10.1055/s-0041-107379
15. Lohr JM, Dominguez-Munoz E, Rosendahl J, Besselink M, Mayerle J, Lerch MM, et al. United European Gastroenterology evidence–based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). UEG Working Group United Eur Gastroenterol J. 2017;5:153-99. doi: 10.1177/2050640616684695
16. Frulloni L, Falconi M, Gabbrielli A, Gaia E, Graziani R, Pezzilli R, et al. Italian consensus guidelines for chronic pancreatitis. Dig Liver Dis. 2010;42(6):381-406. doi: 10.1016/S1590-8658(10)60682-2
17. Dupont HL. Rifaximin: An antibiotic with important biologic effects. Mini Rev Med Chem. 2016;16(3):200-5.
18. Jiang ZD, DuPont HL. Rifaximin: in vitro and in vivo antibacterial activity – a review. Chemotherapy. 2005;51:67-72.
19. Hirota SA. Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders – a focus on the modulation of host tissue function. Mini Rev Med Chem. 2016;16(3):206-17.
20. Cianci R, Frosali S, Pagliari D, Cesaro P, Petruzziello L, Casciano F, et al. Uncomplicated Diverticular Disease: Innate and Adaptive Immunity in Human Gut Mucosa before and after Rifaximin. J Immunol Res. 2014;2014:696812. doi: 10.1155/2014/696812
21. Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun. 2018;70:61-75. doi: 10.1016/j.bbi.2018.02.013
22. Oppenheim JJ, Rosso JL, Gearing AJ. Clinical application of cytokines. Role in pathogenesis, diagnosis and therapy. Cary, NC: Oxford University Press, 1994. 379 p.
23. Melchior C, Aziz M, Aubry T, Gourcerol G, Quillard M, Zalar A, et al. Does calprotectin level identify a subgroup among patients suffering from irritable bowel syndrome? Results of a prospective study. Unit Eur Gastroenterol J. 2017 Mar;5(2):261-9. doi: 10.1177/2050640616650062
24. Labro MT. Anti-inflammatory activity of ansamycins. Expert Rev Anti Infect Ther. 2005;3(1):91-103.
25. Balzan S, de Almeida Quadros C, de Cleva R, et al. Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol. 2007;22(4):464-71. doi: 10.1111/j.1440-1746.2007.04933.x
26. Calanni F, Renzulli C, Barbanti M, et al. Rifaximin: beyond the traditional antibiotic activity. J Antibiot (Tokyo). 2014;67(9):667-70. doi: 10.1038/ja.2014.106
Авторы
И.В. Козлова1, А.П. Быкова1, М.А. Осадчук2
1 ФГБОУ ВО «Саратовский государственный медицинский университет им. В.И. Разумовского» Минздрава России, Саратов, Россия;
2 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
________________________________________________
I.V. Kozlova1, A.P. Bykova1, M.A. Osadchuk2
1 Razumovsky Saratov State Medical University, Saratov, Russia;
2 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia