Consilium MedicumConsilium MedicumConsilium MedicumConsilium Medicum2075-17532542-2170Consilium Medicum9528210.26442/20751753.2020.8.200373ArticlesСтатьиReview ArticleMechanisms of action of rebamipide: systematic reviewМеханизмы действия ребамипида: систематизация литературных данныхAndreevDmitrii N.АндреевДмитрий Николаевич

канд. мед. наук, доц. каф. пропедевтики внутренних болезней и гастроэнтерологии, науч. сотр. лаб. функциональных методов исследования в гастроэнтерологии

dna-mit8@mail.ruKulievaAlla K.КулиеваАлла Киримовна

канд. мед. наук, ассистент каф. пропедевтики внутренних болезней и гастроэнтерологии

Yevdokimov Moscow State University of Medicine and DentistryФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава России15082020228VOL 22, NO8 (2020)ТОМ 22, №8 (2020)414528122021Copyright ©; 2020, Consilium MedicumCopyright ©; 2020, ООО "Консилиум Медикум"2020Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://consilium.orscience.ru/2075-1753/article/view/95282

Rebamipide has been used in clinical practice for the treatment and prevention of various gastrointestinal diseases for 30 years. The principal mechanism of action of the drug is the induction of endogenous synthesis of prostaglandins and an indirect acceleration of ulcer healing. With that, fundamental experimental studies conducted over the past few years have significantly expanded our knowledge of the protective mechanisms of this molecule. This article summarizes the basic data on the mechanisms of action of rebamipide in gastroenterological diseases. The article provides literature data showing that the drug neutralizes lipid peroxidation, improves blood supply to the mucosa, maintains the epithelial barrier by repairing tight cell junctions, and has an antagonistic effect against the colonization activity of Helicobacter pylori.

Ребамипид используется в клинической практике для лечения и профилактики разных заболеваний желудочно-кишечного тракта на протяжении 30 лет. Принципиальным механизмом действия препарата являются индукция эндогенного синтеза простагландинов и опосредованное увеличение скорости рубцевания язвенных дефектов. Вместе с тем фундаментальные экспериментальные исследования, проведенные за последние несколько лет, значительно расширили наши знания о протективных механизмах этой молекулы. В настоящей статье систематизированы основные данные о механизмах действия ребамипида при заболеваниях гастроэнтерологического профиля. Представлены литературные данные, свидетельствующие, что препарат обеспечивает нейтрализацию перекисного окисления липидов, способствует улучшению кровоснабжения слизистой оболочки, поддерживает эпителиальный барьер путем репарации плотных контактов клеток, реализует антагонистическое влияние по отношению к колонизационной активности Helicobacter pylori.

rebamipidemechanism of actionprostaglandinslipid peroxidationfree radicalsangiogenesistight junctionsребамипидмеханизм действияпростагландиныперекисное окисление липидовсвободные радикалыангиогенезплотные контактыNaito Y, Yoshikawa T Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Expert Rev Gastroenterol Hepatol 2010; 4 (3): 261-70.Звяглова М.Ю., Князев О.В., Парфенов А.И. Фармакологический и клинический профиль ребамипида: новые терапевтические мишени. Терапевтический архив. 2020; 92 (2): 104-11. DOI: 10.26442/00403660.2020.02.000569Arakawa T, Higuchi K, Fujiwara Y et al. 15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications. Dig Dis Sci 2005; 50 (Suppl. 1): S3-S11. DOI: 10.1007/s10620-005-2800-9Genta RM. Review article: the role of rebamipide in the management of inflammatory disease of the gastrointestinal tract. Aliment Pharmacol Ther 2003; 18 (Suppl. 1): 8-13. DOI: 10.1046/j.1365-2036.18.s1.5.xArakawa T, Kobayashi K, Yoshikawa T, Tarnawski A. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 1998; 43 (9 Suppl.): 5S-13S.Miller SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum 2006; 36 (1): 3749. DOI: 10.1016/j.semarthrit.2006.03.005Cryer B. Mucosal defense and repair. Role of prostaglandins in the stomach and duodenum. Gastroenterol Clin North Am 2001; 30 (4): 877-vi. DOI: 10.1016/s0889-8553(05)70218-1Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiol Rev 2008; 88 (4): 1547-65. DOI: 10.1152/physrev.00004.2008Маев И.В., Самсонов А.А., Андреев Д.Н. Гастропатии, индуцированные нестероидными противовоспалительными средствами: патогенетически обоснованные подходы к профилактике и терапии. Фарматека. 2016;2: 49-54.Tarnawski AS, Chai J, Pai R, Chiou SK. Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action? Dig Dis Sci 2004; 49 (2): 202-9. DOI: 10.1023/b:ddas.0000017439.60943.5cSun WH, Tsuji S, Tsujii M et al. Induction of cyclooxygenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent. J Pharmacol Exp Ther 2000; 295 (2): 447-52.Murata H, Yabe Y Tsuji S et al. Gastro-protective agent rebamipide induces cyclooxygenease-2 (COX-2) in gastric epithelial cells. Dig Dis Sci 2005; 50 (Suppl. 1): S70-5. DOI: 10.1007/s10620-005-2809-0Suetsugu H, Ishihara S, Moriyama N et al. Effect of rebamipide on prostaglandin EP4 receptor gene expression in rat gastric mucosa. J Lab Clin Med 2000; 136 (1): 50-7. DOI: 10.1067/mlc.2000.107303Tanigawa T, Watanabe T, Ohkawa F et al. Rebamipide, a mucoprotective drug, inhibits NSAIDs-induced gastric mucosal injury: possible involvement of the downregulation of 15-hydroxyprostaglandin dehydrogenase. J Clin Biochem Nutr 2011; 48 (2): 149-53. DOI: 10.3164/jcbn.10-75Iijima K, Ichikawa T, Okada S et al. Rebamipide, a cytoprotective drug, increases gastric mucus secretion in human: evaluations with endoscopic gastrin test. Dig Dis Sci 2009; 54 (7): 1500-7. DOI: 10.1007/s10620-008-0507-4Gaschler MM, Stockwell BR. Lipid peroxidation in cell death. Biochem Biophys Res Commun 2017; 482 (3): 419-25. DOI: 10.1016/j.bbrc.2016.10.086Manda-HandzlikA, Demkow U. Neutrophils: The Role of Oxidative and Nitrosative Stress in Health and Disease. Adv Exp Med Biol 2015; 857: 51-60. DOI: 10.1007/5584_2015_117Iinuma S, Naito Y, Yoshikawa T et al. In vitro studies indicating antioxidative properties of rebamipide. Dig Dis Sci 1998; 43 (9 Suppl.): 35S-39S.Yoshikawa T, Naito Y, Tanigawa T, Kondo M. Free radical scavenging activity of the novel anti-ulcer agent rebamipide studied by electron spin resonance. Arzneimittelforschung 1993; 43 (3): 363-6.Naito Y Yoshikawa T, Tanigawa T et al. Hydroxyl radical scavenging by rebamipide and related compounds: electron paramagnetic resonance study. Free Radic Biol Med 1995; 18 (1): 117-23. DOI: 10.1016/0891-5849(94)00110-6Sakurai K, Sasabe H, Koga T, Konishi T Mechanism of hydroxyl radical scavenging by rebamipide: identification of mono-hydroxylated rebamipide as a major reaction product. Free Radic Res 2004; 38 (5): 487-94. DOI: 10.1080/1071576042000209808Kim CD, Kim YK, Lee SH, Hong KW. Rebamipide inhibits neutrophil adhesion to hypoxia/reoxygena-tion-stimulated endothelial cells via nuclear factor-kappaB-dependent pathway. J Pharmacol Exp Ther 2000; 294 (3): 864-9.Farhadi A, Keshavarzian A, Fitzpatrick LR et al. Modulatory effects of plasma and colonic milieu of patients with ulcerative colitis on neutrophil reactive oxygen species production in presence of a novel antioxidant, rebamipide. Dig Dis Sci 2002; 47 (6): 1342-8. DOI: 10.1023/a:1015382800434Hahm KB, Park IS, Kim YS et al. Role of rebamipide on induction of heat-shock proteins and protection against reactive oxygen metabolite-mediated cell damage in cultured gastric mucosal cells. Free Radic Biol Med 1997; 22 (4): 711-6. DOI: 10.1016/s0891-5849(96)00406-6Kim HK, Kim JI, Kim JK et al. Preventive effects of rebamipide on NSAID-induced gastric mucosal injury and reduction of gastric mucosal blood flow in healthy volunteers. Dig Dis Sci 2007; 52 (8): 1776-82. DOI: 10.1007/s10620-006-9367-yFarre R, Vicario M. Abnormal Barrier Function in Gastrointestinal Disorders. Handb Exp Pharmacol 2017; 239: 193-217.Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 2016; 17 (9): 564-80.Piche T Tight junctions and IBS - the link between epithelial permeability, low-grade inflammation, and symptom generation? Neurogastroenterol Motil 2014; 26 (3): 296-302.Bjbrkman EV, Edebo A, Oltean M, Casselbrant A. Esophageal barrier function and tight junction expression in healthy subjects and patients with gastroesophageal reflux disease: functionality of esophageal mucosa exposed to bile salt and trypsin in vitro. Scand J Gastroenterol 2013; 48 (10): 1118-26. DOI: 10.3109/00365521.2013.828772Thakre-Nighot M, Blikslager AT Indomethacin induces increase in gastric epithelial tight junction permeability via redistribution of occludin and activation of p38 MAPK in MKN-28 Cells. Tissue Barriers 2016; 4 (3): e1187325. DOI: 10.1080/21688370.2016.1187325Андреев Д.Н. Роль нарушения проницаемости слизистой оболочки кишечника в генезе функциональных заболеваний желудочно-кишечного тракта. Consilium Medicum. 2019; 21 (8): 2934. DOI: 10.26442/20751753.2019.8.190539Gweon TG, Park JH, Kim BW et al; Incheon and Western Kyonggi Gastrointestinal Study. Additive Effects of Rebamipide Plus Proton Pump Inhibitors on the Expression of Tight Junction Proteins in a Rat Model of Gastro-Esophageal Reflux Disease. Gut Liver 2018; 12 (1): 46-50. DOI: 10.5009/gnl17078Suzuki T, Yoshida N, Nakabe N et al. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci 2008; 106 (3): 469-77. DOI: 10.1254/jphs.fp0071422Shim S, Jang HS, Myung HW et al. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model. Toxicol Appl Pharmacol 2017; 329: 40-7. DOI: 10.1016/.taap.2017.05.012Jang H, Park S, Lee J et al. Rebamipide alleviates radiation-induced colitis through improvement of goblet cell differentiation in mice. J Gastroenterol Hepatol 2018; 33 (4): 878-86. DOI: 10.1111/gh,14021 ИНФОРМАЦИЯ ОБ АВТОРАХ / INFORMATION ABOUT THE AUTHORSМаев И.В., Андреев Д.Н. Инфекция Helicobacter pylori и ассоциированные заболевания. М.: Ремедиум, 2018.Malfertheiner P Venerito M, Schulz C. Helicobacter pylori Infection: New Facts in Clinical Management. Curr Treat Options Gastroenterol 2018; 16 (4): 605-15. DOI: 10.1007/s11938-018-0209-8Hooi JKY, Lai WY, Ng WK et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 2017; 153 (2): 420-9. DOI: 10.1053/j.gastro.2017.04.022Zamani M, Ebrahimtabar F, Zamani V et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment Pharmacol Ther 2018; 47 (7): 868-76. DOI: 10.1111/apt.14561Coelho E, Magalhaes A, Dinis-Ribeiro M, Reis CA. Mecanismos Moleculares de Adesao e Colonizagao da Mucosa Gastrica pela Helicobacter pylori e suas Implicates Clinicas [Molecular Mechanisms for Adhesion and Colonization of Human Gastric Mucosa by Helicobacter pylori and its Clinical Implications]. Acta Med Port 2016; 29 (7-8): 476-83. DOI: 10.20344/amp.6651Bonsor DA, Sundberg EJ. Roles of Adhesion to Epithelial Cells in Gastric Colonization by Helicobacter pylori. Adv Exp Med Biol 2019; 1149: 57-75. DOI: 10.1007/5584_2019_359Asahi M, Azuma T, Ito S et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med 2000; 191 (4): 593-602. DOI: 10.1084/jem.191.4.593Hayashi S, Sugiyama T, Amano K et al. Effect of rebamipide, a novel antiulcer agent, on Helicobacter pylori adhesion to gastric epithelial cells. Antimicrob Agents Chemother 1998; 42 (8): 1895-9.Lee KH, Kim JY Kim WK et al. Protective effect of rebamipide against Helicobacter pylori-CagA-induced effects on gastric epithelial cells. Dig Dis Sci 2011; 56 (2): 441-8. DOI: 10.1007/s10620-010-1299-xMasamune A, Yoshida M, Sakai Y, Shimosegawa T. Rebamipide inhibits ceramide-induced interleukin-8 production in Kato III human gastric cancer cells. J Pharmacol Exp Ther 2001; 298 (2): 485-92.Aihara M, Azuma A, Takizawa H et al. Molecular analysis of suppression of interleukin-8 production by rebamipide in Helicobacter pylori-stimulated gastric cancer cell lines. Dig Dis Sci 1998; 43 (9 Suppl.): 174S-180S.Choi KW, Lee YC, Chung IS et al. Effect of rebamipide in treatment of Helicobacter pylori-associated duodenal ulcer: attenuation of chemokine expression and nitrosative damage. Dig Dis Sci 2002; 47 (2): 283-91. DOI: 10.1023/a:1013753602149Bray F, Ferlay J, Soerjomataram I et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (6): 394424. DOI: 10.3322/caac.21492Rawla P, Barsouk A. Epidemiology of gastric cancer: global trends, risk factors and prevention. Prz Gastroenterol 2019; 14 (1): 26-38. DOI: 10.5114/pg.2018.80001Carcas LP Gastric cancer review. J Carcinog 2014; 13: 14. DOI: 10.4103/1477-3163.146506Graham DY. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology 2015; 148 (4): 719-31.e3. DOI: 10.1053tj.gastro.2015.01.040Matos JI, de Sousa HA, Marcos-Pinto R, Dinis-Ribeiro M. Helicobacter pylori CagA and VacA genotypes and gastric phenotype: a meta-analysis. Eur J Gastroenterol Hepatol 2013; 25 (12): 1431-41. DOI: 10.1097/MEG.0b013e328364b53eMin DS. A Potential Efficacy of Rebamipide as Anti-gastric Cancer Drug. J Life Sci 2016; 26 (10): 1214 DOI: 10.5352/JLS.2016.26.10.1214Haruma K, Ito M, Kido S et al. Long-term rebamipide therapy improves Helicobacter pylori-associated chronic gastritis. Dig Dis Sci 2002; 47 (4): 862-7. DOI: 10.1023/a:1014716822702Kamada T, Sato M, Tokutomi T et al. Rebamipide improves chronic inflammation in the lesser curvature of the corpus after Helicobacter pylori eradication: a multicenter study. Biomed Res Int 2015; 2015: 865146. DOI: 10.1155/2015/865146Kang DW, Min G, Park DY et al. Rebamipide-induced downregulation of phospholipase D inhibits inflammation and proliferation in gastric cancer cells. Exp Mol Med 2010; 42 (8): 555-64. DOI: 10.3858/emm.2010.42.8.056Kang DW, Noh YN, Hwang WC et al. Rebamipide attenuates Helicobacter pylori CagA-induced selfrenewal capacity via modulation of b-catenin signaling axis in gastric cancer-initiating cells. Biochem Pharmacol 2016; 113: 36-44. DOI: 10.1016/j.bcp.2016.06.003