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УДК: 615.2 DOI:10.33920/med-03-2204-02

Гастропротектор «Ребамипид»: обзор механизмов действия и клинического применения

Фролова А. А. канд. мед. наук, кафедра гастроэнтерологии, ФГБУ ДПО «ЦГМА» УДП РФ
Шиндина Т. С. канд. мед. наук, ФГБУ «Поликлиника № 5» УДП РФ
Масловский Л. В. д-р мед. наук, кафедра гастроэнтерологии, ФГБУ ДПО «ЦГМА» УДП РФ
Максимов М. Л. д-р мед. наук, ФГБОУ ДПО РМАНПО Минздрава России, ФГАОУ ВО РНИМУ имени Н. И. Пирогова Минздрава России
Александрова Е. Б. д-р мед. наук, ФГБУ «Поликлиника № 5» УДП РФ
Кропова О. Е. ФГБУ «Поликлиника № 5» УДП РФ

Препарат «Ребамипид» имеет длительную историю применения как гастропротектор. Однако большое количество экспериментальных данных за последнее время позволило выявить множественные эффекты Ребамипида и расширить область его применения. Целью настоящей публикации является обзор и систематизация знаний о механизмах действия Ребамипида и обсуждение области его клинического применения, имеющей доказательную базу.

Литература:

1. Клиническая фармакология и рациональная фармакотерапия для практикующих врачей: учебник / М. Л. Максимов, Р. А. Бонцевич, И. С. Бурашникова [и др.]; под ред. проф. М. Л. Максимова. — Казань: ИД «МеДДоК», 2021. — 948 с.

2. Naito Y., Yoshikawa T. Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Expert Rev. Gastroenterol. Hepatol. 2010; 4 (3): 261–70.

3. Kleine A., Kluge S., Peskar B. M. Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats. Dig Dis Sci 1993; 38 (8): 1441–9.

4. Sun W. H., Tsuji S., Tsujii M., Gunawan E. S., Kawai N., Kimura A., Kakiuchi Y., Yasumaru M., Iijima H. Induction of cyclooxygenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent. J Pharmacol Exp Ther 2000; 295 (2): 447–52.

5. Weiwei Li, Yunpeng Zhao Rebamipide suppresses TNF-α mediated inflammation in vitro and attenuates the severity of dermatitis in mice. FEBS J 2015; 282 (12): 2317–26.

6. Yoshida N., Yoshikawa T., Iinuma S. Rebamipide protects against activation of neutrophils by Helicobacter pylori. Dig Dis Sci. 1996; 41 (6): 1139–44.

7. Chi Dae Kim, Hyun Hee Kim, Ki Whan Hong Inhibitory Effect of Rebamipide on the Neutrophil Adherence Stimulated by Conditioned Media from Helicobacter pylori-Infected Gastric Epithelial Cells. Journal of Pharmacology and Experimental Therapeutics January. 1999; 288 (1): 133–138.

8. Hong W. S., Jung H. Y., Yang S. K., Myung S. J. The antioxidant effect of rebamipide on oxygen free radical production by H. pylori-activated human neutrophils: in comparison with N-acetylcysteine, ascorbic acid and glutathione. Pharmacol Res. 2001; 44 (4): 293–7.

9. Hong W. S., Jung H. Y., Yang S. K., Myung S. J. The antioxidant effect of rebamipide on oxygen free radical production by H. pylori-activated human neutrophils: in comparison with N-acetylcysteine, ascorbic acid and glutathione. Pharmacol Res. 2001; 44 (4): 293–7.

10. Iinuma S., Naito Y., Yoshikawa T., Takahashi S. In vitro studies indicating antioxidative properties of rebamipide. Dig Dis Sci 1998; 43 (9 Suppl): 35S — 39S.

11. Suzuki T., Yoshida N., Nakabe N., et al. Prophylactic effect of rebamipide on aspirininduced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci. 2008; 106 (3): 469–77.

12. Gweon T., Park J., Kim B., et al. Additive effects of Rebamipide plus proton pump inhibitors on the expression of tight junction proteins in a rat model of gastroesophageal reflux disease. Gut Liver. 2018; 12 (1): 46–50.

13. Santos M. F., McCormack S. A., Guo Z., et al. Rho proteins play a critical role in cell migration during the early phase of mucosal restitution. J Clin Invest. 1997; 100: 216–25.

14. Rao J. N., Guo X., Liu L., et al. Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal epithelial restitution. Am J Physiol Cell Physiol. 2003; 284: 848–59.

15. Takagi T., Naito Y., Uchiyama K., et al. Rebamipide promotes healing of colonic ulceration through enhanced epithelial restitution. World J Gastroenterol. 2011; 17 (33): 3802–9.

16. Katsunori Iijima, Ichikawa T., Okada S., Ogawa M., Koike T., Ohara S., Shimosegawa T. Rebamipide, a Cytoprotective Drug, Increases Gastric Mucus Secretion in Human: Evaluations with Endoscopic Gastrin Test. Digestive Diseases and Sciences. 2009; 54: 1500–1507.

17. Yuriko Yasuda-Onozawa, Osamu Handa Rebamipide upregulates mucin secretion of intestinal goblet cells via Akt phosphorylation. Mol Med Rep. 2017; 16 (6): 8216–8222.

18. Nishizawa T. · Suzuki H. · Nakagawa I. · Minegishi Y. Rebamipide-Promoted Restoration of Gastric Mucosal Sonic Hedgehog Expression after Early Helicobacter Pylori Eradication. Digestion. 2009; 79 (4): 259–62

19. Tarnawski A. S., Chai J., Pai R., Chiou S.-K. Rebamipide Activates Genes Encoding Angiogenic Growth Factors and Cox2 and Stimulates Angiogenesis: A Key to Its Ulcer Healing Action? Digestive Diseases and Sciences. 2004; 49: 202–209.

20. Tomoaki Ishihara, Ken-IchiroTanaka, Saki Tashiro Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis. Biochemical Pharmacology 2010; 79 (11): 1622–1633.

21. Basel A. Abdel-Wahab, Fares E. M. Ali Hepatoprotective effect of rebamipide against methotrexate-induced hepatic intoxication: role of Nrf2/GSK-3β, NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2 signaling pathways. Immunopharmacol Immunotoxicol. 2020; 42 (5): 493–503.

22. Парфенов А. И., Белостоцкий Н. И., Хомерики С.Г. и др. Ребамипид повышает активность дисахаридаз у больных энтеропатией с нарушением мембранного пищеварения. Пилотное исследование. Терапевтический архив. 2019; 91 (2): 8–31.

23. Yuki T., Ishihara S., Rumi M., Ortega-Cava Cesar F. Expression of midkine and receptorlike protein tyrosine phosphatase (RPTP) — beta genes in the rat stomach and the influence of rebamipide. Aliment Pharmacol Ther. 2003; 18 Suppl 1: 106–12.

24. Rebamipide for use in prophylaxis and treatment of celiac disease. European patent application. EP 3 797 771 A1. 2021.

25. Gi Hyeon Seo, Hyuk Lee Chemopreventive Effect of Rebamipide against Gastric Cancer in Patients who undergo Endoscopic Resection for Early Gastric Neoplasms: A Nationwide Claims Study. Digestion. 2019; 100 (4): 221–228.

26. Makiyama K., Takeshima F., Kawasaki H., Zea-Iriarte W. L. Anti-inflammatory effect of rebamipide enema on proctitis type ulcerative colitis: a novel therapeutic alternative. Am J Gastroenterol. 2000; 95: 1838–9.

27. Miyata M., Kasugai K. Rebamipide enemas-new effective treatment for patients with corticosteroid dependent or resistant ulcerative colitis. Dig Dis Sci. 2005; 50 Suppl 1: 119–23.

28. Furuta R., Ando T., Watanabe O., et al. Rebamipide enema therapy as a treatment for patients with active distal ulcerative colitis. J Gastroenterol Hepatol. 2007; 22 (2): 261–7.

29. Satohiro Matsumoto, Kenichiro Tsuji, Satoshi Shirahama Rebamipide enema therapy for left-sided ischemic colitis patients accompanied by ulcers: open label study. World J Gastroenterol. 2008; 14 (25): 4059–64.

30. Андреев Д. Н., Маев И. В. Ребамипид: доказательная база применения в гастроэнтерологии. Терапевтический архив. 2020; 12: 97–104.

31. Akira Terano, Tetsuo Arakawa et al. Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a Japanese population: a randomized, double-blind, placebocontrolled trial. J Gastroenterol. 2007; 42 (8): 690–3.

32. Song K. H., · Lee Y. C., · Fan D.-M., · Ge Z.-Z. Healing Effects of Rebamipide and Omeprazole in Helicobacter pylori-Positive Gastric Ulcer Patients after Eradication Therapy: A Randomized Double-Blind, Multinational, Multi-Institutional Comparative Study. Digestion. 2011; 84: 221–229.

33. Андреев Д. Н., Маев И. В., Дичева Д. Т., Самсонов А. А., Парцваниа-Виноградова Е. В. Эффективность и безопасность применения ребамипида в схеме тройной эрадикационной терапии инфекции Helicobacter pylori: проспективное рандомизированное сравнительное исследование. Терапевтический архив. 2018; 8: 27–32.

34. Hayashi 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.

35. Kyung Hwa Lee, Jee-Yeon Kim Protective effect of rebamipide against Helicobacter pylori-CagA-induced effects on gastric epithelial cells. Dig Dis Sci. 2011; 56 (2): 441–8.

36. Li M, Yin T, Lin B. Rebamipide for chronic gastritis: a meta-analysis. Chinese J Gastroenterol Hepatol. 2015; 24: 667–73.

37. Haruma K., Ito M., Kido S. Long-term rebamipide therapy improves Helicobacter pyloriassociated chronic gastritis. Dig Dis Sci. 2002; 47 (4): 862–7.

38. Hiroto Miwa, Taro Osada Effect of a gastro-protective agent, rebamipide, on symptom improvement in patients with functional dyspepsia: A double-blind placebo-controlled study in Japan. Journal of Gastroenterology and Hepatology. 2007; 21 (12): 1826–31.

39. Mohamed Hasif Jaafar, Sher Zaman Safi, Maw-Pin Tan et al. Efficacy of Rebamipide in Organic and Functional Dyspepsia: A Systematic Review and Meta-Analysis. Dig Dis Sci. 2018; 63 (5): 1250–1260.

40. Masahiro Hasegawa, Noriyuki Horiki, Kyosuke Tanaka et al. The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group. Mod Rheumatol 2013; 23 (6): 1172–8.

41. Naito Y., Yoshikawa T., Iinuma S. Rebamipide protects against indomethacin-induced gastric mucosal injury in healthy volunteers in a double-blind, placebo-controlled study. Dig Dis Sci. 1998; 43 (9 Suppl): 83S — 89S.

42. Мороз Е. В., Каратеев А. Е. Ребамипид: эффективная медикаментозная профилактика НПВП-энтеропатии возможна. Современная ревматология. 2016; 10 (4): 97–105.

43. Katsuyuki Tozawa, Tadayuki Oshima, Takuya Okugawa, Tomohiro Ogawa et al. A randomized, double-blind, placebo-controlled study of rebamipide for gastric mucosal injury taking aspirin with or without clopidogrel. Dig Dis Sci. 2014; 59 (8): 1885–90.

44. Kurokawa S., Katsuki S., Fujita T., et al. A randomized, double-blinded, placebocontrolled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. J Gastroenterol. 2014; 49 (2): 239–44.

45. Soo-Heon Park, Chul-Soo Cho Comparison of Prevention of NSAID–Induced Gastrointestinal Complications by Rebamipide and Misoprostol: A Randomized, Multicenter, Controlled Trial — STORM STUDY. J Clin Biochem Nutr. 2007; 40 (2): 148– 155.

46. Jeong Ho Kim, Soo-Heon Park, Chul-Soo Cho Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity. Gut Liver 2014; 8 (4): 371–9.

47. Ивашкин В. Т., Трухманов А. С., Гоник М. И. Применение ребамипида в лечении гастроэзофагеальной рефлюксной болезни. Терапевтический архив. 2020; 92 (4): 98–104.

48. Yoshida N., Kamada K., Tomatsuri N., et al. Management of recurrence of symptoms of gastroesophageal reflux disease: synergistic effect of rebamipide with 15 mg lansoprazole. Dig Dis Sci. 2010; 55 (12): 3393–8.

49. Su Jin Hong, Soo-Heon Park, Jeong Seop Moon The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study. Gut Liver. 2016; 10 (6): 910–916.

50. Mark Lester Sy, Rei Joseph Prieto, Alex Pang, Michael Angelo Chu et al. Effectiveness of rebamipide in the prevention of esophageal stricture formation in advanced corrosive esophagitis: a prospective randomised control study. Gut 2018; 67 (Suppl 2): A53.2 — A53.

51. Hiroshi Araki, Tomohiro Kato, Fumito Onogi et al. Combination of proton pump inhibitor and rebamipide, a free radical scavenger, promotes artificial ulcer healing after endoscopic submucosal dissection with dissection size >40 mm. J Clin Biochem Nutr. 2012; 51 (3): 185–8.

52. Management of Recurrence of Symptoms of Gastroesophageal Reflux Disease: Synergistic Effect of Rebamipide with 15 mg Lansoprazole Digestive Diseases and Sciences. 2010; 55 (12): 3393–8.

53. Expert Rev Gastroenterol Hepatol 2010 Jun; 4 (3): 261–70. doi: 10.1586/egh.10.25. Rebamipide: a gastrointestinal protective drug with pleiotropic activities Yuji Naito 1, Toshikazu Yoshikawa.

54. Toshio Watanabe, Toshihisa Takeuchi A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of High-Dose Rebamipide Treatment for Low-Dose AspirinInduced Moderate-to-Severe Small Intestinal Damage. PLoS One. 2015; 10 (4): 1–12.

55. Basel A Abdel-Wahab, Fares EM Ali, Saad A Alkahtani, Ali M Alshabi et al. Hepatoprotective effect of rebamipide against methotrexate-induced hepatic intoxication: role of Nrf2/GSK-3β, NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2 signaling pathways. Immunopharmacol Immunotoxicol. 2020; 42 (5): 493–503.

56. Daorui Hou, Maoyi Yang et al. Effects of rebamipide for chronic atrophic gastritis A protocol for systematic review and meta-analysis. Medicine. 2020; 99 (25).

57. Yukie Kohata, Kenichi Nakaha et al. Rebamipide Alters the Esophageal Microbiome and Reduces the Incidence of Barrett’s Esophagus in a Rat Model. Dig Dis Sci. 2015; 60 (9): 2654–61.

58. Su-Jin Moon, Jin-Sil Park, et al. Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction. Arthritis Rheumatol. 2014; 66 (4): 874–85.

59. Hong-Ki Min, Jae-Kyung Kim et al. Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17/Treg cell imbalance in mice with curdlan-induced spondyloarthritis. Journal of Translational Medicine. 2016; 14 (190): 1–9.

60. H Ha, S H Lee, K H Kim Effects of rebamipide in a model of experimental diabetes and on the synthesis of transforming growth factor-beta and fibronectin, and lipid peroxidation induced by high glucose in cultured mesangial cells. J Pharmacol Exp Ther. 1997; 281 (3): 1457–62.

61. Jhun J, Kwon J-E, Kim S-Y, Jeong J-H, Na HS, Kim E-K, et al. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation. PLoS ONE. 2017; 12 (2): 1–14.

62. Tomoyuki Kashima, Hirotaka Itakura,Hideo Akiyama, Shoji Kishi Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: a critical appraisal. Clin Ophthalmol. 2014; 8: 1003–1010.

63. Крумс Л. М., Ахмадуллина О. В., Быкова С. В. Применение ребамипида в терапии целиакии как возможный пример быстрого достижения полной ремиссии. Фарматека. 2021; 2: 115–119.

64. Takemoto T, Namiki M, Yachi A, Masamune O, Ishikawa M, Goto Y, Kimura K, Itoh S, Matsuo Y, Kobayashi M, Oka H, Tsuchiya M, Kurokawa K, Yokoyama I, Okabe H, Miwa T, Kohli Y, Nakazawa S, Takeuchi T, Uchino H, Miyake T, Kawai K, Kamada T, Kobayashi K, Ohshiba S, Tsuji T, Kajiyama G, Shimada Y, Okazaki Y, Kishi S, Nawata H, Tanikawa K, Hayakawa H, Hashimoto S: Effect of rebamipide (OPC-12759) on gastric ulcer healing multicenter, double-blind, cetraxate controlled clinical study. Rinsho Seijin-byo. 1989; 19: 1265– 1291.

65. Yamasaki K., Ishiyama H., Imaizumi T., Kanbe T., Yabuuchi Y. Effect of OPC-12759, a novel antiulcer agent, on chronic and acute experimental gastric ulcer, and gastric secretion in rats. Jpn J Pharmacol. 1989; 49 (4): 441–8.

66. Симаненков В. И., Маев И. В., Ткачева О. Н, Алексеенко С. А., Андреев Д. Н., Бордин Д. С., Власов Т. Д., Воробьёва Н. М., Гриневич В. Б., Губонина И. В., Дробижев М. Ю., Ефремов Н. С., Каратеев А. Е., Котовская Ю. В., Кравчук Ю. А., Кривобородов Г.Г., Кульчавеня Е. В., Лила А. М., Маевская М. В., Полуэктова Е. А., Попкова Т. В., Саблин О. А., Соловьева О. И., Суворов А. Н., Тарасова Г. Н., Трухан Д. И., Федотова А. В. Синдром повышенной эпителиальной проницаемости в клинической практике. Мультидисциплинарный национальный консенсус. Кардиоваскулярная терапия и профилактика. 2021; 20 (1): 121–278.

67. Jun Wang, Xufeng Guo Efficacy and safety of proton pump inhibitors (PPIs) plus rebamipide for endoscopic submucosal dissection-induced ulcers: a meta-analysis. Intern Med. 2014; 53 (12): 1243–8.

68. Звяглова М. Ю., Князев О. В., Парфенов А. И. Фармакологический и клинический профиль ребамипида: новые терапевтические мишени. Терапевтический архив 2020; 2: 104–111.

69. Подходы к лечению кислотозависимых заболеваний: учебно-методическое пособие для врачей / М. Л. Максимов, А. А. Звегинцева и др. — Казань: ИД «МеДДоК», 2020. — 84 с.

1. Klinicheskaia farmakologiia i ratsionalnaia farmakoterapiia dlia praktikuiushchikh vrachei [Clinical pharmacology and rational pharmacotherapy for practitioners]: manual / M. L. Maksimov, R. A. Bontsevich, I. S. Burashnikova [et al.]; ed. prof. M. L. Maksimov. — Kazan: Publishing House «MedDoc», 2021. — 948 p. ISBN 978-5-6045764-9-6 (In Russ.)

2. Naito Y., Yoshikawa T. Rebamipide: a gastrointestinal protective drug with pleiotropic activities // Expert Rev. Gastroenterol. Hepatol. 2010.4 (3). P. 261–70

3. Kleine A., Kluge S., Peskar B. M. Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats //Dig Dis Sci 1993. 38 (8). P.1441–9.

4. Sun W. H., Tsuji S., Tsujii M., Gunawan E. S., Kawai N., Kimura A., Kakiuchi Y., Yasumaru M., Iijima H. Induction of cyclooxygenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent // J Pharmacol Exp Ther 2000.295 (2). P. 447–52.

5. Weiwei Li, Yunpeng Zhao Rebamipide suppresses TNF-α mediated inflammation in vitro and attenuates the severity of dermatitis in mice // FEBS J 2015.282 (12). P. 2317–26.

6. Yoshida N., Yoshikawa T., Iinuma S. Rebamipide protects against activation of neutrophils by Helicobacter pylori // Dig Dis Sci 1996.41 (6). P. 1139–44.

7. Chi Dae Kim, Hyun Hee Kim, Ki Whan Hong Inhibitory Effect of Rebamipide on the Neutrophil Adherence Stimulated by Conditioned Media from Helicobacter pylori-Infected Gastric Epithelial Cells // Journal of Pharmacology and Experimental Therapeutics January 1999.288 (1) P.133–138.

8. Hong W. S., Jung H. Y., Yang S. K., Myung S. J. The antioxidant effect of rebamipide on oxygen free radical production by H. pylori-activated human neutrophils: in comparison with N-acetylcysteine, ascorbic acid and glutathione // Pharmacol Res 2001.44 (4). P. 293–7.

9. Hong W. S., Jung H. Y., Yang S. K., Myung S. J. The antioxidant effect of rebamipide on oxygen free radical production by H. pylori-activated human neutrophils: in comparison with N-acetylcysteine, ascorbic acid and glutathione // Pharmacol Res 2001.44 (4). P. 293–7.

10. Iinuma S., Naito Y., Yoshikawa T., Takahashi S. In vitro studies indicating antioxidative properties of rebamipide // Dig Dis Sci 1998.43 (9 Suppl). P.35S-39S.

11. Suzuki 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). P. 469–77.

12. Gweon T., Park J., Kim B., et al. 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). P.46–50.

13. Santos M. F., McCormack S. A., Guo Z., et al. Rho proteins play a critical role in cell migration during the early phase of mucosal restitution. // J Clin Invest. 1997.100. P.216–25.

14. Rao J. N., Guo X., Liu L., et al. Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal epithelial restitution. // Am J Physiol Cell Physiol. 2003.284. P. 848–59.

15. Takagi T., Naito Y., Uchiyama K., et al. Rebamipide promotes healing of colonic ulceration through enhanced epithelial restitution. // World J Gastroenterol. 2011.17 (33). P. 3802–9.

16. Katsunori Iijima, Ichikawa T., Okada S., Ogawa M., Koike T., Ohara S., Shimosegawa T. Rebamipide, a Cytoprotective Drug, Increases Gastric Mucus Secretion in Human: Evaluations with Endoscopic Gastrin Test // Digestive Diseases and Sciences 2009.54. Р.1500–1507

17. Yuriko Yasuda-Onozawa, Osamu Handa Rebamipide upregulates mucin secretion of intestinal goblet cells via Akt phosphorylation // Mol Med Rep. 2017.16 (6). P. 8216– 8222.

18. Nishizawa T., Suzuki H., Nakagawa I., Minegishi Y. Rebamipide-Promoted Restoration of Gastric Mucosal Sonic Hedgehog Expression after Early Helicobacter Pylori Eradication. // Digestion. 2009.79 (4). P. 259–62

19. Tarnawski A. S., Chai J., Pai R., Chiou S.-K. Rebamipide Activates Genes Encoding Angiogenic Growth Factors and Cox2 and Stimulates Angiogenesis: A Key to Its Ulcer Healing Action? // Digestive Diseases and Sciences.2004.49. Р. 202–209

20. Tomoaki Ishihara, Ken-IchiroTanaka, Saki Tashiro Protective effect of rebamipide against celecoxib-induced gastric mucosal cell apoptosis// Biochemical Pharmacology 2010.79 (11). P.1622–1633

21. Basel A. Abdel-Wahab, Fares E. M. Ali Hepatoprotective effect of rebamipide against methotrexate-induced hepatic intoxication: role of Nrf2 /GSK-3β, NFκβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2 signaling pathways // Immunopharmacol Immunotoxicol 2020.42 (5) P. 493–503.

22. Parfenov A. I., Belostotskii N. I., Khomeriki S. G. et al. Rebamipid povyshaet aktivnost disakharidaz u bolnykh enteropatiei s narusheniem membrannogo pishchevareniia. Pilotnoe issledovanie [Rebamipide increases the activity of disaccharidases in patients with enteropathy with impaired membrane digestion. Pilot study]. // Terapevticheskii arkhiv [Therapeutic Archive]. 2019.91 (2). P. 8–31. (In Russ.)

23. Yuki T., Ishihara S., Rumi M., Ortega-Cava Cesar F. Expression of midkine and receptor-like protein tyrosine phosphatase (RPTP) — beta genes in the rat stomach and the influence of rebamipide // Aliment Pharmacol Ther. 2003.18 Suppl 1. P.106–12

24. Rebamipide for use in prophylaxis and treatment of celiac disease. European patent application. EP 3 797 771 A1. 2021.

25. Gi Hyeon Seo, Hyuk Lee Chemopreventive Effect of Rebamipide against Gastric Cancer in Patients who undergo Endoscopic Resection for Early Gastric Neoplasms: A Nationwide Claims Study // Digestion. 2019.100 (4). Р.221–228.

26. Makiyama K., Takeshima F., Kawasaki H., Zea-Iriarte W. L. Anti-inflammatory effect of rebamipide enema on proctitis type ulcerative colitis: a novel therapeutic alternative. // Am J Gastroenterol. 2000. 95. Р.1838–9.

27. Miyata M., Kasugai K. Rebamipide enemas-new effective treatment for patients with corticosteroid dependent or resistant ulcerative colitis. // Dig Dis Sci. 2005. 50 Suppl 1. Р. 119–23.

28. Furuta R., Ando T., Watanabe O., et al. Rebamipide enema therapy as a treatment for patients with active distal ulcerative colitis. // J Gastroenterol Hepatol. 2007.22 (2). Р. 261–7.

29. Satohiro Matsumoto, Kenichiro Tsuji, Satoshi Shirahama Rebamipide enema therapy for left-sided ischemic colitis patients accompanied by ulcers: open label study // World J Gastroenterol. 2008.14 (25). Р. 4059–64.

30. Andreev D. N., Maev I. V. Rebamipid: dokazatelnaia baza primeneniia v gastroenterologii [Rebamipide: evidence-based application in gastroenterology] // Terapevticheskii arkhiv [Therapeutic Archive] 12. 2020. С. 97–104. (In Russ.)

31. Akira Terano, Tetsuo Arakawa et al. Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a Japanese population: a randomized, double-blind, placebo-controlled trial // J Gastroenterol 2007. 42 (8). Р. 690–3.

32. Song K. H., Lee Y. C., Fan D.-M., Ge Z.-Z. Healing Effects of Rebamipide and Omeprazole in Helicobacter pylori-Positive Gastric Ulcer Patients after Eradication Therapy: A Randomized Double-Blind, Multinational, Multi-Institutional Comparative Study // Digestion 2011. 84. Р. 221–229.

33. Andreev D. N., Maev I. V., Dicheva D. T., Samsonov A. A., Partsvania-Vinogradova E. V. Effektivnost i bezopasnost primeneniia rebamipida v skheme troinoi eradikatsionnoi terapii infektsii Helicobacter pylori: prospektivnoe randomizirovannoe sravnitelnoe issledovanie [Efficacy and safety of rebamipide in the scheme of triple eradication therapy for Helicobacter pylori infection: a prospective randomized comparative study] // Terapevticheskii arkhiv [Therapeutic Archive] 2018. 8. P. 27–32. (In Russ.)

34. Hayashi 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). Р. 1895–9.

35. Kyung Hwa Lee, Jee-Yeon Kim Protective effect of rebamipide against Helicobacter pylori-CagA-induced effects on gastric epithelial cells // Dig Dis Sci. 2011. 56 (2). Р. 441–8.

36. Li M, Yin T, Lin B. Rebamipide for chronic gastritis: a meta-analysis.// Chinese J Gastroenterol Hepatol.2015.24. Р: 667–73.

37. Haruma K., Ito M., Kido S. Long-term rebamipide therapy improves Helicobacter pylori-associated chronic gastritis // Dig Dis Sci 2002. 47 (4). Р. 862–7.

38. Hiroto Miwa, Taro Osada Effect of a gastro-protective agent, rebamipide, on symptom improvement in patients with functional dyspepsia: A double-blind placebo-controlled study in Japan // Journal of Gastroenterology and Hepatology 2007. 21 (12). Р: 1826–31

39. Mohamed Hasif Jaafar, Sher Zaman Safi, Maw-Pin Tan et al. Efficacy of Rebamipide in Organic and Functional Dyspepsia: A Systematic Review and Meta-Analysis // Dig Dis Sci. 2018. 63 (5). Р. 1250–1260.

40. Masahiro Hasegawa, Noriyuki Horiki, Kyosuke Tanaka et al. The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group // Mod Rheumatol 2013. 23 (6). P. 1172–8.

41. Naito Y., Yoshikawa T., Iinuma S. Rebamipide protects against indomethacin-induced gastric mucosal injury in healthy volunteers in a double-blind, placebo-controlled study // Dig Dis Sci 1998. 43 (9 Suppl). Р. 83S-89S.

42. Moroz E. V., Karateev A. E. Rebamipid: effektivnaia medikamentoznaia profilaktika NPVP-enteropatii vozmozhna [Rebamipide: effective drug prevention of NSAID enteropathy is possible] // Sovremennaia revmatologiia [Modern Rheumatology]. 2016. 10 (4). P. 97–105. (In Russ.)

43. Katsuyuki Tozawa, Tadayuki Oshima, Takuya Okugawa, Tomohiro Ogawa et al. A randomized, double-blind, placebo-controlled study of rebamipide for gastric mucosal injury taking aspirin with or without clopidogrel // Dig Dis Sci 2014.59 (8). Р.1885–90.

44. Kurokawa S., Katsuki S., Fujita T., et al. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. // J Gastroenterol. 2014.49 (2). Р. 239–44.

45. Soo-Heon Park, Chul-Soo Cho Comparison of Prevention of NSAID–Induced Gastrointestinal Complications by Rebamipide and Misoprostol: A Randomized, Multicenter, Controlled Trial — STORM STUDY // J Clin Biochem Nutr. 2007.40 (2). Р. 148–155.

46. Jeong Ho Kim, Soo-Heon Park, Chul-Soo Cho Preventive efficacy and safety of rebamipide in nonsteroidal anti-inflammatory drug-induced mucosal toxicity // Gut Liver 2014.8 (4). Р. 371–9.

47. Ivashkin V. T., Trukhmanov A. S., Gonik M. I. Primenenie rebamipida v lechenii gastroezofagealnoi refliuksnoi bolezni [The use of rebamipide in the treatment of gastroesophageal reflux disease]. Terapevticheskii arkhiv [Therapeutic Archive]. 2020.92 (4). P. 98–104. (In Russ.)

48. Yoshida N., Kamada K., Tomatsuri N., et al. Management of recurrence of symptoms of gastroesophageal reflux disease: synergistic effect of rebamipide with 15 mg lansoprazole. // Dig Dis Sci. 2010.55 (12). Р. 3393–8.

49. Su Jin Hong, Soo-Heon Park, Jeong Seop Moon The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study // Gut Liver. 2016.10 (6). Р.910–916.

50. Mark Lester Sy, Rei Joseph Prieto, Alex Pang, Michael Angelo Chu et al. Effectiveness of rebamipide in the prevention of esophageal stricture formation in advanced corrosive esophagitis: a prospective randomised control study // Gut 2018. 67 (Suppl 2). Р. A53.2-A53

51. Hiroshi Araki, Tomohiro Kato, Fumito Onogi et al. Combination of proton pump inhibitor and rebamipide, a free radical scavenger, promotes artificial ulcer healing after endoscopic submucosal dissection with dissection size >40 mm // J Clin Biochem Nutr 2012. 51 (3). Р.185–8.

52. Management of Recurrence of Symptoms of Gastroesophageal Reflux Disease: Synergistic Effect of Rebamipide with 15 mg Lansoprazole March 2010Digestive Diseases and Sciences 55 (12):3393–8

53. Expert Rev Gastroenterol Hepatol 2010 Jun;4 (3):261–70. doi: 10.1586/egh.10.25. Rebamipide: a gastrointestinal protective drug with pleiotropic activities Yuji Naito 1, Toshikazu Yoshikawa

54. Toshio Watanabe, Toshihisa Takeuchi A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of High-Dose Rebamipide Treatment for Low-Dose Aspirin-Induced Moderate-to-Severe Small Intestinal Damage // PLoS One. 2015.10 (4).P 1–12.

55. Basel A Abdel-Wahab, Fares E M Ali, Saad A Alkahtani, Ali M Alshabi et al. Hepatoprotective effect of rebamipide against methotrexate-induced hepatic intoxication: role of Nrf2 /GSK-3β, NF-κβ-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2 signaling pathways // Immunopharmacol Immunotoxicol 2020.42 (5). P. 493–503.

56. Daorui Hou, Maoyi Yang et al. Effects of rebamipide for chronic atrophic gastritis A protocol for systematic review and meta-analysis // Medicine. 2020.99 (25)

57. Yukie Kohata, Kenichi Nakaha et al. Rebamipide Alters the Esophageal Microbiome and Reduces the Incidence of Barrett's Esophagus in a Rat Model // Dig Dis Sci 2015.60 (9). Р. 2654–61.

58. Su-Jin Moon, Jin-Sil Park, et al. Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction // Arthritis Rheumatol 2014.66 (4). Р. 874–85

59. Hong-Ki Min, Jae-Kyung Kim et al. Rebamipide prevents peripheral arthritis and intestinal inflammation by reciprocally regulating Th17/Treg cell imbalance in mice with curdlan-induced spondyloarthritis // Journal of Translational Medicine 2016.14 (190). Р. 1–9

60. H Ha, S H Lee, K H Kim Effects of rebamipide in a model of experimental diabetes and on the synthesis of transforming growth factor-beta and fibronectin, and lipid peroxidation induced by high glucose in cultured mesangial cells //J Pharmacol Exp Ther 1997.281 (3). Р.1457–62.

61. Jhun J, Kwon J-E, Kim S-Y, Jeong J-H, Na HS, Kim E-K, et al. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation. // PLoS ONE 2017.12 (2).Р 1–14

62. Tomoyuki Kashima, Hirotaka Itakura,Hideo Akiyama, Shoji Kishi Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: a critical appraisal // Clin Ophthalmol. 2014. 8. Р.1003–1010

63. Krums L. M., Akhmadullina O. V., Bykova S. V. Primenenie rebamipida v terapii tseliakii kak vozmozhnyi primer bystrogo dostizheniia polnoi remissii [The use of rebamipide in the treatment of celiac disease as a possible example of the rapid achievement of complete remission] // Farmateka 2021.2. P. 115–119. (In Russ.)

64. Takemoto T, Namiki M, Yachi A, Masamune O, Ishikawa M, Goto Y, Kimura K, Itoh S, Matsuo Y, Kobayashi M, Oka H, Tsuchiya M, Kurokawa K, Yokoyama I, Okabe H, Miwa T, Kohli Y, Nakazawa S, Takeuchi T, Uchino H, Miyake T, Kawai K, Kamada T, Kobayashi K, Ohshiba S, Tsuji T, Kajiyama G, Shimada Y, Okazaki Y, Kishi S, Nawata H, Tanikawa K, Hayakawa H, Hashimoto S: Effect of rebamipide (OPC-12759) on gastric ulcer healing multicenter, double-blind, cetraxate controlled clinical study.// Rinsho Seijin-byo 1989.19. Р.1265– 1291,

65. Yamasaki K., Ishiyama H., Imaizumi T., Kanbe T., Yabuuchi Y. Effect of OPC-12759, a novel antiulcer agent, on chronic and acute experimental gastric ulcer, and gastric secretion in rats // Jpn J Pharmacol 1989. 49 (4). Р. 441–8.

66. Simanenkov V. I., Maev I. V., Tkacheva O. N, Alekseenko S. A., Andreev D. N., Bordin D. S., Vlasov T. D., Vorobieva N M., Grinevich V. B., Gubonina I. V., Drobizhev M. Iu., Efremov N. S., Karateev A. E., Kotovskaia Iu. V., Kravchuk Iu. A., Krivoborodov G. G., Kulchavenia E. V., Lila A. M., Maevskaia M. V., Poluektova E. A., Popkova T. V., Sablin O. A., Solovieva O. I., Suvorov A. N., Tarasova G. N., Trukhan D. I., Fedotova A. V. Sindrom povyshennoi epitelialnoi pronitsaemosti v klinicheskoi praktike [Syndrome of increased epithelial permeability in clinical practice]. // Multidistsiplinarnyi natsionalnyi konsensus. Kardiovaskuliarnaia terapiia i profilaktika [Multidisciplinary National Consensus. Cardiovascular Therapy and Prevention]. 2021.20 (1). P. 121–278. (In Russ.)

67. Jun Wang, Xufeng Guo Efficacy and safety of proton pump inhibitors (PPIs) plus rebamipide for endoscopic submucosal dissection-induced ulcers: a meta-analysis // Intern Med. 2014. 53 (12) Р. 1243–8.

68. Zviaglova M. Iu., Kniazev O. V., Parfenov A. I. Farmakologicheskii i klinicheskii profil rebamipida: novye terapevticheskie misheni [Pharmacological and clinical profile of rebamipide: new therapeutic targets] // Terapevticheskii arkhiv [Therapeutic Archive] 2020. No. 2. P. 104–111. (In Russ.)

69. Podkhody k lecheniiu kislotozavisimykh zabolevanii [Approaches to the treatment of acid-related diseases]: a teaching guide for doctors / M. L. Maksimov, A. A. Zvegintseva et al. — Kazan: Publishing House «MedDoc», 2020. — 84 p. (In Russ.)

Среди болезней пищеварительной системы значительное место занимают кислотозависимые заболевания, обусловленные избыточной секрецией соляной кислоты, выделяемой париетальными клетками слизистой оболочки желудка. Ввиду своей высокой распространенности и риска осложнений, эти патологии представляют собой серьезную медико-социальную проблему.

Средствами, оказывающими защитное действие на слизистую оболочку желудка и кишечника, являются гастропротекторы. В данную группу препаратов входит круг лекарственных средств, различных по принципу и механизму действия, таких как мизопростол, соли висмута, а также некоторые препараты растительного происхождения и пр. [1, 68, 69].

Ребамипид относится к фармакологической группе «гастропротекторное средство», является оптически активным производным α-аминокислоты 2(1H)-хинолинона. Его брутто-формула — C19H15ClN2O4 [2, 66, 68].

1. Противовоспалительный

А) обусловленный индукцией экспрессии ЦОГ-2 и увеличением синтеза простагландинов.

В экспериментальной модели показано, что Ребамипид увеличивает экспрессию циклооксигеназы-2 [4], повышает уровень PGE2, 6-keto-PGF1 alpha, тромбоксана B2 и метаболита 15-keto-13,14-dihydro-PGE2 в слизистой оболочке желудка и значительно повышает их секрецию в просвет желудка [3, 4].

Б) обусловленный воздействием на сигнальные провоспалительные молекулы.

Ребамипид снижает воспалительную реакцию, индуцированную ФНО-а, стабилизирует линию макрофагов, прерывает воспалительный сигнальный путь посредством ингибирования ядерного фактора каппа В (nuclear factor kappa B — NF-kappa B) [5].

В) обусловленный воздействием на иммунные клетки.

Показано, что Ребамипид предотвращает воспаление, вызванное H. pylori, посредством ингибирования активности нейтрофилов и снижения продукции провоспалительных цитокинов, таких как ИЛ 8 [6, 7], а также, как было показано выше, стабилизирует линию макрофагов [5].

Для Цитирования:
Фролова А. А., Шиндина Т. С., Масловский Л. В., Максимов М. Л., Александрова Е. Б., Кропова О. Е., Гастропротектор «Ребамипид»: обзор механизмов действия и клинического применения. ГЛАВВРАЧ. 2022;4.
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