Effect of ketotifen on gastrointestinal symptoms, visceral sensitivity and intestinal mast cells in patients with irritable bowel syndrome with diarrheal

doi:10.12092/j.issn.1009-2501.2019.01.011

Abstract

Abstract:

AIM: To investigate the effects of ketotifen on abdominal symptoms, visceral sensitivity and intestinal mast cells in patients with irritable bowel syndrome with diarrhea (IBS-D). METHODS: Patients with IBS-D were randomly divided into ketotifen group and placebo group, the ketotifen group were oral administration of ketotifen tablets, 1 mg, bid for 8 weeks, the control group were received oral placebo for 8 weeks. Gastrointestinal symptoms evaluation scale questionnaire, anorectal sensory function, the number and activity status of mast cell (MC) were measured before and 8 weeks after treatment in these two group. RESULTS: (1) A total of 87 IBS-D patients were included, 44 in ketotifen group and 43 in control group, there was no significant difference in age and sex between the two groups. (2) Total effective rate of improvement of gastrointestinal symptoms in ketotifen group was significantly higher than that in control group (72.7% vs. 34.9%, P<0.01). (3) Compared with before treatment, first sensation, urge to defecation, discomfort/pain sensory thresholds of ketotifen group were significantly increased after treatment (P<0.05), no significant changes were observed in the control group (P>0.05); (4) Compared with before treatment, the number of MC in terminal ileum, the proportion of MC degranulation state in the terminal ileum, ascending colon, sigmoid colon in ketotifen group were significantly decreased after treatment (P<0.05), there was no significant change in the number of MC and the proportion of degranulation state in the control group (P>0.05); (5) 5 patients (11.4%) in ketotifen group went through adverse reactions, mainly manifested as feeling of drowsiness or fatigue, which disappeared after taking the drug one week. CONCLUSION: Ketotifen can significantly relieve the gastrointestinal symptoms and improve the visceral sensitivity of patients with IBS-D, which is closely related to its effect on reducing the number and activity of MC in intestinal mucosa, especially the terminal ileum.

Key words: ketotifen, irritable bowel syndrome with diarrheal, visceral sensitivity, mast cells

CLC Number:

R364.5
R574

WANG Jing, ZHOU Haibin, GU Weigang, WANG Xia, YANG Jianfeng. Effect of ketotifen on gastrointestinal symptoms, visceral sensitivity and intestinal mast cells in patients with irritable bowel syndrome with diarrheal[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(1): 63-70.

References

［1］Gwee KA, Ghoshal UC, Chen M. Irritable bowel syndrome in Asia: Pathogenesis, natural history, epidemiology, and management［J］ . J Gastroenterol Hepatol, 2018, 33(1): 99-110.
［2］Radovanovic-Dinic B, Tesic-Rajkovic S, Grgov S, et al. Irritable bowel syndrome - from etiopathogenesis to therapy ［J］. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2018, 162(1): 1-9.
［3］Craig O. New therapies in Irritable Bowel Syndrome: what works and when ［J］. Curr Opin Gastroenterol, 2018, 34(1): 50-56.
［4］Ohman L, Simren M. New insights into the pathogenesis and pathophysiology of irritable bowel syndrome ［J］. Dig Liver Dis, 2007, 39(3): 201-215.
［5］Martin-Vias JJ, Quigley EM. Immune response in irritable bowel syndrome: A systematic review of systemic and mucosal inflammatory mediators ［J］. J Dig Dis, 2016, 17(9): 572-581.
［6］Boeckxstaens GE, Wouters MM. Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome ［J］. Neurogastroenterol Motil, 2017, 29(6). doi: 10.1111/nmo.13007.
［7］方亮, 张凡勇, 吴继雄. 肠易激综合征患者结直肠黏膜降钙素基因相关肽和P物质表达及与临床症状的相关性［J］. 疑难病杂志, 2017, 16(1): 64-67.
［8］Boyer J, Saint-Paul MC, Dadone B, et al. Inflammatory cell distribution in colon mucosa as a new tool for diagnosis of irritable bowel syndrome: A promising pilot study ［J］. Neurogastroenterol Motil, 2018, 30(1). doi: 10.1111/nmo.13223.
［9］Bashashati M, Moossavi S, Cremon C, et al. Colonic immune cells in irritable bowel syndrome: A systematic review and meta-analysis ［J］. Neurogastroenterol Motil, 2018, 30(1). doi: 10.1111/nmo.13192.
［10］Bednarska O, Walter SA, Casado-Bedmar M, et al. Vasoactive intestinal polypeptide and mast cells regulate increased passage of colonic bacteria in patients with irritable bowel syndrome ［J］. Gastroenterology, 2017, 153(4): 948-960.e3.
［11］Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders ［J］. Gut, 2016, 65(1): 155-168.
［12］白连霞, 郝木红. 酮替芬联合布地奈德治疗支气管哮喘的临床疗效及其安全性［J］. 临床合理用药杂志, 2018, 11(21): 15-16.
［13］Mearin F, Lacy BE, Chang L, et al. Bowel disorders ［J］. Gastroenterology, 2016, pii: S0016-5085(16)00222-5.
［14］Ballou S, Keefer L. The impact of irritable bowel syndrome on daily functioning: Characterizing and understanding daily consequences of IBS ［J］. Neurogastroenterol Motil, 2017, 29(4), doi: 10.1111/nmo.12982.
［15］Weaver KR, Melkus GD, Henderson WA. Irritable bowel syndrome ［J］. Am J Nurs, 2017, 117(6): 48-55.
［16］Yoon H. Mast cell may be the master key to solve the mystery of pathogenesis of irritable bowel syndrome ［J］. Gut Liver, 2016, 10(3): 325-326.
［17］Barbara G, Wang B, Stanghellini V, et al. Mast cell-dependent excitation of visceral- nociceptive sensory neurons in irritable bowel syndrome ［J］. Gastroenterology, 2007, 132(1): 26-37.
［18］An S, Zong G, Wang Z, et al. Activation of protease-activated receptor 4 of mast cells could downregulate proinflammatory cytokines in irritable bowel syndrome ［J］. Gut, 2017, 66(11): 2040-2042.
［19］Cremon C, Carini G, Wang B, et al. Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome ［J］. Am J Gastroenterol, 2011, 106(7): 1290-1298.
［20］Patman G. IBS: Mast cells cause nerves to sprout in patients with IBS ［J］. Nat Rev Gastroenterol Hepatol, 2015, 12(4): 189.
［21］Dothel G, Barbaro MR, Boudin H, et al. Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome ［J］. Gastroenterology, 2015, 148(5): 1002-1011.e4.
［22］Hughes PA, Zola H, Penttila IA, et al. Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms ［J］. Am J Gastroenterol, 2013, 108(7): 1066-1074.
［23］Vicario M, González-Castro AM, Martínez C, et al. Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations ［J］. Gut, 2015, 64(9): 1379-1388.
［24］Piche T. Tight junctions and IBS-the link between epithelial permeability, low-grade inflammation, and symptom generation ［J］. Neurogastroenterol Motil, 2014, 26(3): 296-302.
［25］Liu DR, Xu XJ, Yao SK. Increased intestinal mucosal leptin levels in patients with diarrhea-predominant irritable bowel syndrome ［J］. World J Gastroenterol, 2018, 24(1): 46-57.
［26］Braak B, Klooker TK, Wouters MM, et al. Mucosal immune cell numbers and visceral sensitivity in patients with irritable bowel syndrome: is there any relationship ［J］. Am J Gastroenterol, 2012, 107(5): 715-726.
［27］Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome ［J］. Gut, 2010, 59(9): 1213-1221.
［28］Martínez C, Lobo B, Pigrau M, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier ［J］. Gut, 2013, 62(8): 1160-1168.

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