Trimebutine Maleate Monotherapy for Functional Dyspepsia: A Multicenter, Randomized, Double-Blind Placebo Controlled Prospective Trial

Jannis Kountouras, Emmanuel Gavalas, Apostolis Papaefthymiou, Ioannis Tsechelidis, Stergios A Polyzos, Serhat Bor, Mircea Diculescu, Κhaled Jadallah, Mazurek Tadeusz, Tarkan Karakan, Αnna Bochenek, Jerzy Rozciecha, Piotr Dabrowski, Zeno Sparchez, Orhan Sezgin, Macit Gülten, Niazy Abu Farsakh, Michael Doulberis, Jannis Kountouras, Emmanuel Gavalas, Apostolis Papaefthymiou, Ioannis Tsechelidis, Stergios A Polyzos, Serhat Bor, Mircea Diculescu, Κhaled Jadallah, Mazurek Tadeusz, Tarkan Karakan, Αnna Bochenek, Jerzy Rozciecha, Piotr Dabrowski, Zeno Sparchez, Orhan Sezgin, Macit Gülten, Niazy Abu Farsakh, Michael Doulberis

Abstract

Background and Objectives: Functional dyspepsia (FD) is one of the most common functional gastrointestinal disorders; it has a great impact on patient quality of life and is difficult to treat satisfactorily. This study evaluates the efficacy and safety of trimebutine maleate (TM) in patients with FD. Materials and Methods: Α multicenter, randomized, double-blind, placebo controlled, prospective study was conducted, including 211 patients with FD. Participants were randomized to receive TM 300 mg twice per day (BID, 108 patients) or placebo BID (103 patients) for 4 weeks. The Glasgow Dyspepsia Severity Score (GDSS) was used to evaluate the relief of dyspepsia symptoms. Moreover, as a pilot secondary endpoint, a substudy (eight participants on TM and eight on placebo) was conducted in to evaluate gastric emptying (GE), estimated using a 99mTc-Tin Colloid Semi Solid Meal Scintigraphy test. Results: Of the 211 patients enrolled, 185 (87.7%) (97 (52.4%) in the TM group and 88 (47.6%) in the placebo group) completed the study and were analyzed. The groups did not differ in their demographic and medical history data. Regarding symptom relief, being the primary endpoint, a statistically significant reduction in GDSS for the TM group was revealed between the first (2-week) and final (4-week) visit (p-value = 0.02). The 99 mTc-Tin Colloid Semi Solid Meal Scintigraphy testing showed that TM significantly accelerated GE obtained at 50 min (median emptying 75.5% in the TM group vs. 66.6% in the placebo group, p = 0.036). Adverse effects of low to moderate severity were reported in 12.3% of the patients on TM. Conclusion: TM monotherapy appears to be an effective and safe approach to treating FD, although the findings presented here warrant further confirmation.

Keywords: functional dyspepsia; gastrointestinal function; gastrointestinal motility; trimebutine maleate.

Conflict of interest statement

This work has been financially supported by Galenica A.E. Pharmaceutical Company, Greece.

Figures

Figure 1
Figure 1
Flow chart of the experiment phase.

References

    1. Francis P., Zavala S.R. Functional Dyspepsia. StatPearls Publishing; Treasure Island, FL, USA: 2020.
    1. Lacy B.E., Weiser K.T., Kennedy A.T., Crowell M.D., Talley N.J. Functional dyspepsia: The economic impact to patients. Aliment. Pharmacol. Ther. 2013;38:170–177. doi: 10.1111/apt.12355.
    1. Xiong Y., Xing H., Hu L., Xie J., Liu Y., Hu D. Effects of comfort care on symptoms, gastric motility, and mental state of patients with functional dyspepsia. Medicine. 2019;98:e16110. doi: 10.1097/MD.0000000000016110.
    1. Futagami S., Yamawaki H., Agawa S., Higuchi K., Ikeda G., Noda H., Kirita K., Akimoto T., Wakabayashi M., Sakasegawa N., et al. New classification Rome IV functional dyspepsia and subtypes. Transl. Gastroenterol. Hepatol. 2018;3:70. doi: 10.21037/tgh.2018.09.12.
    1. Mimidis K., Tack J. Pathogenesis of Dyspepsia. Dig. Dis. 2008;26:194–202. doi: 10.1159/000121346.
    1. Futagami S., Shimpuku M., Yin Y., Shindo T., Kodaka Y., Nagoya H., Nakazawa S., Fujimoto M., Izumi N., Ohishi N., et al. Pathophysiology of functional dyspepsia. J. Nippon Med. Sch. 2011;78:280–285. doi: 10.1272/jnms.78.280.
    1. Carbone F., Tack J. Gastroduodenal mechanisms underlying functional gastric disorders. Dig. Dis. 2014;32:222–229. doi: 10.1159/000357854.
    1. Aro P., Talley N.J., Johansson S.-E., Agréus L., Ronkainen J. Anxiety Is Linked to New-Onset Dyspepsia in the Swedish Population: A 10-Year Follow-up Study. Gastroenterology. 2015;148:928–937. doi: 10.1053/j.gastro.2015.01.039.
    1. Winston J.H., Sarna S.K. Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2016;311:G32–G39. doi: 10.1152/ajpgi.00067.2016.
    1. Kim S.Y., Choung R.S., Lee S.K., Choe J.W., Jung S.W., Hyun J.J., Koo J.S., Lee S.W., Shin C. Self-reported Sleep Impairment in Functional Dyspepsia and Irritable Bowel Syndrome. J. Neurogastroenterol. Motil. 2018;24:280–288. doi: 10.5056/jnm17098.
    1. Camilleri M., Tack J.F. Current medical treatments of dyspepsia and irritable bowel syndrome. Gastroenterol. Clin. North Am. 2010;39:481–493. doi: 10.1016/j.gtc.2010.08.005.
    1. Masuy I., Van Oudenhove L., Tack J. Review article: Treatment options for functional dyspepsia. Aliment. Pharmacol. Ther. 2019;49:1134–1172. doi: 10.1111/apt.15191.
    1. Kountouras J., Chatzopoulos D., Zavos C., Boura P., Venizelos J., Kalis A. Efficacy of trimebutine therapy in patients with gastroesophageal reflux disease and irritable bowel syndrome. Hepatogastroenterology. 2002;49:193–197.
    1. Kountouras J., Gavalas E., Doulberis M., Polyzos S.A., Papaefthymiou A., Touloumtzi M., Vardaka E., Kountouras K., Papanikolopoulou K., Katsinelos P. The Effect of Trimebutine and/or Helicobacter pylori Eradication on the Gastroesophageal Reflux Disease, Irritable Bowel Syndrome, and Functional Dyspepsia Overlapping Disorders. J. Neurogastroenterol. Motil. 2019;25:473–474. doi: 10.5056/jnm19033.
    1. Kountouras J., Sofianou D., Gavalas E., Sianou E., Zavos C., Meletis G., Tsiaousi E. Trimebutine as a potential antimicrobial agent: A preliminary in vitro approach. Hippokratia. 2012;16:347–349.
    1. Kountouras J., Doulberis M., Papaefthimiou A., Polyzos S.A. Gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia as overlapping conditions: Focus on effect of trimebutine. Ann. Gastroenterol. 2019;32:318. doi: 10.20524/aog.2019.0366.
    1. Cho K.H., Choi Y.K., Kang J.H., Choi H.G., Yong C.S., Park Y.J. Development of a novel combination tablet containing trimebutine maleate and mosapride citrate for the treatment of functional dyspepsia. Int. J. Pharm. 2010;400:145–152. doi: 10.1016/j.ijpharm.2010.08.047.
    1. Lee S.-Y., Kim M.-Y., Kang S.-Y., Song W.-J., Kang H.-R. A case of trimebutine-induced anaphylaxis. Allergol. Int. 2011;60:555–556. doi: 10.2332/allergolint.10-CR-0289.
    1. Zhong Y., Zhu J., Guo J., Yan R., Li H., Lin Y., Zeng Z. A randomized and case-control clinical study on trimebutine maleate in treating functional dyspepsia coexisting with diarrhea-dominant irritable bowel syndrome. Zhonghua nei ke za zhi. 2007;46:899–902.
    1. el-Omar E.M., Banerjee S., Wirz A., McColl K.E. The Glasgow Dyspepsia Severity Score—A tool for the global measurement of dyspepsia. Eur. J. Gastroenterol. Hepatol. 1996;8:967–971. doi: 10.1097/00042737-199610000-00006.
    1. Eypasch E., Williams J.I., Wood-Dauphinee S., Ure B.M., Schmülling C., Neugebauer E., Troidl H. Gastrointestinal Quality of Life Index: Development, validation and application of a new instrument. Br. J. Surg. 1995;82:216–222. doi: 10.1002/bjs.1800820229.
    1. Aktas A., Caner B., Ozturk F., Bayhan H., Narin Y., Mentes T. The effect of trimebutine maleate on gastric emptying in patients with non-ulcer dyspepsia. Ann. Nucl. Med. 1999;13:231–234. doi: 10.1007/BF03164897.
    1. Lüttecke K. A three-part controlled study of trimebutine in the treatment of irritable colon syndrome. Curr. Med. Res. Opin. 1980;6:437–443. doi: 10.1185/03007998009109464.
    1. Karabulut G.S., Beşer Ö.F., Erginöz E., Kutlu T., Çokuǧraş F.Ç., Erkan T. The incidence of irritable bowel syndrome in children using the rome iii criteria and the effect of trimebutine treatment. J. Neurogastroenterol. Motil. 2013;19:90–93. doi: 10.5056/jnm.2013.19.1.90.
    1. Hiyama T., Yoshihara M., Matsuo K., Kusunoki H., Kamada T., Ito M., Tanaka S., Nishi N., Chayama K., Haruma K. Meta-analysis of the effects of prokinetic agents in patients with functional dyspepsia. J. Gastroenterol. Hepatol. 2007;22:304–310. doi: 10.1111/j.1440-1746.2006.04493.x.
    1. Yang Y.J., Bang C.S., Baik G.H., Park T.Y., Shin S.P., Suk K.T., Kim D.J. Prokinetics for the treatment of functional dyspepsia: Bayesian network meta-analysis. BMC Gastroenterol. 2017;17:1–11. doi: 10.1186/s12876-017-0639-0.
    1. Stanghellini V., Tosetti C., Barbara G., De Giorgio R., Cogliandro L., Cogliandro R., Corinaldesi R. Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome. Am. J. Gastroenterol. 2002;97:2738–2743. doi: 10.1111/j.1572-0241.2002.07062.x.
    1. Triadafilopoulos G., Nguyen L., Clarke J.O. Patients with symptoms of delayed gastric emptying have a high prevalence of oesophageal dysmotility, irrespective of scintigraphic evidence of gastroparesis. BMJ Open Gastroenterol. 2017;4:e000169. doi: 10.1136/bmjgast-2017-000169.
    1. Vijayvargiya P., Camilleri M., Chedid V., Mandawat A., Erwin P.J., Murad M.H. Effects of Promotility Agents on Gastric Emptying and Symptoms: A Systematic Review and Meta-analysis. Gastroenterology. 2019;156:1650–1660. doi: 10.1053/j.gastro.2019.01.249.
    1. Vanheel H., Vicario M., Boesmans W., Vanuytsel T., Salvo-Romero E., Tack J., Farré R. Activation of Eosinophils and Mast Cells in Functional Dyspepsia: An Ultrastructural Evaluation. Sci. Rep. 2018;8:5383. doi: 10.1038/s41598-018-23620-y.
    1. Kozakai Y., Hori K., Aye-Mon A., Okuda H., Harada S., Hayashi K., Ozaki N. The role of peripheral corticotropin-releasing factor signaling in a rat model of stress-induced gastric hyperalgesia. Biochem. Biophys. Res. Commun. 2019;519:797–802. doi: 10.1016/j.bbrc.2019.09.040.
    1. Ji R., Wang P., Kou G., Zuo X., Wang X., Li Y. Impaired gastric mucosal integrity identified by confocal endomicroscopy in Helicobacter pylori-negative functional dyspepsia. Neurogastroenterol. Motil. 2020;32 doi: 10.1111/nmo.13719.
    1. Hussain Z., Jung D.H., Lee Y.J., Park H. The effect of trimebutine on the overlap syndrome model of Guinea pigs. J. Neurogastroenterol. Motil. 2018;24:669–675. doi: 10.5056/jnm18049.
    1. Fan Y., Liu P., Xue W., Zhao W., Pan H. Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent. Front. Pharmacol. 2018;9 doi: 10.3389/fphar.2018.00664.
    1. Wittmann T., Paradowski L., DucrottÉ P., Bueno L., Andro Delestrain M.C. Clinical trial: The efficacy of alverine citrate/simeticone combination on abdominal pain/discomfort in irritable bowel syndrome - A randomized, double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 2010;31:615–624. doi: 10.1111/j.1365-2036.2009.04216.x.
    1. Khdair Ahmad F., Aladily T.N., Altamimi M., Ajour M., Alsaber N., Rawashdeh M. Helicobacter pylori Prevalence and Impact: A Histology-Based Report About Children from an Endemic Country. Int. J. Gen. Med. 2020;13:207–214. doi: 10.2147/IJGM.S240205.
    1. Tack J., Masaoka T., Janssen P. Functional dyspepsia. Curr. Opin. Gastroenterol. 2011;27:549–557. doi: 10.1097/MOG.0b013e32834b7ca8.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel