A Case of Idiopathic Peptic Ulcer Disease Treated Effectively with Trimebutine Maleat.

A 30-year-old man with idiopathic peptic ulcer disease (IPUD) experienced repeated recurrence of ulcerative bleeding despite treatment with lansoprazole and then vonoprazan. Further evaluation suggested that the cause of the ulcer was strong contractile movements of the antrum. This prompted the co-administration of trimebutine maleate (TM) and vonoprazan to relieve the stomach contractions. TM was effective in preventing the recurrence of ulcerative bleeding, and the patient has remained in remission for 4 years. This case highlights the potential efficacy of TM in treating IPUD and the importance of considering hypercontractility as the underlying cause in cases of IPUD.

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

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.

Trimebutine maleate relaxes the isolated rat thoracic aorta: The role of nitric oxide and L-type calcium channels.

Trimebutine maleate (TMB), a widely prescribed drug for functional gastrointestinal disorders, has been reported to regulate smooth muscle contractility by modulating multiple ion channel activities in the gastrointestinal tract. However, its action on isolated aorta has not yet been reported. The aim of the present study was to evaluate in vitro vasorelaxant properties and the underlying pharmacological mechanisms of TMB in isolated rat thoracic aortic rings. Vascular activity experiments were performed on thoracic aorta isolated from Sprague-Dawley rats in vitro, including endothelium-intact and endothelium-denuded aortic rings. TMB (10-10 -10-5  mol/L) induced relaxation in endothelium-intact aortic rings precontracted by phenylephrine with a potency similar to that of carbachol. TMB-induced relaxation was not altered by glibenclamide and atropine in endothelium-intact aortic rings. However, L-NAME and endothelium denudation significantly reduced but not completely reversed the vasorelaxant effect of TMB. Also, TMB-induced relaxation wasn't affected by diclofenac in endothelium-intact aortic rings. TMB at 10-5  mol/L significantly reduced the CaCl2 -induced contractions in endothelium-intact aortic rings stimulated with KCl, but not stimulated with phenylephrine under Ca2+ free conditions. Moreover, TMB at 10-5  mol/L effectively attenuated Bay-K8644-induced contractions in aortic rings. These results suggest that TMB-induced relaxation was mediated by both endothelium-dependent and endothelium-independent manner in isolated rat thoracic aorta. The mechanism of TMB-induced relaxation at low concentrations is partially related to NO- and endothelium-dependent but unrelated to prostanoids formation. However, inhibition of Ca2+ influx through voltage-operated calcium channels and L-type Ca2+ channel blocking effect appears to be involved in the mechanism of vasorelaxant effect of TMB at high concentrations.

The protective impact of adapted trimebutine maleate-loaded nanostructured lipid carriers for alleviating the severity of acute colitis.

Nanoparticles for colon-drug delivery were designed and evaluated to solve many discrepancy issues such as high adverse effects of released drugs, insufficient drug amount at diseased areas, and unintentionally premature drug release to noninflamed GIT regions. Herein, the goal of this work was to convert trimebutine maleate (TMB) into nanostructured lipid carriers (NLC) in order to improve its protective effects in ulcerative colitis. NLC of TMB was prepared by the hot homogenization followed by ultra-sonication method. A full 42-factorial design was used to estimate the produced TMB-NLC. The study design included the exploration of the impact of two independent variables namely lipid mix amount and ratio (glyceryl mono stearate and capryol 90), surfactant concentration (0.5, 1, 1.5, and 2%), on the particle size, polydispersity index, and the entrapment efficiency (EE%). The protective activity of F9 was examined through macroscopical scores, histopathological changes, immunohistochemical localization of tumor necrosis factor-α (TNF-α) and examination of oxidative stress such as reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) against acetic acid-induced colitis in rats. Consistent with our expectations, the orally administered optimized formula (F9) alleviated the severity of colitis in acetic acid-induced rat model of colitis likely owing to the controlled release compared to free TMB. We aimed to develop TMB-loaded NLC for the treatment of acute colitis with the goal of providing a superior drug safety profile over long-term remission and maintenance therapy.

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells.

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/ß-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/ß-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

Generalized Lichen Planus-like Eruption Related to Trimebutine.

Trimebutine is a spasmolytic agent with antimuscarinic effects that is used for the treatment of irritable bowel syndrome (IBS) and lower gastrointestinal tract motility disorders. Lichenoid drug eruptions (LDE) to trimebutine maleate have not been previously reported. Here we present the case of a 50-year-old male patient who developed an extensive lichenoid eruption on his upper and lower extremities and trunk 4 weeks after starting treatment with trimebutine maleate 300 mg once daily for IBS. Two months after discontinuation of the drug and administration of topical treatment with emollients and corticosteroids, the LDE cleared completely with no recurrence. The diagnosis of LDE due to trimebutine was made, based upon the clinical features resembling lichen planus, the histological findings of interface dermatitis, the evidence of a temporal relationship between drug intake and the development of skin lesions, and resolution upon discontinuation of the drug. To the best of the authors' knowledge, LDE following trimebutine maleate intake has not been previously reported. Management of trimebutine-induced LDE includes withdrawal of the causative agent and treatment with potent topical corticosteroids. LEARNING POINTS: Cutaneous adverse events due to trimebutine maleate, an antispasmodic agent frequently used for the treatment of irritable bowel syndrome (IBS), have rarely been reported.Lichenoid drug eruption (LDE), also called drug-induced lichen planus, is an uncommon cutaneous adverse effect of several drugs.Here we report the first case of trimebutine maleate-induced LDE.