Trimebutine Maleate Research Articles

Determination the Anticorrosive Properties of Trimebutine Maleate for Aluminum Corrosion in 2M HCl Gravimetric and Quantum Chemistry Approaches

The present work evaluated the inhibition properties of (R,S)-2-(dimethylamino)-2-phenylbutyl 3,4,5-trimethoxybenzoate or trimebutine maleate (TM) in aluminum corrosion in 2M hydrochloric acid. Tests were carried out using gravimetric methods and density functional theory (DFT). The results indicate that trimebutine maleate is a good inhibitor of aluminum corrosion in 2M hydrochloric acid at low temperatures. Indeed, the inhibition efficiency of this molecule increases with increasing concentration and decreases with increasing temperature. For an inhibitor concentration of 5.2mM and at 298K, we obtained an inhibition efficiency of 93.61%. The adsorption process is spontaneous, exothermic and follows the Langmuir model. The activation parameters were calculated and analyzed. DFT at the B3LYP/6-311G (d.p) level was used to determine molecular parameters such as EHOMO, ELUMO, ΔE, η, S, μ , A, I, χ, ΔN, ω. These theoretical parameters showed that TM is highly reactive and can both donate and receive electrons from aluminum. They thus confirmed the good inhibition performance of the molecule studied. These parameters were used to explain the inhibition efficiencies obtained. Local selectivity was analyzed using Fukui functions and the dual descriptor to determine possible nucleophilic and electrophilic attack sites.

Effect of Trimebutine and Rifaximin on Breath Hydrogen and Methane by Glucose Breath Test in Patients With Functional Bloating: A Randomized Double-blind Clinical Trial.

Drugs that stabilize intestinal motility may improve the efficacy of nonabsorbable antibiotics, such as rifaximin, against small intestinal bacterial overgrowth (SIBO). We compared the efficacy of rifaximin alone with that of its combination with trimebutine maleate against SIBO. We performed a randomized double-blind placebo-controlled trial (https://cris.nih.go.kr, no. KCT0004836) that included patients with functional bloating, no constipation, and SIBO using the hydrogen (H2)-methane (CH4) glucose breath test (GBT). Patients were randomized into 2 groups in a 1:1 ratio, namely rifaximin (1200 mg/day) + trimebutine maleate (600 mg/day) group and rifaximin + placebo group, for 2 weeks. Patients completed a symptom questionnaire and underwent a GBT at baseline and at 1 month after treatment withdrawal. The primary outcome was SIBO eradication. The secondary outcomes included changes in the concentrations of exhaled gases, symptoms, and presence of adverse events. The complete eradication rate of SIBO was 35.9% (14/39) in the rifaximin group, and 34.1% (14/41) in the combined group with no significant differences. In both groups, no significant differences were observed in GBT profiles before and after the treatment, respectively. However total breath H2 and CH4 concentration were conspicuously decreased in the combined group after treatment. The combined group exhibited substantial relief of bloating. The adverse events were similar in the 2 groups. While the combination therapy was not superior over rifaximin alone for SIBO eradication, it improves the symptom of bloating with numerically reducing the concentration of breath H2/CH4.

Retracted: Efficacy and Mechanism of Trimebutine Maleate Combined with Lactulose in the Treatment of Constipation-Predominant Irritable Bowel Syndrome in the Elderly.

[This retracts the article DOI: 10.1155/2022/6125120.].

Assessment of pain intensity and methods of its relief in patients with irritable bowel syndrome

Objective — to develop a questionnaire for assessing the condition of patients with irritable bowel syndrome (IBS); to evaluate clinical effectiveness of personalized diet, synthetic agonist of peripheral opioid receptors m‑, k‑, and d‑ trimebutine maleate, and complex pro‑prebiotic drug (Lactobacillus acidophilus 500 million, Lactobacillus rhamnosus 1 billion, Sacchromyces boulardii 30 million, Bifidobacterium lactis 275 million, Bifidobacterium longum 1 billion, Clostridium butyricum 2 million, Bacillus clausii spores 2 billion, Fructo oligosaccharides 100 mg) in patients with IBS.
 Materials and methods. To evaluate the clinical effectiveness of the treatment, 28 patients with IBS have been examined. The investigated group included 15 (53.6%) patients with IBS and diarrhea, 11 (39.3%) subjects with mixed IBS, and two (7.1%) patients with IBS and constipation. The age of the patients was 32.5±3.1 years; from them 17 (51.7%) were women and 11 (39.3%) men. Nine women (52.9%) and five (45.5%) men were married, and 11 (64.7%) women and 7 (63.3%) men had higher education. The average duration of the disease in women was 3.4±1.8 years, and 3.1±1.5 years in men. The diagnosis of IBS was established according to the Rome criteria IV revision. Defecation was evaluated according to the Bristol stool scale. All patients filled out the «Questionnaire for a patient with irritable bowel syndrome» before the treatment start and during the treatment. The examined patients were prescribed a personalized diet with account their nutritional status, and drug therapy that included trimebutine maleate (film‑coated tablets) in a dose of 200 to 600 mg depending on pain intensity, and synbiotic (Lactobacillus acidophilus, Lactobacillus rhamnosus, Sacchromyces boulardii, Bifidobacterium lactis, Bifidobacterium longum, Clostridium butyricum, Bacillus clausii spores, Fructo oligosaccharides) in a dose of one capsule twice a day, regardless of the severity of the pain syndrome.
 Results. Complex treatment with the use of personalized dietary recommendations, synthetic agonist of peripheral opioid receptors trimebutine maleate and synbiotic that included Lactobacillus acidophilus, Lactobacillus rhamnosus, Sacchromyces boulardii, Bifidobacterium lactis, Bifidobacterium longum, Clostridium butyricum, Bacillus clausii spores, Fructo oligosaccharides, promoted to the decrease of pain syndrome severity, improvement of the psychoemotional state and quality of life of patients.
 Conclusions. The developed questionnaire for a patient with IBS was comprehensible and easy to fill out by patients; it allowed a practitioner to quickly analyze the dynamics of the pain syndrome. Personalized dietary treatment, a differentiated approach in administration of the peripheral opioid receptor agonist trimebutine maleate and synbiotics (Lactobacillus acidophilus, Lactobacillus rhamnosus, Sacchromyces boulardii, Bifidobacterium lactis, Bifidobacterium longum, Clostridium butyricum, Bacillus clausii spores, IBS oligosaccharides) was clinically effective for patients with IBS, it promoted the significant pain relief and improvement of the quality of life of patients.

Comparison of Traditional Chinese Medicine with Trimebutine Maleate in the Treatment of Diarrhea-type Irritable Bowel Syndrome: A Meta-analysis

Comparison of Traditional Chinese Medicine with Trimebutine Maleate in the Treatment of Diarrhea-type Irritable Bowel Syndrome: A Meta-analysis

Repurposing of US-FDA approved drugs against SARS-CoV-2 main protease (Mpro) by using STD-NMR spectroscopy, in silico studies and antiviral assays

SARS-CoV-2 Main protease (Mpro) is a well-known drug target against SARS-CoV-2 infection. Identification of Mpro inhibitors is vigorously pursued due to its crucial role in viral replication. The present study was aimed to identify Mpro inhibitors via repurposing of US-FDA approved drugs by STD-NMR spectroscopy. In this study, 156 drugs and natural compounds were evaluated against Mpro. Among them, 10 drugs were found to be interacting with Mpro, including diltiazem HCl (1), mefenamic acid (2), losartan potassium (3), mexiletine HCl (4), glaucine HBr (5), trimebutine maleate (6), flurbiprofen (7), amantadine HCl (8), dextromethorphan (9), and lobeline HCl (10) in STD-NMR spectroscopy. Their interactions were compared with three standards (Repurposed anti-viral drugs), dexamethasone, chloroquine phosphate, and remdesivir. Thermal stability of Mpro and dissociation constant (Kd) of six interacting drugs were also determined using DSF. RMSD plots in MD simulation studies showed the formation of stable protein-ligand complexes. They were further examined for their antiviral activity by plaque reduction assay against SARS-CoV-2, which showed 55–100% reduction in viral plaques. This study demonstrates the importance of drug repurposing against emerging and neglected diseases. This study also exhibits successful application of STD-NMR spectroscopy combined with plaque reduction assay in rapid identification of potential anti-viral agents.

Efficacy and Mechanism of Trimebutine Maleate Combined with Lactulose in the Treatment of Constipation-Predominant Irritable Bowel Syndrome in the Elderly.

Study on the efficacy and mechanism of trimebutine maleate combined with lactulose in the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in the elderly. From March 2019 to March 2021, 102 elderly patients with IBS-C were randomly divided into the observation group (51 cases) and the control group (51 cases). The observation group was treated with trimebutine maleate combined with lactulose, while the control group was treated with lactulose. Comparison of the clinical effects of the two groups. Comparison of vasoactive intestinal peptide (VIP) levels, neuropeptide Y (NPY) levels, and quality of life scores before and after treatment between the two groups. Documentation of adverse reactions during treatment. The improvement of clinical symptoms in the observation group was significantly better than that in the control group, and the difference is statistically significant (P < 0.05). The level of VIP after treatment in the observation group was significantly lower than that in the control group and before treatment, and the differences were statistically significant (P < 0.05). The level of NPY after treatment in the observation group was significantly higher than that in the control group and before treatment, and the differences were statistically significant (P < 0.05). The scores of dietary restrictions and health worries in the control group after treatment were significantly higher than those before treatment, and the differences were statistically significant (P < 0.05). The scores of anxious, behavioral conflict, dietary restrictions, health worries, social response, and family relationship in the observation group after treatment were significantly higher than those in the control group and before treatment, and the differences were statistically significant (P < 0.05). There were no serious adverse effects in either group during the treatment period, with some patients experiencing dizziness and dry mouth, which improved after discontinuation of the drug, without special intervention. Trimebutine maleate combined with lactulose can improve clinical symptoms and quality of life in elderly patients with IBS-C, and its mechanism of action may be related to the regulation of the body's VIP and NPY levels.

Solubility parameter and solution thermodynamic properties of Form I Trimebutine maleate in six mono-solvents and three binary mixed solvents at different temperatures

The solubility information of drugs in solution is of great significance in the fields of chemistry and pharmacy. Trimebutine maleate is a commonly used drug for treating gastrointestinal disorders, and its solid–liquid balance data are critical for a preliminary study of industrial application. This study investigated the solubility of medicinal crystal form (Form Ⅰ) of Trimebutine maleate at T = 283.15–328.15 K. The molar fraction solubility of Form Ⅰ in six mono-solvents and three binary mixtures were studied. The modified Apelblat equation, the general Buchowski-Ksiazaczak λh model and the new correlative model were used for correlation analysis of the solubility of Form Ⅰ in mono-solvents. The general cosolvency model and Jouyban-Acree-van't Hoff model were used for correlation analysis of the solubility of Form Ⅰ in binary mixed solvents. By comparing the models, the modified Apelblat equation and the general cosolvency model provided more accurate experimental data for predicting the solubility of Form Ⅰ in mono-solvents and binary mixed solvents, respectively. Finally, the apparent thermodynamic properties were calculated by the van't Hoff analysis.

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.

Mechanism of QingHuaZhiXie Prescription Regulating TLR4-IECs Pathway in the Intervention of Diarrhea Predominant Irritable Bowel Syndrome.

To investigate the effect and mechanism of QingHuaZhiXie prescription on diarrhea predominant irritable bowel syndrome (D-IBS), animal models of rats were used in this study. 48 rats were randomly divided into 6 groups, containing one control group, one animal model group (D-IBS group), and four drug intervention groups (low, medium, and high dosage of QingHuaZhiXie prescription and trimebutine maleate intervention group). Abdominal withdrawal reflex (AWR) and Bristol stool form scale were recorded; the expression levels of inflammatory factors (TNF-α and IFN-γ), pathway proteins TLR4, MyD88, NF-κB, and key proteins of tight junction between intestinal epithelial cells (IECs) were detected; the microstructure of intestinal mucosal was observed by hematoxylin and eosin (H&E) staining; MPO activity was detected with immunohistochemical analysis to reflect the inflammation of tissues. Results show that QingHuaZhiXie prescription reduced diarrhea index and intestinal hypersensitivity and intestinal tissue integrity after intervention. MPO activity in QingHuaZhiXie prescription-treated rats was significantly lower relative to their model group. The expression levels of inflammatory factors and TLR4/MyD88/NF-κB pathway proteins were repressed, and the protein levels of occludin and claudin-1 increased. Meanwhile, this study also found that the remission effect of QingHuaZhiXie prescription on D-IBS increased with its dosage increase. Hence, as a therapeutic prescription for D-IBS, QingHuaZhiXie prescription could relieve D-IBS symptoms through balancing the inflammatory factors expression by inhibiting the TLR4/MyD88/NF-κB pathway and maintaining the function and structure of IECs by improving the protein levels of JAM, occludin, claudin-1, and ZO-1.

277P Phase II randomized study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with HR-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B

Abemaciclib-induced diarrhea (AID) occurs about 80-90% of patients, resulting in the impairment of QOL and compliance. Previous reports showed that over 40% patients had constipation due to prophylactic use of loperamide. We hypothesized that bifidobacterial and trimebutine maleate decrease the frequency of AID without increasing constipation.

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/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-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.

Mechanism of Sodium Valproate Combined with Decitabine in Inhibiting Hepatocellular Carcinoma Cells Epithelial-Mesenchymal Transition and Invasion and Metastasis Based on p38 Mitogen-Activated Protein Kinases/Heat Shock Protein 27 Regulating Proliferation by p53 Pathway

To determine the efficacy of trimebutine maleate combined with hyperbaric oxygen therapy on irritable bowel syndrome. Totally 180 patients diagnosed as irritable bowel syndrome who were admitted to our hospital between June 2016 and June 2019 were enrolled and randomized into the control group and the observation group according to the number of visits (each n=90). The control group was treated with trimebutine maleate through oral medication, while the observation group was given hyperbaric oxygen therapy additionally based on the treatment for the control group. Both groups were treated for 4 w. Then the following items of the two groups before and after intervention were evaluated and compared: serum neurotransmitterassociated parameters (5-hydroxytryptamine, somatostatin, substance P, neuropeptide Y), rectal manometry parameters (rectal sensation threshold, rectal defecation threshold, rectal pain threshold and rectal motor index), self-rating anxiety scale score and efficacy. Before treatment, no notable difference was found between the two groups in rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score (all p>0.05). After treatment, the rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score of both groups were greatly improved (all p<0.05) and all these improvements in the observation group were more significant than those in the control group (all p<0.05). In addition, the observation group got notably higher efficacy than the control group (p<0.01). Trimebutine maleate combined with hyperbaric oxygen therapy is effective in the therapy of irritable bowel syndrome, without toxic and side effects, so it is worthy of clinical application.

Efficacy of Trimebutine Maleate Combined With Hyperbaric Oxygen Therapy on Irritable Bowel Syndrome

To determine the efficacy of trimebutine maleate combined with hyperbaric oxygen therapy on irritable bowel syndrome. Totally 180 patients diagnosed as irritable bowel syndrome who were admitted to our hospital between June 2016 and June 2019 were enrolled and randomized into the control group and the observation group according to the number of visits (each n=90). The control group was treated with trimebutine maleate through oral medication, while the observation group was given hyperbaric oxygen therapy additionally based on the treatment for the control group. Both groups were treated for 4 w. Then the following items of the two groups before and after intervention were evaluated and compared: serum neurotransmitterassociated parameters (5-hydroxytryptamine, somatostatin, substance P, neuropeptide Y), rectal manometry parameters (rectal sensation threshold, rectal defecation threshold, rectal pain threshold and rectal motor index), self-rating anxiety scale score and efficacy. Before treatment, no notable difference was found between the two groups in rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score (all p>0.05). After treatment, the rectal manometry indices, serum neurotransmitter-associated indices and self-rating anxiety scale score of both groups were greatly improved (all p<0.05) and all these improvements in the observation group were more significant than those in the control group (all p<0.05). In addition, the observation group got notably higher efficacy than the control group (p<0.01). Trimebutine maleate combined with hyperbaric oxygen therapy is effective in the therapy of irritable bowel syndrome, without toxic and side effects, so it is worthy of clinical application.

Generalized Lichen Planus-like Eruption Related to Trimebutine.

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.

Acupuncture for Adults with Diarrhea-Predominant Irritable Bowel Syndrome or Functional Diarrhea: A Systematic Review and Meta-Analysis.

Objective. To evaluate the clinical effectiveness and safety of acupuncture therapy in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) or functional diarrhea (FD) in adults. Method. Five electronic databases—PubMed, EMBASE, CNKI, VIP, and Wanfang—were searched, respectively, until June 8, 2020. The literature of clinical randomized controlled trials of acupuncture for the treatment of IBS-D or FD in adults were collected. Meta-analysis was conducted by Using Stata 16.0 software, the quality of the included studies was assessed by the RevMan ROB summary and graph, and the results were graded by GRADE. Result. Thirty-one studies with 3234 patients were included. Most of the studies were evaluated as low risk of bias related to selection bias, attrition bias, and reporting bias. Nevertheless, seven studies showed the high risk of bias due to incomplete outcome data. GRADE's assessments were either moderate certainty or low certainty. Compared with loperamide, acupuncture showed more effectiveness in weekly defecation (SMD = −0.29, 95% CI [-0.49, -0.08]), but no significant improvement in the result of the Bristol stool form (SMD = −0.28, 95% CI [-0.68, 0.12]). In terms of the drop-off rate, although the acupuncture group was higher than the bacillus licheniformis plus beanxit group (RR = 2.57, 95% CI [0.24, 27.65]), loperamide group (RR = 1.11, 95% CI [0.57, 2.15]), and trimebutine maleate group (RR = 1.19, 95% CI [0.31, 4.53]), respectively, it was lower than the dicetel group (RR = 0.83, 95% CI [0.56, 1.23]) and affected the overall trend (RR = 0.93, 95% CI [0.67, 1.29]). Besides, acupuncture produced more significant effect than dicetel related to the total symptom score (SMD = −1.17, 95% CI [-1.42, -0.93]), IBS quality of life (SMD = 2.37, 95% CI [1.94, 2.80]), recurrence rate (RR = 0.43, 95% CI [0.28, 0.66]), and IBS Symptom Severity Scale (SMD = −0.75, 95% CI [-1.04, -0.47]). Compared to dicetel (RR = 1.25, 95% CI [1.18, 1.32]) and trimebutine maleate (RR = 1.35, 95% CI [1.13, 1.61]), acupuncture also showed more effective at total efficiency. The more adverse effect occurred in the acupuncture group when comparing with the dicetel group (RR = 11.86, 95% CI [1.58, 89.07]) and loperamide group (RR = 4.42, 95% CI [0.57, 33.97]), but most of the adverse reactions were mild hypodermic hemorrhage. Conclusion. Acupuncture treatment can improve the clinical effectiveness of IBS-D or FD, with great safety, but the above conclusions need to be further verified through the higher quality of evidence.

EFFICACY OF POSTOPERATIVE PARENTERAL TRIMEBUTINE MALEATE IN RECOVERY OF BOWEL FUNCTION FOLLOWING CESAREAN SECTION

Background: Postoperative ileus remains a serious clinical problem. It is one of the most important contributors to increased length of hospitalization and consumption of the health care system resources. Attempts have been made to treat several causes simultaneously to quickly restore normal postoperative bowel motility. Objective: The aim of this study was to estimate the effectiveness of postoperative parentally administered Trimebutine maleate inducing intestinal motility after cesarean section. Patients and Methods: This study included 200 patients who were selected from the outpatient clinic of Obstetrics and Gynecology at Alexandria Armed Forces Hospital. They were classified into two equal groups: Group (1): Control group underwent traditional management (oral intake of clear fluids and I.V fluids), and Group (2): were infused intravenously by a total dose of 300mg of Trimebutine maleate per day divided into 100 mg every 8 hours till first passage of flatus. Each group was subdivided into two equal subgroups: A) GA group underwent cesarean section under general anesthesia, B) SA group underwent cesarean section under spinal analgesia. Results: There was a significant difference between GA and SA of the control group in which the SA group decreased in the time in comparison to the GA group in all the outcome measures. There was a significant difference between GA of the cases group and GA of the control group in which the GA of the cases group decreased in the time in comparison to the GA group of the control in all the outcome measures. There was a significant difference between SA of the cases group and SA of the control group in which the SA of the cases group decreased in the time in comparison to the SA group of the control in all the outcome measures. Regarding pain and distension. There was a significant difference between GA and SA of the control group with more cases in the GA group, there was a significant difference between SA of the control and SA of the cases with more cases with the SA of the control. Conclusion: Trimebutine maleate (GASTREG®) routinely administrated to patients after caesarean section speeds recovery of intestinal function postoperatively by stimulating gastrointestinal motility. So GASTREG is an inexpensive, tolerable and helpful measure to postoperative care after caesarean section and other abdominal surgery.

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: A 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.

Abstract OT2-02-09: Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B

Abstract Background: The standard treatment for estrogen receptor-positive, HER2-negative inoperable and/or recurrent breast cancers is a combination of endocrine therapy and a CDK4/6 inhibitor (abemaciclib). When abemaciclib is administered, 80%-90% of patients experience diarrhea, resulting in the reduction of patient QOL and compliance. Loperamide is recommended for abemaciclib-induced diarrhea as well as chemotherapy induced diarrhea. However, previous reports showed that approximately 40% patients had constipation due to supportive treatment of loperamide. Moreover, the side effects of molecular targeted drugs, including abemaciclib, are not clear in the mechanism, and the effectiveness of coping therapy similar to chemotherapy and the treatment for side effects have not been clearly established. Thus developing new measures to effectively manage abemaciclib-induced diarrhea is an important clinical task, especially prevention of diarrhea without increasing adverse events such as constipation will be important to maintain QOL of patients receiving abemaciclib. Trial Design: This is a multicenter, randomized, open-label Phase II study to evaluate the efficacy and safety of probiotics (bifidobacterial formulation) and trimebutine maleate in treatment of abemaciclib-induced diarrhea. Both Arms A and B will receive hormone therapies (selected by physician in charge*) as directed along with abemaciclib 150 mg bid over the course of 28 days, and simultaneously to initiation of abemaciclib administration, will be given two pills of Biofermin® tid in Both Arms. Once patients experience diarrhea that is grade 6 or greater on the Bristol scale (higher grade than loose stool), salvage therapy using loperamide will be administered in Arm A. In contrast, participants from Arm B will be administered 100 mg trimebutine maleate. Thereafter, following meals, trimebutine maleate tid will be given throughout the trial period of 28 days. Eligibility Criteria: Key eligibility criteria for this trial are: Histologically diagnosed estrogen receptor-positive, HER2-negative breast cancer. Stage IIIB/IIIC breast cancer that is not subjected to surgery for curative intent, Stage IV breast cancer suitable for endocrine therapy. No prior treatment with CDK 4/6 inhibitors, and any type and number of previous treatments will be allowed in the selection criteria except CDK4/6 inhibitors. Specific Aims: The primary endpoint is the percentage of patients who experienced Grade 2 or greater diarrhea during the trial duration of 28 days and key secondary endpoints include safety, frequency and duration of all-grade diarrhea, frequency of emesis and constipation, comparative usage of loperamide in Arms A and B, and QOL/PRO in the 28-day study duration Statistical Design: By using the 40% threshold as the null hypothesis, appropriate statistical analysis will be performed based on a binomial distribution. The significance level will be 2.5%, determined using a one-tailed test. Interval estimation will be appropriately deduced from a binomial distribution. If either arm shows a significant reduction compared with the threshold value, as secondary validation, intergroup comparison of the primary endpoint percentage of diarrhea onset will be performed. In this case, the significance level will be 10%, determined using a two-tailed test. Target Accrual: A total of 50 patients will be enrolled and duration of enrollment will be 1 year. This trial will open to accrual in September 2019. Contact Information: Hiroko Masuda, Showa University Hospital, Tokyo, Japan, hmasuda@med.showa-u.ac.jp Citation Format: Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani. Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-09.

Different aspects in manipulating overlapped spectra used for the analysis of trimebutine maleate and structure elucidation of its degradation products

BackgroundFour rapid, accurate, and validated stability-indicating spectrophotometric methods have been described in the present work for the analysis of trimebutine maleate (TM) in existence of its degradation products in its authentic form and in pharmaceutical formulations excluding any separation steps.ResultsThese methods were a dual-wavelength (DW) method which allows the determination of TM in existence of its degradation products at 243 nm and 269 nm, second derivative (D2) method measured at peak amplitude at 268 nm, ratio difference (RD) method at 242 nm and 278 nm, and constant center coupled with spectrum subtraction (CC-SS) method at 242 nm and 278 nm versus 278 nm. By applying the suggested methods, TM could be quantified in the range of 5.0–60.0 μg/mL with percentage recoveries 99.97 ± 0.40, 100.36 ± 0.58, 99.90 ± 0.42, and 100.15 ± 0.45 for DW, D2, RD, and CC-SS methods, respectively. International Conference on Harmonization guidelines were followed for validation of the described methods, and the application of laboratory-prepared mixtures along with different pharmaceutical drugs including the target drug showed favorable results without any contribution from additives.ConclusionsStatistical comparison was used to compare the proposed and official methods, and satisfactory results for both accuracy and precision were obtained. The results confirm the applicability of the suggested methods for the determination of TM in quality control laboratories.