In vitro and in silico investigation of FDA-approved drugs to be repurposed against Alzheimer's disease.

Alzheimer's disease (AD), one of the main causes of dementia, is a neurodegenerative disorder. Cholinesterase inhibitors are used in the treatment of AD, but prolonged use of these drugs can lead to serious side effects. Drug repurposing is an approach that aims to reveal the effectiveness of drugs in different diseases beyond their clinical uses. In this work, we investigated in vitro and in silico inhibitory effects of 11 different drugs on cholinesterases. The results showed that trimebutine, theophylline, and levamisole had the highest acetylcholinesterase inhibitory actions among the tested drugs, and these drugs inhibited by 68.70 ± 0.46, 53.25 ± 3.40, and 44.03 ± 1.20%, respectively at 1000 µM. In addition, these drugs are bound to acetylcholinesterase via competitive manner. Molecular modeling predicted good fitness in acetylcholinesterase active site for these drugs and possible central nervous system action for trimebutine. All of these results demonstrated that trimebutine was determined to be the drug with the highest potential for use in AD.

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.

Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial (MERMAID, WJOG11318B).

BACKGROUND: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. METHODS: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. RESULTS: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. CONCLUSIONS: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. CLINICAL TRIAL REGISTRATION: jRCT (Japan registry of clinical trials). jRCTs031190154.

Utility of Cilefa Pink B, a food dye in a facile decoration of the first green molecular-size-based fluorescence probe (MSBFP) for determining trimebutine; application to bulk, dosage forms, and real plasma.

This research presents the first novel green molecular-size-based fluorescence probe (MSBFP) as a spectroscopic strategy for detecting the Trimebutine drug. The method used a green, one-pot, direct spectrofluorimetric methodology to validate and assess the medication. Trimebutine drug and Cilefa Pink B formed an immediate ultra-fluorescent complex when mixed in an acidic environment. The fluorimetric study relied on Trimebutine's amplification of the dye response, which correlated to the generated complex's molecular size at 361 nm. Upon complexation, the molecular mass has grown from 504.5 to 1384.4 g mol-1. This growth is proportionally coupled to the drug concentration range of 0.035-1.5 µg mL-1. The lower and upper limits of the sensitivity varied from 0.010 and 0.029 µg mL-1, respectively. Trimebutine-Cilefa Pink B complexes were analyzed to determine optimal values for all the tunable system variables. Also, The International Council for Harmonization (ICH) requirements were successfully met by the system. In addition, this method effectively retrieved the drug in the intended pharmaceutical dosages. A significant achievement was using the developed fluorimetric method to monitor the drug of interest in human biofluids. The environmental friendliness of the planned procedure was then evaluated.

[Visceral sensitivity in diagnostics and treatment of severe irritated bowel syndrome].

BACKGROUND: Irritable bowel syndrome (IBS) is a biopsychosocial model based on the malfunction of "brain-intestinal linking". AIM: To improve diagnostics of the severe IBS accompanied with somatoform disorders by using balloon dilatation test (BDT) and optimize the therapy by using antidepressants from the serotonin and noradrenaline reuptake inhibitor type. MATERIALS AND METHODS: 61 patients with severe IBS and diarrhea were examined, among them 29 female with a median age of 31 years old (24; 36), and 31 male with a median age of 31 (24; 36) years old. All patients were randomized into two groups, group 1 consisted of 30 patients (15 female, 15 male), group 2 consisted of 31 patients (15 female, 16 male). The symptoms of all patients were assessed using the Visual Analogue Pain Scale (VAS Pain), visceral sensitivity index (VIS) was assessed according to the J. Labus questionnaire (2007) and visceral sensitivity threshold was assessed according to the BDT, the psycho-emotional state was assessed using the Beck scale of anxiety and depression and the Spielberger-Khanin scale. Both group patients underwent a comparative effectiveness evaluation between the therapy based on the use of Trimebutine at a dose of 600 mg per day and the SNRI-Duloxetine therapy at a dose of 60 mg per day for 8 weeks. RESULTS: Patients from group with severe IBS and diarrhea who had undergone the antidepressant therapy showed the decrease of pain syndrome from 7 (5; 7) to 2.5 (2; 3) points according to VAS Pain; normalization of stool frequency from 7 (6; 9) to 2 (1; 2) times a day; normalization of stool consistency from 6 (6; 7) to 3 (3; 4) type; and decrease of VIS: first urge from 56 (34; 74) to 95 (80; 98) ml.; as well as the decrease of the depression level (Beck scale) from 26 (23; 32) to 11.5 (10; 13) points and anxiety according to Beck scale from 38 (31; 45) to 11 (10; 12), the decrease of personal anxiety level (Spielberger-Khanin scale) from 42.5 (35; 53) to 22 (20; 24) points, and the decrease of situational anxiety from 40 (37; 49) to 22 (21; 36) points. During the trimebutine therapy in group 1, the clinical symptoms of IBS have persisted. According to the BDT, the visceral sensitivity (HF) threshold remained at a low level. And the indicators of anxiety and depression remained at a high level according to the psychometric scales. CONCLUSION: The insufficient effect of the trimebutine therapy can be explained by the somatoform disorders persistence in patients from group 1. Meanwhile SNRI-duloxetine therapy in group 2 showed a clinical remission of IBS: such as a reliable relief from pain and diarrheal syndrome, as well as an increase in the HF threshold. Thus, Duloxetine is a promising treatment for severe IBS with somatoform disorders. BDT can be used as an objective criterion to diagnose and evaluate the effectiveness of therapy in patients with IBS.

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.

Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages.

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways.

Receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) are potential therapeutic targets in the treatment of acute and chronic inflammatory diseases. We previously reported that trimebutine, a spasmolytic drug, suppresses RAGE pro-inflammatory signaling pathway in macrophages. The aim of this study was to convert trimebutine to a new small molecule using in silico 3D pharmacophore similarity search, and dissect the mechanistic anti-inflammatory basis. Of note, a unique 3-styrylchromone (3SC), 7-methoxy-3-trimethoxy-SC (7M3TMSC), converted from trimebutine 3D pharmacophore potently suppressed both high mobility group box 1-RAGE and lipopolysaccharide-TLR4 signaling pathways in macrophage-like RAW264.7 cells. More importantly, 7M3TMSC inhibited the phosphorylation of extracellular signaling-regulated kinase 1 and 2 (ERK1/2) and downregulated the production of cytokines, such as interleukin-6. Furthermore, 3D pharmacophore-activity relationship analyses revealed that the hydrogen bond acceptors of the trimethoxy groups in a 3-styryl moiety and the 7-methoxy-group in a chromone moiety in this compound are significant in the dual anti-inflammatory activity. Thus, 7M3TMSC may provide an important scaffold for the development of a new type of anti-inflammatory dual effective drugs targeting RAGE/TLR4-ERK1/2 signaling.

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.

The trimebutine effect on Helicobacter pylori-related gastrointestinal tract and brain disorders: A hypothesis.

The localization of bacterial components and/or metabolites in the central nervous system may elicit neuroinflammation and/or neurodegeneration. Helicobacter pylori (a non-commensal symbiotic gastrointestinal pathogen) infection and its related metabolic syndrome have been implicated in the pathogenesis of gastrointestinal tract and central nervous system disorders, thus medications affecting the nervous system - gastrointestinal tract may shape the potential of Helicobacter pylori infection to trigger these pathologies. Helicobacter pylori associated metabolic syndrome, by impairing gut motility and promoting bacterial overgrowth and translocation, might lead to brain pathologies. Trimebutine maleate is a prokinetic drug that hastens gastric emptying, by inducing the release of gastrointestinal agents such as motilin and gastrin. Likewise, it appears to protect against inflammatory signal pathways, involved in inflammatory disorders including brain pathologies. Trimebutine maleate also acts as an antimicrobial agent and exerts opioid agonist effect. This study aimed to investigate a hypothesis regarding the recent advances in exploring the potential role of gastrointestinal tract microbiota dysbiosis-related metabolic syndrome and Helicobacter pylori in the pathogenesis of gastrointestinal tract and brain diseases. We hereby proposed a possible neuroprotective role for trimebutine maleate by altering the dynamics of the gut-brain axis interaction, thus suggesting an additional effect of trimebutine maleate on Helicobacter pylori eradication regimens against these pathologies.

Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics.

L1 syndrome is a rare developmental disorder characterized by hydrocephalus of varying severity, intellectual deficits, spasticity of the legs, and adducted thumbs. Therapy is limited to symptomatic relief. Numerous gene mutations in the L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in L1 syndrome patients, and those affecting the extracellular domain of this transmembrane type 1 glycoprotein show the most severe phenotypes. Previously analyzed rodent models of the L1 syndrome focused on L1-deficient animals or mouse mutants with abrogated cell surface expression of L1, making it difficult to test L1 function-triggering mimetic compounds with potential therapeutic value. To overcome this impasse, we generated a novel L1 syndrome mouse with a mutation of aspartic acid at position 201 in the extracellular part of L1 (p.D201N, hereafter termed L1-201) that displays a cell surface-exposed L1 accessible to the L1 mimetics. Behavioral assessment revealed an increased neurological deficit score and increased locomotor activity in male L1-201 mice carrying the mutation on the X-chromosome. Histological analyses of L1-201 mice showed features of the L1 syndrome, including enlarged ventricles and reduced size of the corpus callosum. Expression levels of L1-201 protein as well as extent of cell surface biotinylation and immunofluorescence labelling of cultured cerebellar neurons were normal. Importantly, treatment of these cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine rescued impaired cell migration and survival as well as neuritogenesis. Altogether, the novel L1 syndrome mouse model provides a first experimental proof-of-principle for the potential therapeutic value of L1 mimetic compounds.

[Efficacy of trimebutine in the treatment of functional gastrointestinal disorders: an observational multicenter study].

AIM: Evaluation of the practice of using trimebutine (tablets, 300 mg, extended release), for the treatment of patients with functional gastrointestinal disorders (FGID) in primary health care. MATERIALS AND METHODS: A prospective observational multicenter non-interventional study was carried out, which included patients of both sexes aged 18 to 60 years with a verified diagnosis of functional gastrointestinal disorders (functional dyspepsia, irritable bowel syndrome, biliary tract dysfunction, sphincter of Oddi dysfunction, postcholecystectomy syndrome). Trimebutine was prescribed in accordance with the instructions for medical use: orally, 300 mg twice per day for 28 days. The severity of simptoms was evaluated by five-point rating scale. RESULTS: The study included 4433 patients, the per protocol sample consisted of 3831 people. The proportion of patients with a significant decrease in the severity of abdominal pain after treatment was 74.73% (95% confidence interval CI 73.3276.11). At the and of the study a statistically significant decrease in the severity of FGID` simptoms was observed: epigastric pain/burning (mean score at the 1st visit was 1.21 [95% CI 1.181.25], at the 2nd visit 0.22 [95% CI 0.20.23]; p0.001), abdominal pain (1st visit 2.01 [95% CI 1.982.04), 2nd visit 0.33 [95% CI 0.310.35]; p0.001), biliary pain (1st visit 1.22 [95% CI 1.181.26], 2nd visit 0.2 [95% CI 0.190.22]; p0.001), postprandial fullness and early satiation (1st visit 1.29 [95% CI 1.251.32], 2nd visit 0.21 [95% CI 0.190.22]; p0.001), severity of heartburn (1st visit 0.92 [95% CI 0.880.95], 2nd visit 0.18 [95% CI 0.170.20]; p0.001), belching (1st visit 1.13 [95% CI 1.091.16], 2nd visit 0.22 [95% CI 0.210.24]; p0.001), as well as abdominal distention (1st visit 1.99 (95% CI 1, 96, 2.03), 2nd visit 0.43 [95% CI 0.410.45]; p0.001). CONCLUSION: The present prospective observational multicenter non-interventional study has demonstrated that trimebutine is an effective approach to treating FGID.

Trimebutine attenuates high mobility group box 1-receptor for advanced glycation end-products inflammatory signaling pathways.

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.

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.

Cytotoxic Mechanism of Excess Polyamines Functions through Translational Repression of Specific Proteins Encoded by Polyamine Modulon.

Excessive accumulation of polyamines causes cytotoxicity, including inhibition of cell growth and a decrease in viability. We investigated the mechanism of cytotoxicity caused by spermidine accumulation under various conditions using an Escherichia coli strain deficient in spermidine acetyltransferase (SAT), a key catabolic enzyme in controlling polyamine levels. Due to the excessive accumulation of polyamines by the addition of exogenous spermidine to the growth medium, cell growth and viability were markedly decreased through translational repression of specific proteins [RMF (ribosome modulation factor) and Fis (rRNA transcription factor) etc.] encoded by members of polyamine modulon, which are essential for cell growth and viability. In particular, synthesis of proteins that have unusual locations of the Shine-Dalgarno (SD) sequence in their mRNAs was inhibited. In order to elucidate the molecular mechanism of cytotoxicity by the excessive accumulation of spermidine, the spermidine-dependent structural change of the bulged-out region in the mRNA at the initiation site of the rmf mRNA was examined using NMR analysis. It was suggested that the structure of the mRNA bulged-out region is affected by excess spermidine, so the SD sequence of the rmf mRNA cannot approach initiation codon AUG.

Green conventional and first-order derivative fluorimetry methods for determination of trimebutine and its degradation product (eudesmic acid). Emphasis on the solvent and pH effects on their emission spectral properties.

In this report, the fluorescence properties of the antimuscarinic drug trimebutine maleate (TRB) were fully studied and characterized. TRB exhibited intrinsic fluorescence that is greatly dependent on the local environmental factors including the solvent nature and the pH. Yet, its fluorescence was not significantly influenced by the existence of some surface active agents and polymer. The outcomes of this investigation verified that TRB fluorescence emission is intense in ethanol: 1.0 M aqueous acetic acid (9:1, v/v) with emission maxima at 357 nm and excitation maxima at 270 nm. Whereas, going towards higher pH causes fluorescence quenching. These conditions permitted ultrasensitive fluorimetric determination of TRB over the concentration range of 2.00-1500.0 ng/mL with a lower detection limit of 0.40ng/mL Application for the determination of TRB in tablets, ampoule and suspension was successfully achieved with %recoveries ranged between 98.21-100.17%. Furthermore, a first order derivative fluorimetric method was validated for resolving and simultaneous determination of TRB and its degradation product and impurity, eudesmic acid (EUA) making use of the pH-mediated fluorescence spectral shift of EUA. An ethanolic solution containing acetate buffer (pH 5.3) was used for this goal with excitation at 255 nm and measurement of the first order derivative peak amplitudes at respective zero-crossing points of 375 and 351 nm over the corresponding concentration ranges of 20.00-500.00 and 10.00-300.00 ng/mL for TRB and EUA, respectively. The two methods were assessed regarding greenness and eco-friendship by the National Environmental Methods Index and analytical eco-scale score approaches which confirmed their excellent greenness and safety.

Trimebutine: a state-of-the-art review.

Trimebutine maleate has been used extensively, since the late 1960's, for the treatment of functional gastrointestinal disorders, including irritable bowel syndrome (IBS). It is usually linked to the antispasmodic class of agents, but its properties make trimebutine an unmatched and multi-tasking compound. The efficacy on relieving abdominal pain has been demonstrated in various clinical studies with different protocols of treatment. The main effect was first believed to be merely due to its antispastic activity, but further evidences expanded the acknowledgement of a broader impact on the gastrointestinal tract. The actions of trimebutine are mediated via an agonist effect on peripheral mu, kappa and delta opiate receptors and a modulation of gastrointestinal peptides release. The final motor effects on the gut are summarized in an acceleration of the gastric emptying, an induction of premature phase III of the migrating motor complex in the small intestine and a modulation of the contractile activity of the colon. Moreover, it has been shown to have a role in regulating the visceral sensitivity. It has been observed that this drug is also a multiple-ion channel modulator in the gut. Its function at various levels, from motility to pain control, makes this drug unique and its spectrum of action can be exploited for the treatment of both hypermotility and hypomotility disorders including irritable bowel syndrome and other functional gastrointestinal diseases. This article provides an overview of the current knowledge on the pharmacological mechanisms of trimebutine and its clinical applications in gastrointestinal disorders. Its biochemical properties and the complex mechanisms of action, along with a well-studied pharmacological safety, make this compound still actual and valuable.

The Effect of Trimebutine and/or Helicobacter pylori Eradication on the Gastroesophageal Reflux Disease, Irritable Bowel Syndrome, and Functional Dyspepsia Overlapping Disorders

No abstract available.

The Effect of Trimebutine on the Overlap Syndrome Model of Guinea Pigs

BACKGROUND/AIMS: Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common gastrointestinal (GI) disorders and these patients frequently overlap. Trimebutine has been known to be effective in controlling FD co-existing diarrhea-dominant IBS, however its effect on overlap syndrome (OS) patients has not been reported. Therefore, we investigated the effect of trimebutine on the model of OS in guinea pigs. METHODS: Male guinea pigs were used to evaluate the effects of trimebutine in corticotropin-releasing factor (CRF) induced OS model. Different doses (3, 10, and 30 mg/kg) of trimebutine were administered orally and incubated for 1 hour. The next treatment of 10 μg/kg of CRF was intraperitoneally injected and stabilized for 30 minutes. Subsequently, intragastric 3 mL charcoal mix was administered, incubated for 10 minutes and the upper GI transit analyzed. Colonic transits were assessed after the same order and concentrations of trimebutine and CRF treatment by fecal pellet output assay. RESULTS: Different concentrations (1, 3, and 10 μg/kg) of rat/human CRF peptides was tested to establish the OS model in guinea pigs. CRF 10 μg/kg was the most effective dose in the experimental OS model of guinea pigs. Trimebutine (3, 10, and 30 mg/kg) treatment significantly reversed the upper and lower GI transit of CRF induced OS model. Trimebutine significantly increased upper GI transit while it reduced fecal pellet output in the CRF induced OS model. CONCLUSIONS: Trimebutine has been demonstrated to be effective on both upper and lower GI motor function in peripheral CRF induced OS model. Therefore, trimebutine might be an effective drug for the treatment of OS between FD and IBS patients.