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.

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.

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.

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: 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.

Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice.

Curing spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity but delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans. We have, therefore, identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration and neurite outgrowth in an L1-dependent manner. Here, we assessed the functions of two L1 mimetics, trimebutine and honokiol, in regeneration following SCI in young adult mice. Using the Basso Mouse Scale (BMS) score, we found that ground locomotion in trimebutine-treated mice recovered better than honokiol-treated or vehicle-receiving mice. Enhanced hindlimb locomotor functions in the trimebutine group were observed at 6 weeks after SCI. Immunohistology of the spinal cords rostral and caudal to the lesion site showed reduced areas and intensities of glial fibrillary acidic protein immunoreactivity in both trimebutine and honokiol groups, whereas increased regrowth of axons was observed only in the trimebutine-treated group. Both L1- and L1 mimetic-mediated intracellular signaling cascades in the spinal cord lesion sites were activated by trimebutine and honokiol, with trimebutine being more effective than honokiol. These observations suggest that trimebutine and, to a lesser extent under the present experimental conditions, honokiol have a potential for therapy in regeneration of mammalian spinal cord injuries.

Prokinetics for the treatment of functional dyspepsia: Bayesian network meta-analysis.

BACKGROUND: Controversies persist regarding the effect of prokinetics for the treatment of functional dyspepsia (FD). This study aimed to assess the comparative efficacy of prokinetic agents for the treatment of FD. METHODS: Randomized controlled trials (RCTs) of prokinetics for the treatment of FD were identified from core databases. Symptom response rates were extracted and analyzed using odds ratios (ORs). A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method in WinBUGS and NetMetaXL. RESULTS: In total, 25 RCTs, which included 4473 patients with FD who were treated with 6 different prokinetics or placebo, were identified and analyzed. Metoclopramide showed the best surface under the cumulative ranking curve (SUCRA) probability (92.5%), followed by trimebutine (74.5%) and mosapride (63.3%). However, the therapeutic efficacy of metoclopramide was not significantly different from that of trimebutine (OR:1.32, 95% credible interval: 0.27-6.06), mosapride (OR: 1.99, 95% credible interval: 0.87-4.72), or domperidone (OR: 2.04, 95% credible interval: 0.92-4.60). Metoclopramide showed better efficacy than itopride (OR: 2.79, 95% credible interval: 1.29-6.21) and acotiamide (OR: 3.07, 95% credible interval: 1.43-6.75). Domperidone (SUCRA probability 62.9%) showed better efficacy than itopride (OR: 1.37, 95% credible interval: 1.07-1.77) and acotiamide (OR: 1.51, 95% credible interval: 1.04-2.18). CONCLUSIONS: Metoclopramide, trimebutine, mosapride, and domperidone showed better efficacy for the treatment of FD than itopride or acotiamide. Considering the adverse events related to metoclopramide or domperidone, the short-term use of these agents or the alternative use of trimebutine or mosapride could be recommended for the symptomatic relief of FD.

Nonmotor gastrointestinal disorders in older patients with Parkinson's disease: is there hope?

Despite the fact that nonmotor symptoms (NMS) like gastrointestinal (GI) complaints are frequently reported in Parkinson's disease (PD), no therapeutic guidelines are available. This study aimed to manage some lower GI-NMS in a group of patients with PD. A total of 40 patients (17 males, 23 females; mean age 76.05±2.09 years) were randomly selected for this study. Patients were confirmed to have PD (modified Hoehn-Yars scale: 2.075±0.4) who had undergone levodopa or dopamine agonist treatment. In the non-motor symptoms questionnaire (NMS-Quest), regarding GI complaints, the following were recorded: abdominal pain, bloating, and constipation of mild-to-moderate severity. Laboratory studies, abdominal ultrasound, and upper and lower digestive endoscopies were performed to rule out organic issues. All patients increased their water intake to 2 L/d and alimentary fiber to 20-25 g/d. Twenty patients received trimebutine 200 mg three times daily half an hour before meals. The other 20 patients received probiotics (60 mg per-tablet of two lactic bacteria: Lactobacillus acidophilus and Bifidobacterium infantis), 2×/d, 1 hour after meals for 3 months along with the reassessment of GI complaints. Our results demonstrated that there were significant statistical differences in all assessed symptoms in the first group: 1.55±0.51 vs 0.6±0.5 (P<0.0001) for abdominal pain; 1.6±0.5 vs 0.45±0.51 (P<0.0001) for bloating; and 1.5±0.51 vs 0.85±0.67 (P=0.0014) for constipation with incomplete defecation. The second group displayed statistical differences only for abdominal pain 1.45±0.51 vs 1.05±0.69 (P=0.00432) and bloating 1.4±0.5 vs 0.3±0.47 (P<0.0001). For constipation with incomplete defecation, there was a slight improvement. Thus, there was no significant statistical difference: 1.35±0.49 vs 1.15±0.49 (P=0.2040). In conclusion, lower GI-NMS are frequently present, isolated or associated with other autonomic issues, even before the diagnosis of PD. Treatment with probiotics could improve abdominal pain and bloating as much as with trimebutine, but less for constipation with incomplete evacuation, where trimebutine showed better results.

Comparative efficacy and safety of trimebutine versus mebeverine in the treatment of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional disorder characterized by chronic or recurrent abdominal pain or discomfort with bowel disturbances. This prospective, randomized clinical trial has been conducted on IBS patients, using trimebutine and Mebeverine in separate group in parallel design to compare the efficacy and safety of Trimebutine 100mg twice daily with mebeverine 135mg twice daily. Patients of 15 to 60 years old and both sexes were included from the out patient department (OPD) of gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from June 2010 to December 2011. A validated IBS-QOL instrument consisted of 34 questions used to assess improvement of quality of life before and after treatment. A total of 140 patients were enrolled in this study. Eighteen patients dropped out. One hundred twenty two patients completed the trial. In this study at the end of 6 weeks therapy, improvement of symptoms was statistically significant. However, differences of improvement between the two groups in relieving various symptoms were not statistically significant. Mean QOL score before treatment was 103 in Trimebutine group and 106 in Mebeverine group. After 6 weeks of treatment mean QOL score was 82 in Trimebutine group and 95 in Mebeverine group indicating improvement in both groups was statistically significant. The difference between the two groups was also significant. No worsening of symptoms and no side effects of the therapeutic agents was observed in any patient during the trial.

[Efficacy of fenoverine and trimebutine in the management of irritable bowel syndrome: multicenter randomized double-blind non-inferiority clinical study].

BACKGROUND/AIMS: Antispasmodic agents have been used in the management of irritable bowel syndrome. However, systematic reviews have come to different conclusions about the efficacy in irritable bowel syndrome. Fenoverine acts as a synchronizer of smooth muscle in modulating the intracellular influx of calcium. We compared fenoverine with trimebutine for the treatment of patients with IBS. METHODS: A multicenter, randomized, double-blind, non-inferiority clinical study was conducted to compared fenoverine with trimebutine. Subjects were randomized to receive either fenoverine (100 mg three times a day) or trimebutine (150 mg three times a day) for 8 weeks. A total of 197 patients were analyzed by the intention-to-treat approach. The primary endpoint was the proportion of patients who had 30% reduction in abdominal pain or discomfort measured by bowel symptom scale (BSS) score at week 8 compared to the baseline. The secondary endpoints were changes of abdominal bloating, diarrhea, constipation, overall and total scores of BSS, and overall satisfaction. RESULTS: At week 8, fenoverine was shown to be non-inferior to trimebutine (treatment difference, 1.76%; 90% CI, -10.30-13.82; p=0.81); 69.23% (54 of 78 patients) of patients taking fenoverine and 67.47% (56 of 83 patients) of patients taking trimebutine showed 30% reduction in abdominal pain or discomfort compared to the baseline. There results of the secondary endpoints were also comparable between the fenoverine group and the trimebutine group. CONCLUSIONS: Fenoverine is non-inferior to trimebutine for treating IBS in terms of both efficacy and tolerability.

[Effectiveness of treatment of pancreatic disorders in children (based on catamnesis)].

In the article results of supervision of the patients with chronic pancreatitis and dysfunction of Oddi's sphincter, pancreatic type, in polyclinic were presented. Among them: 50 children received in clinic therapeutic complex offered by us which included: phytoenzyme, spasmolytic and antioxidant. 50 children were treated in traditional way. Screening of functional condition of the pancreas revealed decreasing percentage of moderate exocrine insufficiency of pancreas (10% of incidences) in children with recurrent course of pancreatitis. In long-lasting course of pancreatitis in this group percentage of patients with moderate exocrine insufficiency was decreased due to 15%. At the same time, in patients with moderate and severe exocrine insufficiency (55 and 20% subsequently) which improves non complete efficiency of basic therapy.

Efficacy of Fenoverine and Trimebutine in the Management of Irritable Bowel Syndrome: Multicenter Randomized Double-blind Non-inferiority Clinical Study / 대한소화기학회지

BACKGROUND/AIMS: Antispasmodic agents have been used in the management of irritable bowel syndrome. However, systematic reviews have come to different conclusions about the efficacy in irritable bowel syndrome. Fenoverine acts as a synchronizer of smooth muscle in modulating the intracellular influx of calcium. We compared fenoverine with trimebutine for the treatment of patients with IBS. METHODS: A multicenter, randomized, double-blind, non-inferiority clinical study was conducted to compared fenoverine with trimebutine. Subjects were randomized to receive either fenoverine (100 mg three times a day) or trimebutine (150 mg three times a day) for 8 weeks. A total of 197 patients were analyzed by the intention-to-treat approach. The primary endpoint was the proportion of patients who had 30% reduction in abdominal pain or discomfort measured by bowel symptom scale (BSS) score at week 8 compared to the baseline. The secondary endpoints were changes of abdominal bloating, diarrhea, constipation, overall and total scores of BSS, and overall satisfaction. RESULTS: At week 8, fenoverine was shown to be non-inferior to trimebutine (treatment difference, 1.76%; 90% CI, -10.30-13.82; p=0.81); 69.23% (54 of 78 patients) of patients taking fenoverine and 67.47% (56 of 83 patients) of patients taking trimebutine showed 30% reduction in abdominal pain or discomfort compared to the baseline. There results of the secondary endpoints were also comparable between the fenoverine group and the trimebutine group. CONCLUSIONS: Fenoverine is non-inferior to trimebutine for treating IBS in terms of both efficacy and tolerability.

Medical treatment for sphincter of oddi dysfunction: can it replace endoscopic sphincterotomy?

AIM: To report the results of a medical management of sphincter of oddi dysfunction (SOD) after an intermediate follow-up period. METHODS: A total of 59 patients with SOD (2 men and 57 women, mean age 51 years old) were included in this prospective study. After medical treatment for one year, the patients were clinically re-evaluated after an average period of 30 mo. RESULTS: The distribution of the patients according to the Milwaukee's classification was the following: 11 patients were type 1, 34 were type 2 and 14 were type 3. Fourteen patients underwent an endoscopic sphincterotomy (ES) after one year of medical treatment. The median intermediate follow-up period was 29.8 ± 3 mo (3-72 mo). The initial effectiveness of the medical treatment was complete, partial and poor among 50.8%, 13.5% and 35%, respectively, of the patients. At the end of the follow-up period, 37 patients (62.7%) showed more than 50% improvement. The rate of improvement in patients who required ES was not significantly different compared with the patients treated conservatively (64.2% vs 62.2%, respectively). CONCLUSION: Our study confirms that conservative medical treatment could be an alternative to endoscopic sphincterotomy because, after an intermediate follow-up period, the two treatments show the same success rates.

[Comparative study on irritable bowel syndrome treated with acupuncture and western medicine].

OBJECTIVE: To compare the differences in the therapeutic effect on irritable bowel syndrome (IBS) between acupuncture at Tianshu (ST 25) and Dachangshu (BL 25) and western medication with Trimebutine Maleate. METHODS: Forty cases were divided randomly into an acupuncture group and a western medication group, 20 cases in each one. In acupuncture group, acupuncture was applied to Tianshu (ST 25) and Dachangshu (BL 25). Ziwu Daojiu needling technique was adopted, once daily. In western medication group, Trimebutine Maleate capsule was administered, 2 capsules in each time, 3 times per day. The assessment on the therapeutic effect was performed in 4 weeks of treatment in two groups. RESULTS: As compared with those before treatment, the time of abdominal pain, the frequency of abdominal pain, the morbidity of abnormal stool appearance, the morbidity of defecation abnormality, the morbidity of mucus stool and the score of bloating or abdominal pain on bowel movement were all reduced after treatment in two groups (all P < 0.01). The results in acupuncture group were much more significant than those in western medication group (the total score: 16.70 +/- 2.40 vs 15.70 +/- 3.01, P < 0.01). The total effective rate in acupuncture group was 95.0% (19/20), which was superior to that of 70.0% (14/20) in western medication group (P < 0.05). CONCLUSION: Acupuncture at Tianshu (ST 25) and Dachangshu (BL 25) may remarkably relieve the clinical symptoms of IBS and its efficacy is superior to that of oral medication with Trimebutine Maleate.

Estudio de bioequivalencia entre dos productos: trimebutina de liberación prolongada de laboratorios Leti SAV vs debridat AP® de laboratorios Pfizer, luego de administar una dosis única de 300 mg en voluntarios sanos / Bioequivalence study of two products trimebutine extended release vs debridat SAV Leti laboratories AP Pzizer after administering a single dose of 300 mg in healthy volunteers

El objetivo del estudio fue evaluar la bioequivalencia entre dos formulaciones de liberación prolongada de trimebutina 300 mg, luego de una administración única en voluntarios sanos, a través de la determinación de su metabolito activo la desmetil-trimebutina. Se trata de un estudio abierto, randomizado, balanceado, con control activo, de dosis simple, cruzado, con dos períodos separados por un período de descanso y secuencial, realizado en 12 voluntarios sanos de ambos sexos. Los voluntarios recibieron de acuerdo al esquema asignado por la aleatorización y en dos períodos, una dosis única por vía oral después de un ayuno de 10 horas, de un comprimido de una formulación conteniendo 300 mg de Trimebutina AP de Laboratorios LETI S.A.V., o del producto de referencia DEBRIDAT AP®, de Laboratorios Pfizer. Después de la última muestra de sangre del primer período hubo un tiempo de lavado de siete días, luego del cual los voluntarios que recibieron el producto test en el primer período recibieron el producto de referencia y viceversa. Las tomas de muestras se realizaron antes de la dosis (tiempo cero), 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 18 h, 24 h y 36 h. El análisis estadístico se realizó utilizando un paquete estadístico del programa Equiv test, empleándose el análisis de la varianza (ANOVA) de los parámetros cinéticos AUC 0-inf, AUC 0-36 h y Cmax y la aplicación de los intervalos de confianza para el 90%. En el análisis comparativo se tomaron los intervalos de confianza con el rango de referencia de 0.8-1.25%. Para la Trimebutina test los valores fueron: Cmax 1343.49 +/- 585.58, AUC 0-36 de 8197.19 +/- 3995.23 y AUC 0-inf de 8198.36 +/- 3995.3. Para la formulación de referencia los valores fueron de: Cmax 1023.99 +/- 587.57, AUC 0-36 7221.15 +/- 3211.97 y AUC 0-inf de 7225.97 +/- 3211.62 sin diferencias significativas entre los grupos...

The objective of this study is to assess the bioequivalence of two sustained release formulations of trimebutine 300 mg, after a single administration in healthy volunteers, through determination of the active metabolite desmethyl-trimebutine. This is an open, randomized, balanced, active controlled, single dose, crossover study with two periods separated by a rest period and sequentially, conducted in 12 healthy volunteers of both sexes. Volunteers were assigned according to the randomization scheme and two periods, a single oral dose after fasting for 10 hours, a tablet formulation containing 300 mg of trimebutine AP LETI SAV Laboratories, or product Reference DEBRIDAT AP®, Pfizer Laboratories. After the last blood sample of the first period there will be a wash time of seven days, after which the volunteers received the test product in the first period will received the reference product and viceversa. The sampling is performed: before dosing (time zero), 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 18 h, 24 h and 36 h. Statistical analysis was performed using a statistical package Equiv test program, using analysis of variance (ANOVA) of the kinetic parameters AUC 0-inf, AUC 0-36h and Cmax and application of confidence intervals for 90%. In the comparative analysis we used the confidence intervals with the reference range of 0.8-1.25%. For the Trimebutine test values were Cmax 1343.49 +/- 585.58, AUC 0-36 of 8197.19 +/- 3995.23 and AUC 0-inf 8198.36 +/- 3995.3. For the formulation of reference values were: Cmax 1023.99 +/- 587.57, AUC 0-36 7221.15 +/- 3211.97 y AUC 0-inf of 7225.97 +/- 3211.62 no significant differences between groups. This study found that the Cmax and AUC, its log-transformed means and confidence intervals 90% away from each other not less than 80% or over 125%, so that both products are considered bioequivalent and therefore interchangeable

Development of a novel combination tablet containing trimebutine maleate and mosapride citrate for the treatment of functional dyspepsia.

To develop a novel combination tablet which contained 100 mg trimebutine maleate and 5 mg mosapride citrate (TMCT) for the treatment of functional dyspepsia, the wet granulation method was used to prepare TMCTs with various amounts of diluents and stabilizers. The levels of impurities, the stability and the dissolution of the TMCTs were investigated. The oral bioavailability of drugs in the TMCTs was then evaluated and compared to the simultaneous oral administration of trimebutine maleate-loaded and mosapride citrate-loaded commercial products in the beagle dog. Among the diluents tested, D-mannitol was selected, since the microcrystalline cellulose and lactose did not inhibit the production of drug impurities due to their hygroscopic properties and chemical interactions, respectively. Furthermore, succinic acid was selected as the stabilizer because it gave the lowest level of total drug impurities of the organic acids tested. The combination tablet of trimebutine maleate and mosapride citrate prepared with D-mannitol and succinic acid gave a total drug content higher than 95% and total impurities lower than 0.5% at 25°C/60% RH and 40°C/75% RH during a 6-month period, indicating that the tablets were stable for at least 6 months. Furthermore, this combination tablet showed a similar dissolution to the trimebutine maleate-loaded and mosapride citrate-loaded commercial products and gave insignificantly different absorption compared to these commercial products in beagle dogs. Thus, the combination tablet of trimebutine maleate and mosapride citrate prepared with D-mannitol and succinic acid would be a stable and effective oral pharmaceutical product for the treatment of functional dyspepsia.