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.

Generalized Lichen Planus-like Eruption Related to Trimebutine

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

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.

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.

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

Background Four 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. Results These 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. Conclusions Statistical 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.

Trimebutine maleate in the treatment of functional biliary disorders: TRIBUNE study results

Introduction. The term «functional disorders of the biliary tract and bile ducts» defines the conditions, which produce typical patterns of biliary pains in the absence of obvious signs of organic lesions of the gallbladder and bile ducts. The materials of the Rome IV consensus present the diagnostic criteria of their main types – functional disorders of the gall bladder and sphincter of Oddi. Vasilenko Clinic of Internal Diseases Propedeutics, Gastroenterology and Hepatology of the University Clinical Hospital No. 2 of Sechenov University carried out a noninterventional observational program to study the experience in using Trimedat® (trimebutine maleate) in the routine outpatient and inpatient practice in the treatment of patients with functional diseases of the biliary tract. Information partners of the program are the Russian Gastroenterological Association (RGA) and the Russian Society for the Study of the Liver (RSSL).Materials and methods. The program included patients of both sexes aged 18 to 65 years with ICD-10 diagnoses «spasm of the sphincter of Oddi» (K 83.4), «postcholecystectomy syndrome» (K 91.5), «other specified diseases of the gallbladder» (K 82.8) , «other specified diseases of the bile ducts» (K 83.8), «disorders of gallbladder and biliary tract in diseases classified elsewhere» (K 87.0), if the clinical picture was consistent with functional biliary disorders according to the Rome IV criteria and in cases when the doctor decided to prescribe Trimedat® therapy. Patients were observed for 28 ± 1 days. The dynamics of biliary pain and discomfort, as well as other symptoms (in particular, nausea, flatulence) were evaluated on the background of the therapy, using the Gastrointestinal Symptom Score Scale, in which the severity of each symptom is estimated by 7 grades (Alekseev N.Yu., 2006) with adding a section to evaluate the biliary disorders. In the presence of criteria for functional disorders of the gallbladder, an ultrasound control of the fraction of its discharge was carried out before and after the therapy.Results. 100 patients (33 (33%) men and 67 (67%) women, the average age 42.2 ± 13.2 years (18–65 years)) were enrolled in the program. In accordance with the Rome IV Consensus, the majority of patients (83 (83%)) had the functional disorders of GB; in 16 (16%) patients with the removed GB, the picture corresponded to the functional disorder of SO, one patient with kept GB was diagnosed with SO dysfunction. The treatment with Trimedate® at a standard dosage resulted in a decrease in the proportion of pain in the epigastric region (in the Scale section evaluating the biliary tract symptoms), the degree of nausea and bloating. Differences between the visits were estimated by the Friedman’s test, p <0.001. In addition, other sections of the scale also showed a decrease in indicators in scores. 79 patients underwent repeated ultrasound cholecystography at the end of treatment. It showed an increase in the fraction of GB emptying.Conclusions. The use of Trimedate® in patients with functional disorders of the gall bladder and sphincter of Oddi resulted in the reduction of the severity of the main symptoms - the severity of biliary pain, nausea, bloating. The patients with GB dysfunction showed an increase in the fraction of GB emptying.