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In this study, a chemiluminescence (CL) method was developed to determine diphenoxylate in tablets and human plasma. This is the first CL method proposed to determine diphenoxylate. Creating three‐dimensional data caused the parallel factor analysis algorithm (PARAFAC) to be used for the first time in CL methods. The method is based on the fact that diphenoxylate enhances the weak CL produced in the reaction of Ru(phen)32+ and acidic Ce(IV), and the concentration of Ce(IV) solution has a different effect on the CL response of diphenoxylate and the blank plasma. The calibration curve was linear from 4.0 × 10−8 to 1.6 × 10−6 mol L−1 (R2 = 0.9954), and the detection limit was 1.3 × 10−8 mol L−1 (S/N = 3). The sampling rate was about 30 samples per hour, and the % RSD for 10 repeated measurements of 4 × 10−7 mol L−1 diphenoxylate was 5.4%. The interference effects of some ions, amino acids, and common additives were also investigated. The CL method was successfully used to determine diphenoxylate in tablets, and the results were statistically confirmed by the reference method. The proposed CL method and the PARAFAC algorithm were successfully used to determine the concentration of diphenoxylate in human blood plasma samples. [ABSTRACT FROM AUTHOR]

Patients with high output enteroatmospheric fistulae (EAF) present a significant challenge to the healthcare system. EAF is a cause of intestinal failure which may necessitate long-term parenteral nutrition. Chyme reinfusion is an enteral nutrition intervention and a potential alternative to parenteral nutrition. A novel chyme reinfusion device developed by The Insides® Company has demonstrated multiple potential benefits in the management of EAF. The aim of this case study is to describe the first use of The Insides® System at a tertiary hospital in south west Sydney for a patient with high-output EAF. [ABSTRACT FROM AUTHOR]

Aloe barbadensis Miller (Aloe) known as a common succulent perennial herb had been traditionally used in constipation for more than 1,000 years. Aloe contained anthraquinones and other active compounds which had laxative effect and could modulate constipation. However, the therapeutic effects and mechanisms of aloe in constipation were still unclear. To explore the therapeutic effects and mechanisms of aloe in treating constipation, we employed network pharmacology, molecular docking, and mice experiments in this study. Our network pharmacology indicated that beta-carotene, sitosterol, campest-5-en-3beta-ol, CLR, arachidonic acid, aloe-emodin, quercetin, and barbaloin were the main active ingredients of aloe in treating constipation. Besides, the MAPK signaling pathway was the principal pathway utilized by aloe in treating constipation. Molecular docking results revealed that beta-carotene and sitosterol were acting as interference factors in attenuating inflammation by binding to an accessory protein of ERK, JNK, AKT, and NF-κB p65. Otherwise, in vivo experiments, we used diphenoxylate-induced constipation mice model to explore the therapeutic effects and mechanisms of aloe. Results showed that aloe modulated the constipation mice by reducing the discharge time of first melena, improving the fecal conditions, increasing the gastric intestinal charcoal transit ratio, and improving the intestinal secretion in small intestine. Besides, aloe played an important regulation in promoting intestinal motility sufficiency and the levels of neurotransmitters balance with 5-HT, SP, and VIP on constipation mice. Moreover, aloe significantly inhibited the mRNA and proteins expressions of ERK, JNK, AKT and NF-κB p65 in colon. Our study proved that aloe could reverse diphenoxylate-induced changes relating to the intestinal motility, intestinal moisture, and inhibition of the MAPK (ERK, JNK)/AKT/NF-κB p65 inflammatory pathway. Our study provided experimental evidences of the laxative effect of aloe, which was beneficial to the further research and development of aloe. [ABSTRACT FROM AUTHOR]

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Qian Tan,1,2,* Jing Hu,3,* Yujing Zhou,1,2 Yunxiao Wan,1,2 Chuanlan Zhang,1,2 Xin Liu,1,2 Xingyao Long,1,4 Fang Tan,5 Xin Zhao1 1Chongqing Collaborative Innovation Center for Functional Food, Chongqing Engineering Research Center of Functional Food, Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 2College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 3Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 4Department of Food Science and Biotechnology, Cha University, Seongnam, 13488, South Korea; 5Department of Public Health, Our Lady of Fatima University, 838 Valenzuela, Philippines*These authors contributed equally to this workCorrespondence: Xin ZhaoChongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Xuefu Main Street 9, Chongqing, 400067, People’s Republic of ChinaTel +86-23-6265-3650Email zhaoxin@cque.edu.cnFang TanDepartment of Public Health, Our Lady of Fatima University, 120 McArthur Highway, 838 Valenzuela, PhilippinesTel +86-23-6265-3650Email tanfang@foods.ac.cnAim: The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. Lactococcus lactis subsp. lactis HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation.Methods: Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay.Results: Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner.Conclusion: LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.Keywords: yak yogurt, lactic acid bacterium, diphenoxylate, constipation, mice

Radiography with contrast media is a diagnostic imaging technique with high-resolution that plays a prominent role in showing the transit time of gastrointestinal system. The purpose of the present research was to evaluate the effects of diphenoxylate and loperamide on the transit time of contrast media from the gastrointestinal in cat. The study was performed on twenty healthy female cat. The cats were divided into four equal groups. The first group (control) was received ketamine with diazepam, 40 min before administration of the contrast media. The second group was received diphenoxylate 0.1 mg/kg, the third group loperamide 0.1 mg/kg, and the fourth group loperamide 0.2 mg/kg, 30 min before administration of contrast media. Tranquilizer drugs were administered to all groups. Then the radiography was performed at times zero, 20, 40 and 60 min, and every hour until reaching the contrast media to colon. All groups that were received drug had a significant difference at the beginning of emptying with control group (p < 0.05). The mean total transit time of the stomach was 52 min for the control group, the diphenoxylate 120, the loperamide 0.1 mg/kg 156 and for the loperamide 0.2 mg/kg 204 min respectively. There was a significant difference between the control and the drug-receiving groups as well as the two groups of diphenoxylate and loperamide 0.2 mg/kg at the time of complete stomach emptying (p < 0.05). In conclusion, it was showed that Loperamide with dosage 0.2 mg/kg had the most delay effect in emptying of the gastrointestinal tract in cat.

PURPOSE: The financial toxicity of anticancer drugs is well-documented, but little is known about the costs of drugs used to manage cancer-associated symptoms. METHODS: We reviewed relevant guidelines and compiled drugs used to manage seven cancer-associated symptoms (anorexia and cachexia, chemotherapy-induced peripheral neuropathy, constipation, diarrhea, exocrine pancreatic insufficiency, cancer-associated fatigue, and chemotherapy-induced nausea and vomiting). Using GoodRx website, we identified the retail price (cash price at retail pharmacies) and lowest price (discounted, best-case scenario of out-of-pocket costs) for patients without insurance for each drug or formulation for a typical fill. We describe lowest prices here. RESULTS: For anorexia and cachexia, costs ranged from $5 US dollars (USD; generic olanzapine or mirtazapine tablets) to $1,156 USD (brand-name dronabinol solution) and varied widely by formulation of the same drug or dosage: for olanzapine 5 mg, $5 USD (generic tablet) to $239 USD (brand-name orally disintegrating tablet). For chemotherapy-induced peripheral neuropathy, costs of duloxetine varied from $12 USD (generic) to $529 USD (brand-name). For constipation, the cost of sennosides or polyethylene glycol was <$15 USD, whereas newer agents such as methylnaltrexone were expensive ($1,001 USD). For diarrhea, the cost of generic loperamide or diphenoxylate-atropine tablets was <$15 USD. For exocrine pancreatic insufficiency, only brand-name formulations were available, range of cost, $1,072 USD-$1,514 USD. For cancer-associated fatigue, the cost of generic dexamethasone or dexmethylphenidate was <$15 USD, whereas brand-name modafinil was more costly ($1,284 USD). For a 4-drug nausea and vomiting prophylaxis regimen, costs ranged from $181 USD to $1,430 USD. CONCLUSION: We highlight the high costs of many symptom control drugs and the wide variation in the costs of these drugs. These findings can guide patient-clinician discussions about cost-effectively managing symptoms, while promoting the use of less expensive formulations when possible. [ABSTRACT FROM AUTHOR]

Objectives: Basil (Ocimum basilicum), which has antispasmodic properties, has been introduced in traditional medicine as a suitable medicine for diarrhea and vomiting. The present study was performed to determine the effect of hydroalcoholic extract of basil on colon histology and severity of diarrhea in rats. Methods: In this experimental study, 56 male Wistar 200±5 g rats were randomly divided into seven equal groups. Solvent group (physiological serum), diphenoxylate group (5 mg/kg), and five groups receiving basil hydroalcoholic extract in doses (100, 200, 400, 600, 800 mg/kg). One hour after taking the drugs, castor oil 2 ml per animal was fed by gavage. The animals were then kept in separate cages for 4 hours and the indicators of excretion number, weight loss percentage, fecal water content and inhibition percentage were recorded. Mice were anesthetized with ether one hour after diarrhea studies and the isolated colon tissue was evaluated microscopically. Data were analyzed by ANOVA and then Tukey test. Level P Results: Diphenoxylate gavage and extracts of 200 and 400 mg/kg, could improve diarrhea caused by castor oil. Histological studies showed that although there was no significant difference between the different groups, the amount (800 mg / kg) of the extract could increase the thickness of the colon wall to some extent. Conclusion: The results show that the hydroalcoholic extract of Ocimum basilicum has diphenoxylate-like properties in reducing the osmotic symptoms of diarrhea and the volume of water excreted, and in the short term can have little effect on colon wall thickness.

This study was to probe the effects of mulberry ferment on constipation (induced by diphenoxylate or loperamide) in mice. Herein, several bioactive substances and antioxidant activities of mulberry ferment were measured, and their effects on defecation, histological structure of ileum and intestinal microflora were investigated. During fermentation, total polyphenols, and flavonoids were increased while the antioxidant activities increased by a large extent. In animal experiments, diphenoxylate caused more serious injuries than loperamide did, and diphenoxylate kept the more unfavorable gut microbiological environment compared with loperamide. Administration of mulberry ferment can increase the fecal moisture content, shorten the first black fecal defecation time, and accelerate the gastro-intestinal transit. Besides, mulberry ferment alleviated ileal tissue organ injuries caused by constipation, suppressed the level of Oscillibacter and Desulfovibrio and increased the Bacteroidales and Bacteroidales_S24-7. In summary, mulberry ferment could be considered as a promising functional food because of their good alleviation on constipation.

In this study, a chemiluminescence (CL) method was developed to determine diphenoxylate in tablets and human plasma. This is the first CL method proposed to determine diphenoxylate. Creating three-dimensional data caused the parallel factor analysis algorithm (PARAFAC) to be used for the first time in CL methods. The method is based on the fact that diphenoxylate enhances the weak CL produced in the reaction of Ru(phen) 3 and acidic Ce(IV), and the concentration of Ce(IV) solution has a different effect on the CL response of diphenoxylate and the blank plasma. The calibration curve was linear from 4.0 × 10 2+ and acidic Ce(IV), and the concentration of Ce(IV) solution has a different effect on the CL response of diphenoxylate and the blank plasma. The calibration curve was linear from 4.0 × 10 -8 to 1.6 × 10 -6  mol L -1 (R 2  = 0.9954), and the detection limit was 1.3 × 10 -8  mol L -1 (S/N = 3). The sampling rate was about 30 samples per hour, and the % RSD for 10 repeated measurements of 4 × 10 -7 diphenoxylate was 5.4%. The interference effects of some ions, amino acids, and common additives were also investigated. The CL method was successfully used to determine diphenoxylate in tablets, and the results were statistically confirmed by the reference method. The proposed CL method and the PARAFAC algorithm were successfully used to determine the concentration of diphenoxylate in human blood plasma samples.-1 diphenoxylate was 5.4%. The interference effects of some ions, amino acids, and common additives were also investigated. The CL method was successfully used to determine diphenoxylate in tablets, and the results were statistically confirmed by the reference method. The proposed CL method and the PARAFAC algorithm were successfully used to determine the concentration of diphenoxylate in human blood plasma samples., (© 2024 John Wiley & Sons Ltd.)

Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.

Functional constipation (FC), characterized by chronic constipation, significantly impacts physiological function and induces psychological stress in patients. However, current clinical treatment options for FC are currently limited. Cistanche deserticola , a traditional Chinese medicine that promotes intestinal moisture and bowel relaxation, contains cistanche total alditol extract (CTAE) as its primary active extract. However, the production of CTAE, its overall efficacy, and potential mechanisms for treating FC have yet to been investigated. This study aimed to reveal the overall efficacy and potential mechanism of action of CTAE in rats with FC using a combination of stable preparation, pharmacodynamics, non-targeted metabolomics, bile acid metabolomics, and western blotting. Fourteen batches of CTAE underwent quality testing. A rat model of FC was developed using diphenoxylate tablets. The comprehensive pharmacodynamic effects of CTAE on FC were evaluated using fecal characteristics (wet weight, dry weight, and water content), intestinal transmission (colonic EMG amplitude, colonic EMG frequency, propulsion length, and propulsion rate), serum and colon biochemical indicators, distribution of interstitial cells of Cajal (ICC), and pathological examination. Non-targeted metabolomics was performed to assess the changes in endogenous metabolite profiles induced by CTAE. Bile acid metabolomics and western blotting analyses were employed to validate the potential mechanisms of action of CTAE. CTAE, with a total content of betaine, mannitol, D-fructose, glucose, and sucrose of (75.67 ± 3.73) %, significantly enhanced intestinal transit, regulated neurotransmitters, increased the expression of c-kit in ICC, and alleviated intestinal inflammation in rats with FC. Non-targeted metabolomics revealed that CTAE significantly alleviated FC-induced metabolic disorders, mainly the biosynthesis of primary bile acids. Targeted metabolomic analysis confirmed that CTAE regulated FC-induced bile acid disorders. Western-blotting results confirmed that CTAE increased the expression of CYP8B1, FGF15, TGR5, and FXR, thereby modulating bile acid synthesis and enterohepatic circulation. CTAE demonstrates significant therapeutic effects on FC, primarily through the regulation of bile acid synthesis and enterohepatic circulation. These findings provide a promising foundation for the development and clinical application of novel CATE-based drugs. [Display omitted] • Producing high-quality and stable CTAE. • CTAE exerts significant therapeutic effects on rat with FC. • Metabolomics reveals that CTAE mainly regulates bile acid metabolism. • BA metabolomics and western-blot confirms the anti-FC mechanism of CTAE. [ABSTRACT FROM AUTHOR]

The effects of Konjac mannan oligosaccharides (KMOS) on diphenoxylate-induced constipation in mice were investigated in the present study. After administration with KMOS at 1800 mg/kg·bw, the weight and number of black feces within 24 h, and the gastrointestinal transit ratio were distinctly increased by 96.8%, 156.5% and 45.3%, respectively. Furthermore, KMOS regulated the levels of enteric nervous system parameters, including motilin, somatostatin, substance P, acetyl cholinesterase, endothelin and vasoactive intestinal peptide. Additionally, KMOS could recover the characteristics of small intestine villi and inhibit the reduction of mucosal thickness. KMOS administration produced more short chain fatty acids and lactic acid compared with the control group. The availability of 5-hydroxytryptamine and the expression of serotonin transporter were ameliorated in the KMOS treatment groups. Collectively, these findings suggested that KMOS could be considered as a functional food material for regulating intestinal function and alleviating constipation.

Functional constipation (FC) is a common and often recurrent functional bowel disorder that seriously affects the quality of life of affected individuals and incurs a significant economic burden on both the individual and society. There is accumulating evidence that intestinal dysbiosis contributes to constipation and that rebalancing the gut microbiota may be a novel therapeutic modality for FC. Electroacupuncture (EA) has been shown to restore the gut microbiota to normal levels in a variety of diseases. Additionally, several high-quality clinical studies have confirmed that EA is an effective, sustained, and safe treatment for FC. However, whether the effects of EA are secondary to changes in the gut microbiota and how EA modulates intestinal dysbiosis induced by constipation are unknown. Therefore, here, we focused on the potential regulatory mechanisms of EA on diphenoxylate-induced constipation in mice by analyzing structural changes in the gut microbiota. Our results showed that EA treatment effectively rebalanced the gut microbiota of constipated mice, mainly by decreasing the Firmicutes/Bacteroidetes ratio, which may represent one way in which EA promotes gastrointestinal motility and alleviates constipation. Our findings lay the foundation for further mechanistic and clinical research into the application of EA in patients with FC. [ABSTRACT FROM AUTHOR]

Chronic constipation has been associated with depression-like behavior. Previous study identified the crucial role of gut microbiota in the development of constipation and depression. Dietary inulin (INU) could regulate gut microbiota. Whether INU treatment could ameliorate constipation induced depression was not clear. For this purpose, male CD-1 mice were administered diphenoxylate (20 mg/kg body weight/day) to induce constipation. We found that INU (10 % in standard diet) alleviated the diphenoxylate-induced constipation, manifested as the increase weight and moisture content of feces. Furthermore, the associated depression and anxiety-like behavior disorders were improved by inhibiting neuro-inflammation and preventing synaptic ultrastructure damage under INU treatment. Moreover, INU pretreatment improved the diphenoxylate-induced gut barrier damage by upregulating tight junction protein expression. INU also reshaped gut microbiota in constipation mice by increasing the relative abundance of Bacteroides and Proteobacteria and downregulating the abundance of Muribacalum and Melaminabacteria. The effects of INU on diphenoxylate-induced depression were abolished by gut microbiota depletion via antibiotic treatment. In addition, INU increased the concentration of short chain fatty acids (SCFAs) in feces contents. Meanwhile, supplementation of SCFAs could also partly improve diphenoxylate-induced depression. In conclusion, INU intake was a potential nutritional intervention strategy to prevent constipation induced depression via microbiota-gut-SCFAs axis., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier B.V.)

Background. Maren pills have been used to treat constipation. Aquaporin 3 (AQP3) plays a vital role in regulating water transfer in the colon. It has been reported that the downregulation of AQP3 can regulate liquid water metabolism and intestinal permeability in irritable bowel syndrome (IBS) rats' colon via NF-κB pathway. In this study, we investigated whether the laxative effect of Maren pills is associated with the regulation of AQP3 and NF-κB signaling pathway in the colon. Methods. The compound diphenoxylate suspension-induced STC rats received Maren pills intragastrically for 1 consecutive week to evaluate the laxative effect of Maren pills involving the regulation of AQP3 and NF-κB signaling pathway. Moreover, human intestinal epithelial cells (HT-29) were treated with drug serum to obtain in vitro data. Results. Our results revealed that treatment with Maren pills increased the stool number, moisture content of feces, and intestinal transit rate in a dose-dependent manner. Maren pills significantly increased the AQP3, fibrosis transmembrane conductance regulator (CFTR), and protein kinase A (PKA) proteins in the colon of rats and in HT-29 cells. Mechanistically, Maren pills obviously inhibited the activation of NF-κB pathway in the colon of rats and in HT-29 cells. Conclusion. These results suggest that the laxative effect of Maren pills is associated with the increased expression of AQP3 by downregulating NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Constipation is characterized by reduced number of bowel movements, dry stools, and difficult defecation. Yangyin Tongmi capsule (YTC), a traditional Chinese formula, is used in the treatment of constipation, while the underlying mechanisms remain unknown. Herein, this work attempted to prove the effects of YTC on constipation treatment and its possible mechanisms. KM mice were randomly divided into four groups (n = 10/group) and treated with double distilled water (Control), diphenoxylate (Model: 10 mg/kg), or diphenoxylate plus low-dose YTC (L-YTC: 0.6 g/kg) or high-dose YTC (H-YTC: 1.2 g/kg). The data indicated that YTC can significantly shorten the discharge time of the first black stool, improve intestinal propulsion rate, and increase the water content and quantity of feces in mice. ELISA suggested that YTC regulate the content of intestinal hormones and neurotransmitters, such as motilin (MTL), gastrin (GT), somatostatin (SST), substance P (SP), acetylcholine (Ach), and nitric oxide (NO). The expression levels of aquaporin 3 (AQP3) and aquaporin 8 (AQP8) in the colon were examined by immunohistochemistry. In the meantime, the expression levels of P2X2, C-kit, and stem cell factor (SCF) in the colon were examined by western blot analysis. The results of this study suggest that YTC has mitigative effects on diphenoxylate-induced constipation by regulating the content of intestinal hormones and neurotransmitters and regulating the expression of related proteins in the colon. [ABSTRACT FROM AUTHOR]

• KMOS promoted bowel movement and defecation to alleviate constipation. • KMOS regulated the enteric nervous system parameters in serum. • KMOS improved the concentration of short chain fatty acids in feces and protected intestinal morphology. • KMOS ameliorated the availability of 5-hydroxytryptamine and the expression of serotonin transporter. The effects of Konjac mannan oligosaccharides (KMOS) on diphenoxylate-induced constipation in mice were investigated in the present study. After administration with KMOS at 1800 mg/kg·bw, the weight and number of black feces within 24 h, and the gastrointestinal transit ratio were distinctly increased by 96.8%, 156.5% and 45.3%, respectively. Furthermore, KMOS regulated the levels of enteric nervous system parameters, including motilin, somatostatin, substance P, acetyl cholinesterase, endothelin and vasoactive intestinal peptide. Additionally, KMOS could recover the characteristics of small intestine villi and inhibit the reduction of mucosal thickness. KMOS administration produced more short chain fatty acids and lactic acid compared with the control group. The availability of 5-hydroxytryptamine and the expression of serotonin transporter were ameliorated in the KMOS treatment groups. Collectively, these findings suggested that KMOS could be considered as a functional food material for regulating intestinal function and alleviating constipation. [ABSTRACT FROM AUTHOR]

Slow transit constipation (STC) is a prevalent gastrointestinal condition with slow transit, and some probiotics can effectively relieve constipation, but the exact mechanisms have not been fully understood. In this study, we evaluate the impact of Lactiplantibacillus plantarum GUANKE (GUANKE) on diphenoxylate-induced slow transit constipation and speculate on the underlying mechanisms in a mouse model. Administration of L. plantarum GUANKE alleviated constipation indexes, including defecation time, fecal output and water content, and gastrointestinal transit ratio. In addition, GUANKE restored the protein expression of constipation-related intestinal factors (aquaporins (AQPs) and interstitial Cajal cells (ICCs)) in colon tissues measured using immunofluorescence staining; regulated the neurotransmitters and hormones, such as increased levels of 5-hydroxytryptamine, substance P, and motilin; and decreased levels of vasoactive intestinal peptide and nitric oxide in serum, as measured by an ELISA. 16S rRNA and correlation analysis of feces indicated that GUANKE administration effectively reduced constipation-induced Prevotella enrichment and suggested a potential contribution of Prevotella to diphenoxylate-induced STC in mice. GUANKE had no effect on short-chain fatty acids (SCFAs) in cecum content. This study revealed that GUANKE may alleviate constipation in mice through regulating intestinal neurotransmitter and hormone release and altering specific bacterial taxa, rather than by affecting SCFAs and the diversity of microbiota in the gut. Further research is needed to confirm if the findings observed in this study will be consistent in other animal studies or clinical trials.

Detarium senegalense JF Gmelin stem bark aqueous extract was investigated for its phytochemical contents as well as its anti-diarrhoea effects. The aqueous extract which is normally used in folkloric medicine was subjected to phytochemical screening. Graded doses of the extract (100, 200 and 400 mg per kg) were administered orally to three groups of rats (n = 5) before induction of diarrhoea with castor oil. Another two groups of animals were treated with normal saline (control) and diphenoxylate, a conventional anti-diarrhoea drug respectively. In two separate experiments, gastrointestinal transits of charcoal meal and gastro-intestinal enteropooling with the same graded doses of the aqueous extracts were used for comparison. The extract produced a significant inhibition of the castor oil induced diarrhoea in the animals. The gastrointestinal transit of charcoal meal was also reduced by the various doses used in this study. However, the intestinal fluid accumulation was only slightly reduced especially by 400 mg/kg dose of the extract. The aqueous extract alone dose dependently reduced the contractile amplitude of the jejunal tissue. The aqueous extract also decreased the contractile amplitude of isolated jejunal segment exposed to 0.2 ml of 10 µg/ml of acetylcholine. Phytochemical analysis of the stem bark extract revealed the presence of secondary metabolites such as alkaloids, tannins, flavonoids, terpenes and steroids, saponins and glycosides. The findings suggest that, the aqueous stem bark extract of D. senegalense possesses antidiarrhoeal effect, which could be related to inhibition of gastro-intestinal motility and secretion. [ABSTRACT FROM AUTHOR]

This study assessed the efficacy and mechanism of action of Yangyin Runchang decoction (YRD) in the treatment of slow-transit constipation (STC). ICR mice were randomly divided into four groups (n=10/group) and treated with saline (normal control; NC), atropine/diphenoxylate (model control; MC; 20 mg/kg), or atropine/diphenoxylate plus low-dose YRD (L-YRD; 29.6 g/kg) or high-dose YRD (H-YRD; 59.2 g/kg). Intestinal motility was assessed by evaluating feces and the intestinal transit rate (ITR). The serum level of stem cell factor (SCF) and changes in interstitial cells of Cajal (ICCs) were also evaluated. Additionally, the expression of SCF and c-kit and the intracellular Ca2+ concentration [Ca2+]I were investigated. Fecal volume and ITR were greater in the L-YRD and H-YRD groups than in the MC group. The serum SCF level was lower in the MC group than in the NC group; this effect was ameliorated in the YRD-treated mice. Additionally, YRD-treated mice had more ICCs and elevated expression of c-kit and membrane-bound SCF, and YRD also increased [Ca2+]I in vitro in isolated ICCs. YRD treatment in this STC mouse model was effective, possibly via the restoration of the SCF/c-kit pathway, increase in the ICC count, and enhancement of ICC function by increasing [Ca2+]i. [ABSTRACT FROM AUTHOR]

This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product. By improving its processing technology, it can incur better biological activity and become a health food. The Shuidouchi-treated mice were evaluated using constipation-related kits, quantitative polymerase chain reaction (qPCR), and Western blot assays. After the mice were fed 72-h-fermented Shuidouchi (72-SDC) for 9 d, the defecation time to excrete the first black stool was lower than that of the control and 24-SDC and 48-SDC groups, but was much higher than that of the normal group. The gastrointestinal (GI) transit of the small intestine of the 72-SDC group was higher than that of the control and the 24-SDC and 48-SDC groups, but lower that of the normal group. Meanwhile, 72-SDC could significantly increase the levels of ghrelin, endothelin-1 (ET-1), vasoactive intestinal peptide (VIP), and acetylcholinesterase (AchE) in the serum of constipated mice compared to the levels in mice in the control group. Moreover, 72-SDC could raise c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GNDF), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein expression levels, and reduce transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels in small-intestinal tissue compared to the levels in the control group. Meanwhile, 72-SDC also raised ghrelin mRNA expression in gastric tissue and transient receptor potential ankyrin 1 (TRPA1) mRNA expression in colon tissue compared to the control group mice; these effects were stronger than those of 24-SDC and 48-SDC. Shuidouchi has good preventative effects on constipation and performs best when fermented for at least 72 h.

Constipation is a common disorder that is a significant source of morbidity among people around the world ranging from 2% to 28%. Dendrobium officinale Kimura et Migo is a traditional herbal medicine and health food used for tonicity of the stomach and promotion of body fluid production in China. This study aimed to prepare the ultrafine powder of Dendrobium officinale (UDO) and investigate its laxative effect and potential mechanism in mice with diphenoxylate-induced constipation. Results indicated that the mean diameter (d50) of UDO obtained by ball milling was 6.56 μm. UDO (62.5, 125, and 250 mg/kg, p.o.) could significantly enhance the gastrointestinal transit ratio and promote fecal output. Moreover, UDO treatment resulted in significant increases in the serum levels of acetylcholinesterase (AChE), gastrin (Gas), motilin (MTL), and substance P (SP), and obviously decreased serum contents of somatostatin (SS). Taken together, UDO, which can be easily obtained through milling to a satisfactory particle size, exhibited obvious laxative effect in diphenoxylate-induced constipated mice, and the mechanism might be associated with elevated levels of AChE, Gas, MTL, SP, and reduced production of SS. UDO has the potential for further development into an alternative effective diet therapy for constipation. [ABSTRACT FROM AUTHOR]

Background: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied., Objectives: In this study, we sought to explore opioid-associated arrhythmia reporting in North America., Methods: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory., Results: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS., Conclusions: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America., Competing Interests: Funding Support and Author Disclosures This publication reflects independent work of the authors and is not a representation of official policies or positions of the American College of Cardiology or any U.S. governmental agency, including the Department of Defense, Veterans Medical Affairs Medical Center, or the Food and Drug Administration. Dr Kao was supported by K08 HL125725. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Lomotil (diphenoxylate atropine combination) has been in use as an antidiarrhoeal agent. Due to presence of opioid (diphenoxylate), there are chances of abuse. The reports of abuse of lomotil have been few in published literature. This chart review aimed to evaluate the characteristics of patients with dependence on lomotil coming to our centre. Materials and Methods: This retrospective chart review was conducted at the Drug De-addiction and Treatment Centre of PGIMER, Chandigarh, India. The records of patients who had presented to the centre with dependence on Lomotil in the last five years were identified, and clinical details were extracted from the records. Results: We identified 41 patients who had presented to our centre with dependence upon lomotil as the primary substance of abuse. The cases were typically married and employed males, educated up to 10 th grade, belonging to a rural Sikh extended or joint family. Most of the patients had taken other opioids too. The number of tablets taken in a day varied from 3- to 250 (median 25). The reasons of initiation were to relieve withdrawals, as a cheap substitute opioid, curiosity, and on suggestion of friends. Conclusion: Lomotil is a medication with a potential of abuse and regulatory controls are required to prevent escalation of misuse of this easily available prescription drug. Lomotil (diphenoxylate and atropine combination) has been used since a long time as an anti-diarrheal agent. Reports of abuse of diphenoxylate had surfaced. We present a series of 41 cases of opioid dependence presenting with the use of the diphenoxylate as the primary substance. The cases were typically married and employed males, educated up to 10 th grade, belonging to a rural Sikh extended or joint family. Most of the patients had taken other opioids too. The number of tablets taken in a day varied from 3 to 250 (median 25). The reasons of initiation of diphenoxylate were to relieve withdrawals, as a cheap substitute opioid, curiosity, and suggestion of friends. Regulatory controls are needed to prevent escalation of use of this easily available prescription opioid.

Objective: To investigate the effects of Mijian Daotong Bowel Suppository (MJDs) on the compound diphenoxylate induced constipation model of male rats and its mechanisms. Methods: Sixty SD male rats were randomly divided into blank group, model group, positive group and MJDs group. The constipation model was established by using compound diphenoxylate gavage. The rats in blank group and model group were treated with saline by enema, the rats in positive group and MJDs group were given Kaisailu and honey decoction laxative suppository by enema, respectively, once a day for 10 days. The body weight, fecal water content, gastric emptying rate (GER) and carbon ink propulsion rate (CIPR) of rats were observed during modeling and administration. The effects of MJDs on the pathological changes of colon tissue in constipation rats were investigated by hematoxylin-eosin (HE) staining. The effect of MJDs on 5-hydroxytryptamine (5-HT) in the colon of constipation rats was investigated by ELISA kit. The effects of MJDs on the expressions of aquaporins 3 (AQP3) and aquaporins 4 (AQP4) in the colon of constipation rats were detected by immunohistochemistry. Results: After 10 days of administration, compared with the blank group, the body weight, fecal water content, carbon ink propulsion rate and colon 5-HT content in the model group were decreased significantly, while the expression levels of AQP3 and AQP4 in the colon were increased significantly ( P ＜0.05, P ＜0.01). Compared with the model group, the fecal water content and colon 5-HT content in the positive group were increased significantly, and the expressions of AQP3 and AQP4 in the colon were decreased significantly. The body weight, fecal water content and colon 5-HT content in the MJDs group were increased significantly, and the expressions of AQP3 and AQP4 was decreased significantly ( P ＜0.05, P ＜0.01). Compared with the positive group, the fecal water content of the MJDs group was decreased significantly, and the expressions of AQP3 and AQP4 in the colon of the MJDs group was decreased significantly ( P ＜0.05, P ＜0.01). Gastric emptying rate was not statistically significant difference between the groups. Conclusion: MJDs has good therapeutic effects on constipation, and its mechanisms may be related to up-regulating the content of 5-HT in the colon and down-regulating the expressions of AQP3 and AQP4 in the colon.