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Background: Early weaning is prone to damage intestinal barrier function, resulting in diarrhea, whereas rutin, as a natural flavonoid with multiple biological functions, shows potential in piglets. Therefore, the effects of dietary rutin on growth, antidiarrheal, barrier function, antioxidant status and cecal microbiota of weaned piglets were investigated with the control group (CON) (basal diet) and Rutin (basal diet+500 mg kg -1 rutin) groups fed for 14 days., Results: The results showed that dietary 500 mg kg -1 rutin significantly decreased diarrhea index, serum diamine oxidase activity and total aerobic bacterial population in mesenteric lymph nodes, whereas it significantly increased the gain-to-feed ratio (G:F) and serum growth hormone content, jejunal villus height and villus height to crypt depth ratio, and also enhanced jejunal claudin-1 and zonula occludens-1 mRNA and protein expression. Meanwhile, dietary rutin significantly decreased inflammation-associated mRNA expression, malondialdehyde (MDA) content, swollen mitochondrial number and mitochondrial area in the jejunum, whereas it increased the total superoxide dismutase (T-SOD) and glutathione peroxidase activities and activated the Nrf2 signaling pathway. Moreover, dietary rutin significantly increased Firmicutes abundance and decreased Campylobacterota abundance, which were closely associated with the decreased diarrhea index and MDA content or increased Claudin-1 expression and T-SOD activity., Conclusion: Dietary 500 mg kg -1 rutin increased G:F by improving intestinal morphology, and alleviated diarrhea by enhancing intestinal barrier, which might be associated with the enhanced antioxidant capacity via activating the Nrf2/Keap1 signaling pathway and the improved cecal microbial composition in weaned piglets. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Purpose: An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3 A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel., Methods: We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured., Results: The plasma exposure (AUC and C max ) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir., Conclusion: These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oriental herbal medicine with the two bioactive constituents, β-eudesmol (BE) and atractylodin (AT), has been used as a remedy for gastrointestinal disorders. There was no scientific evidence reporting their antidiarrheal effect and underpinning mechanisms. Therefore, we aimed to investigate the anti-secretory activity of these two compounds in vitro. The inhibitory effect of BE and AT on cAMP-induced Cl - secretion was evaluated by Ussing chamber in human intestinal epithelial (T84) cells. Short-circuit current (I SC ) and apical Cl - current (I Cl -) were measured after adding indirect and direct cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activator. MTT assay was used to determine cellular cytotoxicity. Protein-ligand interaction was investigated by in silico molecular docking analysis. BE, but not AT concentration-dependently (IC 50 of ~1.05 µM) reduced cAMP-mediated, CFTR inh -172 inhibitable Cl - secretion as determined by transepithelial I SC across a monolayer of T84 cells. Potency of CFTR-mediated I Cl - inhibition by BE did not change with the use of different CFTR activators suggesting a direct blockage of the channel active site(s). Pretreatment with BE completely prevented cAMP-induced I Cl -. Furthermore, BE at concentrations up to 200 µM (24 h) had no effect on T84 cell viability. In silico studies indicated that BE could best dock onto dephosphorylated structure of CFTR at ATP-binding pockets in nucleotide-binding domain (NBD) 2 region. These findings provide the first evidence for the anti-secretory effect of BE involving inhibition of CFTR function. BE represents a promising candidate for the therapeutic or prophylactic intervention of diarrhea resulted from intestinal hypersecretion of Cl ., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Neratinib is approved in the European Union for extended adjuvant treatment of human epidermal growth factor receptor 2-positive/hormone receptor-positive (copositive) early breast cancer ≤1 year of completion of prior trastuzumab-based therapy. Here, we report analyses of the hormone receptor-positive subgroup (N = 1631) from the ExteNET trial performed for the German health technology assessment (HTA)., Results: With 2 years of median follow-up, HTA analyses revealed a significant advantage in disease-free survival (DFS) for neratinib vs. placebo (absolute/relative risk reduction: 4.1/48.2%; hazard ratio [HR] [95% confidence interval {CI}]: 0.45 [0.29; 0.69]; p = 0.0002), consistent with distant DFS (absolute/relative risk reduction: 3.1/46.3%; HR [95% CI]: 0.52 [0.32; 0.84]; p = 0.0082). The 5-year follow-up confirmed this outcome.Quality of life analyses did not show clinically relevant differences over all time points. Only at month 1, the Functional Assessment of Cancer Therapy - General total score revealed a statistically relevant difference to the disadvantage of neratinib classified as clinically relevant. The tolerability profile of neratinib was dominated by gastrointestinal events, mainly diarrhoea (all grades: 94.4%; grade III: 39.4%; no systematic antidiarrhoeal prophylaxis), nausea (all grades/grade III: 43.9/1.6%), vomiting (26.6/3.2%), abdominal pain (23.8/1.9%), fatigue (28.1/1.9%) and rash (14.3/0.4%). No cumulative or irreversible toxicities were observed. As shown in the CONTROL study and instituted via a risk management plan, diarrhoea management can reduce frequency, cumulative duration and severity of diarrhoea., Conclusion: Extended adjuvant neratinib provides a clinically relevant benefit with further incremental reduction of relapse risk in the curative setting. Accordingly, the German HTA authority has granted an added benefit for this new treatment option., Competing Interests: Conflict of interest statement D.L. received consulting fees from Pierre Fabre, AstraZeneca, Novartis, Eli Lilly, Pfizer, Celgene, L'Oreal, Teva, Tesaro and Amgen as well as fees for non-CME services (e.g. speakers' bureaus) from Pierre Fabre, AstraZeneca, Novartis, Eli Lilly, Pfizer, Celgene, L'Oreal, Teva, Tesaro and Amgen. H.T. received consulting fees from Pierre Fabre, Pfizer Pharma GmbH, Mundipharma, ClinSol, Novartis, Lilly, Grünenthal, Vifor, AstraZeneca and Mylan. M.S. received honoraria for the speaker or consultancy role from AMGEN, AstraZeneca, Eisai, Lilly, Myelo Therapeutics, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and Seattle Genetics. He received research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Myelo Therapeutics, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and Roche. He received travel reimbursement from Pfizer and Roche. A.D.H. received consulting fees from Roche, Novartis, Teva, Pfizer, AstraZeneca, Eisai, Hexal, Genomic Health, Lilly, MSD and Pierre Fabre as well as fees for non-CME services (e.g. speakers' bureaus) from Roche, Novartis, Teva, Pfizer, AstraZeneca, Lilly and MSD. N.H. received consulting fees from Pierre Fabre and Roche. S.S. is an employee at AMS Advanced Medical Services GmbH, München, Germany; A.R., L.G. and C.R. are employees at Pierre Fabre Pharma GmbH, Freiburg, Germany, and R.V. is an employee at Pierre Fabre Médicament, Boulogne-Billancourt, France., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Loperamide is a μ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional μ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.

The present study endeavored to develop orodispersible films (ODFs) containing 30 mg racecadotril for pediatric use, which focuses on improving the compliance of pediatric patients and reducing risk of choking. The challenge of this study is to prepare high drug loading ODFs with successful mechanical and physicochemical properties. Compatibilities between drug and different polymers (hydroxypropyl methylcellulose, HPMC; polyvinyl alcohol, PVA; low-substituted hydroxypropyl cellulose, L-HPC; pullulan, PU) were investigated to select stable and safe film-forming polymers. Afterwards, the study explored the maximum amount of racecadotril incorporated into PVA films and PU films. Subsequently, disintegrant (Lycoat RS720, 4-10%, w/w) and plasticizers (glycerol, 2-6%, w/w) were investigated to reduce disintegration time of PVA films and enhance the flexibility of PU films, respectively. Formulation characteristics (appearance, tensile strength, percent elongation, disintegration time, drug content, weight, thickness, pH value, moisture content, moisture uptake, and Q 5min ) of prepared ODFs were examined to obtain the optimal compositions of racecadotril ODFs. Differential scanning calorimetry (DSC) study, powder X-ray diffraction (XRD) study, Fourier transform infrared (FTIR) study, comparative in vitro dissolution study, and pharmacokinetic study in Beagle dogs of optimized racecadotril ODFs were then conducted. Eventually, ODFs containing 50% racecadotril, 38% PVA, 7% Lycoat RS720, 2% sucralose, 2% apricot, and 1% titanium dioxide could achieve desirable mechanical properties, disintegrating within a few seconds and releasing more than 85% drug within 5 min in four dissolution media. An in vivo study showed optimized racecadotril ODF and Hidrasec were bioequivalent in Beagle dogs. In summary, ODFs containing 30 mg racecadotril were successfully prepared by solvent casting method, and it was suitable for the administration to the pediatric patients.

Background: The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting., Methods: We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration., Results: The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 2.8), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration., Conclusions: Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.)., (Copyright © 2020 Massachusetts Medical Society.)

Gut microbial communities are capable of enzymatically transforming pharmaceutical compounds into active, inactive, and toxic metabolites, thus potentially affecting the pharmacokinetics and bioavailability of orally administered medications. Our understanding of the impact and clinical relevance of how gut microbial communities can directly and indirectly affect drug metabolism and, ultimately, clinical outcomes, is limited. Interindividual variability of gut microbial composition may partially explain differences observed in drug efficacy and toxicity in certain patient populations. This review provides an overview of how gut microbial communities can potentially contribute to individual drug response. This review focuses on the current landscape of clinical and preclinical research that defines the microbiome contribution on medication response with the goal of improving medication efficacy and decreasing medication toxicity., (© 2020 Pharmacotherapy Publications, Inc.)

Background: Insulin-like peptide 5 (INSL5) is a hormone stored in colonic enteroendocrine cells that also contain the unrelated hormones, GLP-1 and PYY. It acts at the relaxin family peptide 4, RXFP4, receptor. RXFP4 is expressed by enteric neurons in the colon, and it has been speculated that INSL5, through its action on enteric neurons, might be involved in the control of colonic contractions. Similar to insulin and relaxin, INSL5 consists of A and B peptide chains linked by three disulfide bonds, two between the chains and one intrinsic to the A chain. Because of its complex structure, it is difficult to synthesize and to prepare peptide analogues to investigate its roles. We have recently developed a potent simplified peptide analogue, INSL5-A13 (INSL5 analogue 13)., Methods: In the present work, we have investigated the actions of INSL5-A13 in mice. We investigated the ability of INSL5-A13 to increase the speed of emptying of a bead from the colon, after expulsion had been slowed by the peripherally restricted opioid agonist, loperamide (1 mg/kg)., Key Results: INSL5-A13 was a full agonist at the mouse RXFP4 expressed in HEK cells, with an EC50 of ~9 nmol/L. INSL5-A13 caused an acceleration of colorectal bead propulsion in mice constipated by loperamide in the dose range 0.2 to 60 µg/kg, with an EC50 of ~6 µg/kg in vivo. It also accelerated bead propulsion in untreated mice. Bead expulsion was not accelerated in RXFP4-/- mice., Conclusion and Inferences: Our data suggest that RXFP4 agonists could be useful in the treatment of constipation., (© 2020 John Wiley & Sons Ltd.)

The acute diarrhea is a wide-spread disease. The prescription of enterosorbents is appropriate as a primary measure for the treatment of the acute diarrhea for effective prevention of the fluid and electrolyte loss, as well as method for symptom relief of the attack of the disease. Aim of the study - the antidiarrheal efficacy and safety study of high-dispersion silicon dioxide enterosorbent in tablet dosage form in patients with acute diarrhea. This was randomized, double-blind, placebo-controlled, 4-center study. Acute diarrhea was defined as three and more episodes of watery stool per day either during 48 hours or less before study entry in the patients having normal stool recently. It has been postulated that symptoms and signs of acute diarrhea have to be caused by direct infection of the gastrointestinal tract and did not associated with moderate-to-severe systemic states. 144 patients with established acute diarrhea were randomized into treatment group (enterosorbent "Carbowhite", n = 120) or placebo group. Date collection including severity diarrhea, systemic symptoms was performed at baseline and daily during 7 days. Stool examination and serological assay were performed at baseline. The primary end points were declared as time to complete recovery from acute diarrhea. It has been found that the use of the siliceous enterosorbent ("Carbowhite") allowed to reduce (p < 0.001) the treatment period averagely for 0.9 days (95% confidence interval 0.5-1.2 days) in comparison with placebo. Data of safety monitoring has revealed that both patient groups had negative stool culture, while initiation of antibiotic treatment was run more frequently in placebo group (8.3%) compared to investigational product group (4.1%, P = 0.044). The siliceous enterosorbent "Carbowhite" was well tolerated and reduced the recovery time of the acute episode of the diarrhea in the clinically significant form.

Patients on dialysis are frequently administered high doses of potassium binders such as calcium polystyrene sulfonate (CPS) and sodium polystyrene sulfonate (SPS), which exacerbate constipation. Here, we compare the degree of constipation induced by CPS and SPS using a loperamide-induced constipation model to identify the safer potassium binder. Constipation model was created by twice-daily intraperitoneal administration (ip) of loperamide hydrochloride (Lop; 1 mg/kg body weight) in rats for 3 days. Rats were assigned to a control group, Lop group, Lop + CPS group or Lop + SPS group, and a crossover comparative study was performed. Defecation status (number of feces, feces wet weight, fecal water content and gastrointestinal transit time (GTT)) was evaluated. In the Lop + CPS group, GTT was significantly longer, and fecal water content was reduced. In the Lop + SPS group-although the fecal water content and GTT were unaffected-the number of fecal pellets and the fecal wet weight improved. Thus, SPS was less likely to cause constipation exacerbation than CPS. Considering the high frequency of constipation in dialysis patients with hyperkalemia, preferentially administering SPS over CPS may prevent constipation exacerbation.

Background: Loperamide is a mu-opioid receptor agonist that is available as an over-the-counter anti-motility agent in the US and UK; recommended maximum doses of 12-16 mg/day. Anecdotal reports of non-medical use (NMU) have increased over the past decade with supra-therapeutic doses (70-800 mg/day) associated with cardiotoxicity. Little data exists on the prevalence of loperamide NMU., Aim: The aim of this study was to determine the prevalence of loperamide NMU in the UK and US and to describe characteristics of non-medical loperamide users., Design: The Researched, Abuse, Diversion and Addiction Related Surveillance (RADARS® ) Survey of Nonmedical Use of Prescription Drugs (NMURx) was utilized to study NMU of loperamide among the adult population in the UK and US in 2017. The RADARS® NMURx is anonymous and self-administered online., Methods: A total of 40,029 completed surveys were included (10,019 from the UK and 30,010 from the US). Respondents were asked questions about medical and NMU of loperamide, frequency of and reasons for NMU, route of use problematic drug use markers, and demographics., Results: Prevalence of lifetime loperamide use (95% CI) and lifetime NMU of loperamide were: UK 28.5% (27.67-29.4), and 0.66% (0.5-0.8), respectively; US 33.7% (33.1-34.2), and 5.19% (4.9-5.5), respectively. Problematic drug use markers were elevated in those who reported NMU of loperamide in both the UK and US, however high-risk use was more prevalent in the UK than in the US., Conclusion: NMU of loperamide is common. In the current international environment of opioid addiction involving both therapeutic and illicit opioids, awareness of the NMU of loperamide is important., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Crofelemer, the active compound purified from latex of Croton lechleri, has been shown to improve HIV and traveler's diarrhea and improve pain in women with irritable bowel syndrome-diarrhea (IBS-D). This trial evaluated the effect of crofelemer on abdominal pain in women with IBS-D., Methods: Women with IBS-D were randomized to crofelemer (125 mg) or placebo twice daily for 12 weeks. The primary efficacy endpoint was overall change in percentage of abdominal pain/discomfort-free days. Post hoc analysis for Food and Drug Administration (FDA) monthly responders was performed for stool consistency, abdominal pain, and combined stool consistency and abdominal pain., Results: A total of 240 women were enrolled. There was no significant difference in overall percentage of pain/discomfort-free day between the groups. In post hoc analysis, FDA abdominal pain monthly responders were significantly more likely during months 1 through 2 (58.3% vs 45.0%, P = 0.030) as well as during the entire 3 months (54.2% vs 42.5%, P = 0.037) in the crofelemer group when compared with placebo. However, there was no significant difference in the percentage of FDA stool consistency monthly responders or combined stool consistency and pain monthly responders between the groups. Crofelemer had a safety profile similar to placebo., Discussion: Crofelemer did not significantly improve abdominal pain over placebo by the primary endpoint. However, it did based on the FDA abdominal pain monthly responder endpoint. This suggests that crofelemer may have a role in the treatment of abdominal pain associated with IBS-D. Further studies are warranted to evaluate the potential of crofelemer as a visceral analgesic.

Background: Asphodelus tenuifolius Cav. (Asphodelaceae) has traditional reputability in treatment of diarrhea and constipation but no scientific study has been reported for its gastrointestinal effects. Present study was conducted to evaluate antidiarrheal and laxative activities of the plant., Methods: Aqueous-ethanol crude extract of Asphodelus tenuifolius (At.Cr) was subjected to phytochemical screening and liquid-liquid fractionation. In vivo studies of charcoal meal intestinal transit test, antidiarrheal activity against castor oil induced diarrhea and laxative activity were performed in mice. In vitro experiments were conducted upon rabbit jejunum preparations using standard tissue bath techniques., Results: Phytochemical screening indicated presence of alkaloids, anthraquinones, flavonoids, saponins, steroids, tannins and phenols in At.Cr. In charcoal meal intestinal transit test, At.Cr increased (p < 0.001) intestinal motility at 100 mg/kg dose, but decreased (p < 0.001) it at 500 mg/kg dose, when compared to the control group. At.Cr (300-700 mg/kg) provided protection from castor oil induced diarrhea in mice, which was significant (p < 0.001) at 500 and 700 mg/kg doses, as compared to the saline treated control group. At.Cr (50 and 100 mg/kg) enhanced total and wet feces counts in normal mice, as compared to saline treated control. In jejunum preparations, At.Cr inhibited spontaneous, K + (80 mM) and K + (25 mM) mediated contractions, similar to verapamil. Pre-incubation of jejunum preparations with At.Cr resulted in rightward nonparallel shift in Ca + 2 concentration response curves, similar to verapamil. The spasmolytic activity was concentrated in ethylacetate fraction. Aqueous fraction exhibited spasmogenicity upon spontaneous contractions, which was blocked in presence of verapamil, but remained unaffected by other tested antagonists., Conclusion: The Asphodelus tenuifolius crude extract possesses gut modulatory activity, which may normalize gut functions in diarrhea and constipation. The spasmolytic activity of the extract was found to be mediated through Ca + 2 channel blocking action. The spasmogenic activity, found partitioned in aqueous fraction, possibly involves Ca + 2 influx through voltage gated Ca + 2 channels. The study supports ethnic uses of the plant in diarrhea and constipation.

Purpose: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib., Methods: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1-4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study., Results: A median t max of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CL ss /F 308.2 and 322.1 L/h; mean V zτ /F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: C max 61.2 ng/mL and 49.5 ng/mL; AUC last 1086 ng h/mL and 1153 ng h/mL, and AUC tau 779 ng h/mL and 745 ng h/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%)., Conclusions: Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.

Background: Acute noninfectious diarrhea is a common phenomenon in intensive care unit patients. Multiple treatments are suggested but the most effective management is unknown. A working group of the Eastern Association for the Surgery of Trauma, aimed to evaluate the effectiveness of loperamide, diphenoxylate/atropine, and elemental diet on acute noninfectious diarrhea in critically ill adults and to develop recommendations applicable to daily clinical practice., Methods: The literature search identified 11 randomized controlled trials (RCT) appropriate for inclusion. The Grading of Recommendations Assessment, Development, and Evaluation methodology was applied to evaluate the effect of loperamide, diphenoxylate/atropine, and elemental diet on the resolution of noninfectious diarrhea in critically ill adults based on selected outcomes: improvement in clinical diarrhea, fecal frequency, time to the diarrhea resolution, and hospital length of stay., Results: The level of evidence was assessed as very low. Analyses of 10 RCTs showed that loperamide facilitates resolution of diarrhea. Diphenoxylate/atropine was evaluated in three RCTs and was as effective as loperamide and more effective than placebo. No studies evaluating elemental diet as an intervention in patients with diarrhea were found., Conclusion: Loperamide and diphenoxylate/atropine are conditionally recommended to be used in critically ill patients with acute noninfectious diarrhea., Level of Evidence: Systematic Review/Guidelines, level III.

Upper gastrointestinal (GI) motility is affected by various drugs and diseases. However, changes in upper GI motility during these conditions are not well understood, as there are few quantitative in vivo methods that assess small intestinal motility in mice. Ultrasonography is a noninvasive method for imaging and evaluating the condition of the abdominal organs. The aim of the present study was to establish a novel method for evaluating small intestinal motility by using ultrasonography in mice. We measured GI motility with and without loperamide, an antidiarrheal medication, by intestinal transit using an orally administered dye, a 13 C-octanoic acid breath test, and ultrasonography. Locomotion activity of the duodenal wall was used for quantifying the GI motility observed via ultrasonography. Our results showed that upper GI transit was significantly delayed by loperamide. The 13 C-octanoic acid breath test revealed decreased gastric emptying in loperamide-treated mice. Through ultrasonography, large peristaltic movements were observed in the duodenum of the control mice. In contrast, after treatment with loperamide, these peristaltic movements were suppressed, and the duodenal lumen was enlarged, suggesting decreased duodenal motility. In accordance with these results, quantifiable locomotion activity was also significantly decreased. In conclusion, ultrasonography is an effective in vivo method to quantify small intestinal motility in mice.

The opioid epidemic has left its toll on the United States with millions suffering from an opioid use disorder and tens of thousands dying from overdoses each year. With intentions to combat the crisis, health providers have been prescribing less opioids, which resulted in an unintentional increase in the abuse of other opioid-like substances. Three emerging drugs of abuse have been noted in the literature as having increased abuse potential in light of recent trends. Kratom, an herbal supplement, gabapentin, a prescription nerve pain and anticonvulsant medication, and loperamide, an over-the-counter antidiarrheal medication. These have all displayed opioid-like properties at high doses and used to alleviate opioid withdrawal. Healthcare clinicians and patients might not be aware of the potential risks involved with misusing or abusing these opioid substitutes. This article discusses the increased usage of kratom, gabapentin, and loperamide, the abuse potential, adverse effects and withdrawal symptoms of each drug, and nursing implications that impact inpatient safety and management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

: This case report describes a patient with opioid use disorder who developed cardiac toxicity secondary to non-medical use of loperamide. At recommended doses, loperamide remains in the periphery to treat diarrhea. At high doses, loperamide causes central nervous system (CNS) opioid agonism. Complications of high-dose loperamide have been documented, including cardiotoxicity, and death. This is particularly important in light of the ongoing opioid epidemic. This case presents a patient with sequela of high-dose loperamide as an illicit opioid replacement and the subsequent loperamide toxicity, including significant QTc prolongation. Abrupt cessation of his high-dose loperamide use resulted in opioid withdrawal symptoms, which were treated with buprenorphine. Buprenorphine was selected to avoid possible worsening of QTc secondary to an additional medication, such as methadone. To our knowledge, this is the first description of the use of buprenorphine for treatment of loperamide-associated opioid use disorder. Non-medical use of loperamide requires increased recognition by the health care community, including both physicians and pharmacists, because it can result in marked and life-threatening toxicity.

Chinese dark teas (CDTs) are a special type of tea traditionally consumed by ethnic minorities around the border regions of China. Dark tea produced by the Yao population of Guangxi could help prevent diarrhea following the heavy consumption of food. However, the underlying mechanisms behind this effect are not clear. This study aimed to investigate the function and underlying mechanisms of dark tea by examining the effects of different doses of dark tea on diarrhea in mice caused by Folium Sennae. It was found that dark tea could significantly improve the rate of loose stools and diarrhea index, and had an inhibitory effect on intestine peristalsis in high- and moderate-dose groups. Compared with green tea, significantly decreased levels of water extract, tea polyphenol and amino acid were found in dark tea, whereas the content of both caffeine and gallocatechin was increased. The result of dilution plating showed that Aspergillus niger and Byssochlamys fulva were consistent with microbial diversity as assessed by high-throughput sequencing technology. A total of 12 metabolites related to an anti-diarrhea effect were identified by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). These findings provide a physiological basis for developing dark tea produced by the Yao population of Guangxi as a drink that can regulate and improve the intestinal flora in humans.

Introduction: Loperamide is a readily accessible nonprescription medication that is increasingly being used surreptitiously as an opioid substitute to alleviate the symptoms of acute opioid withdrawal. The objective of this study was to determine the clinical characteristics of patients with loperamide misuse and toxicity., Methods: The ToxIC registry, a nationwide, prospectively collected cohort of patients evaluated by medical toxicologists was searched from November 2011-December 2016 for patients with loperamide exposure. Each record was reviewed to determine the circumstances, dose, clinical presentations, treatment, and outcomes associated with loperamide use., Results: Twenty-six cases were identified, and both the absolute number and relative proportion of overall cases in the ToxIC registry increased annually. The median age was 27 and 54% were male. Of cases with known intent (n = 18), 12(67%) were misuse/abuse, 3(17%) were self-harm/suicide, and 3(17%) were pediatric exploratory ingestions. Circumstances for misuse included taking higher doses than labeled (n =7), avoiding withdrawal (n = 6), and gaining a pleasurable sensation (n =4). The dose was reported in nine cases and ranged from 4 mg to 400 mg. In patients seeking to avoid withdrawal doses were 160-400 mg/day; the most common reported dose was 200 mg. Reported ECG abnormalities included 10 cases of prolonged QTc (>500 ms), which consisted of misuse/abuse (n =6) and self-harm (n =1) exposures; six prolonged QRS (>120 ms); two first degree AV block; seven ventricular dysrhythmias, five of which were single-agent exposures. All but one ECG demonstrated prolonged QTc with a range of 566-749 ms. All patients with dysrhythmias in which dose were reported ingested ≥200 mg., Conclusions: The majority of patients had loperamide toxicity due to misuse/abuse, in-line with national trends. In patients avoiding withdrawal, doses >100 mg were observed. When taken in large doses (>200 mg), loperamide may cause significant cardiovascular effects, including QTc-prolongation and ventricular dysrhythmias.

Background: Fecal incontinence is a socially and emotionally destructive condition that has a negative impact on personal image, self-confidence, and quality of life. Acupuncture is commonly used to treat chronic conditions, including fecal incontinence. However, no relevant systematic review or meta-analysis has been designed to evaluate the effects of acupuncture on fecal incontinence., Methods: We will identify relevant randomized controlled trials (RCTs) from the Cochrane Library, Medline, Embase, PubMed, Springer, Web of Science, China National Knowledge Infrastructure, VIP Chinese Science and Technology Journals Database, Wanfang database, and clinical trial registration center from their inception to February 28, 2019. The primary outcome measures will be clinical effective rate, functional outcomes, and quality of life. Data that meets the inclusion criteria will be extracted and analyzed using RevMan V.5.3 software. Two reviewers will evaluate the studies using the Cochrane Collaboration risk of bias tool. Publication bias will be assessed by funnel plots, Egger test, and Begg test using the Stata software. Acupoints characteristics will be analyzed by Traditional Chinese Medicine inheritance support system., Results: This study will analyze the clinical effective rate, functional outcomes, quality of life, daily average number of fecal incontinence, and effective prescriptions of acupuncture for patients with fecal incontinence., Conclusion: Our findings will provide evidence for the effectiveness and potential treatment prescriptions of acupuncture for patients with fecal incontinence., Prospero Registration Number: PROSPERO CRD42019119680.

Background: Immunocompromised travelers (ICTs) are medically complex and challenging for travel medicine providers. Our study hypothesizes that ICTs have high-risk travel itineraries and do not have adequate immunity against vaccine-preventable infections., Methods: This retrospective review of 321 ICTs from 2004 to 2015 included patients with solid organ transplant (SOT, n = 134), connective tissue disease (CTD, n = 121), inflammatory bowel disease (IBD, n = 46), and human immunodeficiency virus (HIV, n = 20). Variables included immunosuppressive medications, hepatitis A and B vaccination and serology, gamma-globulin use, and antimalarial and antidiarrheal prophylaxis. Chi-square analysis was used for categorical variables and Kruskal-Wallis for continuous variables., Results: Malaria-endemic regions accounted for 38.9% (125/321) of travel destinations. High-risk activities were planned by 37.4% (120/321) of travelers. A significant proportion of HIV patients [70.0% (14/20)] visited friends and relatives, whereas other ICTs traveled for tourism. Hepatitis A and B vaccination rates were 77.3% (248/321) and 72.3% (232/321). Post-vaccination hepatitis A and B serologic testing were completed by 66.1% (41/62) and 61.1% (11/18) of travelers, respectively., Conclusion: ICTs demonstrate differences in travel patterns and risk. Serologic testing was uncommon, and vaccination rates were low. Providers should screen ICTs early for upcoming travel plans and advise vaccine completion prior to departure., (Copyright © 2018 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.)

Traditionally people used Dodonaea viscosa for the treatment of various ailments, including diarrhea. Therefore, this study was aimed to evaluate the antidiarrheal activity of the 80% methanolic leaf extract of D viscosa against castor oil-induced diarrhea in mice models. Different doses of 80% methanolic leaf extract of D viscosa (100, 200, and 400 mg/kg) were evaluated for their antidiarrheal activities using castor oil-induced diarrhea, gastrointestinal transit, and enteropooling models in Swiss albino mice. At all test doses, the plant extract showed significant ( P < .05) inhibition in the frequency of defecation of wet feces and total fecal output as compared to the control group. Similarly, at all dose ranges used the plant extract demonstrated significant ( P < .05) reduction in an intraluminal fluid accumulation as compared to the untreated group. Besides, at higher doses, the plant extract also indicated significant ( P < .05) antimotility activity in comparison with the control. In conclusion, these findings illustrated that the 80% methanolic leaf extract of D viscosa supported the traditional claim of antidiarrheal activity of the plant though further investigations are warranted.

Verbena officinalis L. has a folkloric repute for the management of digestive disorders, including diarrhea. However, the safety and efficacy of the plant material has not been scientifically validated yet. This study was, therefore, aimed to evaluate the overall antidiarrheal activity of the 80% methanol extracts of V officinalis in mice. The antidiarrheal activity of the 80% methanol extracts of the roots (R-80ME) and the leaves (L-80ME) of V officinalis was tested in castor oil-induced diarrhea in mice. R-80ME was further evaluated using charcoal meal and entero-pooling. In each test, group I and group II (controls) received 10 mL/kg distilled water and standard drug (5 mg/kg loperamide), respectively, whereas groups III, IV, and V (test groups) received 100, 200, and 400 mg/kg of the 80ME, respectively. The R-80ME at 200 mg/kg ( P < .01) and 400 mg/kg ( P < .001) significantly delayed the onset of diarrhea compared with negative control. Both R-80ME and L-80ME at 200 and 400 mg/kg significantly decreased the frequency of wet fecal outputs ( P < .01). Generally, 70.24% inhibition of the number of wet fecal output was recorded at R-80ME 400 mg/kg. Results from the charcoal meal test revealed that the R-80ME at 200 ( P < .01) and 400 mg/kg ( P < .001) produced a significant antimotility effect. In entero-pooling test, the R-80ME, at 200 and 400 mg/kg doses ( P < .01), showed a significant decline in both the volume and weight of intestinal contents. The maximum in vivo antidiarrheal index was determined to be 95.25 at dose of 400 mg/kg R-80ME. This study demonstrated that the 80ME, mainly the root extract, produced promising antidiarrheal activity and hence provides a scientific support for acclaimed traditional use of the plant material for treatment of diarrheal diseases.

Objective: Psidium guajava occurs worldwide in tropical and subtropical areas. It has been used to treat inflammation, diabetes, fever, hypertension and ulcers. However, its antidiarrheal and protein conservative activities still need to be investigated., Methods: Fifty-four male rats were divided into normal and diarrheal rats. The normal rats were divided into 4 groups: control, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg) and gallic acid. Treatments were administrated orally in 1 mL saline for a 1-month period. The diarrheal rats were divided into 5 groups: desmopressin (0.2 mg/kg) drug, low-dose P. guajava leaf extract (50 mg/kg), high-dose P. guajava leaf extract (100 mg/kg), gallic acid and an untreated control. Doses were given daily for a 1-month period while the untreated control received no treatment., Results: Diarrhea was responsible for an observed decline in kidney weight and serum sodium, potassium and chloride. Further, diarrhea was positively correlated with a significant increase in urine volume, and excretion of electrolytes, serum urea, creatinine and uric acid in the urine. In contrast, there was a proportional increase in the lipid peroxidation value in diarrhea and a significant decline was observed in serum superoxide dismutase, glutathione peroxidase and glutathione levels in diarrhea. Also, diarrhea inhibited blood proteins. The oral intake of P. guajava leaf extract by diarrheal rats restored all of these parameters to near normal levels. High-dose P. guajava leaf extract was more effective than the same compound at a low dose., Conclusion: P. guajava leaf extract elicited antidiarrheal and protein conservative effects., (Copyright © 2018 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

The leaf of Osyris quadripartita is traditionally used for the management of diarrhea in different parts of Ethiopia. However, its use has not been scientifically validated for its efficacy. The aim of this study was to investigate antidiarrheal activity of hydroalcoholic leaf extract of O. quadripartita in mice models. Different doses of the methanolic leaf extract of O. quadripartita (100, 200, and 400 mg/kg) were tested for antidiarrheal activity using castor oil-induced diarrhea, enteropooling, and gastrointestinal motility models in Swiss Albino mice. The activities of the extract at different doses were compared with standard drugs and negative control groups of mice. The extract at all tested doses resulted in significant reduction ( P < .01) in number of wet feces, whereas significant reduction ( P < .01) in frequency of defecation in castor oil-induced diarrhea was seen at a dose of 400 mg/kg. It also showed a dose-dependent and significant reduction of volume of intestinal content in the enteropooling model at all tested doses and the observed results in 200 and 400 mg/kg were better than the standard drug, loperamide. However, significant antimotility effect was not observed at any of the tested doses. From these results we can conclude that methanolic leaf extract of O. quadripartita showed antidiarrheal activity.

High-dose loperamide is often used for the acute management of chemotherapy-induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Daily intake ranged from 64 mg to 1600 mg, often continuously for weeks or months. In addition, the reported serum levels of loperamide ranged from 22 ng/mL to 210 ng/mL, which is likely significantly higher than that expected from patients taking the recommended doses for chemotherapy-induced diarrhea. Overall, the incidence of serious cardiac events associated with loperamide remains low. In balance, the risk of uncontrolled complications from chemotherapy-induced diarrhea is likely greater than the rare cardiac risk associated with the chronic misuse of much higher doses of loperamide.

Radial artery occlusion (RAO) occurs in 2% to 18% of patients after transradial access (TRA) cardiac catheterization. Using a kaolin-filled pad (QuikClot) reduces compression time during TRA and might reduce RAO. We examined the RAO risk with the kaolin-filled pad after TRA cardiac catheterization.This was a prospective cross-sectional study of 260 patients who underwent TRA cardiac catheterization in a cardiac ward of a Medical Center from 2012 to 2016. Patients were randomly assigned to 1 of 2 groups: the case group (n = 130) was postoperatively treated with a kaolin-filled pad, and the control group (n = 130) was treated with conventional hemostasis. Color duplex ultrasound was used to evaluate the 24-hour and 1-month postoperative radial artery flow velocity, diameter, patency, and RAO risk.RAO risk was not significantly different between the case and control groups after 24 hours (4.6% vs 5.4%, P = .776) or after 1 month (5.4% vs 6.1%, P = .789), regardless of whether it was a first TRA cardiac catheterization (after 24 hours [P = .153] or after 1month [P = .617], respectively) or a repeated TRA cardiac catheterization (after 24 hours [P = .754] or after 1month [P = .753], respectively).Using a kaolin-filled pad after TRA cardiac catheterization did not significantly reduce RAO risk compared with conventional hemostasis.

Background Syzygium guineense (Myrtaceae) has been used in traditional medicine against various ailments, including diarrhoea. This study was conducted to scientifically evaluate the antidiarrheal effects of S. guineense extract and fractions. Methods An ethanol extract of S. guineense leaves was prepared and tested for its effect on small intestinal propulsion in mice and castor oil-induced fluid accumulation in rats. The extract was also evaluated for its effect on itopride-induced small intestine propulsion in mice. Column fractions were also investigated in rats and sub-fractions were tested for activity on spontaneous contractions of isolated rabbit jejunum. Results The results showed that the extract significantly (p<0.05) inhibited intrinsic small intestinal propulsion and itopride-induced propulsive activity, similar to atropine (0.3 mg/kg) although its inhibitory effect against castor oil-induced intestinal fluid accumulation and diarrhoea was statistically insignificant (p>0.05). Column separation yielded 14 fractions, with three fractions producing significant (p<0.001) inhibition of small intestinal propulsion. Sub-fractions 1, 7 and 16 obtained from an active column fraction also exhibited relaxant effects on isolated rabbit jejunum. Spectral analysis (proton, 13C NMR) of sub-fractions 7 and 16 revealed the presence of betulinic acid, ursolic acid, oleanolic acid in 7 and a mixture of luteolin and friedelane-type triterpenes in 16. Conclusions These findings provide scientific evidence that S. guineense leaf extract possess antidiarrhoeal activity and may be potentially beneficial in treatment diarrhoeal disease. The identified compounds may also be implicated in its antidiarrhoeal effects.

Preclinical studies indicate that an optimal diet during pelvic radiotherapy may be able to prevent radiation-induced survivorship diseases that diminish cancer survivors' intestinal health. We do not yet know what this optimal diet might be because scientific studies needed to determine what dietary advice might best be given to patients during treatment. Oncology clinics in Sweden were contacted to determine the nature of dietary advice given to gynaecological and prostate cancer patients at each clinic before, during and after radiotherapy. Reports from these clinics revealed that dietary advice given to patients differs from one clinic to another. This was as expected, since it was known that the scientific evidence needed to identify the best possible diet is not yet available. Clinical studies of the effects of different diets are urgently needed if we are to prevent survivorship diseases that decrease intestinal health.

Background: AG is the most common cause of pediatric consultations among children between 2 and 5 years of age and it still leads to high mortality and morbidity. Its management is based on rehydration therapy, but this treatment is not effective in reducing duration of diarrhea. For this reason, other safer and less expensive interventions, which could be added to oral rehydration therapy, are of great interest., Methods: A pilot, randomized, case-controlled trial was conducted in 60 children affected by AG (< 7 days) with mild-moderate dehydration, according to WHO recommendations, from1 year to 17 years old. Patients were divided into 2 Groups: Group 1 consisting of 30 children treated with Actitan F and standard oral rehydration (SOR); Group 2 consisting of 30 children who received only SOR. Both groups received treatment for seven days, respectively. Patients of Group 1 stopped for their own choice, SOR after the first 24 h and continued only with Actitan F., Results: After 24 h of treatment, the median number of stools was 3.5 for Group 1, and 4 for Group 2. In Group 1 the difference between the number of stools at baseline (n = 5) and after 24 h of treatment (n = 3.5) was significant (p < 0.0001). At the end of treatment, the median duration of diarrhea in Group 1 was 5 days, compared with 4 days in the Group 2, this difference was not statically significant (p 0.48)., Conclusions: Oral administration of Actitan F associated with SOR seems safe and effective treatment in shortening the duration of AG in children. Further studies confirming these data are needed., Trial Registration: NCT03356327 (retrospectively registered).

Background: Diarrheal illnesses in young children cause morbidity and preventable deaths in developing countries. We evaluated two high doses of Salovum® [Antisecretory Factor] to treat diarrhea in young children and followed up for recurrence 6 weeks post treatment., Methods: Forty children, 6-24 months old, admitted with acute diarrhea, to the Outpatient Department of Children's Hospital in Lahore, Pakistan were selected. The patients were randomly allocated to either Group A given 2 sachets, or to Group B, given 4 sachets. Each sachet contained 4gram of Salovum® and was mixed with Oral Rehydration Salt solution. This mixture was administered perorally within the first 30min of treatment. The trained nursing staff observed them for number of stools and consistency over every half hour for a total of 4hours. Follow up for 6 weeks was done daily by telephone, or visits by the mothers. The results demonstrate that Salovum provides a protective effect irrespective of the diarrhea causes., Results: Group B, given 4 sachets of Salovum® showed improved fecal consistency in 80% of the children compared to 50% in Group A within 30minutes of treatment, p=0.004. The number of diarrheal stools decreased over this time from seven to one/two over 4hours in the two groups [p=0.234]. None of the children showed a recurrence of diarrhea over the follow up period., Conclusion: Peroral high doses of Salovum® rapidly and safely counteract diarrhea in children followed by a diarrhea-free period of 6 weeks., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Constipation has a significant influence on quality of life. Patients with constipation have slow waves in their gastrointestinal smooth muscles and less faecal water contents, which are closely associated with down-regulation of the interstitial cells of Cajal (ICC) in the gastrointestinal muscles and the aquaporin protein AQP3 expressed in colon epithelial cells. Recent studies supported that patients with constipation have altered intestinal microbial structures compared with healthy controls. Intestinal dysbiosis might be one possible pathophysiological mechanism causing constipation. Bacterial strains, such as Lactobacillus spp., have shown many beneficial effects on the amelioration of constipation. However, few studies reported the structural changes of intestinal microbiota post-intervention of probiotics. In this study, a bacterial mixture was administrated to rats with loperamide-induced constipation. Effects of the bacterial mixture on small intestine transit (SIT), faecal water content, and the intestinal microbiome in rats were evaluated. Meanwhile, we investigated several factors involved in signalling pathways that regulate function of ICC and expression of AQP3 to discuss the possible underlying molecular mechanisms. Intervention of the bacterial mixture improved SIT and faecal water content in constipated rats. The up-regulation of C-kit/SP signalling pathways in ICC and AQP3 significantly contributed to improvements. These changes were closely associated with the manipulation of intestinal dysbiosis in constipated rats. Furthermore, our results revealed the important role of intestinal microbiota in affecting gut motility through regulation of serotonin biosynthesis. This monoamine neurotransmitter, secreted from enterochromaffin cells, up-regulated both substance P/neurokinin 1 receptors pathway of ICC and the expression of AQP3 in intestinal epithelial cells. Our study suggested that the disrupted microbiome in patients could be a potential therapeutic target for the improvement of constipation.

Ingestion of Bacillus subtilis C-3102 spores (C-3102) has relieved the symptoms of diarrhoea in piglets and changed the composition of gut microbiota in humans. Recently, it was suggested that the composition of the human gut microbiota affects stool consistency. In this study, a double-blind, randomised, placebo-controlled trial was conducted to assess the preventive effects of chronic diarrhoea in healthy volunteers with loose stools by ingestion of C-3102. The results showed that oral doses of C-3102 tablets significantly decreased the Bristol Stool Scale score and stool frequency, and also significantly improved abdominal sounds. With regard to gut microbiota, the relative abundance of Lachnospira, Actinomyces and SMB53 were significantly changed. This study shows that C-3102 could be effective for treating loose stools (Trial registration: UMIN000022583, http://tinyurl.com/ya4refqn ).

Introduction: Diarrhea is a serious public health problem in Mexico and other countries. An alternative widely used in the treatment of diarrhea is the use of medicinal herbs. Infusions of chamomile and star anise, which have anti-inflammatory and antimotility properties, could help alleviate gastrointestinal disorders., Objective: The objective of this study was to determine the effect of the mixture of infusions of star anise and chamomile on the gastrointestinal activity in mice., Material and Method: Ten groups were formed with 10 mice per group. The percentage of advance of the activated charcoal administered through the intestine of the animals was evaluated. The model of diarrhea was induced with castor oil. The infusions were prepared using a mixture with a 50:50 ratio of the herbs, and were administered in a mixture of 10, 20, 40 and 80 mg/kg orally., Results: The results indicate that mixtures 40 and 80 decreased the percentage of advance of activated charcoal, delayed the onset of diarrhea and decreased the number of evacuations compared to the control group., Conclusions: The study suggests that the combination of chamomile and star anise can be used as an alternative antidiarrheal treatment., (Copyright: © 2018 SecretarÍa de Salud.)

The water-soluble protein fraction obtained from Plumeria pudica (LPPp) latex has previously been demonstrated to have anti-inflammatory and antinociceptive effects. In the present study, LPPp was tested for activity against diarrhea induced by castor oil, prostaglandin E 2 (PGE 2 ) or cholera toxin. Different doses of LPPp (10, 20 or 40mg/kg) significantly inhibited the percentage of diarrheal stools (31.18%, 42.97% and 59.70%, respectively) induced by castor oil. This event was followed by significant reduction of both intestinal fluid accumulation (31.42%; LPPp 40mg/kg) and intestinal transit (68.4%; LPPp 40mg/kg). The pretreatment of animals with LPPp (40mg/kg) prevented glutathione and malondialdehyde alterations induced by castor oil. The effects of LPPp against diarrhea induced by castor oil were lost when the fraction was submitted to protein denaturing treatment with heat. LPPp (40mg/kg) also inhibited the average volume of intestinal fluid induced by PGE 2 (inhibition of 46.0%). Furthermore, LPPp (40mg/kg) prevented intestinal fluid secretion accumulation (37.7%) and chloride ion concentration (50.2%) induced by cholera toxin. In parallel, colorimetric assays demonstrated that proteinases, chitinases and proteinase inhibitors were found in LPPp. Our data suggest that the antidiarrheal effect of LPPp is due to its protein content and is probably associated with its anti-inflammatory properties., (Copyright © 2017. Published by Elsevier Masson SAS.)

Objective: Standard triple therapy for Helicobacter pylori has a low eradication rate in Turkey. The aim of this study was to evaluate and compare the effectiveness of 7-day and 14-day lansoprazole, amoxicillin, clarithromycin, and bismuth subsalicylate (LACB) treatment regimens as first-line H. pylori eradication therapies., Materials and Methods: This study included 70 patients with symptoms of dyspepsia and a positive H. pylori stool antigen test (SAT). Thirty-five patients received the modified quadruple therapy regimen for 7 days (LACB-7) whereas the remaining 35 patients received the treatment for 14 days (LACB-14). Eradication was assessed by SAT 1 month after the end of therapy., Results: A total of 64 patients completed the therapy. The cumulative per-protocol (PP) and intention-to-treat (ITT) eradication rates were 89% (n = 57/64) and 81.4% (n = 57/70), respectively. Both the PP and ITT eradication rates were superior in the LACB-14 group, compared with the LACB-7 group (PP: 90.6% vs. 87.5%; ITT: 81.4% vs. 80%, respectively), but these differences were not statistically significant (P = 0.689)., Conclusions: Both the 7-day and 14-day first-line LACB therapies provided a high cure rate, were well tolerated, and were equally effective against H. pylori infection in Turkey.

Background: Fever case management is a major challenge for improved child health globally, despite existence of cheap and effective child survival health technologies. The integrated Community Case Management (iCCM) intervention of paediatric febrile illnesses though adopted by Uganda's Ministry of Health to be implemented by community health workers, has not addressed the inaccess to life-saving medicines and diagnostics. Therefore, the iCCM intervention was implemented in private drug shops and evaluated for its effect on appropriate treatment of paediatric fever in a low malaria transmission setting in South Western Uganda., Methods: From June 2013 to September 2015, the effect of the iCCM intervention on drug seller paediatric fever management and adherence to iCCM guidelines was assessed in a quasi-experimental study in South Western Uganda. A total of 212 care-seeker exit interviews were done before and 285 after in the intervention arm as compared to 216 before and 268 care-seeker interviews at the end of the study period in the comparison arm. The intervention effect was assessed by difference-in-difference analysis of drug seller treatment practices against national treatment recommendations between the intervention and comparison arms. Observed proportions among care-seeker interviews were compared with corresponding proportions from 5795 child visits recorded in patient registries and 49 direct observations of drug seller-care-seeker encounters in intervention drug shops., Results: The iCCM intervention increased the appropriate treatment of uncomplicated malaria, pneumonia symptoms and non-bloody diarrhoea by 80.2% (95% CI 53.2-107.2), 65.5% (95% CI 51.6-79.4) and 31.4% (95% CI 1.6-61.2), respectively. Within the intervention arm, drug seller scores on appropriate treatment for pneumonia symptoms and diagnostic test use were the same among care-seeker exit interviews and direct observation. A linear trend (negative slope, - 0.009 p value < 0.001) was observed for proportions of child cases prescribed any antimicrobial medicine in the intervention arm drug shops., Conclusions: The iCCM intervention improved appropriate treatment for uncomplicated malaria, pneumonia symptoms and diarrhoea. Drug seller adherence to iCCM guidelines was high, without causing excessive prescription of antimicrobial medicines in this study. Further research should assess whether this effect is sustained over time and under routine supervision models.

Introduction: Several research studies have reported on the pharmacological relevance of the medicinal plants used for treating various gastrointestinal disorders and controlling the dietary glucose uptake in the intestinal tract., Methods: Male rats were used to investigate the pharmacological effects of green oak acorn aqueous extract (GOAE) on gastrointestinal physiological parameters in vivo and in vitro. In this respect, the gastro-intestinal motility and hypersecretion essays were evaluated using a simple test meal (10% charcoal in 5% gum arabic) and castor oil induced diarrhea. However, the effect of GOAE on glucose absorption and homeostasis was assessed by the Ussing chamber system and oral glucose tolerance test (OGTT) measures., Results: Various doses of the Quercus ilex aqueous extract (125, 250 and 500mgkg -1 ) administered orally produced a significantly dose-related inhibition of gut meal travel distance in normal rat. The highest intestinal transit reduction of 49.34% was obtained with 500mgkg -1 compared to 58.33% caused by reference drug (clonidine, 1mgkg -1 ). In castor oil induced diarrhea in rat, Q. ilex extract reduced the frequency of defecation, fluid accumulation and electrolyte transport. These effects were associated with decreased histopathological damage and regulation of intracellular mediators disturbance in the intestinal mucosa. In addition, GOAE treatment improved glucose tolerance and significantly and dose-dependently reduced (>50%) the glucose absorption via intestinal epithelium. Phytochemical screening revealed the presence of many bioactive natural compounds., Conclusion: These results suggest that the extract was effective towards reducing diarrhea, fluid accumulation, electrolyte transport and glucose absorption, and no toxic effects of the GOAE presented on this study., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Travelers' diarrhea is a frequent condition, especially in those traveling to high-risk areas. Although antibiotic treatment reduces the duration of diarrhea, it has been suggested adding loperamide could further reduce the symptoms. To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified two systematic reviews including 28 studies overall, of which 15 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalysed data of primary studies and generated a summary of findings table using the GRADE approach. We concluded adding loperamide to antibiotic treatment might accelerate resolution of symptoms in traveler’s diarrhea with minimal or no adverse effects.

Background: Severe cholera is a life-threatening illness of hypovolemic shock and metabolic acidosis due to rapid and profuse diarrheal fluid loss. Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis. After this initial rehydration, for the next 2 days ongoing stool losses are replaced with oral rehydration solution (ORS), which contains sodium chloride, potassium and alkali together with glucose or rice powder as a source of glucose to serve as a carrier for sodium., Results: In actual field trials, antibiotics are given to reduce fluid requirements, but large volumes averaging about 7 liters of i.v. fluid followed by about 14 liters of ORS have been given to adult patients. Disturbing trends during therapy have included overhydration, hyponatremia and polyuria., Conclusions: It is suggested that stool output and fluid requirements could be reduced, if borne out in future research, by avoiding overhydration by restricting ORS intake to match stool output and promoting intestinal reabsorption of luminal fluid by early introduction of glucose without salts into the intestine, more gradual correction of dehydration, giving mineralocorticoid and vasopressin, and infusing glucose or short-chain fatty acids into the proximal colon., (© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study investigated the use of a newly developed chitosan-Ca pectinate microbead formulation for the colon-targeted delivery of anti-A/B toxin immunoglobulin of egg yolk (IgY) to inhibit toxin binding to colon mucosa cells. The effect of the three components (pectinate, calcium chloride, and chitosan) used for the microbead production was examined with the aim of identifying the optimal levels to improve drug encapsulation efficiency, swelling ratio, and cumulative IgY release rate. The optimized IgY-loaded bead component was pectin 5% (w/v), CaCl 2 3% (w/v), and chitosan 0.5% (w/v). Formulated beads were spherical with 1.2-mm diameter, and the drug loading was 45%. An in vitro release study revealed that chitosan-Ca pectinate microbeads inhibited IgY release in the upper gastrointestinal tract and significantly improved the site-specific release of IgY in the colon. An in vivo rat study demonstrated that 72.6% of biologically active IgY was released specifically in the colon. These results demonstrated that anti-A/B toxin IgY-loaded chitosan-Ca pectinate oral microbeads improved IgY release behavior in vivo, which could be used as an effective oral delivery platform for the biological treatment of Clostridium difficile infection (CDI).

Norovirus is a common self-limiting gastrointestinal infection, but in transplant recipients, symptoms can last for months and result in serious health complications. As there is currently no established treatment for chronic norovirus infection in transplant patients, management has been directed at symptom control, trial of various antivirals, and ultimately reductions in immunosuppression. We present 3 cases of chronic norovirus infection in cardiac transplant patients to illustrate various approaches to diagnosis, the prolonged nature of disease symptoms, and treatment options. When managing a transplant recipient with chronic diarrhea, considering a broad differential as well as maintaining a high suspicion for infectious etiologies is key. A stepwise approach to management includes termination of diarrhea-causing medications, trials of nitazoxanide and immunoglobulin, and reductions in immunosuppressive therapies. Although brief discontinuation of immunosuppression is often required to achieve symptom, graft rejection is often a complication.

Study Objective: With the increasing amount of information available on the Internet describing techniques for using loperamide either for self-treatment of opioid withdrawal syndromes or for recreational use (so-called legal highs), the objective was to describe a statewide poison control system's experience with loperamide misuse and abuse, with specific interest in cases of cardiotoxicity, and to determine if reported loperamide misuse or abuse cases have recently increased., Design: Retrospective review., Data Source: Statewide poison control system electronic database., Patients: A total of 224 adults who presented or were referred to a health care facility between January 1, 2002, and November 10, 2015, for intentional ingestions of loperamide, and whose cases were reported to the poison control system by either physicians or nurses at the bedside., Measurements and Main Results: Between 2002 and 2013, the number of yearly calls to the poison control system regarding loperamide cases ranged from 12-19 (mean 16.4, median 17.5 calls). In 2014, a sharp increase to 41 calls was noted. On completion of the study (November 10, 2015), 27 calls had been recorded. Medical outcomes of loperamide exposure for each patient were classified in accordance with the American Association of Poison Control Center's classification system as minor, moderate, or severe. For those patients with known outcomes, 3 resulted in death, 9 had major effects, 49 had moderate effects, and 36 had minor effects. We identified nine reports of patients who developed cardiotoxicity, with eight of them occurring between 2012 and 2015. A spike in the number of cases of loperamide toxicity reported in 2014 and 2015 coincided with an abundance of online instructions on how to abuse this drug. Almost all cases of recorded cardiotoxicity occurred over the last 3 years. Cardiotoxicity from loperamide abuse has only recently been recognized as a potential complication during the last few years, so earlier cases of cardiotoxicity resulting from loperamide abuse were likely missed., Conclusion: Our data suggest that loperamide may be increasing in popularity as a drug of abuse and for treatment of opioid withdrawal symptoms. Given the potential for significant toxicity with loperamide exposure, including life-threatening cardiac dysrhythmias, clinicians should consider obtaining a screening electrocardiogram for patients presenting after acute or chronic high-dose ingestions of loperamide. In addition, increased control over the availability of loperamide may be warranted., (© 2016 Pharmacotherapy Publications, Inc.)

Objective: To compare the effectiveness of zinc supplementation in tablet form with that of the suspension form in the treatment of acute diarrhoea., Methods: A comparative study was carried out at the Liaquat University Hospital, Hyderabad, Pakistan from October 2008 to April 2009, and comprised children aged6-24 months suffering from acute diarrhoea. The patients were divided into two groups on the basis of even and odd numbers. Group A (even numbers) received dispersible zinc tablets, and group B (odd numbers) received zinc suspension. The patients were admitted for 3 days and improvement was checked at the end of 3rd day in terms of decrease in the frequency of stools/day. SPSS 15 was used for data analysis., Results: The 88 patients were divided into two groups of 44(50%) each. Overall, 49(55.7%) patients were male and 39(44.3%) were female. At the end of the 3rd day 51(58%) patients improved, while 37(42%) did not. In the zinc tablet group, improvement was in 32(72%) patients compared to 19(43%) in the zinc suspension group (p<0.05).diarrhoea., Conclusions: The results of tablets preparation were clinically significant in reducing the duration and severity of diarrhoea.

Background: In Shaanxi province, China, the aqueous extract of Rubia cordifolia's aerial part (AERCAP) is traditionally used to manage diarrhea. However, there is no scientific evidence to verify the safety and efficacy of its use. The aim of this study was to investigate the anti-diarrheal and anti-inflammatory effects of AERCAP by using a rodent model., Methods: The anti-diarrheal effects were studied by senna leaf-induced diarrheal and intestinal transit experiments in mice. The anti-inflammatory activity was investigated by trinitrobenzenesulfonic acid (TNBS)-induced colonic inflammation in rats., Results: The results indicated that AERCAP delayed the onset of semi-solid feces, reduced the evacuation index (EI) in senna leaf-induced diarrheal in mice, and inhibited the propulsive movement in castor oil-induced intestinal transit but not in the normal intestinal transit test. The results were compared with the standard anti-diarrheal drug loperamide. Additionally, oral treatment with AERCAP significantly decreased the macroscopic damage area, improved the microscopic structure, and reduced the malondialdehyde (MDA) content, IL-1β and TNF-α levels in colonic tissue compared with the TNBS control group in rats., Conclusions: AERCAP exhibited anti-diarrheal and anti-inflammatory activities in a rodent model. The study validated the traditional use of the plant in Chinese herbal medicine as a valuable natural remedy for the treatment of diarrhea.