Search

Loperamide is an over‐the‐counter peripheral mu‐opioid agonist commonly used to manage diarrhoea. When taken in an excessive dose, loperamide's penetration of the central nervous system increases, leading to euphoria, respiratory depression and other opioid effects. A health warning was released in the United States in 2016 with increased reports of excessive loperamide use leading to cardiac conduction abnormalities such as ventricular tachycardia, prolonged QTc and Torsades des Pointes. The growing number of cases is likely due to the increased restrictions on other opioids. Loperamide use disorder has been managed effectively in the United States and the United Kingdom using buprenorphine. In Australia, there have been recent opioid restrictions limiting easy access to opioids. We describe the case of a 28‐year‐old male who was admitted to hospital on multiple occasions with symptoms relating to loperamide use disorder. Buprenorphine was used to manage withdrawal symptoms in the hospital and maintain abstinence from loperamide in the community through an opioid agonist treatment program. To our knowledge, this is the first case study to describe the successful management of loperamide use disorder with buprenorphine within Australia. Our findings suggest that buprenorphine can be used to manage patients with loperamide associated withdrawal and help them remain abstinent upon discharge. Extramedical use of over‐the‐counter opioid medication may be becoming an emerging trend in Australia, and increased monitoring is warranted to prevent detrimental health outcomes. [ABSTRACT FROM AUTHOR]

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 Cmax) 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. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the impact of lactitol on constipation caused by loperamide in Sprague Dawley rats, with a particular emphasis on its underlying mechanisms and potential health advantages. The lactitol effectively improved fecal parameters, intestinal tissue structure, and the expression of constipation-related gene expression and proteins. Lactitol alleviated fecal weight and water content altered by loperamide and enhanced gastrointestinal transit. The administration also restored mucosal and muscular layer thickness. Mechanistically, lactitol upregulated the mRNA expression and/or protein levels of mucins (MUC2 and MUC4), occludin, claudin-1, and zonula occludens, indicating improved intestinal barrier function. Lactitol positively regulated the composition of cecal microbiota, leading to an increased relative abundance of Bifidobacterium, Lactobacillus, and Romboutsia. Conversely, lactitol decreased the relative abundance of Prevotella, Aerococcus, Muribaculum, Blautia, and Ruminococcus. This study demonstrated the potential of lactitol to relieve constipation by modulating the gut microbiota. These findings suggest that lactitol is an alternative to traditional laxatives and has potential as a health-promoting food sweetener. [ABSTRACT FROM AUTHOR]

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells. The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma. With the increasing knowledge of host–pathogen interactions, especially bacterial strategies for survival and proliferation within host cells, host-directed therapy (HDT) has attracted increased interest and has emerged as a promising anti-infection method for treating intracellular infection. Herein, we applied a cell-based screening approach to a US Food and Drug Administration (FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium (S. Typhimurium). This screening allowed us to identify the antidiarrheal agent loperamide (LPD) as a potent inhibitor of S. Typhimurium intracellular proliferation. LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity. A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) induced by LPD. In addition, LPD treatment effectively protected against S. Typhimurium infection in Galleria mellonella and mouse models. Thus, our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens. Moreover, LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

NMDAR (N-methyl-D-aspartate receptor) antagonist and opioid agonist can induce psychosis in rodents and humans. Loperamide hydrochloride (LH) possesses NMDAR antagonistic and opioid agonistic property but associated with more peripheral effects and limited blood brain barrier (BBB) penetration. So, it is essential to make its nanoformulation to increase BBB penetration and reduce peripheral effects. Thus, this study aimed to develop of LH encapsulated tween 80 coated chitosan nanoformulations and to optimize the formulations for targeting into brain. 32 full factorial design was performed to optimize the preparation to enhance the entrapment of the drug and reduce the particle size of all batches were between 189–278 nm and 80.16–89.38%, respectively. Pure drug LH (1 mg/kg, p.o) and LH loaded tween 80 coating chitosan nanoparticles (LCNP) (dose equal to 1 mg/kg LH, p.o.) were administrated in different group of animals to produce psychosis like behaviors in terms of stereotypic behaviors, hyper-locomotors activity, immobility and increased step down latency. LH and LCNP were administered orally for 15 successive days and behavioral, biochemical and histopathological alterations were studies. In mice, LCNP administration showed to induced behavioral changes similar to psychotic symptoms. However, administration of LH didn't shows significant effect in cognitive symptom. Moreover, LCNP significantly decreased GSH and GABA level and increased MDA. Histopathologically, LCNP was significant to produce perinuclear vacuolization and hyperchromatic nuclei in the brain cortex, which indicates its damaging effects on brain. Thus, the surface modified NPs (LCNP) enhanced the penetration efficacy of LH. These studies revealed that LCNP could be effective chemical model to induce psychosis with good face, predictive and construct validity. [ABSTRACT FROM AUTHOR]

Background: Loperamide is an over-the-counter anti-diarrheal mu-opioid analogue that has appeared more frequently in emergency department patients in excessive doses to mitigate opioid cravings and withdrawal symptoms. Given the concern for its abuse potential and serious cardiotoxicity at high doses, we aimed to describe the cardiac effects in patients with loperamide ingestions reported to the Texas Poison Center Network (TPCN). Methods: Single agent loperamide ingestions for all ages were extracted from the TPCN database from 2004 to 2021. We defined exposure reasons and medical outcomes according to the America's Poison Centers classification system. Results: The TPCN recorded 1,421 single agent loperamide ingestions during this period, with a mean of 79 ingestions annually. Most cases (n=931, 65.5%) occurred in children under six years of age and were evenly split between males and females. Most cases were unintentional (n=904, 64.0%), while 12.7% (n=181) were for abuse, misuse, and suspected suicide. Most cases (72.6%) experienced no or minimal effects. Cardiac events occurred in 33 patients (2.3%) and included tachycardia (n=19, 57.6%), bradycardia (n=10, 30.3%), ventricular tachycardia (n=8, 24.2%), conduction disturbance (n=7, 21.2%), asystole (n=2, 6.1%), and cardiac arrest (n=4, 12.1%). Three of the four cardiac arrest cases were for "suspected suicide," "intentional abuse," and "unknown intent," while the fourth was "unknown relation to the exposure." Most (n=25, 75.8%) cases with a cardiac event were intentional exposures. Conclusions: Most single agent loperamide ingestions reported to the TPCN were unintentional and occurred in patients under six years of age. A portion of patients experienced multiple cardiac events (conduction disturbances, dysrhythmias, and cardiac arrests) related to loperamide ingestions. [ABSTRACT FROM AUTHOR]

BackgroundIt is well known that opiates slow gastrointestinal (GI) transit, via suppression of enteric cholinergic neurotransmission throughout the GI tract, particularly the large intestine where constipation is commonly induced. It is not clear whether there is uniform suppression of enteric neurotransmission and colonic motility across the full length of the colon. Here, we investigated whether regional changes in colonic motility occur using the peripherally-restricted mu opioid agonist, loperamide to inhibit colonic motor complexes (CMCs) in isolated mouse colon.MethodsHigh-resolution video imaging was performed to monitor colonic wall diameter on isolated whole mouse colon. Regional changes in the effects of loperamide on the pattern generator underlying cyclical CMCs and their propagation across the full length of large intestine were determined.ResultsThe sensitivity of CMCs to loperamide across the length of colon varied significantly. Although there was a dose-dependent inhibition of CMCs with increasing concentrations of loperamide (10 nM - 1 μM), a major observation was that in the mid and distal colon, CMCs were abolished at low doses of loperamide (100 nM), while in the proximal colon, CMCs persisted at the same low concentration, albeit at a significantly slower frequency. Propagation velocity of CMCs was significantly reduced by 46%. The inhibitory effects of loperamide on CMCs were reversed by naloxone (1 μM). Naloxone alone did not change ongoing CMC characteristics.DiscussionThe results show pronounced differences in the inhibitory action of loperamide across the length of large intestine. The most potent effect of loperamide to retard colonic transit occurred between the proximal colon and mid/distal regions of colon. One of the possibilities as to why this occurs is because the greatest density of mu opioid receptors are located on interneurons responsible for neuro-neuronal transmission underlying CMCs propagation between the proximal and mid/distal colon. The absence of effect of naloxone alone on CMC characteristics suggest that the mu opioid receptor has little ongoing constitutive activity under our recording conditions.

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.ClinicaltrialsGov registration numberNCT02400476.

Akeberegn Gorems Ayele, Jeylan Sinba Kawet Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Akeberegn Gorems Ayele, Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Zambia Street, PO Box 9086, Addis Ababa, Ethiopia, Tel +251985408322, Email Akeberegn.gorems@aau.edu.etBackground: People frequently complain of long-term constipation. The cost associated with using modern medications to treat constipation is significant, and the probability of encountering side effects is notably high. These limitations restrict their effectiveness in therapy, remain unresolved, and underscore the need for research on alternative therapeutic approaches. Plants of the genus Artemisia have been used to treat constipation. Therefore, the aim of this study was to evaluate the laxative effects of aqueous A. abyssinica leaf and stem extracts of Artemisia abyssinica in mice.Methods: The laxative activity of A. abyssinica leaf and stem extracts was evaluated using three models: laxative activity, gastrointestinal motility, and gastrointestinal secretion. In this study, bisacodyl was used as a standard laxative and loperamide was used to induce constipation.Results: In the laxative test, 200 (P< 0.05) and 400 mg/kg (p< 0.01) doses of plant extract significantly increased the percentage of fecal water content. Moreover, the highest dose of extract increased the frequency of defecation after 12 h (p< 0.05). In the remaining two models, the experimental plans also showed significantly higher gastrointestinal motility and noticeable accumulation of intestinal fluid.Conclusion: The results of this study indicate that aqueous leaf and stem extracts of A. abyssinica have laxative effects.Keywords: laxative, constipation, Artemisia abyssinica, castor oil, loperamide

Constipation, a prevalent gastrointestinal disorder characterized by infrequent bowel movements and associated abdominal discomfort, poses a significant health concern. This study aimed to investigate the pharmacological impact and molecular mechanism of fermented rice extract (FRE). FRE significantly increased fecal number, fecal water content and gastrointestinal transit rate in loperamide-mediated rats. Abnormalities in morphology of colon tissues, along with alterations in antioxidant contents were markedly reversed by FRE. Furthermore, the treatment of constipated rats with FRE accelerated intestinal motility, fortified gut barrier protection, and improved water and salt metabolism in the intestinal tract. Additionally, FRE robustly attenuated inflammation expression, along with suppressing MAPKs phosphorylation in colon tissues of rats. In conclusion, FRE treatment alleviated loperamide-induced constipation by reducing intestinal transit time, modulating oxidative stress and mitigating inflammatory responses. This study underscores FRE as a promising candidate for the management of constipation, emphasizing its potential in regulating oxidative stress, and inflammatory pathways.

Easy access to over-the-counter (OTC) drugs makes it possible to procure active substances that normally used in therapeutic doses do not raise health problems. The use of high doses of OTC drugs containing codeine, loperamide, pseudoephedrine, diphenhydramine or dimenhydrinate, as well as the use of benzidamine systemically raises concerns regarding the increase in units sold. These drugs are used for recreational or euphorizing purposes, including by young women of childbearing age, psychoactive substance users representing a risk group in terms of the possibility of an unplanned pregnancy. Abusive consumption of OTC products during pregnancy is harmful, with consequences for both fetal and late development that can occur in the infant. This literature review presents the risks (teratogenicity, fetal toxicity, neonatal abstinence syndrome, etc.) associated with the use of potentially psychoactive OTC drugs to emphasize the importance of re-evaluating OTC classification and dispensing. [ABSTRACT FROM AUTHOR]

There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis. We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment. 162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P =.66, χ2 test). The difference in proportion was 2.4% (95% CI: –8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P =.028) The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects. [ABSTRACT FROM AUTHOR]

Constipation is a disorder of the gastrointestinal (GI) and some of the main etiological mechanisms are directly related to changes in GI physiology. The capacity to carry out paired assessments and measure GI parameters under the influence of constipation is a relevant point in selecting a suitable methodology. We aimed to perform a non-invasive investigation of gastrointestinal motility in constipated rats using the alternating current biosusceptometry system (ACB). The animals were split into two groups: the pre-induction stage (CONTROL) and post-induction loperamide stage (LOP). We assessed GI motility parameters using the ACB system. Colon morphometric and immunohistochemical analyses were performed for biomarkers (C-kit) for interstitial cells of Cajal (ICC). Our results showed a significant increase in gastrointestinal transit in the LOP group in addition to a reduction in the dominant frequency of gastric contraction and an arrhythmic profile. A change in colonic contractility profiles was observed, indicating colonic dysmotility in the LOP group. We found a reduction in the number of biomarkers for intestinal cells of Cajal (ICC) in the LOP group. The ACB system can evaluate transit irregularities and their degrees of severity, while also supporting research into novel, safer, and more efficient treatments for constipation.

Abstract Background Perturbations of animal-associated microbiomes from chemical stress can affect host physiology and health. While dysbiosis induced by antibiotic treatments and disease is well known, chemical, nonantibiotic drugs have recently been shown to induce changes in microbiome composition, warranting further exploration. Loperamide is an opioid-receptor agonist widely prescribed for treating acute diarrhea in humans. Loperamide is also used as a tool to study the impact of bowel dysfunction in animal models by inducing constipation, but its effect on host-associated microbiota is poorly characterized. Results We used conventional and gnotobiotic larval zebrafish models to show that in addition to host-specific effects, loperamide also has anti-bacterial activities that directly induce changes in microbiota diversity. This dysbiosis is due to changes in bacterial colonization, since gnotobiotic zebrafish mono-colonized with bacterial strains sensitive to loperamide are colonized up to 100-fold lower when treated with loperamide. Consistently, the bacterial diversity of gnotobiotic zebrafish colonized by a mix of 5 representative bacterial strains is affected by loperamide treatment. Conclusion Our results demonstrate that loperamide, in addition to host effects, also induces dysbiosis in a vertebrate model, highlighting that established treatments can have underlooked secondary effects on microbiota structure and function. This study further provides insights for future studies exploring how common medications directly induce changes in host-associated microbiota. Graphical Abstract Video Abstract

Abstract Background Intentional use of high doses of loperamide has been linked to serious cardiac toxicity. The objective of this study is to investigate the characteristics and trends of loperamide cases reported to United States (US) poison centers and to evaluate the changes in reported loperamide cases following US Food and Drug Administration (FDA) warnings, labeling requirements, and packaging restrictions for loperamide starting in 2016, with an emphasis on intentional exposures. Methods Data from the National Poison Data System were analyzed. Results There were 12,987 cases reported to US poison centers from 2010 to 2022, for which, loperamide was the most likely substance responsible for observed clinical effects. Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%). Eight percent (8.1%) of cases were admitted to a critical care unit and 5.0% were admitted to a non-critical care unit. Among cases with a serious medical outcome, most were associated with loperamide abuse (38.0%), intentional-misuse (15.7%), or suspected suicide (27.5%). The majority (60.0%; n = 33) of fatalities were related to abuse, followed by suspected suicide (20.0%; n = 11) and intentional-misuse (5.5%, n = 3). The rate of loperamide cases per 100,000 US population reported to US PCs decreased from 0.44 in 2010 to 0.36 in 2015 (p = 0.0290), followed by an increase to 0.46 in 2017 (p = 0.0013), and then a trend reversal with a decrease to 0.28 in 2022 (p

Siti Hamidatul Aliyah,1,2 Rizky Yulion,1 Santi Perawati1 1Department of Pharmacy, Sekolah Tinggi Ilmu Kesehatan Harapan Ibu Jambi, Jambi, Jambi Province, Indonesia; 2Centre for Biomedical Research, Research Organization for Health, National Research and Innovation Agency (BRIN), Cibinong Science Centre, Bogor, West Java, IndonesiaCorrespondence: Siti Hamidatul Aliyah, Department of Pharmacy, Sekolah Tinggi Ilmu Kesehatan Harapan Ibu Jambi, Jalan Tarmizi Kadir No. 71, Jambi, Jambi Province, Indonesia, Email sitihamidatula@stikes-hi.ac.id

Background: Intentional use of high doses of loperamide has been linked to serious cardiac toxicity. The objective of this study is to investigate the characteristics and trends of loperamide cases reported to United States (US) poison centers and to evaluate the changes in reported loperamide cases following US Food and Drug Administration (FDA) warnings, labeling requirements, and packaging restrictions for loperamide starting in 2016, with an emphasis on intentional exposures. Methods: Data from the National Poison Data System were analyzed. Results: There were 12,987 cases reported to US poison centers from 2010 to 2022, for which, loperamide was the most likely substance responsible for observed clinical effects. Although 46.1% of these cases were associated with minor or no effect, 13.4% resulted in a serious medical outcome, including 59 deaths (0.5%). Eight percent (8.1%) of cases were admitted to a critical care unit and 5.0% were admitted to a non-critical care unit. Among cases with a serious medical outcome, most were associated with loperamide abuse (38.0%), intentional-misuse (15.7%), or suspected suicide (27.5%). The majority (60.0%; n = 33) of fatalities were related to abuse, followed by suspected suicide (20.0%; n = 11) and intentional-misuse (5.5%, n = 3). The rate of loperamide cases per 100,000 US population reported to US PCs decreased from 0.44 in 2010 to 0.36 in 2015 (p = 0.0290), followed by an increase to 0.46 in 2017 (p = 0.0013), and then a trend reversal with a decrease to 0.28 in 2022 (p < 0.0001). The rate of serious medical outcomes related to loperamide increased from 0.03 in 2010 to 0.05 in 2015 (p = 0.0109), which subsequently increased rapidly to 0.11 in 2017 (p < 0.0001), and then demonstrated a trend reversal and decreased to 0.04 in 2022 (p < 0.0001). Conclusions: FDA warnings, labeling requirements, and packaging restrictions may have contributed to the observed trend reversal and decrease in reports to US poison centers of loperamide cases related to intentional misuse, abuse, and suspected suicide. This demonstrates the potential positive effect that regulatory actions may have on public health. These findings contribute to the evidence supporting the application of similar prevention efforts to reduce poisoning from other medications associated with intentional misuse, abuse, and suicide. [ABSTRACT FROM AUTHOR]

Background: Perturbations of animal-associated microbiomes from chemical stress can affect host physiology and health. While dysbiosis induced by antibiotic treatments and disease is well known, chemical, nonantibiotic drugs have recently been shown to induce changes in microbiome composition, warranting further exploration. Loperamide is an opioid-receptor agonist widely prescribed for treating acute diarrhea in humans. Loperamide is also used as a tool to study the impact of bowel dysfunction in animal models by inducing constipation, but its effect on host-associated microbiota is poorly characterized. Results: We used conventional and gnotobiotic larval zebrafish models to show that in addition to host-specific effects, loperamide also has anti-bacterial activities that directly induce changes in microbiota diversity. This dysbiosis is due to changes in bacterial colonization, since gnotobiotic zebrafish mono-colonized with bacterial strains sensitive to loperamide are colonized up to 100-fold lower when treated with loperamide. Consistently, the bacterial diversity of gnotobiotic zebrafish colonized by a mix of 5 representative bacterial strains is affected by loperamide treatment. Conclusion: Our results demonstrate that loperamide, in addition to host effects, also induces dysbiosis in a vertebrate model, highlighting that established treatments can have underlooked secondary effects on microbiota structure and function. This study further provides insights for future studies exploring how common medications directly induce changes in host-associated microbiota. D4g5o9n3n6ov6RfQVkBmi7 Video Abstract [ABSTRACT FROM AUTHOR]

Structural changes in the gut microbiota are closely related to the development of functional constipation, and regulating the gut microbiota can improve constipation. Rifaximin is a poorly absorbed antibiotic beneficial for regulating gut microbiota, but few studies have reported its effects on constipation. The purpose of this study was to investigate the effect of rifaximin on loperamide-induced constipation in SD rats. The results showed that rifaximin improved constipation by increasing serum 5-HT, SP, and the mRNA expression of AQP3, AQP8, and reducing the mRNA expression of TLR2 and TLR4. In addition, rifaximin could regulate the gut microbiota of constipated rats, such as increasing the potentially beneficial bacteria Akkermansia muciniphila and Lactobacillus murinus, reducing the Bifidobacterium pseudolongum. According to metabolomics analysis, many serum metabolites, including bile acids and steroids, were changed in constipated rats and were recovered via rifaximin intervention. In conclusion, rifaximin might improve loperamide-induced constipation in rats by increasing serum excitatory neurotransmitters and neuropeptides, modulating water metabolism, and facilitating intestinal inflammation. Muti-Omics analysis results showed that rifaximin has beneficial regulatory effects on the gut microbiota and serum metabolites in constipated rats, which might play critical roles in alleviating constipation. This study suggests that rifaximin might be a potential strategy for treating constipation. [ABSTRACT FROM AUTHOR]

Background: Liver disease is any disease that negatively affects the normal function of the liver, and it is a major health problem that challenges not only healthcare professionals, but also the pharmaceutical industry and drug regulatory agencies. Similarly, diarrhea is the second leading cause of death among children under five globally next to pneumonia. The available synthetic drugs for the treatment of liver disorders and diarrhoea have limited safety and efficacy. Objective: To evaluate the in vivo hepatoprotective and antidiarrheal activities of hydroalcoholic leaf and fruit extracts of Schinus molle L. (Anacardiaceae) in mice. Methods: Hepatoprotective activity of the extracts was evaluated by using CCl4 induced hepatotoxicity in mice model. In this model, mice were divided into groups and treated as follows. The normal control and toxicant control groups were treated with the vehicle used for reconstitution, the positive control was treated with the standard drug (silymarin), and the test groups were treated with different doses of plant extracts daily in the morning for seven days. Additionally, all groups except the normal control were treated with CCl4 (2 mg/kg, IP) on the 4th day of treatment, 30 min post-dose. On the 7th day, blood was collected from each mouse via a cardiac puncture. The collected blood was centrifuged, and serum levels of ALT, AST, and ALP were determined using an automated chemistry analyser. Data were analysed using one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test.The antidiarrheal activity of the extract was investigated using castor oil-induced diarrhoea, enteropooling, and small intestine transit. The test groups received various doses (100, 200, and 400 mg/kg) of the extract, whereas the positive control received loperamide (3 mg/kg), and the negative control received the vehicle (distilled water, 10 ml/kg). Result: Hepatoprotective activity: The leaf and fruit crude extracts showed significant improvement in the body weight and liver weight of mice compared to the untreated toxicant control. Additionally, treatment with hydromethanol leaf and fruit extracts caused a significant (P 0.05) the level of albumin compared with the toxicant control.Antidiarrheal activity: In the castor oil-induced diarrheal model, the 80 % methanol extract delayed the onset of defaecation and significantly reduced the number and weight of faeces at all tested doses compared to the negative control. In the enteropooling test, 80 ME significantly (P

Loperamide, an oral over-the-counter μ-opioid receptor agonist used to treat diarrhea, acts primarily in the gut and, when used as recommended, has little to no systemic effect. At high doses, it may cause a "high" like other opioids. Recent literature describes an increasing incidence of loperamide misuse and overdose in the setting of the US opioid epidemic. In this case, we describe a 16-year-old with anorexia nervosa who developed dizziness, syncope, and constipation at the time of weight loss. These symptoms were originally attributed to malnutrition; however, after weight restoration, her symptoms worsened. She did not respond to initial management of suspected postural orthostatic tachycardia syndrome (POTS). She then developed acute urinary retention requiring hospitalization. Her symptoms were ultimately found to be caused by chronic surreptitious high-dose loperamide use. Her symptoms rapidly improved after cessation. This case illustrates the non-specific symptoms associated with loperamide misuse and the potential overlap with other common adolescent conditions. Adolescent medicine clinicians must be aware of the signs and symptoms of loperamide misuse as well as familiar with recommendations for both the management of acute complications and the treatment of the substance misuse. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal motility measurements in mice are currently performed under suboptimal conditions, as these nocturnal animals are measured during light conditions. In addition, other stressors, like individual housing, placement in a new cage during observation, and lack of bedding and cage enrichment cause animal discomfort and might contribute to higher variability. Here we aimed to develop a refined method of the widely‐used whole‐gut transit assay. Methods: Wildtype mice (N = 24) were subjected to the standard or refined whole‐gut transit assay, either with or without a standardized slowing in gastrointestinal motility induced by loperamide. The standard assay consisted of a gavage with carmine red, observation during the light period and individual housing in a new cage without cage enrichment. For the refined whole‐gut transit assay, mice were gavaged with UV‐fluorescent DETEX®, observed during the dark period, while pairwise housed in their home cage with cage enrichment. Time until excretion of the first colored fecal pellet was assessed, and pellets were collected to assess number, weight, and water content. Key Results: The DETEX®‐containing pellets were UV‐detectable, allowing to measure the mice in their active period in the dark. The refined method caused less variation (20.8% and 16.0%) compared to the standard method (29.0% and 21.7%). Fecal pellet number, weight, and water content was significantly different between the standard and refined method. Conclusions & Inferences: This refined whole‐gut transit assay provides a reliable approach to measure whole‐gut transit time in mice in a more physiological context, with reduced variability compared to the standard method. [ABSTRACT FROM AUTHOR]

Objectives: This study was done to evaluate the knowledge of community pharmacists--working in Saudi Arabia--regarding over-the-counter opioid-related and opioid-containing medications. Materials and Methods: A quantitative cross-sectional study was conducted using an online questionnaire that was distributed through social media and taken to the community pharmacists in person. A total of 101 responders were reached in a period of around 3 weeks. Results: Most of the pharmacists working in community pharmacies in Saudi Arabia are non-Saudi (85.15%), males (88.12%), and the majority are holders of bachelor's degrees (85.15%). More than half of the participants spend a considerably sufficient time with the patient 6-10 minutes (60.4%). The availability of a private counseling room in community pharmacies is significantly low (21.78%). Only (69.41%) of participants always counsel the patient before dispensing opioid-related medications. Most of the participants (84.76%) believe that all over-the-counter opioid-related and opioid-containing medications should be restricted to avoid drug abuse. Conclusion: A little neglect from pharmacists' side regarding dispensing such medications was observed; thus, there is a significant need to raise their awareness regarding over-the-counter opioid abuse. [ABSTRACT FROM AUTHOR]

SLC26A6 (also known as putative anion transporter 1 [PAT1]) is a Cl-/HCO3- exchanger expressed at the luminal membrane of enterocytes where it facilitates intestinal Cl- and fluid absorption. Here, high-throughput screening of 50,000 synthetic small molecules in cells expressing PAT1 and a halide-sensing fluorescent protein identified several classes of inhibitors. The most potent compound, the pyrazolo-pyrido-pyrimidinone PAT1inh-B01, fully inhibited PAT1-mediated anion exchange (IC50 ~350 nM), without inhibition of the related intestinal transporter SLC26A3 (also known as DRA). In closed midjejunal loops in mice, PAT1inh-B01 inhibited fluid absorption by 50%, which increased to >90% when coadministered with DRA inhibitor DRAinh-A270. In ileal loops, PAT1inh-B01 blocked fluid absorption by >80%, whereas DRAinh-A270 was without effect. In colonic loops, PAT1inh-B01 was without effect, whereas DRAinh-A270 completely blocked fluid absorption. In a loperamide constipation model, coadministration of PAT1inh-B01 with DRAinh-A270 increased stool output compared with DRAinh-A270 alone. These results provide functional evidence for complementary and region-specific roles of PAT1 and DRA in intestinal fluid absorption, with PAT1 as the predominant anion exchanger in mouse ileum. We believe that PAT1inh-B01 is a novel tool to study intestinal ion and fluid transport and perhaps a drug candidate for small intestinal hyposecretory disorders such as cystic fibrosis-related meconium ileus and distal intestinal obstruction syndrome.

Introduction: Loperamide is a non-prescription anti-diarrheal agent targeting µ-opioid receptors in the intestinal tract. At high doses it crosses the blood-brain barrier, where µ-opioid agonism can cause euphoric effects. Misuse has been increasing for both the euphoric effects and as an alternative treatment for opioid dependence and withdrawal.Case Report: Here we report the case of a 30-year-old woman presenting with syncope, who was found to have severe myocardial conduction delays in the setting of chronic loperamide abuse.Conclusion: Treatment with sodium bicarbonate and hypertonic sodium resulted in improvement of her conduction abnormalities. Prior to discharge she was initiated on buprenorphine for her opioid use disorder.