The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose.

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 µM [~1200-fold (×) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 µM (~12,000× FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II/III A-V block in anesthetized guinea pigs at overdose exposures of 879× and 3802× FTPC. In ion-channel studies, loperamide inhibited hERG (IKr), INa, and ICa currents with IC50 values of 0.390 µM, 0.526 µM, and 4.091 µM, respectively (i.e., >1560× FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (≤600× FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide's inhibition of the INa channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition.

Milk fermented by combined starter cultures comprising three Lactobacillus strains exerts an alleviating effect on loperamide-induced constipation in BALB/c mice.

Fermented dairy food, such as yogurt, exhibits some beneficial effects on consumers, including alleviating constipation. In this study, Lactobacillus delbrueckii subsp. bulgaricus DPUL-36, Lactobacillus paracasei DPUL-40 and Lactobacillus paracasei DPUL-44 were used as combined starter cultures at a bacterial cell ratio of 1 : 1 : 1 for reconstituted skim milk fermentation. The milk fermented with the combined starter culture showed good sensory properties. During the storage period, the yogurt showed high lactic acid bacteria vitality and quality stability. Constipated BALB/c mice induced by loperamide (Lop) were orally administered with the combined starter culture fermented milk for 14 days. The results clearly showed that oral administration of the fermented milk relieved Lop-induced constipation in the mice, as evidenced by the significantly increased fecal water content, reduced first black stool time, improved gastrointestinal transmission rate, recovered colon tissue damage, increased level of excitatory neurotransmitters (motilin, gastrin, and substance P) and reduced level of inhibitory neurotransmitters (vasoactive intestinal peptide, somatostatin and endothelin-1) of the mice. Compared with the mice in the Lop group, oral administration of the fermented milk significantly increased the concentrations of acetic acid, propionic acid, butyric acid, isovaleric acid and valeric acid in the feces of the mice, and furthermore, exerted a regulatory effect on the gut microbiota of the mice by up-regulating the abundance of Lactobacillus and Bacteroides, and decreasing the abundance of Helicobacter, Pseudomonas and Porphyromonas. Our results indicated that the combined starter culture fermented milk can effectively alleviate Lop-induced-constipation in BALB/c mice. The relationship between the nutrient profiles and the health promoting function of the yogurt should be further illustrated.

Therapeutic effects of Bombax ceiba flower aqueous extracts against loperamide-induced constipation in mice.

CONTEXT: Bombax ceiba Linnaeus (Bombacaceae) is known as silk cotton tree, the flowers of which are used in many medicinal applications. OBJECTIVE: To investigate the therapeutic effect of B. ceiba flower aqueous extracts (BCE) against loperamide-induced constipation and characterize the chemical composition of BCE. MATERIALS AND METHODS: Sixty male Kunming mice were divided into control (saline), model (10 mg/kg loperamide + saline), phenolphthalein (10 mg/kg loperamide + 10 mg/kg phenolphthalein) and different dosage of BCE (10 mg/kg loperamide + 40, 80 and 160 mg/kg BCE, respectively) groups, and received intragastric administrations for eight days. Faecal water content, number of faeces, first black-stool defecation time and gastrointestinal transit rates were evaluated. Various biochemical and molecular biomarkers were assessed in blood and colon. UPLC-ESI-QTOF-MS/MS was used to tentatively identify the composition of the BCE. RESULTS: BCE treatment (160 mg/kg) could increase faecal water (15.75%), faeces number (11.65%), gastrointestinal transit rate (25.37%) and decrease first black-stool defecation time (24.04%). The BCE (80 mg/kg) increased the serum level of motilin (30.62%), gastrin (54.46%) and substance P (18.99%), and decreased somatostatin (19.47%). Additionally, the BCE (160 mg/kg) reduced the mucosal damage, restored colonic goblet cell function, down-regulated the protein expression of AQP3 (33.60%) and increased c-kit protein expression (11.63%). Twelve known compounds, including protocatechuic acid, chlorogenic acid and rutin, previously reported in B. ceiba, were identified in the BCE. DISCUSSION AND CONCLUSIONS: This study suggested that BCE is a promising agent for the treatment of constipation.

Loperamide induces excessive accumulation of bile acids in the liver of mice with different diets.

Loperamide is a non-prescription medicine normally used for the treatment of diarrhea. The abuse and misuse of loperamide have been demonstrated to have toxic effects on heart. It is still unclear whether the abuse of loperamide can cause hepatic toxicity. The C57BL/6 mice fed with high fat diet (HFD) or normal food diet (NFD) were administrated with loperamide (5 mg/kg/day) intragastrically once a day for two weeks, after that, the feces, blood, hepatic tissues and intestines were harvested for biochemical and histological detection, and the expression of genes related with lipid metabolism was further checked by qRT-PCR (quantitative real-time polymerase chain reaction) and Western blot. The administration of loperamide caused the constipation in mice fed with NFD or HFD. The content of bile acids was significantly reduced in the feces of mice treated with loperamide, but the content of bile acids was significantly increased in the liver of these mice. The results of H&E staining showed that loperamide administration caused the damage of hepatic tissues, especially for mice fed with HFD. The expression of genes related with the biosynthesis of cholesterol and bile acids, including Hmgcr, Lss, Sqle, Fdps, Idi1, Mvk, Cyp7a1 and Ch25h, was all upregulated in the liver of mice treated with loperamide. Conversely, the expression of Abcg5, Abcb11 and Abcc2, which encode genes for transporting cholesterols and bile acids from hepatocytes to bile respectively, was downregulated in the liver of mice treated with loperamide. At the same time, the expression of Fabp6 and Slc51a, which transport bile acids from intestinal lumen into the blood, was all upregulated in the ileum of mice treated with loperamide. The expression of SHP, which inhibits the transcription of Cyp7a1 in hepatocytes, was significantly downregulated in the hepatic tissues of mice treated with loperamide. These results demonstrated that administration of loperamide caused excessive accumulation of bile acids in the liver of mice via upregulating genes for biosynthesis of cholesterol and bile acid and downregulating genes for discharging cholesterol and bile acids in hepatocytes of mice, moreover, the downregulation of SHP in hepatic tissues might be one of the mechanisms of it, especially for mice fed with HFD.

Loperamide-induced Constipation Activates Inflammatory Signaling Pathways in the Mid Colon of SD Rats Via Complement C3 and its Receptors.

BACKGROUND: Complement component 3 (C3) receptors play an important role as inflammatory mediators in the innate immune system, although their mechanisms were not well studied during constipation. OBJECTIVE: The aim of this study is to investigate the regulatory role of C3 and its receptors' downstream signaling during constipation. METHODS: Alterations in the C3, C3a receptor (C3aR), and C3b receptor (C3bR) expressions, PI3K/AKT pathway, RhoA/MLC pathway, MAP kinase pathway, and inflammatory cytokine expressions were measured in the mid colon of loperamide (Lop) treated SD rats. RESULTS: Lop treatment successfully induced constipation phenotypes, including decreased stool parameters and histological structure alterations. The expression levels of C3 were significantly increased, whereas expressions of C3aR and C3bR were decreased during Lop-induced constipation. Moreover, significant upregulation was observed in the phosphorylation levels of PI3K, AKT, and GSK3ß in mid colons of Lop treated SD rats. The expression of RhoA and phosphorylation of MLC were also enhanced in the Lop treated group. Furthermore, a similar pattern was detected in the MAP kinase pathway and inflammatory cytokine expressions. Subsequent to the Lop treatment, the phosphorylation of ERK and p38, as well as the mRNA levels of NF-κB, TNF-α, IL-6 and IL-1α were remarkably increased in the mid colon. CONCLUSION: These results indicate that Lop-induced constipation is tightly linked to the downregulation of C3aR and C3bR expressions, and upregulation of the C3 and C3Rs downstream signaling pathway, including PI3K/AKT, RhoA/MLC, and MAP kinase pathways as well as inflammatory cytokine expressions in the mid colon of SD rats.

Improvement of loperamide-induced slow transit constipation by Bifidobacterium bifidum G9-1 is mediated by the correction of butyrate production and neurotransmitter profile due to improvement in dysbiosis.

A treatment option for constipation that improves the quality of life is needed since available laxatives do not effectively improve the quality of life in patients with constipation. A significant association between gut dysbiosis and constipation is recognized, suggesting that probiotics may be an important option for management of constipation. The underlying mechanism by which probiotics improve constipation remains unclear. In this study, we aimed to evaluate the effects of the probiotic Bifidobacterium bifidum G9-1 (BBG9-1) on loperamide-induced delayed colonic transit constipation and to elucidate its mechanism of action. First, the effect of BBG9-1 was evaluated in a rat model of constipation induced by subcutaneous administration of loperamide. BBG9-1 improved constipation parameters (number of feces, fecal water content, and fecal hardness) in constipated rats. Next, the relationship of organic acids and neurotransmitters to gut microbiota was investigated. BBG9-1 improved dysbiosis and prevented a decrease in butyric acid concentration in the gut, increased serum serotonin, and suppressed an increase in dopamine and a decrease in acetylcholine in serum. Further, an increase in the expression level of tryptophan hydroxylase 1, a 5-HT-synthetizing enzyme, was observed. These results suggest that BBG9-1 improves dysbiosis, which results in an increase in organic acids and improvement of neurotransmission. These actions may increase intestinal mobility, finally leading to alleviating constipation. The probiotic BBG9-1 may, therefore, be a potential option for the treatment of constipation.

Laxative effect and mechanism of Tiantian Capsule on loperamide-induced constipation in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Tiantian capsule (TTC), as a functional food, which consists of four herb medicines, including Aloe vera Burm.f. (25%), leaf juices, dried; Cucurbita moschata Duch. (25%), fructus, dried; Poria cocos (Schw.) Wolf. (12.5%), sclerotium, dried; Tremella fuciformis Berk. (12.5%), fruiting bodies, dried, and one extract xylooligosaccharides (25%) from Maize Cob by enzymolysis, has been commonly used in China to ameliorate constipation. AIM OF THE STUDY: The aim of the work is to elucidate the potential laxative mechanisms of TTC in loperamide-induced constipated rats. MATERIALS AND METHODS: LC-MS/MS was employed for analyzing the TTC extract. The gastrointestinal transit was evaluated by X-ray. The H&E and Alcian-Blue stain were applied to determine the changes of goblet cells and mucus layer, respectively. Meanwhile, levels of neurotransmitters were evaluated by enzyme-linked immunosorbent assay. The protein expressions were also measured by immunohistochemistry and Western blot. RESULTS: Our results showed that TTC administration attenuated constipation responses in aspects of fecal pellets number, water content of feces, stomach emptying and gastrointestinal transit. Further investigations revealed that TTC treatment not only induced the recovery of neurotransmitters, such as motilin, substance P, somatostatin, endothelin and vasoactive intestinal peptide, but also up-regulated the expressions of c-kit and stem cell factor (SCF). Additionally, the number of goblet cells and thickness of the mucus layer were elevated, and the guanylate cyclase C-cGMP signal pathway was also up-regulated after TTC treatment. CONCLUSION: Our findings demonstrated that the laxative effect of TTC in constipation rats is probably due to the regulation of bowel movement and intestinal fluid secretion.

Divergent Electrophysiological Effects of Loperamide and Naloxone in a Sensitive Whole-Heart Model.

Several case reports suggest QT prolongation leading to ventricular arrhythmias with fatal outcome after intoxication with the µ-opioid receptor agonist and anti-diarrheal agent loperamide. The number of cases of loperamide misuse are growing due to its potential stimulating effects. Loperamide intoxications can be treated by naloxone. However, previous reports described a further QT prolongation associated with naloxone administration. Therefore, the aim of this study was to investigate the effects of loperamide and naloxone on the cardiac electrophysiology in a sensitive whole-heart model. Twenty-six hearts of New Zealand White rabbits were retrogradely perfused in a modified Langendorff apparatus. Monophasic action potentials were recorded by endo- and epicardially positioned catheters. Hearts were stimulated at different cycle lengths, thereby obtaining action potential duration at 90% of repolarization (APD90) and QT intervals. Programmed ventricular stimulation was used to assess ventricular vulnerability. Fourteen hearts were perfused with ascending concentrations of loperamide (0.2 µM, 0.35 µM, and 0.5 µM) after obtaining baseline data. Another 12 hearts were treated with naloxone (0.1 µM, 0.5 µM, 2 µM). Loperamide led to a significant increase in QT interval, APD90, and ventricular tachycardia (VT) episodes. In contrast, naloxone led to a decrease in QT interval and APD90. Accordingly, the number of VT episodes was unaltered. To the best of our knowledge, this is the first experimental study that investigated the effects of loperamide and naloxone in a whole-heart model. Loperamide led to a significant increase in action potential duration and QT interval. Simultaneously, the number of ventricular tachycardias was significantly increased. In contrast, naloxone led to a shortening of the action potential duration without altering arrhythmia susceptibility.

Astragaloside IV alleviates mouse slow transit constipation by modulating gut microbiota profile and promoting butyric acid generation.

Gut microbiota and short-chain fatty acids (SCFAs) are associated with the development of various human diseases. In this study, we examined the role of astragaloside IV in modulating mouse gut microbiota structure and the generation of SCFAs, as well as in slow transit constipation (STC). An STC model was established by treating mice with loperamide, in which the therapeutic effects of astragaloside IV were evaluated. The microbiota community structure and SCFA content were analysed by 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. The influence of butyrate on STC was assessed using a mouse model and Cajal cells (ICC). Astragaloside IV promoted defecation, improved intestinal mobility, suppressed ICC loss and alleviated colonic lesions in STC mice. Alterations in gut microbiota community structure in STC mice, such as decreased Lactobacillus reuteri diversity, were improved following astragaloside IV treatment. Moreover, astragaloside IV up-regulated butyric acid and valeric acid, but decreased isovaleric acid, in STC mouse stools. Butyrate promoted defecation, improved intestinal mobility, and enhanced ICC proliferation by regulating the AKT-NF-κB signalling pathway. Astragaloside IV promoted intestinal transit in STC mice and inhibited ICC loss by regulating the gut microbiota community structure and generating butyric acid.

Loperamide toxicity: recommendations for patient monitoring and management.

Who: This position statement is a collaborative effort by the American Academy of Clinical Toxicology (AACT) and the American Association of Poison Control Centers (AAPCC) and has been endorsed by the American College of Medical Toxicology (ACMT). The position statement describes loperamide misuse, proposed mechanisms of toxicity, adverse clinical effects, and recommendations for the acute monitoring and management of patients with loperamide toxicity.Why: Use of high-dose loperamide for its euphoric effects and to self-treat opioid use disorder (in place of evidence-based therapies, like buprenorphine or methadone), is increasing. Despite reports in the medical literature and lay press, many remain unaware of high-dose loperamide use and how to manage patients with loperamide-associated toxicities.Target audience: Providers in Emergency Medicine; Prehospital; Intensive Care; Internal Medicine; Primary Care; Gastroenterology; Addiction Medicine; Pharmacy.

Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms.

Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited, and mechanisms are largely unknown. We investigated the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then, a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic functions were assessed by spectral analysis of heart rate variability (HRV) derived from an electrocardiogram. Serum levels of pancreatic polypeptide (PP), norepinephrine (NE), and acetylcholine (ACh) in colon were assessed. 1) Acute SNS at 5 Hz, 100 µs was found effective in enhancing rectal compliance and accelerating distal colon transit (P < 0.05 vs. sham SNS). 2) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight, and water content of fecal pellets, and accelerated the distal colon transit (29.4 ± 3.7 min with sham SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 3) SNS significantly increased vagal activity (P = 0.035) and decreased sympathetic activity (P = 0.012), assessed by spectral analysis of HRV as well as by the serum PP. 4) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. We concluded that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function.NEW & NOTEWORTHY Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, effects are limited, and mechanisms are largely unknown. This paper shows that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility mediated via the autonomic-cholinergic function.

Radiographic dose-dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea-like behavior.

BACKGROUND: Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). METHODS: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg-1 ). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. KEY RESULTS: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. CONCLUSIONS AND INFERENCES: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated.

Anti-Inflammatory Response and Muscarinic Cholinergic Regulation during the Laxative Effect of Asparagus cochinchinensis in Loperamide-Induced Constipation of SD Rats.

Several types of saponins and herbal plants containing saponins have been reported to have anti-inflammatory or laxative activities. To verify the therapeutic effects of saponin-enriched extracts of Asparagus cochinchinensis (SPA) on the anti-inflammatory response and on the cholinergic regulation in the gastrointestinal system, an alteration on the constipation phenotypes, on the inflammatory responses, and on the muscarinic cholinergic regulation were investigated in the transverse colons of Sprague Dawley (SD) rats with loperamide (Lop)-induced constipation after the treatment of SPA. Significant increases were observed on the total number of stools, the gastrointestinal transit, the thickness of the mucosal layer, the flat luminal surface, the number of paneth cells, and the lipid droplets in the Lop + SPA-treated group as compared to the Lop + Vehicle-treated group. SPA treatment induced the recovery of inflammatory cytokines (TNF-α, IL-1ß) and IL-6), inflammatory mediators (NF-κB and iNOS), the total number of infiltered mast cells, and mucin secretion. Also, some similar improvements were observed on the levels of acetylcholine esterase (AChE) activity and on the phosphorylation of myosin light chains (MLC) as well as the expression of muscarinic acetylcholine receptors M2/M3 (mAChR M2/M3) and their mediators. The results presented herein provide the first strong evidence that SPA stimulates anti-inflammatory responses and the muscarinic cholinergic regulation when exerting its laxative effects in the chronic constipation of Lop-induced models.

Loperamide-induced cardiotoxicity in rats: Evidence from cardiac and oxidative stress biomarkers.

At therapeutic dose, loperamide is a safe over-the-counter antidiarrheal drug but could induce cardiotoxic effect at a supratherapeutic dose. In this study, we use cardiac and oxidative biomarkers to evaluate loperamide-induced cardiotoxicity in rats. Rats were orally gavaged with 1.5, 3, or 6 mg/kg body weight (BW) of loperamide hydrochloride for 7 days. The results after 7 days administration of loperamide, revealed dose-dependent increase (P < 0.05) in aspartate aminotransferase, lactate dehydrogenase, creatine kinase-MB, and serum concentration of cardiac troponin I, total homocysteine, and nitric oxide. A 50% decrease in antioxidant enzymes activity was observed at 6 mg/kg BW. Furthermore, malondialdehyde and fragmented DNA also increased significantly in the heart of the treatment groups. Loperamide provoked cardiotoxicity through oxidative stress, lipid peroxidation, and DNA fragmentation in rats. This study has provided a possible biochemical explanation for the reported cardiotoxicity induced by loperamide overdose.

Loperamide Abuse and Dependence: Clinical Features and Treatment Considerations.

: Opioid use disorder and its associated mortality have become national epidemic problems. Different measures and regulations have been implemented to curb this trend, including stricter opioid prescribing practice. With the decreased access to prescription opioids, individuals with opioid use disorder have explored alternatives including loperamide, a peripheral opioid mu-receptor agonist. There are reports of increased loperamide misuse, dependence, and mortality rate in the past few years from poison control centers, medical examiners' offices, and clinical settings. Here, we report a case of loperamide use disorder, which led to the death of the patient. Associated clinical features and treatment of loperamide use disorder, including management of intoxication and withdrawal, and long-term maintenance therapy are discussed along with potential prescribing and sale regulations to manage this newly emerging substance use disorder.

Quercetin promotes gastrointestinal motility and mucin secretion in loperamide-induced constipation of SD rats through regulation of the mAChRs downstream signal.

CONTEXT: Quercetin (QCT) has been known as a potential therapeutic strategy for gastrointestinal diseases because it contributes to the stabilization of mast cells, the prevention of histamine release and modulation of CaCC chloride channel. OBJECTIVE: We investigated the laxative effect and action mechanism of QCT in Lop-induced constipation model. MATERIALS AND METHODS: Constipation of SD rats was induced by subcutaneous injection of loperamide (Lop) (4 mg/kg weight) in 0.5% Tween 20 twice a day for three days. After 24 h, the constipation group was further treated with 1× PBS (Lop + Vehicle treated group), 10 mg/kg of QCT (Lop + LQCT treated group), 20 mg/kg of QCT (Lop + MQCT treated group) or 40 mg/kg QCT (Lop + HQCT treated group) at once. At 24 h after QCT treatment, the constipation phenotypes were measured and the transverse colon was collected from SD rats. RESULTS: The gastrointestinal motility, the number of stools and histological structures were significantly recovered in Lop + QCT treated group compared with the Lop + Vehicle treated group. Also, above activity of epithelial cells and smooth muscle cells were regulated by the mRNA expression of the muscarinic acetylcholine receptors M2 and M3 (mAChR M2 and M3) and some mediators of their downstream signalling pathway. Finally, laxative effects of QCT on mAChR signalling pathway were significantly inhibited by the treatment of mAChR antagonist in primary smooth muscle of rat intestine cells (pRISMCs). CONCLUSIONS: This study provides the first strong evidence that QCT can be considered an important candidate for improving chronic constipation induced by Lop treatment in animal models.

Brugada-Type Pattern on Electrocardiogram Associated with High-Dose Loperamide Abuse.

BACKGROUND: Loperamide has been increasing in popularity recently for its effects separate from treatment of diarrhea. In large doses or in combination with other agents, it can lead to desirable effects in the central nervous system. However, cardiotoxicity has been reported with its abuse. CASE REPORT: A 49-year-old male who had been chronically abusing loperamide was found to have Brugada-like changes on his electrocardiogram (ECG). He had no other clinical symptoms associated with Brugada syndrome and did not have similar findings on previous ECGs. After abstaining from further loperamide use during hospitalization, this pattern slowly resolved without clinically significant dysrthymias. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with a history of loperamide abuse is at risk for cardiotoxicity. While other dysrhythmias are reported more commonly with loperamide abuse, Brugada-like ECG changes can occur and warrant appropriate consultation and prompt follow-up.

Loperamide cardiotoxicity: "A Brief Review".

Loperamide is a popular antidiarrheal medication that has been used for many years. It is currently gaining more attention among healthcare professionals due to its increasing potential for side effects. At present, it is considered safe enough to be sold over the counter. In contrast with other opioid agonists, loperamide is a peripherally acting µ-receptor agonist exerting its effects mainly on the myenteric plexus of the gastrointestinal longitudinal muscle layer. It decreases peristalsis and fluid secretion resulting in longer gastrointestinal transit time. The bioavailability of the drug is extremely low. Moreover, it is actively excluded from the central nervous system; hence, it lacks the central effects of euphoria and analgesia at the recommended dosages. Loperamide abuse has been steadily increasing in the United States. Abusers typically ingest high doses in desire to achieve a satisfactory central nervous system drug penetration. This has made it a potential over the counter substitute for self-treating opioid withdrawal symptoms and achieving euphoric effects.

Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation.

Constipation is a common affliction which causes discomfort and affects the quality of life of affected individuals. Naringenin (NAR), a natural flavonoid widely found in citrus fruits and tomatoes, has been reported to exhibit various pharmacological effects, such as anti-inflammatory, anti-atherogenic, anti-mutagenic, hepatoprotective and anticancer effects. Increasing evidence has indicated that NAR has potential for use in the treatment of constipation. Thus, the aim of this study was to evaluate the laxative effects of NAR in mice with loperamide-induced (Lop-induced) constipation. The data indicated that NAR relieved Lop-induced constipation in mice based on the changes of fecal parameters (numbers, weight and water content), the intestinal charcoal transit ratio and the histological alteration. ELISA revealed that NAR regulated the production levels of gastrointestinal metabolic components, such as motilin (MTL), gastrin (Gas), endothelin (ET), substance P (SP), acetylcholinesterase (AChE) and vasoactive intestinal peptide (VIP) in serum. The expression levels of enteric nerve-related factors, glial cell line-derived neurotrophic factor (GDNF), transient receptor potential vanilloid 1 (TRPV1), nitric oxide synthase (NOS), c-Kit, stem cell factor (SCF) and aquaporin 3 (AQP3) were examined by western blot analysis and RT-PCR analysis. The results of this study suggest that NAR relieves Lop-induced constipation by increasing the levels of interstitial cells of Cajal markers (c-Kit and SCF), as well as AQP3. Thus, NAR may be effective as a candidate in patients suffering from lifestyle-induced constipation.