AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder associated with significant disease burden. This American Gastroenterological Association Guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS with predominant diarrhea (IBS-D) and is an update of a prior technical review and guideline. METHODS: The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: eluxadoline, rifaximin, alosetron, loperamide, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The guideline panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS: The panel agreed on 8 recommendations for the management of patients with IBS-D. The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).

Protective effect of L-pipecolic acid on constipation in C57BL/6 mice based on gut microbiome and serum metabolomic.

BACKGROUND: Functional constipation (FC) in children affects their growth, development and quality of life. L-pipecolic acid (L-PA) was decreased in FC children based on gut microbiome and serum metabolomic. In this study, loperamide-induced constipation in mice was used to evaluate the effects of L-PA on constipated mice. METHOD: 26 FC and 28 healthy children were recruited. Stool samples and serum samples were subjected to 16S rDNA sequencing and ultra-performance liquid chromatography/quadrupole time of flight (UPLC-Q/TOF-MS) approach, respectively. A loperamide-induced mouse constipation model was developed, and all mice were randomly divided into control (Con), loperamide (Lop) and L-PA (Lop + L-PA) treatment groups (6 mice per group). The mice in the Lop + L-PA group were given L-PA (250 mg/kg, once a day) and loperamide; the Lop group was given loperamide for 1 week, and the Con group was given saline. The fecal parameters and intestinal motility of mice in each group were detected. serum 5-HT levels and colon 5-HT expression were detected by ELISA and immunohistochemistry, respectively; qRT-PCR was used to detect the expression of AQP3 and 5-HT4R mRNA in each group. RESULTS: 45 differential metabolites and 18 significantly different microbiota were found in FC children. The α and ß diversity of gut microbiota in FC children was significantly reduced. Importantly, serum L-PA was significantly reduced in FC children. The KEGG pathway enrichment were mainly enriched in fatty acid biosynthesis, lysine degradation, and choline metabolism. L-PA was negatively associated with Ochrobactrum, and N6, N6, N6-trimethyl-l-lysine was positively associated with Phascolarcrobacterium. In addition, L-PA improved the fecal water content, intestinal transit rate, and increased the serum 5-HT levels in constipated mice. Moreover, L-PA increased the expression of 5-HT4R, reduced AQP3, and regulated constipation-associated genes. CONCLUSIONS: Gut microbiota and serum metabolites were significantly altered in children with FC. The abundance of Phascolarctobacterium and Ochrobactrum and serum L-PA content were decreased in FC children. L-PA was found to alleviate the fecal water content, increase intestinal transit rate and the first black stool defecation time. L-PA improved constipation by increasing 5-HT and 5-HT4R expression while down-regulating AQP3 expression.

Yunpi Tongbian Fang alleviates slow transit constipation induced by loperamide by regulating intestinal microbiota and short-chain fatty acids in rats.

Slow transit constipation (STC) is a prevalent chronic colonic dysfunction disease that significantly impairs the quality of life for affected individuals. Yunpi Tongbian Fang (YPTBF), a traditional Chinese medicine compound, has demonstrated promising clinical efficacy; however, its underlying mechanism remains elusive. In order to assess the laxative properties of YPTBF, which encompasses the influence on gut microbiota, gut metabolites, gut neurotransmitters, and colon histology, an oral administration of YPTBF was conducted for a duration of two consecutive weeks on STC rats induced by loperamide hydrochloride. The results showed that YPTBF improved the symptoms of STC, alleviated the decrease in total fecal volume and fecal water content caused by loperamide-induced constipation, restored intestinal transport function, and HE staining showed the recovery of pathological damage to the colon mucosa. In addition, YPTBF increased the concentrations of 5-HT and ACHE, while reducing the concentrations of VIP and NO. YPTBF adjusted the diversity and abundance of gut microbiota in STC rats, enabling the recovery of beneficial bacteria and promoting the production of acetic acid, propionic acid, and butyric acid. We found that YPTBF can improve constipation in STC rats, possibly by regulating the intestinal microbiota structure and improving SCFAs metabolism.

Polysaccharides from Holothuria leucospilota Relieve Loperamide-Induced Constipation Symptoms in Mice.

A vital bioactive component of marine resources is Holothuria leucospilota polysaccharides (HLP). This study examined whether HLP could regulate intestinal flora to treat loperamide-induced constipation. Constipated mice showed signs of prolonged defecation (up by 60.79 min) and a reduced number of bowel movements and pellet water content (decreased by 12.375 and 11.77%, respectively). The results showed that HLP treatment reduced these symptoms, reversed the changes in related protein expression levels in the colon, and regulated the levels of active peptides associated with the gastrointestinal tract in constipated mice, which significantly improved water-electrolyte metabolism and enhanced gastrointestinal motility. Meanwhile, it was found that intestinal barrier damage was reduced and the inflammatory response was inhibited through histopathology and immunohistochemistry. As a means to further relieve constipation symptoms, treatment with low, medium, and high HLP concentrations increased the total short-chain fatty acid (SCFA) content in the intestine of constipated mice by 62.60 µg/g, 138.91 µg/g, and 126.51 µg/g, respectively. Moreover, an analysis of the intestinal flora's gene for 16S rRNA suggested that the intestinal microbiota was improved through HLP treatment, which is relevant to the motivation for the production of SCFAs. In summary, it was demonstrated that HLP reduced loperamide-induced constipation in mice.

Exploring the Dose-Effect Relationship of Bifidobacterium longum in Relieving Loperamide Hydrochloride-Induced Constipation in Rats through Colon-Released Capsules.

Constipation is a common disease affecting humans. Bifidobacterium longum is reportedly effective in relieving constipation. Current studies generally focus on the dose-response relationship of oral doses; however, the dose-effect relationship of B. longum in the colon, which is the primary site where B. longum exerts constipation-relieving effects, to treat constipation has not been studied. Herein, three strains of B. longum (FGSZY6M4, FJSWXJ10M2, and FSDJN6M3) were packaged in colon-released capsules to explore the dose-effect relationship in the colon. For each strain, three groups of capsules (104, 106, and 108 CFU/capsule, respectively) and one group of free probiotics (108 CFU/mL) were used to explore the colonic dose effect of B. longum. The results showed that the three strains of B. longum improved fecal water content and promoted intestinal motility by regulating gastrointestinal peptide (MTL, GAS, and VIP), aquaporin-3, and 5-hydroxytryptamine levels while promoting gastrointestinal motility and relieving constipation by regulating the intestinal flora composition of constipated rats and changing their metabolite content (short-chain fatty acids). Among the three free bacterial solution groups (108 CFU/mL), FGSZY6M4 was the most effective in relieving constipation caused by loperamide hydrochloride in rats. The optimal effective dose of each strain was 6M4 (104 CFU/day), 10M2 (106 CFU/day), and S3 (108 CFU/day) of the colon-released capsules. Therefore, for some effective strains, the dose of oral probiotics can be reduced by colon-released capsules, and constipation can be relieved without administering a great number of bacterial solutions. Therefore, investigating the most effective dose of B. longum at the colon site can help to improve the efficiency of relieving constipation.

Flavonoids in Amomum tsaoko Crevost et Lemarie Ameliorate Loperamide-Induced Constipation in Mice by Regulating Gut Microbiota and Related Metabolites.

Amomum tsaoko (AT) is a dietary botanical with laxative properties; however, the active ingredients and mechanisms are still unclear. The active fraction of AT aqueous extract (ATAE) for promoting defecation in slow transit constipation mice is the ethanol-soluble part (ATES). The total flavonoids of ATES (ATTF) were the main active component. ATTF significantly increased the abundance of Lactobacillus and Bacillus and reduced the dominant commensals, such as Lachnospiraceae, thereby changing the gut microbiota structure and composition. Meanwhile, ATTF changed the gut metabolites mainly enriched in pathways such as the serotonergic synapse. In addition, ATTF increased the serum serotonin (5-HT) content and mRNA expression of 5-hydroxytryptamine receptor 2A (5-HT2A), Phospholipase A2 (PLA2), and Cyclooxygenase-2 (COX2), which are involved in the serotonergic synaptic pathway. ATTF increased Transient receptor potential A1 (TRPA1), which promotes the release of 5-HT, and Myosin light chain 3(MLC3), which promotes smooth muscle motility. Notably, we established a network between gut microbiota, gut metabolites, and host parameters. The dominant gut microbiota Lactobacillus and Bacillus, prostaglandin J2 (PGJ2) and laxative phenotypes showed the most significant associations. The above results suggest that ATTF may relieve constipation by regulating the gut microbiota and serotonergic synaptic pathway and has great potential for laxative drug development in the future.

Alleviation of loperamide-induced constipation with sticky rice fermented huangjiu by the regulation of serum neurotransmitters and gut microbiota.

BACKGROUND: Huangjiu is an important component of traditional fermented food. It is produced by cereal fermentation. Sticky rice fermented huangjiu is an abundant source of polysaccharides, oligosaccharides, proteins, amino acids, and flavor compounds (POPAF), and it has been used as a dietary supplement and pharmaceutical ingredient. The purpose of this study is to explore the alleviation of constipation using sticky rice fermented huangjiu, with the aim of providing a basis for the nutritional treatment of constipation. RESULTS: Sticky rice fermented huangjiu was more effective in the alleviation of constipation than same concentration of ethanol treatment on serum neurotransmitters, gut microbiota, and intestinal metabolites in this 17 days constipation mouse model. Compared with ethanol treatment, the administration of sticky rice fermented huangjiu to constipated mice increased gastrointestinal motility. It alleviated the decrease in motilin (27.94%), substance P (13.85%), gastrin (63.46%), 5-hydroxytryptamine (4.55%), and short-chain fatty acid (19.80%) levels, and alleviated the increase in somatostatin levels (9.54%). Furthermore, the administration of sticky rice fermented huangjiu regulated the microbiota-mediated gut ecology through alterations in the characteristic taxa. CONCLUSION: The results reveal that sticky rice fermented huangjiu may alleviate loperamide-induced constipation by the regulation of serum neurotransmitters and gut microbiota. These findings reveal that huangjiu is endowed with many functional components by cereal fermentation, and the bioactive substances in huangjiu can be separated and applied for medical treatment or diet therapy in the future. © 2022 Society of Chemical Industry.

Defatted hempseed meal altered the metabolic profile of fermented yogurt and enhanced the ability to alleviate constipation in rats.

BACKGROUND: Hempseeds (Cannabis sativa L.) are rich in easily digestible proteins, fats, polyunsaturated fatty acids, and insoluble fiber and are of high nutritional value. Probiotics have been found to relieve constipation, which solves a health problem that constantly troubles a lot of people. Therefore, the changes in the metabolites of fermented yogurt with or without 10% defatted hempseed meal (10% SHY or 0% SHY respectively) were studied and their laxative effects were examined through animal experiments. RESULTS: Amino acids and peptides, terpene glycosides, carbohydrates, lineolic acids, and fatty acids were found to be the major contributors to the discrimination of the metabolic profile between 0% SHY and 10% SHY. The differentially accumulated metabolites may lead to the discrepancy in the yogurt's functionality. Animal experiments showed that the 10% SHY treatment prevented constipation by increasing feces number, fecal water content, and small intestinal transit rate and reducing inflammatory injury in loperamide-induced constipated rats. Further analysis of the gut microbiota revealed that 10% SHY gavage increased the relative abundances of the Lactobacillus, Allobaculum, Turicibacter, Oscillibacter, Ruminococcus, and Phascolarctobacterium genera in the constipated rats, whereas Akkermansia, Clostridium_XIVa, Bacteroides, Staphylococcus, and Clostridium_IV were decreased. The combination of defatted hempseed meal and probiotics was found to be effective in relieving constipation, probably due to the enriched amino acids and peptides, such as Thr-Leu and lysinoalanine through correlation analysis. CONCLUSION: Our findings indicated that defatted hempseed meal in yogurt altered the metabolic profile and effectively alleviated constipation in rats, which is a promising therapeutic candidate for constipation. © 2023 Society of Chemical Industry.

A Case Report of Torsade de Pointes and Brugada Pattern Associated with Loperamide Misuse and Supratherapeutic Loperamide Concentrations.

BACKGROUND: Loperamide, commonly sold under the brand name Imodium® (Johnson & Johnson, Fort Washington, PA), is a widely available, over-the-counter antidiarrheal medication that possesses µ-opioid agonist properties and can have catastrophic cardiac events when misused or abused. Since the start of the opioid epidemic in the United States, there has been an increasing number of case reports and deaths linking loperamide abuse with cardiac events such as torsades de pointes (TdP) and Brugada syndrome. CASE REPORT: This case report presents a 22-year-old man who presented in cardiac arrest from polymorphic ventricular tachycardia consistent with TdP and a Type 1 Brugada pattern after intentional loperamide abuse. We discuss this patient's management and the proposed pathophysiology of these two cardiotoxicities, of which, to our knowledge, no previously published case report has displayed both in the same patient after a supratherapeutic loperamide ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As the prevalence of opioid dependency and misuse has increased, so, too, has the misuse of un-scheduled medications such as loperamide to achieve central nervous system opioid effects. It is important for the emergency physician to know about and understand loperamide-associated cardiotoxicities such as prolongation of the QRS, unmasking of Brugada patterns, QT prolongation, or ventricular dysrhythmias such as TdP to be able to recognize and treat it.

Loperamide Abuse and Its Sequelae.

INTRODUCTION: Loperamide is an opioid available over the counter and in prescription form. Loperamide functions as a µ-agonist within the enteric nervous system to slow intestinal motility. Its antidiarrheal properties and primarily peripheral activity make loperamide an important tool in the management of inflammatory bowel disease. CASE REPORT: A 42-year-old man was found unconscious in cardiac arrest, and emergency medical personnel restored normal sinus rhythm. Family reported complaints of abdominal pain and that he "went through a lot" of loperamide. In the emergency department, the patient exhibited symptoms consistent with an opioid overdose. Mental status improved after administration of naloxone, an opioid antagonist. An electrocardiogram revealed a prolonged QTc interval, which progressed into Torsades de Pointes rhythm during admission. The patient succumbed from hypoxic brain injury, and there was evidence of acute pancreatitis at autopsy. Loperamide and desmethylloperamide (loperamide metabolite) were detected in blood samples. Cause of death was ruled loperamide toxicity. DISCUSSION: Because of reduced central nervous system activity and associated euphoria at therapeutic doses, loperamide abuse is rarely reported. This case demonstrates that an overdose on loperamide can occur in patients seeking symptom alleviation, and may mimic the presentation of opioid overdose.

Comparative Study of Constipation Exacerbation by Potassium Binders Using a Loperamide-Induced Constipation Model.

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.

Electrocardiographic changes in loperamide toxicity: Case report and review of literature.

INTRODUCTION: Loperamide, an antidiarrheal agent, is a µ-opioid receptor agonist increasingly abused to prevent opioid withdrawal or to produce euphoric effects. At supra-therapeutic doses, loperamide can cause cardiac toxicity due to blockade of Na and IKr channels, resulting in wide QRS rhythms, severe bradycardia, prolonged QTc, polymorphic ventricular tachycardia, cardiac arrest, and death. There are limited data on the cardiotoxic effects of high dose loperamide. METHODS AND RESULTS: A case report of loperamide toxicity is presented and then added to a contemporary review of the literature. In total, the presentation and management of 36 cases of loperamide cardiotoxicity are summarized. The overall median daily dose (interquartile range) of loperamide was 200 (134-400) mg. The median QRS duration was 160 (125-170) ms. The median QTc duration was 620 (565-701) ms. Ventricular tachycardia was experienced by 24/36 (67%) of patients, 20 of which were specified to be polymorphic. Treatment was supportive, providing advanced cardiopulmonary life support and aggressive electrolyte repletion. Isoproterenol infusion or overdrive pacing was employed in 19/36 (53%) of cases. The median time to electrocardiogram normalization or hospital discharge, whichever came first, was 5 (3.5-10) days. CONCLUSION: Loperamide overdose is a toxidrome that remains underrecognized, and in patients with unexplained cardiac arrhythmias, loperamide toxicity should be suspected. Prompt recognition is critical due to the delayed recovery and high risk for life-threatening arrhythmias.

Cardiac Dysrhythmias Associated With Substitutive Use of Loperamide: A Systematic Review.

BACKGROUND: Recently, several deaths secondary to cardiac arrhythmias have been reported in association with substitutive use of loperamide. Therefore, we conducted a systematic review of all reported cases to overview the epidemiologic patterns and clinical outcomes to better elucidate loperamide-induced cardiac complications. AREAS OF UNCERTAINTY: Association between substitutive use of loperamide and cardiac arrhythmias. DATA SOURCES: A comprehensive literature search was conducted across 6 databases using variety of keywords to identify all reports of cardiac side effects associated with loperamide abuse. Only original case reports of cardiac toxicity or cardiac arrhythmias after loperamide abuse or overuse were included. Data were extracted by 2 authors independently using a structured template from the selected reports. Quality assessment of the reports was performed by using a high-quality evaluation tool. RESULTS: Thirteen reports describing 19 cases were included in our review. Except for coronary artery spasm in one case, cardiac arrhythmias were the major reported cardiac adverse event. The average age of patients was 31 years with majority being men (79%). The most common presentation was syncope (63%). All cases were reported in US except for 1 case. Three patients were concomitantly taking cimetidine, which is known to cause inhibition of CYP3A4 and CYP2C8 leading to increased levels of loperamide. Thirteen of 19 patients were successfully treated and discharged in a stable condition. CONCLUSIONS: Our results indicate that measures such as restricting over-the-counter availability of loperamide and increasing awareness regarding loperamide's toxicity are imperative to prevent deaths associated with loperamide abuse.

Laxative effects of triple fermented barley extracts (FBe) on loperamide (LP)-induced constipation in rats.

BACKGROUND: Constipation, a common health problem, causes discomfort and affects the quality of life. This study intended to evaluate the potential laxative effect of triple fermented barley (Hordeum vulgare L.) extract (FBe), produced by saccharification, Saccharomyces cerevisiae, and Weissella cibaria, on loperamide (LP)-induced constipation in Sprague-Dawley (SD) rats, a well-established animal model of spastic constipation. METHODS: Spastic constipation was induced via oral treatment with LP (3 mg/kg) for 6 days 1 h before the administration of each test compound. Similarly, FBe (100, 200 and 300 mg/kg) was orally administered to rats once a day for 6 days. The changes in number, weight, and water content of fecal, motility ratio, colonic mucosa histology, and fecal mucous contents were recorded. The laxative properties of FBe were compared with those of a cathartic stimulant, sodium picosulfate. A total of 48 (8 rats in 6 groups) healthy male rats were selected and following 10 days of acclimatization. Fecal pellets were collected one day before administration of the first dose and starting from immediately after the fourth administration for a duration of 24 h. Charcoal transfer was conducted after the sixth and final administration of the test compounds. RESULTS: In the present study, oral administration of 100-300 mg/kg of FBe exhibited promising laxative properties including intestinal charcoal transit ratio, thicknesses and mucous producing goblet cells of colonic mucosa with decreases of fecal pellet numbers and mean diameters remained in the lumen of colon, mediated by increases in gastrointestinal motility. CONCLUSION: Therefore, FBe might act as a promising laxative agent and functional food ingredient to cure spastic constipation, with less toxicity observed at a dose of 100 mg/kg.

Effects of Motilin Receptor Agonists and Ghrelin in Human motilin receptor Transgenic Mice.

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a µ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.

The unsuspected threat of three opioid-like substitutes.

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.

Loperamide abuse cardiotoxicity. Should loperamide still be an over the counter medication?

Loperamide is an over-the-counter anti-diarrheal medication that is inexpensive, easily accessible, and widely used. It is generally thought to be safe and effective without the potential for abuse. However, recent discovery of its ability to treat opioid withdrawal symptoms at high doses has led to not only its abuse, but also the need to recognize its cardiotoxicity due to the ability to prolong the QTc interval. We report a case of a 33 year old female with a history of opioid dependence who presented to the emergency department with acute onset shortness of breath and generalized weakness who was subsequently found to be in ventricular tachycardia. Electrocardiogram showed prolongation of the QTc and the patient later admitted to ingestion of 70 loperamide pills daily for the past year in order to alleviate her opioid withdrawal symptoms. Due to increased loperamide abuse and toxicity displayed within the last several years, public and health provider awareness should be optimized to fully understand its lethality, and stricter regulations on its availability to the general population should be considered. Even in asymptomatic patients with ECG abnormalities, emergency medicine physicians should admit them for further monitoring and aggressive medical therapy.

Loperamide and cardiac events: Is high-dose use still safe for chemotherapy-induced diarrhea?

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.

Trial Evaluating Ambulatory Therapy of Travelers' Diarrhea (TrEAT TD) Study: A Randomized Controlled Trial Comparing 3 Single-Dose Antibiotic Regimens With Loperamide.

BACKGROUND: Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. METHODS: A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. RESULTS: Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. CONCLUSIONS: Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. CLINICAL TRIAL REGISTRATION: NCT01618591.