Racecadotril Versus Loperamide in Acute Radiation Enteritis: A Randomized, Double-Masked, Phase 3, Noninferiority Trial.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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) CONCLUSIONS: 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.

Loperamide Misuse Mimicking Symptoms of Severe Malnutrition.

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.

Torreya grandis Kernel Oil Alleviates Loperamide-Induced Slow Transit Constipation via Up-Regulating the Colonic Expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R in BALB/c Mice.

SCOPE: Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS: The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION: Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.

Anti-diarrheal effect of piperine possibly through the interaction with inflammation inducing enzymes: In vivo and in silico studies.

Piperine is a natural alkaloid that possesses a variety of therapeutic properties, including anti-inflammatory, antioxidant, antibacterial, and anticarcinogenic activities. The present study aims to assess the medicinal benefits of piperine as an anti-diarrheal agent in a chick model by utilizing in vivo and in silico techniques. For this, castor oil was administered orally to 2-day-old chicks to cause diarrhea. Bismuth subsalicylate (10 mg/kg), loperamide (3 mg/kg), and nifedipine (2.5 mg/kg) were used as positive controls, while the vehicle was utilized as a negative control. Two different doses (25 and 50 mg/kg b.w.) of the test sample (piperine) were administered orally, and the highest dose was tested with standards to investigate the synergistic activity of the test sample. In our findings, piperine prolonged the latent period while reducing the number of diarrheal feces in the experimental chicks during the monitoring period (4 h). At higher doses, piperine appears to reduce diarrheal secretion while increasing latency in chicks. Throughout the combined pharmacotherapy, piperine outperformed bismuth subsalicylate and nifedipine in terms of anti-diarrheal effects with loperamide. In molecular docking, piperine exhibited higher binding affinities towards different inflammatory enzymes such as cyclooxygenase 1 (-7.9 kcal/mol), cyclooxygenase 2 (-8.4 kcal/mol), nitric oxide synthases (-8.9 kcal/mol), and L-type calcium channel (-8.8 kcal/mol), indicating better interaction of PP with these proteins. In conclusion, piperine showed a potent anti-diarrheal effect in castor oil-induced diarrheal chicks by suppressing the inflammation and calcium ion influx induced by castor oil.

Anti-diarrheal drug loperamide induces dysbiosis in zebrafish microbiota via bacterial inhibition.

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. Video Abstract.

Hetong decoction relieves loperamide-induced constipation in rats by regulating expression of aquaporins.

OBJECTIVE: To investigate whether Hetong decoction (, HTT) alleviates constipation via regulating AQPs expression. METHODS: Constipation in rats was induced by loperamide, and rats were randomly assigned into model (saline), HHT-low (95 g/kg), HTT-medium (190 g/kg), HTT-high (380 g/kg) and positive control (mosapride) groups. Then the defecation function, the concentration of serum arginine vasopressin (AVP) and cyclic adenosine monophosphate (cAMP), and the expression of AQP3 and AQP8 in colon tissues were assessed. NCM460 colon cells with AQP3 and AQP8 knockdown or overexpression were exposed to serum from rats that received low or high dose of HTT, followed by detection of AQP3 and AQP8 expression. RESULTS: The model group showed lower fecal weight and water content, weaker intestinal transit, higher serum concentration of AVP and cAMP, increased proximal and distal AQP8 expression, increased proximal but decreased distal AQP3 expression. However, these trends were reversed in both the HTT group (low, medium and high dose) and the positive control group. In NCM460 cells, HTT dose-dependently stabilized AQP3 and AQP8 expression under AQP3/8 plasmid interference or overexpression. CONCLUSIONS: HTT relieves constipation in rats through regulating AQP3 and AQP8 expression.

Rifaximin Ameliorates Loperamide-Induced Constipation in Rats through the Regulation of Gut Microbiota and Serum Metabolites.

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.

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.

Lychee Pulp-Derived Dietary Fiber-Bound Phenolic Complex Upregulates the SCFAs-GPRs-ENS Pathway and Aquaporins in Loperamide-Induced Constipated Mice by Reshaping Gut Microbiome.

This study aimed to investigate the effects of the lychee pulp-derived dietary fiber-bound phenolic complex (DF-BPC) on a murine model of loperamide-induced constipation and its molecular mechanism associated with gut microbiota modification. DF-BPC supplementation mitigated loperamide-induced dyschezia, intestinal hypomotility, and colonic impairment, as evidenced by the increased gastro-intestinal transit rate and mucus cell counts. By comparison, short-chain fatty acids (SCFAs) contents and relative abundances of associated genera (Butyricimonas, Clostridium, and Lactobacillus) were effectively upregulated following DF-BPC supplementation. Notably, DF-BPC significantly enhanced expressions of G protein-coupled receptor (GPR) 41 and 43, reaching 1.43- and 1.62-fold increase, respectively. Neurotransmitter secretions were simultaneously altered in DF-BPC-treated mice, suggesting upregulation of the SCFAs-GPRs-enteric nervous system pathway. The overexpression of aquaporins (AQP3, 8, and 9) was stimulated partly through GPRs activation. Mild inflammation associated with constipation was inhibited by suppressing LBP-TLR4-NF-κB signaling translocation. These findings suggest that DF-BPC from lychee pulp has the potential to alleviate constipation in mice through modifying the gut microbiome.

The Different Ways Multi-Strain Probiotics with Different Ratios of Bifidobacterium and Lactobacillus Relieve Constipation Induced by Loperamide in Mice.

Constipation is currently one of the most common gastrointestinal disorders, and its causes are diverse. Multi-strain probiotics are often considered a more effective treatment than single-strain probiotics. In this study, a constipation model was constructed using loperamide hydrochloride to evaluate the ability of a multi-strain probiotic combination of four different ratios of Bifidobacterium and Lactobacillus to regulate intestinal flora, relieve constipation, and explore the initial mechanism in mice. After four weeks of probiotic intervention, BM1, BM2, and PB2 effectively relieved constipation; however, the pathways involved were different. The Bifidobacteria-dominated formulations BM1 and BM2 mainly changed the composition and structure of the intestinal flora and significantly decreased the relative abundance of Tyzzerella, Enterorhabdus, Faecalibaculum, Gordonibacter, and Mucispirillum in stool; increased the relative abundance of Parabacteroides and the content of short-chain fatty acids (SCFAs) in stool; restored motilin (MTL) and vasoactive intestinal peptide (VIP) levels; and downregulated interleukin 6 (IL-6) and IL-8 levels in serum. This repaired the inflammatory response caused by constipation. Finally, it promoted peristalsis of the gastrointestinal tract, increasing stool water content, and relieving constipation. While Lactobacillus-dominated formula PB2 mainly restored the levels of serum neurotransmitters (MTL, SP (substance P), VIP and PYY (Peptide YY)) and inflammatory factors (IL-1, IL-6 and IL-8), it significantly decreased the relative abundance of Tyzzerella, Enterorhabdus, Faecalibaculum, Gordonibacter and Mucispirillum in stool; it then increased acetic acid content, thereby reducing the level of inflammation and changing stool properties and gastrointestinal motility.

Gastrointestinal Fermentable Polysaccharide Is Beneficial in Alleviating Loperamide-Induced Constipation in Mice.

To investigate the role of gastrointestinal (GI) polysaccharide fermentation in alleviating constipation, two polysaccharide fractions were isolated from a soluble fiber extract with determined anti-constipation activity: a 2.04 kDa neutral fraction (SSP-1) contained 99.29% glucose, and a 41.66 kDa acidic fraction (SSP-2) contained 63.85% uronic acid. After mice were given loperamide for 14 d to induce constipation, the GI transit rate increased significantly in the SSP-1 group (p < 0.05) but not in the SSP-2 group. The stool weight in the SSP-2 group was significantly higher than that in SSP-1 (383.60 mg vs. 226.23 mg) (p < 0.05). Both SSP-1 and SSP-2 groups had significantly increased serum gastrin and motilin levels (p < 0.05) and changes in their fecal short-chain fatty acid (SCFA) profiles, while SSP-1 showed better fermentation properties than SSP-2 in terms of statistically higher fecal contents of acetic acid and total SCFAs (p < 0.05). Bioinformatic analysis indicated that SSP-1 upregulated bacteria such as Oscillibacter to improve SCFA metabolism and stimulate GI hormone secretion, while SSP-2 had less influence on the gut microbiota. These results suggest that the neutral polysaccharide with superior GI fermentation properties exerted beneficial effects on constipation, while the less fermentable pectic fraction might act as a stool-bulking agent.

Broccoli-Derived Exosome-like Nanoparticles Alleviate Loperamide-Induced Constipation, in Correlation with Regulation on Gut Microbiota and Tryptophan Metabolism.

Constipation, a common gastrointestinal dysfunction, damages patients' life quality and predisposes them to other serious diseases. Current strategies against constipation often cause drug dependency and side effects. Here, we demonstrated that broccoli-derived exosome-like nanoparticles (BENs), a natural product with high gastrointestinal stability, ameliorated LOP-induced constipation in mice. Specifically, orally administered BENs (17.5 mg/kg/d) effectively shortened defecation time, sped up intestinal propulsion rate, and increased feces amount in constipated mice. BENs also raised excitatory neurotransmitters SP and MTL and reduced inhibitory neurotransmitters VIP and ET-1. Mechanistically, BENs were taken up by gut microbes, restored LOP-disordered gut microbiota, and altered microbial metabolism of SCFAs and tryptophan, as evidenced by the results of fluorescence microscopy, 16S rRNA gene sequencing, and nontargeted metabolomics. Thereinto, BEN-enriched SCFA-producing microorganisms are closely associated with the feces amount and SP and VIP levels and BEN-elevated indole-3-pyruvic acid and 3-indoleacetic acid are highly linked to ET-1, SP, and MTL levels. Conclusively, BENs, mitigating constipation by regulating gut microbiota and microbial tryptophan metabolism, showed high potential to be developed as alternative regimens for constipation.

Xylooligosaccharides from corn cobs alleviate loperamide-induced constipation in mice via modulation of gut microbiota and SCFA metabolism.

This study aimed to optimize the structure and efficacy of xylooligosaccharides (XOSs) from corn cobs in constipated mice. Structural analysis revealed that XOSs from corn cobs were composed of ß-Xyl-(1 →4)-[ß-Xyl-(1→4)]n-α/ß-Xyl (n = 0-5) without any other substituents. XOS administration significantly reduced the defecation time, increased the gastrointestinal transit rate, restored the gastrointestinal neurotransmitter imbalance, protected against oxidative stress, and reversed constipation-induced colonic inflammation. Fecal metabolite and microbiota analysis showed that XOS supplementation significantly increased short chain fatty acid (SCFA) levels and improved the gut microbial environment. These findings highlighted the potential of XOSs from corn cobs as an active ingredient for functional foods or as a therapeutic agent in constipation therapy.

Comparison of the laxative effects of Korean Gochujang containing different microbiota on loperamide-induced constipation in ICR mice.

The prevalence of constipation, one of the common gastrointestinal (GI) diseases, has been gradually increasing. Gochujang, a traditional Korean fermented paste, has various microbiota and exerts diverse health beneficial effects. However, the ameliorative effect of Gochujang on constipation is unexplored. Seven-week-old ICR mice were divided into five groups: the normal group, the loperamide (LOP) group, the LOP + mosapride citrate (3 mg per kg BW, MOSA) treated group, the LOP + BMG Gochujang (2 g per kg BW) group, and the LOP + VMG Gochujang (2 g per kg BW) group. Gochujang alleviated constipation by increasing defecation frequency and water content in feces by reducing AQP3 mRNA expression. Additionally, Gochujang increased GI transit time and excitatory neurotransmitter levels and decreased inhibitory neurotransmitter levels. Moreover, Gochujang reduced mitogen-activated protein kinase (MAPK) activation and increased the c-Kit/SCF signaling pathway, suggesting that Gochujang regulates the enteric nervous system (ENS). Interestingly, BMG and VMG differently influenced the gut microbiota composition. Both Gochujang groups significantly decreased the Bacteroidetes and Firmicutes ratio compared to the LOP group. However, among Firmicutes genera, Acetatifactor was only reduced in BMG, and VMG only decreased Caproiciproducens and Acutalibacter. In summary, Gochujang effectively alleviated LOP-induced constipation outcomes regardless of their different microbial communities by ameliorating GI motility and changing the gut microbiota composition.

Modulation of gut microbiota ecosystem by a glucan-rich snail mucin heteropolysaccharide attenuates loperamide-induced constipation.

The present study aimed to investigate the effect of oral administration of snail-derived mucin extract (SM) on ameliorating constipation symptoms of loperamide-induced constipated rats (n = 6). The analytical results indicated that SM mainly contains a glucan-rich snail mucin heteropolysaccharide with high molecular weights (108.5-267.9 kDa), comprising primarily of glucose (64.9 %) and galactose (22.4 %) with some deoxyhexoses (5.0 %) and hexosamines (4.9 %). Daily SM administration at doses of 10-40 mg/kg/day to the loperamide-induced constipated rats significantly (p < 0.05) ameliorated the deterioration in fecal parameters, such as numbers and weight of feces, fecal water contents, and gastrointestinal transit ratio. The histomorphometric results showed that the loperamide-induced decreases in the thickness of mucosal and muscularis mucosae layers as well as the distribution of mucin and c-KIT-positive areas were significantly (p < 0.05) improved via SM consumption at all doses tested. SM administration at all doses significantly increased the expression of genes encoding tryptophan hydroxylases (TPH1 and TPH2; p < 0.05), tight junction molecules (OCLN, CLDN1, and TJP1; p < 0.05), and mucin (MUC2 and MUC4; p < 0.05), but significantly decreased the aquaporin-encoding genes (AQP3 and AQP8; p < 0.05). Gut microbial community analysis indicated that SM administration could modulate loperamide-induced dysbiosis by increasing the phyla Actinobacteria (11.72-12.64 % at 10-40 mg/kg doses; p < 0.05) and Firmicutes (79.33 % and 74.24 % at 20 and 40 mg/kg doses; p < 0.05) and decreasing the phyla Bacteroidetes (5.98-12.47 % at 10-40 mg/kg doses; p < 0.05) and Verrucomicrobia (2.21 % and 2.78 % at 20 and 40 mg/kg doses; p < 0.05), suggesting that SM administration is effective in ameliorating constipation by controlling gut microbial communities. These findings can be utilized as fundamental data for developing novel functional materials using SM to prevent or treat constipation.

Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial (MERMAID, WJOG11318B).

BACKGROUND: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. METHODS: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. RESULTS: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. CONCLUSIONS: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. CLINICAL TRIAL REGISTRATION: jRCT (Japan registry of clinical trials). jRCTs031190154.

Crofelemer for the Management of Neratinib-Associated Diarrhea in Patients With HER2+ Early-Stage Breast Cancer.

BACKGROUND: To evaluate the efficacy of crofelemer, a first in class anti-secretory anti-diarrheal agent, to manage neratinib-induced diarrhea in patients with early-stage breast cancer taking adjuvant neratinib. PATIENTS AND METHODS: This single center, open label trial enrolled patients with Stage 2 to 3 HER2+ breast cancer taking adjuvant neratinib. One cohort took prophylactic crofelemer 125 mg bid and loperamide in the first 2 cycles, and as needed in subsequent cycles. The second cohort took dose-escalated neratinib with loperamide as needed (DE cohort). The primary endpoint was incidence of grade ≥ 3 diarrhea in the first 2 cycles. RESULTS: Seven patients in the crofelemer cohort and 4 in the DE cohort were enrolled. In the first 2 cycles, 2 patients (29%) in the crofelemer cohort and 2 patients (50%) in the DE cohort experienced grade 3 diarrhea lasting 1 day on average. After cycle 2, no additional patients in either cohort had grade 3 diarrhea. Five of 7 patients controlled diarrhea with crofelemer alone. There were no grade 4 diarrhea events in either cohort. Three patients in the crofelemer cohort dose-reduced neratinib due to diarrhea in the first 2 cycles. Patients in the crofelemer cohort had an average of 0.58 diarrhea episodes/day. 82% experienced constipation, all grade 1. CONCLUSIONS: This is the first study to investigate crofelemer for neratinib-induced diarrhea and demonstrates crofelemer activity in this setting. Further investigation of crofelemer for diarrhea secondary to cancer treatment is needed.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids.

BACKGROUND: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. OBJECTIVES: In this study, we sought to explore opioid-associated arrhythmia reporting in North America. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. RESULTS: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. CONCLUSIONS: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.