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

Novel combinations of specific opioid agonists like loperamide and oxymorphindole targeting the µ - and δ -opioid receptors, respectively, have shown increased potency with minimized opioid-associated risks. However, whether their interaction is pharmacokinetic or pharmacodynamic in nature has not been determined. This study quantitatively determined whether these drugs have a pharmacokinetic interaction that alters systemic disposition or central nervous system (CNS) distribution. We performed intravenous and oral in vivo pharmacokinetic assessments of both drugs after discrete dosing and administration in combination to determine whether the combination had any effect on systemic pharmacokinetic parameters or CNS exposure. Drugs were administered at 5 or 10 mg/kg i.v. or 30 mg/kg orally to institute for cancer research (ICR) mice and 5 mg/kg i.v. to Friend leukemia virus strain B mice of the following genotypes: wild-type, breast cancer resistance protein ( Bcrp -/- ) (Bcrp knockout), Mdr1a/b -/- [P-glycoprotein (P-gp) knockout], and Bcrp -/- Mdr1a/b -/- (triple knockout). In the combination, clearance of oxymorphindole (OMI) was reduced by approximately half, and the plasma area under the concentration-time curve (AUC) increased. Consequently, brain and spinal cord AUCs for OMI in the combination also increased proportionately. Both loperamide and OMI are P-gp substrates, but administration of the two drugs in combination does not alter efflux transport at the CNS barriers. Because OMI alone shows appreciable brain penetration but little therapeutic efficacy on its own, and because loperamide's CNS distribution is unchanged in the combination, the mechanism of action for the increased potency of the combination is most likely pharmacodynamic and most likely occurs at receptors in the peripheral nervous system. This combination has favorable characteristics for future development. SIGNIFICANCE STATEMENT: Opioids have yet to be replaced as the most effective treatments for moderate-to-severe pain and chronic pain, but their side effects are dangerous. Combinations of opioids with peripheral activity, such as loperamide and oxymorphindole, would be valuable in that they are effective at much lower doses and have reduced risks for dangerous side effects because the µ -opioid receptor agonist is largely excluded from the CNS., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Ion channels have been proposed as therapeutic targets for different types of malignancies. One of the most studied ion channels in cancer is the voltage-gated potassium channel ether-à-go-go 1 or Kv10.1. Various studies have shown that Kv10.1 expression induces the proliferation of several cancer cell lines and in vivo tumor models, while blocking or silencing inhibits proliferation. Kv10.1 is a promising target for drug discovery modulators that could be used in cancer treatment. This work aimed to screen for new Kv10.1 channel modulators using a thallium influx-based assay., Methods: Pharmacological effects of small molecules on Kv10.1 channel activity were studied using a thallium-based fluorescent assay and patch-clamp electrophysiological recordings, both performed in HEK293 stably expressing the human Kv10.1 potassium channel., Results: In thallium-sensitive fluorescent assays, we found that the small molecules loperamide and amitriptyline exert a potent inhibition on the activity of the oncogenic potassium channel Kv10.1. These results were confirmed by electrophysiological recordings, which showed that loperamide and amitriptyline decreased the amplitude of Kv10.1 currents in a dose-dependent manner. Both drugs could be promising tools for further studies., Conclusions: Thallium-sensitive fluorescent assay represents a reliable methodological tool for the primary screening of different molecules with potential activity on Kv10.1 channels or other K + channels., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

In recent years, there has been an emergence of numerous novel drugs. Such toxicity may occur in both adolescents and adults. This article discusses the opioid epidemic and several emerging opioids, including buprenorphine, loperamide, fentanyl, fentanyl derivatives, and others. Kratom, a plant occasionally used for opiate detoxification, along with the sedatives etizolam and phenibut, will be discussed. Lastly, this article discusses the phenethylamines and marijuana., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction that negatively affects work productivity and health-related quality of life (HRQOL). IBS-D therapeutic options are limited and include loperamide, an over-the-counter μ-opioid receptor agonist commonly used as an antidiarrheal agent, and eluxadoline, a mixed μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved in the United States for the treatment of IBS-D in adults. OBJECTIVE: To characterize the effect of eluxadoline on work productivity and HRQOL in patients with IBS-D with previous inadequate response to loperamide. METHODS: The Work Productivity and Activity Impairment Questionnaire for IBS-D (WPAI:IBS-D), Centers for Disease Control and Prevention Healthy Days Core Module (CDC HRQOL-4), and EuroQoL-5 Dimension (EQ-5D) instruments were administered at baseline and week 12 of a phase 4 clinical trial (RELIEF), assessing the efficacy and safety of eluxadoline treatment in adults with IBS-D reporting previous inadequate response to loperamide. Changes from baseline to week 12 for each assessment were evaluated using an analysis of covariance model. Indirect costs were calculated by converting overall work productivity losses into monetary values. RESULTS: A total of 346 patients were randomized to either eluxadoline (n = 172) or placebo (n = 174). From baseline to week 12, compared with placebo, twice-daily treatment with eluxadoline resulted in significantly greater reductions in absenteeism (2.6%; P = 0.046). Numerically greater decreases in presenteeism, overall work productivity loss, and daily activity impairment were also observed in patients receiving eluxadoline compared with those receiving placebo ( P = not significant for each). Numerical reductions in overall work productivity loss from baseline to week 12 translate to approximately 2.4 hours per patient per week (123 hours annually) and correspond to an avoided overall work loss of $4,503 annually for an employee with IBS-D treated with eluxadoline. In addition, from baseline to week 12, treatment with eluxadoline led to a significantly greater reduction in the number of unhealthy days experienced (-1.7 days; P = 0.042), as well as numerical improvements in EQ-5D measures in comparison with placebo ( P = not significant for each). CONCLUSIONS: In patients with IBS-D reporting inadequate response to loperamide, eluxadoline treatment was associated with significant reductions in absenteeism and the number of unhealthy days experienced. Eluxadoline treatment of IBS-D may lead to significant cost savings via mitigation of losses in work productivity. DISCLOSURES: This study was sponsored by Allergan plc (before acquisition by AbbVie, Inc.). Allergan plc and/or AbbVie, Inc., was involved in the study design, collection, analysis, interpretation of the data, writing of the report, and the decision to submit the report for publication. Abel and Burslem are employees of AbbVie, Inc., and own stock/stock options. Brenner has served as a consultant, speaker, and/or advisor for Allergan plc (before acquisition by AbbVie, Inc.), Alnylam, Alpha Sigma, Arena, Bayer, Ironwood Pharmaceuticals, Salix Pharmaceuticals, Shire, Synergy, and Takeda Pharmaceuticals. He is also supported in research by an unrestricted gift from the Irene D. Pritzker Foundation. Sayuk has served as a consultant and speaker for Allergan plc (before acquisition by AbbVie, Inc.), Gi Health Foundation, Ironwood Pharmaceuticals, Salix Pharmaceuticals, and Synergy. Portions of the current work were presented at AMCP Nexus; October 22-25, 2018; Orlando, FL.

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

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

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

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

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

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

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

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

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., (© 2019 John Wiley & Sons Ltd.)

Background: The use of regional and other opioid-sparing forms of anesthesia has been associated with a decrease in the recurrence of certain malignancies. Direct suppression of human natural killer cells by opioids has been postulated to explain this observation. However, the effect of different classes of opioids on suppression of natural killer cell cytotoxicity has not been systematically characterized., Methods: After confirming that freshly isolated natural killer cells from peripheral human blood express opioid receptors, cells were incubated with increasing concentrations of clinically used or receptor-specific opioid agonists. We also evaluated the effect of pretreatment with receptor-specific antagonists or naloxone. Treated natural killer cells were then coincubated with a carboxyfluorescein succinimidyl ester-labeled target tumor cell line, K562. Annexin V staining was used to compare the percent of tumor cell apoptosis in the presence of opioid-pretreated and untreated natural killer cells. Treated samples were compared to untreated samples using Kruskal-Wallis tests with a post hoc Dunn correction., Results: Morphine, methadone, buprenorphine, loperamide, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, and U-50488 significantly decreased natural killer cell cytotoxicity. When natural killer cells were pretreated with naloxone, cyprodime, and nor-binaltorphimine before exposure to morphine, there was no difference in natural killer cytotoxicity, compared to the amount observed by untreated natural killer cells. Fentanyl, O-desmethyltramadol, and [D-Pen2,D-Pen5] enkephalin did not change natural killer cell cytotoxicity compare to untreated natural killer cells., Conclusions: Incubation of isolated natural killer cells with certain opioids causes a decrease in activity that is not observed after naloxone pretreatment. Suppression of natural killer cell cytotoxicity was observed with μ- and κ-receptor agonists but not δ-receptor agonists. These data suggest that the effect is mediated by μ- and κ-receptor agonism and that suppression is similar with many clinically used opioids.

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

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

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.

Background: Among over-the-counter (OTC) drugs, loperamide has recently emerged for its potential of misuse and cardiotoxicity issues. Hence, we aimed here at assessing the loperamide-related cases being reported to the EMA's EudraVigilance (EV) database., Methods: All spontaneous EV reports relating to loperamide misuse/abuse/dependence/withdrawal and cardiotoxicity issues were here retrieved, performing a descriptive analysis., Findings: During the years 2005-2017, EV collected a number of 1,983 (out of a total of 7,895; 25.11%) loperamide-related misuse/abuse/dependence/withdrawal adverse drug reaction (ADR) reports, with a progressively increasing trend since 2014. Most cases were classified as drug use disorder (37.4%) or intentional overdose (25.4%). Loperamide was used on its own in 41.9% of cases; remaining, polydrug, cases included antidepressants; benzodiazepines; and other OTCs. Some 1,085 (1,085/7,895 = 13.7%) cardiovascular ADRs were reported, being conduction abnormalities and EKG alterations the most frequently identified., Conclusions: EV data may support the levels of concern relating to loperamide potential of abuse and associated cardiotoxicity issues., Competing Interests: The authors have declared that no competing interests exist.

Effective drug delivery to the deeper ocular tissues remains an unresolved conundrum mainly due to the expression of multidrug resistance efflux proteins, besides tight junction proteins, in the blood ocular barriers (BOBs). Hence, the purpose of the current research was to investigate the ability of the third-generation efflux protein inhibitors, elacridar (EQ), and tariquidar (TQ), to diminish P-glycoprotein (P-gp) mediated efflux transport of loperamide (LOP), a P-gp substrate, across the BOB in Sprague Dawley rats. Initially, Western blot analysis confirmed the expression of P-gp in the iris-ciliary bodies and the retina choroid in the wild type rats. Next, the ocular distribution of LOP, in the presence and absence of EQ/TQ (at 2 doses), was evaluated. The significantly higher aqueous humor/plasma (D AH ) and vitreous humor (VH)/plasma (D VH ) distribution ratios of LOP in the rats pretreated with EQ or TQ demonstrated effective inhibition of P-gp activity in the BOB. Interestingly, the modulation of P-gp activity by EQ/TQ was more pronounced at the lower dose. The normal functioning and architecture of the retina, as indicated by electroretinography studies, confirmed the cytocompatibility of LOP and EQ/TQ interactions at the doses tested., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The current research was undertaken to determine the existence and magnitude of P-glycoprotein (P-gp) expression on the blood-ocular barriers by studying the ocular penetration of loperamide, a specific P-gp substrate, in P-gp (Mdr1a) knock-out (KO) and wild type (WT) Sprague Dawley rats. A clear, stable, sterile solution of loperamide (1 mg/mL), for intravenous administration, was formulated and evaluated. Ocular distribution was studied in P-gp KO and WT rats following intravenous administration of loperamide (at two doses). The drug levels in plasma, aqueous humor (AH), and vitreous humor (VH) samples were determined with the aid of UHPLC-Q-TOF-MS/MS, and the AH/plasma (D AH ) and VH/plasma (D VH ) distribution ratios were estimated. Electroretinography (ERG), ultrastructural analyses, and histology studies were carried out, in both KO and WT rats, to detect any drug-induced functional and/or structural alterations in the retina. Dose-related loperamide levels were observed in the plasma of both WT and KO rats. The loperamide concentrations in the AH and VH of KO rats were significantly higher compared to that observed in the WT rats, at the lower dose. However, a marked increase in the D AH and D VH was noted in the KO rats. ERG, ultrastructure, and histology studies did not indicate any drug-induced toxic effects in the retina under the test conditions. The results from these studies demonstrate that P-gp blocks the penetration of loperamide into the ocular tissues from the systemic circulation and that the effect is more pronounced at lower plasma loperamide concentrations.

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

Background: Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and changes in bowel habit. The aim of this study was to characterize the effect of loperamide hydrochloride (LOP) and naloxone hydrochloride (NLX), an opioid agonist and antagonist, respectively, on electrolyte equilibrium in ileal and colonic mucosae and to estimate the possible influence of divergent activity of the endogenous opioid system (EOS) on IBS therapy., Methods: Two mouse lines bidirectionally selected for high (HA) and low (LA) swim stress-induced analgesia associated with high and low EOS activity were used in this study. To assess the effect of LOP and NLX on HA/LA lines in vivo, we used the castor oil-induced diarrhea model. Changes in electrolyte equilibrium were determined on the basis of short-circuit current (ΔI sc ) in isolated mouse ileum and colon exposed to LOP and NLX and stimulated by forskolin (FSK), veratridine (VER), and bethanechol (BET)., Key Results: In vivo, we found that LOP significantly prolonged time to appearance of diarrhea in HA and LA lines. In vitro, LOP and NLX increased ΔI sc in FSK- and VER-stimulated colonic tissue, respectively, in HA line. In the ileum, LOP increased ΔI sc in FSK- and VER-stimulated tissue and decreased ΔI sc in BET-stimulated tissues in HA line., Conclusions & Inferences: Individual differences in EOS activity may play a crucial role in the response to the IBS-D therapy, thus some patients may be at an increased risk of side effects such as constipation or diarrhea., (© 2017 John Wiley & Sons Ltd.)

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., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Loperamide is a nonprescription opioid widely used for the treatment of diarrhea. Although it is relatively safe at therapeutic doses, increasing reports describe its misuse and abuse at very high doses either for euphoric effects or to attenuate symptoms of opioid withdrawal. Life-threatening loperamide toxicity can result from the relatively new clinical syndrome of loperamide-induced cardiac toxicity. These patients are often young and may present in cardiac arrest or with unheralded, recurrent syncope in conjunction with ECG abnormalities, including marked QT-interval prolongation, QRS-interval widening, and ventricular dysrhythmias. Features of conventional opioid toxicity may also be present. The mainstays of treatment include advanced cardiac life support and supportive care, although selected patients may be candidates for overdrive pacing, intravenous lipid emulsion, or extracorporeal membrane oxygenation. In patients who survive loperamide toxicity, consideration should be given to the treatment of an underlying opioid use disorder, if present., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

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

Case: A 41year-old male presented with torsades de pointes. The patient was taking over 100mg of loperamide per day to self-medicate for chronic pain. Coronary angiography, cardiac magnetic resonance imaging, and genetic testing were negative for pre-disposing ischemia, cardiomyopathy, or genetic variant respectively., Conclusions: Patients without predisposing genetic or cardiac abnormalities are at risk of life-threatening QTc prolongation and torsades with use of high-dose loperamide. The authors suggest consideration of regulating the quantity of loperamide that can be purchased at a single time similar to the regulations in place for other over-the-counter medications with high potential for misuse., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use., Methods: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016., Results: Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms., Conclusion: The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias., (Published by Elsevier Inc.)

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

Objective: The epidemic of opioid prescription deaths in recent years resulted in the recent rescheduling of hydrocodone-containing products to restrict access to them. Opioid users have recognized that loperamide can ameliorate withdrawal symptoms and also produce euphoria in very high doses. This article discusses the potential for loperamide misuse and abuse and examines trends in the increasing number of published cases of loperamide toxicity., Design: PubMed was used to search MEDLINE for case reports of loperamide abuse., Setting: United States., Main Outcome Measures: Numbers of cases of loperamide misuse, characteristics of patients, reported toxicities., Results: From 1985 to 2016, 54 case reports of loperamide toxicity were published, with 21 cases between 1985 and 2013 and 33 cases between 2014 and 2016. In addition, 179 cases of intentional loperamide misuse were reported to the National Poison Database System between 2008 and 2016, with more than half reported after January 1, 2014., Conclusion: Loperamide misuse and abuse is increasing in the United States, and pharmacists are encouraged to monitor and restrict their sales., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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

Loperamide is widely available as an inexpensive, over-the-counter remedy commonly used for management of diarrhea. Although an opioid, at therapeutic doses it acts primarily on the gastrointestinal tissues; however, larger than recommended amounts facilitate central nervous system (CNS) penetration. Such high doses of loperamide have recently gained popularity among users of opioids to manage withdrawal symptomatology and, less frequently, to achieve psychoactive effects. Chronic loperamide use can result in development of tolerance and, upon abrupt cessation of use, withdrawal. With increasing prevalence of use, side-effects are noted, one particularly being life-threatening cardiac arrhythmias. Users are often not forthcoming and routine drug screens do not detect loperamide, so providers need to be alert to such practices in order to recognize intoxication, be able to screen for use, and facilitate entry into treatment.

Aim: To investigate the effects of Lizhong Tang, a traditional Chinese medicine formula, on gastrointestinal motility in mice., Methods: The in vivo effects of Lizhong Tang on GI motility were investigated by measuring the intestinal transit rates (ITRs) and gastric emptying (GE) values in normal mice and in mice with experimentally induced GI motility dysfunction (GMD)., Results: In normal ICR mice, the ITR and GE values were significantly and dose-dependently increased by Lizhong Tang (ITR values: 54.4% ± 1.9% vs 65.2% ± 1.8%, P < 0.01 with 0.1 g/kg Lizhong Tang and 54.4% ± 1.9% vs 83.8% ± 1.9%, P < 0.01 with 1 g/kg Lizhong Tang; GE values: 60.7% ± 1.9% vs 66.8% ± 2.1%, P < 0.05 with 0.1 g/kg Lizhong Tang and 60.7% ± 1.9% vs 72.5% ± 1.7%, P < 0.01 with 1 g/kg Lizhong Tang). The ITRs of the GMD mice were significantly reduced compared with those of the normal mice, which were significantly and dose-dependently reversed by Lizhong Tang. Additionally, in loperamide- and cisplatin-induced models of GE delay, Lizhong Tang administration reversed the GE deficits., Conclusion: These results suggest that Lizhong Tang may be a novel candidate for development as a prokinetic treatment for the GI tract., Competing Interests: Conflict-of-interest statement: The authors declared that they have no conflicts of interest to this work.

Methylnaltrexone (MNTX) is approved for subcutaneous treatment (MNTX-SC) of opioid induced constipation. MNTX in oral immediate-release (MNTX-IR) and extended-release (MNTX-ER) dosage forms may antagonize the opioid induced delay in oro-cecal transit time (OCT) as measured by using radiolabeled lactulose. Because lactulose acts laxative by its own and efficacy of MNTX on colon transit time (CTT) was unknown, the opioid antagonistic effects MNTX-IR and MNTX-ER (both 500 mg) relative to MNTX-SC (12 mg) were evaluated in 15 healthy subjects with loperamide (LOP, 3 × 4 mg, 12 hourly) induced experimental constipation using the sulfasalazine/sulfapyridine method and radio-opaque markers to measure OCT and whole gut transit time (WGT). MNTX-ER significantly antagonized the LOP effects in 12 of our 15 subjects who responded to LOP with prolongation of WGT by 20.6-74.1 h (OCT by 0.50-10.5 h, CTT by 18.3-73.6 h). MNTX-SC and MNTX-IR were without significant influence. Compared to MNTX-SC, bioavailability of MNTX-IR and MNTX-ER was 1.53-5.49% and 0.11-1.24%, respectively. MNTX-SC and MNTX-IR achieved active serum levels only for ∼ 3-5 h. MNTX-ER antagonized the opioid-induced delay of CTT most likely by local effects on µ-opioid receptors in the colon., (© 2015, The American College of Clinical Pharmacology.)

Antimicrobial drug treatment of travelers' diarrhea is known to increase the risk for colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae. Among 288 travelers with travelers' diarrhea, the colonization rate without medications was 21%. For treatment with loperamide only, the rate was 20%; with antimicrobial drugs alone, 40%; and with loperamide and antimicrobial drugs, 71%.

Background: Fecal incontinence is a devastating condition with few US Food and Drug Administration-approved pharmacologic treatment options. Loperamide and psyllium, both first-line treatments, have different mechanisms of action without any comparative data., Objective: The purpose of this study was to examine the effectiveness and tolerability of loperamide compared with psyllium for reducing fecal incontinence. We hypothesized that psyllium fiber supplementation would be more effective than loperamide for reducing fecal incontinence episodes and have fewer adverse effects., Design: We conducted a randomized, double-blind, placebo-controlled crossover trial comparing loperamide (followed by psyllium) with psyllium (followed by loperamide)., Settings: Our sites included outpatient clinics within a Veterans Affairs medical center and university affiliate., Patients: Participants included community-dwelling adults (n = 80) with at least 1 fecal incontinent episode on a 7-day bowel diary., Intervention: Participants received either daily loperamide (plus placebo psyllium powder) or psyllium powder (plus loperamide placebo) for 4 weeks. After a 2-week washout, participants crossed over to 4 weeks of alternate treatment., Main Outcome Measures: The primary outcome was the number of fecal incontinence episodes from 7-day bowel diaries. Secondary outcomes included symptom severity, quality of life, and tolerability., Results: Mean age was 60.7 ± 10.1 years; 68% were men. After determining nonsignificant carryover effects, combined analyses showed no differences between the loperamide and psyllium groups for reducing fecal incontinent episodes, symptom severity, or quality of life. Within each group, both loperamide and psyllium reduced fecal incontinent episodes and improved symptom severity and quality of life. Constipation occurred in 29% of participants for loperamide vs 10% for psyllium., Limitations: Limitations include the washout period length and dropout rate after crossing over to the second intervention., Conclusions: Both loperamide and psyllium improve fecal incontinence. Loperamide was associated with more adverse effects, especially constipation.

The aim of this work was the development of orodispersible films containing different film forming polymers with focus on different drug loadings of two poorly water soluble APIs. Furthermore, physical stability of films was examined at two different storage conditions. Loperamide hydrochloride (LPH) and ibuprofen (IBU) were used as model drugs. Hydroxypropyl methylcellulose (HPMC) and three different types of hydroxypropyl cellulose (HPC) were used as film forming polymers. Suspensions were characterized with respect to their viscosity and particle sedimentation and films regarding their content uniformity, thickness, mass and stability. Principal component analysis (PCA) was used to evaluate the correlation between the wet film thickness, dry film thickness, mass of the films, API fraction in the suspension and the viscosity of the suspensions. The viscosity of the suspensions was dependent on the drug load and the polymer fraction but less so on the type of the utilized polymer. A correlation between the wet film thickness, the solid fraction and the mass of the films was established with an increase in mass by increasing the wet film thickness or the solid fraction. Films containing 50 mg IBU/6 cm(2) film led to acceptable films. Storage experiments did not lead to an AV below 15 in all cases after storage for three and six months, attributed to the storage conditions and the quality of the films. Nevertheless, the development and production of flexible and homogeneous films of LPH and IBU was successfully achieved., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Biofeedback and medical treatments have been extensively used for moderate fecal incontinence (FI). There is limited data comparing and combining these two treatments. The objective of this study was to evaluate the effect of biofeedback and medical treatments, separately and in combination., Material and Methods: Sixty-four consecutive female patients, referred to a tertiary centre for FI, were included. The patients were randomized to start with either biofeedback (4-6 months) or medical treatment with loperamide and stool-bulking agents (2 months). Both groups continued with a combination of treatments, i.e. medical treatment was added to biofeedback and vice versa. A two-week prospective bowel symptom diary and anorectal physiology were evaluated at baseline, after single- and combination treatments., Results: Fifty-seven patients completed the study. Median number of leakage episodes during two weeks decreased from 6 to 3 (p < 0.0001) from baseline to completion. The patients showed a significant (1) decrease in number of leakages without forewarning (p = 0.04); (2) decrease in number of stools with urgency (p = 0.001); (3) decrease in number of loose stool consistency; and (4) an increase in rectal sensory thresholds, both for maximum tolerable rectal pressure and first sensation (<0.01). The combination treatment was superior to both single treatments in terms of symptoms and functions. There was no significant difference between the two groups at any time point., Conclusions: The combination therapy with biofeedback and medical treatment is effective for symptom relief in FI. The symptom improvement was associated with improved fecal consistency, reduced urgency, and increased rectal sensory thresholds.

High-stoma output is a common problem that can lead to dehydration and electrolyte disturbance. The following report describes three patients with end ileostomy who had high-stoma outputs where conventional medical management was unsuccessful in controlling stoma output. All three patients responded to high-dose loperamide, resulting in significant clinical improvement. High-dose loperamide therapy should be considered in patients with high-stoma output who have failed conventional medical management., (2015 BMJ Publishing Group Ltd.)

Objectives: The potential of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) surface modified with octa-arginine (R8) for central nervous system (CNS) delivery was investigated., Methods: PLGA NPs containing coumarin-6 or loperamide were surface modified using R8 and characterised for size, zeta potential, drug loading and release. We examined the cellular uptake of NPs in Madin-Darby Canine Kidney (MDCK) cells and CNS delivery of loperamide in a mouse model following intranasal (i.n.) and intravenous (i.v.) administration., Key Findings: NPs were 300-350 nm in diameter and of negative zeta potential which neutralised on R8 conjugation. Cellular uptake of R8-PLGA NPs was rapid compared with PLGA NPs and correlated with a high antinociceptive effect in mice by both the i.n. and i.v. routes. Little antinociceptive effect for PLGA NPs was observed reflecting their slow uptake in the in-vitro cell model., Conclusion: This study demonstrates the potential of R8-PLGA NPs as carriers of therapeutic agents to the CNS., (© 2014 Royal Pharmaceutical Society.)

Loperamide is an antidiarrheal medication deemed by the U.S. Food and Drug Administration as safe enough to be sold as an over-the-counter medicine. Unlike other μ-opioid receptor agonists, loperamide acts specifically in the myenteric plexus in the gastrointestinal tract, making the potential for abuse low and reports of toxicity extremely rare. We present a case of a patient previously in good health who developed episodes of cardiac pauses, nonsustained ventricular tachycardia, and eventually runs of sustained ventricular tachycardia with hemodynamic instability. She required cardiopulmonary resuscitation, multiple cardioversions, and placement of a pacemaker. Her medical history was remarkable only for type 2 diabetes and chronic postcholecystectomy diarrhea. Metformin was the only prescription medication she was taking at the time of presentation. However, she reported that she had been taking an entire bottle of Equate brand loperamide (144 mg) daily for ~2 years. Loperamide overdoses associated with ventricular arrhythmias have been reported, but this is the first case to describe a serious ventricular arrhythmia associated with long-term use of a high dose of loperamide. Chronic overtreatment with loperamide may induce life-threatening arrhythmias., (© 2015 Pharmacotherapy Publications, Inc.)

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance-drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro-in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6',7'-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration-time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute(-1)). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance-drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Peripheral opioid receptor targeting has been well established as a novel target in clinical pain management for acute and chronic peripheral inflammatory pain. The physiochemical properties of the peripheral mu-opioid receptor agonist, loperamide HCl, limit the use of the free drug as an analgesic or anti-inflammatory agent, particularly for dermal delivery across intact skin., Objective: Our objective was to manufacture an effective topical formulation containing loperamide using liposomal delivery that would allow loperamide to produce analgesia and anti-inflammatory effects, by penetrating the epidermis to reach peripheral opioid receptors within the dermis of intact skin., Study Design: A randomized, double blind, controlled animal trial., Methods: Thirty-five adult male Wistar rats (200 - 250 g) were randomly divided into 5 groups: loperamide HCl-encapsulated liposomal gel, naloxone methiodide + loperamide HCl-encapsulated liposomal gel, free loperamide gel, empty liposomal gel, and 1% diclofenac gel (Voltaren®). Diclofenac gel was used as a positive control as it is clinically used as a topical analgesic and anti-inflammatory drug. Animals received an intraplantar injection of 150 μl Complete Freund's Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All manufactured formulations were applied topically on both hind paws twice daily, whereas Voltaren gel was applied 3 times a day in accordance with the manufacturer's instructions. The dose administered was 50 μl, which equated to 0.4 mg of loperamide HCl for the loperamide HCl treatment groups (low dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to application of loperamide HCl-encapsulated liposomal gel to determine opioid receptor dependent activity. An investigator blinded to the treatment administered assessed time course of the antinociceptive and anti-inflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively., Results: Application of loperamide HCl in a liposomal gel formulation exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. This formulation produced highly significant analgesic and anti-inflammatory effects over the 48-hour time course studied following topical administration in rats with CFA-induced inflammation of the paw. As expected, the diclofenac gel group showed significant antinociception over the duration of the study; however, this effect was lower in comparison to the loperamide HCl liposomal gel formulation. All other control groups showed no significant antinociceptive effects. In addition, all control groups (1% diclofenac gel, free loperamide gel, and empty liposomal gel) did not demonstrate a significant change in paw volume over 48 hours., Limitations: In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response., Conclusions: The study demonstrates that topically applied loperamide encapsulated within liposomal systems has improved therapeutic efficacy over conventional formulations for the local treatment of acute peripheral inflammatory pain conditions where the skin has remained intact. Once in the inflamed peripheral tissue, loperamide provides analgesic and anti-inflammatory effects in a similar manner to peripheral endogenous opioids. This preparation optimises the retention of drug at the site where action is required.

Objective: This study assessed the efficacy of education and self-treatment with loperamide on diarrhea morbidity and healthcare utilization in a deployed military setting., Method: In this prospective, controlled study, volunteers from military personnel deployed to Incirlik Air Base received either travelers' diarrhea education (non-loperamide group) or education plus a supply of loperamide (loperamide group). Volunteers were surveyed to determine frequency and outcomes of diarrheal illness., Results: 109 deployed personnel were enrolled with 48 assigned to the loperamide group, and 61 to the non-loperamide group. Overall, 41 (38%) service members had at least one diarrheal episode. Only 10 (9%) service members sought treatment from a healthcare provider and the distribution was similar in both groups. Loperamide use for self-treatment was more common in the loperamide group (85%) vs. (57%), [p = 0.02]) but use of antibiotics was similar in both groups (loperamide (30%) vs. non-loperamide (20%)., Conclusions: Provision of loperamide and education did not significantly affect healthcare utilization or antibiotic use to manage diarrheal episodes, when compared to education alone. Further prospective studies will either need a very large patient population to power them or should use other primary end points such a functional assessment in addition to seeking care., (Published by Elsevier Ltd.)

The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3- and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.