Improved work productivity and health-related quality of life in patients with irritable bowel syndrome with diarrhea receiving eluxadoline following inadequate response to loperamide.

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.

Prosecretory effect of loperamide in ileal and colonic mucosae of mice displaying high or low swim stress-induced analgesia associated with high and low endogenous opioid system activity.

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 (ΔIsc ) 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 ΔIsc in FSK- and VER-stimulated colonic tissue, respectively, in HA line. In the ileum, LOP increased ΔIsc in FSK- and VER-stimulated tissue and decreased ΔIsc 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.

Effects of Lizhong Tang on gastrointestinal motility in mice.

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.

Loperamide Versus Psyllium Fiber for Treatment of Fecal Incontinence: The Fecal Incontinence Prescription (Rx) Management (FIRM) Randomized Clinical Trial.

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.

Combination therapy with biofeedback, loperamide, and stool-bulking agents is effective for the treatment of fecal incontinence in women - a randomized controlled trial.

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.

Comparison of in vitro dialysis release methods of loperamide-encapsulated liposomal gel for topical drug delivery.

BACKGROUND: The purpose of this study was to determine the most appropriate dialysis equilibrium method to assess liposomal gel formulations containing hydrophobic drugs, to give the most accurate indication of drug release. METHODS: Loperamide hydrochloride-encapsulated liposomes, composed of L-α-phosphatidylcholine and cholesterol (molar ratio of 2:1), were prepared according to the method of dried lipid film hydration. The liposomes were incorporated into a carbopol gel (0.5%, weight/weight). The release of the drug from the nanoparticles was assessed using a number of variations of the dialysis technique, taking into account solubility parameters and formulation. Method 1 (below saturation point) and Method 2 (above saturation point) used a dilution method to evaluate how drug concentration and solubility affects the in vitro drug-release profile of loperamide hydrochloride, while Methods 3 (below saturation point) and 4 (above saturation point) evaluated how drug concentration and the gel base affect the release profile. RESULTS: In Method 1, the liposomes showed a rapid release of just over 60% in the first 3 hours and then a slower, sustained release to just over 70% at 24 hours. Method 2 showed a gradual, sustained release profile with the liposomes with 55% release at 24 hours. In Method 3, the liposomes showed a rapid burst release of 98% at 2 hours. In Method 4, the liposomal gel had a rapid release of 60% within 3 hours and then a more gradual, sustained release with 86% release at 24 hours. The free drug suspension in Methods 2 and 4 showed a limited release across the dialysis membrane, in comparison to Methods 1 and 3, which showed a complete release in a timely manner. CONCLUSION: This study has demonstrated that the actual method used for equilibrium dialysis plays a significant role in determining the true characteristics of a topical nanoformulation, with Method 3 providing the most accurate indication of the release of a hydrophobic drug from a topical liposomal formulation.

[Clinical efficacy of buzhong yiqi pill combined with imodium in treating post-operational diarrhea in patients of colonic cancer].

OBJECTIVE: To investigate the clinical efficacy of Buzhong Yiqi Pill (BYP) combined with imodium in treating post-operational diarrhea in patients undergoing colonic cancer surgery. METHODS: Eighty patients with diarrhea after colorectal cancer surgery were randomized into two groups equally, the control group were treated with imodium (loperamide hydrochloride) and the treatment group treated by BYP combined with imodium. The therapeutic efficacy was analyzed and evaluated comprehensively depending upon a defecation check table developed from the XU Zhong-fa's 5-item 10-integrable system. RESULTS: After treatment, the improvements of the anal controlling capacity, the defecatory sensation, the frequency of defecation in the treatment group were significantly better than those in the control group (P < 0.01 or P < 0.05). The integral function of defecation in the treatment group was obvionsly improved by the end of treatment when compared with before treatment and the control group (P < 0.01). CONCLUSION: The clinical efficacy of the BYP combined with imodium in treating post-operational diarrhea after colorectal cancer surgery were better than that of imodium alone.

High-dose loperamide in the treatment of 5-fluorouracil-induced diarrhea in colorectal cancer patients.

Thirty-seven colorectal cancer patients with grade 1-4 diarrhea (NCICTC) caused by chemotherapy with 5-FU-containing regimens, received oral loperamide at the initial dose of 4 mg followed by 4 mg every 8 h (total dose 16 mg/24 h). Twenty-five patients (69%) were diarrhea-free and were considered to be treatment responders. Eight-four percent of the patients with grade 1 or 2 diarrhea achieved a response, but only 52% of those with grade 3-4 diarrhea. These data seem to suggest that high-dose loperamide is effective in patients with moderate diarrhea and can be regarded as the treatment of choice. The patients with more severe diarrhea did not respond so well, and should, perhaps, be given first-line treatment with more effective drugs, such as somatostatin analogues (e.g., octreotide).

Lack of influence of intestinal transit on oxidative status in premenopausal women.

OBJECTIVE: There are reasons for believing that diet can alter the risk of malignancy by alteration of the body's oxidative status. Intestinal contents and enterohepatically recirculated substances are influenced by intestinal transit rate. A low fibre diet has been linked to the increase in constipation seen in countries consuming a westernized diet, as well as to the aetiology of many diseases. We studied the effects of altering intestinal transit rates and of wheat bran on oxidative status. DESIGN: 40 premenopausal women were randomized to receive dietary supplements of wheat bran, senna or loperamide for the length of two menstrual cycles. Dietary records, whole gut transit time (WGTT) and plasma lipid peroxides, measured as TBARS (specifically malondialdehyde) were determined at the beginning and end of each intervention. SETTING: University department of Medicine, Bristol Royal Infirmary. RESULTS: 36 volunteers completed the study. WGTT increased in those receiving loperamide and decreased in those receiving senna. The decrease in WGTT was not significant in those receiving wheat bran. Diets did not change. There were no changes in TBARS, cholesterol, triglyceride or TBARS adjusted for cholesterol and triglyceride, during any intervention. CONCLUSIONS: Dietary supplementation with wheat bran and pharmacological alteration of intestinal transit had no influence on oxidative status or on plasma cholesterol or triglycerides.

Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.

The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.

The effects of octreotide, soy polysaccharide, codeine and loperamide on nutrient, fluid and electrolyte absorption in the short-bowel syndrome.

Four agents, which could delay intestinal transit, were tested in six short-bowel patients (jejunal length 30-120 cm) on long-term nutritional/electrolyte replacement therapy. Intestinal transit time of a liquid test meal and nutrient, water and sodium absorption were measured during a control study and with each test agent on separate days. Soy polysaccharide tended to increase transit time, but decreased the absorption of water, sodium and nutrients. Codeine phosphate and loperamide caused inconsistent and clinically unimportant changes. Octreotide, a long-acting analogue of somatostatin, delayed transit and increased water, sodium and calorie absorption from the meal. Octreotide appears to have the potential to reduce the need for electrolyte and nutritional supplements in patients with the short-bowel syndrome.