Chronic Idiopathic Constipation In Adults Research Articles

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

Exploring Pharmacological Treatments for Chronic Idiopathic Constipation in Adults: A Look Back to the Future

Despite great progress in pharmaceutical research, the medical treatment of chronic idiopathic constipation is far from ideal. The aim of the present article was to review literature data, focusing on poorly studied or commercially unavailable/unapproved drugs potentially useful for the treatment of chronic idiopathic constipation in adults. An extensive online literature search was conducted using the keywords "chronic constipation", "colon", "constipation", "drugs", "laxatives", and "treatment", in various combinations between January 1960 and December 2022. The literature search showed the presence of some drugs whose efficacy has only recently been demonstrated by modern investigations, and which are likely to be incorporated into future guidelines, of others that are proven effective and potentially effective on constipated patients but limited by small or relatively old studies, or by side effects which could be used in experienced hands, and of others that might be useful but lack a solid scientific background. Looking into the future for patients with chronic constipation might add some more tools to the therapeutic portfolio, especially for certain subgroups of these patients.

DIAGNOSIS AND MANAGEMENT OF CHRONIC IDIOPATHIC CONSTIPATION: A NARRATIVE REVIEW FROM A BRAZILIAN EXPERT TASK FORCE.

Chronic idiopathic constipation (CIC) is a condition that widely affects the global population, represents relevant healthcare resource utilization and costs, and impacts the individual's well-being. To review the consensus of expert societies and published guidelines on the diagnosis and treatment of CIC in adults, seeking to assist reasoning and decision-making for medical management of patients with CIC and provide a practical reference material. A Brazilian medical task force searched the scientific literature in the following electronic databases: MEDLINE/PubMed, SciELO, EMBASE and Cochrane, using the following descriptors: chronic constipation, diagnosis, management of chronic constipation. In addition, a review of articles on the mechanism of action, safety, and efficacy of therapeutic options available in Brazil was carried out. The diagnostic approach and the understanding of the pathophysiology present in CIC are essential items to indicate the appropriate therapy and to understand the ecosystem of the patient's needs. CIC is a common condition in adults, occurring more frequently in the elderly and in women. Proper management is defined by detailed medical history and physical examination, together with appropriate therapeutics, regardless pharmacological or not, and depending on the best moment of indication. This way, the impact on quality of life is also optimized.

Chronic Idiopathic Constipation in Adults: A Review on Current Guidelines and Emerging Treatment Options.

Chronic idiopathic constipation (CIC) is a common functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation. It has a great impact on the quality of life and on health care system and represents a heavy economic burden. The diagnosis is based on symptoms, classified by the Rome IV criteria. The aim of this review was to evaluate the current therapeutic guidelines for adult CIC and highlight new emerging treatments. In detail, European, French, Spanish and Korean guidelines have been identified and compared. Osmotic laxatives, and in particular polyethylene glycol, represent the first-line therapeutic approach. Stimulant laxatives are recommended as a second-line therapy. Pelvic floor rehabilitation is recommended in patients with ano-rectal dyssynergia. In patients who fail to improve with pharmacological therapies sacral nerve stimulation is considered as last chance before surgery. Surgical approach has however limited indications in selected cases. Inertia coli refractory to any approach and obstructed defecation are two subtypes which can benefit from surgery. Among emerging agents, prucalopride, a prokinetic agent, is recommended as a second-line treatment in refractory CIC patients. In addition, the secretagogues linaclotide and plecanatide and the bile acid transported inhibitor elobixibat can be effective in patients not responsive to a second-line therapeutic regimen, although they are not worldwide commercially available.

Current Opinion on Prucalopride in Gastroparesis and Chronic Constipation Treatment: A Focus on Patient Selection and Safety.

Prucalopride is a third-generation, highly selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist. Many recent studies indicate prucalopride may play an important role in various motility disorders. The aim of this study was to investigate safety and patient selection considerations when using prucalopride as gastroparesis and chronic constipation treatment. We systematically searched PubMed, Embase, the Cochrane Central Register and ClinicalTrials.gov, and we reviewed all studies that evaluated prucalopride for the treatment of gastroparesis and chronic idiopathic constipation in adults. Prucalopride is an effective and safe option based on all the studies currently conducted. Thus, it may be the first-line treatment in the future. Prucalopride has the potential to be useful in the treatment of functional constipation and other forms of gastrointestinal diseases (eg, gastroparesis). Through the research on this potential, prucalopride is expected to be a useful and versatile option for treating gastrointestinal diseases in the future.

Effect of Rosa damascene Mill. Hydroalcoholic Extract on the Treatment of Chronic Idiopathic Constipation in Adults

Effect of Rosa damascene Mill. Hydroalcoholic Extract on the Treatment of Chronic Idiopathic Constipation in Adults

Global Prevalence of Chronic Idiopathic Constipation According to the Rome Criteria: Systematic Review and Meta-Analysis

Background: Chronic idiopathic constipation (CIC) is a common functional bowel disorder in the community, whose prevalence varies across cross-sectional surveys. We performed a contemporaneous systematic review of studies using comparable methodology, and all iterations of the Rome criteria, to estimate global prevalence. Methods: MEDLINE, EMBASE, and EMBASE Classic were searched (from 1990 to December 2020) to identify population-based studies reporting the prevalence of CIC in adults (≥18 years old) according to Rome I, II, III, or IV criteria. Prevalence of CIC was extracted, according to criteria used to define it. Pooled prevalence, according to study location and certain other characteristics, odds ratios (OR), and 95% confidence intervals (CIs) were calculated. Findings: Of 8,174 citations evaluated, 45 studies fulfilled eligibility criteria, representing 80 separate populations, containing 275,260 subjects. Pooled prevalence was 15.3% (95% CI 8.1% to 24.4%) in studies defining CIC according to the Rome I criteria, 10.8% (95% CI 7.3% to 14.8%) using Rome II, 11.3% (95% CI 6.8% to 16.7%) with Rome III, and 10.1% (95% CI 8.7% to 11.6%) when Rome IV criteria were used. Prevalence of CIC was up to two times higher in women, irrespective of definition used. There was significant heterogeneity between studies in all our analyses, which persisted even when the same criteria were applied and similar methodology used. Interpretation: Even when uniform symptom-based criteria are used to define the presence of CIC, prevalence varies between countries. Thus, environmental, cultural, ethnic, dietary, or genetic factors may influence reporting of symptoms. Funding: None Declaration of Interest: None

The Humanistic and Economic Burden of Chronic Idiopathic Constipation in the USA: A Systematic Literature Review.

BackgroundChronic idiopathic constipation (CIC) is a functional gastrointestinal disorder with an estimated prevalence of 16% in the USA; however, the humanistic and economic burden of CIC is poorly characterized.AimThis systematic literature review aimed to assess the humanistic and economic burden of CIC in adults in the USA.MethodsTwo systematic literature searches of English-language publications on the humanistic and economic burden of CIC in adults in the USA were conducted using electronic databases and other resources. Both searches included the terms “chronic idiopathic constipation” and “functional constipation”. Specific terms used in the search on humanistic burden included “quality of life”, “SF-36”, “SF-12”, and “PAC-QOL”; search terms for economic burden included “cost”, “resource use”, “absenteeism”, and “productivity”.ResultsOverall, 16 relevant articles were identified. Health-related quality of life (HRQoL) appeared to be reduced in patients with CIC compared with controls and the general US population. Abdominal (r=0.33–0.49), stool (r=0.23–0.33), and rectal symptoms (r=0.53) appeared to be associated with reduced HRQoL. Younger age and female sex were associated with reduced overall HRQoL and greater symptom severity. Direct outpatient costs were higher in patients with CIC than those without CIC (US$6284 vs US$5254). Patients with CIC and abdominal symptoms reported more days of disrupted productivity per month than those without abdominal symptoms (3.2 days vs 1.2 days). The overall prevalence of complementary and alternative medicine use by patients with CIC was similar to that in the general US population.ConclusionThe reduced HRQoL and increased costs associated with CIC indicate unmet therapeutic need in this disorder. Further research is required to better understand the humanistic and economic burden of CIC in the USA.

Are probiotics useful in the treatment of chronic idiopathic constipation in adults? A review of existing systematic reviews, meta-analyses, and recommendations.

Chronic idiopathic constipation (CIC) has emerged as common problem for contemporary gastroenterology and is one of the most frequent complaints in primary care. Chronic idiopathic constipation significantly affects patients’ quality of life and has an impact on global health and economy. Functional gastrointestinal disorders and bowel disorders, according to Rome IV criteria, result from inappropriate gut-brain interactions. The pathophysiology is complex and poorly understood, with evidence accumulating that gut microbiota can be implicated in the development and function of the enteric nervous system. Gut bacteria modulate gut barrier function, short chain fatty acid synthesis, and bile acid metabolism, factors which play roles in the gut peristalsis regulation. The high prevalence of CIC, with poor treatment outcomes, warrants searches for new forms of therapy, including probiotic therapies. Probiotics are often recommended by medical practitioners, but evidence-based utility in adults with CIC is uncertain. Recommendations/guidelines are often based on results from individual studies, rather than meta-analyses or umbrella reviews. Additionally, meta-analyses often indicate a group of probiotics rather than individual strains, and they create difficulty for physicians in making therapeutic choices. More CIC patient randomised clinical studies utilising well-defined strains, or combinations, are necessary.

Use of prucalopride in adults with chronic idiopathic constipation

ABSTRACTIntroduction: Prucalopride is a selective 5-HT4 receptor agonist with colonic prokinetic activity. It was recently approved by the FDA for the treatment of chronic idiopathic constipation. Before this approval, there were limited options to improve colonic motility in the treatment of chronic idiopathic constipation.Areas covered: We systematically searched PubMed, Embase, ClinicalTrials.gov, and international conference presentations, and we reviewed all studies that evaluated prucalopride for the treatment of chronic idiopathic constipation in adults. In this review, we discuss the pharmacokinetics, pharmacodynamics, receptor interactions, phase I-IV clinical trials, and safety outcomes of prucalopride in adults, including the elderly.Expert opinion: Prucalopride is an effective agent to improve colonic motility, decrease colonic transit time, and increase complete spontaneous bowel movements in patients with chronic idiopathic constipation. Unlike previously available 5-HT4 receptor agonists such as cisapride and tegaserod, prucalopride does not interact with the cardiac hERG potassium channels or other serotonergic receptors in blood vessels and is not associated with an increase in major adverse cardiovascular events. Additionally, prucalopride has demonstrated promise in the treatment of gastroparesis, post-operative ileus, and opioid-induced constipation. Prucalopride directly stimulates colonic motility, differentiating it from all other medications (exclusively osmotic or chloride secretagogues) approved for chronic constipation in the last decade.

Current treatment paradigm and landscape for the management of chronic idiopathic constipation in adults: Focus on plecanatide

Chronic idiopathic constipation (CIC) is a prevalent disorder affecting productivity, quality of life, and health care resource utilization. Nurse practitioners (NPs) play a critical function in managing patients presenting with CIC, with roles including evaluation, diagnosis, treatment decisions, and patient education. For adults with inadequate response or tolerability issues using over-the-counter treatments, three prescription agents (plecanatide, linaclotide, and lubiprostone) are available in the United States to treat CIC, of which plecanatide was mostly recently approved. This review provides NPs with a current overview and summary of plecanatide in the current treatment landscape for CIC. PubMed was searched for the literature regarding clinical practice guidelines and published trial data for lubiprostone, linaclotide, and plecanatide in CIC. Efficacy and safety comparisons between prescription agents are limited beacause of the differences in trial duration and primary end points (all different). Generally, plecanatide and linaclotide demonstrated similar efficacy, with plecanatide demonstrating lower rates of adverse events. The success of CIC treatment can be affected by patient adherence to the regimen, which is dependent on the efficacy and tolerability of treatment. Plecanatide is a promising option for patients whose CIC symptoms are not adequately controlled using their current treatment approach.

Chronic idiopathic constipation in adults: epidemiology, pathophysiology, diagnosis and clinical management.

Chronic idiopathic constipation (CIC) is one of the most common gastrointestinal disorders, with a global prevalence of 14%. It is commoner in women and its prevalence increases with age. There are three subtypes of CIC: dyssynergic defaecation, slow transit constipation and normal transit constipation, which is the most common subtype. Clinical assessment of the patient with constipation requires careful history taking, in order to identify any red flag symptoms that would necessitate further investigation with colonoscopy to exclude colorectal malignancy. Screening for hypercalcaemia, hypothyroidism and coeliac disease with appropriate blood tests should be considered. A digital rectal examination should be performed to assess for evidence of dyssynergic defaecation. If this is suspected, further investigation with high resolution anorectal manometry should be undertaken. Anorectal biofeedback can be offered to patients with dyssynergic defaecation as a means of correcting the associated impairment of pelvic floor, abdominal wall and rectal functioning. Lifestyle modifications, such as increasing dietary fibre, are the first step in managing other causes of CIC. If patients do not respond to these simple changes, then treatment with osmotic and stimulant laxatives should be trialled. Patients not responding to traditional laxatives should be offered treatment with prosecretory agents such as lubiprostone, linaclotide and plecanatide, or the 5-HT4 receptor agonist prucalopride, where available. If there is no response to pharmacological treatment, surgical intervention can be considered, but it is only suitable for a carefully selected subset of patients with proven slow transit constipation.

Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis.

To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δb) in the number of SBM/week and Δb CSBM/week. Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δb in number of SBM/week. Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δb in the number of SBM/week in CIC.

Systematic review with meta-analysis: effect of fibre supplementation on chronic idiopathic constipation in adults.

Chronic idiopathic constipation is a common symptom-based gastrointestinal disorder responsible for a substantial economic health service burden. Current guidelines recommend the use of fibre as a first-line treatment. To investigate the effect of fibre (including prebiotic) supplementation on global symptom response, stool output, gut microbiota composition and adverse events in adults with chronic idiopathic constipation. Medline, EmBase, Web of Science, Scopus and the Cochrane central register of controlled trials were searched through to February 2016. Conference proceedings from 2003 to 2015 were hand-searched. There were no language restrictions. Forest plots with 95% CIs were generated using a random-effects model. The search strategy generated 1072 citations, of which seven individual randomised controlled trials were eligible. Overall, 113 of 147 (77%) patients assigned to fibre responded to therapy, compared with 61 of 140 (44%) allocated to placebo (RR of success to respond 1.71, 95% CI 1.20-2.42, P = 0.003). Fibre significantly increased stool frequency (SMD, standardised mean difference = 0.39; 95% CI 0.03-0.76; P = 0.03) and softened stool consistency (SMD = 0.35; 95% CI 0.04-0.65; P = 0.02) compared with placebo. Flatulence was significantly higher with fibre compared to placebo (SMD 0.56, 0.12-1.00, P = 0.01). Overall quality of evidence was low. This meta-analysis demonstrates that fibre is moderately effective, but also causes moderate gastrointestinal side effects. However, these findings need to be treated with caution due to a high risk of bias. Accordingly, further large, methodologically rigorous trials are required, before any definitive recommendation regarding its risk-benefit profile can be made. PROSPERO registration number CRD42014007005.

Lubiprostone for chronic constipation in adults

Lubiprostone (Amitiza—Sucampo Pharma Europe), a chloride-channel activator is licensed for the treatment of chronic idiopathic constipation in adults. It received a marketing authorisation in the UK in September 2012. In...

Biofeedback for treatment of chronic idiopathic constipation in adults

Biofeedback for treatment of chronic idiopathic constipation in adults

Lubiprostone improves opioid-induced constipation without affecting opioid analgesia

The use of opioids to manage chronic pain may be limited by constipation. Lubiprostone is a locally-acting, type-2 chloride channel activator indicated to treat chronic idiopathic constipation in adults at 24 mcg twice daily (BID). We assessed the safety and efficacy of lubiprostone for treating opioid-induced constipation (OIC) in patients with chronic, noncancer pain. Patients required opioids ≥30 days before and during the study and had <3 spontaneous bowel movements (SBMs)/week during screening. Patients (N=443) were randomized to receive lubiprostone 24 mcg BID or placebo for 12 weeks. The primary efficacy endpoint was change from baseline in SBM frequency at week 8 in patients without study medication dose reductions. Mean changes in morphine equivalent daily dose were similar (P≥.18) in the lubiprostone and placebo groups (months 1, 2, and 3). Mean changes in Brief Pain Inventory-Short Form scores were similar (P≥.0667) in both groups at all times, except for significantly less pain interference at month 2 with lubiprostone (P=.0114). Mean increase in SBM frequency was significantly greater with lubiprostone vs. placebo at week 8 (P=.0188) and overall (P=.0047). Higher percentages of patients treated with lubiprostone vs. placebo reported their first SBM within 24 and 48 hours (significant at 24 [P=.0235] but not 48 hours [P=.0566]). Significant improvements were observed for constipation severity, stool consistency, abdominal discomfort, and straining (all P≤.0246, lubiprostone vs. placebo). The most common adverse events (AEs) with lubiprostone and placebo were nausea (16% vs 6%), diarrhea (10% vs. 3%), and abdominal distension (8% vs. 2%); few patients (6% vs. 3%) discontinued because of an AE and none died. Lubiprostone was well-tolerated and improved SBM frequency without changing analgesic response in patients with chronic noncancer pain and OIC. Supported by Sucampo Pharma Americas, Inc. and Takeda Pharmaceuticals, USA. The use of opioids to manage chronic pain may be limited by constipation. Lubiprostone is a locally-acting, type-2 chloride channel activator indicated to treat chronic idiopathic constipation in adults at 24 mcg twice daily (BID). We assessed the safety and efficacy of lubiprostone for treating opioid-induced constipation (OIC) in patients with chronic, noncancer pain. Patients required opioids ≥30 days before and during the study and had <3 spontaneous bowel movements (SBMs)/week during screening. Patients (N=443) were randomized to receive lubiprostone 24 mcg BID or placebo for 12 weeks. The primary efficacy endpoint was change from baseline in SBM frequency at week 8 in patients without study medication dose reductions. Mean changes in morphine equivalent daily dose were similar (P≥.18) in the lubiprostone and placebo groups (months 1, 2, and 3). Mean changes in Brief Pain Inventory-Short Form scores were similar (P≥.0667) in both groups at all times, except for significantly less pain interference at month 2 with lubiprostone (P=.0114). Mean increase in SBM frequency was significantly greater with lubiprostone vs. placebo at week 8 (P=.0188) and overall (P=.0047). Higher percentages of patients treated with lubiprostone vs. placebo reported their first SBM within 24 and 48 hours (significant at 24 [P=.0235] but not 48 hours [P=.0566]). Significant improvements were observed for constipation severity, stool consistency, abdominal discomfort, and straining (all P≤.0246, lubiprostone vs. placebo). The most common adverse events (AEs) with lubiprostone and placebo were nausea (16% vs 6%), diarrhea (10% vs. 3%), and abdominal distension (8% vs. 2%); few patients (6% vs. 3%) discontinued because of an AE and none died. Lubiprostone was well-tolerated and improved SBM frequency without changing analgesic response in patients with chronic noncancer pain and OIC. Supported by Sucampo Pharma Americas, Inc. and Takeda Pharmaceuticals, USA.

Linaclotide: A New Option for the Treatment of Irritable Bowel syndrome with Constipation and Chronic Idiopathic Constipation in Adults

Chronic idiopathic constipation (CC) and irritable bowel syndrome with predominant constipation (IBS-C) are the 2 most common conditions among functional gastrointestinal disorders. Despite current multiple therapeutic options, treatment remains challenging and dissatisfactory to many patients. Linaclotide is a novel therapeutic agent, which is a guanylate cyclase receptor agonist that stimulates water secretion from the intestinal epithelium by promoting chloride and bicarbonate efflux into the lumen through activation of the cystic fibrosis transmembrane conductance regulator. Clinical trials have demonstrated that linaclotide is effective, safe and well tolerated in patients with CC and IBS-C. This review article highlights the mechanism of action of linaclotide, reviews published literature based on a search of databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), up to February 2013, and compares its utility with other currently available agents.

Prevalence of, and Risk Factors for, Chronic Idiopathic Constipation in the Community: Systematic Review and Meta-analysis

Chronic idiopathic constipation (CIC) is a common functional gastrointestinal disorder in the community, yet no previous systematic review and meta-analysis has estimated the global prevalence, or potential risk factors for the condition. MEDLINE, EMBASE, and EMBASE Classic were searched (up to December 2010) to identify population-based studies reporting the prevalence of CIC in adults (≥15 years), according to self-report, questionnaire, or specific symptom-based criteria. The prevalence of CIC was extracted for all studies, and according to country, age, gender, socioeconomic status, and presence or absence of irritable bowel syndrome (IBS) where reported. Pooled prevalence overall, and according to study location and certain other characteristics, as well as odds ratios (ORs), with 95% confidence intervals (CIs) were calculated. Of the 100 papers evaluated, 45 reported the prevalence of CIC in 41 separate study populations, containing 261,040 subjects. Pooled prevalence of CIC in all studies was 14% (95% CI: 12-17%). The prevalence of CIC was lower in South East Asian studies, and in studies using the Rome II or III criteria. The prevalence of CIC was higher in women (OR: 2.22; 95% CI: 1.87-2.62), and increased with age and lower socioeconomic status. The prevalence was markedly higher in subjects who also reported IBS (OR: 7.98; 95% CI: 4.58-13.92), suggesting common pathogenic mechanisms. Pooled prevalence of CIC in the community was 14%, and of similar magnitude in most geographical regions. Rates were higher in women, older individuals, and those of lower socioeconomic status. Presence of IBS was strongly associated with CIC.

Lubiprostone, but Not Linaclotide, Protects T84 Cells Against Damage to Barrier Function by Interferon-γ

Purpose: Lubiprostone, a prostone derivative, activates ClC-2 chloride channels and is used for the treatment of chronic idiopathic constipation in adults and irritable bowel syndrome with constipation in adult women. Linaclotide is also being developed for these indications. It is a peptide whose structure is closely related to the bacterial heat-stable endotoxin, STa. Lubiprostone has been shown to promote repair of intestinal barrier properties whereas nothing is known of the effect of linaclotide. The aim of the present study was to compare the effect of lubiprostone and linaclotide on loss of barrier function induced by interferon-γ (IFN-γ), a proinflammatory cytokine which reduces transepithelial resistance (TER) in part through reduction of occludin levels. IFN-γ is thought to be involved in the pathology of celiac sprue enteropathy, inflammatory bowel disease, ulcerative colitis and Crohn's disease. Intestinal barrier breakdown can lead to visceral pain. Methods: T84 cells grown on permeable supports were treated with and without 100 ng/mL IFN-γ and with 100 nM lubiprostone, 200 nM of the 13 amino acid active metabolite of linaclotide (CCEYCCNPACTGC) or 0.1% DMSO (vehicle control) daily for 3 days. TER, flux of FITC-labeled E. coli lipopolysaccharide (LPS, bacterial endotoxin preparation) and occludin levels were measured. Results: Incubation with lubiprostone alone did not affect TER, LPS flux or occludin levels. In contrast, linaclotide alone partially reduced TER, increased LPS flux and decreased occludin levels. IFN-γ reduced TER, increased LPS flux and decreased occludin levels. Lubiprostone, but not linaclotide countered the effects of IFN-γ. Conclusion: In this in vitro study, lubiprostone (but not linaclotide) protected against IFN-γ-induced loss of intestinal barrier function and this may involve preservation of occludin levels. Linaclotide alone caused partial barrier breakdown. These findings suggest that treatment with lubiprostone, but not linaclotide, may lead to reduced visceral damage and reduced pain in inflammatory events in the intestine. Supported by Sucampo Pharmaceuticals, Inc. Disclosure: John Cuppoletti is consultant to, has stock options from and is PI on grant from Sucampo Pharmaceuticals, Inc. All other authors are supported by funds from the research grant. Supported by a grant from Sucampo Pharmaceuticals, Inc.