Irritable Bowel Syndrome With Constipation Research Articles

Changes in gut microbiota and blood lipid profile in patients with irritable bowel syndrome in association with obesity

Relevance of research. Irritable bowel syndrome (IBS) is considered the most common disease, the frequency of which reaches 20% of the population. It is often combined with obesity. An important role in the development of bothpathologies is the disturbance of the colonic microbiota.The purpose of the study is to investigate the nature of changes in the colon microflora in patients with IBS with constipation (IBSc) and their development on the background of obesity and to compare the results with the parameters of the lipid blood spectrum.Material and methods. We examined 32 patients with IBS on the background of obesity, 28 – with IBS without any other pathology and 18 healthy persons. All individuals were examined for the species and quantitative composition of the microflora by bacteriological methods, and the lipid profile of the blood by means of enzyme-colorimetric methods on the analytical modular test system Sovas 6000 from Roche Diagnostics firm (Switzerland).Results. It was established that both at IBSc and IBSc on the background of obesity there is a decrease in the level of bifidobacteria in the colonic microbiota by 13.0 and 14.1%, and lactobacillus - by 11.8 and 49.7%, respectively. In patients with this combined pathology, 1.89 and 1.95 times increased the number of clostridia that belong to the class of Firmicutes compared with healthy ones. At the same time, they have an elevated in 1,2 and 4,3 times level of St. Aureus and in 1,5 and 1,9 times E. coli. Increasing the number of Enterobacter cloacea and aeurogenes has also been established in IBSc and in combination with obesity. There are established direct correlational relationships between elevated levels in the intestinal microorganism of clostridium and St. aureus, and low density lipoprotein cholesterol concentration and triglyceride levels. Conclusion. In patients with IBSc and its combination with obesity, there is a decrease in the level of bifido- and lactobacilli, an increase in the number of Clostridia, Staphylococcus aureus, E. coli, Candida and Enterobacteria. Correlation relationships between microbial spectrum with Clostridium, Staphylococcus aureus and cholesterol of low density lipoprotein and triglycerides have been established, indicating the possible role of microorganisms in regulation of the lipid blood spectrum.

Моторная функция кишечника при синдроме раздраженной кишки с запорами

Irritable Bowel Syndrome (IBS) is a functional bowel disease in which relapsing abdominal pain is associated with bowel movements or bowel movements. Despite the numerous works devoted to the investigation of the mechanisms of IBS development, the intestinal motility in this disease has not been studied enough. The aim is to reveal the features of the motor function of the large and small intestine in irritable bowel syndrome with constipation (IBS-C) and in the case of dolichosigma. Material and methods. 84 patients with IBS-C by electromyography in comparison with a group of 25 patients with dolichosigma and a group of 35 patients with functional constipation were examined. The frequency of slow waves of the small and large intestine (patients with functional constipation) and the left parts of the colon (patients with IBS-3 and dolichosigma) by the Conan-M hardware and software complex were measured Results and discussion. IBS-C is characterized by hypomotor dyskinesia of the left divisions with pronounced spastic contractions of the smooth muscles of the circulatory layer of the gut, possibly due to the activity of stimulating serotonergic effects on the spastic activity of the circular muscle layer or inhibitory adrenergic neurons of the intermuscular (Auerbach) nerve plexus. With dolichosigma, hypomotor dyskinesia of the left parts of the colon was revealed due to stretching of the mechanoreceptors of the afferent neurons of the intramural reflex arcs.

A retrospective and prospective 12-month observational study of the socioeconomic burden of moderate to severe irritable bowel syndrome with constipation in Spain

IntroductionThe socioeconomic burden of irritable bowel syndrome with constipation (IBS-C) has never been formally assessed in Spain. Patients and methodsThis 12-month (6-month retrospective and prospective periods) observational, multicentre study assessed the burden of moderate-to-severe IBS-C in Spain. Patients were included if they had been diagnosed with IBS-C (Rome III criteria) within the last 5 years and had moderate-to-severe IBS-C (IBS Symptom Severity Scale score [IBS-SSS] ≥175) at inclusion. The primary objective was to assess the direct cost to the Spanish healthcare system (HS). ResultsA total of 112 patients were included, 64 (57%) of which had severe IBS-C at inclusion. At baseline, 89 (80%) patients reported abdominal pain and distention. Patient quality of life (QoL), measured by the IBS-C QoL and EQ-5D instruments, was found to be impaired with a mean score of 59 and 57 (0–100, worst-best), respectively. Over the 6-month prospective period the mean IBS-C severity, measured using the IBS-SSS showed some improvement (315–234 [0–500, best–worst]). During the year, 89 (80%) patients used prescription drugs for IBS-C, with laxatives being the most frequently prescribed (n=70; 63%). The direct cost to the HS was €1067, and to the patient was €568 per year. The total direct cost for moderate-to-severe IBS-C was €1635. DiscussionThe majority of patients reported continuous IBS-C symptoms despite that 80% were taking medication to treat their IBS-C. Overall healthcare resource use and direct costs were asymmetric, with a small group of patients consuming the majority of resources.

Pelvic Floor Symptom Related Distress in Chronic Constipation Correlates With a Diagnosis of Irritable Bowel Syndrome With Constipation and Constipation Severity but Not Pelvic Floor Dyssynergia.

Background/AimsAlthough symptoms related to the pelvic floor, such as pelvic organ prolapse (POP) and lower urinary tract symptoms (LUTS), are common in patients with chronic constipation (CC), its impact is not clear. Our aims were to investigate the following (1) compare pelvic floor symptom related dysfunction in irritable bowel syndrome with constipation (IBS-C) and functional constipation (FC), and (2) symptom correlation with findings on anorectal manometry (ARM) and balloon expulsion test.MethodsThis was a retrospective analysis of patients with CC undergoing ARM. IBS-C and FC were diagnosed by Rome III criteria. Pelvic Floor Distress Inventory (PFDI-20) was used to measure pelvic floor symptom distress. Constipation Severity Scale was used to assess constipation severity.ResultsA total of 107 patients underwent ARM (64 FC, 43 IBS-C). The overall PFDI-20 score in IBS-C was higher compared with FC patients (118.0 vs 79.2, P = 0.001). In those with IBS-C, POP, LUTS, and colorectal symptoms subscales were all higher compared with FC patients (P < 0.05 for each). On multivariable regression, IBS-C (P = 0.001) and higher constipation severity (P = 0.001) were both independently associated with higher PFDI scores. ARM parameters and abnormal balloon expulsion test did not correlate with PFDI scores.ConclusionsCompared with FC patients, those with IBS-C have significantly higher distress from pelvic floor specific symptoms including POP and LUTS. Higher abdominal pain among IBS-C patients did not entirely explain these findings. A diagnosis of IBS-C and higher constipation severity correlated with PFDI-20 scores, but dyssynergia did not.

Pharmacological and clinical profile of linaclotide (Linzess®), a novel therapeutic agent for irritable bowel syndrome with constipation and chronic constipation

Linaclotide (Linzess® tablets 0.25 mg) is a guanylate cyclase-C (GC-C) agonist with high selectivity and binding affinity to GC-C. In Japan, linaclotide was approved for 〝irritable bowel syndrome with constipation (IBS-C)〟 in December 2016 and 〝chronic constipation (CC) (excluding constipation due to organic disease)〟 in August 2018. Non-clinical studies demonstrated that linaclotide binding to GC-C increases intracellular cyclic guanosine monophosphate (cGMP), resulting in increased fluid secretion and gastrointestinal transit. In rats with colonic hyperalgesia, but not in normal rats, linaclotide suppressed the visceral nociceptive response, mediated by increased submucosal cGMP. In clinical studies in Japan, improvements were observed in the responder rates for global assessment of IBS symptom relief, complete spontaneous bowel movements in patients with IBS-C, and the frequency of spontaneous bowel movement in patients with CC, which were maintained during long-term treatment. Additionally, abdominal bloating, which has been associated with lower quality of life (QOL) and lower satisfaction with other approved therapies, and IBS QOL were improved throughout treatment with linaclotide. Diarrhea, a consequence of linaclotide's mechanism of action, was observed during the clinical studies, but was generally controllable by decreasing the linaclotide dose. No drug resistance was observed during the clinical studies, unlike some other approved agents. These results of non-clinical and clinical studies demonstrate that linaclotide can improve constipation, various abdominal symptoms, and QOL with a favorable safety profile in patients with IBS-C and CC.

Clinical response to linaclotide at week 4 predicts sustained response in irritable bowel syndrome with constipation and improvements in digestive and extra-digestive symptoms.

Background:Linaclotide is approved for the treatment of moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors predictive of a clinical response and improvements in non-IBS symptoms with linaclotide treatment in a Spanish patient population.Methods:In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS <75 plus self-reported response of feeling ‘better’ or ‘much better’ versus the baseline. Digestive nonintestinal and extra-digestive symptom scores were assessed. Baseline characteristics and week 4 clinical response were assessed as predictors of week 12 clinical response.Results:A total of 96 patients were eligible; 91 were female and the mean age was 47.4 years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was not associated with week 12 clinical response; however, clinical response at week 4 was predictive of response at week 12 (OR: 6.5; 95%IC: 2.1–19.8). The most common adverse event was diarrhea inclusive of loose or watery stools (35.4%).Conclusions:Linaclotide improves IBS-C symptoms, including digestive nonintestinal and extra-digestive symptoms. A clinical response at week 4 may predict response at week 12.

Influence of the requirement for abdominal pain in the diagnosis of irritable bowel syndrome with constipation (IBS-C) under the Rome IV criteria using data from a large Japanese population-based internet survey

BackgroundRome III was revised to Rome IV in May 2016. One important change in the Rome IV criteria is that abdominal pain must be present for a diagnosis of irritable bowel syndrome (IBS). Under Rome III, in contrast, patients with abdominal discomfort only could be diagnosed with IBS, but these cases under Rome IV are now classified as unspecified functional bowel disorder (FBD). In a simple comparison of Rome III and Rome IV, it is unclear whether this difference reflects the influence of symptomatic frequency or the presence of abdominal pain. In particular, the influence of abdominal pain restriction on the diagnosis of IBS with predominant constipation (IBS-C) in the Rome IV criteria is largely unknown.MethodsWe reclassified subjects from a Japanese internet survey experiencing abdominal pain or discomfort at least one day each week as surrogate Rome III IBS-C subjects. Among them, we then reclassified subjects experiencing abdominal pain as surrogate Rome IV IBS-C subjects and subjects not experiencing abdominal pain as surrogate Rome IV FBD subjects. Symptoms were quantified and compared between the two groups.ResultsThe surrogate Rome IV IBS-C subjects felt a significantly higher degree of anxiety in their daily lives (p < 0.001) compared with the surrogate Rome IV FBD subjects. The combined female and 20–49 years surrogate Rome IV IBS-C subjects felt a higher degree of anxiety in their daily lives (p < 0.05) than the respective Rome IV FBD subjects.ConclusionsThese results suggest that female IBS-C patients aged 20–49 years with abdominal pain in Rome IV have more anxiety than those without abdominal pain in Rome III. Changes in the diagnostic criteria from Rome III to Rome IV will better identify candidates for the biopsychosocial approach.Trial registrationAlthough this survey was an anonymous internet survey, we obtained informed consent for the study as an online response. The disclosure of this study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (approval number: 2015–1-405).

Long-term treatment with plecanatide was safe and tolerable in patients with irritable bowel syndrome with constipation

Objective: This open-label, multi-center, fixed-dose study (NCT02706483) evaluated the long-term safety and tolerability of plecanatide for the treatment of adults with irritable bowel syndrome with constipation (IBS-C).Methods: Safety and tolerability of once-daily plecanatide 6 mg for up to 53 weeks was assessed in patients with IBS-C who either had been enrolled in one of the phase 3 studies or were study-naïve but met eligibility criteria of the double-blind studies. Safety was assessed by treatment-emergent adverse events (AEs). Patient-reported questionnaires assessed overall IBS symptoms, treatment satisfaction, and desire for treatment continuation. No dose adjustments or treatment interruptions were permitted during the study.Results: Of the 2272 patients enrolled, 1842 (81.1%) completed the study. AEs were experienced by 27.3%, and 4.3% discontinued due to an AE. Most AEs were mild or moderate (90.3%). The incidence of diarrhea, the most commonly reported AE, was low (6.7%), and declined in frequency over time. Diarrhea was the most common cause of AE-related withdrawals (2.7% of patients). At week 53 or end of treatment, 88.2% of patients reported “significant” or “moderate” relief, 72.4% were “very” or “quite” satisfied with treatment, and 76.6% were “very” or “quite” likely to continue treatment.Conclusions: Plecanatide 6 mg was safe and well tolerated in patients with IBS-C treated for up to 53 weeks, with an overall safety profile similar to the 12-week IBS-C studies. Patients reported high rates of relief and satisfaction with treatment, and interest in continuing therapy.Trial registration: ClinicalTrials.gov identifier: NCT02706483.

Efficacy of Tegaserod in IBS-C: Original RCTs and Reanalysis in Patients with Severe Symptoms

Introduction: Tegaserod was approved in the United States in 2002 for women with irritable bowel syndrome with constipation (IBS-C) based on patient subjective global assessment (SGA) of symptoms in three phase 3 RCTs. After a reported imbalance in cardiovascular adverse events in a pooled analysis across 29 clinical trials, it was voluntarily withdrawn from the market in 2007. Re-introduction is currently under consideration. Efficacy of tegaserod for women with IBS-C based on original RCTs was explored using a responder analysis similar to the FDA guidance for IBS-C used to approve more recent therapies. Additionally, a validated IBS quality of life questionnaire (IBS QoL) was used to define a population with severe IBS, in which efficacy was explored. Methods: In the original RCTs, the primary outcome was patient SGA using a 5-point Likert scale collected weekly. Other data in the original RCTs included daily stool frequency and consistency, severity of pain/discomfort, and bloating. The 2012 FDA guidance on IBS-C RCTs recommends using a responder analysis of two co-primary endpoints (Table 1). A severely symptomatic subpopulation was defined by severe abdominal pain and constipation symptoms anchored to IBS QoL assessment. That group was analyzed according to the 2012 trial guidance. Our definition of severe IBS-C (Table 1) was more rigorous than the Rome IV definition, which requires ≥1 day/week of abdominal pain and hard or lumpy stools >25% of the time. This subgroup of subjects in the original RCT database was associated with an IBS QoL score <55, which, through validation studies, indicates patients with the highest symptom frequency and disruption of daily life. Results: Reanalysis of the original RCTs using FDA-recommended co-primary endpoints demonstrated similar therapeutic gains compared to the initial SGA results. This confirms previous expert opinion that SGA assessment of efficacy performs well and produces results similar to the responder analysis currently used. The two approaches capture patient benefit of therapy in different ways (Table 2). Exploratory analysis in patients with severe IBS demonstrated higher efficacy in this subpopulation compared to the overall study based on number needed to treat. Conclusion: Based on the consistent benefit demonstrated by rigorous re-analyses, tegaserod is an effective alternative treatment option for women with IBS-C including those with the most severe symptoms.467_A Figure 1. Different Responder Criteria Used in This Tegaserod Efficacy Reanalysis467_B Figure 2. Comparison of Responder Rates Across Different Responder Criteria and Restricted to Severely Symptomatic Women

Evaluation of the Safety and Tolerability of Plecanatide in CIC and IBS-C Patients Aged 65 and Older

Introduction: Constipation, including Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C), is prevalent in patients aged 65 and older. Currently, there is limited clinical trial safety/tolerability data in older adults. Recently, two CIC and two IBS-C trials with plecanatide were completed which represent the largest Phase 3 trials to date in each of these disorders. All of these trials permitted enrollment of eligible patients up to the age of 80 and 85, respectively. Rome IV supports the concept of CIC and IBS-C as a spectrum of disorders with overlapping symptoms. This suggests that combining the safety populations from these studies would be acceptable and provide for a larger cohort of patients. Therefore, the aim of this study was to perform a safety analysis of plecanatide in patients ≥65 years old. Methods: Safety populations from 4 large Phase 3 trials (2 CIC, 2 IBS-C) were combined for a post-hoc analysis. Patients enrolled in these trials met modified Rome III criteria for CIC and IBS-C, respectively. Upon completion of the two-week baseline period, patients were randomized to either plecanatide 3mg or placebo (pbo). Medication was taken once daily with or without food. Safety assessments were conducted by the collection of spontaneously reported adverse events (AEs) and responses to open ended non-specific questions. AE rates were compared between those patients ≥65 and those <65 using descriptive statistics to assess for increased safety risks to an older population. Results: For those ≥65 years there were 151 plecanatide and 166 pbo patients. For those 2% and >pbo were headache and arthralgia each at 2.6% for the ≥65 group. The overall discontinuation rates and the discontinuation rates due to diarrhea were similar among the two age groups (Table). Conclusion: In these four trials for plecanatide, a meaningful number of patients ≥65 were enrolled. The analysis of the safety data indicates similar AE rates and discontinuation rates for patients ≥65 compared to those <65. These data indicate plecanatide is safe and well tolerated in both groups of patients.427 Figure 1 No Caption available.

Treatment Patterns, Over-the-Counter (OTC) Use, and Outcomes Among Patients With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation: Results from the CONTOR Study

Introduction: Understanding how patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) treat their disease and what drives treatment satisfaction or discontinuation is important when considering new treatment options. Treatment choice may be difficult, due in part to the heterogeneity and/or severity of these disorders. This analysis of the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR) study examined treatment patterns and outcomes among participants with IBS-C or CIC. Methods: CONTOR included fully insured US patients with: both medical and pharmacy benefits and ≥1 medical claim for constipation (ICD-9-CM diagnosis code: 564.0x); or ≥1 claim for IBS (564.1x) or abdominal pain (789.0x) plus ≥1 pharmacy claim for a stool softener/laxative; or ≥1 claim for linaclotide or lubiprostone (October 2014 to November 2016). Over the 12-month study period, participants completed a baseline and quarterly survey, which included the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire and an assessment of overall treatment satisfaction. Monthly surveys collected patient-reported new or discontinued IBS-C/CIC treatments. Association between quality of life and changes in treatment satisfaction was determined by multivariate analyses. Results: Of 2052 CONTOR participants, 93.8% (n=1922) were female; the mean (SD) age was 46.7 (11.9) years. At baseline, the majority of participants reported their IBS-C/CIC treatment included over-the-counter (OTC) medication use (65.4%), while 22.2% reported OTC and prescription treatment (Table 1). The concomitant use of prescription and OTC treatments remained consistent over the study period. The most common reasons for discontinuing any treatment were failure to improve constipation (41.4%), bloating (39.4%), and pain (34.7%); improved symptoms no longer required medication in 28.7% of participants. The odds of becoming satisfied with treatment were higher in participants with improved PACQOL total scores (defined as ≥0.5 improvement from baseline) compared to those with no improvement (p<0.001) (Table 2). Conclusion: The majority of participants with IBS-C or CIC used a variety of treatments to manage their disease. Improved quality of life was associated with treatment satisfaction.423_A Figure 1. Patient-reported baseline medication use423_B Figure 2. Multivariate logistic regression analysis of treatment satisfaction adjusted for PAC-QOL total score, treatment, and baseline characteristics

Impact of Linaclotide on Patient-Reported Constipation Symptoms and Quality of Life: Results From the CONTOR Study

Introduction: Treatment of patients with chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) may provide symptom improvement, which is associated with increased quality of life (QOL), a key factor impacting patients’ perception of treatment satisfaction. This analysis assessed patient-reported outcomes before and on/after initiating linaclotide, based on survey data from the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR). Methods: CONTOR participants included fully insured patients aged ≥8 years, identified via claims from a large, geographically diverse US health insurer, with: ≥1 medical claim for constipation (ICD-9-CM diagnosis code: 564.0x); or ≥1 claim for IBS (564.1x) or abdominal pain (789.0x) plus ≥1 pharmacy claim for a stool softener/laxative; or ≥1 claim for linaclotide or lubiprostone. Over the 1-year study period, participants completed self-administered baseline/quarterly surveys, which assessed treatment satisfaction, symptoms (Patient Assessment of Constipation Symptoms [PAC-SYM]), and QOL (PACQOL). Participants reporting over-the-counter (OTC) constipation treatment who then reported initiating linaclotide regardless of continued OTC treatment were included; those reporting any concomitant lubiprostone use were excluded. Outcomes were measured before and on/after the initiation of linaclotide and for daily and non-daily linaclotide use. Results: 124 participants reported initiating linaclotide after taking an OTC treatment, with demographics similar to the 2052 participants in the overall CONTOR population (Table 1). Linaclotide frequency of use at initiation was daily (53.2%), as needed (33.9%), every other day (8.9%), or weekly (4.0%). A greater proportion of participants were satisfied with their treatment on/after initiating linaclotide vs. before (39.2% vs. 30.2%). Mean PAC-SYM and PAC-QOL scores were lower on/after initiating linaclotide vs. before, indicating better QOL and fewer symptoms, respectively (Table 2). Greater changes in outcomes were observed among patients who reported daily linaclotide use. Conclusion: Among CONTOR participants initiating linaclotide after reporting OTC use, overall treatment satisfaction increased on/after initiating linaclotide, with mild improvement in symptoms and QOL. These results warrant further investigation to assess whether outcomes continue to improve with longer linaclotide use.424_A Figure 1. Baseline demographics and sociodemographic characteristics424_B Figure 2. Results from PAC-SYM and PAC-QOL

An Open Label Long-Term Safety Trial (T3MPO-3) of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation (IBS-C): Presidential Poster Award

Introduction: Tenapanor is a locally acting, minimally absorbed, and selective small molecule inhibitor of the intestinal sodium-hydrogen exchanger-3 (NHE3), which increases intestinal sodium and fluid in a dose-dependent fashion. In preclinical models, tenapanor has also been shown to reduce abdominal pain through inhibition of TRPV-1 signaling and by decreasing intestinal cell permeability. In two previously completed phase 3 trials (T3MPO-1 and T3MPO-2), tenapanor 50 mg twice daily met the primary endpoint and significantly improved the key symptoms of IBS-C compared to placebo (NCT02621892 and NCT02686138). The objective of this trial was to evaluate the long term safety of tenapanor in patients for the treatment of IBS-C in an up to 39 week extension study. Methods: In this open label safety study (NCT02727751), patients who completed either the T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) trial were eligible for enrollment. Visits were scheduled approximately every 13 weeks at which time patients underwent safety assessments at these visits, which including a physical exam, ECG, vital signs, and clinical labs. Adverse events and concomitant medications were recorded. Results: The intention-to-treat population included 240 patients, mean age = 49.6, and 80.8% women. Based on enrollment from each parent study the intended treatment duration ranged from 44 to 56 weeks. 84% of patients completed the study with a mean drug compliance rate of 97.9%. There were no deaths and three SAEs that were not drug related (leukocytosis, cervical fracture, and endometriosis). Overall, no notable changes over time in serum chemistry, hematology, or urinalysis were observed and there was no evidence of differences between cohorts. No notable changes from baseline or evidence of differences between cohorts were observed in physical examination or vital signs. There were no notable changes from baseline in heart rate, QTc interval, QTcB interval, QTcF interval, PR interval, or QRS interval during the study and no evidence of differences between cohorts. No patients experienced abnormal (clinically significant) ECG findings during the study.Diarrhea was the most common adverse event during the treatment period at a rate of 9.2% resulting in a discontinuation rate of 1.6%; there were no cases of severe diarrhea. The overall rate of discontinuations due to AEs was 2.1%. Conclusion: Tenapanor 50 mg BID was generally safe and well-tolerated when administered for up to 52 consecutive weeks.

Impact of symptoms by gender and age in Japanese subjects with irritable bowel syndrome with constipation (IBS-C): a large population-based internet survey

BackgroundIrritable bowel syndrome with constipation (IBS-C) is a representative psychosomatic disorder. Several pathophysiological factors have been linked to IBS symptoms such as the modulation of gastrointestinal motility, visceral hypersensitivity, dysregulation of the gut-brain axis, genetic and environmental factors, sequelae of infection, and psychosocial disorders. It is likely that biopsychosocial aspects of IBS-C underlie its gender and age effects. However, the influence of each symptom of IBS-C by gender and age is not well understood. We hypothesized that the expression rate of each IBS-C symptom in females and in subjects aged 20–49 years was higher than that of subjects who were male and aged 50–79 years.MethodsWe conducted an internet survey of 30,000 adults from the general Japanese population. IBS-C subjects were asked to answer a questionnaire on the degree of anxiety, thoughts about bowel habits, and their dominant gastrointestinal symptoms together with exacerbation factors. The correlation between gender and age and IBS-C symptoms was analyzed.ResultsWhen analyzed by gender, the expression rate of abdominal discomfort, abdominal distention, and abdominal fullness was significantly higher in female than male IBS-C subjects (66.5% vs. 58.7%, p < 0.05; 54.7% vs. 43.6%, p < 0.01; 18.9% vs. 9.6%, p < 0.01, respectively). When analyzed by age, the expression rate of abdominal distention and abdominal pain was significantly higher among IBS-C subjects aged 20–49 years than those aged 50–79 years (55.7% vs. 46.8%, p < 0.05; 36.6% vs. 20.6%, p < 0.001, respectively). In contrast, there was no gender or age differences with regard to the most common and bothersome symptom (abdominal bloating) among IBS-C subjects.ConclusionsThe expression rate of some IBS-C symptoms was higher among females and those aged 20–49 years than males and those aged 50–79 years, respectively. It is important to understand the impact of symptoms by gender and age to evaluate the pathology of IBS-C from a biopsychosocial perspective.Trial registrationAlthough this survey was an anonymous internet survey, we obtained informed consent for the study as an online response. The disclosure of this study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (approval number: 2015–1-405).

Fecal Clostridiales distribution and short-chain fatty acids reflect bowel habits in irritable bowel syndrome.

Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, is classified according to bowel habits as IBS with constipation (IBS-C), with diarrhea (IBS-D), with alternating constipation and diarrhea (IBS-M), and unsubtyped (IBS-U). The mechanisms leading to the different IBS forms are mostly unknown. This study aims to evaluate whether specific fecal bacterial taxa and/or short-chain fatty acids (SCFAs) can be used to distinguish IBS subtypes and are relevant for explaining the clinical differences between IBS subcategories. We characterized five fecal samples collected at 4-weeks intervals from 40 IBS patients by 16S rRNA gene profiling and SCFA quantification. Finally, we investigated the potential correlations in IBS subtypes between the fecal microbial signatures and host physiological and clinical parameters. We found significant differences in the distribution of Clostridiales OTUs among IBS subtypes and reduced levels of SCFAs in IBS-C compared to IBS-U and IBS-D patients. Correlation analyses showed that the diverse representation of Clostridiales OTUs between IBS subtypes was associated with altered levels of SCFAs; furthermore, the same OTUs and SCFAs were associated with the fecal cytokine levels and stool consistency. Our results suggest that intestinal Clostridiales and SCFAs might serve as potential mechanistic biomarkers of IBS subtypes and represent therapeutic targets.

Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis

Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone. In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Serotonin Level and Lipid Metabolism Indices in Patients with Irritable Bowel Syndrome with Constipation Against the Background of Various Degrees of Obesity

Recent research shows that the number of diseases associated with obesity has been increasing. In obese persons, association with functional constipation is noted in 24.0% of cases, and obesity is recorded in 60.0% of patients with functional constipation. Among the possible mechanisms for the development of such a combination are changes in serotonin level in the blood, although the existing data are ambiguous and sometimes controversial.The objective of the study is to investigate the changes in serotonin level in the blood of obese patients in combination with constipation and its relationship with the lipid profile of the blood.Materials and methods. 63 patients with obesity in combination with irritable bowel syndrome with constipation (IBSc), 24 patients with normal body mass index and 10 practically healthy people were examined. 25 patients with obesity and constipation had a body mass index of 32.8±0.24kg/m2, 28 patients – 37.8±kg/m2, and 10 patients – 42.6±0.5kg/m2. In patients with irritable bowel syndrome without obesity, the body mass index was 21.7±0.4kg/m2. The blood serotonin level and lipid profile of the blood was determined in all patients.Results. It was deermined that in case of irritable bowel syndrome with constipation, serotonin level in the blood was reduced. In obesity with IBSc, the concentration of serotonin, on the contrary, was elevated. All patients with IBSc and obesity were marked an elevated level of total cholesterol and triglycerides. A direct correlation between high levels of triglycerides and serotonin concentration in serum of such comorbid patients was detected. The increase in the degree of obesity in the presence of IBSc was accompanied by a decrease in the concentration of cholesterol of high density lipoprotein. Patients with IBSc without excessive body weight had no such deviations.Conclusions. With an increase in the degree of obesity, serotonin level in the blood increases and the lipid blood spectrum worsens.

Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients with Irritable Bowel Syndrome with Constipation (BURDEN IBS-C) Study: Results of an Online Questionnaire.

The BURDEN IBS-C study was conducted to better understand the experiences, attitudes, and unmet needs of sufferers of irritable bowel syndrome with constipation (IBS-C) in comparison to the perceptions and challenges of healthcare providers (HCPs) who treat IBS-C patients. This was an author-developed, online questionnaire using KnowledgePanel® to survey individuals with IBS-C (N = 1311). HCPs participated in a complementary online questionnaire and were recruited separately (N = 331). The study was fielded from June 29, 2016, to January 30, 2017. Most patients had used (86%) and/or were using (76%) over-the-counter treatments for their IBS-C, with 12% currently on prescription therapy. At the time this study was conducted, 66% and 63% were not satisfied/completely satisfied with over-the-counter or prescription treatment, respectively, citing inadequate efficacy (55%) and side effects (39%), most commonly diarrhea, as common reasons for dissatisfaction. IBS-C respondents most commonly reported feeling frustrated (43%) and stressed (28%) regarding IBS-C, though 39% were accepting of IBS-C as part of daily life. HCPs were aligned with patients in thinking that patients were frustrated (76%) and stressed (65%) but HCPs were less likely to recognize that patients had become accepting of their IBS-C (13%). Most HCPs (79%) were not satisfied/completely satisfied with the prescription treatments available at the time this study was conducted. Inadequate response rates to current therapies (55%) and treatment adherence/compliance issues (58%) were the most frequent challenges encountered by HCPs. IBS-C respondents reported that their symptoms impacted productivity and personal activity, on average, 4 and 3days/month, respectively. These results suggest that current management pathways may not be adequately addressing the symptoms and needs of individuals with IBS-C, most notably side effects and lack of efficacy. Patients and HCPs expressed dissatisfaction with over-the-counter and prescription treatments available at the time this study was conducted. Additional treatment options and improved dialogue would be beneficial to HCPs and patients. Synergy Pharmaceuticals Inc.

Linaclotide Attenuates Visceral Organ Crosstalk: Role of Guanylate Cyclase-C Activation in Reversing Bladder-Colon Cross-Sensitization.

Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

Comparative efficacy of prucalopride and tegaserod in patients with predominantly constipated irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) affects 5-20% of all individuals aroun d the world. In Mexico (Veracruz), a prevalence of 16.9% has been documented. Its diagnosis is based on the Rome III criteria, and its treatment has different approaches; within the pharmacological options are the serotonin receptor agonist drugs (5-HT4). The effectiveness of tegaserod has been established in patients with IBS with constipation (IBS-C), considering prucalopride as a drug with therapeutic potential for this condition, since it shows greater affi nity for the 5-HT4 receptor than tegaserod, and accelerates colonic transit. However, more data from randomized controlled trials that prove this are required. Objective: To compare the efficacy of prucalopride versus tegaserod in the treatment of irritable bowel with constipation, by means of the Bristol scale, the global scale of symptoms and associated symptoms. Material and methods: Two groups of patients were established (A and B) in a randomized manner: men and women between 18 and 50 years of age with Rome criteria III for IBS-C; all were given the same diet. In group A, Prucalopride was administered at a dose of 2 mg orally every 24 hours for two weeks. In group B, 6 mg of tegaserod were administered every 12 hours for two weeks. The clinical evolution of each patient was assessed each week during the two weeks of the study period, including the assessments of the adapted and validated Bristol scale, and the global scale of symptoms and associated symptoms. Results: Twenty-two patients were included, 21 (95.5%) female, with a 1:21 ratio; the average age was 37.27 years; 11 (50%) received prucalopride, and the rest, tegaserod. To evaluate the association between the treatment given and the symptoms of «rectal fullness, evacuation effort and evacuation urgency», Fisher’s exact test was used, being not statistically significant (p &gt; 0.05); for «abdominal distension, abdominal movements and Bristol scale», Mann-Whitney U was used, being not statistically signifi cant (p &gt; 0.05); however, for «abdominal pain», with the same test, a statistically signifi cant difference was found (p &lt; 0.05). Of those treated with prucalopride, one (9%) had diarrhea, three (27%) headache, and one (9%) headache and nausea; with tegaserod, two (18%) had diarrhea, two (18%) headache, and one (9%) headache and nausea. Conclusions: Both, prucalopride and tegaserod improve to some degree all the symptoms evaluated for IBS-C, but prucalopride signifi cantly and more promptly improves the symptom of «abdominal pain». It was evidenced that the diarrea event implied change of treatment in both groups.