[Efficacy of newly developed kombucha-based specialized food product for treatment of constipation-predominant irritable bowel syndrome].

According to studies, the prevalence of constipation in the population can reach 27% due to the low intake of dietary fiber. Increasing dietary fiber intake can improve bowel movements. The aim of the study was to assess the efficacy of a non-alcoholic fermented pasteurized kombucha drink enriched with inulin and vitamins in patients with constipation-predominant irritable bowel syndrome (IBS). Material and methods. The study (NCT05164861) was approved by Local Ethics Committee and enrolled subjects with IBS (according to ROME IV). The subjects were randomized to receive either 220 ml of a non-alcoholic drink, based on pasteurized kombucha (KG), enriched with inulin (1.15 g/100 ml) or 220 ml water (control group, CG), for 10 days. Standard examination included evaluation of stool frequency (bowel movements per day), stool form (with the Bristol stool scale) and evaluation of concomitant symptoms (abdominal pain/discomfort, abdominal fullness, bloating, and feeling of incomplete bowel emptying) with the use of 5-point Likert scale before (BL) and 10 days after the start of intervention (EOT). Using visual analog scales (VAS), the palatability of the studied food was assessed at the beginning and end of the observation period. Results. Significant increase of stool frequency was found at the EOT compared to BL in KG (n=20), Mean±SD: 0.60±0.31 to 0.85±0.19 times/day; p=0.004, while there was no change in CG (n=20): 0.63±0.33 vs 0.72±0.28, p=0.6. Mean values of stool scale form increased in KG (3.0±1.2 to 4.4±1.0, p=0.001), while remained unchanged in CG (2.9±1.2 vs 3.4±1.2, p=0.6). Mean values of the Bristol stool scale in KG and CG differed significantly at EOT (p=0.018). Significant decrease in mean values of incomplete bowel emptying feeling was found in KG (1.88±0.78 at BL vs 1.41±0.56 points at EOT, p=0.015), but not in the control group. There were no statistically significant differences between patient's reports of the studied groups for other symptoms (bitterness and dryness in the mouth, heartburn, nausea, abdominal pain and heaviness in the stomach after eating). Conclusion. The effectiveness of a pasteurized fermented non-alcoholic drink based on kombucha enriched with inulin has been proven by reducing the intensity of complaints significant for constipation, normalizing the frequency and consistency of stools.

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

INTRODUCTION: The socioeconomic burden of irritable bowel syndrome with constipation (IBS-C) has never been formally assessed in Spain. PATIENTS AND METHODS: This 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). RESULTS: A 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. DISCUSSION: The 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.

Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders.

BACKGROUND: Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. AIMS: To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. METHODS: Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. RESULTS: The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (lubiprostone 8 mcg BID). The incidence of nausea in lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5-99.1% across indications) and only one event (83.6-88.7%); most events occurred within the first 5 days of treatment. CONCLUSIONS: Nausea was the most common adverse event following the treatment with lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.

Difficult defecation in constipated patients and its relationship to colonic disorders.

BACKGROUND: The importance in constipated subjects of having difficult defecation is poorly known. According to the Rome III criteria, constipated patients are classified as having either irritable bowel syndrome with constipation or functional constipation, depending on the presence and characteristics of abdominal pain. But, the Rome III criteria also identify another group of patients, labeled as suffering from functional anorectal disorders. Within this group, two complaints are akin to being constipated, but not labeled so: having dyssynergic defecation or inadequate defecation. OBJECTIVE: The aim of this study was to search for an association between difficult defecation and colonic transit abnormalities in constipated patients and, thus, shed some light on the definition of constipation according to the Rome III criteria. PATIENTS: Four hundred four consecutive patients (81% female), aged 44.9 ± 16.6 years, with a BMI of 25.5 ± 6.4 kg/m(2) (mean ± SD), suffering from chronic constipation were included in the present study. After filling out a standard Rome III questionnaire, patients were classified as suffering from an irritable bowel syndrome with constipation or functional constipation. In addition, they were classified as complaining of difficult defecation or not. Patients completed the Bristol Stool Form Scale as well as visual analogue scales for constipation, bloating, and abdominal pain. The colonic transit time was measured using radiopaque markers and analyzed according to three sites: the right colon, the left colon, and the rectosigmoid area. RESULTS: Difficult defecation is more frequent in patients with irritable bowel syndrome with constipation (84%) than in patients with functional constipation (68%). It is associated with an increase in constipation and abdominal pain scores on Likert scales, and a longer oroanal transit time, due to a delay in the left part of the colon. CONCLUSIONS: This study demonstrates that difficult defecation is part of a more generalized colorectal dysfunction in both irritable bowel syndrome and in functional constipation patients with an overlap of symptomatology. It also demonstrates the relative inadequacy of the Rome III criteria to describe the relationship between constipation and difficult defecation.

Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin.

BACKGROUND & AIMS: Patients with irritable bowel syndrome with constipation (IBS-C) and patients with functional constipation (FC) have similar symptoms, and these disorders overlap in their diagnostic features. Little is known about their overlap in physiology or the involvement of serotonin signaling. We investigated relationships between platelet-depleted plasma concentrations of serotonin, gastrointestinal symptoms, and motor-sensory function in patients with FC or IBS-C compared with healthy volunteers (controls). METHODS: We measured platelet-depleted plasma concentrations of serotonin in fasting and fed individuals with IBS-C (n = 23; 19-50 years old), FC (n = 11; 25-46 years old), and controls (n = 23; 20-49 years old) recruited in Manchester, UK. We also quantified abdominal and bowel-related symptoms, rectal sensitivity, oro-cecal transit, and colonic (whole intestine) transit. RESULTS: Patients with IBS-C or FC had similar baseline symptoms, bowel habits, oro-cecal and colonic transit, and fasting concentrations of serotonin and response to meal ingestion. Only patients with IBS-C had increased symptoms after ingestion of a meal (P < .001)-these patients tended to have lower sensory thresholds than patients with FC. Defecation frequency in the combined group of patients with IBS-C or FC correlated inversely with serotonin concentration (r = -0.4; P = .03). Serotonin concentration also correlated with pain threshold (r = 0.4; P = .02) and stool threshold (r = 0.5; P = .06), which correlated inversely with defecation frequency (r = -0.3; P = .10). CONCLUSIONS: FC and IBS-C, based on Rome III criteria, are not distinct disorders, symptomatically or physiologically. Instead, they appear to lie in a spectrum of visceral sensitivity modulated by serotonin signaling. Symptom response to meal ingestion should be considered in patient classification.

Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. METHODS: We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 µg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. RESULTS: In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). CONCLUSIONS: We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis.

BACKGROUND & AIMS: Linaclotide is a minimally absorbed, 14-amino acid peptide used to treat patients with irritable bowel syndrome with constipation (IBS-C) or chronic constipation (CC). We performed a meta-analysis to determine the efficacy of linaclotide, compared with placebo, for patients with IBS-C or CC. METHODS: MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched for randomized, placebo-controlled trials examining the effect of linaclotide in adults with IBS-C or CC. Dichotomous results were pooled to yield a relative risk (RR), 95% confidence intervals (CIs), and number needed to treat (NNT). RESULTS: The search identified 7 trials of linaclotide in patients with IBS-C or CC; 6 were included in the analysis. Two of 3 trials of IBS-C used the end point recommended by the U.S. Food and Drug Administration: an increase from baseline of 1 or more complete spontaneous bowel movement (CSBM)/week and a 30% or more reduction from baseline in the weekly average of daily worst abdominal pain scores for 50% of the treatment weeks. On the basis of this end point, the RR for response to treatment with 290 µg linaclotide, compared with placebo, was 1.95 (95% CI, 1.3-2.9), and the NNT was 7 (95% CI, 5-11). For CC, on the basis of data from 3 trials of patients with CC, the RR for the primary end point (more than 3 CSBMs/week and an increase in 1 or more CSBM/week, for 75% of weeks) was 4.26 for 290 µg linaclotide vs placebo (95% CI, 2.80-6.47), and the NNT was 7 (95% CI, 5-8). Linaclotide also improved stool form and reduced abdominal pain, bloating, and overall symptom severity in patients with IBS-C or CC. CONCLUSIONS: On the basis of a meta-analysis, linaclotide improves bowel function and reduces abdominal pain and overall severity of IBS-C or CC, compared with placebo.

Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study.

BACKGROUND: Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. METHODS: Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. KEY RESULTS: A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. CONCLUSIONS: Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.

Tenapanor in the Treatment of Irritable Bowel Syndrome with Constipation: Discovery, Efficacy, and Role in Management.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction (DGBI). IBS significantly impacts the quality of life of patients. Since its pathogenesis is unclear and can be multifactorial, it highlights the need for new and improved pharmaceutical drugs that not only improve bowel symptoms, but also address global IBS symptoms, such as abdominal pain. Tenapanor, a recently Food & Drug Administration (FDA)-approved medication for IBS with constipation (IBS-C), is a small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) that inhibits the absorption of sodium and phosphate in the gastrointestinal tract, resulting in fluid retention and softer stool. Furthermore, tenapanor reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain. Due to its recent approval, tenapanor was not included in the recent IBS guidelines, however, it may be considered for IBS-C patients failing first-line treatment of soluble fiber. In this review article, we aim to provide in-depth information to the reader regarding the design of tenapanor, its development through Phase I, II and III randomized clinical trials, and its role in the treatment of IBS-C.

Constipation-Predominant Irritable Bowel Syndrome (IBS-C): Effects of Different Nutritional Patterns on Intestinal Dysbiosis and Symptoms.

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain associated with defecation or a change in bowel habits. The pathogenesis of IBS is not completely clear, but it is known to be multifactorial and complex. Endogenous and exogenous factors such as abnormal GI motility, low-grade inflammation, increased epithelial permeability and visceral hypersensitivity, but diet and psychosocial aspects are also recognized as important actors. Furthermore, the interaction between diet and gut microbiota has gained interest as a potential contributor to the pathophysiology of IBS. To date, there is no specific diet for IBS with constipation (IBS-C); however, many studies show that fiber intake, especially soluble fiber such as inulin, could have a positive effect on symptoms. This review aims to evaluate the effects of some nutritional components such as fibers but also functional foods, prebiotics, probiotics and symbiotics on symptoms and microbiota in IBS-C subjects.

Development of colonic transit time and ultrasound imaging tools as objective indicators for assessing abnormal defecation associated with food intake: a narrative review based on previous scientific knowledge.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) involve chronic or persistent gastrointestinal symptoms. Laboratory tests show no organic lesions, and the symptoms are due to dysfunction. The most typical FGID is irritable bowel syndrome (IBS). In IBS patients, defecation disorders are common and have adverse effects on daily life. The proper evaluation and analysis of colonic transit are important for the management of defecation disorders in IBS patients. In addition, dietary intake and lifestyle affect colonic transit. An accurate assessment of such factors can guide management, leading to improvements in colonic transit and the resolution of defecation disorders. MAIN TOPIC: The Rome IV diagnostic criteria for IBS are based on subjective symptoms, which must be communicated and explained by the patient, limiting their application. Colonic transit time and ultrasonography are objective tools that can be used to diagnose IBS. In particular, previous studies used colonic transit to accurately distinguish between constipation and normal stool passage and to assess delayed gastrointestinal motility. Diet and lifestyle modifications can improve colonic transit and ameliorate bowel dysfunction. CONCLUSION: Colonic transit can be improved by modifying lifestyle factors. Defecation disorders in IBS patients may be resolved by focusing on such factors. In the future, methods of visualizing defecation disorders due to impaired gastrointestinal motility and objective indicators of the associated abdominal symptoms need to be investigated.

Plecanatide for the treatment of constipation-predominant irritable bowel syndrome.

Introduction: As an analogue of uroguanylin plecanatide binds to the Guanylate Cyclase-C receptor activating fluid and ion secretion in the small intestine with the same pH-dependent binding kinetics as the natural ligand. Plecanatide has been FDA approved as safe and effective for the indications of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C).Areas covered: All clinical trial results supporting approval of plecanatide in IBS-C are reported, evaluated and interpreted in the context of the complex pathophysiology of functional diseases and the barriers that must be overcome for appropriate protocol design and conduct.Expert opinion: The Expert Opinion section discusses safety and efficacy of plecanatide for IBS-C. Broader consideration of some of the inherent challenges in understanding and treating functional gastrointestinal disorders includes: 1. the difficulty of understanding diseases with complex pathophysiology that clinically present with a few simple symptoms, 2. exploring the pathophysiology of functional diseases using pharmacophysiology, 3. value of 'Set Theory' in the evaluation of complex clinical data and 4. physiologic and pathophysiologic insight gained by evaluation 'physiologic redundancy' and 'conservation of function'.

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.

Gut Microbiota and Chronic Constipation: A Review and Update.

Background: Chronic constipation, including functional constipation and constipation-type irritable bowel syndrome, is a prevalent, multifactorial gastrointestinal disorder, and its etiology and pathophysiology remain poorly understood. Recently studies using 16S rRNA-based microbiota profiling have demonstrated dysbiosis of gut microbiota in chronic constipation. Aims: To provide an overview of recent studies for microbiota in chronic constipation and treatments for chronic constipation using probiotics, prebiotics, synbiotics, antibiotics and fecal microbiota transplantation (FMT). Methods: PubMed searches were performed up to 1 August 2018 using keywords: "IBS," "IBS-C," "irritable bowel syndrome," "irritable bowel syndrome with constipation," "functional constipation," "chronic constipation" in combination with "gut microbiota," "dysbiosis," "gut microflora" for microbiota in chronic constipation, and in combination with "probiotics," "prebiotics," "synbiotics," "antibiotics," and "fecal microbiota transplantation." Results: The findings of gut microbiota in functional constipation are inconsistent, and currently no consensus exists. Although no clear consensus exists, compared with healthy subjects, IBS-C patients have a lower level of Actinobacteria, including Bifidobacteria, in their fecal samples and a higher level of Bacteroidetes in their mucosa. In most randomized controlled and parallel-group trials, probiotics, prebiotics, synbiotics, antibiotics, and FMT therapy for chronic constipation were effective with few side effects. However, there are many studies in a small number and the types of probiotics are different, it is difficult to evaluate the effect. Conclusions: Evidence indicates that dysbiosis of gut microbiota may contribute to functional constipation and constipation-type irritable bowel syndrome. Targeting treatments for the dysbiosis of constipation by probiotics, prebiotics, synbiotics, antibiotics, and FMT may be a new option, especially for refractory constipation to conventional therapies.

UK clinical experience up to 52 weeks with linaclotide for irritable bowel syndrome with constipation.

BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. METHODS: This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. RESULTS: In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1-77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [-77.0 (-96.3, -57.7); p < 0.001; n = 124] and baseline to 52 weeks [-70.7 (-95.0, -46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). CONCLUSION: Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice.

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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 3 days/month, respectively. CONCLUSION: 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. FUNDING: Synergy Pharmaceuticals Inc.

Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome.

INTRODUCTION: Uroguanylin interacting with intestinal Guanylate Cyclase C (GC-C) receptors plays an important role in gastrointestinal fluid and electrolyte homeostasis. Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH-sensitive receptor binding. Binding to the GC-C receptor activates intracellular conversion of GTP to cGMP resulting in the stimulation of intestinal fluid secretion. Areas covered: Herein, all published research regarding the development of and clinical experience with plecanatide is reviewed. Clinical study results in patients with Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C) are also reviewed. Success in the treatment of CIC and IBS-C is supported by beneficial effects on stool viscosity, Complete Spontaneous Bowel Movements and visceral sensation. Finally, the discussion within focuses on the importance of plecanatide in understanding the physiology of uroguanylin, the pathophysiology of IBS-C and the potential for development of uroguanylin and guanylin analogs. Expert opinion: Given this broad spectrum of potential activity for GC-C agonists, it would not be surprising to see that the use of agents such as plecanatide in new areas grow to a level even greater than the use for the present CIC and IBS-C indications.

Linaclotide activates guanylate cyclase-C/cGMP/protein kinase-II-dependent trafficking of CFTR in the intestine.

The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays. Expression and activity of GC-C/cGMP pathway components were determined by PCR, western blot, and cGMP assays. Fluid secretion as a marker of CFTR cell surface translocation was determined using in vivo rat intestinal loops. Linaclotide treatment (30 min) induced robust fluid secretion and translocation of CFTR from subapical compartments to the cell surface in rat intestinal loops. Similarly, linaclotide treatment (30 min) of T84 and CaCo-2BBe cells increased cell surface CFTR levels. Linaclotide-induced activation of the GC-C/cGMP/PKGII signaling pathway resulted in elevated intracellular cGMP and pVASPser239 phosphorylation. Inhibition or silencing of PKGII significantly attenuated linaclotide-induced CFTR trafficking to the apical membrane. Inhibition of protein kinase-A (PKA) also attenuated linaclotide-induced CFTR cell surface trafficking, implying cGMP-dependent cross-activation of PKA pathway. Together, these findings support linaclotide-induced activation of the GC-C/cGMP/PKG-II/CFTR pathway as the major pathway of linaclotide-mediated intestinal fluid secretion, and that linaclotide-dependent CFTR activation and recruitment/trafficking of CFTR from subapical vesicles to the cell surface is an important step in this process.

A case-control comparison of direct healthcare-provider medical costs of chronic idiopathic constipation and irritable bowel syndrome with constipation in a community-based cohort.

OBJECTIVE: Patients with constipation account for 3.1 million US physician visits a year, but care costs for patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) compared to the general public have received little study. The study aim was to describe healthcare utilization and compare medical costs for patients with IBS-C or CIC vs matched controls from a community-based sample. METHODS: A nested case-control sample (IBS-C and CIC cases) and matched controls (1:2) for each case group were selected from Olmsted County, MN, individuals responding to a community-based survey of gastrointestinal symptoms (2008) who received healthcare from a participating Rochester Epidemiology Project (REP) provider. Using REP healthcare utilization data, unadjusted and adjusted standardized costs were compared for the 2- and 10-year periods prior to the survey for 115 IBS-C patients and 230 controls and 365 CIC patients and 730 controls. Two time periods were chosen as these conditions are episodic, but long-term. RESULTS: Outpatient costs for IBS-C ($6,800) and CIC ($6,284) patients over a 2-year period prior to the survey were significantly higher than controls ($4,242 and $5,254, respectively) after adjusting for co-morbidities, age, and sex. IBS-C outpatient costs ($25,448) and emergency room costs ($6,892) were significantly higher than controls ($21,024 and $3,962, respectively) for the 10-year period prior. Unadjusted data analyses of cases compared to controls demonstrated significantly higher imaging costs for IBS-C cases and procedure costs for CIC cases over the 10-year period. LIMITATIONS: Data were collected from a random community sample primarily receiving care from a limited number of providers in that area. CONCLUSIONS: Patients with IBS-C and CIC had significantly higher outpatient costs for the 2-year period compared with controls. IBS-C patients also had higher ER costs than the general population.

Colonic response to laxative ingestion as assessed by MRI differs in constipated irritable bowel syndrome compared to functional constipation.

BACKGROUND: Functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) share many symptoms but underlying mechanisms may be different. We have developed a magnetic resonance imaging (MRI) technique to measure intestinal volumes, transit, and motility in response to a laxative, Moviprep(®) . We aim to use these biomarkers to study the pathophysiology in IBS-C and FC. METHODS: Twenty-four FC and 24 IBS-C were studied. Transit was assessed using the weighted average position score (WAPS) of five MRI marker pills, taken 24 h before MRI scanning. Following baseline scan, participants ingested 1 L of Moviprep(®) followed by hourly scans. Magnetic resonance imaging parameters and bowel symptoms were scored from 0 to 4 h. KEY RESULTS: Weighted average position score for FC was 3.6 (2.5-4.2), significantly greater than IBS-C at 2.0 (1.5-3.2), p = 0.01, indicating slower transit for FC. Functional constipation showed greater fasting small bowel water content, 83 (63-142) mL vs 39 (15-70) mL in IBS-C, p < 0.01 and greater ascending colon volume (AC), 314 (101) mL vs 226 (71) mL in IBS-C, p < 0.01. FC motility index was lower at 0.055 (0.044) compared to IBS-C, 0.107 (0.070), p < 0.01. Time to first bowel movement following ingestion of Moviprep(®) was greater for FC, being 295 (116-526) min, compared to IBS-C at 84 (49-111) min, p < 0.01, and correlated with AC volume 2 h after Moviprep(®) , r = 0.44, p < 0.01. Using a cut-off >230 min distinguishes FC from IBS-C with low sensitivity of 55% but high specificity of 95%. CONCLUSION & INFERENCES: Our objective MRI biomarkers allow a distinction between FC and IBS-C.