Constipation-predominant Irritable Bowel Syndrome Research Articles

Crystal forms of a new 5-HT4 receptor agonist DA-6886

DA-6886 is a new 5-HT4 receptor agonist under development for the treatment of constipation-predominant irritable bowel syndrome. The objective of this work was to investigate the existence of polymorphs and pseudopolymorphs of DA-6886. Five crystal forms of DA-6886 have been isolated by recrystallization and characterized by differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, and powder X-ray diffractometry (PXRD). From the DSC and TG data, it was confirmed that Form 2 is \( {\raise0.5ex\hbox{$\scriptstyle 1$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) methanol solvate, Form 3 is 1 methanol solvate, Form 4 is \( 1{\raise0.5ex\hbox{$\scriptstyle 1$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) ethanol solvate, and Form 5 is \( 3{\raise0.5ex\hbox{$\scriptstyle 2$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) hydrate. The PXRD patterns of five crystal forms were different, respectively. In the dissolution studies in pH 6.8 ± 0.05 buffer at 37 ± 0.5 °C, the solubility of Form 2 was the highest. And the dissolution rate at 5 min in water decreased in rank order: Form 2 > Form 4 > Form 1 > Form 3 > Form 5. After storage of 3 months at 2 °C, 24 % relative humidity, Form 1, Form 2, Form 3, and Form 4 were not transformed, but Form 5 (\( 3{\raise0.5ex\hbox{$\scriptstyle 2$} \kern-0.1em/\kern-0.15em \lower0.25ex\hbox{$\scriptstyle 3$}} \) hydrate) was transformed to dihydrate.

Relevance of Colonic Gas Analysis and Transit Study in Patients With Chronic Constipation.

Background/AimsColon transit time (CTT) is a useful diagnostic tool in chronic constipation, but requires good patient compliance. We analyzed the correlation between the gas volume score (GVS) and CTT in patients with chronic constipation.MethodsThe study included 145 consecutive patients (65 men) with chronic constipation. The primary outcome was the correlation between the colon GVS and CTT. Secondary outcomes were the differences in colon GVS according to CTT and subtypes of chronic constipation.ResultsThere were 81 patients with “CTT < 45 hours” and 64 patients with “CTT ≥ 45 hours.” In addition, 88 patients were classified as having functional constipation and 57 were classified as having constipation predominant irritable bowel syndrome (IBS-C). There was no significant correlation between CTT and colon GVS. However, the right colon GVS showed a positive correlation with right CTT (r = 0.255, P = 0.007). The median total colon GVS was significantly higher in patients with “CTT ≥ 45 hours” than in those with “CTT < 45 hours” (5.65% vs 4.15%, P = 0.010). There were no significant differences in colon GVS between the functional constipation and IBS-C.ConclusionsWe were unable to detect a correlation between GVS and CTT in patients with chronic constipation. However, total colon GVS may be a method of predicting slow transit in patients with chronic constipation.

Efficacy of a Chinese Herbal Medicine in Providing Adequate Relief of Constipation-predominant Irritable Bowel Syndrome: A Randomized Controlled Trial

Irritable bowel syndrome (IBS) is the most common chronic functional bowel disorder, with few treatment options. IBS affects 10%-20% of the population; as many as 58% of patients have constipation-predominant IBS (IBS-C). We evaluated efficacy and safety of a standardized, specifically formulated Chinese herbal medicine (CHM) preparation in treatment of patients with IBS-C. We performed a double-blind trial of 125 patients with IBS-C (according to Rome III criteria), who were recruited from 13 medical centers or clinics in Australia from July 2009 through February 2012. Patients were randomly assigned to groups given a standardized extract of 7 selected CHM ingredients (n = 61) or placebo (controls, n = 64) for 8 weeks (5 capsules, twice daily). Subjects were then followed for 16 weeks. Chemical definition, standardization, and stability testing of the formulation were completed. Subjects completed a self-administered, validated binary questionnaire of global symptom improvement at weeks 2, 4, 8, and 16 (primary outcome). Secondary outcomes included results from the self-administered IBS Symptom Severity Scale and the Bristol Stool Form Scale (BSFS), which were completed at weeks 4, 8, and 16. There was statistically and clinically significant (per protocol analyses) improvement among subjects who received CHM (n = 50) vs controls (n = 58) for 8 weeks. A greater proportion of subjects receiving CHM reported adequate relief (P = .010). Compared with controls, the CHM group had improved bowel habits vs controls at week 8, including lower IBS Symptom Severity Scale scores (P < .001), reduced straining during defecation (P = .002), and a significant decrease in hard lumpy stools (P = .031). The CHM group also had increased stool consistency, which was based on the Bristol Stool Form Scale (week 8, P < .001). There was no statistically significant difference between groups in abdominal pain at week 8 (P = .692). The CHM was well-tolerated. In a prospective, controlled study, CHM reduced symptoms of IBS-C, increased bowel satisfaction and stool consistency, and reduced straining and hard lumpy stools, compared with placebo. Clinical trial registration no: ACTRN12609000558224.

The intestinal barrier in irritable bowel syndrome: subtype-specific effects of the systemic compartment in an in vitro model.

BackgroundIrritable bowel syndrome (IBS) is a disorder with multifactorial pathophysiology. Intestinal barrier may be altered, especially in diarrhea-predominant IBS (IBS-D). Several mediators may contribute to increased intestinal permeability in IBS.AimWe aimed to assess effects of tryptase and LPS on in vitro permeability using a 3-dimensional cell model after basolateral cell exposure. Furthermore, we assessed the extent to which these mediators in IBS plasma play a role in intestinal barrier function.Materials and MethodsCaco-2 cells were grown in extracellular matrix to develop into polarized spheroids and were exposed to tryptase (10 - 50 mU), LPS (1 - 50 ng/mL) and two-fold diluted plasma samples of 7 patients with IBS-D, 7 with constipation-predominant IBS (IBS-C) and 7 healthy controls (HC). Barrier function was assessed by the flux of FITC-dextran (FD4) using live cell imaging. Furthermore, plasma tryptase and LPS were determined.ResultsTryptase (20 and 50 mU) and LPS (6.25 – 50 ng/mL) significantly increased Caco-2 permeability versus control (all P< 0.05). Plasma of IBS-D only showed significantly elevated median tryptase concentrations (7.1 [3.9 – 11.0] vs. 4.2 [2.2 – 7.0] vs. 4.2 [2.5 – 5.9] μg/mL; P<0.05) and LPS concentrations (3.65 [3.00 – 6.10] vs. 3.10 [2.60-3.80] vs. 2.65 [2.40 – 3.40] EU/ml; P< 0.05) vs. IBS-C and HC. Also, plasma of IBS-D increased Caco-2 permeability versus HC (0.14450 ± 0.00472 vs. 0.00021 ± 0.00003; P < 0.001), which was attenuated by selective inhibition of tryptase and LPS (P< 0.05).ConclusionBasolateral exposure of spheroids to plasma of IBS-D patients resulted in a significantly increased FD4 permeation, which was partially abolished by selective inhibition of tryptase and LPS. These findings point to a role of systemic tryptase and LPS in the epithelial barrier alterations observed in patients with IBS-D.

Emerging treatments in Neurogastroenterology: Perspectives of guanylyl cyclase C agonists use in functional gastrointestinal disorders and inflammatory bowel diseases.

Functional gastrointestinal disorders (FGID) and inflammatory bowel diseases (IBD) are the most frequent pathologic conditions affecting the gastrointestinal (GI) tract and both significantly reduce patients' quality of life. Recent studies suggest that guanylyl cyclase C (GC-C) expressed in the GI tract constitutes a novel pharmacological target in the treatment of FGID and IBD. Endogenous GC-C agonists - guanylin peptides: guanylin and uroguanylin, by the regulation of water and electrolyte transport, are involved in the maintenance of homeostasis in the intestines and integrity of the intestinal mucosa. Linaclotide, a synthetic agonist of GC-C was approved by Food and Drug Administration and European Medicines Agency as a therapeutic in constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Lately, several preclinical and clinical trials focused on assessment of therapeutic properties of synthetic agonists of uroguanylin, plecanatide, and SP-333. Plecanatide is currently tested as a potential therapeutic in diseases related to constipation and SP-333 is a promising drug in ulcerative colitis treatment. Here, we discuss the most recent findings and future trends on the development of GC-C agonists and their use in clinical trials.

Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome.

Dietary fibre supplements have been advocated for the management of chronic constipation (CC) and irritable bowel syndrome (IBS). Recently, a fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) restricted diet has been recommended for IBS. To systematically examine recent evidence for dietary interventions with fibre in CC and IBS and FODMAP-restricted diet in IBS, and provide recommendations. We searched PUBMED, MEDLINE, OVID and COCHRANE databases from 2004 to 2014. Published studies in adults with CC and IBS and constipation-predominant IBS (IBS-C) that compared fibre with placebo/alternative and FODMAP-restricted diet with alternative were included. Of 550 potentially eligible clinical trials on fibre, 11 studies were found and of 23 potentially eligible studies on FODMAPs, six were found. A meta-analysis was not performed due to heterogeneity and methodological quality. Fibre was beneficial in 5/7 studies in CC and 3/3 studies in IBS-C. FODMAP-restricted diet improved overall IBS symptoms in 4/4 and IBS-C symptoms in 1/3 studies and three studies did not meet inclusion criteria. There were significant disparities in subject selection, interventions and outcome assessments in both fibre and FODMAPs studies. Fibre supplementation is beneficial in mild to moderate CC and IBS-C, although larger, more rigorous and long-term RCTs are needed (Fair evidence-Level II, Grade B). Although the FODMAP-restricted diet may be effective in short-term management of selected patients with IBS (Fair evidence-Level II, Grade C) and IBS-C (Poor evidence-Level III, Grade C), more rigorous trials are needed to establish long-term efficacy and safety, particularly on colonic health and microbiome.

The Effect of a Multi-strain Probiotic on the Symptoms and Small Intestinal Bacterial Overgrowth in Constipation-predominant Irritable Bowel Syndrome: A Randomized, Simple-blind, Placebo-controlled Trial

Background and aim: the qualitative and quantitative difference in the intestinal microbiota between irritable bowel syndrome (IBS) patients and healthy volunteers doesn't raise doubts. Small intestinal bacterial overgrowth(SIBO), reported in 9-35% patients with constipation-predominant of irritable bowel syndrome (IBS-C), is involved in the pathogenesis IBS. Elimination of SIBO can lead to improvement of clinical symptoms. The aim of this study was to assess the efficacy of a bifido- and lactobacillis-containing probiotic Florasan-D on the eradicating SIBO and on the severity of clinical symptoms in patients with IBS-C. Methods: this randomized (1 : 1), simple-blinded, placebo-controlled investigation conducted at one centre in Russia.33 patients with IBS-C (clinical type was determined according to ROME III criteria) were randomized to receive a multi-strainprobiotic Florasan-D containing Bifidobacteriumbifidum, Bifidobacteriumlongum, Bifidobacteriuminfantis, Lactobacillus rhamnosus or placebo for 4 weeks: 16 and 17 persons respectively. The intensity of abdominal pain and bloating was estimated by a visual analogue scale (VAS), stool consistency – by a Bristol stool form scale before and after the intervention. Quality of life was assessed by the Short Form-36 questionnaire (SF-36). All subjects were analysed by lactulose hydrogen breath test with using Gastro+ Gastrolyzer (Bedfont, UK) to determine SIBO. Results: patients treated with multi-strainprobiotic Florasan-D reported a reduction in the severity of clinical symptoms: abdominal pain decreased from 4 to 2 point (р=0,003), stool frequency – from 3 to 7 per week (р=0,001) and stoolconsistency – from type 2 to type 3 by a Bristol stool form scale (р=0,001); SIBO was found in 56,3% patients before treatment and no patients had this syndrome after therapy. Patients treated with placebo reported a reduction the severity of abdominal pain only (р=0,028). SIBO in these patients before treatment was revealed in 52,9% and remained in all patients after it. Conclusions: multi-strainprobiotic Florasan-D is significantly more effective than placebo for reduction of clinical symptoms and SIBO elimination in IBS-C patients.

1020 Efficacy and Safety of Tenapanor in Patients With Constipation Predominant Irritable Bowel Syndrome: A 12-Week, Double-Blind, Placebo-Controlled, Randomized Phase 2B Trial

1020 Efficacy and Safety of Tenapanor in Patients With Constipation Predominant Irritable Bowel Syndrome: A 12-Week, Double-Blind, Placebo-Controlled, Randomized Phase 2B Trial

77 Colonic Microbes Contributing to Hydrogen Generation and Utilization Correlate With Breath Methane and Functional Symptoms in Patients With Chronic Constipation and Constipation Predominant Irritable Bowel Syndrome

77 Colonic Microbes Contributing to Hydrogen Generation and Utilization Correlate With Breath Methane and Functional Symptoms in Patients With Chronic Constipation and Constipation Predominant Irritable Bowel Syndrome

Mo1262 Effects of Baseline Abdominal Pain on Response to Lubiprostone in Patients With Constipation-Predominant Irritable Bowel Syndrome

Background: IBS-D is characterized by a diverse group of core symptoms that include abdominal pain, altered stool consistency, bloating, and urgency. To assess the ability of rifaximin (RFX) to produce a common response to these multiple symptoms, the study design incorporated an open-label (OL) enrichment phase where RFX responders were identified for potential inclusion in a repeat treatment phase. This analysis describes the profile of symptom improvement from the OL enrichment phase. Methods: Subjects with IBS-D (Rome III criteria) with average symptom severity scores of ≥ 3 for abdominal pain (AP, scale 0-10) and bloating (scale 0-6), with ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the 7-day baseline were entered into the OL phase. In OL, all subjects received RFX 550 mg TID for 2 weeks, followed by a 4-week, treatment-free assessment period. A responder, as defined by the FDA composite endpoint, was required to achieve a ≥30% decrease from baseline in mean weekly AP score, and simultaneously respond for stool consistency (SC) with a ≥50% decrease from baseline in number of days/ week with BSS Type 6 or 7 stools, for ≥2 weeks of a 4-week period. In addition to the FDA composite endpoint, additional core symptoms of IBS-D were assessed, including bloating (6-point scale; 0=not at all, 6=a very great deal), urgency (Yes/No during the last 24 hours), and overall IBS symptoms (How bothersome were your symptoms of IBS in the last 24 hours?; 6-point scale; 0 = not at all, 6 = a very great deal). Results: A total 2579 subjects (mean age: 46.4; 68% female) received RFX treatment during the OL phase, of which 2331 were evaluable for efficacy. Based on the pre-specified FDA composite definition of response, which stipulates improvements in both AP and SC on the same weeks, 1074 (46%) subjects were deemed responders in the 4-week follow-up period. Another 14% of subjects responded only to the SC component, while a different 11% of subjects responded only to the AP component. Finally, 1% of subjects experienced improvements for AP and SC, but not on the same weeks of the 4-week assessment period. Collectively, 72% of evaluable subjects experienced improvement on at least one component of the FDA composite endpoint. When all symptoms were evaluated independently (AP, SC, urgency, bloating, and overall IBS symptoms), >50% of subjects were deemed to be responders following a 2-week course of OL RFX (Table). Conclusions: These findings suggest that over 70% of patients experience improvement in at least one of the two symptoms of the FDA composite endpoint. Improvements for bloating, urgency, and overall IBS symptoms, suggest that the benefit of rifaximin may extend beyond symptoms comprising the FDA composite endpoint. Proportion of Responders for IBS-D Symptoms During Open-label Phase

Differentiation of functional constipation and constipation predominant irritable bowel syndrome based on Rome III criteria: a population‐based study

While the Rome III classification recognises functional constipation (FC) and constipation predominant IBS (IBS-C) as distinct disorders, recent evidence has suggested that these disorders are difficult to separate in clinical practice. To identify whether clinical and lifestyle factors differentiate Rome III-defined IBS-C from FC based on gastrointestinal symptoms and lifestyle characteristics. 3260 people randomly selected from the Australian population returned a postal survey. FC and IBS-C were defined according to Rome III. The first model used logistic regression to differentiate IBS-C from FC based on lifestyle, quality-of-life and psychological characteristics. The second approach was data-driven employing latent class analysis (LCA) to identify naturally occurring clusters in the data considering all symptoms involved in the Rome III criteria for IBS-C and FC. We found n=206 (6.5%; 95% CI 5.7-7.4%) people met strict Rome III FC whereas n=109 (3.5%; 95% CI 2.8-4.1%) met strict Rome III IBS-C. The case-control approach indicated that FC patients reported an older age at onset of constipation, were less likely to exercise, had higher mental QoL and less health care seeking than IBS-C. LCA yielded one latent class that was predominantly (75%) FC, while the other class was approximately half IBS-C and half FC. The FC-dominated latent class had clearly lower levels of symptoms used to classify IBS (pain-related symptoms) and was more likely to be male (P=0.046) but was otherwise similar in distribution of lifestyle factors to the mixed class. The latent class analysis approach suggests a differentiation based more on symptom severity rather than the Rome III view.

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

Prevalence of organic disease at colonoscopy in patients with symptoms compatible with irritable bowel syndrome: cross-sectional survey

Objective. Guidelines for the management of irritable bowel syndrome (IBS) encourage a positive diagnosis, but some evidence suggests organic disease may be missed unless investigations are performed. We examined yield of colonoscopy in a cohort of secondary care patients meeting criteria for IBS. Materials and methods. Demographic data, symptoms and findings at colonoscopy were recorded prospectively in consecutive, unselected adults with gastrointestinal (GI) symptoms compatible with IBS according to the Rome III criteria. Prevalence of organic GI disease was compared between those meeting criteria for IBS, according to the presence or absence of co-existent alarm features, and by IBS subtype. Results. A total of 559 patients met Rome III criteria for IBS, of whom 423 reported ≥1 alarm feature and 136 none. There was a significantly higher prevalence of organic GI disease among those reporting alarm features (117 [27.7%]), compared with those without (21 [15.4%]) (p = 0.002). In the latter group of 136 patients, Crohn’s disease was the commonest finding (10 [7.4%] subjects), followed by coeliac disease (4 [2.9%] subjects), and microscopic colitis (3 [2.2%] subjects). Regardless of presence or absence of alarm features, patients with constipation-predominant IBS were less likely to exhibit organic GI disease than those with diarrhea-predominant or mixed IBS (12.7% vs. 32.1% and 23.8%, p = 0.006). Conclusions. One in six patients with symptoms compatible with IBS without alarm features in this selected group exhibited organic GI disease following investigation. Assessment of alarm features in a comprehensive history is vital to reduce diagnostic uncertainty that can surround IBS.

Genetic epidemiology of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder characterized by presence of abdominal pain or discomfort associated with altered bowel habits. It has three main subtypes - constipation predominant IBS (C-IBS), diarrhea predominant IBS (D-IBS) and IBS with mixed features of both diarrhea as well as constipation (M-IBS). Its pathophysiology and underlying mechanisms remain elusive. It is traditionally believed that IBS is a result of multiple factors including hypersensitivity of the bowel, altered bowel motility, inflammation and stress. Initial studies have shown familial aggregation of IBS suggesting shared genetic or environmental factors. Twin studies of IBS from different parts of world have shown higher concordance rates among monozygotic twins than dizygotic twins, and thus suggesting a genetic component to this disorder. Multiple studies have tried to link single-nucleotide polymorphisms (SNPs) to IBS but there is little evidence that these SNPs are functional. Various molecules have been studied and investigated by the researchers. Serotonin, a known neurotransmitter and a local hormone in the enteric nervous system, has been most extensively explored. At this time, the underlying gene pathways, genes and functional variants linked with IBS remain unknown and the promise of genetically-determined risk prediction and personalize medicine remain unfulfilled. However, molecular biological technologies continue to evolve rapidly and genetic investigations offer much promise in the intervention, treatment and prevention of IBS.

Partially hydrolyzed guar gum in the treatment of irritable bowel syndrome with constipation: effects of gender, age, and body mass index.

Background/Aims:Partially hydrolyzed guar gum (PHGG) relieves symptoms in constipation-predominant irritable bowel syndrome (IBS) and may have prebiotic properties. However, the correlation between the effectiveness of PHGG and patient characteristics has not been examined. We aimed to investigate the effect of PHGG in symptom relief on constipation-predominant IBS according to gender, age, and body mass index (BMI).Patients and Methods:Sixty-eight patients with IBS entered a 2-week run-in period, followed by a 4-week study period with PHGG. Patients completed a daily questionnaire to assess the presence of abdominal pain/discomfort, swelling, and the sensation of incomplete evacuation. The number of evacuations/day, the daily need for laxatives/enemas and stool consistency-form were also evaluated. All patients also underwent a colonic transit time (CTT) evaluation.Results:PHGG administration was associated with a significant improvement in symptom scores, use of laxatives/enemas, stool form/consistency and CTT. At the end of the study period and compared with baseline, the number of evacuations improved in women, patients aged ≥ 45 years and those with BMI ≥ 25 (P < 0.05 for all comparisons); abdominal bloating improved in males (P < 0.05), patients < 45 years (P < 0.01) and those with BMI < 25 (P < 0.05). A decrease in the number of perceived incomplete evacuations/day was reported in patients with a BMI ≥ 25 (P < 0.05). Reductions in laxative/enema use were recorded in females (P < 0.05), patients < 45 years (P < 0.01), and patients with BMI < 25 (P < 0.05).Conclusions:Gender, age, and BMI seem to influence the effect of PHGG supplementation in constipated IBS patients. Further studies are needed to clarify the interaction of such parameters with a fiber-enriched diet.

Health Care Cost Associated To Constipation Predominant Irritable Bowel Syndrome In Spain.

Health Care Cost Associated To Constipation Predominant Irritable Bowel Syndrome In Spain.

Clinical and investigative assessment of constipation: a study from a referral center in western India.

Constipation may be primary or secondary. Pathophysiologic subtypes of primary constipation are dyssynergic defecation (DD), slow (STC), and normal transit constipation (NTC). Clinical subtypes are functional constipation (FC) and constipation predominant IBS (C-IBS). The objectives of this paper are to study the clinical profile, categorize and compare various subtypes of primary constipation, and to assess the success of biofeedback therapy (BFT) in a non-randomized, uncontrolled open-label study among patients with DD. Consecutive constipation patients (April 2011 to December 2012) were evaluated. Patients <18years and secondary constipation were excluded. FC and C-IBS were classified by Rome III module. All patients, after excluding secondary constipation, underwent anorectal manometry (ARM) with balloon expulsion test and colon transit study (CTS). Patients with DD were given BFT. Out of 128 patients, 23 %, 58 %, and 19% had secondary constipation, FC, and C-IBS, respectively. Ninety-nine patients had primary constipation. Among those with primary constipation mean age was 53.5 (21-86) years, (77% males). Forty-six, 15, and 40 had NTC, STC, and DD, respectively. Out of those with DD, 34 had paradoxical anal contraction and 6 had impaired rectal propulsion. FC and C-IBS were clinically and pathophysiologically similar except for abdominal pain. Patients with DD were more likely to have history of finger evacuation, straining, incomplete evacuation, sensation of anorectal obstruction than no DD. Sixty-nine percent of the patients with STC had ≤3 stools/week compared to 37% with NTC (p-value 0.018). Thirty out of 40 (75%) patients with DD underwent BFT but 20 completed ≥4 sessions. Seventy percent with ≥4 sessions had improved complete spontaneous bowel movements (CSBM). NTC was the most common subtype of primary constipation. Symptoms of finger evacuation, sensation of anorectal obstruction, incomplete evacuation, and straining were more prevalent in DD. ARM and CTS could easily identify patients with DD and STC.

Ranolazine Blocks NaV1.5 Peak Current and Shear Sensitivity in Human Colonic Circular Smooth Muscle

Introduction:SCN5A-encoded NaV1.5 is a voltage-gated mechanosensitive sodium channel expressed in circular layer smooth muscle cells (SMCs) and interstitial cells of Cajal of human small intestine. In human small intestinal smooth muscle, NaV1.5 contributes to resting membrane potential and slow waves. SCN5A mutations are found in 2-3% of patients with irritable bowel syndrome (IBS). The majority of these SCN5A mutations are associated with constipation predominant IBS. A Na+ current was previously described in colonic circular SMCs, and we recently identified SCN5A mRNA in human colonic circular muscle suggesting NaV1.5 is also expressed in the colon. Ranolazine is a clinically available NaV1.5 antagonist used in cardiac disease that also blocks NaV1.5 mechanosensitivity. Constipation is a common adverse effect of ranolazine. The aim of this study was to examine effect of ranolazine on Na+ current and shear sensitivity in human colonic circular SMCs. Methods: Whole cell inward currents were recorded from freshly dissociated human colonic circular SMCs with and without 50 μmol/L ranolazine in bath. Shear stress was induced by 10 mL/min flow of bath solution containing 0 or 50 μmol/L ranolazine. The distinct time and voltage dependent characteristics of fast activating Na+ current and slower activating Ca2+ current were used to separate the components of inward current. The voltage dependence of activation was fitted by a Boltzmann equation. Comparisons were made by paired t-test of means ±SEM. Results: In colonic circular SMCs, ranolazine (50 μmol/L) inhibited NaV1.5 peak currents by 43±9% (-104±33 to -58±20 pA/pF; n=6; P<0.05). Ranolazine shifted the half-point of the voltage dependence of activation (V1/2) from -37±1.7 to -43±1.4 mV (n=6; P<0.05). Mechanical stimulation by flow (shear stress) increased colonic SMC NaV1.5 peak current by 18±2% (−104±33 to −122±39 pA/pF; n=6; P<0.05). V1/2 was hyperpolarized with shear stress from -37±1.7 to -40±2.2 mV (n=6; P<0.05). Shear stress accelerated time to peak activation at -30 mV from 5.4±0.6 to 2.9±0.4 ms (n=5; P<0.05). Sensitivity to shear was blocked by ranolazine (-58±20 to -60±28 pA/pF; n=6; P=0.2). Ranolazine also blocked change in V1/2 and activation caused by shear (-43±1.4 mv to -43±1.1; n=6; P=0.7 for V1/2 and 2.9±0.4 to 4.3±1.4 ms, n=3; P<0.05 for activation time with ranolozine). Conclusion: Ranolazine blocked human colonic circular SMC Na+ currents and also blocked Na+ current shear sensitivity. These effects of ranolazine may help explain the gastrointestinal side effects of the drug and may be of clinical interest for the treatment of disorders such as diarrhea-predominant IBS. Supported by NIH DK 57266 and DK 57061.

Use of SBI, an Oral Medical Food as an Option for Various Gastrointestinal Disorders

Introduction: Oral medical foods have been used for decades for nutritional support, primarily in institutional settings. It is now possible to utilize prescription medical foods for gastrointestinal (GI) disorders in medical practice. Oral serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown to reduce loose stools, improve stool consistency as well as other symptoms (i.e., abdominal pain, bloating, urgency) in patients with diarrhea predominant irritable bowel syndrome (IBS-D) syndrome and HIV-associated enteropathy. This current assessment followed 18 difficult to treat patients in outpatient medical practice setting using SBI as an addition to standard of care. The population consisted of 18 patients: 14 IBS (2 constipation predominant IBS (IBS-C), 7 IBS-D, 2 Mixed IBS (IBS-M), 3 IBS), 2 Crohn’s disease, 1 J-pouch, and 1 chronic ischemic bowel, and ranged in age from 22-92 years. SBI was added to their current care at a daily dose of either 5 or 10 g and followed for several weeks to determine if treatment helped to address and manage their symptoms. Primary symptoms included abdominal pain, diarrhea, bloating, distention and incontinence. Overall, 16 of the 18 patients showed improved symptoms while 2 patients discontinued therapy. One IBS patient was non-compliant during 8 weeks of therapy and 1 IBS-C patient showed improved bowel movements, but felt the therapy was ineffective and chose to discontinue after 11 weeks of therapy. Of the remaining 16 patients who remained on therapy, they reported an overall improvement in symptoms with improved stool consistency, decreased frequency as well as improvements in abdominal pain, bloating, distention, incontinence, nausea and some reports of improved appetites. Two patients reported a resolution or near resolution of symptoms. In most cases, therapeutic effects of SBI were seen within the first 4 weeks of therapy with continued improvements at subsequent visits. In some cases, the removal of other medications was made given patient response with SBI. GI disorders that result in severe chronic changes in motility can be difficult to treat and many patients fail on conventional drug therapies. The multifaceted mechanism of action and specificity of SBI may help to manage chronic motility problems and other symptoms in these difficult to treat patients. Evidence in animal models has shown that SBI can reduce intra-luminal bacterial products, bind with bacterial lipopolysaccharides, and enhance tight junctions between intestinal epithelial cells. Medical foods are a safe treatment option for patients with IBS and other gastrointestinal disorders. Disclosure - Bryon Petschow, PhD - employee of Entera Health, Inc.

The effect of irritable bowel syndrome on carotid intima-media thickness, pulse wave velocity, and heart rate variability.

Irritable bowel syndrome (IBS), a subgroup of functional somatic disorders, may be associated with autonomic dysfunction (AD). Heart rate variability (HRV), a measure of autonomic dysfunction, may predict survival. The aim of this study was to investigate the effect of IBS on HRV parameters, carotid intima-media thickness (CIMT) and carotid-femoral pulse wave velocity (cf-PWV) as surrogates of AD, subclinical atherosclerosis and arterial stiffness, respectively. Our study was cross-sectional and observational. Thirty consecutive patients with IBS and 30 control participants underwent 24-hour Holter monitoring, cf-PWV assessment and CIMT measurement. The diagnosis of IBS was based on Rome III criteria. There were 24 patients with IBS-Constipation (80%), 4 patients with IBS-Diarrhea (13.3%), and 2 patients with IBS-Mixed (6.7%) in IBS group. Student t-test and χ2 test were utilized in order to compare continuous and categorical variables between two groups, respectively. Biochemical parameters did not differ between groups except for slightly increased creatinine in patients with IBS. cf-PWV and CIMT values were similar between groups. SDNN index and RMSSD were significantly impaired in patients with IBS compared to controls. Frequency analyses revealed lower LF, HF, and VLF in subjects with IBS. We demonstrated decreased parasympathetic modulation in patients with constipation predominant IBS. However, we could not demonstrate any changes in vascular structure and functions measured by carotid intima-media thickness and pulse wave velocity. Our results do not support accelerated atherosclerosis in IBS population.