Search

Glepaglutide is a novel, long-acting, glucagon-like peptide-2 analogue in a stable aqueous formulation for subcutaneous dosing to treat patients with short bowel syndrome. This study was conducted primarily to characterise the pharmacokinetics of glepaglutide in healthy subjects.In this open-label, partially randomised, parallel-group study, healthy subjects were evenly randomised to glepaglutide 5 or 10 mg dosed subcutaneously once weekly for 6 weeks or to a single intravenous infusion of glepaglutide 1 mg. Each group comprised 15 subjects. Blood samples were drawn to determine plasma concentrations of the parent drug and its two main metabolites. Concentrations of glepaglutide were calculated as the sum of these three analytes. Citrulline was included as a pharmacodynamic biomarker. Safety was assessed throughout the study.From a comparison of pharmacokinetic parameters following subcutaneous versus intravenous dosing, it is concluded that the pharmacokinetics of glepaglutide following subcutaneous dosing are primarily determined by slow release of the two main glepaglutide metabolites from a subcutaneous depot. For subcutaneous dosing once weekly, the two main metabolites accounted for98% of the overall glepaglutide exposure at steady state, with the parent drug contributing to less than 1% of exposure. The estimated mean (95% confidence interval) effective half-life for glepaglutide 5 and 10 mg was 124 (73-185) h and 88 (31-146) h, respectively. There was an increase in the citrulline concentration for both glepaglutide subcutaneous dose levels. No safety issues were identified.Slow release of active metabolites following subcutaneous dosing leads to a significantly protracted pharmacokinetic profile for glepaglutide. These results support that once- or twice-weekly subcutaneous dosing of glepaglutide could be an efficacious therapy for intestinal rehabilitation.NCT03279302.

Background: International practice guidelines for high-stool-output (HSO) management in short bowel syndrome (SBS) are available, but data on implementation are lacking. This study describes the approach used to manage HSO in SBS patients across different global regions. Methods: This is an international multicenter study evaluating medical management of HSO in SBS patients using a questionnaire survey. Thirty-three intestinal-failure centers were invited to complete the survey as one multidisciplinary team. Results: Survey response rate was 91%. Dietary recommendations varied based on anatomy and geographic region. For patients without colon-in-continuity (CiC), clinical practices were generally consistent with ESPEN guidelines, including separation of fluid from solid food (90%), a high-sodium diet (90%), and a low-simple-sugar diet (75%). For CiC patients, practices less closely followed guidelines, such as a low-fat diet (35%) or a high-sodium diet (50%). First-line antimotility and antisecretory medications were loperamide and proton-pump inhibitors. Other therapeutic agents (e.g., pancreatic enzymes and bile acid binders) were utilized in real-world practices, and usage varied based on intestinal anatomy. Conclusion: Expert centers largely followed published HSO-management guidelines for SBS patients without CiC, but clinical practices deviated substantially for CiC patients. Determining the reasons for this discrepancy might inform future development of practice guidelines.

This study investigated the prevalence, characteristics, and management of patients with chronic intestinal failure (CIF) in the United States in 2012-2020, based on parenteral support (PS) prescription claims and healthcare utilization.Patients with CIF were identified from the Integrated DataVerse® claims database if they had at least two PS prescriptions within 6 months and a relevant diagnosis. Analysis included prevalence and characteristics of patients with CIF, their travel distance to receive PS prescriptions, and the distribution of PS providers and their prescribing history.Up to 24,048 patients with CIF were identified, equivalent to 75 patients per million. CIF affected people of all ages, being more prevalent in women than in men. Many providers signed PS orders for small patient groups over short time periods, whereas few providers signed PS orders for large patient groups long term, indicating a lack of centralization. The distribution of PS providers suggested a disparity in healthcare coverage in rural vs urban areas, leading to patients traveling considerable distances to receive PS prescriptions. This may be exacerbated by a decline of providers with expertise in CIF and nutrition.Healthcare disparities for patients with CIF have likely been obscured by the lack of CIF-specific diagnostic and procedure codes, obliging providers to code for their patients under other codes. Effective policy changes, including centralized care, revision of reimbursement models, and expansion of nutrition-focused education in addition to the newly introduced International Classification of Diseases codes, are needed to provide the best care for patients.

BackgroundAcute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression.MethodsThe study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis.DiscussionThis study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. BACKGROUND: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. METHODS: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. DISCUSSION: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. TRIAL REGISTRATION: EudraCT no. 2021-000069-34. CLINICALTRIALS: gov NCT04966559. Registered on July 8, 2021.

Background Extensive intestinal resection may lead to short bowel syndrome resulting in intestinal insufficiency or intestinal failure (IF). Intestinal insufficiency and IF involve deficiency of the proglucagon-derived hormones, GLP-1 and GLP-2. Two major problems of short bowel (SB) are epithelial surface loss and accelerated transit. Standard treatment now targets intestinal adaptation with a GLP-2 analogue, to enlarge absorptive surface area. It is possible that additional benefit can be gained from combination of GLP-1 and GLP-2 activity, with the aim to enlarge intestinal surface area and also slow intestinal transit. Methods The GLP-1 and GLP-2 specific effects of the novel dual GLP-1 and GLP-2 receptor agonist dapiglutide (rINN) were characterized in rodents. Furthermore, in a murine SB model of intestinal insufficiency with 40% ileocecal resection, the influence of dapiglutide on intestinal growth, body weight, food intake, volume status and stool water content was tested against vehicle and sham operated male mice. Results Dapiglutide significantly improves oral glucose tolerance, reduces intestinal transit time and promotes intestinal growth. In the SB mouse model, dapiglutide promotes body weight recovery, despite unchanged liquid diet intake. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height, as well as intestinal length. Furthermore, dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. Conclusion Dapiglutide possesses specific and potent GLP-1 and GLP-2 receptor agonist effects in rodents. In the murine SB model, combined unimolecular GLP-1R and GLP-2R stimulation with dapiglutide potently attenuates intestinal insufficiency and potentially also IF. This article is protected by copyright. All rights reserved.

BACKGROUND: Current guidelines recommend that patients with chronic intestinal failure (CIF) should be managed by a multidisciplinary team (MDT). However, the characteristics of real-world IF centers and the patients they care for are lacking. The study aims to describe IF center characteristics as well as characteristics of patients with CIF across different global regions. METHODS: This is an international multicenter study of adult IF centers using a survey. The questionnaire survey included questions regarding program and patient characteristics. Thirty-three investigational centers were invited to participate. Each center was asked to answer the survey questions as one MDT. RESULTS: The survey center response rate was 91%. The median number of patients with CIF per center was 128 (range, 30-380). The most common disciplines reported were gastroenterologist (93%), dietitian (90%), nurse (83%), and advanced practitioner (nurse practitioner and physician assistant, 77%). There were centers that did not have a pharmacist, surgeon, psychologist, and social worker (30%, 37%, 60%, and 70%, respectively). The median full-time equivalents (FTEs) per 100 patients were 1.1 for nurses, 1 for dietitians, 1 for advanced practitioners, and 0.9 for gastroenterologists. Short bowel syndrome was the most common cause of CIF (50%) followed by intestinal dysmotility (20%). CONCLUSION: The majority of centers were managing around 100 patients with CIF. Despite the widespread use of the MDT, there are some variances in team characteristics. Gastroenterologists were the most common physicians supporting MDTs. In IF centers, one FTE of each core discipline was supported to manage 100 patients with CIF. ispartof: NUTRITION IN CLINICAL PRACTICE vol:38 issue:3 pages:657-663 ispartof: location:United States status: accepted

Lifestyle modification is the foundation of treatment recommendations for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The design of clinical trials in NASH may be impeded by the lack of a systematic approach to identify and evaluate how lifestyle changes and/or modifications influence clinical trial outcomes and associated endpoints. Furthermore, there are additional uncertainties regarding the methods that can be utilised to better characterise and quantify lifestyle variables - which can influence disease activity and alter trial endpoints - to allow for comparisons of trial outcomes across different phases of research and/or within drug-classes. This summary by the Liver Forum's Standard of Care Working Group reviews currently available clinical data, identifies the barriers and challenges associated with the standard of care in NAFLD/NASH clinical trials, defines available assessments of lifestyle changes, and proposes approaches to better understand and define the influence of diet and exercise on NASH treatment in the context of different pharmacologic interventions. The ultimate objective is to propose tangible solutions which enable investigators, sponsors, and regulatory authorities to meaningfully interpret clinical trial outcomes and the impact of lifestyle modification on such outcomes as they pertain to phase I-IV clinical trials. (C) 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Background Indications and diagnostic yield of small-bowel video capsule endoscopy (SB-VCE) are communicated in recent clinical academic guidelines. However, guidelines are based mainly on relatively few, small, selection-biased studies at experienced centers, and thus we lack information on indications and diagnostic yield of SB-VCE in the real-world community setting. The aim of the study was to evaluate indications and diagnostic yield of SB-VCE in the real-world community setting. Methods Our local VCE clinical database was used to identify patients undergoing SB-VCE procedures over a 7-year period (2011–2018). Patients were broadly referred and underwent SB-VCE using PillCam™ SB 2 and SB 3 capsule systems. Procedures were reviewed by local endoscopists, who had undergone similar formal SB-VCE review training. Medical reports of the procedures were composed as such. We retrospectively reviewed all reports and gathered data regarding indications and findings. Diagnostic yield was considered positive if SB-VCE visualized any type of clinically significant pathological finding. Results 536 SB-VCE procedures in 516 patients were included in final assessment. Patient mean (± SD) age was 50 ± 20 years with approximately even female/male ratio (275:241). The overall proportion of positive findings was 42% (225/536). The two main indications were obscure gastrointestinal bleeding (occult/anemia or overt/active, OGIB) of 46% (246/536) and definite/suspected Crohn’s disease (CD) of 39% (210/536). Positive SB-VCE findings were obtained in 44% (108/246) of procedures with indication of OGIB and in 50% (104/210) of procedures with indication of CD. Conclusions The indications for SB-VCE are largely consistent with guidelines but with an apparently relatively low diagnostic yield in our real-world community setting.

Background Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. Methods PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer’s lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. Discussion This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. Trial registration ClinicalTrials.govNCT04743570. Registered on 28 January 2021. EudraCT 2020-002313-18.

BackgroundAberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated using qPCR technology.Results Data suggest that PGE2 binds to high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. ConclusionIn conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, indicating a likely predisposition for early CRN development. Moreover, PGE2 potency activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal cancer management.

We read with interest the publication entitled “Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome” ([Hargrove et al., 2020][1]). The authors investigated the pharmacology and pharmacokinetic (PK

Background. The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. Methods. Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) β1, and soluble collagen proteins were measured on days 3 and 5. Results. ZP1849 treatment increased Ki67 (P<0.0001) and IGF-1 (P<0.05) mRNA levels in noninjured colon day 0, and postoperatively in the anastomotic wounds compared to vehicle-treated rats. ZP1849-treated rats had increased (P=0.042) anastomotic breaking strength at day 5 compared with vehicle. COL1A1 and COL3A1 mRNA levels (P<0.0001) and soluble collagen proteins (P<0.05) increased from day 3 to day 5 in ZP1849-treated rats, but not in vehicle-treated rats. COX-2 mRNA and MPO protein levels decreased from day 3 to day 5 (P<0.001) in both groups. ZP1849 treatment reduced TGF-β1 protein levels on day 5 (P<0.001) but did not impact MMP-7 transcription. Conclusions. The GLP-2 analogue ZP1849 increased breaking strength, IGF-1 expression, and cell proliferation, which may be beneficial for colonic anastomotic wound healing.

Mucosal healing determined by endoscopy is currently the remission standard for ulcerative colitis (UC). However, new criteria for remission are emerging, such as histologic normalization, which appears to correlate better to the risk of relapse. Here, we study mucosal healing on a molecular and functional level in quiescent UC. We obtained endoscopic biopsies from 33 quiescent UC patients and from 17 controls. Histology was assessed using Geboes score. Protein and mRNA levels were evaluated for the tight junction proteins claudin-2, claudin-4, occludin, and tricellulin, as well as Cl−/HCO3− exchanger DRA, and cyclo-oxygenase enzymes (COX-1, COX-2). The mucosal activity of COX-1 and COX-2 enzymes was assessed in modified Ussing chambers, measuring electrogenic ion transport (short-circuit current, SCC). Chronic inflammation was present in most UC patients. The protein level of claudin-4 was reduced, while mRNA-levels of claudin-2 and claudin-4 were upregulated in UC patients. Surprisingly, the mRNA level of COX-1 was downregulated, but was unaltered for COX-2. Basal ion transport was not affected, while COX-2 inhibition induced a two-fold larger decrease in SCC in UC patients. Despite being in clinical and endoscopic remission, quiescent UC patients demonstrated abnormal mucosal barrier properties at the molecular and functional level. Further exploration of mucosal molecular signature for revision of current remission standards should be considered.

Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential. Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn’s disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping. Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity. Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD. Jochen M. Schwenk, Mauro D’Amato and Jonas Halfvarson contributed equally.

Background: Cyclooxygenase (COX) activity is increased in endoscopic normal colonic mucosa from patients with colorectal neoplasia (CRN). COX-2 is thought to be the predominant COX isozyme involved in neoplasia. Meanwhile, relative contributions of COX-1 and COX-2 isoforms are unknown. Knowledge about their mutual activity in colonic mucosa is important for diagnostics and targeted therapy for CRN. The aim of this study was to assess the relative function, expression and localization of COX-1 and COX-2 enzymes in colonic non-neoplastic human mucosa and thereby to potentially reveal a mucosal disease predisposition for better treatment. Methods: Biopsies were pinched from normal appearing colonic mucosa in patients undergoing endoscopy. Ussing chamber technique was applied for an indirect assessment of epithelial activity, RT-qPCR for expression and immunohistochemistry for localization of COX-1 and COX-2 enzymes in patients without (ctrls) and with a history of CRN (CRN-pts). Results: Combined COX-1 and COX-2 activity was higher in CRN-pts, p=0.036. COX-2 was primarily localized in absorptive cells, while COX-1 appeared to be restricted to nonenteroendocrine tuft cells of the colonic epithelium. Conclusions: In biopsies from endoscopic normal appearing colonic mucosa, combined activity of COX-1 and COX-2 enzymes is increased in CRN-pts compared with ctrls. This indicates that COX-1 and COX-2 together contribute to an increased proliferation process. Of note, in colonic epithelial cell lining, the COX-1 enzyme seems localized in tuft cells.

PURPOSE: Colonic obstruction causes loss of collagen and impairment of anastomotic integrity by matrix metalloproteinases (MMPs). Unexpectedly, pharmacological MMP inhibition increased anastomotic leakage (AL) in obstructed colon possibly due to the non-selective nature of these compounds and the experimental model applied. We therefore studied the effects of selective MMP inhibition on the healing of anastomoses in colon obstructed by a novel laparoscopic technique.METHODS: Left colon was obstructed in 38 male Sprague-Dawley rats (226-284 g). After 12 h, stenoses were resected and end-to-end anastomoses constructed. Baseline breaking strength was determined in 6 animals on day 0. The remaining 32 rats were randomized to daily treatment with the selective MMP-8, MMP-9, and MMP-12 inhibitor AZD3342 (n = 16) or vehicle (n = 16). On day 3, anastomoses were evaluated for AL and breaking strength. Isolated anastomotic wound tissue was analyzed on total collagen and pepsin-insoluble and pepsin-soluble collagen by hydroxyproline. The soluble collagens were further differentiated into native, measured by Sircol, and fragmented forms.RESULTS: Baseline breaking strength was maintained with AZD3342 but decreased by 25% (P = 0.023) in the vehicle group. The anastomotic breaking strength of AZD3342-treated rats was 44% higher (P = 0.008) than the vehicle-treated rats. Furthermore, the AL rate was reduced (P = 0.037) with AZD3342 compared with vehicle treatment. AZD3342 treatment influenced neither the total or insoluble collagen concentrations nor the degree of fragmentation of the soluble collagen triple helices.CONCLUSION: Selective MMP inhibition increased anastomotic breaking strength and reduced AL after resection of colonic obstruction.

OBJECTIVE: The aim of this study was to investigate plasma levels of serotonin, calcitonin and calcitonin gene-related peptide (CGRP) in the course of acute pancreatitis (AP) taking organ failure, etiology and severity into consideration.MATERIAL AND METHODS: Sixty consecutive patients with alcohol- or gallstone-induced AP were included over a 15-month period. Patients were treated according to a standardized algorithm and monitored for organ specific morbidity and mortality. Organ functions and blood samples were assessed on days 0, 1, 2 and 14 after hospital admission. Twenty healthy volunteers, matched for age and gender, comprised the reference group.RESULTS: Lower levels of serotonin were observed in patients at admission compared to healthy volunteers (p = .021). Serotonin levels increased from day 2 to 14 (p CONCLUSION: Our data suggest serotonin and calcitonin levels to be associated to time-course of AP, and calcitonin levels to organ dysfunction. We hypothesize that serotonin plays a pathogenic role in the compromised pancreatic microcirculation, and calcitonin a role as a biomarker of severity in AP.

The pathogenesis of colorectal neoplasia (CRN) has been associated with altered non-neuronal acetylcholine (ACh) metabolism. The aim of this study was to characterize expression, function and cellular location of ACh-related proteins in biopsies obtained from endoscopic normal appearing sigmoid colon in patients with and without CRN. Messenger-RNA (mRNA) levels of 17 ACh-related proteins were quantified by rt-qPCR. Functional responses to ACh, measured as electrogenic transepithelial short circuit current (SCC), were recorded using the Ussing chamber technique. Finally, cellular localization of choline transporter-like proteins (CTLs) and butyryl-cholinesterase enzyme (BChE) was determined by immunohistochemistry. mRNA expression of CTL1 and CTL4 was increased in patients with CRN (p = 0.002 and p = 0.04, respectively). In functional experiments, baseline SCC was increased in CRN patients. ACh induced rapid biphasic changes in SCC. An initial decreasing phase was observed in the minority of CRN patients vs. the majority of controls (25% vs. 69%, respectively, p = 0.031). For the second increasing phase of SCC, data indicated ACh-activation of two receptors. For both parts of the biphasic response, the half maximal effective concentration and maximal responses showed no difference between patient groups. Immunohistochemistry demonstrated CTL1, 3 and 4 and BChE to be localized to colonic crypt cells. We conclude that CRN is associated with increased expression of CTL1 and CTL4, augmented basal prostaglandin-dependent secretion, and altered functional channel response to ACh in human endoscopic normal appearing colonic mucosa. The immunohistochemical findings support CTL1, CTL3, CTL4 and BChE to be involved in non-neuronal mucosal ACh metabolism. This article is protected by copyright. All rights reserved

IntroductionChronic pancreatitis (CP) is thought to present the end stage of a continuous disease process evolving from acute pancreatitis (AP), over recurrent AP, to early and end-stage CP. Due to the irreversible nature of CP, early detection and prevention is key. Prospective assessment based on advanced imaging modalities as well as biochemical markers of inflammation, fibrosis and oxidative stress may provide a better understanding of the underlying pathological processes and help identify novel biomarkers of disease with the ultimate goal of early diagnosis, intervention and prevention of disease progression. This paper describes the protocol of a prospective multicentre cohort study investigating the fibroinflammatory process involved in progression from acute to CP using state-of-the-art diagnostic imaging modalities and circulating biomarkers of inflammation, fibrosis and oxidative stress.Methods and analysisAdult control subjects and patients at different stages of CP according to the M-ANNHEIM system will be recruited from outpatient clinics at the participating sites and form three cohorts: controls (n=40), suspected CP (n=60) and definitive CP (n=60). Included patients will be followed prospectively for 15 years with advanced MRI and contrast-enhanced endoscopic ultrasound with elastography, assessment of endocrine and exocrine pancreatic function, biochemical and nutritional assessment, and evaluation of pain processing using quantitative sensory testing. Blood samples for a biobank will be obtained. The purpose of the biobank is to allow analyses of potential circulating biomarkers of disease progression, including markers of inflammation, fibrosis and oxidative stress.Ethics and disseminationPermissions from the Regional Science Ethics committee and the Regional Data Protection Agency have been obtained. We will submit the results of the study for publication in peer-reviewed journals regardless of whether the results are positive, negative or inconclusive.

BackgroundInvestigations of colorectal carcinogenesis have mainly focused on examining neoplastic tissue. With our aim of identifying potentially cancer-predisposing molecular compositions, we chose a different approach by examining endoscopically normal appearing colonic mucosa of patients with and without colorectal neoplasia (CRN). Directed by this focus, we selected 18 genes that were previously found with altered expression in colorectal cancer affected mucosa.MethodsBiopsies of colonic mucosa were sampled from 27 patients referred for colonoscopy on suspicion of colorectal disease. Of these, 14 patients had present or previous CRN and the remaining 13 patients served as controls. Using qPCR and Western blot technique, we investigated mRNA and protein expressions. Expressions were investigated for selected kinases in the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), the phosphoinositide 3-kinase/Akt, and the Wnt/-catenin pathways as well as for selected phosphatases and several entities associated with prostaglandin E2 (PGE(2)) signaling. Colonic mucosal contents of PGE(2) and PGE(2) metabolites were determined by use of ELISA.ResultsWe found up-regulation of ERK1, ERK2, Akt1, Akt2, PLA2G4A, prostanoid receptor EP3 and phosphatase scaffold subunit PPP2R1B mRNA expression in normal appearing colonic mucosa of CRN patients compared to controls.ConclusionPresent study supports that even normal appearing mucosa of CRN patients differs from that of non-CRN patients at a molecular level. Especially expression of ERK1 mRNA was increased (p=0.007) in CRN group. ERK1 may therefore be considered a potential candidate gene as predictive biomarker for developing CRN. Further validation in larger cohorts are required to determine such predictive use in translational medicine and clinics. BackgroundInvestigations of colorectal carcinogenesis have mainly focused on examining neoplastic tissue. With our aim of identifying potentially cancer-predisposing molecular compositions, we chose a different approach by examining endoscopically normal appearing colonic mucosa of patients with and without colorectal neoplasia (CRN). Directed by this focus, we selected 18 genes that were previously found with altered expression in colorectal cancer affected mucosa.MethodsBiopsies of colonic mucosa were sampled from 27 patients referred for colonoscopy on suspicion of colorectal disease. Of these, 14 patients had present or previous CRN and the remaining 13 patients served as controls. Using qPCR and Western blot technique, we investigated mRNA and protein expressions. Expressions were investigated for selected kinases in the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), the phosphoinositide 3-kinase/Akt, and the Wnt/-catenin pathways as well as for selected phosphatases and several entities associated with prostaglandin E2 (PGE(2)) signaling. Colonic mucosal contents of PGE(2) and PGE(2) metabolites were determined by use of ELISA.ResultsWe found up-regulation of ERK1, ERK2, Akt1, Akt2, PLA2G4A, prostanoid receptor EP3 and phosphatase scaffold subunit PPP2R1B mRNA expression in normal appearing colonic mucosa of CRN patients compared to controls.ConclusionPresent study supports that even normal appearing mucosa of CRN patients differs from that of non-CRN patients at a molecular level. Especially expression of ERK1 mRNA was increased (p=0.007) in CRN group. ERK1 may therefore be considered a potential candidate gene as predictive biomarker for developing CRN. Further validation in larger cohorts are required to determine such predictive use in translational medicine and clinics.

Summary Background Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. Methods In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4–8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. Findings Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by −592 g/day (95% CI −913 to −272; p=0·002) and −833 g/day (−1152 to −515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. Interpretation Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. Funding Zealand Pharma.

Background: Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing.Methods: Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial.Results: We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial.Conclusions: Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.

BACKGROUND & AIMS: The α4β7 integrin is a validated target in inflammatory bowel disease. This randomized, phase 2b, placebo-controlled, double-blind study evaluated the efficacy and safety of the anti-α4β7 antibody abrilumab in patients with moderate-to-severe ulcerative colitis despite treatment with conventional therapies. METHODS: Patients (total Mayo Score 6-12, recto-sigmoidoscopy score ≥2) with inadequate response or intolerance to conventional therapies were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo. The primary end point was remission (total Mayo Score ≤2 points, no individual sub-score >1 point) for the 2 highest dosages at week 8. Key secondary end points were response and mucosal healing (centrally read) at week 8. RESULTS: For 354 patients who received ≥1 dose of investigational product (placebo, n = 116; 7 mg, n = 21; 21 mg, n = 40; 70 mg, n = 98; 210 mg, n = 79), non-adjusted remission rates at week 8 were 4.3%, 13.3%, and 12.7% for the placebo and abrilumab 70-mg and 210-mg groups, respectively (P < .05 for 70 and 210 mg vs placebo); odds of achieving remission were significantly greater with abrilumab 70 mg (odds ratio 3.35; 90% CI 1.41-7.95; P = .021) and 210 mg (odds ratio 3.33; 90% confidence interval 1.34-8.26; P = .030) than with placebo. Response and mucosal healing rates with these dosages also were significantly greater than with placebo. Higher baseline α4β7 levels on naïve CD4+ T cells were a prognostic indicator for overall outcome, but not a predictive biomarker of abrilumab response. There were no cases of progressive multifocal leukoencephalopathy or deaths. CONCLUSIONS: Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe ulcerative colitis. ClinicalTrials.gov, number NCT01694485. ispartof: GASTROENTEROLOGY vol:156 issue:4 pages:946-+ ispartof: location:United States status: published

Acute pancreatitis is one of the most common causes of gastrointestinal-related hospitalization and the incidence is increasing. Endo- and exocrine pancreatic function can be compromised after acute pancreatitis.The purpose of this study was to explore the long-term consequences of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) on pancreatic function.A follow-up study was carried out with prospective assessment of endo- and exocrine pancreatic function among cases with previous PEP and matched controls from a Danish cohort consisting of 772 patients undergoing first-time ERCP. Pancreatic function was evaluated by faecal-elastase-1 test, blood levels of haemoglobin A1c, C-peptide, vitamin B12, vitamin D and indirectly by changes in body weight.Twenty-nine cases and 49 controls participated in the study. Mean follow-up time (standard deviation) was 58 (21) months. Twelve (41%), eight (28%) and nine (31%) patients had mild, moderate and severe PEP, respectively. There was no difference between cases and controls with regard to pancreatic function parameters and PEP severity was not associated with pancreatic function. Factors associated with pancreatic function impairment included body mass index, alcohol consumption, age and smoking.This study suggests that long-term pancreatic function following PEP is similar to the pancreatic function of other patients with comparable gallstone-related morbidity.

Background Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa. Methods Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry. Results In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p = 0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p = 0.002) and subtype PDE5A (p = 0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p = 0.04) and a higher amount of PDE4B (p = 0.02) in samples from colorectal neoplasia patients. Conclusion In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2980-z) contains supplementary material, which is available to authorized users.

Acid-sensing ion channels (ASICs) are esophageal nociceptors that are candidates to mediate heartburn in non-erosive reflux disease (NERD). Amiloride, a diuretic, is known to inhibit ASICs. For this reason, we sought a role for ASICs in mediating heartburn by determining whether amiloride could block heartburn in NERD induced by esophageal acid perfusion.In a randomized double-blind crossover study, we perfused the esophagus with amiloride or (saline) placebo prior to eliciting acid-induced heartburn in patients with a history of proton pump inhibitor-responsive NERD. Those with NERD and positive modified Bernstein test were randomized to perfusion with amiloride, 1 mmol/l, or placebo for 5 min, followed by repeat acid-perfusion. Heartburn severity and time to onset was measured and the process repeated following crossover to the alternative agent.14 subjects completed the study. Amiloride did not reduce the frequency (100 vs. 100 %) or severity of acid-induced heartburn (Mean 2.50 ± SEM 0.33 vs. 2.64 ± 0.45), respectively. There was a trend towards longer time to onset of heartburn for amiloride versus placebo (Mean 2.93 ± SEM 0.3 vs. 2.36 ± 0.29 min, respectively), though these differences did not reach statistical significance (p0.05).Amiloride had no significant effect on acid-induced heartburn frequency or severity in NERD, although there was a trend towards prolonged time to onset of symptoms.

PURPOSE: Submucosal collagen is paramount for colonic anastomotic integrity. Matrix metalloproteinases (MMPs) mediate collagen degradation that increases the risk of wound dehiscence. Although broad-spectrum MMP inhibitors are beneficial for anastomotic strength, they can cause adverse reactions. Knowledge of specific MMPs responsible for the weakening of anastomoses can be used to optimise MMP inhibition therapy. We aimed to quantify transcript and protein levels of multiple MMPs in colonic anastomoses and evaluate the effect of inhibiting the MMPs that displayed the highest expression levels on anastomotic repair.METHODS: Left-sided colonic anastomoses were made in male Sprague-Dawley rats. After 3 days when biomechanical strength is lowest, MMP mRNA and protein levels were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assays and gelatin zymography. The effects of the MMP-8, MMP-9 and MMP-12 synthetic inhibitor AZD3342 was also studied.RESULTS: MMP-8, MMP-9 and MMP-12 gene and protein expression increased profoundly (p < 0.01), and MMP-13 mRNA and MMP-2 mRNA and protein modestly (p < 0.001) in the anastomoses. MMP-3 mRNA levels were not up-regulated significantly compared with adjacent uninjured colon. Increased anastomotic MMP-12 levels paralleled macrophage infiltration by immunohistochemical analyses. AZD3342 (50 mg/kg) treatment increased the anastomotic breaking strength by 29% (p = 0.015) day 3 compared with vehicle. Improved anastomotic strength was not accompanied with alterations of type I or type III procollagen mRNA but was possibly due to inhibition of the concerted digestive action on the existent submucosal collagens by the targeted MMPs.CONCLUSION: The present findings justify the concept of selective MMP inhibition to enhance anastomotic strength in colon.

Objectives: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. Material: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. Results: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. Conclusion: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.

The aim of this study was to assess the influence of patient body weight on the clinical effect of 100 mg diclofenac administered as a single dose for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).All patients subjected to endoscopic retrograde cholangiopancreatography (ERCP) from 2009 to 2014 were evaluated for inclusion. In total, 772 patients were included of whom 378 (49%) received diclofenac prophylaxis.In the diclofenac prophylaxis group, body weight was higher in patients with PEP (mean ± SD: 82 ± 18 kg) than in patients without PEP (74 ± 18 kg) (p = 0.029). In patients not receiving prophylaxis, body weight was not associated with the occurrence of PEP (mean ± SD: 77 ± 18 vs 75 ± 18 kg, respectively, p = 0.450). In an adjusted analysis, higher patient body weight was inversely associated with the clinical effect of 100 mg diclofenac for the prophylaxis of PEP.High patient body weight was associated with a reduced effect of 100 mg diclofenac for prophylaxis of PEP.

Introduction Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils. Methods Male C57BL6 mice (25–30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 μg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations. Results Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage. Conclusion The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis.

Summary Background Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. Aim To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. Methods Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. Results A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. Conclusion The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

We tested the hypothesis that 25-hydroxyvitamin D3 (25OHD) changes during acute inflammation in humans.Patients with first episode of acute pancreatitis were included. Blood samples were acquired on admission and on days 1, 2, and 14.In total, 73 patients (35 males, median age 59) entered the study. On admission, the distribution of 25-OHD levels was as follows: severely deficient (13 nmol/L) 23%; deficient (13-25 nmol/L) 20%; insufficient (26-50 nmol/L) 40%; and normal (50 nmol/L) 17%. There was a significant fall and linear trend in 25OHD, albumin, and hemoglobin from day 0 to day 2. From day 0 to day 2 the drop in 25OHD was 3.1 nmol/L (95% CI 0.59-5.63). The changes from day 0 to day 2 in 25OHD were associated with changes in C-reactive protein (p = 0.02) but not with leukocyte or monocyte count.The 25OHD levels dropped during the first 2 days of acute pancreatitis beyond what was expected based on 25OHD half-life. This study supports our hypothesis that an acute inflammatory condition utilizes 25OHD, but other mechanisms could interfere.

Aliment Pharmacol Ther 2011; 33: 1113–1122 Summary Background Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor ‘transient receptor potential vanilloid 1’(TRPV1) are a potential drug class for GERD treatment. Aim To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. Methods Twenty-two healthy men (20–31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. Data analysis: intention-to-treat. Results A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10–38%] and 28%, respectively (CI: 14–43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1–3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0–5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported ‘feeling cold’ and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4 ± 0.3 °C and 0.7 ± 0.3 °C, respectively, P

In colectomized patients with ileo stoma, the reflex modulation of small intestinal functions is disturbed, resulting in high enteric stoma outputs and malabsorption. Serotonin has a pivotal role in initiating motor and secretory reflexes involving activation of neuronal 5-HT(3) and smooth muscle muscarinic receptors. We aimed to evaluate the effect of 5-hydroxytryptamine (5-HT), ondansetron and atropine on fasting and stimulated antro-duodeno-jejunal migrating motor complex (MMC) in colectomized patients with ileo stoma compared with healthy subjects. Manometric recordings were obtained in a blinded, age- and gender-matched design. The effects of either standard meal or intravenous 5-HT (10 nmol/kg/min.) treatment with pre-treatment of saline (placebo) or ondansetron (250 μg/kg) or atropine (10 μg/kg) were compared. Adverse effects, blood pressure, heart rate and electrocardiographic data were also evaluated. 5-HT increased the frequency (threefold) and migration velocity (twofold) of MMC phase III in both experimental groups. Ondansetron reduced 5-HT-induced frequency of MMC phase III in patients (p 0.05). Atropine did not change fasting MMC in healthy subjects (p > 0.05). We conclude that 5-HT is a stimulator of MMC phase III and that ondansetron reduces the 5-HT-induced MMC phase III without affecting fasting or postprandial properties in colectomized patients with ileo stoma. Similar effects were observed for 5-HT and atropine in healthy subjects.

Sensory changes are thought to be involved in gastro-esophageal reflux disease (GERD). The esophageal multimodal pain model can be used to investigate sensations in response to distension, heat, electric current and acid.The aim of this study was to provide normal values for this model in the normal state and in the acid induced sensitized state.Fifty-three healthy men (20-38 years old) underwent esophageal stimulation with distension, heat and electrical current before and after sensitization with 0.1 N HCl acid. Stimulus intensities at painful and non-painful thresholds and referred pain areas were measured. The percentage of individual participants sensitized to each modality was calculated. In 22 subjects the pre-acid tests were repeated on three subsequent visits.To reach moderate pain, subjects tolerated mean distension of 29.1 ± 11 mL, heat stimulation time of 141 ± 33 s, and mean current of 17.6 ± 6.4 mA. After acid exposure, significantly reduced thresholds were observed for mechanical (24%), heat (11%) and electrical (14%) stimulation (P values 0.05). The percentage of subjects sensitized, defined as reductions in thresholds of ≥10% or ≥20% after acid perfusion, was as follows: for distension 77%/62%, for heat 48%/28%, and for current 58%/44%. The model showed good reliability (intra-class correlations 0.6).Normal values for healthy young men are now provided for the normal and the sensitized state. The percentage of subjects sensitized after acid stimulation are thoroughly documented, and depends on stimulation type and the cut-off value chosen.

Aim: Retrospectively, to investigate the relationship between body mass index (BMI) and basal electrogenic transport as measured by short-circuit current (SCC) in human duodenal and colonic mucosal biopsies. Methods: The study included biopsies from mucosa of normal appearance in the sigmoid colon and/or distal duodenum. Patients were referred for routine endoscopy (predominantly for monosymptomatic abdominal pain) and had normal endoscopic findings. Biopsies were mounted in miniaturized Ussing chambers and basal SCC was recorded. Patients were divided into two groups on the basis of BMI (≤25 and >25 kg m−2). Statistical significance was assessed by the unpaired t-test or Wilcoxon rank-sum test. Correlation coefficients were calculated by Pearson product moment correlation. Results: In colonic biopsies, basal SCC (mean ± standard deviation) was significantly higher in 59 biopsies from 30 patients with low BMI than in 32 biopsies from 23 patients with high BMI (45 ± 29 μA cm−2 vs. 27 ± 21 μA cm−2, P = 0.016). In duodenal biopsies, mean basal SCC was numerically lower in 38 biopsies from 15 patients with low BMI than in 46 biopsies from 19 patients with high BMI (54 ± 26 μA cm−2 vs. 74 ± 39 μA cm−2, P = 0.069). The correlation coefficient between BMI and SCC was −0.26 (P = 0.06) in colonic biopsies and +0.44 (P = 0.001) in duodenal biopsies. Conclusion: Basal intestinal active electrogenic transport is related to BMI and this relationship may differ in different segments of the intestinal tract.