Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.

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.

Pancreatic function following post-endoscopic retrograde cholangiopancreatography pancreatitis: A controlled cohort study with long-term follow-up.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to explore the long-term consequences of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) on pancreatic function. METHODS: 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. RESULTS: 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. CONCLUSION: This study suggests that long-term pancreatic function following PEP is similar to the pancreatic function of other patients with comparable gallstone-related morbidity.

Activity of neutrophil elastase reflects the progression of acute pancreatitis.

OBJECTIVE: Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP and associated organ failure. METHODS: Seventy-five patients admitted to our surgery department with a first episode of AP during 2004-2005 were age- and sex-matched to 20 healthy volunteers (controls). NE activity was assessed using venous blood samples obtained on patient admission and after 1, 2 and 14 days. One sample was also taken from each control. ANOVA was used for statistical comparison between groups. RESULTS: Baseline NE activity (geometric mean; 95% confidence intervals) differed between patients (58.6 nM of substrate 7-amino-4-methylcoumarin [AMC]/hour; 48.52-70.72) and controls (31.5 nM AMC/hour; 25.5-39.0) (p = 0.0003), and did not correlate with time between symptom onset and admission. Patients with alcohol-induced AP demonstrated higher mean activity (59.1 nM AMC/h; 44.7-78.2) than those with gallstone-induced AP (41.7 nM AMC/h; 33.9-51.4) (p = 0.0496). NE activity was higher overall in patients with predicted severe AP (60.9 nM AMC/h; 48.0-77.2) than in those with predicted mild AP (42.1 nM AMC/h; 34.9-50.8) (p = 0.027). Patients with respiratory failure had higher NE activity (82.5 nM AMC/h; 57.5-118.4) than those without (43.9 nM AMC/h; 37.6-51.3) (p = 0.0024). CONCLUSIONS: NE activity was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis.

Effect of amiloride on experimental acid-induced heartburn in non-erosive reflux disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p > 0.05). CONCLUSIONS: 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.

Mannan-binding lectin and mannan-binding lectin-associated serine protease 2 in acute pancreatitis.

OBJECTIVES: Complement activation may play a prominent role in acute pancreatitis (AP). Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) participate in complement activation. The objective of the present study was to evaluate the role of MBL and MASP-2 as markers in AP with regard to etiology, inflammatory activity, severity, and development of multiorgan failure. METHODS: Sixty patients with AP were included. All patients were diagnosed and treated according to a standardized regimen. Blood samples were obtained immediately on admission and again on days 1, 2, and 14. RESULTS: Both MBL (P < 0.001) and MASP-2 (P = 0.002) levels changed significantly over time, but without any significant relation to severity, multiorgan failure, or mortality. We found significantly higher levels of MBL (P = 0.04) in alcohol- than in gallstone-induced AP, but no significant difference in MASP-2 levels. CONCLUSIONS: The MBL and MASP-2 acted as acute-phase reactants, but overall, they were not markers for severity, multiorgan failure, nor for mortality in AP. Our results suggest that MBL and MASP-2 play only a minor role in the inflammatory response in AP.

Migrating motor complex in colectomized ileo stoma patients.

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) but not in healthy subjects. Atropine reduced 5-HT-induced frequency of MMC phase III in healthy subjects (p < 0.05). Ondansetron did not alter fasting or postprandial MMC in either experimental group (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.

The esophageal multimodal pain model: normal values and degree of sensitization in healthy young male volunteers.

BACKGROUND: 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. AIMS: The aim of this study was to provide normal values for this model in the normal state and in the acid induced sensitized state. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia.

BACKGROUND: The pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect. METHODS: Patients referred for colonoscopy were included and grouped into patients with and without colorectal neoplasia. Patients without endoscopic findings of neoplasia served as controls. Biopsy specimens were obtained from normally appearing mucosa in the sigmoid part of colon. Biopsies were mounted in miniaturized modified Ussing air-suction chambers. Indomethacin (10 microM), various stimulators and inhibitors of prostanoid receptors and ion transport were subsequently added to the chamber solutions. Electrogenic ion transport parameters (short circuit current and slope conductance) were recorded. Tissue pathology and tissue damage before and after experiments was assessed by histology. RESULTS: Baseline short circuit current and slope conductance did not differ between the two groups. Patients with neoplasia were significantly more sensitive to indomethacin with a decrease in short circuit current of 15.1 +/- 2.6 microA x cm(-2) compared to controls, who showed a decrease of 10.5 +/- 2.1 microA x cm(-2) (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups. CONCLUSIONS: Epithelial electrogenic transport is more sensitive to indomethacin in normal colonic mucosa from patients with previous or present colorectal neoplasia compared to colonic mucosa from control patients. Stimulated epithelial electrogenic transport through individual prostanoid subtype receptors EP1, EP2, EP3, and EP4 is not significantly different between neoplasia diseased patients and controls. This indicates that increased indomethacin-sensitive mechanisms in colonic mucosa from neoplasia diseased patients are not related to differences in functional expression of EP receptor subtypes.

Colonic epithelial ion transport is not affected in patients with diverticulosis.

BACKGROUND: Colonic diverticular disease is a bothersome condition with an unresolved pathogenesis. It is unknown whether a neuroepithelial dysfunction is present. The aim of the study was two-fold; (1) to investigate colonic epithelial ion transport in patients with diverticulosis and (2) to adapt a miniaturized Modified Ussing Air-Suction (MUAS) chamber for colonic endoscopic biopsies. METHODS: Biopsies were obtained from the sigmoid part of the colon. 86 patients were included. All patients were referred for colonoscopy on suspicion of neoplasia and they were without pathological findings at colonoscopy (controls) except for diverticulosis in 22 (D-patients). Biopsies were mounted in MUAS chambers with an exposed area of 5 mm2. Electrical responses to various stimulators and inhibitors of ion transport were investigated together with histological examination. The MUAS chamber was easy to use and reproducible data were obtained. RESULTS: Median basal short circuit current (SCC) was 43.8 microA x cm(-2) (0.8 - 199) for controls and 59.3 microA x cm(-2) (3.0 - 177.2) for D-patients. Slope conductance was 77.0 mS x cm(-2) (18.6 - 204.0) equal to 13 Omega x cm(2) for controls and 96.6 mS x cm(-2) (8.4 - 191.4) equal to 10.3 Omega x cm(2) for D-patients. Stimulation with serotonin, theophylline, forskolin and carbachol induced increases in SCC in a range of 4.9 - 18.6 microA x cm(-2), while inhibition with indomethacin, bumetanide, ouabain and amiloride decreased SCC in a range of 6.5 - 27.4 microA x cm(-2), and all with no significant differences between controls and D-patients. Histological examinations showed intact epithelium and lamina propria before and after mounting for both types of patients. CONCLUSION: We conclude that epithelial ion transport is not significantly altered in patients with diverticulosis and that the MUAS chamber can be adapted for studies of human colonic endoscopic biopsies.