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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.

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.

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.

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.

Pain and other types of discomfort are frequent symptoms following the repair of an abdominal hernia. After 1 year, the incidence of light to moderate pain following inguinal hernia repair is as high as 10% and 2% for severe disabling chronic pain. Postoperative chronic pain not only affects the individual patient, but may also have a great impact on relatives and society, and may be a cause of concern for the responsible surgeon. This paper provides an overview of the anatomy, surgical procedures, and disposing factors (age, gender, ethnicity, genotype, previous hernia repair, pain prior to surgery, psychosocial characteristics, and surgical procedures) related to the postoperative pain conditions. Furthermore, the mechanisms for both acute and chronic pain are presented. We focus on inguinal hernia repair, which is the most frequent type of abdominal hernia surgery that leads to chronic pain. Finally, the paper provides an update on the diagnostic and treatment routines for postoperative pain.