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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.

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.

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

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.

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.

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.

The study was designed to determine the prostaglandin EP receptor subtypes functionally involved in electrogenic ion secretion in rat colon. With 30 rats, measurements of short circuit current (SCC) and slope conductance were obtained by Ussing chamber technique. Prostaglandin E2 (PGE(2)) and other EP receptor selective agonists were employed on stripped rat colon pre-treated with indomethacin and theophylline. Receptor-specific agonists were butaprost (EP(2)), sulprostone (EP(1) and EP(3)) and PGE(1) alcohol (OH-PGE(1)) (EP(4)). GW627368X was used as a specific EP(4) receptor antagonist. Forskolin-induced SCC was used as a control of tissue viability. The mean basal SCC was 24.5 +/- 0.9 microA/cm(2) (range 9.8-45.1), and mean basal slope conductance was 23.7 +/- 6.1 mS/cm(2) (range 9.7-39.8). The basal SCC decreased after pre-treatment with indomethacin and increased after pre-treatment with theophylline. PGE(2), butaprost and OH-PGE(1) stimulated maximal increase in SCC (55.8 +/- 4.1, 43.9 +/- 3.8 and 93.9 +/- 2.7 microA/cm(2), respectively), while sulprostone had no apparent effects. GW627368X eliminated OH-PGE(1)-induced SCC and partially PGE(2)-induced SCC, leaving butaprost-induced SCC almost unperturbed. Bumetanide, 20 microM, inhibited between 40% and 80% of the agonist-induced changes in SCC. In conclusion, compilation of the results on induced SCC by subtype specific receptor agonists for EP receptors and the pattern of induced SCCs inhibited by GW627368X indicate the EP(4) receptor subtype as the major mediator of PGE(2)-induced electrogenic ion secretion with a lesser induction through the EP(2) receptor subtype.

The enteric nervous system is involved in most of the physiological and pathophysiological processes in the gastrointestinal tract. This Minireview is part two of three and describes the role of the enteric nervous system in gastrointestinal functions (motility, exocrine and endocrine secretions, blood flow, and immune processes) in health and some disease states. In this context, the functional importance of the enteric nervous system for food intake, the gall bladder, and pancreas will be addressed. In specific, dysmotility, diarrhoea, constipation, non-occlusive intestinal ischaemia (intestinal angina), inflammation, cholelithiasis, cholecystitis, postcholecystectomy syndrome, and pancreatitis can be treated with neuroactive pharmacological agents. For example, serotonin receptor type four agonists can be used for the treatment of constipation, while nitric oxide synthesis inhibitors can be employed for the treatment of intestinal angina.

Gentamicin is used worldwide in the treatment of serious infections in critically ill patients. The therapeutic efficacy of gentamicin is correlated to the peak serum concentration and the adverse effects to the trough concentrations. Information concerning the pharmacodynamics in critically ill patients is scarce, but pharmacokinetic data are available. A once-daily dosage regimen has replaced multiple dosing of gentamicin in most intensive care units. No studies evaluating the superiority of either of these dosage recommendations in critically ill patients have ever been conducted. Based on 8 meta-analyses performed addressing this issue on a wide range of patients and theoretical considerations, we consider a once-daily dosage regimen feasible in critically ill patients. In septic patients the volume of distribution is significantly increased compared to normal patients, implying that the initial dose should be increased in this patient population. Additionally a general trend towards using higher loading doses (5-7 mg/kg) has been observed in USA, and the appropriateness of this dosing strategy is based on a large descriptive American study. We recommend that the initial dosage of gentamicin in critically ill hyperdynamic septic patients should be 7 mg/kg. Optimal and appropriate monitoring of the treatment with gentamicin in the critically ill patient is still an issue for further investigation. The treatment period with gentamicin should be short (3-5 days), bearing the pharmacological properties of aminoglycosides (small volume of distribution and poor tissue penetration) in mind. In patients with reduced renal function the initial dose of gentamicin should also be increased and maintenance dose reduced preferentially by prolonging the dosing intervals. However, the use of aminoglycosides in a high dose regimen in oliguric or anuric patients or patients who present with a rapidly decreasing renal function needs further consideration.

Summary 5-Hydroxytryptamine is a mediator in cholera toxin-induced hypersecretion in the small intestine. The aim of this study was to determine the effect of the 5-hydroxytryptamine receptor antagonists ketanserin, granisetron, ondansetron and tropisetron on cholera toxin-induced hypersecretion in the pig jejunum. Hypersecretion was induced by cholera toxin in ligated jejunal loops. The antagonists were administered subcutaneously at a dose of 100 μg/kg. Furthermore, the effect of intraluminally instilled ondansetron was studied. None of the antagonists altered basal absorption or caused fluid hypersecretion. Cholera toxin caused a dose-dependent electrolyte and fluid hypersecretion. The apparent maximal effect, 6.8 ± 0.4 mg fluid x mg dry loop−1, was reduced by ondansetron, granisetron and tropisetron by about 40 %, 30 %, and 20 %, respectively, whereas ketanserin had no effect. Intraluminal ondansetron reduced the effect of cholera toxin by about 50 %. These results demonstrate that 5-hydroxytryptamine3 antagonists administered subcutaneously reduce the cholera toxin-induced hypersecretion in the pig jejunum. Finally, the results support species differences with respect to the antagonistic effect of the tested drugs in cholera toxin-induced hypersecretion.