Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial.

BACKGROUND: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis. METHODS: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522. FINDINGS: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment. INTERPRETATION: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. FUNDING: Gilead Sciences.

Plecanatide Is Effective and Safe in the Treatment for Chronic Idiopathic Constipation: Results of a Phase II Trial.

BACKGROUND: Many patients with chronic idiopathic constipation (CIC) remain unsatisfied with their treatment options. Plecanatide is a pH-sensitive uroguanylin analog that increases fluid and ion movement into the gastrointestinal lumen, softening stools and encouraging motility, while limiting the risk of diarrhea. AIMS: The objective of this phase 2 study is to evaluate the safety and efficacy of once-daily oral plecanatide in patients with CIC and identify the most effective dose. METHODS: A 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in patients aged 18-75 years and diagnosed with CIC based on modified Rome III criteria (< 3 complete spontaneous bowel movements [CSBMs] per week and infrequent loose stools without the use of laxatives). Participants were randomized to placebo or plecanatide 0.3, 1.0, or 3.0 mg. The primary efficacy endpoint was the proportion of overall CSBM responders. Key secondary endpoints included time to first CSBM, change in CSBM and spontaneous bowel movement (SBM) frequency rates, patient-reported outcomes, safety, and tolerability. RESULTS: Of 951 randomized participants, 946 were included in the modified intent-to-treat population. Plecanatide 0.3 and 3.0 mg significantly increased overall CSBM responder rates compared with placebo (0.3 mg, P = 0.016; 3.0 mg, P = 0.009). Plecanatide was associated with decreased time to first CSBM, significant increases in CSBM and SBM frequency, and decreased patient-reported constipation severity compared with placebo. Diarrhea was the most frequently reported treatment-emergent adverse event. CONCLUSIONS: Plecanatide is a well-tolerated treatment that relieved the symptoms of CIC with a relatively low incidence of diarrhea.

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. METHODS: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. RESULTS: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. CONCLUSIONS: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417.

Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.

OBJECTIVES: Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C). METHODS: Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs). RESULTS: Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0). CONCLUSIONS: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

Responsiveness of Endoscopic Indices of Disease Activity for Crohn's Disease.

OBJECTIVES: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. METHODS: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. RESULTS: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. CONCLUSIONS: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.

BACKGROUND & AIMS: Simultaneous agonism of the µ-opioid receptor and antagonism of the δ-opioid receptor can reduce abdominal pain and diarrhea in patients with irritable bowel syndrome with diarrhea (IBS-D) without constipating side effects. We evaluated the efficacy and safety of a minimally absorbed, µ-opioid receptor agonist and δ-opioid receptor antagonist (eluxadoline) in a phase 2 study in patients with IBS-D. METHODS: We randomly assigned 807 patients to groups that received oral placebo twice daily or 5, 25, 100, or 200 mg oral eluxadoline for 12 weeks. The primary end point was clinical response at week 4, defined by a mean reduction in daily pain score from baseline of ≥ 30%, and of at least 2 points on 0-10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1-7) for at least 66% of daily diary entries during that week. RESULTS: Significantly more patients receiving 25 mg (12.0%) or 200 mg (13.8%) eluxadoline met the primary end point of clinical response than patients given placebo (5.7%; P < .05). Patients receiving eluxadoline at 100 mg and 200 mg also had greater improvements in bowel movement frequency and urgency, global symptoms, quality of life, and adequate relief assessments (P < .05). Additionally, patients receiving 100 mg (28.0%) or 200 mg (28.5%) eluxadoline were significantly more likely than those receiving placebo (13.8%; P < .005) to meet the US Food and Drug Administration response end point during the full 12 weeks of the study. Eluxadoline was well tolerated with a low incidence of constipation. CONCLUSIONS: In a phase 2 study of the mixed µ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D.

Plecanatide Improves Symptoms of Irritable Bowel Syndrome with Constipation: Results of an Integrated Efficacy and Safety Analysis of Two Phase 3 Trials.

Purpose: Patients with irritable bowel syndrome with constipation (IBS-C) experience abdominal pain with altered bowel movements. Plecanatide is indicated as IBS-C treatment in adults. This integrated analysis further characterizes plecanatide efficacy and safety in IBS-C. Patients and Methods: Data pooled from 2 identically designed phase 3 trials included adults with IBS-C randomized to plecanatide 3 mg or 6 mg, or placebo once daily for 12 weeks. A daily diary recorded stool frequency/symptoms, with abdominal pain, bloating, cramping, discomfort, fullness, and straining intensity individually rated. Overall response (primary endpoint) was defined as ≥30% improvement from baseline in average worst abdominal pain severity and increase of ≥1 complete spontaneous bowel movement, during same week (composite), for ≥6 of 12 weeks. Secondary endpoints included sustained response (overall response, plus meeting weekly composite criteria during ≥2 of last 4 treatment weeks) and changes from baseline in individual symptoms. Safety assessments included adverse event monitoring. Results: Overall, 2176 patients (74.0% female; mean [SD] age, 43.5 [14.1] years) were included in efficacy analyses (plecanatide 3 mg [n = 724], 6 mg [n = 723], placebo [n = 729]). A significantly greater percentage of patients achieved overall response with plecanatide 3 mg (25.6%) and 6 mg (26.7%) versus placebo (16.0%; both P < 0.001 vs placebo). A significantly greater percentage of patients were sustained responders with plecanatide 3 mg (24.3%) and 6 mg (25.6%) versus placebo (15.6%; both P < 0.001 vs placebo). Significant improvements from baseline in abdominal discomfort, abdominal fullness, abdominal pain, bloating, and cramping occurred as early as Week 1 (Week 2 for abdominal pain) with plecanatide and were maintained through Week 12 versus placebo. Diarrhea, the most common adverse event, occurred in 4.3% (3 mg), 4.0% (6 mg) and 1.0% (placebo) of patients, leading to study discontinuation in 1.2%, 1.4%, and 0 patients, respectively. Conclusion: Plecanatide is safe and effective for treating global and individual IBS-C symptoms.

Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study.

BACKGROUND: Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. METHODS: Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. KEY RESULTS: A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. CONCLUSIONS: Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.

Effect of preoperative intravenous pantoprazole in elective-surgery patients: a pilot study.

BACKGROUND: This study evaluated the effects of intravenous pantoprazole on gastric volume and acid output in elective-surgical patients. METHODS: This is a multicenter, randomized, pilot study of adult patients receiving intravenous pantoprazole: 40 mg every 24 h, 40 mg every 12 h (q12h) or 80 mg q12h. The first dose was administered 1 h before general anesthesia for surgery. All gastric fluid was aspirated through a nasogastric tube 1 h before dosing and through the postoperative period. Aspirate volume was recorded; pH and H(+) concentrations were measured. RESULT: Twenty-six patients were enrolled and 21 were evaluable. Pantoprazole was well tolerated. All regimens decreased gastric acid output and volume, and increased pH within 1 h of dosing. Effects were sustained for up to 12 h following single-dose administration. CONCLUSIONS: Intravenous pantoprazole administered prior to anesthesia induction may be efficacious for the reduction of gastric volume and acid output, and for pulmonary aspiration prophylaxis in surgical patients.

Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

BACKGROUND: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet. METHODS: We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 µg, 90 µg, or 150 µg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 µg or 300 µg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. FINDINGS: Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 µg and three to placebo (first cohort), nine were allocated to Nexvax2 90 µg and four to placebo (second cohort), eight were allocated to Nexvax2 150 µg and four to placebo (third cohort), and three were allocated to Nexvax2 150 µg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 µg and four to placebo (first cohort), ten were allocated to Nexvax2 300 µg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 µg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 µg because of transient, acute gastrointestinal adverse events with onset 2-5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 µg, seven (78%) of nine who received Nexvax2 90 µg, and five (63%) of eight who received Nexvax2 150 µg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 µg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 µg, and all ten (100%) who received Nexvax2 300 µg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 µg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 µg, five (63%) of eight who received Nexvax2 90 µg, and six (100%) of six who received Nexvax2 150 µg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 µg (p=0·021). INTERPRETATION: The MTD of Nexvax2 was 150 µg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease. FUNDING: ImmusanT.

GRP mediates an inhibitory response of gut-related vagal motor neurons to PVN stimulation.

We previously characterized neurons in the dorsal motor nucleus of the vagus (DMNV) that were modulated by electrical stimulation of the PVN and by gastrointestinal distention. Bombesin has been identified in a subset of PVN neurons projecting to the DMNV. It is currently unknown whether this neurotransmitter is involved in descending communication from PVN to DMNV neurons. In this study we determined whether the specific bombesin antagonist, N-acetyl-GRP(20-26), influenced (1) the basal firing rate of DMNV neurons and (2) the response to electrical current stimulation of the PVN. Our results indicate that N-acetyl-GRP(20-26), significantly attenuated the inhibitory response of DMNV neurons to PVN stimulation. These results provide a possible mechanism by which bombesin regulates gastrointestinal function, body temperature homeostasis, and feeding behaviors.

Lateral hypothalamus modulates gut-sensitive neurons in the dorsal vagal complex.

The lateral hypothalamus (LH) regulates metabolic, behavioral and autonomic functions. The influence of the LH on gastrointestinal function and feeding behavior may be mediated by the dorsal vagal complex (DVC). In the present experiment, we used tract tracing and neurophysiologic techniques to evaluate the interrelationship between the LH and DVC. Using the tracer DiI, we demonstrated that the LH projects to both the nucleus of the solitary tract (NST) and the dorsal motor nucleus of the vagus (DMNV). We determined the effects of electrical stimulation of the LH and/or distention of the gastrointestinal tract on the firing rates of 107 DMNV neurons and 68 NST neurons. As previously reported, the majority of the DMNV neurons were inhibited and the majority of the NST neurons were excited by gastrointestinal distention. Electrical stimulation of the LH significantly changed the spontaneous activities of 71% of the DMNV neurons (46 excited and 30 inhibited). Of the 68 NST neurons characterized, 25 neurons were inhibited and 8 were excited by LH stimulation. In a separate experiment, we characterized the effects of both electrical and chemical stimulation of the LH on 36 DMNV and 14 NST neurons. Glutamate (0.8 nM) induced similar responses in the DVC neurons as electrical stimulation of the LH. The results indicate that the LH influences the electrical activity of DVC neurons. This effect may be the mechanism by which the LH modulates gastrointestinal function and feeding behavior.

Involvement of glutamate in gastrointestinal vago-vagal reflexes initiated by gastrointestinal distention in the rat.

Vago-vagal reflexes play an integral role in the regulation of gastrointestinal function. Although there have been a number of reports describing the effects of various stimuli on the firing rates of vagal afferent fibers and vagal motor neurons, little is known regarding the neurotransmitters that mediate the vago-vagal reflexes. In the present work, we investigated the role of glutamate in the vago-vagal reflex induced by gastrointestinal distention. Using single-cell recording techniques, we determined the effects of gastric and duodenal distention on the firing rates of gut-related neurons in the dorsal vagal complex, in the absence and presence of glutamate antagonists. Kynurenic acid, a competitive glutamate receptor antagonist, injected into the dorsal vagal complex, blocked the neuronal response of neurons in the dorsal motor nucleus of the vagus and the nucleus of the solitary tract to gastrointestinal distention. Injection of glutamate into the nucleus of the solitary tract produced inhibition of dorsal motor nucleus of the vagus neurons that were also inhibited by gastric and/or duodenal distention. Thus, the distention-induced inhibition of dorsal motor nucleus of the vagus neurons may be mediated by glutamate-induced excitation of gut-related nucleus of the solitary tract neurons. To investigate the role of the various glutamate receptor subtypes in the distention-induced events, we studied the effects of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-NMDA receptor antagonist, and DL-2-amino-5-phosphonopentanoic acid (DL-AP5), a selective NMDA receptor antagonist. CNQX injected into the dorsal vagal complex either blocked or attenuated the inhibitory response of the neurons in the dorsal motor nucleus of the vagus and nucleus of the solitary tract neurons to gastric and duodenal distention. In contrast, DL-AP5 had less effect, especially in the vago-vagal reflex elicited by gastric distention. The results suggest (1) distention activates vagal afferents in the gastrointestinal tract; (2) the central branches of the vagal afferents from the gut terminate in the nucleus of the solitary tract and release glutamate that mainly act on non-NMDA receptors; (3) glutamate activates the inhibitory neurons in the nucleus of the solitary tract that project to the dorsal motor nucleus of the vagus; and (4) the inhibitory neurotransmitter suppresses the activity of the dorsal motor nucleus of the vagus neurons. For the excitatory neuronal responses of the dorsal motor nucleus of the vagus neurons to gastrointestinal distention, the possible circuit is that the vagal afferents containing glutamate directly activate the receptors on the dendrites of the dorsal motor nucleus of the vagus.

Fecal Incontinence.

Fecal incontinence is a socially devastating clinical condition. Initial symptomatic treatment includes exclusion of foods that precipitate the problem, increased use of fiber, and drug therapy with loperamide. Persistence of incontinence after these lifestyle modifications requires the physician to evaluate the internal and external anal sphincters. Anal endosonography and manometry provide an evaluation of sphincter structure and function. If an isolated muscle defect is seen, sphincteroplasty can be tried. If this surgical procedure is not indicated, biofeedback may be an option. Biofeedback should be considered for patients with neurogenic fecal incontinence, a weak but structurally intact external sphincter, or a decreased ability to perceive rectal distention. Muscle transposition to create a neosphincter should be offered only by surgeons with extensive experience performing this surgery. Because of the cosmetic sequela of colostomy, this surgery is often considered as a last-step procedure, despite being safe and effective.

Treatment Options for Primary Constipation.

Patients suffering from primary constipation often show symptom improvement with increased intake of fiber. Bulk laxatives are a core component of treatment if dietary fiber is unsuccessful in alleviating symptoms. Although there are a number of commercial laxative preparations available, only polyethylene glycol (PEG), an osmotic laxative, should be used on a daily basis. For the elderly, saline laxatives may be used on a regular basis, provided there are no cardiac or renal comorbid contraindications. Tegaserod, a 5-HT(4) partial receptor agonist, is approved for the treatment of constipation in female patients. The appropriate role of biofeedback remains to be determined. Surgery should be reserved for patients with slow transit constipation refractory to medical therapy. Patients being considered for surgery should be evaluated at institutions with substantial expertise in the investigation and management of this population.

Glutamate mediates an excitatory influence of the paraventricular hypothalamic nucleus on the dorsal motor nucleus of the vagus.

Data have shown that the paraventricular nucleus of the hypothalamus (PVN) and the dorsal motor nucleus of the vagus (DMNV) play important roles in the regulation of gastrointestinal function and eating behavior. Anatomical studies have demonstrated direct projections from the PVN to the DMNV and physiological studies showed that the DMNV mediates many of the effects of PVN stimulation and electrical current stimulation of the PVN excites a subset of DMNV neurons. The aim of this study was to characterize the role of glutamate receptors in the excitatory influence of the PVN on gut-related DMNV neurons. Using single-cell recording techniques, we determined the effects of kynurenic acid, 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX), and DL-2-amino-5-phosphonopentanoic acid (DL-AP5) on the increase in firing rate due to electrical current stimulation of the PVN. In initial experiments, we studied 24 DMNV neurons excited by electrical current stimulation of the PVN. Kynurenic acid, a broad-spectrum glutamate receptor antagonist, prevented the PVN effect in 22 neurons and significantly attenuated the effect in the other cells. Nine of these neurons demonstrated an inhibition in firing rate with PVN stimulation after pretreatment with kynurenic acid. In a separate group of 12 neurons, we determined the effects of CNQX (1.2 nmol) injected into the DMNV. This AMPA receptor antagonist completely blocked the excitatory response to PVN stimulation of six DMNV neurons and significantly attenuated the response of the other six DMNV neurons. The addition of 1.2 nmol DL-AP5, a N-methyl-D-aspartate (NMDA) receptor antagonist, further attenuated the response to PVN stimulation in four of the five DMNV neurons that were still excited after CNQX treatment. The fifth neuron demonstrated PVN- induced inhibition of firing rate after treatment with CNQX and DL-AP5. In a separate group of 11 DMNV neurons excited by electrical stimulation of the PVN, DL-AP5 partially attenuated the excitatory responses of only four DMNV neurons and did not block the excitation of any cells. The mean latency (14 neurons tested) from the PVN to the DMNV was 37.71 +/- 2.40 (SE) ms. Monosynaptic action potentials and excitatory postsynaptic potentials were demonstrated in three DMNV neurons by intracellular recording. Our results indicate that glutamate released from PVN neurons projecting to the DMNV excite the gut-related vagal motor neurons by acting predominantly on the AMPA receptor. The NMDA receptor plays only a minor role in the excitatory effect.

Bleeding Angiodysplasia of the Colon.

Angiodysplasia should be considered in the differential diagnosis of hematochezia, gastrointestinal bleeding of obscure origin, and chronic iron deficiency anemia. Although the current medical literature lacks well-designed studies of the various therapeutic modalities, several conclusions appear warranted. Diagnosis of the bleeding site during colonoscopy and the use of endoscopic hemostasis techniques (electrocautery or laser) controls bleeding and may prevent rebleeding. When rebleeding occurs, it may be from the previously treated site or a different location. Estrogen-progestin therapy has not been shown effective in controlled trials but is used when other options fail. Surgery should be considered only when endoscopic therapy fails and the site of bleeding is localized. With all therapies, patients should be cautioned regarding the risk of recurrent bleeding.

Galanin inhibits gut-related vagal neurons in rats.

Galanin plays an important role in the regulation of food intake, energy balance, and body weight. Many galanin-positive fibers as well as galanin-positive neurons were seen in the dorsal vagal complex, suggesting that galanin produces its effects by actions involving vagal neurons. In the present experiment, we used tract-tracing and neurophysiological techniques to evaluate the origin of the galaninergic fibers and the effect of galanin on neurons in the dorsal vagal complex. Our results reveal that the nucleus of the solitary tract is the major source of the galanin terminals in the dorsal vagal complex. In vivo experiments demonstrated that galanin inhibited the majority of gut-related neurons in the dorsal motor nucleus of the vagus. In vitro experiments demonstrated that galanin inhibited the majority of stomach-projecting neurons in the dorsal motor nucleus of the vagus by suppressing spontaneous activity and/or producing a fully reversible dose-dependent membrane hyperpolarization and outward current. The galanin-induced hyperpolarization and outward current persisted after synaptic input was blocked, suggesting that galanin acts directly on receptors of neurons in the dorsal motor nucleus of the vagus. The reversal potential induced by galanin was close to the potassium ion potentials of the Nernst equation and was prevented by the potassium channel blocker tetraethylammonium, indicating that the inhibitory effect of galanin was mediated by a potassium channel. These results indicate that the dorsal motor nucleus of the vagus is inhibited by galanin derived predominantly from neurons in the nucleus of the solitary tract projecting to the dorsal motor nucleus of the vagus nerve. Galanin is one of the neurotransmitters involved in the vago-vagal reflex.