Summary Background Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is ...challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. Methods We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov , number NCT01899703. Findings Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were −57% (95% CI −73 to −42, p<0·0001) in the NRS, −31% (−42 to −20, p<0·0001) in the PBC-40 itch domain and −35% (−45 to −25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (−23%, 95% CI −45 to −1; p=0·037), PBC-40 itch domain, (−14%, −26 to −1; p=0·034), and 5-D itch scale (−20%, −34 to −7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI −37 to −61, p<0·0001) from 30 to 15 μM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. Interpretation In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. Funding GlaxoSmithKline and National Institute for Health Research.
The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic ...effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients.
A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively.
Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72). When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment.
When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients.
The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).
The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression ...were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS.
Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS.
Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04).
IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohn's disease suggesting possible common underlying pathogenesis.
Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective ...CRF receptor 1 antagonist (CRF(1)) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional-arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state-trait anxiety and hypothalamic-pituitary-adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional-arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF(1) signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF(1) receptor antagonism for patients with stress-sensitive disorders.
Background & Aims Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We ...aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008 , on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). Methods We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level−dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. Results Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls—an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level−dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. Conclusions Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.
AIM:To ascertain whether caecal pH is different in patients with irritable bowel syndrome(IBS),whose primary symptoms are bloating and distension,to healthy controls.METHODS:Motility and pH data were ...reviewed from16 patients with RomeⅢdefined IBS and 16 healthy controls,who had undergone a wireless motility capsule(WMC)study using a standardized protocol.Motility measures were anchored around known anatomical landmarks as identified by compartmental pH changes.Sixty-minute epochs were used to quantify antral,duodenal,ileal,caecal and distal colonic contractility.The maximum and minimum pH was measured either side of the ileo-caecal junction.RESULTS:No differences were seen in motility parameters,compartmental transit times or maximal ileal pH between the two groups.Caecal pH was significantly lower in patients compared to controls(5.12±0.05vs 6.16±0.15,P<0.0001).The ileal:caecalΔchange was greater in patients than controls(-2.63±0.08 vs-1.42±0.11,P<0.0001).There was a significant correlation between caecal pH and right colonic contractility(r=0.54,P=0.002).CONCLUSION:Patients with bloating and distension have a lower caecal pH compared to controls.The measurement of caecal pH using the WMC provides a quantifiable biomarker of fermentation potentially identifying those patients that may preferentially benefit from antibiotic or dietary interventions.
Irritable bowl syndrome (IBS) is a common gastrointestinal disorder with symptoms of abdominal pain, discomfort, and altered bowel function. Antagonists of the type 3 serotonin receptor (5-HT
3) have ...shown promising results in the relief of IBS-associated symptoms. We aimed to confirm these findings by doing a randomised, placebo-controlled trial.
We studied 647 female IBS patients with diarrhoea-predominant or alternating bowel patterns (diarrhoea and constipation). 324 patients were assigned 1 mg alosetron and 323 placebo orally twice daily for 12 weeks, followed by a 4-week post-treatment period. Adequate relief of abdominal pain and discomfort was the primary endpoint; secondary endpoints included improvements in urgency, stool frequency, and stool consistency. Analysis was by intention to treat.
79 (24%) of patients in the alosetron group and 53 (16%) in the placebo group dropped out. The difference in the drop-out rate between groups was mainly due to a greater occurrence of constipation in the alosetron group. A greater proportion of alosetron-treated patients than placebo-treated patients (133 41%
vs 94 29%, respectively) reported adequate relief for all 3 months of treatment (difference 12% 4·7–19·2). Alosetron also significantly decreased urgency and stool frequency, and increased stool firmness. Constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively.
Alosetron was well tolerated and clinically effective in alleviating pain and bowel-related symptoms in this population of women with IBS.
Background and Purpose
Here we have investigated the pharmacokinetics, pharmacodynamics and safety of single doses of camicinal in type 1 diabetes mellitus (T1DM) patients with a history of slow ...gastric emptying with symptoms consistent with gastroparesis.
Experimental Approach
In a randomized, double‐blind, placebo‐controlled, incomplete block, three‐period, two‐centre crossover study, patients received oral administration of placebo and two of the three possible doses of camicinal (25, 50 or 125 mg). Gastric emptying (13C‐octanoic acid breath test), pharmacokinetics and safety were primary outcomes.
Key Results
Nine of the 10 patients enrolled completed the study. Gastric half‐emptying time decreased by −95 min (95% CI: −156.8, −34.2) after a single dose of camicinal 125 mg compared with placebo (52 vs. 147 min, P < 0.05), representing a 65% improvement. A decrease of the gastric half‐emptying time compared with placebo (approximately 39 min) was observed with camicinal 25 and 50 mg, representing a 27% reduction for both doses (not statistically significant). A positive exposure–response relationship was demonstrated across all doses. The effects of camicinal on gastric half‐emptying time were not influenced by fasting glucose levels. Single doses up to 125 mg were well tolerated. Camicinal was well absorbed, exhibiting linear and approximately dose‐proportional pharmacokinetic characteristics and a clear exposure–response relationship with gastric emptying.
Conclusions and Implications
Camicinal significantly accelerated gastric emptying of solids in T1DM patients following administration of a single oral dose. Camicinal was well tolerated and exhibited similar pharmacokinetic characteristics in diabetic patients to those previously reported in healthy volunteers.
Background
Camicinal is a novel, nonmacrolide, motilin receptor agonist that accelerates gastric emptying in critically ill patients with established feed intolerance. The primary question was ...whether the preemptive administration of camicinal increased the provision of enteral nutrition (EN) to critically ill patients with risk factors that predisposed to feed intolerance.
Methods
This was an international, multicenter, parallel‐group, blinded, randomized controlled trial. Patients at risk for feed intolerance, defined as receiving moderate to high doses of vasopressors or opiates, or admitted because of multiple traumatic injuries or with brain injury, received either enteral camicinal 50 mg or placebo daily for a maximum of 7 days, along with EN administered according to a standardized feeding protocol. The primary outcome was the daily adequacy of enteral feed delivered, as assessed by percentage of goal volume (delivered/prescribed × 100) before development of intolerance.
Results
Eighty‐four patients participated. The administration of camicinal did not result in a statistically significant clinical difference in the daily average percentage goal volume delivered (camicinal vs placebo: 77% 95% confidence interval: 71, 83 vs 68% (58, 78); mean difference 9% −5, 23; P = 0.21). Similarly, there were no differences in the percentage goal calories (76% 65, 88 vs 68% 60, 77) and protein (76% 66, 86 vs 70% 61, 80) administered, or the incidence of feed intolerance (15% vs 14%).
Conclusion
The incidence of feed intolerance was low in both groups. In this cohort the preemptive administration of enteral camicinal did not significantly augment the provision of goal EN.
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