Summary Background Highly selective 5‐HT4 agonists have been suggested for the treatment of chronic constipation (CC). Aim To assess the effects of highly selective 5‐HT4 agonists (prucalopride, velusetrag or naronapride) on patient‐important clinical efficacy outcomes and safety in adults with CC. Methods We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5‐HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention‐to‐treat analyses, pooled using a random‐effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Results Main outcomes included stool frequency, Patient‐Assessment of Constipation Quality of Life (PAC‐QOL), PAC of symptoms (PAC‐SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5‐HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23–2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC‐QOL and PAC‐SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5‐HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Conclusion Demonstration of efficacy on patient‐important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4 agonists in the treatment of chronic constipation.
Background Nausea and vomiting are thought to result from upper gastrointestinal dysfunctions. Our clinical observations led to the hypothesis that colonic motor dysfunction is associated with nausea and vomiting. Methods We reviewed electronic medical records (EMR) of 149 patients presenting with complaints of nausea and/or vomiting in a tertiary gastroenterology practice to investigate the association with disorders of colonic motor or evacuation disorders. We extracted demographics, gastric emptying (GE in 149) and colonic transit (CT in 138) of solids, ascending colon emptying half time (AC t1/2), rectal evacuation by anorectal manometry (ARM) in 91 and balloon expulsion test (BE) in 55 patients. We estimated the proportions with delayed GE or CT, based on the 5th percentile of GE (in 319) and CT in 220 healthy volunteers using same method. Key Results Among 11 patients with nausea and/or vomiting with only GE measured, 5 had delayed and 6 normal GE. Among the 149 patients, 77 (52%) patients had evacuation disorders, confirmed by objective tests in 68 patients, and clinical examination in 9 patients. In the 138 patients with both GE and CT measured, 106 (76%) had both normal GE and CT, 11 (8%) only delayed GE, 16 (11%) normal GE with delayed CT, and 5 (3%) delayed GE and CT. Among 21 patients (15%) with delayed CT, 9 had slow AC t1/2 and 12 evacuation disorder. Conclusions & Inferences In patients with chronic nausea and/or vomiting in gastroenterology practice, evaluation of colonic motility and rectal evacuation should be considered, since about half the patients have abnormal functions that conceivably contribute to the presenting nausea and/or vomiting.
P ϭ 0.028). There was significant association of CNR1 rs806378 (P ϭ 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas (P ϭ 0.025), but not pain; the strongest associations for gas ratings were in IBS-D (P ϭ 0.002) and IBSalternating (P ϭ 0.025) subgroups. For CNR1 (AAT)n, gene-byphenotype interactions were observed for colonic transit at 24 (P ϭ 0.06) and 48 h (P ϭ 0.002) and gas (P ϭ 0.046, highest for IBS-D, P ϭ 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.
Relamorelin acts in the colon to significantly reduce symptoms of constipation and accelerate CT in patients with chronic constipation, compared with placebo. ClinicalTrial.Gov registration number: NCT01781104.
Introduction Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. Material and methods Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional-hazards models. Results The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint-free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). Conclusions Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed.
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