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SummaryBackgroundHighly selective 5‐HT4agonists have been suggested for the treatment of chronic constipation (CC).AimTo assess the effects of highly selective 5‐HT4agonists (prucalopride, velusetrag or naronapride) on patient‐important clinical efficacy outcomes and safety in adults withCC.MethodsWe searched the medical literature in January 2013 usingMEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5‐HT4agonists in adults withCC, 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).ResultsMain outcomes included stool frequency, Patient‐Assessment of Constipation Quality of Life (PAC‐QOL),PACof 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‐HT4agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95%CI1.23–2.79); mean ≥1SCBMover baseline (RR = 1.57; 95%CI1.19, 2.06); ≥1 point improvement inPAC‐QOLandPAC‐SYMscores. The only active comparator trial of prucalopride andPEG3350 suggestedPEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5‐HT4agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride.ConclusionDemonstration of efficacy on patient‐important outcomes and a favourable safety profile support the continued use and development of highly selective 5–HT4agonists in the treatment of chronic constipation.

The study objectives were: to mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome (IBS)-diarrhea (IBS-D) phenotype, to assess genes that regulate bile acids in IBS-D, and to explore univariate associations of SNVs with symptom phenotype and quantitative traits in an independent IBS cohort. Using principal components analysis, we identified two groups of IBS-D ( n = 16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced in depth, analyzing SNVs in bile acid genes ( ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared with those of 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and a principal components analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-constipation. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10 of 11 bile acid-regulating genes, with no SNVs in FGF19; 15 nonsynonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 [rs434434 (intronic), rs1966265, and rs351855 (nonsynonymous)] were associated with colonic transit (rs1966265; P = 0.043), fecal bile acids (rs1015450; P = 0.064), and principal components analysis groups (all 3 FGFR4 SNVs; P < 0.05). In the 633-person cohort, FGFR4 rs434434 was associated with symptom phenotype ( P = 0.027) and rs1966265 with 24-h colonic transit ( P = 0.066). Thus exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.

AbstractBackgroundNon‐invasive single photon emission computed tomography (SPECT) has been validated as a test for postprandial gastric volume accommodation, with volumes measured twice over 30 min and averaged. The purpose of this study is to simplify the SPECT measurement of gastric accommodation.MethodsThe primary aim of this study was to compare two postprandial gastric volume measurements with data collected retrospectively from 443 patients and healthy volunteers who had undergone SPECT in the last decade. The differences in the two gastric volumes were compared in the entire group and each subgroup, and the correlation between the two measurements and their differences across a wide range of gastric volumes were plotted.Key ResultsThere was a median difference of <2% (P = 0.041) between postprandial scan 1 (757 mL) and scan 2 (743 mL), with significant correlation (rs = 0.859, P < 0.01) and excellent agreement (SD 60 mL) between the two scans across the entire range of observed postprandial gastric volumes.Conclusions & InferencesA single postprandial scan can detect gastric accommodation with the same accuracy as averaging two postprandial scans. These data support simplifying SPECT measurement of postprandial gastric volume with a scan in the first 15 min after a meal.

Abstract Background There is little information regarding gender‐specific measurements of colonic transit and anorectal function in patients with defecation disorders ( DD ). To compare overall colonic transit by gender in DD . Methods In 407 patients with constipation due to DD diagnosed by a single gastroenterologist (1994–2012), DD was characterized by anorectal manometry, balloon expulsion test, and colonic transit by scintigraphy. The primary endpoint was overall colonic transit (geometric center, GC ) at 24 h ( GC 24). Effects of gender in DD on colonic transit, and comparison with transit in 208 healthy controls were assessed by Mann–Whitney rank sum test. Secondary endpoints were maximum anal resting ( ARP ) and squeeze ( ASP ) pressures. We also tested association of the physiological endpoints among DD females by pregnancy history and among DD patients by colectomy history. Key Results The DD patients were 67 males (M) and 340 females (F). Significant differences by gender in DD patients were observed in GC 24 (median: M: 2.2; F: 1.8; P = 0.01), ARP (median: M: 87.8 mmHg; F: 82.4 mmHg; P = 0.04), and ASP (median: M: 182.4 mmHg; F: 128.7 mmHg; P < 0.001). GC 24 was slower in DD compared with same‐gender healthy controls. GC 24 did not differ among DD females by pregnancy history. Anorectal functions and upper GI transit did not differ among DD patients by colectomy history. Conclusions & Inferences Patients with DD have slower colonic transit compared with gender‐matched controls. Among DD patients, males have higher ARP and ASP , and females have slower colonic transit. Although the clinical significance of these differences may be unclear, findings suggest that interpretation of these tests in suspected DD should be based on same‐gender control data.

OBJECTIVE To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE). RESEARCH DESIGN AND METHODS In a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs). RESULTS At screening, HbA1c was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t1/2 of solids (P = 0.011); mean difference (Δ) in solid GE t1/2 was 68.3 min (95% CI 20–117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t1/2 liquids (all P &lt; 0.14). With a significant (P &lt; 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t1/2 (solids, P = 0.016; liquids, P = 0.024; CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30–90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P &lt; 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131. CONCLUSIONS RM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.

SummaryBackgroundTapentadol is a mu‐opioid receptor agonist and norepinephrine reuptake inhibitor. In clinical trials, tapentadol provided somatic pain relief comparable to mu‐opioids such as oxycodone, with significantly less gastrointestinal adverse effects. The acute effects of tapentadol on gastrointestinal and colonic transit are unclear.AimTo compare acute effects of oral tapentadol and oxycodone on gastric, small bowel and colonic transit of solids in 38 healthy human subjects.MethodsIn a randomised, parallel‐group, double‐blind, placebo‐controlled study of the effects of identical‐appearing tapentadol immediate release (IR), 75 mg t.d.s., or oxycodone IR, 5 mg t.d.s., for 48 h, we measured gastric (GE), small bowel (SBT measured as colonic filling at 6 h) and colonic transit by validated scintigraphy. Drug was commenced on the evening before the start of the transit test. The primary endpoints were overall colonic transit (geometric centre, GC) at 24 h and GE half‐time (t1/2). ancova of transit data included gender or BMI as covariates. Adverse effects were summarised.ResultsAt the doses tested, oxycodone and tapentadol significantly delayed GE t1/2 and SBT, but not overall colonic transit, compared to placebo. Transit profiles in all regions were not significantly different between oxycodone and tapentadol at the doses tested. Both oxycodone and tapentadol were associated with nausea and central effects attributable to central opiate effects.ConclusionsTapentadol significantly delayed gastric emptying t1/2 and small bowel transit, similar to oxycodone. These data suggest that acute administration of tapentadol may not have significant advantages over standard mu‐opioids, in terms of the potential to avoid upper gastrointestinal motor dysfunction.