Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

BACKGROUND: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]). METHODS: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed. KEY RESULTS: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024). CONCLUSIONS & INFERENCES: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

A randomized double-blind trial of clonidine and colesevelam for women with fecal incontinence.

BACKGROUND: Diarrhea and rectal urgency are risk factors for fecal incontinence (FI). The effectiveness of bowel modifiers for improving FI is unclear. METHODS: In this double-blind, parallel-group, randomized trial, women with urge FI were randomly assigned in a 1:1 ratio to a combination of oral clonidine (0.1 mg twice daily) with colesevelam (1875 mg twice daily) or two inert tablets for 4 weeks. The primary outcome was a ≥50% decrease in number of weekly FI episodes. KEY RESULTS: Fifty-six participants were randomly assigned to clonidine-colesevelam (n = 24) or placebo (n = 32); 51 (91%) completed 4 weeks of treatment. At baseline, participants had a mean (SD) of 7.5 (8.2) FI episodes weekly. The primary outcome was met for 13 of 24 participants (54%) treated with clonidine-colesevelam versus 17 of 32 (53%) treated with placebo (p = 0.85). The Bristol stool form score decreased significantly, reflecting more formed stools with clonidine-colesevelam treatment (mean [SD], 4.5 [1.5] to 3.2 [1.5]; p = 0.02) but not with placebo (4.2 [1.9] to 4.1 [1.9]; p = 0.47). The proportion of FI episodes for semiformed stools decreased significantly from a mean (SD) of 76% (8%) to 61% (10%) in the clonidine-colesevelam group (p = 0.007) but not the placebo group (61% [8%] to 67% [8%]; p = 0.76). However, these treatment effects did not differ significantly between groups. Overall, clonidine-colesevelam was well tolerated. CONCLUSIONS AND INFERENCES: Compared with placebo, clonidine-colesevelam did not significantly improve FI despite being associated with more formed stools and fewer FI episodes for semiformed stools.

Inadequate Rectal Pressure and Insufficient Relaxation and Abdominopelvic Coordination in Defecatory Disorders.

BACKGROUND & AIMS: Diagnostic tests for defecatory disorders (DDs) asynchronously measure anorectal pressures and evacuation and show limited agreement; thus, abdominopelvic-rectoanal coordination in normal defecation and DDs is poorly characterized. We aimed to investigate anorectal pressures, anorectal and abdominal motion, and evacuation simultaneously in healthy and constipated women. METHODS: Abdominal wall and anorectal motion, anorectal pressures, and rectal evacuation were measured simultaneously with supine magnetic resonance defecography and anorectal manometry. Evacuators were defined as those who attained at least 25% rectal evacuation. Supervised (logistic regression and random forest algorithm) and unsupervised (k-means cluster) analyses identified abdominal and anorectal variables that predicted evacuation. RESULTS: We evaluated 28 healthy and 26 constipated women (evacuators comprised 19 healthy participants and 8 patients). Defecation was initiated by abdominal wall expansion that was coordinated with anorectal descent, increased rectal and anal pressure, and then anal relaxation and rectal evacuation. Compared with evacuators, nonevacuators had lower anal diameters during simulated defecation, rectal pressure, anorectal junction descent, and abdominopelvic-rectoanal coordination (P < .05). Unsupervised cluster analysis identified 3 clusters that were associated with evacuator status (P < .01), that is, 10 evacuators (83%), 16 evacuators (73%), and 1 evacuator (5%) in clusters 1, 2, and 3, respectively. Each cluster had distinct characteristics (eg, maximum abdominosacral distance, rectal pressure, anorectal junction descent, anal diameter) and correlates that were more (clusters 1-2) or less (cluster 3) conducive to evacuation. Cluster 2 had 16 evacuators (73%) and intermediate characteristics (eg, lower anal resting pressure and relaxation during evacuation; P < .05). CONCLUSIONS: Women with DDs and a modest proportion of healthy women had specific patterns of anorectal dysfunction, including inadequate rectal pressurization, anal relaxation, and abdominopelvic-rectoanal coordination. These observations may guide individualized therapy for DDs in the future.

Effects of psychosensory stimulation on anal pressures: Effects of alfuzosin.

BACKGROUND: Our aim is to explain the lack of clarity in the ways in which anxiety and depression, which are common in defecatory disorders (DD), may contribute to the disorder. In this study, we evaluate the effects of mental stress and relaxation on anal pressures and the mechanisms thereof. METHODS: In 38 healthy women and 36 DD patients, rectoanal pressures were assessed at rest and during mental stressors (ie, word-color conflict [Stroop] and mental arithmetic tests) and mental relaxation, before and after randomization to placebo or the adrenergic α1 -antagonist alfuzosin. KEY RESULTS: During the baseline Stroop test, the anal pressure increased by 6 ± 13 mm Hg (mean ± SD, P = 0.004) in healthy women and 9 ± 10 mm Hg (P = 0.0001) in constipated women. During mental arithmetic, the anal pressure increased in healthy (4 ± 8 mm Hg, P = 0.002) and constipated women (5 ± 9 mm Hg, P = 0.004). After relaxation, anal pressure declined (P = 0.0004) by 3 ± 4 mm Hg in DD patients but not in controls. Alfuzosin reduced (P = 0.0001) anal resting pressure (by 31 ± 19 mm Hg) vs placebo (16 ± 18 mm Hg). However, during the postdrug Stroop test, anal pressure increased (P = 0.0001) in participants who received alfuzosin but not placebo. CONCLUSIONS & INFERENCES: In healthy controls and DD patients, mental stressors likely increased anal pressure by contracting the internal anal sphincter; relaxation reduced anal pressure in DD patients. Alfuzosin reduced anal resting pressure but did not block the Stroop-mediated contractile response, which suggests that this response is not entirely mediated by adrenergic α1 receptors.

Increased nutrient sensitivity and plasma concentrations of enteral hormones during duodenal nutrient infusion in functional dyspepsia.

OBJECTIVES: Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls. METHODS: Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions. RESULTS: Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively. CONCLUSIONS: Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.