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Bharucha A.E.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center
Current Gastroenterology Reports | Year: 2011

Defecatory disorders are a common cause of chronic constipation and should be managed by biofeedback-guided pelvic floor retraining. While anorectal tests are necessary to diagnose defecatory disorders, recent studies highlight the utility of a careful digital rectal examination. While obstetric anal injury can cause fecal incontinence (FI), diarrhea is a more important risk factor for FI among women in the community, who typically develop FI after age 40. Initial management of fecal incontinence should focus on bowel disturbances. Pelvic floor retraining with biofeedback therapy is beneficial for patients who do not respond to bowel management. Sacral nerve stimulation should be considered in patients who do not respond to conservative therapy. © 2011 Springer Science+Business Media, LLC. Source

Bharucha A.E.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center | Isowa H.,Pfizer | Hiro S.,Pfizer | Guan Z.,Pfizer
Neurogastroenterology and Motility | Year: 2013

Background The gastrointestinal effects of antimuscarinic drugs used to treat overactive bladder may be related to the selectivity of these agents for M3-muscarinic receptor subtypes. We compared the effects of non-selective (fesoterodine) and M3-selective (solifenacin) antimuscarinics on gastrointestinal transit in healthy women. Methods Gastric emptying (GE), small-intestinal transit (colonic filling at 6h), colonic transit [geometric center at 24h (GC24; primary endpoint) and 48h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8mg, solifenacin 10mg, or placebo (2:2:1) for 14days. An interim analysis to finalize sample size was conducted. Key Results After 60 subjects [placebo (n=12), fesoterodine (n=25), solifenacin (n=23)] completed the study, the study was terminated due to a prespecified criterion (sample size ≥452.5 needed to provide ≥80% power to demonstrate superiority of fesoterodine over solifenacin in GC24). Compared with baseline, (i) placebo delayed small-intestinal, but not colonic, transit, (ii) fesoterodine significantly increased GE t1/2vs placebo (17.0min; P=0.027), and (iii) fesoterodine and solifenacin delayed small-intestinal (-36.8% and -21.8%, respectively, P<0.001 vs placebo) and colonic transit (GC24: -0.44 and -0.49, respectively, P<0.05 vs placebo; GC48: -0.25 and -0.65, respectively, P>0.05 vs placebo). Solifenacin increased stool hardness from baseline (P=0.010 for difference vs fesoterodine); stool frequency was comparable. Conclusions & Inferences In healthy women, fesoterodine had greater effects on small-intestinal transit and solifenacin had greater effects on colonic transit; the latter finding may explain why solifenacin, but not fesoterodine, increased stool hardness. (ClinicalTrials.gov ID: NCT00892034). © 2012 Blackwell Publishing Ltd. Source

Bharucha A.E.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center | Ravi K.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center | Zinsmeister A.R.,Mayo Medical School
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2010

Although in vitro studies show that muscarinic M3 receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M3-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M3 antagonist darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs. tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 ± 6.4%, mean ± SE], 7.5 mg ER [34.4 ± 6.1%], 15 mg ER [20.4 ± 6.3%)]. Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and tolterodine) half-time for ascending colonic emptying [placebo (12.0 ± 1.5 h), 7.5 mg (18.6 ± 1.9 h), 15 mg (22.9 ± 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 ± 0.2), 7.5 mg (2.4 ± 0.2), 15 mg (1.9 ± 0.2)] but not 48 h. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. With muscarinic antagonists used at clinically approved doses, these findings demonstrate that muscarinic M3 receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M3 antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated. Copyright © 2010 the American Physiological Society. Source

Bharucha A.E.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center | Bharucha A.E.,Clinical and Enteric Neuroscience Translational and Epidemiological Research Program | Low P.,Mayo Medical School | Camilleri M.,Clinical And Enteric Neuroscience Translational And Epidemiological Research Program Center | And 6 more authors.
Gut | Year: 2013

Objectives Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. Design After a 9-day baseline period, 30 patients (mean±SEM age 50±2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. Results 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean6SEM 1.98±0.17 (baseline), 1.84±0.16 (treatment)), pyridostigmine accelerated (1.9660.18 (baseline), 2.45±0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p=0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p≥0.14) than with placebo. Conclusions Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation. Source

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