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Effect of renzapride on transit in constipation-predominant irritable bowel syndrome

  • Michael Camilleri
    Correspondence
    Address requests for reprints to: Michael Camilleri, M.D., Mayo Clinic, Charlton 8-110, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 255-5720
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Sanna McKinzie
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Jean Fox
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Amy Foxx-orenstein
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Duane Burton
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • George Thomforde
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Kari Baxter
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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  • Alan R. Zinsmeister
    Affiliations
    Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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      Background & Aims: The aim of this study was to evaluate the dose-ranging pharmacodynamic effects of renzapride, a 5-hydroxytryptamine 4 (5-HT4) receptor full agonist/5-HT3 receptor antagonist, on gastrointestinal transit and symptoms in patients with constipation-predominant irritable bowel syndrome (C-IBS). Methods: Forty-eight patients (46 women) with C-IBS underwent recording of baseline symptoms for 1 week. Twelve patients per group were randomized (double-blind, parallel design) to 11–14 days of renzapride (1, 2, or 4 mg) or placebo, once daily. Daily bowel habits and weekly satisfactory relief of IBS symptoms were recorded. At the end of treatment, gastric emptying (GE), small bowel transit (SBT), and colon transit (CT) were measured by scintigraphy. The relationship between CT and bowel function was evaluated. Results: A statistically significant linear dose response to renzapride was detected for CT (GC8 h, P = 0.004; GC24 h, P = 0.056), and ascending colon (AC) emptying t1/2 (P = 0.019), but not for GE (t1/2, P = 0.088; or SBT, P = 0.41). AC half-time transit (t1/2) for placebo and 4 mg of renzapride were (median) 17.5 vs. 5.0 hours, respectively. Improved bowel function scores (stool form and ease of passage, but not frequency) were significantly (P < 0.05) associated with accelerated CT. Pharmacokinetic analysis showed linear kinetics of renzapride with a mean t1/2 in plasma of 10 hours. Bowel function and satisfactory relief were not significantly altered by renzapride, although a type II error cannot be excluded. No significant adverse clinical, laboratory, or electrocardiogram (ECG) effects were observed. Conclusions: Renzapride causes clinically significant dose-related acceleration of CT, particularly ascending colonic emptying; this acceleration of transit is associated with improvement of bowel function in female C-IBS patients.

      Abbreviations used in this paper:

      AC (ascending colon), C-IBS (constipation-predominant irritable bowel syndrome), Cmax (maximum concentration), ECG (electrocardiogram), GC (geometric center), 5-HT (5-hydroxytryptamine), IBS (irritable bowel syndrome), t1/2 (pharmacokinetic half-life, transit half-time), Tmax (time at maximum concentration)
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