Pharmacodynamic effects of a novel prokinetic 5-HT4 receptor agonist, ATI-7505, in humans

Authors

  • M. Camilleri,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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      Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Group

  • M. I. Vazquez-roque,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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      Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Group

  • D. Burton,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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      Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Group

  • T. Ford,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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      Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Group

  • S. Mckinzie,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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      Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Group

  • A. R. Zinsmeister,

    1. Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
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  • P. Druzgala

    1. ARYx Therapeutics, Fremont, CA, USA
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Michael Camilleri MD, Mayo Clinic Miles and Shirley Fiterman Center for Digestive Diseases, Charlton 8-110 200, First Street S.W., Rochester, MN 55905, USA.
Tel: +1 507-266-2305; e-mail: camilleri.michael@mayo.edu

Abstract

Abstract  ATI-7505, an investigational 5-HT4 receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T1/2, colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T1/2. Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T1/2 (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T1/2 (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

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