Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans.
ATI-7505, an investigational 5-HT(4) 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) T(1/2), colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T(1/2). 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 T(1/2) (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 T(1/2) (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.
Camilleri
M
M
Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
Vazquez-Roque
M I
MI
Burton
D
D
Ford
T
T
McKinzie
S
S
Zinsmeister
A R
AR
Druzgala
P
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D003106:Colon / Q000502:physiology; D003672:Defecation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007422:Intestines / Q000000981:diagnostic imaging / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011877:Radionuclide Imaging; D018401:Sample Size; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013270:Stomach / Q000000981:diagnostic imaging / Q000502:physiology
D001549:Benzamides; D011812:Quinuclidines; D017366:Serotonin Receptor Agonists; C517618:ATI 7505