Effect of renzapride on transit in constipation-predominant irritable bowel syndrome.
OBJECTIVE
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.
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. camilleri.michael@mayo.edu
Michael
M
Camilleri
Sanna
S
McKinzie
Jean
J
Fox
Amy
A
Foxx-Orenstein
Duane
D
Burton
George
G
Thomforde
Kari
K
Baxter
Alan R
AR
Zinsmeister
D000328:Adult; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003106:Colon / Q000503:physiopathology; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005746:Gastric Emptying / Q000502:physiology; D005772:Gastrointestinal Transit / Q000502:physiology*; D006801:Humans; D007421:Intestine, Small / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C053006:renzapride