Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome.
OBJECTIVE
Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients.


METHODS
Participants underwent 5-day baseline and 5-day treatment periods; gastrointestinal transit (by validated scintigraphy) and bowel function (by daily diaries) were assessed. Treatment effects were compared using analysis of covariance (baseline colonic transit as covariate) with pairwise comparisons of each dose vs placebo.


RESULTS
There was a significant overall treatment effect on ascending colon emptying half-time (P = .015) and overall colonic transit at 48 hours (P = .02) but not overall transit at 24 hours (P = ns), with a significant acceleration by linaclotide 1000 microg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-microg dose. There were significant overall treatment effects on stool frequency, stool consistency, ease of passage, and time to first bowel movement with a strong dose response for stool consistency (overall, P < .001). No safety issues were identified.


CONCLUSIONS
In women with constipation-predominant irritable bowel syndrome, linaclotide 1000 microg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.
Andresen
Viola
V
Clinical Enteric Neuroscience Translational and Epidemiological Research Group, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Camilleri
Michael
M
Busciglio
Irene A
IA
Grudell
April
A
Burton
Duane
D
McKinzie
Sanna
S
Foxx-Orenstein
Amy
A
Kurtz
Caroline B
CB
Sharma
Vineeta
V
Johnston
Jeffrey M
JM
Currie
Mark G
MG
Zinsmeister
Alan R
AR
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003248:Constipation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D003672:Defecation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects
D010455:Peptides; D006162:Guanylate Cyclase; C523483:linaclotide