Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety.
BACKGROUND
Lubiprostone, a locally acting type-2 chloride channel activator, induces intestinal fluid secretion.


OBJECTIVE
To assess efficacy and safety of oral lubiprostone at multiple doses for the treatment of chronic constipation.


METHODS
A total of 129 patients with chronic constipation were randomized to receive lubiprostone (24, 48 or 72 mcg/day) or placebo for 3 weeks. Spontaneous bowel movement (SBM) frequency, rescue medication use, symptom assessments and adverse events (AEs) were tracked.


RESULTS
Over the double-blinded period, mean SBM frequencies were higher for lubiprostone groups (5.1-6.1) vs. placebo (3.8) and the overall difference was statistically significant (P = 0.046). SBM frequencies at week 1 were significantly higher in patients taking lubiprostone 48 or 72 mcg/day (P < or = 0.003) and, at week 2, all three lubiprostone doses yielded significantly higher SBM rates vs. placebo (P < or = 0.020). Significantly larger proportions of patients taking lubiprostone 48 and 72 mcg/day also experienced a SBM on the first treatment day (P < or = 0.009). The most common AEs were nausea, headache and diarrhoea.


CONCLUSIONS
Lubiprostone improved SBM rates in a dose-dependent manner. AEs were tolerable for most patients. Increased AE severity at 72 mcg/day did not provide a clear risk-to-benefit advantage compared with lubiprostone 48 mcg/day, the dose chosen for subsequent Phase 3 studies.
Johanson
J F
JF
Rockford Gastroenterology Associates, Rockford, IL, USA. johnfj@uic.edu
Ueno
R
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D000293:Adolescent; D000328:Adult; D000368:Aged; D000527:Alprostadil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018118:Chloride Channels / Q000378:metabolism*; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005227:Fatty Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D000068238:Lubiprostone; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D018118:Chloride Channels; D005227:Fatty Acids; D005765:Gastrointestinal Agents; D000068238:Lubiprostone; D000527:Alprostadil