Activation of type-2 chloride channels: a novel therapeutic target for the treatment of chronic constipation.
Chronic constipation affects up to 27% of the population and negatively impacts health-related quality-of-life. Prescription medications targeting chronic constipation currently include polyethylene glycol, lactulose and tegaserod, a serotonin type 4 receptor partial agonist. The most recent addition is lubiprostone (Amitiza), a type-2 chloride channel (ClC-2) activator which is a member of a new class of compounds known as prostones. Lubiprostone is a bicyclic fatty acid that acts locally on ClC-2 channels located in the apical membrane of intestinal epithelial cells. This stimulation of chloride secretion induces the passive movement of sodium and water into the intestinal lumen, yielding a net increase in isotonic fluid, which results in improved bowel function. In double-blind, placebo-controlled clinical trials, lubiprostone increased the number of spontaneous bowel movements compared with placebo and was generally well tolerated. The predominant adverse effects were nausea and diarrhea. Lubiprostone represents a new therapeutic class of compounds for the treatment of chronic constipation and will be the focus of this review.
Crowell
Michael D
MD
Mayo Clinic Scottsdale, Division of Gastroenterology and Hepatology, 13400 East Shea Blvd, Scottsdale, AZ 85259, USA. crowell.michael@mayo.edu
Harris
Lucinda A
LA
DiBaise
John K
JK
Olden
Kevin W
KW
D000527:Alprostadil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000502:physiology; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D003967:Diarrhea / Q000139:chemically induced; D005227:Fatty Acids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D000068238:Lubiprostone; D008954:Models, Biological; D009325:Nausea / Q000139:chemically induced; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D000090007:CLC-2 Chloride Channels; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D005227:Fatty Acids; D000068238:Lubiprostone; D000527:Alprostadil