Chronic Constipation: A Possible New Therapeutic Agent

Kurt J. Isselbacher


AccessMedicine from McGraw-Hill 

The drug lubiprostone, a chloride channel activator, was recently shown to be effective in the treatment of chronic constipation. Nevertheless, a large proportion of patients do not experience complete relief with this drug or other currently available approaches.

Linaclotide, a new agent, is a minimally absorbed, 14-amino-acid peptide that increases intestinal fluid secretion and transit via the intestinal guanylate cyclase C (GCC) receptor. Activation of this receptor results in increased fluid secretion as well as an increase in transit. In addition, animal studies show that the drug leads to decreased sensitivity to visceral distention. Recently, Lembo and colleagues (2010) reported the results of a placebo-controlled study evaluating the efficacy of a 4-week treatment with linaclotide in chronic constipation. In this multicenter study, patients were randomized to treatment with placebo or drug at various doses once daily. Patients with irritable bowel syndrome criteria were excluded. The primary endpoint was a change in the mean weekly spontaneous bowel movement frequency. Additional endpoints included improved stool consistency, abdominal discomfort and bloating, and overall evaluation of the relief of constipation.

In a dose-dependent manner, linaclotide significantly increased the frequency of spontaneous bowel movements as well as all the other endpoints that were the objective of the study. Overall, relief of constipation was consistently higher with linaclotide than with placebo. The drug was well tolerated; not surprisingly, the most commonly reported adverse event was diarrhea, which was usually transient and mild.

Linaclotide significantly improves bowel habits and abdominal symptoms in patients with chronic constipation. The drug has a rapid onset of action, and doses of 150 or 300 mg seem to provide the best relief. In an accompanying editorial, Drs. Bharucha and Waldman noted that “linaclotide and other GCC targeted agents expand the spectrum of molecularly based therapeutic options available to treat chronic constipation disorders.”


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