Alternative treatment for secretory diarrhea linked to the cystic fibrosis gene

Secretory diarrhea is the leading cause of death in children less than 5 years of age in developing countries, and a frequent and most unwelcome diagnosis for many adults that is made, on average, up to four times each year. Many common causes of diarrhea exist: bacterial or viral infections resulting from consumption of contaminated food or water; food intolerances; reactions to medicines; bowel disorders and intestinal diseases. Diarrhea results when cells lining the intestine secrete an excess of chloride, via a chloride channel within the cell, as well as sodium in reaction to one of these causal agents. The high level of resulting salt in the intestine causes water removed from the blood to be directed to the gut, thereby producing fluid diarrhea. The most serious and life-threatening development during a bout of diarrhea is dehydration due to continued removal of water from the circulation.

In 1989 the cystic fibrosis gene was identified and found to encode a chloride channel in cells lining the lung. Recognized as the cystic fibrosis transmembrane conductance regulator (CFTR), no compounds were known to inhibit the activity of this channel - until now.

In the December 2 issue of the Journal of Clinical Investigation, Alan Verkman and colleagues at the Cardiovascular Research Institute at the University of California, San Francisco, developed a high-throughput screening assay to identify compounds that inhibit the activity of CFTR. The authors identified an organic compound, thiazolidinone, effective in inhibiting CFTR-mediated chloride secretion. To test the therapeutic value of thiazolidinone the authors investigated it's utility in mice suffering secretory diarrhea. The authors reported a successful reduction of excess intestinal fluid secretion via inhibition of the chloride channel within cells lining the gut.

Will this drug, or its derivatives, be useful in the treatment of secretory diarrhea? In his accompanying commentary Dr. Qais Al-Awqati from the Department of Medicine at Columbia University in New York comments that "the use of the new chloride channel-blockers confers some specificity allowing these compounds to be used in the treatment of diarrhea with impunity". Dr. Al-Awqati does however point out that many infections that cause diarrhea are self-limiting and "the aim of medical therapy remains the prevention and treatment of severe dehydration, making oral rehydration the standard of care". Oral rehydration therapy (ORT), officially endorsed by the World Health Organization and UNICEF in 1975, is the oral administration of a sugar and salts solution that reverses the dehydration caused by diarrhea. In this world of high-tech medicine, it is humbling to observe that such a simple recipe is capable of decreasing the mortality rate associated with diarrheal diseases.

Perhaps the most promising conclusion drawn from the work by Verkman and coworkers is that as researchers have been unable to adequately define how defective CFTR leads to airway disease in current mouse models of cystic fibrosis, highly specific CFTR-inhibitors such as thiazolidinone should be useful in determining the role of this chloride channel. It should also aid drug-mediated creation of a more suitable animal model of cystic fibrosis that more closely mimics this disease in humans.

CONTACT:
Alan S. Verkman
1246 Health Sciences East Tower
Cardiovascular Research Institute
University of California, San Francisco
San Francisco, CA 94143-0521
USA
Phone: 415-476-8530
Fax: 415-665-3847
E-mail: verkman@itsa.ucsf.edu

View this article at http://www.jci.org/cgi/content/full/110/11/1651.

ACCOMPANYING COMMENTARY:
Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors

CONTACT:
Qais Al-Awqati
Department of Medicine and Physiology
Columbia University College of Physicians and Surgeons
630 West 168th Street, New York, NY 10032
USA
Phone: 212-305-3512
Fax: 212-305-3475
E-mail: qa1@columbia.edu

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