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Clin Gastroenterol Hepatol. 2014 Feb;12(2):204-9. doi: 10.1016/j.cgh.2013.12.001. Epub 2013 Dec 4.

Discovery and development of antisecretory drugs for treating diarrheal diseases.

Author information

1
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California; Department of Gastroenterology, Hepatology and Nutrition, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.
2
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California.
3
Departments of Physiology and Medicine, Gastroenterology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, California. Electronic address: Alan.Verkman@ucsf.edu.

Abstract

Diarrheal diseases constitute a significant global health burden and are a major cause of childhood mortality and morbidity. Treatment of diarrheal disease has centered on the replacement of fluid and electrolyte losses using oral rehydration solutions. Although oral rehydration solutions have been highly successful, significant mortality and morbidity due to diarrheal disease remains. Secretory diarrheas, such as those caused by bacterial and viral enterotoxins, result from activation of cyclic nucleotide and/or Ca(2+) signaling pathways in intestinal epithelial cells, enterocytes, which increase the permeability of Cl(-) channels at the lumen-facing membrane. Additionally, there is often a parallel reduction in intestinal Na(+) absorption. Inhibition of enterocyte Cl(-) channels, including the cystic fibrosis transmembrane conductance regulator and Ca(2+)-activated Cl(-) channels, represents an attractive strategy for antisecretory drug therapy. High-throughput screening of synthetic small-molecule collections has identified several classes of Cl(-) channel inhibitors that show efficacy in animal models of diarrhea but remain to be tested clinically. In addition, several natural product extracts with Cl(-) channel inhibition activity have shown efficacy in diarrhea models. However, a number of challenges remain to translate the promising bench science into clinically useful therapeutics, including efficiently targeting orally administered drugs to enterocytes during diarrhea, funding development costs, and carrying out informative clinical trials. Nonetheless, Cl(-) channel inhibitors may prove to be effective adjunctive therapy in a broad spectrum of clinical diarrheas, including acute infectious and drug-related diarrheas, short bowel syndrome, and congenital enteropathies.

KEYWORDS:

CFTR; Ca(2+)-activated Cl(-) channels; CaCC; Chloride Channels; Diarrhea; HIV; ORS; Rotavirus; Small Molecules; cystic fibrosis transmembrane conductance regulator; human immunodeficiency virus; oral rehydration solution

PMID:
24316107
PMCID:
PMC3935719
DOI:
10.1016/j.cgh.2013.12.001
[Indexed for MEDLINE]
Free PMC Article

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