Discovery and Development of Antisecretory Drugs for Treating Diarrheal Diseases. 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 Ca2+ 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 Ca2+-activated Cl- channels, represents an attractive strategy for antisecretory drug therapy.
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