Novel Compound May Treat Acute Diarrhea

Debilitating illness is major cause of child deaths in developing nations

Ferid Murad, M.D., Ph.D.

In a development that may lessen the epidemic of diarrhea-related deaths among children in developing countries, scientists in the laboratory of Nobel Laureate Ferid Murad, M.D., Ph.D., at The University of Texas Health Science Center at Houston have discovered a novel compound that might lead to an inexpensive, easy-to-take treatment. The results of pre-clinical tests appear in the June 16 online edition of the journal Proceedings of the National Academy of Sciences of the United States of America.

The compound - a pyridopyrimidine derivative - targets acute secretory diarrhea caused by E. coli and other enterotoxigenic strains of bacteria, which produce toxins that stimulate the linings of the intestines, causing them to secrete excessive fluid, thereby producing diarrhea.

Diarrhea kills an estimated 1.6 to 2.5 million children every year, according to researchers quoted in the Bulletin of the World Health Organization. Enterotoxigenic strains of bacteria may account for a significant amount of these deaths, according to an article in Clinical Microbiology Reviews. Enterotoxigenic E. coli or ETEC is a leading cause of bacterial diarrhea.

During pre-clinical tests, the compound was associated with a significant reduction in intestinal fluid secretion in an animal model of bacterial diarrhea. It was also linked to reduced fluid build up during laboratory tests on human colon cells. It caused significant decrease in fluid secretion without apparent toxicity.

This unique approach to the treatment of enterotoxigenic diarrhea works by interrupting the diarrhea-causing chain of events that occur when bacterial toxins enter the intestinal tract. The compound slows the transmission of information in the epithelial cells lining the intestines. Consequently, the molecular mediators regulating the secretion of salt and fluid in the gut do not get fully activated. ETEC comes from feces-contaminated food or water and also causes travelers' diarrhea.

In the event of an earthquake, typhoon or other catastrophe, this potential diarrhea treatment could be used to treat outbreaks of enterotoxigenic E. coli caused by contaminated food and water supplies, Murad said. The compound can be placed in a pill for adults and in a liquid for children.

Secretory diarrhea describes the condition when the small intestine, which is normally an absorptive organ, is stimulated to secrete salts and water into the intestinal lumen, often in massive quantities. The resulting diarrhea can lead to profound fluid loss, dehydration, shock and death.

To date, there is no effective way of treating these diarrheas directly. Treatment is indirect and aimed at preventing serious outcomes by minimizing fluid loss using intravenous or, more recently, oral rehydration.

"Dr. Murad and his coworkers have discovered a relatively simple compound that
indirectly inhibits the ability of several bacterial toxins to elevate intracellular levels of cyclic nucleotides, and inhibits fluid secretion by animal small intestine exposed to these toxins," said Stanley G. Schultz, M.D., professor, associate dean for Institutional Advancement and Fondren Chair in Cellular Signaling at The University of Texas Medical School at Houston.

By Rob Cahill, Institutional Advancement

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