Digestive Diseases News Spring 2012
NIDDK Workshop on Acute Diarrheal Diseases Focuses on Translational Approaches for New Drug Development
The National Institute of Diabetes and Digestive and Kidney Diseases hosted a workshop in September 2011 on Translational Approaches for Pharmacotherapy Development for Acute Diarrhea. The workshop brought together investigators to examine the current understanding and challenges of acute diarrhea treatment, the pathogenesis of acute diarrhea, the pathophysiologic mechanisms involved, and the advances needed to develop new drug therapies for treating diarrheal diseases.
Workshop attendees summarized the present-day challenges of treating diarrheal diseases:
- New epidemics of infectious diarrhea—such as the 2011 European Shiga-toxin-producing Escherichia coli and ongoing Haitian cholera outbreaks—have added to the burden of worldwide diarrheal disease.
- Despite improvements in oral rehydration solution (ORS) therapy, its use has dropped since the 1990s, which may be due to several factors including failure to significantly reduce the duration or volume of diarrhea.
- Repeated diarrheal episodes in children have been linked to malnutrition, stunting, and impaired physical and mental development. Further research must determine how to address not only mortality from diarrheal disease, but these long-term effects as well.
- Other than ORS, few safe and effective drugs are available for treating acute diarrhea. New types of drugs may be needed to prevent complications like those described above.
Workshop participants also discussed how the host-microbe interactions that facilitate infection can vary from one case to another. For this reason, targeting a common mechanism involved in how a bacterium, virus, or parasite initially infects a host may not be possible. However, the host response to infection, no matter the cause, may include some common features, such as altered electrolyte and water transport, alterations in tight junction function and regulation, and interactions with certain cellular signaling pathways.
Recent advances have identified genetic variations that are associated with increased susceptibility to acute diarrheal diseases. These discoveries present a need for new screening approaches to learn about new genetic factors as well as susceptibility and response to treatment. The intestinal microbiome should also be examined for its role in affecting susceptibility to infection.
Referencing these elements of diarrhea infection, workshop participants highlighted the possibility for potential drug development based on:
- stimulating sodium absorption
- inhibiting anion secretion
- correcting defects in specific transport proteins or in pathways that regulate transporter function
- targeting factors linked to electrolyte transport, including epithelial tight junctions, signaling by intestinal hormones and neurotransmitters, and the enteric nervous system
- increasing epithelial proliferation and restoration in cases where mucosal destruction also occurs
Attendees recommended additional research into existing candidates for drug development, including zinc, clotrimazole, probiotics, ORS, and antimotility agents. The workshop examined not only the ways that these compounds and mechanisms might yield new treatment options, but also the methods and models for translational research that will produce the most useful results.
In conclusion, the meeting participants created a summary of recommendations for translational research to advance the development of diarrheal disease pharmacotherapy. The recommendations in part addressed research methods, by encouraging more in vivo research in animal models, and more in vitro human models for testing drugs. The summary concluded that a modified ORS should be developed. Finally, the report advised of areas in need of further research inquiry, including in genetic risk factors for diarrheal diseases, the mechanisms involved in pathogenesis, and the impact of early development and aging.
A report of this meeting was published online January 24, 2012, in the journal Gastroenterology, available online at www.gastrojournal.org .
For more information about upcoming meetings and workshops, visit www2.niddk.nih.gov/News/Calendar.
The National Digestive Diseases Information Clearinghouse, an information service of the National Institute of Diabetes and Digestive and Kidney Diseases, has free fact sheets and easy-to-read booklets about diarrhea. For more information or to obtain copies, visit www.digestive.niddk.nih.gov.
NIH Publication No. 12–4552
Page last updated June 8, 2012