Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Novel compound may treat acute diarrhea

18.06.2008
Debilitating illness is major cause of child deaths in developing nations

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.

"This newly discovered compound decreases the formation of ever-present cellular messenger molecules, cyclic guanosine monophosphate and cyclic adenosine monophosphate, caused by various bacterial toxins and might prevent or attenuate the intestinal fluid secretion, diarrhea and dehydration," said Murad, the senior author. "While this research looks extremely promising as a preventive or therapeutic intervention in Third World diarrheal disease and travelers' diarrhea, much work remains to be done to move into clinical trials and eventual therapeutic approval."

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.

There are many causes of secretory diarrhea. The most common, by far, is infestation of the small intestine by certain bacteria, such as cholera or certain strains of E. coli, following ingestion of contaminated water or food. These bacteria multiply in the intestinal tract and produce toxins that bring about elevations of a group of intracellular messengers, cyclic nucleotides, that stimulate intestinal cells to secrete salt and water.

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.

"These findings are a promising lead into what could prove to be a triumph of translational research of staggering importance," Schultz said. "An inexpensive drug that could block the intestinal secretory pathway, with minimal side effects, would be a "magic bullet" that would not only save millions of lives in many parts of the developing world, but would also save the billions of dollars that are lost annually because of diarrhea throughout the world. It would truly be a treatment of diarrhea rather than a treatment of the consequences of diarrhea." Schultz received the 2006 Prince Mahidol Award for Medicine for pioneering research that led to the development of oral rehydration therapy.

Herbert L. DuPont, M.D., professor of infectious diseases and director of the Center For Infectious Diseases at The University of Texas School of Public Health, said, "The approach being taken here is to decrease fluid loss from the intestine, which is directed to the most important body mechanism leading to acute diarrhea."

"Current antidiarrheal therapy is less physiologic, often working through inhibition of intestinal movement leading to potential complications. A drug that stops the loss of fluid and salt from the intestine could save infant lives in developing regions and alleviate suffering that would otherwise be experienced by travelers to the tropics and subtropics," DuPont said.

Travelers' diarrhea affects millions of people annually.

The promising treatment is the result of a 30-year investigation by Murad and long-time colleague Richard L. Guerrant, M.D., director of the Center for Global Health at the University of Virginia School of Medicine, Charlottesville, into the molecular mechanisms of ETEC, which began with the identification of a link between the messenger molecules and a bacterial strain of diarrhea pathogen from Bangladesh.

Murad credits advances in biochemistry with their discovery. "I always thought we would find a compound. We now have the right set of people and right circumstances to solve this. We found this compound while screening a library of chemical substances," Murad said.

This area of molecular medicine is called cell signaling.

"You start with one molecule of a toxin or a hormone," said Alexander Kots, Ph.D., the lead author and an instructor at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), a part of the UT Health Science Center at Houston. "The toxin binds to a target and influences it. Soon you have 10 molecules, then 100, then 1,000 and so forth. This is called signal amplification. One molecule of toxin can produce millions of molecules of water."

Their strategy is to stop the signal amplification process early on, thereby halting enterotoxigenic diarrhea, said co-author Byung-Kwon Choi, Ph.D., a research fellow at the IMM.

"Various bacterial toxins are responsible for increasing the production of intracellular messenger molecules. These molecules contribute to the increase in fluid secretion. We discovered a compound that blocks one of the pathways responsible for ETEC diarrhea. This has never been done before," Murad said.

Besides diarrheal disease, this potential drug, based on its mechanism of action, could have promising effects in other diseases such as inflammatory bowel disease and some endocrine disorders, Murad said.

"The relatively easy chemical synthesis (single step) and a presumed low cost should make it very attractive for therapy of diarrhea in developing countries," Murad wrote in the paper.

Robert Cahill | EurekAlert!
Further information:
http://www.uth.tmc.edu

More articles from Health and Medicine:

nachricht Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

nachricht What does congenital Zika syndrome look like?
24.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>