Diarrhea kills nearly two million children under the age of five each year. It is the world’s second leading cause of death in this age group. Most of the affected children live in developing countries, and have limited access to clean water and modern medical facilities.
Photo courtesy of Saint Louis University
“When children in this country develop severe diarrhea and become lethargic, their parents can take them to the emergency room for IV fluids,” explains Pete Ruminski, executive director of Saint Louis University’s Center for World Health and Medicine. “Even if the diarrhea isn’t severe enough for hospitalization, pediatricians routinely replenish fluid and electrolytes with Gatorade or its equivalent dissolved in clean water.”
Diarrhea can have many causes. Cholera often accompanies major disasters. Infection by amoeba, viruses such as rotavirus, and parasites like giardia all result in the cramping and loss of water and electrolytes in this potentially lethal syndrome. The bacterial E. coli epidemic that has recently sickened thousands of Europeans has diarrhea as one of its manifestations.
Except for opiates, the main drug available to treat the symptoms of diarrhea is Immodium. Immodium keeps the large intestine from contracting, but is not recommended for use in young children.
Different Mechanism for New Diarrhea Drug
Photo courtesy of University of Missouri Saint Louis
The Center for World Health and Medicine together with UMSL’s Medicinal Chemistry Group, headed by John Walker, have teamed with the San Francisco based Institute for One World Health to develop safe and effective anti-diarrhea drugs with a primary mechanism of action different from Immodium’s.
The new drugs are aimed at preventing the massive water and electrolyte secretion that occurs in severe diarrhea. Dehydration and electrolyte imbalance are the main cause of death from diarrheal diseases. A pill that could keep these symptoms under control should be able to bring the children through the acute phase of the disease. Since the intestines would retain normal motility, the infectious agent would be excreted with time.
The scientists working on the anti-diarrheal project already know a great deal about drugs that can inhibit secretion. All of them worked in Pfizer’s Saint Louis drug development group that was disbanded last year. Among them, they have the skills and knowledge needed to bring a drug from the laboratory, through animal testing, and into phase I human testing.
The Center for World Health and Medicine (CWHM) is Ruminski’s brainchild. When the Pfizer restructuring was announced, he read an article in the St. Louis Business Journal that quoted Ray Tate, Vice President of Research at Saint Louis University. Tate remarked how unfortunate it would be for the St. Louis area to lose all this scientific expertise.
Ruminski approached Tate with the suggestion that the university hire a core group of former Pfizer scientists with the skill sets needed to develop drugs for “orphan diseases” and for neglected diseases of the poor (like diarrhea) that don’t have much profit-making potential. The proposal was accepted and the Center for World Health and Medicine was born.
A group of applied scientists such as those at the CWHM adds a unique dimension to the university’s research capabilities. Basic scientists discover and characterize biological phenomena. Drug developers, who are applied scientists, figure out how to exploit the phenomena to create effective drugs.
Peter Ruminski, partially hidden is far left, top row. Members of the diarrhea development team shown are in the top row. From far right in are Brian Bond, Jon Jacobsen, and David Griggs. Ying Yu is absent from the photo.
Photo courtesy of Peter Ruminski
Saint Louis University gave the present team of 12 investigators laboratory space in the school of medicine’s Doisy Research Center. Pfizer donated about 85% of the needed equipment, as well as a number of computers.
At the same time, Chancellor Thomas George and Vice Provost for Research Nasser Arshadi established a medicinal chemistry group of former Pfizer scientists at the University of Missouri in St. Louis. This group of applied organic specialists specializes in designing and synthesizing molecules to target specific biological phenomena. One of their present collaborations is making the molecules that are being tested to inhibit fluid secretion in diarrhea. Molecules that work well in laboratory and animal tests will be further optimized for treating diarrhea. Rounds of testing and optimizing will continue until a molecule is approved for Phase I human testing. Pfizer donated equipment to this group also.
Creating “Drugable” Molecules
The two groups represent years of experience with “drugable” molecules having many different mechanisms of action. To be considered a drugable candidate, a molecule must not only affect its target in the correct way, but must have these characteristics.
- Potency: It should be given in a reasonably sized dose, preferably once a day.
- Stability: It should be metabolized slowly enough to be effective.
- Selectivity: It should have minimum side effects.
- Absorbed by the digestive system: It is desirable to give drugs orally.
The anti-diarrhea drug is a good example of the approach used by these two groups of industrial scientists turned academicians.
The class of drugs being developed for diarrhea were originally intended to target hypertension or congestive heart failure. Some of the molecules in this class got as far as phase III testing in humans, so they are known to be safe and drugable. They were not, however, better than drugs currently on the market for hypertension or heart failure, and thus were not suitable for further commercial development.
When the team, led by Jon Jacobsen and Brian Bond, began looking at possible diarrhea therapies, they realized that some of the abandoned hypertension drugs had an effect on a particular mechanism in the gut that controls water and electrolyte secretion. They decided to try to modify these molecules to optimize their effect on anti-secretory activity.
Each newly modified molecule from Walker’s group at UMSL is first tested in the laboratory by David Griggs, director of cell and molecular biology, and his colleagues. Then, if it passes the lab tests, it is tried in rats by Ying Yu, lead animal pharmacologist. The rats are fed castor oil to induce diarrhea; a good candidate molecule will counteract the castor oil. Humans can also use the castor oil test.
Holistic Approach to Treat and Prevent Diarrhea
Health professionals have known for a long time that most diarrheas would be prevented by availability of clean water. In fact, however, much of the developing world does not have access to clean water. So a quick fix pill is much needed.
Ruminski and his team envision that local physicians in areas where diarrheal diseases are most prevalent would carry out all clinical testing. These local physicians would be partners in the project from the beginning. They would probably work with a medical team from an organization like the World Health Organization (WHO.)
If the pill works to get children through the acute phase of their illness, the door might be open to bring in other strategies like personal water purification systems and education in personal hygiene, in collaboration with SLU’s school of public health and other non-profit organizations. Health care workers might also be able to introduce nutritional strategies, like the peanut butter food distributed by Washington University professors Mark Manary and Patricia Wolff.
The CWHM and the Medicinal Chemistry Group at UMSL are working with partners worldwide on projects to develop treatments for a number of underserved diseases, such as malaria, other parasitic diseases, retinal diseases leading to blindness, and sickle cell disease. In addition to the Institute for OneWorld Health, the CWHM has formed partnerships with the Guanzhou Institutes of Biomedicine and Health in China, Dalhousie University in Nova Scotia, and numerous disease experts both worldwide and local.
This article was originally published in the St. Louis Beacon.