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Former Pfizer researchers work together to fight diarrhea in developing nations

This article first appeared in the St. Louis Beacon, June 22, 2011 - Diarrhea kills nearly 2 million children under the age of 5 each year. Scientists at Saint Louis University, the University of Missouri- St. Louis and an institute in San Francisco are working together to reduce those numbers.

The local scientists working on the anti-diarrheal project all worked in Pfizer's St. Louis drug development group that was disbanded last year.

The Center for World Health and Medicine is the brainchild of Pete Ruminski, now the executive director. When Pfizer's restructuring was announced, he read an article in the St. Louis Business Journal quoting Ray Tate, vice president of research at Saint Louis University. Tate remarked how unfortunate it would be for the area to lose all this scientific expertise.

Ruminski suggested to Tate that the university hire former Pfizer scientists with the skill to develop drugs for rare medical conditions and 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 center, 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.

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 percent of the needed equipment, as well as a number of computers.

At the same time, another group of former Pfizer scientists joined the University of Missouri-St. Louis. These applied organic specialists design and synthesize 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 refined for treating diarrhea. Rounds of lab and animal testing and improvement will continue until a molecule is approved for human testing.

Children Are Most Vulnerable

According to the World Health Organization, diarrhea is the second leading cause of death in children between birth and 5 years of age. Pneumonia is first and malaria is third. Most of the affected children live in developing countries with limited access to clean water and modern medical facilities. Malnutrition makes children more vulnerable to these conditions.

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.

"When children in this country develop severe diarrhea and become lethargic, their parents can take them to the emergency room for IV fluids," Ruminski explained. "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."

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

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.

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 causes of death from diarrheal diseases. A pill that could keep these symptoms under control could bring children through the acute phase of the disease. Since the intestines would retain normal motility, the infectious agent would be excreted with time.

The two groups of scientists represent years of experience with "drugable" molecules having many different mechanisms of action. To be considered a drugable candidate, a molecule must affect its target in the correct way and 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.
  • Absorbable 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 drugs being developed for diarrhea were originally intended for hypertension or congestive heart failure. Some molecules in this class got as far as advanced testing in humans, so they are known to be safe and drugable. However, they weren't an improvement on drugs already on the market for hypertension or heart failure, and thus were not suitable for further commercial development.

When the Saint Louis University 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.

Holistic Approach to Treatment, Prevention

Health professionals have known for a long time that most diarrheas could be prevented by availability of clean water. However, much of the developing world does not have access to clean water. So a quick fix pill is needed.

Ruminski and his team envision that local physicians in areas where diarrheal diseases are most prevalent would carry out all clinical testing, in partnership with an international health entity, like the World Health Organization.

If the anti-diarrheal 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 or other nonprofit organizations. Health-care workers might also introduce nutritional strategies, like the peanut butter food distributed by Washington University professors Mark Manary and Patricia Wolff.

Jo Seltzer is a freelance writer with more than 30 years on the research faculty at the Washington University School of Medicine and seven years teaching technical writing at WU's engineering school.