Mar. 4, 2003 MADISON - To survive and thrive in a decidedly hostile environment, the lowly tapeworm uses a chemical trick to evade the propulsive nature of its intestinal home.
Capitalizing on that tapeworm chemistry, scientists at the University of Wisconsin-Madison believe they may have found a way to slow the transit of drugs through the intestine, making them more effective in their delivery and holding out the promise not only of more effective treatment, but also of lowering dosage and cost, and eliminating wasted medicine.
This new insight comes via the tapeworm Hymenolepis diminuta, a species found in rats and long used as a research model by parasitologists. By sorting through the soup of biochemicals the tapeworm uses to influence muscle activity in the gut, a group led by John Oaks of the School of Veterinary Medicine, and Paul Bass of the School of Pharmacy has isolated a chemical signal factor that may help prolong the time it takes for medicines to move through the small intestine.
"Most oral medications would benefit from prolonged small intestinal residence," says Bass, an emeritus professor of pharmacy. "Almost all drugs we take orally are absorbed from the small intestine. By prolonging the medication's residence time in that organ, we should enhance its absorption and obtain higher blood levels of the medication."
The compound characterized by Oaks and Bass, known in scientific shorthand as cyclic GMP, is a member of a family of compounds known generically as signal factors. Its role is to alter the electrochemical activity of the muscles in the intestine, slowing or shutting down intestinal transit of the host, actions that help the tapeworm obtain a meal or otherwise survive in an organ designed to quickly sweep food along.
"Inside cells, cyclic GMP is a signal molecule," notes Oaks, a professor of comparative bioscience. "It tells cells how to behave. When the tapeworm secretes this signal molecule, the intestine closes off and nothing moves. That suggested to us that the intestine is not digesting material as it normally would."
The cyclic GMP compound, Oaks adds, is cheap and easy to synthesize. Its use as an additive to medicines has been patented by the Wisconsin Alumni Research Foundation.
"Many drugs are absorbed at less than 50 percent from the intestine," says Oaks. "The key will be can we use cyclic GMP with certain kinds of drugs to increase their level of uptake into the blood?"
An example of a drug that might be more effective if it passed through the intestine at a slower pace is Fosamax, a medicine used to combat osteoporosis that is made by the pharmaceutical giant Merck. The company claimed Fosamax sales totaling $1.3 billion in 2000.
"It currently is taken by many women to prevent or treat osteoporosis," Bass says. "But this medication is only 1 percent absorbed. We believe our signal factor could possibly enhance absorption and thereby reduce the amount of medication that is taken."
By lowering dosages of different medications, it might be possible to lower the cost of medicines. Some drugs are prohibitively expensive to produce and reducing dosages could help consumers now contending with the escalating costs of many pharmaceuticals.
Other potential benefits associated with lower dosages include lessened side effects and fewer chemicals released into the environment. A recent survey of surface water in the United States revealed a growing presence of drugs in the environment. The suspected sources are medicines that are not completely metabolized by the humans and animals they are administered to.
"If we could halve the dosage, we could lower the percentage of nonabsorbed drug that ends up in the environment," says Oaks.
The work done by the Wisconsin team, which also included K. Dubear Kroening and Noah P. Zimmerman, was funded in part by a grant from the National Institutes of Health.
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