The University Record, October 15, 1997
By Sally Pobojewski
News and Information Services
University of Michigan scientists have found that iron chelatorsmedications used to "soak up" excess iron in the bloodstreamcan prevent deafness in guinea pigs exposed to antibiotics that damage delicate hair cells in the inner ear.
If clinical trials show that iron chelators work as well in humans as they do in guinea pigs, the research could lead to a safe and inexpensive way to eliminate the threat of deafness to individuals treated with a common class of broad-spectrum antibi otics called aminoglycosides.
Discovered in the 1940s, these antibioticswhich include streptomycin, gentamicin, neomycin and othersare the most widely used antibiotics in the world. Because they are so effective and rarely produce allergic reactions, physicians continue to pres cribe them, even though they are known to cause hearing loss and kidney damage in a significant percentage of individuals who take them.
"In the United States, aminoglycosides are most often used for emergency treatment of people with serious infections who have not responded to other types of antibiotics," says Jochen Schacht, professor of biological chemistry and otolaryngology. " Increasing levels of antibiotic-resistant infections associated with AIDS and a worldwide resurgence of tuberculosis, however, make it likely that their use will increase in the future.
"These drugs are a particularly serious problem in developing countries, especially China and Southeast Asia, where they are inexpensive and widely available without a prescription," Schacht adds.
The fact that aminoglycosides have toxic side-effects has been well-known since the 1940s, but only recentlythanks to 20 years of research by Schacht and colleagues at the U-M and other universitieshave scientists figured out how these drugs do thei r damage.
In 1995, Schacht and his colleagues discovered that gentamicin is not toxic until it combines with iron in the bloodstream and becomes "activated." As these gentamicin-iron molecules form, they trigger production of free radicalsunstable molecules that rip apart and damage cells. Thousands of tiny hair cells in the inner ear are especially vulnerable. Without functional hair cells, the inner ear is unable to detect sounds or transmit signals to auditory neurons leading to the brain. The result is irreversible hearing loss.
"The solution was to avoid the formation of free radicals by preventing the gentamicin from binding with iron in the first place," Schacht says. "That's when we decided to try using iron chelators to absorb the iron and keep it from combining with ge ntamicin."
In an article published in the July 1997 issue of the Journal of Pharmacology and Experimental Therapeutics, Schacht published the results of experiments showing that iron chelators did protect guinea pigs from gentamicin's ototoxic effects.
Equally important, the treatment did not compromise the therapeutic effects of gentamicin. Schacht found that iron chelators did not lower blood serum levels of gentamicin nor affect its ability to kill E. coli bacteria.
"We have the principle nailed down," Schacht says. "Now we must work with pharmaceutical firms to identify the most effective iron chelators and antioxidants available, determine a safe human dosage regimen, and then see if they will prevent hearing loss in people."
The research was funded by the National Institute on Deafness and Other Communication Disorders, National Institutes of Health. Co-investigators on the most recent experiment include Ben-Bo Song, research fellow, and David J. Anderson, professor of e lectrical and computer engineering. The experiments were conducted at the Kresge Hearing Research Institute.