If clinical trials show that iron chelators work as well in humans as they do in guinea pigs, the U-M 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 antibiotics called aminoglycosides.
Discovered in the 1940s, these antibiotics---which include streptomycin, gentamicin, neomycin and others---are the most widely used antibiotics in the world. Because they are so effective and rarely produce allergic reactions, physicians continue to prescribe 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," said Jochen Schacht, a professor of biological chemistry and otolaryngology in the U-M Medical School. "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 added. "Mothers take children with upper respiratory infections to their local pharmacy for an injection. As a result, studies of deaf-mutism in southeastern China showed that two-thirds of the cases were caused by aminoglycosides."
The fact that aminoglycosides have toxic side-effects has been well-known since the 1940s, but only recently---thanks to 20 years of research by Schacht and colleagues at the U-M and other universities---have scientists figured out how these drugs do their 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 radicals---unstable 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 said. "That's when we decided to try using iron chelators to absorb the iron and keep it from combining with gentamicin."
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. In this study, one group of guinea pigs received gentamicin by injection. In addition to gentamicin, another group of animals also received injections of two iron chelators---deferoxamine (DFO) and 2,3-dihydroxybenzoate (DHB). One group of animals also received the antioxidant mannitol. All animals received hearing tests before, during and after treatment. The quantity and physical condition of hair cells in the cochlea or inner ear of all animals were examined in tests conducted at the experiment's conclusion.
While the guinea pigs receiving gentamicin alone experienced significant hearing loss with complete loss of hair cells in certain areas of the cochlea, animals receiving some combination of iron chelators and antioxidant therapy did much better. "The most striking result was achieved with co-injection of gentamicin with DHB and mannitol," Schacht reported. "This regimen yielded complete protection at all measured frequencies in all animals."
Equally important, the treatment did not compromise the therapeutic effects of gentamicin. Schacht found that iron chelators and mannitol did not lower blood serum levels of gentamicin nor affect its ability to kill E. coli bacteria.
"We have the principle nailed down," Schacht said. "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."
Since iron chelators and antioxidants are already approved for clinical use, Schacht said human clinical trials could start "tomorrow." He added that he already has laboratories in China and Thailand, where the problem is most prevalent, which have agreed to conduct the trials, if Schacht can obtain funding.
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, U-M research fellow, and David J. Anderson, U-M professor of electrical and computer engineering. The experiments were conducted at the U-M's Kresge Hearing Research Institute.
EDITORS: A copy of the U-M paper published in the 1997 Journal of Pharmacology and Experimental Therapeutics is available on request.