Aspirin Component Prevents Antibiotic-Induced Deafness

A clinical trial currently under way at a hospital in Xi'an, China, will determine whether aspirin is as effective in people as it is in guinea pigs, according to Jochen Schacht, Ph.D., a biochemist in the otolaryngology department of the U-M Medical School and a consultant on the clinical trial.

Discovered in the 1940s, aminoglycosides---which include streptomycin, gentamicin, neomycin and others---are the most widely used antibiotics in the world even though they are known to cause hearing loss and balance disorders in a significant percentage of individuals who take them.

"These drugs are a serious problem in rural areas of developing countries, especially China and Southeast Asia, where they are widely used because they are so effective and inexpensive," Schacht said. "All too frequently, they are the only affordable drugs available. Studies of deaf-mutism in southeastern China showed that two-thirds of the cases were caused by aminoglycosides."

In the United States and other industrialized countries, aminoglycosides are most often used to treat people with serious infections who have not responded to other antibiotics. "The increasing worldwide threat of antibiotic-resistant tuberculosis in the wake of AIDS, however, makes it likely that their use will increase in the future," Schacht added.

After years of research, Schacht and his colleagues reported in 1995 that gentamicin combines with iron in the body to 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.

In 1997, Schacht published the results of experiments showing that iron chelators---medications used to "soak up" excess iron in the bloodstream---protected guinea pigs from gentamicin's ototoxic effects. One of the chelators tested was 2,3-dihydroxybenzoate or DHB.

In an effort to develop a simple and clinically feasible way to prevent hair cell damage, Schacht and Su-Hua Sha, M.D., a research associate in the U-M Medical School, modified the experiment using a related compound called 2-hydroxybenzoate or salicylate. "Aspirin breaks down to salicylate in the body within 15 to 20 minutes," Schacht said.

In the current study, one group of guinea pigs received injections of gentamicin. Another group received gentamicin and salicylate. A control group received saline solution. All animals were given hearing tests before, during and after treatment. The quantity and physical condition of hair cells in the cochlea or inner ear of the animals were examined at the conclusion of the experiment.

Guinea pigs receiving gentamicin alone had profound hearing loss, up to 70 decibels at some wavelengths, and almost complete destruction of the outer hair cells in the cochlea. Animals receiving gentamicin and salicylate had minor hearing impairment of less than 20 decibels and minimal hair cell damage. The low salicylate doses used in the experiment had no effect on guinea pig auditory thresholds. Use of salicylate did not lower the blood serum levels of gentamicin, nor did it affect the antibiotic's ability to kill E. coli bacteria.

"Salicylate levels providing protection in guinea pigs fall into the lower range recommended for anti-inflammatory therapy in humans," Sha added. "The required serum levels could easily be achieved with moderate doses of aspirin."

The research was funded by the National Institute on Deafness & Other Communication Disorders, National Institutes of Health. The experiments were conducted at the U-M's Kresge Hearing Research Institute.