Dec. 18, 2003 BUFFALO, N.Y. -- Six hundred Marines at Camp Pendleton in California will undergo two weeks of war games in the coming months armed with a new weapon: a drug designed to protect their hearing from the destructive decibels of battle.
For the Marines, it's an opportunity to take part in the fight against noise-induced hearing loss in the military and in society in general.
For researchers at the University at Buffalo's Center for Hearing and Deafness, it's a chance to put to the ultimate test a drug they studied for more than eight years in the laboratory and tested successfully in animals.
The drug to be tested is N-acetylcystine, or NAC, an antioxidant compound approved by the FDA in a different form for loosening mucus in airways or breathing tubes and for treating liver damage from overuse of acetaminophen. Bringing it to the clinical trial stage for use against noise-induced hearing loss involved a series of studies begun in 1995 and a collaboration between UB scientists and military physicians.
Donald H. Henderson, Ph.D., professor of communicable disorders and sciences, and Bo Hua Hu, M.D., research scientist, both from the Center for Hearing and Deafness (CHD), did the basic research, while Richard Kopke, M.D., and Michael Hoeffer, M.D., physicians at the U.S. Naval Medical Center in San Diego, handled the clinical aspects. The patent, which is held by UB and the U.S. Navy, is the first on a drug to prevent noise-induced hearing loss.
Noise-induced hearing loss is one of the most common and devastating occupational injuries in industrialized societies, affecting about 10 million people in the U.S. alone. The villain is oxidative stress, damage caused by too many free oxygen molecules, or free radicals. These rogue molecules kill the delicate hair cells of the inner ear, which convert energy from sound waves into electrical impulses that carry audio stimuli to the brain's hearing center. As hair cells die, hearing diminishes.
Henderson began working with Kopke to investigate ways to make hair cells resistant to oxidative stress when Kopke was a fellow at Albert Einstein College of Medicine. Earlier research conducted separately at the CHD and the Karolinska Institute in Stockholm had shown that exposing animals to low levels of noise for one to 10 days made their ears significantly more resistant to damage from toxic noise: The low-level noise doses appeared to "inoculate" the animals against hearing loss.
Kopke and Henderson then set out to determine why the ear became more damage-resistant with so-called prophylactic exposure by studying the biochemical changes in the ear. They discovered, to their surprise, that repeated non-toxic noise exposure increased the levels of free-radical-destroying antioxidants in the inner ear in much the same way that inoculation with weakened disease-causing organisms primes the body's immune system to produce more disease-fighting cells.
The researchers next worked on producing the same protective effect pharmacologically. They applied several known antioxidant compounds directly to the animals' inner ears and exposed them to toxic continuous noise designed to mimic gunfire. As hoped, the antioxidant drugs kept inner-hair-cell damage to a minimum.
"Those experiments proved our point," said Henderson, "but the results weren't applicable clinically. You can't inject drugs into the inner ears of humans."
Would the drugs still protect the ear if taken internally, was the next question? To find out, Henderson and Hu injected the known antioxidant NAC, already approved for human use, into the study animals' abdomens, and performed the toxic noise test. The answer was "yes:" Delivering the drug systemically was very effective in preventing hearing loss.
Enter American Biohealth Group, LLC, which acquired the license to develop the drug into an easily useable form. That work made possible the upcoming clinical trial using dissolvable NAC. Marines will swallow a glass-full of a drink containing NAC at every meal during the war games. Their hearing tests will be compared with fellow Marines who didn't receive the drug. Results of the clinical trial are expected in Spring 2004. Henderson is a consultant on the clinical trial, headed by Kopke, and is involved in its planning.
Meanwhile, Henderson and center researchers are forging ahead with research on another class of compounds called SRC-inhibitors.
"NAC has promise," said Henderson, "but SRC-inhibitors are even more promising for noise-induced hearing loss. What is equally exciting, other drugs we are interested in may stop the progression of age-related hearing loss as well."
SRC-inhibitors play a direct role in preventing cell death. The center researchers are testing a specific SRC-inhibitor developed by David Hangauer, Ph.D., associate professor of medicinal chemistry in UB's College of Arts and Sciences, who is investigating the compound's potential as an anti-cancer drug. Henderson is collaborating on research into its possibilities for preventing hearing loss with Thomas Nicotera, M.D., research professor at Roswell Park Cancer Institute, who has expertise in the action of free radicals on cell death.
SRC-inhibitors block the early stages of one kind of cell death, which, if allowed to progress, releases an explosion of free radicals, Henderson noted. By preventing free-radical formation, this mode of action allows for a much smaller dose of the drug than is required with NAC, he said.
"To protect inner-ear hair cells through antioxidant activity, you need one molecule of antioxidant for every free-radical molecule, so if you have 50 million free radicals you need a substantial amount of the drug," he said. "To prevent formation of free radicals, you need about 1/500th of that amount.
"Learning how cells die in the inner ear has opened up new opportunities for prevention and treatment," Henderson said. "The three main causes of hearing loss -- noise, ototoxic drugs and aging -- appear to involve the common factor of oxidative stress, either through increased free radical formation or reduced antioxidant availability.
"Loss of hearing is the second most common health problem of the elderly," Henderson noted. "Previous studies of age-related hearing loss showed that treatment with antioxidants may prevent or decrease the deafness that often comes with increasing years. If our work at UB can help decrease hearing loss from both noise and aging, we will have made great strides toward our goal of defeating this disabling condition."
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