Noise-induced hearing loss is a key challenge in otolaryngology today. Interestingly, an older class of antiepileptic drugs, T-type calcium blockers, may hold promise as preventive agents.
In a recently published study, a transnational team of Chinese and US investigators found that mice that were given trimethadione (Tridione) or ethosuximide (Zarontin) and then exposed to loud noises had lower levels of permanent noise-induced hearing loss than did controls.1 The rationale for using these agents was that since calcium dysregulation is known to contribute to noise-induced hearing loss, calcium channel blockers may have preventive value.
In the study, the investigators divided the mice into three groups: a prevention group, which received the medications in drinking water prior to noise exposure; a treatment group, which received the medications after noise exposure; and controls, which received neither medication. The medications were delivered separately in the preventive and treatment groups.
Prevention and Treatment Benefits Documented
The investigators found that trimethadione had significant value as a preventive agent, as measured by auditory brainstem recording. Both agents reduced noise-induced hearing loss as treatments given after noise exposure. Interestingly, male mice showed a greater benefit than did female mice.
Treated mice had higher hair cell count and neuronal density and, therefore, the enhanced preservation of outer hair cells. The drugs were associated with a reduction of approximately five decibels in the permanent threshold shift that can occur after noise exposure. A five-decibel difference is sufficient to make a difference in whether a person can hear ordinary conversation, the investigators noted.
When the investigators conducted immunocytochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR) tests, the findings suggested that the drugs’ protective effects were linked to their action on alpha-1 subunits of calcium channel types in the cochlea. Therefore, the findings should be encouraging of clinical studies to test T-type calcium blockers to prevent and treat noise-induced hearing loss, they wrote.
Hearing Loss a Common Occupational Hazard
How would such a treatment work in people who are vulnerable to noise-induced hearing loss, such as military personnel and construction workers? In separate phone interviews with ENT Today, the study’s senior author and an expert in hearing loss commented on the study’s clinical implications.
“This study is the result of seeing whether drugs that were already approved by the Food and Drug Administration [FDA] had any potential to prevent or treat noise-induced hearing loss,” said senior author Jianxin Bao, PhD. “We found that antiepileptic drugs in this class may have some role, and therefore we tested trimethadione and ethosuximide.” Dr. Bao is a Research Associate Professor of Otolaryngology and head of the Central Institute for the Deaf’s Presbycuscis and Aging Laboratory at Washington University School of Medicine in St. Louis.
Dr. Bao noted that an agent that could prevent or treat hearing loss of this type would have tremendous benefit because so many people are exposed to loud noises in their workplace setting. However, although these two agents were effective in mice, the study’s findings really set the stage for further drug discovery, he stressed.
“These agents are no longer used in the treatment of epilepsy,” he said. “They’re older and are associated with significant adverse effects, such as sedation and dizziness.” Therefore, the quest may now focus on finding drugs with similar calcium channel blocking properties, but with fewer adverse effects, he said. “We want to find drugs with a similar mechanism of action, perhaps other antiepileptic drugs, but with more favorable adverse effect profiles, to see if they are effective against noise-induced hearing loss.”
“The value of studies like this is that they use agents that are already approved by the FDA for another indication,” said Charles Syms III, MD, Clinical Professor of Otology and Neurotology at the University of Texas at San Antonio, where he is also the president of Ear Medical Group. “Therefore, if they have promise for another indication, the clinical trial process could be simplified.”
Earplugs Not an Option in Combat
Dr. Syms agreed with Dr. Bao that there is a high demand for agents that can prevent and treat noise-induced hearing loss. “For soldiers in combat settings, using earplugs is not an option, unlike civilian settings, such as people who operate heavy machinery,” he said. “Soldiers need to be able to hear commands and otherwise respond quickly to the combat environment.”
The findings are sufficiently encouraging that investigators should continue searching for an appropriate therapy for noise-induced hearing loss, Dr. Syms said. “If the side effects can be moderated, such as with a lower dose or a more refined agent, it would be reasonable to conduct clinical trials and to put the research on the ‘fast track’ for this indication,” he said.
Dr. Syms also encouraged the research into other T-type calcium channel blockers. “We know that these two drugs work in an animal model, but we don’t know the exact mechanism,” he said. “Therefore, it would be reasonable to pursue other drugs in this class.” However, he cautioned that just because some drugs within a class have a given effect, it does not mean that all such drugs would.
- Shen H, Zhang B, Shin JH, et al. Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hearing Res 2007;226:52–60.
©2007 The Triological Society