In the General Session of the 2014 Academy of Doctors of Audiology (ADA) Convention held last week in Las Vegas, Kathleen Campbell, PhD, of Southern Illinois University School of Medicine, gave an interesting and lively talk on ototoxicity and the role of pharmaceutical agents in hearing loss management and prevention.
Dr Campbell kicked off her presentation by providing an overview of her longstanding interest in ototoxicity and its many surprising sources, including ototoxic interactions between certain drugs. Even health supplements, which are not regulated, are not always safe for all people at all dosages . She provided the context for her discussion by reporting that hearing loss resulting from ototoxicity is so widespread that otoprotective agents are needed, and likely to become part of clinical practice in the near future.
Dr Campbell, the inventor of several patents for the use of D-methionine (D-met) as a protective agent, disclosed that she receives grant support from the National Institutes of Health and the US Department of Defense. The D-met patents are owned by the SIU School of Medicine, where Dr Campbell is Distinguished Scholar and Professor in the Department of Surgery, and the principal investigator on several funded projects.
When the cure causes harm. Campbell told ADA attendees that there is currently no drug that is FDA approved to prevent or treat hearing loss or tinnitus. A primary focus of her work has been to investigate otoprotective agents for potential use in cancer patients, who often sustain hearing loss during chemotherapy and/or radiation therapy with highly ototoxic drugs. Other patient populations of interest to Dr Campbell are those with cystic fibrosis or tuberculosis and other diseases that require intravenous antibiotics to treat infections, as those patients are also at risk for drug-induced hearing loss and vestibular (balance) problems.
According to Dr Campbell, she and her research teams completed Phase 2 of clinical trials for cisplatin-induced ototoxicity and radiation-induced oral mucositis—inflammation of oral mucosa resulting from ionizing radiation which can be exacerbated by cisplatin chemotherapy. Campbell and her group have received FDA approval and DoD funding for a Phase 3 clinical trial of the use of D-met to prevent noise-induced hearing loss in soldiers during weapons training. Data collection is in progress. They are in the planning stage for additional clinical trials of D-met to prevent aminoglycoside-induced and cisplatin-induced hearing loss.
How much oto-protection can D-met provide? Dr Campbell said that studies thus far show that D-met can provide almost complete protection from cisplatin-induced ototoxicity, while also reducing some other negative side effects of this chemo drug. D-met, the safer component of methionine that is well tolerated by most patients, has also demonstrated excellent protection from radiation-induced oral mucositis, and has shown evidence of providing excellent protection against aminoglycoside-induced hearing loss. In appropriate tumor models and dosing ratios, D-met shows no anti-tumor interference in cancer therapy.
“The idea is to develop a drug that protects normal cells, but not cancer cells,” said Dr Campbell. “I’d like to develop enzyme biomarkers to help determine appropriate doses for each individual, and have patients undergo blood testing as they enter treatment, during treatment and after.”
According to Dr Campbell, aminoglycosides can stay in the inner ear (cochlea) for up to 11 months after treatment, potentially increasing a patient’s risk of noise-induced hearing loss with noise exposure during that timeframe.
Noise as a toxin. During her presentation, Dr Campbell stated that in any discussion of ototoxicity and otoprotective agents, noise should also be viewed as an ototoxin. Her D-met studies have demonstrated that the drug provides excellent protection against noise-induced hearing loss (NIHL) when taken in advance of and during a known exposure to noise. D-met also provides some protection against NIHL when taken only a couple of days prior to noise exposure, and even when started up to 24 hours after noise exposure ends.
The ideal mode of delivery for D-met, according to Dr Campbell, is as an oral agent. While she and others have explored the possibility of delivering D-met directly through the round window of the ear (ie, oral vs injected D-met Otoprotection, Campbell et al 2003), Dr Campbell pointed out, to the amusement of the ADA audience, that this mode of delivery is not always practical.
Beyond D-methionine. Dr Campbell’s presentation also included a discussion of other pharmaceutical agents that are being investigated for their potential as otoprotective drugs. A few of these drugs are now in or are approaching approval for clinical trials. These include a trial of sodium thiosulfate (STS) with STS administration given 7 hours after cisplatin is in progress, two clinical trials of N-acetylcysteine (NAC) showed that the drug didn’t provide significant protection from noise-induced hearing loss, and the early phases of an ebselen clinical trial for temporary threshold shift showed dose-dependent partial protection.
Additional studies for clinical consideration. Dr Campbell concluded her presentation with details of her study methods and findings, and a forward-looking discussion of further studies that should be pursued. She highlighted the need for trials that examine D-met’s potential as a pharmaceutical agent that protects against additional types of hearing damage, and a range of other side effects as well.
For example, according to Dr Campbell, D-met can markedly protect against a CDDP-induced auditory brainstem response (ABR) threshold shift, OHC loss, and strial damage. It can partially protect against CDDP-induced weight loss, and may also provide protection against drug-induced hair loss (alopecia), and drug-related damage to the kidneys, nervous system, and GI system.
As she wrapped up, Dr Campbell provided some interesting side notes on NIHL and the otoprotective properties of certain nutrients, including the naturally-occurring form of D-met that can be found in many cheeses and yogurts. Her comments on the quantities of cheese a person would have to consume in order to achieve the desired levels of D-met required for oto-protection had the ADA audience in stitches, but her point was clear. In her comprehensive studies of ototoxins and otoprotective agents, Dr Campbell has found that even a person’s diet, coupled with certain hereditary factors, is worth exploring for potential protection against toxin-induced hearing loss.
Source: Kathleen Campbell, PhD, Southern Illinois University School of Medicine, ADA 2014 Convention