In the next decade—possibly sooner—new pharmacologic therapies will be developed that will allow audiologists to work with physicians and patients in selecting pharmacologic agents that can be used to prevent or ameliorate a variety of types of hearing loss and possibly tinnitus.
could be given prior to noise exposure that could cause injury to the ear to prevent hearing loss or after injury to restore function before the hearing loss, tinnitus, or perhaps vestibular injury becomes permanent. Preventative and restorative agents are not designed to reverse longstanding permanent hearing loss, which requires regeneration rather than rescue. For example, cochlear hair cell regeneration is the focus of investigation with some interesting results, but this therapy probably will not be approved by the U.S. Food and Drug Administration within the next decade because of complicated issues surrounding treatment safety and efficacy (for more on this topic, see the feature on hair cell regeneration in the May 5 issue).
|Kathleen Campbell and Robert Meech examine a cochlear sample that has been exposed to an aminoglycoside.
It is not surprising that pharmacologic agents could ameliorate hearing loss that results from various cochlear insults. Researchers have known for many years that oxidative stress and inflammatory processes in the cochlea probably trigger noise-, cisplatin-, and aminoglycoside-induced hearing losses. Although different mechanisms underlie these various types of stressors, commonalities exist including free radical formation and alterations in the body's antioxidant pathways (Wang, Puel, & Bobbin, 2007). Researchers also know that these same mechanisms contribute to age-related hearing loss, although the aging individual probably has been exposed to many types of damage-inducing mechanisms.
The Role of Diet
It is also not surprising that many of the pharmacologic agents being investigated for the prevention of hearing loss and tinnitus derive from foods, many of which may be considered "nutraceuticals." Audiologists who have worked with the military or industry have observed the wide variability in the incidence and degree of hearing loss among workers with similar noise exposures. Although researchers don't fully understand the reasons for the underlying variability, both genetics and nutrition may play a role. Genetics and nutrition also may interact to activate or deactivate certain genes that may play a role in a number of diseases including cancer and diabetes.
Researchers already know that diet, stress, and genetics alter susceptibility to drug- or noise-induced hearing loss (NIHL) (Campbell & Rybak, 1996; Seidman & Moneysmith, 2007). In recent news, audiologists have heard that obesity and high-fat diets increase the risk of hearing loss, although it has been known that high-fat diets increase the risk of hearing loss since the 1960s (see review by Campbell & Rybak, 1996). In addition, stress may play a role because high stress alters biochemical status. For example, studies in the 1970s demonstrated that subjects who enjoyed loud music experienced less hearing loss than those who did not.
Further, foods with high antioxidant content may improve health and reduce risk for a wide variety of diseases. In the future, workers may have genetic testing to determine if they are predisposed to hearing loss from noise or exposure to cisplatin or aminoglycoside. Co-exposure to ototoxic agents such as solvents, heavy metals, and tobacco smoke may act in synergy with noise to cause hearing loss (Morata, 1999).
Already, some individuals are being tested for the A1555G mitochondrial mutation prior to the administration of aminoglycoside antibiotics because of concern that this mutation greatly increases the risk of aminoglycoside-induced hearing loss (Schacht, 2007). An increasing number of health care professionals will be counseling patients with exposure to noise or ototoxins about dietary modifications that may help preserve hearing health.
Antioxidants and Anti-inflammatories
Beyond dietary modifications, the next logical step is to administer concentrated amounts of antioxidant or anti-inflammatory compounds, many of which are found in foods—although not in adequate doses to offset noise and ototoxin exposures. The next action is to introduce other drugs not found in foods, but with a good safety profile, to prevent or rescue hearing loss.
Many otoprotective agents are being studied, not because they hold promise for clinical treatment of hearing loss, but because they elucidate the underlying mechanisms of noise- or ototoxin-induced hearing loss. For example, some drugs may not be safe when given systemically or may have toxicities that preclude clinical use, but provide insight in animal studies that may help us develop other useful therapies.
The U.S. Food and Drug Administration (FDA) has not approved drugs for the prevention or treatment of NIHL. Some drugs that have received FDA approval for other uses are being tested for prevention of hearing loss and tinnitus, but may not be safe and effective for this purpose. Audiologists and patients should understand that drugs that are FDA-approved, available over the counter, or found in a health food store are not necessarily safe. For example, cisplatin is a highly toxic chemotherapy drug that received FDA approval because its benefits outweigh the risk (Rybak, Huang, & Campbell, 2007). Many drugs, nutraceutricals, and supplements may not be safe for a particular patient. Even herbals and foods may interact with other medications or may not be advisable for a certain disease or genetic state. Under current law, the content and labeling of bottles of supplements and herbals are not regulated by the FDA for safety and efficacy (Seidman & Moneysmith, 2007).
Promising Pharmacologic Agents
Several pharmacologic agents in or approaching clinical trials appear promising to address several hearing health problems. The following is an overview.
Prevention of NIHL
Development of agents to prevent NIHL is progressing rapidly. These agents are being developed for clinical trials with relatively healthy populations with no concern for interfering with the efficacy of a drug treatment. Consequently, these agents may be less expensive and quicker to bring to market; many are found in the diet in small amounts and are being studied in concentrated dosages.
D-methionine (D-met), a compound under development in my lab, is found in fermented proteins such as cheese and yogurt. Because it has been studied as a part of normal nutrition in humans and other species, much is known about its safety (Campbell & Rybak, 2007). In our animal studies, we have found that D-met can prevent permanent NIHL when it is given before and after noise exposures for the noise exposures we have used to date (Campbell et al., 2007). We can start the administration of D-met up to five hours after the cessation of a six-hour noise exposure and still obtain significant protection from a permanent hearing threshold shift and outer hair cell loss. Some studies also report protection from temporary threshold shift, but others do not.
An additional advantage is that D-met can be administered orally; the commercially prepared orange-flavored preparation we are using (MRX-1024) is stable at 40 degrees celsius for at least 18 months, which is an important issue for military populations. We are now in planning for clinical trials in the military to determine how effectively D-met works in humans.
The positive results with D-met in animal studies are promising—but there is no guarantee that otoprotection will occur in human trials. This information was illustrated in a military study several years ago at the Camp Pendleton Marine Corps base near San Diego, Calif., with N-acetylcysteine (NAC), which is marketed as "The Hearing Pill." NAC reportedly did not provide statistically significant protection of hearing thresholds in the military population in this study, the data and results of which were never published in a peer-reviewed journal (Kopke, 2005). Yet, NAC provided partial protection from NIHL and outer hair cell loss in animals. NAC may be more effective at higher doses, but higher doses reportedly are toxic. Other human studies have also shown no effective threshold protection of NAC in noise-exposed humans (Kramer et al., 2006).
Several other promising agents are in various stages of development. I serve as the audiology monitor for a multicenter clinical trial, funded by the National Institutes of Health, that is investigating a combination of beta carotene (the precursor for vitamin A), vitamin C, vitamin E, and magnesium. Commonly referred to as ACE Mg, this combination was developed at the Kresge Hearing Research Institute at the University of Michigan in Anne Arbor (Le Prell, Hughes, & Miller, 2007). The safety profile of ACE Mg is well known because it is similar to a combination used to prevent the progression of macular degeneration. D-met appears to work primarily as an antioxidant; the ACE vitamins probably work primarily as antioxidants and the magnesium (Mg) probably works as a vasodilator. Noise not only produces oxidative stress in the cochlea, but it also constricts the vasculature of the stria vascularis. Surprisingly, the combination ACE and Mg work much better than would be predicted by the administration of ACE or Mg alone. The reason for that synergy is unclear. Our clinical trials with this compound will determine whether it works as well in humans as it does in animals.
Several other compounds also may hold promise for the protection of NIHL. Ebselen, which contains selenium, works by mimicking one of the enzymes in the glutathione pathway, a major detoxification system in the body. In animals, ebselen must be administered for several days prior to noise exposure but provides significant, although incomplete, protection. L-carnitine (ALCAR), another well-known antioxidant, also has shown good protection against NIHL (Campbell & Rybak, 2007). Resveratrol, a compound found in red wine, may have a number of health benefits, including protection from NIHL, when delivered at high dosages (the equivalent of more than 1,000 bottles of wine a day); it is clear that more concentrated forms of resveratrol are needed. The safety profile of high-dose resveratrol is under investigation.
High doses of aspirin have shown some protection against NIHL in animals; however, the gastrointestinal safety of high-dose of aspirin over an extended period of time is questionable, and the military is not interested in otoprotectants that could exacerbate bleeding on the battlefield. Further, aspirin can reduce or exacerbate NIHL, depending on the particular dosage. Nonetheless, the mechanisms of all these compounds are interesting and help us understand the pathology underlying NIHL. In the future various combinations of agents or otoprotective "cocktails" may allow us to provide optimal protection with minimal side effects.
Protection From Cisplatin-Induced Ototoxicity
Over the last two decades, a number of investigations have focused on putative otoprotective agents for cisplatin, a plantinum-based chemotherapy drug used to treat various cancers (Rybak et al., 2007; Campbell & Rybak, 2007). The primary challenge is to identify a pharmacologic agent that protects the ear as well as other normal tissues without offering protection to tumor cells. Sodium thiosulfate (STS), for example, initially looked promising in animal experiments but was then found to deactivate the cisplatin, reducing its tumor-destroying effects. STS is now being investigated in patients receiving carboplatin to treat brain cancer. In this clinical trial protocol, patients' blood-brain barrier is pharmacologically disrupted so that carboplatin can pass through and reach the brain tumor to destroy cancer cells; hours after the blood-brain barrier closes again, STS is administered to try to protect the ear (Neuwelt et al., 2006).
Another agent, amifostine (Ethyol) is FDA-approved to reduce cisplatin-induced kidney damage, but amifostine has severe side effects and doesn't appear to prevent hearing loss (Hensley et al., 2009). Similarly, other agents that initially showed promise had other side effects or did not provide otoprotection (e.g., diethyldithiocarbamate [DDTC]; glutathione and glutathione ester; fosfomycin; and salicylate [aspirin]). Some agents (e.g., transplatin, lipoic acid, ebselen) of interest need to be fully tested for potential anti-tumor interference in cancers treated with cisplatin. In addition, because many cancer patients who receive cisplatin chemotherapy also receive radiation, it is important that the protective agent not interfere with the efficacy of radiation in killing tumors. For example, NAC reduces cisplatin-induced hearing loss in animal studies yet protects tumor cells from radiation treatment (Vuyyuri et al., 2008); one study, however, suggests that NAC does not interfere with cisplatin's ability to kill tumors in the absence of radiation.
D-met protects against cisplatin-induced hearing loss without interfering with the anti-tumor action of either cisplatin or radiation (Campbell et al., 1996; Gillette-Cloven et al., 2000; Vuyyuri et al., 2008). Although our animal studies with cisplatin were first published in 1996, we are just now preparing our first FDA Phase II human studies of protection from cisplatin-induced hearing loss and radiation-induced oral mucositis for publication and have FDA approval for additional clinicial trials. The drug development process can be long but it must be painstakingly careful to ensure the safety and efficacy of patient treatments. Only the results of the FDA-approved clinical trials will tell us whether or not we have an agent that can significantly help patients.
Protection Against Aminoglycoside-induced Ototoxicity
Progress is being made in protective agents for ototoxicity induced by aminoglycosides, a family of antibiotics, although these agents are not being pursued as actively as those for hearing loss resulting from noise and cisplatin. Biochemist Jochen Schacht at the Kresge Hearing Research Institute at the University of Michigan conducted clinical trials in China using high doses of aspirin in patients receiving aminoglycosides and obtained modest but significant otoprotection. Aminoglycoside-induced hearing loss is a serious problem in rural China and Southeast Asia, where these effective and inexpensive antibiotics are widely used. The results of the clinical trial are encouraging, but high-dose aspirin can have side effects and cannot be used in children, so other otoprotective agents are needed.
Research is underway to investigate other possible agents, including lipoic acid, caspase inhibitors, neurotrophins, and iron chelators; however, these provide only minimal otoprotection or have other side effects and safety issues. In animal studies, we have obtained significant otoprotection with D-met without antimicrobial interference (Campbell et al., 2007). The otoprotection by D-met against aminoglycoside ototoxicity is not as complete as that for noise or cisplatin, but we are working on various dosing regimens to optimize hearing protection.
Optimally a pharmacologic protective agent without significant side effects is needed that can protect against cisplatin-induced hearing loss and other side effects such as kidney, gastrointestinal, and neural damage without shielding tumor cells from cisplatin or radiation treatments. In addition, patients may receive various combinations of noise exposures, cisplatin and radiation treatment, and aminoglycosides, so an agent is needed that can reduce the ototoxicity of all of these cochlear insults with no therapeutic interference.
Additionally, an agent that can be delivered by mouth safely and effectively would ease clinical administration and acceptance. Thus far, D-met appears to meet all these criteria. However, only the results of randomized, placebo-controlled, peer-reviewed, and in most cases, FDA-approved clinical trials of D-met and other putative protective agents will demonstrate which pharmacologic agents should be used to prevent hearing loss. We hope that a number of agents will be found to be effective so that patients will have choices. We have not yet reached our goal—but we are getting close.