RESEARCH: The Ototoxic Drug Dilemma: You Live, Hair Cells Die
BY ANDRA E. TALASKA AND JOCHEN SCHACHT, PH.D.
Searching the World Wide Web for "drug-induced hearing loss" or "ototoxicity" will yield several hundred thousand hits, providing a mix of useful and confusing facts. Anywhere between 100 and 1,000 medical drugs or chemical compounds are claimed to be ototoxic, that is, having the potential to damage hearing. Medications usually come with unwanted side effects; fortunately, most of these side effects rarely manifest themselves.
Side effects are not a necessary evil of modern pharmaceutics; they date back to the beginnings of medicine. Our earliest ancestors were surely aware of the ability of some herbal and mineral remedies to cure or kill. In the case of ototoxicity, the first recorded incidence can perhaps be ascribed to use of mercury vapors to exterminate head lice, as documented by Persian physician Avicenna (985-1037).
The modern recognition of ototoxicity as a potential problem was primarily associated with two medications: salicylate and the aminoglycoside antibiotics. Salicylate, in the form of willow bark, had a millennia-long history as a fever suppressant. After aspirin (acetyl salicylate) began to be widely used in the mid-1800s, it became apparent that tinnitus (ringing in the ears) and hearing loss were possible side effects of its use. Almost a century later, the aminoglycoside antibiotics were heralded as the long-sought cure for tuberculosis, only to find they caused permanent loss of hearing or balance in the first patients.
Aside from these, there are a thousand other ototoxic medications? It's not all that bad. Many such medications are of only historical interest, some are just anecdotally linked to ear damage, and others have exerted their toxicity through freak accidents such as the inadvertent ingestion of potassium bromate, an ingredient used in home hair permanents (see Table 1, p. 40). The compounds that do warrant our attention because of continued use and potentially permanent damage include some industrial solvents, which are of concern to specifi c working populations; chelating agents used in treatment of the blood disorder beta thalassemia; and anticancer drugs of the cisplatin type and the aminoglycoside antibiotics both important for a general patient population.
Let us, however, start with aspirin, arguably the world's most widely used medication. Most consumers will not even be aware of its possible actions on the cochlea, our auditory organ, as it generally requires rather high doses (around four grams per day, as taken against rheumatoid arthritis) to cause such problems. For unknown reasons, aspirin causes auditory sensations of tinnitus and elevated hearing threshold. Fortunately these are temporary symptoms and they subside when use of the drug is halted. No permanent auditory damage has ever been confirmed from aspirin intake, not even in people who attempted suicide by overdosing.
The Lesser of Two Evils
One might assume that, in the realm of modern medicine, we would discard an ototoxic drug in favor of a more perfect solution. In reality, there are many reasons that such drugs cannot be replaced. In most cases, the explanation is simply that there is no known "perfect solution" and the side effects must be accepted for the sake of resolving a more serious condition. That is the case for cisplatin and the related drug carboplatin: There are no other chemotherapy agents as effective against certain neoplasms in particular testicular and ovarian tumors, as well as many sarcomas and carcinomas. Cancer chemotherapy is notoriously riddled with serious side effects. Cancerous tissue has little that distinguishes it from normal human tissue and, hence, substances toxic to tumors also tend to be toxic to surrounding and systemic tissues.
The ototoxicity of cisplatin has long been recognized and has been replicated in tests performed on research animals. In addition to injuring the auditory system, cisplatin may cause kidney and nerve damage. Established clinical regimens and combination therapy with other agents can minimize kidney and nerve damage, particularly since the kidney can repair minor injuries to its cells. In contrast, the incidence of hearing loss remains very high although few will lose their hearing completely. The typical progression is an initial loss of high-frequency hearing in both ears, advancing to the lower range of speech frequencies with continued treatment. A high-frequency hearing loss might go unnoticed by the patient; therefore, it's important to monitor hearing during use of cisplatin. Interestingly, the hearing loss may occur gradually in some patients, or suddenly after a single dosing. Cisplatin ototoxicity almost exclusively affects the cochlea, while aminoglycosides can target both the cochlea and the vestibular (balance) system.
Drugs of Many Uses: Aminoglycoside Antibiotics
Aminoglycoside antibiotics (streptomycin, neomycin, gentamicin and others) were once widely used in the U.S. and elsewhere but are now only cautiously prescribed in industrialized nations. While economically advanced societies can afford alternative antibiotics against gram-negative bacteria, aminoglycosides are frequently the only accessible and affordable antibiotics in developing countries, and often procurable over the counter.
Just like cisplatin, aminoglycosides can be toxic to both the kidneys and ears, with the drugs' ototoxicity being of major concern because of the irreversibility of the ear damage. Ototoxicity will develop very slowly after days or weeks of treatment and may even progress after the end of drug administration. (A small number of individuals carrying a specifi c, maternally-inherited genetic mutation, however, can experience severe hearing loss after receiving only a single dose of an aminoglycoside.) Both ears are typically affected and the high auditory frequencies are lost fi rst, again requiring audiological monitoring for early detection. Since aminoglycosides also have potential to damage the vestibular system, balance may be disturbed, creating a nauseous feeling or unsteady gait. Why some aminoglycosides specifi cally damage the cochlea, some the vestibular system, and some both, remains an enigma. Given an incidence of noticeable auditory or vestibular damage of 10 to 20 percent, therapy with these drugs is saddled with a major problem.
Despite these limitations of use, even advanced healthcare has need of aminoglycosides to fi ght certain life-threatening infections. The World Health Organization also recommends the aminoglycoside streptomycin as part of the fi ve-drug regimen against multidrug-resistant tuberculosis, and aminoglycosides remain in use against other multidrug-resistant bacterial infections. Furthermore, tobramycin is the accepted therapy in cystic fi brosis patients to prevent the build-up of pseudomonas bacteria in their lungs.
Remarkably, these old drugs also perform new tricks. Recently it was discovered that aminoglycosides have the potential to abate certain genetic disorders. Diseases such as cystic fi brosis, Duchenne muscular dystrophy, Usher syndrome and Hurler syndrome are caused by genes with a mutation that generates premature stop signals. The result is truncated and non-functional cell proteins. Experiments in animals and preliminary trials in patients have shown that aminoglycoside therapy can override these stop signals, allowing for a small percentage of normal protein production, thereby alleviating the damage caused by these genetic diseases. If less ototoxic aminoglycosides were available, these drugs could hold promise for millions. As such, the quest for such "designer aminoglycosides" is well underway.
Death of a Hair Cell
The inner ear is a complex organ of sensory cells and supporting structures that work in concert to enable us to process auditory information. Ototoxins may affect any of the tissues but permanent damage is mostly caused by destruction of the "hair cells" (see Figure 1, p. 42). These sensory cells in the cochlea and vestibular organ are directly responsible for the conversion of mechanical energy from sound or movement into nerve impulses to the brain, giving us the sensations of hearing and balance. The catch is that our body is unable to regenerate auditory hair cells, thus leaving us with a permanent hearing loss when they are damaged. Vestibular hair cells have some ability to regenerate, though the repair may be slow and partial. Enabling effi cient regeneration of our sensory cells should resolve the problem of ototoxicity but, while research into regeneration has provided some tantalizing results, clinical application is likely decades away. The current approach to combating ototoxicity therefore must be prevention.
Fortunately, research has made considerable headway into an understanding of hair cell death and survival, culminating in recent clinical trials. Auditory and vestibular damage by aminoglycosides and cisplatin is marked by an accumulation of free radical compounds, or ROS (reactive oxygen species). ROS are the Jekyll and Hyde of cellular physiology. On the one hand, they are normal metabolic products needed in the function of the cell; on the other hand, they are chemically highly aggressive oxidants which have the potential to wreak havoc by modifying or destroying DNA, membranes or proteins. A healthy cell will maintain a balance, utilizing its own antioxidants in order to allow ROS to function without doing damage. Ototoxins shift this precarious balance and, following increases in the number of ROS, cells begin to die. Understanding this common scenario of "oxidative damage" has been highly helpful in designing protective strategies.
Fighting Ototoxicity with Caution and...More Drugs
Our fi rst line of defense against ototoxicity is cautious monitoring of drug dosing, serum levels and early signs of hearing loss.But even the most judicious use of cisplatin and aminoglycosides carries a potential risk. Here is where an understanding of the process of cell damage can guide the design of a pharmacological intervention. Since ROS accumulation is a pivotal step leading to cochlear and vestibular damage, an obvious approach would be to help the cell to regain or maintain its oxidant/antioxidant balance. Counteracting ototoxic drug treatment with antioxidant supplements has successfully limited loss of hearing and balance in animal trials and is clinically proven and effective in limiting other cases of ROS damage. While not all antioxidants will be useful against hearing loss, several compounds have emerged as promising therapeutics since they are either already approved drugs or are available as food supplements. These agents include resveratrol (of red wine fame), vitamin E (alpha-tocopherol) and d-methionine. Animal experimentation with these compounds has indeed been so successful that several clinical trials have expounded on them and shown intriguing results for both cisplatin and aminoglycosides.
Recent preliminary data from a clinical study suggests that cisplatin ototoxicity can be abated by d-methionine in humans. Although the observed protection was small, it pointed in the right direction and has encouraged further exploration. Even more astounding was the result of a clinical trial in which aspirin was used to alleviate the side effects of aminoglycosides. The study, published in the New England Journal of Medicine in 2006, showed a protective effect of salicylate against gentamicin-induced hearing loss. The incidence of hearing loss was reduced by an impressive 75 percent (13 percent of those receiving a placebo were affected, whereas only three percent of those concurrently taking aspirin were affected). Help, it seems, is on the way.
What's Next?
We may assume that pharmacological intervention to abate ototoxicity will become a clinical reality, but there will be other approaches to the problem as well. Basic research is working on several fronts. Gene therapy, whereby specifi c genes are introduced into the inner ear in order to augment cellular antioxidant proteins, has been carried out in animals. Regeneration of hair cells or generation of new hair cells from stem cells is in its infancy, but not without encouraging early results. Finally, novel antibiotics are on the horizon with similar antibacterial properties as aminoglycosides,
but devoid of their problematic side effects. Some patients today must sadly choose to sacrifi ce inner ear hair cells for their greater good but research holds promise that tomorrow's patients can save their lives and keep their hearing too.
Learn more about ototoxins by logging on to www.hearinghealthmag.com to read "Hearing Preservation on the Horizon" in the Winter 2009 archives.
Andra E. Talaska received her B.S. in biological chemistry from the University of Michigan, writing her thesis on the protective action of herbal medications on drug-induced hearing loss. She joined the Biochemistry and Molecular Biology Laboratory at the Kresge Hearing Research Institute in 2003. Her collaborations with Jochen Schacht, Ph.D., have focused on the molecular mechanisms of drug-induced, noise-induced and age-related hearing loss. Jochen Schacht, Ph.D., has been researching the intricacies of the inner ear since 1972 and is a leading expert in research on acquired hearing loss. He obtained his Ph.D. in biochemistry from the University of Heidelberg, Germany, and now is professor of Biological Chemistry in Otolaryngology and director of the Kresge Hearing Research Institute at the University of Michigan. His laboratory investigates mechanisms of hearing loss induced by noise, drugs and age and has recently completed a successful clinical trial to alleviate ototoxicity. Schacht's research on aminoglycoside-induced hearing loss is supported by a grant from the National Institute for Deafness and Other Communication Disorders, National Institutes of Health. Visit his lab online at www.khri.med.umich.edu/research/schacht_lab or e-mail: schacht@umich.edu.
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