Since ancient times, drugs have played out their parts as the good and the bad, for curing and for killing. Such was pronounced in Homer’s Odyssey “… where earth the grain-giver yields herbs in greatest plenty, many that are healing in the cup, and many baneful.” With a swallow of poison hemlock, Socrates was his own executioner, while his contemporaries were medicating their ails with myrrh, black hellebore and opium poppies. But the lines between help and harm are not always so clear. As a case in point, arsenic was administered to patients in the early 20th century for its ability to kill syphilis, which was running rampant. In the end, however, arsenic therapy caused more death and morbidity than it did good.
We rarely hesitate to use a drug for fear of its adverse side effects. The unwelcome side effects of many beneficial drugs, spelled out in the fine print on the package, manifest themselves in only a small percentage of patients. Nonetheless, as a drug distributes to all the tissues in our bodies, its potential side effects may impact all our faculties, including our senses which can be temporarily or permanently compromised. Cholorquine and hydrochloroquine as treatment for rheumatoid arthritis or malaria can damage vision. Many diuretics, including acetazolamide, ethacrynic acid, chlorthalidone and furosemide, cause unpleasant distortion or loss of taste in some patients, while various lipid-lowering drugs can exact the same effects on the sense of smell. Still others may experience hypoesthesia, or diminished sense of touch (tactile, heat or pain), after using the antimalarial drug mefloquine and after an epidural for pain management. Our senses of hearing and balance likewise are vulnerable to the adverse effects of certain drugs.
Ears Under Attack
Though not a new phenomenon, “ototoxicity” (toxicity to the inner ear) as a side effect of a therapeutic drug has received little attention in history as any detriment caused by remedy was a willingly paid and largely ignored price of a cure. One of the earliest records of hearing loss due to the ototoxic capacity of mercury vapors (used to eliminate head lice) is ascribed to the Persian physician Abu Ali al-Hussein Ibn Abdallah Ibn Sina (better known as Avicenna) who lived in 985 to 1037. Hearing loss induced by quinine (a commonly used antimalarial agent) and salicylates (as in aspirin) were documented in the 19th century.
Ototoxicity was catapulted into clinical and public awareness in the 1940s with the advent of streptomycin, a long-sought therapy for tuberculosis. Today, the list of known ototoxins (see table) ranges broadly from chelating agents like deferoxamine administered to patients suffering from elevated iron blood levels, to industrial solvents and chemicals like toluene and carbon monoxide. Additionally, anti-inflammatory drugs, antimalarials, loop diuretics, cancer treatment drugs and many antimicrobial agents have been found to be ototoxic. In fact, roughly 200 over-the-counter and prescription drugs are known to be ototoxic in one way or another.
Before mass pandemonium ensues, it should be mentioned that many of these drugs are rarely used or are monitored closely to limit their side effects. Moreover, a good portion of them also will only cause a temporary impairment of the auditory sense without lasting consequences and aspirin is the most prominent example of such a drug. Taken in too large amounts, patients may experience ringing in the ears and elevation of their hearing threshold, two effects that will completely subside when aspirin ingestion is stopped.
Target: Hair Cells
The intrinsic toxic potential of some drugs in conjunction with the complexity of our inner ear is responsible for the varying consequences from temporary to permanent loss of hearing or balance. Whether a drug action is reversible or permanent, for example, may largely depend on the target of its attack. When inner ear hair cells are attacked, damage tends to be permanent (see figure). Hair cells are the key players in the cochlea, transducing incoming sound into nerve signals that are sent to the brain. Unfortunately, they are very sensitive to damage and most importantly, unable to recover or regenerate once destroyed. We should note, however, that in contrast to the auditory organ, mammalian vestibular hair cells have some capacity to regenerate and, therefore, detriments to the vestibular system may diminish over time.
Damage to some of the supporting structures in the cochlea can cause transient side effects. For example, spiral ganglion neurons, which send auditory signals as electrical impulses to the brain for processing, have more of a capacity to regenerate than do delicate hair cells.
Wolves in Sheep’s Clothing
The drugs in use today that pose the greatest threat of permanent damage to our hearing and balance belong to two therapeutic classes, aminoglycoside antibiotics and platinum-based anticancer agents – drugs whose benefits are as of yet irreplaceable despite the persistence of their serious ototoxicity. Cisplatin, which was introduced clinically in the 1970s, is valued for its efficacy against cancerous tumors whereas aminoglycosides (including streptomycin, neomycin, gentamicin and kanamycin) are highly effective broad-spectrum antibiotics. While a large number of people continue to be affected by their ototoxic detriments, it is important to emphasize that the loss of hearing induced by these drugs does not necessarily mean complete deafness but includes all shades of a measurable decrease in hearing acuity.
In the case of cisplatin and related therapeutics, there is hardly any choice when it comes to specific forms of cancer, such as testicular and ovarian cancers and clinicians will do anything in their power to control and minimize the ototoxic side effects. Nevertheless, 25 percent or more of patients may suffer hearing loss after cisplatin cancer chemotherapy, with children being even more susceptible.
The other major ototoxins, aminoglycoside antibiotics, are being used for two primary reasons. First, they are indispensable to combat some intractable bacteria such as Pseudomonas or the tubercle bacillus. Second, they are very inexpensive to produce and thus the drugs of choice in many developing countries where they may be available largely over the counter. The incidence of hearing loss varies widely, depending on clinical care and monitoring drug levels and side effects, and may range from eight percent under controlled hospital conditions to over 60 percent in loosely monitored use. In fact, unchecked use of these antibiotics was responsible for two-thirds of deaf-mutism in Southeastern China in the 1980s and 1990s, according to surveys of the schools for the Deaf.
In an effort to make the benefits of these drugs available without caveat, intense study has been dedicated to limiting ototoxicity and to developing “otoprotectants” that counteract the ototoxins. The first step in such an endeavor is understanding the complex biochemical and molecular mechanisms that underlie the toxic drug actions so that we can interfere with the very specific changes in the inner ear that lead to hearing loss. The good news is that through scientific research we better understand the ways in which many of these drugs exact their nefarious side effects and, potentially, how to counteract these side effects.
Death of a Hair Cell
Research during the last decade has established reactive oxygen species, or free radicals, as being at the heart of much drug-induced ototoxicity. Free radicals are part of normal cell physiology and always present at low levels in our cells. They are chemically highly reactive and disruptive molecules normally counterbalanced by antioxidants and antioxidant enzymes that help to contain and remove them quickly. When the balance between free radical production and antioxidants is tipped in favor of free radicals, they initiate uncontrolled chain reactions of destruction leading to compromised cell functions and eventually to cell death.
Researchers have observed several ways in which the inner ear responds to free radicals after application of aminoglycosides and cisplatin. Cell death can occur in many ways but the organized fashion with which hair cells are forced out and replaced by supporting cells suggests a prevalence of a controlled and orderly process known as apoptosis. However, a cell does not give up easily and its first response will always be self-defense before succumbing to the onslaught of a drug. Part of understanding ototoxicity is, therefore, also understanding the mechanisms the inner ear employs in an attempt to restore equilibrium and prevent permanent damage. A common example of the way in which cells try to deal with free radicals is an increase in production of detoxifying enzymes, such as superoxide dismutase. Knowledge of both how cells die and how they protect themselves can then aid in discovering treatment to alleviate ototoxicity.
Help Is on the Way
The recent advances in the understanding of ototoxicity and the role of free radicals in cell death have led to the development of rational and successful protective therapies. Small synthetic molecules designed to inhibit one of the many steps in the death cascade have proven effective in protecting hair cells from apoptosis in cell or organ culture. Such laboratory evidence, however, is only the first step to designing a clinically applicable therapy, an end that is likely years or decades away.
Perhaps more important from an immediate clinical perspective, the harmful effects of both aminoglycosides and cisplatin can be mitigated with antioxidants. This type of intervention would act directly on free radicals, upstream of the ensuing cell death pathways, suppressing toxic mechanisms at the very onset. Antioxidant therapy is well-established in clinical practice. Further, some of the compounds effective in animal models are already widely available as medications, over-the-counter drugs or nutritional supplements, like D-methionine, thiosulfate, vitamin E or salicylate. Salicylate, intriguingly, is the active ingredient of aspirin, suggesting a surprisingly simple preventive therapy. In fact, the first clinical trial to protect against aminoglycoside-induced hearing loss was just recently successfully completed in collaboration between our laboratory and colleagues at the Otolaryngology Department of the Fourth Military Medical University in Xi’an, China. Patients were given aspirin to protect them from ototoxic damage or a placebo along with their prescribed dose of gentamicin. The incidence of hearing loss was reduced from 13 percent in the group receiving a placebo to three percent in the aspirin group, an impressive 75 percent reduction in risk of ototoxicity.
It has taken more than half a century to unravel the intricacies of aminoglycoside ototoxicity and over a quarter century for cisplatin. The effort, however, has earned very promising progress in protecting the inner ear from ototoxic drugs. This practical application of research results, whereby an understanding of the molecular mechanisms has led to preventive clinical intervention, is a testimony to the critical importance of basic research. Alleviating ototoxic side effects will have a major impact on the use of the many drugs whose therapeutic efficacy remains unquestioned.
