Experimental treatments to prevent ototoxicity

Timothy C. Hain, MD. Please see our disclaimer.

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Summary: There is evidence that free radical generation plays an important role in auditory toxicity from aminoglycosides, cisplatin and noise. Agents that reduce free radical formation may be protective and manipulations that increase free-radicals are harmful to hearing. Also agents that inhibit programmed cell death (apoptosis), are thought to have some promise in preventing neuronal death, although they also have a propensity to promote tumors.

At this writing, there are exploratory studies done in animals which do show that these agents are protective, but the delivery method is often impractical and the risk/benefit profile of these agents in humans needs to be established. Practically, an agent needs to be sought that can be administered in humans with acceptably low toxicity. At the present writing, no such agent exists, but it is thought that delivery of an agent through the round window via a catheter may eventually prove the most practical method.

The following list of experimental treatments are listed alphabetically. The majority of this information is drawn from the 1998 and 2001 ARO (Association for Research in Otolaryngology) abstract books.

Aspirin. According to Sha and Schacht (1999), in guinea pigs, salicylate (related to aspirin), protected hearing during administration of gentamicin. COMMENT: This is exciting, and promising. Obviously, one would like to know whether this works for vestibulotoxicity, which is a much greater problem than hearing toxicity with gentamicin. Also, human data is needed.

Alpha-lipoic acid, an endogenous thiol compound, was shown to protect against cisplatin auditory toxicity in rats (Whitworth, Rybak and Samani, #532). Ginko Biloba extract was also shown to protect against cisplatin auditory toxicity in rats (Fukawa et al, #533, 1998).

Brain-derived neurotrophic factor (BDNF) reduces the ototoxic effect of gentamicin on guinea pig hair cells (Lopez et al, 1999). COMMENT: Practically, delivering BDNF to the ear of persons undergoing gentamicin treatment would be difficult. What would be most helpful would be an agent that can cause new hair cells to grow.

D-methionine, applied to the round window of chinchilla's, was shown to protect against cisplatin (Korver et al, #536 and #537, 1998). Clinical trials are underway with this agent as well as sodium thiosulfate and N-acetyl Cysteine (Blakely et al, 2002). These drugs probably work via free radical scavaging or drug conjugation

Glial derived neurotrophic factor (GDNF), delivered by a pump or gelfoam to the cochlea,  was reported to protect against gentamicin auditory otoxicity (Shoji et al, #538, 1998), and noise (Shogi et al, 539, Keithly et al, #540, 1998). Of course, these methods of administration are impractical clinically.

Iron: Conlon BJ and Smith DW reported in abstract 530 that iron exacerbates gentamicin ototoxicity to hearing in guinea pigs. Iron assists in the production of free radicals. Watanabe H and others reported in abstract 529 that desferoxamine, an iron chelator, reduced auditory toxicity of cisplatin (an antitumor agent which is ototoxic). Yamasoba, Schacht and Miller (abstract 531) observed that desferoximine protects incompletely against gentamicin, and also against noise induced hearing loss in guinea pigs.

Leupeptin (a calpain inhibitor -- calpain is one of a family of calcium activated proteases that are often active around the time of cell death) given to cochlear cultures protected against aminoglycoside toxicity (Salvi, #11, 2001).

The enzyme SOD (superoxide dismutase) is an oxidative scavenger that protects from free radicals. McFadden et al (#519, 1998) reported that knock-out mice for SOD1 developed cochlear damage. SOD is also involved with familial ALS.

 

REFERENCES:

Blakley BW, Cohen JI, Doolittle ND, Muldoon LL, Campbell KC, Dickey DT, Neuwelt EA. Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 2002 Nov;112(11):1997-2001

Lopez and others. : The protective effect of brain-derived neurotrophic factor after gentamicin ototoxicity.Am J Otol 1999 May;20(3):317-24

Sha SH, Schacht J. Salicylate attenuates gentamicin-induced ototoxicity. Lab Inivest 1999:79(7):807-13

#'s refer to Abstracts of the 21'st midwinter research meeting of the Association for Research in Otolarygology, Feb 15-19, 1998.