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Experimental treatments to prevent ototoxicity

Timothy C. Hain, MD . Page last modified: September 18, 2010

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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.

Aspirin. According to Sha and Schacht (1999), in guinea pigs, salicylate (related to aspirin), protected hearing during administration of gentamicin. A recent paper in humans done in China also suggested that aspirin in a large dose (3 grams/day) protects against hearing loss from gentamicin (Chen et al, 2007). Van De Water (2003) also has suggested that aspirin protects against ototoxicity from cisplatin. COMMENT: This is interesting but it seems to us that one should remain very skeptical that an ototoxic compound (aspirin) should protect against ototoxicity. Obviously, one would like to know whether this works for vestibulotoxicity, which is a much greater problem than hearing toxicity from gentamicin. The paper of Chen et al (2007) is very dubious in as much as gentamicin does not cause hearing loss in the doses given in this paper. To summarize, we need more data here.

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.

Caffeic acid phenethyl ester (CAPE). Bakir and others (2012) found CAPE to be helpful in preventing streptomycin ototoxicity in rats (Bakir et al, 2012).

Calcium channel blockers. Although there is some data that these agents may reduce apoptosis (programmed cell death), nimodipine was not found to be effective in preventing Quinine toxicity in an animal model. (Ochi et al, 2003). Verapamil is protective in an animal model against kanamycin ototoxicity (Zhuravskii et al. 2002)

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.

Lactated ringers. Lactated ringers injected into the middle ear has been reported to protect guinea pigs from cisplatin ototoxicity (Choe et al, 2004). The relevance of this procedure to humans remains to be established.

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.

Steroids. In mice, dexamethasone injection protects against hearing loss from cisplatin (Hill et al, 2008). If a reasonable delivery system can be worked out in humans, this is a potential method of protecting from ototoxicity.

REFERENCES:

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

Copyright August 3, 2016 , Timothy C. Hain, M.D. All rights reserved. Last saved on August 3, 2016