Abstract
Objective: This review will summarise the current state of development of pharmaceutical interventions (prevention or treatment) for medication-induced ototoxicity.
Design: Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise the current state of the science. Details on the stage of development in the market pipeline are provided, along with evidence for clinical safety and efficacy reported.
Study sample: This review includes reports from 44 articles and clinical trial reports regarding agents in clinical or preclinical trials, having reached approved Investigational New Drug status with the Federal Drug Administration.
Results: Vitamins and antioxidants are the most common agents currently evaluated for drug-induced ototoxicity intervention by targeting the oxidative stress pathway that leads to cochlear cell death and hearing loss. However, other strategies, including steroid treatment and reduction of ototoxic properties of the primary drugs, are discussed.
Conclusions: Retention of hearing during and after a life threatening illness is a major quality-of-life issue for patients receiving ototoxic drugs and their families. The agents discussed herein, while not mature enough at this point, offer great promise towards that goal. This review will provide a knowledge base for hearing providers to inquiries about such options from patients and interdisciplinary care teams alike.
Introduction
The term “ototoxic” can be used to refer to any source of non-mechanical damage to the ear, including several medications, many solvents, some heavy metals, and possibly select asphyxiants (Johnson and Morata Citation2010) yet ototoxicity is most often used in the context of clinical, medication-induced hearing loss or vestibular dysfunction. The field of pharmaceutical interventions for noise-induced hearing loss (NIHL), a condition which is also largely a result of toxic metabolic cochlear changes, is worthy of its own review. As such, and coupled with the paucity of research into any treatment modalities for other ototoxic injuries, this review focuses on the current state of the science for preventing or treating ototoxicity as most often seen in the clinical setting: induced by medications. While physicians are ultimately responsible for pharmaceutical treatment decisions, this review aims to inform the audiologist as an interdisciplinary partner and trusted provider in patient care.
The two most common types of ototoxic drugs are (1) cancer-fighting agents, namely platinum-based chemotherapy drugs such as cisplatin and carboplatin, and (2) intravenously administered antibiotics, including aminoglycosides and the glycopeptide vancomycin (reported to exacerbate aminoglycoside-induced ototoxicity). For detailed evidence of the ototoxic properties of these agents, see reviews by Campbell et al. (Citation2003), and Campbell and Fox (Citation2016). A basic summary of the ototoxic mechanisms of action theorised to cause hearing impairments and vestibular dysfunction is provided below (also see reviews in Campbell Citation2007).
Apoptosis, or cell death, is an essential process for the health of all aerobic forms of life (beings with cell respiration reliant upon oxygen). It removes aged or damaged cells, often to clear the way for new development. In the human inner ear, the latter is unfortunately not the case, as mammals cannot regenerate cochlear tissue. Reactive oxygen species (ROS) often serve as the catalyst for the apoptotic pathway. At the inter-cellular level, mitochondria most often create ROS as a by-product of electron transfer. However, various oxidative stressors can trigger the production of excessive ROS, and can produce a type of ROS called free radicals which have an unpaired electron. To return to homeostasis, the free radical will take an electron from surrounding molecules which, in excess, can damage vital cell membrane lipids and proteins by “stealing” their electron. This triggers cell death through either the extrinsic death receptor pathway or the intrinsic mitochondrial pathway (for more detail see Wang and Puel Citation2008 or Jin and El-Deiry Citation2005).
Glutathione (GSH) is a potent natural intracellular antioxidant, an ROS scavenger, an anti-apoptotic agent, and has been shown to protect the cochlea from noise and ototoxic damage (Kopke et al. Citation1997, Citation1999; Yamasoba et al. Citation1998); GSH is one of the auditory system’s strongest inherent defence mechanisms and a common target for intervention approaches. While GSH and other intrinsic defences normally keep the apoptotic process in balance and protect against pathologic ROS over-production, this intrinsic system can become overwhelmed during excessive ROS production secondary to a toxic exposure. If ROS production exceeds inherent or supplemented antioxidant detoxification capabilities and triggers intra-cochlear cell death pathways, cell death can occur, reducing auditory and/or vestibular functionality. Given the hypothesis that most ototoxic agents initiate damaging oxidative stress, approaches for the prevention of ototoxicity-induced auditory sensory loss include targets all along the cell death cascade. These targets include: prevention of ROS initiation; neutralising the damage inflicted by ROS-created free radicals, most notably to the cell membrane lipids; or blocking the subsequent triggers of intrinsic or extrinsic apoptosis prior to cell death (Huang et al. Citation2000).
Protective interventions for each ototoxin are considered with the unique mechanisms of ototoxic action of the drug in mind, taking care not to decrease the therapeutic efficacy of the drug for its intended, often life-saving, purpose. Interventions found to limit the ototoxin’s therapeutic efficacy or further potentiate ototoxic effects cannot be considered (Oishi, Kendall, and Schacht Citation2014).
Common ototoxic medications
Cisplatin is one of the most effective tools against many solid tumour cancer types (Stewart Citation1999; de Castria et al. Citation2013). Unfortunately, like most chemotherapeutic agents, cisplatin has a high incidence of side effects, including ototoxicity that can be seen in nearly all patients treated with higher-dose regimens (Rybak et al. Citation2007). The cochlea sustains damage to the outer and inner hair cells as well as supporting spiral ganglion and stria vascularis cells (Campbell and Fox Citation2016). The primary mechanism of action in each of these areas is thought to be the production of inter-cellular ROS, which can trigger the metabolic apoptotic pathway (Rybak et al. Citation2007; Jamesdaniel, Rathinam, and Neumann Citation2016). Therefore, antioxidant approaches have been widely attempted to prevent apoptosis at the formative stage of ROS development (thus preventing all downstream processes in the cell death cascade) with the ultimate aim to prevent hearing loss.
Aminoglycosides (most commonly tobramycin, gentamicin, amikacin, and kanamycin) are a class of antibiotics approved for treatment of potentially life-threatening infections, especially those caused by gram-negative bacteria, including bacterial endocarditis, peritonitis, and line sepsis (Gilbert Citation2005). While nephrotoxic side effects are generally reversible, severe ototoxic damage most often is not, which can lead to permanent hearing loss, vestibular dysfunction, or both (Lerner et al. Citation1986).
Design and study sample
Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise the current state of the science using compiled search terms developed with the assistance of a medical librarian to include any clinical trials to prevent or treat drug-induced ototoxicity with a chemical agent (). Of the 1343 articles returned on PubMed, 34 articles were determined to be pharmaceutical interventions (prevention or treatment) for drug-induced ototoxicity. Similarly, the ClinicalTrials.gov disease/condition search was for “hearing loss” with “ototoxic OR ototoxicity” added and searched with other advanced search criteria left open to all options. Of the 18 trials returned in the search, 10 were added to the 34 PubMed articles for evaluation and discussion. Details on the stage of development in the market pipeline are summarised below as available, as are the targeted mechanisms of action and evidence for clinical safety and efficacy reported.
Table 1. List of search terms developed with the assistance of a medical librarian to extract and review any clinical trials to prevent or treat drug-induced ototoxicity with a chemical agent in currently published literature.
Table 2. Summary of agents investigated for prevention or treatment of medication-induced ototoxicity in clinical trials to date (in bold font), including other pertinent pre-clinical targets for ototoxic damage (not in bold font).
Agents in or approved for clinical investigations to mitigate medication-induced ototoxicity (see )
Antioxidants and vitamins
Vitamins with magnesium
To date, animal work using vitamins A (specifically, beta carotene, the precursor to vitamin A), C, and E, combined with magnesium (ACE Mg) for otoprotection seems promising (Le Prell, Hughes, and Miller Citation2007). Clinical trials have only occurred for NIHL where results have not demonstrated efficacy (Le Prell et al. Citation2011; Kil et al. Citation2017), but pre-clinical work suggests that this combination may reduce aminoglycoside-induced ototoxicity (Le Prell et al. Citation2014). This combination cannot be safely used in smokers because beta carotene may increase the risk of lung cancer (Omenn Citation1998, Citation2007) and may be problematic in individuals with gastric disorders because of the Mg content. Thus, even if successful in clinical trials, ACE Mg may be contraindicated in several patient populations. However, a 2016 study by Villani et al. suggests that vitamin E alone may provide protection against cisplatin-induced ototoxicity. More research is needed to confirm these preliminary findings and better understand the effects of antioxidant vitamins on the auditory system.
Ebselen (SPI-1005)
Either as a single agent (Rybak et al. Citation2000) or in combination with allopurinol (Lynch et al. Citation2005a, Citation2005b), the anti-inflammatory, anti-oxidant, GSH-mimic ebselen demonstrated some pre-clinical efficacy in reducing cisplatin-induced ototoxicity. Conversely, Lorito et al. (Citation2011) did not find significant cisplatin otoprotection with ebselen, so results are inconsistent. Ebselen was shown to prevent free radical stresses in cochlear explants, thus preventing the ROS damage and subsequent apoptotic death typically seen as a result of cisplatin treatment (Kim et al. Citation2009). Guinea pig studies have also demonstrated ebselen protection from gentamicin-induced ototoxicity, suggesting that protection may extend across multiple ototoxic agents (Takumida, Popa, and Anniko Citation1999).
Two clinical trials to evaluate ebselen for ototoxicity protection are approaching recruitment and enrolment: a phase II study targeting platinum chemotherapy ototoxicity treatment (Kil Citation2016a), and a phase I/II study for the prevention and treatment of aminoglycoside-induced ototoxicity (Kil Citation2016b). Lynch and Kil (Citation2009) previously published a phase I safety study that demonstrated a good safety profile for ebselen in an NIHL population.
N-acetylcysteine (NAC)
Bock et al. first reported in 1983 that N-acetylcysteine (NAC), a glutathione precursor, exacerbated aminoglycoside-induced hearing loss in the guinea pig model. NAC investigations conducted since then have demonstrated protection from aminoglycoside-induced ototoxicity in several human studies (Kocyigit Citation2011; Tokgoz et al. Citation2011). A systematic review with meta-analysis performed by Kranzer and colleagues (Kranzer et al. Citation2015) summarised the evidence for the safety and otoprotective effect of NAC when co-administered with aminoglycosides and did support otoprotective effects, but with side effects of abdominal pain, nausea, vomiting, diarrhoea, and arthralgia increased 1.4–2.2 times. The authors noted that further well-controlled clinical trials are needed. Transtympanic NAC has provided mixed results in two clinical trials to reduce cisplatin-induced ototoxicity: Yoo et al. (Citation2014) found no statistically significant otoprotection, while Riga et al. (Citation2013) reported statistically significant protection only for 8000 Hz using the patient’s opposite ear as a control.
d-methionine (d-met)
Thus far, d-methionine (d-met) has been in clinical trials for noise-induced and cisplatin-induced hearing loss and radiation-induced oral mucositis. A phase I study was published showing a favourable safety profile (Hamstra et al. Citation2010). However, pre-clinical work has also demonstrated efficacy in protection from aminoglycoside-induced ototoxicity, where d-met protected against gentamicin-induced (Sha and Schacht Citation2000), amikacin-induced (Campbell et al. Citation2007), tobramycin-induced (Fox et al. Citation2016), and kanamycin-induced (Campbell et al. Citation2016) hearing loss without antimicrobial interference either in vitro or in vivo (Sha and Schacht Citation2000; Fox et al. Citation2016). Multiple pre-clinical studies have demonstrated d-met protection from cisplatin- and carboplatin-induced hearing loss (Campbell et al. Citation1996, Citation1999, Citation2007; Lockwood et al. Citation2000) as well as in one unpublished clinical trial (Campbell et al. Citation2009).
Cloven et al. (Citation2000) also showed no antitumor interference for cisplatin treatment from d-met. Nonetheless, to avoid risk of antitumor interference, d-met can be applied directly to the round window as a potential otoprotectant (Korver et al. Citation2002), although this application technique precludes possible protection of other systems such as the kidney or neural system.
Coenzyme Q10
Coenzyme Q10 is currently being tested in a clinical trial at the University of Antwerp in Belgium to determine its effects on tinnitus characteristics in patients with chronic tinnitus (Rabau Citation2015). Two pre-clinical studies have suggested that this antioxidant may also have efficacy in ameliorating drug-induced ototoxicity. Fetoni et al. (Citation2012) demonstrated that Q-ter, a soluble formulation of coenzyme Q10, significantly reduced gentamicin-induced auditory evoked response threshold shift and prevented cochlear outer hair cell loss in albino guinea pigs. Astolfi et al. (Citation2016) reported that a solution of coenzyme Q10 terclatrate and Acuval 400, a multivitamin supplement containing antioxidant agents and minerals (Acu-Qter), prevented cisplatin-induced threshold shifts in rats. Thus, this agent may have potential to prevent or treat several auditory disorders.
Alpha-lipoic acid
The antioxidant alpha-lipoic acid was first reported as a protective agent for aminoglycoside-induced ototoxicity by Conlon et al. (Citation1999). Later reports confirmed otoprotection from cisplatin-induced (Rybak, Whitworth, and Somani Citation1999a, Citation1999b) and carboplatin-induced (Husain et al. Citation2005) hearing loss in pre-clinical studies. There is one completed clinical trial listed on ClinicialTrials.gov for protection against cisplatin (Martin Citation2014). To date, no clinical trial results for alpha-lipoic acid and otototoxicity have been published.
Sodium thiosulphate (STS)
For decades the powerful antioxidant sodium thiosulphate (STS; a common antidote to cyanide poisoning) has also shown efficacy to protect against cisplatin-induced ototoxicity (Otto et al. Citation1988; Neuwelt et al. Citation1996). Yet, STS may diminish the cancer fighting properties of the chemotherapy as a cisplatin neutraliser (Jones, Basinger, and Holscher Citation1991; Church et al. Citation1995). Several strategies have been employed in an attempt to use STS to reduce cisplatin-induced ototoxicity without reducing antitumor efficacy. Because STS is typically administered parenterally, injected into the blood stream either by intravenous or intra-arterial administration, and because it has been shown to markedly interfere with cisplatin treatment efficacy, one clinical trial is currently investigating the efficacy of a local STS application via trans-tympanic injections of a STS-hyaluronate gel prior to cisplatin treatments to prevent cisplatin-induced ototoxicity in head and neck cancer patients (Meyer Citation2016). Another approach has been to delay the STS administration by several hours after the cisplatin administration in an attempt to allow tumour kill to first occur prior to administration for the later occurrence of ototoxicity (Muldoon et al. Citation2000; Harned et al. Citation2008). A phase III study which investigated the effects of STS on cisplatin-induced hearing loss in a paediatric population did report a significant reduction in cisplatin-induced hearing loss but reduced both overall survival and event-free (morbidity- or complication-free) survival in children with metastatic disease (Freyer Citation2008). For children with localised disease, event-free survival and overall survival were reduced, but not significantly. Interestingly, STS has been tested for protection from NIHL (Pouyatos et al. Citation2007) and gentamicin-induced hearing loss (Hochman et al. Citation2006) and did not provide protection for either purpose in those studies.
Ginkgo biloba
With a well-established safety profile and known antioxidant properties (Le Bars and Kastelan Citation2000; McKenna, Jones, and Hughes Citation2001), ginkgo biloba has been examined for prevention of hearing loss in animal model experiments and human trials (Fukaya and Kanno Citation1999; Huang, Whitworth, and Rybak Citation2007; Dias Citation2010; Cakil et al. Citation2012; Finkler et al. Citation2012; Dias et al. Citation2015; Ma et al. Citation2015). However, results from these studies have shown weak evidence of efficacy to date. Coupled with results from Miman et al. (Citation2002) that ginkgo biloba may actually potentiate aminoglycoside-induced ototoxicity, further controlled trials are warranted before it can be considered as a viable over-the-counter recommendation.
Other approaches
Amifostine
Multiple clinical trials have been conducted using amifostine, a potent free-radical scavenger, to prevent cisplatin-induced ototoxicity but they have not demonstrated significant protection or reduction of cisplatin-induced hearing loss, including conducting a meta-analysis across multiple clinical trials (Duval and Daniel Citation2012). Currently, amifostine is not recommended for either otoprotection or neuroprotection by the American Society of Clinical Oncology 2008 Clinical Practice Guideline Update Use of Chemotherapy and Radiation Therapy Protectants (Hensley et al. Citation2009). The efficacy of amifostine is included in one active clinical trial as a secondary endpoint on ClinicalTrials.gov without results available (Mason Citation1999).
Steroids
Steroids are commonly used for the treatment of several inner ear diseases and injuries. Dexamethasone and methylprednisolone, with known anti-ROS activity including the ability to increase inherent cochlear ROS defences, have been explored in animal models as protective agents to reduce cisplatin-induced ototoxicity. These steroids have successfully demonstrated potential therapeutic benefits through both histological and functional measures, though intra-tympanic delivery seemed to deliver better results than systemic administration (Waissbluth et al. Citation2013; Özel et al. Citation2016; Sun et al. Citation2016). Only one human study (phase IV) was found in which 34 patients were recruited to receive 0.7 ml of dexamethasone phosphate, 10 mg/ml, injected unilaterally to the middle ear to prevent ototoxicity (Marshak et al. Citation2014). While only 15 participants completed the trial due to morbidity or change in chemotherapy regimen, there was a statistically significant protective effect on hearing. Specifically, less hearing loss and outer hair cell dysfunction were observed in the treated group compared to controls at 6000 Hz in pure tone audiometric results and distortion-product otoacoustic emissions (DPOAE) f2 range results in the 4000–8000 Hz range, respectively (Marshak Citation2015). While additional studies have been conducted in NIHL, further controlled trials are needed across steroids, delivery methods, and patient populations for ototoxicity.
Pantoprazole
An ongoing clinical trial at the Children's Hospital of Philadelphia is investigating Pantoprazole, a proton pump inhibitor (PPI; Balis Citation2016). No results are currently published, but bench research has suggested that pantoprazole may sensitise tumour cells to cisplatin treatment, perhaps reducing the amount of cisplatin required for treatment (Luciani et al. Citation2004; Huang et al. Citation2013). Therefore, one method of reducing ototoxicity may be by reducing the level of the ototoxin while retaining efficacy, rather than directly modifying the mechanism of ototoxic action.
Salicylate
Salicylate has been studied in animal models for both NIHL treatment (Yamashita et al. Citation2005; Coleman et al. Citation2010) as well as ototoxicity prevention (Sha and Schacht Citation1999; see review in Rybak et al. Citation2007), yet it is also well known for causing ototoxicity (see Stypulkowski’s review and mechanisms of action paper for more information, Stypulkowski Citation1990). Two clinical trials have been conducted to determine if the right combination of “enough, but not too much” can be determined to produce an ototoxicity protection strategy against gentamicin (Sha, Qiu, and Schacht Citation2006; Chen et al. Citation2007). These studies did show significant reduction in hearing loss in the treatment groups, no negative impacts to gentamicin therapy, but notable gastric side effects (gastric bleeding), which is a known risk factor for aspirin treatment paradigms (Sha, Qiu, and Schacht Citation2006). Additionally, a phase II study of the efficacy of salicylate in reduction of cisplatin-induced ototoxicity did not yield oto-protective results, although it was well tolerated (Crabb et al. Citation2017). As such, use of salicylate requires more research to determine the safety profile and optimised dosing for each ototoxic insult.
Discussion and conclusions
The number of agents in or approaching clinical trials for protecting against drug-induced ototoxicity is encouraging. The food and drug administration (FDA) drug approval process is necessarily careful, expensive, and arduous. However, promising pre-clinical and clinical trials suggest one or more effective otoprotective agents will receive FDA approval for clinical use in the not-too-distant future. Moreover, many of the current test agents have shown protection against both chemotherapy- and aminoglycoside-induced hearing loss in pre-clinical studies, some with data demonstrating full retention of therapeutic efficacy.
Drug development pipelines for the prevention or treatment of medicine-induced ototoxic hearing loss must be considered in relation to several important factors, including: (a) the primary condition for which the patient is being treated; (b) the interactions ototoxicity-mediating drugs may have on those conditions and/or treatments; (c) population characteristics (e.g. age or sex); (d) delivery methods required to reach full efficacy potential for the proposed mechanism of action; (e) risk-benefit trade-offs for efficacious dosing schedules and patient tolerance, and (f) FDA requirements for approval. For the latter, it is important to understand the differences between an exempt (e.g. nutraceutical agents available at health food stores) versus over-the-counter versus prescription-only designation, what that means to patients and their interdisciplinary care teams, as well as the sort of education and communication about those products that may need to be addressed.
Retention of hearing during and after a life-threatening illness is a major quality of life issue for patients receiving ototoxic drugs and their families. Communication impediment during and after a major lifetime stressor (like illness) can delay progress of treatment and recovery. The goal of patient care is always to extend life duration but also to retain full life capabilities and enjoyment. Certainly hearing is a major factor of the latter, and the agents discussed herein, while not mature enough at this point, offer great promise towards that goal.
| Abbreviations | ||
| ACE Mg | = | vitamin A (beta carotene), C and E combined with magnesium |
| Acu-Qter | = | coenzyme Q10 terclatrate and Acuval 400 |
| D-met, D-methionine | = | DPOAE, Distortion Product Otoacoustic Emission |
| FDA | = | Food and Drug Administration |
| GSH | = | Glutathione |
| NAC | = | N-acetylcysteine |
| PPI | = | proton pump inhibitor |
| Q-ter | = | soluble formulation of coenzyme Q10 |
| ROS | = | reactive oxygen species |
| SPI-1005 | = | ebselen |
| STS | = | sodium thiosulphate |
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The authors would like to thank the special issue editorial committee for inviting this article into the “Ototoxicity: Special Topics in Clinical Monitoring” collection. Additionally, the support and encouragement of the DOD Hearing Center of Excellence (HCE) and the HCE Pharmaceutical Interventions for Hearing Loss (PIHL) Working Group which brought this edition about. Finally, the authors would like to acknowledge and thank Melanie Halford for her copy-editing support and Mrs. Nicole Larionova for her support with the literature search.
Disclosure statement
The authors have no financial interests to disclose. Dr. Campbell’s previous financial interest in d-methionine has since dissolved.
References
- Astolfi, L., E. Simoni, F. Valente, S. Ghiselli, S. Hatzopoulos, M. Chicca, and A. Martini. 2016. “Coenzyme Q10 Plus Multivitamin Treatment Prevents Cisplatin Ototoxicity in Rats.” PLoS One 11 (9): e0162106. doi:10.1371/journal.pone.0162106.
- Balis, F.M. 2016. Pilot Study to Prevent Nephrotoxicity of High-dose Methotrexate by Prolonging the Infusion Duration and Prevent Nephrotoxicity and Ototoxicity of Cisplatin with Pantoprazole in Children, Adolescents and Young Adults with Osteosarcoma. https://clinicaltrials.gov (Identification No. NCT01848457).
- Bock, G.R., G.K. Yates, J.J. Miller, P. Moorjani. 1983. “Effects of N-acetylcysteine on Kanamycin Ototoxicity in the Guinea Pig.” Hearing Research 9 (3): 255–262. doi:10.1016/0378-5955(83)90030-8.
- Cakil, B., F.S. Basar, S. Atmaca, S.K. Cengel, A. Tekat, Y. Tanyeri. 2012. “The Protective Effect of Ginkgo Biloba Extract Against Experimental Cisplatin Ototoxicity: Animal Research Using Distortion Product Otoacoustic Emissions.” Journal of Laryngology & Otology 126 (11): 1097–1101. doi:10.1017/S0022215112002046.
- Campbell, K.C.M., ed. Pharmacology and Ototoxicity for Audiologists. Clifton Park, NY: Thompson Delmar Learning.
- Campbell, K.C.M., and D. Fox. 2016. “Cisplatin-Induced Hearing Loss in Translational Research.” In Audiology, Neurotology, and the Hearing Sciences, edited by Le Prell, Lobarinas, Popper, Fay, 141–164. Springer, Cham: Springer Publishers.
- Campbell, K.C.M., E. Kelly, N. Targovnik, L. Hughes, C. Van Saders, A.B. Gottlieb, M.B. Dorr, and A. Leighton. 2003. “Audiologic Monitoring for Potential Ototoxicity in a Phase I Clinical Trial of a New Glycopeptide Antibiotic.” Journal of the American Academy of Audiology 14 (3): 157–168; quiz 170–171. doi:10.3109/14992027.2010.540722.
- Campbell, K.C.M., S.M. Martin, R.P. Meech, T.L. Hargrove, S.J. Verhulst, and D.J. Fox. 2016. “D-methionine (D-met) Significantly Reduces Kanamycin-Induced Ototoxicity in Pigmented Guinea Pigs.” International Journal of Audiology 55 (5): 273–278. doi:10.3109/14992027.2016.1143980.
- Campbell, K.C.M., R.P. Meech, J.J. Klemens, M.T. Gerberi, S.S.W. Dyrstad, D.L. Larsen, D.L. Mitchell, et al. 2007.” Prevention of Noise- and Drug-induced Hearing Loss with D-Methionine.” Hearing Research 226 (1–2): 92–103. doi:10.1016/j.heares.2006.11.012.
- Campbell, K.C.M., R.P. Meech, L.P. Rybak, L.F. Hughes. 1999. “D-Methionine Protects Against Cisplatin Damage to the Stria Vascularis.” Hearing Research 138 (1–2): 13–28. doi:10.1016/S0378-5955(99)00142-2.
- Campbell, K.C.M., R. Nayar, S. Borgonha, L.F. Hughes, A. Rehemtulla, B. Ross, and P. Sunkara. 2009. “Oral D-methionine (MRX-1024) Significantly Protects Against Cisplatin-Induced Hearing Loss: A Phase II Study in Humans.” Abstracts of the Association for Research in Otolaryngology, 32: 7.
- Campbell, K.C.M., L.P. Rybak, R.P. Meech, and L. Hughes. 1996. “D-Methionine Provides Excellent Protection from Cisplatin Ototoxicity in the Rat.” Hearing Research 102 (1–2): 90–98. doi:10.1016/S0378-5955(96)00152-9.
- Chen, Y., W.G. Huang, D.J. Zha, J.H. Qiu, J.L. Wang, S.H. Sha, and J. Schacht. 2007. “Aspirin Attenuates Gentamicin Ototoxicity: from the Laboratory to the Clinic.” Hearing Research 226 (1–2): 178–182. doi:10.1016/j.heares.2006.05.008.
- Church, M.W., J.A. Kaltenbach, B.W. Blakley, D.L. Burgio. 1995. “The Comparative Effects of Sodium Thiosulfate, Diethyldithiocarbamate, Fosfomycin and WR-2721 on Ameliorating Cisplatin-Induced Ototoxicity.” Hearing Research 86 (1–2): 195–203. doi:10.1016/0378-5955(95)00066-D.
- Cloven, N.G., A. Re, M.T. McHale, R.A. Burger, P.J. DiSaia, G.S. Rose, K.C. Campbell, and H. Fan. 2000. “Evaluation of D-methionine as a Cytoprotectant in Cisplatin Treatment of an Animal Model for Ovarian Cancer.” Anticancer Research 20 (6B): 4205–4209. doi:10.1016/j.phrs.2008.01.001.
- Coleman, J., X. Huang, J. Liu, R. Kopke, and R. Jackson. 2010. “Dosing Study on the Effectiveness of Salicylate/N-Acetylcysteine for Prevention of Noise-Induced Hearing Loss.” Noise & Health 12 (48): 159.
- Conlon, B.J., J.M. Aran, J.P. Erre, and D.W. Smith. 1999. “Attenuation of Aminoglycoside-Induced Cochlear Damage with the Metabolic Antioxidant Alpha-Lipoic Acid.” Hearing Research 128 (1–2): 40–44. doi:10.1016/S0378-5955(98)00195-6.
- Crabb, S.J., K. Martin, J. Abab, I. Ratcliffe, R. Thornton, B. Lineton, M. Ellis, et al. 2017. “COAST (Cisplatin Ototoxicity Attenuated by Aspirin Trial): A Phase II Double-Blind, Randomized Controlled Trial to Establish if Aspirin Reduces Cisplatin Induced Hearing-Loss.” European Journal of Cancer 87: 75–83. doi:10.1016/j.ejca.2017.09.033.
- de Castria, T.B., E.M. da Silva, A.F. Gois, and R. Riera. 2013. “Cisplatin Versus Carboplatin in Combination with Third‐Generation Drugs for Advanced Non‐small Cell Lung Cancer.” Cochrane Library 16 (8): CD009256. doi:10.1002/14651858.CD009256.pub2.
- Dias, M.A. 2010. The protective effect of Ginkgo biloba extract on cisplatin-induced ototoxicity in humans. https://clinicaltrials.gov (Identification No. NCT01139281).
- Dias, M.A., A.L. Sampaio, A.R. Venosa, A. Meneses Ede, and C.A. Oliveira. 2015. “The Chemopreventive Effect of Ginkgo Biloba Extract 761 Against Cisplatin Ototoxicity: A Pilot Study.” International Tinnitus Journal 19 (2): 12–19. doi:10.5935/0946-5448.20150003.
- Duval, M., and S.J. Daniel. 2012. “Meta-Analysis of the Efficacy of Amifostine in the Prevention of Cisplatin Ototoxicity.” Journal of Otolaryngology – Head & Neck Surgery 41 (5): 309–315.
- Fetoni, A.R., S.L. Eramo, R. Rolesi, D. Troiani, and G. Paludetti. 2012. “Antioxidant Treatment with Coenzyme Q-ter in Prevention of Gentamycin Ototoxicity in An Animal Model.” Acta Otorhinolaryngologica Italica 32 (2): 103–110.
- Finkler, A.D., A. Ferreira da Silveira, G. Munaro, and C.D. Zanrosso. 2012. “Otoprotection in Guinea Pigs Exposed to Pesticides and Ginkgo Biloba.” Brazilian Journal of Otorhinolaryngology 78 (3): 122–128. doi:10.1590/S1808-86942012000300020.
- Fox, D.J., M.D. Cooper, C.A. Speil, M.H. Roberts, S.C. Yanik, R.P. Meech, T.L. Hargrove, S.J. Verhulst, L.P. Rybak, and K.C. Campbell. 2016. “D-Methionine Reduces Tobramycin-Induced Ototoxicity Without Antimicrobial Interference in Animal Models.” Journal of Cystic Fibrosis 15 (4): 518–530. doi:10.1016/j.jcf.2015.06.005.
- Freyer, D.R. 2008. Sodium Thiosulfate in Preventing Hearing Loss in Young Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor, Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or Other Malignancy. https://clinicaltrials.gov (Identification No. NCT00716976).
- Freyer, D.R., L. Chen, M.D. Krailo, K. Knight, D. Villaluna, B. Bliss, B.H. Pollock, et al. 2017. “Effects of Sodium Thiosulfate Versus Observation on Development of Cisplatin-Induced Hearing Loss in Children with Cancer (ACCL0431): A Multicentre, Randomised, Controlled, Open-Label, Phase 3 Trial.” Lancet Oncology 18 (1): 63–74. doi:10.1016/S1470-2045(16)30625-8.
- Fukaya, H., and H. Kanno. 1999. “Experimental Studies of the Protective Effect of Ginkgo Biloba Extract (GBE) on Cisplatin-Induced Toxicity in Rats.” Nihon Jibiinkoka Gakkai Kaiho 102 (7): 907–917. [Japanese]. doi:10.3950/jibiinkoka.102.907.
- Gilbert, D. 2005. “Aminoglycosides.” In Principles and Practice of Infectious Diseases: Sixth Edition, edited by Mandell, Bennett, Dolin, 328–356. New York: Churchill Livingstone.
- Hamstra, D.A., A. Eisbruch, M.U. Naidu, G.V. Ramana, P. Sunkara, K.C. Campbell, B.D. Ross, and A. Rehemtulla. 2010. “Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy With or Without Cisplatinum for Head and Neck Cancer.” Clinical Cancer Research 16 (9): 266–276. doi:10.1158/1078-0432.CCR-09-3318.
- Harned, T.M., O. Kalous, A. Neuwelt, J. Loera, L. Ji, P. Iovine, R. Sposto, E.A. Neuwelt, and C.P. Reynolds. 2008.” Sodium Thiosulfate Administered Six Hours After Cisplatin Does Not Compromise Antineuroblastoma Activity.” Clinical Cancer Research 14 (2): 533–540. doi:10.1158/1078-0432.CCR-06-2289.
- Hensley, M.L., K.L. Hagerty, T. Kewalramani, D.M. Green, N.J. Meropol, T.H. Wasserman, G.I. Cohen, et al. 2009. “American Society of Clinical Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy and Radiation Therapy Protectants.” Journal of Clinical Oncology 27 (1): 127–145. doi:10.1200/JCO.2008.17.2627.
- Hochman, J., B.W. Blakley, M. Wellman, and L. Blakley. 2006. “Prevention of Aminoglycoside-Induced Sensorineural Hearing Loss.” Journal of Otolaryngology 35 (3): 153–156.
- Huang, S., M. Chen, X. Ding, X. Zhang, and X. Zou. 2013. “Proton Pump Inhibitor Selectively Suppresses Proliferation and Restores the Chemosensitivity of Gastric Cancer Cells by Inhibiting STAT3 Signaling Pathway.” International Immunopharmacology 17 (3): 585–592. doi:10.1016/j.intimp.2013.07.021.
- Huang, T., A.G. Cheng, H. Stupak, W. Liu, A. Kim, H. Staecker, P.P. Lefebvre, et al. 2000. “Oxidative Stress-Induced Apoptosis of Cochlear Sensory Cells: Otoprotective Strategies.” International Journal of Developmental Neuroscience 18 (2–3): 259–270. doi:10.1016/S0736-5748(99)00094-5.
- Huang, X., C.A. Whitworth, and L.P. Rybak. 2007. “Ginkgo Biloba Extract (EGb 761) Protects Against Cisplatin-Induced Ototoxicity in Rats.” Otology & Neurotology 28 (6): 828–833. doi:10.1097/MAO.0b013e3180430163.
- Husain, K., C. Whitworth, S.M. Somani, and L.P. Rybak. 2005. “Partial Protection by Lipoic Acid Against Carboplantin-Induced Ototoxicity in Rats.” Biomedical and Environmental Sciences 18 (3): 198–206.
- Jamesdaniel, S., R. Rathinam, and W.L. Neumann. 2016. “Targeting Nitrative Stress for Attenuating Cisplatin-Induced Downregulation of Cochlear LIM Domain only 4 and Ototoxicity.” Redox Biology 10: 257–265. doi:10.1016/j.redox.2016.10.016.
- Jin, Z., and W.S. El-Deiry. 2005. “Overview of Cell Death Signaling Pathways.” Cancer Biology & Therapy 4 (2): 139–163.
- Johnson, A.-C., and T. Morata. 2010. “Occupational Exposure to Chemicals and Hearing Impairment.” Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals 44 (4): 1–190.
- Jones, M.M., M.A. Basinger, and M.A. Holscher. 1991. “Relative Effectiveness of Some Compounds for the Control of Cisplatin-Induced Nephrotoxicity.” Toxicology 68 (3): 227–247. doi:10.1016/0300-483X(91)90072-9.
- Kil, J. 2016a. Safety and Efficacy Study of SPI-1005 for Prevention of Chemotherapy Induced Hearing Loss. https://clinicaltrials.gov (Identification No. NCT01451853).
- Kil, J. 2016b. SPI-1005 for Prevention and Treatment of Aminoglycoside Induced Ototoxicity. https://clinicaltrials.gov (Identification No. NCT02819856).
- Kil, J., E. Lobarinas, C. Spankovich, S.K. Griffiths, P.J. Antonelli, E.D. Lynch, and C.G. Le Prell. 2017. “Safety and Efficacy of Ebselen for the Prevention of Noise-Induced Hearing Loss: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial.” Lancet 390 (10098): 969–979. doi:10.1016/S0140-6736(17)31791-9.
- Kim, S.J., C. Park, A.L. Han, M.J. Youn, J.H. Lee, Y. Kim, E.S. Kim, et al. 2009. “Ebselen Attenuates Cisplatin-Induced ROS Generation Through Nrf2 Activation in Auditory Cells.” Hearing Research 251 (1–2): 70–82. doi:10.1016/j.heares.2009.03.003.
- Kocyigit, I. 2011. Protective Effect of N-acetylcysteine Against Ototoxicity. https://clinicaltrials.gov (Identification No. NCT01271088).
- Kopke, R.D., W. Liu, R. Gabaizadeh, A. Jacono, J. Feghali, D. Spray, P. Garcia, H. Steinman, B. Malgrange, R.J. Ruben, and L. Rybak. 1997. “Use of Organotypic Cultures of Corti's Organ to Study the Protective Effects of Antioxidant Molecules on Cisplatin-Induced Damage of Auditory Hair Cells.” American Journal of Otolaryngology 18 (5): 559–571.
- Kopke, R., K.A. Allen, D. Henderson, M. Hoffer, D.M. Frenz, and T. Van De Water. 1999. “A Radical Demise: Toxins and Trauma Share Common Pathways in Hair Cell Death.” Annals of the New York Academy of Sciences 884 (1): 171–191. doi:10.1111/j.1749-6632.1999.tb08641.x.
- Korver, K.D., L.P. Rybak, C. Whitworth, and K.C. Campbell. 2002. “Round Window Application of D-Methionine Provides Complete Cisplatin Otoprotection.” Otolaryngology – Head and Neck Surgery 126: 683–689. doi:10.1067/mhn.2002.125299.
- Kramer, S., L. Dreisbach, J. Lockwood, K. Baldwin, R. Kopke, S. Scranton, and M. O'Leary. 2006. “Efficacy of the Antioxidant N-Acetylcysteine (NAC) in Protecting Ears Exposed to Loud Music.” Journal of the American Academy of Audiology 17(4): 265–278. doi:10.3766/jaaa.17.4.5.
- Kranzer, K., W.F. Elamin, H. Cox, J.A. Seddon, N. Ford, and F. Drobniewski. 2015. “A Systematic Review and Meta-Analysis of the Efficacy and Safety of N-Acetylcysteine in Preventing Aminoglycoside-Induced Ototoxicity: Implications for the Treatment of Multidrug-Resistant TB.” Thorax 70 (11): 1070–1077. doi:10.1136/thoraxjnl-2015-207245.
- Le Bars, P.L., and J. Kastelan. 2000. “Efficacy and Safety of a Ginkgo Biloba Extract.” Public Health Nutrion 3 (4A): 495–499.
- Le Prell, C.G., L.F. Hughes, and J.M. Miller. 2007. “Free Radical Scavengers Vitamins A, C, and E Plus Magnesium Reduce Noise Trauma.” Free Radical Biology and Medicine 42 (9): 1454–1463. doi:10.1016/j.freeradbiomed.2007.02.008.
- Le Prell, C.G., A.C. Johnson, A.C. Lindblad, Å., Skjönsberg, M. Ulfendahl, K. Guire, G.E. Green, K.C.M. Campbell, and J.M. Miller. 2011. “Increased Vitamin Plasma Levels in Swedish Military Personnel Treated with Nutrients Prior to Automatic Weapon Training. Noise and Health 13 (55): 432. doi:10.4103/1463-1741.90317.
- Le Prell, C.G., C. Ojano-Dirain, E.W. Rudnick, M.A. Nelson, S.J. DeRemer, D.M. Prieskorn, and J.M. Miller. 2014. “Assessment of Nutrient Supplement to Reduce Gentamicin-Induced Ototoxicity.” Journal of the Association for Research in Otolaryngology 15 (3): 375–393. doi:10.1007/s10162-014-0448-x.
- Lerner, S.A., B.A. Schmitt, R. Seligsohn, and G.J. Matz. 1986. “Comparative Study of Ototoxicity and Nephrotoxicity in Patients Randomly Assigned to Treatment with Amikacin or Gentamicin.” American Journal of Medicine 80 (6B): 98–104. doi:10.1016/0002-9343(86)90486-9.
- Lockwood, D.S., D.L. Ding, J. Wang, and R.J. Salvi. 2000. “D-Methionine Attenuates Inner Hair Cell Loss in Carboplatin-Treated Chinchillas.” Audiology and Neurotology 5 (5): 263–266. doi:10.1159/000013890.
- Lorito, G., S. Hatzopoulos, G. Laurell, K.C.M. Campbell, J. Petruccelli, P. Giordano, K. Kochanek, et al. 2011. “Dose-Dependent Protection on Cisplatin-Induced Ototoxicity – An Electrophysiological Study on the Effect of Three Antioxidants in the Sprague–Dawley Rat Animal Model.” Medical Science Monitor 17 (8): BR179–BR186. doi:10.12659/MSM.881894.
- Luciani, F., M. Spada, A. De Milito, A. Molinari, L. Rivoltini, A. Montinaro, M. Marra, et al. 2004. “Effect of Proton Pump Inhibitor Pretreatment on Resistance of Solid Tumors to Cytotoxic Drugs.” Journal of the National Cancer Institute 96 (22): 1702–1713. doi:10.1093/jnci/djh305.
- Lynch, E.D., R. Gu, C. Pierce, and J. Kil. 2005a. “Combined Oral Delivery of Ebselen and Allopurinol Reduces Multiple Cisplatin Toxicities in Rat Breast and Ovarian Cancer Models While Enhancing Anti-tumor Activity.” Anticancer Drugs 16 (5): 569–579. doi:10.1097/00001813-200506000-00013.
- Lynch, E.D., R. Gu, C. Pierce, and J. Kil. 2005b. “Reduction of Acute Cisplatin Ototoxicity and Nephrotoxicity in Rats by Oral Administration of Allopurinol and Ebselen.” Hearing Research 201 (1–2): 81–89. doi:10.1016/j.heares.2004.08.002.
- Lynch, E.D., and J. Kil. 2009. “Development of Ebselen, A Glutathione Peroxidase Mimis, for the Prevention and Treatment of Noise-Induced Hearing Loss.” Seminars in Hearing 30 (1): 47–55. doi:10.1055/s-0028-1111106.
- Ma, W., J. Hu, Y. Cheng, J. Wang, X. Zhang, and M. Xu. 2015. “Ginkgolide B Protects Against Cisplatin-Induced Ototoxicity: Enhancement of Akt–Nrf2–HO-1 Signaling and Reduction of NADPH Oxidase.” Cancer Chemotherapy and Pharmacology 75: 949–959. doi:10.1007/s00280-015-2716-9.
- Marshak, T.M., M. Steiner, M. Kaminer, L. Levy, and A., Shupak. 2014. “Prevention of Cisplatin-Induced Hearing Loss by Intratympanic Dexamethasone: A Randomized Controlled Study.” Otolaryngology – Head and Neck Surgery 150 (6): 983–990. doi:10.1177/0194599814524894.
- Marshak, T.M. 2015. Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone treatment. https://clinicaltrials.gov (Identification No. NCT01372904).
- Martin, D.L. 2014. Alpha-lipoic acid in preventing hearing loss in cancer patients undergoing treatment with cisplatin. https://clinicaltrials.gov (Identification No. NCT00477607).
- Mason, J.R. 1999. Amifostine Followed by High Dose Chemotherapy in Treating Patients With Hematologic Cancer or Solid Tumors. https://clinicaltrials.gov (Identification No. NCT 00003269).
- McKenna, D.J., K. Jones, and K. Hughes. 2001. “Efficacy, Safety, and Use of Ginkgo Biloba in Clinical and Preclinical Applications.” Alternative Therapies in Health And Medicine 7 (5): 70–86, 88–90.
- Meyer, F. 2016. Efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity (STS001). https://clinicaltrials.gov (Identification No. NCT02281006).
- Miman, M.C., O. Ozturan, M. Iraz, T., Erdem, and E. Olmez. 2002. “Amikacin Ototoxicity Enhanced by Ginkgo Biloba Extract (EGb 761).” Hearing Research 169 (1–2): 121–129. doi:10.1016/S0378-5955(02)00385-4.
- Muldoon, L.L., M.A. Pagel, R.A. Kroll, R.E. Brummett, N.D. Doolittle, E.G. Zuhowski, M.J. Egorin and E.A. Neuwelt. 2000. “Delayed Administration of Sodium Thiosulfate in Animal Models Reduces Platinum Ototoxicity Without Reduction of Antitumor Activity.” Clinical Cancer Research 6 (1): 309–315.
- Neuwelt, E.A., R.E. Brummett, L.G. Remsen, R.A. Kroll, M.A. Pagel, C.I. McCormick, S. Guitjens, and L.L. Muldoon. 1996. “In vitro and Animal Studies of Sodium Thiosulfate as A Potential Chemoprotectant Against Carboplatin-Induced Ototoxicity.” Cancer Research 56 (4): 706–709.
- Oishi, N., A. Kendall, and J. Schacht. 2014. “Metformin Protects Against Gentamicin-Induced Hair Cell Death in Vitro but not Ototoxicity in Vivo.” Neuroscience Letters 583: 65–59. doi:10.1016/j.neulet.2014.09.028.
- Omenn, G.S. 1998. “Chemoprevention of Lung Cancer: The Rise and Demise of Beta-Carotene.” Annual Review of Public Health 19: 73–99. doi:10.1146/annurev.publhealth.19.1.73.
- Omenn, G.S. 2007. “Chemoprevention of Lung Cancers: Lessons from CARET, the Beta-Carotene and Retinol Efficacy Trial, and Prospects for the Future.” European Journal of Cancer Prevention 16 (3): 184–191. doi:10.1097/01.cej.0000215612.98132.18.
- Otto, W.C., R.D. Brown, L. Gage-White, S. Kupetz, M. Anniko, J.E. Penny, and C.M. Henley. 1988. “Effects of Cisplatin and Thiosulfate Upon Auditory Brainstem Responses of Guinea Pigs.” Hearing Research 35 (1): 79–85. doi:10.1016/0378-5955(88)90042-1.
- Özel, H.E., F. Özdoğan, S.G. Gürgen, E. Esen, S. Genç, and A. Selçuk. 2016. “Comparison of the Protective Effects of Intratympanic Dexamethasone and Methylprednisolone Against Cisplatin-Induced Ototoxicity.” Journal of Laryngology & Otology 130 (3): 225–234. doi:10.1017/S0022215115003473.
- Petremann, M., C.T. Van Ba, A. Broussy, C. Romanet, and J. Dyhrfjeld-Johnsen. 2017. Oral Administration of Clinical Stage Drug Candidate SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in Rats. Otology and Neurotology 38 (9): 1355–1361. doi:10.1097/MAO.0000000000001546.
- Pouyatos, B., C. Gearhart, A. Nelson-Miller, S. Fulton, and L. Fechter. 2007. “Oxidative Stress Pathways in the Potentiation of Noise-Induced Hearing Loss by Acrylonitrile.” Hearing Research 224 (1–2): 61–74. doi:10.1016/j.heares.2006.11.009.
- Rabau, S. 2015. The Effect of Coenzyme Q10 on Hearing and Tinnitus Characteristics of Chronic Tinnitus Patients. https://clinicaltrials.gov (Identification No. NCT02353650).
- Riga, M.G., L. Chelis, S. Kakolyris, S. Papadopoulos, S. Stathakidou, E. Chamalidou, N. Xenidis, et al. 2013. “Transtympanic Injections of N-Acetylcysteine for the Prevention of Cisplatin-Induced Ototoxicity: A Feasible Method with Promising Efficacy.” American Journal of Clinical Oncology 36 (1): 1–6. doi:10.1097/COC.0b013e31822e006d.
- Rybak, L.P., K. Husain, C. Morris, C. Whitworth, and S. Somani. 2000. “Effect of Protective Agents Against Cisplatin Ototoxicity.” American Journal of Otolaryngology 21 (4): 513–520.
- Rybak, L.P., K. Husain, C. Whitworth, and S.M. Somani. 1999. “Dose Dependent Protection by Lipoic Acid Against Cisplatin-Induced Ototoxicity in Rats: Antioxidant Defense System. Toxicological Sciences 47 (2): 195–202. doi:10.1093/toxsci/47.2.195.
- Rybak, L.P., C.A. Whitworth, D. Mukherjea, and V. Ramkumar. 2007. “Mechanisms of Cisplatin-Induced Ototoxicity and Prevention.” Hearing Research 226 (1–2): 157–167. doi:10.1016/j.heares.2006.09.015.
- Rybak, L.P., C. Whitworth, S. Somani. 1999. “Application of Antioxidants and Other Agents to Prevent Cisplatin Ototoxicity.” Laryngoscope 109 (11): 1740–1744. doi:10.1097/00005537-199911000-00003.
- Sha, S.H., J.H. Qiu, and J. Schacht. 2006. “Aspirin to Prevent Gentamicin-Induced Hearing Loss.” New England Journal of Medicine 354 (17): 1856–1857. doi:10.1056/NEJMc053428.
- Sha, S.H., and J. Schacht. 1999. Salicylate Attenuates Gentamicin-induced Ototoxicity. Laboratory Investigation 79: 807–813.
- Sha, S. H., and J. Schacht. 2000. “Antioxidants Attenuate Gentamicin-Induced Free Radical Formation in Vitro and Ototoxicity in Vivo: D-Methionine is a Potential Protectant.” Hearing Research 142 (1–2): 34–40. doi:10.1016/S0378-5955(00)00003-4.
- Stewart, L. 1999. “Chemotherapy for Advanced Ovarian Cancer.” Cochrane Library. 1: CD001418. doi:10.1002/14651858.CD001418.
- Stypulkowski, P.H. 1990. “Mechanisms of Salicylate Ototoxicity.” Hearing Research 46 (1–2): 113–145. doi:10.1016/0378-5955(90)90144-E.
- Sun, C., X. Wang, D. Chen, X. Lin, D. Yu, and H. Wu. 2016. “Dexamethasone Loaded Nanoparticles Exert Protective Effects Against Cisplatin-Induced Hearing Loss by Systemic Administration.” Neuroscience Letters 619: 142–148. doi:10.1016/j.neulet.2016.03.012.
- Takumida, M., R. Popa, and M. Anniko. 1999. “Free Radicals in the Guinea Pig Inner Ear Following Gentamicin Exposure.” Journal for Oto-Rhino-Laryngology and Its Related Specialties 61 (2): 63–70. doi:10.1159/000027643.
- Tokgoz, B., C. Ucar, I. Kocyigit, M. Somdas, A. Unal, A. Vural, M. Sipahioglu, et al. 2011. “Protective Effect of N-Acetylcysteine from Drug-Induced Ototoxicity in Uraemic Patients with CAPD Peritonitis.” Nephrology Dialysis Transplantation 26 (12): 4073–4078. doi:10.1093/ndt/gfr211.
- Villani, V., C. Zucchella, G. Cristalli, E. Galiè, F. Bianco, D. Giannarelli, S. Carpano, G. Spriano, and A. Pace. 2016. “Vitamin E Neuroprotection Against Cisplatin Ototoxicity: Preliminary Results from a Randomized, Placebo‐Controlled Ttrial.” Head & Neck 38 (S1): E2118. doi:10.1002/hed.24396.
- Waissbluth, S., P. Salehi, X. He, S.J. Daniel. 2013. “Systemic Dexamethasone for the Prevention of Cisplatin-Induced Ototoxicity.” European Archives of Oto-Rhino-Laryngology 270 (5): 1597–1605. doi:10.1007/s00405-012-2150-0.
- Wang, J., J.-L. Puel. 2008. “From Cochlear Cell Death Pathways to New Pharmacological Therapies.” Mini-Reviews in Medicinal Chemistry 8 (10): 1006–1019. doi:10.2174/138955708785740599.
- Yamashita, D., H.Y. Jiang, C.G. Le Prell, J. Schacht, and J.M. Miller. 2005. “Post-exposure Treatment Attenuates Noise-Induced Hearing Loss.” Neuroscience 134 (2): 633–642. doi:10.1016/j.neuroscience.2005.04.015.
- Yamasoba, T., A.L. Nuttall, C. Harris, Y. Raphael, and J.M. Miller. 1998. “Role of Glutathione in Protection Against Noise-Induced Hearing Loss.” Brain Research 784 (1–2): 82–90. doi:10.1016/S0006-8993(97)01156-6.
- Yoo, J., S.J. Hamilton, D. Angel, K. Fung, J. Franklin, L.S. Parnes, D. Lewis, et al. 2014. “Cisplatin Otoprotection Using Transtympanic L-N-Acetylcysteine: A Pilot Randomized Study in Head and Neck Cancer Patients. Laryngoscope 124 (3): E87–E94. doi:10.1002/lary.24360.