Semin Hear 2019; 40(02): 162-176
DOI: 10.1055/s-0039-1684045
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Otoprotectants: From Research to Clinical Application

Colleen G. Le Prell
1   School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
26 April 2019 (online)


There is an urgent need for otoprotective drug agents. Prevention of noise-induced hearing loss continues to be a major challenge for military personnel and workers in a variety of industries despite the requirements that at-risk individuals use hearing protection devices such as ear plugs or ear muffs. Drug-induced hearing loss is also a major quality-of-life issue with many patients experiencing clinically significant hearing loss as a side effect of treatment with life-saving drug agents such as cisplatin and aminoglycoside antibiotics. There are no pharmaceutical agents approved by the United States Food and Drug Administration for the purpose of protecting the inner ear against damage, and preventing associated hearing loss (otoprotection). However, a variety of preclinical studies have suggested promise, with some supporting data from clinical trials now being available as well. Additional research within this promising area is urgently needed.


Funding for previously completed clinical trials evaluating prevention of temporary threshold shift in humans was provided by U01 DC 008423 from the National Institutes of Health – National Institute on Deafness and other Communication Disorders (NIH-NIDCD). Clinical trial material used in that study included a tablet formulation of ACEMg developed by OtoMedicine, Inc. and a capsule formulation of ACEMg developed by Hearing Health Sciences, Inc. Specifically, NCT00808470 was a clinical trial completed at the University of Florida under the oversight of C. Le Prell with funding from the National Institutes of Health using clinical trial material provided by Hearing Health Science, Inc., and the study completed by the Karolinska Institute team was coordinated out of the University of Florida by C. Le Prell with funding from the National Institutes of Health and using clinical trial material provided by OtoMedicine, Inc. Additional funding and clinical trial material were provided via contracts to the University of Florida by Sound Pharmaceuticals, Inc. (Ebselen, SPI-105) and Edison Pharmaceuticals, Inc. (Vincerinone, EPI-743). Specifically, NCT01444846 was a clinical trial completed at the University of Florida under the oversight of C. Le Prell with funding and clinical trial material provided by Sound Pharmaceuticals Inc. and NCT02257983 was a clinical trial completed at the University of Florida under the oversight of C. Le Prell with funding and clinical trial material provided by Edison Pharmaceuticals, Inc. Colleen Le Prell consults with various pharmaceutical companies engaged in the development of novel agents with potential auditory applications on an ongoing basis.

  • References

  • 1 Hoffman HJ, Dobie RA, Losonczy KG, Themann CL, Flamme GA. Declining prevalence of hearing loss in US adults aged 20 to 69 years. JAMA Otolaryngol Head Neck Surg 2017; 143 (03) 274-285
  • 2 Agrawal Y, Platz EA, Niparko JK. Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004. Arch Intern Med 2008; 168 (14) 1522-1530
  • 3 Carroll YI, Eichwald J, Scinicariello F. , et al. Vital signs: noise-induced hearing loss among adults - United States 2011–2012. MMWR Morb Mortal Wkly Rep 2017; 66 (05) 139-144
  • 4 Yankaskas K. Prelude: noise-induced tinnitus and hearing loss in the military. Hear Res 2013; 295: 3-8
  • 5 Beach E, Williams W, Gilliver M. Hearing protection for clubbers is music to their ears. Health Promot J Austr 2010; 21 (03) 215-221
  • 6 Bockstael A, Keppler H, Botteldooren D. Musician earplugs: appreciation and protection. Noise Health 2015; 17 (77) 198-208
  • 7 Casali JG, Ahroon WA, Lancaster JA. A field investigation of hearing protection and hearing enhancement in one device: for soldiers whose ears and lives depend upon it. Noise Health 2009; 11 (42) 69-90
  • 8 Casali JG. Powered electronic augmentations in hearing protection technology circa 2010 including active noise reduction, electronically-modulated sound transmission, and tactical communications devices: review of design, testing, and research. Int J Acoust Vib 2010; 15: 168-186
  • 9 Clasing JE, Casali JG. Warfighter auditory situation awareness: effects of augmented hearing protection/enhancement devices and TCAPS for military ground combat applications. Int J Audiol 2014; 53 (Suppl. 02) S43-S52
  • 10 World Health Organization. Hearing loss due to recreational exposure to loud sounds: a review. 2015 . Available at: . Accessed February 28, 2019
  • 11 Le Prell CG, Siburt HW, Lobarinas E, Griffiths SK, Spankovich C. No reliable association between recreational noise exposure and threshold sensitivity, distortion product otoacoustic emission amplitude, or word-in-noise performance in a college student population. Ear Hear 2018; 39 (06) 1057-1074
  • 12 Campbell KCM, Le Prell CG. Drug-induced ototoxicity: diagnosis and monitoring. Drug Saf 2018; 41 (05) 451-464
  • 13 Hammill TL, Campbell KC. Protection for medication-induced hearing loss: the state of the science. Int J Audiol 2018; 57 (Suppl. 04) S67-S75
  • 14 Hammill TL. An evidence-base and implementation framework for promoting best practices in pharmaceutical interventions for hearing loss (PIHL) Research. Doctoral thesis, The University of Texas at Austin, Texas; 2017
  • 15 Le Prell CG, Bao J. Prevention of noise-induced hearing loss: potential therapeutic agents. In: Le Prell CG, Henderson D, Fay RR. , et al, eds. Noise-Induced Hearing Loss: Scientific Advances, Springer Handbook of Auditory Research. New York: Springer Science + Business Media, LLC; 2012: 285-338
  • 16 Le Prell CG, Lobarinas E. Strategies for assessing antioxidant efficacy in clinical trials. In: Miller JM, Le Prell CG, Rybak LP. , eds. Oxidative Stress in Applied Basic Research and Clinical Practice: Free Radicals in ENT Pathology. New York: Humana Press; 2015: 163-192
  • 17 Le Prell CG, Roth K, Campbell KCM. Towards clinical pharmacologic otoprotection. In: Hatzopoulos S, Ciorba A, Krumm M. , eds. Advances in Audiology and Hearing Science, Vol 2: Otoprotection, Regeneration and Telemedicine. New Jersey: Apple Academic Press; , in press; 2018
  • 18 Kil J, Lynch E. Methods for treating hearing loss. Patent no. 7,820,640. Issued by United States Patent Trademark Office. Assigned to Sound Pharmaceuticals, Inc.; 2010
  • 19 Kil J, Pierce C, Tran H, Gu R, Lynch ED. Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase. Hear Res 2007; 226 (1-2): 44-51
  • 20 Pourbakht A, Yamasoba T. Ebselen attenuates cochlear damage caused by acoustic trauma. Hear Res 2003; 181 (1-2): 100-108
  • 21 Kim SJ, Park C, Han AL. , et al. Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res 2009; 251 (1-2): 70-82
  • 22 Lynch ED, Kil J. Compounds for the prevention and treatment of noise-induced hearing loss. Drug Discov Today 2005; 10 (19) 1291-1298
  • 23 Lynch ED, Gu R, Pierce C, Kil J. Ebselen-mediated protection from single and repeated noise exposure in rat. Laryngoscope 2004; 114 (02) 333-337
  • 24 Yamasoba T, Pourbakht A, Sakamoto T, Suzuki M. Ebselen prevents noise-induced excitotoxicity and temporary threshold shift. Neurosci Lett 2005; 380 (03) 234-238
  • 25 Rybak LP, Husain K, Morris C, Whitworth C, Somani S. Effect of protective agents against cisplatin ototoxicity. Am J Otol 2000; 21 (04) 513-520
  • 26 Lynch ED, Gu R, Pierce C, Kil J. Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen. Hear Res 2005; 201 (1-2): 81-89
  • 27 Lynch ED, Gu R, Pierce C, Kil J. 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 2005; 16 (05) 569-579
  • 28 Lorito G, Hatzopoulos S, Laurell G. , et al. Dose-dependent protection on cisplatin-induced ototoxicity - an electrophysiological study on the effect of three antioxidants in the Sprague-Dawley rat animal model. Med Sci Monit 2011; 17 (08) BR179-BR186
  • 29 Kil J, Lobarinas E, Spankovich C. , et al. Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2017; 390 (10098): 969-979
  • 30 Lynch ED, Kil J, Le Prell CG. Human Clinical Studies in Research in Audiology and the Hearing Sciences. Springer Handbook of Auditory Research. New York: Springer; 2016: 105-139
  • 31 Le Prell CG, Dell S, Hensley B. , et al. Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects. Ear Hear 2012; 33 (06) e44-e58
  • 32 Le Prell CG, Fulbright A, Spankovich C. , et al. Dietary supplement comprised of β-carotene, vitamin C, vitamin E, and magnesium: failure to prevent music-induced temporary threshold shift. Audiol Neurotol Extra 2016; 6 (02) 20-39
  • 33 Miller JM, Le Prell CG, Schacht J, Prieskorn D. Composition and method of treating hearing loss. Patent no. 7,951,845. Issued by United States Patent Trademark Office. Assigned to The Regents of the University of Michigan; 2011
  • 34 Miller JM, Green GE, Le Prell CG. Method for treating hearing loss. RE46,372 E, Re-issue of US 9,144,565. Method for treating hearing loss, Issued 2015. Issued by United States Patent Trademark Office. Assigned to The Regents of the University of Michigan; 2017
  • 35 Le Prell CG, Hughes LF, Miller JM. Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma. Free Radic Biol Med 2007; 42 (09) 1454-1463
  • 36 Le Prell CG, Dolan DF, Bennett DC, Boxer PA. Nutrient plasma levels achieved during treatment that reduces noise-induced hearing loss. Transl Res 2011; 158 (01) 54-70
  • 37 Le Prell CG, Gagnon PM, Bennett DC, Ohlemiller KK. Nutrient-enhanced diet reduces noise-induced damage to the inner ear and hearing loss. Transl Res 2011; 158 (01) 38-53
  • 38 Tamir S, Adelman C, Weinberger JM, Sohmer H. Uniform comparison of several drugs which provide protection from noise induced hearing loss. J Occup Med Toxicol 2010; 5: 26-32
  • 39 Cascella V, Giordano P, Hatzopoulos S. , et al. A new oral otoprotective agent. Part 1: Electrophysiology data from protection against noise-induced hearing loss. Med Sci Monit 2012; 18 (01) BR1-BR8
  • 40 Le Prell CG, Ojano-Dirain C, Rudnick EW. , et al. Assessment of nutrient supplement to reduce gentamicin-induced ototoxicity. J Assoc Res Otolaryngol 2014; 15 (03) 375-393
  • 41 Le Prell CG, DeRemer S, Rudnick EW, Nelson MA, Goldstein A. Effects of dietary nutrients on amikacin ototoxicity in guinea pigs: reduced hearing loss and increased hair cell survival. Abstr Assoc Res Otolaryngol 2013; 36: 502
  • 42 Le Prell CG, Johnson A-C, Lindblad A-C. , et al. Increased vitamin plasma levels in Swedish military personnel treated with nutrients prior to automatic weapon training. Noise Health 2011; 13 (55) 432-443
  • 43 Weijl NI, Elsendoorn TJ, Lentjes EG. , et al. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur J Cancer 2004; 40 (11) 1713-1723
  • 44 Villani V, Zucchella C, Cristalli G. , et al. Vitamin E neuroprotection against cisplatin ototoxicity: preliminary results from a randomized, placebo-controlled trial. Head Neck 2016; 38 (Suppl. 01) E2118-E2121
  • 45 Kharkheli E, Kevanishvili Z, Maglakelidze T, Davitashvili O, Schacht J. Does vitamin E prevent gentamicin-induced ototoxicity?. Georgian Med News 2007; (146) 14-17
  • 46 Spankovich C, Le Prell CG. Healthy diets, healthy hearing: National Health and Nutrition Examination Survey, 1999-2002. Int J Audiol 2013; 52 (06) 369-376
  • 47 Spankovich C, Le Prell CG. Associations between dietary quality, noise, and hearing: data from the National Health and Nutrition Examination Survey, 1999-2002. Int J Audiol 2014; 53 (11) 796-809
  • 48 Curhan SG, Stankovic KM, Eavey RD, Wang M, Stampfer MJ, Curhan GC. Carotenoids, vitamin A, vitamin C, vitamin E, and folate and risk of self-reported hearing loss in women. Am J Clin Nutr 2015; 102 (05) 1167-1175
  • 49 Péneau S, Jeandel C, Déjardin P. , et al; SU.VI.MAX 2 Research Group. Intake of specific nutrients and foods and hearing level measured 13 years later. Br J Nutr 2013; 109 (11) 2079-2088
  • 50 Kopke RD, Floyd RA. Methods for treating acute acoustic trauma. Patent no. 8,420,595. Issued by United States Patent Trademark Office. Assigned to Oklahoma Medical Research Foundation; 2013
  • 51 Kopke RD, Henderson D, Hoffer ME. Prevention or reversal of sensorineural hearing loss (SNHL) through biologic mechanisms. Patent no. 6,649,621. Issued by United States Patent Trademark Office. Assigned to The United States of America as represented by the Secretary of the Navy; 2003
  • 52 Elbini Dhouib I, Jallouli M, Annabi A, Gharbi N, Elfazaa S, Lasram MM. A minireview on N-acetylcysteine: An old drug with new approaches. Life Sci 2016; 151: 359-363
  • 53 Samuni Y, Goldstein S, Dean OM, Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta 2013; 1830 (08) 4117-4129
  • 54 Kopke RD, Jackson RL, Coleman JKM, Liu J, Bielefeld EC, Balough BJ. NAC for noise: from the bench top to the clinic. Hear Res 2007; 226 (1-2): 114-125
  • 55 Riga MG, Chelis L, Kakolyris S. , et al. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol 2013; 36 (01) 1-6
  • 56 Yoo J, Hamilton SJ, Angel D. , et al. Cisplatin otoprotection using transtympanic L-N-acetylcysteine: a pilot randomized study in head and neck cancer patients. Laryngoscope 2014; 124 (03) E87-E94
  • 57 Dickey DT, Muldoon LL, Doolittle ND, Peterson DR, Kraemer DF, Neuwelt EA. Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models. Cancer Chemother Pharmacol 2008; 62 (02) 235-241
  • 58 Thomas Dickey D, Muldoon LL, Kraemer DF, Neuwelt EA. Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model. Hear Res 2004; 193 (1-2): 25-30
  • 59 Aladag I, Guven M, Songu M. Prevention of gentamicin ototoxicity with N-acetylcysteine and vitamin A. J Laryngol Otol 2016; 130 (05) 440-446
  • 60 Toppila E, Starck J, Pyykko I, Miller JM. Protection against acute noise with antioxidants. Presented at Nordic Noise: An International Symposium on Noise and Health, in Nobel Forum, Karolinska Institutet, Stockholm, Sweden; 2002
  • 61 Kramer S, Dreisbach L, Lockwood J. , et al. Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music. J Am Acad Audiol 2006; 17 (04) 265-278
  • 62 Doosti A, Lotfi Y, Moossavi A, Bakhshi E, Talasaz AH, Hoorzad A. Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers. Noise Health 2014; 16 (71) 223-227
  • 63 Kopke R, Slade MD, Jackson R. , et al. Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial. Hear Res 2015; 323: 40-50
  • 64 Lin CY, Wu JL, Shih TS. , et al. N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers. Hear Res 2010; 269 (1-2): 42-47
  • 65 Lindblad AC, Rosenhall U, Olofsson A, Hagerman B. The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial. Noise Health 2011; 13 (55) 392-401
  • 66 Gilles A, Ihtijarevic B, Wouters K, Van de Heyning P. Using prophylactic antioxidants to prevent noise-induced hearing damage in young adults: a protocol for a double-blind, randomized controlled trial. Trials 2014; 15: 110
  • 67 Yıldırım M, Inançlı HM, Samancı B, Oktay MF, Enöz M, Topçu I. Preventing cisplatin induced ototoxicity by N-acetylcysteine and salicylate. Kulak Burun Bogaz Ihtis Derg 2010; 20 (04) 173-183
  • 68 Vural A, Koçyiğit İ, Şan F. , et al. Long-term protective effect of N-acetylcysteine against amikacin-induced ototoxicity in end-stage renal disease: a randomized trial. Perit Dial Int 2018; 38 (01) 57-62
  • 69 Kocyigit I, Vural A, Unal A. , et al. Preventing amikacin related ototoxicity with N-acetylcysteine in patients undergoing peritoneal dialysis. Eur Arch Otorhinolaryngol 2015; 272 (10) 2611-2620
  • 70 Tokgoz B, Ucar C, Kocyigit I. , et al. Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis. Nephrol Dial Transplant 2011; 26 (12) 4073-4078
  • 71 Kranzer K, Elamin WF, Cox H, Seddon JA, Ford N, Drobniewski F. 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 2015; 70 (11) 1070-1077
  • 72 Feldman L, Sherman RA, Weissgarten J. N-acetylcysteine use for amelioration of aminoglycoside-induced ototoxicity in dialysis patients. Semin Dial 2012; 25 (05) 491-494
  • 73 Zesiewicz T, Salemi JL, Perlman S. , et al. Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia. Neurodegener Dis Manag 2018; 8 (04) 233-242
  • 74 Martinelli D, Catteruccia M, Piemonte F. , et al. EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome. Mol Genet Metab 2012; 107 (03) 383-388
  • 75 Kouga T, Takagi M, Miyauchi A. , et al. Japanese Leigh syndrome case treated with EPI-743. Brain Dev 2018; 40 (02) 145-149
  • 76 Sadun AA, Chicani CF, Ross-Cisneros FN. , et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol 2012; 69 (03) 331-338
  • 77 Enns GM, Kinsman SL, Perlman SL. , et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab 2012; 105 (01) 91-102
  • 78 Shrader WD, Amagata A, Barnes A. , et al. α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg Med Chem Lett 2011; 21 (12) 3693-3698
  • 79 Fetoni AR, Troiani D, Eramo SL, Rolesi R, Paludetti Troiani G. Efficacy of different routes of administration for Coenzyme Q10 formulation in noise-induced hearing loss: systemic versus transtympanic modality. Acta Otolaryngol 2012; 132 (04) 391-399
  • 80 Fetoni AR, De Bartolo P, Eramo SL. , et al. Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense. J Neurosci 2013; 33 (09) 4011-4023
  • 81 Hirose Y, Sugahara K, Mikuriya T, Hashimoto M, Shimogori H, Yamashita H. Effect of water-soluble coenzyme Q10 on noise-induced hearing loss in guinea pigs. Acta Otolaryngol 2008; 128 (10) 1071-1076
  • 82 Morimitsu T, Hagiwara T, Ide M, Matsumoto I, Okada S. Effect of intermittent sound stimulation on cochlear microphonics and the possible preventive effect of coenzyme Q10. Hear Res 1980; 3 (02) 155-166
  • 83 Sergi B, Fetoni AR, Paludetti G. , et al. Protective properties of idebenone in noise-induced hearing loss in the guinea pig. Neuroreport 2006; 17 (09) 857-861
  • 84 Astolfi L, Simoni E, Valente F. , et al. Coenzyme Q10 plus multivitamin treatment prevents cisplatin ototoxicity in rats. PLoS One 2017; 12 (09) e0185525
  • 85 Staffa P, Cambi J, Mezzedimi C, Passali D, Bellussi L. Activity of coenzyme Q 10 (Q-Ter multicomposite) on recovery time in noise-induced hearing loss. Noise Health 2014; 16 (72) 265-269
  • 86 Scasso F, Sprio AE, Canobbio L. , et al. Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: A pilot study. Heliyon 2017; 3 (02) e00251
  • 87 Kerr DS. Review of clinical trials for mitochondrial disorders: 1997-2012. Neurotherapeutics 2013; 10 (02) 307-319
  • 88 Wang J, Van De Water TR, Bonny C, de Ribaupierre F, Puel JL, Zine A. A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 2003; 23 (24) 8596-8607
  • 89 Dinh CT, Van De Water TR. Blocking pro-cell-death signal pathways to conserve hearing. Audiol Neurotol 2009; 14 (06) 383-392
  • 90 Selivanova O, Brieger J, Heinrich UR, Mann W. Akt and c-Jun N-terminal kinase are regulated in response to moderate noise exposure in the cochlea of guinea pigs. ORL J Otorhinolaryngol Relat Spec 2007; 69 (05) 277-282
  • 91 Murai N, Kirkegaard M, Järlebark L, Risling M, Suneson A, Ulfendahl M. Activation of JNK in the inner ear following impulse noise exposure. J Neurotrauma 2008; 25 (01) 72-77
  • 92 Guitton MJ, Wang J, Puel JL. New pharmacological strategies to restore hearing and treat tinnitus. Acta Otolaryngol 2004; 124 (04) 411-415
  • 93 Coleman JK, Littlesunday C, Jackson R, Meyer T. AM-111 protects against permanent hearing loss from impulse noise trauma. Hear Res 2007; 226 (1-2): 70-78
  • 94 Eshraghi AA, Wang J, Adil E. , et al. Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity. Hear Res 2007; 226 (1-2): 168-177
  • 95 Suckfuell M, Canis M, Strieth S, Scherer H, Haisch A. Intratympanic treatment of acute acoustic trauma with a cell-permeable JNK ligand: a prospective randomized phase I/II study. Acta Otolaryngol 2007; 127 (09) 938-942
  • 96 Campbell KCM. Therapeutic use of D-methionine to reduce the toxicity of ototoxic drugs, noise, and radiation. Patent no. 6,265,386. Issued by United States Patent Trademark Office. Assigned to Southern Illinois University School of Medicine; 2001
  • 97 Campbell KCM. Therapeutic use of methionine-derivatives to reduce the toxicity of noise. Patent no. 7,423,065. Issued by United States Patent Trademark Office. Assigned to Southern Illinois University School of Medicine; 2008
  • 98 Morris G, Anderson G, Dean O. , et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol 2014; 50 (03) 1059-1084
  • 99 Kim G, Weiss SJ, Levine RL. Methionine oxidation and reduction in proteins. Biochim Biophys Acta 2014; 1840 (02) 901-905
  • 100 Campbell KCM, Meech RP, Klemens JJ. , et al. Prevention of noise- and drug-induced hearing loss with D-methionine. Hear Res 2007; 226 (1-2): 92-103
  • 101 Campbell KCM, Le Prell CG. Potential therapeutic agents. Semin Hear 2012; 33: 97-113
  • 102 Kopke RD, Coleman JK, Liu J, Campbell KC, Riffenburgh RH. Candidate's thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope 2002; 112: 1515-1532
  • 103 Campbell K, Claussen A, Meech R, Verhulst S, Fox D, Hughes L. D-methionine (D-met) significantly rescues noise-induced hearing loss: timing studies. Hear Res 2011; 282 (1-2): 138-144
  • 104 Clifford RE, Coleman JK, Balough BJ, Liu J, Kopke RD, Jackson RL. Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas. Otolaryngol Head Neck Surg 2011; 145 (06) 999-1006
  • 105 Samson J, Wiktorek-Smagur A, Politanski P. , et al. Noise-induced time-dependent changes in oxidative stress in the mouse cochlea and attenuation by D-methionine. Neuroscience 2008; 152 (01) 146-150
  • 106 Cheng PW, Liu SH, Young YH, Hsu CJ, Lin-Shiau SY. Protection from noise-induced temporary threshold shift by D-methionine is associated with preservation of ATPase activities. Ear Hear 2008; 29 (01) 65-75
  • 107 Alagic Z, Goiny M, Canlon B. Protection against acoustic trauma by direct application of D-methionine to the inner ear. Acta Otolaryngol 2011; 131 (08) 802-808 (Stockh)
  • 108 Campbell KC, Meech RP, Rybak LP, Hughes LF. The effect of D-methionine on cochlear oxidative state with and without cisplatin administration: mechanisms of otoprotection. J Am Acad Audiol 2003; 14 (03) 144-156
  • 109 Campbell KC, Rybak LP, Meech RP, Hughes L. D-methionine provides excellent protection from cisplatin ototoxicity in the rat. Hear Res 1996; 102 (1-2): 90-98
  • 110 Campbell KC, Meech RP, Rybak LP, Hughes LF. D-Methionine protects against cisplatin damage to the stria vascularis. Hear Res 1999; 138 (1-2): 13-28
  • 111 Korver KD, Rybak LP, Whitworth C, Campbell KM. Round window application of D-methionine provides complete cisplatin otoprotection. Otolaryngol Head Neck Surg 2002; 126 (06) 683-689
  • 112 Grondin Y, Cotanche DA, Manneberg O. , et al. Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids. Hear Res 2013; 298: 93-103
  • 113 Campbell KC, Martin SM, Meech RP, Hargrove TL, Verhulst SJ, Fox DJ. D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. Int J Audiol 2016; 55 (05) 273-278
  • 114 Fox DJ, Cooper MD, Speil CA. , et al. d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models. J Cyst Fibros 2016; 15 (04) 518-530
  • 115 Li G, Frenz DA, Brahmblatt S. , et al. Round window membrane delivery of L-methionine provides protection from cisplatin ototoxicity without compromising chemotherapeutic efficacy. Neurotoxicology 2001; 22 (02) 163-176
  • 116 Reser D, Rho M, Dewan D. , et al. L- and D- methionine provide equivalent long term protection against CDDP-induced ototoxicity in vivo, with partial in vitro and in vivo retention of antineoplastic activity. Neurotoxicology 1999; 20 (05) 731-748
  • 117 Cloven NG, Re A, McHale MT. , et al. Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer. Anticancer Res 2000; 20 (6B): 4205-4209
  • 118 Campbell KCM. Phase 2 clinical trials: d-methionine to reduce noise-induced hearing loss. Final report for award W81XWH-11-C-0033, 2016 . Available at: . Accessed February 28, 2019
  • 119 Campbell KCM, Nayar R, Borgonha S. , et al. Oral d-methionine (MRX-1024) significantly protects against cisplatin-induced hearing loss: a phase II study in humans. Presented at IX European Federation of Audiology Societies (EFAS) Congress in Tenerife, Spain; 2009
  • 120 Hamstra DA, Eisbruch A, Naidu MU. , et al. Pharmacokinetic analysis and phase 1 study of MRX-1024 in patients treated with radiation therapy with or without cisplatinum for head and neck cancer. Clin Cancer Res 2010; 16 (09) 2666-2676
  • 121 Hamstra DA, Lee KC, Eisbruch A. , et al. Double-blind placebo-controlled multicenter phase II trial to evaluate D-methionine in preventing/reducing oral mucositis induced by radiation and chemotherapy for head and neck cancer. Head Neck 2018; 40 (07) 1375-1388
  • 122 Kisilevsky AE, Zamponi GW. Presynaptic calcium channels: structure, regulators, and blockers. Handb Exp Pharmacol 2008; (184) 45-75
  • 123 Shin HS, Cheong EJ, Choi S, Lee J, Na HS. T-type Ca2+ channels as therapeutic targets in the nervous system. Curr Opin Pharmacol 2008; 8 (01) 33-41
  • 124 Suzuki Y, Inoue T, Ra C. L-type Ca2+ channels: a new player in the regulation of Ca2+ signaling, cell activation and cell survival in immune cells. Mol Immunol 2010; 47 (04) 640-648
  • 125 Uemaetomari I, Tabuchi K, Nakamagoe M, Tanaka S, Murashita H, Hara A. L-type voltage-gated calcium channel is involved in the pathogenesis of acoustic injury in the cochlea. Tohoku J Exp Med 2009; 218 (01) 41-47
  • 126 Shen H, Zhang B, Shin JH. , et al. Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hear Res 2007; 226 (1-2): 52-60
  • 127 Bao J, Hungerford M, Luxmore R. , et al. Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss. Hear Res 2013; 304: 33-40
  • 128 Opperman DA, Reifman W, Schlauch R, Levine S. Incidence of spontaneous hearing threshold shifts during modern concert performances. Otolaryngol Head Neck Surg 2006; 134 (04) 667-673
  • 129 Ramakers GG, Kraaijenga VJ, Cattani G, van Zanten GA, Grolman W. Effectiveness of earplugs in preventing recreational noise-induced hearing loss: a randomized clinical trial. JAMA Otolaryngol Head Neck Surg 2016; 142 (06) 551-558
  • 130 Beach EF, Williams W, Gilliver M. A qualitative study of earplug use as a health behavior: the role of noise injury symptoms, self-efficacy and an affinity for music. J Health Psychol 2012; 17 (02) 237-246
  • 131 Beach EF, Gilliver M, Williams W. Leisure noise exposure: participation trends, symptoms of hearing damage, and perception of risk. Int J Audiol 2013; 52 (Suppl. 01) S20-S25
  • 132 Beach EF, Gilliver M, Williams W. Hearing protection devices: use at work predicts use at play. Arch Environ Occup Health 2016; 71 (05) 281-288
  • 133 Grinn SK, Wiseman KB, Baker JA, Le Prell CG. Hidden hearing loss? No effect of common recreational noise exposure on cochlear nerve response amplitude in humans. Front Neurosci 2017; 11: 465
  • 134 American Speech-Language-Hearing Association. Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. Amer Speech Lang Hear Assn 1994; 36 (Suppl. 12) 11-19
  • 135 Campbell K, Hammill T, Hoffer M, Kil J, Le Prell C. Guidelines for auditory threshold measurement for significant threshold shift (STS). Otol Neurotol 2016; 37 (08) e263-e270
  • 136 Le Prell CG, Brungart DS. Speech-in-noise tests and supra-threshold auditory evoked potentials as metrics for noise damage and clinical trial outcome measures. Otol Neurotol 2016; 37 (08) e295-e302
  • 137 Ryan AF, Kujawa SG, Hammill T, Le Prell C, Kil J. Temporary and permanent noise-induced threshold shifts: a review of basic and clinical observations. Otol Neurotol 2016; 37 (08) e271-e275
  • 138 Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals, Vitamins. Food and Nutrition Board, Institute of Medicine, National Academies of Science; 2004
  • 139 Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals, Elements. Food and Nutrition Board, Institute of Medicine, National Academies of Science; 2004
  • 140 Dietary Reference Intakes (DRIs): Tolerable Upper Intake Levels (UL), Vitamins. Food and Nutrition Board, Institute of Medicine, National Academies of Science; 2004
  • 141 Dietary Reference Intakes (DRIs): Tolerable Upper Intake Levels (UL), Elements. Food and Nutrition Board, Institute of Medicine, National Academies of Science; 2004