Drug
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TABLE, SUPPLEMENTAL DIGITAL CONTENT 1 Drug Indication Species 2-oxothiazolidine-4carboxylate (OTC) 3-aminobenzamide NIHL Guinea Pigs1 NIHL Chinchillas2 Adenosine NIHL Rats3 Acetyl-L carnitine (ALCAR) * NIHL Chinchillas4,5 Adenosine amine congener (ADAC) NIHL Rats6 aFGF NIHL Guinea Pigs7 Allopurinol NIHL Guinea Pigs8,9 Alpha-tocopherol * NIHL Guinea Pigs10 AM-111(D-JNK-inhibitor 1) * Amitriptyline NIHL Chinchillas11,12 NIHL Guinea Pigs13 Ascorbic acid NIHL Guinea Pigs14 CEP-1347/ KT7515 NIHL Guinea Pigs15 Coenzyme Q10 * NIHL Guinea Pigs16 Creatine NIHL Guinea Pigs17 Cyclosporin A NIHL Guinea Pigs18 Deferoxamine mesylate (DFO) Dexamethasone * NIHL Guinea Pigs19 NIHL Guinea Pigs20 ; Diltiazem NIHL Guinea Pigs21 D-methionine * NIHL Chinchilas4,22 ; Guinea Pigs23,24 IPA designation Chemical drug Chemical toxicant Chemical – endogenous mammalian Chemical – endogenous mammalian Chemical reagent Growth factor Chemical drug Chemical drug Chemical drug Chemical drug Chemical – endogenous mammalian Chemical drug Chemical drug Chemical – endogenous mammalian Biologic drug Chemical drug Chemical drug Chemical drug Chemical – endogenous non- Criterion of efficacy 5 dB less TTS and PTS compared to saline controls 10-20 dB less ABR TS, 5-10 % less OHC loss compared to saline controls Up to 20 dB ABR TS recovery, compared to controls with AP 16-25 dB less ABR PTS, 1050% less IHC and OHC loss compared to saline controls 17-30 dB less ABR TS, 16-25 % less IHC and OHC loss compared to vehicle controls 5-20 dB less ABR TS compared to saline controls 16-30 dB less ABR TS compared to NaOH controls 5-12 dB less ABR TS compared to saline controls 16-25 dB less ABR PTS compared to saline controls 10-15 dB less ABR TS compared to saline controls 6 dB less ABR TS compared to controls 199-975 fewer OHCs lost compared to untreated controls Up to 50% less OHC loss compared to saline controls 10-20 dB less ABR TS, 30 % less OHC loss compared to untreated controls 20-25 dB less ABR TS, up to 50% less OHC loss compared to Ringer’s solution controls 5-15 dB less ABR TS compared to saline controls 5-20 dB less ABR TS compared to AP controls ~30% less OHC loss 5-15 dB less ABR TS compared to saline controls 22 mammalian Chemical – endogenous mammalian and Chemical drug Chemical drug D-methionine and N-acetylL-cysteine (DMET/NAC group) NIHL Chinchillas Ebselen * NIHL Guinea Pigs25,26 ; Rats27 Edaravone * NIHL Guinea Pigs28 Ethosuximide NIHL Mice29 Ferulic acid NIHL Guinea Pigs30,31 FK506 (Tacrolimus) NIHL Guinea Pigs18 Furosemide NIHL Mice32,33 GDNF (+DFO and mannitol) NIHL Guinea Pigs19 Glial cell line-derived neurotrophic factor (GDNF) NIHL Guinea Pigs34 Growth factor Glutathione NIHL Guinea Pigs35 Glutathione monoethylester(GEE) + RPIA Idebenone NIHL Chinchillas36 Chemical – endogenous mammalian Chemical other NIHL Guinea Pigs37 Chemical drug Idebenone and vit E NIHL Guinea Pigs38 Leupeptin NIHL Chinchillas39,40 L-NAME NIHL Mice41 Insulin-Like Growth Factor 1 Magnesium * NIHL Guinea Pigs42 ; Rats43 Guinea Pigs44,45 ; Humans 46,47, Chemical drug Chemical – protease inhibitor Chemical drug Growth factor Chemical – endogenous NIHL Chemical drug Chemical drug Chemical – endogenous nonmammalian Chemical drug Chemical drug Growth factor 5-20 dB less ABR TS compared to saline controls Up to 50 dB less ABR TS compared to chloroform controls 15-20 dB less ABR TS compared to saline controls 10-20 dB less ABR PTS compared to untreated controls 10-15 dB less ABR TS compared to untreated controls 20-25 dB less ABR TS, up to 50% less OHC loss compared to Ringer’s solution controls 5-10 dB less ABR PTS compared to saline controls 10-25 dB less ABR TS, 10 % less OHC loss compared to saline controls 10 dB less ABR TS, 10% less OHC loss compared to AP controls 5-20 dB less ABR TS compared to saline controls 10-20 dB less ABR TS compared to untreated controls 20-25 dB less TS, and less OHC loss compared to untreated controls Up to 40 dB less ABR TS compared to untreated controls 10 dB less ABR TS, 60% less OHC loss compared to untreated controls 15-20 dB less ABR TS compared to untreated controls 5-10 dB less ABR TS compared to saline controls 10-15 dB less ABR TS, 15 % less OHC loss compared to mammalian Chemical – endogenous mammalian Chemical drug Mannitol NIHL Guinea Pigs19 MK-801 NIHL Guinea Pigs48 ; Rats49 N-acetylcysteine * NIHL Chemical drug Nerve growth factor(NGF) NIHL Humans50 ; Chinchillas5,51 ; Guinea Pigs48,52 ; Rats53,54 ; Mice32 Humans55 Pravastin NIHL Mice56 Resveratrol * NIHL Rats57 All trans retinoic acid (tretinoin) NIHL Mice58,59 Riluzole NIHL Guinea Pigs60,61 Salicylate and trolox NIHL Guinea Pigs62 Salicylic Acid NIHL Mice63 Sodium Enoxaparin NIHL Humans64 Tempol NIHL Guinea Pigs17 ; Mice2,41 Chemical drug Chemical drug Chemical – endogenous mammalian Chemical drug Chemical drug Chemical drug Chemical drug Chemical drug Trimethadione NIHL Mice29 Chemical drug Vit A,C,E and MG NIHL Guinea Pigs65 ; Mice32 Vitamin B12 NIHL Humans66 Vitamin C * NIHL Guinea Pigs67 Citalopram SNHL Humans68 Chemical – endogenous mammalians and chemical drug Chemical – endogenous mammalian Chemical – endogenous mammalian Chemical Growth factor NaCl controls in guinea pigs; 10 dB less TTS in humans compared to placebo 10-15 dB less ABR TS, 10 % less OHC loss compared to saline controls 10-15 dB less ABR TS, up to 6% less OHC loss compared to NaCl controls 5-25 dB less ABR TS compared to controls in rodents; 3 dB less TTS in humans at least 15 dB of improvement in PTA in 78.6% of treated and 31.8% of untreated people 10-20 dB less ABR TS compared to untreated controls 10-15 dB less ABR TS compared to untreated controls 20-40 dB less ABR TS, 2030% less OHC loss compared to untreated controls 30 dB less TS compared to AP controls 10-30 dB less ABR TS compared to saline controls 15 dB reduced ABR TS compared to saline controls 10-15 dB improvement in PTA compared to placebo controls 10-15 dB less ABR TS, 20 % less OHC loss than untreated controls 10-20 dB less ABR TTS and PTS compared to untreated controls Up to 30 dB less ABR TS, 25% less OHC loss compared to saline controls 15 dB less TTS compared to placebo controls 15 dB less ABR TS compared to untreated controls significant improvement in drug identification of synthetic sentences with an ipsilateral competitive message AM-111(D-JNK-inhibitor 1) * SNHL Guinea Pigs69 ; Gerbils70 Chemical drug EGb 761(gingko biloba extract) SNHL Humans71 Chemical drug Edaravone * SNHL Gerbils72 IGF1 treatment SNHL Humans73 Intratympanic dexamethasone * Intratympanic methylprednisolone SNHL Humans74,75,76,77,78 SNHL Humans,79,80,81,82,83, Chemical drug Growth factor Chemical drug Chemical drug 20-30 dB less ABR TS, 40% less OHC loss compared to untreated controls 10 dB more improvement in PTA compared to untreated controls 15-20 dB less ABR TS compared to saline controls 10-25 dB less ABR TS compared to saline controls 5-10 dB improvement in PTA compared to placebo controls 5-10 dB improvement in PTA compared to placebo controls Intratympanic Dexamethasone + HighDose Prednisone Taper Intratympanic methylprednisolone and systemic therapy Lipo-prostaglandin E1 SNHL Humans85 Chemical drug 10-15 dB improvement in PTA compared to saline controls SNHL Humans81 Chemical drug 10 dB improvement in PTA compared to controls SNHL Humans86 Chemical – endogenous mammalian In diabetics, PTA improved by at least 3dB in 64.7% of treated compared to 37.5% of untreated patients Magnesium * SNHL Humans87,88 10 dB less TTS compared to placebo Oral dexamethasone * SNHL Humans89 Chemical – endogenous mammalian Chemical drug Oral methylprednisolone SNHL Humans89,90,83 Chemical drug Sulforaphane SNHL Mice91 Tapering courses of hydrocortisone SNHL Humans92 Chemical drug Chemical drug Trolox + Ascorbic Acid SNHL Guinea Pigs93 84 Chemical drug at least 20 dB improvement in PTA in 78% of treated people compared to 38% of people receiving placebo at least 20 dB improvement in PTA in 78% of treated people compared to 38% of people receiving placebo 10-20% less OHC and IHC loss compared to controls PTA improvement of at least 10 dB in 87% of treated patients 100-200 A decrease in electric ABR threshold, 2 fold increase in SGN density in treated compared to untreated animals Vitamin A * SNHL Humans94 Vitamin E * SNHL Humans95 Vitamin E + C SNHL Humans96 Zinc SNHL Humans97 Acetyl-L carnitine (ALCAR) * Presbycusis Rats98 Alpha -lipoic acid Presbycusis Rats98 Coenzyme Q10 * Presbycusis Humans99,100 Ethosuximide Presbycusis Mice101 Folic Acid Presbycusis Humans102,103 Geranylgeranylacetone Presbycusis Mice104 Ginkgo biloba extract (EGb761) Presbycusis Rats105 Melatonin * Presbycusis Rats106 Trimethadione Presbycusis Mice101 Vitamin C * Presbycusis Rats106 Vitamin E * Presbycusis Rats106 Allopurinol + ebselen Cisplatin Ototoxicity Rats107 Chemical – endogenous mammalian Chemical drug 42% reduced risk of hearing loss compared to controls Chemical drug and Chemical – endogenous mammalian Chemical drug 10 dB more improvement in PTA compared to control group Chemical – endogenous mammalian Chemical drug Chemical drug Chemical drug Chemical – endogenous mammalian Chemical drug Chemical drug Chemical – endogenous mammalian Chemical drug Chemical – endogenous mammalian Chemical drug Chemical drug 78.8% treated compared to 45.5% untreated patients had 75% recovery rate calculated as hearing gain divided by the difference in hearing level between the affected and unaffected ear 8 dB improvement in PTA and 17% increase in recovery compared to control group 10 dB less ABR TS compared to untreated controls 5 dB less ABR TS compared to untreated controls 5-10 dB less TS compared to placebo controls 5-25 dB less ABR TS compared to untreated controls 1 dB reduction in PTA compared to placebo 5-20 dB less ABR TS compared to untreated controls Up to 20 dB less ASSR TS compared to vehicle treated controls 5-20 dB less ABR TS compared to placebo controls 5-25 dB less ABR TS compared to untreated controls 5-25 dB less ABR TS compared to placebo controls 5-15 dB less ABR TS compared to placebo controls 5-10 dB less ABR TS compared to vehicle treated controls Cisplatin Ototoxicity Cisplatin Ototoxicity Guinea Pigs108 Amifostine Cisplatin Ototoxicity Humans110 ; Hamsters111 Chemical drug Aminoguanidine * Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Rats112 Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Cisplatin Ototoxicity Rats115 Chemical drug Chemical drug Chemical – endogenous nonmammalian Chemical drug Chemical drug Chemical drug Chemical drug Chemical drug Chemical drug Chemical drug Chemical toxicant Chemical drug Chemical drug Chemical toxicant Cisplatin Ototoxicity Cisplatin Ototoxicity Guinea Pigs126 Gentamicin Ototoxicity Gentamicin Ototoxicity Gentamicin Guinea Pigs128 Alpha-tocopherol * Alpha-Tocopherol + tiopronin Dexamethasone+ Vit E D-methionine * Diethyldithiocarbamate (DDTC) Ebselen* Epicatechin Erdosteine LiCl (LithiumChloride) N-acetylcysteine * Resveratrol * SB 216763 Salicylate Sodium Thiosulfate Tiopronin Trolox C Vitamin E * Alpha-tocopherol * Deferoxamine Mannitol Guinea Pigs109 Rats113 Chinchillas114 Rats115 Rats116 Rats117 Mice118 Rats119 Guinea Pigs120 Mice118 Rats121 ; Guinea Pigs122 Rats123 ; Guinea Pigs124 Rats125 Rats127 Guinea Pigs129 Guinea Pigs130 Chemical drug Chemical drug Chemical drug Chemical – endogenous mammalian Chemical drug Chemical drug Chemical – 5-25 dB less ABR TS compared to saline controls 10-30 dB less CAP TS, 2530% less OHC loss compared to untreated controls 13% less hearing loss of 25 dB or more compared to untreated controls in humans 6-26 dB less ABR TS compared to untreated controls Up to 60 dB less ABR TS compared to untreated controls 35-55 dB less ABR TS, 3680% less HC loss compared to untreated controls 15-30 dB less ABR TS compared to untreated controls 15-30 dB less ABR TS compared to untreated controls 25 dB less ABR TS compared to untreated controls 5 dB less TS compared to untreated controls 5-20 dB less ABR TS compared to untreated controls 10-15 dB less ABR TS compared to untreated controls 10-25 dB less ABR TS compared to untreated controls 5-20 dB less ABR TS compared to untreated controls 10-30 dB less ABR TS compared to untreated controls 5-15 dB less ABR TS compared to untreated controls 10-15 dB increased DPOAE responses compared to untreated controls 15-25 dB less ABR TS compared to untreated controls 15-20 dB less ABR TS compared to soybean oil controls 15-30 dB less CAP TS compared untreated controls 30-45 dB less ABR TS compared to untreated controls Up to 50 dB less ABR TS Ototoxicity Melatonin * Gentamicin Ototoxicity Guinea Pigs131 N-acetylcysteine * Gentamicin Ototoxicity Aminoglyc oside Ototoxicity Aminoglyc oside Ototoxicity Humans132 Aminoguanidine * Taurine Guinea Pigs133 Guinea Pigs133 endogenous mammalian Chemical – endogenous mammalian Chemical drug Chemical drug Chemical – endogenous mammalian compared to untreated controls 5-10 dB increased DPOAE response, 20-35% less OHC loss compared to untreated controls 5 dB less TS compared to controls Up to 35 dB less ABR TS, 1520% less OHC loss compared to controls Up to 35 dB less ABR TS, 1520% less OHC loss compared to controls Supplemental Table 1. Alphabetical list of the drugs studied in the metabolomic analyses based on their reported efficacy on different types of sensorineural hearing loss (SNHL) in mammals. Drugs marked with * were studied for different indications, and therefore listed more than once. NIHL = noise induced hearing loss, ABR = Auditory Brainstem Response, AP= Artificial Perilymph, ASSR= Auditory Steady State Responses, CAP= Compound Action Potential, DPOAE= Distortion Product OtoAcoustic Emissions, IHC= Inner Hair Cells, OHC= Outer Hair Cells, PTA= Pure Tone Average, PTS= Permanent Threshold Shift, SGN=Spiral Ganglion Neurons, TTS= Temporary Threshold Shift, TS = Threshold Shift (the authors used this if they did not follow animals for 2-4 weeks to determine if the TS was permanent or temporary). References 1. Yamasoba T, Nuttall a L, Harris C, Raphael Y, Miller JM. Role of glutathione in protection against noise-induced hearing loss. Brain Res 1998;784(1-2):82–90. 2. 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