RESUMEN
OBJECTIVE: To elucidate D-methionine's (D-met) dose and time rescue parameters from steady-state or impulse noise-induced permanent threshold shift (PTS) and determine D-met rescue's influence on serum and cochlear antioxidant levels. DESIGN: Five D-met doses at 0, 50, 100, or 200 mg/kg/dose administered starting at 1, 24, or 36 hours post steady-state or impulse noise exposure. Auditory brainstem responses at baseline and 21 days post-noise measured PTS. Serum (superoxide dismutase [SOD], catalase [CAT],, glutathione reductaseand glutathione peroxidase [GPx]) and cochlear (Glutathione [GSH] and glutathione disulphide [GSSG]) antioxidant levels measured physiological impact. STUDY SAMPLE: Chinchillas (10/study group; 6-8/confirmatory groups). RESULTS: D-met significantly reduced PTS for impulse noise (100 mg [2, 6, 14 and 20 kHz]; 200 mg [2, 14 and 20 kHz]) and steady-state noise (all dosing groups, time parameters and tested frequencies). PTS reduction did not significantly vary by rescue time. D-met significantly increased serum SOD (100 and 200 mg for 24 hour rescue) and GPx (50 mg/kg at 24 hour rescue) at 21 days post-noise. Cochlear GSH and GSSG levels were unaffected relative to control. CONCLUSION: D-met rescues from steady-state and impulse noise-induced PTS even when administered up to 36 hours post-noise and dose-dependently influences serum antioxidant levels even 21 days post-noise. D-met's broad and effective dose/time window renders it a promising antioxidant rescue agent.
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Pérdida Auditiva Provocada por Ruido , Metionina , Humanos , Antioxidantes/farmacología , Pérdida Auditiva Provocada por Ruido/etiología , Pérdida Auditiva Provocada por Ruido/prevención & control , Disulfuro de Glutatión/farmacología , Racemetionina/farmacología , Superóxido Dismutasa/farmacología , Umbral Auditivo , Potenciales Evocados Auditivos del Tronco Encefálico/fisiologíaRESUMEN
Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.
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Oído Interno , Pérdida Auditiva , Ototoxicidad , Audiometría de Tonos Puros/métodos , Umbral Auditivo , Pérdida Auditiva/diagnóstico , Humanos , Ototoxicidad/diagnóstico , Ototoxicidad/etiologíaRESUMEN
OBJECTIVE: Determine if D-methionine (D-met) rescue prevents temporary threshold shift (TTS) from steady-state or impulse noise and determine D-met's impact on serum and cochlear antioxidant levels. DESIGN: D-met at 50, 100 or 200 mg/kg/doses were administered 0, 6 and 18 hours-post noise. ABRs at baseline and 24 hours post-noise measured TTS. Serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels measured physiological influence. Three control groups, with impulse or steady-state or without noise, were saline-injected. STUDY SAMPLE: Ten Chinchillas/group. RESULTS: D-met rescue did not significantly reduce TTS or impact serum CAT, SOD, GPx or GR levels vs. noise-exposed control groups, but TTS was greater in all groups relative to no-noise controls. D-met significantly elevated CAT at 50 mg/kg vs. steady-state controls and SOD at 200 mg/kg vs. impulse noise controls. D-met significantly reduced cochlear GSH/GSSG ratios in the 100 mg/kg D-met group vs. impulse noise controls. CONCLUSIONS: While D-met rescue has reduced permanent threshold shift in previous studies, it did not reduce TTS in this study. However, D-met rescue did alter selective serum and cochlear oxidative state changes 24 hours post-noise relative to controls. Results demonstrate TTS studies do not always predict PTS protection in otoprotectant experimental designs.
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Antioxidantes , Pérdida Auditiva Provocada por Ruido , Animales , Umbral Auditivo/fisiología , Chinchilla , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Disulfuro de Glutatión , Pérdida Auditiva Provocada por Ruido/etiología , Pérdida Auditiva Provocada por Ruido/prevención & control , Metionina , Superóxido DismutasaRESUMEN
OBJECTIVE: Test D-methionine (D-met) as an otoprotectant from kanamycin-induced ototoxicity and determine the lowest maximally protective D-met dose. DESIGN: Auditory brainstem responses (ABR) were measured at 4, 8, 14, and 20 kHz at baseline and two, four, and six weeks after kanamycin and D-met administration initiation. ABR threshold shifts assessed auditory function. Following six-week ABR testing, animals were decapitated and cochleae collected for outer hair cell (OHC) quantification. STUDY SAMPLE: Eight groups of 10 male pigmented guinea pigs were administered a subcutaneous kanamycin (250 mg/kg/dose) injection once per day and an intraperitoneal D-met injection (0 (saline), 120, 180, 240, 300, 360, 420, or 480 mg/kg/day) twice per day for 23 days. RESULTS: Significant ABR threshold shift reductions and increased OHC counts (p ≤ 0.01) were measured at multiple D-met-dosed groups starting at two-week ABR assessments. A 300 mg/kg/day optimal otoprotective D-met dose provided 34-41 dB ABR threshold shift reductions and OHC protection. Lesser, but significant, D-met otoprotection was measured at lower and higher D-met doses. CONCLUSIONS: D-met significantly reduced ABR threshold shifts and increased OHC percentages compared to kanamycin-treated controls. Results may be clinically significant particularly for multidrug-resistant tuberculosis patients who frequently suffer from kanamycin-induced hearing loss in developing countries.
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Antibacterianos/efectos adversos , Pérdida Auditiva Sensorineural/prevención & control , Kanamicina/efectos adversos , Metionina/administración & dosificación , Sustancias Protectoras/administración & dosificación , Animales , Umbral Auditivo/efectos de los fármacos , Cóclea/efectos de los fármacos , Cóclea/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Cobayas , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva Sensorineural/inducido químicamente , MasculinoRESUMEN
OBJECTIVE: This study tested multiple dosing epochs of pre-loaded D-methionine (D-met) for otoprotection from noise-induced hearing loss (NIHL). DESIGN: Auditory brainstem response (ABR) thresholds were measured at baseline, 1 day, and 21 days following a 6-hour 105 dB sound pressure level (SPL) octave band noise (OBN) exposure. Outer hair cell (OHC) counts were measured after day 21 sacrifice. STUDY SAMPLE: Three groups of five Chinchillas laniger each were given a 2-day regimen comprising five doses of D-met (200 mg/kg/dose) intraperitoneally (IP) starting 2, 2.5, or 3 days prior to noise exposure. A control group (n = 5) received five doses of equivalent volume saline IP starting 2.5 days prior to noise exposure. RESULTS: ABR threshold shifts from baseline to day-21 post-noise exposure were reduced in all D-met groups versus controls, reaching significance (p < 0.05) in the 3-day group. D-met groups showed reduced OHC loss relative to controls at day-21 post-noise exposure, reaching significance (p < 0.05) at all frequency regions in the 3-day group and at the 2, 4, and 8 kHz frequency regions in the 2.5-day group. CONCLUSIONS: D-met administration in advance of noise-exposure, without further administration, significantly protects from noise-induced ABR threshold shift and OHC loss.
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Umbral Auditivo/efectos de los fármacos , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva Provocada por Ruido/prevención & control , Metionina/administración & dosificación , Animales , Chinchilla , Citoprotección , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Células Ciliadas Auditivas Externas/patología , Pérdida Auditiva Provocada por Ruido/patología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Pérdida Auditiva Provocada por Ruido/psicología , Masculino , Factores de TiempoRESUMEN
OBJECTIVES: One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. DESIGN: Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. RESULTS: Changes in thresholds after the lowest-level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a "notch" configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0-14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. CONCLUSIONS: These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in future TTS studies, including protective agent evaluations, that some noise exposures have resulted in neural degeneration in animal models, even when both audiometric thresholds and DPOAE levels returned to pre-exposure values.
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Fatiga Auditiva , Reproductor MP3 , Música , Estimulación Acústica/métodos , Adolescente , Adulto , Audiometría de Tonos Puros , Femenino , Humanos , Percepción Sonora/fisiología , Masculino , Emisiones Otoacústicas Espontáneas/fisiología , Estudios Prospectivos , Espectrografía del Sonido , Adulto JovenRESUMEN
BACKGROUND: Sprague-Dawley rats were used as an acute cisplatin ototoxicity model to compare the chemo-protective efficacy of 2 sulphur-containing antioxidants (D-methionine, N-L-acetylcysteine) and 1 seleno-organic compound (ebselen). Each putative chemo-protective agent was tested at 3 different dosages in order to assess the influence of dose on auditory preservation. MATERIAL/METHODS: A total of 40 Sprague-Dawley albino male rats were used in the study. Animals were divided into 10 groups, 3 groups of different doses for each protective agent and a cisplatin-treated control group. The animals were weight-matched before drug exposure to ensure similar weights in all groups. Auditory function was assessed with auditory brainstem responses and distortion product otoacoustic emissions at time zero and at 96 hours post-treatment. RESULTS: At the post-treatment follow-up no significant threshold change at 8 kHz was found in the D-Met- and NAC-treated groups. All ebselen-treated animals presented significant threshold elevations. At 12 and 16 kHz, only the groups treated with 300, 450 mg/kg of D-Met and 475 mg/kg of NAC presented thresholds comparable to the pre-treatment ABR data. The ebselen-treated animals presented significant threshold shifts and showed the highest threshold elevations. The DPOAE data analysis showed that only the animals from the 350 mg/kg D-met group presented lack of statistical differences between the pre and post recordings. CONCLUSIONS: Considering the outcome from the ABR and DPOAE analyses together, only the 350 mg/kg D-met group presented a complete auditory preservation against the 14 mg/kg cisplatin administered i.v. Data from ebselen pre-treated Sprague-Dawley albino male rats demonstrate that ebselen dosages up to 12 mg/kg given by i.p. administration lack auditory preservation in this species.
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Antineoplásicos/toxicidad , Antioxidantes/farmacología , Cisplatino/toxicidad , Células Ciliadas Auditivas Externas/efectos de los fármacos , Modelos Animales , Acetilcisteína/farmacología , Animales , Umbral Auditivo/efectos de los fármacos , Azoles/farmacología , Relación Dosis-Respuesta a Droga , Electrofisiología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Isoindoles , Masculino , Metionina/química , Metionina/farmacología , Compuestos de Organoselenio/farmacología , Emisiones Otoacústicas Espontáneas/efectos de los fármacos , Emisiones Otoacústicas Espontáneas/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
HYPOTHESIS: Moringa extract, a naturally occurring anti-oxidant, protects against aminoglycoside-induced hair cell death and hearing loss within the organ of Corti. BACKGROUND: Reactive oxygen species (ROS) arise primarily in the mitochondria and have been implicated in aminoglycoside-induced ototoxicity. Mitochondrial dysfunction results in loss of membrane potential, release of caspases, and cell apoptosis. Moringa extract has not previously been examined as a protective agent for aminoglycoside-induced ototoxicity. METHODS: Putative otoprotective effects of moringa extract were investigated in an organotypic model using murine organ of Corti explants subjected to gentamicin-induced ototoxicity. Assays evaluated hair cell loss, cytochrome oxidase expression, mitochondrial membrane potential integrity, and caspase activity. RESULTS: In vitro application of moringa conferred significant protection from gentamicin-induced hair cell loss at dosages from 25 to 300âµg/mL, with dosages above 100âµg/mL conferring near complete protection. Assays demonstrated moringa extract suppression of ROS, preservation of cytochrome oxidase activity, and reduction in caspase production. CONCLUSION: Moringa extract demonstrated potent antioxidant properties with significant protection against gentamicin ototoxicity in cochlear explants.
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Aminoglicósidos , Moringa , Aminoglicósidos/toxicidad , Animales , Apoptosis , Muerte Celular , Gentamicinas/toxicidad , Células Ciliadas Auditivas , Ratones , Órgano Espiral , Extractos Vegetales/farmacologíaRESUMEN
PURPOSE: Oral mucositis is a common acute morbidity associated with radiation and/or chemotherapy treatment for cancer. D-Methionine (D-Met), the dextro-isomer of the common amino acid l-methionine, has been documented to protect normal tissues from a diverse array of oxidative insults. EXPERIMENTAL DESIGN: We evaluated if D-Met could selectively prevent radiation-induced oral mucositis using in vitro cell culture models as well as an in vivo model of radiation injury to the oral mucosa in C3H mice. RESULTS: Unlike free-radical scavengers, which protected both normal and transformed tumor cells in vitro from radiation-induced cell death, treatment with d-Met in culture protected nontransformed primary human cells from radiation-induced cell death (protective factor between 1.2 and 1.6; P<0.05) whereas it did not confer a similar protection on transformed tumor cells. D-Met treatment also provided significant protection to normal human fibroblasts, but not to tumor cell lines, from radiation-induced loss of clonogenicity (protection factor, 1.6+/-0.15). D-Met treatment did not alter DNA damage (as measured by histone phosphorylation) following irradiation but seemed to selectively mitigate the loss of mitochondrial membrane potential in nontransformed cells, whereas it did not provide a similar protection to tumor cells. Tumor control of implanted xenografts treated with radiation or concurrent cisplatin and radiation was not altered by D-Met treatment. Pharmacokinetics following administration of a liquid suspension of D-Met in rats showed 68% bioavailability relative to i.v. administration. Finally, in a murine model of mucositis, a dose-dependent increase in protection was observed with the protective factor increasing from 1.6 to 2.6 over a range of oral D-Met doses between 200 and 500 mg/kg (P<0.0003). CONCLUSIONS: D-Met protected normal tissues, but not tumor cells, in culture from radiation-induced cell death; it also protected normal cells from radiation-induced mucosal injury in a murine model but did not alter tumor response to therapy. Further studies on the use of D-Met to protect from oral mucositis are warranted.
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Metionina/farmacología , Protectores contra Radiación/farmacología , Estomatitis/prevención & control , Animales , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos C3H , Radioterapia/efectos adversos , Ratas , Estomatitis/etiología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ELX-02 is an investigational synthetic eukaryotic ribosome-selective glycoside optimized as a translational read-through molecule that induces read through of nonsense mutations, resulting in normally localized full-length functional proteins. ELX-02 is being developed as a therapy for genetic diseases caused by nonsense mutations. Two phase 1a, randomized, double-blind placebo-controlled, single-ascending-dose studies were conducted in healthy human subjects to evaluate the safety and pharmacokinetics of ELX-02. Single subcutaneously injected doses of ELX-02 between 0.3 mg/kg and 7.5 mg/kg showed an acceptable safety profile without severe or serious drug-related adverse events, including a lack of renal and ototoxicity events. Injection of ELX-02 resulted in a rapid time to peak concentration and elimination phase, with complete elimination from the vascular compartment within 10 hours. ELX-02 area under the concentration-time curve to infinity showed dose-exposure linearity (24-fold increase for a 25-fold dose increase), and the maximum concentration showed dose proportionality (17-fold increase for a 25-fold increase). The mean apparent volume of distribution was dose dependent, suggesting an increased distribution and tissue uptake of ELX-02 at higher doses. The primary route of excretion was in the urine, with the majority of the compound excreted unchanged. These results support the evaluation of the safety, pharmacokinetics, and efficacy of repeat dosing in future studies.
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Codón sin Sentido/genética , Furanos , Enfermedades Genéticas Congénitas/genética , Mutación , Adolescente , Adulto , Disponibilidad Biológica , Método Doble Ciego , Femenino , Furanos/administración & dosificación , Furanos/efectos adversos , Furanos/farmacocinética , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Voluntarios Sanos , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Nivel sin Efectos Adversos Observados , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Adulto JovenRESUMEN
Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.
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Nervio Coclear/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Trastornos de la Audición/inducido químicamente , Animales , Ensayos Clínicos como Asunto , Monitoreo de Drogas/métodos , Humanos , Estados UnidosRESUMEN
BACKGROUND: The purpose of this study was to test if oral D-methionine (D-met) reduced mucositis during chemoradiotherapy. METHODS: We conducted a placebo-controlled double-blind randomized phase II trial of D-met (100 mg/kg p.o. b.i.d.) testing the rate of severe (grades 3-4) mucositis. RESULTS: Sixty patients were randomized. Grade 2 + oral pain was higher with placebo (79% vs 45%; P = .0165), whereas grade 2 + body odor was greater with D-met (3% vs 41%; P = .0015). Mucositis was decreased with D-met by the physician (World Health Organization [WHO], P = .007; Radiation Therapy Oncology Group [RTOG], P = .009) and patient functional scales (RTOG, P = .0023). The primary end point of grades 3 to 4 mucositis on the composite scale demonstrated a decrease with D-met (48% vs 24%; P = .058), which was borderline in significance. A planned secondary analysis of a semiquantitative scoring system noted decreased oral ulceration (2.2 vs 1.5; P = .023) and erythema (1.6 vs 1.1; P = .048) with D-met. CONCLUSION: Although not meeting the primary end point, results of multiple assessments suggest that D-met decreased mucositis.
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Quimioterapia Adyuvante/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Metionina/uso terapéutico , Radioterapia Adyuvante/efectos adversos , Estomatitis/prevención & control , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/terapia , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estomatitis/clasificación , Estomatitis/etiologíaRESUMEN
A number of otoprotective agents are currently being investigated. Various types of agents have been found in animal studies to protect against hearing loss induced by cisplatin, carboplatin, aminoglycosides, or noise exposure. For over a decade we have been investigating D-methionine (D-met) as an otoprotective agent. Studies in our laboratory and others around the world have documented D-met's otoprotective action, in a variety of species, against a variety of ototoxic insults including cisplatin-, carboplatin-, aminoglycoside- and noise-induced auditory threshold elevations and cochlear hair cell loss. For cisplatin-induced ototoxicity, protection of the stria vascularis has also been documented. Further D-met has an excellent safety profile. D-met may act as both a direct and indirect antioxidant. In this report, we provide the results of three experiments, expanding findings in D-met protection in three of our translational research areas: protection from platinum based chemotherapy-, aminoglycoside- and noise-induced hearing loss. These experiments demonstrate oral D-met protection against cisplatin-induced ototoxicity, D-met protection against amikacin-induced ototoxicity, and D-met rescue from permanent noise-induced hearing loss when D-met is initiated 1h after noise exposure. These studies demonstrate some of the animal experiments needed as steps to translate a protective agent from bench to bedside.
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Pérdida Auditiva Provocada por Ruido/prevención & control , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Metionina/farmacología , Amicacina/toxicidad , Aminoglicósidos/toxicidad , Animales , Carboplatino/toxicidad , Chinchilla , Cisplatino/toxicidad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Cobayas , Técnicas In Vitro , Masculino , Metionina/administración & dosificación , Ratas , Ratas Wistar , Seguridad , Especificidad de la EspecieRESUMEN
For decades, it has been known that ingested potassium bromate and sodium bromate can induce hearing loss. Hearing loss onset, following high-dose ingestion, is generally rapid occurring within 4-16 h and of a severe to profound degree. Unlike the sensorineural hearing loss which is generally irreversible, bromate-induced tinnitus, which is less well-studied, may reportedly be permanent or temporary. It is not clear whether actual bromate-induced vestibulotoxicity occurs in clinical populations. The primary sites of lesion for bromate-induced ototoxicity appear to be in the cochlea. However, possible effects on the VIIIth nerve and central auditory system have not been fully investigated. Based on animal studies, in the cochlea, bromate damages the stria vascularis, Reissner's membrane, inner and outer hair cells, Claudius cells and inner sulcus cells. Physiologically, bromate reduces the endocochlear potential, cochlear microphonics, and electrophysiologic auditory thresholds. Possible mechanisms are discussed. The effects of long-term low-dose bromate exposure on hearing have not been studied. These effects, if they occur, may not be readily detected in many clinical populations, because idiopathic hearing loss occurs commonly in the population as a whole. Further it is unknown whether or not chronic bromate ingestion may exacerbate noise-induced hearing loss. Further study to determine the maximum safe exposure level for long-term administration and to develop possible antidotes is warranted.
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Bromatos/toxicidad , Cóclea/efectos de los fármacos , Pérdida Auditiva/inducido químicamente , Audición/efectos de los fármacos , Acúfeno/inducido químicamente , Animales , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
BACKGROUND: Tobramycin is a critical cystic fibrosis treatment however it causes ototoxicity. This study tested d-methionine protection from tobramycin-induced ototoxicity and potential antimicrobial interference. METHODS: Auditory brainstem responses (ABRs) and outer hair cell (OHC) quantifications measured protection in guinea pigs treated with tobramycin and a range of d-methionine doses. In vitro antimicrobial interference studies tested inhibition and post antibiotic effect assays. In vivo antimicrobial interference studies tested normal and neutropenic Escherichia coli murine survival and intraperitoneal lavage bacterial counts. RESULTS: d-Methionine conferred significant ABR threshold shift reductions. OHC protection was less robust but significant at 20kHz in the 420mg/kg/day group. In vitro studies did not detect d-methionine-induced antimicrobial interference. In vivo studies did not detect d-methionine-induced interference in normal or neutropenic mice. CONCLUSIONS: d-Methionine protects from tobramycin-induced ototoxicity without antimicrobial interference. The study results suggest d-met as a potential otoprotectant from clinical tobramycin use in cystic fibrosis patients.
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Fibrosis Quística/tratamiento farmacológico , Enfermedades del Oído , Potenciales Evocados Auditivos del Tronco Encefálico , Células Ciliadas Auditivas Externas/patología , Metionina/farmacología , Tobramicina , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/efectos adversos , Monitoreo de Drogas/métodos , Enfermedades del Oído/inducido químicamente , Enfermedades del Oído/prevención & control , Escherichia coli/efectos de los fármacos , Cobayas , Ratones , Sustancias Protectoras/farmacología , Tobramicina/administración & dosificación , Tobramicina/efectos adversosRESUMEN
OBJECTIVES/HYPOTHESIS: Oxidative stress plays a substantial role in the genesis of noise-induced cochlear injury that causes permanent hearing loss. We present the results of three different approaches to enhance intrinsic cochlear defense mechanisms against oxidative stress. This article explores, through the following set of hypotheses, some of the postulated causes of noise-induced cochlear oxidative stress (NICOS) and how noise-induced cochlear damage may be reduced pharmacologically. 1) NICOS is in part related to defects in mitochondrial bioenergetics and biogenesis. Therefore, NICOS can be reduced by acetyl-L carnitine (ALCAR), an endogenous mitochondrial membrane compound that helps maintain mitochondrial bioenergetics and biogenesis in the face of oxidative stress. 2) A contributing factor in NICOS injury is glutamate excitotoxicity, which can be reduced by antagonizing the action of cochlear -methyl-D-aspartate (NMDA) receptors using carbamathione, which acts as a glutamate antagonist. 3) Noise-induced hearing loss (NIHL) may be characterized as a cochlear-reduced glutathione (GSH) deficiency state; therefore, strategies to enhance cochlear GSH levels may reduce noise-induced cochlear injury. The objective of this study was to document the reduction in noise-induced hearing and hair cell loss, following application of ALCAR, carbamathione, and a GSH repletion drug D-methionine (MET), to a model of noise-induced hearing loss. STUDY DESIGN: This was a prospective, blinded observer study using the above-listed agents as modulators of the noise-induced cochlear injury response in the species chinchilla langier. METHODS: Adult chinchilla langier had baseline-hearing thresholds determined by auditory brainstem response (ABR) recording. The animals then received injections of saline or saline plus active experimental compound starting before and continuing after a 6-hour 105 dB SPL continuous 4-kHz octave band noise exposure. ABRs were obtained immediately after noise exposure and weekly for 3 weeks. After euthanization, cochlear hair cell counts were obtained and analyzed. RESULTS ALCAR administration reduced noise-induced threshold shifts. Three weeks after noise exposure, no threshold shift at 2 to 4 kHz and <10 dB threshold shifts were seen at 6 to 8 kHz in ALCAR-treated animals compared with 30 to 35 dB in control animals. ALCAR treatment reduced both inner and outer hair cell loss. OHC loss averaged <10% for the 4- to 10-kHz region in ALCAR-treated animals and 60% in saline-injected-noise-exposed control animals. Noise-induced threshold shifts were also reduced in carbamathione-treated animals. At 3 weeks, threshold shifts averaged 15 dB or less at all frequencies in treated animals and 30 to 35 dB in control animals. Averaged OHC losses were 30% to 40% in carbamathione-treated animals and 60% in control animals. IHC losses were 5% in the 4- to 10-kHz region in treated animals and 10% to 20% in control animals. MET administration reduced noise-induced threshold shifts. ANOVA revealed a significant difference (P <.001). Mean OHC and IHC losses were also significantly reduced (P <.001). CONCLUSIONS: These data lend further support to the growing body of evidence that oxidative stress, generated in part by glutamate excitotoxicity, impaired mitochondrial function and GSH depletion causes cochlear injury induced by noise. Enhancing the cellular oxidative stress defense pathways in the cochlea eliminates noise-induced cochlear injury. The data also suggest strategies for therapeutic intervention to reduce NIHL clinically.
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Acetilcarnitina/farmacología , Cóclea/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Pérdida Auditiva Provocada por Ruido/prevención & control , Metionina/farmacología , Nootrópicos/farmacología , Análisis de Varianza , Animales , Audiometría , Umbral Auditivo , Chinchilla , Cóclea/patología , Modelos Animales de Enfermedad , Femenino , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Pérdida Auditiva Provocada por Ruido/fisiopatología , Estrés OxidativoRESUMEN
Glutathione (GSH) provides an important antioxidant and detoxification pathway. We tested to determine if direct administration of GSH or GSH ester could reduce cisplatin- (CDDP) induced ototoxicity. We tested eight groups of five rats each: a control group, a group receiving 16 mg/kg ip CDDP infused over 30 minutes, and six groups receiving either GSH or GSH ester at 500, 1000, or 1500 mg/kg intraperitoneally 30 minutes prior to 16 mg/kg CDDP. Auditory brainstem response thresholds were measured for click and tone-burst stimuli at baseline and 3 days later. Outer hair cell (OHC) loss was measured for the apical, middle and basal turns. The 500 mg/kg GSH ester reduced hearing loss and OHC loss, but protection decreased as dosage increased, suggesting possible toxicity. GSH was not significantly protective. The best GSH ester protection was less than we have previously reported with D-methionine.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Ácido Gálico/análogos & derivados , Glutatión/análogos & derivados , Glutatión/farmacología , Células Ciliadas Auditivas Externas/efectos de los fármacos , Pérdida Auditiva/inducido químicamente , Estimulación Acústica , Animales , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Modelos Animales de Enfermedad , Ácido Gálico/farmacología , Glutatión/uso terapéutico , Células Ciliadas Auditivas Externas/ultraestructura , Inactivación Metabólica , Inyecciones Intraperitoneales , RatasRESUMEN
This study's purpose was to determine if a correlation exists between cochlear antioxidant activity changes and auditory function after induction of amino-glycoside (AG) ototoxicity. Two groups of five 250-350 g albino guinea pigs served as subjects. For 28 days, albino guinea pigs were administered either 200 mg/kg/day amikacin, or saline subcutaneously. Auditory brainstem response testing was performed prior to the first injection and again before sacrifice, 28 days later. Cochleae were harvested and superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase activities and malondialdehyde levels were measured. All antioxidant enzymes had significantly lower activity in the amikacin group (p < or = 0.05) than in the control group. The difference in cochlear antioxidant enzyme activity between groups inversely correlated significantly with the change in ABR thresholds. The greatest correlation was for the high frequencies, which are most affected by aminoglycosides. This study demonstrates that antioxidant enzyme activity and amikacin-induced hearing loss significantly covary.
Asunto(s)
Amicacina/toxicidad , Antibacterianos/toxicidad , Antioxidantes/metabolismo , Cóclea/enzimología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/enzimología , Amicacina/administración & dosificación , Análisis de Varianza , Animales , Antibacterianos/administración & dosificación , Estudios de Casos y Controles , Catalasa/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Cobayas , Pérdida Auditiva/fisiopatología , Inyecciones Subcutáneas , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/análisis , Superóxido Dismutasa/efectos de los fármacosRESUMEN
D-methionine (D-met) protects against cisplatin (CDDP) ototoxicity, but the mechanisms are not well understood. This study investigated D-met protection of cochlear oxidative state as measured by superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and malondiadehyde (MDA) levels. The design comprised four groups of five rats each: (1) a saline control group, (2) a CDDP-only-treated group, (3) a CDDP group pretreated with D-met, and (4) a group receiving only D-met. Auditory brainstem response testing (ABR) was performed before and 3 days after injection. CDDP alone caused marked hearing loss; significantly reduced SOD, CAT, and GR levels; and increased MDA levels, but D-met pretreatment protected against these changes. These studies suggest that D-met protects cochlear antioxidant enzyme levels from CDDP-induced decrements. The excellent correlation of enzyme levels with hearing loss and weight loss suggests that antioxidant enzyme level protection may underlie, at least in part, D-met's otoprotective action.
Asunto(s)
Antineoplásicos/toxicidad , Antioxidantes/farmacología , Cisplatino/toxicidad , Cóclea/efectos de los fármacos , Pérdida Auditiva/prevención & control , Metionina/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Cóclea/metabolismo , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/metabolismo , Inyecciones Intramusculares , Peroxidación de Lípido/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , RatasRESUMEN
This study describes audiologic methodology and results for evaluating potential ototoxicity in a phase I clinical trial of a new glycopeptide. This study was conducted under good clinical practices, which are regulated by the US Food and Drug Administration (FDA) (21 Code of Federal Regulations), and input from the FDA was sought prior to study implementation. Healthy, normal volunteers underwent extensive medical and audiologic assessments as part of this phase I dose- escalation study of dalbavancin, a new glycopeptide, to assess potential side effects. Audiologic monitoring included air-conduction thresholds in the conventional (0.25-8 kHz) and high-frequency (10-16 kHz) ranges. At baseline, subjects were also tested using word recognition, bone conduction testing if indicated, and tympanometry. Full testing was to be repeated if any subject met the American Speech-Language-Hearing Association (ASHA) 1994 criteria for ototoxic change. However, no subjects demonstrated ototoxic change after receiving dalbavancin, nor were any false-positive results obtained.