The Effects of Riluzole on Cisplatin-induced Ototoxicity

Abstract Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of riluzole hydrochloride i.p., and 8 mg/kg of riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 (p < 0.05) and 3 (p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 (p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of riluzole hydrochloride. Conclusion We can say that riluzolemay have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of riluzole.

Brainstem auditory evoked potentials in children with lead exposure / Potencial evocado auditivo de tronco encefálico em crianças com exposição ao chumbo

Introduction: Earlier studies have demonstrated an auditory effect of lead exposure in children, but information on the effects of low chronic exposures needs to be further elucidated. Objective: To investigate the effect of low chronic exposures of the auditory system in children with a history of low blood lead levels, using an auditory electrophysiological test. Methods: Contemporary cross-sectional cohort. Study participants underwent tympanometry, pure tone and speech audiometry, transient evoked otoacoustic emissions, and brainstem auditory evoked potentials, with blood lead monitoring over a period of 35.5 months. The study included 130 children, with ages ranging from 18 months to 14 years, 5 months (mean age 6 years, 8 months ± 3 years, 2 months). Results: The mean time-integrated cumulative blood lead index was 12 µg/dL (SD ± 5.7, range:2.433). All participants had hearing thresholds equal to or below 20 dBHL and normal amplitudes of transient evoked otoacoustic emissions. No association was found between the absolute latencies of waves I, III, and V, the interpeak latencies I-III, III-V, and I-V, and the cumulative lead values. Conclusion: No evidence of toxic effects from chronic low lead exposures was observed on the auditory function of children living in a lead contaminated area. .

Introdução: Estudos anteriores têm demonstrado efeitos da exposição ao chumbo no sistema auditivo em crianças, porém a exposição deste metal em níveis baixos ainda precisa ser investigada. Objetivo: Investigar os efeitos da exposição crônica ao chumbo no sistema auditivo de crianças com histórico de baixo nível sanguíneo de chumbo por meio de um teste eletrofisiológico. Método: Estudo de coorte transversal contemporânea. Foram realizados imitanciometria, audiometria tonal liminar e vocal, emissões otoacústicas evocadas transientes e potenciais evocados auditivos de tronco encefálico, com o monitoramento sanguíneo de chumbo durante um período de 35,5 meses. Participaram 130 crianças na faixa etária de 18 meses a 14 anos e 5 meses (6a8 m ± 3a2 m). Resultados: A média estimada do índice de pumblemia foi 12 mg/dL (DP ± 5,7). Todos os participantes apresentaram limiares auditivos iguais ou inferiores a 20 dBNA e amplitude normal das emissões otoacústicas evocadas transientes. Não foi encontrada associação entre as latências absolutas das ondas I, III e V e interpicos I-III, III-V e I-V e os valores cumulativos de chumbo. Conclusão: Não foi observada evidência de efeitos tóxicos em baixas exposições crônicas ao chumbo sobre a função auditiva de crianças que vivem em uma área contaminada por este metal. .

Lack of protection against gentamicin ototoxicity by auditory conditioning with noise / Falta de proteção contra a ototoxicidade da gentamicina pelo condicionamento auditivo com ruído

INTRODUCTION: Auditory conditioning consists of the pre-exposure to low levels of a potential harmful agent to protect against a subsequent harmful presentation. OBJECTIVE: To confirm if conditioning with an agent different from the used to cause the trauma can also be effective. METHOD: Experimental study with 17 guinea pigs divided as follows: group Som: exposed to 85 dB broadband noise centered at 4 kHz, 30 minutes a day for 10 consecutive days; group Cont: intramuscular administration of gentamicin 160 mg/kg a day for 10 consecutive days; group Expt: conditioned with noise similarly to group Som and, after each noise presentation, received gentamicin similarly to group Cont. The animals were evaluated by distortion product otoacoustic emissions (DPOAEs), brainstem auditory evoked potentials (BAEPs) and scanning electron microscopy. RESULTS: The animals that were conditioned with noise did not show any protective effect compared to the ones that received only the ototoxic gentamicin administration. This lack of protection was observed functionally and morphologically. CONCLUSION: Conditioning with 85 dB broadband noise, 30 min a day for 10 consecutive days does not protect against an ototoxic gentamicin administration of 160 mg/kg a day for 10 consecutive days in the guinea pig. .

INTRODUÇÃO: O condicionamento auditivo consiste da pré-exposição de um agente lesivo em baixos níveis para proteger contra uma posterior apresentação lesiva. OBJETIVO: Confirmar se o condicionamento com um agente diferente do utilizado para causar o trauma pode ser efetivo. MÉTODO: Estudo experimental com 17 cobaias albinas divididas como a seguir- grupo Som: exposto a um ruído branco de 85 dB centrado em 4 kHz, 30 minutos por dia, por 10 dias consecutivos; grupo Cont: administração intramuscular de gentamicina 160 mg/kg por dia, por 10 dias consecutivos; grupo Expt: condicionado com ruído como o grupo Som. Após cada exposição ao ruído, recebeu gentamicina similarmente ao grupo Cont. Os animais foram avaliados por emissões otoacústicas produto de distorção (EOAPDs), potencial evocado auditivo de tronco encefálico (PEATE) e microscopia eletrônica de varredura (MEV). RESULTADOS: Os animais que foram condicionados com ruído não mostraram qualquer efeito protetor quando comparados com os que receberam apenas a gentamicina em doses ototóxicas. Esta ausência de proteção foi observada tanto funcionalmente quanto morfologicamente. CONCLUSÃO: Os autores concluíram que o condicionamento com ruído branco a 85 dB por 30 minutos, por dia por 10 dias consecutivos, não protege contra uma administração de gentamicina 160 mg/kg/dia, por 10 dias consecutivos. .

Efeito da oxigenação hiperbárica em lesão ototóxica produzida pela amicacina em cobaias / The effects of hyperbaric oxygen therapy upon ototoxic injuries produced by amikacin in guinea pigs

A oxigenação hiperbárica têm favorecido a prevenção e o tratamento de afecções auditivas como a ototoxicidade. OBJETIVO: Estudar os efeitos da oxigenação hiperbárica em lesão ototóxica promovida pela amicacina. Forma de estudo: Experimental. MÉTODO: Avaliados aspectos funcionais de 12 cobaias albinas por meio das emissões otoacústicas produtos de distorção e do potencial evocado auditivo de tronco encefálico, antes e após o uso de amicacina (600 mg/kg/dia) e das sessões com oxigenação hiperbárica (2 ATA, 60 minutos). Aspectos morfológicos foram avaliados por meio de microscopia eletrônica de varredura. Grupos de estudo com três animais: grupo 1 - solução salina + oxigenação hiperbárica; grupo 2 - amicacina 8 dias; grupo 3 - amicacina + 7 dias de repouso e grupo 4 - amicacina + oxigenação hiperbárica. RESULTADOS: Grupo 1 apresentou preservação da funcionalidade e da morfologia durante todo experimento. Grupo 2 demonstrou, ao final do experimento, lesões estatisticamente significantes das células ciliadas com alterações funcionais. Grupos 3 e 4 apresentaram alterações estatisticamente significantes dos aspectos funcionais e morfológicos após o uso da amicacina, mantendo estas alterações após os procedimentos propostos. CONCLUSÃO: A oxigenação hiperbárica não promoveu alterações na morfologia das células ciliadas da cóclea e aos limiares eletrofisiológicos das cobaias submetidas à amicacina.

Hyperbaric oxygen therapy (HBOT) has enhanced the prevention and treatment of auditory ailments such as ototoxicity. OBJECTIVE: To study the effects of HBOT upon ototoxic injuries produced by amikacin. METHOD: This experimental study included 12 albino guinea pigs, whose auditory function was assessed through distortion product otoacoustic emissions (DPOAEs) and brainstem auditory evoked potentials (BAEPs) before and after the administration of amikacin (600 mg/kg/day) and HBOT sessions (2 ATA, 60 minutes). Morphological features were analyzed through scanning electron microscopy. Subjects were divided into four groups, as follows: group 1 - saline solution + HBOT; group 2 - amikacin for 8 days; group 3 - amikacin + seven days of rest; and group 4 - amikacin + HBOT. RESULTS: Group 1 subjects had preserved function and morphology throughout the experiment; Group 2 subjects had statistically significant levels of hair cell injury and functional impairment; Subjects on groups 3 and 4 had statistically significant functional and morphological impairment after the administration of amikacin, which were still present after the proposed procedures had been carried out. CONCLUSION: Hyperbaric oxygen therapy did not change the cochlear hair cell morphology or the electro-physiological thresholds of the guinea pigs given amikacin.

Effect of the ketamine/xylazine anesthetic on the auditory brainstem response of adult gerbils

The auditory brainstem response (ABR) is a test widely used to assess the integrity of the brain stem. Although it is considered to be an auditory-evoked potential that is influenced by the physical characteristics of the stimulus, such as rate, polarity and type of stimulus, it may also be influenced by the change in several parameters. The use of anesthetics may adversely influence the value of the ABR wave latency. One of the anesthetics used for e ABR assessment, especially in animal research, is the ketamine/xylazine combination. Our objective was to determine the influence of the ketamine/xylazine anesthetic on the ABR latency values in adult gerbils. The ABRs of 12 adult gerbils injected with the anesthetic were collected on three consecutive days, or a total of six collections, namely: pre-collection and A, B, C, D, and E collections. Before each collection the gerbil was injected with a dose of ketamine (100 mg/kg)/xylazine (4 mg/kg). For the capture of the ABR, 2000 click stimuli were used with rarefaction polarity and 13 stimuli per second, 80 dBnHL intensity and in-ear phones. A statistically significant difference was observed in the latency of the V wave in the ABR of gerbils in the C and D collections compared to the pre-, A and E collections, and no difference was observed between the pre-, A, B, and E collections. We conclude that the use of ketamine/xylazine increases the latency of the V wave of the ABR after several doses injected into adult gerbils; thus clinicians should consider the use of this substance in the assessment of ABR.

The role of apoptosis in cisplatin-induced ototoxicity in rats / Papel da apoptose na ototoxicidade por cisplatina em ratos

Cisplatin is a chemotherapy agent frequently used to treat different types of neoplasia. Ototoxicity is one of the side-effects which cause significant morbidity and limits its use. This study aimed at assessing the role of apoptosis in cisplatin-induced ototoxicity. DESIGN: experimental study. MATERIALS AND METHODS: male Wistar rats were treated with intraperitoneal cisplatin, in the doses of 24 and 16 mg/kg. The animals were assessed by means of distortion product evoked otoacoustic emissions (DPEOAE) or brainstem evoked auditory potentials (BEAP) in the third (D3) and fourth (D4) days after drug infusion onset. Following that, their cochleas were removed for immunohistochemical studies of apoptosis - TUNEL method. RESULTS: the group treated with 24 mg/kg showed a significant reduction in DPEOAE amplitude, and such fact was not seen with the 16 mg/kg. Both doses caused an increase in BEAP electrophysiological threshold in D3 and D4. Apoptosis was the injury mechanism responsible for the cisplatin-induced ototoxicity - 16 mg/kg dose, when the animals were assessed on D3. CONCLUSION: apoptosis may be involved in the cisplatin-induced ototoxicity, depending on the dose and time of injury assessment.

Cisplatina é um agente quimioterápico frequentemente usado para o tratamento de várias linhagens de neoplasias. A ototoxicidade é um dos efeitos colaterais causadores de significativa morbidade e que limita sua utilização. Este estudo teve por objetivo avaliar o papel da apoptose na ototoxicidade por cisplatina. DESENHO DO ESTUDO: Estudo experimental. MATERIAL E MÉTODO: Ratos Wistar machos foram tratados com cisplatina, via intraperitoneal, nas doses de 24 e 16 mg/kg. Os animais foram avaliados através de emissões otoacústicas evocadas produtos de distorção (EOAPD) ou potenciais auditivos evocados de tronco encefálico (PAETE) no terceiro (D3) e quarto (D4) dias após o início da infusão das drogas. Em seguida suas cócleas foram removidas para estudo de imunoistoquímica para apoptose, método TUNEL. RESULTADOS: O grupo tratado com 24 mg/kg mostrou diminuição significativa da amplitude das EOAPD, fato não observado com a dose de 16 mg/kg. Ambas as doses promoveram aumento do limiar eletrofisiológico pelo PAETE no D3 e D4. A apoptose foi o mecanismo de lesão responsável pela ototoxicidade da cisplatina, dose de 16 mg/kg, quando os animais foram avaliados no D3. CONCLUSÃO: Apoptose pode estar envolvida no mecanismo de ototoxicidade pela cisplatina, na dependência da dose e tempo de avaliação da lesão.

Distortion-product otoacoustic emissions and auditory brainstem responses sensitivity assessment in cisplatin-induced ototoxicity in rats / Avaliação da sensibilidade das emissões otoacústicas produtos de distorção e dos potenciais auditivos evocados de tronco encefálico na ototoxicidade por cisplatina em ratos

Cisplatin (cis-diamminedicloroplatinum) is an antineoplastic drug used in the treatment of a variety of cancers, especially head-and-neck cancer. Its ototoxicity, however, has been noted as a common side-effect which limits its use and causes significant morbidity. AIM: to assess distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA) sensitivity to detect secondary ototoxicity caused by different doses and means of administration of cisplatin in rats. STUDY DESIGN: Experimental. MATERIAL AND METHODS: Male Wistar rats were intraperitoneally (i.p.) injected with 24 mg/kg cisplatin, divided into three equal doses (8mg/kg) or a single i.p. injection of 16 mg/kg. The animals were evaluated by distortion product otoacoustic emission (DPOAE) or brainstem evoked response audiometry (BERA) on the 3rd and 4th days after the cisplatin injection. RESULTS: Treatment with cisplatin 24 mg/kg resulted in significant DPOAE decrease and it raised the BERA electrophysiological threshold. The 16mg/kg dose could not significantly reduce the DPOAE amplitude, but it raised the animals' hearing thresholds - detected by the BERA. CONCLUSION: In rats, BERA was more sensitivity than DPOAE at detecting cisplatin-induced ototoxicity in rats considering different doses and means of administration.

Cisplatina (cisdiaminodicloroplatinum) é um agente quimioterápico usado para o tratamento de várias linhagens de neoplasias, mormente as de cabeça e pescoço. Sua ototoxicidade permanece sendo um dos efeitos colaterais causadores de significativa morbidade e limita sua utilização. OBJETIVO: Avaliar a sensibilidade das emissões otoacústicas evocadas produtos de distorção (EOAPD) e potenciais auditivos evocados de tronco encefálico (PAETE) na detecção da ototoxicidade secundária a diferentes doses e formas de administração de cisplatina em ratos. FORMA DE ESTUDO: Experimental. MATERIAL E MÉTODO: Ratos Wistar machos, administrou-se cisplatina por via intraperitoneal (IP) nas doses de 24 mg/kg, fracionada em três doses diárias ou 16 mg/kg em infusão única. Avaliaram-se os animais através de EOAPD ou PAETE no terceiro (D3) e quarto (D4) dias após o início da infusão das drogas. RESULTADOS: O grupo tratado com 24 mg/kg mostrou diminuição significativa da amplitude das EOAPD e aumento do limiar eletrofisiológico pelo PAETE. A dose de 16 mg/kg não foi capaz de promover redução significativa da amplitude das EOAPD, mas elevou o limiar auditivo dos animais, detectado através de PAETE. CONCLUSÃO: Em ratos, os PAETE foram mais sensíveis que as OEAPD na detecção da ototoxicidade por cisplatina para diferentes doses e formas de administração.

Brainstem auditory evoked potentials (BAEPs) study in chronic arsenic poisoning patients.

OBJECTIVES: To explore the possible neurotoxicity of arsenic to auditory sensory pathways and evaluate roles of BAEPs in the detection of early brain damage resulting from arsenic exposure. DESIGN: Cross-sectional analytic study. MATERIAL AND METHOD: Twenty nine females with skin lesions consistent with arsenical dermatoses and 27 controls who met the inclusion criteria were investigatetd by Auditory Evoked Potentials (AEPs). Case findings resulted from a house-to-house survey in village 12, Ronphibun subdistrict and village 5, Saothong subdistrict, Nakhon Si Thammarat Province, southern Thailand in 1995. RESULTS: Differences between the arsenic-exposed population and the referent group regarding BAEP parameters, BAEP latencies and interpeak latencies were not found. CONCLUSION: Evidence of the abnormalities of the auditory sensory pathways was not found among female patients with arsenical dermtoses in Ronphibun. The role of BAEPs in the detection of brain damage resulting from arsenic exposure could not be demonstrated.

Differential effects of exogenous estrogen versus a estrogen-progesterone combination on auditory evoked potentials in menopausal women.

The study was undertaken to determine the differential effects of estrogen and progestin on auditory evoked responses in postmenopausal women receiving hormone replacement therapy (HRT). Forty-seven women between 45 and 70 years of age attending menopause and HRT clinic were divided into two groups. Group I included 32 women who attained natural menopause and receiving combined estrogen progestin therapy. While group II included 15 surgically menopausal women receiving only estrogen. Evoked potentials were recorded in form of auditory brainstem response (ABR), middle latency response (MLR) & slow vertex response (SVR). There was improvement of conduction in auditory pathways at the level of brainstem and thalamocortical projections as indicated by the decrease in latencies of most of the waves of ABR and/MLR after 6 months of HRT in both the groups. The conduction in association areas, as indicated by SVR, did not show a significant change. The intergroup comparison after therapy revealed a decrease in latency of wave V and I-V interpeak latency in group II indicating that only estrogen users are benefited more. Thus HRT facilitates the process of sensory conduction, which may form one of the mechanisms of improved neuropsychological functions in menopausal women on HRT. The addition of progestin to estrogen does not have a negative or potentiating effect on it.

Auditory evoked responses in postmenopausal women on hormone replacement therapy.

The effect of hormone replacement therapy (HRT) was studied in 32 postmenopausal women on their auditory Evoked Potentials i.e. auditory brainstem response (ABR), Middle latency response (MLR) & slow vertex response (SVR). Recordings were done on computerized evoked potential recorder using 10/20 system of electrode placement and standard click stimuli. A significant improvement in neural transmission was observed as was evidenced by decrease in the ABR wave latencies I, III, IV & V and interpeak latency III-V and I-V after 6 months of HRT. A similar significant decrease was observed in MLR wave latencies of Po, Na & Pa. The SVR wave latencies although found to be decreased after HRT, could not reach the level of statistical significance. There was a significant inverse correlation obtained between latencies of wave I in ABR, Po in MLR and serum estradiol. The results indicate the effect of sex hormone in improving transmission in auditory pathway from periphery through brainstem, thalamus upto cortex. However slow vertex responses indicate that auditory association areas are not much affected. This might have bearing on improvement of neuropsychological functions in postmenopausal women on HRT.

Potenciales provocados auditivos en adictos a la inhalación de solventes orgánicos / Brainstem auditory provoked potentials in addicts' to inhalation of organic solvents

Los solventes orgánicos lesionan a los lípidos de las memebranas de neuronas y de células gliales. Ello nos llevó a investigar, por medio de potenciales provocados auditivos del tallo cerebral (PPATC), si el sistema auditivo se encontraba afectado en sujetos con addición a la inhalación de tíner. Al comparar las latencias de las ondas a las intensidades de 90, 70 y 30 dB, se observaron diferencias estadísticamente significativas consistentes en el alargamiento de las latencias de las ondas III y V a 90 dB y de la onda V a 70 y 30 dB. En los intervalos interonda se observaron diferencias signficativas en el intervalo interonda I-III y I-V a 90 dB y del intervalo I-V a 70 dB, los culaes mostraron mayores valores de latencia promedio en el grupo de toxicómanos. Se encontraron dos pacientes sin respuesta a 30 dB, a los cuales se les realizó un estudio de audiometría a tonos puros mostrando una hipoacusia superficial bilateral. Estos resultados muestran la posibilidad de alteración de la vía auditiva en sujetos con addición al tíner

Brainstem auditory evoked potentials in epileptics on different anti-epileptic drugs.

The effects of anti-epileptic drugs (AEDs) on brainstem auditory evoked potentials (BAEPs) were studied on 32 female patients of epilepsy and 10 age-matched normal healthy females (NS). The patients were divided into 6 groups, those not receiving medication (drug free, DF) and those receiving AEDs: Phenytoin (PHT), Carbamazepine (CBZ), Phenobarbital (PB), a combination of PHT and PB and a combination of CBZ and PB. DF epileptics had shortened were V absolute latency (AL) and I-V interpeak latency (IPL) as compared to NS. Phenytoin and CBZ monotherapy produced a prolongation of wave III AL (by PHT only), wave V AL, wave I-III IPL and I-V IPL, as compared to DF epileptics. Phenytoin monotherapy also prolonged wave III AL and I-III IPL, as compared to NS. When PB in the dosage of 30-60 mg/d was used in combination with PHT the above mentioned changes were not observed. These findings indicate altered neuronal conduction and/or synaptic transmission in epileptics. Anti-epileptic drugs in the dosages studied, with exception of PHT appear to lead towards "normalization" of BAEPs.