Morphological analysis of the vestibular system of guinea pigs poisoned by organophosphate / Análise morfológica do sistema vestibular de cobaias intoxicadas por organofosforado

ABSTRACT INTRODUCTION: The vestibular system is responsible for body balance. There are substances that damage it, causing dizziness; these are termed vestibulotoxic substances. Agrochemicals have been investigated for ototoxicity because of studies that identified dizziness as a recurrent symptom among rural workers' complaints. OBJECTIVE: To histopathologically evaluate the vestibular system in guinea pigs exposed to an organophosphate, and to identify the drug's effects on this system. METHODS: Experimental clinical study. Eighteen guinea pigs were used; six of them poisoned with the organophosphate chlorpyrifos at doses of 0.5 mg/kg/day and seven of them at 1 mg/kg/day; and a control group of five guinea pigs was exposed to distilled water, all for 10 consecutive days. Later, ciliary tufts of saccule and utricle maculae were counted by scanning electron microscopy. RESULTS: Comparing the groups, a one-way ANOVA test for the variable "saccule" ( p = 0.0569) and a Kruskal-Wallis test for the variable "utricle" ( p = 0.8958) were performed, revealing no difference among groups in both variables. CONCLUSION: The histopathologic analysis of the vestibular system of guinea pigs exposed to an organophosphate showed no difference in the amount of ciliary tufts of saccule and utricle maculae at the doses tested, although the result for the variable "saccule" was considered borderline, showing a trend for significance.

RESUMO INTRODUÇÃO: O sistema vestibular é responsável pelo equilíbrio corporal. Existem substâncias que o danificam, causando tontura; são chamadas vestibulotóxicas. Agrotóxicos tornaram-se objeto de investigação da ototoxicidade a partir de pesquisas que apontaram tontura como sintoma recorrente entre as queixas de trabalhadores rurais. OBJETIVO: Constitui-se em avaliar a histopatologia do sistema vestibular de cobaias expostas a organofosforados, identificando os efeitos nesse sistema. MÉTODO: É um estudo clínico experimental, que utilizou 18 cobaias, sendo seis intoxicadas com organofosforadoclorpirifós na dose de 0,5 mg/kg/dia; sete na dose de 1 mg/kg/dia, e grupo controle com cinco cobaias expostas a água destilada, durante 10 dias consecutivos. Posteriormente realizou-se a contagem dos tufos ciliares nas máculas dos sáculos e utrículos através microscopia eletrônica de varredura. RESULTADOS: Na comparação intergrupos, para a variável sáculo realizou-se o teste ANOVA one-way (p = 0,0569); para a variável utrículo, utilizou-se o teste Kruskal-Wallis (p = 0,8958), revelando não haver diferença entre os grupos em ambas as variáveis. CONCLUSÃO: Análise histopatológica do sistema vestibular de cobaias expostas a organofosforado não demonstrou diferença na quantidade de tufos ciliares nas máculas dos sáculos e utrículos nas doses testadas, apesar do resultado para a variável sáculo ser considerado limítrofe mostrando uma tendência a significância.

Ototoxicidade por organofosforados: descrição dos aspectos ultraestruturais do sistema vestibulococlear de cobaias / Organophosphate-related ototoxicity: Description of the vestibulocochlear system ultrastructural aspects of guinea pigs

Os agrotóxicos organofosforados são amplamente utilizados na agricultura, e atualmente fazem parte do grupo de agentes químicos que podem levar à perda auditiva, no qual já estavam incluídos os solventes, os metais e os asfixiantes. OBJETIVO: Analisar a ação ototóxica aguda de um agrotóxico do grupo dos organofosforados na citoarquitetura do sistema vestibulococlear. Trata-se de um estudo experimental prospectivo. MATERIAL E MÉTODO: Foram utilizadas cobaias albinas machos, divididas em três grupos, nos quais se administrou água destilada (grupo 1 - controle), agrotóxico - 0,3mg/Kg/dia (grupo 2), agrotóxico - 3 mg/Kg/dia (grupo 3), durante sete dias consecutivos. O agrotóxico utilizado foi Tamaron BR (metamidofós). A avaliação anatômica da cóclea, sáculo e utrículo foi realizada através da microscopia eletrônica de varredura, após o período de aplicação do agrotóxico. RESULTADOS: As cobaias submetidas ao organofosforado apresentaram alterações morfológicas cocleares, com lesões nas três espiras analisadas, bem como alterações ciliares de sáculo e utrículo, intensificadas de acordo com a dosagem recebida do agente. CONCLUSÃO: As alterações morfológicas observadas nas células ciliadas nos grupos expostos a doses diárias de organofosforado promovem evidências de um efeito agudo degradante dos agrotóxicos no sistema vestibulococlear.

Organophosphate toxic agents are used in agriculture and are currently part of the group of toxic agents which can lead to hearing loss, in which we have solvents, metals and asphyxiation agents. AIM: to analyze the acute ototoxic action of a group of organophosphate agents in the vestibulo-cochlear system. This is a prospective experimental study. MATERIALS AND METHODS: we used male albino guinea pigs, broken down into three groups, to which we provided distilled water (group 1 - control), agrotoxic agent - 0.3mg/Kg/day (group 2), agrotoxic - 3 mg/Kg/day (group 3), during 7 seven consecutive days. The most used agrotoxic agent was Tamaron BR (metamidophos). The anatomical evaluation of the cochlea, saccule and utricle was carried out by means of electronic scanning microscopy after the use of the agrotoxic agent. RESULTS: the guinea pigs submitted to the organophosphate presented cochlear morphological alterations with lesions on the three turns analyzed, as well as cilia alterations in the saccule and utricle, intensified according to the agent dosage. CONCLUSION: the morphological alterations seen in the hair cells exposed to daily doses of organophosphate promote evidences of an acute deleterious effect of agrotoxic agents on the vestibulo-cochlear system.

Cochlear and vestibular toxicity by the use of ototoxic drugs - the regional experience

The objective of the study is to find out the common pharmacologic agents causing ototoxicity in our region with their pattern of presentation and effects on the inner ear. This study was conducted at department of Ear, Nose, Throat, Head and Neck Surgery, Civil Hospital Karachi, over a period of three years from January 1998 to December 2000. A total of 44 patients were included who presented at ENT department with the diagnosis of ototoxicity. The diagnosis was established in each case by taking detailed history, through ENT examination and related investigations. All these patients were followed up regularly for a maximum of six months. Out of44 patients, 32 were male and 12 were female patients with mean age of 42.2 years. Majority of the patients had some form of cochleotoxicity with symptoms of deafness in 95.4% and tinnitus in 36.6% of the cases. Vestibular toxicity with symptoms of vertigo and sense of imbalance were presented in 29.5% of the cases. 26 patients received only one ototoxic drug while 18 patients had received more than one ototoxic drug at one time. Gentamycin was the commonest offending agent for ototoxicity in 40.9% of the cases. In this study no patient of ototoxicity was found due to macrolide antibiotics, salicylates or any non-steroidal anti-inflammatory drugs. Sensori-neural hearing loss in majority of the patients was moderate to severe in nature

Effects of industrial solvents on hearing and balance: a review.

Industrial hearing loss has generally been associated with noise exposure, but there is a growing awareness that industrial solvents can have an adverse effect on the auditory and vestibular systems in man. Both animal experiments and human studies point to an ototoxic effect of industrial solvents, as well as some central auditory and vestibular disturbances. This review examines the research from the last four decades in an attempt to get an overview of the available evidence. Research shows that industrial solvents are ototoxic in rats. The majority of the solvents studied cause a loss of auditory sensitivity in the mid-frequencies in rats, affecting outer hair cells in the order OHC 3 > OHC 2 > OHC 1 . Inner hair cells are generally unaffected. Spiral ganglion cells are most vulnerable to trichloroethylene. Simultaneous exposure to solvents and noise results in a synergistic effect; the pattern of trauma mirrors that due to solvent exposure rather than noise, but is more enhanced. There is a critical level when synergy occurs. The effects of solvents on the vestibular system are neurotoxic and influence the vestibulo-oculomotor system in both animals and humans; humans also present with problems in postural sway. There is a strong suggestion from human studies that solvents are ototoxic in man, but findings show that both the peripheral and central auditory pathways can be affected. Hearing losses can be in the high frequency region or can affect a wider range of frequencies. Hearing loss and balance disturbances can occur at levels below permitted levels of exposure. The synergistic effect of combined exposure to solvents and noise has also been noted in humans, resulting in greater hearing losses than would be expected from exposure to noise and solvents alone. The findings from both human and animal studies indicate that exposure to industrial solvents or to industrial solvents and noise can have an adverse effect on hearing and balance. The implications for industry and hearing conservation are far reaching.

Comparative Vestibulotoxicity of Different Aminoglycosides in the Guinea Pigs

The histopathological alterations in the vestibule due to aminoglycosides are well defined. Although there are reports comparing the vestibulotoxic effects of the many aminoglycosides, this is the first study to compare the effects of the most commonly used aminoglycosides i.e., streptomycin, gentamicin, amikacin and netilmicin administered both transtympanically and systemically. The transtympanic and systemic administration of each aminoglycoside caused similar histopathological alterations in the vestibule. The most severe degeneration in the cristae ampullaris, utriculus and sacculus was observed after streptomycine administration. The severity of the vestibular damage in terms of magnitude was in the order of streptomycine, gentamicin, amikacin, and netilmicin.

Alfa-Glucosidasa con Posible Acción Hidrolítica Sobre Aminoglicósidos en la Sangre y el Vestíbulo de Ratas / Alpha-glucosidase with possible hydrolytic action over aminoglycosides in the blood and vestibule of rats

Antecedentes e hipótesis. La estreptomicina (STP)es un antibiótico aminoglicósido que se usa en el tratamiento de la tuberculosis, con efectos tóxicos importantes sobre la función vestibular. Los antecedentes farmacocinéticos muestran que la STP se acumula en un principio en la parte perilinfática y por mecanismos aún no descritos pasa a la endolinfa donde su principal blanco de acción son los cilios sensorios de las células pilosas vestibulares. Consideramos importante averiguar que parte de la molécula de STP es la responsable de su toxicidad vestibular, y tenemos evidencias que señalan la parte estreptidina (STD)como la porción activa, por lo que se propone que la STP actúa fragmentada por acción de una alfa-glucosidasa que hidroliza el enlace -1,4 con la liberación de la STD y que esté presente ya sea en el vestíbulo, en el torrente sanguíneo o en ambos. Método. Se determinó la actividad de alfa-glucosidasa en el suero y en homogeneizado vestibular de la rata usando p-nitrofenil--d-glucósido como sustrato; siguiendo el p-nitrofenilo (pNP)liberado espectrofotométricamente a 400 nm. Resultados. Se encontró alfa-glucosidasa tanto en el suero como en el vestíbulo de la rata con actividades específicas de 0.035 y 1.3 nmol de pNP/mg proteína/min respectivamente. Conclusión. La actividad encontrada en vestíbulo es semejante a la de la alfa-glucosidasa lisosomal del hígado de la rata (1.5 nmol de pNP/mg proteína/min)por lo que es posible que la alfa-glucosidasa presente en el suero y en el vestíbulo pueda romper a la STP, liberando la parte STD que actuaría sobre el oído

Estreptomicina: propiedades fisicoquímicas y toxicidad vestibular / Streptomycin, physical and chemical characteristics and vestibular toxicity

Propósito: Los antibióticos aminoglucósidos estreptomicina (STP) y kanamicina (KAN) son tóxicos para las células sensoriales del vestíbulo y de la cóclea, respectivamente. Químicamente están constituidos por estreptidina (STD) un derivado del inositol y dos azúcares, la esteptosa (Stosa) y la N-metilglucosamida (nm-GLUN); sin embargo, en la STP, la STD tiene dos sustituyentes guanidino, los que están ausentes en la KAN. Por lo tanto, se propone estudiar si la vestíbulo-toxicidad específica de la STP se debe a los grupos guanidino. Material y Métodos: Se incubaron en vitro, membranas celulares aisladas de los órganos vestibulares, con 3H-espermidina (3H-Spdina), un análogo estructural de la STP. Se midió la capacidad de los siguientes compuestos: STP, STD, KAN, guanidina (GUA) y n-acetilglucosamina (na-GLUN) para desplazarlos específicamente. Resultados: Se encontró que el orden de desplazamiento de la 3HSPdina para esas sustancia era STP=STD KanGUAn-a-GLUN. Conclusiones: Los resultados sugieren fuertemente que la STP debe su especificidad vestibulotóxica, a la presencia de los grupos guanidino en la porción de STD de su molécula, los que interactuarían por sus cargas positivas con estructuras membranales vestibulares relacionadas con la transducción, muy probablemente los cilios sensorios de las células ciliadas vestibulares

Aminoglucósidos, su efecto ototóxico / Aminoglucosides. The ototoxcic effect

Los aminoglucósidos son antibióticos de amplio espectro, especialmente útiles contra microorganismos gramnegativos aerobios. Desde que se introdujo la estreptomicina para el tratamiento de la tuberculosis se identificaron sus posibles efectos tóxicos. Todos los antibióticos de este grupo pueden provocar toxicidad renal, coclear y/o vestibular. El daño renal generalmente es reversible, pero el daño al epitelio sensorial que producen en el oído interno es irreversible. Se ha sugerido que la interferencia con la síntesis de proteínas es el mecanismo central de su toxicidad. En los últimos 50 años, se han identificado factores de riesgo para que la ototoxicidad se presente, incluyendo una forma de hipersensibilidad hereditaria. Aunque se han propuesto estrategias para prevenir del daño, aún es común observar pacientes con sordera y desequilibrio secundarios a la administración de aminoglucósidos. En este documento se ofrece una revisión resumida sobre el efecto ototóxico de los aminoglucósidos. Se comentan algunas estrategias para su prevención y la aplicación terapéutica del efecto vestibulotóxico

Ototoxicidade de drogas medicamentosas / Ototoxicity of drugs

Os medicamentos ototóxicos, sendo os antibióticos aminoglicosídeos mais comuns, podem provocar lesöes irreversíveis nas células ciliadas do órgäo de Corti e das máculas e cristas do sistema vestibular. A lesäo celular está relacionada com a formaçäo de substâncias complexas entre a droga ototóxica e os polifosfoinositídeos da membrana celular. O controle das funçöes auditiva e vestibular deve ser permanente durante a utilizaçäo desses medicamentos, sobretudo se existem fatores de risco. Experimentalmente, as lesöes induzidas têm sido estudadas em animais por métodos eletrofisiológicos, com registro dos potenciais colcleares e dos potenciais do tronco cerebral, e por métodos histológicos, com técnicas de preparaçäo de superfície do órgäo de Corti, microscopia eletrônica e isolamento de células ciliadas em meio de cultura

Da avaliaçäo vestibular em 42 pacientes com ototoxicose / Vestibular evaluation in 42 patients with ototoxicosis

This investigation was developed in "Setor de Equilibriometria das Disciplinas de Otorrinolaringologia e Distúrbios da Comunicaçäo Humana da Escola Paulista de Medicina" and it consisted in the vestivular evaluation of 42 patients treated with gentamycin. The vestibular evaluation was performed and measured according ro MANGABEIRA ALBERNAZ e col., (l986) and in this paper we related the analysis of rotatory and caloric reponses. In facing our study we concluded that the most frequent signals were hiporreflexia or absence of responses in rotatory and caloric tests that indicates the deficit on the vestibular function in these patients