Medicações ototóxicas utilizadas no tratamento oncológico pediátrico: uma revisão sistemática / Ototoxic medications used in treating childhood cancer: a systematic review

RESUMO Objetivo Fazer um levantamento dos medicamentos ototóxicos utilizados no tratamento do câncer pediátrico, apontar os danos das drogas para o sistema auditivo e os métodos utilizados na identificação destes danos nessa população. Estratégia de pesquisa: Foram utilizados periódicos nacionais e internacionais pertinentes ao assunto, acessados eletronicamente em bases de dados da Biblioteca Virtual em Saúde - MS, PubMed, Biblioteca Digital Brasileira de Teses e Dissertações, que envolvessem a população pediátrica com histórico de tratamento oncológico, publicados entre 2007 e 2016, e no Banco de Teses e Dissertações da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Critérios de seleção Foram selecionados estudos que contemplassem os seguintes critérios: estudos observacionais nas línguas portuguesa, inglesa ou espanhola e resumos disponíveis que informassem o método de avaliação do dano auditivo. Resultados A amostra final resultou em 12 artigos. Destes, a audiometria tonal limiar foi o método de avaliação auditiva mais utilizado, estando presente em 10 (84,61%) dos estudos, seguido das emissões otoacústicas (46,15%). Todos os estudos foram desenvolvidos com pacientes que fizeram uso de cisplatina ou derivados da platina e, quanto ao dano auditivo, apenas 1 dos estudos incluídos não relatou presença de alteração na população estudada. Conclusão Os derivados da platina expressam papel importante no tratamento do câncer em diversos níveis e são os agentes ototóxicos mais citados em pesquisas. A cóclea é o local mais afetado, mais especificamente as células ciliadas externas. Os métodos de investigação da alteração auditiva mais utilizados são a audiometria tonal limiar e as emissões otoacústicas.

ABSTRACT Objective The aim of the present study was to perform a literature review on ototoxic medications used for the treatment of childhood cancer and determine the harm caused by such drugs to the auditory system as well as the methods used to identify this harm. Search strategy The electronic databases of the Virtual Health Library (Brazilian Health Ministry), PubMed, Brazilian Digital Library of Theses and Dissertations, and Databank of Theses and Dissertations of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES [Brazilian Coordination for the Advancement of Higher Education Personnel]) were searched for relevant national and international papers involving the pediatric population with a history of treatment for cancer published between 2007 and 2016. Selection criteria Observational studies published in Portuguese, English or Spanish with abstracts available and that informed the method for assessing hearing damage. Results The final sample consisted of 12 articles. Pure-tone threshold audiometry was the used in ten (84.61%) of the studies and otoacoustic emissions were investigated in 46.15%. All studies involved patients who made use of cisplatin or platinum derivatives. Only one of the studies included in the present review reported no changes in hearing in the population studied. Conclusion Platinum derivatives play an important role in the treatment of cancer and are the most widely cited ototoxic agents in studies. The cochlea is the most affected site, specifically the outer hair cells. The most widely used methods for assessing altered hearing are pure-tone threshold audiometry and otoacoustic emissions.

The importance of audiometric monitoring in patients with multidrug-resistant tuberculosis

Abstract INTRODUCTION: A total of 771 cases of multidrug-resistant tuberculosis (MDR-TB) were reported in Brazil in 2014. Treatment of MDR-TB with aminoglycosides can produce serious side effects such as permanent and irreversible hearing loss, which occurs in 5-64% of cases, and severely compromise patient quality of life. The goal of this research was to evaluate auditory and vestibular side effects in patients treated for MDR-TB and to identify associations between these complaints and the type of aminoglycoside used. METHODS: We performed a retrospective review of 599 medical records from patients with MDR-TB who were treated at the Hélio Fraga/Fiocruz Reference Center between 2006 and 2010. Cases without auditory or vestibular complaints and patients who were not treated with aminoglycoside drugs were excluded from the study. RESULTS: Of 164 eligible cases, 55 (33.5%) reported an auditory or vestibular complaint and medication was subsequently suspended, although hearing damage was not confirmed in all cases. Audiometric testing confirmed hearing loss in 11 (21.7%) of 12 cases submitted for evaluation. Hearing loss related to ototoxicity was confirmed in 15 (62.5%) cases. Tinnitus was significantly associated with the use of amikacin and streptomycin. CONCLUSIONS: Evaluations of ototoxicity symptoms were not usually reported in the routine care of patients with MDR-TB. Complaints of tinnitus were associated with amikacin and streptomycin use. These results require confirmation in future studies.

Hearing thresholds at high frequency in patients with cystic fibrosis: a systematic review / Limiares auditivos em altas frequências em pacientes com fibrose cística: revisão sistemática

Abstract Introduction: High-frequency audiometry may contribute to the early detection of hearing loss caused by ototoxic medications. Many ototoxic drugs are widely used in the treatment of patients with cystic fibrosis. Early detection of hearing loss should allow known harmful drugs to be identified before the damage affects speech frequencies. The damage caused by ototoxicity is irreversible, resulting in important social and psychological consequences. In children, hearing loss, even when restricted to high frequencies, can affect the development of language. Objective: To investigate the efficacy and effectiveness of hearing monitoring through high-frequency audiometry in pediatric patients with cystic fibrosis. Methods: Electronic databases PubMed, MedLine, Web of Science and LILACS were searched, from January to November 2015. The selected studies included those in which high-frequency audiometry was performed in patients with cystic fibrosis, undergoing treatment with ototoxic drugs and published in Portuguese, English and Spanish. The GRADE system was chosen for the evaluation of the methodological quality of the articles. Results: During the search process carried out from January 2015 to November 2015, 512 publications were identified, of which 250 were found in PubMed, 118 in MedLine, 142 in Web of Science and 2 in LILACS. Of these, nine articles were selected. Conclusion: The incidence of hearing loss was identified at high frequencies in cystic fibrosis patients without hearing complaints. It is assumed that high-frequency audiometry can be an early diagnostic method to be recommended for hearing investigation of patients at risk of ototoxicity.

Resumo Introdução: A audiometria de altas frequências pode contribuir para a detecção precoce de alterações auditivas causadas por medicações ototóxicas. No tratamento dos pacientes com fibrose cística, existem muitos fármacos ototóxicos amplamente utilizados. A detecção precoce de alterações auditivas deve permitir que sejam identificadas antes que o dano atinja as frequências da fala. A lesão causada pela ototoxicidade é irreversível, traz importantes consequências sociais e psicológicas. Nas crianças, a perda auditiva, mesmo restrita às altas frequências, pode afetar o desenvolvimento da linguagem. Objetivo: Investigar a eficácia e a efetividade do monitoramento da audição por meio da audiometria de altas frequências em pacientes pediátricos com fibrose cística. Método: Foram consultadas as bases de dados eletrônicas PubMed, Medline, Web of Science e Lilacs, de janeiro a novembro de 2015. Foram selecionados os estudos em que foi feita audiometria de altas frequências em pacientes com fibrose cística em tratamento com medicamentos ototóxicos e publicados em português, inglês e espanhol. Para a avaliação da qualidade metodológica dos artigos optou-se pelo uso do sistema Grade. Resultados: No processo de busca feito de janeiro de 2015 a novembro de 2015 foram encontradas 512 publicações, 250 na PubMed, 118 na Medline, 142 na Web of Science e dois na Lilacs. Desses, foram selecionados nove artigos. Conclusão: Identificou-se a ocorrência de perda auditiva em altas frequências em pacientes com fibrose cística sem queixas auditivas. Admite-se que audiometria em altas frequências possa ser um método de diagnóstico precoce a ser recomendado para investigação auditiva de pacientes em risco de ototoxicidade.

High frequency hearing thresholds and product distortion otoacoustic emissions in cystic fibrosis patients, / Limiares auditivos em altas frequências e emissões otoacústicas na fibrose cística

ABSTRACT INTRODUCTION: The treatment of patients with cystic fibrosis involves the use of ototoxic drugs, mainly aminoglycoside antibiotics. Due to the use of these drugs, fibrocystic patients are at risk of developing hearing loss. OBJECTIVE: To evaluate the hearing of patients with cystic fibrosis by High Frequency Audiometry and Distortion Product Otoacoustic Emissions. METHODS: Cross-sectional study. The study group consisted of 39 patients (7-20 years of age) with cystic fibrosis and a control group of 36 individuals in the same age group without otologic complaints, with normal audiometric thresholds and type A tympanometric curves. High Frequency Audiometry and Distortion Product Otoacoustic Emissions tests were conducted. RESULTS: The study group had significantly higher thresholds at 250, 1000, 8000, 9000, 10,000, 12,500, and 16,000 Hz (p = 0.004) as well as higher prevalence of otoacoustic emission alterations at 1000 and 6000 Hz (p = 0.001), with significantly lower amplitudes at 1000, 1400, and 6000 Hz. There was a significant association between alterations in hearing thresholds in High Frequency Audiometry with the number of courses of aminoglycosides administered (p = 0.005). Eighty-three percent of patients who completed more than ten courses of aminoglycosides had hearing loss in High Frequency Audiometry. CONCLUSION: A significant number of patients with cystic fibrosis who received repeated courses of aminoglycosides showed alterations in High Frequency Audiometry and Distortion Product Otoacoustic Emissions. The implementation of ten or more aminoglycoside cycles was associated with alterations in High Frequency Audiometry.

Resumo INTRODUÇÃO: O tratamento dos pacientes com fibrose cística envolve o uso de medicamentos ototóxicos, principalmente de antibióticos aminoglicosídeos. Devido ao uso destes medicamen-tos, os pacientes fibrocísticos apresentam risco de desenvolver perda auditiva. OBJETIVO: Avaliar a audição dos pacientes com fibrose cística pela Audiometria de Altas Frequências (AAF) e Emissões Otoacústicas por Produto de Distorção (EOAPD). MÉTODO: Estudo transversal. O grupo de estudo foi constituído por 39 pacientes com idades entre 7 e 20 anos com fibrose cística e o grupo controle por 36 indivíduos da mesma faixa etária, sem queixas otológicas, com limiares audiométricos normais e curvas timpanométricas tipo A. Foram realizados os exames de audiometria de altas frequências e emissões otoacústicas por produto de distorção. RESULTADOS: O grupo de estudo apresentou limiares significativamente mais elevados em 250; 1000; 8.000; 9.000; 10.000; 12.500 e 16.000 Hz; (p = 0,004) e maior prevalência de alterações nas emissões otoacústicas em 1.000 e 6.000 Hz (p = 0,001); com amplitudes significativamente mais baixas em 1.000; 1.400 e 6.000 Hz. Houve associação significativa entre as alterações dos limiares auditivos na AAF com o número de ciclos de aminoglicosídeos realizados (p = 0,005). Oitenta e três por cento dos pacientes que foram submetidos a mais de 3 ciclos de aminoglicosídeos apresentaram perda auditiva na AAF. CONCLUSÃO: Um número significativo de pacientes com fibrose cística que receberam repetidos ciclos de aminoglicosídeos apresentou alterações na AAF e EOAPD. A realização de 10 ou mais ciclos de aminoglicosídeos esteve associada às alterações na AAF.

Avaliação audiométrica de pacientes em tratamento para tuberculose pulmonar / Audiometric evaluation of patients treated for pulmonary tuberculosis

OBJETIVO: Analisar a condição auditiva de uma população em tratamento para tuberculose pulmonar em dois hospitais de referência no Brasil. MÉTODOS: Estudo descritivo envolvendo 97 pacientes de ambos os sexos, com idade entre 18 anos e 60 anos, que estivessem em tratamento para tuberculose pulmonar ativa, internados ou em acompanhamento ambulatorial em dois hospitais de referência no estado do Rio de Janeiro. Os participantes foram entrevistados e realizaram audiometria tonal liminar. RESULTADOS: Na população estudada, 65 pacientes (67 por cento) eram homens, 52 (54 por cento) estavam em tratamento de primeira linha e 45 (46 por cento) estavam em tratamento de segunda linha, o qual incluía aminoglicosídeos. Tabagismo, uso de bebidas alcoólicas, exposição a ruído e uso de medicamentos ototóxicos foram identificados respectivamente em 65 (67 por cento), 51 (53 por cento), 53 (55 por cento) e 45 (46,4 por cento) pacientes. As queixas auditivas e vestibulares mais frequentemente mencionadas foram tontura, em 28 (28,8 por cento); zumbido, em 27 (27,8 por cento); e hipoacusia, em 23 (23,7 por cento). CONCLUSÕES: Devido ao elevado número de casos de perda auditiva encontrado neste estudo, recomenda-se que todos os pacientes em tratamento para tuberculose sejam submetidos a monitoramento auditivo.

OBJECTIVE: To evaluate the hearing status of patients being treated for pulmonary tuberculosis at referral hospitals in Brazil. Methods: This was a descriptive study involving 97 male and female inpatients/outpatients between 18 and 60 years of age who were undergoing treatment for active pulmonary tuberculosis at one of two referral hospitals in the state of Rio de Janeiro. After being interviewed, all of the patients underwent pure tone audiometry. Results: Of the 97 patients studied, 65 (67 percent) were male, 52 (54 percent) were receiving first-line treatment, and 45 (46 percent) were receiving second-line treatment, which included aminoglycosides. Smoking, alcohol consumption, exposure to noise, and ototoxic medication use were identified in 65 (67 percent), 51 (53 percent), 53 (55 percent), and 45 (46.4 percent) of the patients, respectively. The most common auditory and vestibular complaints were dizziness, in 28 patients (28.8 percent); tinnitus, in 27 (27.8 percent); and hypoacusis, in 23 (23.7 percent). Conclusions: Due to the great number of patients with hearing loss in the present study, we recommend that all patients under tuberculosis treatment be submitted to auditory monitoring.

mtDNA mutations, hearing loss and aminoglycoside treatment in Mexicans / Mutações em DNA mitocondrial, hipoacusia e tratamento de mexicanos com aminoglicosídeos

Streptomycin and aminoglycoside derivatives are commonly used to treat tuberculosis and other stubborn infections; these drugs may alter auditory and/or vestibular function. Mutations in mitochondrial DNA have been associated with hypersensitivity to aminoglycosides; no studies have been conducted in Mexicans, which are very prone to such alterations because aminoglycosides have been prescribed carelessly for many years, irrespective of the ailment to be treated. AIM: We investigated "hot spot" mutations described previously as causing inner ear alterations. METHODS: Hot spot mutations at the 12S rRNA gene and the tRNA Serine (UCN) gene were screened by PCR-RFLP and sequencing in 65 subjects undergoing audiological and vestibular testing. STUDY DESIGN: Experimental. RESULTS: 32 individuals had healthy auditory and vestibular function, whereas 33 subjects had auditory affections. We found none of the previously reported mutations related to aminoglycoside hypersensitivity, or non-syndromic hearing loss. Two hearing-impaired patients that had been treated with streptomycin had the T1189C variant of the mitochondrial 12S rRNA region. CONCLUSION: Mutations related to hearing loss in other ethnic backgrounds were not found in Mexicans. However, the T1189C variant is possibly a putative mutation related to aminoglycoside hypersensitivity and was present in 2 patients.

Derivados de aminoglicosídeos e estreptomicina são comumente utilizados para tratar tuberculose e outras infecções mais resistentes; esses medicamentos podem alterar a função vestibular e/ou auditiva. Mutações no DNA mitocondrial têm sido associadas à hipersensibilidade a aminoglicosídeos; não há estudos conduzidos com mexicanos, que são muito predispostos a tais alterações, uma vez que aminoglicosídeos têm sido exageradamente prescritos há anos, sem associações à doença sendo tratada. OBJETIVO: investigamos mutações "hot spot" previamente descritas como causas de alterações no ouvido interno. MÉTODOS: Mutações hot spot no gene 12S rRNA e gene SerinatRNA (UCN) foram triados pela PCR-RFLP e sequenciados em 65 indivíduos sujeitos a exames audiométricos e vestibulares. Desenho do estudo: Experimental. RESULTADOS: 32 indivíduos com funções auditiva e vestibular normais, e 33 indivíduos com doenças auditivas. Não encontramos nenhuma das mutações previamente relatadas como associadas à hipersensibilidade aos aminoglicosídeos, ou perda auditiva não-sindrômica. Dois pacientes com hipoacusia que haviam sido tratados com estreptomicina tinham a variante T1189C na região 12S rRNA. CONCLUSÃO: Mutações associadas à hipoacusia em outras etnias não foram encontradas em mexicanos. Entretanto, a variante T1189C é possivelmente uma mutação associada à hipersensibilidade a aminoglicosídeos, e esteve presente em dois pacientes.

Comparative nephrotoxic effects of gentamycin and tobramycin

To compare the nephrotoxic effects of two aminoglycosides namely, gentamycin and tobramycin on rabbits. Comparative study. Allama Iqbal Medical College Lahore, from January 2010 to December 2010. The serum levels of creatinine and electrolytes [sodium and potassium] were measured in different groups of rabbits [control group-A, gentamycin group B and tobramycin-group C]. Rabbits in group B and C received laboratory diet and 32 mg/kg/day of gentamycin and tobramycin were given through intramuscular [IM] route twice daily for 7 days. Blood samples were collected on day 1, 10, 16, and 22 of drug administration. Each rabbit of all groups was sacrificed on 22[nd] day of experiment. Kidneys were removed and histological examination of the 4 components of the renal tissue [glomeruli, tubules, blood vessels and interstitial tissue] was carried out. Level of serum creatinine was significantly increased in both experimental groups [B and C] as compared to the control group A. On the other hand, level of serum sodium was insignificantly increased in groups B and C, whereas level of serum potassium was significantly decreased in groups of rabbits receiving gentamycin and tobramycin as compared to control group. There was no significant difference in nephrotoxicity between gentamycin and tobramycin

Once versus individualized multiple daily dosing of aminoglycosides in critically ill patients

The purpose of this study was to evaluate the once daily dosing [ODD] program in critically ill Egyptian patients compared to individualized multiple daily dosing [MDD] in terms of clinical and bacteriological efficacy. In addition, the incidence of nephrotoxicity associated with both regimens in this specific group of patients was assessed. Fifty-two patients with suspected or confirmed bacterial infections admitted to the Critical Care Medicine Department, Kasr El-Aini-Cairo University Hospitals comprised the study population. The amikacin group [30 patients] was sub-divided into 14 patients receiving amikacin ODD [1 g i.v.] and 16 patients receiving amikacin in MDD [500 mg i.v./dose]. The gentamicin group [22 patients] was sub-divided into 10 patients receiving the drug ODD [240 mg i.v.] and 12 patients receiving gentamicin MDD [80 mg i.v./dose]. Amikacin or gentamicin serum levels were determined by the enzyme multiplied immunoassay technique using Emit 2000. MDD regimen was adjusted based on the individual pharmacokinetic parameters using the Sawchuk-Zaske method. There was no significant difference between the two dosing regimens with regard to clinical and antibacterial efficacy or incidence of nephrotoxicity of both gentamicin and amikacin groups. In the ODD regimen, duration of treatment had no effect on increasing incidence of nephrotoxicity unlike the individualized MDD regimen. No dose adjustments were needed in the once daily dosing regimen since trough concentrations have never been above toxic level. The study showed that the ODD regimen is preferred in critically ill patients to individualized MDD as shown by comparable efficacy, nephrotoxicity and lesser need for therapeutic drug monitoring and frequent dose adjustments required in the individualized MDD regimen

Drogas nefrotóxicas / Drug-induced nephrotoxicity

La estructura renal es sensible a la acción de fármacos, especialmente en el túbulo proximal y distal, que están constituidos por células especializadas con gran actividad metabólica dedicada al transporte de solutos. En esta comunicación se describen diversos fármacos que interfieren con el túbulo-intersticio renal en forma aguda o crónica, se explican los mecanismos de daño renal y las formas de evitarlos en el momento del uso clínico de nefrotóxicos. También se hace referencia a aquellos fármacos cuya eliminación es principalmente por filtración glomerular, por lo que su administración debe ajustarse al cálculo de esta variable funcional para evitar toxicidades en órganos y tejidos, incluido el riñón.

Kidney structure and function, especially at the proximal and distal tubule, are sensitive to the toxic action of different substances that are actively transported at those levels. This Communication describes the most common drugs that damage, in an acute or chronic form, the tubuleinterstitial segment of the renal tissue and describe some ways to prevent nephrotoxicity. Also, the paper refers to a second mechanism of damage due to drug accumulation when administered to patients with some degree of renal dysfunction. To avoid renal toxicity the prescription must be adjusted to a calculated renal clearance obtained previous drug administration.

Influência dos polimorfismos da glutationa s-transferase na ototoxicidade dos aminoglicosídeos / Influence of glutathione s-transferase on the ototoxicity caused by aminoglycosides

The process of hair cell damage and death as a result of exposure to noise and ototoxins seems to be mediated by reactive oxygen species. AIM: To investigate the relationship between genetic polymorphisms in the Glutathione S-transferase and the susceptibility to hearing loss induced by aminoglycosides. MATERIALS AND METHODS: Null genotypes were analyzed by multiplex-PCR in the DNA samples from 50 patients and 72 controls. The patients were divided into 3 groups, 10 with hearing loss using aminoglycosides (group A), 20 with hearing loss without exposure to the drug (group B) and 20 hearing individuals who used the antibiotic (group C). STUDY DESIGN: Experimental. RESULTS: Polymorphisms in the GSTM1 and GSTT1 genes were found in 16 percent and 42 percent of patients and in 18 percent and 53 percent of the control group, respectively. After statistical analysis no significant difference was observed between the control groups and A (p=0.86) and (p=0.41), controls and B (p=0.27) and (p=0.24), controls and C (p=0.07) and (p=0.47), controls and A + C (p=0.09) and (p=0.47), C and A (p=0.32) and (p=0.75), GSTT1 and GSTM1, respectively. CONCLUSION: Our data show that polymorphisms in GSTM1 and GSTT1 genes have no influence on the ototoxicity of aminoglycosides.

O processo de morte e danos em células ciliadas devido à exposição ao ruído e ototoxinas parece ser mediado por espécies reativas de oxigênio. OBJETIVO: Investigar a relação entre polimorfismos gênicos na Glutationa S-transferase e a susceptibilidade à deficiência auditiva induzida pelos aminoglicosídeos. CASUÍSTICA E MÉTODO: Genótipos nulos foram analisados por PCR-multiplex em amostras de DNA de 50 pacientes e 72 controles. Os pacientes foram divididos em três grupos, sendo 10 com deficiência auditiva e uso de aminoglicosídeos (grupo A), 20 com deficiência auditiva sem exposição à droga (grupo B), e 20 ouvintes que utilizaram o antibiótico (grupo C). FORMA DE ESTUDO: Experimental. RESULTADOS: Polimorfismos nos genes GSTT1 e GSTM1 foram encontrados em 16 por cento e 42 por cento dos pacientes e em 18 por cento e 53 por cento do grupo controle, respectivamente. Após a análise estatística nenhuma diferença significativa foi observada entre os grupos controle e A (p=0,86) e (p=0,41), controle e B (p=0,27) e (p=0,24), controle e C (p=0,07) e (p=0,47), controle e A+C (p=0,09) e (p=0,47), C e A (p=0,32) e (p=0,75), GSTT1 e GSTM1, respectivamente. CONCLUSÃO: Nossos dados demonstram que polimorfismos na GSTT1 e GSTM1 não exercem influência sobre a ototoxicidade dos aminoglicosídeos.

Mutação mitocondrial C1494T, deficiência auditiva e uso de antibióticos aminoglicosídeos / C1494T mitochondrial dna mutation, hearing loss, and aminoglycosides antibiotics

Tendo em vista a complexidade do mecanismo da audição, não é difícil compreender que a deficiência auditiva possa resultar de ampla variedade de anomalias geneticamente determinadas, bem como de diversos fatores ambientais. Mutações específicas no gene 12S rRNA em DNA mitocondrial são responsáveis por perda da audição não-sindrômica de herança materna, e pelo aumento da susceptibilidade ototóxica dos antibióticos aminoglicosídeos. Objetivo: Neste trabalho, nós avaliamos a presença da mutação C1494T entre os indivíduos ouvintes e com deficiência auditiva que utilizaram aminoglicosídeos e os que não tiveram contato com o antibiótico. Material e método: Foram estudados 20 pacientes com deficiência auditiva neurossensorial não-sindrômica sem histórico de sensibilização aos aminoglicosídeos e 40 recém-nascidos, prematuros e de alto-risco que utilizaram a droga ototóxica, dos quais 20 eram ouvintes e 20 com perda auditiva. As amostras foram analisadas por PCR-RFLP com a enzima de restrição Hph I. Forma de estudo: Experimental. Resultados: A mutação mitocondrial C1494T no gene 12S rRNA não foi detectada em nenhuma das amostras analisadas. Conclusão: Nossos dados sugerem que a deficiência auditiva dos indivíduos analisados não está relacionada com a ototoxicidade da mutação C1494T, demonstrando que esta mutação não é frequente em nossa população.

In view of the complex mechanism of hearing, it is not difficult to understand that hearing impairment may result from a wide variety of genetically determined anomalies and various environmental factors. Specific mutations in the mitochondrial DNA 12S rRNA gene are responsible for maternally inherited non-syndromic hearing loss, and for increased susceptibility to the ototoxicity of aminoglycoside antibiotics. AIM: To asses the presence of C1494T mutation among individuals with normal hearing and hearing impairment who used aminoglycosides and those who had not had contact with the antibiotic. Material and method: The study was composed of 20 patients with nonsyndromic sensorineural hearing loss without prior use of aminoglycosides and 40 premature and high-risk newborns who used ototoxic drugs, of whom 20 had good hearing and 20 had hearing loss. The samples were analyzed by PCR-RFLP with the restriction enzyme Hph I. Study design: Experimental. Results: The mitochondrial 12S rRNA C1494T mutation was not detected in any of the samples analyzed. Conclusion: Our data suggest that the hearing loss of the individuals we analyzed was not related to the ototoxicity of mutation C1494T, showing that this mutation is not frequent in our population.

Role of connexin 26 (GJB2) & mitochondrial small ribosomal RNA (mt 12S rRNA) genes in sporadic & aminoglycoside-induced non syndromic hearing impairment.

Non syndromic hearing impairment is a common sensory disorder, which affects one in 600 newborns. Though more than 50 nuclear genes are involved in causing non syndromic hearing impairment, mutations in the connexin 26 (GJB2) gene explain a high proportion of congenital deafness in several populations worldwide. The diversity of genes and genetic loci implicated in hearing loss defines the complexity of the genetic basis of hearing. This review focuses on the role of connexin 26 and mitochondrial 12S rRNA genes in hearing which will be helpful for better understanding of genes in sporadic and aminoglycosideinduced non syndromic hearing impairment.

Rastreamento da mutação mitocondrial A1555G em pacientes com deficiência auditiva sensorioneural / Screening of the mitochondrial A1555G mutation in patients with sensorineural hearing loss

A mutação mitocondrial A1555G é a principal alteração associada à surdez ocasionada pelo uso de aminoglicosídeos. OBJETIVO: Investigar a prevalência da mutação A1555G em pacientes com deficiência auditiva sensorioneural com e sem uso de antibióticos aminoglicosídeos. MATERIAL E MÉTODO: Estudo em amostras de 27 pacientes com surdez, como casos, e em 100 neonatos, com audição normal, como grupo controle. O DNA foi extraído de leucócitos de amostras de sangue e "primers" específicos foram utilizados para amplificar o gene do citocromo b e a região que abrange a mutação A1555G do DNA mitocondrial, usando as técnicas da Reação em Cadeia da Polimerase e do Polimorfismo no Comprimento de Fragmentos de Restrição. DESENHO CIENTÍFICO: Estudo de casos em corte transversal. RESULTADOS: A região do gene do citocromo b foi amplificada, sendo confirmada a presença do DNA mitocondrial em todas as 127 amostras do estudo. A mutação A1555G não foi identificada nos 27 pacientes com deficiência auditiva e no grupo controle (100 neonatos). CONCLUSÕES: Os resultados são concordantes com estudos que relatam que a mutação A1555G não é prevalente nas Américas. Há interesse na determinação da real prevalência dessa mutação e na investigação de outras mutações que possam ocasionar deficiência auditiva associada ou não ao uso de aminoglicosídeos na população brasileira.

The A1555G mitochondrial mutation is the main alteration associated with aminoglycoside-induced deafness. AIM: to investigate the prevalence of the A1555G mutation in patients sensorineural hearing loss patients with and without aminoglycosides antibiotic use. MATERIAL AND METHOD: a study of 27 cases with deafness as the sample, and 100 neonates with normal hearing as the control group. DNA was extracted from blood leukocyte samples, and specific oligonucleotide primers were designed to amplify the cytochrome b gene and the region which encloses the A1555G mutation of the mitocondrial DNA using the polymerase chain reaction and restriction fragment length polymorphism. DESIGN: a cross-sectional case study. RESULTS: a region of the cytochrome b gene was amplified and the presence of the mtDNA was confirmed in all of the 127 cases. The A1555G mutation was not found in any of the 27 patients with hearing loss or the control group with 100 neonates. CONCLUSION: the results agree with studies stating that the A1555G mutation is not prevalent in the Americas. There is interest in establishing the real prevalence of this mutation and to investigate other mutations that may cause hearing loss, associated or not with the use of aminoglycosides, in the Brazilian population.

Ototoxicity by aminoglycosides a clinical study in an Apex Hospital

To study the drugs causing ototoxicity, their likely mechanism and developing rational approach for prevention and management of this therapeutic problem. Patients attending OPO and IPD with any evidence of drug-induced ototoxicity were included in the study and they were further evaluated by detailed history of drug exposure to find out drug responsible for ototoxicity and then local and audiometric examination of ear was done to find out the type and extent of hearing impairment the relevant drugs produced. 100 patients of ototoxicity caused by various aminoglycosides were studied and observed that Streptomycin is the commonest aminoglycoside and tinnitus is the commonest manifestation of aminoglycoside-induced ototoxicity. Aminogtycoside causes initial high frequency hearing loss which in severe cases also involves normal speech frequencies, a significant hearing loss had already been established in most of the patients before the hearing impairment became apparent to patients or even to prescribing physician, so these drugs should be avoided where possible or preventive measures must be applied at least in high risk individuals

Ototoxicidad por medicamentos / Drug-induced ototoxicity

Se define ototoxicidad a las perturbaciones transitorias o definitivas de la función auditiva, vestibular, o de las dos a la vez, inducidas por sustancias de uso terapéutico. Son muchos los trabajos de investigación que se han dedicado ha este tema quedando aun dudas por resolver debido a las complejas consecuencias donde está envuelto el daño cocleovestibular. El propósito de esta revisión, es presentar las últimas teorías que tratan de explicar desde el punto de vista de la farmacociónética/farmacodinamia, biología celular y molecular el mecanismo por el cual actúan los fármacos involucrados. Lo anteriormente señalado tiene como fin que los últimos adelantos en esta materia, permitan una mejor comprensión que nos lleve a una práctica clínica más segura con relación a la ototoxicidad medicamentosa, dando a conocerlos cuidados y precauciones que se deben tomar antes de administrar un fármaco que se reconoce ototóxico, que puede tener graves consecuencias en la calidad de vida de nuestros pacientes.

Ototoxicity is defined as the transient or definitive perturbations of the auditory and/ or vestibular function, induced by drugs of therapeutic use. Despite a large body of literature devoted to this subject, there are still unanswered questions, due to the complex consequences of cochleovestibular damage. The present study aims to review recent theories that try to explain the mechanism of action of involved drugs, from the viewpoint of pharmacokinetics/pharmacodynamics, cell and molecular biology. Our purpose is that recent advances in this matter could lead to a better understanding and safer clinical practice related to drug-induced ototoxicity, summarizing the care and precautions that should be taken when administering a known ototoxic drug...

Nefrotoxicidade dos aminoglicosídeos / Aminoglycoside nephrotoxicity

Aminoglicosídeos são antibióticos de amplo uso clínico, em função de sua eficácia contra bacilos gram-negativos e de seu sinergismo positivo com outros antibióticos no tratamento de infecções por agentes gram-positivos. São muito utilizados na prevenção e no tratamento de infecções pós-operatórias em cirurgia cardíaca. O principal efeito colateral desta classe de antibióticos é a nefrotoxicidade, que pode ocorrer em até 20 por cento dos pacientes. Embora usualmente reversível, a lesão renal causa maior tempo de internação e, conseqüentemente, maiores custos. Ainda mais importante é o fato de nefrotoxicidade estar associada a maior mortalidade nestes pacientes. Existem alguns fatores de risco conhecidos para nefrotoxicidade, bem como algumas medidas de prevenção. Esta revisão irá descrever os aspectos mais relevantes deste importante efeito colateral do tratamento com aminoglicosídeos.

Aminoglycoside are frequently used due to its high efficacy against gram-negative bacteria and positive synergism with other antibiotics against gram-positive organisms. They are commonly used for prevention and treatment of infection complications after cardiothoracic surgery. The principal side effect of this class of antibiotics is nephrotoxicity, which may occur in up to 20 percent of the exposed patients. Although usually reversible, aminoglycoside-induced renal injury prolongs hospitalization time and increase patients cost. Even more important, the occurrence of nephrotoxicity is associated with higher patient mortality. There are some known risk factors for nephrotoxicity development and some measures that may prevent it. This review will cover the most relevant aspects of this important side effect of aminoglycoside therapy.

Prevención de la insuficiencia renal aguda en el paciente crítico / Prevention of acute renal failure in critical patient

Chronic renal insufficiency (CRI) is common in chronic patients (6 to 23 percent incidence), with a 50 to 70 percent mortality rate which can reach 100 percent when this involves a multiple more than five organ failure. For practical purposes, CRI is classified into prerenal, renal, and postrenal. Knowledge of physiopathological fundamentals and diagnostic elements allows us to take adequate measures to preserve renal function. This article revises renal function protective measures against the principle causes of CRI in chronic patients: ischemic and toxic CRI, i.e. contrast agents, pigments, anfotericine, and aminoglycosides. in ischemic CRI we analyse the key factors in renal perfusion, highlighting the importance of replenishing extracelular volume, and the benefits of using norepinefrine in septic shock. The renal effect of other vasoactive and inotropic drugs such as epinephrine, dobutamine, milrinone, and dopexamine are revised, highlighting the absence of clinical evidence that supports the use of dopamine as a renal function protector. Renal actions and possible favorable effects of diuretic manitol and furosemide are analysed. In toxic CRI, we analyse the beneficial effect of fluids and the use of specific measures such as alkalinization of urine, the use of acetylcysteine, liposomal anfotericine, and single dose aminoglycosides

Perfil audiométrico del niño hipoacúsico egresado de una Unidad de Cuidado Intensivo Neonatal: análisis de 40 casos / Audiometric profiles of hipoacusic children six years after discharge from a Neonatal intensive care unit

Introducción. En este estudio se describe el perfil audiométrico del niño hipoacúsico egresado de una Unidad de Cuidado Intensivo Neonatal (UCIN).Material y métodos. En una clínica de seguimiento pediátrico longitudinal se estudiaron mediante potenciales auditivos evocados de tallo cerebral y audiometrías a 40 niños con hipoacusia adquirida durante su estancia en una UCIN; se describen algunos factores asociados con hipoacusia en el período neonatal, y sus características audiométricas a 6 años de seguimiento longitudinal.Resultados. La edad gestacional promedio al nacer fue de 32.4 semanas con peso promedio de 1 557.5 g. El 0.82 ameritó ventilación mecánica intermitente y el promedio de días estancia en UCIN fue de 22 días.El factor asociado más frecuente fue la exposición a amikacina en 0.95 de los casos, seguido de la hiperbilirrubinemia con 0.82. Se detectaron 5 factores promedio presentes en cada niño. Los resultados de los potenciales auditivos evocados de tallo cerebral indicaron 23 casos (0.57) sin respuesta bilateral y 6 casos (0.15) sólo registraron onda V a 95 dB. La audiometría tonal mostró 0.93 con hipoacusia bilateral, probablemente de tipo sensorio-neural, simétrica, de grado severo a profundo con mayor alteración en las frecuencias agudas; 0.05 presentaron hipoacusia unilateral profunda con audición normal en el lado contrario.Conclusión. Estas observaciones sugieren que en nuestro medio el recién nacido pretérmino con peso promedio de 1 500 g, con historia neonatal complicada, y exposición prolongada a aminoglucósidos e hiperbilirrubinemia está en alto riesgo de presentar hipoacusia, justificando valoración audiológica durante sus primeros meses de vida.

Prevention of ototoxicity of some commonly used drugs. Histopathological study in guinea pigs

This study was done to evaluate the efficacy of the iron-chelator deferoxamine [DFO] to attenuate the ototoxicity induced by aminoglycosides and cisplatin, respectively. It was carried out on 50 healthy pigmented guinea pigs divided into two groups. The results have revealed that there was a prominent damage in the outer hair cells, stria vascularis, myelinated nerve fiber and ganglion cells and that DFO ameliorates these degeneration processes which resulted from GM and cisplatin administration, respectively