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.

Persistência do efeito otoprotetor: qual a duração da otoproteção à amicacina? / Persistence of the otoprotective effect: how long does otoprotection against amikacin lasts?

Há comprovação de que o fenômeno de resistência ocorre quando a dose não lesiva da amicacina protege as células ciliadas contra a ototoxicidade da própria amicacina. OBJETIVO: O objetivo deste trabalho é verificar se o fenômeno de resistência é temporalmente persistente. MÉTODO: Estudo experimental com 14 cobaias albinas (Cavia porcellus) divididas em três grupos. Avaliação da função auditiva por emissões otoacústicas por produto de distorção (EOAPD): na pré-exposição à amicacina, no 15º dia de aplicação da dose não lesiva, no final da aplicação da dose lesiva e antes da decapitação. RESULTADOS: O Grupo A (controle) apresentou função auditiva e padrão histológico normais. No Grupo B (amicacina 20mg/kg/dia intramuscular por 30 dias e dose lesiva (400 mg/kg/dia) por 12 dias) e no Grupo C (mesmo esquema do grupo B, porém mantidos por 60 dias e sacrificados), as OEA-PD confirmaram função auditiva normal no período pré-exposição e manutenção do padrão após dose não lesiva, porém, houve perda importante da função auditiva após término do período de aplicação da dose lesiva. CONCLUSÃO: Não houve manutenção do fenômeno da autodefesa estendida por um período de 30 a 60 dias após a aplicação de doses lesivas de amicacina.

There is evidence that a "resistance phenomenon" occurs when a none-damaging dose of amikacin protects the hair cells from ototoxicity. Our goal is to prove that this resistance is persistent. METHOD: Experimental study - 14 albino guinea pigs (Cavia porcellus) divided into three groups. The auditory function was assessed by distortion product otoacoustic emissions (DPOAE): before exposure to amikacin, on the 15th day after the non-damaging dose was injected, at the end of the damage dose injection and prior to decapitation. RESULTS: Group A (control) presented normal hearing and histological pattern. Group B (amikacin 20mg/kg/day (IM) for 30 days and affecting dose (400 mg / kg / day) for 12 days and Group C (same protocol of Group B, but kept for 60 days and slaughtered), the DPOAE confirmed normal auditory function in the pre-exposure and maintenance of the standard-dose; however, significant loss of auditory function after the end of the damaging dose injection. CONCLUSION: The protection phenomenon did not extended for a period of 30 to 60 days after the application of damaging doses of amykacin.

Relationship between serum ferritin level and amikacin ototoxicity

Aminoglycosides are highly effective against bacteria but have serious side-effects including ototoxicity and nephrotoxicity. One of the theories in aminoglycosides ototoxicity is that Ironaminoglycoside complex causes ototoxicity by creating free radicals. Based on this theory, the relationship between serum iron level and amikacin ototoxicity was studied to determine whether more iron results in more ototoxcity. This prospective cohort study was conducted from August 2005 to October 2008. Patients with amikacin prescription and different serum-ferritin levels were examined. Burned patients with amikacin prescription were divided into Group1 [89 patients; serum-ferritin >150] and Group2 [92 patients, serum-ferritin <150]. Their hearing thresholds and red-blood-cells indices were compared using t- and paired t-test. In comparing the two groups, thresholds of Group1 were higher than Group2 at all frequencies, and the difference was statistically significant [p<0.001]. The maximum threshold shift in Group1 was greater than 20 dB and in Group2, it was less than 10 dB, at 8000Hz. Again, this result was statistically and clinically significant [p<0.001]. Finally, the mean corpuscular volume [MCV] was higher in Group1 than Group2, and [p=0.001]. The results suggest that the level of iron is related to aminoglycoside ototoxicity. More iron can create more ototoxicity, and iron deficiency may inhibit aminoglycoside ototoxicity. An increase in MCV may be due to higher serum ferritin and an indication of more ototoxicity

Green tea extract administration protects against the nephrotoxicity induced by gentamycin and amikacin in rats

Despite their beneficial effects, aminoglycosides including gentamycin [GEN] and amikacin [AK] have considerable nephrotoxic side effects. This study investigaged the effects of green tea [GT] extract on biochemical and morphological kidney damage induced by GEN and AK in rats. Sixty male albino rats were used in this study and divided into 6 groups each contains ten rats. The first group was the control group injected with 0.4 ml saline. Each rat of the second group was given 12.5 ml of green tea extract [3%] twice daily to drink it orally for 25 days. The 3[rd] group received GEN [80mg/kg] once daily intraperitoneally for 10 days. The 4[th] group was administered AK [180 mg/kg] once daily intraperitoneally for 10 days. The 5[th] group received GT extract for 15 days then concomitant with GEN for 10 days. The 6[th] group received GT extract for 15 days then concomitant with AK for 10 days. GEN and AK groups showed significant increase in serum urea and creatinine [Cr] which was significantly decreased in green tea consuming rats before GEN and AK administration. GEN and AK treated rats showed significant decrease in the activity of calalase enzyme and reduced glutathione level in kidney tissues which were significantly increased in GT consuming rats prior to GEN and AK injection. Light microscopic examination of kidney tissues of GEN and AK groups revealed tabular necrosis and degenerative changes which were modulated by the consumption of green tea prior to GEN and AK administration. In conclusion green tea ameliorates and modulates GEN and AK induced-nephrotoxicity and oxidative damage by enhancing the antioxidant defense system

Efeito de fármacos ototóxicos na audição de recém-nascidos de alto risco / Effects of ototoxic drugs in the hearing of high risk newborns

OBJETIVOS: Calcular a incidência da perda auditiva sensorioneural (PASN) em recém-nascidos de alto risco, verificar se existe associação causal entre o uso de fármacos ototóxicos em neonatos de alto risco e a PASN e estabelecer a frequência das mutações genéticas relacionadas à PASN em neonatos de alto risco. MÉTODOS: A pesquisa foi uma coorte retrospectiva e prospectiva realizada em 250 crianças. Foi realizada coleta de dados em prontuários e com os responsáveis, triagem auditiva por emissões otoacústicas-produto de distorção, timpanometria, audiometria com reforço visual, potencial evocado auditivo de tronco encefálico e emissões otoacústicas transientes. A pesquisa das mutações genéticas 35delG e mitocondriais A1555G e A7445G, foi fundamental para avaliar a possibilidade da PASN ser de origem genética não-sindrômica. RESULTADOS: A incidência da PASN foi de 11,6 por cento, as associações causais entre a PASN e os fármacos administrados foram: amicacina e cefotaxima (OR 5,35), cefotaxima e furosemida (OR 7,02), ceftazidima e vancomicina (OR 9,12). A frequência da mutação 35delG foi de 0,8 por cento e para as mutações mitocondriais A1555G e A7445G foi 0 por cento. CONCLUSÃO: A incidência de PASN em recém-nascidos de alto risco foi alta, apresentando importante relação causal com o uso de medicamentos e pequena relação com mutações genéticas.

PURPOSE: To calculate the incidence of sensorineural hearing loss (SNHL), to verify if there is a causal association between the use of ototoxic drugs and SNHL, and to establish the frequency of genetic mutations related to SNHL in high risk newborns. METHODS: The study was a retrospective and prospective cohort research with 250 children. Data was gathered from subjects' charts and with their caregivers. Moreover, subjects were submitted to auditory evaluation with distortion product otoacoustic emissions, timpanometry, visual reinforcement audiometry, auditory brainstem response and transient otoacoustic emissions. The study of the genetic mutation 35delG, and the mitochondrial mutations A1555G and A7445G was essential to evaluate the possibility that SNHL had a non-syndromic genetic origin. The association between the medicine use and the occurrence of hearing loss had been analyzed. RESULTS: The incidence of SNHL in high risk newborns was 11.6 percent, and causal associations between SNHL and the drugs administered were: amikacin and cefotaxime (OR=5.35), cefotaxime and furosemide (OR=7.02), ceftazidime and vancomycin (OR=9.12). The frequencies of the mutation 35deIG and mitochondrial mutations A1555G and A7445G were, respectively, 0.8 percent and 0 percent. CONCLUSION: The incidence of SNHL in high risk newborns was high, showing an important causal relation with the use of ototoxic drugs and a small relation with genetic mutations.

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

Beneficial role of L-thyroxine on hepato-renal toxicity induced by amikacin and potassium dichromate

Amikacin aminoglycoside antibiotic, potassium dichromate and L- thyroxine were employed to study the induction of hepatonephrotoxicity changes using potassium dichromate; the effect of amikacin sulfate aminoglycoside antibiotic on liver and kidney functions in normal rats and in rats subjected to potassium dichromate induced hepatonephrotoxicity and to minimize the undue effect of both potassium dichromate and amikacin by either concomitant or pre-administration of L- thyroxine. The following test parameters were carried out in serum: ALT, AST, isocitrate dehydrogenase, glucose-6- phospatase, total protein, albumin, urea, creatinine and N- acetyl-B- glucosaminidase. The results indicated that the efficient potassium dichromate induced renal impairment required the use of adult rats weighing 250-350 g. The well-marked changes of all the previous test parameters were investigated throughout the experimental period. Among these parameters, serum albumin level seemed to be of a special concern as a risk factor for aminoglycoside nephrotoxicity. The administration of L- thyroxine [10 mug/100 g body wt.] caused an improvement of kidney and liver functions of rats receiving amikacin or potassium dichromate, respectively

Prophylactic and protective effect of L-thyroxine on hepato-renal dysfunction induced by amika.cin and potassium dichromate

The present study was concerned with amikacin's hepatorenal hazards on certain kidney and liver tissue enzymes in normal rats as well as rats subjected to potassium dichromate induced hepatorenal toxicity. Minimizing the undue effects of both amikacin and potassium dichromate by either concomitant or pre-administration of L-thyroxine was also undertaken. Specific enzyme activity of N-acetyl-beta-D- glucosaminidase, NAG [as a marker of lysosomal enzyme], Na-K- ATPase [as a marker of basolateral membrane enzyme] and glucosed-6-phosphatase, G-6-Pase [as a marker of endoplasmic reticulum] as well as liver 5-nucleotidase specific enzyme activity were measured. The association of potassium dichromate, amikacin or both with the membrane binding caused increased lysosomal hydrolase specific enzyme activity extracted from the liver and kidney tissues, reduction of Na- K-ATPase, G-6-Pase and liver 5-nucleotidase activities, membrane damage in renal tubule of the rats as well as the induction of ultrastructural alterations of the liver. Thyroid hormone had an important stimulatory action on the plasma membrane pump that maintained cellular constancy of sodium and potassium. The recorded data may suggest that L- thyroxine administration may enable the cell to resist liver and kidney injury

Células ciliadas isoladas em cultura: um novo modelo para estudo da ototoxicidade / Ciliated cells isolated in culture: a new model for the study of otoxicity

A otoxicidade da Amicacina e a proteçäo por gangliosídeos das células ciliadas externas (CCE) cocleares de cobaias foram estudadas com 3 grupos de 8 animais. O grupo I, controle, o grupo II recebeu Amicacina e o grupo III Amicacina e gangliosídeo. utilizando-se o método de isolamento mecânico das CCE em cultura, 179 +-33 células em cada cobaia normal foram encontradas conservando suas características vitais até 2 horas e meia. O padräo de degeneraçäo vital foi observado e descrito. As lesöes provocadas pela Amicacina foram intensas. A análise estatística foi significativa na comparaçäo entre o grupo I e os grupos II e III, mas o resultado entre os grupos II e III näo demonstraram efeitos significativos na proteçäo das células pelos gangliosídeos contra os efeitos da Amicacina. Concluiu-se que esta técnica utilizada pela primeira vez para estudo da otoxicidade, constitui um modelo válido importante, simples e rápido, que permite estudo minucioso das lesöes em células isoladas "in vitro" provocadas por drogas ototóxicas

Nefrotoxicidad por aminoglucosidos / Aminoglycoside nephrotoxicity

Se realizo un estudio prospectivo durante 18 meses (1990-1991) en el Hospital Pediatrico Docente "Jose Luis Miranda" de Santa Clara, con el objetivo de determinar el comportamiento de la nefrotoxicidad por aminoglucosidos y se realizaron complementarios al inicio y final del tratamiento. Se encontro cilindruria como hallazgo mas frecuente en el sedimento urinario. La creatinina serica se altero en el 10 porciento de los casos tratados con aminoglucosidos no combinados, y las mayores alteraciones se relacionaron con las altas dosis e intervalos frecuentes de administracion. La velocidad de filtracion glomerular se altero en el 16,7 porciento, y esto se relaciono con los mismos factores que alteraron la creatinina serica. La urea serica no se altero, y ningun paciente tuvo manifestaciones clinicas. Los intervalos de administracion poco frecuentes disminuyeron los costos hospitalarios por paciente hasta en un 50 porciento, y por concepto de examenes complementarios se ahorro un 70 porciento

Control farmacológico de amikacina en niños con sepsis neonatal / Pharmacological control of amikacine in childrenwith neonatal sepsis

La Amikacina es un antibiótico aminoglucósido utilizado en el tratamiento de infecciones causadas por microorganismos gramnegativos, principales agentes etiológicos de la sepsis neonatal. Su desventaja radica tanto en la alta posibilidad de producir ototoxicidad y nefrotoxicidad, como en el rango estrecho entre la cantidad mínima efectiva y la cantidad mínima tóxica. En el Presente estudio se analizó la relación dosis concentración en 20 niños menores de dos meses de edad con sepsis tratados con amikacina, de la que se determinarón los niveles séricos cada cinco días, durante los 15 días de tratamiento. Con base en una evaluación clínico-farmacocinética de cada uno de los casos, la dosis se ajustó cuando fue necesario. Los resultados mostraron una correlación estadísticamente significativa entre la vida media de eliminación con la superficie y el peso corporal (p menor 0.01 ; r = 0.7 y r = 0.75 respectivamente). No se encontró correlación con y entre otros parámetros cinéticos ni clínicos, por lo que fue necesario individualizar las dosis para obtener una evolución adecuada de los casos.