Aspects on the Ototoxic Potential of Netilmicin

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Abstract
The organ culture system using the 16th gestational day inner ear explant from fetal mice was used for ototoxicity screening of netilmicin. Organ cultures were incubated in 1, 10, 100 and 1 000 μg/ml, respectively, of netilmicin base in the nutrient solution. After constant exposure to the drug during 5 days, the inner ears (N = 56) were analyzed morphologically at the light and electron microscopic levels. All specimens were serially sectioned. Exposure to 1 and 10 μg/ml of netilmicin base, doses that are reached during in vivo conditions in man, did not cause morphological damage to hair cells as observed in the light microscope at the end of the 5–day period. At the ultrastructural level, minor changes characteristic for arninoglycosides occurred in hair cell mitochondria. lncubation with 100 and 1 000 μg/ml of netilmicin base caused morphological changes in many types of epithelia and not only in vestibular hair cells. This indicates a general sign of toxicity of netilmicin in these doses. The dose response relationship with regard to inner ear pathology was obvious in the vestibular part of the labyrinth. In the cochlea, however, few cytological changes occurred independent of dose. As compared with gentamicin, exposure in the same concentrations as in the present study and under similar experimental conditions, the less ototoxic effect of netilmicin was obvious. The results of the present study indicate that the less ototoxic potential of netilmicin as compared with other aminoglycosides is probably due to the drug itself and not primarily due to a poor penetration of netilmicin into the inner ear.