Evaluation of ototoxicity of amikacin (BB-K8) by animal test (author's transl)

Abstract

Seventy Hartley strain guinea pigs (350 g body weight at start of the experiment) were used. BB-K8, gentamicin (GM) and kanamycin (KM) were given to the animals intramuscularly for 28 days at following various doses: (see article) These guinea pigs underwent a differential frequency pinna reflex test in wide frequency range from 20KHz to 0.5 KHz before the administration, during the injection and after the last one. For histopathological examination of the inner ears the guinea pigs were subjected to intravital fixation with Wittmaack's fixative under nembutal general anesthesia. Blocks including the bilateral temporal bones were removed from the skulls and then fixed in the same fixative for 1 similar to 2 weeks. After routine procedure for decalcification, dehydration and celloidin embedding, horizontal serial sections of the inner ears were made and stained with hematoxylin-eosin. The differential frequency pinna relfex test in the 70 guinea pigs indicated positive pinna reflex in 90% at 20KHz and in 100% at 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz before start of the administration. Administration of the antibiotics for 28 days occasionally resulted in the pinna reflex loss which always involved the highest frequency, 20 KHz and then was followed in relatively regular succession by 15, 12, 10, 8, 6, 4, 3, 2, 1 and 0.5 KHz (Tables 1 similar to 8). On the other hand, histopathological examination of the inner ears disclosed that the loss of the outer hair cells in the spiral organ which are the most sensitive to the ototoxic antibiotics, occurred always at the basal end of the spiral organ and then spread from there to upper portion of the spiral organ (Tables 9 similar to 16). Based on the differential frequency pinna reflex test in the wide frequency range and extensive histopathological examination of the inner ears, ototoxicity of BB-K8 is considered to be more mild than GM. However, there was not so remarkable difference in ototoxicity between BB-K8 and KM in the present experiment. The result or examination of the guinea pigs received BB-K8 at 40 mg/kg and 100 mg/kg respectively for 28 days suggests that BB-K8 at expecting clinical dose, 500 mg per day (for 28 days) may be safe from ototoxicosis in the inner ears. In the vestibular organs of the animals received BB-K8 there was no decrease in number of the hair cells.