OTOTOXICITY TESTS FOR T-2588 IN RATS

Abstract

Ototoxic effects of T-2588 on the spiral and the vestibular organs of the inner ear were investigated in 50 rats of Sprague-Dawley strain. Fifty female rats were divided into 5 groups consisting of 2 T-2588-test groups at dose levels of 500 and 1,000mg/kg/day, respectively, and 2 kanamycin (KM) groups at dose levels of 200 and 400mg/kg/day, respectively, and the control group. The administration of T-2588 was done orally through gastric tube daily for 5 weeks. The ototoxic effect was evaluated by the differential frequency pinna reflex test with frequency ranging from 200Hz to 20,000Hz before, during and after the administration of a test substance, then investigated histopathologically on serial celloidin sections of the bilateral temporal bones.
The results were summarized below.
1. In any rat receiving either level of T-2588, pinna reflex impairment was not detected at any frequencies. And there was no noticeable change either in the cochlea or in the vestibulum.
2. In 10 rats which received KM at a dose level of 200mg/kg/day, there was no impairment in pinna reflex, but, histopathologically, the loss of outer hair cells was observed, though inner hair cells were present. In the vestibular organ, a scattered loss of hair cells was observed in 8 rats.
3. One of 9 rats which received KM at a dose level of 400mg/kg/day showed the loss of pinna reflex in the frequency range tested. This rat showed histopathologically extensive loss of both outer and inner hair cells. In other rats showing no impaired pinna reflex, the loss of outer hair cells was rather extensive, but inner hair cell loss was unilaterally confined in the basal end of the first turn. In the vestibular organs of all rats, a scattered loss of hair cells was observed.