ラットにおけるT-1220 (Piperacillin) の聴器毒性とその安全性の評価について

抄録

T-1220 is a newly developed semisynthetic compound of aminobenzylpenicillin and has a broad spectrum of antibacterial activity.
The present animal test was carried out to evaluate ototoxicity and safety of T-1220 to auditory system in 45 rats of Wistar strain. T-1220 was given to 20 rats at doses of 500 mg/kg and 1, 000 mg/kg i. v. daily for 4 weeks. As control test, kanamycin (KM) and physiological saline were administered for 4 weeks. KM was given to 20 rats at doses of 200 mg/kg and 400 mg/kg i. m. daily for 4 weeks and physiological saline was injected to 5 rats i. v. daily for 4 weeks. Differential frequency pinna reflex test in wide range from 20, 000 Hz to 200 Hz was performed before and during the administration weekly to measure frequency range of increased threshold and loss of pinna reflex in the rats.
The following results were obtained.
1) The differential frequency pinna reflex test revealed that pinna reflex in non-treated animals was more sensitive in 200, 2, 000, 3, 000, 4, 000, 6, 000, 8, 000, 10, 000, 12, 000, 15, 000 and 20, 000 Hz in the. rats than in Hartley guinea pigs.
2) In 10 rats receiving KM at 200 mg/kg/day i. m. for 4 weeks, there was no animal with pinna reflex loss at any frequencies tested. Increase in threshold of pinna reflex was almost within 10 dB.
3) In 8 rats given KM at dose of 400 mg/kg/day i. m. for 4 weeks (2 rats were died at 2 nd week), 2 showed extensive loss of pinna reflex extending from 20, 000 Hz to 200 Hz, and another one indicated loss of pinna reflex in range from 20, 000 Hz to 2, 000 Hz. Loss of pinna reflex limited to 20, 000 Hz to 15, 000 Hz occurred in another one rat. Another one showed increase in threshold (14 to 16 dB) in 15, 000, 12, 000, 10, 000 and 8, 000 Hz. 18 dB increase in threshold at 15, 000 Hz was seen in one animal.In the remaining 2, increase in threshold was less than 10 dB.
4) In 10 rats treated with T-1220 at dose of 500 mg/kg i. v. daily for 4 weeks, there was no animal with loss of pinna reflex. Increase in threshold amost always remained within 10 dB.
5) In 10 rats given T-1220 at dose of 1, 000 mg/kg i. v. daily for 4 weeks, there was no animal with loss of pinna reflex. Increase of threshold almost always remained within 10 dB.
6) The present study suggests that administration of T-1220 at doses of 2, 000 mg/day and 4, 000 mg/ day, respectively, may be enough safe in man to auditory system.