氨基苷类抗生素威替米星、奈替米星和庆大霉素SD大鼠耳毒性的比较研究

Comparative ototoxicity of aminoglycoside antibiotics: wetimicin,netilmicin and gentamicin in SD rats

目的通过昕功能测试和形态学观察，比较氨基苷类抗生索威替米星（WT）、奈替米星（NTL）和庆大霉素（GM）的耳毒性。方法225只SD大鼠，鼠龄5～6周，体重（180±20）g，按体重随机分为对照组（生理盐水）和WT，NTL，GM3种抗生素25，50，100mg／kg，9个给药组。1次／d，肌内注射连续15d。每组中的16～18只大鼠在给药15d后，其余6只动物在结束给药后15d分别进行听觉脑干诱发电位（ABR）的阈值测试和光镜、扫描电镜和透射电镜观察，比较3种抗生素的即时和延迟耳毒性。结果实验结束时WT低、中、高剂量组ABR阈值的均值与对照组比较，非常接近。只有中剂量组NTL在6kHz的阈值明显高于WT组；结束给药后15d，中剂量组click和4kHz的平均阈值高于WT组，且差异有显著性（P〈0．05）。实验结束时GM组与WT组比较，低剂量组除click，中剂量组除4kHz外，各剂量组其余各频率的阈值均明显高于WT组（P〈0．05）；结束给药后15d，只有中剂量组各频率阈值仍然高于WT组且差异有显著性（P〈0．05），而低、高剂量组的阈值与WT组则差异无显著性。形态学显示3种抗生素各剂量组的毛细胞缺失率无明显差异，基底膜表面和毛细胞内部的超微结构均未见明显损害。结论肌内注射大剂量WT连续15d，不形成即时耳蜗功能和形态学损害，也不产生延迟性听力损伤。威替米星的耳毒性相当于或略低于奈替米星，显著低于庆大霉素。

Objective To compare the ototoxicity of aminoglycoside antibiotics： wetimicin （WT）, netilmicin（NTL） and gentamiein（GM） in SD rats. Methods Two hundred and twenty-five SD rats, weighing 780 ± 20 g, 5-6 weeks old, were randomly divided into control （saline） and WT （25, 50, 100 mg/kg）, NTL （25, 50, 100 mg/kg） and GM （25, 50, 100 mg/kg） groups, The antibiotics or saline were injected intramuscularly （once daily） for 15 days. The thresholds of auditory brainstem response （ABR） were measured immediately and 15 days after dosing. The cochleae were dissected for counting hair cells under light microscope. The cochlear ultrastructure was observed with transmission and scanning electron microscope, Results There was no difference in ABR thresholds between control group and the low, middle and high dose WT groups immediately and 15 days after dosing. The mean threshold of ABR at 6 kKHz in NTL 50 mg/kg group was higher than that in WT group immediately after dosing （P〈0. 05）. There was significant difference （P〈0. 05） in the mean thresholds at click and 4 kHz between WT group and NTL 50 mg/kg group 15 days after dosing. In each dose of OM, the mean thresholds at every frequency were higher than those in WT group indicating that hearing loss occurred after dosing. There was statistically significant difference （P〈 0. 05） in most corresponding thresholds between OM group and WT group （except thresholds at click in OM 25 mg/kg group and at 4 KHz in 50 mg/kg group）. The elevation of ABR threshold was only observed in OM 50 mg/kg group 15 days after dosing. Like the cochleae in control group, no obvious missing of inner and outer hair cells was found under light microscopy in all test groups. Both SEM and TEM showed no ultrastructural impairment in cochlear hair cells in all groups. Conclusions There is no evidence of ototoxicity of WT at the dose ranges tested. Under the same conditions the ototoxicity of WT is equal to or less than that induced by NTL but significantly less than that induced by GM.