Hill Gerhard W, Morest D Kent, Parham Kourosh
Division of Otolaryngology, Departments of Surgery, University of Connecticut Health Center, Farmington, Connecticut, USA.
Otol Neurotol. 2008 Oct;29(7):1005-11. doi: 10.1097/MAO.0b013e31818599d5.
Intratympanic (IT) application of dexamethasone will reduce ototoxicity associated with systemic cisplatin therapy.
Cisplatin is a common chemotherapeutic drug often dose-limited by ototoxicity attributed to the formation of reactive oxygen and nitrogen species damaging critical inner ear structures. Steroids have been shown to reduce formation of reactive oxygen species and thus may reduce ototoxicity. In the present pilot study, we test this hypothesis by IT administration of dexamethasone in a novel murine model of cisplatin ototoxicity.
Click- and pure-tone-evoked auditory brainstem responses (ABRs) in young CBA/J mice were measured. The first phase consisted of a dosing study to identify the optimal cisplatin dose for ototoxicity. In the next phase, ABR thresholds were measured in cisplatin-treated mice after 5 days of IT injection of 24 mg/ml of dexamethasone in 1 ear and normal saline in the opposite ear to serve as controls.
Intraperitoneal injection of 14 mg/kg of cisplatin induces significant hearing loss (click-evoked ABR threshold elevation = 12 +/- 7 dB, mu +/- standard error of the mean) with acceptable mortality (20%). The ears that received IT dexamethasone in cisplatin-treated mice had minimal ABR threshold shifts with the click, 8 and 16 kHz of stimuli. There was no significant difference between IT dexamethasone and IT saline ears at 32 kHz.
IT dexamethasone protected the mouse ear against cisplatin-induced ototoxicity in a frequency-dependent manner. The present results suggest that IT dexamethasone may be a safe, simple, and effective intervention that minimizes cisplatin ototoxicity without interfering with the chemotherapeutic actions of cisplatin.
鼓膜内（IT）应用地塞米松将降低与全身顺铂治疗相关的耳毒性。
顺铂是一种常见的化疗药物，其剂量常受耳毒性限制，耳毒性归因于活性氧和氮物种的形成，这些物质会损害内耳关键结构。类固醇已被证明可减少活性氧的形成，因此可能降低耳毒性。在本初步研究中，我们通过在一种新型顺铂耳毒性小鼠模型中IT给予地塞米松来验证这一假设。
测量年轻CBA/J小鼠的点击声和纯音诱发的听觉脑干反应（ABR）。第一阶段包括一项给药研究，以确定耳毒性的最佳顺铂剂量。在下一阶段，在顺铂治疗的小鼠中，对一只耳朵IT注射24mg/ml地塞米松，对侧耳朵注射生理盐水作为对照，5天后测量ABR阈值。
腹腔注射14mg/kg顺铂可导致显著听力损失（点击声诱发的ABR阈值升高 = 12 ± 7dB，平均值±标准误），死亡率可接受（20%）。在顺铂治疗的小鼠中，接受IT地塞米松的耳朵在点击声、8kHz和16kHz刺激下ABR阈值变化最小。在32kHz时，IT地塞米松组和IT生理盐水组耳朵之间无显著差异。
IT地塞米松以频率依赖的方式保护小鼠耳朵免受顺铂诱导的耳毒性。目前的结果表明，IT地塞米松可能是一种安全、简单且有效的干预措施，可在不干扰顺铂化疗作用的情况下将顺铂耳毒性降至最低。
