Salt Alec N, Gill Ruth M, Plontke Stefan K
Department of Otolaryngology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Laryngoscope. 2008 Oct;118(10):1793-800. doi: 10.1097/MLG.0b013e31817d01cd.
OBJECTIVES/HYPOTHESIS: To establish safe dosing protocols for the treatment of patients with Meniere's disease with intratympanic gentamicin.
A validated computer model of gentamicin dispersion in the inner ear fluids was used to calculate cochlear drug levels resulting from specific clinical delivery protocols. Dosing in the cochlea was compared with changes of hearing sensitivity for 568 patients reported in 19 publications.
Cochlear drug levels were calculated based on the concentration and volume of gentamicin applied, the time the drug remained in the middle ear, and on the specific timing of injections. Time courses were quantified in terms of the maximum concentration (Cmax) and the area under the curve of the drug at specific cochlear locations.
Drug levels resulting from single, "one-shot" injections were typically lower than those from repeated or continuous application protocols. Comparison of hearing sensitivity changes with gentamicin dosing revealed a flat curve with a near-zero mean for lower doses, suggesting that hearing changes with doses over this range were probably unrelated to the applied drug. Higher intracochlear doses were generated with repeated or continuous delivery protocols, which in some cases caused substantial hearing losses and an increased incidence of deafened ears.
One-shot application protocols produce gentamicin doses in the cochlea that have minimal risk to hearing at the frequencies tested. Repeated or continuous application protocols result in higher doses that in some cases damage hearing. The high variability of hearing changes, even with low gentamicin doses, calls into question the rationale for using individual hearing changes to titrate the applied dose.
目的/假设：建立鼓室内注射庆大霉素治疗梅尼埃病患者的安全给药方案。
使用经过验证的庆大霉素在内耳液中扩散的计算机模型，计算特定临床给药方案所产生的耳蜗药物水平。将耳蜗内的给药情况与19篇出版物中报道的568例患者的听力敏感度变化进行比较。
根据所应用庆大霉素的浓度和体积、药物停留在中耳的时间以及注射的具体时间来计算耳蜗药物水平。根据特定耳蜗位置处药物的最大浓度（Cmax）和曲线下面积对时间进程进行量化。
单次“一次性”注射所产生的药物水平通常低于重复给药或持续给药方案所产生的药物水平。将听力敏感度变化与庆大霉素给药情况进行比较，发现较低剂量时曲线较为平缓，平均接近零，这表明在此剂量范围内听力变化可能与所应用药物无关。重复给药或持续给药方案会产生较高的耳蜗内剂量，在某些情况下会导致明显的听力损失和耳聋发生率增加。
一次性给药方案在耳蜗内产生的庆大霉素剂量，在所测试频率下对听力的风险最小。重复给药或持续给药方案会导致更高的剂量，在某些情况下会损害听力。即使庆大霉素剂量较低，听力变化的高度变异性也让人质疑使用个体听力变化来滴定给药剂量的合理性。
