Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hear Res. 2012 Jan;283(1-2):14-23. doi: 10.1016/j.heares.2011.11.012. Epub 2011 Dec 8.
It has been widely believed that drug entry from the middle ear into perilymph occurs primarily via the round window (RW) membrane. Entry into scala vestibuli (SV) was thought to be dominated by local, inter-scala communication between scala tympani (ST) and SV through permeable tissues such as the spiral ligament. In the present study, the distribution of the ionic marker trimethylphenylammonium (TMPA) was compared following intracochlear injections or applications to the RW niche, with or without occlusion of the RW membrane or stapes area. Perilymph TMPA concentrations were monitored either in real time with TMPA-selective microelectrodes sealed into ST and SV, or by the collection of sequential perilymph samples from the lateral semi-circular canal. Local inter-scala communication of TMPA was confirmed by measuring SV and ST concentrations following direct injections into perilymph of ST. Application of TMPA to the RW niche also showed a predominant entry into ST, with distribution to SV presumed to occur secondarily. When the RW membrane was occluded by a silicone plug, RW niche irrigation produced higher concentrations in SV compared to ST, confirming direct TMPA entry into the vestibule in the region of the stapes. The proportion of TMPA entering by the two routes was quantified by perilymph sampling from the lateral semi-circular canal. The TMPA levels of initial samples (originating from the vestibule) were markedly lower when the stapes area was occluded with silicone. These data were interpreted using a simulation program that incorporates all the major fluid and tissue compartments of the cochlea and vestibular systems. From this analysis it was estimated that 65% of total TMPA entered through the RW membrane and 35% entered the vestibule directly in the vicinity of the stapes. Direct entry of drugs into the vestibule is relevant to inner ear fluid pharmacokinetics and to the growing field of intratympanic drug delivery.
人们普遍认为，药物从中耳进入外淋巴主要通过圆窗（RW）膜。人们认为，镫骨区（SV）的进入主要由镫骨鼓室（ST）和 SV 之间通过螺旋韧带等可渗透组织的局部、跨区之间的通讯来主导。在本研究中，比较了经圆窗龛内注射或应用后，RW 膜或镫骨区闭塞与否，离子标记物三甲苯铵（TMPA）的分布。通过将 TMPA 选择性微电极密封在 ST 和 SV 中实时监测外淋巴中的 TMPA 浓度，或通过从外侧半规管收集连续的外淋巴样本来监测。通过直接将 TMPA 注入 ST 中的外淋巴，测量 SV 和 ST 浓度，证实了 SV 和 ST 之间的局部跨区 TMPA 通讯。将 TMPA 应用于 RW 龛也显示出主要进入 ST，推测 SV 的分布是次要的。当 RW 膜被硅酮塞阻塞时，RW 龛冲洗产生的 SV 浓度比 ST 高，这证实了 RW 龛内 RW 膜直接进入镫骨区域。通过从外侧半规管收集外淋巴来定量分析 TMPA 经两条途径进入的比例。当用硅酮阻塞镫骨区域时，来自前庭的初始样本（起源于前庭）的 TMPA 水平明显降低。这些数据通过一个模拟程序进行了分析，该程序包含了耳蜗和前庭系统的所有主要液体和组织隔室。根据该分析，估计有 65%的 TMPA 通过 RW 膜进入，35%直接进入镫骨附近的前庭。药物直接进入前庭与内耳液药代动力学和日益发展的鼓室内药物输送领域有关。
