INNER EAR FLUID INTERACTIONS

 描述(由申请人提供)：耳部局部药物应用被广泛使用，并具有治疗一系列内耳疾病的巨大潜力。然而，一些药物的药代动力学特性使它们不适合在耳朵中达到预期目的。沿耳蜗线的分布主要受血液排泄率的影响。快速消除的药物不会从应用地点扩散远，地塞米松是一种小的非极性分子，可以从外淋巴中迅速消除(中场休息22分钟)。地塞米松用于治疗耳蜗病，如特发性突聋。这严重限制了它的传播距离，并将阻止治疗浓度达到人类的语言频率区域。相比之下，前药物地塞米松磷酸是极性的，亲水性的，更好地保留在外淋巴液中，因此预计它将沿着耳蜗进一步分布。许多其他正在使用或正在开发的药物也面临着类似的挑战。这笔赠款中的项目将描述一系列药物的药代动力学特性，并将它们与特定的分子特性(大小、亲脂性、极性)联系起来。在……里面 目标1我们将测量一系列具有不同物理性质的类固醇的清除率。 这需要使用新的技术来均匀地将药物加载到外淋巴液中，并收集代表耳朵不同区域的多个纯净的外淋巴液样本。具有最低排除率的类固醇将被确定，因此最适合用于人工耳蜗术。在目标2中，我们将建立类固醇在鼓室内应用后的进入途径和分布。最近的研究表明，一些物质比鼓阶外淋巴更容易通过圆窗进入前庭外淋巴。了解不同药物进入耳朵的位置对于了解听觉和前庭区域的分布差异至关重要。药物在较长时间使用后的空间分布将与清除率相关，以验证依赖性。将通过药物治疗对圆形窗口和踝骨的药物进入速率进行操纵，目的是优化药物进入耳蜗或前庭的具体情况。在目标3中，我们将同样量化局部应用庆大霉素及其荧光类似物(GTTR)的消除、进入途径和内耳分布。这些研究将确定局部应用后目前尚不清楚的前庭和耳蜗毛细胞的途径，并将确定广泛使用的荧光类似物是否与本地药物具有类似的药代动力学。在目标4中，3个实验目标积累的动力学过程知识将被纳入计算机模型，供该领域的其他人免费使用。这些项目将建立内耳药代动力学的基本科学原理，这些原理源于临床相关药物的可靠措施。这些发现将影响动物和人类的局部递送，并有助于确保无效的药物递送不再是治疗失败的原因。

 DESCRIPTION (provided by applicant): Local drug applications to the ear are in widespread use and hold tremendous potential for the treatment of a spectrum of inner ear disorders. However, some drugs have pharmacokinetic properties that make them unsuitable for their intended purpose in the ear. Distribution along the cochlea is dominated by the rate of elimination to blood. Drugs that are rapidly eliminated do not spread far from the application site Dexamethasone, which is used as a therapy for cochlear disorders such as idiopathic sudden hearing loss, is a small, non-polar molecule that is rapidly eliminated from the perilymph (22 min half-time). This severely limits how far it spreads and would prevent therapeutic concentrations reaching speech frequency regions of humans. In contrast, the pro-drug dexamethasone phosphate, is polar, hydrophilic, and better retained in perilymph so it would be expected to distribute further along the cochlea. Similar challenges face many other drugs in use or in development. The projects in this grant will characterize the pharmacokinetic properties of a range of drugs and relate them to specific molecular properties (size, lipophilicity, polarity). In Aim 1 we will measure elimination rates for a range of steroids with different physical properties. This requires the use of novel techniques both to load perilymph uniformly with drug and to collect multiple, pure perilymph samples representing different regions of the ear. Steroids with the lowest elimination rates and therefore most appropriate for cochlear therapy will be identified. In Aim 2 we will establish entry routes and distribution of steroids following intratympanic applications. Recent studies have shown that some substances enter the vestibular perilymph via the stapes more readily than perilymph of scala tympani via the round window. Knowledge of where different drugs enter the ear is crucial to understanding distribution differences between auditory and vestibular regions. Spatial distribution of drugs following longer applications will be correlated with elimination rates to verify the dependence. Manipulations of drug entry rates at the round window and stapes by pharmacological treatments will be performed with the goal of optimizing drug entry specifically into the cochlea or vestibule. In Aim 3, we will similarly quantify elimination, entry routes and inner ear distribution for locally applied gentamicin and its fluorescent analog (GTTR). These studies will establish the presently unknown routes to vestibular and cochlear hair cells following local application and will determine whether the widely-used fluorescent analog has similar pharmacokinetics to the native drug. In Aim 4, accumulated knowledge of kinetic processes from the 3 experimental aims will be incorporated into a computer model that is made freely-available for others in the field to use. These projects will establish basic scientific principlesof inner ear pharmacokinetics derived from reliable measures with clinically-relevant drugs. The findings will impact local delivery in both animals and humans and help ensure that ineffective drug delivery is no longer a cause of treatment failure.