INNER EAR FLUID INTERACTIONS

描述（由申请人提供）：内耳局部给药已广泛应用于临床实践，许多新的治疗方法正在开发中。然而，由于获得纯淋巴周围样品的技术困难以及圆窗应用产生的高度可变的淋巴周围药物水平，我们大多数关于药物在耳中的药代动力学的知识都是不可靠的。在过去的项目期间，我们开发了淋巴管周围采样的新方法和高度控制的药物递送方法，当它们结合在一起时，首次允许进行有意义的药代动力学研究。我们第一个目标的实验研究将使用阳离子和阴离子标记物来量化物质在耳蜗和前庭系统中的分布，然后从密封在淋巴管周围不同位置的移液管直接注射。电荷在决定物质是否进入内淋巴中的作用将被研究。体内浓度测量将允许对主要溶质分布和消除特性进行量化，并将进一步验证流体取样程序的测量结果。当我们了解了促进分布和从耳中消除的基本过程后，将使用顺序采样方法进行临床相关药物庆大霉素（阳离子）和地塞米松（阴离子）的药代动力学研究。阴离子药物水杨酸盐的药代动力学和药效学也将被研究，作为一种引起耳朵短暂敏感性变化的药物，可以用作药物分布的间接测量。第二个目标将集中在影响淋巴周围药物水平的其他因素，当药物应用于淋巴内。这包括研究药物从中耳消除的速度，以及施加的体积如何影响淋巴周围浓度。将评估体积稳定（凝胶）或定时释放（凝胶或PLGA纳米颗粒）给药到耳蜗的优点。结合这些实验研究，将开发基于解剖学的药物在动物和人耳液体和组织空间分布的综合1-D数学模型。增强的模型将允许对复杂的实验方案进行定量解释，并将允许对人类药物分布模式进行现实的预测。将向该领域的其他小组提供模型，以便对各种动物和人类数据进行定量解释。这些项目的结果将为利用药物在耳中的应用进行生理学研究提供基础科学基础，并将允许药物或其他物质进入人耳以优化特定目的。

DESCRIPTION (provided by applicant): Local drug deliveries to the inner ear have become widely used in clinical practice and many new therapies are being developed. However, most of our knowledge of drug pharmacokinetics in the ear is unreliable due to both the technical difficulties in obtaining pure perilymph samples and the highly variable perilymph drug levels produced by round window applications. In the past project period, we developed novel methods of perilymph sampling and highly controlled methods of drug delivery that, when combined, allow meaningful pharmacokinetic studies to be performed for the first time. The experimental studies in our first aim will use cationic and anionic markers to quantify the distribution of substances throughout the cochlear and vestibular systems, following direct injections from pipettes sealed into perilymph at different locations. The role of electrical charge in determining whether substances enter endolymph will be studied. Concentration measurements in vivo will allow the major solute distribution and elimination properties to be quantified and will further validate measurements from fluid sampling procedures. When we understand the basic processes contributing to distribution and elimination from the ear, pharmacokinetic studies of the clinically relevant drugs gentamicin (a cation) and dexamethasone (an anion) will be performed using sequential sampling methods. The pharmacokinetics and pharmacodynamics of the anionic drug salicylate will also be studied, as an agent causing transient sensitivity changes of the ear that can be used as an indirect measure of drug distribution. A second aim will focus on additional factors influencing perilymph drug levels when the drugs are applied intratympanically. This includes study of the rate of drug elimination from the middle ear and how the applied volume affects perilymph concentration. The merits of volume stabilized (gels) or timed release (gel or PLGA nanoparticles) delivery of drugs to the cochlea will be evaluated. In conjunction with these experimental studies, comprehensive 1-D, anatomically based, mathematical models of drug distribution in the fluid and tissue spaces of animal and human ears will be developed. The enhanced models will permit complex experimental protocols to be interpreted quantitatively and will allow realistic prediction of drug distribution patterns in humans. Models will be made available to other groups in the field, permitting quantitative interpretation of a variety of animal and human data. Results from these projects will provide a basic scientific foundation for physiologic studies utilizing drug applications to the ear and will allow the delivery of drugs or other substances to the ears of humans to be optimized for specific purposes. PUBLIC HEALTH RELEVANCE: In many cases, ears affected by diseases would benefit from treatments using locally applied drugs. At present, drug delivery protocols are developed by trial and error in humans, sometimes to the detriment of the patient. This project seeks to develop an understanding of pharmacokinetics in the ear that will, in conjunction with computer models, allow drug treatment protocols to be scientifically based.