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，许多新疗法正在开发中。然而，由于获取纯外淋巴液样本的技术困难和圆窗应用产生的高度可变的外淋巴液药物浓度，我们对药物在耳朵中的药代动力学的大部分知识是不可靠的。在过去的项目期间，我们开发了外淋巴采样的新方法和高度受控的药物输送方法，当它们结合在一起时，第一次能够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，然后从不同位置的吸管直接注射到外淋巴液中。电荷在决定物质是否进入内淋巴中的作用将被研究。体内浓度测量将使主要溶质分布和消除特性得以量化，并将进一步验证流体采样程序的测量结果。当我们了解了导致耳部分布和消除的基本过程后，临床相关药物庆大霉素(阳离子)和地塞米松(阴离子)的药代动力学研究将使用顺序抽样方法进行。阴离子药物水杨酸盐的药代动力学和药效学也将被研究，作为一种可引起耳朵瞬时敏感性变化的试剂，可用作药物分布的间接测量。第二个目标将集中在当药物在鼓室内应用时影响外淋巴液药物水平的其他因素。这包括研究药物从中耳中排出的速度以及施药量如何影响外淋巴液浓度。将评估容量稳定(凝胶)或定时释放(凝胶或PLGA纳米颗粒)给药到耳蜗处的优点。与这些实验研究相结合，将开发一种全面的一维、基于解剖学的药物在动物和人类耳朵的液体和组织空间中分布的数学模型。增强的模型将允许对复杂的实验方案进行定量解释，并将允许对药物在人体内的分布模式进行现实预测。模型将提供给该领域的其他小组，允许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应用于耳朵的生理学研究提供基本的科学基础，并将使药物或其他物质输送到人类耳朵的特定目的得到优化。 公共卫生相关性：在许多情况下，受疾病影响的耳朵将受益于使用当地应用的药物进行治疗。目前，药物给药方案是通过在人体内反复试验来开发的，有时会损害患者的健康。这个项目寻求发展对耳朵药物动力学的理解，结合计算机模型，允许药物治疗方案建立在科学的基础上。

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.