Kinetics of reciprocating drug delivery to the inner ear.
Kinetics of reciprocating drug delivery to the inner ear.
复制标题
药物往复输送至内耳的动力学。
DOI：
10.1016/j.jconrel.2011.02.021
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Sewell,WilliamF
中科院分区：
文献类型：
--
作者：
Pararas,ErinELeary;Chen,Zhiqiang;Fiering,Jason;Mescher,MarkJ;Kim,ErnestS;McKenna,MichaelJ;Kujawa,SharonG;Borenstein,JeffreyT;Sewell,WilliamF
往复给药是一种将可溶性药物通过单管直接输送到体内封闭的液体空间而不伴随液体体积变化的方法。它是理想的药物输送到小，敏感和独特的液体空间，如耳蜗。我们通过测量流动参数变化对药物在整个耳蜗长度分布的影响，表征了耳蜗内往复给药到中耳膜的药代动力学。通过监测DNQX（一种可逆谷氨酸受体阻滞剂）的效果来评估分布，DNQX是一种可逆的谷氨酸受体阻滞剂，通过往复流动曲线直接给药到豚鼠内耳。然后，我们使用迭代曲线拟合方法和计算流体动力学模型模拟了这些参数对分布的影响。我们的研究结果与假设一致，即往复递送将药物分布到耳蜗底部的体积中，并表明在耳蜗更远端区域分布的主要决定因素是扩散。流速的增加使药物分布在更大的体积内，并向顶端延伸。在短时间内（少于2小时），根尖延伸虽然很小，但显著增强了药物的根尖定向输送。在较长的时间（5小时）或较长的距离（3毫米）中，维持基底鼓膜的药物浓度可能比增加流速更有利于延长根尖输送。这些观察结果表明，这种往复技术能够为耳蜗内封闭的流体空间提供受控的递送动力学，并且可能适用于其他应用，例如局部脑和视网膜递送。
Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2 h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (> 5 h) or greater distances (> 3 mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery.