Kinetics of Drug Penetration Across the Cornea at a Microscopic Level

微观水平上药物穿过角膜的渗透动力学

基本信息

  • 批准号:
    7681034
  • 负责人:
  • 金额:
    $ 18.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-01 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Kinetics of Drug Penetration across the Cornea at a Microscopic Level Drugs applied topically to the eye access the intraocular tissues predominantly by penetration across the multi-layered cornea, consisting of a stratified epithelial layer, a thick collagenous stroma and a leaky monolayer of endothelium. Previous studies on topical drug kinetics to the eye have focused mainly on compartmental modeling of transport across the cornea. Such models have disregarded the inherent heterogeneity in the cornea, rendering them incapable of making sufficiently accurate predictions. The disregard for the heterogeneity in the cornea stems from the fact that experimental transcorneal concentration profiles of drugs are unavailable and difficult to obtain. Accordingly, only the average values of the drugs in the cornea, which are usually measured, have been employed in the development of pharmacokinetic modeling of topical drugs to the eye. This project will employ a novel custom-built confocal scanning microfluorometer to measure transcorneal profiles of a series of fluorescent compounds employed as drug analogs across rabbit cornea mounted in vitro. The resulting transcorneal concentration profiles will be employed to develop a phenomenologically-based non-compartmental pharmacokinetic model. The resulting model will then be employed to predict pharmacokinetics for topical administration of the fluorescent drug analogs. These predictions will be compared with in vivo data, which will be obtained for the same fluorescent compounds using another custom-built ocular spot-fluorometer. The latter instrument can measure average fluorescence from the cornea and anterior chamber. Overall, the results from this project involving in vivo and in vitro experiments is expected to yield detailed mechanistic understanding of topical drug kinetics and eventually enable rational drug design as well as the development of optimal drug dosage regimen. PUBLIC HEALTH RELEVANCE: More than 90% of the drugs to the eye are administered by topical administration. In this project, we propose to investigate how the topically administered drugs penetrate across the cornea into the eye. We expect to obtain a mechanistic understanding of the penetration, which is needed for rational drug design and optimal design of dosage regimen.
描述(申请人提供):药物在微观水平上通过角膜渗透的动力学研究局部应用于眼睛的药物主要通过穿过多层角膜进入眼内组织,多层角膜由分层的上皮层、厚厚的胶原质基质和渗漏的单层内皮组成。以前关于眼部局部药物动力学的研究主要集中在跨角膜转运的隔室模型上。这些模型忽视了角膜固有的异质性,导致它们无法做出足够准确的预测。对角膜中的异质性的忽视源于这样一个事实,即药物经角膜的实验浓度分布是不可获得的,并且很难获得。因此,只有角膜中药物的平均值,通常是测量的,才被用于建立局部药物对眼睛的药代动力学模型。该项目将使用一种新的定制共聚焦扫描显微荧光仪来测量一系列用作药物类似物的荧光化合物在体外安装的兔角膜的经角膜轮廓。由此得到的经角膜浓度分布将被用来开发基于现象的非隔室药代动力学模型。然后,所得到的模型将用于预测局部给药荧光药物类似物的药代动力学。这些预测将与体内数据进行比较,体内数据将使用另一种定制的目标点荧光仪获得相同荧光化合物的数据。后一种仪器可以测量角膜和前房的平均荧光。总体而言,该项目涉及体内和体外实验的结果有望对局部药物动力学产生详细的机理理解,并最终使合理的药物设计以及最佳药物剂量方案的开发成为可能。与公共卫生相关:90%以上的眼部药物是通过局部给药的方式给药。在这个项目中,我们打算研究局部给药是如何穿过角膜进入眼睛的。我们期望从机理上了解渗透,这是合理的药物设计和最佳给药方案设计所必需的。

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Microtubule stabilization opposes the (TNF-alpha)-induced loss in the barrier integrity of corneal endothelium.
  • DOI:
    10.1016/j.exer.2009.08.004
  • 发表时间:
    2009-12
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Shivanna, Mahesh;Srinivas, Sangly P.
  • 通讯作者:
    Srinivas, Sangly P.
Dynamic regulation of barrier integrity of the corneal endothelium.
Microtubule disassembly breaks down the barrier integrity of corneal endothelium.
  • DOI:
    10.1016/j.exer.2009.03.019
  • 发表时间:
    2009-09
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Jalimarada, Supriya S.;Shivanna, Mahesh;Kini, Vidisha;Mehta, Dolly;Srinivas, Sangly P.
  • 通讯作者:
    Srinivas, Sangly P.
Elevated cAMP opposes (TNF-alpha)-induced loss in the barrier integrity of corneal endothelium.
cAMP 升高可对抗 (TNF-α) 引起的角膜内皮屏障完整性丧失。
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    2.2
  • 作者:
    Shivanna,Mahesh;Srinivas,SanglyP
  • 通讯作者:
    Srinivas,SanglyP
Cell signaling in regulation of the barrier integrity of the corneal endothelium.
  • DOI:
    10.1016/j.exer.2011.09.009
  • 发表时间:
    2012-02
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Srinivas SP
  • 通讯作者:
    Srinivas SP
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SANGLY P SRINIVAS其他文献

SANGLY P SRINIVAS的其他文献

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{{ truncateString('SANGLY P SRINIVAS', 18)}}的其他基金

Molecular mechanisms of cold storage-induced damage to the corneal endothelium
冷藏引起角膜内皮损伤的分子机制
  • 批准号:
    10741168
  • 财政年份:
    2023
  • 资助金额:
    $ 18.51万
  • 项目类别:
Kinetics of Drug Penetration Across the Cornea at a Microscopic Level
微观水平上药物穿过角膜的渗透动力学
  • 批准号:
    7511172
  • 财政年份:
    2008
  • 资助金额:
    $ 18.51万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6914435
  • 财政年份:
    2003
  • 资助金额:
    $ 18.51万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6774686
  • 财政年份:
    2003
  • 资助金额:
    $ 18.51万
  • 项目类别:
Myocilin-induced ER Stress in Trabecular Meshwork Cells
肌纤蛋白诱导的小梁网细胞内质网应激
  • 批准号:
    6686910
  • 财政年份:
    2003
  • 资助金额:
    $ 18.51万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6324068
  • 财政年份:
    1995
  • 资助金额:
    $ 18.51万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    2851741
  • 财政年份:
    1995
  • 资助金额:
    $ 18.51万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6164684
  • 财政年份:
    1995
  • 资助金额:
    $ 18.51万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    6518537
  • 财政年份:
    1995
  • 资助金额:
    $ 18.51万
  • 项目类别:
VOLUME REGULATION IN CORNEAL ENDOTHELIUM
角膜内皮的体积调节
  • 批准号:
    2165380
  • 财政年份:
    1995
  • 资助金额:
    $ 18.51万
  • 项目类别:

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