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
- 来源:
- 关键词:AbbreviationsChemicalsComputer AssistedConfocal MicroscopyCorneaCustomDataDevelopmentDiffusionDrug Administration RoutesDrug DesignDrug KineticsDrug TransportEndotheliumEpithelialExhibitsEyeFluoresceinFluoresceinsFluorescenceFluorescence MicroscopyGoalsHeterogeneityIn VitroInvestigationLeadMeasuresMicroscopicMicroscopyModelingMolecular ModelsMolecular StructureMolecular WeightOryctolagus cuniculusPenetrationPharmaceutical PreparationsPhysiologicalPrincipal InvestigatorScanningSeriesSkinSpottingsStructureTechniquesThickTimeTissuesTopical applicationTreatment ProtocolsValidationanaloganterior chamberbasechemical propertydesigndosagein vivoinsightinstrumentionizationknowledge baselipophilicitymembermolecular modelingmonolayernovelpharmacokinetic modelprogramspublic health relevanceresearch studystem
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(由申请人提供):在显微镜水平下药物透过角膜的动力学局部应用于眼睛的药物主要通过透过多层角膜进入眼内组织,所述多层角膜由分层上皮层、厚的胶原基质和渗漏的单层内皮组成。以前的研究局部药物动力学的眼睛主要集中在跨角膜运输的房室模型。这些模型忽略了角膜中固有的异质性,使得它们无法做出足够准确的预测。忽略角膜中的异质性是因为药物的实验性经角膜浓度曲线不可用且难以获得。因此,在局部药物对眼睛的药代动力学建模的开发中,仅采用了通常测量的角膜中药物的平均值。本项目将采用一种新型的定制共焦扫描显微荧光计来测量一系列荧光化合物作为药物类似物在体外安装的兔角膜上的跨角膜分布。将采用所得的经角膜浓度曲线开发基于现象学的非房室药代动力学模型。然后将采用所得模型来预测局部施用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个定制的眼用点荧光计获得相同的荧光化合物。后一种仪器可以测量来自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预计将产生对局部药物动力学的详细机制理解,并最终实现合理的药物设计以及最佳药物剂量方案的开发。公共卫生相关性:超过90%的眼部药物是通过局部给药进行给药的。在这个项目中,我们建议调查如何局部给药的药物穿透角膜进入眼睛。我们期望获得一个机制的理解,这是需要合理的药物设计和最佳设计的剂量方案。
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.
- DOI:10.1097/opx.0b013e3181d39464
- 发表时间:2010-04
- 期刊:
- 影响因子:0
- 作者:Srinivas SP
- 通讯作者:Srinivas SP
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:
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