Ocular Disposition of Antimicrobial Agents

抗菌药物的眼部分布

基本信息

批准号：
7167438
负责人：
Ashim K. Mitra
金额：
$ 30.06万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-11-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7167438
关键词：
Acute Acyclovir Adrenal Cortex Hormones Affinity Amino Acid Transporter Amino Acids Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antioxidants Antiviral Agents Applications Grants Ascorbic Acid Biological Availability Cells Conscious Cornea Cytomegalovirus DNA Drug resistance Epithelial Epithelial Cells Erythromycin Esters Exhibits Fluoroquinolones Funding Glutamates Glycine Grant Herpesviridae Herpesvirus 1 Human Human Herpesvirus 2 Human Herpesvirus 4 Hydrolysis In Vitro Inflammation Keratitis Laboratories Lead Levaquin Liquid substance Macrolides Mediating Membrane Methylprednisolone Microdialysis Modeling Molecular National Institute of Allergy and Infectious Disease Ofloxacin Oryctolagus cuniculus P-Glycoprotein P-Glycoproteins Penetration Peptides Permeability Pharmaceutical Preparations Phenylalanine Prednisone Prodrugs Property Proteins Quinidine RNA Viruses Reporting Research Research Contracts Research Institute Research Personnel Role Simplexvirus Solubility Steroids System Techniques Therapeutic Time Tissues Topical application Treatment Efficacy Valine Viral Virus Diseases absorption anterior chamber antimicrobial drug ascorbate corneal epithelium cytotoxicity design efflux pump eye center improved in vivo inhibitor/antagonist lipophilicity novel nucleoside analog prednisolone programs uptake

项目摘要

DESCRIPTION (provided by applicant): The long term objective of this competing renewal grant application is to develop novel prodrug strategies to improve corneal permeability of topically applied antimicrobial agents employed in the treatment of both bacterial and viral corneal stromal and epithelial keratitis. In this grant proposal we aim to characterize the ascorbate carrier systems expressed on the corneal membrane. We also propose to synthesize amino acid, peptide and ascorbate ester prodrugs of erythromycin, levofloxacin and ofloxacin and ascorbate ester prodrugs of ACV, targeted towards the respective transporters expressed on the corneal membrane, and to evaluate their ability to circumvent P-gp and MRP mediated efflux. The specific aims of this renewal application are a) To synthesize derivatives of erythromycin, levofloxacin and ofloxacin targeting amino acid (phenylalanine and glutamate prodrugs), peptide (valine, valine-valine and glycine-valine prodrugs) and ascorbate (ascorbic acid prodrugs) transporters expressed on the cornea and to evaluate these conjugates with respect to their b) physiochemical properties and cytotoxicity; c) bio- reversion in ocular fluids and cell homogenates, d) uptake, transport and simultaneous bioreversion across isolated rabbit cornea, and human and rabbit primary corneal epithelial cell cultures, e) affinity for P-gp and MRP efflux pumps, f) in vitro antibacterial efficacy and g) in vivo antibacterial efficacy against bacterial keratitis in the rabbit model. In vitro and in vivo studies will be conducted by Dr. William Suling at the Southern Research Institute, Birmingham, AL and by Dr. James Hill at the LSU Eye Center, New Orleans, LA, respectively. Uptake and transport of erythromycin, levofloxacin and ofloxacin prodrugs will be studied across isolated rabbit cornea, human and rabbit primary corneal epithelial cell cultures (rPCEC), alone, in combination and in the presence of topically applied anti-inflammatory steroids (prednisolone, prednisone and 6-alpha-methylprednisolone). We propose to synthesize ascorbate prodrug of ACV study transport and simultaneous bio-reversion across isolated rabbit corneas, and human and rabbit primary corneal epithelial cell cultures; antiviral efficacy against in vitro viral screens of HSV-1, HSV-2, CMV, VZV and EBV and in vivo antiviral efficacy against HSV-1 (McKrae strain) induced acute epithelial and stromal keratitis in the rabbit model. In vitro and in vivo studies will be conducted by Dr. Sam Ananthan and Dr. Earl Kern under NIAID funded research contract and by Dr. James Hill. In vivo ocular bioavailability of erythromycin, levofloxacin, ofloxacin and ACV and their prodrugs will be examined following topical application (alone, in combination or in the presence of prednisolone, prednisone and 6-alpha-methylprednisolone as inhibitors of corneal efflux pumps) in both anesthetized and conscious rabbit models by employing ocular microdialysis technique.

描述（由申请人提供）：这种竞争性更新授予申请的长期目标是开发新型的前药策略，以提高用于治疗细菌和病毒角膜基质和病毒角膜基质和上皮性角膜炎的局部应用抗菌剂的角膜渗透性。在这项赠款建议中，我们旨在表征角膜膜上表达的抗坏血酸载体系统。我们还建议将氨基酸，肽和抗坏血酸酯酯类前药，左氧氟沙星，左氧氟沙星和Ofloxacin和Acv的抗坏血酸酯前药，旨在朝向角膜膜上表达的相应转运蛋白，并评估其在角膜膜上的能力，并评估了它们的per p-gp p-gp和Merp Medied Medied Medied Medied Medied Medied Medied felf。此更新应用的具体目的是a）靶向氨基酸（苯丙氨酸和谷氨酸前药），肽，瓣膜，缬氨酸，瓣膜 - 竞争量和甘氨酸 - 乙他 - 毒性生产（丙糖）和丙糖酸盐（替代品）（丙烯酸酯）（苯丙氨酸和丙氨酸）的丙霉素和丙氧酸酯（丙氨酸）（丙烯酸酯）（丙烯酸酯）（替代品）（替代品）（替代品）（替代品），将促霉素，左丙霉素和氧有星的衍生物合成a）a）a）a）。评估这些结合物相对于它们的b）生理学特性和细胞毒性； c）在眼部液体和细胞匀浆中的生物逆转，d）跨孤立的兔角膜的摄取，运输和同时生物循环，以及人类和兔子原发性角膜上皮细胞培养，e）P-gp和MRP外交泵的亲和力，f）抗体抗体抗体抗体抗体抗体抗体抗体，模型。体外和体内研究将由伯明翰南部研究所的William Suling博士分别由洛杉矶新奥尔良LSU眼中中心的James Hill博士进行。将在孤立的兔角膜，人类和兔子原发性角膜上皮细胞培养物（RPCEC）中，组合，结合以及存在局部施用的抗抑制型抗抑制剂（前硝基固醇，prednisol）predniSNISNISN-ARPERPRPRPRPRPRPRPROPEN，将研究红霉素，左氧氟沙星和氧氟沙星前药的摄取和运输。我们提议合成ACV研究的抗坏血酸前药，并同时跨孤立的兔角膜以及人类和兔子原发性角膜上皮细胞培养物进行生物逆转；针对HSV-1，HSV-2，CMV，VZV和EBV的体外病毒筛查的抗病毒功效，以及针对HSV-1（MCKRAE菌株）的体内抗病毒疗效诱导了兔模型中的急性上皮和基质角膜炎。体外和体内研究将由Sam Ananthan博士和Earl Kern博士根据Niaid资助的研究合同以及James Hill博士进行。局部应用（单独使用，单独或组合或在存在泼尼松酮，泼尼松酮和6-α-甲基甲基甲醇的efflux pumbit）中，将检查红霉素，左霉素，氧氟沙星和ACV及其前药的体内眼部生物利用度及其前药。微透析技术。