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dc.contributor.advisorMitra, Ashim K., 1954- advisoren
dc.contributor.authorGunda, Sriram
dc.date.issued2012-10-02
dc.date.submitted2012 Summeren
dc.descriptionTitle from PDF of title page, viewed on October 2, 2012en
dc.descriptionDissertation advisor: Ashim K. Mitraen
dc.descriptionVitaen
dc.descriptionIncludes bibliographic references (p. 188-199)en
dc.descriptionThesis (Ph.D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2012en
dc.description.abstractHerpes simplex virus infections (HSV) in the eye are one of the leading causes of blindness across the world. Current available treatment options to treat HSV infections are solutions of trifluorothymidine (TFT), idoxuridine (IDU), and vidarabine, ganciclovir (GCV) gel and acyclovir (ACV) ointments. Some of the problems associated with thymidine analogues are their ocular and systemic toxicities in long term usage. Even though GCV and ACV have good efficacies against HSV, their limited solubility, poor corneal absorption and diminished ocular bioavailability limits their effectiveness. Ointments and gels are also prescribed to be applied 5-9 times per day, which not only hampers the visibility of patients but also affect their daily life. Often, these antiviral agents are administered along with steroids to reduce the corneal inflammation. Application of ointments and gels restrict the concomitant usage of topical steroids solutions. To address the above issues, goals were set to prepare high dose topical aqueous solutions and to increase ocular bio-availability of GCV. A series of dipeptide monoester prodrugs and amino acid monoester and diester prodrugs were designed to target the nutrient transporters peptide transporter (hPEPT1) and sodium dependent neutral and cationic transporter (B [super 0,+]), respectively. The overall objectives of this study are to evaluate cytotoxicity and uptake of prodrugs in rabbit corneal epithelial cells in vitro, and also to estimate corneal absorption, aqueous humor pharmacokinetics and antiviral activity on rabbit models. Pharmacokinetic studies were performed on rabbit models using ocular microdialysis models. Pharmacokinetic parameters were estimated for all the prodrugs and were compared with the parent drug. A prodrug with best pharmacokinetic properties was selected to study for its antiviral activity against HSV-1 in virus inoculated corneal epithelial keratitis rabbit models. In conclusion, L-Tyrosine-L-Valine-GCV among peptide ester prodrugs and L-Valine-GCV among the amino acid ester prodrugs exhibited superior corneal absorption and bioavailability in comparison with GCV. This might be due to the absorption of these drugs via both transcellular passive diffusion and hPEPT1 mediated transport across corneal epithelium. L-Tyrosine-L-Valine-GCV was also found to have excellent antiviral activity in comparison with currently available product, TFT.en_US
dc.description.tableofcontentsIntroduction -- Literature review -- Cytotoxicity assays of amino acid and di-peptide prodrugs of gcv on rabbit primary corneal epithelial cells (RPCEC) -- Anterior chamber pharmacokinetics of l-arginine and amino acid monester prodrugs of gcv in rabbit eyes and their interaction with B [super 0,+] transporter on the rabbit cornea and rabbit primary corneal epithelial cells (RPCEC) -- Anterior chamber pharmacokinetics of di-peptide monester produrgs of gcv in rabbit eyes and absorption of prodrugs targeting pepti transporter on the rabbit corneal epithelium -- Oral administration and systemic pharmocokinetics of gcv and dipeptide monoester prodrug L-tyr-l-val-gcv in jugular wein cannulated Sprague Dawley rats -- In vivo antiviral efficacy, survival analysis and modeling of l-tyr-l-val-gdv monester on hsv-1 induced rabbit epithelial keratitis model -- Summary and recommendations -- Letter of permissionen
dc.format.extentxvi, 200 pagesen
dc.identifier.urihttp://hdl.handle.net/10355/15604
dc.publisherUniversity of Missouri--Kansas Cityen
dc.subject.lcshHerpes simplex virusen
dc.subject.lcshOcular pharmacologyen
dc.subject.lcshGancicloviren
dc.subject.meshHerpes Simplex-- drug therapyen
dc.subject.meshGancicloviren
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Pharmacyen
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Chemistryen
dc.titleOcular pharmacokinetics and efficacy of various amino acid and dipeptide prodrugs of gancicloviren_US
dc.typeThesisen_US
thesis.degree.disciplinePharmacyeng
thesis.degree.disciplineChemistryeng
thesis.degree.grantorUniversity of Missouri--Kansas Cityen
thesis.degree.levelDoctoralen
thesis.degree.namePh.D.en


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