Ocular pharmacokinetics and efficacy of various amino acid and dipeptide prodrugs of ganciclovir

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Ocular pharmacokinetics and efficacy of various amino acid and dipeptide prodrugs of ganciclovir

Please use this identifier to cite or link to this item: http://hdl.handle.net/10355/15604

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dc.contributor.advisor Mitra, Ashim K., 1954- en
dc.contributor.author Gunda, Sriram
dc.date.accessioned 2012-10-02T20:01:10Z
dc.date.available 2012-10-02T20:01:10Z
dc.date.issued 2012-10-02
dc.date.submitted 2012 Summer en
dc.identifier.uri http://hdl.handle.net/10355/15604
dc.description Title from PDF of title page, viewed on October 2, 2012 en
dc.description Dissertation advisor: Ashim K. Mitra en
dc.description Vita en
dc.description Includes bibliographic references (p. 188-199) en
dc.description Thesis (Ph.D.)--School of Pharmacy and Dept. of Chemistry. University of Missouri--Kansas City, 2012 en
dc.description.abstract Herpes 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.tableofcontents Introduction -- 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 permission en
dc.format.extent xvi, 200 pages en
dc.language.iso en_US en_US
dc.publisher University of Missouri--Kansas City en
dc.subject.lcsh Herpes simplex virus en
dc.subject.lcsh Ocular pharmacology en
dc.subject.lcsh Ganciclovir en
dc.subject.mesh Herpes Simplex-- drug therapy en
dc.subject.mesh Ganciclovir en
dc.subject.other Dissertation -- University of Missouri--Kansas City -- Pharmacy en
dc.subject.other Dissertation -- University of Missouri--Kansas City -- Chemistry en
dc.title Ocular pharmacokinetics and efficacy of various amino acid and dipeptide prodrugs of ganciclovir en_US
dc.type Thesis en_US
thesis.degree.discipline Pharmaceutical Sciences and Chemistry en
thesis.degree.grantor University of Missouri--Kansas City en
thesis.degree.name Ph.D. en
thesis.degree.level Doctoral en


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