Purchase this article with an account.
R. Jain, S. Majumdar, Y.E. Nashed, A.K. Mitra; Dipeptide Monoester Ganciclovir Prodrugs for Treating HSV–1–Induced Corneal Epithelial and Stromal Keratitis: in vitro and in vivo Evaluations . Invest. Ophthalmol. Vis. Sci. 2006;47(13):79.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To evaluate a series of dipeptide monoester ganciclovir (GCV) prodrugs with the goal of improving ocular bioavailability of GCV from topical ophthalmic solutions.
Solubility, logP, pH–stability profile, permeability, interaction with corneal peptide transporter and in vivo efficacy against herpes simplex virus type 1 (HSV–1) ocular disease in the rabbit model were studied.
Val–Val–GCV, Tyr–Val–GCV, and Gly–Val–GCV were more stable in aqueous solution than Val–GCV showing no measurable degradation even after 7 days at 37oC, within the pH range of 1.4 – 5.4. Tyr–Val–GCV and Val–Tyr–GCV were the most lipophilic among the prodrugs synthesized and were predicted to have an n–octanol/water partition coefficient 33 times greater than that of GCV. All the prodrugs had much higher aqueous solubility than the parent drug. Transcorneal permeability of Val–GCV and Val–Val–GCV was 7– to 8–fold greater than that of GCV, in the presence of a proton gradient, and was significantly decreased in the presence of Gly–Pro. Val–Val–GCV (1% w/v) provided significantly better therapeutic activity than trifluorothymidine (1% w/v) against HSV–1 epithelial keratitis and equivalent therapeutic activity against stromal keratitis in the rabbit eye model.
Val–Val–GCV demonstrates excellent corneal permeability and chemical stability, high aqueous solubility, and substantial in vivo antiviral activity against the HSV–1.
This PDF is available to Subscribers Only