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Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations.
J Ocul Pharmacol Ther 2005; 21(6):463-74JO

Abstract

PURPOSE

The aim of this study was to evaluate a series of dipeptide monoester ganciclovir (GCV) prodrugs with the goal of improving ocular bioavailability of GCV from topical ophthalmic solutions.

METHODS

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.

RESULTS

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 d at 37 degrees C, 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 of the prodrugs had a much higher aqueous solubility than the parent drug. Transcorneal permeability of Val-GCV and Val-Val-GCV was seven- to eightfold 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.

CONCLUSIONS

Val-Val-GCV demonstrates excellent corneal permeability and chemical stability, high aqueous solubility, and substantial in vivo antiviral activity against the HSV-1.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, 64110-2499, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16386088

Citation

Majumdar, Soumyajit, et al. "Dipeptide Monoester Ganciclovir Prodrugs for Treating HSV-1-induced Corneal Epithelial and Stromal Keratitis: in Vitro and in Vivo Evaluations." Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, vol. 21, no. 6, 2005, pp. 463-74.
Majumdar S, Nashed YE, Patel K, et al. Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. J Ocul Pharmacol Ther. 2005;21(6):463-74.
Majumdar, S., Nashed, Y. E., Patel, K., Jain, R., Itahashi, M., Neumann, D. M., ... Mitra, A. K. (2005). Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics, 21(6), pp. 463-74.
Majumdar S, et al. Dipeptide Monoester Ganciclovir Prodrugs for Treating HSV-1-induced Corneal Epithelial and Stromal Keratitis: in Vitro and in Vivo Evaluations. J Ocul Pharmacol Ther. 2005;21(6):463-74. PubMed PMID: 16386088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. AU - Majumdar,Soumyajit, AU - Nashed,Yasser E, AU - Patel,Kunal, AU - Jain,Ritesh, AU - Itahashi,Motoki, AU - Neumann,Donna M, AU - Hill,James M, AU - Mitra,Ashim K, PY - 2006/1/3/pubmed PY - 2006/2/4/medline PY - 2006/1/3/entrez SP - 463 EP - 74 JF - Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics JO - J Ocul Pharmacol Ther VL - 21 IS - 6 N2 - PURPOSE: The aim of this study was to evaluate a series of dipeptide monoester ganciclovir (GCV) prodrugs with the goal of improving ocular bioavailability of GCV from topical ophthalmic solutions. METHODS: 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. RESULTS: 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 d at 37 degrees C, 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 of the prodrugs had a much higher aqueous solubility than the parent drug. Transcorneal permeability of Val-GCV and Val-Val-GCV was seven- to eightfold 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. CONCLUSIONS: Val-Val-GCV demonstrates excellent corneal permeability and chemical stability, high aqueous solubility, and substantial in vivo antiviral activity against the HSV-1. SN - 1080-7683 UR - https://www.unboundmedicine.com/medline/citation/16386088/Dipeptide_monoester_ganciclovir_prodrugs_for_treating_HSV_1_induced_corneal_epithelial_and_stromal_keratitis:_in_vitro_and_in_vivo_evaluations_ L2 - https://www.liebertpub.com/doi/full/10.1089/jop.2005.21.463?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -