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In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model.
Invest Ophthalmol Vis Sci 2003; 44(6):2529-34IO

Abstract

PURPOSE

A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis.

METHODS

The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 microL of 10(5) plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 microL of 10(5) PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group. Lesions were evaluated by slit lamp examinations over a 2-week period after infection. Aqueous humor samples and corneas were analyzed for drug concentrations at the end of each experiment. Cytotoxicity of VVACV in comparison with val-acyclovir (VACV), ACV, and TFT was evaluated in cellular proliferation assays.

RESULTS

The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT. The prodrug was also less cytotoxic than TFT, which is the only effective drug currently licensed and routinely used for topical treatment of ocular herpes infections in the United States.

CONCLUSIONS

The less cytotoxic and highly water-soluble prodrug VVACV, which showed excellent in vivo activity against HSV-1 in rabbit epithelial and stromal keratitis, is a promising drug candidate for treatment of ocular HSV infections.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 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)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12766053

Citation

Anand, Banmeet S., et al. "In Vivo Antiviral Efficacy of a Dipeptide Acyclovir Prodrug, Val-val-acyclovir, Against HSV-1 Epithelial and Stromal Keratitis in the Rabbit Eye Model." Investigative Ophthalmology & Visual Science, vol. 44, no. 6, 2003, pp. 2529-34.
Anand BS, Hill JM, Dey S, et al. In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Invest Ophthalmol Vis Sci. 2003;44(6):2529-34.
Anand, B. S., Hill, J. M., Dey, S., Maruyama, K., Bhattacharjee, P. S., Myles, M. E., ... Mitra, A. K. (2003). In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Investigative Ophthalmology & Visual Science, 44(6), pp. 2529-34.
Anand BS, et al. In Vivo Antiviral Efficacy of a Dipeptide Acyclovir Prodrug, Val-val-acyclovir, Against HSV-1 Epithelial and Stromal Keratitis in the Rabbit Eye Model. Invest Ophthalmol Vis Sci. 2003;44(6):2529-34. PubMed PMID: 12766053.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. AU - Anand,Banmeet S, AU - Hill,James M, AU - Dey,Surajit, AU - Maruyama,Koichi, AU - Bhattacharjee,Partha S, AU - Myles,Marvin E, AU - Nashed,Yasser E, AU - Mitra,Ashim K, PY - 2003/5/27/pubmed PY - 2003/6/13/medline PY - 2003/5/27/entrez SP - 2529 EP - 34 JF - Investigative ophthalmology & visual science JO - Invest. Ophthalmol. Vis. Sci. VL - 44 IS - 6 N2 - PURPOSE: A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis. METHODS: The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 microL of 10(5) plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 microL of 10(5) PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group. Lesions were evaluated by slit lamp examinations over a 2-week period after infection. Aqueous humor samples and corneas were analyzed for drug concentrations at the end of each experiment. Cytotoxicity of VVACV in comparison with val-acyclovir (VACV), ACV, and TFT was evaluated in cellular proliferation assays. RESULTS: The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT. The prodrug was also less cytotoxic than TFT, which is the only effective drug currently licensed and routinely used for topical treatment of ocular herpes infections in the United States. CONCLUSIONS: The less cytotoxic and highly water-soluble prodrug VVACV, which showed excellent in vivo activity against HSV-1 in rabbit epithelial and stromal keratitis, is a promising drug candidate for treatment of ocular HSV infections. SN - 0146-0404 UR - https://www.unboundmedicine.com/medline/citation/12766053/In_vivo_antiviral_efficacy_of_a_dipeptide_acyclovir_prodrug_val_val_acyclovir_against_HSV_1_epithelial_and_stromal_keratitis_in_the_rabbit_eye_model_ L2 - http://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.02-1251 DB - PRIME DP - Unbound Medicine ER -