In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model.
OBJECTIVE
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.
Anand
Banmeet S
BS
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64110-2499, USA.
Hill
James M
JM
Dey
Surajit
S
Maruyama
Koichi
K
Bhattacharjee
Partha S
PS
Myles
Marvin E
ME
Nashed
Yasser E
YE
Mitra
Ashim K
AK
D000212:Acyclovir / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D002522:Chlorocebus aethiops; D003315:Cornea / Q000378:metabolism; D003319:Corneal Stroma / Q000187:drug effects* / Q000821:virology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000302:isolation & purification*; D016849:Keratitis, Herpetic / Q000188:drug therapy* / Q000821:virology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D014271:Trifluridine / Q000627:therapeutic use; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000998:Antiviral Agents; D011355:Prodrugs; C473736:val-valacyclovir; D014633:Valine; D000077483:Valacyclovir; D014271:Trifluridine; D000212:Acyclovir