IDU and TFT are nucleoside analogues that are incorporated into the viral DNA, causing disruption of viral DNA synthesis. At present, topical application of TFT is the gold standard in the treatment of HSV keratitis, although cytotoxicity limits its use. One of the mechanisms for the antiviral activity of Ara-A may involve inhibition of DNA polymerase and terminating the viral DNA chain.
4 ACV is specifically activated by viral thymidine kinase and then phosphorylated by cellular enzymes to ACV triphosphate, which binds preferentially to HSV-1 DNA polymerase and blocks viral replication.
34 In superficial herpes keratitis, the clinical efficacy of 3% ACV ophthalmic ointment applied five times a day for up to 14 days has been reported.
5 However, ACV ointment has not been approved by the U.S. Food and Drug Administration for clinical use against HSV keratitis in the United States.
5 33 In addition, ACV ointment is not effective against stromal keratitis or when deeper ocular tissues are involved.
28 VACV, a drug of choice for genital herpes, increases the bioavailability of ACV by five- to sixfold due to its recognition by hPEPT1 after oral absorption.
35 36 However, because of its limited stability in solution, formulation of higher concentrations of VACV into stable aqueous drops is not feasible,
15 and, therefore, this drug cannot be used against HSV epithelial and stromal keratitis. Thus, the development of a safe, long-acting, effective, nontoxic, and stable topical antiviral drops that require less frequent doses for fewer days or lower concentrations would represent a significant improvement over the currently available antiviral drugs.