Acyclovir is a synthetic acyclic p.r.n. nucleoside analogue with in vitro inhibitory activity against Herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella-zoster, Epstein-Barr and cytomegalovirus. In cell cultures, the inhibitory activity of acyclovir for Herpes simplex virus is highly selective. Cellular thymidine kinase does not effectively utilize acyclovir as a substrate. Herpes simplex virus-coded thymidine kinase, however, converts acyclovir into acyclovir monophosphate, a nucleotide. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication. Acyclovir triphosphate also inhibits cellular alpha-DNA polymerase but to a lesser degree. In vitro, acyclovir triphosphate can be incorporated into growing chains of DNA by viral DNA polymerase and to a much smaller extent by cellular alpha-DNA polymerase. When incorporation occurs, the DNA chain is terminated. Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpesvirus-infected cells. Thus, acyclovir is much less toxic in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form; 3) cellular alpha-DNA polymerase is less sensitive to the effects of the active form.

The relationship between in vitro susceptibility of Herpes simplex virus to antiviral drugs and clinical response has not been established. The techniques and cell culture types used for determining in vitro susceptibility may influence the results obtained. Using a quantitative assay to determine the acyclovir concentration producing 50% inhibition of viral cytopathic effect (ID₅₀), 28 HSV-1 clinical isolates has a mean ID₅₀ of 0.17 mcg/ml and 32 HSV-2 clinical isolates had a mean ID₅₀of 0.46 mcg/ml. Results from other studies using different assays have yielded mean ID₅₀ values for clinical HSV-1 isolates of 0.018, 0.03 and 0.043 mcg/ml and for clinical HSV-2 isolates of 0.0027, 0.36 and 0.03 mcg/ml, respectively.

Two clinical pharmacology studies were performed with acyclovir ointment 5% in adult immunocompromised patients, at risk of developing mucocutaneous Herpes simplex virus infections or with localized varicella-zoster infections. These studies were designed to evaluate the dermal tolerance, systemic toxicity and percutaneous absorption of acyclovir.

In one of these studies, which included 16 inpatients, the complete ointment or its vehicle were randomly administered in a dose of 1 cm strips (25 mg acyclovir) four times a day for seven days to an intact skin surface area of 4.5 square inches. No local intolerance, systemic toxicity or contact dermatitis were observed. In addition, no drug was detected in blood and urine by radioimmunoassay (sensitivity, 0.01 mcg/ml).

The other study included eleven patients with localized varicella-zoster. In this uncontrolled study, acyclovir was detected in the blood of 9 patients and in the urine of all patients tested. Acyclovir levels in plasma ranged from <0.01 to 0.28 mcg/ml in eight patients with normal renal function, and from <0.01 to 0.78 mcg/ml in one patient with impaired renal function. Acyclovir excreted in the urine ranged <0.02 to 9.4 percent of the daily dose. Therefore systemic absorption of acyclovir after topical application is minimal.

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