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Acyclovir: An overview

ACYCLOVIR SHORTAGE

In early 2009, there was a shortage of intravenous (IV) acyclovir in the United States due to a temporary disruption in manufacturing supplies [1]. The shortage has resolved as of April 20, 2009; intravenous acyclovir is available through APP Pharmaceuticals (888-386-1300) or Bedford Laboratories (800-562-4797).

IV acyclovir is the drug of choice for the following indications: herpes simplex virus (HSV) encephalitis, neonatal HSV infection, disseminated HSV, disseminated varicella-zoster infections, and severe varicella pneumonia.

INTRODUCTION

Acyclovir is widely used in the treatment of herpesvirus infections particularly herpes simplex virus (HSV) and varicella-zoster virus (VZV). An overview of the mechanisms of action of and resistance to acyclovir and its major clinical uses will be provided here. Treatment of the specific clinical syndromes is described in greater detail on the appropriate topic reviews.

MECHANISM OF ACTION

Acyclovir (9-[2-hydroxymethyl]guanine) is a nucleoside analog which selectively inhibits the replication of HSV (types 1 and 2) and VZV. After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase; this step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymes.

Acyclovir triphosphate, acting as an analog to deoxyguanosine triphosphate (dGTP), competitively inhibits viral DNA polymerase; incorporation of acyclovir triphosphate into DNA results in chain termination because the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides. Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio which makes the inhibition of native DNA polymerase clinically unimportant [2,3].
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