Therapeutic Uses

Intravenous cidofovir is approved for the treatment of CMV retinitis in HIV-infected patients. Intravenous cidofovir (5 mg/kg once a week for 2 weeks followed by dosing every 2 weeks) increases the time to progression of CMV retinitis in previously untreated patients and in those failing or intolerant of ganciclovir and foscarnet therapy. CMV viremia may persist during cidofovir administration. Maintenance doses of 5 mg/kg are more effective but less well tolerated than 3 mg/kg doses. Intravenous cidofovir has been used for treating acyclovir-resistant mucocutaneous HSV infection, adenovirus disease in transplant recipients, and progressive multifocal leukoencephalopathy or extensive molluscum contagiosum in HIV patients. Reduced doses (0.25—1 mg/kg every 2—3 weeks) without probenecid may be beneficial in BK virus nephropathy in renal transplant patients.

Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been used in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neo-plasia in women. Intralesional cidofovir induces remissions in adults and children with respiratory papillomatosis.

Docosanol

Docosanol is a long-chain saturated alcohol that is FDA approved as a 10% over-the-counter cream for the treatment of recurrent orolabial herpes. Topical treatment beginning within 12 hours of prodromal symptoms or lesion onset reduces healing time by ~1 day and is well tolerated. Treatment initiation at papular or later stages provides no benefit.

Famciclovir and Penciclovir chemistry and antiviral activity Famciclovir is a diacetyl ester prodrug of 6-deoxy penciclovir. Penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl] guanine) is an acyclic guanine nucleoside analog.

Penciclovir resembles acyclovir in its spectrum of activity and potency against HSV and VZV. It also inhibits HBV.

mechanisms of action and resistance Penciclovir inhibits viral DNA synthesis. In HSV- or VZV-infected cells, penciclovir is phosphorylated initially by viral TK. Penciclovir triphosphate competitively inhibits viral DNA polymerase (Figure 49-2). Although penciclovir triphosphate is approximately one one-hundredth times as potent as acyclovir triphosphate in inhibiting viral DNA polymerase, it is present in infected cells at much higher concentrations and for more prolonged periods. The prolonged intracellular half-life of penciclovir triphosphate, 7-20 hours, provides prolonged antiviral effects. Because penciclovir has a 3'-hydroxyl group, it is not an obligate chain terminator but does inhibit DNA elongation.

Resistance during therapy is low. TK-deficient, acyclovir-resistant herpesviruses are cross resistant to penciclovir.

ABSORPTION, DISTRIBUTION, AND ELIMINATION

Oral penciclovir has low (5%) bioavailability, while famciclovir is well absorbed orally and converted rapidly to penciclovir by side chain deacetylation and purine ring oxidation. The bioavailability of penciclovir is ~70% after oral administration of famciclovir. Food slows absorption without reducing overall bioavailability. A small quantity of the 6-deoxy precursor but no famciclovir is detectable in plasma. The volume of distribution is ~twice the volume of total-body water. The t1/2 of elimination of penciclovir is 2 hours, and >90% is excreted unchanged in the urine. Following oral famciclovir administration, nonrenal clearance accounts for ~10% of each dose,

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