mycophenolic-acid and Herpes-Genitalis

The immunosuppressive agent mycophenolate mofetil (MMF) has been approved for use in kidney transplant recipients and may thus be used concomitantly for the treatment of intercurrent herpesvirus infections with drugs such as acyclovir (ACV), ganciclovir (GCV), and penciclovir (PCV). We found that MMF and its parent compound mycophenolic acid (at concentrations that are attainable in plasma) strongly potentiate the antiherpesvirus (herpes simplex virus [HSV] type 1 [HSV-1], HSV-2, thymidine kinase-deficient [TK-] HSV-1, both wild-type and TK- varicella-zoster virus, and human cytomegalovirus) activities of ACV, PCV, and GCV (up to 350-fold increases in their activities). The mechanism of potentiation was found to reside in the depletion of endogenous dGTP pools, which favored the inhibitory effect of the triphosphate of ACV, GCV, or PCV on the viral DNA polymerase. The combination of topically applied 5% MMF with 0.1% ACV strongly protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used singly had no protective effect. Interestingly, the combination of topically applied 5% MMF with 5% ACV was also highly effective in protecting against TK- HSV-2-induced cutaneous lesions (that were refractory to ACV treatment) in athymic nude mice. Topical therapy with MMF was very well tolerated, and no signs of irritation were observed. When given perorally at 200 mg/kg of body weight/day, MMF potentiated to some extent the growth retardation induced by GCV in young NMRI mice. These observations may have clinical implications (i) for those transplant recipients who receive both MMF and either ACV, GCV, or PCV and (ii) for the treatment of ACV-resistant mucocutaneous HSV infections.

Topics: Acyclovir; Animals; Antiviral Agents; Cells, Cultured; Chlorocebus aethiops; Deoxyguanine Nucleotides; Drug Synergism; Drug Therapy, Combination; Ganciclovir; Guanine; Herpes Genitalis; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Immunosuppressive Agents; Mice; Mice, Nude; Mycophenolic Acid; Vero Cells

We demonstrate that the novel immunosuppressive agent mycophenolate mofetil (MMF), that has been approved for use in kidney transplant recipients, strongly potentiates the antiviral activity of acyclovir in murine models for herpesvirus infections. Hairless mice that were infected intracutaneously with herpes simplex virus type 1 were treated systemically with ACV (20 mg/kg per day) and topically with 5% MMF. Combined use of both drugs resulted in an almost complete protection, whereas single use of either compound had virtually no effect. When athymic-nude mice were infected with an ACV-resistant (ACVr)-thymidine kinase-deficient (TK-) HSV-2 strain, combined use of systemically administered ACV (100 mg/kg per day) and topically applied MMF (5%) protected 60% of the animals against the infection, whereas all mice treated with either drug alone succumbed. Since transplant recipients under MMF therapy may develop opportunistic herpesvirus infections, requiring treatment with acyclovir (or valaciclovir), our findings have important implications for the treatment of these herpesvirus infections.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Synergism; Herpes Genitalis; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Mice; Mice, Nude; Mycophenolic Acid