Author:

Keywords:

Acyclovir, Animals, Antiviral Agents, Cells, Cultured, Cercopithecus aethiops, Deoxyguanine Nucleotides, Drug Synergism, Drug Therapy, Combination, Ganciclovir, Herpes Genitalis, Herpes Simplex, Herpesvirus 1, Human, Herpesvirus 2, Human, Immunosuppressive Agents, Mice, Mice, Nude, Mycophenolic Acid, Vero Cells, Science & Technology, Life Sciences & Biomedicine, Microbiology, Pharmacology & Pharmacy, HUMAN-IMMUNODEFICIENCY-VIRUS, HERPES-SIMPLEX VIRUS, TRANSPLANT RECIPIENTS, RIBAVIRIN, 2',3'-DIDEOXYINOSINE, INFECTIONS, PROPHYLAXIS, RESISTANT, PHOSPHORYLATION, CHEMOTHERAPY, Chlorocebus aethiops, Guanine, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, 3107 Microbiology, 3207 Medical microbiology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

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.