Novel Anticytomegalovirus Activity of Immunosuppressant Mizoribine and Its Synergism with Ganciclovir

Abstract

Cytomegalovirus (CMV) infection is a prominent infection in transplant recipients. The immunosuppressive drug mizoribine was shown to have anti-CMV activity in vitro and was reported to have an anti-CMV effect in renal transplantation. This study characterized the anti-CMV activity of mizoribine in vitro and its synergistic activity with ganciclovir. Mizoribine suppressed replication and at the EC 50 for plaque inhibition of 12.0 g/ml.Mizoribine and ganciclovir exerted a strong synergism in anti-CMV activity. Mizoribine depletes guanosine nucleotides by inhibiting inosine monophosphate dehydrogenase and may increase the ratio of ganciclovir to guanosine in treated cells, resulting in a strong synergistic augmentation of the anti-CMV activity of ganciclovir. Two clinical isolates with UL97 mutations were less susceptible to mizoribine than the Towne strain but were equally susceptible in the presence of guanine. Two mizoribine-resistant strains were isolated after culture for 3 months with 100 g/ml mizoribine, but they were as sensitive to ganciclovir as the parent Towne strain. The anti-CMV activity of mizoribine was antagonized by 2Ј-deoxyguanosine. Mizoribine inhibited CMV replication directly, and the sequence of mizoribine-resistant mutants of UL97 and UL54 was identical to that of the parent Towne strain, indicating the different anti-CMV action from ganciclovir, foscarnet, and maribavir. Mizoribine as an immunosuppressive and anti-CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir.

High‐dose mizoribine combined with calcineurin inhibitor (cyclosporine or tacrolimus), basiliximab and corticosteroids for renal transplantation: A Japanese multicenter study

“…Kuramoto et al . reported MZR as an immunosuppressive and anti‐CMV drug in the clinical regimen was suggested to suppress replication of CMV in vivo and control CMV infection in transplant recipients in combination with ganciclovir . The present results suggest that MZR exerts antiviral activity, and can be considered an advantageous agent for use in combination therapy for CMV infection in renal transplant recipients.…”

Neutralizing Anti-gH Antibody of Varicella-Zoster Virus Modulates Distribution of gH and Induces Gene Regulation, Mimicking Latency

“…The resultant supernatants were used as the cell-free virus stocks, and their virus titers ranged from 3.3 ϫ 10 3 to 2.3 ϫ 10 5 PFU/ml in this study. The Towne strain of cytomegalovirus (CMV) (18,28) and rhinovirus 13 (13) were propagated in HEL cells, and adenovirus 5 (19) was propagated in Hep2 cells. CMV, rhinovirus 13, and adenovirus 5 were prepared from the infected cells by three cycles of freezing and thawing.…”

Post-marketing surveillance study of the long-term use of mizoribine for the treatment of lupus nephritis: 2-Year results

“…A report showed that MZR has an effect that directly inhibits CMV plaque formation in vitro, and that MMF exhibits no such effect. The report also indicated a synergistic effect on the anti-CMV activity of MZR when it is used in combination with ganciclovir [23]. MZR, owing to such an effect, may inhibit the reproduction of CMV and exhibit some kind of inhibitory effect on CMV infections.…”