Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro

Brickelmaier, Margot; Lugovskoy, Alexey A.; Kartikeyan, Ramya; Reviriego-Mendoza, Marta M.; Allaire, Norm; Simon, Kenneth J.; Frisque, Richard J.; Gorelik, Leonid

doi:10.1128/aac.01614-08

Cited by 227 publications

(179 citation statements)

References 57 publications

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“…Seeking alternative antiviral drugs to address JCV has been attempted by using a high-throughput screening approach of approved drugs. Mefloquine, a well-known antimalarial therapy, showed potential in this in vitro screen [55]. As it was known to reach presumed therapeutic concentrations in brain and has a reasonable safety profile, an international randomized study to treat PML was undertaken.…”

Section: Progressive Multifocal Leukencephalopathymentioning

confidence: 99%

Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls

Haubenberger

Clifford

2016

Neurotherapeutics

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Clinical trials in neurovirology illustrate the special challenges confronting investigators planning to study these conditions, as well as the contributions of successful trials in establishing appropriate management for these devastating diseases. This article reviews key examples of progress in neurovirology that have been spurred by clinical trials, emphasizing human herpes virus encephalitis, HIV, and JC virus. Clinical trials in the setting of neurovirological diseases are characterized by specific challenges, which may include small sample sizes, clinical presentations from life-threatening conditions to chronic courses of disease, regional and temporally restricted outbreaks scenarios, and the unavailability of validated diagnostic tests that can be rapidly deployed at the bedside. This review aims to highlight these methodological challenges and pitfalls in designing and executing clinical neurovirology trials, as well as to outline innovative trial designs, which could be useful in addressing common challenges.

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Section: Progressive Multifocal Leukencephalopathymentioning

confidence: 99%

Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls

Haubenberger

Clifford

2016

Neurotherapeutics

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“…Mirtazapine inhibits the entry of JC virus into glial cells via serotonergic receptor [15]. In contrast, mefloquine inhibits the viral DNA replication in infected cells [55]. Therefore, combinational usage of both mirtazapine and mefloquine could introduce either additive or synergistic effects on the treatment of PML patients.…”

Section: Mefloquinementioning

confidence: 99%

“…Of these, mefloquine, an anti-malarial drug, has been to achieve efficacious concentrations in the brain. Mefloquine inhibits viral DNA replication in infected cells, but does not inhibit the entry of JC virus to glial cells [55].…”

Section: Mefloquinementioning

confidence: 99%

A New Therapeutic Option for Progressive Multifocal Leukoencephalopathy after Allogeneic Hematopoietic Cell Transplantation

Yoshida¹,

Masaie²,

Hino³

et al. 2017

J Clin Infect Dis Pract

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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of central nervous system caused by human polyoma virus, JC virus, which can occur in the patients with severe immune compromised condition. PML is a rare disease, seen in hematologic malignancies, organ transplantation, and HIV infected patients. PML is often fatal, because of the lack of effective anti-viral drug for JC virus. Clinical observations of survival improvement in HIV-positive patients after the introduction of combination antiretroviral therapy (cART) could suggest the importance of restoration of immune response.In the setting of PML after allogeneic hematopoietic cell transplantation (HCT), it is very difficult to reduce or stop immunosuppressants to restore immune response, because of graft versus host disease (GVHD) and so on. Therefore, new anti-viral drugs against JC virus should be needed. Recently, mirtazapine (antagonists of 5-HT 2 serotonergic receptor) and mefloquine (anti-malarial drug), have been shown to have anti-viral activities against JC virus even in the clinical setting as well as in vitro experiments. Several case reports using each drug have been found in recent years. A controlled study for PML patients treated with or without mirtazapine has shown superior survival rate at 1-year in the patients treated with mirtazapine, although statistical significance was not observed. Concomitant usage of both mirtazapine and mefloquine could be expected to induce more effective anti-viral activities, because the mechanism of each drug to inhibit JC virus proliferation is independent. Indeed, some case reports have shown the efficacies of these drugs for the treatment of the patients with PML including after allogenic HCT patients.Controlled study should be required to identify the efficacies of the combinational treatment of both mirtazapine and mefloquine for the treatment of PML patients after allogenic HCT.

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“…13,14 Supportive therapy with mefloquine and mirtazapine were prescribed for some patients at the diagnosis of PML, but there was no difference between the treated and non-treated groups in the use of either mefloquine or mirtazapine. 6 There was no clear evidence for mefloquine that this drug led to improved outcomes.…”

mentioning

confidence: 99%