Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus

Chono, Koji; Katsumata, Kiyomitsu; Suzuki, Hiroshi; Shiraki, Kimíyasu

doi:10.1016/j.antiviral.2012.12.006

Cited by 31 publications

(24 citation statements)

References 29 publications

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“…Virus titers were determined at 48 h or 24 h post-infection for HSV-1 or HSV-2 respectively due to the different replication time of the two viruses. The IC 50 values for plain acyclovir are consistent with previously published values [ 27 , 28 ]. No antiviral activity was exerted by the unloaded NS at tested doses (see Figure 4 ).…”

Section: Resultssupporting

confidence: 91%

Acyclovir-Loaded Chitosan Nanospheres from Nano-Emulsion Templating for the Topical Treatment of Herpesviruses Infections

et al. 2018

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Acyclovir is not a good candidate for passive permeation since its polarity and solubility limit is partitioning into the stratum corneum. This work aims to develop a new topical formulation for the acyclovir delivery. New chitosan nanospheres (NS) were prepared by a modified nano-emulsion template method. Chitosan NS were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and an in vitro release study. The in vitro skin permeation experiment was carried out using Franz cells and was equipped with porcine skin. Biological studies were performed on the Vero cell line infected by HSV-1 and HSV-2 strains. The acyclovir loaded chitosan NS appeared with a spherical shape, a size of about 200 nm, and a negative zeta potential of about 40.0 mV. The loading capacity of the drug was about 8.5%. In vitro release demonstrated that the percentage of acyclovir delivered from the nanospheres was approximately 30% after six hours. The in vitro skin permeation studies confirmed an improved amount of permeated acyclovir. The acyclovir-NS complex displayed a higher antiviral activity than that of free acyclovir against both the HSV-1 and the HSV-2 strain. The acyclovir-loaded NS showed no anti-proliferative activity and no signs of cytotoxicity induced by NS was detected. Confocal laser scanning microscopy confirmed that the NS are taken up by the cells.

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Section: Resultssupporting

confidence: 91%

Acyclovir-Loaded Chitosan Nanospheres from Nano-Emulsion Templating for the Topical Treatment of Herpesviruses Infections

et al. 2018

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“…Also, the acyclovir/tenofovir combination against HSV-2 showed no synergy (data not shown). A recent study did demonstrate synergistic anti-HSV-2 activity of acyclovir with other classes of antiviral agents such as the helicase-primase inhibitor amenamevir [37]. Griffithsin, the most potent natural occurring peptide with anti-HIV activity in pM range [38], [39], lacks anti-herpes virus activity in vitro and was therefore not tested in combination with LabyA1.…”

Section: Discussionmentioning

confidence: 99%

The Lantibiotic Peptide Labyrinthopeptin A1 Demonstrates Broad Anti-HIV and Anti-HSV Activity with Potential for Microbicidal Applications

et al. 2013

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Lantibiotics are peptides, produced by bacteria, that contain the noncanonical amino acid lanthionine and many of them exhibit antibacterial activities. The labyrinthopeptin A1 (LabyA1) is a prototype peptide of a novel class of carbacyclic lantibiotics. Here, we extensively evaluated its broad-spectrum activity against HIV and HSV in vitro, studied its mechanism of action and evaluated potential microbicidal applications. LabyA1 exhibited a consistent and broad anti-HIV activity (EC50s: 0.70–3.3 µM) and anti-HSV activity (EC50s: 0.29–2.8 µM) in cell cultures. LabyA1 also inhibited viral cell-cell transmission between persistently HIV-infected T cells and uninfected CD4+ T cells (EC50∶2.5 µM) and inhibited the transmission of HIV captured by DC-SIGN+-cells to uninfected CD4+ T cells (EC50∶4.1 µM). Time-of-drug addition studies revealed that LabyA1 acts as an entry inhibitor against HIV and HSV. Cellular and virus binding studies combined with SPR/FLIPR technology showed that LabyA1 interacted with the HIV envelope protein gp120, but not with the HIV cellular receptors. LabyA1 also demonstrated additive to synergistic effects in its anti-HIV-1 and anti-HSV-2 activity with anti(retro)viral drugs in dual combinations such as tenofovir, acyclovir, saquinavir, raltegravir and enfuvirtide. LabyA1 can be considered as a novel lead peptide as it had profound antiviral activity against HIV and HSV. Pre-treatment of PBMCs with LabyA1 neither increased the expression of the activation markers CD69 and CD25, nor enhanced HIV replication, nor significantly induced various inflammatory cytokines/chemokines. LabyA1 also did not affect the growth of vaginal Lactobacilli populations. Based on the lack of toxicity on the vaginal Lactobacillus strains and its synergistic/additive profile in combination with clinically approved anti(retro)virals, it deserves further attention as a potential microbicide candidate in the prevention of sexual transmitted diseases.

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“…Preclinical pharmacology studies of amenamevir have demonstrated that amenamevir inhibits the replication of acyclovir-resistant strains of HSV-1, HSV-2, and VZV, with half-maximal effective concentrations similar to those exhibited against acyclovir-sensitive strains [ 21 ]. Initial pharmacokinetic results from two phase 1 studies (studies 15L-CL-002 and 15L-CL-003) have shown that amenamevir exhibits less than dose proportional pharmacokinetics after single and multiple doses [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies

et al. 2017

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IntroductionAmenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella–zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants.MethodsFour randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5–2400 mg) or daily (300 or 600 mg/day) for 7 days.ResultsFollowing single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUCinf) and C max. After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUCinf increased by about 90%. In the bioavailability study, AUCinf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported.ConclusionAmenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUCinf almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated.FundingAstellas Pharma.Trial registrationClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).Electronic supplementary materialThe online version of this article (10.1007/s12325-017-0642-4) contains supplementary material, which is available to authorized users.

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Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus

Cited by 31 publications

References 29 publications

Acyclovir-Loaded Chitosan Nanospheres from Nano-Emulsion Templating for the Topical Treatment of Herpesviruses Infections

Acyclovir-Loaded Chitosan Nanospheres from Nano-Emulsion Templating for the Topical Treatment of Herpesviruses Infections

The Lantibiotic Peptide Labyrinthopeptin A1 Demonstrates Broad Anti-HIV and Anti-HSV Activity with Potential for Microbicidal Applications

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies

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