Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protectio...

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Bibliographic Details
Published in:Archives of virology 2018-09, Vol.163 (9), p.2349-2358
Main Authors: Lee, Andrew C. Y., To, Kelvin K. W., Zhang, Anna J. X., Zhu, Houshun, Li, Can, Zhang, Ricky R., Hung, Ivan F. N., Kao, Richard Y. T., Chan, Kwok-Hung, Yuen, Kwok-Yung
Format: Article
Language:English
Subjects:
Animals
Antiviral activity
Antiviral agents
Antiviral Agents - administration & dosage
Antiviral drugs
Biomedical and Life Sciences
Biomedicine
Body weight loss
Clarithromycin
Clarithromycin - administration & dosage
Drug Approval - legislation & jurisprudence
Drug Evaluation, Preclinical
Drug Therapy, Combination
Exo-a-sialidase
Female
Flufenamic Acid - administration & dosage
Humans
IL-1β
Infectious Diseases
Inflammation
Influenza
Influenza A
Influenza A Virus, H1N1 Subtype - drug effects
Influenza A Virus, H1N1 Subtype - physiology
Influenza, Human - drug therapy
Influenza, Human - metabolism
Influenza, Human - mortality
Influenza, Human - virology
Interleukin-1beta - genetics
Interleukin-1beta - metabolism
Lung - virology
Medical Microbiology
Mice
Mice, Inbred BALB C
Original Article
RANTES
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
United States
United States Food and Drug Administration
Virology
Zanamivir
Zanamivir - administration & dosage
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Summary:Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P  = 0.0083) or zanamivir monotherapy (88% versus 26%, P  = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1β, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.
ISSN:0304-8608
1432-8798
DOI:10.1007/s00705-018-3852-4