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Arch Virol. 2018 Sep;163(9):2349-2358. doi: 10.1007/s00705-018-3852-4. Epub 2018 May 7.

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

Lee ACY1, To KKW1,2,3,4, Zhang AJX1,2,3,4, Zhu H5, Li C1, Zhang RR1, Hung IFN4,5, Kao RYT1,2,3,4, Chan KH1,2,3,4, Yuen KY6,7,8,9,10.

Author information

1
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
2
State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China.
3
Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China.
4
Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China.
5
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
6
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. kyyuen@hku.hk.
7
State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, China. kyyuen@hku.hk.
8
Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Hong Kong SAR, China. kyyuen@hku.hk.
9
Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong SAR, China. kyyuen@hku.hk.
10
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hong Kong SAR, China. kyyuen@hku.hk.

Abstract

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.

PMID:
29736671
DOI:
10.1007/s00705-018-3852-4
[Indexed for MEDLINE]

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