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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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| Published in: | Archives of virology 2018-09, Vol.163 (9), p.2349-2358 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1007/s00705-018-3852-4 |
| format | article |
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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.</description><identifier>ISSN: 0304-8608</identifier><identifier>EISSN: 1432-8798</identifier><identifier>DOI: 10.1007/s00705-018-3852-4</identifier><identifier>PMID: 29736671</identifier><language>eng</language><publisher>Vienna: Springer Vienna</publisher><subject>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</subject><ispartof>Archives of virology, 2018-09, Vol.163 (9), p.2349-2358</ispartof><rights>Springer-Verlag GmbH Austria, part of Springer Nature 2018</rights><rights>Archives of Virology is a copyright of Springer, (2018). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-33e21c8d67212697a00bbb36b4ea2b8f18ca403e5723b6ed36eeab96c222ca473</citedby><cites>FETCH-LOGICAL-c372t-33e21c8d67212697a00bbb36b4ea2b8f18ca403e5723b6ed36eeab96c222ca473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29736671$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Andrew C. Y.</creatorcontrib><creatorcontrib>To, Kelvin K. W.</creatorcontrib><creatorcontrib>Zhang, Anna J. X.</creatorcontrib><creatorcontrib>Zhu, Houshun</creatorcontrib><creatorcontrib>Li, Can</creatorcontrib><creatorcontrib>Zhang, Ricky R.</creatorcontrib><creatorcontrib>Hung, Ivan F. N.</creatorcontrib><creatorcontrib>Kao, Richard Y. T.</creatorcontrib><creatorcontrib>Chan, Kwok-Hung</creatorcontrib><creatorcontrib>Yuen, Kwok-Yung</creatorcontrib><title>Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice</title><title>Archives of virology</title><addtitle>Arch Virol</addtitle><addtitle>Arch Virol</addtitle><description>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.</description><subject>Animals</subject><subject>Antiviral activity</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - administration & dosage</subject><subject>Antiviral drugs</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Body weight loss</subject><subject>Clarithromycin</subject><subject>Clarithromycin - administration & dosage</subject><subject>Drug Approval - legislation & jurisprudence</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Therapy, Combination</subject><subject>Exo-a-sialidase</subject><subject>Female</subject><subject>Flufenamic Acid - administration & dosage</subject><subject>Humans</subject><subject>IL-1β</subject><subject>Infectious Diseases</subject><subject>Inflammation</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Influenza A Virus, H1N1 Subtype - drug effects</subject><subject>Influenza A Virus, H1N1 Subtype - physiology</subject><subject>Influenza, Human - drug therapy</subject><subject>Influenza, Human - metabolism</subject><subject>Influenza, Human - mortality</subject><subject>Influenza, Human - virology</subject><subject>Interleukin-1beta - genetics</subject><subject>Interleukin-1beta - metabolism</subject><subject>Lung - virology</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Original Article</subject><subject>RANTES</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>United States</subject><subject>United States Food and Drug Administration</subject><subject>Virology</subject><subject>Zanamivir</subject><subject>Zanamivir - administration & dosage</subject><issn>0304-8608</issn><issn>1432-8798</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kU1PHSEUhonR1KvtD3DTkLhxIZaPGWCWxq82MenGrgkwZ66YGeYW7kyiP6K_uYxX26RJN0A4z3k44UXohNELRqn6kstCa0KZJkLXnFR7aMUqwYlWjd5HKypoRbSk-hAd5fxEabkQ9Qd0yBslpFRshX49pLDpAftxcCHabRgjHjt8e31J7GaTxhla3KZpnXGIvp_aENe466cOoh2Cx9aH9hz73qawfUzj8OxDxDa2-MUuwBwSDsOrJuM8pTnMtl_8GWZIUJzFBfHFlhMuPviIDjrbZ_j0th-jH7c3D1dfyf33u29Xl_fEC8W3RAjgzOtWKs64bJSl1DknpKvAcqc7pr2tqIBaceEktEICWNdIzzkvFSWO0dnOW2b7OUHemiFkD31vI4xTNpwKyZffogU9_Qd9GqcUy3QLVVeqadRCsR3l05hzgs5sUhhsejaMmiUsswvLlLDMEpapSs_nN_PkBmj_dLynUwC-A3IpxTWkv0__3_obOhihbA</recordid><startdate>20180901</startdate><enddate>20180901</enddate><creator>Lee, Andrew C. 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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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-33e21c8d67212697a00bbb36b4ea2b8f18ca403e5723b6ed36eeab96c222ca473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Antiviral activity</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - administration & dosage</topic><topic>Antiviral drugs</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Body weight loss</topic><topic>Clarithromycin</topic><topic>Clarithromycin - administration & dosage</topic><topic>Drug Approval - legislation & jurisprudence</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Therapy, Combination</topic><topic>Exo-a-sialidase</topic><topic>Female</topic><topic>Flufenamic Acid - administration & dosage</topic><topic>Humans</topic><topic>IL-1β</topic><topic>Infectious Diseases</topic><topic>Inflammation</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Influenza A Virus, H1N1 Subtype - drug effects</topic><topic>Influenza A Virus, H1N1 Subtype - physiology</topic><topic>Influenza, Human - drug therapy</topic><topic>Influenza, Human - metabolism</topic><topic>Influenza, Human - mortality</topic><topic>Influenza, Human - virology</topic><topic>Interleukin-1beta - genetics</topic><topic>Interleukin-1beta - metabolism</topic><topic>Lung - virology</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Original Article</topic><topic>RANTES</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><topic>United States</topic><topic>United States Food and Drug Administration</topic><topic>Virology</topic><topic>Zanamivir</topic><topic>Zanamivir - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Andrew C. 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Y.</au><au>To, Kelvin K. W.</au><au>Zhang, Anna J. X.</au><au>Zhu, Houshun</au><au>Li, Can</au><au>Zhang, Ricky R.</au><au>Hung, Ivan F. N.</au><au>Kao, Richard Y. T.</au><au>Chan, Kwok-Hung</au><au>Yuen, Kwok-Yung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice</atitle><jtitle>Archives of virology</jtitle><stitle>Arch Virol</stitle><addtitle>Arch Virol</addtitle><date>2018-09-01</date><risdate>2018</risdate><volume>163</volume><issue>9</issue><spage>2349</spage><epage>2358</epage><pages>2349-2358</pages><issn>0304-8608</issn><eissn>1432-8798</eissn><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.</abstract><cop>Vienna</cop><pub>Springer Vienna</pub><pmid>29736671</pmid><doi>10.1007/s00705-018-3852-4</doi><tpages>10</tpages></addata></record> |
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| 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 |
| title | Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice |
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