Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza▿
Identifieur interne : 000263 ( Pmc/Corpus ); précédent : 000262; suivant : 000264Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza▿
Auteurs : Alison Budd ; Lisa Alleva ; Mohammed Alsharifi ; Aulikki Koskinen ; Victoria Smythe ; Arno Müllbacher ; Jeff Wood ; Ian ClarkSource :
- Antimicrobial Agents and Chemotherapy [ 0066-4804 ] ; 2007.
Abstract
Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (
Url:
DOI: 10.1128/AAC.00219-07
PubMed: 17562808
PubMed Central: 1932503
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<author><name sortKey="Mullbacher, Arno" sort="Mullbacher, Arno" uniqKey="Mullbacher A" first="Arno" last="Müllbacher">Arno Müllbacher</name>
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<author><name sortKey="Clark, Ian" sort="Clark, Ian" uniqKey="Clark I" first="Ian" last="Clark">Ian Clark</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza<xref ref-type="fn" rid="fn2">▿</xref>
</title>
<author><name sortKey="Budd, Alison" sort="Budd, Alison" uniqKey="Budd A" first="Alison" last="Budd">Alison Budd</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
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<author><name sortKey="Alleva, Lisa" sort="Alleva, Lisa" uniqKey="Alleva L" first="Lisa" last="Alleva">Lisa Alleva</name>
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<author><name sortKey="Alsharifi, Mohammed" sort="Alsharifi, Mohammed" uniqKey="Alsharifi M" first="Mohammed" last="Alsharifi">Mohammed Alsharifi</name>
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</affiliation>
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<author><name sortKey="Koskinen, Aulikki" sort="Koskinen, Aulikki" uniqKey="Koskinen A" first="Aulikki" last="Koskinen">Aulikki Koskinen</name>
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<author><name sortKey="Smythe, Victoria" sort="Smythe, Victoria" uniqKey="Smythe V" first="Victoria" last="Smythe">Victoria Smythe</name>
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<author><name sortKey="Mullbacher, Arno" sort="Mullbacher, Arno" uniqKey="Mullbacher A" first="Arno" last="Müllbacher">Arno Müllbacher</name>
<affiliation><nlm:aff id="aff1"></nlm:aff>
</affiliation>
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<author><name sortKey="Wood, Jeff" sort="Wood, Jeff" uniqKey="Wood J" first="Jeff" last="Wood">Jeff Wood</name>
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<author><name sortKey="Clark, Ian" sort="Clark, Ian" uniqKey="Clark I" first="Ian" last="Clark">Ian Clark</name>
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<series><title level="j">Antimicrobial Agents and Chemotherapy</title>
<idno type="ISSN">0066-4804</idno>
<idno type="eISSN">1098-6596</idno>
<imprint><date when="2007">2007</date>
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<front><div type="abstract" xml:lang="en"><p>Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (<italic>n</italic>
= 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (<italic>n</italic>
= 46) (<italic>P</italic>
= 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Antimicrob Agents Chemother</journal-id>
<journal-id journal-id-type="publisher-id">aac</journal-id>
<journal-title>Antimicrobial Agents and Chemotherapy</journal-title>
<issn pub-type="ppub">0066-4804</issn>
<issn pub-type="epub">1098-6596</issn>
<publisher><publisher-name>American Society for Microbiology</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">17562808</article-id>
<article-id pub-id-type="pmc">1932503</article-id>
<article-id pub-id-type="publisher-id">0219-07</article-id>
<article-id pub-id-type="doi">10.1128/AAC.00219-07</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Antiviral Agents</subject>
</subj-group>
</article-categories>
<title-group><article-title>Increased Survival after Gemfibrozil Treatment of Severe Mouse Influenza<xref ref-type="fn" rid="fn2">▿</xref>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Budd</surname>
<given-names>Alison</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="fn" rid="fn1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alleva</surname>
<given-names>Lisa</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="fn" rid="fn1">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alsharifi</surname>
<given-names>Mohammed</given-names>
</name>
<xref ref-type="aff" rid="aff1">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Koskinen</surname>
<given-names>Aulikki</given-names>
</name>
<xref ref-type="aff" rid="aff1">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Smythe</surname>
<given-names>Victoria</given-names>
</name>
<xref ref-type="aff" rid="aff1">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Müllbacher</surname>
<given-names>Arno</given-names>
</name>
<xref ref-type="aff" rid="aff1">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wood</surname>
<given-names>Jeff</given-names>
</name>
<xref ref-type="aff" rid="aff1">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Clark</surname>
<given-names>Ian</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="corresp" rid="cor1">*</xref>
</contrib>
</contrib-group>
<aff id="aff1">School of Biochemistry and Molecular Biology,<label>1</label>
John Curtin School of Medical Research,<label>2</label>
Statistical Consulting Unit, Australian National University, Canberra ACT 0200, Australia<label>3</label>
</aff>
<author-notes><fn id="cor1"><label>*</label>
<p>Corresponding author. Mailing address: School of Biochemistry and Molecular Biology, Australian National University, Canberra ACT 0200, Australia. Phone: 61.2.6125.4363. Fax: 61.2.6125.0313. E-mail: <email>ian.clark@anu.edu.au</email>
</p>
</fn>
<fn id="fn1"><label>†</label>
<p>A.B. and L.A. contributed equally to this study.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>8</month>
<year>2007</year>
</pub-date>
<pub-date pub-type="epub"><day>11</day>
<month>6</month>
<year>2007</year>
</pub-date>
<volume>51</volume>
<issue>8</issue>
<fpage>2965</fpage>
<lpage>2968</lpage>
<history><date date-type="received"><day>13</day>
<month>2</month>
<year>2007</year>
</date>
<date date-type="rev-recd"><day>29</day>
<month>3</month>
<year>2007</year>
</date>
<date date-type="accepted"><day>24</day>
<month>5</month>
<year>2007</year>
</date>
</history>
<copyright-statement>Copyright © 2007, American Society for Microbiology</copyright-statement>
<copyright-year>2007</copyright-year>
<self-uri xlink:title="pdf" xlink:href="zac00807002965.pdf"></self-uri>
<abstract><p>Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (<italic>n</italic>
= 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (<italic>n</italic>
= 46) (<italic>P</italic>
= 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.</p>
</abstract>
</article-meta>
</front>
<floats-wrap><fig position="float" id="f1"><label>FIG. 1.</label>
<caption><p>Effect of gemfibrozil on survival of BALB/c mice with severe influenza. Mice were infected with influenza virus A/Japan/305/57 and treated with vehicle or 20 mg/kg, 40 mg/kg, or 60 mg/kg gemfibrozil once daily from days 4 to 10 after virus exposure. These results are from a single experiment (vehicle, <italic>n</italic>
= 9; 20 mg/kg, <italic>n</italic>
= 10; 40 mg/kg, <italic>n</italic>
= 9; 60 mg/kg, <italic>n</italic>
= 10).</p>
</caption>
<graphic xlink:href="zac0080766910001"></graphic>
</fig>
<fig position="float" id="f2"><label>FIG. 2.</label>
<caption><p>Effect of 60 mg/kg gemfibrozil on survival of BALB/c mice with severe influenza. Mice were infected with influenza virus A/Japan/305/57 and treated with vehicle or 60 mg/kg gemfibrozil once daily from days 4 to 10 after virus exposure. These results are pooled from four separate experiments (vehicle, <italic>n</italic>
= 50; gemfibrozil, <italic>n</italic>
= 46). Statistical analysis using the log rank test determined the increase in survival time with gemfibrozil treatment to be significant (<italic>P</italic>
= 0.0026).</p>
</caption>
<graphic xlink:href="zac0080766910002"></graphic>
</fig>
<fig position="float" id="f3"><label>FIG. 3.</label>
<caption><p>Effect of 60 mg/kg gemfibrozil on survival of BALB/c mice with severe systemic inflammation. Mice were given 30 mg/kg LPS (<italic>E. coli</italic>
serotype O111:B4) and treated with a single dose of vehicle or 60 mg/kg gemfibrozil either 1 h before or 2 h after LPS injection. These results are from a single experiment; <italic>n</italic>
= 20 for each group. Statistical analysis using the log rank test determined that a single dose of 60 mg/kg gemfibrozil 1 h before LPS significantly increased survival (<italic>P</italic>
< 0.001).</p>
</caption>
<graphic xlink:href="zac0080766910003"></graphic>
</fig>
<table-wrap position="float" id="t1"><label>TABLE 1.</label>
<caption><p>Weight loss in mice infected with influenza virus (A/Japan/305/57) given gemfibrozil once daily from days 4 to 10 after virus exposure</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Gemfibrozil dose (mg/kg/day)</th>
<th colspan="1" rowspan="2" align="center" valign="middle">No. of mice that survived/total</th>
<th colspan="5" rowspan="1" align="center" valign="bottom">Avg % day 0 body wt ± SD on indicated day p.i. (no. of mice remaining on that day)
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">4</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">6</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">8</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">10</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">12</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">0</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">1/9</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">86.8 ± 4.0 (9)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">76.0 ± 3.4 (6)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">68.9 ± 3.7 (3)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">69.1 ± 8.5 (2)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">71.1 ± 12.7 (2)<xref ref-type="table-fn" rid="t1fn1"><italic>a</italic>
</xref>
</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">20</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">3/10</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">87.9 ± 6.3 (10)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">77.5 ± 6.0 (8)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">75.1 ± 3.6 (5)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">75.2 ± 7.7 (4)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">79.0 ± 13.1 (4)<xref ref-type="table-fn" rid="t1fn2"><italic>b</italic>
</xref>
</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">40</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">4/9</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">87.0 ± 5.3 (9)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">75.6 ± 5.3 (9)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">72.2 ± 12.8 (6)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">73.4 ± 16.2 (5)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">77.1 ± 17.2 (4)</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">60</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">5/10</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">86.5 ± 4.6 (10)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">77.1 ± 4.5 (9)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">73.2 ± 9.3 (7)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">78.0 ± 11.9 (5)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">81.8 ± 14.4 (5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1fn1"><label>a</label>
<p>After day 12 there was one more death, on day 17.</p>
</fn>
<fn id="t1fn2"><label>b</label>
<p>After day 12 there was one more death, on day 14.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap position="float" id="t2"><label>TABLE 2.</label>
<caption><p>Weight loss in mice infected with influenza virus (A/Japan/305/57) given 60 mg/kg gemfibrozil once daily from days 4 to 10 after virus exposure</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Gemfibrozil dose (mg/kg/day)</th>
<th colspan="1" rowspan="2" align="center" valign="middle">No. of mice that survived/total</th>
<th colspan="1" rowspan="2" align="center" valign="middle">Median survival time (days)</th>
<th colspan="1" rowspan="2" align="center" valign="middle">95% confidence interval (days)</th>
<th colspan="4" rowspan="1" align="center" valign="bottom">Avg % day 0 body wt ± SD on indicated day p.i. (no. of mice remaining on that day)
<hr></hr>
</th>
</tr>
<tr><th colspan="1" rowspan="1" align="center" valign="bottom">6</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">8</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">10</th>
<th colspan="1" rowspan="1" align="center" valign="bottom">12</th>
</tr>
</thead>
<tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">0</td>
<td colspan="1" rowspan="1" align="center" valign="top">13/50</td>
<td colspan="1" rowspan="1" align="center" valign="top">8</td>
<td colspan="1" rowspan="1" align="center" valign="top">7-10</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">76.1 ± 4.2 (47)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">70.3 ± 3.8 (29)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">68.3 ± 8.7 (19)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">70.8 ± 13.0 (16)<xref ref-type="table-fn" rid="t2fn2"><italic>b</italic>
</xref>
</td>
</tr>
<tr><td colspan="1" rowspan="1" align="left" valign="top">60</td>
<td colspan="1" rowspan="1" align="center" valign="top">24/46</td>
<td colspan="1" rowspan="1" align="center" valign="top">NA<xref ref-type="table-fn" rid="t2fn1"><italic>a</italic>
</xref>
</td>
<td colspan="1" rowspan="1" align="center" valign="top">10+</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">76.7 ± 5.2 (45)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">71.1 ± 7.1 (36)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">71.7 ± 11.1 (30)</td>
<td colspan="1" rowspan="1" align="char" char="." valign="top">77.0 ± 13.4 (25)<xref ref-type="table-fn" rid="t2fn3"><italic>c</italic>
</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t2fn1"><label>a</label>
<p>NA, median survival time cannot be reported, as more than half the mice survived the experiment.</p>
</fn>
<fn id="t2fn2"><label>b</label>
<p>After day 12 there were three more deaths, two on day 13 and one on day 17.</p>
</fn>
<fn id="t2fn3"><label>c</label>
<p>After day 12 there was one more death, on day 13.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-wrap>
</pmc>
</record>
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