Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model
Identifieur interne : 003597 ( Main/Merge ); précédent : 003596; suivant : 003598Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model
Auteurs : Dale L. Barnard [États-Unis] ; Craig W. Day [États-Unis] ; Kevin Bailey [États-Unis] ; Matthew Heiner [États-Unis] ; Robert Montgomery [États-Unis] ; Larry Lauridsen [États-Unis] ; Kie-Hoon Jung [États-Unis] ; Joseph K.-K. Li [États-Unis] ; Paul K. S. Chan [Hong Kong] ; Robert W. Sidwell [États-Unis]Source :
- Antiviral research [ 0166-3542 ] ; 2008.
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Abstract
Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC90 = 8.3 ± 2.8 μM, but without selectivity. Various substitutions in the basic phenothiazine structure did not promote efficacy. Phenazine ethosulfate was the most potent compound by VYR assay (EC90 = 6.1 ± 4.3 μM). All compounds were toxic (IC50 = 6.6-74.5 μM) except for phenoxathiin (IC50 = 858 ± 208 μM) and 10-(alpha-diethylamino-propionyl) phenothiazine.HCl (IC50 =195 ± 71.2 μM). Consequently, none were selective inhibitors of SARS-CoV replication (SI values <1-3.3 μM). These data portended the poor efficacy of promazine in a SARS-CoV mouse lung replication model. Intraperitoneal treatment with promazine using a prophylactic (-4 h)/therapeutic regimen of 1, 10, or 50 mg/(kg day) did not reduce virus lung titers at day 3, yet prolonged virus replication to 14 days. Similar therapeutic promazine doses were not efficacious. Thus, promazine did not affect SARS-CoV replication in vitro or in vivo, nor were any other phenothiazines efficacious in reducing virus replication. Therefore, treating SARS infections with compounds like promazine is not warranted.
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Day</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Bailey, Kevin" sort="Bailey, Kevin" uniqKey="Bailey K" first="Kevin" last="Bailey">Kevin Bailey</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Heiner, Matthew" sort="Heiner, Matthew" uniqKey="Heiner M" first="Matthew" last="Heiner">Matthew Heiner</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Montgomery, Robert" sort="Montgomery, Robert" uniqKey="Montgomery R" first="Robert" last="Montgomery">Robert Montgomery</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Lauridsen, Larry" sort="Lauridsen, Larry" uniqKey="Lauridsen L" first="Larry" last="Lauridsen">Larry Lauridsen</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Jung, Kie Hoon" sort="Jung, Kie Hoon" uniqKey="Jung K" first="Kie-Hoon" last="Jung">Kie-Hoon Jung</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Li, Joseph K K" sort="Li, Joseph K K" uniqKey="Li J" first="Joseph K.-K." last="Li">Joseph K.-K. Li</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Biology, Utah State University, 5305 Old Main Hill</s1><s2>Logan, UT 84322-5305</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Chan, Paul K S" sort="Chan, Paul K S" uniqKey="Chan P" first="Paul K. S." last="Chan">Paul K. S. Chan</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital</s1><s2>Shatin, New Territories</s2><s3>HKG</s3><sZ>9 aut.</sZ></inist:fA14><country>Hong Kong</country><wicri:noRegion>Shatin, New Territories</wicri:noRegion><orgName type="university">Université chinoise de Hong Kong</orgName><placeName><settlement type="city">Sha Tin</settlement></placeName></affiliation></author><author><name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0298379</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0298379 INIST</idno><idno type="RBID">Pascal:08-0298379</idno><idno type="wicri:Area/PascalFrancis/Corpus">000276</idno><idno type="wicri:Area/PascalFrancis/Curation">000712</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000271</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000271</idno><idno type="wicri:doubleKey">0166-3542:2008:Barnard D:is:the:anti</idno><idno type="wicri:Area/Main/Merge">003597</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model</title><author><name sortKey="Barnard, Dale L" sort="Barnard, Dale L" uniqKey="Barnard D" first="Dale L." last="Barnard">Dale L. Barnard</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Day, Craig W" sort="Day, Craig W" uniqKey="Day C" first="Craig W." last="Day">Craig W. Day</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Bailey, Kevin" sort="Bailey, Kevin" uniqKey="Bailey K" first="Kevin" last="Bailey">Kevin Bailey</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Heiner, Matthew" sort="Heiner, Matthew" uniqKey="Heiner M" first="Matthew" last="Heiner">Matthew Heiner</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Montgomery, Robert" sort="Montgomery, Robert" uniqKey="Montgomery R" first="Robert" last="Montgomery">Robert Montgomery</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Lauridsen, Larry" sort="Lauridsen, Larry" uniqKey="Lauridsen L" first="Larry" last="Lauridsen">Larry Lauridsen</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Jung, Kie Hoon" sort="Jung, Kie Hoon" uniqKey="Jung K" first="Kie-Hoon" last="Jung">Kie-Hoon Jung</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Li, Joseph K K" sort="Li, Joseph K K" uniqKey="Li J" first="Joseph K.-K." last="Li">Joseph K.-K. Li</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Department of Biology, Utah State University, 5305 Old Main Hill</s1><s2>Logan, UT 84322-5305</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author><author><name sortKey="Chan, Paul K S" sort="Chan, Paul K S" uniqKey="Chan P" first="Paul K. S." last="Chan">Paul K. S. Chan</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital</s1><s2>Shatin, New Territories</s2><s3>HKG</s3><sZ>9 aut.</sZ></inist:fA14><country>Hong Kong</country><wicri:noRegion>Shatin, New Territories</wicri:noRegion><orgName type="university">Université chinoise de Hong Kong</orgName><placeName><settlement type="city">Sha Tin</settlement></placeName></affiliation></author><author><name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill</s1><s2>Logan, UT 84322-5600</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Utah</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Antipsychotic</term><term>Antiviral</term><term>Mouse</term><term>Neuroleptic</term><term>Promazine</term><term>Psychotropic</term><term>Replication</term><term>Severe acute respiratory syndrome</term><term>Severe acute respiratory syndrome virus</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Antipsychotique</term><term>Neuroleptique</term><term>Relation structure activité</term><term>Promazine</term><term>Antiviral</term><term>Syndrome respiratoire aigu sévère</term><term>Virus syndrome respiratoire aigu sévère</term><term>Réplication</term><term>Modèle animal</term><term>Souris</term><term>Psychotrope</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC<sub>90</sub> = 8.3 ± 2.8 μM, but without selectivity. Various substitutions in the basic phenothiazine structure did not promote efficacy. Phenazine ethosulfate was the most potent compound by VYR assay (EC<sub>90</sub> = 6.1 ± 4.3 μM). All compounds were toxic (IC<sub>50</sub> = 6.6-74.5 μM) except for phenoxathiin (IC<sub>50</sub> = 858 ± 208 μM) and 10-(alpha-diethylamino-propionyl) phenothiazine.HCl (IC<sub>50</sub> =195 ± 71.2 μM). Consequently, none were selective inhibitors of SARS-CoV replication (SI values <1-3.3 μM). These data portended the poor efficacy of promazine in a SARS-CoV mouse lung replication model. Intraperitoneal treatment with promazine using a prophylactic (-4 h)/therapeutic regimen of 1, 10, or 50 mg/(kg day) did not reduce virus lung titers at day 3, yet prolonged virus replication to 14 days. Similar therapeutic promazine doses were not efficacious. Thus, promazine did not affect SARS-CoV replication in vitro or in vivo, nor were any other phenothiazines efficacious in reducing virus replication. Therefore, treating SARS infections with compounds like promazine is not warranted.</div></front></TEI><affiliations><list><country><li>Hong Kong</li><li>États-Unis</li></country><region><li>Utah</li></region><settlement><li>Sha Tin</li></settlement><orgName><li>Université chinoise de Hong Kong</li></orgName></list><tree><country name="États-Unis"><region name="Utah"><name sortKey="Barnard, Dale L" sort="Barnard, Dale L" uniqKey="Barnard D" first="Dale L." last="Barnard">Dale L. Barnard</name></region><name sortKey="Bailey, Kevin" sort="Bailey, Kevin" uniqKey="Bailey K" first="Kevin" last="Bailey">Kevin Bailey</name><name sortKey="Day, Craig W" sort="Day, Craig W" uniqKey="Day C" first="Craig W." last="Day">Craig W. Day</name><name sortKey="Heiner, Matthew" sort="Heiner, Matthew" uniqKey="Heiner M" first="Matthew" last="Heiner">Matthew Heiner</name><name sortKey="Jung, Kie Hoon" sort="Jung, Kie Hoon" uniqKey="Jung K" first="Kie-Hoon" last="Jung">Kie-Hoon Jung</name><name sortKey="Lauridsen, Larry" sort="Lauridsen, Larry" uniqKey="Lauridsen L" first="Larry" last="Lauridsen">Larry Lauridsen</name><name sortKey="Li, Joseph K K" sort="Li, Joseph K K" uniqKey="Li J" first="Joseph K.-K." last="Li">Joseph K.-K. Li</name><name sortKey="Montgomery, Robert" sort="Montgomery, Robert" uniqKey="Montgomery R" first="Robert" last="Montgomery">Robert Montgomery</name><name sortKey="Sidwell, Robert W" sort="Sidwell, Robert W" uniqKey="Sidwell R" first="Robert W." last="Sidwell">Robert W. Sidwell</name></country><country name="Hong Kong"><noRegion><name sortKey="Chan, Paul K S" sort="Chan, Paul K S" uniqKey="Chan P" first="Paul K. S." last="Chan">Paul K. S. Chan</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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