Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections?
Identifieur interne : 000D97 ( Pmc/Curation ); précédent : 000D96; suivant : 000D98Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections?
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 [République populaire de Chine] ; Robert W. Sidwell [États-Unis]Source :
- Antiviral Research [ 0166-3542 ] ; 2008.
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.
Url:
DOI: 10.1016/j.antiviral.2007.12.005
PubMed: 18423639
PubMed Central: 2582943
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Chan</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital, Shatin, New Territories, Hong Kong</wicri:regionArea></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="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18423639</idno><idno type="pmc">2582943</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582943</idno><idno type="RBID">PMC:2582943</idno><idno type="doi">10.1016/j.antiviral.2007.12.005</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000D97</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D97</idno><idno type="wicri:Area/Pmc/Curation">000D97</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000D97</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections?</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="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></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="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author><author><name sortKey="Bailey, Kevin" sort="Bailey, Kevin" uniqKey="Bailey K" first="Kevin" last="Bailey">Kevin Bailey</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author><author><name sortKey="Heiner, Matthew" sort="Heiner, Matthew" uniqKey="Heiner M" first="Matthew" last="Heiner">Matthew Heiner</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author><author><name sortKey="Montgomery, Robert" sort="Montgomery, Robert" uniqKey="Montgomery R" first="Robert" last="Montgomery">Robert Montgomery</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author><author><name sortKey="Lauridsen, Larry" sort="Lauridsen, Larry" uniqKey="Lauridsen L" first="Larry" last="Lauridsen">Larry Lauridsen</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></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="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></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="1"><nlm:aff id="aff2">Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305</wicri:regionArea></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="1"><nlm:aff id="aff3">Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital, Shatin, New Territories, Hong Kong</wicri:regionArea></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="1"><nlm:aff id="aff1">Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600</wicri:regionArea></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Barnard, D L" uniqKey="Barnard D">D.L. Barnard</name></author><author><name sortKey="Hill, C L" uniqKey="Hill C">C.L. Hill</name></author><author><name sortKey="Gage, T L" uniqKey="Gage T">T.L. Gage</name></author><author><name sortKey="Matheson, J L" uniqKey="Matheson J">J.L. Matheson</name></author><author><name sortKey="Huffman, J H" uniqKey="Huffman J">J.H. Huffman</name></author><author><name sortKey="Sidwell, R W" uniqKey="Sidwell R">R.W. Sidwell</name></author><author><name sortKey="Otto, M J" uniqKey="Otto M">M.J. Otto</name></author><author><name sortKey="Schinazi, R F" uniqKey="Schinazi R">R.F. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Antiviral Res</journal-id><journal-id journal-id-type="iso-abbrev">Antiviral Res</journal-id><journal-title-group><journal-title>Antiviral Research</journal-title></journal-title-group><issn pub-type="ppub">0166-3542</issn><issn pub-type="epub">1872-9096</issn><publisher><publisher-name>Published by Elsevier B.V.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18423639</article-id><article-id pub-id-type="pmc">2582943</article-id><article-id pub-id-type="publisher-id">S0166-3542(07)00501-3</article-id><article-id pub-id-type="doi">10.1016/j.antiviral.2007.12.005</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections?</article-title><subtitle>Lack of efficacy of promazine on SARS-CoV replication in a mouse model</subtitle></title-group><contrib-group><contrib contrib-type="author"><name><surname>Barnard</surname><given-names>Dale L.</given-names></name><email>dale.barnard@usu.edu</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author"><name><surname>Day</surname><given-names>Craig W.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Bailey</surname><given-names>Kevin</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Heiner</surname><given-names>Matthew</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Montgomery</surname><given-names>Robert</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Lauridsen</surname><given-names>Larry</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Kie-Hoon</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Joseph K.-K.</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author"><name><surname>Chan</surname><given-names>Paul K.S.</given-names></name><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author"><name><surname>Sidwell</surname><given-names>Robert W.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA</aff><aff id="aff2"><label>b</label>Department of Biology, Utah State University, 5305 Old Main Hill, Logan, UT 84322-5305, USA</aff><aff id="aff3"><label>c</label>Department of Microbiology, Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, 1/F Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China</aff><author-notes><corresp id="cor1"><label>⁎</label>Corresponding author. Tel.: +1 435 779 2696; fax: +1 435 797 3959. <email>dale.barnard@usu.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>11</day><month>1</month><year>2008</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>8</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>11</day><month>1</month><year>2008</year></pub-date><volume>79</volume><issue>2</issue><fpage>105</fpage><lpage>113</lpage><history><date date-type="received"><day>20</day><month>6</month><year>2006</year></date><date date-type="accepted"><day>13</day><month>12</month><year>2007</year></date></history><permissions><copyright-statement>Copyright © 2008 Published by Elsevier B.V.</copyright-statement><copyright-year>2008</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract><p>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.</p></abstract><kwd-group><title>Keywords</title><kwd>Promazine</kwd><kwd>Anti-psychotic</kwd><kwd>SARS-CoV</kwd><kwd>Coronavirus</kwd><kwd>Mouse model</kwd><kwd>Phenothiazines</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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