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 : 000156 ( Psycho/Analysis ); précédent : 000155; suivant : 000157Is 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.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (administration et posologie), Antiviraux (pharmacologie), Antiviraux (toxicité), Antiviraux (usage thérapeutique), Cellules Vero, Chimioprévention, Cytokines (analyse), Femelle, Phénothiazines (administration et posologie), Phénothiazines (pharmacologie), Phénothiazines (toxicité), Phénothiazines (usage thérapeutique), Poumon (anatomopathologie), Poumon (virologie), Rouge neutre (métabolisme), Réplication virale, Souris, Souris de lignée BALB C, Structure moléculaire, Survie cellulaire, Syndrome respiratoire aigu sévère (), Syndrome respiratoire aigu sévère (traitement médicamenteux), Virus du SRAS ().
- MESH :
- administration et posologie : Antiviraux, Phénothiazines.
- analyse : Cytokines.
- anatomopathologie : Poumon.
- métabolisme : Rouge neutre.
- pharmacologie : Antiviraux, Phénothiazines.
- toxicité : Antiviraux, Phénothiazines.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- usage thérapeutique : Antiviraux, Phénothiazines.
- virologie : Poumon.
- Pascal (Inist)
- Animaux, Antipsychotique, Cellules Vero, Chimioprévention, Femelle, Neuroleptique, Relation structure activité, Promazine, Antiviral, Réplication virale, Souris, Souris de lignée BALB C, Structure moléculaire, Survie cellulaire, Syndrome respiratoire aigu sévère, Virus du SRAS, Virus syndrome respiratoire aigu sévère, Réplication, Modèle animal, Souris, Psychotrope.
English descriptors
- KwdEn :
- Animal model, Animals, Antipsychotic, Antiviral, Antiviral Agents (administration & dosage), Antiviral Agents (pharmacology), Antiviral Agents (therapeutic use), Antiviral Agents (toxicity), Cell Survival, Chemoprevention, Chlorocebus aethiops, Cytokines (analysis), Female, Lung (pathology), Lung (virology), Mice, Mice, Inbred BALB C, Molecular Structure, Mouse, Neuroleptic, Neutral Red (metabolism), Phenothiazines (administration & dosage), Phenothiazines (pharmacology), Phenothiazines (therapeutic use), Phenothiazines (toxicity), Promazine, Psychotropic, Replication, SARS Virus (drug effects), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (prevention & control), Severe acute respiratory syndrome, Severe acute respiratory syndrome virus, Structure activity relation, Vero Cells, Virus Replication.
- MESH :
- chemical , administration & dosage : Antiviral Agents, Phenothiazines.
- chemical , analysis : Cytokines.
- chemical , metabolism : Neutral Red.
- chemical , pharmacology : Antiviral Agents, Phenothiazines.
- chemical , therapeutic use : Antiviral Agents, Phenothiazines.
- chemical , toxicity : Antiviral Agents, Phenothiazines.
- drug effects : SARS Virus.
- drug therapy : Severe Acute Respiratory Syndrome.
- pathology : Lung.
- prevention & control : Severe Acute Respiratory Syndrome.
- virology : Lung.
- Animals, Cell Survival, Chemoprevention, Chlorocebus aethiops, Female, Mice, Mice, Inbred BALB C, Molecular Structure, Vero Cells, Virus Replication.
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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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>Animals</term><term>Antipsychotic</term><term>Antiviral</term><term>Antiviral Agents (administration & dosage)</term><term>Antiviral Agents (pharmacology)</term><term>Antiviral Agents (therapeutic use)</term><term>Antiviral Agents (toxicity)</term><term>Cell Survival</term><term>Chemoprevention</term><term>Chlorocebus aethiops</term><term>Cytokines (analysis)</term><term>Female</term><term>Lung (pathology)</term><term>Lung (virology)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Molecular Structure</term><term>Mouse</term><term>Neuroleptic</term><term>Neutral Red (metabolism)</term><term>Phenothiazines (administration & dosage)</term><term>Phenothiazines (pharmacology)</term><term>Phenothiazines (therapeutic use)</term><term>Phenothiazines (toxicity)</term><term>Promazine</term><term>Psychotropic</term><term>Replication</term><term>SARS Virus (drug effects)</term><term>Severe Acute Respiratory Syndrome (drug therapy)</term><term>Severe Acute Respiratory Syndrome (prevention & control)</term><term>Severe acute respiratory syndrome</term><term>Severe acute respiratory syndrome virus</term><term>Structure activity relation</term><term>Vero Cells</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (administration et posologie)</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (toxicité)</term><term>Antiviraux (usage thérapeutique)</term><term>Cellules Vero</term><term>Chimioprévention</term><term>Cytokines (analyse)</term><term>Femelle</term><term>Phénothiazines (administration et posologie)</term><term>Phénothiazines (pharmacologie)</term><term>Phénothiazines (toxicité)</term><term>Phénothiazines (usage thérapeutique)</term><term>Poumon (anatomopathologie)</term><term>Poumon (virologie)</term><term>Rouge neutre (métabolisme)</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Structure moléculaire</term><term>Survie cellulaire</term><term>Syndrome respiratoire aigu sévère ()</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Virus du SRAS ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Antiviral Agents</term><term>Phenothiazines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>Cytokines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Neutral Red</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Phenothiazines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiviral Agents</term><term>Phenothiazines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antiviral Agents</term><term>Phenothiazines</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Antiviraux</term><term>Phénothiazines</term></keywords><keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>Cytokines</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Rouge neutre</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Phénothiazines</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" qualifier="toxicité" xml:lang="fr"><term>Antiviraux</term><term>Phénothiazines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antiviraux</term><term>Phénothiazines</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Lung</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Survival</term><term>Chemoprevention</term><term>Chlorocebus aethiops</term><term>Female</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Molecular Structure</term><term>Vero Cells</term><term>Virus Replication</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Antipsychotique</term><term>Cellules Vero</term><term>Chimioprévention</term><term>Femelle</term><term>Neuroleptique</term><term>Relation structure activité</term><term>Promazine</term><term>Antiviral</term><term>Réplication virale</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Structure moléculaire</term><term>Survie cellulaire</term><term>Syndrome respiratoire aigu sévère</term><term>Virus du SRAS</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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