Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine
Identifieur interne : 000477 ( Istex/Corpus ); précédent : 000476; suivant : 000478Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine
Auteurs : Nisar A. Shaikh ; Eugene Downar ; Jagdish ButanySource :
- Molecular and Cellular Biochemistry [ 0300-8177 ] ; 1987-08-01.
English descriptors
- KwdEn :
- Teeft :
- Acid phospholipases, Alveolar macrophages, Amiodarone, Amiodarone serum levels, Amorphous light, Assay, Assay mixture, Assay tubes, Biochem pharmacol, Biochemical observations, Biochim biophys acta, Biol chem, Bovine liver, Buffy, Buffy coat preparations, Cationic, Cationic amphiphiles, Characteristic cytoplasmic inclusion bodies, Chloroquine, Chlorpromazine, Chronic amiodarone treatment, Chronic therapy, Chronic treatment, College hospital, Control activity, Cumulative dose, Cytoplasmic, Cytoplasmic inclusion bodies, Cytoplasmic inclusions, Downar, Generalized phospholipidosis, Higher concentrations, Inclusion, Inclusion bodies, Inhibition, Inhibitory effect, Inhibitory effects, Ischemia, Leukocyte, Lipid, Liver lysosomes, Lower phase, Lysosomal, Lysosomal accumulations, Lysosomal homogenate, Lysosomal inclusions, Lysosomal phospholipase, Lysosomal phospholipases, Lysosome, Macrophage, Membrane phospholipases, Membrane phospholipids, Myocardial ischemia, Normal individuals, Other cationic amphiphiles, Other drugs, Phospholipase, Phospholipase activities, Phospholipase activity, Phospholipases, Phospholipid, Phospholipid catabolism, Phospholipid losses, Phospholipidosis, Polymorphonuclear leukocytes, Reaction products, Shaikh, Sigma chemical, Simple relationship, Solvent front, Specific activity, Standard assay conditions, Tertiary amine, Total inhibition, Toxic effects, Uranyl acetate.
Abstract
Abstract: Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.
Url:
DOI: 10.1007/BF00223481
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ISTEX:FBB5BAE4DE480A524BAE62C540F26AAAB94B5FA1Le document en format XML
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Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.</div></front></TEI><istex><corpusName>springer-journals</corpusName><keywords><teeft><json:string>amiodarone</json:string><json:string>chloroquine</json:string><json:string>lysosomal</json:string><json:string>phospholipase</json:string><json:string>phospholipid</json:string><json:string>phospholipases</json:string><json:string>chlorpromazine</json:string><json:string>cytoplasmic</json:string><json:string>ischemia</json:string><json:string>lysosome</json:string><json:string>leukocyte</json:string><json:string>shaikh</json:string><json:string>buffy</json:string><json:string>lipid</json:string><json:string>macrophage</json:string><json:string>assay</json:string><json:string>downar</json:string><json:string>phospholipidosis</json:string><json:string>cationic</json:string><json:string>inclusion</json:string><json:string>lysosomal inclusions</json:string><json:string>lysosomal phospholipases</json:string><json:string>myocardial ischemia</json:string><json:string>amorphous light</json:string><json:string>cytoplasmic inclusions</json:string><json:string>inhibitory effects</json:string><json:string>standard assay conditions</json:string><json:string>cationic amphiphiles</json:string><json:string>simple relationship</json:string><json:string>acid phospholipases</json:string><json:string>membrane phospholipids</json:string><json:string>inhibitory effect</json:string><json:string>buffy coat preparations</json:string><json:string>phospholipase activity</json:string><json:string>inclusion bodies</json:string><json:string>phospholipase activities</json:string><json:string>cumulative dose</json:string><json:string>uranyl acetate</json:string><json:string>sigma chemical</json:string><json:string>specific activity</json:string><json:string>assay mixture</json:string><json:string>reaction products</json:string><json:string>generalized phospholipidosis</json:string><json:string>solvent front</json:string><json:string>control activity</json:string><json:string>polymorphonuclear leukocytes</json:string><json:string>toxic effects</json:string><json:string>liver lysosomes</json:string><json:string>inhibition</json:string><json:string>phospholipid catabolism</json:string><json:string>cytoplasmic inclusion bodies</json:string><json:string>biochemical observations</json:string><json:string>normal individuals</json:string><json:string>amiodarone serum levels</json:string><json:string>biochim biophys acta</json:string><json:string>assay tubes</json:string><json:string>tertiary amine</json:string><json:string>chronic treatment</json:string><json:string>lysosomal homogenate</json:string><json:string>chronic therapy</json:string><json:string>total inhibition</json:string><json:string>bovine liver</json:string><json:string>lower phase</json:string><json:string>lysosomal phospholipase</json:string><json:string>chronic amiodarone treatment</json:string><json:string>characteristic cytoplasmic inclusion bodies</json:string><json:string>phospholipid losses</json:string><json:string>other cationic amphiphiles</json:string><json:string>higher concentrations</json:string><json:string>other drugs</json:string><json:string>alveolar macrophages</json:string><json:string>college hospital</json:string><json:string>lysosomal accumulations</json:string><json:string>biochem pharmacol</json:string><json:string>biol chem</json:string><json:string>membrane phospholipases</json:string></teeft></keywords><author><json:item><name>Dr. Nisar A. Shaikh</name><affiliations><json:string>Departments of Medicine & Clinical Biochemistry, University of Toronto, MSS 1A8, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Eugene Downar</name><affiliations><json:string>Department of Medicine, University of Toronto, & Women's College Hospital, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Jagdish Butany</name><affiliations><json:string>Department of Pathology, University of Toronto, & Toronto General Hospital, Toronto, Canada</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>amiodarone</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>phospholipases</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>lysosomes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cytoplasmic inclusions</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chloroquine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chlorpromazine</value></json:item></subject><articleId><json:string>BF00223481</json:string><json:string>Art7</json:string></articleId><arkIstex>ark:/67375/1BB-S4HWG393-B</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>OriginalPaper</json:string></originalGenre><abstract>Abstract: Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.</abstract><qualityIndicators><score>9.746</score><pdfWordCount>4782</pdfWordCount><pdfCharCount>28290</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>10</pdfPageCount><pdfPageSize>555 x 738 pts</pdfPageSize><refBibsNative>false</refBibsNative><abstractWordCount>247</abstractWordCount><abstractCharCount>1788</abstractCharCount><keywordCount>6</keywordCount></qualityIndicators><title>Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</title><pmid><json:string>2823097</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Molecular and Cellular Biochemistry</title><language><json:string>unknown</json:string></language><publicationDate>1987</publicationDate><copyrightDate>1987</copyrightDate><issn><json:string>0300-8177</json:string></issn><eissn><json:string>1573-4919</json:string></eissn><journalId><json:string>11010</json:string></journalId><volume>76</volume><issue>2</issue><pages><first>163</first><last>172</last></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Cardiology</value></json:item><json:item><value>Medical Biochemistry</value></json:item><json:item><value>Oncology</value></json:item><json:item><value>Biochemistry, general</value></json:item></subject></host><namedEntities><unitex><date></date><geogName></geogName><orgName></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName></persName><placeName></placeName><ref_url></ref_url><ref_bibl></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/1BB-S4HWG393-B</json:string></ark><categories><wos><json:string>1 - 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sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>1987</publicationDate><copyrightDate>1987</copyrightDate><doi><json:string>10.1007/BF00223481</json:string></doi><id>FBB5BAE4DE480A524BAE62C540F26AAAB94B5FA1</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-S4HWG393-B/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-S4HWG393-B/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/1BB-S4HWG393-B/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher scheme="https://scientific-publisher.data.istex.fr">Kluwer Academic Publishers</publisher><pubPlace>Dordrecht</pubPlace><availability><licence><p>Martinus Nijhoff Publishers, 1987</p></licence><p scheme="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</p></availability><date>1987-01-10</date></publicationStmt><notesStmt><note type="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note><note>Original Article</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</title><author xml:id="author-0000" corresp="yes"><persName><forename type="first">Nisar</forename><surname>Shaikh</surname></persName><roleName type="degree">Dr.</roleName><affiliation>Departments of Medicine & Clinical Biochemistry, University of Toronto, MSS 1A8, Toronto, Canada</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Eugene</forename><surname>Downar</surname></persName><affiliation>Department of Medicine, University of Toronto, & Women's College Hospital, Toronto, Canada</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Jagdish</forename><surname>Butany</surname></persName><affiliation>Department of Pathology, University of Toronto, & Toronto General Hospital, Toronto, Canada</affiliation></author><idno type="istex">FBB5BAE4DE480A524BAE62C540F26AAAB94B5FA1</idno><idno type="ark">ark:/67375/1BB-S4HWG393-B</idno><idno type="DOI">10.1007/BF00223481</idno><idno type="article-id">BF00223481</idno><idno type="article-id">Art7</idno></analytic><monogr><title level="j">Molecular and Cellular Biochemistry</title><title level="j" type="sub">An International Journal for Chemical Biology in Health and Disease</title><title level="j" type="abbrev">Mol Cell Biochem</title><idno type="pISSN">0300-8177</idno><idno type="eISSN">1573-4919</idno><idno type="journal-ID">true</idno><idno type="issue-article-count">10</idno><idno type="volume-issue-count">2</idno><imprint><publisher>Kluwer Academic Publishers</publisher><pubPlace>Dordrecht</pubPlace><date type="published" when="1987-08-01"></date><biblScope unit="volume">76</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="163">163</biblScope><biblScope unit="page" to="172">172</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1987-01-10</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Key words</head><item><term>amiodarone</term></item><item><term>phospholipases</term></item><item><term>lysosomes</term></item><item><term>cytoplasmic inclusions</term></item><item><term>chloroquine</term></item><item><term>chlorpromazine</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Life Sciences</head><item><term>Cardiology</term></item><item><term>Medical Biochemistry</term></item><item><term>Oncology</term></item><item><term>Biochemistry, general</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1987-01-10">Created</change><change when="1987-08-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-S4HWG393-B/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//Springer-Verlag//DTD A++ V2.4//EN" URI="http://devel.springer.de/A++/V2.4/DTD/A++V2.4.dtd" name="istex:docType"></istex:docType><istex:document><Publisher><PublisherInfo><PublisherName>Kluwer Academic Publishers</PublisherName><PublisherLocation>Dordrecht</PublisherLocation></PublisherInfo><Journal><JournalInfo JournalProductType="ArchiveJournal" NumberingStyle="Unnumbered"><JournalID>11010</JournalID><JournalPrintISSN>0300-8177</JournalPrintISSN><JournalElectronicISSN>1573-4919</JournalElectronicISSN><JournalTitle>Molecular and Cellular Biochemistry</JournalTitle><JournalSubTitle>An International Journal for Chemical Biology in Health and Disease</JournalSubTitle><JournalAbbreviatedTitle>Mol Cell Biochem</JournalAbbreviatedTitle><JournalSubjectGroup><JournalSubject Type="Primary">Life Sciences</JournalSubject><JournalSubject Type="Secondary">Cardiology</JournalSubject><JournalSubject Type="Secondary">Medical Biochemistry</JournalSubject><JournalSubject Type="Secondary">Oncology</JournalSubject><JournalSubject Type="Secondary">Biochemistry, general</JournalSubject></JournalSubjectGroup></JournalInfo><Volume><VolumeInfo VolumeType="Regular" TocLevels="0"><VolumeIDStart>76</VolumeIDStart><VolumeIDEnd>76</VolumeIDEnd><VolumeIssueCount>2</VolumeIssueCount></VolumeInfo><Issue IssueType="Regular"><IssueInfo TocLevels="0"><IssueIDStart>2</IssueIDStart><IssueIDEnd>2</IssueIDEnd><IssueArticleCount>10</IssueArticleCount><IssueHistory><CoverDate><Year>1987</Year><Month>8</Month></CoverDate></IssueHistory><IssueCopyright><CopyrightHolderName>Martinus Nijhoff Publishers</CopyrightHolderName><CopyrightYear>1987</CopyrightYear></IssueCopyright></IssueInfo><Article ID="Art7"><ArticleInfo Language="En" ArticleType="OriginalPaper" NumberingStyle="Unnumbered" TocLevels="0" ContainsESM="No"><ArticleID>BF00223481</ArticleID><ArticleDOI>10.1007/BF00223481</ArticleDOI><ArticleSequenceNumber>7</ArticleSequenceNumber><ArticleTitle Language="En">Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</ArticleTitle><ArticleCategory>Original Article</ArticleCategory><ArticleFirstPage>163</ArticleFirstPage><ArticleLastPage>172</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2004</Year><Month>7</Month><Day>21</Day></RegistrationDate><Received><Year>1987</Year><Month>1</Month><Day>10</Day></Received><Accepted><Year>1987</Year><Month>4</Month><Day>22</Day></Accepted></ArticleHistory><ArticleCopyright><CopyrightHolderName>Martinus Nijhoff Publishers</CopyrightHolderName><CopyrightYear>1987</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants><ArticleContext><JournalID>11010</JournalID><VolumeIDStart>76</VolumeIDStart><VolumeIDEnd>76</VolumeIDEnd><IssueIDStart>2</IssueIDStart><IssueIDEnd>2</IssueIDEnd></ArticleContext></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff2"><AuthorName DisplayOrder="Western"><Prefix>Dr.</Prefix><GivenName>Nisar</GivenName><GivenName>A.</GivenName><FamilyName>Shaikh</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff3"><AuthorName DisplayOrder="Western"><GivenName>Eugene</GivenName><FamilyName>Downar</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff4"><AuthorName DisplayOrder="Western"><GivenName>Jagdish</GivenName><FamilyName>Butany</FamilyName></AuthorName></Author><Affiliation ID="Aff1"><OrgDivision>Departments of Medicine & Clinical Biochemistry</OrgDivision><OrgName>University of Toronto</OrgName><OrgAddress><Postcode>MSS 1A8</Postcode><City>Toronto</City><Country>Canada</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgDivision>Department of Medicine</OrgDivision><OrgName>University of Toronto, & Women's College Hospital</OrgName><OrgAddress><State>Toronto</State><Country>Canada</Country></OrgAddress></Affiliation><Affiliation ID="Aff4"><OrgDivision>Department of Pathology</OrgDivision><OrgName>University of Toronto, & Toronto General Hospital</OrgName><OrgAddress><State>Toronto</State><Country>Canada</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Clinical Sciences Division, Medical Sciences Bldg., Rm. 7363</OrgDivision><OrgName>University of Toronto</OrgName><OrgAddress><Street>1 King's College Circle</Street><Postcode>M5S 1A8</Postcode><City>Toronto</City><State>Ont.</State><Country>Canada</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En"><Heading>Abstract</Heading><Para>Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca<Superscript>2+</Superscript>-dependent phospholipase A and C activities. Phospholipase A<Subscript>2</Subscript> activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca<Superscript>2+</Superscript>-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca<Superscript>2+</Superscript>-dependent membrane phospholipases and Ca<Superscript>2+</Superscript>-independent acid phospholipases.</Para></Abstract><KeywordGroup Language="En"><Heading>Key words</Heading><Keyword>amiodarone</Keyword><Keyword>phospholipases</Keyword><Keyword>lysosomes</Keyword><Keyword>cytoplasmic inclusions</Keyword><Keyword>chloroquine</Keyword><Keyword>chlorpromazine</Keyword></KeywordGroup></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Amiodarone — an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="termsOfAddress">Dr.</namePart><namePart type="given">Nisar</namePart><namePart type="given">A.</namePart><namePart type="family">Shaikh</namePart><affiliation>Departments of Medicine & Clinical Biochemistry, University of Toronto, MSS 1A8, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eugene</namePart><namePart type="family">Downar</namePart><affiliation>Department of Medicine, University of Toronto, & Women's College Hospital, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jagdish</namePart><namePart type="family">Butany</namePart><affiliation>Department of Pathology, University of Toronto, & Toronto General Hospital, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Kluwer Academic Publishers</publisher><place><placeTerm type="text">Dordrecht</placeTerm></place><dateCreated encoding="w3cdtf">1987-01-10</dateCreated><dateIssued encoding="w3cdtf">1987-08-01</dateIssued><copyrightDate encoding="w3cdtf">1987</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r=0.02) or amiodarone serum levels (r=0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1–8 mg/assay) by all three drugs in the order: chlorpromazine > amiodarone > chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.</abstract><note>Original Article</note><subject lang="en"><genre>Key words</genre><topic>amiodarone</topic><topic>phospholipases</topic><topic>lysosomes</topic><topic>cytoplasmic inclusions</topic><topic>chloroquine</topic><topic>chlorpromazine</topic></subject><relatedItem type="host"><titleInfo><title>Molecular and Cellular Biochemistry</title><subTitle>An International Journal for Chemical Biology in Health and Disease</subTitle></titleInfo><titleInfo type="abbreviated"><title>Mol Cell Biochem</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">1987-08-01</dateIssued><copyrightDate encoding="w3cdtf">1987</copyrightDate></originInfo><subject><genre>Life Sciences</genre><topic>Cardiology</topic><topic>Medical Biochemistry</topic><topic>Oncology</topic><topic>Biochemistry, general</topic></subject><identifier type="ISSN">0300-8177</identifier><identifier type="eISSN">1573-4919</identifier><identifier type="JournalID">11010</identifier><identifier type="IssueArticleCount">10</identifier><identifier type="VolumeIssueCount">2</identifier><part><date>1987</date><detail type="volume"><number>76</number><caption>vol.</caption></detail><detail type="issue"><number>2</number><caption>no.</caption></detail><extent unit="pages"><start>163</start><end>172</end></extent></part><recordInfo><recordOrigin>Martinus Nijhoff Publishers, 1987</recordOrigin></recordInfo></relatedItem><identifier type="istex">FBB5BAE4DE480A524BAE62C540F26AAAB94B5FA1</identifier><identifier type="ark">ark:/67375/1BB-S4HWG393-B</identifier><identifier type="DOI">10.1007/BF00223481</identifier><identifier type="ArticleID">BF00223481</identifier><identifier type="ArticleID">Art7</identifier><accessCondition type="use and reproduction" contentType="copyright">Martinus Nijhoff Publishers, 1987</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Martinus Nijhoff Publishers, 1987</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-S4HWG393-B/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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