"Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.
Identifieur interne : 001672 ( Main/Corpus ); précédent : 001671; suivant : 001673"Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.
Auteurs : Alexandre Gérard ; Serena Romani ; Audrey Fresse ; Delphine Viard ; Nadège Parassol ; Aurélie Granvuillemin ; Laurent Chouchana ; Fanny Rocher ; Milou-Daniel DriciSource :
- Therapie [ 1958-5578 ]
English descriptors
- KwdEn :
- Adverse Drug Reaction Reporting Systems (statistics & numerical data), Aged (MeSH), Azithromycin (administration & dosage), Azithromycin (adverse effects), COVID-19 (MeSH), Chloroquine (administration & dosage), Chloroquine (adverse effects), Coronavirus Infections (drug therapy), Drug Combinations (MeSH), Electrocardiography (MeSH), Female (MeSH), France (epidemiology), Heart Diseases (chemically induced), Heart Diseases (epidemiology), Humans (MeSH), Hydroxychloroquine (administration & dosage), Hydroxychloroquine (adverse effects), Long QT Syndrome (chemically induced), Long QT Syndrome (epidemiology), Lopinavir (administration & dosage), Lopinavir (adverse effects), Male (MeSH), Middle Aged (MeSH), Off-Label Use (MeSH), Pandemics (MeSH), Pharmacovigilance (MeSH), Pneumonia, Viral (drug therapy), Risk Factors (MeSH), Ritonavir (administration & dosage), Ritonavir (adverse effects).
- MESH :
- chemical , administration & dosage : Azithromycin, Chloroquine, Hydroxychloroquine, Lopinavir, Ritonavir.
- chemical , adverse effects : Azithromycin, Chloroquine, Hydroxychloroquine, Lopinavir, Ritonavir.
- geographic , epidemiology : France.
- chemically induced : Heart Diseases, Long QT Syndrome.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- epidemiology : Heart Diseases, Long QT Syndrome.
- statistics & numerical data : Adverse Drug Reaction Reporting Systems.
- Aged, COVID-19, Drug Combinations, Electrocardiography, Female, Humans, Male, Middle Aged, Off-Label Use, Pandemics, Pharmacovigilance, Risk Factors.
Abstract
INTRODUCTION
COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences.
METHODS
Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.
RESULTS
In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication.
DISCUSSION AND CONCLUSION
"Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.
DOI: 10.1016/j.therap.2020.05.002
PubMed: 32418730
PubMed Central: PMC7204701
Links to Exploration step
pubmed:32418730Le document en format XML
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Electronic address: pharmacovigilance@chu-nice.fr.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020 Jul - Aug</date><idno type="RBID">pubmed:32418730</idno><idno type="pmid">32418730</idno><idno type="doi">10.1016/j.therap.2020.05.002</idno><idno type="pmc">PMC7204701</idno><idno type="wicri:Area/Main/Corpus">001672</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">001672</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">"Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.</title><author><name sortKey="Gerard, Alexandre" sort="Gerard, Alexandre" uniqKey="Gerard A" first="Alexandre" last="Gérard">Alexandre Gérard</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Romani, Serena" sort="Romani, Serena" uniqKey="Romani S" first="Serena" last="Romani">Serena Romani</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fresse, Audrey" sort="Fresse, Audrey" uniqKey="Fresse A" first="Audrey" last="Fresse">Audrey Fresse</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Viard, Delphine" sort="Viard, Delphine" uniqKey="Viard D" first="Delphine" last="Viard">Delphine Viard</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Parassol, Nadege" sort="Parassol, Nadege" uniqKey="Parassol N" first="Nadège" last="Parassol">Nadège Parassol</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Granvuillemin, Aurelie" sort="Granvuillemin, Aurelie" uniqKey="Granvuillemin A" first="Aurélie" last="Granvuillemin">Aurélie Granvuillemin</name><affiliation><nlm:affiliation>Centre régional de pharmacovigilance, 21079 Dijon, France.</nlm:affiliation></affiliation></author><author><name sortKey="Chouchana, Laurent" sort="Chouchana, Laurent" uniqKey="Chouchana L" first="Laurent" last="Chouchana">Laurent Chouchana</name><affiliation><nlm:affiliation>Centre régional de pharmacovigilance Paris-Cochin, 75014 Paris, France.</nlm:affiliation></affiliation></author><author><name sortKey="Rocher, Fanny" sort="Rocher, Fanny" uniqKey="Rocher F" first="Fanny" last="Rocher">Fanny Rocher</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</nlm:affiliation></affiliation></author><author><name sortKey="Drici, Milou Daniel" sort="Drici, Milou Daniel" uniqKey="Drici M" first="Milou-Daniel" last="Drici">Milou-Daniel Drici</name><affiliation><nlm:affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France. Electronic address: pharmacovigilance@chu-nice.fr.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Therapie</title><idno type="eISSN">1958-5578</idno></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adverse Drug Reaction Reporting Systems (statistics & numerical data)</term><term>Aged (MeSH)</term><term>Azithromycin (administration & dosage)</term><term>Azithromycin (adverse effects)</term><term>COVID-19 (MeSH)</term><term>Chloroquine (administration & dosage)</term><term>Chloroquine (adverse effects)</term><term>Coronavirus Infections (drug therapy)</term><term>Drug Combinations (MeSH)</term><term>Electrocardiography (MeSH)</term><term>Female (MeSH)</term><term>France (epidemiology)</term><term>Heart Diseases (chemically induced)</term><term>Heart Diseases (epidemiology)</term><term>Humans (MeSH)</term><term>Hydroxychloroquine (administration & dosage)</term><term>Hydroxychloroquine (adverse effects)</term><term>Long QT Syndrome (chemically induced)</term><term>Long QT Syndrome (epidemiology)</term><term>Lopinavir (administration & dosage)</term><term>Lopinavir (adverse effects)</term><term>Male (MeSH)</term><term>Middle Aged (MeSH)</term><term>Off-Label Use (MeSH)</term><term>Pandemics (MeSH)</term><term>Pharmacovigilance (MeSH)</term><term>Pneumonia, Viral (drug therapy)</term><term>Risk Factors (MeSH)</term><term>Ritonavir (administration & dosage)</term><term>Ritonavir (adverse effects)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Azithromycin</term><term>Chloroquine</term><term>Hydroxychloroquine</term><term>Lopinavir</term><term>Ritonavir</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Azithromycin</term><term>Chloroquine</term><term>Hydroxychloroquine</term><term>Lopinavir</term><term>Ritonavir</term></keywords><keywords scheme="MESH" type="geographic" qualifier="epidemiology" xml:lang="en"><term>France</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Heart Diseases</term><term>Long QT Syndrome</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Heart Diseases</term><term>Long QT Syndrome</term></keywords><keywords scheme="MESH" qualifier="statistics & numerical data" xml:lang="en"><term>Adverse Drug Reaction Reporting Systems</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>COVID-19</term><term>Drug Combinations</term><term>Electrocardiography</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Off-Label Use</term><term>Pandemics</term><term>Pharmacovigilance</term><term>Risk Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>INTRODUCTION</b></p><p>COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication.</p></div><div type="abstract" xml:lang="en"><p><b>DISCUSSION AND CONCLUSION</b></p><p>"Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32418730</PMID><DateCompleted><Year>2020</Year><Month>09</Month><Day>01</Day></DateCompleted><DateRevised><Year>2021</Year><Month>01</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1958-5578</ISSN><JournalIssue CitedMedium="Internet"><Volume>75</Volume><Issue>4</Issue><PubDate><MedlineDate>2020 Jul - Aug</MedlineDate></PubDate></JournalIssue><Title>Therapie</Title><ISOAbbreviation>Therapie</ISOAbbreviation></Journal><ArticleTitle>"Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers.</ArticleTitle><Pagination><MedlinePgn>371-379</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0040-5957(20)30091-3</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.therap.2020.05.002</ELocationID><Abstract><AbstractText Label="INTRODUCTION" NlmCategory="BACKGROUND">COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication.</AbstractText><AbstractText Label="DISCUSSION AND CONCLUSION" NlmCategory="CONCLUSIONS">"Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.</AbstractText><CopyrightInformation>Copyright © 2020 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gérard</LastName><ForeName>Alexandre</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Romani</LastName><ForeName>Serena</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fresse</LastName><ForeName>Audrey</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Viard</LastName><ForeName>Delphine</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Parassol</LastName><ForeName>Nadège</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Granvuillemin</LastName><ForeName>Aurélie</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Centre régional de pharmacovigilance, 21079 Dijon, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chouchana</LastName><ForeName>Laurent</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Centre régional de pharmacovigilance Paris-Cochin, 75014 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rocher</LastName><ForeName>Fanny</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drici</LastName><ForeName>Milou-Daniel</ForeName><Initials>MD</Initials><AffiliationInfo><Affiliation>Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France. Electronic address: pharmacovigilance@chu-nice.fr.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>French Network of Pharmacovigilance Centers</CollectiveName></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>05</Month><Day>07</Day></ArticleDate></Article><MedlineJournalInfo><Country>France</Country><MedlineTA>Therapie</MedlineTA><NlmUniqueID>0420544</NlmUniqueID><ISSNLinking>0040-5957</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004338">Drug Combinations</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C558899">lopinavir-ritonavir drug combination</NameOfSubstance></Chemical><Chemical><RegistryNumber>2494G1JF75</RegistryNumber><NameOfSubstance UI="D061466">Lopinavir</NameOfSubstance></Chemical><Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber><NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>83905-01-5</RegistryNumber><NameOfSubstance UI="D017963">Azithromycin</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>O3J8G9O825</RegistryNumber><NameOfSubstance UI="D019438">Ritonavir</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName></SupplMeshList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D016907" MajorTopicYN="N">Adverse Drug Reaction Reporting Systems</DescriptorName><QualifierName UI="Q000706" MajorTopicYN="N">statistics & numerical data</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017963" MajorTopicYN="N">Azithromycin</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000086382" MajorTopicYN="N">COVID-19</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004338" MajorTopicYN="N">Drug Combinations</DescriptorName></MeshHeading><MeshHeading><DescriptorName 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