Brief Report: Hydroxychloroquine does not induce hemolytic anemia or organ damage in a "humanized" G6PD A- mouse model.
Identifieur interne : 000B13 ( Main/Curation ); précédent : 000B12; suivant : 000B14Brief Report: Hydroxychloroquine does not induce hemolytic anemia or organ damage in a "humanized" G6PD A- mouse model.
Auteurs : Benjamin E. Zuchelkowski [États-Unis] ; Ling Wang [États-Unis] ; Sebastien Gingras [États-Unis] ; Qinzi Xu [États-Unis] ; Minying Yang [États-Unis] ; Darrell Triulzi [États-Unis] ; Grier P. Page [États-Unis] ; Victor R. Gordeuk [États-Unis] ; Daniel B. Kim-Shapiro [États-Unis] ; Janet S. Lee [États-Unis] ; Mark T. Gladwin [États-Unis]Source :
- PloS one [ 1932-6203 ] ; 2020.
Descripteurs français
- KwdFr :
- Afro-Américains (MeSH), Animaux (MeSH), Déficit en glucose-6-phosphate-déshydrogénase (anatomopathologie), Humains (MeSH), Hydroxychloroquine (effets indésirables), Hydroxychloroquine (usage thérapeutique), Infections à coronavirus (traitement médicamenteux), Modèles animaux de maladie humaine (MeSH), Mâle (MeSH), Pandémies (MeSH), Pneumopathie virale (traitement médicamenteux), Souris (MeSH).
- MESH :
- anatomopathologie : Déficit en glucose-6-phosphate-déshydrogénase.
- effets indésirables : Hydroxychloroquine.
- traitement médicamenteux : Infections à coronavirus, Pneumopathie virale.
- usage thérapeutique : Hydroxychloroquine.
- Afro-Américains, Animaux, Humains, Modèles animaux de maladie humaine, Mâle, Pandémies, Souris.
English descriptors
- KwdEn :
- African Americans (MeSH), Animals (MeSH), COVID-19 (MeSH), Coronavirus Infections (drug therapy), Disease Models, Animal (MeSH), Glucosephosphate Dehydrogenase Deficiency (pathology), Humans (MeSH), Hydroxychloroquine (adverse effects), Hydroxychloroquine (therapeutic use), Male (MeSH), Mice (MeSH), Pandemics (MeSH), Pneumonia, Viral (drug therapy).
- MESH :
- chemical , adverse effects : Hydroxychloroquine.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- pathology : Glucosephosphate Dehydrogenase Deficiency.
- chemical , therapeutic use : Hydroxychloroquine.
- African Americans, Animals, COVID-19, Disease Models, Animal, Humans, Male, Mice, Pandemics.
Abstract
BACKGROUND
Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population.
STUDY DESIGN AND METHODS
Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ.
RESULTS
Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ.
CONCLUSIONS
Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency.
DOI: 10.1371/journal.pone.0240266
PubMed: 33007039
PubMed Central: PMC7531777
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<term>Glucosephosphate Dehydrogenase Deficiency (pathology)</term>
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<term>Hydroxychloroquine (adverse effects)</term>
<term>Hydroxychloroquine (therapeutic use)</term>
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<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Glucosephosphate Dehydrogenase Deficiency</term>
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<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Hydroxychloroquine</term>
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<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
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<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Hydroxychloroquine</term>
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<keywords scheme="MESH" xml:lang="en"><term>African Americans</term>
<term>Animals</term>
<term>COVID-19</term>
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<term>Humans</term>
<term>Male</term>
<term>Mice</term>
<term>Pandemics</term>
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<term>Animaux</term>
<term>Humains</term>
<term>Modèles animaux de maladie humaine</term>
<term>Mâle</term>
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<front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b>
</p>
<p>Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>STUDY DESIGN AND METHODS</b>
</p>
<p>Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>RESULTS</b>
</p>
<p>Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b>
</p>
<p>Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency.</p>
</div>
</front>
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<ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0240266</ELocationID>
<Abstract><AbstractText Label="BACKGROUND">Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population.</AbstractText>
<AbstractText Label="STUDY DESIGN AND METHODS">Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ.</AbstractText>
<AbstractText Label="RESULTS">Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ.</AbstractText>
<AbstractText Label="CONCLUSIONS">Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zuchelkowski</LastName>
<ForeName>Benjamin E</ForeName>
<Initials>BE</Initials>
<Identifier Source="ORCID">0000-0002-0747-292X</Identifier>
<AffiliationInfo><Affiliation>Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Ling</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gingras</LastName>
<ForeName>Sebastien</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Xu</LastName>
<ForeName>Qinzi</ForeName>
<Initials>Q</Initials>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Minying</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Triulzi</LastName>
<ForeName>Darrell</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Department of Pathology, Division of Transfusion Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Page</LastName>
<ForeName>Grier P</ForeName>
<Initials>GP</Initials>
<AffiliationInfo><Affiliation>RTI International, Research Triangle Park, Durham, NC, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gordeuk</LastName>
<ForeName>Victor R</ForeName>
<Initials>VR</Initials>
<AffiliationInfo><Affiliation>Division of Hematology and Oncology, University of Illinois at Chicago School of Medicine, Chicago, IL, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim-Shapiro</LastName>
<ForeName>Daniel B</ForeName>
<Initials>DB</Initials>
<AffiliationInfo><Affiliation>Department of Physics, Wake Forest University, Winston-Salem, NC, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Janet S</ForeName>
<Initials>JS</Initials>
<AffiliationInfo><Affiliation>Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gladwin</LastName>
<ForeName>Mark T</ForeName>
<Initials>MT</Initials>
<AffiliationInfo><Affiliation>Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, PA, United States of America.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>R01 HL098032</GrantID>
<Acronym>HL</Acronym>
<Agency>NHLBI NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>5R01HL098032</GrantID>
<Acronym>NH</Acronym>
<Agency>NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2020</Year>
<Month>10</Month>
<Day>02</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>PLoS One</MedlineTA>
<NlmUniqueID>101285081</NlmUniqueID>
<ISSNLinking>1932-6203</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>4QWG6N8QKH</RegistryNumber>
<NameOfSubstance UI="D006886">Hydroxychloroquine</NameOfSubstance>
</Chemical>
</ChemicalList>
<SupplMeshList><SupplMeshName Type="Protocol" UI="C000705127">COVID-19 drug treatment</SupplMeshName>
</SupplMeshList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D001741" MajorTopicYN="N">African Americans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000086382" MajorTopicYN="N">COVID-19</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004195" MajorTopicYN="Y">Disease Models, Animal</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005955" MajorTopicYN="N">Glucosephosphate Dehydrogenase Deficiency</DescriptorName>
<QualifierName UI="Q000473" MajorTopicYN="Y">pathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006886" MajorTopicYN="N">Hydroxychloroquine</DescriptorName>
<QualifierName UI="Q000009" MajorTopicYN="Y">adverse effects</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
</MeshHeading>
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<CoiStatement>I have read the journal's policy and the authors of this manuscript have the following competing interests: MTG is a co-inventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning, which have been licensed by Globin Solutions, Inc. Dr. Gladwin is a shareholder, advisor, and director in Globin Solutions, Inc. Dr. Gladwin is also co-inventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and is now licensed to Globin Solutions and Hope Pharmaceuticals. Dr. Gladwin is a principal-investigator in a research collaboration with Bayer Pharmaceuticals to evaluate riociguate as a treatment for patients with SCD. Consulting Agreements: Dr. Gladwin is actively serving as a scientific consultant for Actelion, Pfizer, Bayer Healthcare, Complexa, Novartis and United Therapeutics. He previously served as a consultant for Acceleron Pharma, Inc., Sujana Biotech, Epizyme, Inc., Catalyst Biosciences, Inc. and Modus Therapeutics. Dr. Gladwin is also on Bayer HealthCare LLC’s Heart and Vascular Disease Research Advisory Board. LW reports as a shareholder in Globin Solutions, Inc.</CoiStatement>
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