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Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. A...

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Autores principales: Baralić, Katarina, Jorgovanović, Dragica, Živančević, Katarina, Antonijević Miljaković, Evica, Antonijević, Biljana, Buha Djordjevic, Aleksandra, Ćurčić, Marijana, Đukić-Ćosić, Danijela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483129/
https://www.ncbi.nlm.nih.gov/pubmed/32920000
http://dx.doi.org/10.1016/j.taap.2020.115237
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author Baralić, Katarina
Jorgovanović, Dragica
Živančević, Katarina
Antonijević Miljaković, Evica
Antonijević, Biljana
Buha Djordjevic, Aleksandra
Ćurčić, Marijana
Đukić-Ćosić, Danijela
author_facet Baralić, Katarina
Jorgovanović, Dragica
Živančević, Katarina
Antonijević Miljaković, Evica
Antonijević, Biljana
Buha Djordjevic, Aleksandra
Ćurčić, Marijana
Đukić-Ćosić, Danijela
author_sort Baralić, Katarina
collection PubMed
description Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are “old”, their pharmacological and toxicological profile in SARS-CoV-2 – infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.
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spelling pubmed-74831292020-09-11 Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach Baralić, Katarina Jorgovanović, Dragica Živančević, Katarina Antonijević Miljaković, Evica Antonijević, Biljana Buha Djordjevic, Aleksandra Ćurčić, Marijana Đukić-Ćosić, Danijela Toxicol Appl Pharmacol Article Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are “old”, their pharmacological and toxicological profile in SARS-CoV-2 – infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders. Elsevier Inc. 2020-11-01 2020-09-11 /pmc/articles/PMC7483129/ /pubmed/32920000 http://dx.doi.org/10.1016/j.taap.2020.115237 Text en © 2020 Elsevier Inc. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Baralić, Katarina
Jorgovanović, Dragica
Živančević, Katarina
Antonijević Miljaković, Evica
Antonijević, Biljana
Buha Djordjevic, Aleksandra
Ćurčić, Marijana
Đukić-Ćosić, Danijela
Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title_full Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title_fullStr Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title_full_unstemmed Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title_short Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach
title_sort safety assessment of drug combinations used in covid-19 treatment: in silico toxicogenomic data-mining approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483129/
https://www.ncbi.nlm.nih.gov/pubmed/32920000
http://dx.doi.org/10.1016/j.taap.2020.115237
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