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Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach.
Toxicol Appl Pharmacol. 2020 11 01; 406:115237.TA

Abstract

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.

Authors+Show Affiliations

Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: katarinab@pharmacy.bg.ac.rs.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: evica.antonijevic@pharmacy.bg.ac.rs.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: biljana.antonijevic@pharmacy.bg.ac.rs.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: aleksandra.buha@pharmacy.bg.ac.rs.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: marijana.curcic@pharmacy.bg.ac.rs.Department of Toxicology "Akademik Danilo Soldatović", Center for Toxicological Risk Assessment, University of Belgrade - Faculty of Pharmacy, Serbia. Electronic address: danijela.djukic.cosic@pharmacy.bg.ac.rs.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32920000

Citation

Baralić, Katarina, et al. "Safety Assessment of Drug Combinations Used in COVID-19 Treatment: in Silico Toxicogenomic Data-mining Approach." Toxicology and Applied Pharmacology, vol. 406, 2020, p. 115237.
Baralić K, Jorgovanović D, Živančević K, et al. Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach. Toxicol Appl Pharmacol. 2020;406:115237.
Baralić, K., Jorgovanović, D., Živančević, K., Antonijević Miljaković, E., Antonijević, B., Buha Djordjevic, A., Ćurčić, M., & Đukić-Ćosić, D. (2020). Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach. Toxicology and Applied Pharmacology, 406, 115237. https://doi.org/10.1016/j.taap.2020.115237
Baralić K, et al. Safety Assessment of Drug Combinations Used in COVID-19 Treatment: in Silico Toxicogenomic Data-mining Approach. Toxicol Appl Pharmacol. 2020 11 1;406:115237. PubMed PMID: 32920000.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach. AU - Baralić,Katarina, AU - Jorgovanović,Dragica, AU - Živančević,Katarina, AU - Antonijević Miljaković,Evica, AU - Antonijević,Biljana, AU - Buha Djordjevic,Aleksandra, AU - Ćurčić,Marijana, AU - Đukić-Ćosić,Danijela, Y1 - 2020/09/11/ PY - 2020/05/18/received PY - 2020/07/11/revised PY - 2020/09/08/accepted PY - 2020/9/14/pubmed PY - 2020/10/21/medline PY - 2020/9/13/entrez KW - Anti-COVID-19 Therapy KW - Azithromycin KW - Chloroquine KW - Lopinavir KW - Ritonavir KW - in silico Approach SP - 115237 EP - 115237 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 406 N2 - 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. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/32920000/Safety_assessment_of_drug_combinations_used_in_COVID_19_treatment:_in_silico_toxicogenomic_data_mining_approach_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(20)30363-X DB - PRIME DP - Unbound Medicine ER -