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

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.

An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease

“…On the other hand, some of the drugs, like Lopinavir, induced CCL2 mRNA expression and protein secretion, CCL3 protein expression, IL1B mRNA expression, IL6 protein expression and secretion. Similarly, Atazanavir increased CCL2 and CCL3 protein expression, while Ritonavir increased IL6 mRNA expression, protein expression and secretion, CCL2 protein expression and secretion, as well as CCL3 protein expression [89] . Conclusively, several identified drugs (lopinavir, ritonavir, atazanavir) may increase secretion of pro‐inflammatory cytokines, which might aggravate cytokine storm.…”

Construction of an autophagy interaction network based on competitive endogenous RNA reveals the key pathways and central genes of SARS-CoV-2 infection in vivo

“…As BCL2L1 is the most important hub gene in the autophagy interaction network, the importance of BCL2L1 was further highlighted in this study. Baralić et al evaluated the safety of drug combinations for COVID-19 treatment using an in silico toxicogenomic data-mining approach, and found that the drug combination of chloroquine and azithromycin affected the expression of BCL2L1 in vivo [ 37 ]. Moreover, Liu et al reported that matrine could reduce COVID-19 with liver damage by increasing the expression of BCL2L1 [ 38 ].…”

Mechanisms of Damage to the Cardiovascular System in COVID-19

“…В другом исследовании была оценена безопасность комбинаций лекарственных препаратов, используемых для лечения COVID-19 [75], методом сбора токсикогеномных данных, чтобы понять профиль безопасности двух выбранных стратегий лечения COVID-19: ритонавир/лопинавир и хлорохин/гидроксихлорохин + азитромицин. Использовались доступные базы данных, предсказавшие молекулярные механизмы побочных реакций.…”