Metronidazole, acyclovir and tetrahydrobiopterin may be promising to treat COVID-19 patients, through interaction with interleukin-12.

COVID-19 patients have shown overexpressed serum levels of several pro-inflammatory cytokines, leading to a high mortality rate due to numerous complications. Also, previous studies demonstrated that the metronidazole (MTZ) administration reduced pro-inflammatory cytokines and improved the treatment outcomes for inflammatory disorders. However, the effect and mechanism of action of MTZ on cytokines have not been studied yet. Thus, the current study aimed to identify anti-cytokine therapeutics for the treatment of COVID-19 patients with cytokine storm. The interaction of MTZ with key cytokines was investigated using molecular docking studies. MTZ-analogues, and its structurally similar FDA-approved drugs were also virtually screened against interleukin-12 (IL-12). Moreover, their mechanism of inhibition regarding IL-12 binding to IL-12 receptor was investigated by measuring the change in volume and area. IL-12-metronidazole complex is found to be more stable than all other cytokines under study. Our study also revealed that the active sites of IL-12 are inhibited from binding to its target, IL-12 receptor, by modifying the position of the methyl and hydroxyl functional groups in MTZ. Three MTZ analogues, metronidazole phosphate, metronidazole benzoate, 1-[1-(2-Hydroxyethyl)-5-nitroimidazol-2-yl]-N-methylmethanimine-oxide, and two FDA-approved drugs acyclovir (ACV), and tetrahydrobiopterin (THB) were also found to prevent binding of IL-12 to IL-12 receptor similar to MTZ by changing the surface and volume of IL-12 upon IL-12-drug/ligand complex formation. According to the RMSD results, after 100 ns MD simulations of human IL-12-MTZ/ACV/THB drug complexes, it was also observed that each complex was swinging within a few Å compared to their corresponding docking poses, indicating that the docking poses were reliable. The current study demonstrates that three FDA-approved drugs, namely, metronidazole, acyclovir and tetrahydrobiopterin, are potential repurposable treatment options for overexpressed serum cytokines found in COVID-19 patients. Similar approach is also useful to develop therapeutics against other human disorders.

Antiviral and anti-inflammatory therapies in COVID-19 / Antivirális és gyulladásellenes kezelési lehetoségek COVID-19-ben.

Összefoglaló. Az új típusú koronavírus-fertozés (COVID-19) nagy terhet ró az egészségügyi ellátórendszerre és a társadalomra. A betegségnek három nagy szakasza van, melyek alapvetoen meghatározzák a kezelést. Az I-IIA fázisban az antivirális, míg a IIB-III. fázisban a gyulladásgátló kezelés áll elotérben, melyhez intenzív terápiás, szupportív kezelés csatlakozik. A jelen ajánlás kizárólag a gyógyszeres kezelésre vonatkozik, és a rendelkezésre álló bizonyítékok alapján foglalja össze a terápiás lehetoségeket. Emellett egy javasolt kezelési algoritmust is tartalmaz. Orv Hetil. 2021; 162(17): 643-651. Summary. The novel coronavirus infection (COVID-19) places a heavy burden on the health care system and our society. There are three major stages in the disease that fundamentally determine treatment approaches. Phases I-IIA require primarily antiviral treatment. In phases IIB-III, anti-inflammatory treatment is needed accompanied by intensive and supportive care. This recommendation applies only to pharmacotherapy and summarizes the therapeutic options based on the available evidence. It also includes a proposed treatment algorithm. Orv Hetil. 2021; 162(17): 643-651.

New Decade, Old Debate: Blocking the Cytokine Pathways in Infection-Induced Cytokine Cascade.

OBJECTIVES: Our understanding of the immunopathogenesis of coronavirus disease 2019 is evolving; however, a "cytokine storm" has been implicated. Ongoing clinical trials are evaluating the value of anticytokine therapies to treat patients with coronavirus disease 2019. This review summarizes the existing literature evaluating the efficacy and safety of anticytokine therapy to tackle the dysregulated immune response to infectious pathogens, discusses potential reasons for failure, applicability to coronavirus disease 2019, and future direction. DATA SOURCES: Medline, PubMed, ClinicalTrials.gov, and media reports. STUDY SELECTION: The studies were included by author consensus. DATA EXTRACTION: Data were selected for inclusion after reviewing each study by author consensus. DATA SYNTHESIS: "Cytokine storm" is a nonspecific term, encompassing systemic inflammatory response to infectious pathogens, autoimmune conditions, cancers, trauma, and various chemotherapies. Like bacterial sepsis, viral pathogens may fuel immunopathogenesis by inducing a dysregulated autoamplifying cytokine cascade, ultimately leading to organ injury. This narrative review discusses what we know of the immune milieu of coronavirus disease 2019 versus noncoronavirus disease 2019 sepsis and/or acute respiratory distress syndrome, summarizes the existing literature on cytokine inhibitors in patients with sepsis and/or acute respiratory distress syndrome, and discusses possible reasons for recurrent failure. In doing so, it aims to assist decisions regarding the use of anticytokine therapy in patients with coronavirus disease 2019, as many regions of the world confront the second wave of the pandemic. CONCLUSIONS: As ongoing clinical trials determine the efficacy and safety of anticytokine therapy in patients with coronavirus disease 2019, clinicians should uphold caution when incorporating it into treatment protocols, while maintaining focus on established evidence-based practices and the mantra of "less is more."