Subject(s)
Azetidines , COVID-19 Drug Treatment , Humans , Purines , Pyrazoles , SARS-CoV-2 , SulfonamidesABSTRACT
A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.
Subject(s)
Azetidines/pharmacology , Azetidines/therapeutic use , Coronavirus Infections/complications , Inflammation/drug therapy , Inflammation/etiology , Janus Kinases/antagonists & inhibitors , Pneumonia, Viral/complications , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Area Under Curve , Azetidines/administration & dosage , Azetidines/adverse effects , Betacoronavirus , COVID-19 , Clinical Trials as Topic , Cytokines/metabolism , Drug Interactions , Humans , Interferon Type I/biosynthesis , Metabolic Clearance Rate , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Purines , Pyrazoles , SARS-CoV-2 , Signal Transduction/drug effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effectsABSTRACT
The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic ß-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.