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1.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1801319

ABSTRACT

Remdesivir and Baricitinib have recently been approved by FDA for the treatment of moderate to severe COVID-19 pneumonia. However, there is limited research work available to assess their beneficial effects. MATERIAL: We conducted retrospective study comparing remdesivir and baricitinib-remdesivir combination therapy in hospitalized adults with moderate to severe Covid-19. All the patients received remdesivir for 5 days and one subgroup had received baricitinib (≤14 days) along with remdesivir. The decision to administer remdesivir only or remdesivir along with baricitinib was the treating clinician's discretion. The primary outcome was to assess the 28-day mortality. OBSERVATION: A total of 50 patients with moderate or severe COVID-19 pneumonia had received either remdesivir alone or both remdesivir and baricinitib during the duration of 1st April 2021 to 30th June 2021in our hospital. The 28-day mortality was 9.091% in the combination group and 14.29% in the remdesivir only group (risk difference= -5.195%, risk ratio for death=0.3634; 95% CI, 0.1281, 3.161; p=0. 0.3086). Patients who had a FiO2 requirement of 100% at any point of time had 100% mortality, irrespective of the drug received. CONCLUSION: Baricitinib and remdesivir combination was superior to remdesivir alone in reducing 28-day mortality among patients with moderate to severe Covid-19, although this difference was statistically insignificant.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Azetidines , COVID-19/drug therapy , Humans , Purines , Pyrazoles , Retrospective Studies , SARS-CoV-2 , Sulfonamides
2.
Clin Immunol ; 238: 109016, 2022 05.
Article in English | MEDLINE | ID: covidwho-1797060

ABSTRACT

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Deoxyribonucleases , Respiratory Insufficiency , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/therapeutic use , COVID-19/drug therapy , Deoxyribonucleases/therapeutic use , Humans , Purines/therapeutic use , Pyrazoles/therapeutic use , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , SARS-CoV-2 , Sulfonamides/therapeutic use , Treatment Outcome
3.
Medicina (Kaunas) ; 58(4)2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1776285

ABSTRACT

Background and Objectives: Tocilizumab and baricitinib have been observed to improve the outcomes of patients with coronavirus disease 2019 (COVID-19). However, a comparative evaluation of these drugs has not been performed. Materials and Methods: A retrospective, single-center study was conducted using the data of COVID-19 patients admitted to Hokkaido University hospital between April 2020 and September 2021, who were treated with tocilizumab or baricitinib. The clinical characteristics of the patients who received tocilizumab were compared to those of patients who received baricitinib. Univariate and multivariate logistic regression analyses of the outcomes of all-cause mortality and improvement in respiratory status were performed. The development of secondary infection events was analyzed using the Kaplan-Meier method and the log-rank test. Results: Of the 459 patients hospitalized with COVID-19 during the study, 64 received tocilizumab treatment and 34 baricitinib treatment, and those 98 patients were included in the study. Most patients were treated with concomitant steroids and exhibited the same severity level at the initiation of drug treatment. When compared to each other, neither tocilizumab nor baricitinib use were associated with all-cause mortality or improvement in respiratory status within 28 days from drug administration. Conclusions: Age, chronic renal disease and early administration of TCZ or BRT from the onset of COVID-19 were independent prognostic factors for all-cause mortality, whereas anti-viral drug use and the severity of COVID-19 at baseline were associated with an improvement in respiratory status. Secondary infection-free survival rates of patients treated with tocilizumab and those treated with baricitinib did not significantly differ. The results suggest that both tocilizumab and baricitinib could be clinically equivalent agents of choice in treatment of COVID-19.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , Azetidines , COVID-19/drug therapy , Humans , Purines , Pyrazoles , Retrospective Studies , Sulfonamides , Treatment Outcome
5.
J Org Chem ; 87(6): 3922-3933, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1768760

ABSTRACT

A series of tricyclic and polycyclic pyrido[1,2-e]purine derivatives were designed and synthesized via a two-step, one-pot reaction of 2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various derivatives of pyrido[1,2-e]purine were also synthesized by substituting the chlorine atom with secondary amines. After careful physiochemical and pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular dynamics approaches. The in silico results revealed that among all of the studied compounds, the morpholine/piperidine-substituted pyrido[1,2-e]purine derivatives are the best candidates as effective inhibitors of SARS-CoV-2.


Subject(s)
COVID-19 , Peptide Hydrolases , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , Purines , SARS-CoV-2
7.
Respir Investig ; 60(3): 418-424, 2022 May.
Article in English | MEDLINE | ID: covidwho-1751178

ABSTRACT

In this retrospective cohort study, we evaluated the efficacy of baricitinib in the treatment of coronavirus disease 2019 (COVID-19). Among 404 adult patients with COVID-19 who were admitted to our hospital between October 23, 2020, and July 31, 2021, 229 patients with respiratory failure were included. Among these, 41 patients in the baricitinib group and 41 patients in the control group were selected by propensity score matching to adjust for background factors. We compared the survival rates of the two groups at 30 and 60 days after admission. The 30-day survival rate was significantly higher in the baricitinib group than in the control group. However, there was no significant difference in 60-day survival in the two groups. Baricitinib may improve the early prognosis of patients with respiratory failure associated with COVID-19. However, efforts should be made to improve the long-term prognosis.


Subject(s)
COVID-19 , Respiratory Insufficiency , Adult , Azetidines , COVID-19/complications , COVID-19/drug therapy , Humans , Propensity Score , Purines , Pyrazoles , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/etiology , Retrospective Studies , SARS-CoV-2 , Sulfonamides
8.
J Labelled Comp Radiopharm ; 65(6): 156-161, 2022 May 30.
Article in English | MEDLINE | ID: covidwho-1739180

ABSTRACT

Baricitinib, typically applied as a treatment for rheumatoid arthritis, has recently attracted the attention of clinicians and researchers as a potential treatment for COVID-19. Naturally, there has been a need for the preparation of the isotope-labelled analogue of baricitinib to probe the pharmacokinetics of baricitinib in this new role. As such, we have developed a simple synthetic route to deuterated [2 H5 ]baricitinib, facilitating its formation over four steps and in a 29% overall yield based on starting [2 H5 ]ethanethiol (19% if we start with [2 H5 ]bromoethane instead). A critical component of the overall process involves the synthesis of [2 H5 ]ethanesulfonyl chloride, and we describe in detail the two routes that were explored to optimize this step.


Subject(s)
Azetidines , COVID-19 , Azetidines/pharmacokinetics , COVID-19/drug therapy , Chlorides , Humans , Purines , Pyrazoles , Sulfonamides
9.
Nutrients ; 12(6)2020 Jun 10.
Article in English | MEDLINE | ID: covidwho-1725886

ABSTRACT

Infection caused by the SARS-CoV-2 coronavirus worldwide has led the World Health Organization to declare a COVID-19 pandemic. Because there is no cure or treatment for this virus, it is emergingly urgent to find effective and validated methods to prevent and treat COVID-19 infection. In this context, alternatives related to nutritional therapy might help to control the infection. This narrative review proposes the importance and role of probiotics and diet as adjunct alternatives among the therapies available for the treatment of this new coronavirus. This review discusses the relationship between intestinal purine metabolism and the use of Lactobacillus gasseri and low-purine diets, particularly in individuals with hyperuricemia, as adjuvant nutritional therapies to improve the immune system and weaken viral replication, assisting in the treatment of COVID-19. These might be promising alternatives, in addition to many others that involve adequate intake of vitamins, minerals and bioactive compounds from food.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/therapy , Diet/methods , Immunomodulation/physiology , Pneumonia, Viral/therapy , Probiotics/therapeutic use , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/microbiology , Humans , Lactobacillus gasseri/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/microbiology , Purines/immunology , Purines/metabolism , SARS-CoV-2 , Virus Replication/immunology
12.
Lancet Respir Med ; 10(4): 327-336, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1665591

ABSTRACT

BACKGROUND: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation. METHODS: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups. INTERPRETATION: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings. FUNDING: Eli Lilly and Company.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Adolescent , Adult , Azetidines , COVID-19/drug therapy , Critical Illness , Double-Blind Method , Humans , Purines , Pyrazoles , Respiration, Artificial , SARS-CoV-2 , Standard of Care , Sulfonamides , Treatment Outcome
13.
Nat Med ; 28(1): 39-50, 2022 01.
Article in English | MEDLINE | ID: covidwho-1641982

ABSTRACT

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/therapy , Complement Inactivating Agents/therapeutic use , Glucocorticoids/therapeutic use , Immunologic Factors/therapeutic use , Immunomodulation , Protein Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Azetidines/therapeutic use , Bradykinin/analogs & derivatives , Bradykinin/therapeutic use , Bradykinin B2 Receptor Antagonists/therapeutic use , COVID-19/immunology , Dexamethasone/therapeutic use , Drug Combinations , Factor Xa Inhibitors/therapeutic use , Heparin/therapeutic use , Humans , Hydrocortisone/therapeutic use , Imatinib Mesylate/therapeutic use , Immunization, Passive , Interferon beta-1a/therapeutic use , Interferon beta-1b/therapeutic use , Interferon-gamma/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Kallikrein-Kinin System , Piperidines/therapeutic use , Purines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , SARS-CoV-2 , Sulfonamides/therapeutic use
14.
Mol Cell Biochem ; 477(3): 711-726, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1616202

ABSTRACT

The novel coronavirus pandemic has emerged as one of the significant medical-health challenges of the current century. The World Health Organization has named this new virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first detection of SARS-CoV-2 in November 2019 in Wuhan, China, physicians, researchers, and others have made it their top priority to find drugs and cures that can effectively treat patients and reduce mortality rates. The symptoms of Coronavirus Disease 2019 (COVID-19) include fever, dry cough, body aches, and anosmia. Various therapeutic compounds have been investigated and applied to mitigate the symptoms in COVID-19 patients and cure the disease. Degenerative virus analyses of the infection incidence and COVID-19 have demonstrated that SARS-CoV-2 penetrates the pulmonary alveoli's endothelial cells through Angiotensin-Converting Enzyme 2 (ACE2) receptors on the membrane, stimulates various signaling pathways and causes excessive secretion of cytokines. The continuous triggering of the innate and acquired immune system, as well as the overproduction of pro-inflammatory factors, cause a severe condition in the COVID-19 patients, which is called "cytokine storm". It can lead to acute respiratory distress syndrome (ARDS) in critical patients. Severe and critical COVID-19 cases demand oxygen therapy and mechanical ventilator support. Various drugs, including immunomodulatory and immunosuppressive agents (e.g., monoclonal antibodies (mAbs) and interleukin antagonists) have been utilized in clinical trials. However, the studies and clinical trials have documented diverging findings, which seem to be due to the differences in these drugs' possible mechanisms of action. These drugs' mechanism of action generally includes suppressing or modulating the immune system, preventing the development of cytokine storm via various signaling pathways, and enhancing the blood vessels' diameter in the lungs. In this review article, multiple medications from different drug families are discussed, and their possible mechanisms of action are also described.


Subject(s)
Antiviral Agents/immunology , COVID-19/drug therapy , /pharmacology , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antiviral Agents/pharmacology , Azetidines/immunology , Azetidines/pharmacology , COVID-19/etiology , Dexamethasone/immunology , Dexamethasone/pharmacology , Famotidine/immunology , Famotidine/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/immunology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Infliximab/immunology , Infliximab/pharmacology , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Melatonin/immunology , Melatonin/pharmacology , Purines/immunology , Purines/pharmacology , Pyrazoles/immunology , Pyrazoles/pharmacology , Sulfonamides/immunology , Sulfonamides/pharmacology
16.
J Allergy Clin Immunol ; 149(2): 569-578, 2022 02.
Article in English | MEDLINE | ID: covidwho-1587444

ABSTRACT

Our understanding of risk factors and interventions influencing outcomes from coronavirus disease 2019 (COVID-19) has continued to evolve, revealing advances emerging from hypotheses formed at the start of the pandemic. Epidemiologic studies have shown that asthma control, rather than a diagnosis of asthma, is a determinant of COVID-19 severity. Clinical outcomes in patients with primary immunodeficiencies, even in those with impaired cellular immunity, are variable. IL-6 has emerged as a reliable biomarker of COVID-19 severity, and large clinical trials have shown the potential for improving outcomes through inhibition of IL-6 signaling in some patients. Studies of genetic risk factors for severe COVID-19 have also revealed the importance of interferon homeostasis in the defense against severe acute respiratory syndrome coronavirus 2. Because COVID-19 vaccines constitute the primary tool for ending this pandemic, strategies have been developed to address potential allergic and immune-mediated reactions. Here, we discuss advances in our understanding of COVID-19 risk factors and outcomes within the context of allergic and immunologic mechanisms.


Subject(s)
Antiviral Agents/therapeutic use , Asthma/therapy , Biological Products/therapeutic use , COVID-19/therapy , Immunologic Deficiency Syndromes/therapy , SARS-CoV-2/drug effects , Antibodies, Monoclonal/therapeutic use , Asthma/immunology , Asthma/mortality , Asthma/virology , Azetidines/therapeutic use , Biomarkers/metabolism , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/mortality , Immunologic Deficiency Syndromes/virology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/immunology , Prognosis , Purines/therapeutic use , Pyrazoles/therapeutic use , Risk Factors , SARS-CoV-2/pathogenicity , Sulfonamides/therapeutic use , Survival Analysis , Treatment Outcome
17.
Molecules ; 27(1)2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1580565

ABSTRACT

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.


Subject(s)
Azetidines/pharmacokinetics , Drug Carriers/chemistry , Drug Liberation , Liposomes/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Purines/pharmacokinetics , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Male , Purines/administration & dosage , Purines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Wistar , Sulfonamides/administration & dosage , Sulfonamides/chemistry
18.
Infection ; 50(2): 295-308, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1568416

ABSTRACT

PURPOSE: The Coronavirus disease 2019 (COVID-19) pandemic is one of the most devastating global problems. Regarding the lack of disease-specific treatments, repurposing drug therapy is currently considered a promising therapeutic approach in pandemic situations. Recently, the combination therapy of Janus kinase (JAK) inhibitor baricitinib has been authorized for emergency COVID-19 hospitalized patients; however, this strategy's safety, drug-drug interactions, and cellular signaling pathways remain a tremendous challenge. METHODS: In this study, we aimed to provide a deep insight into the baricitinib combination therapies in severe COVID-19 patients through reviewing the published literature on PubMed, Scopus, and Google scholar databases. We also focused on cellular and subcellular pathways related to the synergistic effects of baricitinib plus antiviral agents, virus entry, and cytokine storm (CS) induction. The safety and effectiveness of this strategy have also been discussed in moderate to severe forms of COVID-19 infection. RESULTS: The severity of COVID-19 is commonly associated with a dysregulated immune response and excessive release of pro-inflammatory agents, resulting in CS. It has been shown that baricitinib combined with antiviral agents could modulate the inflammatory response and provide a series of positive therapeutic outcomes in hospitalized adults and pediatric patients (age ≥ two years old). CONCLUSION: Baricitinib plus the standard of care treatment might be a potential strategy in hospitalized patients with severe COVID-19.


Subject(s)
COVID-19 , Janus Kinase Inhibitors , Adult , Azetidines , COVID-19/drug therapy , Child , Child, Preschool , Humans , Janus Kinase Inhibitors/therapeutic use , Purines , Pyrazoles , SARS-CoV-2 , Sulfonamides
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