Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(2), P. 451 - 463

Published: Jan. 16, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve globally dominant subvariants. Here we compared their replication cell lines and primary airway cultures measured host responses infection. We discovered that subvariants BA.4 BA.5 have improved suppression innate immunity when earlier BA.1 BA.2. Similarly, more recent (BA.2.75 XBB lineages) also triggered reduced immune activation. This correlated increased expression viral antagonists Orf6 nucleocapsid, reminiscent VOCs Alpha Delta. Increased levels suppressed infection by decreasing IRF3 STAT1 signalling transcription factor phosphorylation nuclear translocation. Our data suggest convergent evolution antagonist a common pathway link subvariant dominance evasion.

Language: Английский

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DrugCentral 2023 extends human clinical data and integrates veterinary drugs

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1276 - D1287

Published: Dec. 3, 2022

DrugCentral monitors new drug approvals and standardizes information. The current update contains 285 drugs (131 for human use). New additions include: (i) the integration of veterinary (154 animal use only), (ii) addition 66 documented off-label uses iii) identification adverse events from pharmacovigilance data pediatric geriatric patients. Additional enhancements include chemical substructure searching using SMILES 'Target Cards' based on UniProt accession codes. Statistics interests following: 60% covered are on-market with expired patent exclusivity coverage, 17% off-market, 23% active patents coverage; 59% oral, 33% parenteral 18% topical, at level ingredients; (iii) only 3% all only; however, 61% also approved use; (iv) dogs, cats horses by far most represented target species drugs; (v) physicochemical property profile is very similar to that drugs. Use cases azaperone, sedative swine, ruxolitinib, a Janus kinase inhibitor.

Language: Английский

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Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

Critical Care, Journal Year: 2023, Volume and Issue: 27(1)

Published: Jan. 10, 2023

Abstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients COVID-19 were randomised 4 mg once daily or placebo, added standard of care. The primary endpoint was all-cause mortality within 60 days. Participants remotely followed day 90 safety and patient related outcome measures. Results Two hundred ninety-nine screened, 284 275 received study drug placebo included the modified intent-to-treat analyses (139 receiving baricitinib 136 placebo). Median age (IQR 49–69) years, 77% male 35% had at least one dose SARS-CoV2 vaccine. There 21 deaths each group, 15.1% group 15.4% (adjusted absolute difference 95% CI − 0.1% [− 8·3 8·0]). In sensitivity analysis censoring observations after discontinuation rescue therapy (tocilizumab/increased steroid dose), proportions death 5.8% versus 8.8% (− 3.2% 9.0 2.7]), respectively. 148 serious adverse events 46 (33.1%) 155 51 (37.5%) placebo. subgroup analyses, there potential interaction between vaccination status treatment allocation 60-day mortality. subsequent post hoc significant occurrence events, more respiratory complications severe infections treated baricitinib. Vaccinated average 11 years older, comorbidities. Conclusion This clinical trial evidence therefore underpowered conclude survival benefit COVID-19. We observed possible signal participants, who older Although based post-hoc analysis, these findings warrant further investigation other real-world studies. Trial registration registered NCT04891133 (registered May 18, 2021) EUClinicalTrials.eu ( 2022-500385-99-00 ).

Language: Английский

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COVID-19-Related ARDS: Key Mechanistic Features and Treatments

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(16), P. 4896 - 4896

Published: Aug. 20, 2022

Acute respiratory distress syndrome (ARDS) is a heterogeneous historically characterized by the presence of severe hypoxemia, high-permeability pulmonary edema manifesting as diffuse alveolar infiltrate on chest radiograph, and reduced compliance integrated system result widespread compressive atelectasis fluid-filled alveoli. Coronavirus disease 19 (COVID-19)-associated ARDS (C-ARDS) novel etiology caused acute coronavirus 2 (SARS-CoV-2) that may present with distinct clinical features viral pathobiology unique to SARS-CoV-2. In particular, injury vascular endothelium, accompanied microthrombi in microcirculation, can lead presentation which severity impaired gas exchange becomes uncoupled from lung capacity mechanics. The purpose this review highlight key mechanistic C-ARDS discuss implications these have its treatment. some patients C-ARDS, rigid adherence guidelines derived trials pre-COVID era not be appropriate.

Language: Английский

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An important call: Suggestion of using IL-10 as therapeutic agent for COVID-19 with ARDS and other complications

Virulence, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 14, 2023

The global coronavirus disease 2019 (COVID-19) pandemic has a detrimental impact on public health. COVID-19 usually manifests as pneumonia, which can progress into acute respiratory distress syndrome (ARDS) related to uncontrolled TH17 immune reaction. Currently, there is no effective therapeutic agent manage with complications. currently available anti-viral drug remdesivir an effectiveness of 30% in SARS-CoV-2-induced severe Thus, need identify agents treat and the associated lung injury other host immunological pathway against this virus typically involves THαβ response. immunity triggered by type 1 interferon interleukin-27 (IL-27), main effector cells response are IL10-CD4 T cells, CD8 NK IgG1-producing B cells. In particular, IL-10 exerts potent immunomodulatory or anti-inflammatory effect anti-fibrotic for pulmonary fibrosis. Concurrently, ameliorate ARDS, especially those caused viruses. Owing its activity anti-pro-inflammatory effects, review, suggested possible treatment COVID-19.

Language: Английский

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Repurposing Drugs for the Treatment of COVID-19 and Its Cardiovascular Manifestations

Circulation Research, Journal Year: 2023, Volume and Issue: 132(10), P. 1374 - 1386

Published: May 11, 2023

COVID-19 is an infectious disease caused by SARS-CoV-2 leading to the ongoing global pandemic. Infected patients developed a range of respiratory symptoms, including failure, as well other extrapulmonary complications. Multiple comorbidities, hypertension, diabetes, cardiovascular diseases, and chronic kidney are associated with severity increased mortality COVID-19. infection also causes complications, myocarditis, myocardial injury, heart arrhythmias, acute coronary syndrome, venous thromboembolism. Although variety methods have been many clinical trials launched for drug repositioning COVID-19, treatments that consider manifestations comorbidities specifically limited. In this review, we summarize recent advances in experimental repositioning, high-throughput screening, omics data-based, network medicine-based computational particular attention on those We discuss prospective opportunities potential repurposing drugs treat complications

Language: Английский

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Future of the current anticoronaviral agents: A viewpoint on the validation for the next COVIDs and pandemics

Biocell, Journal Year: 2023, Volume and Issue: 47(10), P. 2133 - 2139

Published: Jan. 1, 2023

Despite the global decline in severity of coronavirus disease 2019 (COVID-19) cases, still represents a major concern to relevant scientific and medical communities. The primary drug scientists, virologists, other concerned specialists this respect is find ready-to-use suitable potent anticoronaviral therapies that are broadly effective against different species/strains coronaviruses general, not only current previous (e.g., recently-appeared severe acute respiratory syndrome 2 "SARS-CoV-2"), i.e., antiviral agents for treatment and/or prophylaxis any coronaviral infections, including those coming ones from next species strains (if any). As an expert field, I tried, up-to-date perspective "viewpoint" article, evaluate suitability applicability using currently-available diseases (COVIDs) pandemics, highlighting most important general guidelines should be considered pandemics therapeutic points view.

Language: Английский

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The AI-Assisted Identification and Clinical Efficacy of Baricitinib in the Treatment of COVID-19

Vaccines, Journal Year: 2022, Volume and Issue: 10(6), P. 951 - 951

Published: June 15, 2022

During the current pandemic, vast majority of COVID-19 patients experienced mild symptoms, but some had a potentially fatal aberrant hyperinflammatory immune reaction characterized by high levels IL-6 and other cytokines. Modulation this has proven to be only method reducing mortality in severe critical COVID-19. The anti-inflammatory drug baricitinib (Olumiant) recently been strongly recommended WHO for use because it reduces risk progressive disease death. It is Janus Kinase (JAK) 1/2 inhibitor approved rheumatoid arthritis which was suggested early 2020 as treatment In review AI-assisted identification baricitinib, its antiviral properties, efficacy clinical trials are discussed compared with those modulators including glucocorticoids, IL-1 receptor blockers JAK inhibitors. Baricitinib inhibits both virus infection cytokine signalling not important management “non-immunological”, so should remain effective if new SARS-CoV-2 variants escape control. repurposing an example how advanced artificial intelligence (AI) can quickly identify candidates that have benefit previously unsuspected therapeutic areas.

Language: Английский

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Baricitinib treatment for hospitalized patients with severe COVID-19 on invasive mechanical ventilation: a propensity score-matched and retrospective analysis

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 22, 2025

Introduction Baricitinib is a selective inhibitor of Janus kinase (JAK)1 and JAK2, which associated with clinical improvement in non-severe COVID-19 patients. But severe patients, the effectiveness baricitinib still controversial. Methods A propensity score-matched retrospective study was conducted to evaluate patients requiring invasive mechanical ventilation (IMV). Results total number 48 treated were included, assigned control group by score matching. The mean ages high both (baricitinib vs. group: 78.80 ± 9.04 82.57 9.27), most unvaccinated (62.5% 66.7%. had higher proportion hypertension (73.9% 45.5%, p = 0.006). Control level creatine kinase-myocardial band (247.50 104.50, 0.021). Patients more likely receive nirmatrelvir/ritonavir (39.6% 16.7%, 0.017) intravenous immunoglobin (14.6% 0, 0.007). significantly lower all-cause 28-days mortality than (72.9% 89.6%, 0.004). Conclusion present revealed reduced on IMV. treating IMV needs be further investigated through future studies.

Language: Английский

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Redefining the Greenness of Quantitative Analytical Methods for Drugs: A Case Study of a Multipurpose Novel Janus Kinase Inhibitor

Green Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 100210 - 100210

Published: Jan. 1, 2025

Language: Английский

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