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1.
Viruses ; 13(12)2021 11 27.
Article in English | MEDLINE | ID: covidwho-1574265

ABSTRACT

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.


Subject(s)
Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Virus Diseases/metabolism , Viruses/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Immunity, Innate , Inflammation , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/antagonists & inhibitors , Virus Diseases/drug therapy , Virus Diseases/immunology , Viruses/classification , Viruses/drug effects
2.
Expert Rev Anti Infect Ther ; 20(3): 425-434, 2022 03.
Article in English | MEDLINE | ID: covidwho-1429083

ABSTRACT

BACKGROUND: Currently, JAK-inhibitors are repurposed for therapy of Covid-19 because of their ability in restraining immune response, yet the corroboration regarding their advantage is still unclear. This study sought to analyze the efficacy of JAK-inhibitors to ameliorate the outcomes of Covid-19 sufferer.Research design and methods: Using specific keywords, we comprehensively go through the potential articles on ClinicalTrials.gov, Europe PMC, and PubMed sources until June 2nd, 2021. All published studies on JAK-inhibitors and Covid-19 were collected. RESULTS: There were 14 studies with 4,363 Covid-19 patients contained in the meta-analysis. Based on our data, we suggested that JAK-inhibitors corresponded with increased recovery rate (RR 1.17; 95%CI: 1.01-1.36, p= 0.040, I2 = 91%, random-effect modeling); shortened time to recovery (mean difference -0.96; 95%CI: -1.15, -0.77, p< 0.00001, I2 = 28%, random-effect modeling); reduction of clinical deterioration risk (RR 0.66; 95%CI: 0.48-0.89, p= 0.008, I2 = 57%, random-effect modeling); and reduction of Covid-19 mortality (RR 0.52; 95%CI: 0.36-0.76, p= 0.0006, I2 = 33%, random-effect modeling). CONCLUSIONS: This study propose that JAK-inhibitors perhaps provide advantageous effects on Covid-19 outcomes. JAK-inhibitors may be given during 1-2 weeks of disease to optimize its beneficial effects in halting the exaggerated immune response.


Subject(s)
COVID-19 , Janus Kinase Inhibitors , COVID-19/drug therapy , Europe , Humans , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Janus Kinases , SARS-CoV-2
3.
Indian J Pharmacol ; 53(3): 226-228, 2021.
Article in English | MEDLINE | ID: covidwho-1282691

ABSTRACT

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/pharmacology , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , COVID-19/epidemiology , COVID-19/immunology , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/immunology , Disease Progression , Drug Resistance, Viral , Humans , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukins/antagonists & inhibitors , Interleukins/immunology , Janus Kinase Inhibitors/pharmacology , Recurrence
4.
Commun Biol ; 4(1): 654, 2021 06 02.
Article in English | MEDLINE | ID: covidwho-1253994

ABSTRACT

SARS-CoV-2 infection of human airway epithelium activates genetic programs leading to progressive hyperinflammation in COVID-19 patients. Here, we report on transcriptomes activated in primary airway cells by interferons and their suppression by Janus kinase (JAK) inhibitors. Deciphering the regulation of the angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, is paramount for understanding the cell tropism of SARS-CoV-2 infection. ChIP-seq for activating histone marks and Pol II loading identified candidate enhancer elements controlling the ACE2 locus, including the intronic dACE2 promoter. Employing RNA-seq, we demonstrate that interferons activate expression of dACE2 and, to a lesser extent, the genuine ACE2 gene. Interferon-induced gene expression was mitigated by the JAK inhibitors baricitinib and ruxolitinib, used therapeutically in COVID-19 patients. Through integrating RNA-seq and ChIP-seq data we provide an in-depth understanding of genetic programs activated by interferons, and our study highlights JAK inhibitors as suitable tools to suppress these in bronchial cells.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , Interferons/pharmacology , Janus Kinase Inhibitors/pharmacology , Transcriptional Activation/drug effects , COVID-19/genetics , Cell Line , Humans , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Transcriptome/drug effects
5.
J Clin Pharmacol ; 61(10): 1274-1285, 2021 10.
Article in English | MEDLINE | ID: covidwho-1192122

ABSTRACT

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Azetidines/pharmacology , COVID-19 , Inflammation/drug therapy , Purines/pharmacology , Pyrazoles/pharmacology , Sulfonamides/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Humans , Janus Kinase Inhibitors/pharmacology , Risk Assessment , SARS-CoV-2 , Treatment Outcome
6.
Food Chem Toxicol ; 150: 112087, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1188569

ABSTRACT

Coronavirus disease-19 (COVID-19) is a complex disease that causes illness ranging from mild to severe respiratory problems. It is caused by a novel coronavirus SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2) that is an enveloped positive-sense single-stranded RNA (+ssRNA) virus belongs to coronavirus CoV family. It has a fast-spreading potential worldwide, which leads to high mortality regardless of lows death rates. Now some vaccines or a specific drug are approved but not available for every country for disease prevention and/or treatment. Therefore, it is a high demand to identify the known drugs and test them as a possible therapeutic approach. In this critical situation, one or more of these drugs may represent the only option to treat or reduce the severity of the disease, until some specific drugs or vaccines will be developed and/or approved for everyone in this pandemic. In this updated review, the available repurpose immunotherapeutic treatment strategies are highlighted, elucidating the crosstalk between the immune system and SARS-CoV-2. Despite the reasonable data availability, the effectiveness and safety of these drugs against SARS-CoV-2 needs further studies and validations aiming for a better clinical outcome.


Subject(s)
Antiviral Agents/pharmacology , Inflammation/etiology , SARS-CoV-2/drug effects , Adrenal Cortex Hormones/pharmacology , Adrenal Cortex Hormones/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/immunology , Interferons/pharmacology , Interferons/therapeutic use , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , SARS-CoV-2/immunology
9.
Leukemia ; 35(4): 1121-1133, 2021 04.
Article in English | MEDLINE | ID: covidwho-725732

ABSTRACT

Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , Compassionate Use Trials , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , Aged , Aged, 80 and over , Biomarkers , COVID-19/diagnosis , COVID-19/metabolism , Combined Modality Therapy , Comorbidity , Female , Humans , Janus Kinase Inhibitors/pharmacology , Male , Middle Aged , Nitriles , Prospective Studies , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , Severity of Illness Index , Treatment Outcome , Viral Load
10.
Acta Haematol ; 144(3): 314-318, 2021.
Article in English | MEDLINE | ID: covidwho-691035

ABSTRACT

COVID-19 has rapidly become a major concern for the health systems worldwide. Its high contagiousness and associated mortality demand the discovery of helpful interventions with promising safety profile. Here, we report 3 severe COVID-19 cases, which achieved rapid and sustained improvement in outcome with the use of ruxolitinib, a JAK/STAT pathway inhibitor.


Subject(s)
COVID-19/pathology , Hematologic Diseases/drug therapy , Janus Kinase Inhibitors/therapeutic use , Adult , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/virology , Ferritins/analysis , Fibrin Fibrinogen Degradation Products/analysis , Hematologic Diseases/etiology , Humans , Janus Kinase Inhibitors/pharmacology , Male , Middle Aged , Nitriles , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Pyrimidines , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , Thorax/diagnostic imaging , Tomography, X-Ray Computed
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