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Trend of PO2/FiO2 ratio (black circles) and of respiratory rate (gray triangles) from baseline to day 15 of treatment. The larger effect of ruxolitinib was observed after 7 days of treatment
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Ruxolitinib is an anti‐inflammatory drug that inhibits the Janus kinase‐signal transducer (JAK‐STAT) pathway on the surface of immune cells. The potential targeting of this pathway using JAK inhibitors is a promising approach in patients affected by coronavirus disease 2019 (COVID‐19). Ruxolitinib was provided as a compassionate use in patients con...
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Background and aim:
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... Consecutively, the Janus kinase (JAK) 1/2 inhibitor baricitinib was approved for treatment of COVID-19 in 2021 [17,18]. Simultaneously, efficacy of ruxolitinib was tested in several stages of COVID-19 [19][20][21][22][23][24][25]. Ruxolitinib is a potent and selective inhibitor of Janus kinases (JAK) 1 and 2, with modest to marked selectivity against tyrosine kinase (TYK) 2 and JAK3, respectively. ...
... In a study on COVID-19 pneumonia, ruxolitinib appeared to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in a predefined 8-point ordinal scale and pro-inflammatory state [25]. Moreover, in a compassionate use program, ruxolitinib rapidly reduced the systemic inflammation, which accompanied COVID-19, thereby improving respiratory function and reducing the need of oxygen support [24]. Kelmenson and Cron defined the question of optimal timing of cytokine inhibition within the course of COVID-19 as crucial [14]. ...
Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2–31). On day 7, median CIS declined to 6 (range, 1–13); 71% of patients (CI 64–77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3–5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.
... A higher dose (20 mg bid in the first 48 h) in the early stage would improve clinical efficacy in reducing severe respiratory distress [118]. For those patients with no need for mechanical ventilation, compassionate use of Ruxolitinib (5 mg/twice daily) showed a significant reduction of inflammation biomarkers [119]. Initiating Ruxolitinib treatment immediately after respiratory symptoms begin to deteriorate, will achieve the best treatment result [118,120]. ...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic continues to spread globally. The rapid dispersion of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 drives an urgent need for effective treatments, especially for patients who develop severe pneumonia. The excessive and uncontrolled release of pro-inflammatory cytokines has proved to be an essential factor in the rapidity of disease progression, and some cytokines are significantly associated with adverse outcomes. Most of the upregulated cytokines signal through the Janus kinase–signal transducer and activator of transcription (JAK/STAT) pathway. Therefore, blocking the exaggerated release of cytokines, including IL-2, IL-6, TNF-α, and IFNα/β/γ, by inhibiting JAK/STAT signaling will, presumably, offer favorable pharmacodynamics and present an attractive prospect. JAK inhibitors (JAKi) can also inhibit members of the numb-associated kinase (NAK) family, including AP2-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK), which regulate the angiotensin-converting enzyme 2 (ACE-2) transmembrane protein and are involved in host viral endocytosis. According to the data released from current clinical trials, JAKi treatment can effectively control the dysregulated cytokine storm and improve clinical outcomes regarding mortality, ICU admission, and discharge. There are still some concerns surrounding thromboembolic events, opportunistic infection such as herpes zoster virus reactivation, and repression of the host’s type-I IFN-dependent immune repair for both viral and bacterial infection. However, the current JAKi clinical trials of COVID-19 raised no new safety concerns except a slightly increased risk of herpes virus infection. In the updated WHO guideline, Baricitinb is strongly recommended as an alternative to IL-6 receptor blockers, particularly in combination with corticosteroids, in patients with severe or critical COVID-19. Future studies will explore the application of JAKi to COVID-19 treatment in greater detail, such as the optimal timing and course of JAKi treatment, individualized medication strategies based on pharmacogenomics, and the effect of combined medications.
... The addition of baricitinib did not substantially reduce mortality in hospitalized patients with COVID-19. Combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function [62,63] 17 Baricitinib, ruxolitinib, tofacitinib JAK/STAT inhibitor Reduce excessive inflammation [64,65] Monoclonal antibodies against SARS-CoV-2 ...
Ever since it was first reported in Wuhan, China, the coronavirus-induced disease of 2019 (COVID-19) has become an enigma of sorts with ever expanding reports of direct and indirect effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on almost all the vital organ systems. Along with inciting acute pulmonary complications, the virus attacks the cardiac, renal, hepatic, and gastrointestinal systems as well as the central nervous system (CNS). The person-to-person variability in susceptibility of individuals to disease severity still remains a puzzle, although the comorbidities and the age/gender of a person are believed to play a key role. SARS-CoV-2 needs angiotensin-converting enzyme 2 (ACE2) receptor for its infectivity, and the association between SARS-CoV-2 and ACE2 leads to a decline in ACE2 activity and its neuroprotective effects. Acute respiratory distress may also induce hypoxia, leading to increased oxidative stress and neurodegeneration. Infection of the neurons along with peripheral leukocytes’ activation results in proinflammatory cytokine release, rendering the brain more susceptible to neurodegenerative changes. Due to the advancement in molecular biology techniques and vaccine development programs, the world now has hope to relatively quickly study and combat the deadly virus. On the other side, however, the virus seems to be still evolving with new variants being discovered periodically. In keeping up with the pace of this virus, there has been an avalanche of studies. This review provides an update on the recent progress in adjudicating the CNS-related mechanisms of SARS-CoV-2 infection and its potential to incite or accelerate neurodegeneration in surviving patients. Current as well as emerging therapeutic opportunities and biomarker development are highlighted.
... Mortara y otros (20) en su ensayo clínico señalaron que el ruxolitinib redujo rápidamente la inflamación sistémica, mejorando así la función respiratoria y la necesidad de apoyo de oxígeno, lo cual evitó la progresión de la enfermedad y el uso de ventilación invasiva, resultado similar al obtenido por el autor con el uso de Jusvinza en la insuficiencia respiratoria aguda, la cual mejora el pronóstico y la evolución de los pacientes. ...
RESUMEN Introducción: Jusvinza es un péptido ligando alterado inhibidor de la citoquina IL-17. Objetivo: Demostrar la eficacia de Jusvinza en los pacientes graves y críticos con neumonía grave secundaria a la infección por SARS-CoV-2. Métodos: Estudio epidemiológico, retrospectivo, realizado en cuidados intensivos del Hospital Provincial Doctor León Cuervo Rubio, Pinar del Río (marzo del 2020 a julio del 2021). La información se obtuvo de las historias clínicas de 123 pacientes graves y críticos con diagnóstico de neumonía grave por COVID-19. Se estudiaron variables de respuesta (administración de Jusvinza y su relación con el estado al egreso, condición de los pacientes, modalidad de ventilación mecánica), variables humorales y clínicas antes y después del tratamiento y su eficacia. Se usó el programa estadístico MEDCAL. Resultados: Se administró Jusvinza al 76,42 % de los pacientes, la mayoría de ellos egresó vivo 65 (52,85 %), los graves tuvieron mejor evolución (34; 36,17 %), con mortalidad muy baja (4; 4,26 %), así como los no ventilados (24; 25,53 %), con baja mortalidad (2; 2,13 %). Aumentó la probabilidad de egresar vivos (OR: 1,58; IC: 0,6703-3,7347; p = 0,2951), disminuyó el riesgo de morir en un 8,5 % (IC: 16,38-16,547). Hubo una mejor evolución de las variables clínicas y humorales de los egresados. Se necesita tratar 11,7 (IC: 11,48-11,947) pacientes para obtener el beneficio. Revista Cubana de Medicina Intensiva y Emergencias. 2022;21(3):e940 Esta obra está bajo una licencia https://creativecom m ons.org/licenses/b y-nc/4.0/deed.es_E S Conclusiones: Jusvinza demuestra ser un medicamento eficaz, aumenta la probabilidad de egresar vivos, disminuye el riesgo de morir y no presenta reacciones adversas significativas. Palabras clave: péptido ligando alterado; eficacia; estado al egreso; ventilación mecánica. ABSTRACT Introduction: Jusvinza is an altered peptide ligand inhibitor of the cytokine IL-17.
... The end goal of this treatment is to stop or prevent further damage to the organs in severely affected COVID-19 patients. A pilot study concluded that in an initial group of patients impacted by COVID-19, though not in extreme respiratory distress needing invasive ventilation, the use of Rux as a compassionate treatment reduces the hyper inflammatory state, leading to more efficient ventilation and faster recovery [73]. ...
... The end goal of this treatment is to stop or prevent further damage to the organs in severely affected COVID-19 patients. A pilot study concluded that in an initial group of patients impacted by COVID-19, though not in extreme respiratory distress needing invasive ventilation, the use of Rux as a compassionate treatment reduces the hyper inflammatory state, leading to more efficient ventilation and faster recovery [73]. ...
In December 2019, a novel coronavirus (COVID-19) unleashed an unprecedented and unanticipated pandemic, causing widespread concern. More than three million deaths have been documented since the first incidence of COVID-19 discovered in China. Several arduous efforts have been made by the governments of various countries worldwide to prevent and control the SARS-CoV-2 infection. This review article discusses an update on all kinds of therapeutic interventions currently applied or developed to treat SARS-CoV-2 condition, including the repurposing of drugs such as Remdesivir, Favipiravir, Ivermectin, etc . We also discuss CRISPR’s potential involvement in antiviral therapy, convalescent plasma therapy, and immunomodulators in combination to tackle the cytokine storms and present a comprehensive overview on many vaccines that have been created to date or are under trials, as well as their platforms and efficacy. Moreover, this article also discusses the mechanism of action of every therapeutic intervention.
... Ruxolitinib treatment for COVID-19 has also been reported in 14 patients with severe systemic hyperinflammation [30] and in a patient with tocilizumab-refractory severe COVID-19 infection [31]. Lastly, the outcome of the patients treated with ruxolitinib in a compassionate use program (CUP) has been already reported in four different monocentric case series, which showed an improvement of pulmonary function and a decreased need for supportive oxygen [32][33][34], normalization of lymphocyte count and a reduction of inflammatory markers [34,35], and a reduction in mortality when compared with the control group (Table 1) [33]. Notwithstanding, there is some concern about the side effects of ruxolitinib based on a report of two cases of cutaneous rash/purpura [36]. ...
... Ruxolitinib treatment for COVID-19 has also been reported in 14 patients with severe systemic hyperinflammation [30] and in a patient with tocilizumab-refractory severe COVID-19 infection [31]. Lastly, the outcome of the patients treated with ruxolitinib in a compassionate use program (CUP) has been already reported in four different monocentric case series, which showed an improvement of pulmonary function and a decreased need for supportive oxygen [32][33][34], normalization of lymphocyte count and a reduction of inflammatory markers [34,35], and a reduction in mortality when compared with the control group (Table 1) [33]. Notwithstanding, there is some concern about the side effects of ruxolitinib based on a report of two cases of cutaneous rash/purpura [36]. ...
Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.
... Overall, 14 studies (one randomized controlled trial, five observational studies, and eight case reports) investigating the efficacy and safety of ruxolitinib in moderate-severe COVID-19 pneumonia were retrieved [30][31][32][33][34][35][36][37][38][39][40][41][42][43]. Main features of included studies are shown in Table 3. ...
... However, no significant difference in mortality rate and duration of hospitalization was reported. Several observational studies [32,41,42] reported a rapid clinical improvement in 80-90% of patients with moderate-severe COVID-19 pneumonia, although no comparison with other repurposed agents was performed. Interestingly, Gaspari et al. [35] reported two cases of severe skin AEs with ruxolitinib in a COVID-19 setting. ...
We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered.
The ORF3a is a large accessory protein in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which plays an important role in virulence and viral replication; especially in inflammasome activation and apoptosis. However,, the existing cryo-EM structure of SARS-CoV-2 ORF3a is incomplete, . making it challenging to understand its structural and functional features. The aim of this study is to investigate the dynamic behaviors of the full-sequence homology model of ORF3a and compare it with the cryo-EM structure using microsecond molecular dynamics simulations. The previous studies indicated that the unresolved residues of the cryo-EM structure are not only involved in the pathogenesis of the SARS-CoV-2 but also exhibit a significant antigenicity. The dynamics scenario of homology model revealed higher RMSD, Rg, and SASA values with stable pattern when compared to the cryo-EM structure. Moreover, the RMSF analysis demonstrated higher fluctuations at specific positions (1-43, 97-110, 172-180, 219-243) in the model structure, whereas the cryo-EM structure displayed lower overall drift (except 1-43) in comparison to the model structure.Secondary structural features indicated that a significant unfolding in the transmembrane domains and β-strand at positions 166 to 172, affecting the stability and compactness of the cryo-EM structure , whereas the model exhibited noticeable unfolding in transmembrane domains and small-coiled regions in the N-terminal. , The results from molecular docking and steered molecular dynamics investigations showed the model structure had a greater number of non-bonding interactions, leading to enhanced stability when compared to the cryo-EM structure. Consequently, higher forces were necessary for unbinding of the baricitinib and ruxolitinib inhibitors from the model structure.. Our findings can help better understanding of the significance of unresolved residues at the molecular level. Additionally, this information can guide researchers for experimental endeavors aimed at completing the full-sequence structure of the ORF3a.Communicated by Ramaswamy H. Sarma.
Abstract
The year 2020 is characterised by the COVID-19 pandemic that has quelled more than half a million lives in recent months. We are still coping with the negative repercussions of COVID-19 pandemic in 2021, in which the 2nd wave in India resulted in a high fatality rate. Regardless of emergency vaccine approvals and subsequent meteoric global vaccination drives in some countries, hospitalisations for COVID-19 will continue to occur due to the propensity of mutation in SARS-CoV-2 virus. The immune response plays a vital role in the control and resolution of infectious diseases. However, an impaired immune response is responsible for the severity of the respiratory distress in many diseases. The severe COVID-19 infection persuaded cytokine storm that has been linked with acute respiratory distress syndrome (ARDS), culminates into vital organ failures and eventual death. Thus, safe and effective therapeutics to treat hospitalised patients remains a significant unmet clinical need. In that state, any clue of possible treatments, which save patients life, can be treasured for this time point. Many cohorts and clinical trial studies demonstrated that timely administration of immunomodulatory drugs on severe COVID-19 patients may mitigate the disease severity, hospital stay and mortality. This article addresses the severity and risk factors of hypercytokinemia in COVID-19 patients, with special emphasis on prospective immunomodulatory therapies.
