Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Zhang, Xiuhong; Zhang, Yan; Qiao, Wei; Zhang, Ji; Qi, Zhigang

doi:10.1016/j.intimp.2020.106749

Cited by 153 publications

(155 citation statements)

References 33 publications

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“…Baricitinib is a kinase inhibitor that competes with ATP (adenosine triphosphate) to effectively and reversibly inhibit both JAK1 and JAK2 with high selectivity hindering the pro-inflammatory signals of several cytokines like IL-6, IL-12, IL-23, etc., intracellularly [ 101 ]. Recently a pilot study done by Cantini et.al showed that Baricitinib possesses good safety and efficacy profiles in COVD-19 patients showing no side effects [ 102 ].…”

Section: Jak/stat Inhibitors As Therapeutic Agents Against Covid-19mentioning

confidence: 99%

“…Baricitinib is evident to be the safer approach in patients with moderate COVID-19 inhibiting release of cytokines as an anti-inflammatory agent and endocytosis of SARS-CoV-2 virions [ 103 ]. It also plays a vital role in blocking proteins of the host cell responsible for the viral reproduction, and being an anti-inflammatory agent, also reduces the inflammation in ARDS patients as well [ 101 ].…”

Section: Jak/stat Inhibitors As Therapeutic Agents Against Covid-19mentioning

confidence: 99%

“…It can overcome complications due to immune hyperactivation by the JAK/STAT signal transduction pathway and potentially knockdown the hyper inflammation reducing the lung impairment and restoring the PaO2/FiO2 ratio in COVID-19 patients[100]. General reproduction, and being an anti-inflammatory agent, also reduces the inflammation in ARDS patients as well[102].Recently, phase III clinical trials were initiated by Eli Lilly employingBaricitinib (NCT04421027)…”

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confidence: 99%

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JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Satarker

Tom²,

Shaji³

et al. 2020

Postgraduate Medicine

130

124

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As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer has implicated us to re-look into its signaling cascades drawing attention towards the JAK/STAT pathway. Considered as a major signaling mediator of cytokines and chemokines, the JAK/STAT pathway has significantly contributed to the worsening of COVID-19. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 infection triggers the inflammation via the JAK/STAT pathway mainly through its structural and non-structural proteins leading towards the development of cytokine storms. This produces various inflammatory markers in the host that determine the disease severity. Therefore, inhibiting JAK/STAT signaling with JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib could hamper the inflammatory cascade and reduce inflammation. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains to be speculative for which further investigations are required.

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Section: Jak/stat Inhibitors As Therapeutic Agents Against Covid-19mentioning

confidence: 99%

Section: Jak/stat Inhibitors As Therapeutic Agents Against Covid-19mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Satarker

Tom²,

Shaji³

et al. 2020

Postgraduate Medicine

130

124

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“…(94). Baricitinib and ruxolitinib are selective inhibitors of JAK1/JAK2 which is responsible for multiple cellular signals including the proinflammatory IL-6 and works as immunomodulator decreasing the cytotoxic T lymphocytes and increasing the regulatory T cells (97,98). A phase 2/3 clinical trial (NCT04358614) showed that all clinical characteristics and respiratory function parameters significantly improved in the baricitinib-treated group compared to the baseline, and no serious infections, cardiovascular and hematologic adverse effects occurred after treatment (29).…”

Section: Other Blockersmentioning

confidence: 99%

Controlling Cytokine Storm Is Vital in COVID-19

et al. 2020

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Corona virus disease 2019 (COVID-19) has caused a global outbreak and severely posed threat to people’s health and social stability. Mounting evidence suggests that immunopathological changes, including diminished lymphocytes and elevated cytokines, are important drivers of disease progression and death in coronavirus infections. Cytokine storm not only limits further spread of virus in the body but also induces secondary tissue damage through the secretion of large amounts of active mediators and inflammatory factors. It has been determined that cytokine storm is a major cause of deaths in COVID-19; therefore, in order to reverse the deterioration of severe and critically ill patients from this disease, the cytokine storm has become a key therapeutic target. Although specific mechanisms of the occurrences of cytokine storms in COVID-19 have not been fully illuminated, hyper-activated innate immune responses, and dysregulation of ACE2 (angiotensin converting enzyme 2) expression and its downstream pathways might provide possibilities. Tailored immunoregulatory therapies have been applied to counteract cytokine storms, such as inhibition of cytokines, corticosteroids, blood purification therapy, and mesenchymal stem cell therapy. This review will summarize advances in the research of cytokine storms induced by COVID-19, as well as potential intervention strategies to control cytokine storms.

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“…[9] These inhibitors have proved helpful in "off-label" indications, where excessive cytokine release plays a central role in the disease progression. [10] While the hypothesis of JAK-inhibitors successfully combating high levels of cytokine expression in SARS-CoV-2 infection has been shown in some small studies, [11] their effect on a larger population has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

Walz

Cohen

Rebaza

et al. 2020

Preprint

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Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 – 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 – 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 – 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 – 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 – 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

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Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Cited by 153 publications

References 33 publications

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

Controlling Cytokine Storm Is Vital in COVID-19

JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

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