Barat and M. against COVID-19 for its well-known powerful and fast anti-inflammatory effect; nevertheless, the high rate of viral and microbial reactivation observed in the hematological setting might represent a caveat in its prolonged use in the COVID-19. 3.5. Tyrosine kinase inhibitors Another class of drugs already employed in the treatment of GVHD that could help to win the COVID-19 challenge are the tyrosine kinase inhibitors (TKIs), already successfully employed in treatment of chronic myeloid leukemia (CML), Philadelphia-positive acute lymphoblastic leukemia and stromal gastro-intestinal tumor (GIST) . Imatinib has been the first TKI licensed for CML treatment, followed by Nilotinib, Dasatinib, Bosutinib (second generation TKIs) and Ponatinib (third generation TKI). All TKIs, and especially those of second and third generation, in CML offer high rates of complete hematological, cytogenetic and molecular responses , necessary key for treatment discontinuation (TFR), that has success in about 40 % of patients . Different studies focused on TFR explored the impact of TKIs on the Acetanilide immunological response, showing that this class of drugs play a positive effect on NK cells whose number and activated status is fundamental for maintaining deep molecular response without treatment [55,56]. Moreover, TKIs are able Acetanilide to restore the immunocompromised status observed in CML patients at diagnosis by reducing myeloid-derived suppressor cells, re-activating T and NK cells, and reducing the expression of PD-1 on T and NK lymphocytes and of PD-L1 on the microenvironment and on Acetanilide neoplastic clone . Imatinib Acetanilide has been employed with success also in GVHD, but mainly in its chronic form, where it was successful in about 60 %60 % of cases . From the safety point of view, in a series of 19 cases only one Acetanilide pneumonitis and one CNS infection by JCV have been reported . In another cohort with sclerodermic GVHD Imatinib was compared to Dasatinib: one of the 4 patients receiving Imatinib had pneumonitis versus 2 of the 5 cases treated with Dasatinib . Two trials proposing Imatinib in COVID-19 have been already registered in the clinical GSN trials.gov website (“type”:”clinical-trial”,”attrs”:”text”:”NCT04357613″,”term_id”:”NCT04357613″NCT04357613, “type”:”clinical-trial”,”attrs”:”text”:”NCT04356495″,”term_id”:”NCT04356495″NCT04356495), both involving elderly patients. In a third study, Imatinib will be compared to hidroxicloroquine, Lopinavir/ritonavir, and Baricitinib (“type”:”clinical-trial”,”attrs”:”text”:”NCT04346147″,”term_id”:”NCT04346147″NCT04346147). and models that would support the use of Bosutinib as a powerful anti-inflammatory agent. This TKI is today indicated for treatment of CML Imatinib-intolerant or resistant patients . Differing from Dasatinib, whose pro-inflammatory action is supported by the high rate of pleural effusion, Bosutinib resolved this adverse event in 17/20 cases presenting effusion during treatment with Dasatinib. Moreover, the safety of Bosutinib from the immunological point of view is supported by the quite total absence of infective adverse events . Moreover, in a model of membranous glomerulonephritis, Bosutinib was able to ameliorate renal damage by reducing expression of IL2R, IL4R, and by inhibiting JAK2/JAK3 (that sustain the inflammatory pathway) . In another murine model of intra-cerebral hemorrhage with brain injury caused by post-bleeding inflammation, Bosutinib once more showed its anti-inflammatory action: inhibiting SIK-2, it activates CREB and IkB, so blocking the NF-kB-derived inflammation. Moreover, Bosutinib shifted the macrophagic response from M1 to M2, and decreased pro-inflammatory cytokines production . Bosutinib and Nilotinib were also used and compared in a murine model of Alzheimers disease (where brain plaques are considered a consequence of hyper-inflammation). In this context, both TKIs decreased inflammation by reducing TNF alpha, IL4, IL6, IL3, and IL2 levels and increasing IL10 and CX3CL1, but, in comparison with Nilotinib, Bosutinib improved IL-10 and CX3CL1 also in the peripheral blood . Therefore, the anti-inflammatory profile of Bosutinib is definitely obvious. About its security, in the BEFORE trial, where Bosutinib and Imatinib were compared in 536 CML individuals in 1st collection, grade 3/4 illness rate was 3.4 % in the Bosutinib versus 4.9 % in the Imatinib arm, with only 0.4 % of upper respiratory tract infections in.
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- Abbreviations: CON, control; CANA, canagliflozin; AMPK, AMP-activated proteins kinase; ACC, acetyl-CoA carboxylase
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