COVID-19 Imatinib: Hope and Attention

Despite the unquestionable progress achieved with the first vaccine against SARS-CoV-2 infection, the COVID-19 pandemic continues to affect thousands of people worldwide. There is a shortage. In addition to this serious situation, we face the challenge of managing new cases in a subgroup of fully vaccinated people who are at high risk of developing severe COVID-19. As a result, the search for potential therapies for COVID-19 continues, regulating treatments with antiviral activity or increased inflammatory responses observed in some patients that are not always predictable. I'm trying to identify a possible treatment. In this regard, the diversion of previously approved drugs under other conditions remains the primary strategy in the fight against the virus. In this search, not only safe and effective molecules, but also easy-to-manage, manufacturing and distribution costs reduce resource inequality to maintain the healthiest, especially in low-income countries. We also need to focus on the molecules that contribute. Patients at a disadvantage.Imatinib mesylate, the leading BCR-ABL tyrosine kinase inhibitor, may meet these criteria. The possibility of imatinib has been rarely investigated in COVID-19,1Morales-Ortega A Rivas-Prado L Frutos-Pérez B et al.Early clinical experience with imatinib in COVID-19: Search for dual effects. The drug is widely used as a first-line therapy for chronic myelogenous leukemia, has been indicated for other symptoms (such as gastrointestinal stromal tumors), and is considered optimal safety since its first approval 20 years ago. Shows the sex profile. During this time, other potential effects of imatinib have been identified, including antiviral properties against other β-coronaviruses in vitro by interfering with the early stages of the viral life cycle.2Coleman CM Sisk JM Mingo RM Nelson EA White JM Freeman MB Abelson kinase inhibitors are potent inhibitors of the fusion of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. However, the exact effect of imatinib on SARS-CoV-2 survival remains controversial due to inconsistent preclinical results.3Han Y Duane X Yang L et al.Identification of SARS-CoV-2 inhibitors using lung and colon organoids., FourZhao H Menden Hall M Daininger MW Imatinib is not a potent anti-SARS-CoV-2 drug. Furthermore, the possibility that imatinib exerts antiviral effects through mechanisms that are not directly related to impaired viral-cell interactions, such as upregulation of genes involved in the response to the virus, cannot be ruled out.FiveGarin Berti S Petrini M Barate C et al.Tyrosine kinase inhibitors have antiviral effects in patients affected by chronic myelogenous leukemia. It is a model that may support their use in the fight against SARS-CoV-2. These unknowns represent some of the many challenges that need to be addressed in connection with the use of this tyrosine kinase inhibitor as an antiviral agent.Imatinib is also a possible immunomodulator capable of reducing pro-inflammatory cytokines, chemokines, and vascular adhesion molecules, according to preclinical models and observations in a small number of patients with chronic inflammatory disease or chronic myelogenous leukemia. It has been suggested.6Ciarcia R Screw MT Gardiero M et al.Imatinib treatment inhibits the production of IL-6, IL-8, NF-KB, AP-1 and regulates intracellular calcium in CML patients., 7Hui KP Chang MC Rye KL et al.The role of epithelial-endothelial cell interactions in the pathogenesis of SARS-CoV-2 infection. However, the molecular mechanism by which this drug may play a role in this immunoregulation is not completely clear and needs further elucidation.Finally, imatinib is associated with the prevention of pulmonary endothelial barrier dysfunction observed in some inflammatory conditions and may lead to alleviation of pulmonary capillary leakage.To Lancet Respiratory Medicine, Jurjan Aman and colleagues8Aman J Devil E Botros L et al.Imatinib in patients with severe COVID-19: randomized, double-blind, placebo-controlled, clinical trial. This potential in the first randomized, double-blind, placebo-controlled clinical trial to evaluate imatinib in inpatients with COVID-19 who require oxygen supplementation to maintain peripheral oxygen saturation above 94%. I investigated the impact.According to their results, treatment with imatinib did not change the time to oxygenation and mechanical ventilation discontinuation for more than 48 consecutive hours (unadjusted hazard ratio). 0.95 Primary endpoint). However, 28-day mortality (unadjusted HR0.51) compared to the placebo group , P 0.034), duration of mechanical ventilation (median duration 12 days) vs The 7th P 0 · 0080), and length of stay in the intensive care unit (median duration 15 days) vs The 8th ; p 0 ・ 025) was lower in patients in the imatinib group. In addition, the safety profile of imatinib also appeared to be optimal, consistent with the data available from the usual indications, after a thorough analysis of its side effects.These findings provide a reason for hope, as they indicate the expansion of therapeutic weapons against COVID-19, but should be interpreted with caution. In this regard, a follow-up period of studies greater than 28 days was more beneficial and allowed clearer judgments about survival and readmission potential that could have unmeasured effects on reported results. ..Similarly, other open questions investigated in further studies include the optimal dose and duration of imatinib treatment, the optimal time to start treatment after the onset of symptoms, and in combination with other drugs such as dexamethasone. Related to possible interactions when taken (up to 276 given Of 385 patients in the study8Aman J Devil E Botros L et al.Imatinib in patients with severe COVID-19: randomized, double-blind, placebo-controlled, clinical trial.), CYP3A4 inducing action can reduce exposure to imatinib.9Recoché I Rousseau V Bourrel R et al.Drug-drug interactions with imatinib: observational study.Since the pandemic began about a year and a half ago, COVID-19 provides initial data on potentially beneficial treatments, especially after witnessing the unexpected results of randomized trials of previously large enough previous treatment approaches. The number of patients who have learned that their enthusiasm for receiving should be relieved. This fact will undoubtedly condition our view of new treatments for SARS-CoV-2 infection until the inherent uncertainty is resolved.In other words, I also learned not to give in to so-called optimism bias.TenWhat is the meaning of optimism bias in clinical research? As easy as we did at the beginning of this unprecedented global health crisis. It is precisely this evolving view that reclaims the thoughtful judgment of promising data from well-known drugs that have been reused as treatments for new challenges such as COVID-19.DB-B is the lead investigator in an unsponsored randomized trial investigating the role of imatinib and baricitinib in patients with COVID-19 (NCT04346147); AM-O, AIF-S, JGdT, JVSM-L are collaborators of this project.References1.1.Morales-Ortega A Rivas-Prado L Frutos-Pérez B et al.Early clinical experience with imatinib in COVID-19: Search for dual effects.J infection. 2021; 82: 186-2302.2.Coleman CM Sisk JM Mingo RM Nelson EA White JM Freeman MB Abelson kinase inhibitors are potent inhibitors of the fusion of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.J Virol. 2016; 90: 8924-89333.3.Han Y Duane X Yang L et al.Identification of SARS-CoV-2 inhibitors using lung and colon organoids.Nature. 2021; 589: 270-2754.4.Zhao H Menden Hall M Daininger MW Imatinib is not a potent anti-SARS-CoV-2 drug.leukemia. 2020; 34: 3085-30875.5.Garin Berti S Petrini M Barate C et al.Tyrosine kinase inhibitors have antiviral effects in patients affected by chronic myelogenous leukemia. It is a model that may support their use in the fight against SARS-CoV-2.Front on col. 2020; Ten14286.6.Ciarcia R Screw MT Gardiero M et al.Imatinib treatment inhibits the production of IL-6, IL-8, NF-KB, AP-1 and regulates intracellular calcium in CML patients.J cell physiology. 2012; 227: 2798-28037.Hui KP Chang MC Rye KL et al.The role of epithelial-endothelial cell interactions in the pathogenesis of SARS-CoV-2 infection.Clinical infections 2021; ()8.8.Aman J Devil E Botros L et al.Imatinib in patients with severe COVID-19: randomized, double-blind, placebo-controlled, clinical trial.Lancet Respirit Med. 2021; ()9.9.Recoché I Rousseau V Bourrel R et al.Drug-drug interactions with imatinib: observational study.Medicine (Baltimore). 2016; 95e507610.10.What is the meaning of optimism bias in clinical research?The lancet. 2006; 367: 449-450Article informationPublication historyidentificationDOI: https://doi.org/10.1016/S2213-2600(21)00266-6Copyright© 2021 Elsevier Ltd. All rights reserved.ScienceDirectAccess this article on ScienceDirect Linked articlesImatinib in patients with severe COVID-19: randomized, double-blind, placebo-controlled, clinical trialThis study failed to achieve key results because imatinib did not reduce the time to discontinuation of ventilation and oxygenation for more than 48 consecutive hours in COVID-19 patients in need of oxygenation. Observed effects on survival (although diminished after adjustment of baseline imbalance) and duration of mechanical artificial respiration indicate that imatinib may provide clinical benefits to inpatients with COVID-19. As suggested, further research is needed to verify these findings. Full text PDF Pictures Credit