Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.     

吉瑞替尼致不良反应文献分析

目的 分析吉瑞替尼相关不良反应的临床特征,为临床安全合理用药提供参考。方法 检索中国知网、维普、万方、PubMed、Embase数据库关于吉瑞替尼相关不良反应的个案报道或病例分析,并进行统计分析。结果 共纳入文献13篇,共涉及患者20例,其中男性7例（35%）,女性13例（65%）;年龄分布以50岁以上患者居多（14例,70%）;原患疾病主要为复发性或难治性急性髓系白血病（19例,95%）;大部分不良反应发生在2个月以内（16例,80%）;不良反应主要累及神经系统（25%）,胃肠系统（17.5%）和皮肤系统（17.5%）,其中严重急性肾损伤、免疫相关性肠炎和颅内出血是新发不良反应。大部分患者对症治疗后均好转,2例患者因颅内出血后出现并发症而死亡。结论 临床应加强对吉瑞替尼相关不良反应的防范,保障患者用药安全。     

临床药师参与吉瑞替尼致QTc间期延长的病例分析

目的 探讨临床药师在1例急性髓系白血病患者应用吉瑞替尼引起QTc间期延长的病例中的作用,为此类患者的药物治疗和监护提供参考。方法 临床药师及时发现1例急性髓系白血病患者心电图异常情况,通过分析患者基础疾病、诊疗过程、治疗用药及其潜在相互作用参与临床诊疗。结果 临床药师怀疑QTc间期延长很可能是吉瑞替尼引起的不良反应,建议立即停用该药,复查心电图。医师采纳此建议,及时停止可疑药品吉瑞替尼药物治疗,3 d后复查心电图,患者QTc数值恢复至正常范围内。结论 临床药师参与临床诊疗过程,可为患者提供更优质的药学服务。     

The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance

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FLT3突变型急性髓性白血病的靶向治疗药物吉列替尼

吉列替尼于2018年11月28日获美国食品药物管理局(FDA)批准用于治疗有FLT3突变的复发或难治性急性髓性白血病。FDA对该药物的Ⅲ期临床试验进行了中期分析,该文对吉列替尼针对的靶点及药物临床前、临床试验的结果进行了综述,以促进合理使用该药物。