流行性感冒发病率高,传染性强,且流感并发症的发病率和死亡率最高。2018年10月,美国食品药品管理局(Food and Drug Administration,FDA)加速批准新型的帽依赖性核酸内切酶抑制剂baloxavir marboxil上市,用于治疗12岁及以上有流感症状且...流行性感冒发病率高,传染性强,且流感并发症的发病率和死亡率最高。2018年10月,美国食品药品管理局(Food and Drug Administration,FDA)加速批准新型的帽依赖性核酸内切酶抑制剂baloxavir marboxil上市,用于治疗12岁及以上有流感症状且不超过48 h的急性单纯型流感患者。临床研究显示,baloxavir marboxil对流感有较好的客观缓解率。本文对其药理作用、临床评价、安全性及用法用量等进行简要概述。展开更多
Baloxavir marboxil is a polymerase acidic(PA)endonuclease inhibitor,which is approved by the U.S Food and Drug Administration(FDA)on October 25,2018,for the treatment of uncomplicated influenza patients aged 12 years ...Baloxavir marboxil is a polymerase acidic(PA)endonuclease inhibitor,which is approved by the U.S Food and Drug Administration(FDA)on October 25,2018,for the treatment of uncomplicated influenza patients aged 12 years and older.In the present work,we reviewed the pharmacodynamics,pharmacokinetics,drug interactions,clinical trials and adverse reactions of baloxavir marboxil.展开更多
目的评价玛巴洛沙韦治疗流行性感冒(以下简称“流感”)的有效性、安全性和经济性,以期为医院新药引进和临床用药决策提供循证参考。方法检索PubMed、Embase、Web of Science、Cochrane Library、Epistemonikos、中国生物医学文献数据库...目的评价玛巴洛沙韦治疗流行性感冒(以下简称“流感”)的有效性、安全性和经济性,以期为医院新药引进和临床用药决策提供循证参考。方法检索PubMed、Embase、Web of Science、Cochrane Library、Epistemonikos、中国生物医学文献数据库、中国知网、维普网、万方数据库及卫生技术评估(HTA)相关学术机构官方网站及数据库,经文献筛选、资料提取、质量评价后,对研究结果进行描述性分析。结果共纳入11篇文献,包括6篇系统评价(SR)/Meta分析、5篇经济学研究。与安慰剂相比,玛巴洛沙韦在缩短流感患者症状缓解时间(TTAS)和退热时间(TTRF)、降低治疗后24h和48h病毒滴度相对于基线的变化水平、降低支气管炎发生率等方面差异有统计学意义(P<0.05)。与神经氨酸酶抑制剂(NAIs)相比,玛巴洛沙韦在缩短流感患者TTRF,降低流感并发症、肺炎、支气管炎发生率等方面差异无统计学意义(P>0.05);多数研究认为玛巴洛沙韦在缩短TTAS方面差异无统计学意义(P>0.05);仅有极低质量文献认为玛巴洛沙韦可显著降低患者治疗后24 h和48 h病毒滴度相对于基线的变化水平。安全性方面,玛巴洛沙韦与帕拉米韦、扎那米韦相比,不良事件(AEs)发生率和药物相关不良事件(DRAEs)发生率差异无统计学意义(P>0.05)。部分研究认为玛巴洛沙韦AEs和DRAEs发生率较安慰剂、奥司他韦、拉尼米韦更低。现有经济学研究显示,在中国与奥司他韦相比、在日本与拉尼米韦相比,玛巴洛沙韦均更具有成本-效果优势。结论与安慰剂相比,玛巴洛沙韦治疗流感具有良好的有效性、安全性和经济性。与NAIs(奥司他韦)相比,玛巴洛沙韦在中国有良好的经济学优势,但在安全性和有效性方面尚需开展更多高质量研究。展开更多
Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(...Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.展开更多
文摘流行性感冒发病率高,传染性强,且流感并发症的发病率和死亡率最高。2018年10月,美国食品药品管理局(Food and Drug Administration,FDA)加速批准新型的帽依赖性核酸内切酶抑制剂baloxavir marboxil上市,用于治疗12岁及以上有流感症状且不超过48 h的急性单纯型流感患者。临床研究显示,baloxavir marboxil对流感有较好的客观缓解率。本文对其药理作用、临床评价、安全性及用法用量等进行简要概述。
文摘Baloxavir marboxil is a polymerase acidic(PA)endonuclease inhibitor,which is approved by the U.S Food and Drug Administration(FDA)on October 25,2018,for the treatment of uncomplicated influenza patients aged 12 years and older.In the present work,we reviewed the pharmacodynamics,pharmacokinetics,drug interactions,clinical trials and adverse reactions of baloxavir marboxil.
基金supported by the National Science and Technology Major Project (2018ZX097110003-005-002)the Key-Area Research and Development Program of Guangdong Province (2022B1111020002)+3 种基金the National Natural Science Foundation of China (NSFC) (32170159,and 82174055)supported by the National Science Fund for Distinguished Young Scholars (81925025)the Innovative Research Group (81621005)of the NSFCthe Innovation Fund for Medical Sciences (2019-I2M-5-049)of the Chinese Academy of Medical Sciences.
文摘Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.
