基于文本挖掘和生物医学数据库的新型冠状病毒肺炎药物发现

目的 基于文本挖掘技术和生物医学数据库对新型冠状病毒肺炎（COVID-19）相关文献进行数据挖掘分析，探究COVID-19及其主要症状发热、咳嗽、呼吸障碍相关基因靶点，筛选潜在有效的化学药和中药。方法 使用GenCLiP 3网站获取COVID-19和其主要症状咳嗽、发热、呼吸障碍共4个关键词的共有靶点，在METASCAPE数据库中对其进行基因本体（GO）和通路富集分析，再利用String数据库和Cytoscape软件构建共有靶点的蛋白质相互作用网络，筛选获得核心基因，运用DGIdb数据库、SymMap数据库针对核心基因进行中西医治疗药物预测。结果 获得COVID-19及其主要症状共有基因靶点28个，其中有IL2、IL1B、CCL2等核心基因16个，使用DGIdb数据库筛选获得与16个关键靶点相互作用的化学药包括沙利度胺、来氟米特、环孢素等28种，中药包括虎杖、黄芪、芦荟等70味。结论 COVID-19及其主要症状的病理机制可能和CD4、KNG1、VEGFA等28个共有基因相关，可能通过介导TNF、IL-17等信号通路参与COVID-19病理过程。潜在有效药物可能通过作用相关靶点通路起到治疗COVID-19的作用。     

Exploring the potential of exosomes in diagnosis and drug delivery for pancreatic ductal adenocarcinoma

Pancreatic cancer (PC) is a cancer of the digestive system, and pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90% of all PC cases. Exosomes derived from PDAC (PDAC-exosomes) promote PDAC development and metastasis. Exosomes are nanoscale vesicles secreted by most cells, which can carry biologically active molecules and mediate communication and cargo transportation among cells. Recent studies have focused on transforming exosomes into good drug delivery systems (DDSs) to improve the clinical treatment of PDAC. This review considers PDAC as the main research object to introduce the role of PDAC-exosomes in PDAC development and metastasis. This review focuses on the following two themes: (a) the great potential of PDAC-exosomes as new diagnostic markers for PDAC, and (b) the transformation of exosomes into potential DDSs.     

连续性血液净化治疗患儿静脉留置导管感染风险预测体系的构建及应用

目的:探讨连续性血液净化治疗患儿静脉留置导管感染风险因素,据此构建风险预测体系,并检验其实际应用效果,以期为临床预防护理提供依据。方法:选取医院2018年4月—2020年4月收治的400例连续性血液净化治疗患儿,按两组基础资料具有匹配性原则将其分为构建组300例、验证组100例,统计构建组中静脉留置导管感染患儿例数,通过单因素分析、多因素Logistic回归分析筛选静脉留置导管感染的独立危险因素,据此构建风险预测体系,并检验其在验证组中的应用效果。结果:经统计得到,构建组中静脉留置导管感染患儿共66例,感染发生率为22.00%;单因素分析得到,连续性血液净化治疗患儿静脉留置导管感染风险因素有穿刺部位、导管留置时间、插管次数、血流速度、血红蛋白、遵医依从性、抗生素使用时间、操作人员手卫生(P<0.05);多因素Logistic回归分析得到,连续性血液净化治疗患儿静脉留置导管感染独立风险因素有股静脉置管、导管留置时间>7 d、血流速度>180 mL/min、血红蛋白<100 g/L、遵医依从性差、抗生素使用时间>7 d(P<0.05);构建得到连续性血液净化治疗患儿静脉留置导管感染风险预测体系为P=1/[1+e^(-(-1.935+1.635×股静脉置管+1.740×导管留置时间>7 d+1.725×血流速度>180 mL/min+2.241×血红蛋白<100 g/L+2.089×遵医依从性差+1.331×抗生素使用时间>7 d))],ROC曲线分析显示,曲线下面积AUC=0.881,灵敏度为86.67%,特异性为97.14%,准确率为94.00%。结论:连续性血液净化治疗患儿静脉留置导管感染风险大,且风险因素复杂,研究构建的静脉留置导管感染风险预测体系灵敏度高、特异性强,评估准确率高。     

The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

1. Download : Download high-res image (161KB)
2. Download : Download full-size image

     

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

欧洲药物战略（2020）及其对中国医药领域的启示

在当前国际制药技术出现重大创新和变革、药品研发技术信息化和数字化程度不断发展，以及新型冠状病毒肺炎（COVID-19）疫情大流行的背景下，欧盟委员会为满足未竟临床需求、激励行业创新、增强监管系统应变能力、巩固欧盟药品监管体系国际地位，于2020年底发布了《欧洲药物战略》（Pharmaceutical Strategy for Europe，PSE）。PSE被视为欧洲未来5年卫生政策的“基石”，对欧洲制药领域发展和管理具有重要指导意义。通过对PSE制定背景及发展战略目标、具体举措等内容进行梳理分析，并结合中国COVID-19疫情防控与行业发展、药品科学监管与鼓励创新等实际工作提出政策建议。     

Repurposing of parenterally administered active substances used to treat pain both systemically and locally

Pain is a constant in our lives. The efficacy of drug therapy administered by the parenteral route is often limited either by the physicochemical characteristics of the drug itself or its adsorption–distribution–metabolism–excretion (ADME) mechanisms. One promising alternative is the design of innovative drug delivery systems that can improve the pharmacokinetics |(PK) and/or reduce the toxicity of traditionally used drugs. In this review, we discuss several products that have been approved by the main regulatory agencies (i.e., nano- and microsystems, implants, and oil-based solutions), highlighting the newest technologies that govern both locally and systemically the delivery of drugs. Finally, we also discuss the risk assessment of the scale-up process required, given the impact that this approach could have on drug manufacturing.Teaser: The management of pain by way of the parenteral route can be improved using complex drug delivery systems (e.g., micro- and nanosystems) which require high-level assessment and shorten the regulatory pathway.