抗新冠肺炎药物研究进展

新冠病毒引发的急性呼吸道传染病造成了全球大流行的新冠肺炎,严重危害世界公共卫生安全,迫切需要研发有效治疗新冠肺炎的药物。综述了疫情暴发初期抗新冠肺炎药物研发的进展,重点介绍“老药新用”、小分子及抗体创新药物研发和中药等。通过“老药新用”研究发现多个老药具有抑制新冠病毒复制作用,其中瑞德西韦、法匹拉韦、氯喹和羟氯喹等进入临床研究,尤其是瑞德西韦成为被美国FDA批准用于新冠肺炎治疗的首个药物。针对新冠病毒识别宿主细胞受体的S蛋白开展的抗体发现和靶向3CL蛋白酶及RNA依赖的RNA聚合酶等新冠病毒复制过程中的关键蛋白质开展小分子抑制剂发现是抗新冠肺炎创新药物研究中的主要方向。此外,中药在防治新冠肺炎中发挥了重要作用,金花清感颗粒、莲花清瘟胶囊、血必净注射液、双黄连口服液、清肺排毒汤、化湿败毒方、宣肺败毒方等都进入了新冠肺炎治疗的临床研究及应用。     

关于新冠病毒疫苗研发的思考

新冠病毒(SARS-CoV-2)疫苗能否研发成功引起全社会关注。目前,大多数新冠肺炎病人可以自然康复,没有明确证据证明新冠病毒可以长期在体内潜伏,而且康复的患者血清可以治疗新冠肺炎病人,这些都预示着新冠病毒疫苗研发可能会成功。另一方面,新冠病毒疫苗研发也可能失败,主要原因是疫苗可能引起抗体依赖增强(antibody-dependent enhancement, ADE),即疫苗诱导的抗体可能增强病毒的感染能力。另外,疫苗也可能引起免疫性肺损伤。当前,疫苗的种类很多,包括传统型的疫苗和新型疫苗。从理论上来说,所有已经有的疫苗种类和技术都可以尝试用在新冠病毒疫苗的研究上。     

全球抗病毒药物研发进展与展望

病毒是危害人体健康的主要病原体之一,病毒感染和传播造成的传染性疾病严重威胁人类健康。目前,艾滋病、病毒性肝炎等发病率高、治愈率低的病毒性疾病仍在全球蔓延,流感病毒、冠状病毒等呼吸道病毒不断发生变异,2019年以来,新冠病毒引起的全球疫情对世界各国产生巨大影响,疫情走向还存在很大不确定性,开发安全有效的抗病毒药物成为应对病毒性疾病的重要手段。拟在总结全球抗病毒药物研发整体现状的基础上,分析抗艾滋病病毒、肝炎病毒、新冠病毒等重点领域的新药研发进展,提出抗病毒药物的发展建议,为未来研发更加高效的抗病毒药物提供指引和参考。     

新型冠状病毒抗原快速检测研发现状及展望*

新型冠状病毒肺炎疫情的全球大流行,对全球公共健康、社会和经济运转造成了重大影响。在药物研发迟滞及疫苗有效性未得到充分验证的情况下,对人群进行大规模的快速筛查,寻找潜在的感染者(尤其是轻症和无症状患者),并进行集中隔离,切断传播途径和保护易感人群是首要的任务。因此对于SARS-CoV-2感染,早期诊断尤为重要。总结现有市场上的新冠病毒抗原快速检测产品,对全球抗原快速检测市场进行分析,概述其研发的动向并展望了我国在新冠抗原检测新方法、新技术方面的自主创新能力。     

抗新型冠状病毒单克隆中和抗体药物研发进展*

随着新型冠状病毒肺炎(COVID-19)疫情在全球的不断蔓延,开发有效的治疗药物迫在眉睫。中和抗体作为最有希望的新型冠状病毒特异性治疗药物,已经在临床研究中展现很好的治疗效果。对抗新冠病毒单克隆中和抗体药物研发的进展、涉及的主要技术和主要临床试验结果进行了总结,以期为包括COVID-19在内的新发、突发传染病中和抗体药物研发提供参考。     

新冠肺炎大流行中的真菌感染CSCD

目前,新冠病毒引起的新冠肺炎全球大流行已造成4.9亿多人感染,617万多人死亡。由于新冠肺炎患者免疫力低下以及治疗药物的不良反应,机会性真菌感染明显增加,患者并发/继发真菌性感染。值得注意的是,这次新冠肺炎大流行中的真菌感染主要由曲霉、念珠菌和毛霉引起。鉴于新冠病毒高度适应人类、具有极强的传播能力以及目前市场缺乏特效药物和疫苗,在未来相当长的一段时间内,新冠病毒和真菌的合并感染将是临床医学和科学界的一个难题。     

新冠病毒中和单克隆抗体及纳米抗体研究进展北大核心CSCD

由严重急性呼吸系统综合征冠状病毒2型(severe acute respiratory syndrome coronavirus-2,SARS-CoV-2)引起的疾病被命名为新型冠状病毒肺炎(coronavirus disease 2019,COVID-19),是一种具有强传染性、高易感性、长潜伏期的传染病。病毒刺突蛋白受体结合结构域(receptor binding domain,RBD)和细胞血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)之间的相互作用使得SARS-CoV-2顺利进入细胞。本文对SARS-CoV-2与ACE2的相关作用机制进行了简单概述,对目前针对SARS-CoV-2中和单克隆抗体、纳米抗体的最新研究进展进行了总结,探讨了新冠肺炎的发展过程和抗体药物的研究方向,以期为包括新冠肺炎在内的新发、突发传染病中和抗体药物的研发提供参考。     

新冠肺炎遗传易感基因的研究进展

新型冠状病毒(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)感染人体后,个体间存在显著不同的新冠肺炎(corona virus disease 2019,COVID-19)临床症状。机体遗传因素在新冠病毒感染后的临床转归过程中发挥重要的作用。以全基因组关联研究(genome-wide association studies, GWAS)为代表的遗传关联研究方法,已成功鉴定了多个与新冠肺炎相关的易感基因,为新冠肺炎防诊治措施的研发提供了理论基础。本文综述了新冠肺炎遗传易感基因的研究进展,包括多种表型、多个人群、多种遗传变异类型的新冠肺炎全基因组关联研究以及易感基因区域的精细定位研究等,旨在为新冠肺炎遗传易感基因的后续研究提供参考。     

新冠肺炎COVID-19临床治疗的药物选择

新型冠状病毒病COVID-19,如大多数病毒感染疾病一样,除了疫苗以外,尚无特效药,也没有针对性的治疗方法。在临床上,药物治疗主要是针对患者在感染病毒以后,免疫系统被激活到极限程度或者失去控制,从而给患者带来伤害。本研究系统地回顾了新冠肺炎爆发以来的临床治疗案例,结合中国国家卫健委发布的《新型冠状病毒病肺炎诊疗方案(试行第一至七版)》,提出了治疗新冠肺炎COVID-19临床药物的选择策略,评估了各种目前应用于临床实践的西药的疗效和风险,旨在为临床医生在药物选择上提供理论依据和临床上的案例。     

2021年东兴市冷藏食品、外包装新冠肺炎病毒检测结果分析

对东兴市冷藏食品及其外包装被新冠病毒污染的情况进行分析。东兴市2021年新冠检测冷藏食品3 852份、食品外包装3 476份，共7 328份标本。在3 852份食品中检出新冠病毒核酸阳性2例、在3 476份食品外包装中检出新冠病毒核酸阳性12例。冷藏食品及其外包装中均可能存在新冠病毒，应加强进口冷藏食品的闭环管理，加强对新冠病毒的核酸检测和工作人员的安全培训，提高工作人员的防护意识；还要打击边境走私活动，严防新冠病毒“偷渡”。     

中枢神经系统疾病治疗性抗体药物应用进展

单克隆抗体药物是一种新兴的治疗药物,具有高选择性,被用于多种疾病的治疗,如肿瘤、免疫疾病等,也可以用于中枢神经系统疾病,如阿尔茨海默病、帕金森病、中风和脑肿瘤等。然而,因为血脑屏障低通透性,限制了抗体药物在中枢神经系统疾病治疗中的应用,在很多神经系统疾病临床试验中,抗体药物并没有取得预期效果。如今,人们利用血脑屏障上内源性转运蛋白介导,设计了可以通过血脑屏障的抗体药物。对通过血脑屏障治疗性抗体药物研发进展及其应用前景进行了综述。     

我国创新药研发模式与价值评估(I)

创新药研发对企业研发能力要求高,目前我国大部分药企仍然处于仿创阶段,但随着政策环境的改善,国家不断释放鼓励创新信号, 创新型药企不断涌现,传统药企积极布局,创新药物迎来发展机遇。借鉴国外创新药研发经验,探讨我国创新药的 3 种研发模式及估值方法, 解析创新药研发的机遇与风险。     

·我国创新药研发模式与价值评估(II)

创新药研发对企业研发能力要求高,目前我国大部分药企仍然处于仿创阶段,但随着政策环境的改善,国家不断释放鼓励创新信号, 临前所未有的挑战,呼唤历史发展的转折点。 3.1 由仿到创的大型创新药企——1.0模式 2015 年临床数据自查、仿制药一致性评价、化学药 国内当下的政策环境和市场环境,使得我国创新 品注册分类改革工作方案、上市许可人制度试点、药监市 朱迅 创新型药企不断涌现,传统药企积极布局,创新药物迎来发展机遇。借鉴国外创新药研发经验,探讨我国创新药的 3 种研发模式及估值方法, 解析创新药研发的机遇与风险。     

抗体药物的发展与应用

早期抗体药物是鼠源单克隆抗体,存在免疫原性强、半衰期短等问题。历经数十年的发展,抗体药物从最初的鼠源单抗,逐步发展为人鼠嵌合抗体、人源化抗体及全人源化抗体。通过片段重组、位点修饰、药物偶联等方法,科研人员研发了包括抗体融合蛋白、抗体偶联药物、双特异性抗体、小分子抗体片段等形式多样的抗体药物。抗体药物在恶性肿瘤、自身免疫病、感染性疾病的治疗上发挥重要作用。通过对抗体药物人源化历程,不同类型的抗体结构和特点,以及抗体药物在新型冠状病毒肺炎治疗中的应用进行综述,并对抗体药物的发展前景进行展望,以期为我国抗体药物的研发提供参考。     

Web Resources for Pharmacogenomics

Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research,pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings.     

我国核酸药物市场分析及对策建议

近年来,因兼具基因修饰和传统药物的双重特点,核酸药物已逐渐成为精准生物医学和疾病治疗的热点。为进一步推动我国核酸药物行业创新发展,采用定量分析和定性分析相结合的方法,对国内外核酸药物获批/授权、市场和研发情况进行分析,揭示全球ASO、siRNA、RNA aptamer及mRNA等四大类核酸药物的产业发展态势,系统梳理我国支持核酸药物创新发展的政策与措施,明确未来的技术主攻方向和应用潜力。面对国内基因治疗的迫切需求及核酸药物创制的严峻形势,研究提出推动源头创新、完善成果转移转化机制和营造良好竞争环境等对策建议。     

帕瑞昔布钠在术后镇痛中应用的研究进展

手术方式的不断完善和创新,对术后镇痛提出了更高要求。非甾体抗炎药为我国临床术后镇痛常用的一类药物,近年来应用范围仍在不断扩大,但总结长期术后镇痛用药经验发现,传统的非甾体抗炎药易引起胃肠道毒性反应和血小板抑制,因此迫切需要寻找一种安全、有效的术后镇痛药物。帕瑞昔布钠是一种环氧合酶-2(COX-2)特异性抑制剂,注射使用,可用于术后不同程度疼痛的短期治疗,近年来已被临床实践证实具有良好的疗效和较高的安全性。本文结合已经发表的临床研究报道对该药物在术后镇痛中的应用进展进行综述,旨在对该药物的作用机制、疗效、安全性有一个系统性的认识。     

以PD-1 为靶点的抗肿瘤药物专利现状分析

PD-1(程序性死亡受体1)是一种重要的免疫抑制分子,其与癌症的治疗密切相关。目前FDA(美国食品药品监督管理局)已经批准了PD-1抑制剂抗体作为癌症治疗药,因此,PD-1具有极高的研究和应用价值。目前在专利领域,全球各大药企均已经开始专利布局,而在中国申请的专利也是日趋增多,对于我国企业来说,把握时机提前布局专利申请,有利于识别竞争对手,抢占市场。本文通过分析以PD-1为靶点的药物专利现状,特别是研究的重点领域,专利申请的国内重点布局等方面,为国内的申请人未来的研发方向和专利布局提供适当的指引。     

Intracellular antibody capture: A molecular biology approach to inhibitors of protein–protein interactions

Many proteins of interest in basic biology, translational research studies and for clinical targeting in diseases reside inside the cell and function by interacting with other macromolecules. Protein complexes control basic processes such as development and cell division but also abnormal cell growth when mutations occur such as found in cancer. Interfering with protein–protein interactions is an important aspiration in both basic and disease biology but small molecule inhibitors have been difficult and expensive to isolate. Recently, we have adapted molecular biology techniques to develop a simple set of protocols for isolation of high affinity antibody fragments (in the form of single VH domains) that function within the reducing environment of higher organism cells and can bind to their target molecules. The method called Intracellular Antibody Capture (IAC) has been used to develop inhibitory anti-RAS and anti-LMO2 single domains that have been used for target validation of these antigens in pre-clinical cancer models and illustrate the efficacy of the IAC approach to generation of drug surrogates. Future use of inhibitory VH antibody fragments as drugs in their own right (we term these macrodrugs to distinguish them from small molecule drugs) requires their delivery to target cells in vivo but they can also be templates for small molecule drug development that emulate the binding sites of the antibody fragments. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.     

The effect of pharmaceutical innovation on longevity: Evidence from the U.S. and 26 high-income countries

This study examines the impact that pharmaceutical innovation, which accounts for most private biomedical research expenditure, has had on longevity. We perform two types of two-way fixed-effects analyses, which control for the effects of many potentially confounding variables. First, we analyze long-run (2006–2018) changes in longevity associated with different diseases in a single country: the U.S. Then, we analyze relative longevity levels associated with different diseases in 26 high-income countries during a single time period (2006–2016). The measure of longevity we analyze, mean age at time of death, is strongly positively correlated across countries with life expectancy at birth. The measure of pharmaceutical innovation we use is the mean vintage (year of initial world launch) of the drugs used to treat each disease in each country. Changes in the vintage distribution of drugs are due to both entry of new drugs and exit of old drugs. Our analysis of U.S. data indicates that the diseases for which there were larger increases in drug vintage tended to have larger increases in the longevity of Americans of all races and both sexes. In other words, the lower the mean age of the drugs, the higher the mean age at death. We test, and are unable to reject, the “parallel trends” hypothesis. We estimate that the 2006–2018 increase in drug vintage increased the mean age at death of Americans by about 6 months (66% of the observed increase). Controlling for sex, race, and education has only a small effect on the estimate of the vintage coefficient. The estimates indicate that drug vintage did not have a significant effect on the mean age at death of decedents with less than 9 years of education. Drug vintage had a positive and significant effect on the mean age at death of decedents with at least 9 years of education, and a larger effect on the mean age at death of decedents with at least 13 years of education. The finding that pharmaceutical innovation has a larger effect on the longevity of people with more education is consistent with previous evidence that more educated people are more likely to use newer drugs. Our analysis of data on 26 high-income countries indicates that the higher the vintage of drugs available to treat a disease in a country, the higher mean age at death was, controlling for fixed disease and country effects. The increase in drug vintage is estimated to have increased mean age at death in the 26 countries by 1.23 years between 2006 and 2016—73% of the observed increase. We obtain estimates of the cost of pharmaceutical innovation—its impact on drug expenditure—as well as estimates of an important benefit of pharmaceutical innovation—the number of life-years gained from it—and of their ratio, i.e., the incremental cost-effectiveness ratio. Estimates of the cost per life-year gained for the U.S. and the 26 countries are $35,817 and $13,904, respectively. Both figures are well below per capita GDP in the respective regions, suggesting that, overall, pharmaceutical innovation was highly cost-effective.