Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

甲型流感病毒非结构蛋白1抑制干扰素抗病毒反应的研究进展

IFN-α/β是机体对抗外来病原体的第一道防线，其产生和后续激活的细胞信号转导可诱导具有抑制病毒感染和复制作用的IFN刺激基因的表达。然而，大多数病毒可通过表达一种或多种蛋白抵抗宿主细胞的抗病毒反应。流感病毒非结构蛋白1（nonstructural protein 1，NS1）作为多功能毒力因子，在流感病毒感染过程中起重要作用。此文概述了NS1的结构与功能及抑制IFN-α/β产生和抗病毒效应作用的机制，为研究流感病毒致病机理提供参考。     

益心舒胶囊治疗病毒性心肌炎的临床观察

目的：观察益心舒胶囊对病毒性心肌炎临床疗效。方法：将115例病毒性·,22肌炎患者以随机抽样法分为治疗组和对照组，其中治疗组60例，对照组55例，2组患者均常规给予5％葡萄糖注射液250ml＋三磷酸腺苷（ATP）40mg＋辅酶A200＋维生素C5．0g静脉滴注治疗，1日1次，治疗2周；治疗组患者在常规治疗的基础上，口服益心舒胶囊1次3粒，1日3次，疗程为4周。观察治疗前后2组患者的临床症状、心电图及心肌酶谱等变化。结果：治疗组患者临床症状、心电图、心肌酶谱的改变均明显优于对照组，2组比较差异有统计学意义（P〈0．05）；2组患者治疗前后血尿常规、肝肾功能等各项指标均无异常变化，未见明显不良反应。结论：益心舒胶囊治疗病毒性心肌炎有良好疗效，且安全性好，体现了中药的独特优势。     

Evaluation of five circulating strains of variant infectious bursal disease virus (varIBDV) for their immunogenicity as broiler breeder vaccines and protective efficacy in neonatal broiler chicks

The majority of infectious bursal disease virus (IBDV) strains circulating in the broiler chicken industry in Canada are variant strains (varIBDV). Despite high levels of maternally derived antibodies (MtAb), the circulating varIBDVs can establish infection and cause severe immunosuppression in broiler chicks. The objective of this study was to evaluate circulating varIBDVs as broiler breeder vaccine candidates and investigate their protective efficacy against varIBDV challenge in their progeny chicks. Six groups of breeders (20 females/group) were vaccinated with varIBDV strains, SK09, SK10, SK11, SK12, and SK13 or saline at the age of 13 weeks and antibody response was determined by ELISA at 3–7-, and 20- weeks post-vaccination. We also included commercial chicks for the comparison. Results showed that SK-09 is the most antigenic strain, followed by SK-10, SK-12, and SK-13. In contrast, SK-11 showed the lowest antibody response, and over time, antibody titers steadily decreased. Eggs from breeders were collected at 21-week post-vaccination and incubated to produce their respective progenies. The serum antibody titer in day-old chicks showed a successful MtAb transfer. Progeny chicks (n = 40/group) were orally challenged with varIBDV-SK-09 strain at 6 days of age and serum antibody titer (19 d and 35 d of age), bursa to body weight ratio (19 d and 35 d of age), bursal viral load (9 d and 19 d of age) was examined to assess the protection against IBDV. Following the challenge, we found a significant increase in the antibody titers in MtAb-free and commercial vaccine groups than in the varIBDV groups, both at 19 d and 35 d of age. The BBW ratio and viral load data indicated a significant homologous and heterologous protection against varIBDV-SK-09 challenge by SK-09 and SK-10 MtAbs, respectively. Overall, this study demonstrated the feasibility of developing breeder vaccines using circulating varIBDV as candidate vaccine antigens.     

慢性乙型肝炎患者病毒复制与肝纤维化五项联合检测的临床应用

目的探讨慢性乙型肝炎患者乙型肝炎病毒(HBV)DNA复制与肝纤维化五项指标:透明质酸(HA)、Ⅲ型前胶原N端肽(PⅢPN)、Ⅳ型胶原(CⅣ)、层粘连蛋白(LN)、甘胆酸(CG)联合检测的临床意义。方法选取2018年7月至2019年9月在汉川市人民医院确诊的慢性乙型肝炎患者109例为研究对象,选取40例健康体检者为对照组,按HBV DNA的载量,将研究对象分为低载量组(104copy/mL)39例,中载量组[(104～106)copy/mL]33例,高载量组(106copy/mL)37例,对照组(500 copy/mL)40例。分别检测HBV DNA和肝纤维化五项,采用SPSS 19.0统计学软件对数据进行统计分析。结果低载量组和中载量组肝纤五项检测结果与对照组比较,差异无统计学意义(P0.05);高载量组肝纤五项检测结果与对照组比较,差异有统计学意义(P0.05)。随着HBV DNA载量的增加,肝纤五项各检测指标的数值也在增加。肝纤五项(HA、PⅢPN、CⅣ、LN、CG)的ROC曲线下面积(AUC)分别为0.556、0.763、0.742、0.420、0.695,其中PⅢPN的AUC最大,表明PⅢPN比其他指标对肝脏疾病的诊断准确率最高;LN的AUC最小,0.5,表明其单独诊断的准确率低。结论 HBV DNA载量与血清肝纤维化五项指标联合检测是慢性乙型肝炎患者病情监测的一个良好指标,临床应及时关注慢性乙型肝炎患者病毒复制与肝纤维化水平,延缓肝硬化的发生。     

更昔洛韦治疗小儿手足口合并病毒性脑炎122例疗效观察

目的：探讨更昔洛韦治疗小儿手足口合并病毒性脑炎的临床疗效。方法：122例患儿按入院顺序随机分为研究组和对照组，各61例，所有患儿均根据临床不良反应给予对症的物理降温、水电解质平衡纠正、补液、抗病毒治疗、脑神经营养等，研究组在此基础上加用更昔洛韦。结果：经治疗研究组患儿总有效率明显高于对照组，数据经统计学比较具有显著差异(P<0.05)。患儿退热时间比较两组间数据无显著差异(P>0.05)，研究组疱疹消退时间、神经体征缓解时间和平均住院时间均明显短于对照组，数据经统计学比较具有极显著差异(P<0.01)。结论：更昔洛韦不仅可达到更好的治疗效果，还有助于提高治疗效率、加快改善患儿的临床不良反应，适合于手足口病合并病毒性脑炎的临床治疗。     

儿童细菌性脑膜炎与病毒性脑炎临床及实验室检查特点

目的研究儿童细菌性脑膜炎与病毒性脑炎临床特点及血清基质蛋白金属酶-9(MMP-9)、降钙素原(PCT)、β2-微球蛋白(β2-MG)及C-反应蛋白(CRP)水平,分析各指标对两者鉴别诊断价值。方法选取2017年10月-2019年10月郑州大学附属儿童医院细菌性脑膜炎和病毒性脑炎患儿共80例,其中细菌性脑膜炎组49例,病毒性脑炎组31例,观察患儿症状,同时检测血清MMP-9、PCT、β2-MG和CRP水平并进行比较,作受试者工作特征曲线(ROC)分析各指标对细菌性脑膜炎和病毒性脑炎鉴别诊断价值。结果细菌性脑膜炎组患儿意识障碍、囟门张力增加和肺炎发生率高于病毒性脑炎组,精神萎靡、嗜睡和皮疹发生率低于病毒性脑炎组,差异有统计学意义(P<0.05);细菌性脑膜炎组血清MMP-9、PCT、β2-MG和CRP水平高于病毒性脑炎组,差异有统计学意义(P<0.05);意识障碍、肺炎以及血清CRP和PCT水平对细菌性脑膜炎和病毒性脑炎患儿鉴别诊断的敏感度分别为46.93%、46.93%、75.51%和83.67%,特异度分别为77.42%、80.65%、83.87%和90.32%,各指标联合诊断的曲线下面积为0.917,敏感度为91.84%,特异度为83.87%。结论细菌性脑膜炎和病毒性脑炎患儿临床特点和血清MMP-9、PCT、β2-MG和CRP水平均存在明显差异,综合各项指标进行分析可为临床鉴别诊断提供参考信息。