浅析中药注射剂的安全性评价

为了提高中药注射剂非临床安全性评价的质量,减少临床不良反应的发生,本文明确提出中药注射荆安全性评价应该进行安全性药理学、急毒、长毒、局部刺激、溶血性、过敏性、光毒性、生殖毒性、遗传毒性、致癌、药代毒代等11项实验,并且,指出在今后的工作中应该加强研究的规范化,注重过敏性、溶血性、刺激性试验研究,强调对已上市品种安全性的再评价,重视配伍用药的安全性评价。     

符合GLP法规的计算机系统管理

目的:讨论GLP管理与计算机管理在药物安全评价领域中如何有效的结合。方法:分析药物安全评价中计算机系统如何符合GLP法规管理的基本原则。结果:将计算机管理纳入到GLP日常管理的范围,能保证所使用的系统安全可靠,数据真实有效。结论:符合GLP法规的计算机管理将确保药物安全评价工作更加规范。     

对药物非临床实验管理规范（GLP）的历史回顾及其辩证思考

药品非临床实验管理规范（G凹）是国家为保证新药临床前研究安全性试验资料的优质、真实、完整和可靠,针对药物安全性评价研究机构制定的基本要求。本文回顾了GLP的出现及发展历程,客观辩证了在GLP发展过程中新药研发与安全评价的关系、GLP实施与新药开发的矛盾等,提出对于我国未来GLP发展的见解。     

组织病理学评估及同行评议的原始数据及GLP符合性解读

组织病理学评估是药物非临床安全性评价的重要环节，组织病理学同行评议不仅可以确保诊断术语的一致性和准确性，而且可以提高病理诊断的准确性和病理学报告的质量。因为GLP质量体系的核心是原始数据，所以要确保最终病理学报告能够真实反映原始数据。组织病理学评估和同行评议的原始数据是病理学报告重建和保证报告质量的基础。本文对国内外GLP法规对原始数据的定义、美国FDA对病理学原始数据的规定、国内外监管机构对组织病理学同行评议中原始数据的规定、不同类型组织病理学同行评议中的原始数据以及组织病理学同行评议的GLP符合性进行分析，希望为我国GLP机构更好地开展组织病理学评估及同行评议提供一定参考。     

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non‐human primate model of Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease‐modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon‐like peptide‐1 (GLP‐1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD‐linked amyloid‐β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non‐human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD‐related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP‐1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Recognition of H3K9 methylation by GLP is required for efficient establishment of H3K9 methylation,rapid target gene repression,and mouse viability

GLP and G9a are major H3K9 dimethylases and are essential for mouse early embryonic development. GLP and G9a both harbor ankyrin repeat domains that are capable of binding H3K9 methylation. However, the functional significance of their recognition of H3K9 methylation is unknown. Here, we report that the histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes that are premethylated at H3K9. These stimulation events function in cis and are dependent on the H3K9 methylation binding activities of ankyrin repeat domains of GLP and G9a. Disruption of the H3K9 methylation-binding activity of GLP in mice causes growth retardation of embryos, ossification defects of calvaria, and postnatal lethality due to starvation of the pups. In mouse embryonic stem cells (ESCs) harboring a mutant GLP that lacks H3K9me1-binding activity, critical pluripotent genes, including Oct4 and Nanog, display inefficient establishment of H3K9me2 and delayed gene silencing during differentiation. Collectively, our study reveals a new activation mechanism for GLP and G9a that plays an important role in ESC differentiation and mouse viability.     

Renal crystal formation after combined or sequential oral administration of melamine and cyanuric acid

We evaluated renal melamine–cyanurate crystal spherulite formation after single and repeated ingestion of both melamine (MEL) and cyanuric acid (CYA) in catfish and trout. MEL and CYA were co-administered orally over a range of doses, 0.1–20 mg/kg body weight (bw) of each compound, either once or repeatedly for 4, 14 or 28 days (d). In catfish, the No Observable Adverse Effects Levels (NOAELs) for crystal formation for single, 4 d or 14 d dosing were 10, 2.5 and 0.5 mg/kg bw, respectively. In trout, the respective NOAELs were 2.5, 2.5 and 0.5 mg/kg bw. No renal crystals formed in catfish fed 0.1 mg/kg bw of each compound for 28 d. Sequential administration of 20 mg/kg bw of MEL followed by 20 mg/kg bw of CYA or vise-versa, with waiting periods of 1, 3, 7, 14 or 21 d between compound dosing also induced renal crystal formation in fish. These studies show that both catfish and trout are sensitive, non-mammalian models, for renal crystal formation following MEL and CYA ingestion. Since fish generally excrete chemicals more slowly than mammals, they may provide a “worst case scenario” model for higher risk populations, such as infants or persons with compromised renal function.     

对GLP的认识

[目的 ]介绍GLP的概念和意义。 [方法 ]总结本单位实践经验。 [结果 ]GLP国际统称英文名为“GoodLaboratoryPractice ,简称GLP” ,从词意可译成“实行标准 (或好的 )实验室”。GLP的性质是一个规范的管理性文件 ;它的作用是使实验室工作规范标准 ,使每一个记录、每一个数据有根有据有理 ,有据可查 ,保证其研究质量 ;它的目的是提高新药安全评价的水平和保证人们用药安全有效 ;它的适用范围不仅是药物的临床前研究 ,也包括其他化合物 (包括人类直接或间接用的一切物品 ,如食品、保健品、农药、医疗产品、日用品等 )的疗效、机制、毒性等研究 ;它的研究内容以常规临床前研究为主。要实施GLP ,做好GLP实验室的工作 ,首先必须对GLP要有一个全面、深入的、充分的认识 ,只有充分认识GLP的性质、作用和意义 ,才会知道GLP的重要性和必要性 ,才会去实施执行GLP。才能做好GLP工作。[结论 ]从提高对GLP的认识着手 ,严格执行GLP ,才能提高实验室工作质量     

A 90-day oral toxicity study on a new strain of Lactobacillus paracasei in rats

Lactobacillus paracasei is a species of bacteria that has been suggested to have probiotic benefits. To investigate the subchronic toxicity of L. paracasei GW080, a 90-feeding study was conducted in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and treated with 0, 1.25, 2.5, and 5.0 g/kg body weight (approximately equivalent to 0, 2.5 × 10⁹, 5.0 × 10⁹ and 1 × 10¹⁰ cfu/kg bw) of test material by gavage for 90 days. Daily clinical observations and weekly measurement of body weights and food consumption were conducted. Blood samples were obtained on day 46 and day 91 for the measurement of hematology and clinical chemistry parameters. Animals were euthanized for necropsy. Selected organs were weighted and recorded. Histological examination was performed on all tissues from animals in the control and high dose groups. No mortality, body weight, food consumption or treatment-related findings in clinical observations, macroscopic or microscopic examinations were observed. Differences between treated and control groups in some hematology and clinical chemistry parameters were not considered treatment-related. The no-observed-adverse-effect-level (NOAEL) for L. paracasei GM080 was considered to be 5.0 g/kg body weight (approximately equivalent to 1 × 10¹⁰ cfu/kg bw) for both genders, the highest dose tested.