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《中国药理学与毒理学杂志》2017,(6)
药物性肝损伤(DILI)是导致药物研发终止或从市场撤回的重要原因之一,建立可预测、高通量的临床前检测系统以评估临床潜在的肝毒性是药物研发的迫切需要。基于细胞成像的高内涵筛选(HCS)技术,允许同时检测多个细胞参数,通过实时监测多种信号通路阐明细胞损伤的机制,具有高度的敏感性和特异性。目前已有多种肝细胞模型用于高内涵毒性筛选。本文介绍了HCS技术,回顾了近年来利用高内涵成像技术获得的药物肝毒性资料,探讨了其在肝毒性机制探索中的应用,以及高内涵成像技术在DILI研究中的作用。 相似文献
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高内涵分析在新药发现毒理学中的应用进展 总被引:1,自引:1,他引:0
在新药发现早期开展发现毒理学研究是提高新药研发效率的重要策略之一。高内涵分析(HCA)是基于高效新药筛选需求发展起来的一项新技术,其主要特点是基于活细胞、多参数、实时、高通量,能够实现化合物多种生物活性、毒性的早期、快速地检测,为发现毒理学研究提供了高效的技术手段。目前,HCA已用于多种靶器官细胞毒性、遗传毒性、神经毒性、血管毒性、生殖毒性等检测以及毒理学分子机制的研究,本文就HCA在新药发现毒理学方面的应用进展进行综述。 相似文献
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几类常用药物的肝毒性 总被引:2,自引:0,他引:2
药物的不良反应无疑是医务工作者在工作中经常面临的问题,而药源性肝病在药物常见不良反应中占相当比率。非甾体抗炎药、降压药、降糖药、抗惊厥药、降血脂药和抗精神失常药都是临床常用药物,让医生充分了解这些药物的肝毒性对于提高临床用药的安全性是非常重要的。 相似文献
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高内涵药物筛选方法的研究及应用 总被引:7,自引:0,他引:7
高通量药物筛选 (high throughputscreening,HTS)是 20世纪 80年代中期产生的为寻找先导物针对大量样品进行药理活性评价分析的一种技术手段,在创新药物的研究和开发中发挥了重要作用。本室于 1998年在国内率先将其用于创新药物的研究,已发现一批具有潜在研究价值的化合物 [1, 2]。近年来在药物发现领域又出现了一个新概念———高内涵药物筛选 (high contentscreening,HCS)。本文就高内涵药物筛选目前的研究和应用情况作一讨论。1 高通量药物筛选与高内涵药物筛选高通量药物筛选是以药物发现的基本规律为基础,应用药理学、生物化学… 相似文献
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抗逆转录病毒药物的肝毒性 总被引:2,自引:0,他引:2
刘靖 《国外医学(药学分册)》2005,32(5):335-338
肝毒性是与应用抗逆转录病毒药物(ART)相关的不良反应,在治疗HIV感染时可增加患者的发病率和病死率,影响HIV感染的治疗.可能的机制包括直接的药物毒性、丙型肝炎病毒和(或)乙型肝炎病毒同时感染中的免疫重建、与肝相关的过敏性反应和线粒体毒性,还可能涉及其他致病途径.高活性抗逆转录病毒药物治疗(HAART)与转氨酶水平的升高相关.在HAART中每个单独的药物在肝毒性的发展中所起的作用难以确定.仍不清楚大多数ART肝毒性的发病率. 相似文献
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丙戊酸药物肝毒性的研究进展 总被引:1,自引:0,他引:1
药物肝毒性是临床医师和患者十分关注的问题。英国药物安全委员会对1964~2000年间英国儿童致死性药物副作用统计发现,最常见的死因为肝功衰竭,占15.11%(50/331)。引起肝功衰竭的主要药物是丙戊酸盐类药物(Valproic acid,VPA),占9.37%(31/331)。VPA引起的致死性肝坏死更容易发生在婴儿。因此,深入研究VPA肝毒性的发生机理和防治措施,对防治该药毒副作用,促进该药在临床的安全应用,均有重要意义。 相似文献
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药物肝毒性临床监测及其存在的问题 总被引:5,自引:2,他引:3
肝脏是药物在体内代谢的最主要场所,很多药物在体内发挥防治疾病作用的同时,也会在肝内生物转化过程中引起毒性反应,甚至造成致命性的暴发性肝功能衰竭.在已上市应用的化合性或生物性药物中,有1100种以上的药物具有潜在的肝毒性,很多药物的赋形剂、中草药以及保健药亦有导致肝损伤的可能[1].充分认识药物肝毒性的危险性,密切观察用药后出现的肝脏生化检测异常,采用较为规范的药物性肝损伤的诊断标准,特别注意防止发生重症药物性肝损伤等问题,在药物肝毒性的临床检测中具有重要意义. 相似文献
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Yadolah Fakhri Mohammad Rasoul Hadiani Hassan Keramati Rokhsane Hosseini Pouya Bigard Moradi 《Toxin reviews》2017,36(4):313-321
Recently, the exposure to heavy metals from bottled waters raised huge concerns. In this context, for the first time the risk of non-carcinogenic exposure by the heavy metals in Iranian drinking water was assessed. Therefore, by using the obtained data in our previous published study, the target hazard quotient (THQ) and total target hazard quotient (TTHQ) by considering to the sexuality of consumers were calculated. THQ in females were determined as significantly higher (p?.05) in comparison with the males. The rank order of heavy metals based on THQ was As?>?Pb?>?Hg?>?Cd?>?Cu, respectively. The minimum and maximum of THQ for the males were observed in age groups of?+65 and 1–3?years, respectively. The minimum and maximum of THQ for females were noted in age groups of 11–14 and 1–3?years, respectively. Since TTHQ for all ages were less than 1 (p?.05), the consumers are not exposed to the non-carcinogenic risk by the heavy metals in the bottled water. 相似文献
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Environmental risk assessment of pharmaceutical drug substances--conceptual considerations 总被引:2,自引:0,他引:2
Drugs, i.e. active ingredients of human medicinal products, may be introduced into the environment after use in patients by sewage effluent pathways and consequently are detected at low concentrations in sewage effluents and in surface waters. Legal requirements in a number of geographical regions (Europe, US, and intended in Canada) demand environmental risk assessments (ERA) for new drug substances. Existing regulatory concepts of ERA are based initially on a set of short-term ecotoxicological studies in three to four different species, environmental behavior and the application of assessment factors to correct for the ERA inherent uncertainty. Based on theoretical considerations and the experience with a very limited, but well investigated, number of examples while considering that drugs are highly biologically active compounds, the appropriateness of this risk assessment procedure for all drug substances might be questioned. Indeed, e.g. long-term effects may occur at much lower concentrations and follow different toxicodynamic mechanism than extrapolated from short-term studies., In such cases, the application of assessment factors for deriving chronic no-observed effect concentration (NOECs) appears to be problematic. Although long-term tests with a variety of organisms would provide a complete database for the evaluation of the environmental risks, this is unachievable for all drugs due to time, money and animal welfare constraints. In order to avoid unnecessary testing, a concept is presented, which makes use of pharmacological and toxicological, as well as pharmaco- and toxicokinetic information derived from mammals during drug substance development. Useful data for adoption in a case-by-case testing strategy can be obtained by evaluating (a) the pharmacological activity, which indicates specific targets in mammalian species and may allow for an analysis, whether a similar target is available in aquatic species; (b) the mammalian toxicity, which may indicate, which targets are most susceptible to adverse effects; (c) the difference between acute and chronic effects in mammals, since the magnitude of this difference may indicate, whether long-term effects are expected at significantly lower levels than acute effects; (d) the (pharmacologically and toxicologically) effective plasma levels in mammalian test organisms, which may be compared with the relevant exposure scenario for the environment. Additionally, activity classes of compounds may be established based on experience with specific substances, in order to develop an appropriate test strategy. The above preliminary considerations should support decisions on the selection of candidate substances for chronic effects studies and for the appropriate selection of test species and endpoints to monitor. Generally, ecologically relevant endpoints such as impairment of growth, development and reproduction should be used to assess the ecotoxicologic effects. 相似文献
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Advances in high content screening for drug discovery 总被引:5,自引:0,他引:5
Cell-based target validation, secondary screening, lead optimization, and structure-activity relationships have been recast with the advent of HCS. Prior to HCS, a computational approach to the characterization of the functions of specific target proteins and other cellular constituents, along with whole-cell functions employing fluorescence cell-based assays and microscopy, required extensive interaction among the researcher, instrumentation, and software tools. Early HCS platforms were instrument-centric and addressed the need to interface fully automated fluorescence microscopy, plate-handling automation, and seamless image analysis. HCS has since evolved into an integrated solution for accelerated drug discovery by encompassing the workflow components of assay and reagent design, robust instrumentation for automated fixed-end-point and live cell kinetic analysis, generalized and specific BioApplication software (Cellomics, Pittsburgh, PA) modules that produce information on drug responses from cell image data, and informatics/bioinformatics solutions that build knowledge from this information while providing a means to globalize HCS throughout an entire organization. This review communicates how these recent advances are incorporated into the drug discovery workflow by presenting a real-world use case. 相似文献
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目的:构建超说明书用药风险评估体系,实现超说明书用药风险分级管理,为医疗实践提供操作指导.方法:利用德尔菲法、问卷调查法和进行小组研讨会等方法,考察超说明书用药过程中可能发生的风险条目,调查各超说明书用药风险条目的可能性并完成严重性量化评估.根据评估结果,利用风险矩阵分析及Borda序值法进行风险分级.结果:超说明书用... 相似文献
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Objectives: Company observational post-marketing studies (COPS) claim to provide essential data about drug risks and effectiveness in
special populations not admitted to pre-approval clinical trials. Since COPS are often mainly regarded as a marketing activity,
this study-based analysis tries to evaluate the scientific contributions of COPS.
Material and methods: Thirty-five COPS were identified by hand-searching through medical journals, writing to pharmaceutical manufacturers and
using MEDLINE. Fourteen COPS evaluated cardiovascular drugs, 9 evaluated NSAIDs and 12 evaluated various other indications.
Results: Thirty-five COPS listed effectiveness, 31 listed safety and 8 listed patient compliance as principal objectives. Not a single
COPS included a control group. Seventeen of 21 evaluable COPS mentioned extensive exclusion criteria similar to those in clinical
trials. Median observation time was 8 weeks, too short for chronic diseases and for adverse drug reactions with longer latency
periods. One new adverse event was regarded. Global assessments of the outcomes by physicians dominated and were not based
on objective clinical findings. None of the studies specified any details concerning the standardisation of observations or
quality-control procedures.
Discussion and conclusion: The current COPS scheme does not contribute significantly to our knowledge of drug safety and the effects in special populations.
Despite serious criticism over the past 20 years, the poor quality of COPS – compared with dramatic improvements of pre-approval
trials – implies a need for detailed guidelines for non-experimental phase IV research, similar to the Good Clinical Practice-Guideline
of the European Community.
Received: 13 June 1997 / Accepted in revised form: 4 August 1997 相似文献
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Yadolah Fakhri Anoushiravan Mohseni-Bandpei Gea Oliveri Conti Yahya Zandsalimi Nazak Amanidaz 《Toxin reviews》2017,36(4):342-351
Long-term intake of water with high content of trihalomethanes (THMs) such as chloroform (CHCl3) is hazardous for human health. Some studies have shown that clinical effects of THMs in drinking water may be yet observed to doses lower to standard limit. In our study, we performed a meta-analysis to assess both the mean concentration of CHCl3 in Iranian drinking water and the relative health effects by long-term exposure to safe dose of CHCl3 in the male and female age groups and in female categories. We applied the Target Hazard Quotient (THQ) for the evaluation of the noncarcinogenic risk of CHCl3. Meta-analysis (14 studies) showed that the average concentration of CHCl3 was 24?µg/l (95%CI:18.1–30.1?µg/l), I2?=?99.88, p?.001. Minimum and maximum concentrations of CHCl3 was related to Mashhad (3.5?±?0.5?µg/l) and Mazandaran (57.3?±?13.1?µg/l) province, respectively. The average concentration of CHCl3 in the all studied provinces was lower than USEPA (70?µg/l) and national standard limits (200?µg/l). The minimum and maximum THQ was related to?<0.5 and 15–19?years age groups in both the males and females. The rank order of THQ in the female categories was females aging 15–44 (0.074)>?non-pregnant and non-lactating females age 4–15 (0.071)?>?pregnant (0.071)?>?lactating (0.043). The THQ in the females was higher than males, non-significantly (p?>.05). Except Mazandaran province, in other provinces both males and females, for all age groups, were not exposed to significant risks by non-carcinogenic exposure of CHCl3 in drinking water (THQ <1). 相似文献
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This paper explores the social inclusion of the illicit drug user. It does this through a comparative examination of policy orientations to the social inclusion of people who use drugs. Six policy documents from Canada and Scotland produced in the years 2000 and 2001 were systematically sampled from 42 known documents. A poststructural content analysis adapted from the work of Maarten Hajer and mapped onto an analytic frame derived from Nikolas Rose’s Governing the Soul: The Shaping of the Private Self is conducted. Within the years considered, drug policy texts from Scotland signaled a more punitive approach to drug use and a less socially inclusive approach to people who used drugs than drug policy texts from Canada. The differences in policy directions identified were in keeping with a priori interpretations of each country’s broad approach to illicit drug use and to the social inclusion of the illicit drug user, if not to social inclusion itself. Methodologically, combining the approaches of Hajer and Rose proved complimentary and useful as well as promising for future application to the content analysis of public discourse. 相似文献