网络毒理学及其在中药毒性成分预测中的应用研究

为了了解与掌握网络毒理学研究方法及其在中药毒性成分预测中的应用;简介网络毒理学的概念,分析了网络毒理学的研究思路,总结了相关毒性预测工具与软件,概述了毒性预测的方法与研究思路,重点综述了网络毒理学在中药肝毒性、肾毒性成分、心脏毒性成分与急性毒性成分预测中的具体应用;随着现代计算机技术的发展,网络毒理学已经广泛应用于中医药相关领域,尤其在中药毒性成分预测中,更是发挥着重要的作用;随着中医药的现代化,人们更深刻的认识了中药的毒性成分,迫切需要用现代技术方法对中药毒性进行预测与评价,为进一步认识和发展网络毒理学及其在中药毒性成分预测中的应用提供了参考依据。     

高内涵分析在新药发现毒理学中的应用进展

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。     

深度学习模型在中药毒性预警中的应用和前景

中药潜在毒性成分的早期筛查是中药新药研发面临的一大难题.在基于"结构预警子-毒性"关系开发的机器学习模型中,使用深度学习算法构建的机器学习模型脱颖而出,有望成为新一代中药毒性预测的杰出工具.本文综述了深度学习模型基于"结构预警子-毒性"关系预测化合物毒性的机制以及深度学习模型在预测药物分子的毒性、预测反应性代谢产物的形...     

D101型大孔吸附树脂在分离纯化三萜皂苷方面的应用

大孔吸附树脂是20世纪60年代发展起来的一类吸附剂,具有良好的吸附性能,近10余年来逐渐被应用于中药化学成分的提取分离…和中药新药的开发研制[2],尤其是对水溶性化合物的分离有独特效果[3].笔者在研究中药中三萜皂苷类化学成分的提取分离时,对D101型大孔吸附树脂的应用积累了一定的经验,并取得了较好的分离效果.因此,本文对此方面内容进行了总结,以期促进其在化学领域方面的进一步应用与发展.     

遗传毒性早期初筛试验方法的研究进展

遗传毒性评价是药物临床前安全性评价研究的重要环节,目前ICH推荐的的标准试验组合基本能够满足新化学实体注册遗传毒理学实验数据的需求。然而随着全程式毒理学研究模式的推进,各制药公司越来越重视在创新药物研发早期进行遗传毒性初筛,及早发现具有潜在遗传毒性的候选化合物,降低新药开发的风险。作为在新药研发早期用于遗传毒性初筛的试验方法,除了要求灵敏、快速、经济外,还必须尽量减少化合物的用量,逐步实现高通量和自动化的要求。文中综述了目前研究比较广泛的早期体外遗传毒性初筛试验方法的原理、检测终点和应用进展,为候选化合物的早期遗传毒性初筛工作的深入开展提供技术指导。     

全氟烷酸类化合物的毒理学研究

全氟烷酸类化合物是一类新型的持久性有机污染物,已被广泛应用于工业生产以及生活用品中,在全球各地的环境介质和人群中均检测到了该化合物的存在,该类化合物的环境健康效应已经引起了广泛的关注。本文对该化合物的特征、来源、毒代动力学特征、毒性效应以及相关的机制进行了总结,以进一步了解该化合物毒理学方面的研究进展。     

全氟烷酸类化合物的毒理学研究

全氟烷酸类化合物是一类新型的持久性有机污染物，已被广泛应用于工业生产以及生活用品中，在全球各地的环境介质和人群中均检测到了该化合物的存在，该类化合物的环境健康效应已经引起了广泛的关注。本文对该化合物的特征、来源、毒代动力学特征、毒性效应以及相关的机制进行了总结，以进一步了解该化合物毒理学方面的研究进展。     

近年来中草药化学成分及其衍生物和类似物的合成研究

近十年来我国中草药化学成分及其衍生物和类似物的化学合成研究,已取得了极大的进展。一些中草药有效成分人工合成成功,有的已应用于临床。许多中草药有效成分被选为先导化合物,有目的地进行结构改造,合成了大量新化合物;从构效关系研究中,发现了不少生物活性优于母体的化合物,有的已开发成为新药。这些研究使我国天然药物化学的研究达到了一个新的水平。本文就近十年来的研究进展按化学结构分类综述如下。     

中药一类新药的特殊毒理、药代动力学技术问题的讨论

在国际医药产业竞争日益激烈的今天,随着我国加入WTO,传统的医药产业受到了前所未有的挑战.面对国际医药产业的发展形势,如何使有着几千年传统的中医药在知识经济的时代焕发新的生命力,是我们亟待解决的问题.近年来,中药新药的研发正日渐成为热点,尤其是利用现代科学技术,从中药(或天然药物中)筛选出活性强的有效成分,开发一类中药新药,成为新药研发的一大方向.在这种情况下,中药一类新药的申报品种也日益增多,而目前对中药一类新药的技术审评尚缺乏公认的规范化要求,因此对中药一类新药的药理毒理学研究制定出一个可操作性的技术要求是当前面临的首要任务.本文根据我国药品审评中的实际情况,对中药一类新药的药理毒理学和药代动力学等有关技术研究中的问题进行初步的研讨.     

发现毒理学和病理学在设计更安全的先导化合物中的应用

毒性是药物在开发过程中被淘汰的首要原因。大多数安全性相关的药物淘汰发生在临床前,提示在药物开发过程中早期预测药物的毒性有利于设计出上市概率更高的候选化合物。本文介绍了如何通过早期应用新的分子技术,以及传统重复给药的毒理学研究开展临床前安全性评价,确定具有预测价值的毒性事件。早期识别剂量限制性毒性既有助于化学家和毒理学家了解毒性特点、确定结构与毒性之间的关系,也利于最大限度地减少或避免安全性问题。     

Toxicity assessment of unintentional exposure to multiple chemicals

Typically exposure to environmental chemicals is unintentional, and often the exposure is to chemical mixtures, either simultaneously or sequentially. When exposure occurs, in public health practice, it is prudent to ascertain if thresholds for harmful health effects are exceeded, whether by individual chemicals or by chemicals in combination. Three alternative approaches are available for assessing the toxicity of chemical mixtures. Each approach, however, has shortcomings. As the procedures of each approach are described in this paper, at various steps research needs are identified. Recently, reliance has increased on computational toxicology methods for predicting toxicological effects when data are limited. Advances in molecular biology, identification of biomarkers, and availability of accurate and sensitive methods allow us to more precisely define the relationships between multiple chemical exposures and health effects, both qualitatively and quantitatively. Key research needs are best fulfilled through collaborative research. It is through such collaborations that resources are most effectively leveraged to further develop and apply toxicity assessment methods that advance public health practices in vulnerable communities.     

Toxicity assessment of industrial chemicals and airborne contaminants: transition from in vivo to in vitro test methods: a review

Exposure to occupational and environmental contaminants is a major contributor to human health problems. Inhalation of gases, vapors, aerosols, and mixtures of these can cause a wide range of adverse health effects, ranging from simple irritation to systemic diseases. Despite significant achievements in the risk assessment of chemicals, the toxicological database, particularly for industrial chemicals, remains limited. Considering there are approximately 80,000 chemicals in commerce, and an extremely large number of chemical mixtures, in vivo testing of this large number is unachievable from both economical and practical perspectives. While in vitro methods are capable of rapidly providing toxicity information, regulatory agencies in general are still cautious about the replacement of whole-animal methods with new in vitro techniques. Although studying the toxic effects of inhaled chemicals is a complex subject, recent studies demonstrate that in vitro methods may have significant potential for assessing the toxicity of airborne contaminants. In this review, current toxicity test methods for risk evaluation of industrial chemicals and airborne contaminants are presented. To evaluate the potential applications of in vitro methods for studying respiratory toxicity, more recent models developed for toxicity testing of airborne contaminants are discussed.     

Microbial toxicity and degradation test methodology: An industrial perspective

Numerous federal regulations are concerned with the release or potential release of chemicals to the environment. Testing that has been proposed under the Toxic Substances Control Act for microbiological effects and persistence has certain limitations. Improved and extremely sensitive procedures are now available to assess chemical toxicity to microorganisms and persistence at environmentally realistic concentrations. This paper discusses these aspects and presents preliminary data for a novel method based on thymidine uptake which offers promise as a routine sensitive assay for the effects of chemicals on biomass, and vice versa. The method has been shown to provide useful data about the persistence of chemicals at realistic environmental concentrations.     

A direct resazurin test for measuring chemical toxicity

A rapid, simple, and inexpensive biochemical test for use in the mass screening of chemical compounds for toxicity was developed. The test is based on direct measurement of the inhibition of microbial dehydrogenase activity, as affected by a toxicant, in a well buffered DMSO-resazurin solution. The addition of 5% DMSO to the reaction mixture allows the toxicity determination of compounds with low water solubility, thus facilitating measurement of the effects of important environmental contaminants on microbiota. The test has been applied to 15 selected chemicals which represent a vast range of environmental contaminants. As well as a routine screening procedure for chemical toxicity, this new resazurin test can be used as a tool in the study of structure-activity relationship.     

Chemical fate,bioconcentration, and environmental effects testing: Proposed testing and decision criteria

Chemicals should have a minimum amount of available chemical fate, bioconcentration, and environmental effects data to identify those chemicals with potentially problematic environmental partitioning or persistence, or those with potential to bioconcentrate or cause adverse effects. Professional judgment, estimates of a chemical's mode(s) of action or mechanism of action, and its susceptibility to rapid transport or transformation should be utilized to determine the types of chemical fate, bioconcentration, and environmental effects data that should be available. Data-supported decision criteria should be used to develop additional data to characterize the persistence, bioconcentration, and adverse effects of chemicals that have been identified as potentially problematic. To facilitate an understanding of minimum chemical fate and bioconcentration data that should be available, recommended chemical fate and bioconcentration data from previously published testing schemes or approaches were evaluated. For environmental effects data, the types of organisms recommended for developing aquatic toxicity data in previously published testing schemes or approaches were evaluated. To facilitate an understanding of available testing decision criteria, those criteria that were used (as of December 31, 1988) to propose or require chemical fate, bioconcentration, on aquatic toxicity tests under section 4 of the Toxic Substances Control Act and those criteria recommended in previously reported testing schemes were evaluated. Based on this comprehensive evaluation it was possible to propose (1) a base set of chemical fate and aquatic toxicity tests, (2) organisms for conducting aquatic toxicity tests, and (3) decision logic and testing scheme for developing chemical fate and aquatic toxicity test data.     

Balancing risks

Regulatory policies designed to reduce the health risk of environmental and/or synthetic chemicals generally aim for zero or negligible levels. Foods, on the other hand, especially those with a long history in the human diet, have been treated as essentially safe, even though they too contain various chemicals including nutrients. The recent debate on the presence in food of acrylamide, a possible human carcinogen, is likely to shake up the traditional paradigm held by regulatory agencies on chemical health risks. The current stance on the safety of acrylamide in food seems to be an extension of the traditional approach to assessment of environmental and/or synthetic chemicals. However, even foods which have long been a part of the human diet contain components that do not necessarily meet the safety margins applied to environmental and/or synthetic chemicals. In the future, a greater understanding of the effect of these agents on biological systems as well as the development of analytical methods for testing will result in many questions being raised concerning chemicals in foods, such as acrylamide which is under scrutiny today. Regulatory policies currently employ various standards for controlling chemical risk. These standards are dependent upon the labeling of the chemical in question, e.g., whether carcinogenic or non-carcinogenic, synthetic or natural, or whether a food or industrial chemical. Regardless of labeling, all chemicals to which we are exposed should be evaluated on an equal footing. Then, according to the level of the identified health risk, regulations could or could not be applied based on local circumstances, e.g., public acceptance, voluntary risk vs. involuntary risk, etc. In order to create a standardized system for chemical risk assessment, the introduction of uniform measures is essential. Loss of life expectancy (LLE) is one possible measure to assess chemical health risk. When LLE has been used, animal toxicity data have indicated that an ad libitum diet intake has considerably more impact on health risk than the acrylamide concentration of the ingested food. Reassessing the health effects of chemicals with a system of uniform measures could reveal many risks that need to be preferentially addressed above and beyond keeping minor toxicants to zero or negligible levels. Recognition of such risks may result in changes that conflict with existing regulations. In any case, whether consciously or unconsciously, people have always been exposed to a certain degree of chemical risk in their daily life. Based on the premise that the public can accept some degree of chemical risk in balance with other risks in their lives, regulatory bodies should be able to take a flexible and effective approach. In order to efficiently and comprehensively maximize the protection of our health against potential harm from chemicals using limited public resources, it is now time for regulatory agencies to restructure their policy frameworks across categories for controlling chemical health risks.     

Toxicity Assessment of Industrial Chemicals and Airborne Contaminants: Transition from In Vivo to In Vitro Test Methods: A Review

Exposure to occupational and environmental contaminants is a major contributor to human health problems. Inhalation of gases, vapors, aerosols, and mixtures of these can cause a wide range of adverse health effects, ranging from simple irritation to systemic diseases. Despite significant achievements in the risk assessment of chemicals, the toxicological database, particularly for industrial chemicals, remains limited. Considering there are approximately 80,000 chemicals in commerce, and an extremely large number of chemical mixtures, in vivo testing of this large number is unachievable from both economical and practical perspectives. While in vitro methods are capable of rapidly providing toxicity information, regulatory agencies in general are still cautious about the replacement of whole-animal methods with new in vitro techniques. Although studying the toxic effects of inhaled chemicals is a complex subject, recent studies demonstrate that in vitro methods may have significant potential for assessing the toxicity of airborne contaminants. In this review, current toxicity test methods for risk evaluation of industrial chemicals and airborne contaminants are presented. To evaluate the potential applications of in vitro methods for studying respiratory toxicity, more recent models developed for toxicity testing of airborne contaminants are discussed.     

Reflex modification and the detection of toxicant-induced auditory dysfunction

There are numerous environmental chemicals that adversely impact sensory functioning in exposed populations. Test methods are needed that can rapidly and efficiently assess the potential of chemicals to induce sensory toxicity. Reflex modification of the startle response is a technique that provides rapid, objective and quantitative assessments of sensorimotor function. This procedure has been shown to be sensitive to a variety of neurotoxic compounds. Reflex modification can also provide independent estimates of chemical-induced alterations in both sensory and motor function. Future efforts should focus on expanding the use of this procedure in both the identification and characterization of neurotoxic chemicals.