以克服药品不良反应为目的开发新复方制剂的思路与策略

增强疗效,减少不良反应是新药研发工作的重中之重。复方制剂不但具有降低不良反应发生率,提高药效的作用,还具有研发成本低和研发周期短的特点,因此已经成为新药研发的热点。本文综述了以克服药品不良反应为目的而设计的复方制剂,阐述了通过新的药物组合减少由于药理作用带来的个性不良反应,以及通过新的制剂技术减少血药浓度波动带来的共性不良反应2种复方制剂设计策略出发,以期为复方制剂的研发提供有益的思路。     

浅谈药品研发中的文件管理要求

目的浅谈药品研发中的文件管理要求。方法通过药品研发过程来分析其文件管理要求。结果与结论良好的文件和记录管理是研发质量管理的基本要素,也是药品质量体系的基本要素,能够确保药品研发规范有序标准化地开展。     

全球药品研发进展

本月全球药品研发进展取得成效的药物有32个，比上月减少了1个，获得新药注册、进入注册前阶段和进入Ⅲ期临床研究阶段的药品数量与上月相比变化不大，但首次注册的药品数量有所减少（1个）。     

药物研发的技术要求分析

分析药品研发过程中的技术要求,为制剂研究提供技术参考,帮助药品研发单位结合自身实际,研制出安全、高效的药品。     

全球药品研发进展

本月全球药品研发进展取得成效的药物有33个,比上月增加了8个,处于注册状态和Ⅲ期临床研究阶段的药品数量较上月有所增加,其中首次注册的药品有10个,增幅较大,较上月增加了150％。进入注册前阶段的药品数量与上月持平。进入注册阶段的有13个（10个为全球首次注册的药品,其余3个均为在新市场补充注册的新活性物质和新制剂）,比上月增加了6个。     

欧洲药品管理局复方药物非临床评价技术要求

本文通过分析欧洲药品管理局(EMA)复方药物非临床评价指导原则的起草背景和具体内容,介绍了EMA对复方药物非临床安全性评价的考虑要点,包括复方药物的类型以及不同类型复方药物非临床评价方案,以期为国内复方药物的非临床研究提供参考。文中同时对复方药物非临床评价的毒理学研究内容以及应关注的剂量确定、动物种属选择和时间安排等原则要求作了分析。     

全球药品研发进展（2008．08）

本月全球药品研发进展取得成效的药物有42个,比上月增加2个,除进入Ⅲ期临床研究阶段的药品数量略有下降外,进入注册和注册前阶段的药品数量均略有增加.     

药品研发中多晶型问题的考虑

多晶型现象在固体化学药品研发过程中比较常见。由于多晶型问题可能影响药品的安全有效性和质量可控性,应当针对不同情况采取相应的措施。本文就药品研发中涉及的多晶型现象及相关问题的考虑作简要讨论,供药品研发和评价工作参考。     

全球药品研发进展(2007.10)

本月全球药品研发进展取得成效的药物有36个,比上月增加了4个,获得新药注册的药品数量较上月大幅上升,进入注册前阶段和进入Ⅲ期临床研究阶段的药品数量均较上月有所减少。     

全球药品研发进展(2007.08)

本月全球药品研发进展取得成效的药物有33个，比上月减少了2个，进入注册和注册前阶段的药品数量比上月增加了3个，进入Ⅲ期临床研究阶段的药品数量比上月减少了5个。     

我国发展阶段与职业病防治工作的地位及政策安排

本文从战略层面阐述了职业病防治工作的地位。中国经济社会发展的现实阶段,决定了职业病防治工作应当受到重视;其严峻形势迫使政府不得不引起重视。现阶段,加强职业病防治工作,对中国扩大内需具有重要意义。公共财政政策给予倾斜是加强职业病防治工作的重要举措。     

Identification and assessment of the effects of chemicals on reproduction and development (reproductive toxicology)

Most studies for determining the reproductive toxicity of a chemical have to be conducted with whole animals. Test procedures used to investigate parts or the whole of the reproductive cycle are described in current guidelines. Other techniques, such as in vitro methods, and those for investigating specific events in the cycle, are under development. Epidemiological studies can give valuable information, although they are difficult to perform and interpret in practice. There is a need for more epidemiological studies of exposed populations and for recording and quantifying the concentrations of chemicals to which such populations are exposed. It is suggested that animal experiments should be programmed in a stepwise manner, and should take into account effects seen in previous toxicity studies. The programme of tests for determining reproductive toxic potential should be established on a case-by-case basis, since many factors will influence the choice of studies and the sequence in which they should be performed.     

Defining the role of ECVAM in the development, validation and acceptance of alternative tests and testing strategies

The background to the establishment of the European Centre for the Validation of Alternative Methods (ECVAM) is reviewed, and the main events at the opening of the Centre and an ECVAM symposium on practical aspects of validation are summarized. Finally, recommendations made to ECVAM for consideration in developing the Centre's strategy are listed.     

Specific antibody responses of primary cells from different cell sources are able to predict immunotoxicity in vitro

Alternative methods for the prediction of immunotoxicity are highly desirable. However, until now no in vitro test for this purpose has been fully validated or accepted by regulatory authorities. MD cultures are in vitro equivalent to the widely used ex vivo primary T cell dependent antibody responses (TDAR), which has been identified in a regulatory context as a main functional test for immunotoxicological investigations. The purpose of the present study was to use MD cultures of spleen and blood cells to compare data from three different chemicals using SRBC as antigen in two different species. Using this approach we were able to show that cell sources from both rats and mice were able to correctly predict all tested compounds and to clearly distinguish immunosuppressants from control substances. Furthermore, animal studies can be refined by using MD cultures of PBMC. During a 28d benzo(a)pyrene treatment of rats we were able to follow the kinetic of an immune response by in vitro analyses. Additionally evaluation of in vitro antibody responses of spleen cells and PBMC from rats treated with cyclophosphamide revealed similar results compared to the conventional ex vivo plaque forming cell assay (PFCA).In conclusion, investigation of in vitro antibody responses is a sensitive and reliable approach for detection of a compound induced specific effect on the immune system. MD cultures may not only replace the ex vivo TDAR in the future, but their implementation in routine toxicology also enables refinement of existing in vivo studies by reducing the numbers of animals.     

Graphical display of histopathology data from toxicology studies for drug discovery and development: An industry perspective

Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, and tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses. A subgroup of the FDA-PhUSE Nonclinical Working Group conducted intra-industry surveys regarding the use of graphical displays of histopathology data. Visual cues, use-cases, the value of cross-domain and cross-study visualizations, and limitations were topics for discussion in the context of the surveys. The subgroup came to the following conclusions. Graphical displays appear advantageous as a communication tool to both pathologists and non-pathologists, and provide an efficient means for communicating pathology findings to project teams. Graphics can support hypothesis-generation which could include cross-domain interactive visualizations and/-or aggregating large datasets from multiple studies to observe and/or display patterns and trends. Incorporation of the SEND standard will provide a platform by which visualization tools will be able to aggregate, select and display information from complex and disparate datasets.     

Selection of data sets for FAIRification in drug discovery and development: Which,why, and how?

Despite the intuitive value of adopting the Findable, Accessible, Interoperable, and Reusable (FAIR) principles in both academic and industrial sectors, challenges exist in resourcing, balancing long- versus short-term priorities, and achieving technical implementation. This situation is exacerbated by the unclear mechanisms by which costs and benefits can be assessed when decisions on FAIR are made. Scientific and research and development (R&D) leadership need reliable evidence of the potential benefits and information on effective implementation mechanisms and remediating strategies. In this article, we describe procedures for cost–benefit evaluation, and identify best-practice approaches to support the decision-making process involved in FAIR implementation.     

Safety assessment of diacylglycerol oil as an edible oil: A review of the published literature

Diacylglycerol oil is an edible oil with taste and usability characteristics comparable to naturally occurring oils. The objective of this review is to examine literature on diacylglycerol oil to assess its safety-in-use. Feeding rats with unheated or heated diacylglycerol oil at levels up to 5.5% in diet for 90 days did not cause any toxic effects. In chronic studies, dietary administration of diacylglycerol oil (up to 5.3%) to rats for 2 years or at 9.5% to Beagle dogs for 1 year had no adverse effects. Genotoxicity studies of unheated and heated diacylglycerol oil did not reveal any genotoxic effects. Carcinogenicity studies in rodents demonstrate that diacylglycerol oil is non-carcinogenic. In a two-generation reproductive and developmental toxicity study, gavage administration of diacylglycerol oil at dose levels of 5.0 ml/kg body weight/day did not reveal any adverse effects. In several human clinical investigations, administration of diacylglycerol oil at levels up to 0.5 g/kg body weight/day for up to 1 year did not cause adverse effects. Collectively, there is sufficient qualitative and quantitative scientific evidence available from animal and human studies suggesting that intake of diacylglycerol oil is safe for human consumption when used in a manner similar to other edible oils.     

Safety evaluation of the human-identical milk monosaccharide sialic acid (N-acetyl-d-neuraminic acid) in Sprague-Dawley rats

N-Acetyl-d-neuraminic acid (Neu5Ac) is the predominant form of sialic acid (Sia) in humans, while other mammals express Sia as a mixture with N-glycolyl-d-neuraminic acid (Neu5Gc). Neu5Ac occurs in highest levels in the brain and in breast milk, and is therefore, coined a human-specific milk monosaccharide, and is thought to play an important nutritional role in the developing infant. Synthesized human-identical milk monosaccharide (HiMM) Neu5Ac is proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of HiMM Neu5Ac, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. Neu5Ac was without maternal toxicity or compound-related adverse effects on female reproduction and on the general growth and development of offspring at a maternal dietary level of up to 2%, equivalent to a dose of 1895 mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 2% (highest level tested), corresponding to doses of 974 and 1246 mg/kg bw/day in males and females, respectively. Neu5Ac also was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of Neu5Ac both in infant formula and as a food ingredient at levels equivalent to those found naturally in human breast milk.     

An overview of values for the threshold of toxicological concern

An overview of values for the threshold of toxicological concern (TTC) is presented. This comprises the more established TTC values, including those that have been endorsed by regulatory bodies, and those that have more recently been proposed and may still need further development. The overview is structured by use/exposure scenario and provides, in particular, key information on the underlying databases. It is aimed to support the application of the TTC approach in the risk assessment of chemicals whereby it is important to be aware under which circumstances a certain TTC value can be applied. Some recommendations for potential future developments to further improve the TTC approach are also being made.     

The application of post-market monitoring to novel foods.

The role of post-market monitoring (PMM) in the safety assessment of novel foods is critically discussed in order to derive guidelines as to in which situations the application of PMM might be warranted. Available data sources on food consumption and health status, and the methodologies for generating such data are reviewed. The paper suggests improvements to make them more applicable for PMM purposes. It is concluded that any PMM programme must be a hypothesis-driven scientific exercise. PMM can have a role as a complement to, but not as a replacement for, a comprehensive pre-market safety assessment. Its use may be appropriate to confirm that product use is as predicted in the pre-market assessment; to provide reassurance that effects observed in the pre-market assessment occur with no greater frequency or intensity in the post-market phase than anticipated; and to investigate the significance of any adverse effects reported by consumers after market-launch. However PMM is insufficiently powerful to test the hypothesis that any effects seen in the pre-market assessment are absent in the post-market phase. Current methodologies place limitations on what PMM can achieve. PMM should only be used when triggered by or when the focus is on specific evidence-based questions.