Successful drug development despite adverse preclinical findings part 1: processes to address issues and most important findings

Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail.     

不同因素对深澳湾波纹巴非蛤滤水率的影响

笔者于2013年12月采用实验生态学方法,在室内进行不同体质量不同投饵时间、不同饵料密度对波纹巴非蛤[Paphia undulata(Born)〗滤水率的影响实验。结果表明:(1)波纹巴非蛤的滤水率(FR)随着体质量的增大而增大,单位体质量的滤水率(FR')随着其规格的增大而减小,FR'=0.330 3W-0.356 9(R2=0.996 5)。(2)分别以金藻和扁藻作为饵料,测定了8:00,14:00及20:00这3个时间点的滤水率,滤水率在8:00最大,14:00及20:00依次减小,3个时间点滤水率差异显著(P0.05)。(3)以金藻和扁藻作为混合藻,滤水率随着藻密度的增加而增大,当浓度超过3.06×105cell·L-1,滤水率反而下降。     

基于熵权的模糊物元模型在城市人居环境质量综合评价中的应用

基于城市人居环境质量优劣的模糊性和单项指标评价结果的不相容性,在物元分析的基础上,结合模糊集理论和欧氏贴近度概念,建立了城市人居环境质量评价的模糊物元模型,并应用信息熵所反映数据本身的效用值来计算指标的权重系数,有效避免了权重分配困难的问题和主观判断城市人居环境质量优越标准的不确定性。实例研究表明,运用熵模糊物元模型评价城市人居环境质量状况,方法是可行的,结论是可靠的。     

扬麦16“灌浆快”与颖果显微结构和内源生长素的关系

扬麦16是长江中下游麦区种植面积最大的品种,具有灌浆速度快、粒重高等特点。为探明扬麦16"灌浆快"与颖果结构和内源生长素的关系,以宁麦13为对照,显微观察了扬麦16颖果维管束、胚乳细胞和传递细胞发育的变化特征,测定了千粒重和生长素含量。结果表明,扬麦16胚乳中淀粉体和蛋白体发育好,胚乳充实饱满,最终粒重高;灌浆过程中扬麦16颖果内源生长素水平高,促进了同化物向籽粒的调运和胚乳细胞的分裂;扬麦16颖果维管束发达,筛管面积大,韧皮部卸载能力强;扬麦16颖果传递细胞分化早,细胞壁内突结构发达,养分转运能力强。     

阴离子聚丙烯酰胺处理医院污水的研究

研究自制的阴离子聚丙烯酰胺(APAM)对医院污水(色度125倍、悬浮物含量1 241 mg/L、COD 2 351 mg/L)的絮凝特性,并探讨聚合氯化铝(PAC)对APAM的助凝作用,考察了APAM的投加量、分子量对絮凝效果的影响。结果表明:加入PAC 66.0 mg/L、APAM 1.2 mg/L,对原水的絮凝效果最佳,色度降低率61.60%,悬浮物含量(SS)降低率67.61%,COD降低率20.88%。色度、SS、COD降低率均优于市购的APAM(Mw1 000×10~4、Mw2 000×10~4)。     

一种语言判断矩阵元素与优先权重的逻辑关系

提出了一种语言判断矩阵的元素与优先权重的含参数的逻辑关系,并对参数的选取进行了分析,最后给出了算例说明.     

加强甜玉米鲜食期籽粒品质变化研究

研究加强甜玉米和普通玉米2种不同类型玉米鲜食期籽粒品质变化,以明确各品质变化的动态规律。试验采用不同基因型的玉米材料,测定果穗鲜食期可溶性总糖含量、水分含量、蛋白质含量和百粒鲜重,并进行相关分析。结果表明：鲜食期籽粒发育过程中加强甜玉米可溶性总糖含量和积累速度高于普通玉米;水分的下降速度加强甜玉米比普通玉米慢;蛋白质含量加强甜玉米略低于普通玉米,蛋白质的积累与籽粒鲜重的增加过程基本一致;鲜粒重积累速度加强甜玉米低于普通玉米;授粉13d和授粉28d加强甜玉米和普通玉米蛋白质含量和鲜粒重都相近。     

河蚌滤水率对环境氨氮浓度的响应(英文)

在水温和水体悬浮颗粒物浓度保持相对恒定的条件下,在静水系统中,利用半现场实验法,研究了不同体重(以软组织干重计算)的河蚌在4个外界水体氨氮水平下的滤水特征,其中,氨氮浓度依靠河蚌自身排泄和逐步添加氯化铵获得。结果表明,在固定的氨氮水平下,单位体重滤水率Fr随体重w增加而下降;在试验的体重和氨氮浓度(n)范围内,体重和氨氮浓度对河蚌耗氧均具有主效应,且产生交互效应,单位体重滤水率的自然对数y′=lnFr=0.90±1.29-1.91±0.74lnw-0.51±0.45lnn+0.57±0.40lnnlnw-0.07±0.07wlnn,表明在试验范围内,滤水率随氨氮浓度和体重的增加而降低,而体重和氨氮浓度的交互效应对河蚌滤水率产生增益效应。     

Effect of Nutrient Type on Chemical Composition and Dry Matter Partitioning of Cassava （Manihot esculenta Crantz）

The objective of our study was to determine the effects of four types of fertilisers enrichments （manure potassic （K）, phosphatic （P）, phosphatic and potassic （PK） and nitrogenized, phosphated and potassic （NPK）） on chemical composition and dry matter in cassava （Manihot esculenta） organs （clone 1171） during harvest period. The pots experiment was laid out in randomised complete bloc design with five treatments and four replications. Water, nitrogen, potassium, phosphorus, sodium, total proteins and total lipids contents of the leaves, shoots and tubers were determined. After 9 months growing period, results showed that fertilizer types enriched with K, PK and NPK significantly increased the organic compounds contents of the leaves （P〈0.05）. Furthermore, fertilizers with high phosphorus content significantly increased the lipid contents of the leaves （25%）. Fertilizers enriched with NPK positively influenced the biomass partitioning in Manihot esculenta. Application of fertilizers enriched with NPK led to higher levels of total proteins in the leaves and tubers （70 mg g DM^-1 and 30 mg g DM^-1 respectively） compared to control （17 mg g DM^-1 and 9 mg g DM^-1 respectively）. These results help to demonstrate the value of these fertilizers enrichment to improve the chemical composition and dry matter partitioning of cassava.     

Relationships between numbers of main stems and yield components of potato (Solanum tuberosum L. cv. Erntestolz) as influenced by different daylengths

Summary The relationshops between numbers of main stems and some measures of growth and yield, as well as total tuber yield, were examined for potatoes grown under different daylengths. Leaf area, tuber number and tuber yield per plant increased significantly with increasing daylength and number of main stems. Numbers of main stems and leaf area were correlated positively with tuber number and tuber yield and negatively with average tuber weight. The correlations were stronger with stem number than with leaf area and were differently affected by daylength. Standard regression coefficients indicated that stem number has strong positive and negative relationships with tuber number and average tuber weight, respectively. Since tuber number was a better determinant of yeild than average tuber weight, the final relationship between the numbers of main stems and tuber yield remained positive for all daylengths. Determinants that will best explain variation in tuber total yield, tuber number, and average tuber weight are suggested.