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.     

内蒙古锡林浩特地区土壤-牧草-家畜系统中Cu、Fe、Zn、Mn、Mg、Se六种元素含量的分析

对内蒙古锡林浩特地区土壤，牧草，家畜（羊）被毛中6种元素含量进行了测定。结果表明：土壤硒含量于缺乏的临界水平；尖草，羊草及针草中锌含量低于羊正常生长对锌的需求数量，兔毛草及羊草中的硒的含量很低，不能满足其正常生长需要，被毛中硒含量低于临界值，提示羊群缺硒。     

牛体外受精时老化卵对受精率与染色体异常发生的影响

通过延长体外培养时间得到牛老化卵，对其体外受精率与染色体的异常发生进行了研究，体外受精48h后的受精率，46h培养组与22h和34h培养组之间差异显著（P＜0．05），随着老化时间的延长，受精率及胚胎发育速度明显降低。染色体分析结果表明，46h组的受精卵的染色体异常发生率为61．6％，22h组44．6％，2组之间差异显著（P＜0．05），单倍体（n=31)的发生率也随着老化时间的延长而增加，这些单倍体的性染色体的构成表明，含有X－性染色体的胚的出现率显著高于含有Y－染色体的胚的出现率（P＜0．05）。单倍体的发生是由卵的老化而引起单一配子的孤雌发生，体外培养时间的延长对正常的2倍体的性别无明显影响。     

实验性雏鸡佝偻病的病理学研究——Ⅱ.形态学观察

4日龄 Aiboi Acies肉鸡健雏80只随机分为4组,分别喂给钙-磷缺乏(Ca 0.02％,P0.30％)、缺钙(Ca 0.02％,PO.71％)、缺磷(Ca 0.95％,PO.30％)和正常对照(Ca 0.95％PO.71％)日粮三周,进行了系统的病理形态学观察。缺磷组病变表现为肋骨头肿大,长骨骨骺生长板之肥大带明显增宽,骨小梁减少;缺钙组和钙-磷缺乏组病变表现为肋骨增粗弯曲,长骨骨骺生长板之增生带显著增宽,海绵骨类骨组织和结缔组织大量增生,成骨细胞和破骨细胞丰富。结果表明,钙缺乏和磷缺乏所致病变显著不同,为鉴别诊断提供了科学依据。     

Changes in nutrient balance,methane emissions,physiologic biomarkers,and production performance in goats fed different forage-to-concentrate ratios during lactation

The objective was to determine the effect forage-to-concentrate (F:C) ratio and stage of lactation on methane emissions, digestibility, nutrient balance, lactation performance, and metabolic responses in lactating goats. Twenty Murciano-Granadina dairy goats were used in an experiment divided into 3 periods: early (30 d), mid (100 d), and late (170 d) lactation. All goats were fed a diet with 35:65 F:C (FCL) during early-lactation. Then, 1 group (n = 10 goats) remained on FCL through mid- and late-lactation while the other group (n = 10 goats) was fed a diet with 50:50 F:C at mid-lactation (FCM) and 65:35 (FCH) at late lactation. A greater proportion of concentrate in the diet was associated with greater overall intake and digestibility (P < 0.05). Energy balance was negative in early-lactation (−77 kJ/kg of BW^0.75, on average) and positive for FCL at mid- and late-lactation (13 and 35 kJ/kg of BW^0.75, respectively). Goats fed FCM and FCH maintained negative energy balance throughout lactation. Plasma concentrations of non-esterified fatty acids at mid-lactation were greater for FCM than FCL (680 mEq/L), and at late-lactation concentrations were greater for FCH and FCL (856 mEq/L). A similar response was detected for plasma β-hydroxybutyrate. Methane emission was greater (P < 0.05) for FCM than FCH (1.7 g CH₄/d). This study demonstrated that differences in F:C across stages of lactation lead to distinct metabolic responses at the level of the rumen and tissues.     

草粮轮作与农田生态平衡——兼论 Ladino 白三叶的生态经济效益

利用无性繁殖法定植Ｌａｄｉｎｏ白三叶（Ｔｒｉｆｏｉｕｍｒｅｐｅｎｓ）和雅安逸生白三叶（Ｔ．ｒｅｐｅｎｓ），地上部生物量前者比后者表现出极显著差异；地下部生物量和贮氮量表现为显著差异。后作玉米产量，Ｌａｄｉｎｏ白三叶地为６．２９ｔ／ｈａ大于雅安逸生白三叶地（６．１５ｔ／ｈａ）；农田生态系统里前者表现为正氮平衡，后者表现为负氮平衡，前者土壤固相、液相和气相比为１∶０．５∶０．２５明显优于后者；前者Ｃ／Ｎ比适中，后者Ｃ／Ｎ过窄，其抗性雅安逸生白三叶低于Ｌａｄｉｎｏ白三叶。三种种子直播的豆科牧草的生态经济特性表现为南苜蓿（Ｍｅｄｉｃａｇｏｈｉｓｐｅｄａ）大于苕子（Ｖｉｃｉａｃｏｒａｃｃａ），紫云英（Ａｓｔｒａｇａｌｕｓｓｉｎｉｃｕｓ）则介于两者之间。草粮轮作周期证明，Ｌａｄｉｎｏ白三叶和南苜蓿以及苕子是无性繁殖和有性繁殖的最佳材料，值得广泛推广利用。     

低蛋白质氨基酸平衡饲粮对生长猪生长性能和氮素减排的影响研究

试验旨在研究饲喂低蛋白质氨基酸平衡饲粮对生长猪生长性能和氮排泄量的影响,采用单因子完全随机设计,将144头平均体重30 kg左右的杜长大三元杂种生长母猪分成3组,每组设6个重复,每个重复8头猪,对照组饲喂实测粗蛋白质含量为18.10%的普通饲粮,试验1组、试验2组分别饲喂实测粗蛋白质含量为16.08%和14.12%的氨基酸平衡饲粮。试验期37 d,前7 d为预试期,正试期30 d。结果显示,3组日采食量、日增重、料重比指标均没有显著差异(P0.05),而日氮素总排泄量试验1组、试验2组分别比对照组减少18.69%、38.68%,3组之间差异均显著(P0.05),且试验1组、试验2组猪每增重1 kg所需要的饲料成本分别较对照组节省0.11和0.23元。综合考虑,生长猪饲喂低蛋白质氨基酸平衡饲粮,可以作为实现养殖效益与环保双赢的主要技术措施予以推广。     

Phenotypic plasticity induced using high ambient temperature during embryogenesis in domesticated zebrafish,Danio rerio

Ambient temperature during early stages of life has a substantial effect on physiological processes, eliciting phenotypic plasticity during zebrafish developmental stages. Zebrafish are known to possess a noteworthy ability to modify their phenotype in dependence of environmental factors. However, there is a poor understanding of the effects of temperature during embryogenesis, which influences the biological functions such as survival ability and masculinization in later developmental stages. Since the middle embryonic phase (pharyngula period) is genetically the most conserved stage in embryogenesis, it is very susceptible to embryonic lethality in developmental processes of vertebrates. Here, we tested the effect of transient perturbations (heat shock) during early development (5–24 hr post‐fertilization; hpf) at 35°C compared to control group at 28°C, on survival ability of zebrafish to study the embryonic and post‐embryonic mortality. We studied the variation of heat‐induced masculinization among and across the families in response to high temperature. Furthermore, morphometric traits of adult zebrafish at different developmental time points were measured in order to estimate the temperature × sex interaction effect. We found the highest embryonic mortality around the gastrula and segmentation periods in both experimental groups, with significantly lower survival ability in the temperature‐treated group (73.30% ± 0.58% vs. 70.19% ± 0.57%, respectively). A higher hatching success was observed in the control group (71.08% ± 0.61%) compared to the heat‐induced group (67.95% ± 0.60%). A distinct reduction in survival ability was also observed in both experimental groups during the first two weeks after hatching, followed by a reduced level of changes thereafter. We found sex ratio imbalances across all families, with 25.2% more males under temperature treatment. Our study on growth performance has shown a positive effect of increased temperature on growth plasticity, with a greater impact on female fish in response to high ambient temperature.     

Risk Factors for Lamb Mortality in Sahelian Sheep on a Breeding Station in Ghana

A retrospective cohort study was designed to examine the effect of sex, season of birth, type and year of birth, and birth weight on lamb mortality. The method used involved analysis of breeding records for Sahelian sheep kept on a breeding station at Pong-Tamale in northern Ghana from 1994 to 2000. The pre-weaning and post-weaning mortalities were 10% (n = 505) and 19% (n = 453), respectively, while the overall mortality from birth up to 12 months of age was 28% (n = 505). Compared to the pre-weaning period, the post-weaning period recorded significantly higher proportions of deaths in male, single-born, lambs born in the rainy or dry seasons, and in lambs with low (<3 kg) or high (> or =3 kg) birth weight. The odds and risks of death for male lambs were about one and a half times those for females at post-weaning. Lambs born in the dry season had significantly higher mortality than those born in the rainy season. Lambs that died by the time of weaning were not significantly different in weight at birth from those that survived. The mean birth and weaning weights of single-born lambs were significantly higher than those for twins. The mean pre-weaning ADG was significantly higher in lambs born as singles compared to that for twins. The season of birth had influence on mean birth weight, with those born in the rainy season having significantly higher weights than those born in the dry season. The year of birth significantly affected birth weight, weaning weight, weight at 12 months and ADG at all stages of the lambs' life. The study concluded that the most significant risk factors for lamb mortality included sex of the lamb, season of birth and birth weight. The last two could be manipulated, to some extent, to reduce lamb mortality.     

不同苜蓿品种在青岛地区的适应性

2007-2010年,在青岛地区对引进的23个国内外苜蓿品种进行了膜侧种植、无灌溉、无施肥模式的田间试验,观测分析了各品种产草量、株高、茎叶比等指标。结果表明,23个苜蓿品种在青岛普遍生长良好,国外品种生产性能优于国内品种;播种当年干草产量膜侧种植组明显高于直接播种组,干草产量增幅(除甘农4号、新疆大叶和牧歌401外)均在50%以上;干草产量与年均日照时数、年均温的灰色关联度分别达到0.795 5和0.878 9,而与年均降水量关联度仅为0.569 1;株高最高的是WL323为87.8 cm,最低的是敖汉苜蓿,仅74.7 cm;供试23个品种的干草产量与株高均存在显著性差异,株高与草产量相关系数达到0.65以上,具有很高的正相关性;茎叶比最低的是牧歌401,仅为1.22,绝大多数苜蓿品种的茎叶比有逐年增加的趋势。综合评价认为供试23个苜蓿品种中的WL323、牧歌401、驯鹿3个品种综合生产性能较好,适宜在青岛地区辅以膜侧种植模式进行大面积推广。