Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials

Objective: Laboratory data are key evaluation procedures for Phase I clinical pharmacology for two reasons. Firstly, laboratory data are used within the screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluation and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common variation and a significant abnormality, which is considered to be a LAE. This report presents laboratory data distribution, reference values and reference changes and, based on previously published new methods, suggests inclusion limits at screening and laboratory adverse event limits for analysis during study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volunteers were recruited in one centre (Association de Recherche Thérapeutique). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same conditions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of data. Reference changes were also defined as the 2.5–97.5% interval of distribution of the variations between the end of treatment and baseline. Inclusion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, standard deviation, minimal and maximal values and the 2.5–97.5% interval for each laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies. Received: 30 July 1998 / Accepted in revised form: 25 November 1998     

Reference ranges of echocardiographic measurements in the Dutch population

Reference ranges for echocardiographic measurements were determinedin 609 healthy Dutch subjects, using height, weight, age, sex,RR-interval and blood pressure (in adults only) as determinants.Endsystolic as well as end-diastolic measurements of the aorticroot as well as left ventricular inner diameter, posterior andseptal thickness were taken, as was the left atrial end-systolicdiameter. Multiple linear regression was performed of the form: =A.(age)^B.(height)^C.(weight)^D.(RR-interval)^E.(sex)^F. The residuals were calculated in order to determine the percentilelimits by means of linear interpolation. Sex and weight weresignificant determinants in all the echocardiographic parametersstudied. The results were presented twofold, with a simple versionfor males and females separately, using only weight as a determinantand allowing graphical presentation, and secondly a complexversion taking into account all determinants, which can onlybe solved with help of a calculator.     

The use of a safety factor in setting health based permissible levels for occupational exposure

Summary When adequate human observations are not or scarcely available, permissible levels for occupational exposure have to be extrapolated from animal experiments. Taking into account experimental conditions, e. g., duration of exposure ( 3 months), animal species, knowledge of no- (adverse-) effect level or minim al-(adverse-) level, presence of data on human observations, the authors worked out a procedure for extrapolation. This procedure should only be applied for systemic non-carcinogenic effects. The proposed procedure is to be regarded as tentative and as suggestion for international discussion.The evaluation starts with a safety factor = 10 for extrapolation from dose/kg b. w. in long-term animal experiments to exposure of adult workers (40 h/wk); this factor corresponds to a safety factor = 3–10 for extrapolation from doses presented as concentrations in air. If long-term experimental exposure is 24 h daily, the safety factor can be lowered to the minimum value of 1. If only short-term exposure studies are available, the safety factor may have to be increased to a maximum of 400.     

Evaluation of the UK breast screening programmes

National breast screening programmes were set up in the UK inthe early 1990s. Although they are quality-assured and publishprocess measures of performance, there is a lack of data linkingthe screening process to breast cancer mortality. A new analysisof trends in England and Wales suggests that the effect of screeninghas been to reduce mortality by 8% over 10 years in those eligiblefor screening in 1990.     

试论健康价值观

健康是人类最宝贵的财富。健康价值观是指个体对健康各方面(包括生理功能、心理功能和社会功能等)的价值进行评价的稳定的内部标准和主观看法。健康价值观及其对它的测评研究有着不断完善和进取的发展过程,其结构也有着不同的划分。健康价值观受父母教养方式、文化环境、社会科技的进步、受教育程度及重大生活事件等因素的影响。对健康价值观的研究在理论上和实践应用中都有着重要的意义。     

Quality of Life in the General Norwegian Population, Measured by the Quality of Life Scale (QOLS-N)

The main aim of the present study was to derive norms or reference values from the general Norwegian population for the Norwegian version of the Quality of Life Scale (QOLS-N). In addition, associations between socio-demographic and health variables on the level of quality of life were examined. The sample consisted of 1893 subjects from a total of 4000 randomly selected Norwegian citizens representative of the entire Norwegian population, aged 19-81. The subjects received a mailed questionnaire containing the QOLS-N. Results show that the mean quality of life score was 84.1 (SD 12.5). Women reported a higher quality of life than men. People with higher levels of education reported a higher quality of life. Those who were married or cohabitating reported the highest quality of life and those who were unemployed reported a lower quality of life than those who worked. In addition, people reporting long-term diseases or health problems scored significantly lower on quality of life. These results could serve as reference values for the level of quality of life, as measured by the QOLS-N in the Norwegian population.     

妊娠期口服葡萄糖负荷试验合理血糖界值的探讨

目的 探讨目前适合我国卫生经济条件的妊娠期葡萄糖负荷试验(GCT)的筛查界值.方法 资料来源于2006年4月1日至2006年9月30日在全国18个城市25家医院保健并进行首次50 g GCT的16 286例孕妇,对其GCT结果进行统计和分析.结果 以NDDG标准诊断妊娠期糖尿病(GDM),50 g GCT的界值选取7.2 mmol/L时的敏感度和特异度分别为98.2%和59.0%,选取7.8 mmol/L时分别为96.0%和73.0%,选取8.3 mmol/L时分别为90.2%和81.5%;以ADA标准诊断GDM,选取GCT界值为7.2 mmol/L时敏感度为97.9%,特异度为60.4%;选取7.8 mmol/L时分别为96.2%和74.7%;而选取8.3 mmol/L则分别为87.0%和83.1%.以NDDG标准诊断妊娠期糖代谢异常(包括GDM及妊娠期糖耐量受损),选取7.2 mmol/L时敏感度和特异度分别为97.7%和61.4%,选取7.8 mmol/L时分别为95.4%和75.8%,选取8.3 mmol/L时分别为84.9%和84.1%.结论 据我国目前的卫生经济情况,以7.8 mmol/L作为50 g GCT的界值是合理的.     

手工搬举作业的最大可接受搬举重量

目的对手工搬举作业的最大可接受搬举重量（MAWL）进行研究,为我国制订手工搬举作业劳动负荷的标准提供依据.方法 用心理物理学方法对13名男性和10名女性受试者的MAWL进行了研究,并与推荐搬举重量限值进行比较.结果 男女受试者的MAWL均随着搬举高度的上升逐渐降低.当搬举高度超过肩关节时,MAWL急剧下降.男性受试者在水平距离25 cm处,其推荐搬举重量均大于MAWL,但在水平距离45、63cm处,推荐值均小于MAWL.男性受试者的平均MAWL比女性受试者高30.8%.在同一高度,随着水平距离的增加,MAWL逐渐下降,男女受试者结果一致.男性受试者不对称搬举时,扭转的角度越大,MAWL越低.扭转角度和搬举能力呈负相关（r=-0.996 6,P＜0.01）.不同扭转角度的推荐搬举重量限值均比MAWL低,且差异有统计学意义（P＜0.01）.结论 美国国家职业安全卫生研究所（NIOSH）搬举方程对于水平距离和不对称的校正是充分的,但对于高度的校正是不足的,尤其是对于过肩的搬举作业是不适合的,对于过肩搬举作业的推荐搬举重量限值还应降低.NIOSH搬举方程应考虑性别因素的影响,可加入性别常数项S;如果性别为男性,则S=1;如果性别为女性,则S=0.692.     

药学高职教育的价值取向与课程设计

以执业药师岗位群为目标,确立药学高职教育的专业方向并设计相关课程;以高职教育特征和学历层次定位为依据,指导课程大纲的制定;依照现代高职人才的通用价值标准设立技能拓展和素质培养课程。在专业定位、学历层次定位和高职教育通用价值标准的三维坐标中确立药学高职教育的价值取向,并引领教育改革的方向。     

基于文献报道的中药化学成分与CYP450s 相互作用研究

目的：使用复杂网络技术研究中药化学成分与CYP450s的关系,为中药分子机理研究和新药开发提供参考。方法：本文基于120篇文献报道,通过人工摘录的方式收集中药化学成分和CYP450s的相关信息,使用Cytoscape 2.8.2作为分析工具,构建化学成分与CYP450s的复杂网络图,并计算了点度中心度、接近中心度、中间中心度以及中药化学成分节点的相似度。结果：本文采集了169个中药化学成分和25种CYP450s的相关信息。CYP2C19、CYP1A2、CYP3A4等CYP450s和槲皮素、银杏内酯A、黄芩素等化学成分为目前研究的热点酶和热点中药化学成分。相似度较高的欧前胡素和银杏内酯B,槲皮素和黄芩素等化学成分可能存在协同相互作用。结论：复杂网络计算可以很好地辅助中药协同作用机理研究和新药开发工作。