Relationship between biological variation and delta check rules performance

ObjectivesThe performance of delta check rules has been considered to be dependent on the biological variation characteristics of the analyte of interest. The assumed relationships have not been formally studied. The mathematical relationship between biological variation and delta check rules is explored in this study.Design and methodsFrom the mathematical model for absolute difference delta check, the threshold for specificity and sensitivity are observed to be normalized differently. For specificity, the threshold is normalized by the within-subject biological variation (expressed as a coefficient of variation, ${\mathit{CV}}_i$), whereas for sensitivity the threshold is normalized by the between-subject biological variation (expressed as a coefficient of variation, ${\mathit{CV}}_g$). This highlights the different roles the two biological variations play in affecting the absolute difference distribution for correct and switched patient samples. Analogous to absolute difference delta checks, for relative difference delta checks, the expressions for specificity and sensitivity are scaled by ${\mathit{CV}}_i$ and ${\mathit{CV}}_g,$ respectively. However, the expressions are independent of ${\mu }_g$(the average of the population).ResultsA comparison between the mathematical model and empirical/ historical laboratory data obtained from patients was conducted for both absolute and relative difference delta checks. In general it was found that the specificity obtained from the historical laboratory data was less than the model predicted values, while on the other hand, good correspondence was obtained between the experimental sensitivity and predicted sensitivity.ConclusionsThe difference in within-subject biological variation in different patients may contribute to the observed discrepancy in predicted and empirical delta check performance.     

Analytical Quality by Design Approach in RP-HPLC Method Development for the Assay of Etofenamate in Dosage Forms

By considering the current regulatory requirement for an analytical method development, a reversed phase high performance liquid chromatographic method for routine analysis of etofenamate in dosage form has been optimized using analytical quality by design approach. Unlike routine approach, the present study was initiated with understanding of quality target product profile, analytical target profile and risk assessment for method variables that affect the method response. A liquid chromatography system equipped with a C₁₈ column (250×4.6 mm, 5 μ), a binary pump and photodiode array detector were used in this work. The experiments were conducted based on plan by central composite design, which could save time, reagents and other resources. Sigma Tech software was used to plan and analyses the experimental observations and obtain quadratic process model. The process model was used for predictive solution for retention time. The predicted data from contour diagram for retention time were verified actually and it satisfied with actual experimental data. The optimized method was achieved at 1.2 ml/min flow rate of using mobile phase composition of methanol and 0.2% triethylamine in water at 85:15, % v/v, pH adjusted to 6.5. The method was validated and verified for targeted method performances, robustness and system suitability during method transfer.     

Development of a new biomechanical indicator for primary blast-induced brain injury

Primary blast-induced traumatic brain injury (bTBI) has been observed at the boundary of brain tissue and cerebrospinal fluid (CSF). Such injury can hardly be explained by using the theory of compressive wave propagation, since both the solid and fluid materials have similar compressibility and thus the intracranial pressure (ICP) has a continuous distribution across the boundary. Since they have completely different shear properties, it is hypothesized the injury at the interface is caused by shear wave. In the present study, a preliminary combined numerical and theoretical analysis was conducted based on the theory of shear wave propagation/reflection. Simulation results show that higher lateral acceleration of brain tissue particles is concentrated in the boundary region. Based on this finding, a new biomechanical vector, termed as strain gradient, was suggested for primary bTBI. The subsequent simple theoretical analysis reveals that this parameter is proportional to the value of lateral acceleration. At the boundary of lateral ventricles, high spatial strain gradient implies that the brain tissue in this area (where neuron cells may be contained) undergo significantly different strains and large velocity discontinuity, which may result in mechanical damage of the neuron cells.     

N-亚硝胺类基因毒性杂质的研究进展

自“缬沙坦事件”之后，N-亚硝胺类基因毒性杂质引起了业界的广泛关注。本文概述了药物中N-亚硝胺类基因毒性杂质和相关检测方法的研究进展，以及近20年来国内外有关药物中基因毒性杂质监管指南的完善历程。N-亚硝胺类基因毒性杂质作为一类高反应活性的基因毒性杂质，主要来源于药物合成过程中发生的副反应，以及药物在储存或者运输过程中发生的氧化或还原等反应。所有的动物实验表明，N-亚硝胺类具有很强的致癌性。在理论上，所有药物都存在N-亚硝胺类杂质或被N-亚硝胺类杂质污染的风险，由于该类化合物在药物中常以痕量形式存在，在分析检测过程中药物基质干扰大，因此建立便捷、高效的分析方法是非常有必要的。     

Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution

This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method.     

Development and validation of ultra-performance liquid chromatography method for the determination of meloxicam and its impurities in active pharmaceutical ingredients

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利奈唑胺致血小板减少症发生状况及相关影响因素分析研究

目的：对使用利奈唑胺的住院患者进行回顾性调查分析,探讨利奈唑胺致相关性血小板减少症的发生情况及其影响因素。方法： 采用回顾性病例研究,对2015年6月至2017年12月某院260例使用利奈唑胺致相关性血小板减少症的发病情况进行分析,采用t检验（参数）和 Mann-Whitney U 检验（非参数）,χ2检验逐个分析各指标的组间差异性;采用条件Logistic回归分析不良反应/事件发生的影响因素及其标准回归系数（影响程度）。检验水准α=0.05。结果：纳入研究的260例患者中,有67例发生血小板减少症,发生比例为25.77%。单因素分析年龄分组中＞65岁人群中发病率较高,为35.40%（χ2=9.80,P=0.02）;≥3个联合用药组中发病率较高,为34.07%（χ2=11.02,P=0.01）。分析表明,实验室检查指标血小板基础值、用药天数、白蛋白、血清肌酐、尿素氮、尿酸与血小板减少症有关（P<0.05）。多因素Logistic回归分析提示：血小板基础值、用药天数、胆红素、肌酐与血小板减少症的发生密切相关。ROC诊断曲线预测分析曲线下面积为0.738,灵敏度68.71%,特异度71.50%,Youden指数0.40。结论：使用利奈唑胺后发生血小板减少症的发生率较高;单因素分析显示应重点关注高龄（≥65岁）、联合用药（≥3种）、基础血小板值低的患者;多因素分析显示,血小板基础值、用药天数、胆红素、肌酐与血小板减少症的发生密切相关。     

重庆地区58例正常(牙合)成人X线头影测量Holdaway法分析

目的建立重庆地区恒牙期正常牙合汉族成人Holdaway分析法各项测量项目的正常值,评价其软组织的结构特征,探讨软组织侧貌的性别、地域及种族差异。方法将58例重庆籍恒牙期正常牙合汉族人头颅X线侧位片扫描入计算机,用计算机定点,并自动测出Holdaway分析法的各项指标,得出均值与标准差;与北京人、日本人及白种人进行比较,作软硬组织的相关分析,建立软组织与相关硬组织的逐步回归方程。结果得出Holdaway分析法各项正常值,男女比较部分测量值有显著性差异。与北京人比较部分测量值有差异,与日本人比较各测量值无差异,与白种人比较,大部分测量值有极显著性差异;部分软、硬组织之间存在相关性。结论软、硬组织之间既相关又独立,硬组织的结构形态不能完全反映软组织的侧貌外形,需要由软组织的头影测量来进行补充。软组织测量值在不同种族间有极显著性差异。上、下颌基骨的位置,骨组织的侧貌突度都对软组织的侧貌形态有一定影响。