Development of a bioanalytical method for the quantification of sinococuline in human plasma and its application in phase I clinical pharmacokinetic study

A selective, highly sensitive, precise, and novel bioanalytical method has been developed and validated to quantify sinococuline, an active constituent present in the phytopharmaceutical drug product containing Cocculus hirsutus plant extract, in vivo. Chromatographic separation was achieved on a Luna Omega Polar-C18 bonded analytical column maintained at 45°C. The isocratic mobile phase consisted of methanol and ammonium formate buffer (60:40, v/v) at acidic pH with a low flow rate of 0.250 mL/min. Detection was performed on an API 4000 mass spectrometer using electrospray ionization in positive polarity and multiple reaction monitoring mode to achieve a lower limit of quantification of 1.50 ng/mL. Excellent accuracy and precision were obtained after extracting the analyte from plasma samples using a chemical analogue as an internal standard in the absence of an isotope-labeled compound. The extraction efficacy was evidenced from recovery study, and the analyte was found to be stable in plasma. Validation study demonstrated linearity with coefficient of correlation, r ≥ 0.99, and minimal matrix effect. This bioanalytical method was successfully applied to evaluate pharmacokinetic parameters of sinococuline from a phase I clinical trial of an aqueous extract of C. hirsutus in healthy human volunteers.     

A dried blood spot assay with HPLC–MS/MS for the determination of larotrectinib in mouse blood and its application to a pharmacokinetic study

Larotrectinib is a first-generation tropomyosin kinase inhibitor, approved for the treatment of solid tumors. In this paper, we present a validated dried blood spot (DBS) method for the quantitation of larotrectinib from mouse blood using HPLC–MS/MS, which was operated under multiple reaction monitoring mode. To the DBS disc cards, acidified methanol enriched with internal standard (IS; enasidenib) was added and extracted using tert-butyl methyl ether as an extraction solvent with sonication. Chromatographic separation of larotrectinib and the IS was achieved on an Atlantis dC₁₈ column using 10 mm ammonium formate–acetonitrile (30:70, v/v) delivered at a flow-rate of 0.80 ml/min. Under these optimized conditions, the retention times of larotrectinib and the IS were ~0.93 and 1.37 min, respectively. The total run time was 2.50 min. Larotrectinib and the IS were analyzed using positive ion scan mode and parent–daughter mass to charge ion (m/z) transitions of 429.1 → 342.1 and 474.1 → 267.1, respectively, were used for the quantitation. The calibration range was 1.06–5,080 ng/ml. No matrix effect or carryover was observed. Hematocrit did not influence DBS larotrectinib concentrations. All of the validation parameters met the acceptance criteria. The applicability of the validated method was shown in a mouse pharmacokinetic study.     

QEPAS系统中石英音叉模态仿真计算与研究

对石英音叉增强型光声光谱(QEPAS)系统中常用的石英音叉进行了有限元模态计算，获得石英音叉前6阶振型与模态频率，认知了第4阶对称摆动振型为有效振动，利用单因素法分析了石英音叉的音臂长度l₁、音臂宽度w₁、音臂厚度t、音臂切角θ、音臂圆孔直径d及音臂圆孔高度h对低阶有效共振频率(Fre)的影响，敏感度依次为： l₁> w₁>d>θ>t>h，考虑实际设计情形，筛选出了l₁，w₁，d与h四个石英音叉设计变量，采用Box-Behnken实验设计方案与RSM(response surface methodology)方法，以Fre为函数目标，建立l₁，w₁，d与h的二次回归响应面模型，得到了参数之间的交互作用，利用Design-Expert软件对响应面模型进行设计参数反求，结果表明，在15 000 Hz≤Fre≤25 000 Hz计算区域内误差较小，基本满足QEPAS系统的计算需求，所提出的研究与设计方法具有一定通用性，可为QEPAS系统中石英音叉结构参数设计提供参考。     

HPLC with fluorescence detection assay of perampanel,a novel AMPA receptor antagonist,in human plasma for clinical pharmacokinetic studies

Perampanel (Fycompa®), a novel α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged ≥12 years) with refractory partial‐onset seizures. To support therapeutic drug monitoring, a simple high‐performance liquid chromatography (HPLC) assay with fluorescence detection was developed to determine perampanel concentrations in human plasma and validated to support clinical trials. Human plasma samples (1.0 mL) were processed by liquid extraction using diethyl ether, followed by chromatographic separation on a YMC Pack Pro C₁₈ column (150 × 4.6 mm i.d., 5 µm) with isocratic elution of acetonitrile–water–acetic acid–sodium acetate (840:560:3:1.8, v/v/v/w) at a flow rate of 1.0 mL/min. Column eluent was monitored at excitation and emission wavelengths of 290 and 430 nm, respectively. The assay was linear (range 1.0–500 ng/mL) and this could be extended to 25 µg/mL by 50‐fold dilution integrity. No endogenous peaks were detected in the elution of analytes in drug‐free blank human plasma from six individuals and no interference was observed with co‐medications tested. Intra‐ and inter‐batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. Validation data demonstrated that our assay is simple, selective, reproducible and suitable for therapeutic drug monitoring of perampanel. Copyright © 2015 John Wiley & Sons, Ltd.     

Preliminary Contribution to the Quantification of HMF in Honey by Electrochemical Biosensor Chips

Several hydroximethylfurfural (HMF) microbiosensors, based on a microelectrode configuration built by photolithographic techniques, have been developed. Two different biosensors based on the aldehyde dehydrogenase (ALDH) enzyme coupling with NADH oxidase (NOD) or diaphorase (Diaph) are described. Experimental variables were optimized using experimental design methodology, by central composite designs, taking the intensity registered for a given HMF solution as response. Given the reproducibility (residual standard deviation (RSD), 7.20%), repeatability (RSD=3%) and limit of detection (LOD)=1.68×10^?4 mol dm^?3 (α=β=0.05 and a replicate) reached by the ALDH‐Diaph microbiosensor under the optimum conditions, the analysis of HMF in honey was successfully accomplished.     

Students’ conceptual understanding of a function and its derivative in an experimental calculus course

Calculus has been witnessing fundamental changes in its curriculum, with an increased emphasis on visualization. This mode for representing mathematical concepts is gaining more strength due to the advances in computer technology and the development of dynamical mathematical software. This paper focuses on the understanding of the function and its derivative as viewed by students of a reformed Calculus 1 course offered in two experimental sections at the Lebanese American University in Beirut, Lebanon. Results have shown that the general approach adopted in the course proved to be unpopular for a great majority of the students, but rewarding for others. Interviews conducted with some students and a study of their performance on very specific exam questions reveal that for most students, the algebraic representation of a function still dominated their thinking; however, these students showed an almost complete understanding of the derivative, particularly the idea of the instantaneous rate of change and/or the slope of a curve at a given point. Furthermore, very few of these students referred to the mechanical methods for finding derivatives.     

混合位级正交试验设计的极差分析方法

本文指出，在混合位级的正交试验设计中，以往的极差分析方法存在着不足。本文给出了极差的修正方法，并用大量实例做了数值验证，说明这个修正确实很有效     

涡旋柔性弹簧及组件性能实验研究

本文利用TSL系列弹簧刚度实验仪对用于斯特林制冷机中的单片柔性弹簧及柔性弹簧组件进行了实验研究。测试了四种不同尺寸弹簧刚度的动态特性,研究了单片弹簧的轴向刚度、径向刚度以及力矩特性,然后对柔性弹簧组件进行了实验研究,指出了不同组合方法下的刚度及弯矩特性,得到的数据可以作为斯特林制冷机设计的参考。     

地源热泵的运行特性模拟研究

依据圆柱源理论,建立起了耦合地面热泵机组和地下埋管换热器特性的模拟模型,该模型可用于长期运行的地源热泵系统的短时间步长运行特性模拟。探讨了模拟过程中有关参数的确定方法,并运用所建模型对地源热泵的冬季和夏季运行特性进行了模拟。运行特性模拟与实验数据的验证结果表明,所建模型可以对地源热泵的运行特性做出符合实际的预测。     

双预脉冲驱动X射线激光实验研究

 在“星光-Ⅱ”激光装置上进行了双预脉冲驱动类氖铬X射线激光实验，介绍了实验方法和实验结果，并对结果进行了简短讨论。由于目前“星光”装置输出能量较低，所进行的双预脉冲驱动未能显著提高X射线激光强度，改变预脉冲幅度时X射线激光强度也未有显著变化。利用MED103程序进行了模拟计算，其结果与实验结果一致。