Development and validation of LC–MS/MS method for amlexanox in rat plasma and its application in preclinical pharmacokinetics

Amlexanox, an anti-inflammatory and anti-allergic agent, has been widely used clinically for the treatment of canker sores, asthma, and allergic rhinitis. Recently, amlexanox has received considerable attention in curing nonalcoholic fatty liver diseases and hepatitis virus infection. Herein, we first established a sensitive high-performance liquid chromatography-tandem mass spectrum (LC–MS/MS) method for the determination of amlexanox in rat plasma. Propranolol was used as the internal standard (IS). Using a simple protein precipitation method, the amlexanox and IS were separated with Capcell Pak C18 column (2.0 × 50 mm, 5 μm) and eluted with water and acetonitrile each containing 0.1% formic acid using gradient elution condition at a flow rate of 0.4 mL·min⁻¹. Amlexanox and IS were detected by a triple quadrupole mass in multiple reactive monitoring (MRM) under the transitions of m/z 299.2 → 281.2 and m/z 259.9 → 116.1 with positive electrospray ionization, respectively. The calibration curves of amlexanox were established with the range of 50 to 2000 ng·mL⁻¹ (r² > 0.99). The validation method consisted of selectivity, accuracy, precision, carryover effect, matrix effect, recovery, dilution effect, and stability. The fully validated method was successfully applied to the pharmacokinetic study of amlexanox in Wistar rats.     

Theoretical Design of Biodegradable Phthalic Acid Ester Derivatives in Marine and Freshwater Environments

The biodegradability of phtalic acid esters in marine and freshwater environments was characterized by their binding free energy with corresponding degrading enzymes. According to comprehensive biodegradation effects weights, the binding free energy values were converted into dimensionless efficacy coefficient using ratio normalization method. Then, considering comprehensive dual biodegradation effects value and the structural parameters of PAEs in both marine and freshwater environments, a 3D-QSAR pharmacophore model was constructed, five PAE derivatives (DBP−COOH, DBP−CHO, DBP−OH, DINP−NH₂, and DINP−NO₂) were screened out based on their environmental friendliness, functionality and stability. The prediction of biodegradation effects on five PAE derivatives by biodegradation models in marine and freshwater environment increased by 15.90 %, 15.84 %, 27.21 %, 12.33 %, and 8.32 %, and 21.57 %, 15.21 %, 20.99 %, 15.10 %, and 9.74 %, respectively. By simulating the photodegradation path of the PAE derivative molecular, it was found that DBP−OH can generate ^.OH and provides free radicals for the photodegradation of microplastics in the environment.     

A simple three‐wave approximate Riemann solver for the Saint‐Venant‐Exner equations

Erosion and sediments transport processes have a great impact on industrial structures and on water quality. Despite its limitations, the Saint‐Venant‐Exner system is still (and for sure for some years) widely used in industrial codes to model the bedload sediment transport. In practice, its numerical resolution is mostly handled by a splitting technique that allows a weak coupling between hydraulic and morphodynamic distinct softwares but may suffer from important stability issues. In recent works, many authors proposed alternative methods based on a strong coupling that cure this problem but are not so trivial to implement in an industrial context. In this work, we then pursue 2 objectives. First, we propose a very simple scheme based on an approximate Riemann solver, respecting the strong coupling framework, and we demonstrate its stability and accuracy through a number of numerical test cases. However, second, we reinterpret our scheme as a splitting technique and we extend the purpose to propose what should be the minimal coupling that ensures the stability of the global numerical process in industrial codes, at least, when dealing with collocated finite volume method. The resulting splitting method is, up to our knowledge, the only one for which stability properties are fully demonstrated.     

Generalized Jacobi spectral Galerkin method for fractional pantograph differential equation

This work is concerned with the extension of the Jacobi spectral Galerkin method to a class of nonlinear fractional pantograph differential equations. First, the fractional differential equation is converted to a nonlinear Volterra integral equation with weakly singular kernel. Second, we analyze the existence and uniqueness of solutions for the obtained integral equation. Then, the Galerkin method is used for solving the equivalent integral equation. The error estimates for the proposed method are also investigated. Finally, illustrative examples are presented to confirm our theoretical analysis.     

蛋白质-多糖复合体系在活性物质传递中的应用

蛋白质-多糖复合体系作为生物活性物质传递系统的壁材,有着人工合成聚合物或无机物等其他材料不可比拟的多重优势。本文就蛋白质和多糖之间的连接方式及蛋白质-多糖复合体系形成传递系统的多种形式进行了综述,以及对此领域的发展趋势进行了展望。结合蛋白质和多糖的结构特点,二者之间的链接方式分为非共价结合的物理共聚,和共价结合的美拉德偶联、化学交联、酶催化交联等方式,文中分别对各种连接方式的原理和机理,以及其影响因素做了深入阐述。以蛋白质-多糖复合体系为壁材对活性物质的传递形式大体上分成乳化系统、胶束、纳米凝胶、分子复合物以及壳核结构等系统。不同的活性物质的特征和传递需求,可针对性地选择合适结构的蛋白质和多糖种类以及二者的连接方式和传递系统的形式。并且,随着研究的逐步发展和推进,此领域的发展趋势朝着智能化和靶向性的方向进行。目前活性物质的蛋白质-多糖复合体系的传递系统,还依然面临着系统设计、评价和应用等多方面的挑战,这就要求我们在更全面更深入了解认识其对活性物质影响和功效的基础上,安全合理地设计和深入细致地评价活性成分的传递系统。     

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.     

基于串联两阶段网络DEA模型的供应链规模收益分析

数据包络分析(DEA)是评价供应链系统(Supply chain system)间相对有效性的一种重要的工具,但是传统的DEA不考虑供应链的内部结构,对系统效率评价偏高;而本文所研究两阶段串联供应链系统,考虑把部分中间产品作为最终产品输出,增加额外中间投入的情形.基于所提出的供应链系统结构,本文建立相应的串联结构下的网络DEA模型,并针对所建立模型进行相关理论的研究,给出了串联结构下的生产可能集和规模收益情况判定方法.最后,进行数值实验,以验证我们提出的结论.