Trans-ferulic acid-4-β-glucoside (FAG) is a monomer extracted from Radix Aconiti Lateralis Preparata, which is a potential candidate for the prevention and treatment of the cold injury. To determine the concentration FAG in rats, it is essential to develop an ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method. The chromatographic separation was achieved by ACQUITY UPLC BEH C18 column(2.1×50mm, 1.7μm). A Xevo triple quadrupole tandem mass spectrometer was used to quantitative determination of FAG in the negative ion mode. The standard calibration curve was linear over the concentration range of 0.1-100 μg/mL and 0.0626-31.28 μg/g for rat plasma and liver tissue homogenates samples, separately. The inter-and intra-batch precision (RSD%) of the assay was ≤ 8.29% and accuracy (RE%) ranged from -7.41 to 10.99%. The matrix effect was between 92.99 and 102.39%. The oral absolute bioavailability of FAG was obtained as 1.80%. The results of tissue distribution suggested that FAG spread rarely in liver and brown adipose, which was not propitious to exert its ability to treat cold injury. In general, the above studies were significant to provide necessary information for further study.

目的 探讨灵芝乙醇提取物(GLEE)对非小细胞肺癌A549细胞增殖抑制的作用及分子机制.方法 建立A549肺癌荷瘤鼠模型,每日ig给予荷瘤鼠50、100、150 mg·kg-1的GLEE,计算抑瘤率、肿瘤体积及脏器系数;用Western blot法分析GLEE对A549细胞中相关蛋白表达的影响;用RNA-seq分析GLEE对A549细胞中基因表达的影响.结果 实验的第16～20天,50、100、150mg·kg-1GLEE显著抑制肿瘤生长,抑瘤率分别为24.52％、40.69％、51.35％;在蛋白水平,GLEE通过下调Bcl-2,上调Bax和激活Caspase-3诱导细胞凋亡;火山图显示:A549细胞中4572个基因上调,4464个基因下调.结论 GLEE对非小细胞肺癌A549细胞增殖具有显著抑制作用,其诱导细胞的凋亡可能是通过线粒体途径.

Trans-ferulic acid-4-β-glucoside (FAG) is a monomer extracted from Radix Aconiti Lateralis Preparata, which is a potential candidate for the prevention and treatment of cold injury. To determine the concentration of FAG in rats, it is essential to develop an ultra-performance liquid chromatography coupled with MS/MS method. Chromatographic separation was achieved by an Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm). A Xevo triple quadrupole tandem mass spectrometer was used to quantitatively determine FAG in the negative-ion mode. The standard calibration curve was linear over the concentration range of 0.1-100 μg/mL and 0.0626-31.28 μg/g for rat plasma and liver tissue homogenate samples, respectively. The inter- and intra-batch precision (% relative standard deviation) of the assay was ≤8.29%, and accuracy (% relative error) ranged from -7.41 to 10.99%. The matrix effect was between 92.99 and 102.39%. The oral absolute bioavailability of FAG was obtained as 1.80%. The results of tissue distribution suggested that FAG spread rarely in the liver and brown adipose, which was not propitious to exert its ability to treat cold injury. In general, these studies were significant to provide necessary information for further study.

目的 初步评价反式阿魏酸-4-β-葡萄糖苷(FAG)的安全性.方法 单次给药毒性试验采用最大耐受量法,观察给予药物后动物的毒性反应.重复给药毒性试验将大鼠随机分为对照组和0.5、1、2 g·kg-1剂量组,连续灌胃给药28 d,停药恢复28 d,观察记录大鼠的外观体征、体重、摄食量和各项毒理学指标.结果 单次给药毒性试验结果显示:小鼠灌胃给予8 g·kg-1FAG可引起雄性小鼠体重增长缓慢,但可恢复;灌胃给予4 g·kg-1FAG对大鼠无明显毒性反应.重复给药毒性试验结果显示:高剂量组大鼠出现体重增加和体脂升高,血液学指标出现不同程度的异常改变;低、中、高剂量组的肝脏器指数均明显升高;高剂量组的肾小管管型病变显著增多,以上异常改变停药后均可恢复.结论 FAG小鼠和大鼠单次给药的最大耐受量分别为8、4 g·kg-1,约相当于起效剂量的29.6、20.8倍;重复给药试验未见明显毒性反应剂量为0.5 g·kg-1.FAG在临床应用时应重点监测体重、血脂、血液学相关指标及肝、肾功能的变化.

目的 评价番茄红素固体纳米胶柬(以下简称胶束)的质量,并研究其在大鼠体内的药动学行为.方法 考察胶柬的微观结构、粒径及分布、平均载药量、包封率、人工胃液或人工肠液中的释放特性.比较番茄红素油溶液(LPO)与胶束在大鼠体内的药动学特征.结果 胶束遇水分散后形成的胶束粒径及分布都较均匀,平均载药量为1.401％±0.008％,包封率为90.26％ ±0.87％;在人工胃液中释放的程度较低,而在人工肠液中表现为持续释放.灌胃给予大鼠胶束和IPO后,以LPO为参比,胶束的相对生物利用度为183.48％.结论 将番茄红素制成胶束后,其口服生物利用度得到了一定程度的提高,改善了番茄红素因溶解度低,生物利用度低下的问题,为胶束的开发提供了参考.

The orally available novel small molecule drug ZWF is under preclinical development for an anticancer purpose. The present study aimed to assess the viability of developing ZWF as a form of oral formulation for clinical application based on the principles of biopharmaceutics and pharmacokinetics. The crucial physicochemical properties of ZWF were determined by in vitro assays. The in situ gastrointestinal absorption characteristics and in vivo pharmacokinetic behaviors of ZWF in rats were characterized. The solubility of ZWF showed a highly pH-dependent profile, decreasing from 25,392.89 to 20.48 μg/mL as the solution pH increased from 1.0 to 5.8. In PBS with a pH of 1.0 to 5.8, the LogP value of ZWF ranged from −2.35 to 2.20 and was gradually increased as the pH value increased. ZWF was partially absorbed in the stomach, and the favorable absorption sites were the duodenum, jejunum, and ileum. Pharmacokinetic studies showed that the AUC(0-t) and Cmax values of ZWF after its oral administration as a suspension prepared with 0.5% CMC-Na were increased by 18.97% and 40% than that with normal saline, providing a model oral formulation of ZWF with ideal bioavailability and system exposure in rats. From the perspective of oral absorption, ZWF possessed appealing qualities as a drug candidate and could be prepared as an oral preparation for clinical application. The present study has established a fundamental foundation for the development and quality evaluation of the ZWF oral formulations.

药物代谢动力学是定量研究药物(包括外来化学物质)在生物体内吸收、分布、排泄和代谢(简称体内过程)规律的一门学科.在动物或人体实验的基础上建立数学模型,求算相应的药物代谢动力学参数后,可以对药物在体内过程进行预测.新药和新制剂均需要进行动物或人体药物代谢动力学试验,以了解其药物代谢动力学过程. 本研究应用药物代谢动力学方法,对样品酒与参比酒进行乙醇代谢动力学研究,属于已上市产品的药物代谢动力学应用探索性研究.通过对给予既定相同剂量供试样品后机体血液乙醇浓度的经时变化特征研究,建立酒代谢动力学的试验方法,有效筛选在代谢动力学指标上具有优势的酒样,为实际产品开发和产品评估提供有效的方法.

Supersaturation drug delivery system (SDDS) based on amorphous solid dispersion (ASD) is a widely used strategy to improve oral absorption of poorly water-soluble drugs by achieving a supersaturated state where drug concentration is significantly higher than drug solubility. However, dissolved drugs tend to recrystallize in gastrointestinal (GI) tract if without effective stabilizing excipients. In this paper, well-recognized polymer (polyvinylpyrrolidone, PVP) and lipid (phosphatidylcholine, PC) excipients are combined as ASD carrier, aiming at investigating the effects on evolution of in vitro supersaturation and in vivo plasma concentration of a model poorly soluble drug indomethacin (IND). Fundamental aspects including polymer/lipid composition ratio, drug loading (DL) degree and administration dose were investigated. The in vitro dissolution profiles of ASDs were assessed by supersaturation degree, duration, maximum achievable drug concentration and dose-normalized efficiency, and correlated with in vivo pharmacokinetic data. Results showed that both in vitro and in vivo concentration-time profiles of IND were significantly varying with abovementioned factors. Solution viscosity, solid-state properties and morphology of ASDs were related to the results. This study revealed fundamental mechanisms of PVP/PC mixture effect on IND supersaturation and oral bioavailability, demonstrating that polymer/lipid mixture could be used as a promising carrier to alter supersaturation profile and oral bioavailability of SDDS products.