利用共聚焦显微镜研究siRNA/CLDs复合物的胞内分布

刁怡萍, 孙晶, 杨梦依, 徐波, 张礼和, 杨振军

2016, 25(12): 859-868. DOI: 10.5246/jcps.2016.12.096

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研究siRNA在胞内的运输过程有助于阐明其在细胞质基质中的动力学性质及过程。本文报道了激光共聚焦扫描显微镜技术用于研究siRNA及其肽缀合物与胱氨酸骨架阳离子脂质体递送系统(siRNA/CLD)的胞内分布过程。发现siRNA在胞质内分布动力学与3′-单肽-siRNA缀合物/CLD递送系统的入胞途径紧密相关, 其中具有较好抗肿瘤活性的3′-pAs-siRNA/CLD, 具有较快的细胞摄取及溶媒体逃逸过程, 并能在A375细胞中潴留较长的时间。该方法高效、可定量并可视化, 不仅能够测定siRNA在胞内的浓度, 也能够定量分析其与细胞亚结构的共定位关系, 进一步可系统研究siRNA及其缀合物在胞质内的动力学分布过程。

单动物个体—单观测值型数据药物动力学参数估算方法的对比研究

郭廷杰, 尹安玥, 周田彦, 卢炜

2016, 25(12): 869-875. DOI: 10.5246/jcps.2016.12.097

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在临床前药物动力学研究中, 通常无法获得每只动物个体的完整药物动力学观测数据。在某些情况下, 每只动物个体只能提供一个观测数据。人们并不知道如何有效利用此类数据进行药物动力学参数的估算。本研究旨在比较一种新方法和传统方法在估算“单动物个体—单观测值”型数据的药物动力学参数时的优劣。本研究假设共有15只动物分别单次静脉注射相同剂量的药物, 每只动物提供一个观测数据。共有5个观测时间点, 每个观测时间点包括三个观测数据。数据仿真采用符合一级消除的一室模型。清除率(CL)和表观分布容积(V)的个体间变异均包含10%、30%和50%三个水平, 统计模型选定为比例型残差模型, 也包括三个水平: 10%、30%和50%。本研究对比了药物动力学参数估算的两种方法(传统方法和有限重复抽样法), 传统方法(M1)直接对原始数据(即“单动物个体—单观测值”型数据)进行参数估算, 而有限重复抽样法(M2)则是按照观测时间点对原始数据进行排列组合, 将其扩展为一套由含有完整药物动力学数据的虚拟动物个体组成的新的数据集, 本研究中共243 ()只虚拟动物个体。本研究共重复了100次仿真, 仿真与参数估算均采用NONMEM软件完成。结果显示, M2方法所估算的CL和V与其相应的仿真值更接近, 但在不同IIV及残差的组合下稍有差异。总体而言, M2方法的优势随着残差的增大而减小, 其也同样收到IIV大小的影响, IIV增大时M2优势亦会下降。同M1方法类似, M2方法对参数的IIV也没有还原能力。与传统方法相比, 有限重复抽样法在估算“单动物个体—单观测值”型数据药物动力学参数时可以提供更加可靠的结果。与个体间变异相比, 估算结果主要收到残差大小的影响。

Spectrophotometric and spectrofluorimetric methods for the determination of ropinirole content in pharmaceutical dosage forms

Effat Souri, Milad Torabadi, Maliheh Barazandeh Tehrani

2016, 25(12): 876-881. DOI: 10.5246/jcps.2016.12.098

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Two simple and rapid spectrofluorimetric and spectrophotometric methods were described for the determination of ropinirole hydrochloride content in pharmaceutical dosage forms. Both methods are based on the reaction of ropinirole hydrochloride and eosin Y in aqueous medium at pH 4.0. Quenching of the fluorescence intensity of eosin Y at 540 nm upon excitation at 350 nm was used for the determination of ropinirole hydrochloride levels after ion-pair complex formation. Also, the absorbance increase of eosin Y at 546 nm after ion-pair complex formation was used for spectrophotometric measurements. Both methods showed linear relationships between the fluorescence quenching or absorbance increase and ropinirole concentration in the range of 6–150 µg/mL and 50–500 µg/mL for spectrofluorimetric and spectrophotometric methods, respectively. As no organic solvents were used in these two methods, they could be categorized as green analytical methods. Both methods were accurate (Error<1.2%) and precise (CV<1.9%), as shown by statistical analysis results. Both methods were used for determination of ropinirole hydrochloride content in pharmaceutical dosage forms without any significant interference from associated impurities.

口服和厚朴酚对大鼠脑缺血再灌注(I-R)损伤和SHRsp脑卒中的保护作用

刘晓岩, 胡振宇, 陈世忠, 王坚成, 王银叶

2016, 25(12): 882-891. DOI: 10.5246/jcps.2016.12.099

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和厚朴酚静脉注射对脑缺血再灌注损伤有保护作用, 本研究采用大鼠脑缺血再灌注损伤和自发性高血压易卒中(SHRsp)模型观察口服和厚朴酚微乳对大鼠脑卒中的保护作用。用血管收缩实验、原代大鼠主动脉内皮细胞和原代大鼠脑微血管内皮细胞损伤模型进一步探讨其作用机制。研究结果显示: 口服和厚朴酚微乳可明显减小I-R大鼠的脑梗死体积和神经行为学评分, 并降低脑组织水含量。该制剂也明显减小SHRsp卒中大鼠的神经行为学评分, 显著增加存活率。和厚朴酚明显抑制KCl和苯肾上腺素诱导的大鼠主动脉收缩反应, 增加大鼠主动脉内皮细胞NO的释放; NO合成酶抑制剂L-NAME可减弱和厚朴酚对血管收缩的抑制作用。和厚朴酚可增加大鼠主动脉内皮细胞p-eNOS水平和NO的释放。在缺糖缺氧/复糖复氧(OGD)损伤的大鼠脑微血管内皮细胞, 和厚朴酚明显增加细胞存活率, 增加eNOS和p-eNOS的水平。这些结果提示: 和厚朴酚微乳口服对大鼠脑缺血再灌注(I-R)损伤和SHRsp 脑卒中具有明显保护作用, 这些作用与其内皮细胞保护作用和促进eNOS表达与活化有关。

Activity of tamarindus indica pulp water extract in high carbohydrate diet rats as a treatment for obesity and insulin resistance

Finna Setiawan, Elin Yulinah Sukandar, Sukrasno, Ketut Adnyana I

2016, 25(12): 892-897. DOI: 10.5246/jcps.2016.12.100

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Obesity is often identified as a nutritional disorder, and this condition continues to be one of the most important yet preventable health hazards. It may be a complex group of diseases and should be characterized as a syndrome that results from an imbalance between energy intake and expenditure. Furthermore, obesity is associated with several diseases such as diabetes mellitus, atherosclerosis, cardiovascular diseases, osteoarthritis, and hypertension. In previous studies, we found that in Asia, especially in the Asean region, carbohydrates are heavily represented in the diet. Therefore, we used a high carbohydrate diet to induce obesity in rats. The aim of this study was to evaluate the potency of Tamarindus indica pulp as an anti-obesity agent in a high carbohydrate diet animal model. The antiobesity effect was evaluated in this in vivo model at doses of 75 mg/kg·bw and 225 mg/kg·bw. Treatment was started in week 3 and week 9, and biochemical characteristics were measured every 3 weeks. In the end of the study period, insulin resistance and adiponectin levels were measured. TIWE (Tamarindus indica water extract) at a dose of 75 mg/kg·bw showed better efficacy than at a dose of 225 mg/kg·bw, and treatment started on week 3 was better than treatment started on week 9. TIWE has an anti-obesity effect associated insulin resistance by increasing adiponectin levels and insulin sensitivity, which can impact body weight, triglyceride levels, blood glucose levels, and body fat.

马齿苋的化学成分及其生物活性研究

金天云, 沈涛, 周明星, 李爱玲, 封达, 郑博伦, 巩洁, 孙佳伟, 李玲玉, 向兰

2016, 25(12): 898-905. DOI: 10.5246/jcps.2016.12.101

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对中药马齿苋的化学成分特别是有机酸类成分进行深入研究, 并对其抗炎和醌还原酶诱导活性进行筛选。通过聚酰胺、硅胶、葡聚糖凝胶等柱色谱方法进行分离纯化, 利用核磁共振波谱等数据鉴定结构。共分离鉴定了20个化合物, 分别为丁二酸 (1)、丁二酸单甲酯 (2)、L-苹果酸 (3)、L-苹果酸-1-甲酯 (4)、L-苹果酸-4-甲酯 (5)、L-苹果酸二甲酯 (6)、L-柠檬酸-6-乙酯 (7)、L-柠檬酸-1-甲酯 (8)、L-柠檬酸-1,5-二甲酯 (9)、4-羟基-5-甲基-呋喃-3-甲酸 (10)、5-羟甲基糠酸 (11)、硬脂酸 (12)、L-焦谷氨酸 (13)、环-(酪氨酸-亮氨酸) (14)、L-异亮氨酸 (15)、(−)-dehydrovomifoliol (16)、(−)-epiloliolide (17)、3,4-二羟基苯乙醇 (18)、丁二酰亚胺 (19)、尿嘧啶 (20)。其中14个化合物2, 4–8, 10, 11, 13–18为首次从马齿苋中分离得到。化合物18 (12.5 μM)具有抗炎活性, 对脂多糖诱导RAW264.7巨噬细胞中一氧化氮的产生具有强的抑制作用, 且可提高Hepa lclc7 细胞的醌还原酶活性; 化合物16 (50 μM)具有弱的醌还原酶诱导活性, 其它化合物未显示出抗炎和醌还原酶诱导活性。