Effects of Two Natural Bisbenzylisoquinolines,Curine and Guattegaumerine,Extracted from Isolona hexaloba on Rhodamine Efflux by Abcb1b from Rat Glycocholic-Acid-Resistant Hepatocarcinoma Cells

To develop new therapeutic molecules, it is essential to understand the biological effects and targets of clinically relevant compounds. In this article, we describe the extraction and characterization of two alkaloids from the roots of Isolona hexaloba—curine and guattegaumerine. The effect of these alkaloids on the multidrug efflux pump ABCB1 (MDR1/P-Glycoprotein) and their antiproliferative properties were studied. Compared to verapamil, a widely used inhibitor of P-gp, curine and guattegaumerine were found to be weak inhibitors of MDR1/P-Glycoprotein. The highest inhibition of efflux produced by verapamil disappeared in the presence of curine or guattegaumerine as competitors, and the most pronounced effect was achieved with curine. Altogether, this work has provided new insights into the biological effects of these alkaloids on the rat Mdr1b P-gp efflux mechanism and would be beneficial in the design of potent P-gp inhibitors.     

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

We describe herein a highly regio‐ and enantioselective Pd‐catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all‐carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine‐ and pyrazino‐oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well‐tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O‐methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.     

维拉帕米对肺静脉急性电重构的影响

探讨维拉帕米对短阵快速剌激肺静脉后肺静脉有效不应期及有效不应期频率适应性的影响。对8条成年杂种犬采用自身前后对照的方法,第一部分实验:首先分别测量起搏周长(PCL)分别为300 ms、400 ms时肺静脉有效不应期(PV-ERP),接着以1:1起搏肺静脉的最快频率刺激肺静脉10 min,分别在刺激中止后即刻、5 min、10 min时重复测量PV-ERP。第二部分实验:完成上述实验后15 min给予维拉帕米,再次重复第一部分实验内容。结果:短阵快速刺激肺静脉可以引起PV-ERP明显缩短,PV-ERP频率适应性下降,即肺静脉发生了急性电重构,应用维拉帕米后虽然不能逆转上述改变,但是明显减小改变的程度。说明维拉帕米一定程度上抑制了肺静脉急性电重构的程度。     

钙拮抗剂异博定增强博来霉素A_5对人肝癌BEL-7402细胞的毒性作用

应用肿瘤细胞增殖抑制、克隆形成、流式细胞术,研究了钙拮抗剂异博定(Ver)与博来霉素A_5(BLM A_5)对人肝癌BEL-7402细胞的影响.结果表明:无细胞毒性作用的Ver(20μmol)增强BLM A_5对人肝癌BEL-7402细胞增殖抑制作用达4倍;100μmol Ver增强BLM A_5毒性达11倍;与BLM A_5单独作用比较,Ver使G_2M期细胞进一步增多.另外,提高胞外钙浓度能增加BLM A_2对人肝癌BEL-7402细胞的增殖抑制作用.     

盐酸维拉帕米药物树脂复合物的制备及其体外释药动力学

口服药物树脂控释给药系统;交换反应动力学;盐酸维拉帕米药物树脂复合物的制备及其体外释药动力学     

Phytochemical Analysis,Antispasmodic, Myorelaxant,and Antioxidant Effect of Dysphania ambrosioides (L.) Mosyakin and Clemants Flower Hydroethanolic Extracts and Its Chloroform and Ethyl Acetate Fractions

Dysphania ambrosioides (L.) Mosyakin and Clemants is an annual or ephemeral perennial herb used traditionally in the Mediterranean region in folk medicine to treat various illnesses, including those related to the digestive system. This study aims to assess the antispasmodic, myorelaxant, and antioxidant effects of D. ambrosioides flower hydroethanolic extract and its chloroform and ethyl acetate fractions in a comparative study to evaluate the result of the extraction type on the potential activity of the extract. Both rat and rabbit jejunum were used to evaluate the antispasmodic and myorelaxant effect, while the antioxidant effect was evaluated using DPPH, a ferric reducing power assay, and a beta-carotene bleaching test. LC/MS-MS analysis was carried out to reveal the composition of the different types of extract. Following the results, the hydroethanolic extract showed a significant myorelaxant effect (IC₅₀ = 0.39 ± 0.01 mg/mL). Moreover, it was shown that the hydroethanolic extract demonstrated the best antispasmodic activity (IC₅₀ = 0.51 ± 0.05 mg/mL), followed by the ethyl acetate (IC₅₀ = 4.05 ± 0.32 mg/mL) and chloroform (IC₅₀ = 4.34 ± 0.45 mg/mL) fractions. The antioxidant tests showed that the hydroethanolic extract demonstrated high antioxidant activity, followed by the ethyl acetate and chloroform fractions. The LC/MS-MS analysis indicates that the plant extract was rich in flavonoids, to which the extract activity has been attributed. This study supports the traditional use of this plant to treat digestive problems, especially those with spasms.     

Development and Validation of a Chiral Liquid Chromatographic Assay for Enantiomeric Separation and Quantification of Verapamil in Rat Plasma: Stereoselective Pharmacokinetic Application

A novel, fast and sensitive enantioselective HPLC assay with a new core–shell isopropyl carbamate cyclofructan 6 (superficially porous particle, SPP) chiral column (LarihcShell-P, LSP) was developed and validated for the enantiomeric separation and quantification of verapamil (VER) in rat plasma. The polar organic mobile phase composed of acetonitrile/methanol/trifluoroacetic acid/triethylamine (98:2:0.05: 0.025, v/v/v/v) and a flow rate of 0.5 mL/min was applied. Fluorescence detection set at excitation/emission wavelengths 280/313 nm was used and the whole analysis process was within 3.5 min, which is 10-fold lower than the previous reported HPLC methods in the literature. Propranolol was selected as the internal standard. The S-(−)- and R-(+)-VER enantiomers with the IS were extracted from rat plasma by utilizing Waters Oasis HLB C18 solid phase extraction cartridges without interference from endogenous compounds. The developed assay was validated following the US-FDA guidelines over the concentration range of 1–450 ng/mL (r² ≥ 0.997) for each enantiomer (plasma) and the lower limit of quantification was 1 ng/mL for both isomers. The intra- and inter-day precisions were not more than 11.6% and the recoveries of S-(−)- and R-(+)-VER at all quality control levels ranged from 92.3% to 98.2%. The developed approach was successfully applied to the stereoselective pharmacokinetic study of VER enantiomers after oral administration of 10 mg/kg racemic VER to Wistar rats. It was found that S-(−)-VER established higher C_max and area under the concentration-time curve (AUC) values than the R-(+)-enantiomer. The newly developed approach is the first chiral HPLC for the enantiomeric separation and quantification of verapamil utilizing a core–shell isopropyl carbamate cyclofructan 6 chiral column in rat plasma within 3.5 min after solid phase extraction (SPE).     

异博定增强平阳霉素对体外培养人喉癌细胞的毒性及机制

为探讨钙拮抗剂异博定是否能增强平阳霉素对人癌细胞的毒性,利用体外培养人喉癌细胞对二药单用和合用效果进行了比较研究.结果表明,非抑制浓度的异博定使平阳霉素的半抑制浓度显著下降;平阳霉素与异博定联合处理后,细胞存活率下降到单用平阳霉素的1/16～1/43;异博定能增强平阳霉素对人喉癌细胞的毒性,原因之一是异博定促进了细胞对平阳霉素的吸收,使药物在细胞内的积聚增加,但对该药外排无显著影响.     

P-糖蛋白抑制剂维拉帕米对龙血素A、B、C在大鼠体内药物动力学影响

研究灌胃给予大鼠龙血竭后,P糖蛋白抑制剂维拉帕米对其有效成分龙血素A、B、C在大鼠血浆中的药物动力学影响.将SD大鼠随机分为对照组和抑制剂组并单次给药,对照组灌胃给予大鼠5 g/kg龙血竭,抑制剂组联合给予大鼠维拉帕米(1 mg/kg)和龙血竭(5 g/kg).收集两组相同系列时间的血浆样本,采用HPLC-MS/MS的方法对龙血素A、B、C在大鼠血浆中的浓度测进行检测,求算两组血浆样本药物动力学参数.与对照组相比,抑制剂组大鼠龙血素A、B、C的血药浓度-时间曲线下面积分别增加109.4%,78.5%,22.8%,血药峰浓度分别增加69.6%,115.0%,42.1%,龙血素A、B的达峰时间均延长、龙血素C的达峰时间无变化,三者的生物半衰期(T_0.5)均变小,说明P糖蛋白抑制剂能够引起龙血素A、B、C在大鼠体内的血浆药物动力学参数变化,龙血素A、B、C均有可能为P糖蛋白的潜在底物.