左旋氨氯地平的临床疗效与生物学特性

目的 通过观察手性药物左旋氨氯地平在治疗轻、中度高血压的临床疗效,分析手性药物的生物学特性.方法 入选62例轻、中度高血压患者,随机分为左旋氨氯地平治疗组30例,氨氯地平治疗组32例,观察8周后两组血压变化及不良反应情况.结果 左旋氨氯地平治疗轻、中度高血压的总有效率为86.7％,氨氯地平的总有效率为87.5％,无显著性差异,但不良反应方面,左旋氨氯地平低于氨氯地平.结论 手性药左旋氨氯地平是高效、安全的抗高血压药.氨氯地平的有效活性成分是其左旋异构体.     

盐酸依格列汀合成工艺研究

目的 研究盐酸依格列汀(1)的合成工艺。方法 以 2,4,5-三氟苯乙酸为原料,经缩合、氨化、NaBH4还原三步反应得到消旋依格列汀,再经酒石酸拆分、盐酸成盐得到目标产物盐酸依格列汀。其中,拆分后所得的另一对映异构体S-依格列汀通过N-氯代、消除后顺利回收烯胺中间体。结果 制备工艺总收率26.9%,化学纯度为99.9%,光学纯度 ee 值为99.8%;烯胺中间体回收率为92.3%(以拆分所得依格列汀剩余的对映异构体量计算)。结论 该工艺收率高,步骤短,成本低廉、操作简便,适应工业化生产。此外,本文也为手性胺类药物的高效制备提供了一种极具吸引力的策略。     

应用膝关节旋转半月板解剖型和固定半月板解剖型假体手术治疗膝退行性骨关节炎的临床分析

目的探讨应用膝关节旋转半月板解剖型和固定半月板解剖型假体治疗膝退行性骨关节炎的临床疗效。方法2009年2月—2013年1月选择在我院进行住院治疗的膝退行性骨关节炎患者132例,根据随机原则分为观察组与对照组各66例,行人工膝关节置换手术治疗,分别将旋转膝关节假体和固定膝关节假体进行人工植入固定,采用美国膝关节外科学会的评分系统(KSS)对患膝在术后当日与术后3个月进行膝关节评分和功能评分。结果所有患者都顺利完成手术,术中无严重并发症发生。随访3个月,观察组与对照组的总显效率分别为93.9%和80.3%,组间比较差异有统计学意义(P<0.05)。观察组的髌骨不稳、感染和下肢深静脉血栓形成等并发症发生率明显低于对照组,差异有统计学意义(P<0.05)。两组术后当天的膝关节评分和功能评分比较无统计学差异,术后3个月时评分都明显上升,同时评分在组内与组间比较有统计学差异(P<0.05)。结论人工膝关节置换手术治疗膝退行性骨关节炎有较好的预后,而旋转假体的应用能更加有效改善患膝屈伸活动和功能,疗效满意。     

Cocaine adulteration with the anthelminthic tetramisole (levamisole/dexamisole): Long‐term monitoring of its intake by chiral LC–MS/MS analysis of cocaine‐positive hair samples

Recent studies indicate that not only the anthelminthic levamisole but also the racemate tetramisole (R‐/S‐phenyltetraimidazothiazole, PTHIT) was found as an adulterant for cocaine. We herein report on the investigation of the prevalence of PTHIT among cocaine‐positive hair samples and the discrimination of the presence of its stereoisomers levamisole and dexamisole. Cocaine‐positive hair samples were collected in a forensic context in 2015 and mainly 2017 (n = 724). Cocaine and PTHIT concentrations have been determined by achiral liquid chromatography–tandem mass spectrometry (LC–MS/MS). For distinction of levamisole/dexamisole chiral LC–MS/MS was performed. Cocaine hair concentrations ranged from 500 (cut‐off) to approximately 800 000 pg/mg. The study demonstrates a strong prevalence of PTHIT in cocaine users' hair (87%, n = 627). PTHIT hair concentrations ranged from below LLOQ 3.5 to approximately 61 000 pg/mg (median: 260 pg/mg). Surprisingly, enantiomeric ratios of levamisole/dexamisole ranged from 0.17 to 1.34 (median: 0.63). Therefore, PTHIT‐adulterated street cocaine samples (n = 24) seized between 2013 and 2016 were tested. Samples mainly contained racemic tetramisole (87.5%), only one sample contained levamisole only and two samples contained non‐racemic PTHIT. Our experiments suggest that the presence of tetramisole in biological samples may have hitherto been underestimated. Most probably higher dexamisole than levamisole concentrations in hair specimens arise from stereoselective metabolism and/or elimination. This is particularly important in light of the different pharmacological activities of the two enantiomers and potentially different adverse effects. Toxicological interpretations in intoxication cases with adulterated cocaine should not only consider levamisole but also tetramisole and terminology in scientific contributions should be used accordingly.     

亲和毛细管整体柱在牛血清白蛋白与奈福泮对映体相互作用研究中的应用

利用胃蛋白酶键合的有机聚合物整体柱在电色谱中对手性药物奈福泮的拆分能力,采用前沿分析法同时对奈福泮的两个对映体与牛血清白蛋白(BSA)的相互作用情况进行了考察。经过优化后建立的电色谱条件为:胃蛋白酶修饰的聚(甲基丙烯酸环氧丙酯-乙二醇二甲基丙烯酸酯)毛细管整体柱作为分离通道(32 cm×75 μm,有效长度22 cm),运行缓冲液为pH 5.5的15 mmol/L醋酸铵,样品溶剂为pH 7.4的50 mmol/L醋酸铵,运行电压为5.0 kV,电压进样10 kV×6 s,检测波长为215 nm。此时奈福泮两个对映体平台峰彼此完全分离,结合体系中BSA对对映体在电色谱中的分离和检测均无影响,测得两个对映体与BSA的结合常数分别为443和527 L/mol,结合位点数均为1.0,结合位点为Sudlow site Ⅱ。     

Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W

Congenital stationary night blindess-2 (incomplete congenital stationary night blindness (iCSNB) or CSNB-2) is a nonprogressive, X-linked retinal disease which can lead to clinical symptoms such as myopia, hyperopia, nystagmus, strabismus, decreased visual acuity, and impaired scotopic vision. These clinical manifestations are linked to mutations found in the CACNA1F gene which encodes for the Ca(v)1.4 voltage-gated calcium channel. To better understand the physiological effects of these mutations, three missense mutants, F742C, G1007R and R1049W, previously shown to be mutated in patients with CSNB-2, were transiently expressed in human embryonic kidney (HEK) tsA-201 cells and characterized using whole-cell patch clamp. The G1007R mutation is located in transmembrane segment 5 (S5) of domain III and R1049W is located in the extracellular linker between S5 and the P-loop of domain III. Both mutants produced full length proteins that targeted to the membrane but did not support ionic currents. In 20 mM Ba(2+), F742C (S6 domain II) produced a approximately 21 mV hyperpolarizing shift in half activation potential (V(a[1/2])) and a approximately 23 mV hyperpolarizing shift in half inactivation potential (V(h[1/2])). Additionally, F742C displayed slower inactivation kinetics and a smaller whole cell conductance (G(max)). In physiological 2 mM Ca(2+), F742C produced a approximately 19 mV hyperpolarizing shift in V(a[1/2]). These findings suggest that the pathology of CSNB-2 in patients with these missense mutations in the Ca(v)1.4 calcium channel is the result in either a gain of function (F742C) or a loss of function (G1007R, R1049W).     

单细胞基因组和转录组的共测定方法研究进展

单细胞测序提供了大量样品测序所不能提供的异质性等信息。然而由于细胞生长发育受多种因素调节,仅依靠基因型或者表型信息无法全面、准确地说明问题。因此,开发单细胞基因组转录组共测定技术为研究基因变异与表型变异间的关系提供了强有力的工具。目前,单细胞基因组与转录组共测定技术主要分为全细胞裂解法（如：G&T-Seq、DR-Seq）,细胞膜裂解法（如：SIDR、微流控芯片法）以及其他方法（如：Simul-Seq、Gel-Seq）。本文对这几类技术进行了简要介绍,并对其前景进行了展望。     

环糊精及其衍生物在药物分离分析中的应用进展

近年来,环糊精及其衍生物在药物尤其是手性药物分离分析中的应用受到了广泛关注。本文通过查阅有关文献,对CD及其衍生物在高效液相色谱、气相色谱、毛细管电泳色谱、薄层色谱、超,临界流体色谱、高速逆流色谱以及膜分离等方法中的应用作了系统介绍,具有十分重要的参考价值。     

HIV蛋白酶抑制剂的关键中间体——手性氨基环氧烷合成研究进展

拟肽类HIV蛋白酶抑制剂是临床治疗艾滋病的主要药物,它们的共性结构片段——（2R, 3S）-3-氨基-4-苯基-2-丁醇从关键中间体手性氨基环氧烷得到,笔者对该中间体的合成研究进行归纳和总结。     

阿维莫泮合成中Aza-Michael加成反应的优化

目的改进阿维莫泮关键中间体的合成工艺。方法在阿维莫泮的手性诱导合成—（3R,4R）-4-（3-羟苯基）-3,4-二甲基哌啶与α,β-不饱和酯（或酰胺）的Aza-Michael加成反应中,添加硝酸铈铵（CAN）可以提高反应的立体选择性和收率,缩短反应时间。结果当底物为α,β-不饱和酰胺时,加入硝酸铈铵,-20℃下反应6 h,两个非对映异构体产物的比例为15.5∶1,收率达到88%。结论该路线简捷,昂贵的哌啶原料消耗少,具有较好的应用价值。