阿托伐他汀的全合成研究进展

介绍了近20年来利用消旋体拆分法、非对映选择性醇醛缩合法、Paal-Knorr反应、环加成法、双羰基不对称还原法等,完成阿托伐他汀全合成的研究进展。分析了各条路线的关键步骤,讨论了各方法的特点。参考文献27篇。     

阿托伐他汀联合缬沙坦对慢性肾炎的临床疗效分析

目的研究阿托伐他汀联合缬沙坦对慢性肾炎的临床疗效。方法以2014年1月—2016年6月慢性肾炎患者90例随机分为两组。单一药物组采用缬沙坦治疗,联合用药组采用阿托伐他汀联合缬沙坦治疗。比较两组患者慢性肾炎治疗总有效率;治疗前和治疗后患者肾功能指标、舒张压、收缩压的差异。结果联合用药组患者慢性肾炎治疗总有效率高于单一药物组,P0.05;治疗前两组肾功能指标、舒张压、收缩压比较无显著差异,P0.05;治疗后联合用药组肾功能指标、舒张压、收缩压改善幅度更大,P0.05。结论阿托伐他汀联合缬沙坦对慢性肾炎的临床疗效确切,可有效改善患者血压和肾功能,值得推广应用。     

活细胞单分子力谱研究阿托伐他汀对ICAM-1与CD11b相互作用的影响

调节细胞黏附的整合素蛋白CD11b与其配体ICAM-1的相互作用在动脉粥样硬化的炎症进程中起至关重要的作用.阿托伐他汀(Atorvastatin,ATV)作为他汀类药物中的主要成员,以其良好的降脂作用广泛应用于动脉粥样硬化疾病的临床治疗,同时大量证据表明ATV还具有独立的抗炎作用,但其具体分子机制尚未完全明确.我们应用活细胞单分子力谱法研究了ATV干预对ICAM-1/CD11b相互作用的影响.结果表明原子力显微镜(AFM)在活细胞表面测得单对黏附分子ICAM-1/CD11b的相互作用力值约为40pN,ATV不能通过直接阻断ICAM-1或CD11b影响其单分子黏附力,而抗ICAM-1单克隆抗体则有效降低了此对黏附分子作用力.此外,流式结果表明ATV干预有效抑制了肿瘤坏死因子(TNF-α)诱导的人脐静脉内皮细胞(HUVEC)表面ICAM-1表达增加.本研究建立的方法模型可作为活细胞体系研究临床药物影响细胞黏附分子间相互作用及抗炎机制的重要手段.     

氟伐他汀钠的合成

以氟苯为起始原料,通过两步反应得N-(4-氟苯甲酰甲基)-N-(1-甲基乙基)苯胺(5);5在ZnCl2存在下环化得3-(4′-氟苯基)-1-(1′-甲基乙基)吲哚(6);6与3-N-甲基-N-苯基胺基丙烯醛发生Vilsmeier-Haauc反应得(E)-3-[3′-(4″-氟苯基)-1′-(1″-甲基乙基)吲哚-2′-基]-2-丙烯醛(8);8经缩合、还原、水解得氟伐他汀钠,总收率10.5%.     

匹伐他汀钙的合成方法研究进展

综述了降血脂药物匹伐他汀钙的合成方法和最新研究进展。参考文献21篇。     

荧光光度法测定瑞舒伐他汀钙含量的研究

优化荧光分光光度法测定瑞舒伐他汀钙含量的方法,建立方法学,并用紫外-分光光度法验证结果的可靠性。在激发波长250nm,发射波长516nm的条件下采用荧光分光光度法测定瑞舒伐他汀钙片中的瑞舒伐他汀钙的含量。以荧光强度为指标,考察pH值、甲醇浓度和时间等3个因素,选定最佳条件,结果的准确性和可靠性用紫外-分光光度法进行验证。荧光强度与瑞舒伐他汀钙浓度在3.17～39.72mg·L~(-1)范围内具有良好的线性关系,回归方程F=13.96C+145.71(r=0.999 8),检出限为0.38mg·L~(-1),平均回收率为98.4%,RSD 1.05%。最佳实验条件为:pH值6.7,时间10 min,甲醇浓度为95%。对正交试验数据进行统计分析,具有统计学意义(P0.05)。结果显示用荧光分光光度法测定瑞舒伐他汀钙含量特异性好,灵敏度高,检测限低。采用紫外-分光光度法进行验证,结果一致。     

纳米钯电化学适配体传感器用于血管内皮生长因子的检测

基于目标诱导适配体片段连接,以修饰于电极表面的纳米Pd作为适配体固定平台,构建检测血管内皮生长因子(VEGF)的电化学适配体传感器。方法将VEGF适配体切成两段,其一为捕获探针,通过Pd-S键固定在以电沉积和二硫苏糖醇(DTT)封闭相结合法制备的纳米钯修饰电极表面;其二为信号探针,3'端修饰有二茂铁基团。由于VEGF与适配体之间强的相互作用,可连接此两段适配体序列并在电极表面形成稳定的适配体复合物,此时二茂铁靠近电极表面,产生电信号,从而实现对VEGF的检测。结果表明,在pH 7. 0的Tris-HCl缓冲溶液中,二茂铁的峰电流与VEGF浓度在5～40 pmol/L范围呈良好线性关系,检测限为0. 4 pmol/L。     

氟伐他汀中间体3-(4-氟苯基)-1-(1-异丙基)-1H-吲哚的合成

以苯胺为原料,经异丙基化、与2-氯-1-(4-氟苯基)乙酮缩合、催化分子内环合制得合成氟伐他汀的关键中间体——3-(4-氟苯基)-1-(1-异丙基)-1H-吲哚,总收率高于90%,其结构经1HNMR确证。     

Fe_3O_4纳米粒子与慢病毒载体共同感染内皮祖细胞的促血管新生和MRI示踪的应用

采用化学共沉淀法制备了柠檬酸钠修饰Fe_3O_4纳米粒子(NPs),使用胎牛血清(FBS)改善Fe_3O_4NPs的分散性.实验表明Fe_3O_4NPs尺寸均匀,且具有良好的稳定性,FBS浓度小于5%(体积分数)时,Fe_3O_4NPs无聚集沉淀;在300 K下,饱和磁化强度达到74.86×10~(-3)A·m~2/g(74.86 emu/g);核磁共振T2序列成像时,75μg/m L Fe_3O_4NPs与慢病毒载体(LV)共同标记内皮祖细胞(EPCs)成像效果良好;而且EPCs具有稳定过表达目的基因血管内皮生长因子(VEGF)的能力.利用Fe_3O_4NPs与LV共同感染EPCs,可有效促进大鼠血管生成.说明修饰后的EPCs兼具核磁共振成像(MRI)示踪和促血管生成双重功能.     

重组内皮抑素的质谱分析及对内皮细胞周期的影响

采用质谱、圆二色谱、荧光光谱与细胞周期分析技术研究了重组内皮抑素的蛋白结构和对内皮细胞的作用机制.研究发现,以包涵体方式表达的蛋白中会有未被降解的N末端甲硫氨酸产物,重组内皮抑素在G₂期阻断内皮细胞的生长.表明内皮抑素引发内皮细胞凋亡与细胞周期相关,为抗血管生成治疗肿瘤研究奠定了实验基础.     

Biological Assessment of the NO-Dependent Endothelial Function

Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO.     

Stimulation of Microvascular Networks on Sulfonated Polyrotaxane Surfaces with Immobilized Vascular Endothelial Growth Factor

Modulation of material properties and growth factor application are critical in constructing suitable cell culture environments to induce desired cellular functions. Sulfonated polyrotaxane (PRX) surfaces with immobilized vascular endothelial growth factors (VEGFs) are prepared to improve network formation in vascular endothelial cells. Sulfonated PRXs, whereby sulfonated α‐cyclodextrins (α‐CDs) are threaded onto a linear poly(ethylene glycol) chain capped with bulky groups at both terminals, are coated onto surfaces. The molecular mobility of sulfonated PRX surfaces is modulated by tuning the number of threading α‐CDs. VEGF is immobilized onto surfaces with varying mobility. Low mobility and VEGF‐immobilization reinforce cell proliferation, yes‐associated protein activity, and rhoA, pdgf, ang‐1, and pecam‐1 gene expression. Highly mobile surfaces and soluble VEGF weakly affect these cell responses. Network formation is strongly stimulated in vascular endothelial cells only on low‐mobility VEGF‐immobilized surfaces, suggesting that molecular mobility and VEGF immobilization synergistically control cell function.     

全视网膜激光光凝术联合玻璃体腔内注射康柏西普对增生性糖尿病视网膜病变患者视功能恢复的影响

本文分析了全视网膜激光光凝术(PRP)联合玻璃体腔内注射康柏西普对增生性糖尿病视网膜病变(PDR)患者视功能恢复的影响。选取大足区人民医院2016年8月~2018年8月收治的PDR患者86例(86眼),按照治疗方法分为手术组和联合组,各43例。手术组采用Carl Zeiss Meditec AG激光治疗仪在眼底荧光血管造影(FFA)引导下行PRP治疗,联合组则术前72 h于玻璃体腔内注射康柏西普0.1 mL,再行PRP治疗。采用ETDRS视力表测量两组患者术前和术后4个月的视力,非接触式眼压计测量眼压,光学相干断层扫描(OCT)检查黄斑中心凹视网膜厚度(CMT),FFA检查眼底视网膜无灌注区和新生血管消退情况,统计两组患者术后并发症发生情况。术后4个月,两组视力、CMT较术前均有变化,且联合组视力较手术组明显提高,CMT较手术组明显下降,差异有统计学意义(P<0.05)。联合组视网膜无灌注区和新生血管消退率均明显高于手术组,差异有统计学意义(P<0.05)。联合组术后视网膜脱离、眼高压及视网膜出血等并发症发生率为4.65%,明显低于手术组的23.26%,差异有统计学意义(P<0.05)。研究结果显示,PRP联合玻璃体腔内注射康柏西普治疗PDR,可明显提高患者视力,降低CMT,促进已形成的无灌注区或新生血管消退,延缓视网膜新生血管增殖,改善视功能,且安全性较高,值得临床推广应用。     

小剂量丙泊酚联合氯胺酮镇静对骨科小儿认知功能影响及安全性研究

目的分析应用小剂量丙泊酚(PPF)联合氯胺酮(KTM)镇静麻醉对于骨科患儿认知功能的影响情况并评价镇静治疗用药的安全性。方法将7~12岁的骨科患儿64例随机分成观察组(36例,0.25 mg/kg的PPF+0.25 mg/kg的KTM)和参照组(28例,0.5 mg/kg的PPF+0.5 mg/kg的KTM),在换药镇静前后各12 h采用自制认知功能量表对两组患儿进行评价,并记录、比较镇静后12 h内两组患儿的意识恢复时间、不良反应发生情况。结果认知功能评分方面,两组患儿在换药镇静前无显著差异(P0.05),而在换药镇静后观察组明显高于对照组(P0.05);在安全性上,与对照组相比,观察组患儿的意识恢复时间更短、不良反应发生率更低,且存在显著差异(P0.05)。结论采用小剂量的PPF联合KTM在换药时对骨科患儿进行镇静治疗,可有效减少PPF对患儿神经系统、认知能力的影响及相关不良反应,并促使患儿在镇静治疗后快速恢复意识,值得在骨科临床中应用、实践。     

Sensitive,High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Analysis of Atorvastatin and Its Pharmacologically Active Metabolites in Serum for Supporting Precision Pharmacotherapy

The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed. A method is presented for the analysis of these substances in serum. Method validation included the estimation of the quantitative relationship between the concentrations and the standard deviations (SD), which supports the optimal incorporation of TDM results into nonparametric pharmacokinetic models. The concentrations of the analytes were evaluated in human subjects receiving ATR. The method’s performance improved by taking the sums of acid and lactone concentrations into account. The concentration–SD relationship was linear, and we recommend applying Theil’s regression for estimating the assay error. All analytes could be detected by 2 h post dose in the samples of human subjects. The changes in metabolite/parent drug concentration ratios in time depended on the dose. The method is suitable for the TDM of ATR with a focus on precision pharmacotherapy.     

Expression of Soluble Vascular Endothelial Growth Factor Receptor-2 and Its Effect on Proliferation of Vascular Endothelial Cells

Vascular endothelial growth factors(VEGFs)respectively bind to each of three receptor tyrosine kinases (RTKs),known as Flt-1,KDR and Flt-4.Since VEGFs and their respective families of receptor tyrosine...     

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.     

A PVC Membrane Sensor for Potentiometric Determination of Atorvastatin in Biological Samples and Pharmaceutical Preparations

The present article reports for the first time the use of Aliquat 336S‐atorvastatin as an electroactive material in a poly(vinyl chloride) matrix membrane sensor plasticized with ortho‐nitrophenyl‐octylether (o‐NPOE) or dioctylphthalate (DOP) for determination of atorvastatin in biological samples (human plasma) and in pharmaceutical preparations. The sensor shows fast, stable and reproducible response over the concentration range of 1.0×10^?7–1.0×10^?2 mol L^?1 atorvastatin with anionic slopes of 60.94±0.2 and 58.22±0.2 and pH range of 5.0–9.0 for o‐NPOE and DOP plasticized based membrane sensors, respectively. The response time of the sensor is stable and fast (10 s). Results were achieved with average recoveries of 99.5 % and 99.3 % and mean standard deviations of ±1.1 % and ±1.4 % for o‐NPOE and DOP plasticized based membrane sensors, respectively. The sensor exhibits high selectivity towards atorvastatin in the presence of many anions, drug excipients and diluents. Validation of the method according to the quality assurance standards shows suitability of the proposed sensors for use in the quality control assessment of the drug.     

缬沙坦联合氨氯地平治疗社区老年原发性高血压合并糖尿病的临床效果及安全性

目的探究在治疗老年性原发性高血压合并糖尿病患者中采用缬沙坦联合氨氯地平治疗的效果以及术后安全性,评估其临床意义,为临床治疗做出指导。方法以天津市滨海新区杭州道街社区卫生服务中心2013年5月—2014年6月间收诊的80例原发性高血压合并糖尿病老年患者的临床资料作为研究对象,按治疗方式不同将患者分成氨氯地平合并缬沙坦组40例(实验组)和单纯缬沙坦组40例(对照组)。测定分析两组患者治疗后情况,包括患者血压水平变化、空腹血糖、饭后2 h血糖以及胰岛素等指标,记录治疗情况。结果治疗后实验组血压水平下降的程度优于对照组(P0.05)。实验组空腹血糖等指标对比对照组均具有显著优势(P0.05)。结论联合氨氯地平缬沙坦治疗高血压合并糖尿病患者在血压下降水平、血糖前后变化水平等方面明显优于单纯使用缬沙坦治疗,不良反应发生率低,值得临床推广使用。