盐酸多奈哌齐治疗阿尔茨海默病的临床疗效和安全性观察

目的探讨盐酸多奈哌齐对阿尔茨海默病(Alzheimer's disease,AD)治疗的有效性及安全性。方法32例AD患者随机分为对照组、治疗组,治疗组给予盐酸多奈哌齐治疗24周,对照组只给予维生素E治疗24周。治疗前后采用阿尔茨海默病评定量表的认知次级量表(ADAS-cog)和简易智能精神状态检查量表(MMSE)及日常生活能力量表(ADL)进行疗效评定。结果治疗组治疗16周后较治疗前ADAS-cog、MMSE及ADL评分有明显改善,治疗组治疗后16周末和治疗后24周末,ADAS-cog评分分别为20.6±6.5(P<0.05)和19.7±6.9(P<0.05),MMSE评分分别为23.0±2.6和27.1±2.9(P<0.01)及ADL评分分别为25±7和23±8(P<0.01),而对照组患者评分无明显改变,治疗患者无明显药物不良反应。结论盐酸多奈哌齐可以安全地用于治疗阿尔茨海默病。     

Synthesis and evaluation of novel xanthene-based thiazoles as potential antidiabetic agents

A series of xanthene-based thiazoles was synthesized and characterized by different scpectroscopic methods, i.e. Proton nuclear magnetic resonance (¹H NMR), carbon nuclear magnetic resonance (¹³C NMR), infrared spectroscopy, carbon hydrogen nitrogen analysis, and X-ray crystallography. The inhibition potencies of 18 newly synthesized thiazole derivatives were investigated on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase (α-Amy), and α-glycosidase (α-Gly) enzymes in accordance with their antidiabetic and anticholinesterase ability. The synthesized compounds have the highest inhibition potential against the enzymes at low nanomolar concentrations. Among the 18 newly synthesized molecules, 3b and 3p were superior to the known commercial inhibitors of the enzymes and have a much more effective inhibitory potential, with IC₅₀: 2.37 and 1.07 nM for AChE, 0.98 and 0.59 nM for BChE, 56.47 and 61.34 nM for α-Gly, and 152.48 and 124.84 nM for α-Amy, respectively. Finally, the optimized 18 compounds were subjected to molecular docking to describe the interaction between thiazole derivatives and AChE, BChE, α-Amy, and α-Gly enzymes in which important interactions were monitored with amino acid residues of each target enzyme.     

微波消融对老年原发性肝癌患者肝功能的影响

目的比较老年组与中青年组原发性肝癌(HCC)患者微波消融治疗后肝功能、胆碱酯酶、白蛋白等实验室检测指标的变化。方法回顾性地研究2013年1月1日至2013年12月31日于解放军总医院介入超声科行超声引导下微波消融治疗的单发HCC患者343例,其中老年组(年龄60岁)131例,中青年组(年龄≤60岁)212例。结果老年组患者微波消融治疗后白细胞(WBC)、丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TB)均较治疗前明显升高,血清白蛋白(A1b)及胆碱酯酶(ChE)较治疗前明显下降(P0.01),中青年组HCC患者微波消融治疗后WBC、ALT、AST、TB显著升高(P0.01),而消融治疗后ChE轻度升高及Alb轻度下降,但与治疗前相比差异无统计学意义(P0.05)。将两组患者消融治疗前后WBC、ChE、ALT、AST、A1b、TB的差值进行组间比较,发现中青年组患者ALT升高较老年组患者明显(P=0.048),余指标消融治疗前后改变两组之间差异均无统计学意义(P0.05)。结论微波消融治疗后两组患者均出现反映肝功能的指标明显升高,反映肝脏储备功能的ChE和Alb在老年患者较中青年患者下降更加明显,说明老年患者肝脏储备功能更差。     

Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer’s dementia

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Synthesis,in silico and in vitro studies of hydrazide-hydrazone imine derivatives as potential cholinesterase inhibitors

A series of hydrazide-hydrazone imine derivative compounds (3a–k) were synthesized and their structures characterized using FTIR, ¹H, and ¹³C (NMR) spectroscopic methods. In addition, molecular structures of compounds 3a, 3d, and 3g were elucidated by X-ray diffraction technique. In vitro inhibition activities of hydrazide-hydrazone imine derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated. Compound 3i (IC₅₀ = 2.01 μM) exhibited the best inhibitory activity against AChE, comparable to the control Galantamine (IC₅₀ = 2.60 μM). Against BChE, compound 3h (IC₅₀ = 2.83 μM) showed the best inhibitory property which is higher control Galantamine (IC₅₀ = 3.70 μM). The Ki values of compound 3i (Ki = 0.63 μM) and compound 3h (Ki = 0.94 μM) that have the strongest inhibitory potential were determined against AChE and BChE, respectively. According to the docking result, the most stable conformation of AChE and compound 3i showed that it has a binding affinity of −10.82 kcal/moL. The binding affinity of the most stable conformation formed by BChE and compound 3h is −8.60 kcal/moL. Finally, in silico results and pharmacokinetic parameters of ADME showed that these compounds have good oral bioavailability properties.     

Efficacy and safety of pemafibrate in patients with hypertriglyceridemia in clinical settings: A retrospective study

Background and aimsRecently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings.Methods and resultsWe evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved.ConclusionIn this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.     

Design,synthesis and the evaluation of cholinesterase inhibition and blood-brain permeability of daidzein derivatives or analogs

In the present study, a series of derivatives and analogs of daidzein were designed and synthesized to investigate cholinesterase inhibition and blood–brain barrier permeability. The enzyme assay showed that most of the compounds containing a tertiary amine group exhibit moderate cholinesterase inhibition, 7-hydroxychromone derivatives (absence of B ring of daidzein scaffold) only have a weaker bioactivity, while those compounds without the tertiary amine group have no bioactivity. Among them compound 15a (4’-N,N-dimethylaminoethoxy-7-methoxyisoflavone) appeared the best inhibitory activity (IC₅₀: 2.14 ± 0.31 μmol/L) and higher selectivity for AChE over BuChE (Ratio: 7.07). It was selected for the further investigation by UPLC-MS/MS. The results show that C_Brain/Serum of compound 15a in mice was more than 2.87 within 240 min. This discovery may provide worthy information for the future development of central nervous drugs including but not limited to cholinesterase inhibitors.     

BNP、CRP、WBC、Lp（a）、ChE在老年肺部感染中的水平及其意义

目的 探讨B型脑钠肽（BNP）、C反应蛋白（CRP）、白细胞计数（WBC）、脂蛋白a[（Lp（a）]、胆碱酯酶（ChE）在老年肺部感染患者中的水平及意义。方法 选取2010年1月—2017年12月南京大学医学 院附属鼓楼医院老年肺部感染患者79例，根据肺炎严重程度指数（PSI），Ⅰ级患者21例，Ⅱ、Ⅲ级患者35例，Ⅳ、Ⅴ级患者23例。检测患者BNP、CRP、WBC、Lp（a）和ChE水平。结果 Ⅳ、Ⅴ级患者BNP、CRP、WBC和Lp（a）高于Ⅰ级和Ⅱ、Ⅲ级患者（P?<0.05），而ChE低于Ⅰ级和Ⅱ、Ⅲ级患者（P?<0.05）；Ⅱ、Ⅲ级患者BNP、CRP、WBC和Lp（a）分别高于Ⅰ级患者（P?<0.05），而ChE低于Ⅰ级患者（P?<0.05）；死亡 患者的PSI评分、BNP、CRP、WBC和Lp（a）分别高于存活患者（P?<0.05），而ChE低于存活患者（P?<0.05）；BNP、CRP、WBC、Lp（a）与PSI评分呈正相关（r?=0.433、0.410、0.382和0.390，均P?<0.05），而ChE与PSI评分呈负相关（r?=-0.421，P?<0.05）。结论 BNP、CRP、WBC、Lp（a）和ChE水平与老年肺部感染患者病情程度、预后有一定关系，对临床救治判断有一定指导作用。