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中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议

作者： JIANG De-chun~(1,2) WANG Li~2 WANG Yu-qin~1 LU Wei~(3,4) BAI Xiang-rong~1 1 Department of Pharmacy,Xuan-wu Hospital,Capital Medical University,beijing 100083,Chinta 2 Department of Pediatrics,First Hospital,Peking University,beijing 100083,china 3 Department of Pharmaceuties,School of Pharmaceutical Science,Peking University,beijing 100083,china 4 state key lab.of natural and biomimetic drugs,beijing 100083,china

AIM:To establish a population pharmacokinetic/pharma- codynamic(PK/PD)model for valproate(VPA)in chil- dren with epilepsy in china,and promote reasonable use of antiepileptie drug in clinical practice. METHODS:Sparse data of VPA serum concentrations from 417 pediatric children were *** patients were divided into three groups:Population PK-Index group,n=317;Population PK-Valid group,n=100;115 of the total 417 subjects were also included in the Population PD *** PK parameters of VPA were estimated based on the data from population PK-Index *** the validation procedure,the serum concentra- tions of VPA from the population PK-Valid group were pre- dicted by base and final models *** assess the accuracy and precision of the predictions,mean prediction error(MPE),mean square(t prediction error(MSPE), root mean squared prediction error(RMSPE),weight-resi- dues(WRES)and its 95% confidence intervals(95%CI) were all calculated,then compared between the two mode- *** population PD group,’all of the 115 patients were VPA *** of epilepsy treatment was di- vided into 5 grades according to the percentage of seizure frequency decreased(PSFD%).The value of PSFD% 100%,75%-100%,50%-75%,25%-50%,or less than 25 % are corresponding to grade 1 to *** pop- ulation PD group,the quantitative relationship between the VPA serum concentrations and the probability for its effica- cy score was characterized by logistic regression. RESULTS:Population PK of VPA was described by one- compartment model with first order *** the final model,K,V/F,CL/F are0.251+2.24·(1-HS)(/ h),2.88+0.157·WT(L),0.106+0.0157· AGE(L/h),*** final model was validated internally and *** regression showed that VPA serum concentrations and corresponding peak proba- bility for its efficacy were(25μg/mL,grade 5,50%), (32 μg/mL,grade 4,32.3%),(50 μg/mL,grade 3, 26.3%),(67 μg/mL,grade 2,36.5%),and(78 μg,/mL,grade 1,50% ),respecti

关键词： population pharmacokinetics/pharmacodynamics valproate epileptic children Bayesian approach NONMEM individualized dosage regimen

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药物动力学/药效动力学在研究药物相互作用中的应用—反应曲面模型法研究瑞芬太尼与七氟醚联合应用(英文)

药物动力学/药效动力学在研究药物相互作用中的应用—反应曲面模...

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中国药理学会临床药理学专业委员会会议暨第十次全国临床药理学学术会议

作者： YANG Lu~1 YANG Ba-xian~2 ZHANG Li-ping~1 BI Shan-shan~3 LU Wei~(3,4) 1 Department of Anesthesiology,Third Hospital,Peking University,beijing 100083,china 2 Department of Anesthesiology,People’s Hospital,Peking University,beijing 100083,china 3 Deptartment of Pharmaceutics,School of Pharmaceutical Science,Peking University,beijing 100083,china 4 state key lab.of natural and biomimetic drugs,beijing 100083,china

目的：全麻中两种以上的药物合并应用比单一麻醉剂更为有效。本研究是为确定中国成年患者全麻期间合并应用七氟醚与瑞芬太尼时药物相互作用的方式,并以反应曲面模型法对其进行表述。方法：1．试验设计：研究采用平行实验设计,65例病人(A... 详细信息

目的：全麻中两种以上的药物合并应用比单一麻醉剂更为有效。本研究是为确定中国成年患者全麻期间合并应用七氟醚与瑞芬太尼时药物相互作用的方式,并以反应曲面模型法对其进行表述。方法：1．试验设计：研究采用平行实验设计,65例病人(ASA Ⅰ级,各项指标正常,无长期服用阿片类药物史)入选本次试验,随机选定并维持一定的呼末七氟醚浓度[≤2MAC(0．3％-3．4％)],逐渐增加靶控输注的瑞芬太尼浓度(≤10 ng/mL),观察不同浓度组合时患者对喉镜置入刺激的反应以确定麻醉是否完全。2．反应曲面模型法进行药物动力学/药效动力学分析：两药合用的效果通过对喉镜置入时的反应进行评估,0和1分别代表有或没有体动反应。以下面的药效学模型表述体动反应消失的概率(P) 其中 Us,Ur 分别为标准化的七氟醚与瑞芬太尼水平;U为达最大效应一半时的药物综合标准化水平;r 为形状因子;I(Q)为药物相互作用的强度函数。模型通过作图、目标函数改变以及参数的生理/ 临床学的合理性等几方面进行评价。 p=((Us+Ur))/([U/I(Q)]+(Us+Ur)) 结果与结论：研究表明瑞芬太尼与七氟醚合用时为协同式相互作用,上述反应曲面模型与实际观测值有较好的拟合。应用 NONMEM 得到喉镜置入刺激时的参数(RSE%)为 U=6．62(10．6),C= 1．71%(12．9),C=12．4 ng/mL(19．0),I= 2．31,Q=0．706。所得数值的加权残差均小于3。结果表明与传统方法相比,反应曲面模型法可以得到较好的拟合质量,为药物相互作用的研究提供了一种新颖思路和有效手段。

关键词： drug-drug interactions synergy response-surface

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3D-QSAR study on phenoxy-alkylamine compounds of α_1-adrenoceptor antagonist

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Chinese Science Bulletin 2001年第4期46卷 303-306页

作者： FANG Hao, LU Jingfen, XIA Lin & ZHANG LineDepartment of Medicinal Chemistry, china Pharmaceutical University, Nanjing 210009, china state key laboratory of natural and biomimetic drugs, beijing Medical University, beijing 100083, china Department of Medicinal Chemistry China Pharmaceutical University Nanjing China state key laboratory of natural and biomimetic drugs Beijing Medical University Beijing China

The study of three-dimensional quantitative structure-activity relationship (3D-QSAR) of DDPH and its derivatives that have been known with their activity parameters has been developed using the comparative molecular field analysis (CoMFA) method. Here, (+)-DDPH crystal structure was selected as the active conformation model and comparisons between the influences of different charge calculation methods and grid setup were conducted. The coefficients of cross-validation (q2) and regression (r2) are 0.481 and 0.997, respectively. The standard error (SE) is 0.102. The research result suggests that the steric field makes more contributions to the activity than the electrostatic field. This model can help us not only in improving our understanding of the receptor-ligand interactions, but also in predicting the activity of derivatives and designing new compounds with better potency.

关键词： CoMFA. α1 -adrenoceptor antagonist.

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Metal binding discrimination of the calmodulin Q41C/K75C mutant on Ca^(2+) and La^(3+)

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Science china Chemistry 2010年第4期53卷 797-806页

作者： XU Kun, YANG XiaoDa & WANG Kui state key laboratory for natural and biomimetic drugs Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, beijing 100191, china 1. state key laboratory for natural and biomimetic drugs Peking University Health Science Center Beijing 100191 China2. Department of Chemical Biology School of Pharmaceutical Sciences Peking University Health Science Center Beijing 100191 China

Calmodulin (CaM) is a multifunctional Ca2+-binding protein regulating the activity of many enzymes in response to fluctuation of the intracellular Ca2+ level. It has been shown that a CaM Q41C/K75C mutant (CaMSS) with a disulfide bond in the N-terminal domain exhibits greatly reduced affinity to Ca2+. In the present study, the experimental results revealed a unique metal binding pattern in CaMSS towards La3+ and Ca2+ separately: the mutant protein binds Ca2+ at site Ⅰ, Ⅲ and IV; however, it binds La3+ at site Ⅰ, Ⅱ and IV. A putative mechanism was proposed which is the conformation of site Ⅱ (or siteⅢ) of CaMSS could be altered and thus loses its metal ion affinity in response to metal binding in the opposite terminal domain possibly through the long range domain interaction. The present work may offer new perspectives for understanding the mechanisms of specific metal ion affinity in CaM and for CaM-based protein design.

关键词： calmodulin lanthanum calcium long range interaction

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Brain-derived neurotrophic factor protects neurons from GdCl_3-induced impairment in neuron-astrocyte co-cultures

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中国科学：化学英文版 2010年第10期53卷 2193-2199页

作者： XIA Qing, FENG XuDong, YUAN Lan, WANG Kui & YANG XiaoDa state key laboratory of natural and biomimetic drugs and Department of Chemical Biology School of Pharmaceutical Sciences, Peking University, beijing 100191, china 1. state key laboratory of natural and biomimetic drugs and Department of Chemical Biology School of Pharmaceutical Sciences Peking University Beijing 100191 China

Gadolinium (Gd3+) complexes are important contrast agents in medical magnetic resonance imaging (MRI) and of great potential value in brain research. In order to better understand the mechanisms of the action of Gd3+ on neurons in the complex central nervous system (CNS), the neurotoxic actions of GdCl3 have been investigated in both neuron monoculture and astrocyte-neuron co-culture systems. Measurements of lactate dehydrogenase release showed that GdCl3 causes significant cell death of monocultured neurons as a result of reactive oxygen species (ROS) generation and down-regulation of brain-derived neurotrophic factor (BDNF). However, GdCl3 does not affect the viability and BDNF expression of astrocytes. Both co-culturing of neurons with astrocytes and addition of BDNF ameliorated GdCl3-induced neurotoxicity by decreasing ROS generation and facilitating recovery of BDNF levels. The results obtained suggest that astrocytes in the CNS may protect neurons from GdCl3-induced impairment through secreting BDNF and thus up-regulating BDNF expression and interfering with Gd3+-induced cell signaling in neurons. A possible molecular mechanism is suggested which should be helpful in understand- ing the neurotoxic actions of gadolinium probes .

关键词： gadolinium brain-derived neurotrophic factor BDNF co-culture astrocytes neurons

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Characterization of γ′ precipitates in a nickel base superalloy quenching from aging temperature at different rates

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Rare Metals 2010年第2期29卷 204-208页

作者： LI Hongyu, SONG Xiping, WANG Yanli, and CHEN Guoliang state key lab for Advanced Metals and Materials, University of Science and Technology beijing, beijing 100083, china state key lab for Advanced Metals and Materials University of Science and Technology Beijing

The characteristics of γ′ precipitates in a superalloy quenched from 1050°C at different rates were investigated using field emission scanning electron microscope（FESEM）.When quenched from 1050°C, the size of primary aging γ′ precipitates has a small increase in the specimens that experienced iced-brine-quenching, oil-quenching, and air-cooling-quenching conditions and a drastic increase in the specimen that experienced a furnace-cooling-quenching *** cooling γ′ precipitates have unimodal distributions after quenching at the air-cooling rate and bimodal distributions after quenching at the furnace-cooling rate, but there are not these distributions in the specimens that experienced iced-brine-quenching and oil-quenching *** aging at 760°C, the size of primary aging γ′ precipitates appears unaffected in the specimens that experienced iced-brine-quenching, oil-quenching, and air-cooling-quenching ***, it has a drastic increase in the specimen that experienced a furnace-cooling-quenching condition, and it is interesting that the bigger cooling γ′ precipitates have a coalescence and octodendritic *** microhardness study indicates that the hardness has no variation in the specimens that experienced iced-brine-quenching, oil-quenching, and air-cooling-quenching conditions and has a drastic decrease in the specimens that experienced a furnace-cooling-quenching condition and obtains the minimum microhardness value 390.8 HV.

关键词： superalloys precipitates quenching rate microhardness

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Tetra-n-butylammonium Hydroxide:an Efficient Catalyst for N-Alkylation of Pyrimidines and Purines

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Chemical Research in Chinese Universities 2006年第4期22卷 451-454页

作者： ZHANG Zhi-li~ , ZHOU Shou-xin, WANG Xiao-wei, WANG Hong-tao, CHEN Yan-li and LIU Jun-yi Department of Chemical Biology, School of Pharmaceutical Sciences state key laboratory of natural and biomimetic drugs, Peking University, beijing 100083, P. R. china [a]Department of Chemical Biology School of Pharmaceutical Sciences state key laboratory of natural and biomimetic drugs Peking University Beijing 100083 P. R. China

An efficient procedure for N-alkylation of pyrimidines and purines in the presence of tetra-n-butylammonium hydroxide（TBAH） is described. The method is very practical and the alkylation can occur at room temperature... 详细信息

关键词： Tetra-n-butylammonium hydroxide N-Alkylation Purine Pyrimidine

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Some interesting CH_2CH_3 spin systems in several diethyl malonate indene derivatives studied with NMR and molecular modeling

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Science china Chemistry 2009年第7期52卷 937-942页

作者： ZHANG Long1, HE WeiWei1, LIANG YongMin2 & CUI YuXin1 1 state key laboratory of natural and biomimetic drugs, School of Pharmaceutical Sciences, Peking University, beijing 100191, china 2 state key laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, china state key laboratory of natural and biomimetic drugs School of Pharmaceutical Sciences Peking University Beijing 100191 China state key laboratory of Applied Organic Chemistry Lanzhou University Lanzhou 730000 China

While studying the electrophilic cyclization of acetylenic malonates in synthesizing malonate indene derivatives with high regio and stereo-selectivity, we found that the CH2 and CH3 protons of two COOCH2CH3 groups in some diethyl malonate indene derivatives showed very interesting spin-spin coupling and signal multiplicity. To explain those phenomena, we synthesized several diethyl malonate indene derivatives, and then used 1H NMR spectra and molecular modeling to investigate the CH2CH3 spin system of these two COOCH2CH3 groups in detail. The results showed that the spin systems of CH3CH2 of the two COOCH2CH3 groups in those compounds may exist in different froms (AMX3, ABX3 and A2X3), and the effect of the aromatic ring induced by the phenyl group at the end of the triple bond is the main reason responsible for those phenomena.

关键词： electrophilic cyclization spin-spin coupling signal multiplicity molecular modeling spin system aromatic ring

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A New Efficient Synthesis of Bisphenol A Diether Bis-imidazoles and Bis-benzimidazoles

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Chinese Chemical Letters 1998年第10期9卷 917-918页

作者： Cheng He ZHOU Jun WEI Zhong Jun LI Ru Gang XIE Meng Shen CAI( Department of Bioorganic Chemistry, state key laboratory of natural and biomimetic drugs,School of Pharmaceutical Sciences, beijing Medical University, Beding 100083 Depotment of Chemistry beijing Med Univ Sch Pharmaceut Sci Dept Bioorgan Chem State Key Lab Nat & Biomimet Drugs Beijing 100083 Peoples R China Sichuan Union Univ Sch Sci Dept Chem Chengdu 610064 Peoples R China

A new efficient synthesis of bisphenol A diether bis-imidazoles and bis-benzimidazoles by bromoalkylation and imidazolylation or benzimidazolylation two-step reactions from commercial bisphenol A, imidazole, 2-methyli... 详细信息

关键词： bisphenol A imidazole benzimidazole ether synthesis

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MEAM Potential with Angular Dependence for TiAl

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Rare Metals 2001年第1期20卷 13-17页

作者： Xiaodong Ni, Xitao Wang, Guoliang Chen (Physics Department, University of Science and Technology beijing, beijing 100083, china state key laboratory for Advanced Metals and Materials, University of Science and Technology beijing, beijing 100083, china) Univ Sci & Technol beijing Dept Phys Beijing 100083 Peoples R China Univ Sci & Technol beijing State Key Lab Adv Met & Mat Beijing 100083 Peoples R China

The modified embedded atom method (MEAM) is an empirical extension of the embedded atom method (EAM) that includes angular forces. By fitted to the lattice constants, the cohesive energy, the APE (anti-phase boundary) energy, and the vacancy formation energy of TiAl, an accurate MEAM potential is obtained for the TiAl system with L10 structure. The calculation results of the properties of TiAl are in good agreement with experiments and the results of first principle (F.P.) calculations.

关键词： embedded atom method TiAl alloy angular dependence potential intermetallics

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