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Model-based meta-analysis of pharmacokinetics of direct-acting antiviral agents,ledipasvir and sofosbuvir,in healthy subjects and chronic HCV patients

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Journal of Chinese Pharmaceutical Sciences 2015年第12期24卷 773-779页

作者：王鹤川李良任宇鹏周田彦卢炜北京大学医学部药学院药剂学系北京100191 北京大学医学部天然药物及仿生药物国家重点实验室北京100191

A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and ***-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of *** lag was observed in concentration-time profiles of both ledipasvir and *** aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.

关键词： Ledipasvir Sofosbuvir GS331007 Population pharmacokinetic modeling Hepatitis C Model-based meta-analysis

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1,5-二(2-羟基苯亚甲基)-二氨基硫脲与银配合物的合成、表征及抗癌活性研究

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无机化学学报 2001年第6期17卷 911-916页

作者：朱巧军戴荣斌李勤喜曲建强王流芳吴集贵崔景荣兰州大学化学化工学院北京大学医学部天然药物及仿生药物国家重点实验室北京100083

In order to develop novel antitumor d rugs,1,5-bis(2-hydroxybenzylidene)-thiocarbohydrazide(HL)and its Ag ?Complex([Ag2L]·NO3)have been prepared and characterize d by elemental analysis,IR,UV,1 H NMR and molar conductance,*** inhibitory effects of them on five tumor cell lines,including HL-60,Bel-7402,EJ,HCT-8and A431 have been measured by using MTT(Dimethoxyneotetrazolium)colorimetric assay and SRB(Sulforhodamine B)*** result indicated that the Ag Complex has str onger inhibitory effect on the five t umor cell lines than the ligand,especially showed very stro ng effect on HL-60cell and Bel-7402c *** the exposure concentration of the complex was 10-5mol·L-1,The inhibitory rate is over 96%.

关键词：抗肿瘤药物细胞系抗肿瘤作用银配合物 1,5-2(2-羟基苯亚甲基)-二氨基硫脲合成表征

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Two alkaloids as α-amylase inhibitors: enzyme kinetics and molecular modeling investigations

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Journal of Chinese Pharmaceutical Sciences 2015年第2期24卷 80-87页

作者：梁毅裴芬王弘陈世忠北京大学医学部药学院天然药物化学系北京100191 北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191

In the present study, we studied the inhibitory effects of chelidonine and rutaecarpin on porcine pancreatic a-amylase （PPA） catalyzed hydrolysis using 2-chloro-4-nitrophenyl-4-O-β-D-galactopyranosylmaltoside （Gal-G2-α-CNP）. We, for the first time, provided kinetic report and detailed inhibitory effects of both compounds on PPA. Lineweaver-Burk plot revealed that the inhibition was a mixed-noncompetitive type, and only one molecule of inhibitor bound to the enzyme or to the enzyme-substrate complex. Kinetic constants calculated from secondary plots were in millimole range. Dissociation constants of enzyme-inhibitor complex （KEI） were 0.9 mM and 3.5 mM, respectively. Moreover, dissociation constants of enzyme-inhibitor-substrate complex （KESI） were 0.04 mM and 0.31 mM, respectively. These data indicated that the inhibition was more inclined to competitive to Gal-G2-α-CNP hydrolysis. Further molecular docking study manifested that hydrogen bonding formed between acarbose and aspartic acid （Asp300）, histidine （His305） and glycine （Gly3-6）, while hydrogen bonding was observed between chelidonine and glutamic acid （Glu233）, lysine （Lys200） and His305. In addition, rutaecarpine had only one hydrogen bond with Lys200. Our data indicated that chelidonine and rutaecarpine were two promising drug candidates, and chelidonine possessed stronger inhibitory effect compared with rutaecarpine.

关键词： α-Amylase inhibitors Kinetic analysis Molecular modeling Chelidonine Rutaecarpine

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The preparation and characteristics of febuxostat SiO2 solid dispersions

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Journal of Chinese Pharmaceutical Sciences 2014年第7期23卷 463-470页

作者：宋文丁杜若宋平钟婷张卫强赵阳王超张烜张强北京大学医学部药学院药剂学系北京100191 北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191

In the present research, we selected Sylysia as a porous material and febuxostat（FBT） as model drug to prepare the FBT SiO2 solid dispersions using a solvent evaporation method. We firstly established an HPLC method for determining FBT in our prepared FBT SiO2 solid dispersions. And then, the characteristics of FBT SiO2 solid dispersions were investigated, including differential scanning calorimetry（DSC）, powder X-ray diffraction（PXRD）, scanning electron microscope（SEM）, particle size and distribution. The solubility and dissolution of FBT SiO2 solid dispersion were also evaluated. The results of DSC and PXRD showed that the FBT existed in an amorphous state in FBT SiO2 solid dispersions. The SEM and particle size results indicated that the shape and average particle size of FBT SiO2 solid dispersions was similar to the Sylysia. The solubility and dissolution of FBT in FBT SiO2 solid dispersions were significantly enhanced compared with the pure FBT. In conclusion, we successfully prepared FBT SiO2 solid dispersions to increase the solubility and dissolution rate of the poorly water-soluble FBT.

关键词： Febuxostat Sylysia Solid dispersion Solubility and dissolution

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The anti-tumor efficacy of c9,t11-CLA-PTX and t10,c12-CLA-PTX on MCF-7 breast cancer cells:in vitro and in vivo

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Journal of Chinese Pharmaceutical Sciences 2014年第11期23卷 751-759页

作者：杨科李星火李丹柯曦宇张烜张强北京大学医学部药学院药剂学系北京100191 北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191

Considering the results of our previous research that conjugated linoleic acid mixture-paclitaxel （CLA-mixture-PTX） possesses anti-tumor activity against melanoma and brain glioma, the purpose of this study was to investigate the potential anti-tumor efficacy of cis-9, trans- 1 1-conjugated linoleic acid-paclitaxel （c9, tl 1-CLA-PTX） and trans- 1 O, cis- 12-conjugated linoleic acid-paclitaxel （tl0, c12-CLA-PTX） on MCF-7 breast cancer cell line in vitro and in vivo. The in vitro cytotoxicity, apoptosis induction effect and cell cycle arresting effect of c9, t1 1-CLA-PTX and t10, c12-CLA-PTX were investigated. The in vitro cellular uptake of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX in MCF-7 cells were also analyzed. Besides, the anti-tumor activity of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX was evaluated in MCF-7 tumor bearing nude mice in vivo. The in vitro cytotoxicity results showed that the value of ICs0 of the tl 0, c l2-CLA-PTX is （0.17±0.02） μM, compared with that of （1.08±0.15） μM in CLA-mixture-PTX and （6.50±1.20） μM in c9, tl 1-CLA-PTX treatment group （P〈0.01）. Both tl0, cl2-CLA-PTX and c9, t l 1-CLA-PTX increased the percentage of total apoptotic cells compared with that of control （P〈0.01）. And the rank of apoptosis induction efficacy was t 10, c 12-CLA-PTX〉CLA-mixture-PTX〉c9, t 11-CLA-PTX （P〈0.01）. Compared with untreated cells, the tl0, c12-CLA-PTX and c9, tl 1-CLA-PTX arrested cell cycle progression at the S and G2-M phase. The amount of cellular uptake of t 10, c 12-CLA-PTX was significantly higher than that of CLA-mixture-PTX （P〈0.01）, which was significantly higher than that of c9, t1 1-CLA-PTX （P〈0.01）. The rank of in vivo anti-tumor activity was tl0, c12-CLA-PTX〉CLA-mixture-PTX〉 c9, t1 1-CLA-PTX （P〈0.01）. In conclusion, our study demonstrated that both tl0, cl2-CLA-PTX and c9, tl 1-CLA-PTX has significant anti-tumor activity in MCF-7 cell line. And while c9, tl 1-CLA-PTX showed weaker inhibitory effect than CLA-mixture-PTX, stronger inhibitory effect wa

关键词： c9 tl 1-CLA-PTX t10 c12-CLA-PTX Apoptosis Cell cycle Cellular uptake Anti-tumor efficacy

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Simultaneous determination of seven alkaloids and two flavonoid glycosides in Wuzhuyu decoction by RP-HPLC-DAD

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Journal of Chinese Pharmaceutical Sciences 2012年第4期21卷 338-344页

作者：胡传芹杨秀伟北京大学医学部天然药物及仿生药物国家重点实验室药学院天然药物学系北京100191

A reversed-phase high-performance liquid chromatography （RP-HPLC） method with diode array detector was established to simultaneously determine nine bioactive compounds in Wuzhuyu decoction, namely dehydroevodiamine, isorhanmetin-7-O- rutinoside, 10-hydroxyrutaecarpine, diosmetin-7-O-13-D-glucopyranoside, evodiamine, rutaecarpine, 1-metbyl-2-n-nonyl-4（1H） quinolone, evocarpine, and dihydroevocarpine. The RP-HPLC assay was performed on a reversed-phase Cl8 column with a gradient elution. The mobile phases consisted of methanol and water containing 1% （v/v） acetic acid. The flow rate was 1.0 mL/min and the detection wavelength was set at 300 nm. All calibration curves showed good linearity （r2〉0.9941） within test ranges. The results of intra-day precision, inter-day precision, and accuracy were satisfactory. The overall recoveries were in the range of 90.13%-102.48%. The method was successfully applied to quantify nine bioactive compounds in six samples. Baseline resolution for all nine major compounds was achieved. This method could be used as a suitable quality control assay for Wuzhuyu decoction.

关键词： High-performance liquid chromatography Wuzhuyu decoction Alkaloids Flavonoid glycosides

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高尿酸血症模型的建立及降尿酸药物的研究进展

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中国病理生理杂志 2021年第7期37卷 1283-1294页

作者：吴芃王亮李海涛乔攀爽张奥周虹北京大学医学部基础医学院药理学系天然药物及仿生药物国家重点实验室北京100191

高尿酸血症(hyperuricemia)指血清尿酸(uric acid)浓度男性高于416.4μmol/L(7.0 mg/dL),女性高于356.9μmol/L(6.0 mg/dL)[1]。高尿酸血症的发生可能是由于尿酸生成过多和(或)肾脏、肠道排泄减少导致血清尿酸浓度过度增加[2-4]。流行... 详细信息

高尿酸血症(hyperuricemia)指血清尿酸(uric acid)浓度男性高于416.4μmol/L(7.0 mg/dL),女性高于356.9μmol/L(6.0 mg/dL)[1]。高尿酸血症的发生可能是由于尿酸生成过多和(或)肾脏、肠道排泄减少导致血清尿酸浓度过度增加[2-4]。流行病学研究显示,高尿酸血症已成为一个严重的公共卫生问题,2017年的数据显示,我国高尿酸血症患病率为13.0%,其中男性为18.5%,女性为8.0%[5]。

关键词：高尿酸血症痛风嘌呤代谢降尿酸药物

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介导糖尿病肾病线粒体损伤的相关信号通路

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中国病理生理杂志 2020年第9期36卷 1696-1703页

作者：夏华钦王亮吴芃李海涛张奥周虹北京大学医学部基础医学院药理学系天然药物及仿生药物国家重点实验室北京100191

糖尿病(diabetes mellitus,DM)是一组由于胰岛素的作用和(或)分泌缺欠而引起的以慢性高血糖和葡萄糖不耐受为主要特征的代谢性综合征。根据世界糖尿病联盟统计,2017年糖尿病的世界发病率(20~79岁)为8.8%,预计到2045年会达到9.9%。2017年... 详细信息

糖尿病(diabetes mellitus,DM)是一组由于胰岛素的作用和(或)分泌缺欠而引起的以慢性高血糖和葡萄糖不耐受为主要特征的代谢性综合征。根据世界糖尿病联盟统计,2017年糖尿病的世界发病率(20~79岁)为8.8%,预计到2045年会达到9.9%。2017年,中国大陆糖尿病患病率为10.9%,约有1.144亿糖尿病患者(20~79岁),位居世界第一,占世界糖尿病患者总数的1/4以上。

关键词：糖尿病肾病线粒体损伤信号通路

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Docking and field-based QSAR studies of S-DABOs as HIV-1 reverse transcriptase inhibitors

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Journal of Chinese Pharmaceutical Sciences 2017年第7期26卷 512-520页

作者：樊宁宁刘振明王孝伟刘俊义北京大学医学部药学院化学生物学北京100191 北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191

HIV-1 reverse transcriptase（RT） inhibitors are major components of HAART（highly active antiviral therapy）. The S-DABOs（dihydro-alkylthio-benzyl-oxopyrimidines） series and their similar skeletons have exhibited preferable activities to inhibit HIV-1 RT. In the present study, we generated field-based QSAR models using common structure alignment, which was characterized by Gaussian steric, electrostatic, hydrophobic, hydrogen bond donor, hydrogen bond acceptor and aromatic ring fields（R2 = 0.8421, RCV2 = 0.5949 for the training set, Q2 = 0.5486, Pearson-r = 0.7460 for the test set）. Docking, pocket surface and contour map analyses were carried out. Key pharmacophore features were investigated, including（i） π-π interaction with residue Tyr181, Tyr188 and Trp229, σ-π interaction with His236,（ii） hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The docking analysis and field-based QSAR models could provide reasonable guidance in the rational design of potent HIV-1 RT inhibitors.

关键词： HIV-1 reverse transcriptase S-DABOs Molecular docking Field-based QSAR

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Butaselen and cisplatin synergistically inhibit human cancer cells proliferation

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Journal of Chinese Pharmaceutical Sciences 2017年第8期26卷 595-604页

作者：邹乔陈伊凡郑小青徐彬瑗刘禹锡曾慧慧北京大学医学部药学院天然药物及仿生药物国家重点实验室北京100191 北京大学医学部药学院化学生物学系北京100191

Cisplatin （CDDP）, a platinum-containing drug, has been widely used in the therapy of many types of cancers today. However, the side effects of CDDP have limited its clinical application. Butaselen （BS）, a TrxR inhibitor designed by our group, has shown anti-tumor effects in vivo and in vitro. In this study, we investigated the combinatory effects of BS and CDDP on BEL-7402 cells, LoVo cells, HeLa cells and A549 cells. We observed synergistic effects when BS and CDDP were used in combination, especially in BEL-7402 cells. Apoptosis analysis also revealed that the combination treatment of BS and CDDP （1：1） for 48 h induced higher apoptotic effects in BEL-7402 cells. A further study in BEL-7402 cells showed that the synergistic effect might be mediated by the sharp reduction of ratio of Bcl-2/Bax protein. Taken together, the combination of CDDP and BS might be of great potential for chemotherapy.

关键词： Butaselen Cisplatin Synergistic effect Bcl-2 Bax

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