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Population pharmacokinetics of valproate in Chinese children with epilepsy

Acta Pharmacologica Sinica 2007年第10期28卷 1677-1684页

作者： De-chun JIANG~(2,3),Li WANG~4,Yu-qin WANG~(2,6),Lin LI~3,Wei LU~5,Xiang-rong BAI~2~2 department of Pharmacy,Xuan-wu Hospital of Capital medical university,Beijing 100053,china ~4 department of Pediatrics,Peking universityFirst Hospital,Beijing 100034,china ~3 department of pharmacology,Xuan-wu Hospital of Capital medical university,Education Ministry KeyLaboratory for Neurodegenerative Diseases,Beijing 100053,china ~5 School of Pharmaceutical Science,Peking university,Beijing 100083,china department of Pharmacy Xuan-wu Hospital of Capital Medical University Beijing China department of pharmacology Xuan-wu Hospital of Capital Medical University Education Ministry Key Laboratory for Neurodegenerative Diseases Beijing China department of Pediatrics Peking University First Hospital Beijing China School of Pharmaceutical Science Peking University Beijing China

Aim:The aim of the present study is to establish a population pharmacokinetic（PPK） model of valproate （VPA） in Chinese epileptic children to promote thereasonable use of anti-epileptic ***:Sparse data of VPA serumconcentrations from 417 epileptic children were *** patients weredivided into 2 groups:the PPK model group （n=317） and the PPK valid group（n=100）.The PPK parameter values of VPA were calculated by NONMEM soft-ware using the data of the PPK model group.A basic model and a final modelwere set *** validate the 2 models,the concentrations of PPK valid groupwere predicted by each model,*** mean prediction error （MPE）,mean squared prediction error （MSPE）,root mean squared prediction error（RMSPE）,weight residues （WRES）,and the 95% confidence intervals （95%CI） were also ***,the values between the 2 models were ***:The PPK of VPA was determined by a 1-compartment model with afirst-order absorption *** basic model was:Ka=3.09 (h-1),V/F=20.4（L）,CL/F=0.296 （L/h）.The final model was:Ka=0.251+2.24·（1-HS）(h-1),V/F=2.88+0.157·WT （L）,CL/F=0.1060.98·CO+0.0157·AGE （L/h）.For thebasic model,the MPE,MSPE,RMSPE,WRES,and the 95% CI were-23.53（-30.36,-16.70）,3728.96 （2872.72,4585.20）,39.62 （34.34,44.90）,and-0.06 （-0.14,0.02）,*** the final model,the MPE,MSPE,RMSPE,WRES,and the95% CI were-1.16 （-4.85,2.53）,1002.83 （1050.64,1143.61）,23.04 （21.12,24.96）,and0.08 （-0.04,0.20）,*** final model was more optimal than the ***:The PPK model of VPA in Chinese epileptic children wassuccessfully *** will be valuable to facilitate individualized dosageregimens.

关键词： population pharmacokinetics valproic acid epilepsy children Bayesian method NONMEM software individualized dosage regimens

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Binding of PLCδ1PH-GFP to Ptdlns(4,5)P2 prevents inhibition of phospholipase C-mediated hydrolysis of Ptdlns(4,5)P2 by neomycin

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Acta Pharmacologica Sinica 2005年第12期26卷 1485-1491页

作者： Chuan WANG Xiao-na DU Qing-zhong JIA Hai-lin ZHANG~2 department of pharmacology Hebei medical university,Shijiazhuang 050017,china department of pharmacology Hebei Medical University Shijiazhuang China

Aim:To investigate the effects of the pleckstrin homology(PH)domain of phos-pholipase Cδ1(PLCδ1PH)on inhibition of phospholipase C(PLC)-mediated hy-drolysis of phosphatidylinositol 4,5-bisphosphate[PtdIns(4,5)P2]by ***:A fusion construct of green fluorescent protein(GFP)and PLCδ1PH(PLCδ1PH-GFP),which is known to bind PtdIns(4,5)P2specifically,together withlaser-scanning confocal microscopy,was used to trace PtdIns(4,5)***:Stimulation of the type 1 muscarinic receptor and the bradykinin 2 recep-tor induced a reversible PLCδ1PH-GFP translocation from the membrane to thecytosol in COS-7 *** inhibitor U73122 blocked the ***,a known PtdIns kinase inhibitor,did not affect the translocationinduced by ACh,but blocked recovery after translocation,indicating thatPtdIns(4,5)P2hydrolysis occurs through receptor-mediated PLC ***,a commonly used phospholipase C blocker,failed to block the recep-tor-induced PLCδ1PH-GFP translocation,indicating that neomycin is unable toblock PLC-mediated Ptdlns(4,5)Pe ***,in the absence of PLCδ1PH-GFP expression,neomycin abolished the receptor-induced hydrolysis ofPtdIns(4,5)P2 by ***:Although PLCδ1PH and neomycin bind toPtdIns(4,5)P2 in a similar way,they have distinct effects on receptor-mediatedactivation of PLC and PtdIns(4,5)P2 hydrolysis.

关键词： phosphatidylinositol 4,5-bisphosphate neomycin phospholipase C pleckstrin homology domains competitive binding acetylcholine green fluorescent proteins

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Passive sensitization increases histamine-stimulated calcium signaling and NF-κB transcription activity in bronchial epithelial cells

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Acta Pharmacologica Sinica 2006年第6期27卷 708-714页

作者： Si JIN~(2,5)Dan TIAN~3 Jian-guo CHEN~4 Li-ping ZHU~2 Sheng-yuan LIU~2 Di-xun WANG~2 2 department of Pathophysiology,Tongji medical College,Huazhong university of Science and Technology Key Laboratory of Pulmonary Disease of Ministry of Health of china,Wuhan 430030,china 3 department of Pathology,Tongji medical College.Huazhong university of Science and Technology.Wuhan 430030,china 4 department of pharmacology,Tongji medical College,Huazhong university of Science and Technology,Wuhan 430030,china department of Pathophysiology Tongji Medical College Huazhong University of Science and Technology Key Laboratory of Pulmonary Disease of Ministry of Health of china Wuhan China department of Pathology Tongji Medical College Huazhong University of Science and Technology Wuhan China department of pharmacology Tongji Medical College Huazhong University of Science and Technology Wuhan China

Aim:To find out if the two aspects of asthma（chronic airway inflammation andbronchial hyperresponsiveness）are related to hypersensitivity of calcium signal-ing in bronchial epithelial ***:Porcine bronchial epithelial cells（PBEC）were divided into sensitized（S）and nonsesitized（N）*** group S,the cellswere preincubated with serum from ovalbumin sensitized guinea *** group N,the cells were preincubated with serum from nonsensitized guinea *** calcium imaging and ELISA-based NF-κ3 activity were used to evaluate thehistamine-stimulated intracellular free calcium level and NF-κB activity,***:First,0.1μmol/L histamine could induce [Ca2+]ioscillationsin PBEC of group S,but not in group ***,1/Jmol/L histamine could induce[Ca2+]ioscillations of PBEC in both group S and group *** [Ca2+]ioscillationfrequency of PBEC was significantly higher in group S than in group N,thoughthe[Ca2+]ioscillation amplitude showed no difference between the two ***,when 10 μmol/L histamine was used to stimulate PBEC a transient initialincrease followed by a sustained elevation（FSE）of [Ca2+]iwas observed in PBECin both *** amplitude of the FSE of [Ca2+]iin PBEC was significantlyhigher in group S than in group *** subsequent NF-κB activity was in accor-dance to the calcium oscillation frequency evoked by histamine,but not to ***:It was suggested that the increased sensitivity of calciumsignaling in bronchial epithelial cells might contribute to the exorbitant inflamma-tion or increased susceptibility in asthmatic airway epithelial cells.

关键词： asthma histamine calcium signaling bronchi epithelial cell nuclear factor of kappaB

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Effects of Ganoderma lucidum polysaccharides on proliferation and cytotoxicity of cytokine-induced killer cells

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Acta Pharmacologica Sinica 2005年第9期26卷 1130-1137页

作者： Xiao-ling ZHU Zhi-bin LIN department of pharmacology,School of Basic medical Science,Peking university Health Science Center,Beijing 100083,china department of pharmacology School of Basic Medical Science Peking University Health Science Center Beijing 100083 China

Aim:To study the effects(and the mechanisms thereof)of Ganoderma lucidumpolysaccharides(G/-PS)on the proliferation and the anti-tumor activity of cytokine-induced killer(CIK)cells,and to make use of CIK cells as a means to investigatethe interactions between Gl-PS and ***:CIK cells were preparedby using the standard protocol as a positive *** groups alsounderwent the standard protocol,except that Gl-PS(400 mg/L or 100 mg/L)wasadded and the dose of anti-CD3 and interleukin-2 they received was reduced by50% and 75%,*** negative controls,Gl-PS in the experimentalprotocol was replaced with soluble starch or methylcellulose(400 mg/L or 100 mg/L).CIK cell proliferation,cytotoxicity,and phenotype were determined by using theTrypan blue exclusion method,MTT assay,and flow ***:Bysynergizing cytokines,Gl-PS(400 mg/L or 100 mg/L)could decrease the amountof cytokine in lymphokine activated killer(LAK)cells and CIK cells culture,buthad no significant effect on the proliferation,cytotoxicity,or phenotype of LAKcells,or CIK cells induced by cytokines at higher doses alone,in which CIK cellsexpanded about 80-fold and the main effectors,CD3~+NK1.1~+ cells,expanded bymore than 15%.The cytotoxicity of CIK cells in experimental groups was 79.3%±4.7%,76.9%±6.8% versus the positive control 80.7%±6.8% against P815(P>0.05)and 88,9%±5.5%,84.7%±7.9% versus the positive control 89.8%±4.5% againstYAC-1(P>0.05).The activity of GI-PS could mostly be blocked by ***:GI-PS was shown to be a promising biological response modifier andimmune *** effect of GI-PS on CIK cells is possibly mediated prima-rily through complement receptor type 3.

关键词： Ganoderma lucidum polysaccharides cell proliferation cytotoxicity immunomodula-tion

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Evaluation of 2 celecoxib derivatives:analgesic effect and selectivity to cyclooxygenase-2/1

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Acta Pharmacologica Sinica 2005年第12期26卷 1505-1511页

作者： Zhi-hong LU~(2,4) Xiao-yun XIONG~2 Bang-le ZHANG~2 Guo-cheng LIN~3 Yu-xiang SHI~4 Zhen-guo LIU~2 Jing-ru MENG~2 Yu-mei ZHOU~3 Qi-bing MEI~(3,6) 2 department of pharmacology,3 department of Radioactive Isotopes,and 4 department of Anesthesiology,Xijing Hospital,Fourth Military medical university,Xi'an 710032,china 5 department of Foreign Languages,Fourth Military medical university,Xi'an 710032,china department of pharmacology Xijing Hospital Fourth Military Medical University Xi'an China department of Foreign Languages Fourth Military Medical University Xi'an China department of Anesthesiology Xijing Hospital Fourth Military Medical University Xi'an China department of Radioactive Isotopes Xijing Hospital Fourth Military Medical University Xi'an China

Aim:To evaluate the analgesic effects of 2 celecoxib derivatives and their inhibi-tory effects on cyclooxygenase（COX）.Methods:Four antinociceptive assayswere used:the acetic acid-induced writhing test,hot plate test,hot tail-flick testand formalin *** doses were used in the analgesic assays and ED50valueswere *** the selectivity assay,macrophages were incubated with testcompounds at various concentrations and then stimulated with calcimycin orlipopolysaccharide（LPS）.The amounts of 6-keto-prostaglandin F1α(6-keto-PGF1α)and prostaglandin E2（PGE2）in the supernatant were examined by radioimmunoas-say（RIA）.The selectivity of the test compounds was expressed as the ***-1/***:Celecoxib and its 2 derivatives had a significant analge-sic *** ED50values of celecoxib,PC-406 and PC-407 were 94.2,67.9,and 63.3mg/kg,respectively,for the acetic acid-induced writhing test;104.7,89.1,and 30.0mg/kg,respectively,for the hot tail-flick response test;60.7,56.7,and 86.2 mg/kg,respectively,for the hot plate response test;67.1,55.8,and 68.8 mg/kg,respectively,for the formalin-induced *** is,the EDs0 of PC-406 was the lowest forthe formalin and hot plate tests,which focus on changes above the spinal cordlevel;however,the EDs0 of PC-407 was lowest for the tail-flick and writhing tests,which focus on changes at the spinal cord *** and PC-407 inhibitedCOX-1 with IC50values of 39.8 and 27.5 nmol/L,***-406 inhibitedCOX-1 with an IC50value of more than 1000 nmol/*** IC50values for the effectof celecoxib,PC-406 and PC-407 on COX-2 were 4.8,8.9,and 1.9 nmol/L *** ***-1]***-2ratios for celecoxib and PC-407 were 8.3 and 14.4,*** PC-406,the ratio was greater than ***:Derivatives ofcelecoxib via substitution with an isopropyl or naphthyl group at the 5 position inthe pyrazole ring still have analgesic effects and the ability to selectively *** wit

关键词： cyclooxygenase inhibitors celecoxib pain selectivity mice

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Expression of pro-inflammatory and anti-inflammatory cytokines in brain of atherosclerotic rats and effects of Ginkgo biloba extract

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Acta Pharmacologica Sinica 2005年第7期26卷 835-839页

作者： Ya-bin JIAO~2 Yao-cheng RUI~3 Tie-jun LI Peng-yuan YANG Yan QIU department of pharmacology,School of Pharmacy,the Second Military medical university,Shanghai 200433,china 2 Now in department of pharmacology,School of Pharmacy,Shanghai university of Traditional Chinese Medieine,Shanghai 201203,china. department of pharmacology School of Pharmacy the Second Military Medical University Shanghai China

Aim:To study the protein and mRNA expressions of pro-inflammatory and anti-inflammatory cytokines in the brain of rats with atherosclerosis(AS)and theeffects of Ginkgo biloba extract(GbE)on expressions of ***:The expermental model of AS in rats were established by intraperitioneal injectionof vitamin D3 with high fat/cholesterol *** 100 mg/kg was administered torats by *** 8 weeks,the expressions of IL-1β,TNF-α,IL-10,and 1L-10R in thebrain tissues of AS rats were detected by enzyme-linked immunosorbant assay,immunohistochemistry,Western blotting,and reverse transcriptase polymerasechain ***:The protein and mRNA expressions of IL-1β,TNF-α,andIL-10 in the brains were markedly higher in AS groups than that in control groups(6.11±0.15,1.55±0.14,0.54±0.04 ng/g wet weight vs 0.80±0.14,0.33±0.09,and0.33±0.02 ng/g wet weight,respectively).The protein and mRNA expres-sions of IL-1β and TNF-α in the brains were markedly lower in GbE groups(3.82±0.54,0.95±0.08 ng/g wet weight)than that in AS groups,the protein andmRNA expressions of IL-10 and 1L-10R in the brains were markedly higher in GbEgroups(0.85±0.06 ng/g wet weight)than that in AS ***:GbEinhibited production of pro-inflammatory cytokines IL-1β and TNF-α,but up-regulated the production of anti-inflammatory cytokines,1L-10 and IL-10R in brain,which might be related with its anti-AS actions.

关键词： atherosclerosis cytokine interleukin-1 tumor necrosis factor interleukin-10 Ginkgo biloba rats

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Pharmacokinetics of CPU0213,a novel endothelin receptor antagonist,after intravenous administration in mice

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Acta Pharmacologica Sinica 2006年第3期27卷 367-371页

作者： Li GUAN~2 Yu FENG~2 Min JI~4 De-zai DAI~(2,3) ~2Research Division of pharmacology,and ~4Center of New Drug Research and Development.china Pharmaceutical university,nanjing 210009.china Research Division of pharmacology China Pharmaceutical University Nanjing China Center of New Drug Research and Development China Pharmaceutical University Nanjing China

Aim:To determine the pharmacokinetics associated with acute toxic doses ofCPU0213,a novel endothelin receptor antagonist in mice after a single intrave-nous ***:Concentrations in serum and the pharmacokineticparameters of CPU0213 were assayed by high pressure liquid chromatography(HPLC)following a single intravenous bolus of CPU0213 at concentrations of 25,50,and 100 mg/kg in *** intravenous acute toxicity of CPU0213 was alsoassessed in ***:A simple,sensitive and selective HPLC method wasdeveloped for quantitative determination of CPU0213 in mouse *** con-centration-time data conform to a 2-compartment model after iv administration ofCPU0213 at concentrations of 25,50,100 mg/*** corresponding distributionhalf-lives(T1/2α) were 3.6,4.2,1.1 min and the elimination half-lives(T1/2β)were39.4,70.3,61.9 *** was a linear increase in C0proportional to dose,and thesame as AUC0-tand AUC0-∞.AUC0-tand AUC0-∞were 4.511,13.070,23.666 g·min·L-1and 4.596,13.679,24.115 g·min·L-1,*** intravenous LD50was 315.5mg/***:First order rate pharmacokinetics were observed for CPU0213within the range of doses used,and the acute toxicity of CPU0213 is mild.

关键词： CPU0213 high pressure liquid chromatography mice pharmacokinetics acute toxicity

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Therapeutic effect of osthole on hyperlipidemic fatty liver in rats

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Acta Pharmacologica Sinica 2007年第3期28卷 398-403页

作者： Yan ZHANG Mei-lin XIE~2 Lu-jia ZHU Zhen-lun GU department of pharmacology,medical School of Soochow university Suzhou 215123,china department of pharmacology Medical School of Soochow University Suzhou China

Aim:To study the effects of osthole on hyperlipidemic fatty liver and investigatethe possible ***:A rat model with hyperlipidemic fatty liverwas successfully established by feeding fatty milk for 6 *** experimentalrats were then treated with 5-20 mg/kg osthole for 6 *** mouse hyperlipi-demic model was induced by feeding fatty milk when they were treated with 10-20mg/kg osthole for 3 ***:After treatment with osthole,the levels of ratserum total cholesterol(TC),triglyceride(TG)and low density lipoprotein-choles-terol significantly decreased as compared with the fatty liver model group(P3 weeks(P<0.05 or P<0.01).Importantly,the histological evaluation of rat liver demonstrated that ostholedramatically decreased lipid accumulation(P<0.01).Conclusion:Osthole wasfound to have therapeutic effects on fatty milk-induced rat fatty liver;the mecha-nisms might be associated with its anti-oxidation and the elevation of the activi-ties of LPL and HL.

关键词： osthole hyperlipidemic fatty liver pharmacology

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Beneficial effect of Iptakalim on rotenone--induced Parkinson's disease model in ras

Beneficial effect of Iptakalim on rotenone--induced Parkinso...

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第十一届全国神经药理学术会议

作者： YANG Yong LONG Yan DING Jian--Hua HU Gang department of pharmacology & Neurobiology, nanjing medical university, nanjing 210029

Parkinson’s disease (PD) is a common neurodegenerative disorder of unknown etiology,the cardinal features ofwhich include tremor,rigidity,slowness of movement and postural *** pathological hallmarks are the loss of thenigrostriatal dopaminergic neurons and the presence of neuronal proteinacious cytoplasmic inclusions,known as *** final common pathway in the demise of these cells may involve dopamine - dependent oxidative ***-none,a mitochondrial poison whose relevance to the etiology of PD is unknown,represents the most recent approach tomodeling PD in *** it is widely used to produce the model of PD in cells and in *** studies revealed a new

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Influences of 3-methylcholanthrene,phenobarbital and dexamethasone on xenobiotic metabolizing-related cytochrome P450 enzymes and steroidogenesis in human fetal adrenal cortical cells

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Acta Pharmacologica Sinica 2006年第8期27卷 1093-1096页

作者： Hui WANG~2 Min HUANG Ren-xiu PENG Jiang LE department of pharmacology,Basic medical School of Wuhan university,Wuhan 430071,china department of pharmacology Basic Medical School of Wuhan University Wuhan China

Aim:To explore the influence and possible mechanism of xenobiotics on adrenalsteroidogenesis during fetal ***:Primary human fetal adrenalcortical cells were prepared,cultured and treated with 3-methylcholanthrene,phe-nobarbital and *** activities of 7-ethoxyresorufin O-dealkylase,benzphetamine,aminopyrine and erythromycin N-demethylases were measuredby enzyme *** the same time,quantitative analysis of steroid hormonescortisol,aldosterone,testosterone and progesterone were carried out in culturalmedium by ***:The activities of benzphetamine andaminopyrine N-demethylase were increased in the cultural fetal adrenal cells treatedwith phenobarbital(0.25-1 mmol/L)for ***(25-100 μmol/L)alsoincreased the activity of erythromycin *** activity of 7-ethoxyresorufin O-dealkylase was undetected in the cells treated without andwith 3-methylcholanthrene(0.5-2μmol/L).Meanwhile,the contents of mediumcortisol,aldosterone and progesterone were decreased after treatment with ***,aldosterone and progesterone concentrations werealso slightly decreased with *** enhanced the pro-ductions of cortisol and progesterone *** trend of testosteroneconcentration was uncertain after 3-methylcholanthrene,phenobarbital or dexam-ethasone ***:3-Methylcholanthrene,phenobarbital or dex-amethasone could interfere with the synthesis of cortisol,aldosterone and proges-terone in primary human fetal adrenal cortical cells,which likely act throughxenobiotic metabolizing-related cytochrome P450 isoform activation.

关键词： xenobiotics steroidogenesis adrenal glands cytochrome P-450 enzyme system fetal development

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