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Population pharmacokinetic model of valproate and prediction of valproate serum concentrations in children with epilepsy

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Acta Pharmacologica Sinica 2004年第12期25卷 10-17页

作者： De-chun JIANG, Li WANG2 department of pediatrics, peking university First hospital, TherapeuticDrug Monitoring and Clinical Toxicology, Center of peking university, beijing 100034, china department of pediatrics Peking University First Hospital Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University Beijing 100034 China

AIM: Using sparse data of valproate (VPA) serum concentrations to build a population pharmacokinetic (PPK) model of VPA in Chinese children with epilepsy and to predict serum concentrations for new patients using a Bayesian approach. METHODS: Two hundred epileptic children, whose VPA serum concentrations were collected, were divided randomly into two groups (A and B, n=100 each). The PPK parameter values of group A were calculated to establish a PPK Model by using the NPEM Program of USC*PACK software. Based on it, VPA serum concentrations of group B were predicted with the Bayesian Fitting Program of the USC*PACK software. To assess the accuracy and precision of prediction, a paired-comparisons t-test was run between predicted and ob- served concentrations, and then the mean prediction error (MPE), mean square prediction error (MSPE), root mean square prediction error (RMSPE), and coincidence rates for different percentages of prediction error were all calculated. RESULTS: Optimum PPK parameters were: Ka, 2.522±2.743 h-1; Vs, 0.329±0.496 L/kg; and Kel, 0.0438±0.0384 h-1. For group B, there was no significant difference between predicted and observed concentrations. MPE was -0.43 mg/L, MSPE was 115.40 (mg/L)2, and RMSPE was 5.47 mg/L. The coincidence rates for percent- ages of prediction error, which were less than 5 %, 10 %, 15 %, 20 %, 25 %, and 30 %, were 62 %, 74 %, 82 %, 85 %, 89 %, and 93 %, respectively. CONCLUSION: A PPK model of VPA in epileptic children was successfully established. Based on it, VPA serum concentrations can be predicted accurately with a Bayesian approach.

关键词： pharmacokinetics valproic acid epilepsy Bayes theorem USC*PACK software

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Interaction between hydrogen sulfide/cystathionine γ-lyase and carbon monoxide/heme oxygenase pathways in aortic smooth muscle cells

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Acta Pharmacologica Sinica 2006年第12期27卷 1561-1566页

作者： Hong-fang JIN~2 Jun-bao DU~(2,4)Xiao-hui LI~2 Yan-fei WANG~2 Yin-fang LIANG~2 Chao-shu TANG~3 2 department of pediatrics,peking university First hospital,beijing 100034,china 3 Institute of Cardiovascular Research,peking university First hospital,beijing 100034,china department of pediatrics Peking University First Hospital Beijing 100034 China Institute of Cardiovascular Research Peking University First Hospital Beijing 100034 China

Aim:To investigate the interaction between hydrogen sulfide（H2S）/cystathion-ine γ-lyase（CSE）and carbon monoxide（CO）/heme oxygenase（HO）pathways inaortic smooth muscle cells（ASMC）.Methods:The ASMCs were divided into thefollowing groups:（1）the control group;（2）the zinc protoporphyrin（ZnPP）20μmol/L group;（3）the propargylglycine（PPG）2 mmol/L,4 mmol/L and 10 mmol/Lgroups;and（4）the sodium hydrosulfide（NariS）1×10-5mol/L,1×10-4mol/L and1×10-3mol/L *** of the groups was further divided into 6h,12h,18hand 24h *** CO level,represented by carboxyhemoglobin（HbCO）content was measured using a spectrophotometric method and H2S content wasdetected by a sensitive electrode *** and HO-1 expressions were de-tected by Western ***:The H2S content in the medium and CSEexpression by ASMC were markedly increased by ZnPP compared with the con-trol *** content in the medium and HO-1 expression by the ASMCstarted strengthening following 24h treatment with PPG at 2 mmol/L,but werefurther strengthened following 18h and 24h treatment with PPG at 4 mmol/Lcompared with the controls（P4mol/Ldecreased the HbCO level in the medium and HO-1 expression by the ASMC after6h and 12h treatment,while NariS at 1×10-3mol/L decreased them at all timepoints of the ***:The results suggested that endogenousCO/HO and H2S/CSE pathways inhibited each other in ASMC under physiologi-cal conditions.

关键词： hydrogen sulfide cystathionine γ-lyase carbon monoxide heme oxygenase

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Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence

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Acta Pharmacologica Sinica 2005年第11期26卷 1290-1296页

作者： Li-ping ZHANG, Li WANG~2 department of pediatrics, peking university First hospital, beijing 100034, china departmentofpediatrics PekingUniversityFirstHospitalBeijing100034China

Aim: Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated. Methods: The mRNA of preproNPY and its receptors (Y1, Y2, and Y5) in the hippocampus were determined by competitive RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry. Results: A decrease of preproNPY mRNA in the hippocampus was found in tolerant and dependent rats. The level of preproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol-induced seizures. Immunohistochemistry indicated a decrease of NPY-immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y,and Y5decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y2increased in tolerant rats but decreased in dependent rats. Conclusion: A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long-term treatment with FZP. Y,, Y2, and Y5mRNA were also altered in FZP tolerance and dependence.

关键词： benzodiazepines neuropeptide Y flura zepam

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Interaction between en- dogenous nitric oxide and carbon monoxide in the pathogenesis of hypoxic pulmonary hypertension

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Chinese Science Bulletin 2003年第1期48卷 86-90页

作者： SHI Yun, DU Junbao, GUO Zhiliang, ZENG Chaomei & TANG Chaoshu department of pediatrics, the First hospital, peking university, beijing 100034, china Correspondence should be addressed to Du Junbao (e-mail: junbaodu@ ***) department of pediatrics First Hospital Peking University Beijing 100034 China

The aim of the study was to investigate the in-teraction between nitric oxygenase (NOS)/ nitric oxide (NO) and heme oxygenase (HO)/ carbon monoxide (CO) system in the pathogenesis of hypoxic pulmonary hypertension. On a rat model of hypoxic pulmonary hypertension, the pulmo-nary artery pressure was measured, and NO formation and expression of NOS in pulmonary tissues were examined after treatment with ZnPP-IX, an HO-1 inhibitor. The pulmonary artery pressure, CO formation and expression of HO-1 in pulmonary tissues were examined after treatment with L-NAME, a NOS inhibitor. We found that pulmonary hy-pertension developed after 2-week hypoxia, while the con-centration of NO in the pulmonary tissue homogenates and the expression of NOS in intrapulmonary artery endothelial cells decreased markedly. ZnPP-IX worsened pulmonary hypertension of hypoxic rats. However, it increased endoge-nous production of NO and the expression of NOS obviously. The concentration of CO in the pulmonary tissue homoge-nates and the expression of HO-1 in intrapulmonary artery smooth muscle cells increased markedly with hypoxic pul-monary hypertension. L-NAME worsened pulmonary hy-pertension of hypoxic rats, but inhibited CO formation and HO-1 expression (P < 0.01). The results of this study sug-gested that endogenous NOS/NO and HO/CO systems might interact with each other and therefore play an important regulating role in hypoxic pulmonary hypertension.

关键词：低氧肺源性高血压病理发生内源性NO CO 一氧化碳一氧化氮

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Nitric oxide modulates hypoxic pulmonary smooth muscle cell proliferation and apoptosis by regulating carbon monoxide pathway

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Acta Pharmacologica Sinica 2007年第1期28卷 28-35页

作者： Yan-fei WANG~2 Hong TIAN~2 Chao-shu TANG~(3,4) Hong-fang JIN~2 Jun-bao DU~(2,4,5)2 department of pediatrics,peking university First hospital,beijing 100034,china 3 Institute of Cardiovascular Diseases,peking university First hospital,beijing 100034,china,4 Key Laboratory of Molecular Cardiovascular Diseases,Ministry of Education,beijing 100034,china departmentofpediatrics PekingUniversityFirstHospitalBeijing100034China InstituteofCardiovascularDiseases PekingUniversityFirstHospitalBeijing100034China KeyLaboratoryofMolecularCardiovascularDiseases MinistryofEduc

Aim:To explore the role of carbon monoxide(CO)in the regulation of hypoxicpulmonary artery smooth muscle cell(PASMC)proliferation and apoptosis bynitric oxide(NO).Methods:PASMC of Wistar rats was cultured in vitro in thepresence of a NO donor,sodium nitroprusside,or an inhibitor of heine oxygenase(HO),zinc protoporphyrin-IX,or under both normoxic and hypoxic *** and carboxyhemoglobin in PASMC medium were detected *** proliferating and apoptotic percentage of PASMC wasmeasured by flow *** expression of HO-1 mRNA in PASMC wasanalyzed by fluorescent real-time quantitative PCR,and the proliferating cell nuclearantigen and caspase-3 were examined by immunocytochemical ***:The results showed that hypoxia suppressed NO generation from PASMC,whichpromoted hypoxic PASMC proliferation and induced ***,hy-poxia induced HO-1 expression in PASMC and promoted CO production fromPASMC,which inhibited PASMC proliferation and regulated PASMC *** upregulated the expression of HO-1 mRNA in hypoxic PASMC;NO also inhib-ited proliferation and promoted apoptosis of hypoxic PASMC,possibly by regu-lating the production of ***:The results indicated that CO couldinhibit proliferation and regulate apoptosis of PASMC,and NO inhibited prolifera-tion and promoted apoptosis of hypoxic PASMC,possibly by regulating the pro-duction of CO.

关键词： hypoxia proliferation apoptosis carbon monoxide nitric oxide

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Hydrogen sulfide:a novel gasotransmitter in cardiovascular system

Hydrogen sulfide:a novel gasotransmitter in cardiovascular s...

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第八届海峡两岸心血管科学研讨会

作者： Jun-bao Du (department of pediatrics,peking university First hospital,beijing 100034,china)

Hydrogen sulfide(HS) is a well -known toxic gas with the smell of rotten *** studies have shown that HS is generated in vivo in human and animal organisms and that it participates in many pathophysiological *** is produced endogenously in mammalian *** is produced endogenously in mammalian tissues from L - cysteine metabolism mainly by 3 enzymes;cystathionine β -synthetase (CBS),cystathionineγ-lyase(CSE) and 3 - mercaptosulfurtransferase(MST).Amongst them CSE plays a major role in generationg HS in cardiovascular tissues under both physiological and pathophysiological conditions. The mRNA of this enzyme was expressed solely in vascular smooth muscle cells(VSMCs),as detected by RT - PCR and in situ *** found that it was located in the smooth muscle layer of the artery wall and in the *** studies shows that endogenous production of HS is vascular tissue - specific. The physiological function of HS in the cardiovascular system has been wildly *** HS in rat vascular tissues,as a vascular relaxant factor,could maintain the basal blood pressure balance in a physiological ***,it could suppress the proliferation of cultured VSMCs through the mitogen - activated rotein kinase(MAPK) pathway in a dose - dependant manner in ***,HS could be endogenously produced by heart tissue,as a physiological cardiac function regulator,mediated by the K channel pathway. The pathophysiological significance is very *** are the first research group to investigate the possible pathophysiologic significance of HS in a variety of cardiovascular *** found that endogenous HS played important roles in the development of pulmonary hypertension,systemic hypertension,athrosclerosis, shock,heart failure,COPD and so on,indicating that HS has an important potential implication in medical sciences.

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Sodium hydrosulfide alleviated pulmonary vascular structural remodeling induced by high pulmonary blood flow in rats

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Acta Pharmacologica Sinica 2006年第8期27卷 971-980页

作者： Xiao-hui LI~2 Jun-bao DU~(2,6) Ding-fang BU~3 Xiu-ying TANG~4 Chao-shu TANG~5 ~1department of pediatrics,peking university First hospital,Key Laboratory of Molecular Cardiovascular Diseases,Ministry of Education ~3 Laboratory Center ~4Laboratory of Electron Microscopy,peking university First hospital,beijing 100034,china ~5department of Physiology,peking university Health Science Center,beijing 100083,china department of pediatrics Peking University First Hospital Key Laboratory of Molecular Cardiovascular Diseases Ministry of Education

Aim:To explore the possible role of endogenous hydrogen sulfide （H2S）,a novelgasotransmitter,in the pathogenesis of pulmonary vascular structural remodeling（PVSR） induced by high pulmonary blood ***:Thirty-two Sprague-Dawley male rats were randomly divided into sham,shunt,sham+NaHS （a H2Sdonor） and shunt+NaHS *** in shunt and shunt+NaHS groups under-went an abdominal aorta-inferior vena cava shunt,and rats in shunt+NaHS andsham+NaHS groups were intraperitoneally injected with *** was inves-tigated using optical microscope and transmission electron *** H2S was evaluated by sulfide-sensitive *** oxide synthase（NOS）,heme oxygenase （HO-1）,proliferative cell nuclear antigen （PCNA） andextracellular signal-regulated kinase （ERK） activation were analyzed by ***:After 11 weeks of shunting,PVSR developed with a decrease inlung tissue H2S production and an increase in nitric oxide （NO）.However,lungtissue carbon monoxide （CO） did not *** the treatment with NaHS for11 weeks,H2S donor ameliorated PVSR and downregulated PCNA expression andERK activation with an increase in lung tissue CO production and HO-1 proteinexpression but a decrease in NO production,NOS activity and eNOS proteinexpression in shunted ***:H2S exerted a regulatory effect on PVSRinduced by high pulmonary blood ***,H2S down-regulated theERK/MAPK signal pathway,inhibited the NO/NOS pathway and enhanced theCO/HO pathway in rats with high pulmonary blood flow.

关键词： hydrogen sulfide pulmonary hypertension structure remodeling nitric oxide/nitric oxide synthase carbon monoxide/heme oxygenase

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Population pharmacokinetics of valproate in Chinese children with epilepsy

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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 univer.ityfirst 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 ment of Pharmacy Xuan-wu Hospital of Capital Medical University Beijing 100053 China. wangyuqin8682@***.

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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Alterations of NR2B and PSD-95 expression and synaptic localization after early-life epileptiform discharges in developing neurons

Alterations of NR2B and PSD-95 expression and synaptic local...

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中国神经科学学会第四次会员代表大会暨第七届全国学术会议

作者： Qian JIANG,Ye WU,Jingmin WANG,Xiru WU,Yuwu JIANG~* department of pediatrics,peking university First hospital,beijing 100034,china

＜正＞As an extreme form of abnormally synchronized activity,epilepsy may modify patterns of organization in the nervous *** is clear that enhanced glutamatergic excitatory synaptic transmission with alterations in the expression of ionotropic glutamate receptors is a mechanism critical for seizure susceptibility and ***,the exact quomodo and the roles of regulated N-methyl-D-aspartate receptor（NMDAR） composition and expression of a major postsynaptic density（PSD） scaffolding molecule,PSD-95,are as yet *** study protein expression changes after epileptiform discharges in cultured immature rat cortical neurons,we divided cells into three groups which were transiently exposed to regular Neurobasal/B27（Control group）,physiological solution（PS group） and magnesium-free physiological solution（MGF group） at cultured day *** at three different culture ages（DIV7,DIV12 and DIV17） were collected for immunoblotting *** found a decrease in expression of NR2B NMDAR subunits and PSD-95（P ＜ 0.05） shortly after insult（within 24 hours）,which may show that brief magnesium-free media treatment of primary cultured rat cortical neurons,an in vitro model of seizure brain injury,has a major influence on the expression of NR2B subunits and PSD-95. Furthermore,we used confocal time-lapse microscopy to characterize the subcellular localization of these NMD ARs and PSD-95 and examine alterations of their co-localization patterns.

关键词： Epileptiform discharges Development Cortical neurons NMDAR subunits PSD-95 Protein expression Confocal Co-localization

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血管迷走性晕厥的诊断与防治

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实用儿科临床杂志 2008年第13期23卷 973-975页

作者：杜军保北京大学第一医院儿科

晕厥是引起一过性意识丧失最常见的原因,引起晕厥的病因主要有器质性晕厥、神经介导的反射性疾病、代谢性疾病和精神性疾病,其中自主神经介导性晕厥最常见。自主神经介导性晕厥主要包括血管迷走性晕厥(VVS)、体位性心动过速综合征(POTS... 详细信息

晕厥是引起一过性意识丧失最常见的原因,引起晕厥的病因主要有器质性晕厥、神经介导的反射性疾病、代谢性疾病和精神性疾病,其中自主神经介导性晕厥最常见。自主神经介导性晕厥主要包括血管迷走性晕厥(VVS)、体位性心动过速综合征(POTS)及直立性低血压(OH)等。直立倾斜试验(HUT)是VVS诊断中的重要客观检查手段,它包括基础直立倾斜试验(BHUT)和舌下含化硝酸甘油激发的倾斜试验(SNHUT)。VVS的治疗主要包括直立训练等物理疗法、增加患儿盐和液体的摄入量及药物治疗等。

关键词：血管神经性晕厥诊断治疗儿童

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