丙戊酸钠对卡马西平药代动力学的影响

目的:考察丙戊酸钠对卡马西平药代动力学的影响。方法:6名健康志愿者分别口服单剂量卡马西平片以及卡马西平和丙戊酸钠片,采用荧光偏振免疫法测定卡马西平血药浓度,经3p97程序处理,计算卡马西平的药代动力学参数以及丙戊酸钠对卡马西平药代动力学参数的影响。结果:合用丙戊酸钠后,卡马西平的Ke,CL/F明显增加,而T_(1/2Ke),AUC_(0-t)明显减小(P<0.05)。结论:丙戊酸钠可加速卡马西平的排泄,使卡马西平的半衰期缩短,生物利用度减小。     

丙戊酸钠对卡马西平药代动力学的影响

目的：考察丙戊酸钠对卡马西平药代动力学的影响。方法：6名健康志愿分别口服单剂量卡马西平片以及卡马西平和丙戊酸钠片，采用荧光偏振免疫法测定卡马西平血药浓度，经3p97程序处理，计算卡马西平的药代动力学参数以及丙戊酸钠对卡马西平药代动力学参数的影响。结果：合用丙戊酸钠后，卡马西平的Ke,CL/F明显增加，而T1/2Ke,AUC0-1明显减小（P＜0．05）。结论：丙戊酸钠可加速卡马西平的排泄，使卡马西平的半衰期缩短，生物利用度减小。     

癫痫儿童服用丙戊酸钠或卡马西平后血同型半胱氨酸的变化

目的:探讨癫痫儿童服用抗癫痫药物丙戊酸钠或卡马西平后血同型半胱氨酸( homocysteine,hcy)水平的变化,以便减少其潜在风险及不利影响.方法:选取67例癫痫患儿,按使用药物分为卡马西平组与丙戊酸钠组.卡马西平和丙戊酸钠的剂量分别为10 ～20 mg/(kg·d)和10～40 mg/(kg·d),并依据血药浓度适度调整剂量,疗程2～5年.在用药前、用药后6个月、用药后1年监测hcy水平,比较各组hcy水平变化.结果:共有67例患儿完成本研究,丙戊酸钠组36例,卡马西平组31例.丙戊酸钠组和卡马西平组hcy在用药前分别为(6.94±2.47)μmoL/L、(8.11±3.04) μmol/L,两组比较差异无统计学意义(P＞0.05);6个月时分别为(7.42±2.51) μmol/L、( 8.39±2.75) μmol/L,两组比较差异无统计学意义(P＞0.05);1年后分别为(8.92±2.81) μmol/L、(10.45±3.98) μmol/L,两组hcy水平均较前明显升高(P＜0.01).相关分析未发现癫痫发作及抗癫痫药物浓度与hcy呈明显相关性(P＞0.05).结论:丙戊酸钠或卡马西平引起hcy水平升高,6月以后更明显,临床需注意定期监测癫痫患儿的hcy水平并适当予以干预.     

卡马西平联合丙戊酸钠治疗额叶癫痫的疗效分析

目的:分析卡马西平联合丙戊酸钠治疗额叶癫痫的疗效.方法:分析我院于2016年4月～2017年4月收治的124例额叶癫痫患者临床资料,按照临床医治药物不同分为两组,行单纯卡马西平医治的设为对照组(62例),联合丙戊酸钠医治的设为治疗组(62例),比较两组临床疗效及安全性.结果:与治疗组比较,对照组治疗总有效率更低(P<0.05);与治疗组比较,对照组不良反应总发生率更高(P<0.05).结论:额叶癫痫行卡马西平联合丙戊酸钠治疗可取得确切疗效,且安全性高,可临床推广.     

托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫的效果观察

目的分析托吡酯、卡马西平与丙戊酸钠治疗脑炎继发癫痫效果。方法选取我院在2014年2月至2016年2月期间收治的150例脑炎继发癫痫患者为本次研究对象,并根据用药的不同分成3组,托吡酯组、卡马西平组以及丙戊酸钠组,每组患者各50例。托吡酯组给予托吡酯药物的口服治疗、卡马西平组给予卡马西平药物的口服治疗、丙戊酸钠组给予丙戊酸钠药物的口服治疗。分析三组患者的治疗效果以及不良反应发生情况,并进行对比。结果托吡酯组的有效率为82%;卡马西平组有效率为78%;戊酸钠组有效率为80%,三组患者的总有效率差异不显著,无统计学意义(P>0.05);托吡酯组、卡马西平组以及丙戊酸钠组患者的不良反应发生率分别为6.0%、20%、12%,卡马西平组不良反应发生率明显高于丙戊酸钠组和托吡酯组,丙戊酸钠组患者的不良反应发生率明显高于托吡酯组,三组差异对比有统计学意义(P<0.05)。结论对于脑炎继发癫痫患者的治疗而言,采用托吡酯、卡马西平以及丙戊酸钠均可达到理想的临床疗效,但卡马西平药物以及丙戊酸钠药物的不良反应发生率较高,托吡酯药物药物不良反应发生率较低,可以有效提升患者的安全性,应用价值较高。     

丙戊酸钠与苯妥英钠或卡马西平相互作用的血浓度观察

本文报告丙戊酸钠和苯妥英钠或卡马西平合用治疗各型癫痫９０例，丙戊酸钠使苯妥英钠和卡马西平血浓度下降；苯妥英钠和卡马西平是强有力的肝酶诱导剂，使丙戊酸钠血浓度降低，作者认为，抗癫痫药之间的相互作用错综复杂，临床上最好选择单一用药，昼避免联合用药。     

护肝宁片对卡马西平在大鼠体内药物动力学的影响

探讨了护肝宁片对卡马西平在大鼠体内药物动力学的影响.大鼠随机分为生理盐水对照组和护肝宁片给药组.护肝宁片连续给药10d后,灌胃给予卡马西平(50mg/kg),用HPLC法测定卡马西平的血药浓度.采用非隔室模型分析方法计算卡马西平的药物动力学参数.单用卡马西平及与护肝宁片合用后,两组的Ke、t1/2、CL、cmax、tmax无显著性差异(P>0.05),而AUC则有显著性差异(P<0.05).结果表明,口服护肝宁片可降低卡马西平的吸收,但不影响卡马西平的体内代谢.     

卡马西平联合丙戊酸钠治疗颞叶癫痫

目的探讨卡马西平及丙戊酸钠联合治疗颞叶癫痫的临床疗效。方法收集2011年1月至2013年12月期间,我院收治的颞叶癫痫患者88例,随机分为观察组与对照组,对照组予以卡马西平单药治疗,观察组在对照组的基础上加用丙戊酸钠治疗,比较两组的临床疗效。结果观察组的治疗总有效率为88.6%,对照组为61.4%,观察组显著高于对照组(P<0.05);观察组的不良反应率为18.2%,对照组为22.7%,两组无明显差异(P>0.05)。结论卡马西平及丙戊酸钠联合治疗颞叶癫痫疗效显著,不良反应少,值得推广应用。     

卡马西平联合丙戊酸钠治疗继发性癫痫的疗效研究

目的:探讨分析卡马西平联合丙戊酸钠治疗继发性癫痫的临床疗效。方法:在我院所收治的继发性癫痫患者中选取95例作为研究对象,分为3组,分别进行单纯卡马西平、单纯丙戊酸钠以及卡马西平联合丙戊酸钠治疗,比较三者治疗效果差异。结果:卡马西平联合丙戊酸钠治疗的总有效率(93.0%)明显比另2组(76.0%和86.0%)高,具有统计学意义。结论:卡马西平联合丙戊酸钠治疗继发性癫痫的疗效更高,不良反应的发生率较低。     

对比分析卡马西平联合丙戊酸钠、单用卡马西平治疗癫痫的临床疗效及其不良反应

目的:分析卡马西平联合丙戊酸钠、单用卡马西平治疗癫痫的疗效及不良反应。方法:选择我院2018年1—12月收治的癫痫患者62例作为研究对象,按照治疗方法的不同分为研究组(卡马西平联合丙戊酸钠治疗)和对照组(卡马西平治疗),比较两组治疗前后的癫痫发作次数和每次发作时间、MoCA评分、HAMD评分、HAMA评分。结果:研究组临床指标在治疗后均显著优于对照组(P<0.05);两组不良反应发生率比较差异无统计学意义(P>0.05)。结论:卡马西平联合丙戊酸钠能有效改善癫痫发作次数和发作时间,提高认知水平,有利于情绪功能改善,疗效突出,安全性高,值得推广。     

Population pharmacokinetics of lamotrigine with data from therapeutic drug monitoring in German and Spanish patients with epilepsy

This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.     

Carbamazepine metabolism in humans: effect of concurrent anticonvulsant therapy

Free and total carbamazepine (CBZ) and carbamazepine-epoxide (CBZ-EP) plasma levels were obtained on 113 patients with epilepsy (18-61 years old) controlled on either monotherapy or coadministration with either phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), or all three. A subset of patients were administered tetradeuterium labeled CBZ to evaluate the effects of autoinduction and coadministration of VPA on the kinetics of CBZ and its metabolite CBZ-EP. Polytherapy had variable effect on free and total CBZ plasma levels compared to monotherapy. Coadministered PHT (co-PHT), or all three anticonvulsants together (PHT, PB, and VPA: co-AEDs) decreased free and total CBZ plasma levels. No change was noted for coadministered VPA (co-VPA). Compared to monotherapy the free and total CBZ-EP levels increased with co-VPA, less with coadministered PB (co-PB), and no change with co-PHT or co-AEDs. Protein binding of CBZ and CBZ-EP was not affected by any antiepileptic drugs studied. The free and total CBZ-EP/CBZ ratio was tripled with co-VPA or co-AED's, and doubled with co-PHT or co-PB. Isotope labeling did not demonstrate any differences in half-life (t1/2), plasma clearance (Cl), or volume of distribution (Vd). Compared to naive controls, monotherapy and co-VPA decreased CBZ t1/2 by 50%, and more than doubled the CBZ Cl without a significant change in the Vd. Autoinduction is one explanation for these changes with chronic CBZ therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model.

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.     

Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.     

NONMEM法估算中国癫痫患者卡马西平的清除率

目的　考察中国癫痫患者卡马西平的群体药动学参数。方法　癫痫病例来自上海、北京两地 4所医院 ,采集服用卡马西平的 5 92例患者的稳态血药浓度 (n =70 3)。NONMEM程序估算分析时 ,采用一级吸收和消除的药动学模型并固定吸收速率、生物利用度和表观分布体积参数。结果　体重 (TBW )、剂量 (Dose)、合用丙戊酸钠 (VPA)且其日剂量大于 2 0mg·kg-1·d-1、苯妥英 (PHT)、苯巴比妥 (PB)和年龄大于 6 5岁的老年人 (ELDER)均为卡马西平清除率(CL)的影响因素。性别、合用氯硝西泮、妥吡酯不改变卡马西平的清除率。最终模型为 :CL(CL/F) (L/h) =1 32·Dose(g·kg-1·d-1) 0 42 1·TBW (kg) 0 .691·1 2 0 VPA·1 4 3PHT·1 14 PB·0 836 ELDER。讨论　根据中国癫痫患者的群体药动学模型 ,结合患者服用的剂量、体重和合并用药可估算其清除率 ,制定给药方案     

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one-compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: $?rm Cl?left (?rm L/h ?right )=0?rm. 004?times TBW?times Dose ?0.304??rm ?times 1.363?,?rm CBZ?times 1. 541?,?rm PHT?times 1.397?,?rm PB.$ The inter-individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter-individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter-individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately.     

The effect of carbamazepine on valproic acid disposition in adult volunteers.

1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg-1 day-1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/- 0.18 s.d. to 1.26 +/- 0.24 l h-1 (P less than 0.05) as did clearance of free VPA (20.8 +/- 7.6 to 37.0 +/- 13.6 l h-1). Mean VPA elimination rate constant increased from 0.051 +/- 0.011 to 0.067 +/- 0.011 h-1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/- 130.5 to 475.7 +/- 75.7 mg l-1 h (P less than 0.05) after CBZ administration. Mean serum VPA half-life decreased from 14.0 +/- 2.4 to 10.6 +/- 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/- 16.7 to 27.0 +/- 10.4 micrograms ml-1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.     

注射用帕尼培南/倍他米隆的人体药动学研究

目的:考察注射用帕尼培南/倍他米隆在呼吸系统感染患者体内的药动学。方法:15名受试者静脉滴注注射用帕尼培南/倍他米隆(0.5g/0.5g)后,采用高效液相色谱(HPLC)法测定帕尼培南、倍他米隆的血药浓度,计算药动学参数。结果:帕尼培南、倍他米隆的平均药动学参数分别为t1/2α(0.30±0.20)、(0.10±0.05)h,t1/2β(1.4±0.3)、(0.61±0.20)h,AUC0～6.5h(42±8)、(20±5)mg·h·L-1,CLs(10.8±1.5)、(29.7±8.5)L·h-1,Vd(10.2±0.9)、(8.8±1.5)L。结论:帕尼培南/倍他米隆在呼吸系统感染患者体内的药动学及药效学评价可以指导临床应用。     

芪嘧啶的药代动力学

本文报告芪嘧啶在大鼠(150 mg/kg)和家兔(100mg/kg)一次ig的药代动力学研究结果。采用分光光度法测定生物样品中的药物浓度,用3P87实用药代动力学程序处理药物浓度数据,并自动算出各项动力学参数和C-T曲线图。主要参数t_(1/2ke),t_(peak),C_(max),CL和V_d在大鼠分别为6.55 h,1.32 h,9.5μg/ml,1.46 L·kg~1·h~1和13.8 L/kg,家兔分别为1.98h,1.00h,7.1μg/ml,4.09L·kg~1·h~(-1)和11.7 L/kg。结果表明药物在大鼠肝中达峰时间短,峰浓度高,清除较慢,在肝、肾含量高于其它组织。由尿粪排泄量小,72 h累计量仅为给药量的11.5％,而且排泄速度慢,一次给药后72 h仍有一定量药物由粪尿排泄。     

盐酸小檗碱在Beagle狗静脉注射和口服药动学研究

传统观念认为小檗碱口服吸收差,而近年来,临床口服小檗碱用来治疗心律失常及充血性心衰.为解决其中的矛盾,本实验建立了HPLC方法(最低检测限为2μg·L~(-1))研究Beagle狗po和iv小檗碱的药代动力学、100 mg静脉注射的药—时曲线符合二室模型,K.为10.18 h~(-1),T_(1/2u)为0·15·h~(-1)T_1/2β为12.59·h~(-1),CL为60.70 L·h~(-1),AUC达1979.31 μg·L~(-1)V_d为699.53L。280 mg·kg~(-1)组发生呕吐·仅一狗可计算P—K参数,T_(max)为3.71h,C_(max)为15.46 μg·L~(-1),AUC为777.29μg·h~(-1)·L~(-1).T T_(1/za)0.63 h·T_(1/z)el34.82h,V_a为125.41L,K.为0.02·h~(-1),CL为2.64 L·h~(-1),45 mg·kg~(-1)一次口服以及45 mg·kg~(-1)Bid连续给药1wk的血药浓度都在10μg·L~(-1)以下。700 mg·kg~(-1)组因发生严重呕吐.腹泻,药物吸收差.血浓度在10 μg·L~(-1)以下,不能计算P—K参数.