冰片对卡马西平在家兔体内药代动力学的影响

目的观察冰片对卡马西平(carbam azep ine,CBZ)及10,11-环氧化卡马西平(10,11-epoxide carbam azep ine,ECBZ)在家兔体内药动学过程的影响。方法CBZ和冰片灌胃给药,高效液相法检测家兔血浆和脑脊液中CBZ及ECBZ的浓度,并计算药动学参数。结果冰片和CBZ合用可使CBZ的药动学参数T12(ka)、Tpeak、AUC增大而Ka和CL减少;ECBZ的药动学参数T12(ke)和Tpeak增大而Ke减少;ECBZ的脑血比提高。结论冰片可提高CBZ的生物利用度,减慢代谢,并促进血脑屏障对ECBZ的通透性。     

水溶性水飞蓟素对大鼠体内卡马西平药动学的影响研究

目的:研究水溶性水飞蓟素对大鼠体内卡马西平(CBZ)药动学的影响。方法:取18只大鼠随机均分为对照组(生理氯化钠溶液)、水溶性水飞蓟素普通剂量(50 mg/kg)组、水溶性水飞蓟素高剂量(100 mg/kg)组,灌胃给予相应药物,每日1次,连续给药7 d,末次给药1 h后所有大鼠灌胃给予CBZ 50 mg/kg。分别于给药前及给予CBZ后0.5、1、1.5、2、4、6、8、10、12 h眼眶取血,以地西泮为内标,以高效液相色谱法测定血浆中CBZ及其代谢产物10,11-环氧卡马西平(ECBZ)的浓度,并利用Win Nolin 5.2药动学软件计算药动学参数。结果:与对照组比较,水溶性水飞蓟素普通剂量组和水溶性水飞蓟素高剂量组大鼠体内CBZ的Ka明显增加[(0.31±0.22)vs.(2.66±3.12)、(5.26±4.58)h-1,P<0.05],ECBZ的AUC0-12 h[(53.87±7.31)vs.(70.65±12.79)、(68.44±4.62)mg·h/L,P<0.05]、cmax[(7.20±0.87)vs.(8.82±0.54)、(8.19±0.38)mg/L,P<0.05]明显增加,其余药动学参数比较差异无统计学意义。结论:水溶性水飞蓟素连续服用可促进CBZ在大鼠体内的吸收,同时有促进CBZ体内代谢的趋势,临床上两者合用时应注意潜在的药物相互作用。     

非线性混合效应模型法研究卡马西平在癫痫儿童中的群体药动学

目的:考察卡马西平(CBZ)在癫痫儿童中的群体药动学参数。方法:采集我院的866例儿童癫痫患者服用CBZ常规治疗及监测的资料数据,利用Michaelis-Menten一级消除药物动力学模型,非线性混合效应模型程序估算癫痫儿童服用CBZ的群体药动学参数。结果:癫痫儿童卡马西平群体药动学主要参数Ke、Vd、CL在单用CBZ组分别为0.091h-1、0.502L.kg-1和0.046L.h-1.kg-1;性别、身高以及合并氯硝西泮、妥吡酯对CBZ清除率未见明显影响;儿童年龄、体质量、肝肾功能异常以及合并丙戊酸、苯巴比妥、苯妥因为CBZ清除率影响的重要因素,并且均增加CBZ的清除率。结论:根据癫痫儿童的群体药动学模型,结合患儿的年龄、体质量、肝肾功能、服药剂量以及合并用药等资料,估算其清除率,预测患儿体内的药物浓度,制定个体化给药方案。     

卡马西平健康人体药物动力学特性

目的:建立测定卡马西平(CBZ)的高效液相色谱法。分析CBZ在健康受试者体内药动学特性,探讨临床应用个体差异的原因。方法:12名健康受试者单剂量(200 mg)口服CBZ片,HPLC法测定血浆样品药物浓度。结果:CBZ的线性范围为(0.05～10)μg·ml~(-1),最低检测浓度为0.05μg·ml~(-1),方法平均回收率为94.4%。单剂量口服CBZ后血浆浓度符合一级吸收一房室模型,其主要药动学参数为:C_(max)为(4.71±0.99)μg·ml~(-1),t_(max)为(16±12)h,AUC为(361.62±49.43)μg·h·ml~(-1),t_(1/2)= (38.39±6.37)h。结论:该法测定血浆中CBZ浓度高效、灵敏、准确,CBZ体内药动学特性存在明显个体差异。     

卡马西平在癫痫患儿中的群体药动学研究

目的:研究卡马西平(CBZ)在癫痫患儿中的群体药动学。方法:回顾性收集我院119例服用CBZ的门诊癫痫患儿的稳态血药浓度(n=122)。用非线性混合效应模型(NONMEM)法进行数据分析,定量考察年龄、性别、体重、日剂量和合用其他抗癫痫药对CBZ清除率的影响。采用一房室开放模型和一级吸收和消除的药动学模型,按照固定吸收速率常数文献值,最终求算CBZ的清除率。结果:最终拟合群体药动学模型为:CL=0.593·(体重/28.5)0.63·日剂量0.569。性别、合用丙戊酸钠不影响CBZ的清除率。结论:用NONMEM法估算CBZ的清除率和推荐剂量,可为临床制订个体化给药方案、提高疗效、降低药物的毒副作用提供依据。     

地塞米松对注射用双黄连中绿原酸在大鼠体内的药动学影响

目的探讨与地塞米松磷酸钠注射液合用时注射用双黄连中绿原酸在大鼠体内血药浓度及相关药动学参数的影响。方法24只SD大鼠,雌雄各半,随机分成2组,尾静脉给药后采用反相高效液相色谱法,测定单独给予注射用双黄连及与地塞米松合用后不同时间点的大鼠体内绿原酸血药浓度,并对所得数据用DAS2.0软件进行分析,求出其主要药动学参数。结果静脉给药后,绿原酸在大鼠体内符合二室开放模型,在单用和复合给药时的分布半衰期(t1/2α)、总消除率(Cl)和药-时曲线下面积(AUC)等主要药动学参数均有显著性差异。结论在给药剂量下,单用和合用的血药浓度变化有较大差异;两者合用时,地塞米松对绿原酸的药动学有显著影响,促进大鼠体内绿原酸的消除,从而加速双黄连的代谢。     

氨氯地平对心衰大鼠体内地高辛药动学的影响

目的研究氨氯地平与地高辛合用对心衰大鼠体内地高辛的药动学影响.方法采用腹主动脉狭窄方法制作大鼠心衰模型,实验分地高辛单用组和地高辛与氨氯地平合用组,采用荧光偏振免疫法检测血浆中地高辛的浓度,药-时数据经DASver 1.0软件处理,确定单用组与合用组的药动学参数.结果合用氨氯地平后,地高辛的达峰时间由0.67 h推迟为1.00 h,AUC0-24由(15.2±6.0)μg·L-1·h减少为(13.6±4.1)μg·L-1·h,经配对t检验,2组间主要药动学参数T1/2a,T1/2β,AUC0-24,CL/F,Gmax均无显著性差异(P＞0.05).结论氨氯地平对心衰大鼠体内地高辛的药动学过程无影响.     

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.     

卡马西平固体脂质纳米粒的制备及其药动学研究

目的制备并评价卡马西平固体脂质纳米粒(CBZ-SLN),考察其单次给药后在小鼠体内的药动学过程。方法采用高温乳化-低温固化法制备CBZ-SLN,并对其进行评价;小鼠随机分为CBZ-SLN组、卡马西平(CBZ)+维拉帕米(Ver)组、CBZ-SLN+Ver、CBZ+SLN组和CBZ组,每组50只,分别腹腔注射后,收集10、15、30、45、60、120、240、360、480和600 min血浆与脑组织,并采用HPLC测定卡马西平的浓度。结果 CBZ-SLN多为球形,平均粒径为(310.20±10.04)nm,Zeta电位为(-30.50±0.98)m V,包封率为(70.9±3.0)%;与CBZ组相比,CBZ-SLN组和CBZ+Ver组CBZ的AUC分别增加88%和64%,t1/2显著增加,而CL显著降低。此外,与CBZ组和CBZ+SLN组相比,CBZ-SLN组和CBZ+Ver组CBZ脑药浓度显著增加。结论 CBZ-SLN具有一定的缓释性,且可有效提高CBZ的脑药浓度,这可能与CBZ-SLN抑制P-糖蛋白(P-gp)对CBZ的外排,增加其在脑内的驻留有关。     

高效液相色谱法同时检测兔血浆和脑脊液中的卡马西平及其环氧化物

目的建立家兔血浆和脑脊液中卡马西平（CBZ）及其活性代谢产物环氧化卡马西平（ECBZ）的高效液相色谱（HPLC）分析方法，并研究其药动学过程。方法选择奥卡西平为内标，采用Hypersil ODS（250 mm×4.6 mm，5 μm）色谱柱，以乙腈:水（63∶37）为流动相，流速0.8 mL·min^-1，柱温30 ℃，在紫外波长为210 nm处检测。所得数据用3P87药动学程序处理，求出有关的药动学参数。结果CBZ和ECBZ在0.05～10.00 mg·L^-1 的浓度范围内线性关系良好（r＝0.999 9），平均回收率为99.6%～105.4%，日内、日间精密度RSD均＜7%。结论该方法简便、准确、灵敏度高，可用于CBZ和ECBZ的检测及药动学研究。     

国产与进口卡马西平治疗癫痫的前瞻性多中心开放性随机对比观察

目的 研究进口及国产卡马西平治疗癫痫的疗效与耐受性。方法134例癫痫部分性发作有或无继发性全身发作患者随机分入试验组(进口卡马西平组)(66例)或对照组(国产卡马西平组)(68例)。每月随访1次共6次,对比2组的疗效及药物不良反应。结果 试验组仍有发作的病人数逐月减少;对照组虽有下降但波动大。试验组有效率及完全控制率高于对照组(P<0.05)。两组药物不良反应的出现率及严重程度无差异。综合满意程度,试验组高于对照组。进口卡马西平对部分性发作(有或无继发性全身发作)的疗效高于国产卡马西平。2组药物不良反应的出现率无差异。结论 进口卡马西平疗效好于国产卡马西平。     

高效液相色谱法测定人血清中卡马西平浓度及其临床应用

本文建立了高效液相色谱法测定人血清中卡马西平浓度，以μＢｏｎｄａｐａｋＣ１８（１０ｍｍ）为固定相，甲醇－乙腈－水（４５：１０：４５）为流动相，硝基安定为内标，检测波长为２５４ｎｍ。方法最低检测限为２．５ｎｇ（Ｎ／Ｓ＝３），血清中最低检测浓度为０．２５ｍｇ／Ｌ，卡马西平血清浓度在２～１４ｍｇ／Ｌ范围内线性关系良好（γ＝０．９９９７），方法回收率为９９．的％，不同浓度水平测定结果的日内变异系数＜３．２％，日间变异系数＜６．２％。方法操作简便、快速，尤宜常规应用。临床应用结果满意。     

不同剂量卡马西平在家兔体内的药物动力学

本文采用高效液相法（ＨＰＬＣ）测定了卡马西平的血药浓度，在１８只家兔体内观察不同剂量下药物浓度变化和药动学参数差异。结果发现家兔在两种剂量下均有双峰现象，这一现象估计与肠－肝循环有关，两组剂量的Ｔ１／２间有显著差异，高剂量组的平均Ｔ１／２比低剂量的下降一半。这一结论应引起临床医师的注意     

A pharmacological study of the effect of carbamazepine on neuromuscular transmission in the rat diaphragm

The effects of carbamazepine (0.042-0.42 mM) on neuromuscular transmission were studied on the isolated rat phrenic nerve diaphragm preparation using standard pharmacological and electrophysiological methods. Carbamazepine decreased (1) the antidromic activity of the phrenic nerve, (2) the amplitude of the endplate potential (EPP) and miniature endplate potential (MEPP), (3) the quantal content of the endplate potential, (4) the indirectly-elicited twitch tension, (5) the muscle contracture in chronically denervated muscle induced by acetylcholine (ACh) and (6) the amplitude of the compound phrenic nerve action potential, in a concentration-dependent manner. The antidromic activity of the phrenic nerve was the most affected, while the phrenic nerve compound action potential was least affected. However, the IC50 for carbamazepine (the concentration of carbamazepine that inhibited 50% of the response) was in the same order of concentration, i.e. 0.11-0.3 mM. Compared with the effect of carbamazepine on the indirectly-elicited twitch tension with its actions described above, it is concluded that carbamazepine interfered with the neuromuscular activity by inhibiting pre- and postsynaptic process and conduction in the phrenic nerve.     

HPLC法同时测定人血清中卡马西平、环氧化卡马西平和苯妥英

目的:建立同时测定人血清中苯妥英、卡马西平及其代谢物10,11-环氧化卡马西平浓度的HPLC法。方法:用含内标氯唑沙宗的乙腈沉淀样品中蛋白,取上清液进样。分析柱为YWG-C_(18)(4.6mm×200mm,10μm),流动相为乙腈-甲醇-水(13:25:62),检测波长为214 nm。结果:卡马西平、10,11-环氧化卡马西平和苯妥英的标准曲线范围分别为0.4～16,0.2～8,1～40μg·mL~(-1),最低检测浓度分别为0.2,0.1,0.5μg·mL~(-1)。三者的方法回收率近100％,日内和日间精密度均小于6％,内源性物质和常用药物均不干扰测定。结论:该方法操作简便,灵敏、准确,适用于治疗药物监测。     

不同厂家卡马西平片溶出度考察

目的：对国内５个厂家生产的卡马西平片进行了溶出度考察。方法：按中国的药典１９９５年版溶出度测定法第二法测定卡马西平片的溶出度。结果：提取参数（Ｔ５０,Ｔｄ,ｍ）,并对参数进行相关性研究。结论：各厂产品溶出度参数差异有极显著性（Ｐ〈０．０１）。Ｂ、Ｄ、Ｅ厂生产的卡马西平片溶出度符合中国药典规定,Ａ、Ｃ厂生产的卡马西平片溶 出度不符合规定。     

Quantitation of the Relative Amounts of Anhydrous Carbamazepine (C15H12N2O) and Carbamazepine Dihydrate (C15H12N2O · 2H2O) in a Mixture by Solid-State Nuclear Magnetic Resonance (NMR)

The application of solid state nuclear magnetic resonance (NMR) for the quantitation of the relative amounts of carbamazepine anhydrate (I) and Carbamazepine dihydrate (II) in a mixture is presented. The techniques of cross polarization, dipolar decoupling, and magic angle spinning have been used to obtain high-resolution NMR spectra of the samples in the solid state. Although the chemical shifts of I and II were similar, the proton spin lattice relaxation time of II was much shorter than that of I. A delay time of 10 sec between pulses resulted in saturation of the signal from I and in a spectrum arising solely from II. The dependence of the observed signal intensity on the contact time was evaluated for II and glycine, the internal standard, to allow theoretical estimation of the peak area ratios. Various molar ratios of I and II were then mixed with glycine, and the resulting peak area ratios of II to the area of the alpha and the carbonyl carbons of glycine was linearly related to the relative proportion of II in the mixture.     

Inhibition of epoxidation of carbamazepine by valproic acid in the isolated perfused rat liver

The effect of valproic acid on carbamazepine epoxidation in the perfused liver was investigated in two separate studies. In study I, significant decreases were observed both in the intrinsic clearance of carbamazepine and the intrinsic formation clearance of carbamazepineepoxide in the presence of therapeutic concentrations of valproate. The same inhibitory effect of valproate was also observed in liver preparations from a group of animals pretreated with carbamazepine. Study II focused on the effect of valproate and carbamazepine on the apparent Michaelis-Menten parameters (V _max,m,K_m,m)associated with the intrinsic formation clearance of carbamazepineepoxide in the perfused liver. Valproate had no statistically significant effect on either the V _max,morthe K_m,m of epoxidation, although the K_m,m value was 43% higher in the presence of valproate. However, the ratio of V _max,m and K_m,m (intrinsic formation clearance) was significantly reduced by valproate. The V _max,m and K_m,m values obtained in study II predicted a significant decrease in the intrinsic formation clearance of carbamazepineepoxide, consistent with the results of study I. Carbamazepine pretreatment was associated with significant increases in apparent V _max,m and K_m,m of epoxide formation. This work was supported in part by NINCDS research grant NS-04053 and NIGMS research grant l P01 GM32165-01.     

Determination of the Relative Amounts of Anhydrous Carbamazepine (C15H12N2O) and Carbamazepine Dihydrate (C15H12N2O · 2H2O) in a Mixture by Powder X-ray Diffractometry

A powder x-ray diffraction technique has been developed to quantify the relative amounts of anhydrous carbamazepine (C₁₅H₁₂N₂O) (I) and carbamazepine dihydrate (C₁₅H₁₂N₂O · 2H₂O) (II) when they occur as a mixture. The theoretical basis of this technique was developed by Alexander and Klug (Anal. Chem. 20:886–889, 1948). The powder x-ray diffraction patterns of I and II revealed that the lines with d-spacings of 6.78 and 9.93 were unique to I and II, respectively. The ratio of the integrated intensity of the 6.78 line in a mixture of I and II to the intensity of the 6.78 line in a sample consisting of only I was calculated as a function of weight fraction of I in the mixture. These ratios were also experimentally determined, and there was a good agreement between the theoretical and the experimental intensity ratios. Similarly good agreements between the theoretical and the experimental intensity ratios for the 9.93 line of II were obtained. The samples were compressed into tablets and subjected to x-ray analysis. When compressed to a certain pressure, the particles tended to orient the same way in replicate samples resulting in highly reproducible intensity values. Compression into tablets was necessary because the powder samples yielded unsatisfactory results.