卡马西平与丙戊酸配伍对大鼠电刺激皮层惊厥阈值及癫痫患者血药浓度的影响
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摘要
目的1探讨不同剂量卡马西平和丙戊酸镁配伍对大鼠电刺激皮层惊厥阈值及其血药浓度的影响。
2分析部分临床患者的卡马西平与丙戊酸镁相互配伍后的血清药物浓度间的相互关系。
方法1观察大鼠惊厥阈值动态变化趋势和血药浓度
通过建立大鼠电刺激皮层惊厥阈值和颈静脉置管模型,模型稳定后,将40只模型稳定的大鼠随机分为4组,每组10只,即①CBZ40mg/kg+VPM90mg/kg(高剂量组)②CBZ20mg/kg+VPM 68 mg/kg(中剂量组)③CBZ10mg/kg+VPM45mg/kg(低剂量组)④假阳性对照组(实验时仅给予生理盐水)。前三组的药物均在研磨后加等量生理盐水配成浓度为10%的水溶液,然后灌胃给药,早晚各1次(8：00 Am与20：00 Pm),连续10次,共5 d,于末次给药前0.5h与给药后0.5 h、1h、2h、4h、8 h与12h(共7个时间点)测定大鼠的惊厥阈值。并在末次给药后4h抽取静脉血,离心后用荧光偏振免疫分析法检测血药浓度(峰浓度),
2对部分难治性癫痫患者的卡马西平和丙戊酸的血清药物浓度关系进行了临床观察。
选难治性癫痫患者32名,分为两组,分别先服用卡马西平和丙戊酸镁1周,使用荧光偏振免疫分析法测定其血药浓度,然后分别加用丙戊酸镁和卡马西平,两者服用1周后再测定血药浓度。
结果
1.CBZ与VPM不同剂量联合应用时的抗电刺激大鼠皮层惊厥效应比较
给药组在给药后的各个时间点所测的惊厥阈值高于对照组,差异有统计学意义(P<0.05),末次给药前30 min,高剂量组惊厥阈值高于中低剂量组,差异有统计学意义(P<0.05),给药后12h内各时间点不同剂量联合组间惊厥阈值比较差异无统计学意义(P>0.05)。
2.CBZ与VPM不同联合组的时效关系比较
三种不同剂量组的抗癫痫作用均在给药后30 min开始起效,4 h达高峰,维持抗惊厥作用12 h,且其抗惊厥作用逐渐达峰,又逐渐下降,期间波动不大。中剂量组所达到的惊厥阈值与低剂量组的基本一致。
3.不同剂量CBZ与VPM组合时在大鼠体内的血清药物浓度比较
高剂量组峰浓度高于中低剂量组,差异有统计学意义(P<0.05).中剂量组峰浓度高于低剂量组,差异有统计学意义(P<0.05)。随着给药剂量的增加,其血药浓度也增加,但低剂量组的血药浓度仍在有效浓度范围内。
4.不同剂量CBZ与VPM配伍后对患者血清药物浓度的相互影晌
卡马西平的血药浓度在添加小剂量丙戊酸镁后无明显变化,差异无统计学意义(P>0.05),丙戊酸镁的血药浓度在添加小剂量的卡马西平后无明显变化,差异无统计学意义(P>0.05)
结论1.不同剂量卡马西平和丙戊酸镁配伍在大鼠电刺激皮层惊厥阈值测定模型的抗惊厥作用无明显差异,其血药浓度随配伍剂量的升高而升高。
2.不同剂量的卡马西平和丙戊酸镁配伍对癫痫患者血清药物浓度的影响不大。
Objective 1.To observe the influence of the combination of carbamazepine(CBZ)and valproate magnesium (VPM) on the threshold for localized seizure in direct cortical stimulation (TLS) model rats and the serum drug concentration.
2.nalysis the inter-relationship of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) on the serum drug concentration of some clinical patients.
Methods
1.The seizure threshold of dynamic change trend and blood drug concentration of rats were observed. The convulsive threshold model was established by direct cortical stimulation and ugular vein catheterization model was found. When the model was stabilized,Forty stable model rats were randomly divided into four groups. N=10.The rats received intragastric administration of CBZ40mg/kg+VPA90mg/kg (high dose group), CBZ20mg/kg+VPA68mg/kg(medium dose group),CBZ10mg/kg+VPA45mg/kg(low dose group) or normal saline (control group), respectively. Three groups of drugs were milling-in and added partes aequales normal saline, collocated with concentrations of 10% of the aqueous solution. Then intragastric administration each one time sooner or later (8:00 Am and 20:00 Pm).after ten times of administration,The convulsive threshold was detected after thirty minutes before the last administration and administration behind thirty minutes, one hours, two hours, four hours, eight hours and twelve hours (seven time points). And taking blood after the last administration four hour. The serum drug concentration peak concentration) was detected after centrifugation with fluorescence polarization immunoassay(FPIA).
2.The serum drug concentration curve of CBZ and VPA in patients with refractory epilepsy was analyzed.
Selected 32 patients with refractory epilepsy were divided into two groups, first The patients take carbamazepine and valproate magnesium and detect the serum drug concentration with fluorescence polarization immunoassay(FPIA) after one week, Then adding valproate magnesium and carbamazepine respectively.and detecting ampho-concentration after one week,
Results 1.Compare with the effect of electrical stimulation cortex convulsion when the combination of arbamazepine (CBZ) and valproate magnesium (VPM) the convulsive threshold in treatment group which after administration at various time points was higher than those in control group, The difference was statistically significant (P<0.05),At 30 min before the last administration, the convulsive threshold in high dose group was higher than those in low dose and medium dose groups, The difference was statistically significant (P<0.05), but there was no significant difference among drug groups at each time point. The difference was no statistically significant(P>0.05)
2.Compare with the time-effect relationship of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) After administration for 30 min, all three different doses of drugs worked, and the threshold peaked after administration for 4 h. The anti-convulsion effect of high, medium and low dose drugs maintained 12 h, and the anti-convulsant effect gradually reached the peak, then decreased gradually, Little fluctuation was seen during the period. The convulsant threshold which to reach the same with the low dose group
3.Comparison of serum drug concentration of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) in rats. The peak concentration in high dose group was higher than those in medium dose groups, The difference was statistically significant (P<0.05), The peak concentration in medium dose groups was higher than those in low dose groups, The difference was statistically significant (P<0.05), Plasma drug concentration curve of rats showed that the higher the dose was, the higher the peak concentration was. In low dose group,the blood concentration was still in the effective blood drug concentration range.
4.the influence of the combination of carbamazepine (CBZ) and valproate magnesium (VPM)on the patients' serum drug concentration. In epilepsy patients, the addition of CBZ or VPA did not influence the plasma concentration of original drugs. The difference was no statistically significant(P>0.05)
Conclusion
1.The effect of the combination of carbamazepine (CBZ) and valproate acid (VPA) has no significant difference on the threshold for localized seizure in direct cortical stimulation (TLS) model rats, and their serum drug concentration increase with the drug dose.
2.1n epilepsy patients, the combination of CBZ or VPA has no influence on the plasma concentration.
2分析部分临床患者的卡马西平与丙戊酸镁相互配伍后的血清药物浓度间的相互关系。
方法1观察大鼠惊厥阈值动态变化趋势和血药浓度
通过建立大鼠电刺激皮层惊厥阈值和颈静脉置管模型,模型稳定后,将40只模型稳定的大鼠随机分为4组,每组10只,即①CBZ40mg/kg+VPM90mg/kg(高剂量组)②CBZ20mg/kg+VPM 68 mg/kg(中剂量组)③CBZ10mg/kg+VPM45mg/kg(低剂量组)④假阳性对照组(实验时仅给予生理盐水)。前三组的药物均在研磨后加等量生理盐水配成浓度为10%的水溶液,然后灌胃给药,早晚各1次(8：00 Am与20：00 Pm),连续10次,共5 d,于末次给药前0.5h与给药后0.5 h、1h、2h、4h、8 h与12h(共7个时间点)测定大鼠的惊厥阈值。并在末次给药后4h抽取静脉血,离心后用荧光偏振免疫分析法检测血药浓度(峰浓度),
2对部分难治性癫痫患者的卡马西平和丙戊酸的血清药物浓度关系进行了临床观察。
选难治性癫痫患者32名,分为两组,分别先服用卡马西平和丙戊酸镁1周,使用荧光偏振免疫分析法测定其血药浓度,然后分别加用丙戊酸镁和卡马西平,两者服用1周后再测定血药浓度。
结果
1.CBZ与VPM不同剂量联合应用时的抗电刺激大鼠皮层惊厥效应比较
给药组在给药后的各个时间点所测的惊厥阈值高于对照组,差异有统计学意义(P<0.05),末次给药前30 min,高剂量组惊厥阈值高于中低剂量组,差异有统计学意义(P<0.05),给药后12h内各时间点不同剂量联合组间惊厥阈值比较差异无统计学意义(P>0.05)。
2.CBZ与VPM不同联合组的时效关系比较
三种不同剂量组的抗癫痫作用均在给药后30 min开始起效,4 h达高峰,维持抗惊厥作用12 h,且其抗惊厥作用逐渐达峰,又逐渐下降,期间波动不大。中剂量组所达到的惊厥阈值与低剂量组的基本一致。
3.不同剂量CBZ与VPM组合时在大鼠体内的血清药物浓度比较
高剂量组峰浓度高于中低剂量组,差异有统计学意义(P<0.05).中剂量组峰浓度高于低剂量组,差异有统计学意义(P<0.05)。随着给药剂量的增加,其血药浓度也增加,但低剂量组的血药浓度仍在有效浓度范围内。
4.不同剂量CBZ与VPM配伍后对患者血清药物浓度的相互影晌
卡马西平的血药浓度在添加小剂量丙戊酸镁后无明显变化,差异无统计学意义(P>0.05),丙戊酸镁的血药浓度在添加小剂量的卡马西平后无明显变化,差异无统计学意义(P>0.05)
结论1.不同剂量卡马西平和丙戊酸镁配伍在大鼠电刺激皮层惊厥阈值测定模型的抗惊厥作用无明显差异,其血药浓度随配伍剂量的升高而升高。
2.不同剂量的卡马西平和丙戊酸镁配伍对癫痫患者血清药物浓度的影响不大。
Objective 1.To observe the influence of the combination of carbamazepine(CBZ)and valproate magnesium (VPM) on the threshold for localized seizure in direct cortical stimulation (TLS) model rats and the serum drug concentration.
2.nalysis the inter-relationship of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) on the serum drug concentration of some clinical patients.
Methods
1.The seizure threshold of dynamic change trend and blood drug concentration of rats were observed. The convulsive threshold model was established by direct cortical stimulation and ugular vein catheterization model was found. When the model was stabilized,Forty stable model rats were randomly divided into four groups. N=10.The rats received intragastric administration of CBZ40mg/kg+VPA90mg/kg (high dose group), CBZ20mg/kg+VPA68mg/kg(medium dose group),CBZ10mg/kg+VPA45mg/kg(low dose group) or normal saline (control group), respectively. Three groups of drugs were milling-in and added partes aequales normal saline, collocated with concentrations of 10% of the aqueous solution. Then intragastric administration each one time sooner or later (8:00 Am and 20:00 Pm).after ten times of administration,The convulsive threshold was detected after thirty minutes before the last administration and administration behind thirty minutes, one hours, two hours, four hours, eight hours and twelve hours (seven time points). And taking blood after the last administration four hour. The serum drug concentration peak concentration) was detected after centrifugation with fluorescence polarization immunoassay(FPIA).
2.The serum drug concentration curve of CBZ and VPA in patients with refractory epilepsy was analyzed.
Selected 32 patients with refractory epilepsy were divided into two groups, first The patients take carbamazepine and valproate magnesium and detect the serum drug concentration with fluorescence polarization immunoassay(FPIA) after one week, Then adding valproate magnesium and carbamazepine respectively.and detecting ampho-concentration after one week,
Results 1.Compare with the effect of electrical stimulation cortex convulsion when the combination of arbamazepine (CBZ) and valproate magnesium (VPM) the convulsive threshold in treatment group which after administration at various time points was higher than those in control group, The difference was statistically significant (P<0.05),At 30 min before the last administration, the convulsive threshold in high dose group was higher than those in low dose and medium dose groups, The difference was statistically significant (P<0.05), but there was no significant difference among drug groups at each time point. The difference was no statistically significant(P>0.05)
2.Compare with the time-effect relationship of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) After administration for 30 min, all three different doses of drugs worked, and the threshold peaked after administration for 4 h. The anti-convulsion effect of high, medium and low dose drugs maintained 12 h, and the anti-convulsant effect gradually reached the peak, then decreased gradually, Little fluctuation was seen during the period. The convulsant threshold which to reach the same with the low dose group
3.Comparison of serum drug concentration of the combination of carbamazepine (CBZ) and valproate magnesium (VPM) in rats. The peak concentration in high dose group was higher than those in medium dose groups, The difference was statistically significant (P<0.05), The peak concentration in medium dose groups was higher than those in low dose groups, The difference was statistically significant (P<0.05), Plasma drug concentration curve of rats showed that the higher the dose was, the higher the peak concentration was. In low dose group,the blood concentration was still in the effective blood drug concentration range.
4.the influence of the combination of carbamazepine (CBZ) and valproate magnesium (VPM)on the patients' serum drug concentration. In epilepsy patients, the addition of CBZ or VPA did not influence the plasma concentration of original drugs. The difference was no statistically significant(P>0.05)
Conclusion
1.The effect of the combination of carbamazepine (CBZ) and valproate acid (VPA) has no significant difference on the threshold for localized seizure in direct cortical stimulation (TLS) model rats, and their serum drug concentration increase with the drug dose.
2.1n epilepsy patients, the combination of CBZ or VPA has no influence on the plasma concentration.
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[1]杨藻宸.药理学和药物治疗学(上册).北京：人民卫生出版社,2000.570.
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[3]FerendelliJA.Relating pharmacology to clinical practice:the pharma cologic basis of rational polypharmacy.Neurology,1995,45(Suppl2):12-16.
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[13]夏运岳,金鸿滨,赖世福.丙戊酸钠对卡马西平药动学的影响.江苏医药与临床研究,2002,10(2)：7-8.
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[1]杨藻宸.药理学和药物治疗学(上册).北京：人民卫生出版社,2000.570.
[2]Reynolds EH, Shorvon SD. Monotherapy of polytherapy for epilepsy? Epilepsia. 1981,22:1-10.
[3]FerendelliJA.Relating pharmacology to clinical practice:the pharma cologic basis of rational polypharmacy.Neurology,1995,45(Suppl2):12-16.
[4]Lammers NW, Hekster YA, Keyser A, etal. Monotherapy of polyther apfor epilepsy revisited:a quantitative assessment.Epilepsia,1995,36 (5):440-446.
[5]金有豫.药理学.第5版,北京：人民卫生出版社,2001：8—12.
[6]牛争平,刘玉玺洋金花对电刺激大鼠皮层惊厥阂值及海马神经元形态结构的影响.中国药物与临床2005 5(11)；846-849.
[7]牛晓军,马永刚等卡马西平对青霉素点燃惊厥大鼠脑内GABA-A受体mRNA表达的作用.中国药理学通报.2008.24(1)：128～32。
[8]陈国俊.丙戊酸抗癫痫机制.临床神经病学杂志.1993,6(2)：124-125.
[9]周孝达,乐卫东,陈俊宁.丙戊酸钠的药物动力学及血药浓度监测中国神经精神疾病杂志,1987,13(3)；137-140.
[10]王晓娥,冯义,康雁.抗癫痫药物血药浓度测定的临床意义 中国医院药学杂志,1992.12(9)：422-423.
[11]卢建丙戊酸钠在儿科患者中的应用.实用儿科临床杂志,1995,10(3)：173-174
[12]耿磊钰,刘玉玺.丙戊酸镁、丙戊酸镁缓释片与德巴金缓释片药效时效关系的比较研究.国际神经病学神经外科学杂志2006,33(5)：406-409.
[13]夏运岳,金鸿滨,赖世福.丙戊酸钠对卡马西平药动学的影响.江苏医药与临床研究,2002,10(2)：7-8.
[14]John SD,Philip N.Effects of discontinuation of phenytoin,carbamaz epine, and valproate on concomitant antiepileptic medication. Epilepsia,1991,32(1):101-105.
[15]沈锦相.临床不合理用药15例分析.云南精神医学杂志,1994,2：5.
[16]高伟吴立文宋雪利卡马西平联合丙戊酸钠治疗额叶癫痫的疗效研究 中国神经精神疾病杂志20099：539-542。
[17]Bourgeois BFD. Anticonvulsant potency and neurotoxicity of valproate alone and in combination with carbamazepine or phenobarbital. Clin Neur-opharmacol,1988, (11): 348-359.
[18]Meizhen Sun,Yuxi Liu,Mingzheng Wang, et al. Combination of carbamazepine and valproate in different dose proportions in maximal electroshock seizure model in mice. Epilepsy Res,2002,51:5-11.
[19]Krupp E,Loscher W. Anticonvulsant drug effects in the direct cortical ramp-stimulation model in rats:comparison with conventional seizure models. J Pharmacol Exp Ther,1998, 285:1137-1149.
[20]Cynthia LH,James Z,Elaine C,et al. Combination valproate carbamazepine theray in partial e pilepsies resistant to carbamazepine monotherapy. J Epilpsy,1993,6:9-1-94.
[21]Dean JC, Penry JK. Carbamazepine/ valproate therapy in 100 patients with partial seizures failing carbamazepine monotherapy:Long-term follow2up. Epilepsia,1988,29 (5):687.
[22]孙美珍,刘玉玺,王伟等卡马西平与丙戊酸镁以2：1比例配伍应用治疗难治性癫痫的疗效.山西医科大学学报.2005,36(6)728-729.
[23]Charles LP,Stanislaw J. Selection of antiepileptic drug polytherapy based on mechanisms of action:the evidence reviewed. Epilepsia,2004,41 (11):1364-1374.
[24]Pisani F, Caputo M, Fazio A, etal. Interaction of carbamazepine 10,11-epoxide. an active metabolite of carbamazepine, with vaproate, a pharmacokinetic study. Epilepsia, 1990.31:339.