丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的Meta分析

目的分析癫痫患者血浆同型半胱氨酸水平变化与丙戊酸单药治疗间的关系。方法选择epileDsv、valproate、homocysteine和epilep。为检索词,计算机检索1990年1月-2013年8月美国国立医学图书馆、科学引文索引数据库、荷兰医学文摘等数据库,获得丙戊酸单药治疗与癫痫患者血浆同型半胱氨酸水平间关系的相关英文文献,均为丙戊酸单药治疗的癫痫患者与正常对照受试者血浆同型半胱氨酸水平比较的病例．对照临床研究。通过Newcastle—Ottawa量表独立进行文献质量评价和数据提取,Stata12．0统计软件行Meta分析。结果共纳入符合条件的英文文献8篇,包括266例行丙戊酸单药治疗的癫痼患者和489例正常对照受试者,所有纳入文献质量评分均〉6分。Meta分析显示,丙戊酸单药治疗组患者血浆同型半胱氨酸水平显著高于正常对照组[标准化均数差（SMD）：0．620,95％CI：0．320-0．920;P=0．000];经异质性检验存在显著异质性（I^2=65．600％,P=0．005）,根据不同地区和受试者年龄差异行进一步亚组分析,结果显示西亚组癫痫患者异质性风险（I^2=47．400％,P=0．107）较整体（I^2=65．600％,P=0．005）降低。采用敏感性分析评价Meta分析之稳定性,当任何一项研究被剔除后,相应的SMD值均不发生变化,表明分析结果稳定性良好。结论丙戊酸单药治疗可显著增加癫痫患者血浆同型半胱氨酸水平,后者是否受种族因素的影响尚待进一步研究。     

Early effect of sodium valproate and carbamazepine monotherapy on homocysteine metabolism in children with epilepsy

Plasma total homocysteine (p-tHcy), serum folate (s-F), serum vitamin B-12 (s-B12) and plasma pyridoxal-5'-phosphate (p-PLP) were measured in epileptic children before and after a 20-week period of sodium valproate (group A, n=32) and carbamazepine (group B, n=20) monotherapy. P-tHcy significantly increased in both groups, s-F and s-B12 significantly increased in group A, while s-F and p-PLP significantly decreased in group B. Our study showed an early effect of antiepileptic drug treatment on homocysteine metabolism.     

A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy

PURPOSE: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state. METHODS: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS). RESULTS: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug. CONCLUSIONS: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.     

Correlations between UGT2B712 gene polymorphisms and plasma concentrations of carbamazepine and valproic acid in epilepsy patients

Purpose

The study aims to detect the polymorphisms in uridine diphosphate glucuronyl transferase (UGT) 2B712 and investigate the corresponding effects on the blood concentrations of valproic acid (VPA) and carbamazepine (CBZ).

Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital

Serum lipids, lipoproteins and apolipoproteins A and B were measured in 101 epileptic patients receiving chronic treatment with valproic acid, carbamazepine or phenobarbital and in 75 age- and sex-matched control subjects. In relation to controls, subjects treated with valproic acid showed significantly lower values of total and LDL-cholesterol levels; subjects treated with carbamazepine showed significantly higher values of HDL-cholesterol and apolipoprotein A concentrations and subjects treated with phenobarbital showed significantly higher values of total cholesterol, HDL-cholesterol, apolipoprotein A and apolipoprotein B levels. The total cholesterol/HDL-cholesterol ratio was significantly lower in patients receiving valproic acid or carbamazepine but not in the phenobarbital-treated group. Changes in serum lipids profile did not correlate with drug plasma concentrations nor the duration of the treatment.     

Effects of valproate and carbamazepine on serum levels of homocysteine,vitamin B12, and folic acid

Homocysteine (HMC) is a sulfur containing amino acid, which plays a role in methionine metabolism. Folic acid (FA) and vitamin B12 (B12) are essential for remethylization of HMC to methionine. HMC level increases in the deficiency of these vitamins. Hyperhomocysteinemia causes vascular endothelial damage, which causes atherosclerosis. The aim of this study is to investigate the effect of valproate (VA) and carbamazepine (CBZ) on the serum levels of HMC, B12, and FA.Thirty-six children receiving CBZ and 30 children receiving VA for epilepsy for the last 1-year period and 29 healthy children as control were the population of this study. After 6 h of fasting serum HMC, B12, and FA levels were measured and results were compared statistically.Mean values of HMC, FA, and B12 levels in control group were 9.2+/-2.7 micromol/l, 9.0+/-2.0 ng/ml, and 342+/-162 pg/ml, in VA group 14.0+/-6.8 micromol/l, 7.3+/-2.9 ng/ml, and 368+/-159 pg/ml, in CBZ group 16.0+/-13.1 micromol/l, 7.5+/-3.3 ng/ml, and 285+/-158 pg/ml, respectively. Serum HMC levels were higher in VA and CBZ groups than control group (P<0.01 and P<0.05, respectively). Serum FA levels were lower in VA and CBZ groups compared to control group (P<0.05). Serum levels of B12 were not different between VA and control groups (P>0.05). In CBZ group serum B12 levels were lower than control group (P<0.05).FA may be added to the treatment protocol (if the patients take only CBZ, then B12 should also be added) for patients taking these antiepileptic drugs to decrease the degenerative effect of VA and CBZ on vascular endothelium.     

Free level monitoring of carbamazepine and valproic acid: clinical significance

The recently available ultrafiltration technique facilitates determination of the free drug serum concentration of several antiepileptic drugs. For this reason a reappraisal of the clinical significance of free level monitoring was thought necessary. In this study on 203 patients receiving carbamazepine monotherapy and 101 patients receiving valproic acid monotherapy, the total and free drug levels were correlated with therapeutic outcome and side effects. Our investigations indicated no closer correlation between free concentration and seizure reduction or side effects than between total concentration and effectiveness or side effects. However, we found a close correlation between total and free concentrations.     

Effect of valproic acid therapy on zinc metabolism in children with primary epilepsy

The effect of long-term treatment with valproic acid (VPA) on zinc (Zn) metabolism was studied in 15 children with absence seizures. During treatment with VPA the erythrocyte Zn content was significantly lower than that found in controls matched for sex and age. Plasma and urine values of Zn and of copper were within normal limits. It is suggested that the anticonvulsive action of VPA may be mediated through its effect on the metabolism of Zn in the brain and the concomitant changes in the activity of the enzymes glutamic acid decarboxylase and carbonic anhydrase.     

Effect of valproic acid on perampanel pharmacokinetics in patients with epilepsy

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight‐adjusted dose ratio (C/D; [μg/mL]/mg kg^?1 d^?1) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12‐66 years), 114 plasma samples were collected. Twenty‐eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (?56%, P < .001) in group A (1.79 ± 0.80) versus group B (4.05 ± 2.16) and increased (P < .001) in group C (6.72 ± 4.04) compared with groups A (+275%), B (+66%), and D (2.76 ± 2.00, +143%). Our study documents the unpublished higher PMP C/D in patients cotreated with VPA. These findings have both theoretical relevance, suggesting better characterization of PMP metabolic pathways with ad hoc studies, and clinical usefulness in managing patients on AED polytherapy.     

Serum concentrations of immunoglobulins in patients with epilepsy treated with carbamazepine

The concentrations of IgA, IgG and IgM were determined in sera of 16 patients, all of whom had partial epilepsy and had received CBZ as the only drug since the beginning of therapy. Fifty-three healthy subjects served as controls. Serum concentrations of IgA and IgG were significantly higher in patients than in controls (IgA: P = 0.05; IgG: P = 0.01). The concentration of IgM was not significantly different from that of the controls (P = 0.1). The IgG serum levels in the controls were lower with increasing age. Furthermore, IgG serum levels were higher with increasing CBZ concentrations.     

The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy

The aim of the present study was to assess the effect of long-term carbamazepine (CBZ), valproic acid (VPA) and phenobarbital (PB) treatment on serum lipids and apolipoproteins in epileptic children. Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TGs) were measured and the LDL-C/HDL-C and TC/HDL-C ratios were calculated in 320 children and adolescents (129 receiving CBZ, 127 receiving VPA and 64 receiving PB) suffering from various types of epilepsy. Additionally, in a subgroup of 181 children (68 CBZ; 78 VPA; 35 PB) apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), HDL2-C and HDL3-C were measured and apoA-I/apoB and HDL2-C/HDL3-C ratios were calculated. Results of the measurements were compared with those of 169 age-and sex-matched healthy controls. None of the variables considered was significantly correlated with time elapsed since start of treatment or with drug concentration in serum. TC and LDL-C serum levels were high in children receiving CBZ or PB and low in those treated with VPA. Serum LDL-C level exceeded 130 mg/dl in 27.9% of CBZ-group, 31.8% of the subjects receiving PB, but only in 7% of those receiving VPA and in 11.8% of control group subjects. CBZ-treated children also showed high HDL-C and HDL3-C values. In the group receiving VPA, HDL2-C, HDL2-C/HDL3-C ratio and apo B were significantly lower than in the control group. Mean apoA-I levels were low in all treated groups: by contrast, in neither group did TGs, VLDL-C levels and TC/HDL-C or LDL-C/HDL-C ratios differ significantly from the corresponding control group. Our results suggest that the effects of long-term AED therapy on lipid profile and, particularly, on apolipoprotein serum levels increase risk of atherosclerosis-related disease. Moreover, these results confirm our previously reported increased risk in CBZ and PB-treated patients.     

The metabolic syndrome in overweight epileptic patients treated with valproic acid

Purpose: To evaluate the presence of metabolic syndrome (MS) in children and adolescents treated with valproate (VPA). Methods: One hundred fourteen patients (54 male and 60 female) were studied. These patients were followed from the beginning of therapy for at least 24 months; at the end of follow‐up, 46 patients (40.4%) had a considerable increase in body weight, whereas the other patients (59.6%) remained with the same weight. The MS was defined as having at least three of the following: abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. Results: Forty‐six patients developed obesity; 20 (43.5%) of 46 patients developed MS. Abnormal glucose homeostasis was identified in 45% of patients. High total serum cholesterol concentrations were noted in 10 (50%), high serum triglyceride concentrations in 7 (35%), and low high‐density lipoprotein (HDL) in 15 (75%) of the 20 subjects with MS. However, there were no significant differences in the features of MS between boys and girls with MS. Conclusions: Patients who gain weight during VPA therapy can develop MS with a possible risk of cardiovascular disease.     

丙戊酸镁联合苯妥英钠治疗外伤性癫疗效分析

目的 探讨采用丙戊酸镁联合苯妥英钠治疗外伤性癫的临床疗效.方法选取自2007-02-2011-02我院住院和门诊外伤性癫患者150例,按照治疗方式分为丙戊酸镁治疗组(A组)50例,苯妥英钠治疗组(B组)50例和联合两药治疗组(C组)50例.观察统计3组患者的治疗效果并对获得数据进行统计学分析.结果 (1)在控制癫发作频率和发作持续时间的效果方面,3组患者治疗后均优于治疗前,差异具有统计学意义(P＜0.05);A组和B组差异无统计学意义(P＞0.05);C明显优于A组和B组,差异具有统计学意义(P＜0.05).(2)在治疗的总体有效率方面,C组明显优于A组和B组,差异具有统计学意义(P＜0.05);A组和B组差异无统计学意义(P＞0.05).(3)在药物不良反应发生率方面3组之间比较差异无统计学意义(P＞0.05).结论丙戊酸镁联合苯妥英钠治疗外伤性癫具有显著临床疗效,不增加药物的不良反应.     

丙戊酸联合拉莫三嗪治疗不同类型癫痫患者的疗效及对细胞因子的影响

目的探讨丙戊酸联合拉莫三嗪治疗不同类型癫痫患者的疗效及对细胞因子的影响。方法选择2018年10月至2019年10月孟州市人民医院收治的78例癫痫患者作为研究对象,根据癫痫类型将患者分为部分性发作组(PS组)33例、全面性发作组(GS组)26例、继发全面性发作组(SGS组)19例,利用丙戊酸联合拉莫三嗪对入组的癫痫患者进行治疗,比较3组患者治疗的有效率及细胞因子水平。结果治疗后PS组、GS组、SGS组的治疗有效率分别为79%(26/33)、88%(23/26)和79%(15/19),3组比较及组间比较差异均未见统计学意义(P>0.05)。3组在治疗后血清白介素-2(IL-2)、白介素-6(IL-6)、肿瘤坏死因子(TNF-α)水平均显著低于治疗前(P<0.05);治疗后3个组血清IL-6、TNF-α和IL-2水平比较差异均未见统计学意义(P>0.05)。PS组、GS组、SGS组不良反应发生率分别为6%(2/33)、8%(2/26)和5%(1/19),差异均未见统计学意义(P>0.05)。结论丙戊酸联合拉莫三嗪在不同类型的癫痫患者治疗中均取得满意成效,血清炎症因子均得到显著改善。     

Lack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy

PURPOSE: To determine whether levetiracetam (LEV) affects plasma concentrations of carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy. METHODS: The potential for interaction of LEV with other antiepileptic drugs (AEDs) was assessed using plasma drug levels obtained in a randomized placebo-controlled phase III trial of adjunctive LEV in children receiving one or two concomitant AEDs. Multiple plasma AED levels at baseline and during adjunctive treatment with LEV or placebo were compared by repeated measures analysis of covariance and mean concentration ratios (treatment/baseline) were estimated with their 90% confidence intervals (CI). RESULTS: The study population included 187 children receiving any concomitant AED alone or in combination. The geometric mean concentrations at baseline and during LEV treatment were carbamazepine 8.4 microg/ml versus 8.1 microg/ml (coefficient of variation, CV = 30%; n = 35); valproic acid 83.8 versus 82.5 microg/ml (CV = 38%; n = 23); topiramate 7.3 versus 7.2 microg/ml (CV = 82%; n = 28); lamotrigine 8.2 versus 7.7 microg/ml (CV = 62%; n = 22). For each AED, the mean concentration ratios (LEV/baseline) and their 90% CIs showed that AED concentrations were unaffected by concomitant LEV administration. No differences were observed between LEV and placebo. CONCLUSIONS: LEV does not affect plasma concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine in children with epilepsy.     

Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial

Animal studies and a preliminary clinical observation suggest that nutritional supplementation with long chain omega-3 fatty acids (omega-3 FAs) may be useful in the nonpharmacological treatment of patients with epilepsy. Omega-3 FAs increase seizure thresholds, and lower inflammatory mediators, which are increased in patients with epilepsy. In this first randomized, placebo-controlled parallel group trial of omega-3 FA supplementation with 1 g eicosapentaenoic acid (EPA) and 0.7 g docosahexaenoic acid (DHA) daily, 57 patients completed a 12-week double-blind phase. Seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained. The supplementation produced a significant increase in EPA and DHA concentrations and a reciprocal fall in arachidonic and linoleic acid concentrations. No change in serum AED concentrations was detected. Further studies are required to examine different omega-3 FA preparations, different doses, longer treatment duration, and larger sample sizes.     

The bone mineral content alterations in pediatric patients medicated with levetiracetam,valproic acid,and carbamazepine

AimThe negative effect of antiepileptic drugs on bone health has been previously documented. However, which antiepileptic drug is safer in regard to bone health is still questionable. Our aims were to investigate the bone mineral density alterations in pediatric patients who receive antiepileptic medication for a minimum of two years and to compare the results of these drugs.Materials and methodsFifty-nine patients (32 males, 27 females; mean age: 8.6 ± 4.6 years) and a control group (13 males, 7 females; mean age: 7.6 ± 3.3 years) were included in the study. The patients were receiving necessarily the same antiepileptic drugs (AEDs) for at least two years, and none of the patients had mental retardation or cerebral palsy. The patients were divided into three groups: group 1 (patients receiving levetiracetam (LEV), n = 20), group 2 (patients receiving carbamazepine (CBZ), n = 11), and group 3 (patients receiving valproic acid (VPA), n = 28). Plasma calcium (Ca), phosphorus (P), parathyroid hormone (PTH), alkaline phosphatase (ALP), vitamin D levels, and bone mineral density (BMD) values of femur and vertebras (L1-4) and z-scores (comparative results of BMD values of the patients with the age- and gender-matched controls in device database) of the groups were compared.ResultsThe differences between P, PTH, ALP and age, Ca and BMD results, and vitamin D levels of the patients in all four groups was not statistically significant according to Kruskal–Wallis test (p > 0.05). The z-score levels of all the patient and control groups were also not statistically significantly different compared with each other.ConclusionIn contrast to previous reports in pediatric patients, our study has documented that there is not a considerable bone loss in patients receiving long-term AED medication. Although levetiracetam has been proposed as bone-protecting medication, we did not observe any difference between AEDs regarding bone mineral density after two years of treatment.