丙戊酸单药治疗癫痫患者疗效的生物信息学分析

癫痫是最常见的慢性神经元性疾病之一,以神经元持续性的异常放电导致中枢神经系统功能失常为特征.任何年龄均会发病,全世界约7000万患者,其反复发作影响患者的身体健康,对患者及其家人的生活、心理及经济等方面造成负担[1].使用抗癫痫药物( antiepileptic drugs,AEDs)是控制癫痫发作最基础、最有效的治疗...     

精神分裂症患者血浆同型半胱氨酸水平的Meta分析

目的 探讨精神分裂症患者与健康者血浆同型半胱氨酸(homocysteine,Hcy)水平的差异,为预防精神分裂症提供依据.方法 计算机检索PubMed、EMbase、Cochrane Library、万方数据库、中国知网全文数据库、维普中文期刊数据库以及中国学位论文全文数据库中关于精神分裂症患者血浆Hcy水平的病例对照研究,应用分析软件RevMan 5.1 对Hcy 水平和高同型半胱氨酸血症(hyperhomocysteinemia,HHcy)检出率进行Meta 分析.结果 共有19篇文献纳入分析.Meta分析结果示,精神分裂症组与对照组之间Hcy水平的均数差(mean differ-ence,MD)为4.94μmol/L(95%CI:4.34~5.54),精神分裂症组Hcy水平高于对照组(P＜0.01);精神分裂症组与对照组HHcy 检出率的比值比OR 为6.48(95%CI:4.54~9.25),精神分裂症组HHcy 检出率高于对照组(P＜0.01).结论 精神分裂症患者的Hcy水平高于健康者.     

丙戊酸镁治疗癫痫

丙戊酸镁治疗癫痫张敬军，陈青，孙思琴丙戊酸镁是继丙戊酸钠、癫痫安之后合成的另一丙戊酸类药，国外７０年代开始用于临床，国内应用尚少，本文单用丙戊酸镁治疗各型癫痫８３例，并监测血浓度，现就临床疗效、血浓度测定、脑电图变化及其不良反应加以分析及讨论。１资料...     

丙戊酸钠对癫痫患者血同型半胱氨酸、叶酸、维生素B_(12)水平的影响

目的探讨丙戊酸钠(VPA)对血同型半胱氨酸(Hcy)、叶酸(Fol)、维生素B12(VitB12)浓度的影响。方法分别检测VPA单药治疗癫痫患者的血Hcy、Fol、VitB12浓度,并与未服用抗癫痫药的癫痫患者组及健康对照组比较。结果 VPA组患者血Hcy浓度明显高于癫痫对照组和正常对照组(P<0.01),Fol浓度低于癫痫对照组和正常对照组(P<0.05),VitB12浓度在VPA组有升高趋势。结论 VPA可引起癫痫患者血Hcy水平升高和Fol水平降低,长期服用VPA的癫痫患者应监测血Hcy、Fol、VitB12浓度,及时补充B族维生素、Fol有利于减少血栓事件的发生。     

丙戊酸单药治疗与癫患者血浆同型半胱氨酸水平间关系的Meta分析

目的分析癫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epilepsy、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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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,Stata 12.0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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(I2=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患者异质性风险(I2=47.400%,P=0.107)较整体(I2=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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。     

丙戊酸钠和卡马西平对癫痫患者血同型半胱氨酸、叶酸、维生素B12水平的影响

目的探讨丙戊酸钠(VPA)和卡马西平(CBZ)对癫痫患者血同型半胱氨酸(Hcy)、叶酸、维生素(Vit)B12水平的影响。方法检测VPA组、CBZ组、未服药组患者和正常对照组血Hcy、叶酸、VitB12浓度,并对结果进行比较。结果与未服药组及正常对照组比较,VPA组和CBZ组的血浆Hcy水平显著升高(均P<0.01),血清叶酸水平显著降低(均P<0.05);且VPA组血清VitB12水平有升高趋势,CBZ组血清VitB12水平有降低趋势,但差异均无统计学意义。结论 VPA和CBZ可引起癫痫患者的血浆Hcy水平升高和血清叶酸水平降低,对血清VitB12水平无显著影响。     

丙戊酸治疗癫痫持续状态

癫痫持续状态(Status Epilepticus SE)即"癫痫在短时间内频繁发作, 其中部分性发作未合并意识障碍者每次发作持续30 min以上; 全身性发作有意识障碍者在2次发作间期意识未恢复称为癫痫持续状态".     

丙戊酸钠单药治疗新诊断儿童全面性癫痫失败原因分析

目的 探讨丙戊酸钠单药治疗新诊断儿童全面性癫痫失败原因、影响因素。方法 前瞻性、开放性收集新诊断全面性癫痫病例,均接受丙戊酸钠单药治疗,随访到治疗2年以后。根据疗效分为对照组与疗效差2组,收集一般临床资料、脑电图等,采用Logistic回归分析治疗失败原因。结果 231例患儿完成本研究,2年时有62例因疗效差而改用其他药物,169例患儿疗效可,3例依从性差,1例因副作用改药。两组脑电图异常率(疗效差组90.32%vs.对照组61.54%),头颅MRI异常率(疗效差组45.16%vs.对照组23.08%),首次发病年龄{疗效差组0.50(0.42,2.50)岁vs.对照组0.75(1.50,5.16)}岁等比较有统计学意义(P0.05)。单因素分析发现智能是否正常、出生窒息史、头颅MRI异常、首次发作年龄等有统计学意义(P0.05)。进一步多因素回归分析发现首发年龄低(OR=2.124,P=0.004)、智能障碍(OR=10.535,P=0.000),头颅MRI异常(OR=1.603,P=0.020),出生时有窒息(OR=1.913,P=0.027)为丙戊酸钠治疗全面性癫痫疗效差的独立危险因素。结论 丙戊酸钠单药治疗全面性癫痫失败主要原因为疗效差,其次为依从性差、不良反应等。疗效差风险因素有首发年龄低、智能障碍、头颅MRI异常及出生时有窒息等。     

奥卡西平和丙戊酸钠对癫痫患者血浆同型半胱氨酸和不对称二甲基精氨酸水平的影响

目的探讨奥卡西平和丙戊酸钠对癫痫患者血浆同型半胱氨酸(Hcy)和不对称二甲基精氨酸(ADMA)水平的影响。方法选取2010—2014年我院收治的癫痫患者84例,随机分为2组,分别应用奥卡西平与丙戊酸钠单药治疗,测定患者血浆Hcy和ADMA水平并与健康人群比较。结果两种药物单药治疗的临床疗效无明显差异(P0.05),而血浆Hcy与ADMA水平明显高于健康对照组(P0.05);治疗时间与血浆Hcy与ADMA水平呈正相关(P0.05)。结论奥卡西平与丙戊酸钠均能有效治疗癫痫,缓解症状,但药物治疗会导致患者体内Hcy与ADMA水平升高,长期服用应当监测血清Hcy、ADMA指标,及时采取有效措施预防脑血管事件的发生。     

丙戊酸镁与碳酸锂治疗躁狂发作对照研究国内文献Meta分析

目的探讨丙戊酸镁治疗躁狂发作的疗效和不良反应。方法用Meta分析方法对14项丙戊酸镁与碳酸锂治疗躁狂发作对照研究文献再分析。结果丙戊酸镁治疗躁狂发作其治疗前后组内比较,加权平均效应d=17.50,95%CI为14.54～20.46,效应极强（Z=11.59,P〈0.01）。丙戊酸镁与碳酸锂治疗躁狂发作比较,加权平均效应d=0.50,95%CI为-0.57～1.58,差异无统计学意义（Z=0.92,P〉0.05）。结论丙戊酸镁与碳酸锂治疗躁狂发作的疗效及不良反应相当。     

丙戊酸治疗成人癫(癎)致血浆肉毒碱下降

目的观察丙戊酸(valproic acid,VPA)治疗成人癫患者后患者血浆游离肉毒碱改变规律,并探讨导致其改变的相关因素。方法VPA治疗组为41例成人癫患者,其中接受VPA单药治疗者33例,联合其他抗癫药物治疗者8例,30例非VPA治疗的成人癫患者作为癫对照组,包括其他抗癫药物治疗的患者14例,和未进行药物治疗的患者16例。33名同龄健康者作为正常对照,用酶循环法测定血浆游离肉毒碱浓度,3组间进行比较。结果VPA治疗组血浆游离肉毒碱浓度(31.43±11.75μmol/L)明显低于正常对照组(43.25±12.57μmol/L)和非VPA治疗的癫对照组(40.71±12.83μmol/L,P均<0.05)。血浆游离肉毒碱浓度与VPA剂量、VPA疗程、其他抗癫药物、年龄、性别、血ALT、AST无相关性。结论VPA治疗成人癫可能导致血浆游离肉毒碱水平下降,其下降程度和VPA无剂量和疗程依赖性,也不受患者的生理状态以及其他抗癫药物的影响。     

Effects of valproic acid on sleep in children with epilepsy

Purpose:   Parents frequently report increased sleep duration in their children during treatment with valproic acid (VPA). We assessed sleep duration and sleep behavior before and after tapering VPA in children treated for more than 6 months.
Methods:   Sleep variables were assessed by questionnaire, diary, and actigraphy (for 7 consecutive days and nights) before and 8–12 weeks after termination of VPA.
Results:   Forty-six children (age range 1.7–17.4 years) completed the study. The questionnaire data showed no significant difference in bed and wake time, duration of sleep, and time to fall asleep before and after ending VPA treatment, although some qualitative measures on daytime sleepiness improved after tapering VPA. The actigraphy data revealed that the average sleep amount without VPA was reduced in 33 children (9 of them >30 min) and longer in 13 children (1 of them >30 min). The mean Assumed Sleep Time per Day decreased by 15.2 min or 9.5 min when the physiologic decrease of sleep duration within 0.3 years was considered. Also mean Actual Sleep Time per Day was significantly reduced after VPA termination (−15.2min; after correction −10.7 min). The reduction was only significant in children older than age 6 years.
Discussion:   Termination of VPA after long-term treatment leads to a significant reduction of sleep duration in children older than 6 years of age. The change was small in the majority, but considerable in a subgroup of children.     

丙戊酸和托吡酯对癫(癎)患儿游离肉毒碱的影响

目的探讨丙戊酸(VPA)和托吡酯(TPM)对癫癎患儿游离肉毒碱的影响。方法35例癫癎患儿,年龄6～8岁,男20例,女15例,其中12例予VPA单药治疗,11例予TPM单药治疗,12例予VPA及TPM联合治疗6～8个月。15例健康儿童作为正常对照组。测定血浆游离肉毒碱的浓度。结果VPA组血浆游离肉毒碱的浓度明显低于对照组及TPM组,VPA-plus- TPM组与VPA组比较差异无显著性,TPM组与对照组比较差异无显著性。结论VPA可降低癫癎患儿血浆游离肉毒碱水平,而TPM对血浆游离肉毒碱无明显影响。     

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).

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.     

Evaluation of serum lipids and carotid artery intima media thickness in epileptic children treated with valproic acid

The aim of this study is to evaluate the carotid artery intima media thickness and serum lipids in pediatric patients with epilepsy treated with valproic acid. The study included 44 pediatric epileptic and 40 healthy children. Intima media thickness of left common carotid artery and fasting lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) were assessed. Although we did not observe any differences regarding serum lipid profiles, intima media thickness of common carotid artery was significantly higher in epileptic patients treated with valproic acid. We suggest that this increase in intima media thickness of common carotid artery may be due to epilepsy and/or valproic acid treatment.     

Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy

PURPOSE: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids. METHODS: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay. RESULTS: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means +/- SD: 425 +/- 184 vs. 350 +/- 145 micromol/L, respectively, for total VPA, p = 0.002, and 55 +/- 37 vs. 39 +/- 25 micromol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 +/- 5.2 to 9.7 +/- 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 +/- 81 to 115 +/- 121 ml/h/kg, p = 0.029). CONCLUSIONS: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.     

Diurnal variation of valproic acid plasma levels and day-night reversal in monkey.

Four normal monkeys each equipped with an EEG plug and two indwelling catheters for drug infusion and sampling, respectively, were administered valproic acid (VPA) before and after a 12-hr light, 12-hr dark phase shift. Before day-night reversal, diurnal oscillations of VPA plasma levels under steady-state intravenous constant-rate infusions were 30-50%, with maximum concentrations during the dark phase of the cycle. After reversal, maximum VPA plasma concentrations tended to follow the dark phase shift. The correlation was not perfect, nor was the sleep cycle completely reversed since the animals slept less after the phase shift. Possible mechanisms of the diurnal plasma level fluctuations and the importance of oscillations of this magnitude to clinical drug regimens are discussed.     

Concentration of metabolites of valproic acid in plasma of epileptic patients

With the help of synthetic reference substances, five metabolites of valproic acid (VPA) could be quantitated by gas chromatography in the plasma of 26 epileptic patients undergoing chronic therapy with sodium valproate. The products of beta-oxidation, i.e., 2-en-VPA, 3-hydroxy-VPA, and 3-keto-VPA were found to be the major metabolites of VPA in plasma, whereas the intermediates of omega-oxidation, 4-hydroxy-VPA and 5-hydroxy-VPA, were present only in markedly lower concentrations. It was thus confirmed that in addition to the excretion of VPA as the glucuronide, beta-oxidation is the preferred metabolic pathway of VPA in man. However, taking the anticonvulsant activity of the metabolites as derived from animal experiments into consideration, none of the metabolites found in human plasma seems to contribute markedly to the therapeutic effect of VPA. Thus, in most patients, VPA seems responsible for more than 90% of the antiepileptic activity during continued medication in man.     

Survival analysis for valproic acid use in adult glioblastoma multiforme: A meta-analysis of individual patient data and a systematic review

PurposeGlioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, and patients that undergo the maximum tumor resection that is safely possible and standard radiochemotherapy only achieve a median survival time of 14.6 months. Several clinical studies have reported that valproic acid could prolong survival of GBM patients. However, the results of these studies are inconsistent. We examined relevant studies and conducted a meta-analysis to assess the effects of VPA on survival times and recurrence.MethodsA bibliographic search was performed in the EMBASE, MEDLINE, ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials databases to identify potentially relevant articles or conference abstracts that investigated the effects of VPA on the outcome of glioma patients. Five observational studies were included.ResultsPooled estimates of the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Our meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44–0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59–0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52–0.84 vs. patients treated by administration of non-AEDs. No heterogeneity was observed in the subset analysis.ConclusionThe results of our study suggest that glioblastoma patients may experience prolonged survival due to VPA administration. Sub-analysis confirmed the benefit of VPA use compared to a non-AEDs group and an other-AEDs group. Further RCTs of this subject should be performed.