BACKGROUND & AIMS: :Objective: Status epilepticus (SE) is a common neurologic emergency. The present study constitutes a meta-analysis of published randomized control trials (RCTs) evaluating the use of intravenous sodium valproate (VPA) in SE.Methods: MEDLINE and Cochrane databases were comprehensively searched, while retrieved RCTs and meta-analyses were manually screened. Prespecified outcome measures included seizure-cessation, 24 h-efficacy, constitute (liver enzyme increase, arrhythmias, bone-marrow suppression, hypotension and respiratory depression) and severe (life-threatening) adverse events (AEs). Evidence synthesis was performed when appropriate, using Random-Effects (RE) or Fixed-Effects (FE) model based on heterogeneity between trials (homogeneity assumed when PQ > 0.1 and I2 < 50%). Outcomes were assessed using Odds-Ratios (ORs) and 95%Confidence-Intervals (95% CIs). Every available comparison was investigated in terms of efficacy and tolerability.Results:Thirteen studies were retrieved and five comparisons were available, four of which involved two or more studies. Results were compatible with no significant difference between VPA and Phenytoin both in terms of efficacy and tolerability [seizure-cessation: FE-OR = 1.99, 95% CI = (0.83-4.75), 24 h-efficacy: FE-OR = 1.32, 95% CI = (0.60-2.89), composite AEs: FE-OR = 0.45, 95% CI = (0.17-1.21)]. Phenobarbital proved more commonly associated with composite AEs than VPA [seizure-cessation: RE-OR = 0.68, 95% CI = (0.05-9.44), 24 h-efficacy: RE-OR = 0.88, 95% CI = (0.02-33.9), composite AEs: FE-OR = 0.26, 95% CI = (0.09-0.82), severe AEs: FE-OR = 0.30, 95% CI = (0.04-2.28)]. Diazepam was determined inferior to VPA concerning safety issues [seizure-termination: FE-OR = 0.77, 95% CI = (0.34-1.79), severe respiratory depression: FE-OR = 0.06, 95% CI = (0.01-0.48), severe hypotension: FE-OR = 0.09, 95% CI = (0.01-0.72)]. The combination of Lorazepam (LZP) with VPA and the combination of LZP with Levetiracetam presented no difference in efficacy [24h-efficacy: FE-OR = 0.68, 95% CI = (0.37-1.24)].Conclusions: Although, additional high-quality RCTs are warranted, according to our results, VPA can be considered a safe and effective option in the management of SE.

背景与目标： 目的: 癫痫持续状态 (SE) 是常见的神经系统急症。本研究构成了对已发表的评价静脉内丙戊酸钠 (VPA) 在SE中使用的随机对照试验 (rct) 的荟萃分析。方法: 对MEDLINE和Cochrane数据库进行全面搜索，同时对检索的rct和meta分析进行人工筛选。预设的结局指标包括癫痫发作停止，24小时疗效，构成 (肝酶增加，心律失常，骨髓抑制，低血压和呼吸抑制) 和严重 (危及生命) 不良事件 (ae)。适当时，使用基于试验之间异质性的随机效应 (RE) 或固定效应 (FE) 模型进行证据合成 (当PQ> 0.1且I2 <50% 时假定同质性)。使用比值比 (ORs) 和95% 置信区间 (95% CIs) 评估结果。每个可用的比较都在疗效和耐受性方面进行了调查。结果: 检索了13项研究，并进行了5项比较，其中4项涉及两项或更多项研究。结果与VPA和苯妥英在疗效和耐受性方面无显着差异 [癫痫停止: FE-OR = 1.99，95% CI = (0.83-4.75)，24 h-疗效: FE-OR = 1.32，95% CI = (0.60-2.89)，复合AEs: FE-OR = 0.45，95% CI = (0.17-1.21)]。苯巴比妥被证明与复合AEs比VPA更常见 [癫痫停止: RE-OR = 0.68，95% CI = (0.05-9.44)，24小时疗效: RE-OR = 0.88，95% CI = (0.02-33.9)，复合AEs: FE-OR = 0.26，95% CI = (0.09-0.82)，严重AEs: FE-OR = 0.30，95% CI = (0.04-2.28)]。关于安全性问题 [癫痫终止: FE-OR = 0.77，95% CI = (0.34-1.79)，严重呼吸抑制: FE-OR = 0.06，95% CI = (0.01-0.48)，严重低血压: FE-OR = 0.09，95% CI = (0.01-0.72)]。劳拉西泮 (LZP) 与VPA的组合和LZP与左乙拉西坦的组合在疗效上没有差异 [24h-功效: FE-OR = 0.68，95% CI = (0.37-1.24)]。结论: 尽管根据我们的结果，需要额外的高质量rct，在SE的管理中，VPA可以被认为是安全有效的选择。

BACKGROUND & AIMS: BACKGROUND:Differences in response to treatment have been observed for bipolar disorder (BPD) patients with manic or mixed episodes. This post-hoc analysis examined the maintenance effect of aripiprazole in combination with lithium or valproate in subpopulations of patients entering a relapse prevention study with either manic or mixed bipolar episodes. METHODS:A long-term relapse prevention study of BPD patients with manic or mixed episodes included a single-blind stabilization phase, in which patients were stabilized with single-blind aripiprazole plus lithium or valproate (maintaining stability for 12 weeks), and a double-blind relapse assessment phase, where patients were randomized to aripiprazole or placebo plus lithium or valproate for up to 52 weeks. Lithium and valproate groups were pooled. RESULTS:The time to relapse of any mood episode was longer in the adjunctive aripiprazole group versus the lithium/valproate monotherapy group for the manic (p<0.01) but not mixed population (p=0.59). The LOCF analysis indicated a significantly greater reduction in YMRS total score from baseline with continued aripiprazole versus placebo at 52 weeks in both manic (treatment difference=-3.32, p<0.01) and mixed episode populations (treatment difference=-2.56, p=0.02). Overall, adverse event profiles were similar between the populations. LIMITATION:The lithium and valproate subgroups were combined. CONCLUSIONS:The continuation of aripiprazole in stabilized BPD patients treated with lithium or valproate increased the time to relapse of any mood episode for manic but not mixed patients; both groups achieved greater stability in YMRS total score with adjunctive aripiprazole. Thus, adjunctive aripiprazole may be more appropriate for stabilized patients with manic episodes.

背景与目标：

BACKGROUND & AIMS: :Both lithium and valproate are well-established treatments for bipolar disorder. Studies have also found that lithium is effective at reducing suicidal behaviors in patients with mood disorders. Impulsivity is a validated endophenotype of both bipolar disorder and suicidal behavior. We assessed effects of treatment with lithium or valproate on cognitive impulsivity in selectively bred mice previously shown to manifest relatively high levels of cognitive impulsivity. Mice were trained in the delay-discounting paradigm, a measure of cognitive impulsivity reflecting a behavioral bias towards immediacy, and then treated with lithium, valproate, or control chow. After 3 weeks of drug treatment, mice were tested at various delays to a large, delayed reward. Drug treatment continued during this time. Lithium reduced impulsivity, whereas valproate had no effect on choice behavior. Both drugs increased the number of choice trials and reinforcer intake, but effects on choice behavior did not depend on these motivational changes. To our knowledge, this is the first study demonstrating lithium's effects to reduce cognitive impulsivity. Future studies may focus on the ability of putative pharmacotherapies for patients at risk for bipolar disorder or suicide to modify the impulsive choice dimension of this diseases.

背景与目标： : 锂和丙戊酸盐都是公认的双相情感障碍治疗方法。研究还发现，锂能有效减少情绪障碍患者的自杀行为。冲动是双相情感障碍和自杀行为的有效内表型。我们评估了锂或丙戊酸盐治疗对先前显示出相对较高水平的认知冲动的选择性繁殖小鼠的认知冲动的影响。在延迟折扣范式中对小鼠进行训练，该范式是一种认知冲动的度量，反映了对即时性的行为偏见，然后用锂，丙戊酸盐或对照食物进行治疗。经过3周的药物治疗后，对小鼠进行了各种延迟测试，以获得较大的延迟奖励。在此期间继续进行药物治疗。锂降低了冲动性，而丙戊酸盐对选择行为没有影响。两种药物都增加了选择试验的数量和增强剂的摄入量，但是对选择行为的影响并不取决于这些动机的变化。据我们所知，这是第一项证明锂降低认知冲动作用的研究。未来的研究可能集中在对有双相情感障碍或自杀风险的患者进行推定的药物疗法的能力，以改变这种疾病的冲动选择维度。

BACKGROUND & AIMS: :A single oral dose of 500 mg sodium valproate had no effect on prolactin, growth hormone and cortisol secretion in 10 migraine patients when compared with five healthy controls and four migraine patients receiving placebo. Basal values of prolactin (PRL), cortisol and growth hormone (GH) were within the normal range, though PRL basal levels were lower in three patients (21.5%) in the migraine group.

背景与目标： : 与五名健康对照者和四名接受安慰剂的偏头痛患者相比，单次口服500 mg丙戊酸钠对10名偏头痛患者的催乳素，生长激素和皮质醇分泌没有影响。催乳素 (PRL)，皮质醇和生长激素 (GH) 的基础值在正常范围内，尽管偏头痛组的三名患者 (21.5%) 的PRL基础水平较低。

BACKGROUND & AIMS: PURPOSE:Sodium valproate (VPA) is a broad-spectrum anti-epileptic drug usually well tolerated. We conducted a pilot study to assess the feasibility, efficacy and side-effects of VPA in the treatment of convulsive epilepsy in primary care settings in rural China as an alternative to phenobarbital. METHODS:People with convulsive epilepsy were identified at primary health care level and provided with VPA monotherapy. Local trained physicians identified participants, managed treatment, and carried out the follow-up, whilst diagnoses were confirmed by a neurologist. Participants were followed for 12 months. Efficacy was assessed from the percentage reduction in seizure frequency and by retention of treatment. Tolerability was assessed by reports of treatment-emergent effects. RESULTS:Of 532 people enrolled, 512 completed the assessment. Most (431 people, 84%) had a decrease in seizure frequency of at least 50% and 218 became seizure-free. Treatment retention was 96% at one year. VPA was well tolerated and only 47 people reported adverse events which were mostly mild. Only two people discontinued VPA due to side-effects. CONCLUSION:In this 12-month assessment, VPA had favourable efficacy, few side effects and overall good acceptability. It was also relatively cheap. VPA is, therefore, a suitable alternative to phenobarbital as treatment of convulsive epilepsy in rural areas of China.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS:In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS:Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION:Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING:National Institute of Neurological Disorders and Stroke, National Institutes of Health.

背景与目标：

BACKGROUND & AIMS: :Valproate is principally effective in manic aspects of bipolar disorder. Tolerability has been somewhat more favorable for valproate than comparators, with the frequent adverse effects being gastrointestinal disturbances and weight gain. Total cholesterol and low-density lipoproteins are reduced by valproate. Valproate is effective and well tolerated when combined with lithium or antipsychotic drugs. Valproate is efficacious in mixed and euphoric mania. In studies of maintenance versus placebo and active comparators, patients initially treated with divalproex for mania had more robust long-term benefits than in the full sample analyses. In maintenance treatment, patients whose valproate serum levels were between 75 and 99 microg/ml had longer time to discontinuation for any reason or a new mood episode than did patients receiving placebo. The profile of utility in bipolar disorders is principally for core features of manic symptomatology (e.g., impulsivity, hyperactivity and irritability), with little evidence of benefit for anxiety or psychosis. Valproate appears useful in other disorders that have behavioral dimensions inclusive of the domains that valproate benefits in bipolar disorders, such as schizophrenia.

背景与目标： : 丙戊酸盐主要在躁郁症的躁狂方面有效。丙戊酸的耐受性比对照者更有利，常见的不利影响是胃肠道紊乱和体重增加。总胆固醇和低密度脂蛋白被丙戊酸盐降低。丙戊酸与锂或抗精神病药物合用有效且耐受性良好。丙戊酸盐在混合和喜快躁狂症中有效。在维持与安慰剂和活性比较者的研究中，与全样本分析相比，最初接受双丙戊酸钠治疗躁狂症的患者具有更强大的长期益处。在维持治疗中，丙戊酸盐血清水平在75至99 microg/ml之间的患者由于任何原因或新的情绪发作而停药的时间比接受安慰剂的患者更长。双相情感障碍的实用性主要是针对躁狂症状的核心特征 (例如，冲动，多动和易怒)，几乎没有证据表明对焦虑或精神病有益。丙戊酸盐似乎在其他具有行为维度的疾病中有用，包括在双相情感障碍 (例如精神分裂症) 中丙戊酸盐有益的领域。

BACKGROUND & AIMS: BACKGROUND:This is an updated version of the Cochrane Review previously published in 2019. Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS. OBJECTIVES:To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other. SEARCH METHODS:For the latest update we searched the Cochrane Register of Studies (CRS Web, 22 September 2020) and MEDLINE (Ovid, 1946 to September 21, 2020). CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA:Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo. DATA COLLECTION AND ANALYSIS:Outcome measures were: 1. proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; 2. individuals with a 50% or greater reduction in seizure frequency; 3. normalisation of EEG and/or negative hyperventilation test; and 4. adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence for the outcomes derived from all included studies. MAIN RESULTS:On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials (RCTs) to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, seizure freedom was higher in patients taking ethosuximide (70/154, 45%) than in patients taking lamotrigine (31/146, 21%; P < 0.001), with no difference between valproate (64/146, 44%) and ethosuximide (70/154, 45%; P > 0.05). In this study, the frequency of treatment failures due to intolerable adverse events was significantly different among the treatment groups, with the largest proportion of adverse events in the valproic acid group (48/146, 33%) compared to the ethosuximide (38/154, 25%) and the lamotrigine (29/146, 20%) groups (P < 0.037). Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. This study provided high certainty of the evidence for outcomes for which data were available. However, the certainty of the evidence provided by the other included studies was low, primarily due to risk of bias and imprecise results because of the small sample sizes. Hence, conclusions regarding the efficacy of ethosuximide, valproic acid and lamotrigine derive mostly from this single study. AUTHORS' CONCLUSIONS:Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.

背景与目标：

BACKGROUND & AIMS: :Forty-six children with refractory epilepsy (12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 20 with undetermined epilepsy) were treated by high-dose (serum level above 100 micrograms/ml) valproate (VPA) therapy. Monotherapy was used with 34 patients and two drugs with 12. Serum VPA concentrations ranged from 105.1 to 198.4 micrograms/ml. Assessment of initial response to treatment, after the serum level had reached the appropriate level, showed seizures to be completely controlled in 15 (32.6%) of 46 patients and improved in 12 (26.1%) (50% or more). Follow-up of more than 6 months after the time of initial response showed control of seizures in 14 (30.4%) and improvement in 11 (23.9%). The initial effect on EEG was the disappearance of epileptic discharges in 3 (6.5%) of 46 patients and marked improvement in 15 (32.6%). Follow-up revealed the disappearance of epileptic discharges in 7 (15.2%) and marked improvement in 9 patients (19.6%). High-dose VPA therapy was especially effective for West syndrome and for epilepsy with continuous spike-waves during slow-wave sleep. Control of atypical absences and myoclonic seizures was relatively good. Hypofibrinogenemia and thrombocytopenia were sometimes encountered but these side effects were reversible with reduction of dosage.

背景与目标： : 46例难治性癫痫患儿 (12例症状性全身性癫痫，14例症状性部分性癫痫，20例未确定癫痫) 接受大剂量 (血清水平高于100微克/毫升) 丙戊酸钠 (VPA) 治疗。单药治疗34例，两种药物12例。血清VPA浓度范围为105.1至198.4微克/毫升。在血清水平达到适当水平后，对治疗的初始反应的评估显示，46例患者中有15例 (32.6% 例) 的癫痫发作得到完全控制，而12例 (26.1% 例) (50% 例或以上) 的癫痫发作得到改善。初始反应时间后超过6个月的随访显示14例 (30.4%) 癫痫发作得到控制，11例 (23.9%) 改善。对EEG的最初影响是46例患者中有3例 (6.5% 例) 癫痫放电消失，而15例 (32.6% 例) 明显改善。随访显示7例 (15.2% 例) 癫痫放电消失，9例 (19.6% 例) 明显改善。大剂量VPA治疗对West综合征和慢波睡眠期间持续尖峰波的癫痫特别有效。非典型缺勤和肌阵挛发作的控制相对较好。有时会遇到低纤维蛋白原血症和血小板减少症，但随着剂量的减少，这些副作用是可逆的。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: Previous work in this laboratory has suggested that the nonlinear disposition of valproic acid (VPA) in the rat may be due to nonlinear distribution of VPA into the liver. The present study was undertaken to elucidate further the hepatobiliary disposition of VPA. VPA (0.1-2 mmol/L) was incubated with isolated rat hepatocytes in vitro. Uptake of [(3)H]-VPA was linear from 10 to 50 seconds, with minimal (<7 percent) biotransformation. The initial velocity of VPA uptake varied in proportion with the extracellular concentration and was temperature independent, suggesting that VPA traverses the hepatocyte membrane predominantly by passive diffusion. In separate studies, the hepatobiliary disposition of VPA (20mg) was examined in the isolated perfused rat liver (IPL). A pharmacokinetic model was developed to describe the influence of phenobarbital on the hepatobiliary disposition of VPA and valproate glucuronide (V-G) in the IPL; all processes governing VPA and V-G disposition appeared to be linear. Acute administration of phenobarbital to the liver (1.12 mg) decreased the rate constant for canalicular egress of V-G (0.0489 +/- 0.0266 vs. 0.164 +/- 0.075 min(-1)). In vivo pretreatment with phenobarbital (75 mg/kg/d x 5 d) before liver isolation decreased the biliary excretion of both VPA (1.06E-04 +/- 0.27E-04 vs. 2.76E-04 +/- 0.45E-04 min(-1)) and V-G (5.63E- 03 +/- 1.98E-03 vs. 1.74E-02 +/- 0.5E-02 min(-1)), and increased the apparent volume of distribution of VPA (84.6 +/- 2.2 vs. 72.3 +/- 2.1 mL). In vivo phenobarbital pretreatment a changed V-G excretion from a formation to an elimination rate-limited process. These results are consistent with phenobarbital-associated impairment of canalicular egress of some organic anions. This work further supports the utility of pharmacokinetic modeling in(1) determining the rate-limiting steps in hepatobiliary drug disposition and (2) identifying sites of drug interactions within the hepatobiliary system that may not be evident based on conventional mass-balance analysis.

背景与目标： 该实验室先前的工作表明，丙戊酸 (VPA) 在大鼠中的非线性分布可能是由于VPA在肝脏中的非线性分布所致。本研究旨在进一步阐明VPA的肝胆分布。将VPA (0.1-2 mmol/L) 与分离的大鼠肝细胞体外孵育。[(3)H]-VPA的摄取在10至50秒之间是线性的，具有最小 (<7%) 的生物转化。VPA摄取的初始速度与细胞外浓度成比例变化，并且与温度无关，这表明VPA主要通过被动扩散穿过肝细胞膜。在单独的研究中，在分离的灌注大鼠肝脏 (IPL) 中检查了VPA (20mg) 的肝胆分布。建立了药代动力学模型来描述苯巴比妥对IPL中VPA和丙戊酸葡糖醛酸苷 (v-g) 的肝胆分布的影响; 控制VPA和v-g处置的所有过程似乎都是线性的。向肝脏急性施用苯巴比妥 (1.12 mg) 降低了V-G小管流出的速率常数 (0.0489/- 0.0266 vs. 0.164/- 0.075分钟 (-1))。肝隔离前用苯巴比妥 (75 mg/kg/d x 5 d) 进行体内预处理可降低VPA的胆汁排泄 (1.06E-04/-0.27e-04与2.76e-04/-0.45e-04 min(-1)) 和V-G (5.63E- 03 +/-1.98e-03对1.74e-02 +/-0.5e-02 min(-1))，并增加VPA的表观分布体积 (84.6 +/- 2.2对72.3 +/- 2.1 mL)。体内苯巴比妥预处理将v-g排泄从形成改变为消除速率受限的过程。这些结果与苯巴比妥相关的某些有机阴离子的小管出口受损是一致的。这项工作进一步支持药代动力学模型在以下方面的实用性 :( 1) 确定肝胆药物处置中的限速步骤，以及 (2) 根据常规的质量平衡分析确定肝胆系统内药物相互作用的位点。

BACKGROUND & AIMS: OBJECTIVES:To review signs and symptoms of valproate-induced hyperammonaemic encephalopathy without hepatotoxicity in the psychiatric setting, explore its mechanisms, and give recommendations for prevention and treatment. METHODS:Medline search with keywords valproate, ammonia, hyperammonaemia, encephalopathy, and then cross-references to articles obtained through this search. Only cases with indication of valproate for psychiatric condition were included. RESULTS:Fourteen cases published in the psychiatric setting are reviewed. Valproate-induced hyperammonaemic encephalopathy is a rare adverse event, occurring almost equally in men and women, with a large age range, and reported in two patients with mental retardation. Symptoms appeared either a few days after initiation of valproate therapy, or after several months or years. The main symptoms were fluctuations in consciousness and disorientation. Clinical severity was not related to blood ammonia levels. All patients recovered after valproate-induced hyperammonaemic encephalopathy diagnosis and treatment, usually involving discontinuation of valproate. CONCLUSIONS:Valproate-induced hyperammonaemic encephalopathy is rare and usually reversible in patients without urea cycle disorders when valproate is discontinued. Therapy with carnitine is recommended. Special caution should be used in patients with mental retardation. Psychiatrists should suspect valproate-induced hyperammonaemic encephalopathy when consciousness deteriorates.

背景与目标：

BACKGROUND & AIMS: WHAT IS KNOWN AND OBJECTIVE:Hydralazine is an inhibitor of DNA methyltransferases, whereas valproate interferes with histone deacetylation. In combination, they show a marked synergism in reducing tumour growth as well as development of metastasis and inducing cell differentiation. Hydralazine is metabolized by the highly polymorphic N-acetyltransferase 2. The current pilot study was performed to analyse the pharmacokinetic parameters of a single dose of hydralazine in 24 h (one tablet with 83 mg for slow acetylators and one tablet with 182 mg for fast acetylators) and three fixed doses of valproate (one tablet of controlled liberation with 700 mg every 8 h) in healthy genetically selected volunteers. Selection was performed based on their NAT2 activity as deduced from their genotype. METHODS:An open label non-randomized single arm study was conducted in two groups of six healthy volunteers of both genders aged 20-45 years with a body mass index 22·2-26·9 which were classified as fast or slow acetylators after genotyping 3 SNPs that cover 99·9% of the NAT2 variants in the Mexican population. Blood samples were collected predose and serially post-dose in an interval of 48 h. Hydralazine and valproate concentrations were determined by ultra-high performance liquid chromatography (UPLC) coupled to tandem mass spectroscopy (MS/MS). RESULTS AND DISCUSSION:The AUC0-48 h and Cmax of hydralazine were almost identical (1410 ± 560 vs. 1446 ± 509 ng h/mL and 93·4 ± 16·7 vs. 112·5 ± 42·1 ng/mL) in both groups with NAT2 genotype-adjusted doses, whereas the multidose parameters of valproate were not significantly affected neither by the selection of the NAT2 genotype (AUC0-48 h 2064 ± 455 vs. 1896 ± 185 μg h/mL; Cmax 96·4 ± 21·1 vs. 88·8 ± 7·2 μg/mL, for the fast and slow acetylators, respectively) nor the co-administration of 83 or 182 mg of hydralazine. WHAT IS NEW AND CONCLUSION:Comparable hydralazine exposures (differences in AUC0-inf of only 7%) were observed in this study with genetic selection of volunteers and concomitant dose adjustment. However, the conclusions have yet to be confirmed with a full-powered 2 × 2 crossover study.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Previous studies have shown a high prevalence of aggressive behavior in abstinent heroin users who are on methadone maintenance therapy (MMT) compared with healthy controls. Some studies suggest that olanzapine and valproate may be effective in managing aggressive behavior and preventing a relapse of substance misuse in patients on methadone regime. AIM:The aim of the present study was to evaluate and compare the effectiveness of these medications in the management of aggressive behavior and prevention of relapse in patients maintained on methadone. PATIENTS AND METHODS:Two hundred and one patients on MMT were randomized into two treatment groups of olanzapine (2.5-15 mg) and sodium valproate (600-1000 mg). Both groups were treated for 12 weeks. Patients visited the clinic twice weekly to receive medication. Patients' urine samples were screened for trace of any illicit substances on each visit. Upon each consultation, the clinicians, using overt aggression scale-modified version (OAS-M), assessed the degree and frequency of aggressiveness in each patient. RESULTS:Fifty three patients completed the trial. Both medications significantly reduced the overt aggression and subscales of irritability, aggression and suicidality. Improvement was more pronounced in the group treated with olanzapine. The mean percentages of positive urine samples for morphine, cannabis and methamphetamine abuse for the 12 weeks period of the study were not significantly different between the two groups. CONCLUSIONS:Both olanzapine and sodium valproate are useful as an adjunctive agent in reducing aggressive behavior in heroin dependent individuals who are on MMT, but the beneficial effect of olanzapine was greater than sodium valproate in this respect.  

背景与目标：

BACKGROUND & AIMS: :Valproic acid (VPA) has been reported as inhibitor of histone deacetylases (HDACs). Several reports indicated that HDACs play a crucial role in the pathogenesis of fibrosis and hepatic stellate cell (HSC) activation. The present study was aimed to evaluate the anti-fibrotic effect of VPA against thioacetamide (TAA)-induced hepatic fibrosis and activation of the HSC in rat. VPA and TAA were administrated intraperitoneally at the dose of 400 and 200 mg/kg each at 2 days interval, respectively for a period of 6 weeks. Administration of TAA significantly increased the absolute and relative liver weight, aspartate aminotransferase and alanine aminotransferase levels, which were significantly decreased by VPA treatment as compared to TAA control. VPA treatment prevents the TAA-induced activation of HSC and decreases collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Interestingly, VPA co-treatment led to significantly increase the DNA damage and apoptosis in the activated HSC as compared to TAA control. Further, TAA decreased the expression of matrix metalloproteinase-2 (MMP-2), while VPA co-treatment significantly increased the expression of MMP-2 as compared to respective control. The present study clearly demonstrated that VPA treatment significantly alleviates TAA-induced activation of HSC and subsequent hepatic fibrosis.

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