左乙拉西坦和苯妥英钠治疗儿童惊厥性癫痫持续状态疗效与安全性meta分析

目的评估左乙拉西坦(LEV)和苯妥英钠(PHT)治疗儿童惊厥性癫痫持续状态(CSE)的疗效与安全性。方法检索PubMed、Web of Science、Cochrane Library、Embase、中国知网(CNKI)、万方数据库、中国生物医学文献数据库(CBM)和维普中文科技期刊数据库(VIP),检索时限均为各数据建库起至2020年7月17日,筛选静脉滴注PHT(对照组)以及静脉滴注LEV(干预组)治疗儿童CSE患者的前瞻性随机对照试验(RCT)。提取符合纳入标准的研究资料并评价质量,使用Rev Man 5.3软件行meta分析。结果纳入7项RCT,共计1 647例CSE患儿。meta分析结果显示,LEV组60分钟内临床癫痫发作完全控制率(75.04%)略高于PHT组(71.43%),但差异无统计学意义(RR=1.06,95%CI:1.00～1.13,P=0.06);LEV组24小时内临床复发率(RR=0.93,95%CI:0.50～1.74,P=0.83)、死亡率(RR=0.89,95%CI:0.18～4.48,P=0.89)、入住ICU率(RR=1.11,95%CI:0.96～1.28,P=0.17)与PHT组相比,差异无统计学意义;LEV组的不良事件总发生率低于PHT组,差异有统计学意义(RR=0.74,95%CI:0.60～0.92,P=0.006)。结论对于苯二氮卓类药物治疗失败后的儿童CSE患者,LEV和二线首选药物PHT的疗效相当,但不良事件总发生率低,可考虑作为PHT的合适替代品。     

Use of levetiracetam in treating epilepsy associated with other medical conditions

OBJECTIVE: This prospective, open-label study was conducted to evaluate the effectiveness, tolerability, and safety of levetiracetam in patients with epilepsy in whom unfavorable metabolism, complex drug interactions, or direct toxic effects of antiepileptic drugs (AEDs) had caused a worsening of comorbid conditions. METHODS: Study design included the introduction of levetiracetam, discontinuation of other AEDs, and a serial assessment comprising electroencephalograms and blood tests at baseline and 2, 6, and 12 months. Of 21 patients, 16 had partial and five generalized epilepsy. Concomitant pathologies were gastroenterological (six), vascular (four), endocrinological (four), or complex conditions including hematological (four) or dermatological (three) disease. A change of regimen was necessitated by drug-drug interactions in four patients, direct real or potential toxic effects of previous AEDs in 13, and a combination of interactions/toxic effects in four. RESULTS: After 12 months, 12 patients were seizure-free, nine had reductions in seizure frequency of 50-75%, and improvement in concomitant medical conditions was observed. No side effects were reported. CONCLUSION: Levetiracetam appears to be effective, well tolerated, and safe in patients with epilepsy and other medical conditions that are difficult to manage because of drug interactions or AED-related side effects.     

Levetiracetam in a broad population of patients with refractory epilepsy: interim results of the international SKATE trial

OBJECTIVE: To prospectively assess the safety and efficacy of levetiracetam in patients with uncontrolled focal epilepsy, in a common practice-based setting. PATIENTS AND METHODS: In this phase IV, open-label, 16-week community-based study, adult patients with focal seizures initially received levetiracetam 1,000 mg/day. Throughout the study, the dose was adjusted in increments of 1,000 mg (maximum 3,000 mg/day) to achieve seizure control and maintain tolerability. The outcome parameters were the percentage reduction in partial and total seizure frequency per week from historical baseline, global evaluation scale (GES), and adverse events (AE). RESULTS: Seven hundred and thirty-one patients were included in this analysis and 84.4% completed the study. The median percent reduction in all seizures was 47.8%, and 49.3% for all partial seizures. The 50% responder rate was 49%, and the seizure-free rate was 17.2% for all partial seizures. Approximately 60% of patients showed moderate to marked improvement on the GES. The majority of AE were of mild to moderate severity; the most commonly reported being asthenia, somnolence, headache, and dizziness. CONCLUSION: Levetiracetam is both efficacious and safe as an add-on therapy in patients with refractory epilepsy treated by clinicians in their daily practice.     

Effect of Morin on pharmacokinetics of Piracetam in rats,in vitro enzyme kinetics and metabolic stability assay using rapid UPLC method

The aim of this study was to investigate the effect of Morin on the pharmacokinetics of Piracetam in rats, in vitro enzyme kinetics and metabolic stability (high throughput) studies using human liver microsomes in UPLC. For pharmacokinetics studies, male Wistar rats were pretreated with Morin (10 mg/kg) for one week and on the last day, a single dose of Piracetam (50 mg/kg) was given orally. In another group, both Morin and Piracetam were co‐administered to evaluate the acute effect of Morin on Piracetam. The control group received oral distilled water for one week and administered with Piracetam on the last day. As Morin is an inhibitor of P‐ Glycoprotein (P‐gp) and CYP 3A, it was anticipated to improve the bioavailability of Piracetam. Amazingly, relative to control, the areas under the concentration time curve and peak plasma concentration of Piracetam were 1.50‐ and 1.45‐fold, respectively, greater in the Morin‐pretreated group. However, co‐administration of Morin had no significant effect on these parameters. Apart from the aforementioned merits, the results of this study are further confirmed by clinical trials; Piracetam dosages should be adjusted to avoid potential drug interaction when Piracetam is used clinically in combination with Morin and Morin‐containing dietary supplements. The in vitro enzyme kinetics were performed to determined km, V_max & CL_ins. The in vitro metabolic stability executed for the estimation of metabolic rate constant and half‐life of Piracetam. These studies also extrapolate to in vivo intrinsic hepatic clearance (Cl_{int, in vivo}) from in vitro intrinsic hepatic clearance (CL_{int, in vitro})_. Copyright © 2012 John Wiley & Sons, Ltd.     

左乙拉西坦儿童生理发育药动学模型的建立和剂量优化

目的:探讨生理发育因素对左乙拉西坦(LEV)在儿童体内药动学特征的影响,评价和优化LEV给药剂量,促进个体化用药.方法:根据203例0.42～15岁癫痫患者的LEV血药浓度及相关临床资料建立群体药动学模型,考察生理发育因素对LEV药动学参数的影响方式和强度.基于模型,模拟和评价不同体质量和年龄段的儿童患者的LEV给药方...     

Rapid dosage titration of levetiracetam in children

STUDY OBJECTIVE: To report our experience with rapid titration of levetiracetam regimens in children and adolescents who were unresponsive to or intolerant of other antiepileptic drugs. METHODS: A retrospective chart review was performed to identify patients with childhood epilepsy who underwent a rapid titration to full doses of levetiracetam in 2 weeks or less. Data regarding demographics, disease characteristics, previous use of antiepileptics, levetiracetam dosage titration schedule, and clinical outcomes were collected and analyzed. RESULTS: Eight children (seven girls, one boy) aged 19 months-17 years were identified. The levetiracetam dosage was titrated to full maintenance doses over 2-14 days (mean 10 days). All patients demonstrated greater than 50% reduction in seizure frequency, with six patients (75%) becoming seizure free. Only one patient experienced a clinically significant adverse event. CONCLUSION: Rapid dosage titration of levetiracetam is feasible and well tolerated in children who require rapid escalation to therapeutic doses.     

Connectivity and Neuronal Synchrony during Seizures

There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along the lamellar, but not the septotemporal, axis during evoked seizures. During kindling, neuronal synchrony increased along the lamellar axis, while synchrony along the septotemporal axis remained relatively low. Additionally, the theta phase distribution demonstrated that CA1 pyramidal cell firing became preferential for theta oscillation negative peak as kindling progressed in the lamellar direction but not in the trans-lamellar direction. Last, event synchronization demonstrated that neuronal firings along the lamellar axis were more synchronized than those along the septotemporal axis. There was a marked decrease in synchronization and phase preference after treatment with phenytoin and levetiracetam. The synchrony structure of CA1 pyramidal neurons during seizures and epileptogenesis depends on anatomic connectivity and plasticity.SIGNIFICANCE STATEMENT We could improve the efficacy of brain stimulation to treat seizures by understanding the structure of synchrony. Electrical stimulation may disrupt seizures by desynchronizing neurons, but there is an uncertainty on which groups of neurons fire synchronously or chaotically during seizures. Here, we demonstrate that neurons linked by excitatory connections fire synchronously during seizures, and this synchrony is modulated by epileptogenesis and antiseizure drugs. Closed-loop brain stimulation carefully targeted to disrupt synchrony may improve the treatment of seizures.