Anticonvulsant potency of common antiepileptic drugs in the gerbil

In gerbils, 'minor' (myoclonic) and 'major' (clonic-tonic) seizures were induced by blowing at the animals with compressed air. The anticonvulsant ED50 of the following drugs was determined after oral administration against both types of seizures: phenytoin, phenobarbital, carbamazepine, sodium valproate, ethosuximide, and diazepam. Valproate, ethosuximide, and diazepam were most potent against 'minor' seizures which could not or only partially be suppressed by phenytoin or carbamazepine, respectively. The 'grand mal' drugs phenytoin, phenobarbital, and carbamazepine were, on the other hand, more potent against 'major' than against 'minor' seizures. When phenobarbital was administered for several days, a strong induction of hepatic microsomal enzymes occurred.     

Certain aspects of interaction between sodium valproate and other anticonvulsant drugs in the therapy of epilepsy in children.

The serum valproate (VPA) concentration and the clinical effects of polytherapy with other antiepileptic drugs: phenobarbital (PB), clonazepam (CZP), diazepam (DZ), clobazam (CLO), ethosuximide (ESX) were estimated. VPA serum levels were reduced when this drug was combined with phenobarbital. Clobazam given together with valproate led to an increase in the serum concentration of the former drug. VPA serum levels were without significant changes when the drug was combined with either ethosuximide or 1-4-benzodiazepines. The best therapeutical effects were found after polytherapy sodium valproate with ethosuximide and clobazam in primary generalized seizures.     

丙戊酸钠缓释片治疗不同年龄段癫痫患者血药浓度监测分析

目的：监测丙戊酸钠缓释片治疗不同年龄段癫痫患者的血药浓度,并对数据进行分析,为临床合理用药提供参考。方法：2013年1月-2015年12月,收治癫痫患者123例,其中成人41例（成人组）,儿童60例（儿童组）,老人22例（老人组）;3组均用丙戊酸钠缓释片规律治疗（20~30 mg·kg^-1·d^-1,1~2次/d,po）,并采用高效液相色谱法进行血药浓度测定。结果：丙戊酸钠缓释片治疗儿童、成人、老人癫痫疗效肯定（有效率分别达80.00%,95.12%与95.45%）;药品不良反应（ADR）与血药浓度间有统计学意义（P<0.05）,且当血药浓度>100 mg·L^-1时ADR明显增多,达60.00%;3组间比较ADR发生情况无统计学意义（P>0.05）;在降低各类型癫痫发作频次、疗效方面和血药浓度控制方面成人组和老人组均优于儿童组（P<0.05）。结论：丙戊酸钠缓释片治疗儿童、成人和老人癫痫均有效,但仍存差异。丙戊酸钠缓释片治疗成人和老人癫痫是适宜的,但对于年龄偏小的儿童来说并不是最好的,此为临床用药提供参考。不良反应随血药浓度上升而明显增多,临床用药时应注意血药浓度监测。     

Riluzole enhances the anti-seizure action of conventional antiepileptic drugs against pentetrazole-induced convulsions in mice

Riluzole, a pre- and postsynaptic modulator of glutamate transmission, administered alone at doses of 5 and 10 mg/kg did not affect pentetrazole-evoked seizures in mice. However, it enhanced the anti-seizure action of valproate, phenobarbital, ethosuximide, although not that of clonazepam, in this model of experimental epilepsy. Keeping in mind that riluzole did not change plasma levels of antiepileptic drugs, a pharmacokinetic interaction, at least in terms of free plasma levels, does not seem probable. Regarding undesired effects, riluzole (5 mg/kg) and its combination with valproate did not produce any motor or long-term memory impairment. In contrast, the concomitant treatment of riluzole (5 mg/kg) with valproate (144 mg/kg), phenobarbital (4.9 mg/kg), or ethosuximide (90 mg/kg), resulted in a moderate motor deficit, but not long-term memory impairment in the tested mice. In conclusion, the results of the present study suggest that riluzole might occur effective as an additive drug in the treatment of myoclonic or absence epilepsy in humans.     

Comparison of antiepileptic action of valproate and ethosuximide in adult and immature rats

The antiepileptic action of ethosuximide and valproate was studied in immature rats in the pentetrazole (PTZ) model. Valproate antagonized the effect of PTZ in rats of all ages, while ethosuximide was effective only in rats of 25 or more days of age: in 18 day old rats it modified the PTZ seizure pattern and was ineffective in younger animals or only slightly affected the PTZ seizure pattern. Similarly, the ECoG studies have shown that valproate antagonizes PTZ action at all ages, while ethosuximide only in mature rats.     

Fatal valproate overdose in a newborn baby

Valproate is a widely used drug in the treatment of epilepsy in children and adults. However, it is not safe for patients under two years of age, especially during the newborn period. This study presents a case of fatal valproate overdose in a 26-day-old female newborn, who is the youngest patient in the literature.     

Inhibition of human aromatase complex (CYP19) by antiepileptic drugs.

Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from transfected insect cells using dibenzylfluorescein as substrate. The drugs inhibiting CYP19 were: lamotrigine, oxcarbazepine, tiagabine, phenobarbital, phenytoin, ethosuximide, and valproate. The inhibitory effects (50% reduction in activity compared to enzymes without inhibitor present) were in the range of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered.     

Effect of sodium valproate on phenobarbital serum levels in children and adults

The influence of sodium valproate on serum levels of phenobarbital during combination treatment was studied in 29 children and 50 adults with epilepsy. Steady-state drug levels in serum were determined immediately prior to drug administration using immunoenzymatic analysis. The serum level/dose ratio of phenobarbital increased significantly (p less than 0.001) when sodium valproate was added to the treatment. The increase had a mean value of 50.9% in adults and 112.5% in children, suggesting marked interindividual variability in the intensity of the interaction. Almost half of the patients required a decrease in the dose of phenobarbital prescribed. The interaction was more pronounced in patients with high serum levels of phenobarbital, while the dose of phenobarbital and the serum levels and dose of sodium valproate did not seem to affect the extent of the interaction. Close monitoring of the serum levels of phenobarbital is recommended during simultaneous treatment with sodium valproate.     

Testing of prototype antiepileptics in hippocampal slices

Summary The effects of six prototype anticonvulsant drugs, phenytoin, carbamazepine, midazolam, phenobarbital, ethosuximide and sodium valproate, were evaluated in two different experimental models of epileptiform activity using the in vitro slice preparation from the rat hippocampus. The relative potencies of the agents were determined: a) in the complete absence of synaptic transmission by recording spontaneous burst firing from the CA 1 pyramidal cell layer in a low calcium high magnesium solution and b) during blocked synaptic inhibition by observing the activity of each drug upon orthodromically evoked population spikes in penicillin containing medium. The rank order of potencies was a) in low Ca²⁺: carbamazepine, phenytoin, midazolam, phenobarbital, valproate, ethosuximide; b) in penicillin containing medium: midazolam, phenobarbital, carbamazepine, phenytoin, valproate, ethosuximide. These observations illustrate that the use of multiple paradigms is warranted when examining the mechanisms of action of new anticonvulsants.     

Pharmacokinetics, drug interactions, and tolerability of valproate

Valproate is a branched-chain carboxylic acid with an extensive history of use as an antiepileptic drug. In recent years, multiple uses for valproate have been found in psychiatry. As divalproex sodium, it is currently approved for the treatment of manic episodes associated with bipolar disorder and for migraine headache prophylaxis. Accumulating evidence suggests it may also be beneficial in several anxiety disorders. Valproate's pharmacokinetic profile has been extensively studied, mostly within the context of treatment of epilepsy. This review summarizes valproate's pharmacokinetics, drug interactions, and tolerability as an aid to promote individualized pharmacotherapy. Valproate is characterized by dose-limited absorption, nonlinear plasma protein binding, and multiple metabolic pathways of elimination. Pharmacokinetic drug interactions involving valproate result from its susceptibility to the effects of both enzyme induction and inhibition, along with an ability for weak to moderate inhibition of the metabolic elimination of other drugs. Valproate has an extensive record of use across the lifespan and a good record of tolerability. Some precautions are warranted in its use, but valproate is generally safe whether administered alone or in combination with other therapies.     

Effects of some anti-epileptic, neuroleptic and gabaminergic drugs on convulsions induced by D,L-allylglycine.

The antagonism of various seizure and time-related components of the convulsions resulting after IV injection of D,L-allylglycine into male Wistar rats were assessed in a standard test procedure. Trimethadione and ethosuximide did not antagonize the seizure components, whereas clonazepam, phenobarbital, diphenylhydantoin, primidone, valproate sodium, aminoxyacetic acid, etomidate, acetazolamide, flunarizine, pipamperone and baclofen did. The allylglycine test may thus represent a relatively specific method of differentiating between drugs effective against partial or generalized convulsive seizures from those effective against absence seizures. The neuroleptics haloperidol and pimozide were completely inactive in contrast to their reported antagonism of bicuculine seizures. The spectra of the active substances are discussed with respect to Principal Component and Cluster Analysis. Noteworthy are the similarities between baclofen and etomidate; between aminoxyacetic acid, phenobarbital and valproate sodium; and between diphenylhydantoin and flunarizine.     

The Effect of Valproate on the Metabolism of Phenobarbital in the Rat

Valproate has been shown to interact with all major antiepileptic drugs. The interaction with phenobarbital is the most clinically significant. The mechanism of the interaction was evaluated in the in vivo rat and in vitro liver perfusion system. Phenobarbital and parahydroxyphenobarbital (PbOH) were administered with and without valproate treatment. In vivo, after administration of PbOH, valproate caused a significant inhibition of both the renal clearance of unchanged PbOH (40%) and the formation clearance (ClF) of its glucuronide conjugate (44%). When coadministered with phenobarbital, valproate caused a significant decrease in the total plasma clearance of phenobarbital (95.4 ± 29.0 to 65.8 ± 20.2 ml/hr/kg), with no apparent effect on the phenobarbital renal clearance or the ClF of PbOH. Valproate did cause a significant inhibition (50%) of formation of a minor metabolite, metahydroxyphenobarbital. The largest effect of valproate appears to be on unknown pathways of phenobarbital elimination. In the isolated perfused rat liver, the ClF of PbOH and its glucuronide conjugate were determined. Valproate caused a small (10%) but significant decrease in the ClF of PbOH. As seen in vivo, the most significant effect of valproate was on the ClF of the PbOH glucuronide (66% decrease). In conclusion, inhibition of PbOH formation by valproate cannot account entirely for the increased plasma concentrations of phenobarbital that occur when valproate is added to therapy. A complete understanding of the mechanism will require a complete accounting of the phenobarbital dose in rat or in humans.     

341 例癫痫患儿用药特点分析

目的：探讨癫痫患儿临床用药特点,为临床合理应用抗癫痫药物提供参考。方法：回顾性分析2018年2月至2018年8月西北妇女儿童医院和西安交通大学第二附附属医院收治的341例癫痫患儿临床资料,对其用药方案选择及发作控制率进行统计分析。结果：341例癫痫患儿中,男女比例1.04∶1,年龄9个月~19岁,其中1~3岁患儿占比最大,为32.55%。经抗癫痫药物治疗,341例患儿Ⅲ级以上总体发作控制率为84.45%。单药治疗、双药治疗和三种及以上联合治疗Ⅱ级以上控制率分别为94.45%、69.63%和45.56%。单药治疗中使用率前3位的药物分别为左乙拉西坦、苯巴比妥和卡马西平;多药治疗中使用率前3位的药物分别为左乙拉西坦、丙戊酸钠和托吡酯。单药治疗以左乙拉西坦为主,联合治疗主要以左乙拉西坦＋丙戊酸钠或托吡酯为主。结论：儿童癫痫发病以婴幼儿期最多,药物治疗总体控制率较高,新型抗癫痫药和传统抗癫痫药在治疗选择中使用率相当,新型抗癫痫药物左乙拉西坦在各发作类型及各种治疗方案中使用率最高。治疗药物选择主要为左乙拉西坦、苯巴比妥和卡马西平,抗癫痫药物联合治疗方案主要为丙戊酸钠+左乙拉西坦和丙戊酸钠+氯硝西泮+左乙拉西坦。     

Influence of calcium channel inhibitors upon the anticonvulsant efficacy of common antiepileptics against pentylenetetrazol-induced convulsions in mice

Among three calcium channel inhibitors studied, nifedipine (20 mg/kg) moderately inhibited pentylenetetrazol (115 mg/kg, s.c.)-induced convulsions, whilst diltiazem (up to 20 mg/kg) and verapamil (up to 20 mg/kg) were without effect. The combinations of nifedipine (10 and 20 mg/kg) with valproate (100 mg/kg) or phenobarbital (6.25 mg/kg) resulted in significant protection against pentylenetetrazol-induced seizures. Combined treatment of nifedipine (5-20 mg/kg) with ethosuximide (100 mg/kg) also provided a clearcut anticonvulsant action. The antiepileptic drugs alone, in the above doses, were ineffective. The combination of diltiazem (10-20 mg/kg) and ethosuximide (100 mg/kg) produced protection against pentylenetetrazol, comparable to that of ethosuximide (200 mg/kg) alone. No pharmacokinetic interactions were found in the case of ethosuximide, whilst nifedipine (10 mg/kg) increased the levels of phenobarbital and valproate in plasma. The combination of diltiazem with the remaining antiepileptics were ineffective. Verapamil (up to 20 mg/kg) was without effect upon the action of the antiepileptic drugs tested. Finally, none of the calcium channel inhibitors studied influenced the action of diazepam (0.2 mg/kg). It may be concluded that combinations of ethosuximide, with either nifedipine or diltiazem, may be promising for the treatment of absence epilepsy.     

丙戊酸托吡酯治疗儿童特发性全身性癫痫疗效比较研究

目的：评价丙戊酸和托吡酯治疗儿童特发性全身性癫痫的疗效及耐受性。方法：对1999年10月至2003年4月来我院的152例首诊特发性全身性癫痫并接受丙戊酸或/和托吡酯治疗的病人进行随访。并对结果进行分析。结果：丙戊酸单药治疗完全控制率为63．41％。托吡酯单药治疗完全控制率40．00％,二者有显著差异;丙戊酸部分控制者添加托吡酯治疗31．25％完全控制,托吡酯治疗部分控制者添加丙戊酸后36．84％发作停止。无显著差异。两种药物的不良反应均较轻且耐受性较好。结论：丙戊酸是治疗儿童特发性全身性癫痫的最有效药物之一。如丙戊酸未能完全控制发作。添加托吡酯治疗疗效好。     

New anti-epileptic drugs for the 21st century

Prior to 1993, there were only six major drugs available in the US for the treatment of patients with epilepsy. These included phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), primidone (PRIM), valproic acid/sodium valproate (VPA) and ethosuximide (ESX). Of these drugs, VPA has the broadest spectrum of activity and ESX the most limited. Despite these six agents, as well as several secondary drugs, it is estimated that over 30% of patients have inadequate seizure control, while others, whose disease is adequately controlled, suffer from bothersome adverse events (AEs). Since 1993, ten new drugs have entered the worldwide market (not all in the US). Those released include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LVT), zonisamide (ZNS), clobazam (CLB) and vigabatrin (VGB). The purpose of this article is to review each of the above drugs, looking at efficacy, safety, tolerability and where they may play a role in the current treatment of epilepsy.     

New anti-epileptic drugs for the 21st century

Prior to 1993, there were only six major drugs available in the US for the treatment of patients with epilepsy. These included phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), primidone (PRIM), valproic acid/sodium valproate (VPA) and ethosuximide (ESX). Of these drugs, VPA has the broadest spectrum of activity and ESX the most limited. Despite these six agents, as well as several secondary drugs, it is estimated that over 30% of patients have inadequate seizure control, while others, whose disease is adequately controlled, suffer from bothersome adverse events (AEs). Since 1993, ten new drugs have entered the worldwide market (not all in the US). Those released include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LVT), zonisamide (ZNS), clobazam (CLB) and vigabatrin (VGB). The purpose of this article is to review each of the above drugs, looking at efficacy, safety, tolerability and where they may play a role in the current treatment of epilepsy.     

Effect of acute and chronic anticonvulsant administration on endogenous γ-hydroxybutyrate in rat brain

The effect of acute and chronic administration of ethosuximide, trimethadione, sodium valproate, clonazepam, phenobarbital, and diazepam on brain concentrations of γ-hydroxybutyrate (GHB) was determined by gas-liquid chromatography. The dose and time to sacrifice for each drug was determined by testing for effectiveness against GHB-induced absence seizures in the rat using an automated frequency analysis for quantitation of the electrocorticogram. Acute administration of ethosuximide, trimethadione, and sodium valproate, produced an increase in whole brain GHB. Ethosuximide, trimethadione, and phenobarbital given chronically produced a decrease in whole brain GHB. All changes took place in subcortex and cerebellum. Acute ethosuximide treatment produced a greater increase in GHB concentration at higher doses. The acute changes with the drugs coincided with the onset of anticonvulsant effect, but were short-lived and, in the case of ethosuximide and trimethadione, followed by a significant depression in GHB concentrations. The anti-petit mal action of these anticon-vulsants may be related to their effect on GHB in brain.     

Moving beyond sodium valproate: choosing the right anti-epileptic drug in children

ABSTRACT

Introduction: Sodium valproate is a widely used anti-epileptic drug with a broad spectrum of activity and mechanism of action. It has consequently been the first-line drug for most seizure types in children for the past fifty years. A wide range of side effects come along with these exceptional properties, including teratogenicity and neuro-cognitive impairments in offspring. Therefore, epilepsy treatment in children and adolescents should be reassessed in light of newer antiepileptic drugs as well as a more targeted-approach with older drugs.

Areas covered: The authors review the main concerns of valproate use in terms of adverse effects on different systems and drug interactions. The current alternatives to valproate in absence, myoclonic, tonic-clonic and focal onset seizures in children/adolescents are also reviewed.

Expert opinion: There are several issues that research should address in antiepileptic therapy and in clinical studies with children, given the peculiarity of this population. Future perspectives in epilepsy therapy should now lead towards an individualized treatment.