Pharmacology of antiepileptic drugs in the gerbil—I. Pharmacokinetics

Pharmacokinetic data for antiepileptic drugs were determined in gerbils. The drugs had the following elimination half-lives: phenytoin 2.1 hr; phenobarbital 10.6 hr; carbamazepine 1.8 hr; valproate 0.69 hr; ethosuximide 1.4 hr and diazepam 1.15 hr. Diazepam was predominantly metabolized via 3-hydroxydiazepam to oxazepam which had the longest half-life (2 hr) of the metabolites.     

Pharmacodynamics and common drug-drug interactions of the third-generation antiepileptic drugs

Introduction: Anticonvulsants that belong to the third generation are considered as ‘newer’ antiepileptic drugs, including: eslicarbazepine acetate, lacosamide, perampanel, brivaracetam, rufinamide and stiripentol.

Areas covered: This article reviews pharmacodynamics (i.e. mechanisms of action) and clinically relevant drug-drug interactions of the third-generation antiepileptic drugs.

Expert opinion: Newer antiepileptic drugs have mechanisms of action which are not shared with the first and the second generation anticonvulsants, like inhibition of neurotransmitters release, blocking receptors for excitatory amino acids and new ways of sodium channel inactivation. New mechanisms of action increase chances of controlling forms of epilepsy resistant to older anticonvulsants. Important advantage of the third-generation anticonvulsants could be their little propensity for interactions with both antiepileptic and other drugs observed until now, making prescribing much easier and safer. However, this may change with new studies specifically designed to discover drug-drug interactions. Although the third-generation antiepileptic drugs enlarged therapeutic palette against epilepsy, 20–30% of patients with epilepsy is still treatment-resistant and need new pharmacological approach. There is great need to explore all molecular targets that may directly or indirectly be involved in generation of seizures, so a number of candidate compounds for even newer anticonvulsants could be generated.     

Caffeine and the anticonvulsant potency of antiepileptic drugs: experimental and clinical data

Caffeine (1,3,7-trimethylxanthine) is the most commonly ingested stimulant in the world. The daily consumption of this methylxanthine in coffee, tea and soft drinks is approximately 200 mg per person, which yields a pharmacologically active blood concentration. Experimental data indicate that caffeine may either lower the convulsive threshold in experimental models of epilepsy or induce seizure activity in doses over 400 mg/kg in rodents. Interestingly, animal data have demonstrated that caffeine, at doses far below its convulsive potential, diminishes the protective effects of conventional antiepileptic drugs (AEDs--carbamazepine, phenobarbital, phenytoin, valproate) and the newer AED, topiramate against electroconvulsions in mice. However, in contrast to these AEDs, caffeine did not impair the anticonvulsant efficacy of other newer AEDs, lamotrigine, tiagabine, and oxcarbazepine in this experimental model of epileptic seizure. Although limited, the clinical data generally confirm the experimental findings, suggesting increased seizure frequency in epileptic patients who began ingesting caffeine in high quantities. Thus far, no analysis has been performed in epileptic patients to determine whether the hazardous effects of caffeine are dependent upon individual antiepileptic treatments. These data clearly indicate that methylxanthines should be avoided in epileptic patients.     

Anticonvulsant potency of unmetabolized diazepam

The anticonvulsant potencies of diazepam and its metabolites desmethyldiazepam and oxazepam against convulsions elicited by intravenous injection of pentetrazole were determined in mice at times from 1-30 min after intravenous administration. Diazepam had its maximal potency (ED50 0.53 mumol/kg) at 1 min when only traces of desmethyldiazepam could be detected in plasma and brain. During the next 30 min, the drug was rapidly transformed to desmethyldiazepam and oxazepam, and its anticonvulsant ED50 rose by a factor of about 4. From the concentrations in brain at 50% protection, a potency ratio of 1.0:0.37:0.33 could be calculated for diazepam, desmethyldiazepam and oxazepam.     

三种常用抗癫痫药物对儿童注意力的影响

目的 :了解苯巴比妥、卡马西平、丙戊酸钠对癫痫患儿注意力的影响。方法 :4 5例患儿随机分组服用这三种药物 ,分别在服药前及服药后 6个月、1年、2年时用NJ2 2型注意力测试仪测试患儿的注意力 ,比较服药前后及三种药物间的注意力缺陷值变化。结果 :三组患儿服药后 6个月、1年、2年后注意力缺陷值改变不显著 (P >0 0 5 ) ,三种药物间注意力缺陷值比较无显著差异 (P >0 0 5 )。结论 :三种药物单药常规剂量时对患儿注意力没有明显的不良影响     

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice

Backgroundβ₂-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used β₂-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures.MethodsSeizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals’ motor coordination and memory processes was also evaluated.ResultsSingle SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective β₂-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals’ motor performance and memory after both single and 7 days administration.ConclusionsPresented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving β₂-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.     

Anticonvulsant action in the epileptic gerbil of novel inhibitors of GABA uptake

Two novel inhibitors of GABA uptake, namely SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid) and SKF 100330-A (N-[4,4-diphenyl-3-butenyl]-guvacine) were tested for anticonvulsant effects in genetically seizure-prone gerbils. Both compounds proved able to block major (generalized tonic-clonic) seizures initiated in gerbils by air blast stimulation. The respective anticonvulsant ED50s for SKF 100330-A and SKF 89976-A were 1.6 and 4.1 mg/kg i.p., respectively. Comparison with other GABA uptake inhibitors, namely ethyl and methyl esters of (-)- and (+)-nipecotic acid and (+/-)-cis-4-hydroxynipecotic acid, showed that the novel uptake inhibitors were considerably more potent. Similarly, comparison with common antiepileptic drugs demonstrated that SKF 100330-A and SKF 89976-A were more potent than phenobarbital and valproic acid to block seizures in gerbils. Only benzodiazepines surpassed these GABA uptake inhibitors in anticonvulsant potency. Observation of behaviour indicated that the novel compounds exerted no side-effects in anticonvulsant doses. These data indicate that SKF 100330-A and SKF 89976-A deserve interest as potential antiepileptic drugs with a very selective mechanism of action.     

Anticonvulsant drugs in the treatment of substance withdrawal

Although detoxification cannot, in itself, be considered a treatment for addiction, it is one of the most pivotal phases. In order to facilitate entry into recovery and/or rehabilitation programs, a detoxification treatment has to be experienced as easy and safe by the patient. In consideration of the many inconveniences related to standard withdrawal treatments, there is an interest in developing alternative pharmacological strategies. The main rationales for using anticonvulsants in substance-abuse patients are their lack of addiction potential, evidence support a role of kindling mechanisms in withdrawal syndromes and their efficacy in comorbid psychiatric disorders. The available data currently support the utilization of carbamazepine as a treatment for detoxification from benzodiazepines, alcohol and opiates, and as a useful agent to reduce cocaine consumption. The use of valproate is well corroborated for alcohol detoxification and it seems to be a promising treatment for the reduction of cocaine use; however, it has been found to be ineffective against benzodiazepine withdrawal symptoms. Some preliminary data suggest that lamotrigine could be useful in opiate and cocaine dependence. Gabapentin shows potential as a treatment for cocaine dependence, and some case reports have stimulated interest in this agent for alcohol and benzodiazepine detoxification. Due to its particular pharmacological profile, topiramate is one of the most interesting newer anticonvulsants. It has been found to be efficacious in opiate and possibly benzodiazepine detoxification and also has theoretical potential as a preventive therapy.     

New antiepileptic drugs that are second generation to existing antiepileptic drugs

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, ～ 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.     

New antiepileptic drugs that are second generation to existing antiepileptic drugs

In the last decade, 10 new antiepileptic drugs (AEDs) have been introduced that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug interactions. However, despite the large therapeutic range of old and new AEDs, approximately 30% of the patients with epilepsy are still not seizure free and, consequently, there is a substantial need to develop new AEDs. The new AEDs currently in development can be divided into two categories: drugs with completely new chemical structures such as lacosamide (formally harkoseride), retigabine, rufinamide and talampanel; and drugs that are derivatives or analogues of existing AEDs that can be regarded as second-generation or follow-up compounds of established AEDs. This article focuses on the second category and thus critically reviews the following second-generation compounds: eslicarbazepine acetate or BIA-2-093 and 10-hydroxy carbazepine (carbamazepine derivatives); valrocemide and NPS 1776 (isovaleramide; valproic acid derivatives); pregabalin and XP13512 (gabapentin derivatives); brivaracetam (ucb 34714) and seletracetam (ucb 44212; levetiracetam derivatives); and fluorofelbamate (a felbamate derivative). In addition, a series of valproic acid derivatives that are currently in preclinical stage has also been evaluated because some lead compounds of this series have a promising potential to become new antiepileptics and CNS drugs. For any of these follow-up compounds to become a successful second generation to an existing AED, it has to be more potent, safer and possess favourable pharmacokinetics, including low potential for pharmacokinetic and pharmacodynamic drug interactions.     

新型抗癫痫药之间及其与传统抗癫痫药的相互作用和机制*

分别综述了几种新型抗癫痫药（托吡酯、非氨酯、奥卡西平、拉莫三嗪、唑尼沙胺、左乙拉西坦、噻加宾、加巴喷丁及氨己烯酸）与传统抗癫痫药联合应用时以及这些新型抗癫痫药之间的相互作用及其发生机制，阐明细胞色素P450酶和葡萄糖苷酸转移酶在新型抗癫痫药的相互作用中的意义及重要性。为临床合理联合应用提供理论依据，提高抗癫痫治疗的可靠性、安全性和有效性。     

抗癫痫药的药物基因组学研究进展

抗癫痫药的疗效和副作用存在着显著的个体差异,现认为药物基因组学在个体差异中发挥了重要作用.本文通过整理、分析近几年的文献,阐述抗癫痫药基因多态性在药物代谢、转运和不良反应等方面的作用,从而为临床个体化用药提供参考.     

Influence of some beta-adrenoceptor antagonists on the anticonvulsant potency of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Pharmacokinetics of antiepileptic drugs in pregnancy

A substantial proportion of women with epilepsy experience seizure deterioration during pregnancy. This is most likely explained by a drop in plasma levels of antiepileptic drugs (AEDs) as a consequence of altered drug pharmacokinetics. It has been known for many years that gestation induces the elimination of standard AEDs (phenytoin, barbiturates, carbamazepine and valproate). In general, newer AEDs have more simple pharmacokinetic properties and it should, therefore, be expected that the pharmacokinetics of these drugs are influenced in a simpler manner by physiological changes, such as pregnancy. However, within the last few years it has been established that the elimination of several newer AEDs is significantly accelerated during pregnancy. This is particularly the case for glucuronidated AEDs (i.e., lamotrigine) and the pharmacological active metabolite of oxcarbazepine (metabolite 10-hydroxycarbazepine). Recent observations show it is probable that the elimination of levetiracetam is also increased during pregnancy. Pharmacokinetic alterations during pregnancy show wide interindividual variability and the effects on the plasma levels are mostly unpredictable. Regular routine drug monitoring during pregnancy is therefore recommended. The future perspective involves the development of pharmacogenetic charting, which may assist in providing an individualized treatment strategy and refine preconceptional therapeutic planning to ensure the best possible health for the mother and developing child.     

Anticonvulsant drugs. An update

A considerable amount of information is now available concerning the clinical pharmacology of the anticonvulsant drugs. Some of the more important data are reviewed in this article. In recent years, valproic acid (or sodium valproate) has found a place as a major anticonvulsant agent, while older drugs such as troxidone and sulthiame seem to be disappearing from use. Although much information is available, the essential mechanisms of action of the anticonvulsant drugs are still not understood, either at a molecular or at an electrophysiological level. The pharmacokinetics of the anticonvulsants in common use are now reasonably well documented, though some minor questions are still to be answered. Numerous interactions between anticonvulsants and endogenous substances or other drugs administered concurrently (including other anticonvulsants) have been recorded, but much work still needs to be done to elucidate the frequency and mechanisms of the various interactions. Many adverse effects of the anticonvulsants are known, but further unwanted effects of long-established drugs continue to emerge from time to time, including the still somewhat controversial matter of anticonvulsant-related dysmorphogenesis. The use of valproic acid and its sodium salt has been associated with a worrying incidence of serious liver and pancreatic toxicity. Adequate basic data are now available to put the clinical use of anticonvulsants on a rational basis, but much work remains to be done in this area. In particular, the question of 'therapeutic ranges' of plasma concentrations of the various drugs needs to be reinvestigated in a rigorous statistical fashion, and in relation to different clinical types of epilepsy. The usefulness of monitoring free rather than total drug concentrations also needs further investigation. The ultimate test of the validity of all background scientific pharmacological information about anticonvulsants is its usefulness in the treatment of patients with epilepsy.     

The follow-up of antiepileptic drugs

All antiepileptic medications have potential side-effects. Some are rather specific like diplopia for carbamazepin or lamotrigin, whereas others are not, like fatigue or unsteadiness. Most are dose-related and can therefore be alleviated by dose reduction (e.g. somnolence or tremor) but a few are idiosyncratic (e.g. rash) and require cessation of the causative agent. Some can be detected and followed-up on a clinical basis but others necessitate specific examinations.