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.     

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.     

利伐沙班与抗癫痫药物相互作用的研究进展

心房颤动（房颤）导致的卒中是其严重并发症,非瓣膜性房颤导致脑梗死患者并发癫痫的风险比其他原因卒中患者更高,可能需要利伐沙班联合抗癫痫药物治疗。新型口服抗凝药物利伐沙班是口服直接Xa因子抑制剂,同时是CYP3A4和P-糖蛋白（P-gp）的底物,某些抗癫痫药物对CYP3A4和/或P-gp有诱导作用,与利伐沙班合用,可使利伐沙班血药浓度下降,血栓风险增加。对利伐沙班与丙戊酸钠、卡马西平、苯巴比妥、奥卡西平、左乙拉西坦以及其他抗癫痫药物合用的相互作用进行综述,并根据相关研究和病例报道给出推荐意见,为临床合理用药提供参考。     

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。     

Interactions with antiepileptic drugs.

Most of the currently available antiepileptic drugs have a low therapeutic ratio and therefore a drug interaction causing elevation of the serum level of one of these compounds can readily lead to drug intoxication. Phenytoin, in particular, is vulnerable because its metabolism is dose-related and at therapeutic serum levels the enzyme system involved in its degradation is easily inhibited by concurrent drug administration. As multiple drug therapy has traditionally been practised in the management of epilepsy, clinically important interactions are common. Furthermore, most of the drugs used in the treatment of major epilepsies are potent inducers of hepatic microsomal enzymes and can therefore stimulate the metabolism of concurrently-administered drugs to such an extent that they may be rendered ineffective. The use of one drug alone is recommended, where possible, in the management of epilepsy.     

Pharmacokinetic interaction between albendazole sulfoxide enantiomers and antiepileptic drugs in patients with neurocysticercosis

The aim of the present investigation was to determine the interaction between the antiepileptic drugs (AEDs) phenytoin, carbamazepine, and phenobarbital and the enantioselective metabolism of albendazole. Thirty-two adults with a diagnosis of the active form of intraparenchymatous neurocysticercosis and treated with albendazole at the dose of 7.5 mg/kg every 12 hours for 8 days were studied. The patients were divided into four groups based on the combined use of AEDs or not: control group (n = 9), phenytoin group (n = 9 patients treated with 3-4 mg/kg/d sodium phenytoin), carbamazepine group (n = 9 patients treated with 10-20 mg/kg/d carbamazepine), and phenobarbital group (n = 5 patients treated with 1.5-4.5 mg/kg/d phenobarbital). Serial blood collections were carried out on day 8 of albendazole treatment during the last 12-hour dose interval. Plasma concentrations of the (+)- and (-)-albendazole sulfoxide (ASOX) and albendazole sulfone (ASON) metabolites were determined by high-performance liquid chromatography using a chiral phase column and fluorescence detection. The pharmacokinetic parameters were analyzed by analysis of variance followed by the Tukey-Kramer test. The results are reported as means. The following differences (P < 0.05) were observed between the control and the phenytoin, carbamazepine, and phenobarbital groups, respectively: (+)-ASOX area under the concentration-time curve for 0 to 12 hours after treatment (AUC(0-12)) 6.1, 2.1, 3.1, 2.4 microg/h/mL; (+)-ASOX maximum plasma concentration (C(max)) 0.8, 0.3, 0.4, 0.3 microg/mL; (+)-ASOX half-life (t1/2) 8.0, 3.8, 4.1, 4.9 h; (-)-ASOX AUC(0-12) 1.8, 0.4, 0.6, 0.5 microg/h/mL; (-)-ASOX C(max) 0.2, 0.06, 0.1, 0.1 microg/mL; (-)-ASOX (t(1/2)) 4.3, 1.9, 2.2, 2.1 h; ASON AUC(0-12) 0.5, 0.2 microg/h/mL; ASON C(max) 0.8, 0.3, 0.4, 0.3 microg/mL; ASON (t(1/2)) 8.0, 3.8, 4.1 h. The results show that phenytoin, carbamazepine, and phenobarbital induce to approximately the same extent the oxidative metabolism of albendazole in a nonenantioselective manner. Notably, a significant reduction in the plasma concentration of the active ASOX metabolite was observed in patients with neurocysticercosis treated with these AEDs.     

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Rationale

Antiepileptic drugs (AEDs) have been available for many years; yet, new members of this class continue to be identified and developed due to the limitations of existing drugs, which include a propensity for cognitive impairment. However, there is little preclinical information about the cognitive effects they produce, which clinically include deficits in attention and slowing of reaction time.

Objectives

The purpose of this study was to profile two first-generation AEDs, phenytoin and valproate, and three second-generation AEDs, levetiracetam, pregabalin and lacosamide. Initially, each drug was examined across a range of well characterised preclinical seizure tests, and then each drug was evaluated in the five-choice serial reaction time test (5-CSRTT) based on efficacious doses from the seizure tests.

Materials and methods

Each AED was tested for anti-seizure efficacy in either (1) the maximal electroshock seizure test, (2) s.c. PTZ seizure test, (3) amygdala-kindled seizures and (4) the genetic absence epilepsy rat of Strasbourg model of absence seizures. On completion of these studies, each drug was tested in rats trained to asymptotic performance in the 5-CSRTT (0.5 s SD, 5 s ITI, 100 trials). Male rats were used in all studies.

Results

Each AED was active in at least one of the seizure tests, although only valproate was active in each test. In the 5-CSRT test, all drugs with the exception of levetiracetam, significantly slowed reaction time and increased omissions. Variable effects were seen on accuracy. The effect on omissions was reversed by increasing stimulus duration from 0.5 to 5 s, supporting a drug-induced attention deficit. Levetiracetam had no negative effect on performance; indeed, reaction time was slightly increased (i.e. faster).

Conclusions

These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.     

Sexual dysfunction related to antiepileptic drugs in patients with epilepsy

Introduction: Epilepsy is a common disease that is mostly treated with antiepileptic drugs (AEDs). However, the sexual dysfunction (SD) side effects related to the use of AEDs have not received sufficient attention.

Areas covered: The purpose of this review is to examine the current evidence on SD-related side effects of AEDs. The incidence, clinical features and major types of SD are summarized. Furthermore, various AEDs that may cause SDs are addressed in detail. Finally, we briefly summarize the treatments for SD related to AEDs.

Expert opinion: SD related to AEDs is common. Symptoms include erectile dysfunction (ED), hyposexuality, hypersexuality and ejaculatory dysfunction. Traditional AEDs such as valproate and enzyme-inducing AEDs (EIAEDs) may produce high incidences of decreased libido. Recently, sexual function changes related to new AEDs have been reported. Topiramate, pregabalin and gabapentin may cause SD, whereas oxcarbazepine, lamotrigine and levetiracetam may improve sexual function. Although the treatment for SD related to AEDs remains unclear, switching to another AED may be an option. Further studies are necessary to better understand and treat SD related to AEDs.     

CNS adverse events associated with antiepileptic drugs

A variety of newer antiepileptic drugs (AEDs) are now available for treating patients with epilepsy in addition to the 'conventional' drugs that have been available throughout a large part of the last century. Since these drugs act to suppress the pathological neuronal hyperexcitability that constitutes the final substrate in many seizure disorders, it is not surprising that they are prone to causing adverse reactions that affect the CNS.Information on adverse effects of the older AEDs has been mainly observational. Equally, whilst the newer drugs have been more systematically studied, their long-term adverse effects are not clearly known. This is illustrated by the relatively late emergence of the knowledge of visual field constriction in the case of vigabatrin, which only became known after several hundred thousand patient-years of use. However, older drugs continue to be studied and there has been more recent comment on the possible effect of valproate (valproic acid) on cognition following exposure to this drug inutero.With most AEDs, there are mainly dose-related adverse effects that could be considered generic, such as sedation, drowsiness, incoordination, nausea and fatigue. Careful dose titration with small initial doses can reduce the likelihood of these adverse effects occurring. Adverse effects such as paraesthesiae are more commonly reported with drugs such as topiramate and zonisamide that have carbonic anhydrase activity. Weight loss and anorexia can also be peculiar to these drugs. Neuropsychiatric adverse effects are reported with a variety of AEDs and may not be dose related. Some drugs, such as carbamazepine when used to treat primary generalized epilepsy, can exacerbate certain seizure types. Rare adverse effects such as hyperammonaemia with valproate are drug specific. There are relatively very few head-to-head comparisons of AEDs and limited information is available in this regard.In this review, we discuss the available literature and provide a comprehensive summary of adverse drug reactions of AEDs affecting the CNS.     

Bone loss associated with use of antiepileptic drugs

Importance of the field: Epilepsy is a neurological disorder associated with several comorbidities, one of them being reduced bone health. As the bone loss most often is insidious and asymptomatic, they are usually not recognized, and thus untreated. The key message of this paper is to make clinicians aware of the problem.

Areas covered in this review: This article reviews data from basic and clinical studies of bone loss associated with usage of antiepileptic drugs (AEDs) within the last 4 decades.

What the reader will gain: The reader will learn that there is accumulating evidence of biochemical abnormalities indicating a disturbed bone metabolism, a decreased bone density and a 2 – 6 times increased risk of fractures among those with epilepsy compared to the general population. These findings most likely have many causes, both internal and external, but long-term use of AEDs seems to play an important role. Enzyme-inducing drugs, such as phenytoin, phenobarbital and carbamazepine, but also the enzyme inhibitor valproate, appear to have bone-depleting properties. Reduced bone density may be detected during the first 1 – 5 years of treatment. Although many theories have been launched, the exact mechanisms by which the the drugs affect bone architecture are not fully understood.

Take home message: We recommend clinicians to promote osteoprotective behavior among their epilepsy patients; that is, sunlight exposure and weight-bearing exercise as well as avoidance of risk factors such as bone-depleting drugs other than AEDs, smoking and heavy alcohol consumption. Enzyme inducing drugs should be avoided, if possible. Bone mineral density screening should be assessed on an individual basis, taking risk factors for bone loss into account. All patients taking AEDs on long-term basis ought to have adequate amounts of dietary calcium and vitamin D, and those who have developed bone loss should in addition be given specific antiosteoporotic treatment.     

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.     

Neuroprotective effects of antiepileptic drugs

Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.     

Therapeutic monitoring of the new antiepileptic drugs

Objective: To discuss the potential value of therapeutic drug monitoring (TDM) of the new antiepileptic drugs gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. Methods: A review of studies of the relationship between plasma concentrations and effects of new antiepileptic drugs is provided. Furthermore, the potential value of TDM of these drugs is discussed in relation to their mode of action and their pharmacokinetic properties. The various methods that are available for analysing plasma concentrations of the new antiepileptic drugs are also briefly reviewed. Results: The available information on the relationship between plasma concentrations and effects of the new drugs is scarce. For most drugs, wide ranges in concentrations associated with seizure control are reported, and a considerable overlap with drug levels among non-responders and also with concentrations associated with toxicity is often noted. However, very few studies have been designed primarily to explore the relationship between drug plasma concentrations and effects. Consequently, there are no generally accepted target ranges for any of the new antiepileptic drugs. Although the available documentation clearly is insufficient, the pharmacological properties of some of the drugs, in particular lamotrigine, zonisamide and, possibly, oxcarbazepine, topiramate and tiagabine, suggest that they may be suitable candidates for TDM. Conclusion: TDM of some of the new antiepileptic drugs may be of value in selected cases, although routine monitoring in general cannot be recommended at this stage. Further systematic studies designed specifically to investigate concentration–effect relationships of the new antiepileptic drugs are urgently needed. Received: 16 September 1999 / Accepted in revised form: 9 October 1999     

Qualitative study of the interaction mechanism of estrogenic drugs with tubulin

Synthetic estrogenic drugs (E-diethylstilbestrol, erythro-hexestrol and E,E-dienestrol) inhibit tubulin assembly and erythro-hexestrol and E,E-dienestrol lead to the formation of twisted ribbon structures. For the inhibitory effect on tubulin assembly, estrogenic drugs seem to interact directly with tubulin 6S on site(s) analogous to the colchicine-site, but independent of the GTP- and vinblastine-sites. This binding does not involve tubulin tryptophanyl residues or sulfhydryl groups. The influence of temperature, calcium and magnesium on the formation of twisted ribbon structures induced by the binding of estrogenic drugs to microtubular protein and tubulin has also been studied. This formation is strongly magnesium-dependent whereas preformed twisted ribbon structures are calcium- and chilling-insensitive.     

Spectroscopic study of the interaction of coumarin anticoagulant drugs with polyvinylpyrrolidone

The interaction of coumarin anticoagulants with polyvinylpyrrolidone (PVP) was investigated using a fluorescence technique. The fluorescence intensities of warfarin and phenprocoumon were greatly enhanced following binding to PVP, while the fluorescence of 4-hydroxycoumarin was little enhanced in the presence of PVP. The enhanced fluorescence of warfarin and phenprocoumon bound to PVP can be explained by their incorporation into the hydrophobic environment in the PVP and by a decrease in the internal rotation of the alpha-substituted benzyl group in the drugs. The binding parameters of warfarin and phenprocoumon were estimated by the Klotz method; the binding constants for phenprocoumon and warfarin were found to be 2.6 X 10(4) and 2.2 X 10(4) M-1, respectively. The 13C-NMR measurements suggest the lactone moiety in the 4-hydroxycoumarin and the substituted benzene ring play an important role in the binding to PVP.     

Mechaism of neuromuscular blockade with some antiepileptic drugs.

Effects of four antiepileptic drugs, viz., diphenylhydantoin, trimethadione, phenobarbitone and ethosuximide, were studied on different in vitro and in vivo skeletal muscle preparations which consisted of frog rectus, rat phrenic nerve diaphragm and cat gastrocnemius sciatic nerve preparations. A dose related blockade of neuromuscular transmission was seen with all the compounds tested. The blockade was mainly confined to the neuromuscular junction, although direct stimulation of muscle was slightly affected. The blockade was partially antagonized by physostigmine, adrenaline, succinylcholine, choline, tetraethylammonium and KCl and was additive to that due to tubocurarine. Moreover, the drugs were found to possess moderate local anaesthetic activity. The blockade was therefore considered to be partly due to curariform activity and partly due to their local anaesthetic activity.