Interactions between two enantiomers of losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model--an isobolographic analysis

The aim of this study was the isobolographic evaluation of interactions between two enantiomers of losigamone, AO-242 [(+)-5(R)-alpha(S)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone] and AO-294 [(-)-5(S)-alpha(R)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone], and valproate, carbamazepine, phenytoin, or phenobarbital in the maximal electroshock test in mice. Both enantiomers interacted additively with conventional antiepileptic drugs at all studied fixed dose ratios (1:3, 1:1, 3:1). Furthermore, AO-242, AO-294 and antiepileptics applied alone, as well as combinations of enantiomers and antiepileptics did not affect motor performance in the chimney test. Significant impairment of long-term memory (passive-avoidance task) was noted only in the case of valproate alone, given at the dose equal to its median effective dose (ED(50)) against maximal electroshock. All other antiepileptics and their combinations with AO-242 or AO-294 did not impair memory of mice. Enantiomers did not affect the brain concentrations of antiepileptic drugs, indicating a pharmacodynamic nature of the observed interactions. In conclusion, the present results suggest both AO-242 and AO-294 as promising candidate drugs in the add-on therapy of refractory epilepsy.     

Influence of losigamone on the pharmacokinetics of a combined oral contraceptive in healthy female volunteers

OBJECTIVES: The influence of the new antiepileptic drug losigamone (CAS 112856-44-7/123783-52-8) on the pharmacokinetics of a combined oral contraceptive containing ethinylestradiol (CAS 57-63-6) and levonorgestrel (CAS 797-63-7) was investigated in 16 healthy women. METHODS: This phase I study consisted of 3 periods with an uncontrolled first period and a double-blind, placebo-controlled, cross-over design in the second and third period. All subjects received a single dose of 200 mg losigamone (1 tablet) in period 1 (on day 14) as well as multiple doses of losigamone (3 tablets = 600 mg per day) or placebo for 15 days in periods 2 and 3. During all three periods an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel was given. Single-dose pharmacokinetics was investigated on day 14 of period 1. Multiple-dose pharmacokinetic investigations were performed on day 15 of periods 2 and 3. The samples were assayed to derive pharmacokinetic data of ethinylestradiol and levonorgestrel. In addition, the concentrations of losigamone racemate (AO-33) and its enantiomers AO-242 and AO-294 were determined in these samples. RESULTS: The mean values of the pharmacokinetic parameters AUC and Cmax of ethinylestradiol and levonorgestrel after multiple-dose treatment with losigamone or placebo were quite similar and met the criteria for bioequivalence. The 90% confidence intervals of the log-transformed ratios of the geometric means of the primary pharmacokinetic variables were included in the respective acceptance ranges of 80% to 125% (AUC) and 70% to 143% (Cmax). CONCLUSIONS: The study demonstrated that multiple doses of losigamone did not influence the multiple dose kinetics of ethinylestradiol and levonorgestrel. The single- and multiple-dose kinetics of 200 mg losigamone and its enantiomeres did not differ from each other in a significant way. The combination of losigamone and the combined oral contraceptive was well tolerated and no serious adverse events occurred. It can be stated that the antiepileptic drug losigamone and the combined contraceptive do not interact each others metabolism.     

Comparison of the effects of losigamone and its isomers on maximal electroshock induced convulsions in mice and on three different patterns of low magnesium induced epileptiform activity in slices of the rat temporal cortex

Summary Losigamone (AO-33) is a recemate of a tetronic acid derivative. The effects of losigamone and its three isomers (AO-242, AO-294 and AO-23) were compared on maximal electroshock (MES) induced convulsions in mice and on different patterns of extracellularly recorded, low Mg ²⁺ induced epileptiform activity in slices of the rat temporal cortex. Lowering Mg ²⁺ induced recurrent short discharges in areas CA3 and CA1 while ictaform events that lasted for many seconds were induced in the entorhinal cortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the entorhinal cortex changed their characteristics after one to two hours to recurrent discharges of 0.8 to 10 s. Afterdischarges and interictal events were absent. 50 M AO-242 showed a similar efficacy to 50 M AO-33 in reducing and blocking epileptiform discharges in areas CA1 and CA3 while 50 M AO-294 and 50 M AO-23 had weaker effects than 50 M AO-33. Concentrations of 50 M and 100 M AO-242 showed a similar efficacy to AO-33 on ictaform events in the entorhinal cortex. Late recurrent discharges were also blocked by AO-33 and AO-242 although at higher concentrations (300 M). The in vitro observations are with respect to order of efficacy in accordance with the in vivo data obtained in the maximal electroshock test in mice. The order of potency in the MES test was AO-242>AO-33AO-294 AO-23. The results show that the erythro-isomer AO-23, although active, is much less potent than AO-33. Of the two optical isomers of losigamone the (+) isomer AO-242 is more active than the (–) form AO-294. Send offprint requests to C. L. Zhang at the above address     

Isobolographic analysis of interactions among losigamone analog AO-620 and two conventional antiepileptic drugs

In the present study, we investigated pharmacodynamic interactions among AO-620, a losigamone analog, and two conventional antiepileptic drugs, valproate (VPA) and phenobarbital (PB). Experiments were conducted in the maximal electroshock test in mice. Isobolographic analysis of the obtained data revealed pure additive interactions between AO-620 and PB applied at three dose ratios of 1:1, 1:3 and 3:1. Antagonism was observed when AO-620 was co-administered with VPAat the ratio of 3:1, while additive interactions were seen in two remaining proportions (1:3 and 1:1). Surprisingly, the interaction pattern of AO-620 appeared quite different from that of losigamone.     

Genetic animal models of epilepsy as a unique resource for the evaluation of anticonvulsant drugs. A review

Genetic animal models of epilepsy comprise genetically predisposed animal species in which seizures either occur spontaneously or in response to sensory stimulation. The major advantage of these naturally occurring epilepsies in animals as models of human epilepsy is that they simulate the clinical situation more closely than any other experimental epilepsy. Models with idiopathic spontaneous recurrent seizures are epileptic dogs, tottering mice, and rats with spike-wave absence (petit mal) seizures. In dogs, the most common seizure type are generalized tonic-clonic (grand mal) seizures. Recent epidemiological and antiepileptic drug efficacy studies strongly suggest that epileptic dogs offer a valuable model for human grand mal epilepsy. In tottering mice, two types of spontaneous recurrent seizures occur: spike-wave absence seizures and focal motor seizures. Both types differ in sensitivity to common antiepileptic drugs, which closely resembles the absence and focal types of epilepsy in humans. Spontaneously recurrent spike-wave absence seizures in rats can be selectively blocked by drugs effective in petit mal (absence) epilepsy in man, demonstrating the validity of this new petit mal model for anticonvulsant drug screening. Models with reflex seizures comprise photosensitive baboons (Papio papio) and fowl, audiogenic seizure susceptible mice and rats, and gerbils with seizures in response to different sensory stimuli. With respect to seizure types and drug efficacies in these species, rats and chickens may represent suitable models for grand mal epilepsy, whereas baboons offer a useful model of photomyoclonic seizures. Gerbils can be subdivided into animals with minor (myoclonic) and major (mostly generalized tonic-clonic) seizures, which respond differently to antiepileptic drugs and seem to provide interesting models for petit mal and grand mal epilepsy in man. In conclusion, the data summarized in this review emphasize that genetic animal models of epilepsy offer unique approaches to the evaluation of antiepileptic drugs used or usable in man.     

Calcium modulation in epilepsy

The ideal antiepileptic drug (AED) should correct the aberrant pathophysiology of epileptogenesis without interfering with normal neurotransmission A new group of drugs with antiepileptic efficacy, without sedative properties, would be an exciting prospect. Theoretical considerations and results from experimental animal models of epilepsy have put forward the possibility that calcium (Ca2+) antagonists may form such a group. The initiation of epileptogenic activity in the neuron is thought to be connected with the phenomenon known as "intrinsic burst firing", which is activated by an inward Ca2+ current. Ca2+ is described as the primary mediator of "excitotoxic" neuronal damage. Both necrotic and apoptotic cell death is associated with Ca2+ entry into the cells during status epilepticus. The Ca2+ channel blockers depressed epileptic depolarizations of neurons. In this review, we present anticonvulsant effects of cinnarizine, flunarizine, nifedipine, nimodipine, nicardipine, amlodipine, isradipine, niguldipine, diltiazem, verapamil and dantrolene in animal models of seizures. Also, a detailed analysis of interactions between Ca2+ blockers and AEDs was performed. Clinical trials in intractable epilepsy support to a certain degree antiepileptic properties of Ca2+ antagonists.     

Third-generation antiepileptic drugs: mechanisms of action,pharmacokinetics and interactions

This review briefly summarizes the information on the molecular mechanisms of action, pharmacokinetic profiles and drug interactions of novel (third-generation) antiepileptic drugs, including brivaracetam, carabersat, carisbamate, DP-valproic acid, eslicarbazepine, fluorofelbamate, fosphenytoin, ganaxolone, lacosamide, losigamone, pregabalin, remacemide, retigabine, rufinamide, safinamide, seletracetam, soretolide, stiripentol, talampanel, and valrocemide. These novel antiepileptic drugs undergo intensive clinical investigations to assess their efficacy and usefulness in the treatment of patients with refractory epilepsy.     

Antiepileptic effects of single and repeated oral administrations of S-312-d, a novel calcium channel antagonist, on tonic convulsions in spontaneously epileptic rats

We investigated the effects of single and repeated administrations of S-312-d (methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno-[2,3-b]pyridine-5-carboxylate), a newly synthesized L-type Ca(2+)-channel blocker, on tonic convulsions and absence-like seizures in the spontaneously epileptic rat (SER: zi/zi, tm/tm), a genetically based animal model of human epilepsy. Single oral administrations of S-312-d dose-dependently inhibited tonic convulsions and the effects lasted for more than 2 h, although they did not attenuate the absence-like seizures. We also examined the effects of repeated administrations of S-312-d at 1 mg/kg once a day for 4 days on SER. A significant decrease in the number and total duration of tonic convulsions was observed 45 and 75 min after the first administration of the drug, respectively. The effects lasted for 24 h without changes in the background EEG or blood pressure. This inhibitory effect on the tonic convulsions was gradually strengthened by subsequent daily administrations of S-312-d and lasted for 3 days after the cessation of drug treatment. In contrast, the repeated treatment with S-312-d did not influence absence-like seizures of SER. These results suggest that S-312-d is a candidate drug that has antiepileptic effects against the convulsive seizures in human epilepsy.     

Nifedipine affects the anticonvulsant activity of topiramate in various animal models of epilepsy

Topiramate (TPM), a new generation antiepileptic drug was investigated for its anticonvulsant effects in various models of genetically determined and chemically induced epilepsy in rodents. In addition, based on recent electrophysiological data suggesting that TPM may interact with L-type Ca(2+) channels, we evaluated the effects of a concomitant administration of L-type Ca(2+) channel modulators on TPM's antiepileptic properties. TPM, dose-dependently, protected against audiogenic seizures in DBA/2 mice. Concomitant treatment with TPM and a low dose of L-type Ca(2+) channel antagonists nifedipine or verapamil or with the L-type Ca(2+) channel agonist, S(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid methyl ester (Bay k 8644) was able to increase the ED(50) for this drug. TPM also protected against seizures induced by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), 4-aminopyridine (4-AP) and pentylenetetrazole (PTZ), but this activity was not significantly modified by nifedipine. TPM, dose-dependently, reduced the number and duration of epileptic spike-wave discharges (SWDs) both in WAG/Rij rats and lethargic (lh/lh) mice, two genetic models of absence epilepsy. Nifedipine decreased TPM's activity in WAG/Rij rats but paradoxically enhanced it in lh/lh mice, whereas Bay k 8644 displayed opposite effects in both absence models. These results confirm TPM's broad spectrum of anticonvulsant activity and support the proposal that a modulation of neuronal L-type Ca(2+) channel activity plays an important role in its antiepileptic activity.     

Investigation of phenobarbital-carbamazepine-valproic acid interactions using population pharmacokinetic analysis for optimisation of antiepileptic drug therapy: an overview

Antiepileptic drugs are associated with a wide range of drug interactions. Although monotherapy with antiepileptic drugs is preferred, patients with multiple seizure types or refractory disease generally require various combinations of antiepileptic drugs. Pharmacokinetic interactions between antiepileptic drugs represent a major complication of epilepsy treatment with polytherapy. It is important to be aware of possible interactions, so as to anticipate clinical effects and to reduce the risk of both toxicity and seizures worsening when a drug is added to, or withdrawn from, the patient's antiepileptic drug regimen. This report is an overview of the drug-drug interactions between antiepileptic drugs (phenobarbital<-->carbamazepine, carbamazepine<-->valproic acid and phenobarbital<-->valproic acid) by population pharmacokinetic analysis.     

Determination of risk factors associated with seizure relapse after antiepileptic drug withdrawal

There is no consensus regarding the time of antiepileptic drug withdrawal and the relevant risk factors for seizure relapse. In this study, we aimed to determine the seizure relapse rates and the associated risk factors for seizure relapse in childhood epilepsy. Two-hundred sixty-six epileptic patients who discontinued the antiepileptic drug therapy after a seizure-free period of at least two years, were enrolled into the study. The data of the patients regarding sex, febrile convulsion history, family history, age at onset, type of epilepsy, total number of seizures and antiepileptic drugs, seizures during treatment, mental status, first and last electroencephalography, brain imaging findings, etiological factors and seizure relapse in the first two years after antiepileptic drug withdrawal were obtained from the patients’ files. Univariate logistic regression analysis was performed for each variable. The variables which were found to be statistically significant in univariate analysis, were included in multivariate logistic regression analysis. The overall seizure relapse rate after antiepileptic drug withdrawal was 19.2%. There were no significant differences for seizure relapse rate after antiepileptic drug withdrawal between patient groups with respect to sex, family history, type of epilepsy, febrile convulsion history, seizures before treatment, first electroencephalography findings, brain imaging findings and etiology. However, there were statistically significant differences for seizure relapse rate among patient groups concerning age at onset of epilepsy, new seizure during treatment, the total number of antiepileptic drugs, mental status, and last electroencephalography findings. We imply that the clinical status of the patients should be considered before the cessation of drug therapy rather than the etiological factors or laboratory findings.     

单唾液酸四己糖神经节苷脂钠治疗脑外伤癫痫疗效分析

目的评价用单唾液酸四己糖神经节苷脂钠(神经节苷脂)联合高压氧及常规抗癫痫药物综合与单纯高压氧及常规抗癫痫药物治疗脑外伤癫痫的疗效。方法常规抗癫痫药物联合高压氧治疗脑外伤癫痫为对照组(73例),对照组基础上加用神经节苷脂静脉点滴为治疗组(77例),观察临床症状和脑电图。结果与对照组相比:试验组神经节苷脂给药越早,疗效指标改变越好。多个不同的发作类型,疗程结束的脑电图显示均有显著改善,其中以单纯部分性发作类型及全面性发作类型患者尤为明显。结论神经节苷脂联合高压氧综合治疗脑外伤癫痫是一种有效的治疗手段。     

Principles of treatment of epilepsy

Epilepsy is a common chronic neurological condition with a prevalence of 4-8 per 1000. The present classification of epilepsy is based on: 1) the etiology, which distinguishes symptomatic epilepsies from those that are idiopathic and cryptogenic, and 2) the localization of the disorder in the brain, separating the generalized seizures from epilepsies with partial or focal onset. The majority of patients with epilepsy will go into remission and two-thirds will remain so 2 years after drug withdrawal. The impact of epilepsy on individual patients varies. Employment, driving and learning may constitute major problems. There is a small but definite increase in mortality in patients suffering from epilepsy. Treatment of epilepsy usually involves long-term medical treatment, with the ultimate aim being no seizures and no drugs. Before starting treatment, the diagnosis of epilepsy should be assured. Initiation of antiepileptic drug therapy needs a full and adequate discussion with the patient and the choice of the minimum effective dose of an appropriate monotherapy. Nonpharmacological treatments may be necessary at a relatively early stage if pharmacologic treatment is ineffective. In choosing between different anti-epileptic drugs, consideration should be given to the efficacy of the drug for an individual patient and the tolerability of the drug. There is good evidence from many studies that the chief factor determining relative effectiveness is likely to be the spectrum and incidence of adverse effects of antiepileptic drugs. Some 20% of patients developing epilepsy have a chronic disorder uncontrolled by drugs. In patients receiving and complying with optimal doses of a single antiepileptic drug, the addition of further agents is likely to result in a significant improvement in seizure control in only about 10% of patients, but inevitably it increases the risks of dose-related, idiosyncratic and chronic toxicity due to both pharmacokinetic and pharmacodynamic drug interactions. For this group of patients an appropriate aim may not be complete remission of seizures but a compromise of reduced seizure frequency with less severe seizures, to be achieved with one or, at most, two drugs. The management of these patients with unremitting seizures constitutes a treatment challenge for epileptologists.     

Effect of phenytoin on sodium and calcium currents in hippocampal CA1 neurons of phenytoin-resistant kindled rats.

About 20-30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms explaining why some patients' respond and others prove resistant to antiepileptic drugs are poorly understood. It has been proposed that pharmacoresistance is related to reduced sensitivity of sodium channels in hippocampal neurons to antiepileptic drugs such as carbamazepine or phenytoin. In line with this proposal, a reduced effect of carbamazepine on sodium currents in hippocampal CA1 neurons was found in the rat kindling model of temporal lobe epilepsy (TLE), i.e. a form of epilepsy with the poorest prognosis of all epilepsy types in adult patients. To address directly the possibility that neuronal sodium currents in the hippocampus play a crucial role in the pharmacoresistance of TLE, we selected amygdala-kindled rats with respect to their in vivo anticonvulsant response to phenytoin into responders and nonresponders and then compared phenytoin's effect on voltage-activated sodium currents in CA1 neurons. Furthermore, in view of the potential role of calcium current modulation in the anticonvulsant action of phenytoin, the effect of phenytoin on high-voltage-activated calcium currents was studied in CA1 neurons. Electrode-implanted but not kindled rats were used as sham controls for comparison with the kindled rats. In all experiments, the interval between last kindled seizure and ion channel measurements was at least 5 weeks. In kindled rats with in vivo resistance to the anticonvulsant effect of phenytoin (phenytoin nonresponders), in vitro modulation of sodium and calcium currents by phenytoin in hippocampal CA1 neurons did not significantly differ from respective data obtained in phenytoin responders, i.e. phenytoin resistance was not associated with a changed modulation of the sodium or calcium currents by this drug. Compared to sham controls, phenytoin's inhibitory effect on sodium currents was significantly reduced by kindling without difference between the responder and nonresponder subgroups. Further studies in phenytoin-resistant kindled rats may help to elucidate the mechanisms that can explain therapy resistance.     

脑梗死患者继发性癫痫的发病特点及临床治疗分析

目的探讨脑梗死后继发癫痫的发病特点及临床治疗效果。方法对2007年5月至2011年2月收治的53例脑梗死后发生癫痫患者的发作时间、发作类型与发病机制进行临床分析。结果本组病例抗癫痫疗效满意,45例癫痫发作停止,8例应用抗癫痫药物维持治疗。14例强直一阵挛持续状态中2例死于脑疝或肺部感染、全身衰竭。结论脑梗死后癫痫的发生和病灶部位及梗死发作时间有关,皮层受累更易引起癫痫,癫痫发作和病灶大小及严重程度无明确关系。     

Rational combinations of antiepileptic drugs for refractory epilepsy

Although epilepsy surgery is most effective for patients with intractable epilepsy, a majority of them is not eligible for the surgery. Most of patients with refractory epilepsy are eventually treated with polypharmacy in hope of seizure control. Therefore, rational combinations of antiepileptic drugs are needed to control intractable seizures. Drug combinations should be rationally chosen based on the evidence of synergic efficacy and on avoidance of neurotoxicity. Several clinical studies suggest that the combination of valproate with lamotrigine has synergic antiepileptic effect. It has also been reported that the combination of carbamazepine with lamotrigine paradoxically decreases efficacy and increases toxicity. Animal studies using isobolography suggest that the combinations of topiramate with lamotrigine or levetiracetam are also promising on both seizure control and neurotoxicity. Clinical research is needed to examine these combinations.     

Brivaracetam for the treatment of epilepsy

INTRODUCTION: Epilepsy is one of the most common neurological disorders, affecting about 1% of the population worldwide. With currently available antiepileptic drugs, one-third of patients continue to suffer from seizures even when treated at maximally tolerated dosages, either in monotherapy or in various drug combinations. Pharmacoresistance is associated with physical risks, reduced life expectancy, reduced quality of life and impairments in social opportunities. The acetamide derivate levetiracetam (LEV) that primarily targets the synaptic vesicle protein 2A has been one of the most successful second-generation antiepileptic drugs. AREAS COVERED: This article reviews a rationally designed LEV derivative, brivaracetam (BRV), which has an increased affinity to the LEV-binding site. BRV has shown some efficacy in the treatment of progressive myoclonus epilepsy and is under development to be used as an add-on treatment of focal epilepsy. Evidence is given for possible advantages related to the higher intrinsic antiepileptic efficacy of BRV and its antiepileptic potential in relation to a wide spectrum of epilepsy forms and for possible disadvantages related to hepatic metabolism and to a lower therapeutic index related to additional intrinsic activity at the sodium channel. An update on pharmacodynamic, pharmacokinetic and study data published until 2010 on BRV is given. EXPERT OPINION: BRV is a rationally developed third-generation antiepileptic drug with higher binding to SV2A and additional mechanisms of actions. Animal studies are promising regarding its efficacy in a wide spectrum of epilepsy models. Clinical studies have shown good tolerability at dosages of up to 50 mg/day but have yet to identify the optimal dose range and to prove an additional value of the drug in terms of seizure control.     

Challenges in the clinical development of new antiepileptic drugs.

The very nature of epilepsy makes the clinical development of new antiepileptic drugs a lengthy and costly process. The underlying disease mechanisms are largely unknown, reflecting the paucity of animal models that mirror the human condition. The risks of untreated epilepsy usually preclude the use of placebo as a control treatment except in patients receiving background medication. Thus, new AEDs must first display a treatment effect in patients with seizures known to be resistant to drug therapy, using study designs that are confounded by the potential pharmacodynamic and pharmacokinetic interactions associated with polytherapy. Moreover, the unpredictable nature of epilepsy often means lengthy clinical trials. Clinical development for antiepileptic drugs is inevitably more complex and time-consuming than for many other drugs. As a result the interval between product approval and loss of patent is often shorter. Creative methods of accelerating the development process without compromising the quality of research are needed.     

Remacemide--a novel potential antiepileptic drug

Epilepsy belongs to common diseases of the brain. It affects approximately 1% of the population. The aim of epilepsy therapy is to keep the patient free of seizures without interfering with normal brain function. Unfortunately, about 30% of all epilepsies remain without control. In this situation patients require polytherapy which is usually a combination of antiepileptic drugs (AEDs) acting via different mechanisms of action. Many potential AEDs have been developed but the proportion of patients failing to respond to drug treatment has not been fundamentally changed. The aim of this review was to assemble current literature data on remacemide, a novel AED, which is suggested for the treatment of epilepsy. Remacemide hydrochloride is a low-affinity NMDA receptor blocker as well as Na(+) fast-channel blocker. The drug exerts anticonvulsant activity both in various animal seizure models and in clinical studies. In addition to its antiseizure properties, the drug seems to provide neuroprotection. Remacemide holds promise to serve as neuroprotectant not only in seizures but perhaps in other neurodegenerative conditions in humans as well.     

Levetiracetam: a novel antiepileptic drug.

Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. Levetiracetam has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. Recommended starting dosages are considered to be clinically effective; therefore, patients can have some protection from seizures soon after they begin levetiracetam. The most common adverse effects observed with levetiracetam are mild and include somnolence, asthenia, and dizziness. Clinical experience and data from meta-analyses indicate that levetiracetam is well tolerated, with efficacy comparable or slightly better than that observed with other new antiepileptic drugs. Levetiracetam may be particularly useful in patients who are unresponsive to other antiepileptic drugs, patients receiving drugs with increased potential for drug interactions, or those with hepatic impairment.