levetiracetam and stiripentol

Recently, the treatment strategy for pediatric epilepsy has been dramatically changed in Japan, because of the approval of new-generation antiepileptic drugs. Since 2006, a total of 6 new antiepileptic drugs, including gabapentin (GBP; adults/pediatric patients: 2006/2011 [year of approval]), topiramate (TPM; 2007/2013), lamotrigine (LTG; 2008/2008), levetiracetam (LEV; 2010/2013), stiripentol (STP; 2012/2012), and rufinamide (RUF; 2013/2013), have been introduced. Thus far, valproate (VPA) and carbamazepine (CBZ) have been first indicated for "generalized" epilepsy and "focal" epilepsy syndromes/types, respectively, in Japan. However, the approval of these new drugs could allow us to choose more effective and less toxic ones at an early stage of treatment. In this chapter, we describe the latest domestic and foreign guidelines for the treatment of pediatric epilepsy.

Topics: Adolescent; Amines; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Cyclohexanecarboxylic Acids; Dioxolanes; Drug Approval; Drug Substitution; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Infant; Lamotrigine; Levetiracetam; Patient Education as Topic; Piracetam; Practice Guidelines as Topic; Topiramate; Triazines; Triazoles; Valproic Acid

New antiepileptic drugs (AEDs) that have been used in many other countries for more than 10 years have only recently became available for use in Japan. Gabapentin, topiramate, lamotrigine and levetiracetam were licensed for use in Japan between 2006 and 2010. Stiripentol for Dravet syndrome and rufinamide for Lennox-Gastaut syndrome were also approved in 2012 and 2013 as orphan drugs. Clinical trials of other new AEDs such as oxcarbazepine, vigabatrin, lacosamide, and perampanel are in progress. In this review, the general characteristics of the new AEDs are discussed with regards to their effectiveness, tolerability, drug interaction, safety and mechanisms of action. The effectiveness, of the new AEDs compared with established AEDs is also discussed. Clinical applications of the new AEDs, focusing on gabapentin, topiramate, lamotrigine and levetiracetam are also discussed based on our domestic experience as well as overseas reports.

Topics: Amines; Anticonvulsants; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Dioxolanes; Drug Approval; Drug Interactions; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Japan; Lamotrigine; Levetiracetam; Piracetam; Safety; Topiramate; Triazines; Triazoles

Topics: Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsies, Partial; Epilepsy; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Oxcarbazepine; Piracetam; Pregabalin; Topiramate; Triazines; Vigabatrin; Zonisamide

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.

Topics: Acetates; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Phenytoin; Piracetam; Propylene Glycols; Thiazines; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

Epilepsy is one of the most common neurological disorders. Even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications. There is, therefore, a need for more potent and effective antiepileptic drugs and drugs with fewer adverse effects, particularly CNS effects. Drugs for the treatment of partial seizures are particularly needed. With major advances in our understanding of the basic neuropathology, neuropharmacology and neurophysiology of epilepsy, numerous candidate novel antiepileptic drugs have been developed in recent years. This review comparatively evaluates the pharmacokinetics, efficacy and adverse effects of 12 new antiepileptic drugs namely vigabatrin, lamotrigine, gabapentin, oxcarbazepine, felbamate, tiagabine, eterobarb, zonisamide, remacemide, stiripentol, topiramate and levetiracetam (ucb-L059). Of the 12 drugs, vigabatrin, lamotrigine and gabapentin have recently been marketed in the UK. Five of these new drugs have known mechanisms of action (vigabatrin, lamotrigine, tiagabine, oxcarbazepine and eterobarb), which may provide for a more rational approach to the treatment of epilepsy. Oxcarbazepine, remacemide and eterobarb are prodrugs. Vigabatrin, gabapentin and topiramate are more promising on the basis of their pharmacokinetic characteristics in that they are excreted mainly unchanged in urine and not susceptible to significant pharmacokinetic interactions. In contrast, lamotrigine, felbamate and stiripentol exhibit significant drug interactions. Essentially, all the drugs are effective in partial or secondarily generalised seizures and are effective to varying degrees in other seizure types. Particularly welcome is the possible effectiveness of zonisamide in myoclonus and felbamate in Lennox-Gastaut syndrome. In relation to adverse effects, CNS effects are observed with all drugs, however, gabapentin, remacemide and levetiracetam appear to exhibit least. There is also the possibility of rational duotherapy, using drugs with known mechanisms of action, as an additional therapeutic approach. The efficacy of these 12 antiepileptic drug occurs despite the fact that candidate antiepileptic drugs are evaluated under highly unfavourable conditions, namely as add-on therapy in patients refractory to drug management and with high seizure frequency. Thus, whilst candidate drugs wh

Topics: Acetamides; Acetates; Amines; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Nipecotic Acids; Oxcarbazepine; Phenobarbital; Phenylcarbamates; Piracetam; Propylene Glycols; Risk Factors; Tiagabine; Topiramate; Triazines; Vigabatrin; Zonisamide

The use of therapeutic drug monitoring (TDM) for antiseizure medications (ASMs) may contribute to treatment optimization in individual patients. This study included patients with Dravet syndrome as they often require close monitoring because of polypharmacy with various ASMs. The aim was to use long-term TDM to investigate pharmacokinetic variability of ASMs in these patients.. Retrospective data from patients with Dravet syndrome were collected from the TDM database at the Section for Clinical Pharmacology, National Center for Epilepsy in Norway (2008-2018). Concentration/(dose/kg)ratios (C/D ratios) were calculated for the ASMs and the concentration (C/C ratio) for N-desmethylclobazam. In patients with at least 3 measurements, the CV for C/D ratios for intrapatient and interpatient variability was calculated.. Fifty-three patients (30 male patients/23 female patients) between 2 and 50 years of age (mean, 16 years) were included. Pharmacokinetic variability of the total number of measurements of valproate (n = 417), clobazam and N-desmethylclobazam (n = 328), and levetiracetam (n = 238) was determined. Interpatient variability was more pronounced than intrapatient variability (coefficient of variations: valproate, 65% vs. 24%; levetiracetam, 71% vs. 27%; and clobazam/N-desmethylclobazam, 47%/77% vs. 35%/55%) (P < 0.01). Comedication with stiripentol (n = 16) increased the C/D ratio of valproate by 63% and of clobazam by 133% and the C/C ratio of N-desmethylclobazam/clobazam by 104% (P < 0.05). Younger age also contributed to pharmacokinetic variability.. Long-term TDM revealed extensive variability in serum concentrations over time; the variability was lowest for levetiracetam, moderate for valproate, and highest for clobazam. Pharmacokinetic variability and interactions can thus be identified and adjusted to facilitate decision making to achieve the optimal treatment outcome.

Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Clobazam; Dioxolanes; Drug Monitoring; Epilepsies, Myoclonic; Epilepsy; Female; Humans; Levetiracetam; Male; Middle Aged; Norway; Retrospective Studies; Valproic Acid; Young Adult

There is strong evidence for the use of the ketogenic diet (KD) in Dravet syndrome (DS). The purpose of this study was to evaluate both effectiveness and tolerability in comparison with various antiepileptic drugs (AEDs).. 32 children (19 males) with genetically confirmed DS treated at our center since 1999 were analyzed retrospectively. Data collected from patients' files included type of mutation, age at treatment initiation and treatment lag, overall seizure frequency and frequency of different seizure types, especially prolonged seizures and status epilepticus (SE). Efficacy and safety of the KD were evaluated. In addition, the effect on seizure count was compared with that of various AED regimen and the vagus nerve stimulation (VNS).. Overall response to the KD was 70% at 3 months and 60% at 12 months. No SE occurred while patients were on the diet, and the frequencies of prolonged generalized and myoclonic seizures were reduced. No severe side effects requiring withdrawal of the KD were observed. Although the effect of the KD was independent of age at initiation, it had to be withdrawn due to noncompliance more frequently in solid fed older children compared with infants treated with the liquid ketogenic formula. The KD was not significantly inferior to the current gold standard AED triple combination of Stiripentol+Valproate+Clobazam (89%), Bromides (78%), Valproate alone (48%), Topiramate (35%) and VNS (37%) and significantly more effective than Levetiracetam (30%; p=0.037, Pearson's Chi-square).. These data suggest that the KD ranks among currently used AEDs as an effective treatment for seizures in DS. According to our results (good effect on SE and prolonged seizures, good tolerability, less compliance problems due to formula treatment) the KD should be considered as an early treatment option in infants with DS.

Topics: Adolescent; Anticonvulsants; Benzodiazepines; Bromides; Child; Child, Preschool; Clobazam; Diet, Ketogenic; Dioxolanes; Epilepsies, Myoclonic; Female; Fructose; Humans; Infant; Levetiracetam; Male; Piracetam; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Vagus Nerve Stimulation; Valproic Acid; Young Adult

The syndrome of malignant migrating partial seizures in infancy is a devastating, age-specific, epileptic encephalopathy, which still presents an aetiological, pathophysiological and therapeutic problem. In this study, we present two patients who were diagnosed with the disease, based on electroclinical symptoms. The patients were treated with a combination of sodium bromide, stiripentol and levetiracetam. The first patient unequivocally responded, following a course of ineffective conventional drugs, and the second, who was diagnosed and treated immediately, showed a more significant therapeutic response. Antiepileptic drugs, previously reported to be beneficial in case reports, when given concomitantly, may substantially reduce the number and severity of seizures, without influence on psychomotor development. [Published with video sequences].

Topics: Anticonvulsants; Bromides; Dioxolanes; Drug Therapy, Combination; Electroencephalography; Epilepsies, Partial; Female; Humans; Infant; Infant, Newborn; Levetiracetam; Piracetam; Sodium Compounds; Treatment Outcome