topiramate 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

New advances in the knowledge on the physiopathogenesis of epilepsy and their relationship with sodium and calcium channels and with the excitatory and inhibitory neurotransmitters actions have recently been developed. These knowledges have produced the research on new antiepileptic drugs which action places have specially based on the known impaired mechanisms. As the conventional drugs, the new therapeutic tool have produced a great advance in the therapy of epileptic events, specially in the refractory seizures, which represent 25-30% of the whole group of epilepsies. In the present work, we review the new drugs, ones have been registered, in order to their pharmacological properties, their efficacy their safety and their clinical indications as first-election or adjuvant drugs. We also discuss their known side adverse effects.

Topics: Acetates; Amines; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Benzodiazepinones; Carbamazepine; Clobazam; Cyclohexanecarboxylic Acids; Dioxolanes; Epilepsy; Felbamate; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Isoxazoles; Lamotrigine; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; 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

During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.

Topics: Acetamides; Acetates; Amines; Aminocaproates; Anticonvulsants; Carbamazepine; Cyclohexanecarboxylic Acids; Dioxolanes; Felbamate; Flunarizine; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lamotrigine; Nipecotic Acids; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Tiagabine; Topiramate; Triazines; Vigabatrin

Dravet syndrome (DS) is an intractable epilepsy syndrome. The three-drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide.. We present a case of DS, in which treatment with CLB could not be continued because of the appearance of adverse reactions to it. Replacement with topiramate (TPM) proved to be markedly effective.. It is suggested that combination therapy with VPA, TPM and STP is for DS epilepsy.

Topics: Anticonvulsants; Child, Preschool; Dioxolanes; Drug Therapy, Combination; Epilepsies, Myoclonic; Epilepsy; Female; Fructose; Humans; Topiramate; Valproic Acid

Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome.. Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated.. Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations.. Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.

Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Clobazam; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Dioxolanes; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Fructose; Humans; Infant; Male; Polymorphism, Genetic; Retrospective Studies; Topiramate; Valproic Acid

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 purpose of this study was to assess the effectiveness and tolerability of topiramate (TPM) as add-on therapy in children with Dravet syndrome and considered unsatisfactorily controlled using stiripentol. All the 36 patients having been treated with TPM in our centre in 2001 were retrospectively evaluated. Seventy percent of them still received stiripentol when TPM was introduced. The association of both drugs did not need any particular adaptation of dosages. The mean TPM follow-up was 13.3 months (4-25 months) and the mean optimal TPM dose was 3.2 mg/kg/d (0.6-9.2 mg/kg/d). Twenty eight children (78 %) showed more than 50 % reduction in the frequency of generalized tonic-clonic seizures and status epilepticus (SE), whereas 8 % had more than 50 % increase. Six patients (17 %) remained seizure-free for at least 4 months. The most frequently reported side-effects were gastrointestinal and behavioural disturbances. TPM had to be stopped in 17 % of patients, because of poor tolerability and/or lack of efficacy. Topiramate seems therefore to be helpful in Dravet syndrome, even in patients not satisfactorily controlled by stiripentol. Both drugs can be easily and safely associated.

Topics: Anticonvulsants; Dioxolanes; Drug Therapy, Combination; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Retrospective Studies; Seizures, Febrile; Status Epilepticus; Topiramate; Treatment Outcome