Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

BACKGROUND AND OBJECTIVES: Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. METHODS: We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. RESULTS: Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. DISCUSSION: Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Management of corticosteroid-dependent eosinophilic interstitial nephritis: A case report.

INTRODUCTION: Drug-induced acute interstitial nephritis (DI-AIN) is an important cause of acute kidney injury. In renal biopsy specimens, tubulitis with eosinophilic infiltration is suggestive of DI-AIN. Although corticosteroid therapy and discontinuation of the offending drug can improve renal dysfunction in most cases of DI-AIN, some patients experience AIN recurrence, leading to corticosteroid dependency. Corticosteroid-dependent eosinophilic interstitial nephritis presents a difficult dilemma in diagnosis and information regarding optimum management is limited. PATIENT CONCERNS: A 25-year-old man, who received treatment with carbamazepine, zonisamide, valproate, and lacosamide for temporal lobe epilepsy, showed an increase in serum creatinine level from 0.98 to 1.29 mg/dL over a period of 6 months. Although he exhibited no symptoms, his serum creatinine level continued to increase to 1.74 mg/dL. DIAGNOSIS: Renal biopsy revealed tubulitis and interstitial inflammatory infiltrates with eosinophils. Immunological and ophthalmological examinations showed no abnormal findings, and thus, his renal dysfunction was presumed to be caused by DI-AIN. Although oral prednisolone (PSL) administration (40 mg/d) and discontinuation of zonisamide immediately improved his renal function, AIN recurred 10 months later. The increase in PSL dose along with discontinuation of valproate and lacosamide improved renal function. However, 10 months later, recurrent AIN with eosinophilic infiltration was confirmed by further biopsy. The patient was therefore diagnosed with corticosteroid-dependent eosinophilic interstitial nephritis. INTERVENTIONS: To prevent life-threatening epilepsy, carbamazepine could not be discontinued; hence, he was treated with an increased dose of PSL (60 mg/d) and 1500 mg/d of mycophenolate mofetil (MMF). OUTCOMES: MMF was well tolerated and PSL was successfully tapered to 5 mg/d; renal function stabilized over a 20-month period. LESSONS: The presence of underdetermined autoimmune processes and difficulties in discontinuing the putative offending drug discontinuation are contributing factors to corticosteroid dependency in patients with eosinophilic interstitial nephritis. MMF may be beneficial in the management of corticosteroid-dependent eosinophilic interstitial nephritis by reducing the adverse effects related to high-dose and long-term corticosteroid use.

1,3,4-Oxadiazol-2-ylbenzenesulfonamides as privileged structures for the inhibition of monoamine oxidase B.

The present study investigates the monoamine oxidase (MAO) inhibition properties of a series of ten 5-aryl-1,3,4-oxadiazol-2-ylbenzenesulfonamides. The target compounds were synthesized by dehydration of the corresponding N,N'-diacylhydrazines with phosphorus oxychloride to yield the 1,3,4-oxadiazole cycle with concomitant transformation of the sulfonamide to the sulfonyl chloride group. Treatment with aqueous ammonia in acetonitrile regenerated the target sulfonamides. The results of the enzymology document that these compounds are potent and specific MAO-B inhibitors with the most potent compound exhibiting an IC50 value of 0.0027 µM. An analysis of the structure-activity relationships shows that the 4-benzenesulfonamides are significantly more potent MAO-B inhibitors than the corresponding 3-benzenesulfonamides, and that the corresponding N,N'-diacylhydrazine synthetic precursors are weak MAO inhibitors. Although MAO inhibition by oxadiazole compounds are known, this is the first report of nanomolar MAO inhibition potencies recorded for sulfonamide derivatives. MAO-B specific inhibitors such as those discovered here may be of interest in the treatment of neurodegenerative disorders such as Parkinson's disease.

Garcinol, an effective monoamine oxidase-B inhibitor for the treatment of Parkinson's disease.

Loss of dopamine containing neurons in the substantia nigra pars compacta of midbrain, and resultant depletion of dopamine in the striatum is the cause of Parkinson's disease (PD), which is associated with motor abnormalities. Replenishment of dopamine by oral supplementation of its precursor, the levodopa (L-DOPA), remains the primary mode of treatment of PD, despite its potential side-effects after prolonged use in patients. To reduce the daily dosing of L-DOPA in patients, inhibitors of dopamine catabolizing enzymes, particularly monoamine oxidase-B (MAO-B), are prescribed. The most widely used MAO-B inhibitor to maintain the bioavailability of dopamine in the brain of PD patients is L-deprenyl, despite of its potential side-effects. The present study identified Garcinol as a potential candidate in the treatment paradigm of PD by virtue of its exorbitant MAO-B inhibitory potential. The inhibitory potential is comparable to the known MAO-B inhibitors, which was evaluated using molecular docking technique. Owing to its known antioxidant, anti-inflammatory and catechol-o-methyl transferase inhibitory potential, the molecule would confer neuroprotection as well, and thus, the present study is of immense significance in the treatment paradigm of PD.

Current and emerging medications for overweight or obesity in people with comorbidities.

Recently, the recognition of obesity as a complex disease that requires chronic management has become more widespread. There has also been a movement away from a focus on body mass index alone, and toward the management of obesity-related comorbidities as well as excess weight. This article examines the current and emerging pharmacological options for weight management in people with overweight or obesity who have, or are at a high risk of, weight-related comorbidities. In the USA, the current options for pharmacological weight management are phentermine (indicated for short-term use only), orlistat, combined phentermine/topiramate extended release, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg. Currently, orlistat, naltrexone/bupropion and liraglutide 3.0 mg are approved in Europe. All of the above-mentioned medications have shown weight-loss efficacy versus placebo. Those approved for long-term weight management have also been associated with improvements in weight-related comorbidities, such as hypertension, prediabetes, diabetes or dyslipidaemia, or related biomarkers. As with all drugs, the safety and tolerability profiles of medications for weight management should be considered alongside their efficacy to ensure correct use. Additional medications for weight management that are in clinical development include bupropion/zonisamide and beloranib. The field of obesity treatment is advancing with a number of medications being recently approved, and with other pharmacological options emerging.

Tardive dyskinesia (syndrome): Current concept and modern approaches to its management.

Tardive dyskinesia is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking psychotropic drugs. The pathophysiology of tardive dyskinesia is complex, multifactorial and still not fully understood. A number of drugs were tried for the management of this motor disturbance, yet until now no effective and standard treatment has been found. It is very disappointing to realize that the introduction of antipsychotics from the second generation has not significantly decreased the prevalence and incidence of tardive dyskinesia. Therefore, the management of this motor disturbance remains an actual topic as well as a challenge for clinicians. This review summarizes recent relevant publications concerning the treatment of tardive dyskinesia.

Management and monitoring of patients treated with zonisamide: the OZONE study.

AIM: To characterise patients treated with zonisamide in everyday practice and describe the effectiveness and tolerability of treatment. METHODS: This was an observational, longitudinal, naturalistic study, conducted by neurologists in France. Patients who had started zonisamide treatment at least three months prior to inclusion were eligible. Data were collected at routine consultations at inclusion (Visit 1) and three to six months later (Visit 2). At Visit 1, investigators documented epilepsy-related variables based on patient records before initiation of zonisamide and at inclusion. At Visit 2, the investigators re-evaluated seizure activity and rated effectiveness. Adverse events were also documented. RESULTS: A total of 428 patients were included in the study based on evaluation by 132 neurologists. Zonisamide was initiated at a daily dose of 50 mg and 25 mg in 61% and 31.8% of patients, respectively. The median maintenance dose was 300 mg/day. Prior to initiation of zonisamide, the mean seizure frequency was 16.0 seizures/month. This was reduced to 8.7 seizures/month at Visit 1 and to 7.1 seizures/month at Visit 2. The response rate and proportion of seizure-free patients was 61.9 and 31.1% at Visit 1 and 65.9 and 25.6% at Visit 2, respectively. The frequency of seizures at Visit 2 decreased significantly (p<0.05) for all seizure type subgroups, except for simple partial seizures. Responder rates were >60% for all analysed subgroups. The proportion of seizure-free patients was significantly higher in patients receiving bitherapy, compared to the others (p=0.007). The most frequently reported adverse event was somnolence (5.1%); three serious adverse events were reported. CONCLUSION: In everyday practice, zonisamide is principally used in association with other antiepileptic drugs for the treatment of focal epilepsy in adults. It is effective in improving seizure control and quality of life, and is generally well-tolerated.

Riluzole elevates GLT-1 activity and levels in striatal astrocytes.

Drugs which upregulate astrocyte glutamate transport may be useful neuroprotective compounds by preventing excitotoxicity. We set up a new system to identify potential neuroprotective drugs which act through GLT-1. Primary mouse striatal astrocytes grown in the presence of the growth-factor supplement G5 express high levels of the functional glutamate transporter, GLT-1 (also known as EAAT2) as assessed by Western blotting and ³H-glutamate uptake assay, and levels decline following growth factor withdrawal. The GLT-1 transcriptional enhancer dexamethasone (0.1 or 1 µM) was able to prevent loss of GLT-1 levels and activity following growth factor withdrawal. In contrast, ceftriaxone, a compound previously reported to enhance GLT-1 expression, failed to regulate GLT-1 in this system. The neuroprotective compound riluzole (100 µM) upregulated GLT-1 levels and activity, through a mechanism that was not dependent on blockade of voltage-sensitive ion channels, since zonasimide (1 mM) did not regulate GLT-1. Finally, CDP-choline (10 µM-1 mM), a compound which promotes association of GLT-1/EAAT2 with lipid rafts was unable to prevent GLT-1 loss under these conditions. This observation extends the known pharmacological actions of riluzole, and suggests that this compound may exert its neuroprotective effects through an astrocyte-dependent mechanism.

The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics.

PURPOSE: The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. METHODS: Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. RESULTS: The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB-kindled rats showed more rapid development of the seizure stage and AD duration than AMG-kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB-kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB-kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB-kindled seizures. Zonisamide was not effective at any dose tested in AMG-kindled rats. DISCUSSION: OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics.

Effects of zonisamide on neurotransmitter release associated with inositol triphosphate receptors.

To clarify the antiepileptic mechanisms of zonisamide (ZNS), we determined the interaction between ZNS and inositol-1,4,5-triphosphate receptor (IP3R) on exocytosis of GABA and glutamate in rat frontal cortex using microdialysis. ZNS increased basal GABA release, but not glutamate, concentration-dependently, and reduced concentration-dependently K(+)-evoked GABA and glutamate releases. Inhibition and activation of IP3R reduced and enhanced basal and K(+)-evoked GABA releases, respectively. The K(+)-evoked glutamate release was reduced and enhanced by IP3R antagonist and agonist, respectively, whereas basal glutamate release was increased by IP3R agonist but not affected by IP3R antagonist. Under extracellular Ca(2+) depletion, IP3R agonist increased basal GABA and glutamate releases. The latter effects of IP3R agonist were weakly enhanced by ZNS, but such stimulatory action of ZNS was abolished by extracellular Ca(2+) depletion. In contrast, ZNS inhibited the stimulatory effect of IP3R agonist on K(+)-evoked release. The stimulatory effect of IP3R agonist on basal release was regulated by N-type voltage-sensitive Ca(2+) channel (VSCC) rather than P- and L-type VSCCs, whereas the stimulatory effect of IP3R agonist on K(+)-evoked release was regulated by P- and L-type VSCCs rather than N-type VSCC. These results suggest that ZNS-activated N-type VSCC enhances IP3R-associated neurotransmitter release during resting stage, whereas ZNS-induced suppression of P- and L-type VSCCs possibly attenuates IP3R-associated neurotransmitter release during neuronal hyperexcitability. Therefore, the combination of both of these two actions of ZNS on IP3R-associated neurotransmitter release mechanism seems to be involved, at least in part, in the mechanisms of antiepileptic and neuroprotective actions of ZNS.

Drug monitoring: simultaneous analysis of lamotrigine, oxcarbazepine, 10-hydroxycarbazepine, and zonisamide by HPLC-UV and a rapid GC method using a nitrogen-phosphorus detector for levetiracetam.

A high-performance liquid chromatography (HPLC) assay using UV detection is described for the simultaneous measurement of the newer generation anti-epileptic medications lamotrigine, oxcarbazepine (parent drug and active metabolite 10- hydroxycarbazepine), and zonisamide. Detection of all four compounds can be done at 230 nm; however, there is a potential interference with zonisamide in patients on clonazepam therapy. Therefore, the method uses dual wavelength detection: 230 nm for oxcarbazepine and 10-hydroxycarbazepine and 270 nm for lamotrigine and zonisamide. In addition, a simple gas chromatography method using a nitrogen-phosphorus detector is described for the measurement of levetiracetam, another of the recently approved anti-epileptic medications. For both methods, limits of quantitation, linearities, accuracies, and imprecisions cover the therapeutic range for drug monitoring of patients. A wide variety of clinical drugs, including other anti-epileptic drugs, do not interfere with these assays. These procedures would be of special interest to clinical laboratories, particularly due to the limited availability of immunoassays for newer generation anti-epileptic medications and that therapeutic uses of these drugs are expanding beyond epilepsy to other neurologic and psychiatric disorders.

Clinical pharmacology and mechanism of action of zonisamide.

Antiepileptic drugs (AEDs) suppress seizures by selectively modifying the excitability of neurons and blocking seizure firing with minimal disturbance of nonepileptic activity. All AEDs have been shown to work by at least one of 3 main mechanisms of action: through modulation of voltage-gated ion channels, enhancement of synaptic inhibition, and inhibition of synaptic excitation. Zonisamide is a novel AED that has a broad combination of complementary mechanisms of action, which may offer a clinical advantage over other antiepileptic agents. By altering the fast inactivation threshold of voltage-dependent sodium channels, zonisamide reduces sustained high-frequency repetitive firing of action potentials. Zonisamide also inhibits low-threshold T-type calcium channels in neurons, which may prevent the spread of seizure discharge across cells. In addition, zonisamide is a weak inhibitor of carbonic anhydrase. However, this mechanism is not believed to contribute to the antiepileptic activity of zonisamide. Although zonisamide also seems to alter dopamine, serotonin, and acetylcholine metabolism, it is not clear to what extent these effects on neurotransmitters are involved in the clinical actions of the drug. In addition to these actions, recent evidence suggests that zonisamide may exert neuroprotective actions, independent of its antiepileptic activity. These potential effects may be important in preventing neuronal damage caused by recurrent seizures. Therefore, it seems that the multiple pharmacological actions of zonisamide may contribute to the seizure reductions observed in a wide range of epilepsies and may help to preserve efficacy in individual patients despite possible changes in electrophysiological status.

[New medications; zonisamide]. / Nieuwe geneesmiddelen; zonisamide.

Zonisamide is an adjuvant for the treatment of patients with partial epilepsy, with or without secondary generalisation. It affects, among other things, the voltage-sensitive sodium and calcium channels, thus disrupting synchronised neuronal firing; as a result, it diminishes the spread of seizure discharges.

Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center.

We evaluated our clinical experience with zonisamide, a broad-spectrum antiepileptic drug, in a group of children with predominantly medically refractory epilepsy. A retrospective chart review was conducted on patients at our tertiary referral center following Institutional Review Board approval. Observers documented reports of seizure frequency, and seizure types were identified either clinically or by prior video-electroencephalography monitoring. We identified 68 patients (age range 1.9-18.1 years [median 6.9 years]; male to female ratio 1.3:1) treated with zonisamide for 0.7 to 28.9 months; at the last visit, 22% and 78% were on monotherapy and adjunctive therapy, respectively. The median duration of treatment and maintenance dose at the end of the follow-up were 11.2 months and 8.0 mg/kg/day, respectively. Seizure types included generalized (primary generalized tonic-clonic, myoclonic, tonic, atonic, absence) and partial (simple, complex, and secondarily generalized tonic-clonic seizures); 10 (15%) patients had both partial and generalized seizures. Sixteen (25.8%) patients were seizure free, although five of them were already in remission prior to starting zonisamide. Thirteen (21.0%) patients had a > 50% seizure reduction, 10 (16.1%) patients had a < 50% seizure reduction, 14 (22.6%) had no improvement in baseline seizures, and 9 (14.5%) reported having increased seizures. The latter were mostly associated with dosage alterations in concomitant antiepileptic drugs. Common side effects were central nervous system related, including behavioral or psychiatric (23.5%), cognitive dysfunction (12.0%), and sedation (10.3%). Eleven (16.2%) patients ultimately discontinued zonisamide, but only five were strictly due to side effects. Zonisamide is clinically effective against multiple seizure types in a significant proportion of children with epilepsy across a broad age range. Drug discontinuation as a result of side effects is uncommon.

Interaction between carbamazepine, zonisamide and voltage-sensitive Ca2+ channel on acetylcholine release in rat frontal cortex.

To clarify the mechanisms of action of antiepileptic drugs (AEDs), carbamazepine (CBZ) and zonisamide (ZNS), on exocytosis mechanisms, the present study determined the concentration-dependent action of CBZ and ZNS, as well as the interaction between these AEDs and voltage-sensitive Ca(2+) channel (VSCC) activity on basal, Ca(2+)- and K(+)-evoked acetylcholine (ACh) release in frontal cortex of freely moving rat using in vivo microdialysis. Perfusion with therapeutic-relevant concentrations of CBZ and ZNS increased basal ACh release, which was regulated by N-type VSCC predominantly and P-type VSCC weakly, whereas supratherapeutic-relevant concentrations of these AEDs reduced this release. The 3.4 mM Ca(2+)-evoked release, which was regulated by N-type VSCC selectively, but not by P-type VSCC, was increased by therapeutic-relevant concentrations of CBZ and ZNS, whereas this release was reduced by supratherapeutic-relevant concentrations of them. The 50 mM K(+)-evoked release, which was regulated by P-type VSCC predominantly and N-type VSCC weakly, was decreased by CBZ and ZNS, in a concentration-dependent manner. These findings indicate that the interplay between enhancement of basal ACh release and reduction of depolarization-related ACh release in the frontal cortex are at least partially involved in a common mechanism of antiepileptic action between CBZ and ZNS.

Zonisamide monotherapy in newly diagnosed infantile spasms.

PURPOSE: We determined the short-term efficacy of zonisamide (ZNS) monotherapy in newly diagnosed patients with infantile spasms (IS). METHODS: Eleven hospitals participated in this open, prospective trial. ZNS 3-10 mg/kg/day was administered as the second-choice drug to 11 newly diagnosed patients with IS (cryptogenic 3, symptomatic 8) who failed to respond to high-dose vitamin B6. RESULTS: Four infants with symptomatic IS had cessation of spasms and disappearance of the hypsarrhythmia. In these responders, the spasms ceased after a few days (1-5 days) of treatment at a dose of ZNS 4-5 mg/kg/day which produced plasma ZNS concentrations ranging from 5.2 to 16.3 microg/ml (mean 9.8 microg/ml). There were two relapses (50%) 4-6 weeks after cessation of seizures, however. Relapse was predicted by effects of ZNS on EEG; the 2 infants in whom an abnormal EEG persisted had relapses, whereas the 2 whose EEG normalized remained seizure-free (follow-up 20 and 26 months). No adverse reactions were noted. CONCLUSIONS: ZNS may be effective in the initial treatment of selected patients with IS.

[Treatment of the epilepsy: new drugs]. / Tratamiento de la epilepsia: nuevas drogas.

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.

Investigational antiepileptic drugs for the treatment of childhood seizure disorders: a review of efficacy and safety.

Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.