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Introducción. El levetiracetam (LEV) es un antiepiléptico aprobado por el Instituto de Salud Pública de Chile como terapia concomitante en crisis epilépticas en niños mayores de cuatro años. Sin embargo, es ampliamente indicado desde el periodo neonatal, lo que hace necesario evaluar su utilización fuera de ficha técnica. Objetivo. Determinar el perfil de prescripción-indicación de LEV en el tratamiento de las crisis epilépticas en menores de cuatro años en un hospital de alta complejidad del sur de Chile. Población y método. Estudio observacional, descriptivo y retrospectivo. Se revisaron las historias clínicas de quienes iniciaron tratamiento con LEV entre 2014 y 2019, y se recopilaron datos sobre variables sociodemográficas, farmacológicas y clínicas. El análisis se basó en la descripción del perfil de los pacientes, prescripción, seguimiento y seguridad. Resultados. Se incluyeron 68 pacientes: 40 (58,8 %) de sexo masculino, 49 (72,1 %) con edad gestacional ≥ 37 semanas. La etiología principal de la epilepsia fue de tipo estructural (35,3 %); el LEV se utilizó principalmente en niños diagnosticados con malformación del sistema nervioso central (17,6 %) y predominó la monoterapia (55,9 %). En el 50 % se usó LEV para crisis focales. Cinco niños (7,3 %) presentaron trastornos de tipo psiquiátrico clasificados como probables reacciones adversas al medicamento. Conclusión. El LEV se utilizó en niños con diferentes diagnósticos con baja frecuencia de eventos adversos. El perfil de utilización varió en los diferentes grupos etarios. Es necesario identificar en futuros estudios la efectividad especialmente en el recién nacido y en epilepsias refractarias.

Introduction. Levetiracetam (LEV) is an antiepileptic drug approved by the Chilean Institute of Public Health as concomitant therapy for epileptic seizures in children older than 4 years of age. However, it is widely prescribed from the neonatal period, which makes it necessary to evaluate its off-label use. Objective. To determine the prescription-indication profile of LEV in the treatment of epileptic seizures in children younger than 4 years in a tertiary care hospital in southern Chile. Population and method. Observational, descriptive, and retrospective study. The medical records of patients who started treatment with LEV between 2014 and 2019 were reviewed, and data on sociodemographic, pharmacological, and clinical variables were collected. The analysis was based on the description of the profile of patients, prescriptions, follow-up, and safety. Results. A total of 68 patients were included: 40 (58.8%) were males, 49 (72.1%) were born at a gestational age ≥ 37 weeks. The main etiology of epilepsy was structural (35.3%); LEV was mostly used in children diagnosed with central nervous system malformation (17.6%), and monotherapy was the prevailing dosage (55.9%). LEV was used for focal seizures in 50% of cases. Five children (7.3%) had psychiatric disorders, classified as probable adverse drug reactions. Conclusion. LEV was used in children with various diagnoses, with a low rate of adverse events. The profile of drug use varied in the different age groups. Future studies are needed to identify effectiveness, especially in newborn infants and patients with refractory epilepsy.

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Introduction. Levetiracetam (LEV) is an antiepileptic drug approved by the Chilean Institute of Public Health as concomitant therapy for epileptic seizures in children older than 4 years of age. However, it is widely prescribed from the neonatal period, which makes it necessary to evaluate its off-label use. Objective. To determine the prescription-indication profile of LEV in the treatment of epileptic seizures in children younger than 4 years in a tertiary care hospital in southern Chile. Population and method. Observational, descriptive, and retrospective study. The medical records of patients who started treatment with LEV between 2014 and 2019 were reviewed, and data on sociodemographic, pharmacological, and clinical variables were collected. The analysis was based on the description of the profile of patients, prescriptions, follow-up, and safety. Results. A total of 68 patients were included: 40 (58.8%) were males, 49 (72.1%) were born at a gestational age ≥ 37 weeks. The main etiology of epilepsy was structural (35.3%); LEV was mostly used in children diagnosed with central nervous system malformation (17.6%), and monotherapy was the prevailing dosage (55.9%). LEV was used for focal seizures in 50% of cases. Five children (7.3%) had psychiatric disorders, classified as probable adverse drug reactions. Conclusion. LEV was used in children with various diagnoses, with a low rate of adverse events. The profile of drug use varied in the different age groups. Future studies are needed to identify effectiveness, especially in newborn infants and patients with refractory epilepsy.

Introducción. El levetiracetam (LEV) es un antiepiléptico aprobado por el Instituto de Salud Pública de Chile como terapia concomitante en crisis epilépticas en niños mayores de cuatro años. Sin embargo, es ampliamente indicado desde el periodo neonatal, lo que hace necesario evaluar su utilización fuera de ficha técnica. Objetivo. Determinar el perfil de prescripción-indicación de LEV en el tratamiento de las crisis epilépticas en menores de cuatro años en un hospital de alta complejidad del sur de Chile. Población y método. Estudio observacional, descriptivo y retrospectivo. Se revisaron las historias clínicas de quienes iniciaron tratamiento con LEV entre 2014 y 2019, y se recopilaron datos sobre variables sociodemográficas, farmacológicas y clínicas. El análisis se basó en la descripción del perfil de los pacientes, prescripción, seguimiento y seguridad. Resultados. Se incluyeron 68 pacientes: 40 (58,8 %) de sexo masculino, 49 (72,1 %) con edad gestacional ≥ 37 semanas. La etiología principal de la epilepsia fue de tipo estructural (35,3 %); el LEV se utilizó principalmente en niños diagnosticados con malformación del sistema nervioso central (17,6 %) y predominó la monoterapia (55,9 %). En el 50 % se usó LEV para crisis focales. Cinco niños (7,3 %) presentaron trastornos de tipo psiquiátrico clasificados como probables reacciones adversas al medicamento. Conclusión. El LEV se utilizó en niños con diferentes diagnósticos con baja frecuencia de eventos adversos. El perfil de utilización varió en los diferentes grupos etarios. Es necesario identificar en futuros estudios la efectividad especialmente en el recién nacido y en epilepsias refractarias.

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Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Levetiracetam (LEV) is an antiepileptic drug whose mechanism of action at the genetic level has not been fully described. Therefore, the aim of the present work was to evaluate the relevant gene expression changes in the dentate gyrus (DG) of LEV-treated rats with pilocarpine-induced TLE. Whole-transcriptome microarrays were used to obtain the differential genetic profiles of control (CTRL), epileptic (EPI), and EPI rats treated for one week with LEV (EPI + LEV). Quantitative RT-qPCR was used to evaluate the RNA levels of the genes of interest. According to the results of the EPI vs. CTRL analysis, 685 genes were differentially expressed, 355 of which were underexpressed and 330 of which were overexpressed. According to the analysis of the EPI + LEV vs. EPI groups, 675 genes were differentially expressed, 477 of which were downregulated and 198 of which were upregulated. A total of 94 genes whose expression was altered by epilepsy and modified by LEV were identified. The RT-qPCR confirmed that LEV treatment reversed the increased expression of Hgf mRNA and decreased the expression of the Efcab1, Adam8, Slc24a1, and Serpinb1a genes in the DG. These results indicate that LEV could be involved in nonclassical mechanisms involved in Ca2+ homeostasis and the regulation of the mTOR pathway through Efcab1, Hgf, SLC24a1, Adam8, and Serpinb1a, contributing to reduced hyperexcitability in TLE patients.

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ABSTRACT Purpose: To evaluate using optical coherence tomography angiography the macular and optic nerve head blood flow in pediatric patients with epilepsy treated with levetiracetam for at least 12 months. Methods: This study included 33 pediatric patients with epilepsy and 30 sex- and age-matched healthy volunteer children were included in the study. Optical coherence tomography angiography was used to evaluate the optic nerve head and macular perfusion changes. The mean ocular perfusion pressures were also calculated. Patients who were using multiple antiepileptic drugs or had a prior history of using different drugs were excluded. Results: The choriocapillaris flow area was significantly lower in the Study Group than in the Control Group (p=0.006). However, the foveal avascular zone and vessel densities of the macula in the superficial capillary plexus, deep capillary plexus, and optic nerve head of the study group were not significantly different from those of the control group (p>0.05). Moreover, no significant difference in means of mean ocular perfusion pressure was found between the two groups (p=0.211). No obvious correlation was found between treatment duration and optical coherence tomography angiography parameters or mean ocular perfusion pressure. Conclusion: Choroidal perfusion was reduced in children taking levetiracetam compared with that in the control group, whereas retinal perfusion was not affected in this optical coherence tomography angiography study.

RESUMO Objetivo: Avaliar através de angiotomografia de coerência óptica o fluxo sanguíneo macular e da cabeça do nervo óptico em pacientes pediátricos com epilepsia tratados com levetiracetam por pelo menos 12 meses. Método: Trinta e três pacientes pediátricos com epilepsia e 30 crianças voluntárias saudáveis pareadas por sexo e idade foram incluídos no estudo. A angiotomografia de coerência óptica foi utilizada para avaliar as alterações da perfusão da cabeça do nervo óptico e da macular. As médias das pressões de perfusão ocular também foram calculadas. Pacientes em uso de múltiplas drogas antiepilépticas ou com história prévia de uso de diferentes drogas foram excluídos do estudo. Resultado: A área do fluxo coriocapilar foi significativamente menor no Grupo Estudo do que no Grupo Controle (p=0,006). Entretanto, a zona avascular foveal e as densidades vasculares no plexo capilar superficial e profundo da região macular e na cabeça do nervo óptico não foram significativamente diferentes daquelas de olhos saudáveis (p>0,05). Também não houve diferença significativa entre os dois grupos em relação às médias da pressão de perfusão ocular (p=0,211). Nenhuma correlação aparente foi encontrada entre a duração do tratamento e os parâmetros da angiotomografia de coerência óptica ou a média da pressão de perfusão ocular. Conclusão: Em crianças usando levetiracetam, a perfusão coroidal mostrou-se reduzida em comparação ao grupo controle, enquanto a perfusão retiniana não foi afetada neste estudo com angiotomografia de coerência óptica.

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Introducción: Las mioclonías son contracciones musculares paroxísticas de corta duración o pérdida abrupta del tono muscular, denominadas mioclonías positivas y negativas, respectivamente. Se presenta un caso clínico de mioclonías positivas y negativas generalizadas y se pretende describir los múltiples mecanismos fisiopatológicos y etiologías que lo desencadenan. Presentación del caso: Hombre de 35 años, con diabetes mellitus tipo 1 complicada con enfermedad renal diabética en hemodiálisis, desarrolló una bacteriemia asociada a catéter por Staphylococcus aureus y presentó mioclonías positivas y negativas. Se identificaron como posibles desencadenantes la uremia, la infección y los fármacos con potencial promioclónico; el hallazgo incidental de una lesión isquémica en núcleo caudado no explicaba la semiología encontrada en el paciente. Se hizo el control y retiro de todos los factores promioclónicos enunciados, junto a manejo farmacológico con levetiracetam, y con ello se logró el control de los síntomas. Discusión: Los pacientes con enfermedad renal crónica son susceptibles a la acumulación de productos tóxicos de tipo guanidinas, que tienen potencial para producir mioclonías. Además, las infecciones, el uso de fármacos con potencial promioclónico y lesiones estructurales como las isquemias corticales son etiologías que deben considerarse en el diagnóstico diferencial. El mayor impacto en los síntomas se observa con el control del factor desencadenante, y, en caso de persistir, la terapia farmacológica proporciona buenos resultados. Conclusión: Las mioclonías son trastornos del movimiento relativamente comunes en la enfermedad renal crónica. La identificación del desencadenante es crucial para su manejo junto al uso de fármacos con actividad antimioclónica.

Introduction: Myoclonus are paroxysmal muscle contractions of short duration or abrupt loss of muscle tone, called positive and negative myoclonus respectively. A clinical case of generalized positive and negative myoclonus is presented and the aim is to describe the multiple pathophysiological mechanisms and etiologies that trigger it. Case presentation: A 35-year-old man with type 1 diabetes mellitus complicated by diabetic kidney disease on hemodialysis developed catheter-associated bacteremia due to Staphylococcus aureus and presented positive and negative myoclonus. Uremia, infection, and drugs with pro-myoclonic potential were identified as possible triggers; The incidental finding of an ischemic lesion in the caudate nucleus did not explain the semiology found in the patient. The control and removal of all the pro-myoclonic factors mentioned was carried out, along with pharmacological management with levetiracetam, thus achieving control of the symptoms. Discussion: Patients with chronic kidney disease are susceptible to the accumulation of guanidine-type toxic products, which have the potential to produce myoclonus. Furthermore, infections, the use of drugs with pro-myoclonic potential and structural lesions such as cortical ischemia are etiologies that should be considered in the differential diagnosis. The greatest impact on symptoms is observed with the control of the triggering factor and if it persists, pharmacological therapy provides good results. Conclusion: Myoclonus are relatively common movement disorders in chronic kidney disease. Identification of the trigger is crucial for its management along with the use of drugs with anti-myoclonic activity.

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Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable.

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Background: Levetiracetam has a favorable pharmacology profile to be used subcutaneously. However, its subcutaneous use is still considered off-label as this is beyond its license. The evidence base for its safety, tolerability, and efficacy is limited to observational studies. Objectives: To report the safety and efficacy of subcutaneous levetiracetam in Latino patients on home care. Design: Observational retrospective case series study. Subjects: Consecutive sample of Latino adults with life-limiting illnesses. Methods: A case series framework with 4 domains (selection, ascertainment, causality, and reporting) to ensure reporting quality was used. Additionally, 8 relevant outcomes established in a previous comprehensive review, were collected and reported. Adverse reactions were documented using the Common Terminology Criteria for Adverse Events. Results: Fifteen Latino patients with oncological and non-oncological diagnoses received subcutaneous levetiracetam for a mean of 21 days on home care. Levetiracetam was most frequently initiated subcutaneously due to loss of the oral route. The average dosage of subcutaneous levetiracetam was 1200 mg. Only 1 patient required a dose adjustment, and only 2 patients experienced a total of 5 seizures during the therapy trial. No adverse reactions were reported. Conclusions: Subcutaneous levetiracetam appears to be effective and safe. This case series of Latino patients in home care expands the evidence of its use in the home care setting. The preliminary data reported by now on multiple case series warrants robust trials.

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Levetiracetam (LEV) is an anticonvulsant for epilepsy. The toxic effects of this medication in tissues have been associated with redox state imbalance, which can lead to salivary gland dysfunction. Therefore, the current work investigated the effects of LEV on the biochemical, functional, and redox parameters of the parotid and submandibular glands in rats. For this, male Wistar rats (Rattus norvegicus albinus) were randomly divided into 3 groups (n = 10/group): Control (0.9% saline solution), LEV100 (100 mg/kg), and LEV300 (300 mg/kg). After 21 consecutive days of intragastric gavage treatments, pilocarpine stimulated saliva secretion was collected for salivary biochemical analysis. The extracted salivary glands were utilized for histomorphometry and redox state analyses. Our results showed that LEV300 increased plasma hepatotoxicity markers and reduced salivary amylase activity and the acinar surface area of the parotid gland. Total oxidant capacity and oxidative damage to lipids and proteins were higher in the parotid gland, while total antioxidant capacity and uric acid levels were reduced in the submandibular gland of the LEV100 group compared to Control. On the other hand, total oxidant capacity, oxidative damage to lipids and proteins, total antioxidant capacity, and uric acid levels were lower in both salivary glands of the LEV300 group compared to Control. Superoxide dismutase and glutathione peroxidase activities were lower in the salivary glands of treated animals compared to Control. In conclusion our data suggest that treatment with LEV represents a potentially toxic agent, that contributes to drug-induced salivary gland dysfunction.

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Epilepsy is a neurological disorder in which it has been shown that the presence of oxidative stress (OS) is implicated in epileptogenesis. The literature has shown that some antiseizure drugs (ASD) have neuroprotective properties. Levetiracetam (LEV) is a drug commonly used as an ASD, and in some studies, it has been found to possess antioxidant properties. Because the antioxidant effects of LEV have not been demonstrated in the chronic phase of epilepsy, the objective of this study was to evaluate, for the first time, the effects of LEV on the oxidant-antioxidant status in the hippocampus of rats with temporal lobe epilepsy (TLE). The in vitro scavenging capacity of LEV was evaluated. LEV administration in rats with TLE significantly increased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, but did not change glutathione peroxidase (GPx) activity, and significantly decreased glutathione reductase (GR) activity in comparison with epileptic rats. LEV administration in rats with TLE significantly reduced hydrogen peroxide (H2O2) levels but did not change lipoperoxidation and carbonylated protein levels in comparison with epileptic rats. In addition, LEV showed in vitro scavenging activity against hydroxyl radical (HO•). LEV showed significant antioxidant effects in relation to restoring the redox balance in the hippocampus of rats with TLE. In vitro, LEV demonstrated direct antioxidant activity against HO•.

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BACKGROUND: Seizures are common in palliative care patients and its control is essential in the management of these patients as it helps to reduce suffering at the end of life. Subcutaneous levetiracetam has been used off-license for seizure control in palliative care. OBJECTIVE: The objective of the study was to describe our experience with subcutaneous levetiracetam in two hospitals in Bogota, Colombia. METHODS: We conducted a retrospective review of patients treated with subcutaneous levetiracetam in two hospitals in Colombia during 2019-2021. Data were extracted from medical records, and participants were followed up as outpatients. RESULTS: Twenty-one patients were included into the study. No severe adverse effects or rise in ictal frequency were documented. Twelve patients died during hospitalization and nine continued treatments as outpatients. The principal diagnosis was structural focal epilepsy. The daily dose of levetiracetam ranged from 1,000 mg to 3,000 mg, and the duration of treatment varied among subjects between 1 and 360 days. CONCLUSION: Subcutaneous levetiracetam was well tolerated and effective in controlling seizures in palliative care when oral administration or intravenous access was not an option. Randomized controlled trials are needed to elucidate the efficacy and tolerability of subcutaneous levetiracetam in clinical practice.

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BACKGROUND AND HYPOTHESIS: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. STUDY RESULTS: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. CONCLUSIONS: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

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Abstract The aim of the present study was to investigate the usefulness of multidrug resistance protein 1 (MDR1) and neuropeptide Y (NPY) levels in predicting the efficacy of levetiracetam (LEV) plus oxcarbazepine (OXC) treatment administered to children with epilepsy and to determine their prognosis. Overall, 193 children with epilepsy admitted to the hospital were enrolled and randomly divided into two groups according to different treatment methods: group A (n = 106, treated with LEV plus OXC combination) and group B (n = 87, treated with OXC only). After treatment, compared with group B, group A exhibited a remarkably higher total effective rate and a significantly lower total adverse reaction rate. Areas under the curve for MDR1 and NPY for predicting ineffective treatment were 0.867 and 0.834, whereas those for predicting epilepsy recurrence were 0.916 and 0.829, respectively. Electroencephalography abnormalities, intracranial hemorrhage, neonatal convulsion, premature delivery, and MDR1 and NPY levels were independent risk factors for poor prognosis in children with epilepsy. Serum MDR1 and NPY levels exhibited a high predictive value for early epilepsy diagnosis, treatment efficacy assessment, and prognostication in children with epilepsy treated with LEV plus OXC combination.

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El síndrome de hipersensibilidad a medicamentos, con eosinofilia y síntomas sistémicos (DRESS de sus siglas en inglés) es un síndrome muy infrecuente que se caracteriza por erupción dérmica, eosinofilia y compromiso sistémico. Inicialmente fue descrito asociado a medicamentos anticrisis (antiepilépticos), pero posteriormente ha sido descrito en asociación a otros medicamentos. Entre los medicamentos anticrisis, se ha descrito predominantemente su asociación a fármacos aromáticos o con estructura similar: fenitoína, carbamazepina, fenobarbital, oxcarbazepina y lamotrigina. Entre los medicamentos anticrisis no aromáticos, se ha descrito su presentación en algunos pacientes expuestos a gabapentina, zonisamida, valproato, rufinamida y raramente a levetiracetam. La severidad del síndrome se relaciona al tiempo de exposición al fármaco, por lo que su detección precoz es de vital importancia. Describimos el primer caso en nuestro país, de un paciente con DRESS inducido por levetiracetam y revisamos los infrecuentes reportes de DRESS en pacientes expuestos a levetiracetam descritos en la literatura.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a very rare syndrome characterized by skin rash, eosinophilia and systemic compromise. This was initially described in association with antiseizures drugs, but later it was described in association with other drugs. Among antiseizure drugs, it has been described association with aromatic drugs as phenytoin, carbamazepine, phenobarbital, oxcarbazepine and lamotrigine; and non-aromatic antiseizure drugs as gabapentin, zonisamide, valproate, rufinamide and rarely to levetiracetam. The severity of the syndrome is related to the time of exposure to the drug, so early detection is of vital importance. We describe the first case in our country, of a patient with DRESS induced by levetiracetam, and we review the infrequent scientific reports of DRESS in patients exposed to levetiracetam.

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Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel drugs, new molecular targets, and a better understanding of the mechanisms of action of existing drugs is still crucial. Levetiracetam (LEV) is an AED that has been shown to be effective in seizure control and is well-tolerable, with a novel mechanism of action through an interaction with the synaptic vesicle protein 2A (SV2A). Moreover, LEV has other molecular targets that involve calcium homeostasis, the GABAergic system, and AMPA receptors among others, that might be integrated into a single mechanism of action that could explain the antiepileptogenic, anti-inflammatory, neuroprotective, and antioxidant properties of LEV. This puts it as a possible multitarget drug with clinical applications other than for epilepsy. According to the above, the objective of this work was to carry out a comprehensive and integrative review of LEV in relation to its clinical uses, structural properties, therapeutical targets, and different molecular, genetic, and systemic action mechanisms in order to consider LEV as a candidate for drug repurposing.

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OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication prescribed to women during childbearing age. The impact of LEV on placental transporters is poorly understood. This study aimed to assess the effect of LEV exposure on the messenger RNA (mRNA) expression of placental transporters for hormones and nutrients and to correlate their expression with the drug's serum concentration in pregnant mice. METHODS: Studies were conducted on gestational days (GD) 13 and 18, following oral treatment with 100 mg/kg LEV or the vehicle every 24 h after weaning. Serum LEV measurements were performed by High-performance liquid chromatography with a UV detector (HPLC-UV). The weight, height, and width of the fetuses were also analyzed. In addition, the placental expression of transporters xCt, Lat1, Oatp4a1, Fr-α, Rfc, and Snat4 was evaluated through semi-quantitative real-time polymerase chain reaction (qPCR). The Kruskal-Wallis and the Mann-Whitney U tests were used to determine the statistical significance (p < .05). The correlation between serum LEV concentration and placental gene expression was evaluated using the Spearman test. RESULTS: The weight, height, and width were lower in the fetuses exposed to LEV compared with the control group (p < .05). The number of fetuses was lower in the LEV-exposed group than in the control GD 13 group (p < .001). No significant differences were detected in the mRNA expression level at GD 13. At GD 18, the expression of Lat1, Oatp4a1, xCT, and Snat4 was higher in the group treated with LEV compared with the control group (p < .05), whereas the expression of Rfc was lower (p < .05). No correlation was identified between serum LEV concentrations and gene expression levels. SIGNIFICANCE: The repression of the Rfc transcript by LEV at GD 18 suggests that the protein expression would be abolished contributing to the observed intrauterine growth restriction (IUGR). Furthermore, the significant increase in mRNA of xCt, Snat4, Oatp4a1, and Lat1 might be a compensatory mechanism for fetal survival at GD 18.

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Synaptic vesicle protein 2A (SV2A), the target of the antiepileptic drug levetiracetam (LEV), is expressed ubiquitously in all synaptic terminals. Its levels decrease in patients and animal models of epilepsy. Thus, changes in SV2A expression could be a critical factor in the response to LEV. Epilepsy is characterized by an imbalance between excitation and inhibition, hence SV2A levels in particular terminals could also influence the LEV response. SV2A expression was analyzed in the epileptic hippocampus of rats which responded or not to LEV, to clarify if changes in SV2A alone or together with glutamatergic or GABAergic markers may predict LEV resistance. Wistar rats were administered saline (control) or pilocarpine to induce epilepsy. These groups were subdivided into untreated or LEV-treated groups. All epileptic rats were video-monitored to assess their number of seizures. Epileptic rats with an important seizure reduction (>50%) were classified as responders. SV2A, vesicular γ-aminobutyric acid transporter and vesicular glutamate transporter (VGLUT) expression were assessed by immunostaining. SV2A expression was not modified during epilepsy. However, responders showed ≈55% SV2A-VGLUT co-expression in comparison with the non-responder group (≈40%). Thus, SV2A expression in glutamatergic terminals may be important for the response to LEV treatment.

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ABSTRACT Background: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. Objective: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. Methods: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. Results: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. Conclusion: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

RESUMO Introdução: A epilepsia afeta cerca de 50 milhões de pessoas em todo o mundo e aproximadamente 30% desses pacientes apresentam epilepsia refratária, com possíveis consequências na qualidade de vida, morbidade e mortalidade prematura. Objetivo: O objetivo do tratamento com fármacos antiepilépticos (FAEs) é permitir que os pacientes permaneçam sem crises epilépticas com boa tolerabilidade. O levetiracetam (LEV) é um FAE de amplo espectro, com mecanismo de ação único, diferente dos demais e que demonstra ser eficaz e seguro no tratamento de adultos e crianças. Métodos: Estudo de fase III, multicêntrico, randomizado, duplo-cego e controlado por placebo avalia a eficácia e a segurança do LEV em crianças e adultos (4-65 anos) como tratamento adjuvante para crises de início focal em 114 pacientes já tratados com até três FAEs. A análise de eficácia primária foi baseada na proporção de pacientes que apresentaram redução ≥50% no número médio de crises epilépticas focais semanais, durante 16 semanas. Os pacientes foram randomizados para receber placebo ou LEV, titulado a cada duas semanas de 20 mg/kg/dia ou 1.000 mg/dia até 60 mg/kg/dia ou 3.000 mg/dia. Resultados: LEV foi significativamente superior ao placebo (p=0,0031), com 38,7% dos participantes no grupo LEV e 14,3% no grupo controle que apresentaram redução das crises focais. LEV apresenta bom perfil de segurança com eventos adversos semelhantes ao placebo. Conclusão: Corroborando com os resultados da literatura, o levetiracetam mostra-se eficaz e seguro para crianças e adultos com epilepsia focal refratária.

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BACKGROUND: The current study is a reanalysis in the time domain of EEG data collection in healthy adults during an oddball paradigm using levetiracetam (LEV) vs. placebo acute administration. Specifically, the event-related potential (ERP) technique provides a tool for exploring the EEG responses to a specific event/stimulus. One of the ERP components widely studied is the P300 component, which is associated with the last stage of information processing and a general measurement of "cognitive efficiency." METHODS: The sample was composed of thirteen healthy right-handed individuals randomized to participate under two conditions: LEV and placebo. Electrophysiological measures were collected before and after drug intake. We explored the oddball paradigm, which is commonly used with healthy individuals to investigate the stages of information processing. RESULTS: The electrophysiological results showed a main effect of condition on P300 amplitude for the frontal (F3, Fz, F4), central (C3, Cz, C4), and parietal electrodes (P3, Pz, P4). The post hoc comparisons (Scheffé's test) demonstrated the significant differences between electrodes. Regarding P300 latency, all regions represented a main effect of condition. A P300 latency reduction was observed during LEV condition compared with placebo. CONCLUSION: Our study observed the ERP component-P300-through the variation of its amplitude and latency to evaluate a supposed higher CNS efficiency when participants were under the LEV effect. Our findings sustain this premise, mainly due to reducing in P300 latency for the LEV condition, supporting the neural efficiency hypothesis.

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Background: Seizure control is challenging in the palliative care setting. Subcutaneous (SC) levetiracetam (LEV) is currently an off-label route of administration and effectiveness, tolerability, and pharmacokinetics studies for this route are scarce. Objectives: This prospective study aimed at evaluating effectiveness and tolerability of SC LEV as well as characterizing its pharmacokinetics. Subjects: Patients (n = 7) who attended the palliative care clinic between September 2018 and January 2019 with diagnosis of seizures, ≥18 years, and in need of SC route of administration were included in the study. Measurements: LEV plasma levels were determined using high-performance liquid chromatography and pharmacokinetic analysis were performed using Monolix 2018R2 (France). pH and osmolality of the three SC infusion solutions were also determined. Results: Seven patients took part in the study. Seizures were controlled in six out of seven patients with doses of 1000 and 3000 mg/day. Adverse effects were mild. pH and osmolality of the SC infusion solutions were within the accepted values reported in the literature. Mean plasma LEV concentrations were 14.4 mg/L (1000 mg/day) and 27.7 mg/L (2000 mg/day). The population clearance (2.5 L/h) and the elimination half-life (10.4 hours) were successfully estimated. Conclusions: Based on this data, SC LEV was effective and well tolerated. Pharmacokinetic parameters for the SC route were successfully determined.

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