Long­term effects of vitexin against development of pentylenetetrazole­induced kindling in rats.

Evidence is provided that the glycosylated flavonoid vitexin (apigenin­8­C­beta­D­glucopyranoside) attenuates pentylenetetrazole (PTZ)­induced acute tonic­clonic seizures in rats. However, the effects of chronic and systemic vitexin in PTZ­kindled rats remain unknown. The aim of this work was to investigate the effect of long­term treatment with vitexin in the PTZ­kindling model of epilepsy. Male Wistar rats received intraperitoneal injections of PTZ at a subconvulsive dose of 35 mg/kg every other day for 29 days. Either saline containing dimethyl sulfoxide - DMSO 1%  (vehicle), diazepam (2 mg/kg; positive control) or vitexin (2.5 mg/kg) was administered intraperitoneally 30 min before each PTZ injection. The behavioral reactions were recorded by 30 min immediately after each PTZ injection. Furthermore, on the 31st day, that is, 48 h after the latter dose of PTZ, the animals were euthanized and renal and hepatic biochemical markers were evaluated in blood serum. Chronic treatment with either diazepam or vitexin attenuated the seizures provoked by PTZ injections. Neither diazepam nor vitexin caused changes in renal levels of creatinine and urea and in hepatic levels of aspartate aminotransferase and alanine aminotransferase. Our findings suggest that chronic administration of vitexin attenuates the progression of PTZ­induced kindling without causing side effects on kidneys and liver.

Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients.

AIMS: To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System. METHODS: Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH]. RESULTS: Wide (22-fold) interindividual variation in [PTH] was observed (2.2-47.5 mg/l). [PTH] associated significantly (Kruskal-Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere-Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10-20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér's V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211). CONCLUSION: Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline 'strong' recommendation for phenytoin dosing adjustments in PMs.

Polymorphism and Pharmacological Assessment of Carbamazepine.

This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.

Repositioning pinacidil and its anticonvulsant and anxiolytic properties in murine models.

Epilepsy, frequently comorbid with anxiety, is a prevalent neurological disorder. Available drugs often have side effects that hinder adherence, creating a need for new treatments. Potassium channel activators have emerged as promising candidates for treating both epilepsy and anxiety. This study aimed to evaluate the potential anticonvulsant and anxiolytic effects of pinacidil, an ATP-sensitive potassium channel activator used as antihypertensive, in rats. Our results indicate that pinacidil at 10 mg/kg (i.p.) fully protected animals from seizures induced by pentylenetetrazol (PTZ) and provided 85.7%, 100% and 100% protection against pilocarpine-induced seizures at 2.5, 5 and 10 mg/kg (i.p.), respectively. Although the 2.5 and 5 mg/kg (i.p) doses did not significantly protect the animals from PTZ-induced seizures, they did significantly increase the latency to the first seizure. Pinacidil also demonstrated mild anxiolytic activity, particularly at 10 mg/kg (i.p), evidenced by increased time spent in the open or illuminated areas of the Elevated Plus Maze (EPM) and Light-Dark Box (LDB) and increased exploratory activity in the Open Filed, EPM and LDB. Pinacidil did not affect locomotor performance, supporting its genuine anticonvulsant effects. This study holds significant medical and pharmaceutical value by characterizing pinacidil's anticonvulsant and anxiolytic effects and highlighting its potential for therapeutic repositioning.

[Epilepsy or functional neurological disorder. Diagnostic strategies]. / Epilepsia o trastorno neurológico funcional. Estrategias para el diagnóstico.

A seizure is the manifestation of symptoms or signs produced by excessive or synchronous neuronal activity in the brain. It usually presents as brief, self-limited episodes of involuntary movements that can affect a part or the entire body and that are sometimes accompanied by loss of consciousness and sphincter control. Epilepsy may be considered after a single unprovoked seizure in a patient with a high risk of recurrence. Paroxysmal non-epileptic disorders are defined as episodes of sudden onset and short duration that imitate an epileptic seizure, caused by a brain dysfunction of diverse origin that, unlike epilepsy, is not due to excessive neuronal discharge. Its incidence is much higher than epilepsy and it can appear at any age. It is important for diagnosis to analyze the triggering factors, the details of each episode, physical examination and only proceed to basic complementary tests such as video-electroencephalogram in case of doubt or for diagnostic confirmation. There is a tendency to overdiagnose epilepsy and excessive use of anticonvulsant drugs. Those that can most frequently be confused are syncope, "daydreams" and pseudoseizures.

Una convulsión es la manifestación de signos o síntomas producidos por una actividad neuronal excesiva o sincrónica en el cerebro. Suele presentarse como episodios breves, autolimitados, de movimientos involuntarios que pueden afectar a una parte del cuerpo o su totalidad y que, en ocasiones, se acompañan de pérdida de la conciencia y control de esfínteres. Puede considerarse epilepsia una sola crisis no provocada en un paciente con un elevado riesgo de recurrencia. Los trastornos paroxísticos no epilépticos se definen como episodios de aparición brusca y de breve duración que imitan a una crisis epiléptica, originados por una disfunción cerebral de origen diverso que a diferencia de la epilepsia no obedecen a una descarga neuronal excesiva. Su incidencia es mucho más elevada que la epilepsia y pueden aparecer a cualquier edad. Es importante para el diagnóstico analizar los factores desencadenantes, los pormenores de cada episodio, examen físico y solamente proceder a los exámenes complementarios básicos como video-electroencefalograma en caso de duda o para confirmación diagnóstica. Existe la tendencia a sobrediagnosticar epilepsia y al uso excesivo de fármacos anticonvulsivos. Los que con mayor frecuencia se pueden confundir son los síncopes, ensoñaciones y las pseudocrisis.

[Non-surgical treatment of refractory epilepsy in children]. / Tratamiento no quirúrgico de la epilepsia refractaria en niños.

Approximately 30% of people with epilepsy will be refractory. This manuscript reviews current evidencebased non-surgical treatment modalities for pediatric refractory epilepsy, including pharmacological and dietary strategies.

Aproximadamente el 30% de las personas con epilepsia será refractaria. Este manuscrito revisa las modalidades actuales y basadas en la evidencia de tratamientos no quirúrgicos para la epilepsia refractaria pediátrica, incluyendo estrategias farmacológicas y dietéticas.

Effect of Levetiracetam on Oxidant-Antioxidant Activity during Long-Term Temporal Lobe Epilepsy in Rats.

Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant-antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant-antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups' oxidant markers. However, the ratios of SOD/hydrogen peroxide (H2O2), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state.

Levetiracetam versus carbamazepine monotherapy in the management of pediatric focal epilepsy: A systematic review and meta-analysis of randomized controlled trials.

Levetiracetam (LEV) and carbamazepine (CBZ) are effective monotherapies for focal epilepsy in children. However, the best drug remains controversial. Therefore, we performed a systematic review and meta-analysis comparing LEV and CBZ monotherapy in the management of pediatric focal epilepsy (PFE). We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) published until February 2024 comparing LEV and CBZ monotherapy in PFE. Statistical analysis was performed using R version 4.2.2, heterogeneity was assessed using I2 statistics, and the risk of bias was evaluated using the RoB-2 tool. Risk Ratios (RR) with p < 0.05 were considered significant. The outcomes of interest were seizure freedom, any adverse events, adverse events leading to treatment discontinuation, dermatologic adverse events, and the frequency of at least one seizure, defined as the proportion of patients experiencing one or more seizures during the treatment period. Four RCTs comprising 381 children with a mean age of 7.32 to 9.28 years were included, of whom 186 (48.8%) received LEV monotherapy. There was no significant difference between groups (RR: 1.15; 95% CI 0.88-1.50; p = 0.31; I2 = 90%) regarding seizure freedom. The frequency of at least one seizure (RR: 0.71; 95% CI 0.52-0.97; p = 0.03; I2 = 8%) and dermatologic adverse events (RR: 0.24; 95% CI 0.09-0.64; p < 0.01; I2 = 0%) were both significantly lower in the LEV group. There were no significant differences in the presence of any adverse events (RR: 0.58; 95% CI 0.33-1.01; p = 0.05; I2 = 36%) or adverse events leading to treatment discontinuation (RR: 0.67; 95% CI 0.13-3.42; p = 0.63; I2 = 30%).Conclusion: In monotherapy, LEV was more advantageous than CBZ for PFE, with a lower frequency of seizures and fewer dermatological adverse events. However, both drugs are equally effective in achieving seizure freedom, adverse events without specification, and those that lead to treatment discontinuation. Our findings have important implications for clinical practice and decision-making in this condition.

Dexamethasone attenuates low-frequency brainwave disturbances following acute seizures induced by pentylenetetrazol in Wistar rats.

Seizures are neurological disorders triggered by an imbalance in the activity of excitatory and inhibitory neurotransmitters in the brain. When triggered chronically, this imbalance can lead to epilepsy. Critically, many of the affected individuals are refractory to treatment. Given this, anti-inflammatory drugs, in particular glucocorticoids, have been considered as a potential antiepileptogenic therapy. Glucocorticoids are currently used in the treatment of refractory patients, although there have been contradictory results in terms of their use in association with antiepileptic drugs, which reinforces the need for a more thorough investigation of their effects. In this context, the present study evaluated the effects of dexamethasone (DEX, 0.6 mg/kg) on the electroencephalographic (EEG) and histopathological parameters of male Wistar rats submitted to acute seizure induced by pentylenetetrazol (PTZ). The EEG monitoring revealed that DEX reduced the total brainwave power, in comparison with PTZ, in 12 h after the convulsive episode, exerting this effect in up to 36 h (p < 0.05 for all comparisons). An increase in the accommodation of the oscillations of the delta, alpha, and gamma frequencies was also observed from the first 12 h onwards, with the accommodation of the theta frequency occurring after 36 h, and that of the beta frequency 24 h after the seizure. The histopathological analyses showed that the CA3 region and hilum of the hippocampus suffered cell loss after the PTZ-induced seizure (control vs. PTZ, p < 0.05), although DEX was not able to protect these regions against cell death (PTZ vs. DEX + PTZ, p > 0.05). While DEX did not reverse the cell damage caused by PTZ, the data indicate that DEX has beneficial properties in the EEG analysis, which makes it a promising candidate for the attenuation of the epileptiform wave patterns that can precipitate refractory seizures.

Use of artisanal and non-regulated cannabis-based products for the treatment of epilepsy in a low-income population.

INTRODUCTION: Several artisanal and non-regulated cannabis-based products used for the treatment of epilepsy are available and can be easily obtained. Many of these preparations lack proper quality validation and exhibit cannabinoid contents significantly different from those stated on their labels, along with the presence of potentially harmful compounds. This study aims to evaluate the frequency of use and prescription patterns of these products among patients with epilepsy from a low-income population. METHODS: Observational and cross-sectional study. A survey was conducted on patients with epilepsy at a public hospital in Bogotá, Colombia. RESULTS: A total of 380 patients were evaluated, with 10.3 % (n = 39) reporting the use of artisanal and non-regulated cannabis-based products for the treatment of epilepsy. Among these patients, 84.6 % (n = 33) used the product on their own initiative, without a medical recommendation. Only 7.7 % (n = 3) of the patients had a record of the consumption of these products in their medical history. Age (p = 0.002), type of therapeutic response (p = 0.01), number of previous antiseizure medications used (p < 0.01), and non-pharmacological treatment such as vagal nerve stimulation (p < 0.01) showed a statistically significant association with the utilization of these products. CONCLUSION: One in ten patients with epilepsy has used artisanal and non-regulated cannabis-based products for the treatment of their condition. The majority of patients used these products on their own initiative, without a medical recommendation. The prevalence of consuming these products was higher among younger individuals with uncontrolled epilepsy, who had previously used multiple antiseizure medications and other non-pharmacological alternatives such as vagal nerve stimulation.

Evaluating a Venom-Bioinspired Peptide, NOR-1202, as an Antiepileptic Treatment in Male Mice Models.

Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.

Perfil de prescripción de levetiracetam en niños menores de cuatro años atendidos en un hospital de alta complejidad de Chile / Levetiracetam prescription profile in children younger than 4 years treated at a tertiary care hospital in Chile

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.

The reality of epilepsy in primary care in Rio de Janeiro: the importance of educational projects for better patient care.

BACKGROUND: The Basic Health Unit (Unidade Básica de Saúde - UBS, in Portuguese) is the first point of contact in the public healthcare system for people with epilepsy. Primary care professionals need to appropriately diagnose, treat, and refer, if necessary, to tertiary services. OBJECTIVE: To evaluate the knowledge of UBS professionals on the management of patients with epilepsy in Rio de Janeiro. METHODS: Online questionnaires were performed on the topic of epilepsy before and after exposure to classes taught by epileptologists. RESULTS: A total of 66 doctors participated, 54.5% of whom were residents or trained in family medicine. The majority had from 1 to 3 years of practice. Insecurity prevailed in the management of pregnant women and the elderly. Around 59.1% of the participants referred patients with seizures without examinations. A total of 78% of the participants did not correctly classify seizure types, and 2/3 did not define drug-resistant epilepsy. Induction and broad-spectrum drugs were common. The therapeutic decision depended on availability in the basic health unit (UBS) (81.8%), dosage (60.6%), side effects (34.8%), and age (36.4%). Comorbidities and sex influenced 1/4 of the sample. For 23% of the participants, the type of crisis did not affect the choice. Regarding typical non-pharmacological options, 75% of the participants were aware of cannabidiol, 40.9% of surgery, 22.7% of ketogenic diet, and 22.8% of deep brain stimulation/vagus nerve stimulation (DBS/VNS). A total of 90.2% indicated the need for training. CONCLUSION: There are deficits in the knowledge of UBS professionals in the management of epilepsy. Specialized training is imperative to optimize the care offered within SUS.

ANTECEDENTES: A Unidade Básica de Saúde (UBS) é o primeiro contato no sistema público de saúde para pessoas com epilepsia. Profissionais de atenção primária precisam diagnosticar, tratar e encaminhar adequadamente, se necessário, a serviços terciários. OBJETIVO: Avaliar o conhecimento dos profissionais das UBSs sobre o manejo de pacientes com epilepsia no Rio de Janeiro. MéTODOS: Foram realizados questionários online sobre o tema da epilepsia pré e pós exposição a aulas ministradas por epileptólogos. RESULTADOS: Participaram 66 médicos, sendo 54,5% residentes ou formados em medicina da família. A maioria tinha de 1 a 3 anos de prática. A insegurança prevaleceu no manejo de gestantes e idosos. Cerca de 59,1% dos participantes encaminhavam pacientes com crises sem exames. Um total de 78% dos participantes não classificou corretamente tipos de crises, e 2/3 não definiram epilepsia farmacorresistente. Fármacos indutores e de amplo espectro foram comuns. A decisão terapêutica dependeu da disponibilidade na Unidade Básica de Saúde (UBS) (81,8%), posologia (60,6%), efeitos colaterais (34,8%) e idade (36,4%). Comorbidades e sexo influenciaram 1/4 da amostra. Para 23% dos participantes, o tipo de crise não afetou a escolha. Quanto a opções não farmacológicas típicas, 75% conheciam o canabidiol, 40,9% a cirurgia, 22,7% a dieta cetogênica, 22,8% a estimulação cerebral profunda/estimulação do nervo vago (ECP/ENV). Um total de 90,2% dos participantes indicou necessidade de treinamento. CONCLUSãO: Há déficits no conhecimento dos profissionais das UBSs no manejo da epilepsia. O treinamento especializado é imperativo para otimizar o cuidado oferecido no âmbito do SUS.

An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?

INTRODUCTION: Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored. AREAS COVERED: Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective. EXPERT OPINION: In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.

BACKGROUND AND OBJECTIVE: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. METHODS: MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). RESULTS: Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. CONCLUSIONS: The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.

Multi-target Phenylpropanoids Against Epilepsy.

Epilepsy is a neurological disease with no defined cause, characterized by recurrent epileptic seizures. These occur due to the dysregulation of excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Psychopharmaceuticals have undesirable side effects; many patients require more than one pharmacotherapy to control crises. With this in mind, this work emphasizes the discovery of new substances from natural products that can combat epileptic seizures. Using in silico techniques, this review aims to evaluate the antiepileptic and multi-target activity of phenylpropanoid derivatives. Initially, ligand-based virtual screening models (LBVS) were performed with 468 phenylpropanoid compounds to predict biological activities. The LBVS were developed for the targets alpha- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), voltage-gated calcium channel Ttype (CaV), gamma-aminobutyric acid A (GABAA), gamma-aminobutyric acid transporter type 1 (GAT-1), voltage-gated potassium channel of the Q family (KCNQ), voltage-gated sodium channel (NaV), and N-methyl D-aspartate (NMDA). The compounds that had good results in the LBVS were analyzed for the absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and later, the best molecules were evaluated in the molecular docking consensus. The TR430 compound showed the best results in pharmacokinetic parameters; its oral absorption was 99.03%, it did not violate any Lipinski rule, it showed good bioavailability, and no cytotoxicity was observed either from the molecule or from the metabolites in the evaluated parameters. TR430 was able to bind with GABAA (activation) and AMPA (inhibition) targets and demonstrated good binding energy and significant interactions with both targets. The studied compound showed to be a promising molecule with a possible multi-target activity in both fundamental pharmacological targets for the treatment of epilepsy.

Association between Frequency of Seizures and Number of Antiseizure Medications (ASM) in Patients with Epilepsy.

The literature has shown the relevance of nutritional and metabolic aspects in patients with epilepsy. This study evaluated the relationship between clinical variables and plasma proteins and compared the variables between seizure frequency and neurological examination. A pilot study was carried out with eighty-four (n = 84) adults patients with epilepsy. The relationship between clinical variables of the disease (age at disease onset, neurological examination, current type and frequency of seizures, duration of disease, amount of antiseizure medications-ASM used and type and etiology of epilepsy) and plasma proteins (albumin and transferrin) was investigated. In the statistical analysis, the chi-square, Fisher, Mann-Whitney, Kruskal-Wallis tests, Spearman coefficient and univariate logistic regression were used. There was a significant association between the use of antiseizure medications (ASM) (p = 0.0105) and altered neurological examination (p = 0.0049), compared with the frequency of seizures, and between albumin and gender (p = 0.0005), and albumin and etiology of epilepsy (p = 0.0186). There was a significant low-intensity and inverse linear correlation (coefficient = -0.31363, p = 0.0037) between albumin and disease duration. In the logistic regression model, a significant association was only observed between the number of ASM and the frequency of seizures (p = 0.0120; OR = 3.368; 95% CI = 1.305-8.691). There was no association between plasma proteins and the outcomes of seizure frequency and neurological examination. The number of ASM and not protein metabolism was associated with frequency of seizures in patients with epilepsy.

Neuroprotective effects of chlorogenic acid against oxidative stress in rats subjected to lithium-pilocarpine-induced status epilepticus.

Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter the structure and functioning of the brain, resulting in diverse manifestations. Antiepileptic drugs (AEDs) can be very effective in 30% of patients in controlling seizures. Several factors contribute to this: drug resistance, individual variability, side effects, complexity of epilepsy, incomplete understanding, comorbidities, drug interactions, and no adherence to treatment. Therefore, research into new AEDs is important for several reasons such as improved efficacy, reduced side effects, expanded treatment options, treatment for drug-resistant epilepsy, improved safety profiles, targeted therapies, and innovation and progress. Animal models serve as crucial biological tools for comprehending neuronal damage and aiding in the discovery of more effective new AEDs. The utilization of antioxidant agents that act on the central nervous system may serve as a supplementary approach in the secondary prevention of epilepsy, both in laboratory animals and potentially in humans. Chlorogenic acid (CGA) is a significant compound, widely prevalent in numerous medicinal and food plants, exhibiting an extensive spectrum of biological activities such as neuroprotection, antioxidant, anti-inflammatory, and analgesic effects, among others. In this research, we assessed the neuroprotective effects of commercially available CGA in Wistar rats submitted to lithium-pilocarpine-induced status epilepticus (SE) model. After 72-h induction of SE, rats received thiopental and were treated for three consecutive days (1st, 2nd, and 3rd doses). Next, brains were collected and studied histologically for viable cells in the hippocampus with staining for cresyl-violet (Nissl staining) and for degenerating cells with Fluoro-Jade C (FJC) staining. Moreover, to evaluate oxidative stress, the presence of malondialdehyde (MDA) and superoxide dismutase (SOD) was quantified. Rats administered with CGA (30 mg/kg) demonstrated a significant decrease of 59% in the number of hippocampal cell loss in the CA3, and of 48% in the hilus layers after SE. A significant reduction of 75% in the cell loss in the CA3, shown by FJC+ staining, was also observed with the administration of CGA (30 mg/kg). Furthermore, significant decreases of 49% in MDA production and 72% in the activity of SOD were seen, when compared to animals subjected to SE that received vehicle. This study introduces a novel finding: the administration of CGA at a dosage of 30 mg/kg effectively reduced oxidative stress induced by lithium-pilocarpine, with its effects lasting until the peak of neural damage 72 h following the onset of SE. Overall, the research and development of new AEDs are essential for advancing epilepsy treatment, improving patient outcomes, and ultimately enhancing the quality of life for individuals living with epilepsy.