Effects of adjunctive eslicarbazepine acetate on neurocognitive functioning in children with refractory focal-onset seizures.

Abstract Purpose This was a phase-II, randomized, double-blind (DB), placebo-controlled study aimed to evaluate neurocognitive effects of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). Methods Children (6–16 years old) with FOS were randomized (2:1) to ESL or placebo. Treatment started at 10 mg/kg/day, was up-titrated up to 30 mg/kg/day (target dose), and maintained for 8 weeks, followed by one-year open-label follow-up. The primary endpoint was change from baseline to the end of maintenance period in the composite Power of Attention assessed with the Cognitive Drug Research (CDR) system. Behavioral and emotional functioning and quality of life (QOL), secondary endpoints, were assessed with Child Health Questionnaire-Parent Form 50 (CHQ-PF50), Child Behavior Checklist (CBCL), and Raven's Standard Progressive Matrices (SPM). Efficacy was evaluated through changes in standardized seizure frequency (SF), responder rate, and proportion of seizure-free patients. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). Results One hundred and twenty-three patients were randomized. A noninferiority analysis failed to reject the null hypothesis that the change from baseline in the Power of Attention score in the ESL group was at least 121 ms inferior to the placebo group for all age groups. The CDR scores showed no differences between placebo and ESL in Power of Attention (1868.0 vs 1759.5), Continuity of Attention (1.136 vs − 1.786), Quality of Working Memory (− 0.023 vs − 0.024), and Speed of Memory (− 263.4 vs − 249.6). Nonsignificant differences between placebo and ESL were seen for CHQ-PF50, CBCL scores, and Raven's SPM. Episodic Memory Index showed significant negative effect on ESL. Efficacy results favored the ESL group (SF least square [LS] means 1.98 vs 4.29). The TEAEs had a similar incidence between treatment groups (41.0% vs 47.5%). Conclusions Overall ESL did not produce statistically significant effects on neurocognitive and behavioral functioning in patients with epilepsy aged 6 to 16 years. Additionally, ESL was effective in reducing seizure frequency and was well-tolerated

Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus

Background: Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a latrunculin A solution (4 μM, 1 μl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month. Results: Oral administration of ESL (100 mg/kg), previous to latrunculin A microperfusion, completely prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite. Conclusion: ESL treatment prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice.This study was sponsored by BIAL – Portela & Cª, S.A.S

A LOGÍSTICA REVERSA DE MEDICAMENTOS VENCIDOS NAS FARMÁCIAS DA REGIÃO DO CENTRO DE BELO HORIZONTE

O Brasil é considerado um dos maiores consumidores de medicamentos no mundo. Pesquisas apontam que os restos de medicamentos encontrados nos domicílios são destinados de forma incorreta. Medicamentos e seus metabolitos chegam à natureza nas mais diversas formas, tais como liberação através das descargas domiciliares, resíduos industriais e hospitalares. A legislação enquadra os medicamentos como substâncias Químicas que podem oferecer riscos à saúde pública e ao meio ambiente. Conforme a Política Nacional de Resíduos Sólidos (PNRS) é papel da cadeia produtiva, importadores, distribuidores e comerciantes de produtos, seus resíduos e suas embalagens serem sujeitos à logística reversa, mas a lei não contempla resíduos de medicamentos domiciliares e nem aborda a responsabilidade compartilhada de cada entidade da cadeia farmacêutica. Este estudo objetiva descrever a estrutura e os processos de logística reversa de medicamentos nas farmácias de Belo Horizonte. Foram selecionadas cinco drogarias no centro de Belo Horizonte, que pertencem a grandes redes do varejo farmacêutico do Brasil. Os resultados mostraram que o descarte consciente de medicamentos é de baixa abrangência no município e que a logísticas reversa é praticada em poucas drogarias. Além disso, foi observado que na maioria das farmácias existe deficiência em equipamentos para o descarte seguro de medicamentos, além de informações sobre o descarte consciente para o consumidor. Diante do exposto, conclui-se uma necessidade imediata, por parte das redes de farmácias em adotar campanhas de descarte adequado, além de iniciativas governamentais e sociedades privadas para integrar na gestão de resíduos sólidos.

Aging increases oxidative stress and renal expression of oxidant and antioxidant enzymes that are associated with an increased trend in systolic blood pressure

The aim of this study was to investigate whether the effects of aging on oxidative stress markers and expression of major oxidant and antioxidant enzymes associate with impairment of renal function and increases in blood pressure. To explore this, we determined age-associated changes in lipid peroxidation (urinary malondialdehyde), plasma and urinary hydrogen peroxide (H2O2) levels, as well as renal H2O2 production, and the expression of oxidant and antioxidant enzymes in young (13 weeks) and old (52 weeks) male Wistar Kyoto (WKY) rats. Urinary lipid peroxidation levels and H2O2 production by the renal cortex and medulla of old rats were higher than their young counterparts. This was accompanied by overexpression of NADPH oxidase components Nox4 and p22phox in the renal cortex of old rats. Similarly, expression of superoxide dismutase (SOD) isoforms 2 and 3 and catalase were increased in the renal cortex from old rats. Renal function parameters (creatinine clearance and fractional excretion of sodium), diastolic blood pressure and heart rate were not affected by aging, although slight increases in systolic blood pressure were observed during this 52-week period. It is concluded that overexpression of renal Nox4 and p22phox and the increases in renal H2O2 levels in aged WKY does not associate with renal functional impairment or marked increases in blood pressure. It is hypothesized that lack of oxidative stress-associated effects in aged WKY rats may result from increases in antioxidant defenses that counteract the damaging effects of H2O2

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences. SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period. KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (/dL) and ESL 1200 mg QD (/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small. SIGNIFICANCE: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations

Identification of some Amazonian species of Culex (Culex) and Culex (Melanoconion) by morphotyping and barcoding

Os mosquitos Culex spp. apresentam características idiossincráticas e sua baixa variabilidade dificulta sua identificação. O objetivo do nosso estudo foi analisar a região 5 'do gene da subunidade I do citocromo oxidase (coI) para a identificação taxonômica de espécies de Culex que foram previamente diagnosticadas em subgêneros Culex e Melanoconion em condições de campo. Dez sequências de espécimes foram analisadas pelo Automatic Barcode Gap Discovery (ABGD). Todas as sequências apresentaram 94-99% de identidade quando comparadas com outras sequências de espécies de Culex disponíveis no GenBank. Cinco partições iniciais suportaram 80-88 grupos de espécies. Entre eles, oito conjuntos continham os espécimes do presente estudo. Das 10 sequências de mosquitos, cinco não formaram nenhum cluster consistente, e as demais apresentaram alguma consistência no diagnóstico taxonômico nas condições de campo. Nossos resultados sugerem que algumas sequências do gene coI de espécimes podem pertencer a espécies do subgênero Melanoconion, cuja sequência 5' coI é desconhecida ou inédita no GenBank.Culex spp. mosquitoes have idiosyncratic characteristics and its low variability makes difficult their identification. The aim of our study was to analyze the 5' region of the cytochrome oxidase subunit I gene (coI) for the taxonomic identification of Culex species which were previously morphotyped and diagnosed in Culex and Melanoconion subgenera at the field conditions. Ten specimen sequences were analyzed by the Automatic Barcode Gap Discovery (ABGD). All sequences showed 94-99% identity when compared to other Culex species sequences available from GenBank. Five initial partitions supported 80-88 species groups. Among them, eight sets contained the specimens of the present study. Of the 10 mosquito sequences, five did not form any consistent cluster, and the remaining showed some consistency in the taxonomic diagnosis at the field conditions. Our results suggest that some coI gene sequences of specimens may belong to species of the subgenus Melanoconion, whose 5’ coI sequence is unknown or unpublished in GenBank

Effect of saline load and metoclopramide on the renal dopaminergic system in patients with heart failure and healthy controls

Dopamine of renal origin has natriuretic/diuretic actions by activating D-1-like receptors of the nephron. Saline load increases renal dopamine production and natriuresis in healthy subjects, and, under these conditions, the activation of D-2-like receptors also produces natriuresis/diuresis. Metoclopramide is a D-2-like receptor antagonist. Patients with heart failure (HF) have an increased renal dopamine-synthesizing efficiency. However, the effect of salt loading was not explored in HE We hypothesized that HF patients respond to salt loading with increased production of renal dopamine and that metoclopramide antagonizes this response. This was a randomized, controlled, crossover study exploring the effect of NaCl and metoclopramide on renal dopaminergic, sympathetic, renin-angiotensin-aldosterone, and arginine-vasopressin (AVP) systems activity on sodium handling in 9 HF patients and 9 controls. NaCl markedly increased renal dopamine production and natriuresis in both groups. Metoclopramide blunted these responses in HF patients but not in controls. NaCl decreased renin and aldosterone plasma levels in controls but not in HF patients. In these patients B-type natriuretic peptide (BNP) levels increased, but AVP was not affected. HF patients respond to salt loading with increased natriuresis. However, the mechanisms for this response are different from those found in healthy subjects. Metoclopramide has antinatriuretic effects only in HF patients

Antiepileptogenesis after Stroke - Trials and Tribulations: Methodological Challenges and Recruitment Results of a Phase II Study with Eslicarbazepine Acetate.

There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicentre, randomised, double-blind, placebo-controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral haemorrhage or acute ischaemic stroke were randomised to receive ESL 800 mg/day or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is occurrence of a first unprovoked seizure within 6 months after randomisation ('failure rate'). Secondary efficacy assessments include occurrence of a first unprovoked seizure during 12 months after randomisation and during the entire study; functional outcomes (Barthel Index original 10-item version; National Institutes of Health Stroke Scale); post-stroke depression (Patient Health Questionnaire-9; PHQ-9); and overall survival. Safety assessments include evaluation of treatment-emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behaviour (PHQ-9 question 9). The protocol aimed to randomise approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID-19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomised. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol