Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program.

OBJECTIVE: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. METHODS: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. RESULTS: A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. SIGNIFICANCE: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.

Gut Microbiota Profile Changes in Patients with Inflammatory Bowel Disease and Non-Alcoholic Fatty Liver Disease: A Metagenomic Study.

Gut microbiota imbalances have a significant role in the pathogenesis of Inflammatory Bowel Disease (IBD) and Non-Alcoholic Fatty Liver Disease (NAFLD). Herein, we compared gut microbial composition in patients diagnosed with either IBD or NAFLD or a combination of both. Seventy-four participants were stratified into four groups: IBD-NAFLD, IBD-only, NAFLD-only patients, and healthy controls (CTRLs). The 16S rRNA was sequenced by Next-Generation Sequencing. Bioinformatics and statistical analysis were performed. Bacterial α-diversity showed a significant lower value when the IBD-only group was compared to the other groups and particularly against the IBD-NAFLD group. ß-diversity also showed a significant difference among groups. The higher Bacteroidetes/Firmicutes ratio was found only when comparing IBD groups and CTRLs. Comparing the IBD-only group with the IBD-NAFLD group, a decrease in differential abundance of Subdoligranulum, Parabacteroides, and Fusicatenibacter was found. Comparing the NAFLD-only with the IBD-NAFLD groups, there was a higher abundance of Alistipes, Odoribacter, Sutterella, and Lachnospira. An inverse relationship in the comparison between the IBD-only group and the other groups was shown. For the first time, the singularity of the gut microbial composition in IBD and NAFLD patients has been shown, implying a potential microbial signature mainly influenced by gut inflammation.

Selenoprotein-P1 (SEPP1) Expression in Human Proximal Tubule Cells after Ischemia-Reperfusion Injury: An In Vitro Model.

Background and Objectives: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (Na2SeO3) and to evaluate the expression of SEPP1 as a marker of injury. Materials and Methods: HK-2 cells were pre-incubated with 100 nM Na2SeO3 for 24 h, and then, treated for 24 h with CoCl2 (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. Results: The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. Conclusions: Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients.

Background: In kidney transplantation (Ktx) recipients, cardiovascular (CV) disease remains the leading cause of death. Abnormal carotid intima-media thickness (IMT) represents a valid indicator of incipient atherosclerosis also in this setting. Cathepsin-K (CatK) is a cysteine protease involved in vascular remodelling, as well as in progressive atherosclerosis. In this study we evaluated clinical predictors of CatK in Ktx recipients, with a particular focus on its possible relationships with subclinical atherosclerosis. Methods: Circulating CatK was measured in 40 stable Ktx recipients together with several laboratory, clinical and echocardiography parameters. 30 healthy subjects and 30 hemodialysis (HD) patients served as controls for CatK values. Carotid IMT was measured in Ktx and these subjects were then categorized according to age-gender reference cut-offs of normal IMT. Results: CatK levels were similar in Ktx recipients and healthy subjects but significantly reduced as compared to HD (p = 0.0001). In Ktx, at multivariate analyses CatK was associated with the LV end-diastolic volume (LVEDVi) ( ß = 0.514; p = 0.05), Ktx vintage ( ß = -0.333; p = 0.05) and mean IMT ( ß = -0.545; p = 0.05); this latter robust inverse association was confirmed also in another multivariate model with IMT as the dependent variable. Logistic regression analyses confirmed the beneficial meaning of CatK increase towards subclinical atherosclerosis [Odds Ratio (OR) 0.761; 95% Confidence Interval (CI) 0.569-0.918, p = 0.04]. At Receiver Operating Characteristics (ROC) analyses, CatK held a remarkable discriminatory power in identifying Ktx patients with abnormally increased IMT [Area Under the Curve (AUC) 0.763; 95% CI 0.601-0.926; p = 0.001]). Conclusions: In Ktx recipients, reduced CatK levels reflect the time-dependent improvement in the uremic milieu, cardiac adaptations and, above all, the severity of subclinical atherosclerosis. CatK measurement in Ktx may therefore hold significance for improving early CV risk stratification.

Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals.

Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.

Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies.

INTRODUCTION: Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target. AREA COVERED: This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation. EXPERT OPINION: The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin's role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin's mechanisms and potential antiepileptogenic effects.

Pharmacodynamic rationale for the choice of antiseizure medications in the paediatric population.

In the landscape of paediatric epilepsy treatment, over 20 anti-seizure medications (ASMs) have gained approval from Drug Regulatory Agencies, each delineating clear indications. However, the complexity of managing drug-resistant epilepsy often necessitates the concurrent use of multiple medications. This therapeutic challenge highlights a notable gap: the absence of standardized guidelines, compelling clinicians to rely on empirical clinical experience when selecting combination therapies. This comprehensive review aims to explore current evidence elucidating the preferential utilization of specific ASMs or their combinations, with a primary emphasis on pharmacodynamic considerations. The fundamental objective underlying rational polytherapy is the strategic combination of medications, harnessing diverse mechanisms of action to optimize efficacy while mitigating shared side effects. Moreover, the intricate interplay between epilepsy and comorbidities partly may influence the treatment selection process. Despite advancements, unresolved queries persist, notably concerning the mechanisms underpinning drug resistance and the paradoxical exacerbation of seizures. By synthesizing existing evidence and addressing pertinent unresolved issues, this review aims to contribute to the evolving landscape of paediatric epilepsy treatment strategies, paving the way for more informed and efficacious therapeutic interventions.

The attitudes, knowledge and confidence of healthcare professionals about cannabis-based products.

BACKGROUND: Use of cannabis-based products is becoming more frequent, and it is important that healthcare professionals are informed and confident about them when making evidence-based decisions about their use. This study aimed to gain an international perspective on the attitudes, knowledge, and confidence of healthcare professionals about cannabis-based products. METHODS: An online questionnaire regarding these products was completed by 1580 healthcare professionals (neurologists, psychiatrists, general practitioners, pharmacists and nurses) from 16 countries across Asia, Europe, Oceania, South America, and the Middle East. RESULTS: Respondents expressed a high level of interest in cannabis-based products (median score 9 out of 10) and reported that they felt knowledgeable about them (median score 6 out of 7). They reported a high level of confidence when providing patients with information on cannabis-based products, returning median scores of 6 and 5 out of 7 for their legality and regulations, and their benefits and risks, respectively. Despite this, healthcare professionals sought further information on cannabis-based products across areas including legality, neurobiology, and scientific evidence. Finally, 59% (n = 930) of respondents considered robust clinical trial evidence as the most important factor to ensure patient safety in the context of these products. Few nominally significant differences emerged between healthcare professionals from different specialities or regions. CONCLUSION: In conclusion, this large survey of attitudes held by healthcare professionals towards cannabis-based products revealed a high level of interest and a demand for more information. Limitations of this study include potential sample bias and limited external validity.

Cenobamate as add-on therapy for drug resistant epilepsies: effectiveness, drug to drug interactions and neuropsychological impact. What have we learned from real word evidence?

Background: Cenobamate (CNB) is an anti-seizure medication (ASM) approved in 2021 in Europe for adjunctive treatment of focal-onset seizures in adults who were not adequately controlled with at least two previous ASMs. Methods: seizure outcome, treatment-emergent adverse events, neuropsychological profile, and blood levels of CNB and concomitant ASM were analyzed in a real world setting in two different Italian epilepsy centers in the context of CNB early access program. All patients performed a general cognitive evaluation, while 32 patients underwent the administration of a battery of neuropsychological tests at baseline and 6 months after CNB treatment. We performed CNB quantification in plasma in 31 patients at different doses in the range of 100-400 mg/day (65 measures). Results: we enrolled 54 patients with a median age of 27.9 years. The mean follow-up was 10.7 months. Most (91%) completed the efficacy analysis. At last follow-up visit, a 69.5% median seizure reduction was registered. Thirty-two patients (59.2%) had a ≥50% reduction of seizures that was ≥75% in 20 (42.0%) cases, whilst 10 (20.2%) patients were seizure-free. The most common adverse events were somnolence (53.1%), dizziness (28.1%) and diplopia (12.5%). The correlation between CNB dose and plasma concentration, revealed a significant linear correlation (r = 0.86, p < 0.0001), and there was a significant difference in mean plasma concentration/dose administered ratio (C/D ratio) between patients taking or not at least one inducer (0.10 ± 0.04 [(µg/mL)/(mg/day)]; n = 47 vs. 0.13 ± 0.05 [(µg/mL)/(mg/day)]; n = 18, p = 0.04). CNB dose was inversely correlated (r = -0.31, p = 0.02) to the C/D ratio of Carbamazepine blood levels. and positively correlated (r = 0.74, p < 0.0001) with an increased plasma concentration of the active Clobazam metabolite N-desmethylclobazam. General Anxiety Disorder-7 showed a significant improvement of score from baseline evaluation of 6.82 to follow-up 6 months evaluation of 4.53 (p = 0.03). Conclusion: In this real-world study, we registered a clinically meaningful reduction in seizure frequency after CNB administration in most patients along with a good tolerability profile. CNB treatment is correlate to a reduction in symptom severity of anxiety score. Plasma levels measurements confirm that CNB acts both as "victim" and as "perpetrator" of drug-drug interactions.