Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

Dravet Syndrome is a severe, drug-resistant, and rare epileptiform disorder that is typically presented in the first year of life in an otherwise healthy child. It is characterized by prolonged seizures that are often resistant to current anti-epileptic drug regimens, which made them poorly controlled, and almost 50% of patients experience at least four tonic-clonic seizures per month. There are three new medicines: stiripentol, cannabidiol, and fenfluramine, with documented efficacy and safety as adjunctive therapies in pharmacoresistant Dravet syndrome treatment. This study aimed to assess the efficacy and safety of fenfluramine in the treatment of Dravet syndrome. Our study material consisted of publications, which were found in PubMed, Google Scholar, and Embase databases. In order to find the proper publications, the search has been conducted with the use of a combination of keywords like: “fenfluramine”, “Dravet syndrome”, “epilepsy treatment”, “Dravet syndrome pediatric patients”. The first step was to find proper publications from the last 10 years. The second step was to carry out an overview of the found publications. Results of mentioned studies proved that in Dravet syndrome, fenfluramine provided a significantly greater reduction in convulsive seizure frequency compared with placebo. No patient developed valvular heart disease or pulmonary arterial hypertension, the side effects that occurred during its use were mild and the drug was generally well-tolerated. The bioequivalence and tolerability of single oral doses of fenfluramine hydrochloride oral solution in the fed and fasted states support drug administration without regard to meals. Fenfluramine may represent a new important treatment option for Dravet syndrome.

Relationship Between the Pyroptosis Pathway and Epilepsy: A Bioinformatic Analysis

PurposeThis study aimed to analyse the correlation between the pyroptosis pathway and epilepsy using bioinformatics analysis technology. We analyzed the expression of gasdermin D (GSDMD) and gasdermin E (GSDME), the key molecules of pyroptosis, in kainic acid-induced epileptic mice.MethodsWeighted gene co-expression network analysis (WGCNA) was used to construct a signed co-expression network from expression data to screen gene sets closely related to epilepsy. The correlation between the module and epilepsy was verified through module conservative analysis, gene ontology (GO) annotation analysis, and correlation analysis with known epilepsy genes. We obtained currently recognized pyroptosis-related molecules through literature review, and correlation analysis was used to evaluate their correlation with epilepsy. Differentially expressed gene (DEG) analysis was used to analyse expression changes of pyroptosis-related molecules at the transcriptome level, compared to the sham group. We subsequently established a kainic acid-induced status epilepticus (SE) model in mice and validated the mRNA and protein expression of GSDMD and GSDME, the key molecules of pyroptosis, by quantitative reverse transcription PCR (qRT-PCR) and western blotting (WB).ResultsUsing WGCNA, module conservative analysis, and correlation analysis with known epilepsy genes, we screened out a module (a gene set of interest) closely related to epilepsy that was prominently enriched in immune and inflammatory-related biological processes. Correlation analysis results suggest that pyroptosis-related molecules are closely related to this module, but have no obvious correlation with others. DEG analysis of molecules associated with pyroptosis suggests that most of the pyroptosis-related molecules had significantly increased expression after SE, such as IL1b, Casp1, Casp4, Pycard, Gsdmd, Nlrp3, Aim2, Mefv, Tlr2, Tlr3, and Tlr4. qRT-PCR and WB analysis confirmed that the mRNA and protein levels of GSDMD in the mouse hippocampus were significantly upregulated after SE. The mRNA expression of GSDME was not different between the epilepsy group and sham group. However, the WB results showed that the expression of full-length GSDME was decreased and GSDME-N-terminus were significantly increased after SE.ConclusionsOur study highlights that the pyroptosis pathway may be closely related to epilepsy. GSDMD and GSDME, the key executive molecules of pyroptosis, will help to understand the pathogenesis of epilepsy and aid in discovering new targets for anti-epileptic drug treatments.

Learning from the report of the independent medicines and medical devices safety review: “first do no harm”

This is a review of the learning points from the Independent Medicines and Medical Devices Safety Review, 1 chaired by Baroness Julia Cumberlege CBE DL. This system-wide review was initiated by the then Secretary of State for Health and Social Care, following patient-led campaigns. It looked at how the “healthcare system reacted as a whole, and how that response can be made more robust, speedy and appropriate”. We aim to highlight the learning points for doctors in Obstetrics and Gynaecology as these are relevant to our current practice and future changes in our healthcare system. These are: Aims of the review: why it was initiated and how it was conducted Overarching themes and missed opportunities to prevent avoidable harm Three clinical scenarios: their histories, issues and adverse events associated with their use and the current response in Scotland The hormone pregnancy test - Primodos The anti-epileptic drug - sodium valproate Surgical mesh for prolapse & incontinence The recommendations made by the review and implementation guidance Responses to the review, such as apologies issued by BSUG 2 /BAUS 3 /RCOG, 4 and compensations schemes such as the Scottish scheme as recommended by the review

Cognitive Impairment in People with Epilepsy

People with epilepsy frequently have cognitive impairment. The majority of cognitive problems is influenced by a variety of interlinked factors, including the early onset of epilepsy and the frequency, intensity and duration of seizures, along with the anti-epileptic drug treatment. With a systematic review, we investigate significant factors about the cognitive impairment in epilepsy. Most cognitive problems in adult people with epilepsy include memory, attention and executive function deficits. However, which cognitive area is mainly affected highly depends on the location of epileptic activity. Moreover, modifications in signalling pathways and neuronal networks have an essential role in both the pathophysiology of epilepsy and in the mechanism responsible for cognitive impairment. Additionally, studies have shown that the use of polytherapy in the treatment of epilepsy with anti-epileptic drugs (AEDs) heightens the risk for cognitive impairment. It can be challenging to distinguish the contribution of each factor, because they are often closely intertwined.

The Effect of Levetiracetam Treatment on Survival in Patients with Glioblastoma: A Systematic Review and Meta-Analysis.

Background:Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV’s effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted.Method:A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence.Results:From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR=0.89, p=0.094). Significant heterogeneity was observed during pooling of HRs (I2=75%, p<0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC=0.03, p=0.02) and increased with greater proportions of female patients (RC=-0.05, p=0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs.Conclusions:Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.

Sensing the Anti-Epileptic Drug Perampanel with Paper-Based Spinning SERS Substrates

The applications of SERS in therapeutic drug monitoring, or other fields of analytical chemistry, require the availability of sensitive sensors and experimental approaches that can be implemented in affordable ways. In this contribution, we show the production of cost-effective SERS sensors obtained by depositing Lee-Meisel Ag colloids on filter paper either by natural sedimentation or centrifugation. We have characterized the morphological and plasmonic features of the sensors by optical microscopy, SEM, and UV-Vis spectroscopy. Such sensors can be used to quantify by SERS the anti-epileptic drug Perampanel (in the concentration range 1 × 10−4–5 × 10−6 M) by spinning them during the micro-Raman measurements on the top of a custom device obtained from spare part hard disk drives. This approach minimizes laser-induced heating effects and allows averaging over the spatial non-uniformity of the sensor.

Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore

Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide’s effect on NaV1.5 is sensitive to a mutation in the local anesthetic binding site, and that it binds with slow kinetics to the fast-inactivated state of NaV1.7. We recently showed that the NaV1.7-W1538R mutation in the voltage-sensing domain 4 completely abolishes NaV1.7 inhibition by clinically-achievable concentration of lacosamide. Our molecular docking analysis suggests a role for W1538 and pore residues as high affinity binding sites for lacosamide. Aryl sulfonamide sodium channel blockers are also sensitive to substitutions of the W1538 residue but not of pore residues. To elucidate the mechanism by which lacosamide exerts its effects, we used voltage-clamp recordings and show that lacosamide requires an intact local anesthetic binding site to inhibit NaV1.7 channels. Additionally, the W1538R mutation does not abrogate local anesthetic lidocaine-induced blockade. We also show that the naturally occurring arginine in NaV1.3 (NaV1.3-R1560), which corresponds to NaV1.7-W1538R, is not sufficient to explain the resistance of NaV1.3 to clinically-relevant concentrations of lacosamide. However, the NaV1.7-W1538R mutation conferred sensitivity to the NaV1.3-selective aryl-sulfonamide blocker ICA-121431. Together, the W1538 residue and an intact local anesthetic site are required for lacosamide’s block of NaV1.7 at a clinically-achievable concentration. Moreover, the contribution of W1538 to lacosamide inhibitory effects appears to be isoform-specific.

An Atlas of the Quantitative Protein Expression of Anti-Epileptic-Drug Transporters, Metabolizing Enzymes and Tight Junctions at the Blood–Brain Barrier in Epileptic Patients

The purpose of the present study was to quantitatively elucidate the levels of protein expression of anti-epileptic-drug (AED) transporters, metabolizing enzymes and tight junction molecules at the blood–brain barrier (BBB) in the focal site of epilepsy patients using accurate SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Brain capillaries were isolated from focal sites in six epilepsy patients and five normal brains; tryptic digests were produced and subjected to SWATH analysis. MDR1 and BCRP were significantly downregulated in the epilepsy group compared to the normal group. Out of 16 AED-metabolizing enzymes detected, the protein expression levels of GSTP1, GSTO1, CYP2E1, ALDH1A1, ALDH6A1, ALDH7A1, ALDH9A1 and ADH5 were significantly 2.13-, 6.23-, 2.16-, 2.80-, 1.73-, 1.67-, 2.47- and 2.23-fold greater in the brain capillaries of epileptic patients than those of normal brains, respectively. The protein expression levels of Claudin-5, ZO-1, Catenin alpha-1, beta-1 and delta-1 were significantly lower, 1.97-, 2.51-, 2.44-, 1.90- and 1.63-fold, in the brain capillaries of epileptic patients compared to those of normal brains, respectively. Consistent with these observations, leakage of blood proteins was also observed. These results provide for a better understanding of the therapeutic effect of AEDs and molecular mechanisms of AED resistance in epileptic patients.

Low-Cost Drugs Still Relevant in the Present-Day Era

Escalating medical costs contribute to poverty in countries with low resources. The drug costs account for 17 percent of medical expenses. Revisiting time-tested, cost-effective drugs can reduce these costs. Some of them find a place in the WHO Model List of Essential Medicines for Children. The list consists of medicines for a basic healthcare system. They are safe and cost-effective. The present paper identifies co-trimoxazole and chloramphenicol as antimicrobials, chloroquine for malaria, adrenaline, theophylline for asthma, and phenobarbital as an anti-epileptic drug that merits consideration for reviving interest in them and reduce drug treatment costs. What is already known about this subject? • The cost of drugs contributes to rising medical costs. • Medical expenses push a large population below the poverty line. What does this study add? • Rediscovering the relevance of old low-cost drugs is essential. • Revisiting the WHO Model List of Essential Medicines for Children may be useful. • Drugs such as chloramphenicol and theophylline are such examples.