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There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches. Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet’s syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs. Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.

The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically 1 , 2 . This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells 3 . However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy. Lactylation of NBS1 by TIP60 promotes homologous recombination-driven DNA repair and resistance to chemotherapy in cancer cells and links altered cancer cell metabolism to increase genome stability.

The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.

The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs. Graphical Abstract

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma. Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.

Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These “add-on” therapies (mostly to VPA/CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug–drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore, concomitant administration of VPA with topiramate has been associated with encephalopathy and/or hyperammonaemia. Finally, we briefly describe other ASMs used in Dravet syndrome, and current key clinical trials. Graphical abstract

Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy. Synopsis This study highlights the importance of metabolic symbiosis dependent on lactate and lactate dehydrogenase isoforms (LDHA and B) in glioblastoma development. Inhibiting both lactate dehydrogenases may be a novel potential therapeutic approach for targeting glioblastoma. Lactate, which is produced in hypoxic environments, is secreted and taken up by oxidative cells to fuel the Krebs cycle to promote growth and invasion. Only double knockout of LDHA/B abolished lactate production, reduced tumor growth and invasion, and prolonged mouse survival. Tumors that no longer express LDH become more oxidative and more sensitive to radiation. The use of the LDH inhibitor stiripentol in clinical practice may be therapeutically relevant for glioblastoma. Graphical Abstract This study highlights the importance of metabolic symbiosis dependent on lactate and lactate dehydrogenase isoforms (LDHA and B) in glioblastoma development. Targeting both lactate dehydrogenases may be a novel potential therapeutic approach for targeting glioblastoma.

Background Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol ( n  = 2), pharmaceutical-grade cannabidiol ( n  = 3), fenfluramine hydrochloride ( n  = 2), and soticlestat ( n  = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.

Dravet syndrome is a rare but severe epilepsy syndrome that begins in the first year of life with recurrent seizures triggered by fever that are typically prolonged and hemiclonic. The epilepsy is highly drug resistant. Although development is normal at onset, over time, most patients develop moderate-to-severe intellectual disability, behavior disorders, and a characteristic crouch gait. There is a significant mortality, predominantly owing to sudden unexpected death in epilepsy. Complete seizure control is rarely attainable. Initial therapy includes valproic acid and clobazam, but response is typically inadequate. The results of new drugs for Dravet syndrome, including stiripentol, cannabidiol, and fenfluramine, are very promising. Stiripentol was associated with a greater than 50% reduction in convulsive seizure frequency in 71% of cases, when added to valproic acid and clobazam, and also markedly reduced status epilepticus. Pharmaceutical-grade cannabidiol resulted in a median change in monthly motor seizures from baseline of − 36.5%. Fenfluramine was associated with a greater than 50% reduction in seizures of 70%, with one quarter of cases achieving near seizure freedom over the duration of the trial. These agents are generally well tolerated, with few patients discontinuing for adverse effects. There is limited evidence to date regarding improvement in cognition with these newer agents; however, a meaningful change is challenging to assess over short trial periods and requires longer follow-up studies. While current treatments focus predominantly on seizure control, newer therapies including genetic treatments and antisense oligonucleotides can target the SCN1A channelopathy, and thus, may also significantly impact the important co-morbidities associated with this syndrome.

ObjectiveReal-world evidence characterizing the safety profiles of antiseizure medications (ASMs) concerning sleep disturbances remains limited. This study aimed to systematically evaluate the reporting patterns and safety signals of ASMs-related sleep disturbances using data from the FDA Adverse Event Reporting System (FAERS).MethodsWe conducted a retrospective pharmacovigilance study using FAERS data from Q1 2004 to Q2 2025. Disproportionality analyses were performed to identify potential safety signals for sleep-related adverse events (sAEs) associated with ASMs. We further analyzed demographic characteristics, clinical manifestations, and time-to-onset profiles.ResultsAnalysis of 3,118 reports identified significant associations between multiple ASMs and sleep disturbances. Significant signals were detected for sodium channel blockers eslicarbazepine, stiripentol, and cenobamate, as well as for mechanistically diverse agents vigabatrin, pregabalin, brivaracetam, and cannabidiol. The study characterized a broad spectrum of over 30 distinct sleep disturbances, among which insomnia was the most frequently reported preferred term (n = 1,570).ConclusionThis pharmacovigilance study reveals significant associations between various ASMs and sleep disturbances. The distinct disproportionality reporting profiles identified for some agents, which differ from prior evidence, necessitate careful clinical interpretation. Overall, this study elucidates the complex sleep safety profiles of ASMs, offering evidence to support more informed drug selection and monitoring in practice.