Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development

Epilepsia, Journal Year: 2024, Volume and Issue: 65(10), P. 2831 - 2857

Published: July 15, 2024

Abstract For >30 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided a forum for discussion of advances in development new therapies seizures epilepsy. The EILAT XVII conference took place Madrid, Spain, May 5–8, 2024. Participants included basic scientists clinical investigators from industry academia, other health care professionals, representatives lay organizations. We summarize this article information treatments preclinical early discussed at conference. These include AMT‐260, gene therapy designed to downregulate expression Glu2K subunits kainate receptors, treatment drug‐resistant associated with mesial temporal sclerosis; BHV‐7000, selective activator heteromeric Kv7.2/7.3 potassium channels, focal epilepsy; ETX101, recombinant adeno‐associated virus serotype 9 increase Na V 1.1 channel density inhibitory γ‐aminobutyric acidergic (GABAergic) neurons, SCN1A ‐positive Dravet syndrome; GAO‐3‐02, compound structurally related synaptamide, which exerts antiseizure activity least part through an action cannabinoid type 2 receptors; LRP‐661, structural analogue cannabidiol, Lennox–Gastaut syndrome, tuberous sclerosis complex; OV329, inactivator GABA aminotransferase, seizures; PRAX‐628, functionally potent sodium modulator preference hyperexcitable state RAP‐219, negative allosteric transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein γ‐8, rozanolixizumab, humanized anti‐neonatal Fc monoclonal antibody, LGI1 autoimmune encephalitis. Treatments more advanced are summarized Part II report.

Language: Английский

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Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development

Epilepsia, Journal Year: 2024, Volume and Issue: 65(10), P. 2858 - 2882

Published: Aug. 22, 2024

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain May 5-8, 2024. As usual, the core part of conference consisted presentations investigational drugs at various stages development for epilepsy-related indications. Summaries information compounds preclinical or early clinical are included an accompanying publication (Part I). In this article, we provide summaries five more advanced development, i.e. which some antiseizure activity individuals with epilepsy is available. These treatments include azetukalner (XEN1101), a potent, K

Language: Английский

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Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights

Journal of Neurology, Journal Year: 2024, Volume and Issue: 271(6), P. 3063 - 3094

Published: April 12, 2024

Language: Английский

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Withaferin A protects against epilepsy by promoting LCN2-mediated astrocyte polarization to stopping neuronal ferroptosis

Phytomedicine, Journal Year: 2024, Volume and Issue: 132, P. 155892 - 155892

Published: July 17, 2024

Language: Английский

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Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity

Epilepsia, Journal Year: 2024, Volume and Issue: 65(10), P. 2923 - 2934

Published: Aug. 14, 2024

Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from market due to toxicity caused its phenazinium dimer metabolites, leading peripheral skin discoloration and retinal abnormalities. To address undesirable metabolic properties prevent formation dimers, we made chemical modifications RTG, resulting a new derivative, 1025c, N,N'-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide).

Language: Английский

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Therapeutic Advances in Drug-Resistant Epilepsy

American Journal of Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Background: Drug-resistant epilepsy (DRE) is a condition that affects up to 40% of the total population patients with epilepsy. Advancements in pharmaceutical field over recent decades have facilitated significant expansion range available drug options. Nevertheless, prevalence DRE has remained unaltered years. Areas Uncertainty: It not completely understood how new antiseizure medications and therapeutic strategies will impact current burden DRE. Data Sources: A bibliographic search was made MEDLINE make content analysis identified studies on management Therapeutic Advances: The elucidation different underlying mechanisms helped create alternatives for Some drugs under clinical are cenobamate (100% ≥90% sustained seizure reduction), padsevonil (50% radiprodil, NRTX-1001 (good tolerability, safety, pharmacokinetic profiles), BL-001 (favorable safety profile good tolerability). Preclinical also shown promising results LRP-661, cannabidiol derivative superior bioavailability compared actual formulation market. In addition, gene therapies such as CAMK2A-EKC achieved effects control focal cortical dysplasia type II animal models. However, combination surgery novel ways administration, intraventricular delivery valproate, increases possibility success Conclusions: advances pharmacologic still great changes Utilizing established widely recognized continues be viable treatment approach, particularly when complemented by additional modalities physical exercise, ketogenic diet, interventional procedures, surgery.

Language: Английский

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Stimuli-responsive nanoscale drug delivery system for epilepsy theranostics

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Design and synthesis of novel cyclohexanecarboxamides with anticonvulsant effect by activating Nrf2-ARE pathway

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 159, P. 108357 - 108357

Published: March 10, 2025

Language: Английский

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Targeting Kv7 Potassium Channels for Epilepsy

CNS Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 play a critical role in modulating susceptibility to seizures, mutations genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation has long been considered an attractive target search for novel antiseizure medications. Ezogabine (retigabine), first Kv7.2/3 activator introduced 2011 treatment focal was withdrawn from market 2017 due declining use after discovery its association with pigmentation changes retina, skin, mucosae. A formulation ezogabine pediatric (XEN496) recently investigated children KCNQ2-related developmental epileptic encephalopathy, but trial terminated prematurely reasons unrelated safety. Among openers clinical development, azetukalner shown dose-dependent efficacy against drug-resistant seizures good tolerability profile no evidence pigmentation-related adverse effects early studies, it is now under investigation phase III trials generalized tonic-clonic major depressive disorder. Another activator, BHV-7000, completed I studies healthy subjects, excellent at plasma drug concentrations exceed median effective preclinical model anticonvulsant activity, data patients are available date. other activators development as potential medications, pynegabine CB-003 have safety pharmacokinetic results not yet reported. Overall, interest targeting indications remains strong. Future breakthroughs area could come exploitation mechanistic differences action activators, molecules combine mechanisms action.

Language: Английский

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Clinical trials of prevention of acquired epilepsy: New proof‐of‐concept approach to restart trials

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Abstract Approximately 20% of epilepsy is caused by acute central nervous system insults such as traumatic brain injury (TBI), stroke, and infection. There a latent period weeks to years between the insult onset, which offers an opportunity prevent epilepsy. No preventive treatments exist. Their development major unmet need in neurology. For logistical reasons, acquired after TBI, posttraumatic (PTE), most suitable for prevention studies. In past 20 years, preclinical PTE research has flourished, offering potential PTE, but clinical been dormant. The barrier treatment lack viable proof concept (POC) trial design. trials use first late unprovoked seizure outcome measure, necessitates long (~2‐year) follow‐up makes POC studies nonfeasible. A reliable biomarker early detection would allow shorter duration facilitate studies, not yet available. Biomarker, POC, randomized have virtually identical designs terms patient inclusion follow‐up. Done sequentially, take generation complete. We propose novel design that combines discovery biomarker(s) with study uses adaptive POC–phase 3 continuation approach incorporate into phase following interim futility analysis 6 months 25% cohort, population. This establish model prevention, shorten treatment, reopen door

Language: Английский

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