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Clemizole
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Clemizole is a member of the class of benzimidazoles and a histamine H1 blocker used to treat allergies. In pharmaceutical products (very rarely used), clemizole may be employed as clemizole hydrochloride (CAS number 1163-36-6, EC number 214-605-4, molecular formula C19H21Cl2N3) (1).
Virtual screening and zebrafish models in tandem, for drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
David Hernández-Silva, Francisca Alcaraz-Pérez, Horacio Pérez-Sánchez, Maria Luisa Cayuela
A phenotypic screening in which the DD is developed in a period of less than a decade, driving new treatment for a rare disease (Dravet syndrome), is a good example from ‘aquarium-to-bedside’. The zebrafish deficient in scn1lab (homologous to SCN1A) recapitulate key clinical phenotypes in Dravet syndrome, including spontaneous epileptic phenotypes at behavioral and electrophysiological levels [82]. These unique features allow for high-throughput drug screening in the larvae of zebrafish [82,83]. A phenotype-based screen of 320 compounds identified a US Food and Drug Administration (FDA)-approved compound (clemizole) able to inhibit convulsive behaviors and electrographic seizures. Additionally, clemizole (EPX-100) displayed a broad safety profile in a recent phase I clinical studies and is now being researched as an ‘add-on treatment’ in a pivotal phase II clinical trial [84,85].
Novel and emerging therapeutics for genetic epilepsies
Published in Expert Review of Neurotherapeutics, 2021
Ana Pejčić, Slobodan M. Janković, Miralem Đešević, Refet Gojak, Snežana Lukić, Nenad Marković, Miloš Milosavljević
Clemizole hydrochloride (EPX-100) is a first-generation antihistamine that was used in the therapy of itchiness [88]. The anticonvulsant effect of clemizole and its derivates were discovered in experimental in vivo studies on scn1Lab mutant zebrafish models of Dravet syndrome [95,122,123]. The mechanism of action by which clemizole reduces the frequency of seizures is similar to fenfluramine and is most likely the result of modulation of 5-HT2B receptors and stimulation of serotoninergic transmission in the brain [123]. The pharmacokinetics and safety of clemizole hydrochloride were tested in a phase I, placebo-controlled, double-blind, 2-period study (NCT04069689) in three sequential groups of eight healthy subjects each [124]. Six participants in each group received clemizole hydrochloride at three different doses (20, 40, or 80 mg), while the other two participants received a placebo [124,125]. The study was completed in January 2020 and the results showed that it was well-tolerated by both male and female participants [88,125]. After the completion of the first phase of the clinical trial, a phase II multicenter, randomized, double-blind, placebo-controlled study (NCT04462770) began in late 2020 [126]. The efficacy of clemizole hydrochloride as adjunctive therapy will be assessed in 24 patients with Dravet syndrome, 2–17 years old with documented genetic mutations of SCN1A gene [126]. The study will have a 4-week observational period, 4-week titration period, and 12-week maintenance period [126].
Epilepsy: key experimental therapeutics in early clinical development
Published in Expert Opinion on Investigational Drugs, 2020
Claude Steriade, Jacqueline French, Orrin Devinsky
Diverse sodium channel (SCN1A) mutations account for 85% of the epileptic encephalopathy Dravet syndrome. A zebrafish model harboring an SCN1A mutation enabled high-throughput drug screening. Among 320 Food and Drug Administration (FDA) approved compounds screened in this model, clemizole, an antihistamine and Ns4B RNA binding inhibitor, suppressed spontaneous seizures [29]. Clemizole does not act via histaminergic effects but as a high-affinity 5HT2 receptor agonist [30]. This led to the development of synthetic clemizole analogs, with 5-HT receptor binding [31]. EPX-100, one of these analogs, will undergo phase II studies in Dravet syndrome.