{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:56:13Z","timestamp":1785772573408,"version":"3.56.0"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n \n Based on the evidence that fenfluramine\u2010induced anorexia, weight loss, and cardiovascular toxicity are primarily mediated by the\n d<\/jats:italic>\n \u2010enantiomers of fenfluramine and its metabolite norfenfluramine, we investigated pharmacokinetic\/pharmacodynamic correlations for the active enantiomers of fenfluramine and norfenfluramine in the rat maximal electroshock seizure (MES) test. This is part of a series of studies aimed at optimizing selection of an enantiomerically pure compound for development as a safer alternative to racemic fenfluramine.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Median effective concentrations (EC\n 50<\/jats:sub>\n ) in the MES model and median neurotoxic concentrations (TC\n 50<\/jats:sub>\n ) of each enantiomer in plasma and brain were estimated after intraperitoneal administration of\n d<\/jats:italic>\n \u2010fenfluramine,\n l<\/jats:italic>\n \u2010fenfluramine, and\n l<\/jats:italic>\n \u2010norfenfluramine as well as racemates, and compared with the respective median effective (ED\n 50<\/jats:sub>\n ) and neurotoxic (TD\n 50<\/jats:sub>\n ) doses. A newly developed enantioselective assay allowed differentiation of concentrations of each enantiomer after administration of racemates. Protective indexes (PIs) were estimated based on dose (TD\n 50<\/jats:sub>\n \/ED\n 50<\/jats:sub>\n ) and concentration (TC\n 50<\/jats:sub>\n \/EC\n 50<\/jats:sub>\n ) in plasma and brain.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Based on ED\n 50<\/jats:sub>\n , all enantiomers tested had comparable potency, but\n l<\/jats:italic>\n \u2010norfenfluramine had a lower PI than the other enantiomers. Based on EC\n 50<\/jats:sub>\n in plasma and brain,\n l<\/jats:italic>\n \u2010norfenfluramine and\n d<\/jats:italic>\n \u2010fenfluramine had the highest potency, but\n l<\/jats:italic>\n \u2010norfenfluramine was consistently more toxic than the other enantiomers. The PIs of\n d<\/jats:italic>\n \u2010fenfluramine,\n l<\/jats:italic>\n \u2010fenfluramine, and\n l<\/jats:italic>\n \u2010norfenfluramine were 2.7, 2.4, and 1.2, respectively, based on plasma concentrations, and 4.1, 2.8, and 1.2, respectively, based on brain concentrations. Potency estimates for each enantiomer after dosing with racemic fenfluramine and norfenfluramine were consistently lower than after dosing with the pure enantiomers, indicating that both enantiomers contributed to antiseizure activity.\n <\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n \n Based on these results,\n l<\/jats:italic>\n \u2010fenfluramine has more favorable properties than\n l<\/jats:italic>\n \u2010norfenfluramine for potential development as an enantiomerically pure medication. Although our findings are consistent with those previously reported for the MES test in mice and the\n scn1Lab<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mutant zebrafish, they differ from those reported for the audiogenic seizures mouse model. Further studies, preferably in disease\u2010specific models, would be desirable.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/epi.70412","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:23:27Z","timestamp":1785770607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antiseizure potency and neurotoxicity of the enantiomers of fenfluramine and norfenfluramine in rats and correlations with their concentrations in plasma and brain"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4302-2128","authenticated-orcid":false,"given":"Yara","family":"Sheeni","sequence":"first","affiliation":[{"name":"Institute of Drug Research, School of Pharmacy, Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4120-6510","authenticated-orcid":false,"given":"Dinorah","family":"Barasch","sequence":"additional","affiliation":[{"name":"Institute of Drug Research, School of Pharmacy, Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-2219","authenticated-orcid":false,"given":"Tawfeeq","family":"Shekh\u2010Ahmad","sequence":"additional","affiliation":[{"name":"Institute of Drug Research, School of Pharmacy, Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-223X","authenticated-orcid":false,"given":"Emilio","family":"Perucca","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne Melbourne Victoria Australia"},{"name":"Department of Neuroscience, School of Translational Medicine Monash University Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-4171","authenticated-orcid":false,"given":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Institute of Drug Research, School of Pharmacy, Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israel"},{"name":"David R. Bloom Center for Pharmacy Hebrew University of Jerusalem Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2021.107866","article-title":"Fenfluramine repurposing from weight loss to epilepsy: what we do and do not know","volume":"226","author":"Odi R","year":"2021","journal-title":"Pharmacol Ther"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1111\/epi.18342","article-title":"Long\u2010term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome","volume":"66","author":"Scheffer IE","year":"2025","journal-title":"Epilepsia"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s40263-026-01276-x","article-title":"Ameliorating seizures in Dravet syndrome: a review of newly approved and investigational drugs, RNA and gene\u2010based therapies","volume":"40","author":"Balestrini S","year":"2026","journal-title":"CNS Drugs"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/epi4.70200","article-title":"Cost\u2010effectiveness of fenfluramine as add\u2010on treatment in the management of Dravet syndrome: a real\u2010world multicenter study","volume":"11","author":"Cortesi PA","year":"2026","journal-title":"Epilepsia Open"},{"key":"e_1_2_10_6_1","unstructured":"UCB Inc.Fintepla U.S. prescribing information (last revised October 2025). 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