{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:44:40Z","timestamp":1772160280746,"version":"3.50.1"},"reference-count":55,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["HHS 75N95022C00007"],"award-info":[{"award-number":["HHS 75N95022C00007"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The current standard of care for Dravet syndrome (DS) includes polytherapy after inadequate seizure control with one or more monotherapy approaches. Treatment guidelines are often based on expert opinions, and finding an optimal balance between seizure control and adverse drug effects can be challenging. This study utilizes the efficacy and pharmacokinetic assessment of a second\u2010line treatment regimen that combines clobazam and sodium valproate with an add\u2010on drug as a proof\u2010of\u2010principle approach to establish an effective therapeutic regimen in a DS mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We evaluated the efficacy of add\u2010on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia\u2010induced seizures in\n                      <jats:italic>Scn1a<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>A1783V\/WT<\/jats:italic>\n                      <\/jats:sup>\n                      mice. Clobazam, N\u2010desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography\u2013tandem mass spectrometry for the combinations deemed effective against hyperthermia\u2010induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia\u2010induced seizures in\n                      <jats:italic>Scn1a<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>A1783V\/WT<\/jats:italic>\n                      <\/jats:sup>\n                      mice. In\n                      <jats:italic>Scn1a<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>WT\/WT<\/jats:italic>\n                      <\/jats:sup>\n                      mice, brain clobazam and N\u2010desmethyl clobazam concentrations were higher in the triple\u2010drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple\u2010drug therapy than when given alone.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug\u2013drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18104","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T08:30:15Z","timestamp":1725006615000},"page":"3100-3114","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Utilizing an acute hyperthermia\u2010induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7026-9329","authenticated-orcid":false,"given":"Jeffrey A.","family":"Mensah","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Utah  Salt Lake City Utah 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