{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T03:37:47Z","timestamp":1779248267882,"version":"3.51.4"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100024157","name":"Neurelis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100024157","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Diazepam is a cornerstone immediate\u2010use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1\u2009h (0.75, 1.5, or 3\u2009mg\/kg, intraperitoneal); plasma and brains were collected at 10\u2009min and 1, 3, or 6\u2009h following the last dose. Plasma and brain concentrations followed a dose\u2010dependent increase with peak concentrations following the repeat 3\u2009mg\/kg paradigm (180\u2009ng\/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain\u2010to\u2010plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long\u2010acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure\u2010cluster biology in rodent models of epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain language summary<\/jats:title><jats:p>There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24\u2009h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12954","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:40:21Z","timestamp":1718325621000},"page":"1575-1581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Development of a novel dosing paradigm to model diazepam rescue therapy in preclinical seizure and epilepsy\u00a0models"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4788-0175","authenticated-orcid":false,"given":"Michelle","family":"Guignet","sequence":"first","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4550-4408","authenticated-orcid":false,"given":"H. Steve","family":"White","sequence":"additional","affiliation":[{"name":"Center for Epilepsy Drug Discovery, Department of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7624-8825","authenticated-orcid":false,"given":"Sunita N.","family":"Misra","sequence":"additional","affiliation":[{"name":"Formerly of Neurelis, Inc.  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8788-0722","authenticated-orcid":false,"given":"Enrique","family":"Carrazana","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.  San Diego California USA"},{"name":"John A. Burns School of Medicine University of Hawaii  Honolulu Hawaii USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1299-0606","authenticated-orcid":false,"given":"Adrian L.","family":"Rabinowicz","sequence":"additional","affiliation":[{"name":"Neurelis, Inc.  San Diego California USA"},{"name":"Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science Florida Atlantic University  Boca Raton Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn5000056"},{"key":"e_1_2_12_3_1","volume-title":"Valium (diazepam injection, USP). 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