{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T20:45:39Z","timestamp":1778705139877,"version":"3.51.4"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T00:00:00Z","timestamp":1522972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS079202"],"award-info":[{"award-number":["NS079202"]}],"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":[[2018,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Diazepam, administered by the intravenous, oral, or rectal routes, is widely used for the management of acute seizures. Dosage forms for delivery of diazepam by other routes of administration, including intranasal, intramuscular, and transbuccal, are under investigation. In predicting what dosages are necessary to terminate seizures, the minimal exposure required to confer seizure protection must be known. Here we administered diazepam by continuous intravenous infusion to obtain near\u2013steady\u2010state levels, which allowed an assessment of the minimal levels that elevate seizure threshold.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The thresholds for various behavioral seizure signs (myoclonic jerk, clonus, and tonus) were determined with the timed intravenous pentylenetetrazol seizure threshold test in rats. Diazepam was administered to freely moving animals by continuous intravenous infusion via an indwelling jugular vein cannula. Blood samples for assay of plasma levels of diazepam and metabolites were recovered via an indwelling cannula in the contralateral jugular vein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The pharmacokinetic parameters of diazepam following a single 80\u2010\u03bcg\/kg intravenous bolus injection were determined using a noncompartmental pharmacokinetic approach. The derived parameters<jats:italic>V<\/jats:italic><jats:sub>d<\/jats:sub>,<jats:styled-content style=\"fixed-case\">CL<\/jats:styled-content>,<jats:italic>t<\/jats:italic><jats:sub>1\/2\u03b1<\/jats:sub>(distribution half\u2010life) and<jats:italic>t<\/jats:italic><jats:sub>1\/2\u03b2<\/jats:sub>(terminal half\u2010life) for diazepam were, respectively, 608\u00a0mL, 22.1\u00a0mL\/min, 13.7 minutes, and 76.8\u00a0minutes, respectively. Various doses of diazepam were continuously infused without or with an initial loading dose. At the end of the infusions, the thresholds for various behavioral seizure signs were determined. The minimal plasma diazepam concentration associated with threshold elevations was estimated at approximately 70\u00a0ng\/mL. The active metabolites nordiazepam, oxazepam, and temazepam achieved levels that are expected to make only minor contributions to the threshold elevations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Diazepam elevates seizure threshold at steady\u2010state plasma concentrations lower than previously recognized. The minimally effective plasma concentration provides a reference that may be considered when estimating the diazepam exposure required for acute seizure treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14069","type":"journal-article","created":{"date-parts":[[2018,4,23]],"date-time":"2018-04-23T08:36:01Z","timestamp":1524472561000},"page":"935-944","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Determination of minimal steady\u2010state plasma level of diazepam causing seizure threshold elevation in rats"],"prefix":"10.1111","volume":"59","author":[{"given":"Ashish","family":"Dhir","sequence":"first","affiliation":[{"name":"Department of Neurology School of Medicine University of California, Davis Sacramento CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3296-8193","authenticated-orcid":false,"given":"Michael A.","family":"Rogawski","sequence":"additional","affiliation":[{"name":"Department of Neurology School of Medicine University of California, Davis Sacramento CA USA"},{"name":"Department of Pharmacology School of Medicine University of California, Davis Sacramento CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,4,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cn5000056"},{"key":"e_1_2_8_3_1","first-page":"593","volume-title":"Wyllie's treatment of epilepsy. 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