{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T14:39:52Z","timestamp":1774276792439,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T00:00:00Z","timestamp":1441152000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Upsher-Smith Laboratories, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To compare the pharmacokinetics, pharmacodynamics, and tolerability of <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261, a midazolam formulation optimized for intranasal delivery, versus midazolam intravenous (<jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>) solution administered intranasally (<jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IN<\/jats:styled-content>) or intravenously (<jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>) in healthy adults.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this phase 1, five\u2010way crossover, open\u2010label study, 25 healthy adults (aged 18\u201342\u00a0years) were randomly assigned to receive 2.5, 5.0, and 7.5\u00a0mg <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261; 2.5\u00a0mg <jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content>; and 5.0\u00a0mg <jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IN<\/jats:styled-content>. Blood samples were collected for 12\u00a0h post dose to determine pharmacokinetic profiles. Pharmacodynamic assessments of sedation and psychomotor impairment also were conducted. Adverse events, oxygen saturation, and vital signs were recorded.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Increasing <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261 dose corresponded with increases in midazolam area under the concentration time curve (<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content>) and maximum observed plasma concentration (C<jats:sub>max<\/jats:sub>), with all doses demonstrating rapid median time to C<jats:sub>max<\/jats:sub> (T<jats:sub>max<\/jats:sub>; 10\u201312\u00a0min). <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261 also demonstrated increased absorption, with a 134% relative bioavailability, compared with the same <jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IN<\/jats:styled-content> dose. <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261 was associated with dose\u2010dependent increases in sedation and psychomotor impairment (p<jats:italic>\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.05); however, these effects lasted &lt;4\u00a0h and generally did not differ from <jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IN<\/jats:styled-content> or\u00a0<jats:styled-content style=\"fixed-case\">MDZ<\/jats:styled-content>\u2010inj <jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content> at comparable doses. No serious adverse events (<jats:styled-content style=\"fixed-case\">SAE<\/jats:styled-content>s) or deaths were\u00a0reported, and no treatment\u2010emergent adverse events (<jats:styled-content style=\"fixed-case\">TEAE<\/jats:styled-content>s) led to study discontinuation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Compared with intranasal delivery of a midazolam formulation intended for <jats:styled-content style=\"fixed-case\">IV<\/jats:styled-content> delivery, <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261, optimized for intranasal administration demonstrated improved bioavailability with similar pharmacodynamic effects. Therefore, <jats:styled-content style=\"fixed-case\">USL<\/jats:styled-content>261 may be a preferable alternative to the currently approved rectal diazepam treatment for intermittent bouts of increased seizure activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.13131","type":"journal-article","created":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T20:09:25Z","timestamp":1441224565000},"page":"1723-1731","source":"Crossref","is-referenced-by-count":30,"title":["Pharmacokinetics, pharmacodynamics, and safety of <scp>USL<\/scp>261, a midazolam formulation optimized for intranasal delivery, in a randomized study with healthy volunteers"],"prefix":"10.1111","volume":"56","author":[{"given":"Lindy L.","family":"Bancke","sequence":"first","affiliation":[{"name":"Upsher\u2010Smith Laboratories, Inc Maple Grove Minnesota U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather A.","family":"Dworak","sequence":"additional","affiliation":[{"name":"Upsher\u2010Smith 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