Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome
Objective 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...
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| Veröffentlicht in: | Epilepsia (Copenhagen) 2024-10, Vol.65 (10), p.3100-3114 |
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| creator | Mensah, Jeffrey A. Johnson, Kristina Freeman, Tia Reilly, Christopher A. Rower, Joseph E. Metcalf, Cameron S. Wilcox, Karen S. |
| description | Objective
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‐line treatment regimen that combines clobazam and sodium valproate with an add‐on drug as a proof‐of‐principle approach to establish an effective therapeutic regimen in a DS mouse model.
Methods
We evaluated the efficacy of add‐on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. Clobazam, N‐desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography–tandem mass spectrometry for the combinations deemed effective against hyperthermia‐induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.
Results
Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N‐desmethyl clobazam concentrations were higher in the triple‐drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple‐drug therapy than when given alone.
Significance
A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug–drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.
Illustration of study design. |
| doi_str_mv | 10.1111/epi.18104 |
| format | Article |
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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‐line treatment regimen that combines clobazam and sodium valproate with an add‐on drug as a proof‐of‐principle approach to establish an effective therapeutic regimen in a DS mouse model.
Methods
We evaluated the efficacy of add‐on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. Clobazam, N‐desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography–tandem mass spectrometry for the combinations deemed effective against hyperthermia‐induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.
Results
Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N‐desmethyl clobazam concentrations were higher in the triple‐drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple‐drug therapy than when given alone.
Significance
A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug–drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.
Illustration of study design.</description><identifier>ISSN: 0013-9580</identifier><identifier>ISSN: 1528-1167</identifier><identifier>EISSN: 1528-1167</identifier><identifier>DOI: 10.1111/epi.18104</identifier><identifier>PMID: 39212337</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Anticonvulsants - administration & dosage ; Anticonvulsants - pharmacokinetics ; Anticonvulsants - therapeutic use ; antiseizure drugs ; Cannabidiol ; Cannabidiol - administration & dosage ; Cannabidiol - pharmacokinetics ; Cannabinoids ; Clobazam - pharmacokinetics ; Dioxolanes - pharmacokinetics ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Dravet syndrome ; Drug interaction ; Drug therapy ; Drug Therapy, Combination ; Epilepsies, Myoclonic - drug therapy ; Fenfluramine ; Fenfluramine - pharmacokinetics ; Fever ; Hyperthermia ; Hyperthermia - drug therapy ; hyperthermia‐induced seizure model ; Liquid chromatography ; Male ; Mass spectroscopy ; Mice ; Mice, Transgenic ; NAV1.1 Voltage-Gated Sodium Channel - genetics ; Pharmacokinetics ; Seizures ; Seizures - drug therapy ; Sodium ; Sodium valproate ; Stiripentol ; triple‐drug therapy ; Valproic acid ; Valproic Acid - pharmacokinetics ; Valproic Acid - therapeutic use</subject><ispartof>Epilepsia (Copenhagen), 2024-10, Vol.65 (10), p.3100-3114</ispartof><rights>2024 The Author(s). published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2784-af397e2d7a64f10052b6e29110c543206c39dd11c0a8f4cab9dca439c1068f0b3</cites><orcidid>0000-0001-7026-9329 ; 0000-0002-5006-1982 ; 0000-0003-2660-8826 ; 0000-0003-3629-7902 ; 0000-0002-1510-0405</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fepi.18104$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fepi.18104$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39212337$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mensah, Jeffrey A.</creatorcontrib><creatorcontrib>Johnson, Kristina</creatorcontrib><creatorcontrib>Freeman, Tia</creatorcontrib><creatorcontrib>Reilly, Christopher A.</creatorcontrib><creatorcontrib>Rower, Joseph E.</creatorcontrib><creatorcontrib>Metcalf, Cameron S.</creatorcontrib><creatorcontrib>Wilcox, Karen S.</creatorcontrib><title>Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome</title><title>Epilepsia (Copenhagen)</title><addtitle>Epilepsia</addtitle><description>Objective
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‐line treatment regimen that combines clobazam and sodium valproate with an add‐on drug as a proof‐of‐principle approach to establish an effective therapeutic regimen in a DS mouse model.
Methods
We evaluated the efficacy of add‐on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. Clobazam, N‐desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography–tandem mass spectrometry for the combinations deemed effective against hyperthermia‐induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.
Results
Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N‐desmethyl clobazam concentrations were higher in the triple‐drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple‐drug therapy than when given alone.
Significance
A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug–drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.
Illustration of study design.</description><subject>Animals</subject><subject>Anticonvulsants - administration & dosage</subject><subject>Anticonvulsants - pharmacokinetics</subject><subject>Anticonvulsants - therapeutic use</subject><subject>antiseizure drugs</subject><subject>Cannabidiol</subject><subject>Cannabidiol - administration & dosage</subject><subject>Cannabidiol - pharmacokinetics</subject><subject>Cannabinoids</subject><subject>Clobazam - pharmacokinetics</subject><subject>Dioxolanes - pharmacokinetics</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Dravet syndrome</subject><subject>Drug interaction</subject><subject>Drug therapy</subject><subject>Drug Therapy, Combination</subject><subject>Epilepsies, Myoclonic - drug therapy</subject><subject>Fenfluramine</subject><subject>Fenfluramine - pharmacokinetics</subject><subject>Fever</subject><subject>Hyperthermia</subject><subject>Hyperthermia - drug therapy</subject><subject>hyperthermia‐induced seizure model</subject><subject>Liquid chromatography</subject><subject>Male</subject><subject>Mass spectroscopy</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>NAV1.1 Voltage-Gated Sodium Channel - genetics</subject><subject>Pharmacokinetics</subject><subject>Seizures</subject><subject>Seizures - drug therapy</subject><subject>Sodium</subject><subject>Sodium valproate</subject><subject>Stiripentol</subject><subject>triple‐drug therapy</subject><subject>Valproic acid</subject><subject>Valproic Acid - pharmacokinetics</subject><subject>Valproic Acid - therapeutic use</subject><issn>0013-9580</issn><issn>1528-1167</issn><issn>1528-1167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp10c9uFSEUBnBiNPZaXfgChsSNLqY9wPyBpalVmzTRhV0TBs70UmeGERjN7aqP0L1v55NIvdWFiSxg88t3TvgIec7giJVzjIs_YpJB_YBsWMNlxVjbPSQbACYq1Ug4IE9SugKAru3EY3IgFGdciG5DflxkP_prP19SM1Nj14x0u1sw5i3GyZufN7d-dqtFRxP66zUizZhywY4uWxMnY8MXP2P2lqa8Oo-J5kALMf3o05aGJfvJjNSFdDck4qWfcE7Ul2l0CmvCcjscaRjo22i-YaZpN7sYJnxKHg1mTPjs_j0kF-9OP598qM4_vj87eXNeWd7JujKDUB1y15m2HhhAw_sWuWIMbFMLDq0VyjnGLBg51Nb0yllTC2UZtHKAXhySV_vcJYava1ldTz5ZHEczY1lQC1BKQgNdU-jLf-hVWONcttOCMalkK3ld1Ou9sjGkFHHQSyyfEHeagb5rTJfG9O_Gin1xn7j2E7q_8k9FBRzvwXc_4u7_Sfr009k-8hePWKNx</recordid><startdate>202410</startdate><enddate>202410</enddate><creator>Mensah, Jeffrey A.</creator><creator>Johnson, Kristina</creator><creator>Freeman, Tia</creator><creator>Reilly, Christopher A.</creator><creator>Rower, Joseph E.</creator><creator>Metcalf, Cameron S.</creator><creator>Wilcox, Karen S.</creator><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7026-9329</orcidid><orcidid>https://orcid.org/0000-0002-5006-1982</orcidid><orcidid>https://orcid.org/0000-0003-2660-8826</orcidid><orcidid>https://orcid.org/0000-0003-3629-7902</orcidid><orcidid>https://orcid.org/0000-0002-1510-0405</orcidid></search><sort><creationdate>202410</creationdate><title>Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome</title><author>Mensah, Jeffrey A. ; Johnson, Kristina ; Freeman, Tia ; Reilly, Christopher A. ; Rower, Joseph E. ; Metcalf, Cameron S. ; Wilcox, Karen S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2784-af397e2d7a64f10052b6e29110c543206c39dd11c0a8f4cab9dca439c1068f0b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Anticonvulsants - administration & dosage</topic><topic>Anticonvulsants - pharmacokinetics</topic><topic>Anticonvulsants - therapeutic use</topic><topic>antiseizure drugs</topic><topic>Cannabidiol</topic><topic>Cannabidiol - administration & dosage</topic><topic>Cannabidiol - pharmacokinetics</topic><topic>Cannabinoids</topic><topic>Clobazam - pharmacokinetics</topic><topic>Dioxolanes - pharmacokinetics</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Dravet syndrome</topic><topic>Drug interaction</topic><topic>Drug therapy</topic><topic>Drug Therapy, Combination</topic><topic>Epilepsies, Myoclonic - drug therapy</topic><topic>Fenfluramine</topic><topic>Fenfluramine - pharmacokinetics</topic><topic>Fever</topic><topic>Hyperthermia</topic><topic>Hyperthermia - drug therapy</topic><topic>hyperthermia‐induced seizure model</topic><topic>Liquid chromatography</topic><topic>Male</topic><topic>Mass spectroscopy</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>NAV1.1 Voltage-Gated Sodium Channel - genetics</topic><topic>Pharmacokinetics</topic><topic>Seizures</topic><topic>Seizures - drug therapy</topic><topic>Sodium</topic><topic>Sodium valproate</topic><topic>Stiripentol</topic><topic>triple‐drug therapy</topic><topic>Valproic acid</topic><topic>Valproic Acid - pharmacokinetics</topic><topic>Valproic Acid - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mensah, Jeffrey A.</creatorcontrib><creatorcontrib>Johnson, Kristina</creatorcontrib><creatorcontrib>Freeman, Tia</creatorcontrib><creatorcontrib>Reilly, Christopher A.</creatorcontrib><creatorcontrib>Rower, Joseph E.</creatorcontrib><creatorcontrib>Metcalf, Cameron S.</creatorcontrib><creatorcontrib>Wilcox, Karen S.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Epilepsia (Copenhagen)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mensah, Jeffrey A.</au><au>Johnson, Kristina</au><au>Freeman, Tia</au><au>Reilly, Christopher A.</au><au>Rower, Joseph E.</au><au>Metcalf, Cameron S.</au><au>Wilcox, Karen S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome</atitle><jtitle>Epilepsia (Copenhagen)</jtitle><addtitle>Epilepsia</addtitle><date>2024-10</date><risdate>2024</risdate><volume>65</volume><issue>10</issue><spage>3100</spage><epage>3114</epage><pages>3100-3114</pages><issn>0013-9580</issn><issn>1528-1167</issn><eissn>1528-1167</eissn><abstract>Objective
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‐line treatment regimen that combines clobazam and sodium valproate with an add‐on drug as a proof‐of‐principle approach to establish an effective therapeutic regimen in a DS mouse model.
Methods
We evaluated the efficacy of add‐on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. Clobazam, N‐desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography–tandem mass spectrometry for the combinations deemed effective against hyperthermia‐induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.
Results
Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia‐induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N‐desmethyl clobazam concentrations were higher in the triple‐drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple‐drug therapy than when given alone.
Significance
A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug–drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.
Illustration of study design.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39212337</pmid><doi>10.1111/epi.18104</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-7026-9329</orcidid><orcidid>https://orcid.org/0000-0002-5006-1982</orcidid><orcidid>https://orcid.org/0000-0003-2660-8826</orcidid><orcidid>https://orcid.org/0000-0003-3629-7902</orcidid><orcidid>https://orcid.org/0000-0002-1510-0405</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0013-9580 |
| ispartof | Epilepsia (Copenhagen), 2024-10, Vol.65 (10), p.3100-3114 |
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| subjects | Animals Anticonvulsants - administration & dosage Anticonvulsants - pharmacokinetics Anticonvulsants - therapeutic use antiseizure drugs Cannabidiol Cannabidiol - administration & dosage Cannabidiol - pharmacokinetics Cannabinoids Clobazam - pharmacokinetics Dioxolanes - pharmacokinetics Disease Models, Animal Dose-Response Relationship, Drug Dravet syndrome Drug interaction Drug therapy Drug Therapy, Combination Epilepsies, Myoclonic - drug therapy Fenfluramine Fenfluramine - pharmacokinetics Fever Hyperthermia Hyperthermia - drug therapy hyperthermia‐induced seizure model Liquid chromatography Male Mass spectroscopy Mice Mice, Transgenic NAV1.1 Voltage-Gated Sodium Channel - genetics Pharmacokinetics Seizures Seizures - drug therapy Sodium Sodium valproate Stiripentol triple‐drug therapy Valproic acid Valproic Acid - pharmacokinetics Valproic Acid - therapeutic use |
| title | Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome |
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