Utilizing an acute hyperthermia-induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome

IF 6.6 1区 医学 Q1 CLINICAL NEUROLOGY
Epilepsia Pub Date : 2024-08-30 DOI:10.1111/epi.18104
Jeffrey A. Mensah, Kristina Johnson, Tia Freeman, Christopher A. Reilly, Joseph E. Rower, Cameron S. Metcalf, Karen S. Wilcox
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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.

Abstract Image

利用急性高热诱发癫痫发作试验和药代动力学研究,在小鼠德雷维综合征模型中确定最佳给药方案。
目的:目前治疗德雷维特综合征(Dravet Syndrome,DS)的标准包括在一种或多种单药治疗方法无法充分控制癫痫发作后采用多种治疗方法。治疗指南通常以专家意见为基础,在癫痫发作控制和药物不良反应之间找到最佳平衡点具有挑战性。本研究利用氯巴扎姆和丙戊酸钠与一种附加药物相结合的二线治疗方案的疗效和药代动力学评估,作为在 DS 小鼠模型中建立有效治疗方案的原理验证方法:我们评估了在氯巴赞和丙戊酸钠基础上添加斯奇潘托、大麻二酚、氯卡西林或芬氟拉明等附加疗法对Scn1aA1783V/WT小鼠热疗诱导的癫痫发作的疗效。使用液相色谱-串联质谱法定量检测了被认为对高热惊厥有效的氯巴扎姆、N-去甲基氯巴扎姆(氯巴扎姆的活性代谢物)、丙戊酸钠、施蒂芬妥和大麻二酚在血浆和大脑中的浓度。浓度数据通过凤凰 WinNonLin 非室分析法计算药代动力学参数:结果:在 Scn1aA1783V/WT 小鼠中,较高剂量的斯奇潘托或大麻二酚与氯巴扎铵和丙戊酸钠合用可有效抑制高热惊厥。在 Scn1aWT/WT 小鼠中,三药联合疗法的脑内氯巴扎姆和 N-去甲基氯巴扎姆浓度高于氯巴扎姆单药疗法。三联疗法中脑内的斯利潘托和大麻二酚浓度高于单独用药时的浓度:意义:多药策略可能是一种实用的临床前方法,可用于确定治疗 DS 的有效化合物。本研究中使用的化合物之间的药物相互作用可能解释了某些多药疗法的增效作用。
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来源期刊
Epilepsia
Epilepsia 医学-临床神经学
CiteScore
10.90
自引率
10.70%
发文量
319
审稿时长
2-4 weeks
期刊介绍: Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
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