Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA, USA.
Bioanalysis and Pharmacokinetics Core Facility, UC Davis Medical Center, Sacramento, CA, USA.
Epilepsia. 2018 Oct;59 Suppl 2(Suppl 2):220-227. doi: 10.1111/epi.13999. Epub 2018 Feb 17.
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog, ganaxolone, are positive allosteric modulators of synaptic and extrasynaptic γ-aminobutyric acid (GABA) receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The 2 neuroactive steroids are being investigated as treatments for SE, including as a treatment for SE induced by chemical threat agents. Intramuscular injection is the preferred route of administration in the prehospital treatment of SE. The objective of this study was to assess the efficacy of intramuscular allopregnanolone and ganaxolone in the treatment of SE induced by the chemical threat agent tetramethylenedisulfotetramine (TETS). The test agents were administered 40 minutes after the onset of SE when mice are refractory to treatment. Allopregnanolone and ganaxolone (each at 3 mg/kg) terminated SE in, respectively, 92% and 75% of animals, and prevented mortality in 85% and 50% of animals; the mean times to termination of behavioral seizures were, respectively, 172 ± 16 and 447 ± 52 seconds. In a separate series of experiments, mice were dosed with the neuroactive steroids by intramuscular injection, and plasma and brain levels were sampled at various time points following injection to estimate pharmacokinetic parameters. Plasma C (maximum concentration) values for allopregnanolone and ganaxolone were 645 and 550 ng/mL, respectively. Brain exposure of both steroids was approximately 3-fold the plasma exposure. Two-compartment pharmacokinetic analysis revealed that the central compartment V (volume of distribution), CL (clearance), t (terminal half-life), and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively, 4.95 L/kg 12.88 L/kg/h,16 minutes, 97%, and 5.07 L/kg, 8.35 L/kg/h, 25 minutes, 95%. Allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route. Allopregnanolone is more rapidly acting and modestly more effective, possibly because it has greater potency on GABA receptors.
Allopregnanolone（5α-孕烷-3α-醇-20-酮）及其合成的 3β-甲基类似物 ganaxolone 是突触和 extrasynaptic γ-氨基丁酸（GABA）受体的正变构调节剂，在多种动物癫痫模型中具有抗癫痫作用，包括癫痫持续状态（SE）模型。这 2 种神经活性甾体类化合物正在被研究用于治疗 SE，包括作为化学威胁剂诱导的 SE 的治疗方法。肌肉内注射是院前治疗 SE 的首选给药途径。本研究旨在评估肌肉内注射 allopregnanolone 和 ganaxolone 治疗化学威胁剂四亚甲基二砜四胺（TETS）诱导的 SE 的疗效。当小鼠对治疗产生抗性时，在 SE 发作后 40 分钟给予测试药物。Allopregnanolone 和 ganaxolone（分别为 3mg/kg）分别使 92%和 75%的动物 SE 终止，并使 85%和 50%的动物免于死亡；行为性癫痫发作终止的平均时间分别为 172±16 秒和 447±52 秒。在另一系列实验中，通过肌肉内注射向小鼠给药神经活性甾体类化合物，并在注射后不同时间点采集血浆和大脑样本，以估计药代动力学参数。Allopregnanolone 和 ganaxolone 的血浆 C（最大浓度）值分别为 645 和 550ng/mL。两种类固醇的大脑暴露量约为血浆暴露量的 3 倍。两室药代动力学分析显示，allopregnanolone 和 ganaxolone 的中央室 V（分布容积）、CL（清除率）、t（半衰期）和 F（肌肉内生物利用度）值分别为 4.95L/kg、12.88L/kg/h、16 分钟、97%和 5.07L/kg、8.35L/kg/h、25 分钟、95%。当通过肌肉内途径给药时，allopregnanolone 和 ganaxolone 对 TETS 诱导的 SE 均有效。Allopregnanolone 起效更快，效果略好，可能是因为它对 GABA 受体的效力更大。
