Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus.
Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus.
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DOI：
10.1111/epi.13999
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发表时间：
2018-10
期刊：
影响因子：
5.6
通讯作者：
Rogawski MA
中科院分区：
文献类型：
--
作者：
Zolkowska D;Wu CY;Rogawski MA
Allopregnanolone (5α-pregnan-3α-ol-20-one) and its synthetic 3β-methyl analog ganaxolone are positive allosteric modulators of synaptic and extrasynaptic GABAA receptors that exhibit antiseizure activity in diverse animal seizure models, including models of status epilepticus (SE). The two 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 pre-hospital 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 min 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 s and 447 ± 52 s. 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 Cmax values for allopregnanolone and ganaxolone were 645 ng/ml and 550 ng/ml, respectively. Brain exposures of both steroids were approximately 3-fold the plasma exposure. Two compartment pharmacokinetic analysis revealed that the central compartment Vd, CL, t½ (terminal half-life) and F (intramuscular bioavailability) values for allopregnanolone and ganaxolone were, respectively 4.95 L/kg, 12.88 L/kg/hr, 16 min, 97% and 5.07 L/kg, 8.35 L/kg/hr, 25 min, 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 GABAA receptors.
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影响因子：
5.3
作者：
Naylor, DE;Liu, HT;Wasterlain, CG
通讯作者：
Wasterlain, CG
影响因子：
4.7
作者：
Kokate, TG;Cohen, AL;Rogawski, MA
通讯作者：
Rogawski, MA
影响因子：
5.3
作者：
Kapur, J;Macdonald, RL
通讯作者：
Macdonald, RL
影响因子：
2.2
作者：
Reddy, Doodipala S.;Rogawski, Michael A.
通讯作者：
Rogawski, Michael A.
DOI：
10.1081/clt-120026523
发表时间：
2003-01-01
期刊：
JOURNAL OF TOXICOLOGY-CLINICAL TOXICOLOGY
影响因子：
--
作者：
Barrueto, F;Furdyna, PM;Nelson, LS
通讯作者：
Nelson, LS