比较 valnoctamide 和 sec-butylpropylacetamide（SPD）在终止小儿大鼠神经毒剂诱导的惊厥中的疗效。
Comparative efficacy of valnoctamide and sec-butylpropylacetamide (SPD) in terminating nerve agent-induced seizures in pediatric rats.
机构信息
Nerve Agent Countermeasures, Medical Toxicology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.
Research Support Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.
出版信息
Epilepsia. 2019 Feb;60(2):315-321. doi: 10.1111/epi.14630. Epub 2019 Jan 7.
OBJECTIVES
Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic-VCD), sec-butylpropylacetamide (racemic-SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats.
METHODS
Female and male postnatal day (PND) 21, 28, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED ) of the drugs.
RESULTS
SPD-ED values in the VX model were the following: PND21, 53 mg/kg (male) and 48 mg/kg (female); PND28, 108 mg/kg (male) and 43 mg/kg (female); and PND70, 101 mg/kg (male) and 40 mg/kg (female). SPD-ED values in the sarin model were the following: PND21, 44 mg/kg (male) and 28 mg/kg (female); PND28, 79 mg/kg (male) and 34 mg/kg (female); and PND70, 53 mg/kg (male) and 53 mg/kg (female). VCD-ED values in the VX model were the following: PND21, 34 mg/kg (male) and 43 mg/kg (female); PND28, 165 mg/kg (male) and 59 mg/kg (female); and PND70, 87 mg/kg (male) and 91 mg/kg (female). VCD-ED values in the sarin model were the following: PND21, 45 mg/kg (male), 48 mg/kg (female); PND28, 152 mg/kg (male) 79 mg/kg (female); and PND70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital-ED values in the VX model were the following: PND21, 43 mg/kg (male) and 18 mg/kg (female); PND28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital-ED values in the sarin model were the following: PND21, 32 mg/kg (male) and 32 mg/kg (female); PND28, 58 mg/kg (male) and 97 mg/kg (female); and PND70, 65 mg/kg (female).
SIGNIFICANCE
SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.
目的
儿童和成人可能成为民用神经毒剂暴露的受害者之一。本研究评估了瓦诺卡酰胺（消旋-VCD）、仲丁基丙酰胺（消旋-SPD）和苯巴比妥在阻止未成年和成年大鼠的神经毒剂发作中的疗效。
方法
先前植入脑电图（EEG）电极的雌性和雄性出生后第 21 天（PND21）、28 天（PND28）和 70 天（成年）大鼠（PND21）接受致痫剂量的神经毒剂沙林或 VX 暴露，连续记录 EEG。在发作开始后 5 分钟，用 SPD、VCD 或苯巴比妥治疗动物。用上下法在连续的动物中确定药物的抗惊厥中位数有效剂量（ED ）。
结果
沙林模型中 SPD-ED 值如下：PND21，53mg/kg（雄性）和 48mg/kg（雌性）；PND28，108mg/kg（雄性）和 43mg/kg（雌性）；PND70，101mg/kg（雄性）和 40mg/kg（雌性）。VX 模型中 SPD-ED 值如下：PND21，44mg/kg（雄性）和 28mg/kg（雌性）；PND28，79mg/kg（雄性）和 34mg/kg（雌性）；PND70，53mg/kg（雄性）和 53mg/kg（雌性）。VX 模型中 VCD-ED 值如下：PND21，34mg/kg（雄性）和 43mg/kg（雌性）；PND28，165mg/kg（雄性）和 59mg/kg（雌性）；PND70，87mg/kg（雄性）和 91mg/kg（雌性）。沙林模型中 VCD-ED 值如下：PND21，45mg/kg（雄性），48mg/kg（雌性）；PND28，152mg/kg（雄性），79mg/kg（雌性）；PND70，97mg/kg（雄性），79mg/kg（雌性）。VX 模型中苯巴比妥-ED 值如下：PND21，43mg/kg（雄性）和 18mg/kg（雌性）；PND28，48mg/kg（雄性）和 97mg/kg（雌性）。沙林模型中苯巴比妥-ED 值如下：PND21，32mg/kg（雄性）和 32mg/kg（雌性）；PND28，58mg/kg（雄性）和 97mg/kg（雌性）；PND70，65mg/kg（雌性）。
意义
在沙林和 VX 诱导的癫痫持续状态模型中，SPD 和 VCD 均在未成年和成年大鼠中表现出抗惊厥活性。苯巴比妥在未成年大鼠中有效，而在成年大鼠中，需要更高剂量的药物，同时伴有毒性。总体而言，与年龄较大的动物相比，PND21 动物需要的药物更少就能停止发作，并且总体而言，雄性需要的药物比雌性多。
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