Abstract：
Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.
摘要：
地西泮是一种基石的即时使用的抗癫痫治疗，可以延长癫痫患者癫痫发作之间的持续时间。然而,由于缺乏合适的临床前模型,我们对间歇性抢救治疗对疾病进展的机制理解受到限制.具体来说,地西泮的药代动力学在人类和实验动物之间差异很大。这里,我们在大鼠中开发了一种新的重复挽救疗法给药模式,以维持在人类中观察到的延长的治疗浓度.大鼠接受了三个剂量的地西泮，间隔1小时（0.75、1.5或3mg/kg，腹膜内）；最后一次给药后10分钟和1、3或6小时收集血浆和大脑。血浆和脑浓度遵循剂量依赖性增加，重复3mg/kg范例（180ng/mL）后的峰值浓度相当于地西泮鼻喷雾剂人体研究中观察到的血浆水平。在这种范例中，脑血浆比增加表明地西泮在大脑中的积累可能在作用部位起长效作用。总的来说,我们重复地西泮给药模式模拟了在人类中看到的药物浓度和积累，提供了一种临床前工具来研究苯二氮卓类药物抢救治疗对啮齿动物癫痫模型中癫痫发作集群生物学的影响。简单语言总结：还有更多关于地西泮如何在24小时内仅在两次或更多次癫痫发作时使用它的人的大脑中发挥作用（这被称为癫痫发作集群）。动物的伦理研究可用于了解体内药物的更多信息。在这项研究中,我们发现，在大鼠体内服用三剂地西泮给人的药物量与一剂相同。我们现在可以测试患有癫痫的大鼠，看看这种药物如何在需要癫痫发作时服用的人身上起作用。
