Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
Epilepsy Behav. 2015 Aug;49:20-5. doi: 10.1016/j.yebeh.2015.02.027. Epub 2015 Mar 26.
Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. The mechanisms involved in RSE are incompletely understood. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. The pilocarpine and lithium-pilocarpine rat models are widely used in this respect. In these models, resistance to diazepam and other antiseizure drugs (ASDs) develops during SE so that an SE that is longer than 30 min is difficult to suppress. Furthermore, because all ASDs used in SE treatment are much more rapidly eliminated by rodents than by humans, SE recurs several hours after ASD treatment. Long-term consequences include hippocampal damage, behavioral alterations, and epilepsy with spontaneous recurrent seizures. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group. Based on data from diverse seizure models, we hypothesized that cholinergic mechanisms are involved in the mechanisms underlying ASD resistance of SE. We, therefore, developed an intravenous drug cocktail, consisting of diazepam, phenobarbital, and the anticholinergic scopolamine. This drug combination irreversibly terminated SE when administered 60, 90, or 120 min after SE onset. The efficacy of this cocktail in terminating SE was comparable with the previously reported efficacy of polytherapies with the glutamate receptor antagonist ketamine. Furthermore, when injected 60 min after SE onset, the scopolamine-containing cocktail prevented development of epilepsy and hippocampal neurodegeneration, which was not observed with high doses of diazepam or a combination of phenobarbital and diazepam. Our data add to the existing preclinical evidence that rational polytherapy can be more effective than monotherapy in the treatment of SE and that combinatorial therapy may offer a clinically useful option for the treatment of RSE. This article is part of a Special Issue entitled "Status Epilepticus".
药物难治性癫痫持续状态（RSE）是一种严重的医疗急症，死亡率高达40%，且存在严重长期后果的风险。RSE所涉及的机制尚未完全明确。动物模型对于制定更有效的癫痫持续状态（SE）终止治疗策略以及预防其长期后果具有重要意义。毛果芸香碱和锂 - 毛果芸香碱大鼠模型在这方面被广泛应用。在这些模型中，SE发作期间会出现对苯二氮䓬类药物和其他抗癫痫药物（ASD）的耐药性，以至于持续超过30分钟的SE难以被抑制。此外，由于SE治疗中使用的所有ASD在啮齿动物体内的消除速度比在人类体内快得多，ASD治疗数小时后SE会复发。长期后果包括海马损伤、行为改变以及伴有自发反复癫痫发作的癫痫。在本综述中，讨论了比单一疗法更有效的不同合理联合治疗SE的方法，包括我们团队最近开发的一种新型联合治疗方法。基于来自多种癫痫发作模型的数据，我们推测胆碱能机制参与了SE对ASD耐药的潜在机制。因此，我们开发了一种静脉注射药物合剂，由地西泮、苯巴比妥和抗胆碱能药物东莨菪碱组成。在SE发作后60、90或120分钟给药时，这种药物组合可不可逆地终止SE。这种合剂终止SE的疗效与先前报道的谷氨酸受体拮抗剂氯胺酮联合治疗的疗效相当。此外，在SE发作后60分钟注射时，含东莨菪碱的合剂可预防癫痫和海马神经变性的发生，而高剂量地西泮或苯巴比妥与地西泮联合使用则未观察到这种效果。我们的数据补充了现有的临床前证据，即合理联合治疗在SE治疗中可能比单一疗法更有效，并且联合治疗可能为RSE的治疗提供一种临床上有用的选择。本文是名为“癫痫持续状态”的特刊的一部分。
