候选药物的不良反应,癫痫发作是药物开发中的一个严重问题。改进扣押责任评估系统对于选择好的候选人至关重要。首先,通过多电极阵列系统在大鼠海马脑片中进行体外电生理测量,以确认电诱发的群体尖峰(PS)面积的增加,多个种群高峰(MPS)的发生,因此,五种阳性对照化学品的缉获责任:piclotoxin,4-氨基吡啶,戊四唑,青霉素G,和氯丙嗪.阿司匹林,阴性对照,不影响PS面积或产生MPS。此外,巴氯芬,抗惊厥药物,减少PS面积并抑制PS面积的增加或piclotoxin诱导的MPS的发生。碳青霉烯类抗生素的癫痫发作可能性的比较研究表明,替南>卡宾>欧美酸和菲尼巴克斯。尽管导致PS面积大幅减少,毒扁豆碱,顺铂,和帕罗西汀仍然产生MPSs。因此,PS面积的增加或MPS的发生被认为是癫痫发作责任的重要评估参数。相比之下,体外电生理测量无法检测苯海拉明或氟伏沙明的癫痫发作责任。对脑室内给药这些药物引起的体内小鼠行为变化的后续研究清楚地检测到了惊厥。使用海马脑片的体外电生理研究结合体内行为观察研究通过侧脑室注射给药的候选药物可以实施评估即使少量的癫痫发作的可能性,尤其是在药物开发的早期阶段。
An adverse effect of drug candidates, seizure is a serious issue in drug development. Improving evaluation systems for seizure liability is crucial for selecting good candidates. Firstly, in vitro electrophysiological measurement by a multielectrode array system in rat hippocampal brain slices was employed to confirm an increase in electrically evoked population spike (PS) area, the occurrence of multiple population spikes (MPSs), and thereby the seizure liability of five positive control chemicals: picrotoxin, 4-aminopyridine, pentylenetetrazole, penicillin G, and chlorpromazine. Aspirin, a negative control, did not affect PS area or generate MPSs. Furthermore, baclofen, an anticonvulsant drug, decreased PS area and inhibited the increase in PS area or occurrence of MPSs induced by picrotoxin. A comparative study of seizure liability among carbapenem antibiotics revealed that tienam > carbenin > omegacin and finibax. Despite leading to a strong decrease in PS area, physostigmine, cisplatin, and paroxetine still produced MPSs. Therefore, the increase in PS area or the occurrence of the MPS are considered significant evaluation parameters for seizure liability. In contrast, the in vitro electrophysiological measurement could not detect the seizure liability of diphenhydramine or fluvoxamine. A follow-up study of in vivo mouse behavioral change induced by intracerebroventricular administration of these drugs clearly detected convulsions. The in vitro electrophysiological study using hippocampal brain slices combined with in vivo behavior observation study of drug candidates administered by intracerebroventricular injection can implement to assess the seizure liability of even small amounts, especially in the early stages of drug development.