基于斑马鱼模型探讨熄风胶囊治疗癫痫的时-量-效-毒关系

Medication safety in children has become the hot issue concerned by the government, society and academic circles. Xi Feng capsule has been applied to treating epilepsy in clinic for long,but it has a long medication cycle and scorpio,one of its component,contains toxicity.Our project team’s previous clinical and experimental studies proved that the curative effect of Xi Feng capsule was reliable. However, its security research, especially about the long-term effects on children and pregnant women,is still inadequate. The project is to make epilepsy modle with the larval and female adult zebrafish,which is characteristic of high throughput screening and visualization research. It is to use the experimental means and methods of high-resolution computer vision tracking,precise drug delivery with microinjection and zebrafish embryos in site hybridization. The project will take different dosage and intervention time of Xi Feng capsule and scorpio as the related factors to evaluate its curative effect,the acute toxicity,chronic toxicity,toxicity on organs, genitals and development, etc.It will help know medication security, clear the toxic target organs,and get the best time-dose threshold to ensure the effective treatment and medication safety from groping relationships among time,dosage,efficacy and Toxicity.This study will provide experiment basis for the safe and effective use of Xifeng capsule in clinical .For another,it will also provide some ideas and methods for carrying out safety evaluation experiment of traditional Chinese medicine containing toxic materials.

儿童用药的安全性问题已成为政府、社会、学界关注的热点问题。熄风胶囊治疗癫痫在临床应用已久，但其用药周期长，而且含“有毒”药材全蝎。前期项目组从临床和实验角度充分证实了熄风胶囊疗效可靠；然而目前其安全性研究尚薄弱，尤其是对儿童的长远影响以及妊娠期女性用药对胎儿的影响。故本项目拟以具有高通量、研究可视化特点的斑马鱼幼鱼和雌鱼成鱼进行癫痫造模，采用计算机视觉高通量追踪、显微注射精确给药，斑马鱼胚胎原位杂交等实验手段和方法，将熄风胶囊及全蝎的不同用药剂量、不同干预时长作为相关因素，对疗效以及急毒、慢毒、生长发育影响、各器官毒性，生殖毒性、发育毒性进行全面评价，在回答其安全性问题，明确毒性靶器官的同时，探讨熄风胶囊治疗癫痫的“时-量-效-毒”关系，得出有效且安全的最佳“时间-剂量阈”，从而为临床安全有效使用熄风胶囊提供实验依据，并为含毒性药材的中药复方开展安全性评价的实验研究提供一些思路和方法。

癫痫，中医认为由本虚标实，气机逆乱所致；“本虚”责之于肾精亏虚，“标实”为临床表现风和痰之见症；且本病常反复发作，日久不愈。据此拟定益肾填精、豁痰息风、化瘀通络的治疗方法，研制出院内制剂熄风胶囊。在我国，癫痫患儿认知损害的发生率为30%-40%，目前西医对疾病的控制方面取得了肯定的效果，但对认知损害缺乏有效的治疗手段。熄风胶囊可通过良性调控皮层等机制，可达到控制癫痫发作，改善学习、认知能力的目的。临床研究表明，抗癫痫药物存在不同程度的致畸率，同时目前国内尚未见到抗癫痫中药对妊娠期女性患者胚胎和子代影响的相关研究报道，熄风胶囊是否影响儿童的生长发育，目前的相关研究证据尚不够充足。本项目拟以具有高通量、研究可视化特点的斑马鱼为实验动物并进行癫痫.造模，采用计算机视觉高通量追踪、显微注射精确给药，斑马鱼胚胎原位杂交等实验手段和方法，探讨熄风胶囊和全蝎干预癫痫模型的“时-量-效”关系，同时评价其对斑马鱼幼鱼及其幼鱼癫痫模型的急性毒性、慢性毒性，生长发育影响，各器官毒性，以及对斑马鱼雌性成鱼及其癫痫模型的生殖毒性，发育毒性（特指母体用药对胚胎的影响），鉴别其毒性靶器官，明确其安全性结论，探讨熄风胶囊和全蝎的“时-量-效-毒”关系，从而摸索熄风胶囊取得最佳疗效且安全的“时间-剂量阈”，为安全有效合理使用熄风胶囊提供一定实验依据。