常山碱盐急性毒性及其与青蒿素类药物联合用药增效减毒作用  

Acute toxicity of Dichroa alkali salt and efficacy enhancement and toxicity alleviation in combination with artemisinin and its derivatives

作　　者：李思迪[1] 李春[1] 代宝强[1] 张广平[1] 盛益华[1] 李建荣[1] 叶祖光[1] 

机构地区：[1]中国中医科学院中药研究所,北京100700

出　　处：《中国药理学与毒理学杂志》2016年第8期808-814,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家科技重大专项(2014ZX09304-307);国家科技重大专项(2015ZX09501004)~~

摘　　要：目的探索常山碱盐(DAS)和青蒿素类药物联合用药以达到增效减毒的可能性。方法用小鼠对DAS进行急性毒性实验,观察小鼠的腹泻率、死亡率、半数致死剂量(LD_(50))、LD_(90)、半数腹泻剂量(DD_(50))和DD_(90),明确DAS安全剂量;采用ip接种疟原虫制备的鼠疟感染小鼠模型进行体内抗疟实验(ig给药,每天1次,连续4 d),比较单用DAS或青蒿素类药物、以及DAS联合青蒿素、双氢青蒿素(Dih)、蒿甲醚、青蒿琥酯时的抗疟效价。动态采集尾静脉血,涂片并吉姆萨染色法染色,显微镜下观察疟疾小鼠疟原虫的转阴以及复燃情况,计算转阴率和抗复燃率,并计算半数有效剂量(ED_(50))和ED_(90)等。结果在急性毒性实验中,DAS的安全剂量为0.5 mg·kg^(-1)。鼠疟的体内抗疟实验中,单用DAS 0.25和0.5 mg·kg^(-1)对疟疾小鼠疟原虫的转阴和抗复燃作用较差。与单用DAS 0.5 mg·kg^(-1)或单用青蒿素、Dih、蒿甲醚和青蒿琥酯相比较,DAS与青蒿素(274,392和560 mg·kg^(-1))、Dih(52,80和123 mg·kg^(-1))、蒿甲醚(10,20,40和80 mg·kg^(-1))和青蒿琥酯(32.5,65.0和130.0 mg·kg^(-1))联合应用时疟疾小鼠疟原虫的转阴率和抗复燃率均明显提高(P<0.05,P<0.01)。DAS 0.5 mg·kg^(-1)和上述青蒿素类药物联用,与青蒿素类药物单用比较,效价分别提高了0.8,0.2,1.0和0.6倍,同时联合用药组(包括达到与单用DAS同样疗效的联用剂量组)均未发现小鼠腹泻或死亡。结论 DAS安全窗较窄,通过与青蒿素及其衍生物联合用药,可达到增效减毒抗疟的目的。OBJECTIVE To explore the possibility that Dichroa alkali salt （DAS） can enhance effi- cacy and reduce toxicity when combined with artemisinin and its derivatives. METHODS Kunming mice were used in acute toxicity test of DAS. Diarrhea rate, mortality, 50% lethal dose （LD50）, LD90, 50% diarrhea dose （DD50） and DD90were determined, and the safe dose of DAS was defined. An animal model of malaria was established by inoculating strains of the parasite in an antimalarial in vivo experiment. The model mice were ig given drugs, once a day, for 4 d. The titer was compared between alone use and combined use of DAS with artemisinin and its derivatives. Blood of the caudal vein was dynamically collected for blood smear. Gemsa dying assay was used to observe whether the change of the parasite and its revival under a microscope in each group. Finally, negative conversion ratio, anti-revival ratio, 50% effective dose （ED50） and EDgo were calculated. RESULTS The safe dose of DAS was 0.5 mg. kg-1 in acute toxicity test. While a low dose of DAS （0.25 and 0.5 mg· kg-1） was alone used, negative conversion ratio was relatively low and anti-revival effect was not obvious. In vivo experiments of anti-mouse malaria indicated that compared with alone use of DAS 0.5 mg. kg-1 or artemisinin with its derivatives artemisinin, dihydroartemisinin （Dih）, artemether and artesunate, negative conversion ratio and anti-revival ratio were increased significantly （P〈0.01, P〈0.05） when DAS 0.5 mg·kg-1 andartemisinin （ 134, 192, 274, 392 and 560 mg· kg-1）, Dih （52,80 and 123 mg· kg-1 ）, artemether （ 10,20, 40 and 80 mg· kg-1） and artesunate （32.5,65.0 and 130.0 mg. kg-1） were used in combination. When DAS 0.5 mg · kg-1 and artemisinin with its four derivatives were in combination used, the titer was increased 1.8, 1.2, 2.0 and 1.6 times compared with alone use of artemisinin and its derivatives, respectively. In addition, diarrhea or death didn＇t occur in combined groups. CONCLUSION DAS has a narr

关 键 词：常山碱盐 青蒿素 衍生物 疟疾 增效减毒 

分 类 号：R965[医药卫生—药理学]