常山碱盐灌胃给药抗疟药效及急性毒性

Anti-malarial Efficacy and Acute Toxicity of Dichroa Alkali Salt by Intragastric Administration

目的：研究常山碱盐（dichroa alkali salt,DAS）抗疟药效及急性毒性作用,了解DAS作为抗疟药的成药性。方法：采用腹腔接种伯氏疟原虫制备鼠疟感染模型,进行体内抗疟药效评价（灌胃给药,每天1次,连续4 d）,动态采集尾静脉血,涂片并吉姆萨染色,镜下观察疟疾小鼠疟原虫的转阴及复燃情况,计算转阴率和复燃率,并计算半数有效剂量（50%effective dose,ED50）。采用ICR小鼠对DAS进行急性毒性实验,观察小鼠一般状态,腹泻及死亡情况,计算半数腹泻剂量（50%diarrhea dose,DD50）和半数致死剂量（50%lethal dose,LD50）,苏木精-伊红（HE）染色观察主要脏器的组织病理学变化。结果：鼠疟体内实验发现,DAS在较低剂量即可使感染小鼠全部转阴,但不能有效抗复燃,ED50为0.6 mg·kg（-1）,95%置信区间为0.5-0.7 mg·kg（-1）。小鼠急性毒性研究发现,给予DAS后,动物活动减少、行为倦怠,毛色无光、畏冷、进食、饮水欠佳,轻者腹泻、重者便血甚至死亡;DD50为7.9 mg·kg（-1）,95%置信区间为6.3-10.0 mg·kg（-1）,LD50为10.8 mg·kg（-1）,95%置信区间为8.5-13.8 mg·kg（-1）;大体解剖发现,给药组小鼠胃明显膨大,脾脏、盲肠萎缩,肠道内容物呈泔水样变化;HE染色发现不同剂量组肝脏、脾脏、胃和盲肠出现了不同程度的病理组织学损伤。以DD50和LD50为指标,计算DAS的治疗指数（therapeutic index,TI）分别为13.17,18.00。结论：DAS在较低剂量即可使感染疟原虫的模型小鼠全部转阴,但是毒性大,安全窗窄。

Objective： To understand the druggability of dichroa alkali salt（ DAS） as an antimalarial drug by investigating its antimalarial efficacy and toxicity characteristics. Method： The animal models of malaria were established by inoculating strains of the parasite in an antimalarial experiment in vivo. The model mice received drugs by intragastric administration,once daily,for 4 d. Blood from the caudal vein was dynamically collected for blood smear. Giemsa staining assay was used to observe the negative conversion and revival of parasite under a microscope in each group. Finally,negative conversion ratio,anti-revival ratio,and 50% effective dose（ ED50） were calculated. ICR mice were used to study the acute toxicity of DAS,observe their general state,diarrhea and death. 50% diarrhea dose（ DD50） and 50% lethal dose（ LD50） were calculated,while hematoxylineosin（ HE） staining was used to observe the histopathological changes of the main organs. Result： The antimalarial experimental results showed that DAS was effective in antimalarial treatment at a lower dose,with an ED50 of 0. 6 mg·kg（-1） and a 95% confidence interval of 0. 5 to 0. 7 mg·kg（-1）,but no obvious effect was observed in anti-revival. The acute toxicity experiment of mice showed that after DAS was given,the mice activities were decreased,the behavior was sluggish,and the hair color was dull; the mice were in fear of cold,with poor food and water intake. Diarrhea was found in the mice with mild toxic degree,and hematochezia and death were even found in those with severe toxic degree; DD50 was 7. 9 mg·kg（-1）,with 95% confidence interval of 6. 3-10. 0 mg·kg（-1）; LD50 was 10. 8 mg·kg（-1）,with 95% confidence interval of 8. 5-13. 8 mg·kg（-1）. The general anatomy results showed that the stomach of mice in treatment group was obviously extended,with atrophy in spleen and cecum,and swill like changes in intestinal contents. HE staining showed that the liver,spleen,stomach and cecum had different degrees of histopathological injury. With DD50 and LD50 as the indicators,the therapeutic index（ TI） of DAS was calculated as 13. 17 and 18. 00 respectively. Conclusion： DAS is effective but toxic for malaria at an even lower dose,with narrow safe dose window.