中国中药杂志

2011, v.36(14) 1889-1894

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雄黄的毒性研究
Toxicity study of realgar

梁爱华;李春英;王金华;薛宝云;李化;杨滨;王京宇;解清;Odd Georg Nilsen;
LIANG Aihua1 ,LI Chunying1,WANG Jinhua1,XUE Baoyun1,LI Hua1,YANG Bing1,WANG Jingyu2,XIE Qing2,Odd Georg Nilsen3 (1.Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China;2.School of Public Health,Peking University,Beijing 100083,China;3.Faculty of Medicine,Norwegian University of Science and Technology,Trondheim 7006,Norway)

摘要(Abstract):

目的:研究雄黄的毒性特点,提出雄黄的相对安全用药剂量和用药时间建议,为雄黄的临床安全用药提供科学依据。方法:小鼠单次灌胃给药,测定LD50。采用SD大鼠随机分为对照组和雄黄5,10,20,80,160 mg.kg-1.d-1(相当于药典剂量高限的1/2,1,2,8,16倍)剂量组,各剂量组均每日灌胃给药1次,连续3个月,于给药后1,2,3个月和停药1个月,测定尿液定性、血常规以及血清生化指标,并观察肝、肾、心、脑等主要脏器的组织形态学变化,确定无明显不良作用水平(NOA-EL)。以世界卫生组织认为的人群内对化合物的敏感性差异倍数(10)乘以药理学上按照体表面积折算大鼠与人剂量的倍数(约为6)作为安全系数(60),结合NOAEL估计不同用药周期内的相对安全剂量。参照我国相关的技术指导原则规定的1个月动物长期毒性试验支持临床试验用药周期2周的方法,估计雄黄相对安全的用药时间。结果:在雄黄中As2S2质量分数为90%,可溶性砷为1.696 mg.g-1情况下,给小鼠单次灌胃给药的LD50为20.5 g.kg-1(等于摄入可溶性砷34.8 mg.kg-1),相当于人日用量约12 812倍。而给大鼠反复灌胃给药时,雄黄超过一定剂量用药达到2个月或以上时,可造成肾脏和肝脏病理损害,其中肾脏显示更为敏感。大鼠灌胃雄黄1,2,3个月的无明显毒性剂量(NOAEL)分别为160,20,10 mg.kg-1.d-1(累积摄入可溶性砷8.14,2.04,1.53 mg.kg-1)。估计临床使用雄黄的相对安全剂量范围为10~160 mg(依用药时间不同)。结论:反复使用雄黄时,建议在可溶性砷≤1.7 mg.g-1的条件下,雄黄用药1~2周时,剂量不超过160 mg;用药2~4周时,剂量不超过20 mg;如果降低剂量至10 mg或以下,则在用药6周内相对安全。
Objective: To investigate the toxicity of realgar and provide the scientific basis for safety use of realgar in clinic.Method: Acute toxicity was tested by single oral administration.Chronic toxicity of realgar was tested at different dose levels(5,10,20,80,160 mg·kg-1·d-1) which correspond to 1/2,1,2,8,16 times of human dose levels.The rats were treated with the test substances through oral administration once daily for successively 90 days.Urinary qualitative test,blood routine examination,serum chemistry measurement,and histomorphologic observation were conducted at day 30,60 and 90.Toxic changes related to the treatment of realgar and no-observed adverse effect level(NOAEL) was evaluated.Result: With the content of 90% total arsenic and 1.696 mg·g-1 soluble asenic,LD50 of Realgar with oral administration was 20.5 g·kg-1(corresponding to 34.8 mg·kg-1 soluble arsenic),equivalent to 12 812 times of clinical daily dose for an adult.Realgar can cause kidney toxicity or/and liver toxicity after administration for over 30,60 or 90 days respectively.The kidney was more sensitive to realgar than liver.Based on repeated dose toxicity study,NOAELs were 160 mg·kg-1·d-1 for 30 day′s administration,20 mg·kg-1·d-1 for 60 day′s administration,10 mg·kg-1·d-1 mg·kg-1·d-1 for 90 day′s administration respectively.Thus,for safety use of realgar,it is recommended that the daily doses of realgar(with soluble arsenic ≤1.7 mg·g-1) for an adult of the body weight about 60 kg could be 10-160 mg depending on the variation of the treatment duration.Conclusion: Long term use of realgar can cause kidney and liver pathological change,so the doses and administration duration should be limited.The suggestion is as follows: realgar which contains soluble arsenic ≤1.7 mg·g-1 should be used less than 2 weeks at daily dose 160 mg,less than 4 weeks at the dose of 20 mg and less than 6 weeks at the dose of 10 mg.

关键词(KeyWords): 雄黄;砷;毒性
realgar;arsenic;toxicity

Abstract:

Keywords:

基金项目(Foundation): 国家“重大新药创制”科技重大专项(2009ZX09301-005);; 国家科技部科研院所基础研究专项基金(2002DEB20067);; 国家“十一五”科技支撑计划项目(2006BAI55B02-03)

作者(Author): 梁爱华;李春英;王金华;薛宝云;李化;杨滨;王京宇;解清;Odd Georg Nilsen;
LIANG Aihua1 ,LI Chunying1,WANG Jinhua1,XUE Baoyun1,LI Hua1,YANG Bing1,WANG Jingyu2,XIE Qing2,Odd Georg Nilsen3 (1.Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China;2.School of Public Health,Peking University,Beijing 100083,China;3.Faculty of Medicine,Norwegian University of Science and Technology,Trondheim 7006,Norway)

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