藏药佐太安全性研究及其复方当佐的临床安全观察初探

佐太是含重金属藏药的典型代表,迄今仍缺乏现代安全性评价数据。该研究通过佐太的急性毒性试验、亚急性毒性试验、单次给药汞分布试验、长期汞蓄积毒性试验及其复方当佐的临床安全性初步观察,以期获得佐太的药用安全数据。急性毒试验发现：半数致死量试验的各组KM小鼠未出现死亡和中毒现象,未做出佐太LD₅₀;佐太的最大耐受量为80 g·kg^-1。亚急性毒性试验发现：佐太在低剂量（13.34 mg·kg^-1·d^-1）和中剂量（53.36 mg·kg^-1·d^-1）时可降低Wistar大鼠血清ALT,AST,Crea水平,且在低剂量时具有显著性差异;高剂量（2 000 mg·kg^-1·d^-1）佐太可显著增加血清ALT,AST,Crea,MDA水平;血清BUN和GSH水平随着剂量增加而降低,呈显著性量效关系。单次给药分布试验发现：佐太单次给药24 h后,Wistar大鼠的肾脏、肝脏及肺中汞含量出现升高趋势,且在肾脏中呈显著剂量依赖性。长期蓄积毒性试验发现：KM小鼠在临床等效剂量（6.67 mg·kg^-1·day^-1）给药佐太4.5个月、停药1.5个月,从2.5个月时肾脏开始出现显著性汞蓄积,停药后又逐步降低,而肝、脾和脑中汞含量及血清ALT,AST,TBIL,BUN,Crea均无显著性变化;在给药4.5个月时KM小鼠肾、肝和脾组织有轻微结构性变化,停药后又恢复正常;佐太组动物体重增加与对照组之间无显著性差异。当佐临床安全观察发现：受试者在临床剂量下服药当佐1个月,血清生化、血常规和尿常规各指标均无不良变化。该研究证实了传统藏药佐太的毒性极低,其临床配伍药用安全性较好,在临床剂量下和临床服药周期内对机体无不良作用,但长期大剂量用药可能会对肾脏等产生一定的影响。

Study on safety of Tibetan medicine Zuotai and preliminary study on clinical safety of its compound Dangzuo

Zuotai (gTso thal) is a typical representative of Tibetan medicines containing heavy metals, but there is still lack of modern safety evaluation data so far. In this study, acute toxicity test, sub-acute toxicity test, one-time administration mercury distribution experiment, long-term mercury accumulative toxicity experiment and preliminary study on clinical safety of Compound Dangzuo were conducted in the hope of obtain the medicinal safety data of Zuotai. In the acute toxicity test, half of KM mice given the lethal dose of Zuotai were not died or poisoned, and LD₅₀ was not found. The maximum tolerated dose of Zuotai was 80 g·kg^-1. In the sub-acute toxicity test, Zuotai could reduce ALT, AST, Crea levels in serums under low dose (13.34 mg·kg^-1·d^-1) and medium dose (53.36 mg·kg^-1·d^-1), with significant difference under low dose, and increase the levels of ALT, AST, MDA, Crea in serums under high dose (2000 mg·kg^-1·d^-1); besides, the levels of BUN and GSH in serums reduced with the increase in dose of Zuotai, indicating a significant dose-effect relationship. In the one-time administration distribution experiment, the content of mercury in rat kidney, liver and lung increased after the one-time administration with Zuotai, with a significant dose-dependent relationship in kidney. In the long-term mercury accumulative toxicity experiment, KM mice were administered with equivalent doses of Zuotai for 4.5 months and then stopped drug administration for 1.5 months. Since the 2.5^th month, they showed significant mercury accumulation in kidney, which gradually reduced after drug withdrawal, without significant change in mercury content in liver, spleen and brain and ALT, AST, TBIL, BUN and Crea in serum. At the 4.5^th month after drug administration, KM mice showed slight structural changes in kidney, liver and spleen tissues, and gradually recovered to normal after drug withdrawal. Besides, no significant difference in weight gain was found between the Zuotai group and the control group. According to the findings of the clinical safety study of Dangzuo, after subjects administered Dangzuo under clinical dose for one month, their serum biochemical indicators, blood routine indicators and urine routine indicators showed no significant adverse change. This study proved that traditional Tibetan medicine Zuotai was slightly toxic, with a better safety in clinical combined administration and no adverse effects on bodies under the clinical dose and clinical medication cycle. However, long-term high-dose administration of Zuotai may have a certain effect on kidney.