经皮反复给予玉红膏对大鼠器官毒性的研究

Organ toxicity of Yuhong Ointment(玉红膏) after repeated transdermal administration in rats

目的观察经皮反复给予玉红膏对大鼠肝、肾功能及心、脑、肝、肾、脾等主要脏器组织形态学的影响,为临床安全用药提供实验数据。方法 SPF级SD大鼠100只,体重200 g,雌雄各半。用抽签法随机分为基质对照组、1倍浓度玉红膏组(轻粉含量0.4%)、2倍浓度玉红膏组(轻粉含量0.8%)、4倍浓度玉红膏组(轻粉含量1.6%)和1.6%轻粉组,每组20只。制备大鼠皮肤破损模型,经破损皮肤涂抹不同浓度玉红膏,1次/d,连续28 d。分别于给药前、给药14、28 d和停药28 d测定各组大鼠血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、尿素氮(BUN)、肌酐(Cr)和N-乙酰-β-D氨基葡萄糖苷酶(NAG)水平;给药28 d和停药28 d时每组各处死10只大鼠,取心、脑、肝、肾、脾等脏器称重,计算脏器系数,并取肝、肾、脾组织观察形态学改变。结果不同浓度玉红膏组和1.6%轻粉组大鼠ALT、AST、BUN、Cr和NAG水平与同期基质对照组比较差异无统计学意义(均P>0.05);停药28 d时,1.6%轻粉组大鼠血清Cr含量高于基质对照组(P<0.05)。给药28 d与停药28d时,2和4倍浓度玉红膏组、1.6%轻粉组大鼠的肾脏系数均明显高于基质对照组(均P<0.05)。各组大鼠心、脑、肝、脾脏器系数的差异均无统计学意义(均P>0.05)。给药28 d时各组大鼠肝、肾、脾组织均无明显形态学改变。结论经皮反复给予玉红膏未发现大鼠出现明显的器官毒性反应,高浓度的玉红膏可能导致大鼠发生可逆转的肾损伤。提示临床长期大量应用玉红膏应监测患者的肾功能。

Objective To observe the effects of Yuhong Ointment on rat＇s liver and kidney functions and histomorphology of heart,brain,liver,kidney and spleen after transdermal administration repeatedly,in order to provide experimental evidences for safe use of Yuhong Ointment in clinical practice. Methods A total of 100 SPF SD rats of equal number of both genders,weighting 200 g,were divided into 5 groups：matrix control group,1 time concentration of Yuhong Ointment group（containing 0.4% calomel）,2 times concentration of Yuhong Ointment group（containing 0.8%calomel）,4 times concentration of Yuhong Ointment group（containing 1.6%calomel） and calomel group（containing 1.6% calomel） by drawn lots randomly,each group comprised 20 rats.The model of rat＇s skin injury was prepared.Yuhong Ointment in different concentrations were applied on the skin-impaired once daily for 28 days.The levels of alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,blood urea nitrogen（BUN）,creatinine（Cr） and N-acetyl beta-D glucosaminidase（NAG） of rats in different groups were measured before treatment,14 and 28 days after treatment,and 28 days after drug withdrawal,respectively. Ten rats in every group were sacrificed on 28 days after treatment and 28 days after drug withdrawal, respectively.The heart,brain,liver,kidney,and spleen of rats in different groups were taken and weighed up.The organ coefficients were calculated and the histomorphological changes of liver,kidney and spleen were examined.Results There were no statistically significant differences in levels of serum ALT、AST、 BUN、Cr and NAG in rats among the different concentrations of Yuhong Ointment groups,1.6%calomel group and matrix control group（all P0.05）.The level of serum Cr in rat of 1.6%calomel group was significantly higher than that of matrix control group 28 days after drug withdrawal（P0.05）.The kidney coefficients of rats in 2 times and 4 times concentration of Yuhong Ointment group and 1.6%calomel group were significantly higher than that in the matrix control group（P0.05） on 28 days after treatment and 28 days after drug withdrawal.The differences of coefficients of heart,brain,liver,and spleen of rats in different groups were not statistically significant（all P0.05）.There were no obvious morphological changes in liver,kidney and spleen in different groups 28 days after treatment.Conclusions No obvious toxic reactions were observed in rats after transdermal administration of Yuhong Ointment repeatedly.The high concentrations of Yuhong Ointment maybe bring reversible kidney injury.The kidney function of patient who received large volume of Yuhong Ointment for long-term should be monitored.