实验论著
Hu Zhonghui;Wu Chunqi;Wang Quanjun;Wang Qingxiu;Luo Yongwei;Yang Baohua;Lu Shujie;Liao Mingyang
2010, 12(1): 10-7.
Objective: To study the toxic effects of two kinds of Lianbizhi injections on rats in order to provide experimental evidence for the causes of adverse reactions. Methods:Two kinds of Lianbizhi injections were used in this experiment as follows: Lianbizhi A containing andrographolide sodium bisulfis 98.7% and other related substance 1.3%, Lianbizhi B containing andrographolide sodium Bisulfis 49.1% and other related substance 50.9%. Seventy SPF male SD rats were randomly divided into 7 groups: the low-dose (400 mg/kg), moderatedose (800 mg/kg), and highdose (1 600mg/kg) Lianbizhi A groups, the lowdose (50 mg/kg), moderatedose (100 mg/kg), and highdose (200mg/kg) Lianbizhi B groups, and the empty control group (normal saline). Each group comprised 10 rats. All rats received respectively a single intravenous injection of Lianbizhi 10 mL/kg via caudal vein. The presentation of rats was observed within 3 hours after drug administration. The rats’urine was collected within 0~6, 7~12, 13~18 and 19~24 hours after drug administration. The levels and values of acetone bodies, occult blood, BUN, creatinine (Crea), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), N-acetyl-β-D-glucosaminidase (NAG) , and β2 microglobulin (β2-MG) were measured. The blood was collected from rat’s hearts, and the biochemical indexes were measured. Finally, the rats were sacrificed. Their organs were weighed, organ coefficient was calculated, and histopathological changes in the kidney were observed. Results: Two rats in the highdose Lianbizhi B group developed convulsion and erect hair, and they recovered 30 minutes later. No abnormal manifestation was found in rats in other groups. The number of rats having positive ketones in urine[≥(+2)] in high-, moderate-, and low-dose Lianbizhi A groups and highdose Lianbizhi B group was more than that in the control group. The number of rats having positive occult blood in urine[≥(+2)] in the high-, moderate-dose Lianbizhi A groups and high-, moderate-, and low-dose Lianbizhi B groups was more than that in the control group. The BUN levels in the highdose Lianbizhi A group were (319±108) mmol/L before drug administration and increased to (488±139) mmol/L within 7~12 hours after drug administration. The difference was statistically significant (P<0.05). The Crea levels in the high-, moderate-, and low-dose Lianbizhi A groups as well as high- and moderate-dose Lianbizhi B groups were respectively (3 338±1534),(3502±1457),(3428±1 729),(3 305±922),and (3 480±870) mol/L before drug ministration and increased respectively to (6 137±1 544), (5 847±1 319), (5 630±1 622), (5 613±1 968), and (5 218±1 496) mol/L within 7~12 hours after drug administration. The differences were statistically significant (all P<0.05). In addition, the Crea levels in high and moderatedose Lianbizhi A groups were markedly higher than that [(4 326±576) mol/L] in the control group (P<0.05). The increase in Crea levels was related to the dose of andrographolide sodium bisulfis(r=0.790 9). The ALP level in the high-dose Lianbizhi A group was (152±61) U/L within 7~12 hours after drug administration, which was higher than that [(99±37)U/L] in the control group. The ALP level in the high-dose Lianbizhi B group was (143±42)U/L within 7~12 hours after drug administration, which was higher than that [(94±42)U/L] before drug administration and that in the control group. The differences were statistically significant (all P<0.05). The LDH levels in the high, moderate, and lowdose Lianbizhi A groups as well as high-and moderate-dose Lianbizhi B groups were respectively (19±7), (18±11), (18±8), (17±5), and (17±10)U/L before drug administration, and then increased respectively to (88±56), (80±27), (50±17), (57±16), and (28±6)U/L within 0~6 hours after drug administration. The LDH levels in the high-, moderate-, and low-dose Lianbizhi A groups as well as highdose Lianbizhi B groups increased respectively to (44±21), (36±17), (34±13), and (31±7)U/L within 7~12 hours after drug administration. The differences were statistically significant (all P<0.05). In addition, the LDH levels in the high-, moderate-, and low-dose Lianbizhi A groups as well as high and moderatedose Lianbizhi B groups were higher than that [(18±10)U/L] at the same time periods in the control group, the LDH levels in the high-, moderate-, and low-dose Lianbizhi A groups as well as high-dose Lianbizhi B groups were higher than that [(23±7)U/L] at the same time periods in the control group. The differences were statistically significant (all P<005). The increase in LDH levels was related to the dose of andrographolide sodium bisulfis(r=0.899 0). The NAG levels in the high- and moderate-dose Lianbizhi A groups were respectively (0.30±0.04) and (0.31±0.04) U/L within 0~6 hours after drug administration; the NAG levels in the high-, moderate-, and low-dose Lianbizhi A groups were respectively (0.45±0.07), (0.40±0.18), and (0.37±0.14) U/L within 7~12 hours after drug administration; the NAG levels in the high-, moderate-, and low-dose Lianbizhi A groups as well as high-, moderate-, and low-dose Lianbizhi B groups were respectively (0.35±0.09), (0.31±0.06), (0.39±0.18), (0.60±0.09), (0.57±0.06), and (0.33±0.08)U/L within 13~18 hours after drug administration; the NAG levels in the moderate-and low-dose Lianbizhi A groups as well as high-, moderate-, and low-dose Lianbizhi B groups were respectively (0.32±0.03), (0.39±0.14), (0.32±0.07), (0.34±0.05), and (0.29±0.08)U/L within 19~24 hours after drug administration; which were higher than those [(0.26±0.05), (0.22±0.06), (0.24±0.07), and (0.24±0.06)U/L] in the control group. The differences were statistically significant (P<0.05). The β2MG levels in the high-dose Lianbizhi B group was (1.03±0.45) mg/L within 19~24 hours after drug administration, and it was (0.54±0.24)mg/L in the control group; the difference was statistically significant (P<0.05). The increase in NAG and β2-MG levels was associated with the amount of other related substance (r=0.874 9,r=0.981 9). There were no statistically significant differences in biochemical results in rats between the drugexposed groups and the control group. No marked changes in the appearance of rat’s organs, histopathology, and organ coefficient were found. Conclusion: The potential nephrotoxic effects of Lianbizhi injection on rats is related to its purity and dosage; high amount of other related substance and high dosage of the drug could increase renal damage.