右旋硫辛酸注射液对大鼠毒性试验的研究

Study on Toxicity Test of Rats with R-α-Lipoic Acid Injection

关键词:  硫辛酸注射液  长期毒性试验  无毒反应剂量  血小板

Key words:  lipoic acid injection  the chronic toxicity study  no-toxic-effect dose  platelet

摘要:

目的 研究长期重复静脉注射右旋硫辛酸注射液对大鼠的毒性，并探讨导致血小板减少的机制。方法 180只大鼠随机分成溶媒对照组，右旋低、中、高剂量组，左旋对照组及消旋对照组。静脉给药，连续4周，停药后部分动物恢复4周，给药结束后样本进行各项指标检测。结果 右旋高剂量组、消旋对照组以及左旋对照组大鼠出现自主活动降低、流涎、脱毛、体质量增长缓慢等毒性症状，症状在停药后均可恢复。右旋高剂量组和消旋对照组受试动物血小板计数减少，停药4周后可恢复。右旋高剂量组、消旋对照组以及左旋对照组受试动物出现肝功能轻微损害以及肝细胞变性现象，其中左旋对照组肝细胞变性程度较重，停药4周后肝脏损害均有所减轻。右旋高剂量组的骨髓涂片结果显示巨核细胞数目及形态大致正常，大鼠血清血小板相关抗体IgG水平未发生变化，血小板中活性氧堆积。结论 右旋硫辛酸注射液长期毒性试验最大无毒性反应剂量为40 mg·kg^-1，其引起血小板减少可能是通过非免疫性机制导致的。

Abstract:

OBJECTIVE To study the toxicity of R-α-lipoic acid(R-α-LA) in rats by intravenous injection long-term consecutive administration and explore the mechanism of blood platelet reduction. METHODS One hundred eighty Rats were randomly divided into 6 groups:the control group, the R-α-LA low dose group, the R-α-LA medium dose group, the R-α-LA high dose group, the L-LA control group and the LA control group. Rats were administered for 4 weeks by intravenous injection. Same animals were observed during 4 weeks after drug withdrawal. Samples were tested after the end of drug administration. RESULTS It showed toxic symptoms such as decreased autonomic activity, salivation, hair loss, and slow weight gain in R-α-LA high dose group, L-LA control group and LA control group. These toxic symptoms could be recovered during recovery period. The platelet counts in R-α-LA high dose group and LA control group were reduced. But it recovered during recovery period. It showed mild liver function damage and hepatocyte degeneration in R-α-LA high dose group, L-LA control group and LA control group. The L-LA control group of liver cell degeneration was heaviest. Liver damage was alleviated after recovery period. The pathological results of the R-α-LA high dose group showed that the number and morphology of megakaryocytes was normal and the levels of platelet-related antibody IgG did not change in serum. The level of reactive oxygen species(ROS) in platelets was accumulated in R-α-LA high dose group. CONCLUSION The maximum non-toxic response dose of the R-α-LA was 40 mg·kg^-1. Its thrombocytopenia may be caused by non-immune mechanisms.