小儿消积止咳口服液临床用量4个疗程给药对幼龄小鼠的安全性评价

Study on adverse reaction of Xiaoer Xiaoji Zhike Oral liquid on juvenile mice under a long-term clinical dosage

目的参考小儿消积止咳口服液的临床用量,探讨4个临床疗程(20 d)下,该品对幼龄小鼠潜在的毒性表现和受累的毒靶器官;以探索方中槟榔和槟榔碱对儿童临床用药风险的影响。方法根据产品说明书、临床应用情况和槟榔及槟榔碱毒理学研究报道,选择幼龄小鼠分别给予小儿消积止咳口服液(4.29、17.16 g·kg^(-1))、槟榔浸膏(0.24、0.96 g·kg^(-1))、槟榔碱(0.49、5.46 mg·kg^(-1))ig给药20 d后,观察小鼠一般情况及体质量变化,检测血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、乳酸脱氢酶(LDH)、尿素氮(BUN)、肌酐(Cr)水平,病理学观察肝、肾、心、脾组织病理变化,用免疫组化方法分析心肌细胞凋亡蛋白的表达情况。结果小儿消积止咳口服液、槟榔浸膏及槟榔碱各剂量组对小鼠体质量增长没有显著影响;与对照组相比,肝、肾功能相关的血液生化学指标无显著差异,大体解剖及苏木精-伊红(HE)染色显示各给药组肝、肾、心、脾等脏器未见明显的组织病理学改变,心肌细胞凋亡相关蛋白Bcl-2相关X蛋白(Bax)、半胱氨酸蛋白酶-8(Caspase-8)、消皮素D(GSDMD)表达量均未见显著升高。结论小儿消积止咳口服液、组方中的槟榔及所含成分槟榔碱对幼龄小鼠在临床用量范围内、经4倍给药疗程连续给药,均未造成明确的毒性,表明小儿消积止咳口服液临床应用风险可控。

Objective Based on the administration of Xiaoer Xiaoji Zhike Oral Liquid under four clinical procedures(20 d),to investigate its potential toxicity and target organs of toxicity in juvenile mice.Further to anticipate the clinical risks of Arecae Semen and arecoline in children.Methods According to the instructions and available studies,juvenile mice were ig given Xiaoer Xiaoji Zhike Oral Liquid(4.29,17.16 g·kg^(-1)),Bing Lang Jin Gao(0.24,0.96 g·kg^(-1)),and arecoline(0.49,5.46 mg·kg^(-1))for 20 d.The body weight of mice,serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH),urea nitrogen(BUN),creatinine(Cr)were observed.Histopathology of the liver,kidney,heart,and spleen detected by HE staining.Finally,cardiomyocyte apoptosis proteins were detected by immunohistochemistry.Results The body weight of mice was not significantly affected after the administration of Xiaoer Xiaoji Zhike Oral Liquid,Bing Lang Jin Gao and arecoline.There were no remarkable differences in blood biochemical indices related to liver and kidney function compared to the control group.No obvious histopathological changes were observed in organs such as liver,kidney,heart and spleen.Bcl-2-related X protein(Bax),caspase-8,and gasdermin D(GSDMD)were not significantly altered.Conclusion Within the clinical dosage range and after a fourfold administration course,neither of Xiaoer Xiaoji Zhike Oral Liquid,and it contained arecae semen and arecoline have posed toxic side effects in juvenile mice,demonstrating that the risk of the clinical application of Xiaoer Xiaoji Zhike Oral Liquid is controlled.