癌变·畸变·突变 ›› 2021, Vol. 33 ›› Issue (6): 466-469,474.doi: 10.3969/j.issn.1004-616x.2021.06.012

• 检测研究 • 上一篇    下一篇

抗HIV药物齐夫多定、拉夫米定和克力芝联合用药的急性经口毒性和致突变作用

葛宪民, 李彬, 黄超培, 高玉秋, 罗海兰, 杨慧, 王彦武, 温平镜, 蓝光华, 陈欢欢, 孟琴, 罗柳红, 邓月琴, 刘帅凤, 吴秀玲   

  1. 广西壮族自治区疾病预防控制中心, 广西 南宁 530028
  • 收稿日期:2021-07-02 修回日期:2021-09-22 出版日期:2021-11-30 发布日期:2021-12-04
  • 通讯作者: 黄超培,E-mail:gxhcp@163.com E-mail:gxhcp@163.com
  • 作者简介:葛宪民,E-mail:gxgexm@sina.com;李彬,E-mail:lb771@163.com。
  • 基金资助:
    广西壮族自治区科技厅重点研发计划项目(桂科AB17195010);国家传染病防治科技重大专项(2018ZX10715008);广西八桂学者艾滋病防控关键技术岗位专项(桂办公厅发[2019]79号)

Acute oral toxicity and mutagenicity of combined drugs for anti HIV

GE Xianmin, LI Bin, HUANG Chaopei, GAO Yuqiu, LUO Hailan, YANG Hui, WANG Yanwu, WEN Pingjing, LAN Guanghua, CHEN Huanhuan, MENG Qin, LUO Liuhong, DENG Yueqin, LIU Shuaifeng, WU Xiuling   

  1. Guangxi Center for Disease Prevention and Control, Nanning 530028, Guangxi, China
  • Received:2021-07-02 Revised:2021-09-22 Online:2021-11-30 Published:2021-12-04

摘要: 目的: 高效抗反转录病毒药物的联合治疗,可使HIV母婴垂直传播(PMTCT)大幅降低。为了评价抗HIV药物联合用药的安全性,本研究检测联合药物齐夫多定(AZT)、拉夫米定(3TC)和克力芝(LPV/r)的急性经口毒性和致突变性。方法: 将AZT、3TC和LPV/r 3种药片按2∶1∶2比例混在一起,粉碎成粉末,用纯水将联合药物混合配成有效成分为250 mg/mL的混悬液,然后按0.02 mL/g给小鼠灌胃1次(有效成分为5 000 mg/kg),进行急性经口毒性试验;采用平板掺入法,联合药物设50、158、500、1 581、5 000 μg/皿5个剂量组进行细菌回复突变试验;设500、1 000、2 000 mg/kg剂量组进行小鼠体内微核试验和精原细胞染色体畸变试验检测其致突变性。结果: 在给予联合药物后,小鼠未出现中毒体征和死亡,LD50>5 000 mg/kg。在加与不加S9代谢活化系统两种条件下,该联合药物5个剂量组的5种试验菌株(TA97a、TA98、TA100、TA102、TA1535)的回变菌落数与自发回变的菌落数相接近,回复突变试验结果为阴性。该联合药物500、1 000、2 000 mg/kg剂量组雌、雄性小鼠的微核细胞率在4.4‰~5.2‰之间,与阴性对照组(1.2‰~1.4‰)间的差异均有统计学意义(P<0.01),并高出本实验室正常本底值(0.4‰~3.6‰),为阳性试验结果。该联合药物500、1 000、2 000 mg/kg剂量组的精原细胞染色体畸变细胞率为0.4%~0.8%,与阴性对照组(0.4%)比较,差异均无统计学意义(P>0.05)。结论: 在本试验条件下,抗HIV联合药物AZT、3TC和LPV/r无急性经口毒性作用,体外细菌回复突变试验和小鼠精原细胞染色体畸变试验结果为阴性,但骨髓细胞微核试验结果为阳性,该联合药物的致突变性有待进一步探讨和验证。

关键词: 齐夫多定, 拉夫米定, 克力芝, 联合用药, 急性毒性, 致突变性

Abstract: OBJECTIVE: Combined-therapy intervention with highly effective antiretroviral drugs can significantly reduce vertical transmission of HIV from mothers to children (PMTCT). In order to evaluate their safety,acute oral toxicity and potential mutagenicity of a combined drug consisting of zivdodine,lamivudine and aletra for PMTCT were evaluated. METHODS: Tablets of zivdodine,lamivudine and aletra were mixed in a ratio of 2:1:2 and crushed into powder,and then mixed with pure water to prepare a suspension with an effective component concentration of 250 mg/mL. The suspension was given orally to mice once according to the volume of 0.02 mL/g body mass (5 000 mg/kg dose) to observe its acute oral toxicity. Mutagenicity of the combined drugs was studied by reverse mutation test of bacteria,with 5 dose groups of 50,158,500, 1 581 and 5 000 μg/dish (active ingredient),according to the flat mixing method. The mutagenicity of the drugs was detected also by micronucleus test and chromosome aberration test in mammals with dose of 500, 1 000 and 2 000 mg/kg (by active ingredient,the same below). RESULTS: No signs of poisoning and death was found after given the combined drugs to the mice,the LD50 was more than 5 000 mg/kg. The number of revertant colonies of five test strains (TA97a,TA98,TA100,TA102,TA1535) in five dose groups of the combined drugs,with or without S9 metabolic activation system,were close to that of spontaneous revertant colonies,it was a negative result. However,the micronucleus rates of female and male animals in 500,1 000 and 2 000 mg/kg dose group of the combined drugs were between 4.4‰ and 5.2‰,which were significantly different from that of the negative control group (1.2‰-1.4‰),P<0.05,and were higher than the normal background value of our laboratory (0.4‰-3.6‰). Chromosome aberration rates of spermatogonia of animals in 500,1 000 and 2 000 mg/kg dose group of the combined drugs were 0.4%-0.8%,which were not significantly different from that of the negative control group (0.4%),P>0.05. CONCLUSION: Under our experimental conditions,the combined drugs showed no acute oral toxicity,no mutagenic effect in vitro and no chromosome aberration effect of spermatogonia in mice,but the micronucleus test of bone marrow cells was positive. Therefore,mutagenicity of the combined drugs needs to be further explored and verified.

Key words: zivdodine, lamivudine, aletra, combined drugs, acute toxicity, mutagenicity

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