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  

Acute oral toxicity and mutagenicity of combined drugs for anti HIV

作　　者：葛宪民[1] 李彬[1] 黄超培[1] 高玉秋[1] 罗海兰 杨慧 王彦武[1] 温平镜 蓝光华[1] 陈欢欢[1] 孟琴[1] 罗柳红[1] 邓月琴 刘帅凤[1] 吴秀玲[1] 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(Guangxi Center for Disease Prevention and Control,Nanning 530028,Guangxi,China)

机构地区：[1]广西壮族自治区疾病预防控制中心,广西南宁530028

出　　处：《癌变．畸变．突变》2021年第6期466-469,474,共5页Carcinogenesis,Teratogenesis & Mutagenesis

基　　金：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)。

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/m L的混悬液,然后按0.02m L/g给小鼠灌胃1次(有效成分为5000 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、1581、5000μg/皿5个剂量组进行细菌回复突变试验;设500、1000、2000 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>5000 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、1000、2000 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、1000、2000 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。OBJECTIVE:Combined-therapy intervention with highly effective antiretroviral drugs cansignificantly reduce vertical transmission of HIV from mothers to children(PMTCT).In order to evaluate theirsafety,acute oral toxicity and potential mutagenicity of a combined drug consisting of zivdodine,lamivudineand aletra for PMTCT were evaluated.METHODS:Tablets of zivdodine,lamivudine and aletra were mixed ina ratio of 2∶1∶2 and crushed into powder,and then mixed with pure water to prepare a suspension with aneffective component concentration of 250 mg/m L.The suspension was given orally to mice once according tothe volume of 0.02 m L/g body mass(5000 mg/kg dose)to observe its acute oral toxicity.Mutagenicity of thecombined drugs was studied by reverse mutation test of bacteria,with 5 dose groups of 50,158,500,1581 and 5000μg/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 500,1000 and 2000 mg/kg(by active ingredient,the same below).RESULTS:No signs of poisoning and deathwas found after given the combined drugs to the mice,the LD50 was more than 5000 mg/kg.The number ofrevertant colonies of five test strains(TA97 a,TA98,TA100,TA102,TA1535)in five dose groups of thecombined drugs,with or without S9 metabolic activation system,were close to that of spontaneous revertantcolonies,it was a negative result.However,the micronucleus rates of female and male animals in 500,1000 and 2000 mg/kg dose group of the combined drugs were between 4.4‰and 5.2‰,which were significantlydifferent from that of the negative control group(1.2‰-1.4‰),P<0.05,and were higher than the normalbackground value of our laboratory(0.4‰-3.6‰).Chromosome aberration rates of spermatogonia of animals in500,1000 and 2000 mg/kg dose group of the combined drugs were 0.4%-0.8%,which were notsignificantly different from that of the negative control group(0.4%),P>0.05.CONCLUSION:Under ourexperimental conditions,the co

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 

分 类 号：R394.6[医药卫生—医学遗传学]