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