Observation on subacute toxicity of antisense oligonucleotides flutide in rats

GUO Ming-gang; LU Dan-dan; LIU Chao; SHEN Lian-zhong

Abstract：Objective:To study the subacute toxicity of antisense oligonucleotides(ASON) against influenza virus Flutide(FT) in Wistar rats and provide important animal experimental data for the clinical trials research.Methods:48 Wistar rats with half males and half females were divided randomly into 4 groups:vehicle control group and FT 10.0,30.0,100.0 mg· kg-1· d-1 groups.Wistar rats were administered with FT continuously for 14 days and recovered for 14 days after stopping administration.At the end of treatment and recovery periods,hematology and serum biochemical indexed were determined.The organs were examined pathologically and weighed to obtain organ weights.The bone marrow smears were also examined.Results:At the end of treatment periods,compared with the vehicle control group,％ RETIC of male rats peripheral blood of FT each dosage groups were decreased(P ＜ 0.01),PLT of male rats peripheral blood of FT 100.0 mg· kg-1· d-1 group were decreased (P ＜ 0.01).BUN,CREA and CK of both male and female rats peripheral serum of FT 100.0 mg· kg-1· d-1 group were increased(P ＜0.05,P ＜0.01),furthermore,BUN of male rats peripheral serum of FT 100.0 mg·kg-1 ·d-1 group was higher than female rats(P ＜0.01).The kidney organ weights and coefficients of both male and female rats FT30.0,100.0 mg·kg-1·d-1 groups were increased(P ＜0.05,P ＜0.01),and the body weights were decreased (P ＜ 0.01).At the end of recovery periods,compared with vehicle control group,％ RETIC,PLT of female rats of FT 100.0 mg·kg-1 ·d-1 group and the kidney organ weights and coefficients of female rats of 30.0 mg· kg-1 · d-1 group were increased,simultaneously the results of counting and classification of bone marrow smears showed that granulocyte series and erythrocyte series decreased (P ＜ 0.05).The rest of indexes returned to normal.Histopathological examination showed that the different degrees of degeneration and necrosis of renal tubule,cell debris cast,protein cast,basophilic tubular forming were found in FT 10.0,30.0,100.0 mg·kg-1· d-1 groups,above all,the toxic injury of male rats was more serious than female rats.The different level histocytes were infiltrated in cardiac interstitium,hepatic portal area,splenic marginal zone.Conclusion:FT has toxic effects on kidney,heart,liver and spleen of Wistar rats and showed gender differences.