| More than 30 years after the introduction of the nitroimidazoles and benzimidazoles, there have been few new innovations in treating intestinal parasitic infections. Mean- while, these infections remain among the leading causes of morbidity and mortality in the world today. With this background, it is noteworthy to recognize recent advances with the development of nitazoxanide (NTZ), a product developed specifically for the treatment of intestinal parasitic infections. NTZ, 2-acetolyloxy -N-(5-nitro 2-thiazolyl) benzamide (Fig. 1a), was first described in 1984 as a human cestocidal drug which was effective in a single dose against Taenia saginata and Hymenolepis nana. Recent studies have shown that NTZ can inhibite anaerobic bacteria (Trichomonas vaginalis,Entamoeba histolytica and Clostridium perfringens) and in the microaerophile Helicobacter pyloris,plus with the intestinal parasite protozoa and helminth.NTZ is available on the market in America and some parts of Latin America.In Switzerland and France, NTZ has been granted in the veterinary field applications. However,NTZ is not available in our country. There are few toxocity reports of NTZ in our country, therefore ,it is of great significance to carry out toxocity researches.According to the National standards, the Ames test was conducted with plate infilration and repeated once to ensure the results. Positive controls used in this study were 2-aminoanthracene and Mitomatin. Vehicle control (DMSO) was used with all tester strains. Both in the presence and absence of S9, Salmonella typhimurium tester strains TA97, TA98, TA100 and TA102 were used in this study. Blow the dose of 250.0μg/plate, the number of revertants is similar to that of the vehicle control group.Bacteria cannot exsit at 500ug/ plate,which shows that NTZ is a nonmutagenic factor. Mouse bone marrow micronucleus test were orally administered with NTZ by 24-hour interval method at the dose of 2.5g/kg·bw, 1.25g/kg·bw and 0.625g/kg·bw. We counted 1,000 polychromatic erythrocytes of every mouse and the ratio of poly- chromatic erythrocytes to mature red blood cell.The micronucleus rate of positive control group is 26.7‰, which is diffrential compared to the other groups, which indicated that NTZ cannot induce micronucleus rate change. The mice were orally treated once a day with NTZ and vehicle respectively for 5 days, then sacrificed 30 days later to calculate sperm malformation rates. On the 3d, obvious clinical reactions were found, including fluffy fur, decreased actions, decreased food consumption, weight loss. And some died in the high dose. And the hematological findings discoverred that ulceration of colon. All the animals recoverred without any therapeutic intervention.The sperm abnormality rate of positive control group is much higher than the other groups, which showed a negative results.The ecotoxicity of nitazoxanide was researched by the acute toxicity test of Brachydanio rerio and Eisenia foetida. Brachydanio rerio acute toxicity test was conducted in stagnant water according to OECD. Observe the reaction of the Brachydanio rerio and record the deaths at 24h, 48h, 72h and 96h. As soon as poisoned by NTZ, the Brachydanio rerio appearred more slowly wandering, dyspnoeic and anaesthetic. White floccules were also seen around Brachydanio rerio. Five hours later, some of them were found dead. The results showed that the LC50 of nitazoxanide on Brachydanio rerio in stagnant water was 2.312mg/L at 24h, with a confidence interval 2.125 mg/L~2.515mg/L, 2.033mg/L at 48h and 72h, with a confidence interval 1.782 mg/L~2.318mg/L, 1.968mg/L at 96h, with a confidence interval 1.717 mg/L~2.256mg/L respectively, which demonstrated that nitazoxanide was a high toxical material to fish.Both filter paper method and the natural soil method were used in Eisenia foetida acute toxicity test recommended by OECD. The LC50 of nitazoxanide using filter paper method was 1.50μg/cm2 at 24h, 0.81μg/cm2 at 48h, respectively and the LC50 using natural soil method was 119.44mg/kg at 24h, with a confidence interval 103.72 mg/kg~ 137.55mg/kg,108.44mg/kg at 48h to 4d, with a confidence interval 95.92mg/ kg~122.60mg/kg, 98.45mg/kg at 7d with a confidence interval 88.62mg/kg~ 109.37mg/kg and 95.33mg/kg at 10d to 14d with a confidence interval 84.32mg/kg~ 107.78mg/kg, which demonstrated that NTZ was a low toxical material to earthworm. Leishmania donovani, which is a kind of intracellular parasite, can infect both mammals and reptiles. It is also the cause of human kala-azar, an important parasitic disease in China. In this experiment, the NTZ was used to impact the activation of protein disulfide isomerase, which is used to catalyze the formation, breakage and rearrangement of disulfide bond in proteins to study the mechanism of NTZ against Leishmania. According to biochemical methods, insulin was taken as the substrate to determine and compare the activity of NTZ in the range of 6.25μg ? ml-1~200μg ? ml-1, and establishment the control and the positive control group.The results is in the dose range of 6.25μg ? ml -1~100μg ? ml-1,the absorbance of the mixture at 650nm inctrease as the dose increase,indicating the possible role of NTZ in the PDI enzyme. |
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