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大多数临床应用的抗血吸虫药物有致突变性。本文对几种降低或消除这种毒性的方法进行了讨论。1. 羟蒽酮的结构改变导致类似物的合成,其诱变和致癌作用以及急性毒性明显降低,而其抗血吸虫作用则相当于羟蒽酮。2. 当用2种高度敏感的鼠伤寒沙门氏菌株,在有或无肝微粒体的情况下测试时,一种新的高效抗血吸虫药物,4-异硫氰基-4-′硝基二苯胺,即硝硫氰胺无诱变作用。但啮齿动物试服较大剂量的硝硫氰胺后,在动物的尿中产生诱变代谢物。当这种药物给予无菌的大鼠时,则无诱变性。因此,将硝硫氰胺转变为诱变剂需要有代谢活性的肠道微生物。这种诱变活性能为单剂红霉素与硝硫氰胺合并用药所防止。用这种抗菌剂合并治疗并不减低异硫氰酸酯的抗血吸虫作用。所以,这种化合物的诱变作用能够完全与它的抗血吸虫性质相分离。同样,合并给予抗菌素几乎也能完全消除另一种抗血吸虫药物羟氨喹的诱变作用。3. 给予酚的抗氧化剂缩丁基对羟基茴香醚(BHA)可明显降低苯(α)嵌二萘(BP)的致癌活性,也平行地明显降低 BP 在小鼠尿中的诱变活性。这些观察进一步证实细菌诱变性试验的可预测性。合有 BHA 的饲料可明显降低羟蒽酮、IA-4的 N-氧化物、敌百虫和吡喹酮等4种抗血吸虫药物,以及一种肠道抗蠕虫药甲苯咪唑的诱变作用。先用 BHA 治疗也协同肠道抗菌剂明显降低抗滴虫和抗阿米巴药物灭滴灵(Flagyl)在体内的诱变活性。这些研究的结果对于改进药物的安全度已揭示了新的原则和机会。
Most clinical applications of anti-schistosome drugs mutagenic. This article discusses several ways to reduce or eliminate this toxicity. 1. Hydroxyanthrone structural changes led to the synthesis of analogues, its mutagenicity and carcinogenic effects and acute toxicity was significantly reduced, and its anti-schistosome effect is equivalent to hydroxyanthrone. 2. When using two highly sensitive Salmonella typhimurium strains tested with or without liver microsomes, a new highly effective anti-schistosome drug, 4-isothiocyanato-4 ’nitrodiphenylamine , That is, nitrosamines no mutagenic effect. However, rodents try larger doses of nitrosamines to produce mutagenic metabolites in the urine of animals. When the drug is administered to sterile rats, it is not mutagenic. Therefore, converting nitrites to mutagens requires metabolically active gut microbes. This mutagenic activity for the single agent erythromycin and nitrocytamine combined with medication to prevent. Combination therapy with this antimicrobial agent does not reduce the anti-schistosome effect of isothiocyanates. Therefore, the mutagenicity of this compound can be completely separated from its anti-schistosome properties. Similarly, the combined administration of antibiotics almost completely abolished the mutagenesis of hydroxyquinolone, another anti-schistosome drug. 3. Antioxidants given phenolic antioxidants Butyl p-hydroxyanisole (BHA) significantly reduced the carcinogenic activity of Benzene (α) -mediated naphthalene (BP), and significantly reduced the mutagenic activity of BP in the urine of mice in parallel. These observations further confirm the predictability of bacterial mutagenicity tests. The combination of feed with BHA can significantly reduce the four kinds of anti-schistosomiasis drugs such as hydroxyanthrone, IA-4 N-oxide, trichlorfon and praziquantel, and the mutagenic effect of an antibacterial drug mebendazole. Treatment with BHA also synergistically with intestinal antibacterial agents significantly reduced the in vivo mutagenic activity of the anti-trichomonad and anti-amebolide Flagyl. The results of these studies have revealed new principles and opportunities for improving the safety of medicines.