Jenkins D C, Topley P, Rapson E B
Department of Biochemical Microbiology, Wellcome Research Laboratories, Beckenham, Kent.
Parasitology. 1987 Aug;95 ( Pt 1):165-71. doi: 10.1017/s0031182000057644.
The cidal properties of some phenolic, halogenated diphenyl, salicylanilide, benzimidazole and diaminophenoxyalkane anthelmintics, against 6-week-old worms of Fasciola hepatica were assessed in vitro. In a conventional fluke culture medium containing RPMI 1640, supplemented with serum with or without rabbit erythrocytes or pink-ghosts, only the halogenated diphenyl and salicylanilide compounds showed activity at concentrations equal to or less than 100 microM. However, when basal, serum and cell-free RPMI 1640 was used, all compounds other than diamphenethide were highly active, their minimum lethal concentrations being some 25-125 times lower under these conditions. The inclusion of rabbit liver microsomes in the basal culture medium resulted in diamphenethide exhibiting cidal activity equivalent to that seen when its free-amine active metabolite was assayed. The possibility that the activity of many of these compounds was masked in vitro because of their serum binding properties is discussed. Recommendations are made that in vitro screens for new fasciolicides should be carried out in serum-free medium and that additional replicates containing mammalian liver microsomes and liver cytosolic extracts be included as means for the metabolic activation of certain otherwise undetectable prodrugs.
在体外评估了一些酚类、卤代二苯、水杨酰苯胺、苯并咪唑和二氨基苯氧基烷类驱虫药对6周龄肝片吸虫的杀灭特性。在含有RPMI 1640的传统吸虫培养基中，添加有或没有兔红细胞或红细胞影的血清，只有卤代二苯和水杨酰苯胺类化合物在浓度等于或低于100微摩尔时表现出活性。然而，当使用基础的、无血清和无细胞的RPMI 1640时，除了硫双二氯酚之外的所有化合物都具有高活性，在这些条件下它们的最低致死浓度要低约25 - 125倍。在基础培养基中加入兔肝微粒体后，硫双二氯酚表现出的杀灭活性等同于对其游离胺活性代谢物进行检测时所观察到的活性。讨论了由于这些化合物的血清结合特性导致其在体外活性被掩盖的可能性。建议在无血清培养基中进行新的杀片形吸虫剂的体外筛选，并加入含有哺乳动物肝微粒体和肝细胞质提取物的额外重复实验，作为某些原本无法检测到的前药代谢活化的手段。
