Kılıç Süloğlu Aysun, Koçkaya Evrim, Karacaoğlu Elif, Selmanoğlu Güldeniz, Loğoğlu Elif
Arh Hig Rada Toksikol. 2015 Mar;66(1):63-72. doi: 10.1515/aiht-2015-66-2521.
Triazole fungicide fluconazole has become the most widely used antifungal agent in the world, mainly because of its ability to penetrate well into body fluids and tissues. However, it has been reported to interact with many drugs and because of its common use, the risk of resistance to fluconazole increases. This calls for new anti-fungal drugs that would be able to replace it. In 2006, a new thialo benzene derivative - 2,4-dithiophenoxy-1-iodo-4-bromo benzene (C18H12S2IBr) - was synthesised with a carbon backbone similar to fluconazole, and, according to the early in vitro tests, much greater efficiency. Followed an in vitro test of its cytotoxicity, in which the new drug showed promising results as an alternative to fluconazole. The aim of this study was take the next step and test C18H12S2IBr toxicity in vivo. We opted for a four-week test on Wistar rats, in which the new antifungal agent was orally applied at doses two and a half and five times lower than those of fluconazole. There were no changes in daily food and water consumption, but weight gain in female rats and relative organ weights changed in the treated groups, pointing to sex-related differences in drug metabolism and effects. Fluconazole significantly increased leukocytes and lowered neutrophils whereas C18H12S2IBr did not, while other haematological changes in respect to the vehicle control were similar between the treated groups. Differences in cytochrome c in the liver and kidney suggested greater apoptotic effect of the new drug, but interpretation remains inconclusive, considering that other key indicators (biochemistry and histopathology) do not support greater toxicity. Considering that C18H12S2IBr is more active at lower concentrations and has comparable toxic effects to fluconazole in rats, this new compound shows some promise in the treatment of fungal infections. Future, more detailed animal studies are needed, that will include drug interactions and molecular toxicity pathways. If the results are promising, clinical studies should follow.
三唑类杀菌剂氟康唑已成为世界上使用最广泛的抗真菌药物，主要是因为它能够很好地渗透到体液和组织中。然而，据报道它会与许多药物相互作用，并且由于其广泛使用，对氟康唑产生耐药性的风险增加。这就需要能够替代它的新型抗真菌药物。2006年，一种新的噻吩苯衍生物——2,4 - 二硫代苯氧基 - 1 - 碘 - 4 - 溴苯（C18H12S2IBr）——被合成出来，其碳骨架与氟康唑相似，并且根据早期的体外试验，其效率要高得多。在对其细胞毒性进行体外试验之后，这种新药作为氟康唑的替代品显示出了有前景的结果。本研究的目的是进一步在体内测试C18H12S2IBr的毒性。我们选择对Wistar大鼠进行为期四周的试验，在试验中，新型抗真菌剂的口服剂量比氟康唑低二点五倍和五倍。每日食物和水的消耗量没有变化，但治疗组中雌性大鼠的体重增加以及相对器官重量发生了变化，这表明药物代谢和作用存在性别差异。氟康唑显著增加白细胞并降低中性粒细胞，而C18H12S2IBr则没有，并且在治疗组之间，相对于赋形剂对照组的其他血液学变化相似。肝脏和肾脏中细胞色素c的差异表明新药具有更大的凋亡作用，但考虑到其他关键指标（生物化学和组织病理学）并不支持更大的毒性，因此解释仍无定论。鉴于C18H12S2IBr在较低浓度下更具活性，并且在大鼠中具有与氟康唑相当的毒性作用，这种新化合物在治疗真菌感染方面显示出了一些前景。未来需要进行更详细的动物研究，包括药物相互作用和分子毒性途径。如果结果有前景，应随后进行临床研究。
