In vivo toxicity of a new antifungal agent 2,4-dithiophenoxy-1-iodo-4-bromo benzene: a follow up on our in vitro study

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 re

Triazolni antifungalni lijek flukonazol danas je najrašireniji antimikotik u svijetu, mahom zato što dobro prodire u tjelesne tekućine i tkiva. Primijećeno je međutim da ulazi u interakciju s drugim lijekovima, a zbog česte uporabe sve je veći i rizik od stvaranja rezistencije na njega. Stoga se traži njegova dostojna zamjena. Godine 2006. sintetiziran je novi derivat tialobenzena - 2,4-ditiofenoksi-1-jodo-4-bromobenzen (C18H12S2IBr). Iako je ugljikova osnovica tog derivata slična onoj flukonazolu, u prvim in vitro istraživanjima pokazao se puno djelotvorniji. Uslijedilo je in vitro istraživanje njegove citotoksičnosti, u kojem se novi spoj pokazao obećavajućom zamjenom za flukonazol. Cilj je ovog istraživanja bio otići korak dalje i istražiti toksičnost C18H12S2IBr in vivo. Odlučili smo se za četverotjedno istraživanje na štakorima Wistar, kojima se je novi antimikotik davao na usta u dozama dva i pol i pet puta nižima od uobičajene doze flukonazola. U životinja nisu primijećene promjene u konzumiranju hrane i vode, ali je relativna težina organa u ženki bila drugačija u odnosu na kontrolnu skupinu, što upućuje na razlike između spolova u metabolizmu lijeka. Za razliku od C18H12S2IBr, flukonazol je prouzročio značajno povišenje razine leukocita i smanjenje neutrofila. Ostale hematološke promjene u odnosu na kontrolnu skupinu bile su slične u skupina koje su primale bilo flukonazol bilo novi lijek. Razlike u imunolokalizaciji citokroma c u jetrima i bubrezima pokazatelj su snažnijeg apoptotičkog učinka novoga lijeka, ali se zbog drugih ključnih pokazatelja (biokemijskih i histopatoloških) ne može ništa zaključiti jer oni ne odgovaraju nalazima citokroma c. S obzirom na to da C18H12S2IBr snažnije djeluje od flukonazola pri nižim koncentracijama, uz podjednake toksične učinke u štakora, ovaj je novi spoj nesumnjivo obećavajuća alternativa liječenju gljivičnih infekcija. Potrebna su daljnja, podrobnija istraživanja u životinja, koja će obuhvatiti interakcije spojeva i