title: Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections.
abstract: Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-α and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.
authors.affiliation: Department of Pathology, Faculty of Medicine, "Vasile Goldis" Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Folk
authors.affiliation: Department of Bioethics, Faculty of Medicine, "Vasile Goldis" Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania.
authors.forename: Coralia
authors.initials: C
authors.lastname: Cotoraci
authors.affiliation: Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania.
authors.forename: Cornel
authors.initials: C
authors.lastname: Balta
authors.affiliation: Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania.
authors.forename: Maria
authors.initials: M
authors.lastname: Suciu
authors.affiliation: Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania.
authors.forename: Hildegard
authors.initials: H
authors.lastname: Herman
authors.affiliation: Faculty of Veterinary Medicine, Department of Chemistry, Biochemistry and Molecular Biology, Banat University of Agricultural Sciences and Veterinary Medicine "King Mihai I of Romania" Timisoara, 119 Calea Aradului, 300645 Timisoara, Romania.
authors.forename: Oana Maria
authors.initials: OM
authors.lastname: Boldura
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Bucharest, 91-95 Splaiul Independentei, 050095 Bucharest, Romania.
authors.forename: Sorina
authors.initials: S
authors.lastname: Dinescu
authors.affiliation: Department of Pathology, Faculty of Medicine, "Vasile Goldis" Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania.
authors.forename: Lucian
authors.initials: L
authors.lastname: Paiusan
authors.affiliation: Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania.
authors.forename: Aurel
authors.initials: A
authors.lastname: Ardelean
authors.affiliation: Institute of Life Sciences, Vasile Goldis Western University of Arad, 86 Rebreanu, 310414 Arad, Romania; Department of Histology, Faculty of Medicine, "Vasile Goldis" Western University of Arad, 86 Rebreanu Street, 310414 Arad, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Hermenean
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D005437:Flucytosine / Q000008:administration & dosage* / Q000009:adverse effects; D005658:Fungi / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D007239:Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000666:Amphotericin B; D005437:Flucytosine