Low nephrotoxicity of an effective amphotericin B formulation with cationic bilayer fragments.
OBJECTIVE
Evaluation of nephrotoxicity of a novel amphotericin B (AMB) formulation with dioctadecyldimethylammonium bromide (DODAB) bilayer fragments (DOD/AMB).


METHODS
Dose-dependent cytotoxicity of DOD/AMB was evaluated in vitro against cultured kidney epithelial cells in culture. For in vivo experiments, Swiss Webster female mice were injected intraperitoneally for 10 consecutive days with 0.4 mg/kg/day AMB in the form of traditional bile salt desoxycholate (DOC)/AMB or DOD/AMB. Body and spleen weight, and biochemical and histopathological data were obtained at days 11 and 180 after injection.


RESULTS
Nephrotoxicity of the novel formulation was lower than that of Fungizone (DOC/AMB), which is the traditional AMB formulation using DOC. Dose-dependent cytotoxicity of DOD/AMB was lower than that exhibited by DOC/AMB. At day 11, DODAB and DOD/AMB caused loss of body weight and increase in spleen weight, which were not observed for DOC/AMB, although the changes were reversible and weights returned to control values at day 180. Ten days after injection, biochemical parameters for hepatic and renal function remained unaltered. At day 180, renal cortex histopathology revealed leucocytic infiltration and moderate hydropic degeneration of the renal tubules in the DODAB and DOD/AMB groups, in contrast to more severe lesions observed for the DOC/AMB group such as tubular cystic degeneration and glomerular injury, which were absent for the former groups.


CONCLUSIONS
The DOD/AMB formulation exhibited differential cytotoxicity and low nephrotoxicity, but there were also important aspects of general toxicity that will require evaluation with full-scale toxicity protocols.
Lincopan
Nilton
N
Departamento de Análises Clínicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, CP 66083, Avenida Lineu Prestes 580-Butantã, CEP 05315-970, São Paulo, Brazil.
Mamizuka
Elsa M
EM
Carmona-Ribeiro
Ana M
AM
D016475:3T3 Cells; D000666:Amphotericin B / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D002176:Candida albicans / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008051:Lipid Bilayers / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D018675:Toxicity Tests; D014709:Vero Cells
D000935:Antifungal Agents; D004338:Drug Combinations; D008051:Lipid Bilayers; D000644:Quaternary Ammonium Compounds; C015831:dimethyldioctadecylammonium; D000666:Amphotericin B