title: Toxicity of an effective amphotericin B formulation at high cationic lipid to drug molar ratio.
abstract: Therapeutic activity of an effective and less nephrotoxic amphotericin B (AMB) formulation with dioctadecyldimethylammonium bromide (DODAB) bilayer fragments (named DODAB/AMB) inspired this toxicity survey in mice. At low drug to lipid molar ratios, hepatotoxicity, spleen damage and blood changes in comparison to DOC/AMB (sodium desoxycholate/amphotericin B, Fungizone) are evaluated ultimately showing toxic effects associated to DODAB only. Swiss Webster female mice were given DODAB, DODAB/AMB or DOC/AMB intraperitonially (ip) for 10 consecutive days (0.4 mg/kg/day AMB; 80 mg/kg/day DODAB) and repeated dose-toxicity was evaluated at the end of the treatment period (on day 11) and after a recovery period of 6 months from biochemical and hematological parameters plus histopathological examination of spleen and liver. Both at day 11 and 180, DODAB in the formulation administered ip causes irreversible changes in spleen such as fibrosis and leukocytes infiltration as a consequence of the administration route. Whereas focal necrosis is induced by DODAB in liver at day 180, DOC/AMB causes more severe multifocal necrosis both at day 11 and day 180. In the kidneys, the novel formulation preserves integrity of tubules and glomeruli in contrast to the serious damage caused by DOC/AMB as shown previously. The majority of the toxic effects observed for the novel formulation were due to the DODAB carrier used at 10mg/mL, i.e., at a rather high concentration and further studies should minimize DODAB dose.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, Avenida Lineu Prestes 748 - Butantã, CEP 05513-970 São Paulo, Brazil.
authors.forename: Nilton
authors.initials: N
authors.lastname: Lincopan
authors.forename: Primavera
authors.initials: P
authors.lastname: Borelli
authors.forename: Ricardo
authors.initials: R
authors.lastname: Fock
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Mamizuka
authors.forename: Ana M
authors.initials: AM
authors.lastname: Carmona-Ribeiro
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000633:toxicity*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D005260:Female; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D051379:Mice; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage* / Q000633:toxicity; D013154:Spleen / Q000187:drug effects
chemical_list: D000644:Quaternary Ammonium Compounds; C015831:dimethyldioctadecylammonium; D000666:Amphotericin B