JAC Advance Access published online on July 29, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg351
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Centro Galénico,
Facultad de Farmacia, Universidad de Navarra, 31080 Pamplona
* Corresponding author. E-mail: jmirache{at}unav.es.
Received 16 January 2003
; revised 16 May 2003
; accepted 1 June 2003
Objective: To study the toxicity and
activity of two new amphotericin B formulations: poly( Materials and methods: The toxicity of these
formulations was evaluated in erythrocytes, J774.2 macrophages and
LLCPK1 renal cells, as well as in mice. Activity was determined
in clinical isolates and in neutropenic mice. Mice were made neutropenic
with 5-fluorouracil, infected with Candida albicans and
treated with the antifungal formulations for three consecutive
days. AmB association in cells and accumulation in kidneys and liver
of animals was quantified by HPLC. Results: Both formulations decreased between
8- and 10-fold the MIC of the polyene against clinical isolates of C. albicans. However, their activity was lower
than or equal to that of AmB-deoxycholate when it was assessed against C. albicans-infected macrophages. When given as
a single intravenous dose in mice, AmB-MM and AmB-NP had an LD50 of
9.8 and 18.6 mg/kg, respectively, compared with 4 mg/kg for AmB-deoxycholate.
Comparison of residual infection burdens in the liver and kidneys
showed that AmB-deoxycholate (0.5 mg/kg) was more effective and
faster in eradicating yeast cells than polymeric formulations. This
fact can be related to a lower AmB accumulation inside macrophages
and in liver and kidneys (about 1.5 mg drug/g tissue) of mice, compared
with those detected for AmB-deoxycholate (4 mg drug/g). Overall,
the efficacy of these formulations at 2 mg/kg was equal to that
of AmB-deoxycholate at 0.5 mg/kg. Conclusions: AmB-MM and AmB-NP decreased the in vivo antifungal activity of AmB, and higher
concentrations were therefore necessary to obtain a similar therapeutic
effect. However, these higher concentrations were achievable owing
to the reduced toxicity of these formulations.
Keywords: Candida albicans, micelles,
nanospheres, poloxamer
Polymeric carriers for amphotericin B: in
vitro activity, toxicity and therapeutic efficacy against systemic
candidiasis in neutropenic mice
2 UMR 8612, Faculté de Pharmacie,
Université Paris-Sud,
5 av. J.-B. Clément, 92296 Châtenay-Malabry
3 Servicio de Farmacología, Clínica
Universitaria, 31008 Pamplona
4 LPBC, UMR CNRS 7033, Université P.
et M. Curie, 4 place Jussieu, case 138, F-75252 Paris cedex 05,
France
5 Departamento
de Microbiología, Facultad de Medicina,
Universidad de Navarra, 31080 Pamplona, Spain
-caprolactone) nanospheres
coated with poloxamer 188 (AmB-NP) and mixed micelles with the same
surfactant (AmB-MM).
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