Affiliation:
1. Department of Parasitology, Hebrew University-Hadassah Medical School,1
2. Department of Dermatology, Hadassah Medical Organization,2 and
3. Department of Medicinal Chemistry, School of Pharmacy-Faculty of Medicine, Hebrew University of Jerusalem,3 Jerusalem, Israel
Abstract
ABSTRACT
In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED
50
s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, for
Leishmania major
promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on
Leishmania infantum
-infected macrophages was more marked, with ED
50
s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with
L. major
were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
50 articles.
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