TY - JOUR
T1 - A novel injectable water-soluble amphotericin B-arabinogalactan conjugate
AU - Falk, Rama
AU - Domb, Abraham J.
AU - Polacheck, Itzhack
PY - 1999/8
Y1 - 1999/8
N2 - New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 μg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.
AB - New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 μg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.
UR - http://www.scopus.com/inward/record.url?scp=0032819384&partnerID=8YFLogxK
U2 - 10.1128/aac.43.8.1975
DO - 10.1128/aac.43.8.1975
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C2 - 10428922
AN - SCOPUS:0032819384
SN - 0066-4804
VL - 43
SP - 1975
EP - 1981
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 8
ER -