AMPHOTERICIN-B LIPOSOMES WITH PROLONGED CIRCULATION IN BLOOD - IN-VITRO ANTIFUNGAL ACTIVITY, TOXICITY, AND EFFICACY IN SYSTEMIC CANDIDIASISIN LEUKOPENIC MICE

Pegylated amphotericin B (AmB) liposomes (PEG-AmB-LIP) were compared,v ith laboratory-prepared nonpegylated AmB liposomes (AmB-LIP), a formul ation with a lipid composition the same as that in AmBisome, as well a s with industrially prepared AmBisome regarding their in vitro antifun gal activities, toxicities, blood residence times, and therapeutic eff icacies. Killing of Candida albicans (>99.9%) during short-term (6-h) incubation was observed at 0.2 mg of AmB per liter for AmB desoxychola te, 0.4 mg of AmB per liter for PEG-AmB-LIP, 0.8 mg of AmB per liter f or AmB-LIP, and 12.8 mg of AmB per liter for AmBisome. The maximum tol erated doses of PEG-AmB-LIP, AmB-LIP, and AmBisome were 15, 19, and >3 1 mg of AmB per kg of body weight, respectively, In contrast to AmB-LI P, tile blood residence time of PEG-AmB-LIP was prolonged and dose ind ependent, In a model of systemic candidiasis in leukopenic mice at a d ose of 5 mg of AmB per kg, PEG-AmB-LIP was completely effective and Am B-LIP was partially effective, whereas AmBisome was not effective, AmB -LIP at 11 mg of AmB per kg was partially effective. AmBisome at 29 mg of AmB per kg was completely effective, In conclusion, the therapeuti c efficacies of AmB liposomes can be improved by preparing AmB liposom es in which a substantial reduction in toxicity is achieved while anti fungal activity is retained, In addition, therapeutic efficacy is favo red by a prolonged residence time of AmB liposomes in blood.