Treatment of experimental invasive aspergillosis with novel amphotericin B/cholesterol-sulfate complexes.
An immunosuppressed rabbit model of invasive aspergillosis was used to evaluate a novel micellar preparation of cholesterol sulfate complexed to amphotericin B. The acute LD50 of amphotericin B-deoxycholate was 5.1 mg/kg versus 20 mg/kg for the amphotericin/cholesterol-sulfate complexes. Amphotericin B-deoxycholate given iv at a dose of 1.5 mg/kg was more effective in sterilizing liver and kidney than the amphotericin/cholesterol-sulfate complexes given iv at 1.5-4.5 mg/kg, but infection persisted in the lungs of all rabbits treated with those doses. Infection persisted even when the rabbits were given a lethal dose of amphotericin B-deoxycholate (4.5 mg/kg), but a dose of 15 mg/kg of the amphotericin/cholesterol-sulfate complexes sterilized tissues and was associated with no acute lethality. Equivalent doses of the amphotericin/cholesterol-sulfate complexes were less effective than amphotericin B-deoxycholate, but a fourfold decrease in acute lethality improved the therapeutic index of amphotericin B. The amphotericin/cholesterol-sulfate complexes appear to be an improved means of amphotericin B delivery and may improve therapy for invasive aspergillosis.
Patterson
T F
TF
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Miniter
P
P
Dijkstra
J
J
Szoka
F C
FC
Ryan
J L
JL
Andriole
V T
VT
D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy*; D001921:Brain / Q000382:microbiology; D002788:Cholesterol Esters / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D003840:Deoxycholic Acid / Q000627:therapeutic use; D004338:Drug Combinations; D007165:Immunosuppression Therapy; D007668:Kidney / Q000382:microbiology; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008823:Micelles; D011817:Rabbits
D002788:Cholesterol Esters; D004338:Drug Combinations; D008823:Micelles; D003840:Deoxycholic Acid; D000666:Amphotericin B; C007045:cholesteryl sulfate