title: Toxicity and efficacy differences between liposomal amphotericin B formulations in uninfected and Aspergillus fumigatus infected mice.
abstract: Because of the reduced toxicity associated with liposomal amphotericin B preparations, different amphotericin B liposome products have been made. In the present study, we compared the amphotericin B liposomal formulations, AmBisome(®) (AmBi) and Lambin(®) (Lbn), in uninfected and Aspergillus fumigatus infected mice, using several in vitro and in vivo toxicity and efficacy assays. The results showed that the formulations were significantly different, with Lbn 1.6-fold larger than AmBi. Lbn was also more toxic than AmBi based on the RBC potassium release assay and intravenous dosing in uninfected mice given a single 50 mg/kg dose (80% mortality for Lbn vs. 0% for AmBi). Renal tubular changes after intravenous daily dosing for 14 days were seen in uninfected mice given 5 mg/kg Lbn but not with AmBi. Survival following A. fumigatus challenge was 30% for 10 mg/kg Lbn and 60% for 10 mg/kg AmBi. When the BAL and lungs were collected 24 h after the second treatment, AmBi at 10 or 15 mg/kg or 15 mg/kg Lbn lowered the BAL fungal burden significantly vs. the controls (P ≤ 0.05), while there was no difference in lung fungal burden amongst the groups. In contrast, lung histopathology at this same early timepoint showed that AmBi was associated with markedly fewer fungal elements and less lung tissue damage than Lbn. In conclusion, given the differences in size, toxicity, and efficacy, AmBi and Lbn were not physically or functionally comparable, and these differences underscore the need for adequate testing when comparing amphotericin B liposome formulations.
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Olson
authors.affiliation: Charles River Laboratories, Pathology Associates, Frederick, Maryland, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Schwartz
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
authors.forename: D
authors.initials: D
authors.lastname: Hahka
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Gilead Sciences, Inc., San Dimas, California, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bunch
authors.affiliation: Gilead Sciences, Inc., San Dimas, California, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Jensen
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Adler-Moore
mesh_terms: D061605:Administration, Intravenous; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology; D015169:Colony Count, Microbial; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006651:Histocytochemistry; D007684:Kidney Tubules / Q000187:drug effects; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B
keywords: RBC toxicity; aspergillosis; intravenous toxicity; liposomal amphotericin B; nephrotoxicity