title: Liposomal Formulation Decreases Toxicity of Amphotericin B In Vitro and In Vivo.
abstract: BACKGROUND
  Liposomal amphotericin B is locally delivered to treat fungal orthopaedic infections but little is known about local tissue toxicity, if any, that might be associated with local delivery.
  
  
  OBJECTIVE
  (1) Is liposomal amphotericin B cytotoxic in vitro? (2) Is locally delivered liposomal amphotericin B toxic to tissue in vivo?
  
  
  METHODS
  Mouse fibroblasts (BA LB/3T3 A31) and osteoblasts (MC3T3) were exposed to two formulations of amphotericin B (liposomal and deoxycholate) at concentrations of 0, 1, 5, 10, 100, 500, and 1000 μg/mL. Cell viability was determined by MTT assay after 1, 3, and 5 hours of exposure and a proliferation assay after 1, 4, and 7 days of exposure and then after 3 recovery days without drug. Tissue exposure occurred by local delivery of liposomal amphotericin B, 200 or 800 mg/batch antifungal-loaded bone cement (ALBC), or amphotericin B deoxycholate, 800 mg/batch ALBC in rat paraspinal muscles. White blood cell count (WBC) and serum amphotericin B levels were obtained on Days 1 and 3. Rats were euthanized at 2 and 4 weeks and semiqualitative histopathology was performed.
  
  
  RESULTS
  Liposomal amphotericin B is cytotoxic in vitro but not toxic to tissues in vivo. All cells survived concentrations up to 1000 μg/mL for 5 hours, 100% ± 0%, but none survived ≥ 100 μg/mL for 7 days, 0% ± 0%. Fibrosis was seen adjacent to ALBC without inflammation or necrosis, indistinguishable from controls for both liposomal amphotericin B doses. Amphotericin B serum levels were all less than 1 µg/mL and WBC counts were all normal.
  
  
  CONCLUSIONS
  In vitro cytotoxicity to liposomal amphotericin B occurred but no adverse tissue reaction was seen in vivo.
  
  
  CONCLUSIONS
  Local delivery of liposomal amphotericin B in ALBC was well tolerated by mouse tissue; however, clinical studies are needed to confirm this finding in humans.
authors: Orthopaedic Department, Banner Good Samaritan Medical Center, 1320 N 10th Street, Phoenix, AZ, 85006, USA.
authors: Justin
authors: J
authors: Roberts
authors: Josh
authors: J
authors: Bingham
authors: Alex C
authors: AC
authors: McLaren
authors: Ryan
authors: R
authors: McLemore
mesh_terms: D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D001843:Bone Cements; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000935:Antifungal Agents; D001843:Bone Cements; C068538:liposomal amphotericin B; D000666:Amphotericin B