Murine airway histology and intracellular uptake of inhaled amorphous itraconazole.
Aerosolization of amorphous itraconazole may be a safe and effective method of pulmonary delivery. Our objective was to evaluate the histologic effects, immunogenic potential, and cellular uptake of aerosolized amorphous itraconazole. Mice received amorphous itraconazole (30mg/kg), excipient placebo, or saline control by nebulization every 12h for up to 12 days. Broncho-alveolar lavage (BAL) and formalin fixation of both lungs were conducted. BAL supernatant was assayed for IL-12 by ELISA, and cellular components were analyzed by high performance liquid chromatography-mass spectroscopy. Coronal sections of the entire lung were stained, viewed by light microscopy, and the Cimolai histopathologic inflammatory score was obtained for each lobe. No evidence of bronchiolar, peribronchiolar or perivascular inflammation was found in any treatment group, nor were epithelial ulceration or repair observed. The Cimolai histopathologic scores for amorphous itraconazole, excipient, and saline control on days 3 and 8 did not differ between groups. ELISA analysis showed no cytokine induction of IL-12. Itraconazole was detected within cells collected from BAL fluid on days 1, 3, 8 and 12. Aerosolized administration of amorphous itraconazole or excipients does not cause inflammation or changes in pulmonary histology and are not associated with pro-inflammatory cytokine production.
Vaughn
Jason M
JM
University of Texas at Austin College of Pharmacy, 1 University Station, A1900, Austin, TX 78712, United States.
Wiederhold
Nathan P
NP
McConville
Jason T
JT
Coalson
Jacqueline J
JJ
Talbert
Robert L
RL
Burgess
David S
DS
Johnston
Keith P
KP
Williams
Robert O
RO
Peters
Jay I
JI
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D005260:Female; D007249:Inflammation / Q000139:chemically induced; D018664:Interleukin-12 / Q000096:biosynthesis; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR
D000336:Aerosols; D018664:Interleukin-12; D017964:Itraconazole