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Comparison of Oral, Intranasal and Aerosol Administration of Amiodarone in Rats as a Model of Pulmonary Phospholipidosis.

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  • معلومة اضافية
    • المصدر:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101534003 Publication Model: Electronic Cited Medium: Print ISSN: 1999-4923 (Print) Linking ISSN: 19994923 NLM ISO Abbreviation: Pharmaceutics Subsets: PubMed not MEDLINE
    • بيانات النشر:
      Original Publication: Basel, Switzerland : MDPI
    • نبذة مختصرة :
      'Foamy' alveolar macrophages (FAM) observed in nonclinical toxicology studies during inhaled drug development may indicate drug-induced phospholipidosis, but can also derive from adaptive non-adverse mechanisms. Orally administered amiodarone is currently used as a model of pulmonary phospholipidosis and it was hypothesized that aerosol administration would produce phospholipidosis-induced FAM that could be characterized and used in comparative inhalation toxicology. Han-Wistar rats were given amiodarone via (1) intranasal administration (6.25 mg/kg) on two days, (2) aerosol administration (3 mg/kg) on two days, (3) aerosol administration (10 mg/kg) followed by three days of 30 mg/kg or (4) oral administration (100 mg/kg) for 7 days. Alveolar macrophages in bronchoalveolar lavage were evaluated by differential cell counting and high content fluorescence imaging. Histopathology and mass-spectrometry imaging (MSI) were performed on lung slices. The higher dose aerosolised amiodarone caused transient pulmonary inflammation ( p < 0.05), but only oral amiodarone resulted in FAM ( p < 0.001). MSI of the lungs of orally treated rats revealed a homogenous distribution of amiodarone and a putative phospholipidosis marker, di-22:6 bis-monoacylglycerol, throughout lung tissue whereas aerosol administration resulted in localization of both compounds around the airway lumen. Thus, unlike oral administration, aerosolised amiodarone failed to produce the expected FAM responses.
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    • Grant Information:
      NC/L001683/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; NC/L001683/1 National Centre for the Replacement Refinement and Reduction of Animals in Research; NC/C013203/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; NC/C013109/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; NC/CO13203/1 National Centre for the Replacement Refinement and Reduction of Animals in Research
    • Contributed Indexing:
      Keywords: amiodarone; di-22:6 bis-monoacylglycerol; foamy alveolar macrophages; high content analysis; mass spectrometry imaging; phospholipidosis
    • الموضوع:
      Date Created: 20190720 Latest Revision: 20220518
    • الموضوع:
      20231215
    • الرقم المعرف:
      PMC6680908
    • الرقم المعرف:
      10.3390/pharmaceutics11070345
    • الرقم المعرف:
      31319538