A Study to Investigate the Ability of Inhaled Amiodarone to Induce ‘Foamy’ Alveolar Macrophages in Male Wistar Han Rats
Aateka Patel1,2, Ewelina Hoffman3, Doug Ball4, Jan Klapwijk5, Karen Cartwright5, Clive Page1, Lea Ann Dailey6, Ben Forbes2
1Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, U.K
2Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, King’s College London, 150 Stamford Street, London SE1 9NH, UK
3Centre for Topical Drug Delivery and Toxicology, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK
4Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnelswood Road, Stevenage, Herts, SG1 2NY, UK
5Translational Medicine and Comparative Pathobiology, GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, UK
6Institute of Pharmaceutical Technology and Biopharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06108 Halle (Saale), Germany
Summary
Inhaled therapies for asthma were first developed in the 1960s and remain the preferred route of administration for treating the disease. They enable the topical delivery of therapeutically effective doses of drug into the airways eliciting local effects within the lungs whilst minimising systemic exposure. However, pre-clinical development of inhaled dry powder therapies presents a number of challenges. One is the alveolar macrophage (AM) response commonly induced in inhalation studies that is observed as an increase in the number of AM or in the appearance of vacuolated ‘foamy’ macrophages (FM). Amiodarone is a prototypic cationic amphiphilic drug, well-known for its ability to induce FM when administered systemically. This study investigated whether a foamy macrophage effect can be induced by amiodarone 10 mg/kg (day 1) and 30 mg/kg (days 2, 3 and 4) administered over 4 days by inhalation. Rat AM were obtained through bronchoalveolar lavage (BAL) on days 1 and 7 post-administration of four consecutive doses of aerosolised amiodarone (10, 30, 30, 30 mg/kg). Control animals were exposed to air. AM responses were evaluated using conventional histopathology and BAL assessment. The number of AM in the lungs did not increase over the course of the treatment. However, neutrophil recovery was significantly elevated at day 1 post dosing (p<0.05) and eosinophil recovery was increased on day 7 post dosing (p<0.001). Although macrophage numbers were not altered, some ‘foamy’ AM were observed at both time points (p<0.01). These findings indicate that inhaled amiodarone elicits transient pulmonary inflammation and induces some AM vacuolisation.
