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Validation of the Human Ozone Challenge Model as a Tool for Assessing Anti-Inflammatory Drugs in Early Development

From the Pulmonary Research Institute, Großhansdorf, Germany (O. Holz, F. Kanniess, S. Janicki, H. Magnussen, K. Richter); Hospital Großhansdorf, Center for Pneumology and Thoracic Surgery, Großhansdorf, Germany (O. Holz, H. Magnussen, R. A. Jörres); GlaxoSmithKline, King of Prussia, Pennsylvania (R. Tal-Singer, R. S. J. Vessey); London, United Kingdom (K. J. Simpson, A. Gibson); and Occupational and Environmental Medicine, LMU Munich, Germany (R. A. Jörres).

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double-dummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development.

Key Words: Ozone challenge • drug profiling • induced sputum • exhaled breath condensate

Address for reprints: Olaf Holz, Hospital Großhansdorf, Center for Pneumology and Thoracic Surgery, Wöhrendamm 80, D-22927 Großhansdorf, Germany.