Author(s): Lazaar AL, Sweeney LE, MacDonald AJ, Alexis NE, Chen C,
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Abstract WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. WHAT THIS STUDY ADDS: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. AIMS: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. METHODS: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers. RESULTS: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70\%) relative to placebo was observed following administration of SB-656933 400 mg (95\% CI 60\%, 77\%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55\% (95\% CI 20\%, 75\%) and 74\% (95\% CI 55\%, 85\%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8\% (95\% CI 9.2, 50.3) and 50.5\% (95\% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. CONCLUSIONS: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
This article was published in Br J Clin Pharmacol
and referenced in Journal of Genetic Syndromes & Gene Therapy