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SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans.

AbstractWHAT 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.
AuthorsAili L Lazaar, Lisa E Sweeney, Alexander J MacDonald, Neil E Alexis, Chao Chen, Ruth Tal-Singer
JournalBritish journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 72 Issue 2 Pg. 282-93 (Aug 2011) ISSN: 1365-2125 [Electronic] England
PMID21426372 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Copyright© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.
Chemical References
  • CD11b Antigen
  • CXCL1 protein, human
  • Chemokine CXCL1
  • Phenylurea Compounds
  • Receptors, Interleukin-8B
  • SB 656933
  • Sulfonamides
  • Ozone
  • Peroxidase
Topics
  • Administration, Oral
  • Adolescent
  • Adult
  • Bronchitis (chemically induced, immunology, prevention & control)
  • CD11b Antigen (metabolism)
  • Chemokine CXCL1 (antagonists & inhibitors)
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Leukocyte Count
  • Male
  • Middle Aged
  • Neutrophil Activation (drug effects)
  • Neutrophils (immunology)
  • Ozone (adverse effects)
  • Peroxidase (metabolism)
  • Phenylurea Compounds (pharmacokinetics, pharmacology)
  • Receptors, Interleukin-8B (antagonists & inhibitors, metabolism)
  • Single-Blind Method
  • Sputum (enzymology)
  • Sulfonamides (pharmacokinetics, pharmacology)
  • Young Adult

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