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.
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Authors | Aili L Lazaar, Lisa E Sweeney, Alexander J MacDonald, Neil E Alexis, Chao Chen, Ruth Tal-Singer |
Journal | British journal of clinical pharmacology
(Br J Clin Pharmacol)
Vol. 72
Issue 2
Pg. 282-93
(Aug 2011)
ISSN: 1365-2125 [Electronic] England |
PMID | 21426372
(Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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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
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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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