The effects of a CXCR1/CXCR2 antagonist on neutrophil migration in mild atopic asthmatic subjects.

Abstract

BACKGROUND:

Neutrophils are effector cells recruited to airways in patients with asthma. Migration of neutrophils occurs predominantly through activation of the CXCR1 and CXCR2 receptors by CXC chemokines, including IL-8 and Gro-α. The dual CXCR1/CXCR2 antagonist SCH 527123 has been developed to target neutrophil migration to alleviate airway neutrophilia. This study investigated the effects of SCH 527123 on neutrophil levels within the bone marrow, peripheral blood and airways, and on isolated bone marrow and peripheral blood neutrophil migration from mild allergic asthmatics.

METHODS:

Thirteen subjects with mild allergic asthma completed a double blind, placebo-controlled, multi-center crossover study and were randomized to daily dosing of 30 mg SCH 527123 and placebo for 8 days. Subjects provided bone marrow, peripheral blood and sputum samples pre-dosing and on the last day of dosing. Neutrophil numbers were quantified in all samples and chemotaxis assays were performed on neutrophils purified from bone marrow and peripheral blood.

RESULTS:

Neutrophil numbers fell significantly in the peripheral blood and sputum following treatment with SCH 527123 compared to placebo treatment. No change in neutrophil numbers was observed in bone marrow. SCH 527123 reduced IL-8-induced migration of purified peripheral blood neutrophils (p < 0.05), but had limited effects on migration of neutrophils purified from bone marrow.

CONCLUSIONS:

The results from this study demonstrate that oral administration of the dual CXCR1/CXCR2 antagonist SCH 527123 reduces neutrophil levels in the circulation and airways through inhibition of migration. There were no toxic effects of SCH 527123 on granulocytic progenitor cells in the bone marrow.

• Authors: Candice M Todd, Brittany M Salter, Desmond M Murphy, Richard M Watson, Karen J Howie, Joanne Milot, Jonathan Sadeh, Louis-Philippe Boulet, Paul M O'Byrne, Gail M Gauvreau
• Journal: Pulmonary pharmacology & therapeutics (Pulm Pharmacol Ther) Vol. 41 Pg. 34-39 (12 2016) ISSN: 1522-9629 [Electronic] England
• PMID: 27640067 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• 2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide
• Benzamides
• Cyclobutanes
• Receptors, Interleukin-8A
• Receptors, Interleukin-8B

Topics

• Adult
• Asthma (drug therapy, physiopathology)
• Benzamides (adverse effects, pharmacology)
• Cell Movement (drug effects)
• Cross-Over Studies
• Cyclobutanes (adverse effects, pharmacology)
• Double-Blind Method
• Female
• Humans
• Male
• Neutrophils (drug effects, metabolism)
• Receptors, Interleukin-8A (antagonists & inhibitors)
• Receptors, Interleukin-8B (antagonists & inhibitors)
• Sputum (metabolism)
• Young Adult