SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects.
SCH527123 is a novel, selective CXC chemokine receptor 2 antagonist that inhibits neutrophil activation and modulates neutrophil trafficking in animal models, characteristics that may be beneficial in the treatment of conditions with unbalanced pulmonary neutrophilia, such as chronic obstructive pulmonary disease. The purpose of this proof-of-principle study was to determine whether SCH527123 inhibits ozone-induced neutrophil recruitment in healthy humans. In a randomised, double-blind, placebo-controlled, three-way crossover study, oral SCH527123 (50 mg once daily, 4 days), prednisolone (50 mg once), or placebo was alternated with 2-week washouts. 18 healthy ozone responders (>20% increase in sputum neutrophils) underwent ozone challenge tests (250 ppb, 3 h intermittent exercise) 1 h after the last treatment dose. Sputum was induced at 3 h post-challenge. After SCH527123 treatment, the ozone challenge resulted in significantly lower sputum neutrophil counts (0.13x10(6).mL(-1)) compared with prednisolone (0.84x10(6).mL(-1); p<0.001) or placebo (2.98x10(6).mL(-1); p<0.001). Comparable results were obtained for total cell count, percentage of sputum neutrophils, and for interleukin-8 and myeloperoxidase in sputum supernatant. Post-challenge, SCH527123 inhibited neutrophilia in peripheral blood but significantly less than in sputum. All treatments were safe and well tolerated. SCH527123 causes significant attenuation of ozone-induced airway neutrophilia in healthy subjects. Further evaluation in a large trial of patients with pulmonary disorders is warranted.
Holz
O
O
Pulmonary Research Institute, Hospital Grosshansdorf, Germany.
Khalilieh
S
S
Ludwig-Sengpiel
A
A
Watz
H
H
Stryszak
P
P
Soni
P
P
Tsai
M
M
Sadeh
J
J
Magnussen
H
H
D000328:Adult; D001549:Benzamides / Q000494:pharmacology*; D018592:Cross-Over Studies; D003503:Cyclobutanes / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013183:Sputum / Q000201:enzymology / Q000276:immunology; D055815:Young Adult
C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D001549:Benzamides; D003503:Cyclobutanes; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; D009195:Peroxidase