title: Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial.
abstract: BACKGROUND
  Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor.
  
  
  OBJECTIVE
  In this study, we investigated the role of CCR3 agonists in asthma by observing the effect of a small molecule antagonist of the CCR3 receptor (GW766994) on sputum eosinophil counts in patients with eosinophilic asthma.
  
  
  METHODS
  Clinical and physiological outcomes, the chemotactic activity of sputum supernatant for eosinophils and the presence of eosinophil progenitors in sputum and blood samples were also studied.
  
  
  RESULTS
  In a double-blind parallel group study, 60 patients with asthma were randomized to 300 mg of GW766994 twice daily or matching placebo for 10 days followed by prednisone 30 mg for 5 days. Of these patients, 53 had a sputum eosinophil count > 4.9% at baseline. Despite plasma concentrations of drug consistent with > 90% receptor occupancy during the dosing period, the CCR3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells (CD34(+) 45(+) IL-5Rα(+)) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV1 ; however, there was a modest but statistically significant improvement in PC20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC20 is statistically significant, it is not of clinical significance.
  
  
  CONCLUSIONS
  In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.
authors.affiliation: Division of Respirology, McMaster University, Hamilton, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Neighbour
authors.forename: L-P
authors.initials: LP
authors.lastname: Boulet
authors.forename: C
authors.initials: C
authors.lastname: Lemiere
authors.forename: R
authors.initials: R
authors.lastname: Sehmi
authors.forename: R
authors.initials: R
authors.lastname: Leigh
authors.forename: A R
authors.initials: AR
authors.lastname: Sousa
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: N
authors.initials: N
authors.lastname: Dallow
authors.forename: J
authors.initials: J
authors.lastname: Gilbert
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.forename: D
authors.initials: D
authors.lastname: Hall
authors.forename: P
authors.initials: P
authors.lastname: Nair
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D001991:Bronchitis / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D008875:Middle Aged; D011657:Pulmonary Eosinophilia / Q000150:complications*; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors*; D012129:Respiratory Function Tests; D013183:Sputum / Q000166:cytology / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; C000593393:GW766994; D008782:Methylurea Compounds; D054397:Receptors, CCR3
keywords: CCR3; asthma; clinical trial; eotaxin; sputum eosinophils