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Safety and efficacy of an oral CCR 3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo‐controlled clinical trial
Author(s) -
Neighbour H.,
Boulet L.P.,
Lemiere C.,
Sehmi R.,
Leigh R.,
Sousa A. R.,
Martin J.,
Dallow N.,
Gilbert J.,
Allen A.,
Hall D.,
Nair P.
Publication year - 2014
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12244
Subject(s) - sputum , medicine , eosinophil , asthma , methacholine , eosinophilia , immunology , placebo , gastroenterology , pharmacology , respiratory disease , lung , pathology , tuberculosis , alternative medicine
Summary Background Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR 3 receptor. Objective In this study, we investigated the role of CCR 3 agonists in asthma by observing the effect of a small molecule antagonist of the CCR 3 receptor ( GW 766994) 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 GW 766994 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 CCR 3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells ( CD 34 + 45 + IL ‐5Rα + ) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW 766944 compared to placebo. There was no improvement in FEV 1 ; however, there was a modest but statistically significant improvement in PC 20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC 20 is statistically significant, it is not of clinical significance. Conclusions and Clinical Relevance In conclusion, this study calls into question the role of CCR 3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR 3 receptor may contribute to airway hyperresponsiveness.