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Setipiprant, a selective CRTH 2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics
Ist Teil von
Clinical and experimental allergy, 2014-08, Vol.44 (8), p.1044-1052
Erscheinungsjahr
2014
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
Summary
Background
CRTH
2 is a G‐protein‐coupled receptor on
T
helper2 cells that mediates pro‐inflammatory effects of prostaglandin
D
2 in allergic responses.
Objective
To investigate the tolerability and pharmacokinetics of setipiprant (
ACT
‐129968), a selective orally active
CRTH
2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen‐induced airway responses.
Methods
In this 3‐centre, double‐blinded, placebo‐controlled, cross‐over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo
b.i.d
. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV
1
until 10 h post‐allergen. Airway responsiveness to methacholine and exhaled nitric oxide (e
NO
) were measured pre‐ and post‐dosing. The effects of both treatments on the allergen‐induced airway responses were compared by a paired Student's
t‐
test.
Results
Fifteen subjects completed the study per‐protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter‐subject variability. Compared with placebo, setipiprant significantly reduced the allergen‐induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (
AUC
(3–10 h)
) by on average 25.6% (
P
= 0.006) and significantly protected against the allergen‐induced airway hyperresponsiveness (
AHR
) to methacholine (
P
= 0.0029). There was no difference in the early asthmatic response (
EAR
) or in allergen‐induced changes in e
NO
between treatments.
Conclusion and Clinical Relevance
Setipiprant at multiple oral doses was well tolerated and reduced both the allergen‐induced
LAR
and the associated
AHR
in allergic asthmatics. Our findings confirm that
CRTH
2 may be a promising target for the treatment of allergic disorders.
Sprache
Englisch
Identifikatoren
ISSN: 0954-7894
eISSN: 1365-2222
DOI: 10.1111/cea.12357
Titel-ID: cdi_crossref_primary_10_1111_cea_12357
Format
–
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