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CRTH2 antagonist, BI 671800 (BI), reduces nasal symptoms and inhibits nasal cytokines and eosinophils in SAR patients exposed to grass pollen in an environmental challenge chamber (ECC)

 
: Krug, Norbert; Gupta, A.; Badorrek, Philipp; Müller, Meike; Casper, Anja; Pivovarova, A.; Hilbert, J.; Koenen, R.; Hohlfeld, Jens M.; Wood, C.

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A4185
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
English
Abstract
Fraunhofer ITEM ()

Abstract
RATIONALE: Allergic rhinitis is a Th2 driven inflammatory disorder in which prostaglandin D2 (PGD2) is a key inflammatory component. PGD2 is released primarily by mast cells with TH2 cells, dendritic cells, and macrophages being secondary sources. PGD2 binds to its receptor (CRTH2) on basophils, mast cells, eosinophils, and TH2 cells releasing chemokine/inflammatory mediators. Targeting the CRTH2 receptor is a promising new therapy to reduce the allergic inflammation.
METHODS: 146 grass sensitive SAR patients received one of 3 BI treatment doses (50, 200, 400 mg BID) or fluticasone propionate (FP) nasal spray 200 mcg or montelukast (MT) 10 mg daily for 2 weeks in a two way partial cross-over design. Each patient received placebo for their other 2 week treatment period. Subjects were exposed to Dactylis glomerata (4,000 grains/m3 over 6 h) in an ECC. Nasal symptoms (TNSS) were evaluated as the primary endpoint. Other endpoints included PGD2 induced eosinophil shape change (ESC), cytokines and eosinophils in nasal secretion and lavage.
RESULTS: TNSS was significantly reduced compared to placebo for FP , BI 200 mg and MT (adj. mean difference, 95%CI, % difference): FP-1.64 (95% CI -2.18,-1.11),- 33%), 200 mg BI -0.85 (95% CI -1.40,-0.30), -17%), MT -0.74 (95% CI -1.31,-0.17), -15%) , 400 mg BI -0.51 (95% CI -1.09, 0.06), -10%), and 50 mg BI -0.4 (95% CI -1.01, 0.20), -8%). Inhibition of nasal IL-4, IL-5, IL-13, and eotaxin production was observed for BI, and FP. Reduction in absolute and % nasal eosinophils was observed for all treatments. Dose related reduction in ESC was seen only for BI but was not seen for FP, MT, or placebo.
CONCLUSION: BI 671800 at a dose of 200 mg twice a day reduced TNSS vs. placebo over a 6 hour allergen challenge period; and at the end of the 6 hours showed a reduction in TH-2 inflammatory cytokines as well as a reduction in the number and % of nasal eosinophils compared to placebo.

: http://publica.fraunhofer.de/documents/N-226445.html