Fluticasone propionate results in improved glucocorticoid receptor binding affinity and reduced oral glucocorticoid requirements in severe asthma.
BACKGROUND
Inhaled glucocorticoids (iGC) have become important first line agents in the management of moderate-to-severe asthma. Severe asthma is associated with reduced glucocorticoid receptor (GCR) binding affinity.


METHODS
To evaluate the potential impact of inhaled fluticasone propionate on markers of airway inflammation [GCR binding affinity (Kd) and eosinophil cationic protein (ECP)] and oral GC requirements in steroid-dependent asthmatics, we examined the effects of fluticasone propionate (FP) 500 microg or 1000 microg BID and placebo in a double-blind, randomized study of 13 steroid-dependent asthmatics at a single center. Glucocorticoid receptor binding affinity and ECP values were obtained at baseline, 4, 6, 26, and 52 weeks after patients were enrolled into the study. Oral GC dose and FEV1 values were also recorded at each visit.


RESULTS
Inhaled FP resulted in large reductions in oral GC requirement by 6 weeks of therapy while no reduction was seen in the placebo group. All patients in the FP 2000 microg/d group who continued double-blind therapy at 52 weeks were able to eliminate oral prednisone use. In contrast, every patient in the placebo group had to be withdrawn from the study due to poor asthma control. Associated with the oral GC dose reduction on high dose FP therapy, were improvements in GCR binding affinity with the GCR Kd falling from 42.5 nM at baseline to 19.5 nM at 6 weeks (P=.08). The GCR KD values remained stable thereafter with values of 23.5 nM at 26 weeks (P=.02) and 19.5 nM at 52 weeks (P=.01). In addition, high dose FP therapy resulted in reductions in serum ECP values.


CONCLUSIONS
This study suggests that high dose FP therapy results in significant oral GC sparing effects associated with improved GCR binding affinity and reductions in serum ECP levels in patients with steroid-dependent asthma.
Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver 80206, USA.
S R
SR
Nimmagadda
J D
JD
Spahn
H S
HS
Nelson
J
J
Jenkins
S J
SJ
Szefler
D Y
DY
Leung
D000284:Administration, Oral; D000328:Adult; D000730:Androstadienes / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001798:Blood Proteins / Q000032:analysis; D004311:Double-Blind Method; D047091:Eosinophil Granule Proteins; D005260:Female; D000068298:Fluticasone; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008168:Lung / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D012260:Ribonucleases
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D000068298:Fluticasone; D012260:Ribonucleases