Repeated dosing effects of mediator antagonists in inhaled corticosteroid-treated atopic asthmatic patients.
BACKGROUND
The anti-inflammatory effects of repeated dosing with mediator antagonists as add-on therapy to that with inhaled corticosteroids (ICSs) in patients with asthma remain to be fully established.


OBJECTIVE
We elected to evaluate the effects of repeated dosing with fexofenadine (FEX) and montelukast (ML) at clinically recommended doses in ICS-treated asthmatic patients using adenosine monophosphate (AMP) bronchial challenge as the primary outcome.


METHODS
Eighteen atopic asthmatic patients receiving a mean (+/- SEM) dose of 631 +/- 104 micro g daily of ICSs, which remained unchanged throughout the entire study, were randomized in double-blind, cross-over fashion to receive FEX, 180 mg, ML, 10 mg, or placebo (PL) for 1 week. There was a 1-week washout period prior to each randomized treatment. Measurements of the provocative concentration of a substance (ie, AMP) causing a 20% fall in FEV(1) (PC(20)) were made after each washout period and randomized treatment period.


RESULTS
The values for AMP PC(20) after the washout period prior to each randomized treatment were not significantly different (FEX, 74 +/- 15 mg/mL; ML, 73 +/- 18 mg/mL; PL, 71 +/- 19 mg/mL). There were significant improvements (p < 0.05) in AMP PC(20) with the use of FEX (127 +/- 38 mg/mL) and ML (121 +/- 27 mg/mL) compared to PL (78 +/- 23 mg/mL). Spontaneous recovery after AMP challenge, as determined by area under the 60-min time-response curve, was significantly enhanced (p < 0.05) with the use of ML (352 +/- 95%.min [corrected]) compared to FEX (758 +/- 140%.min) and PL (683 +/- 134%.min [corrected]). Both FEX and ML significantly suppressed (p < 0.05) the levels of exhaled nitric oxide, while only ML significantly reduced (p < 0.05) the peripheral blood eosinophil count compared to PL. Morning and evening peak expiratory flow were significantly higher (p < 0.05), and the frequency of salbutamol rescue was significantly reduced (p < 0.05) with FEX and ML compared to PL.


CONCLUSIONS
Repeated dosing with FEX and ML as add-on therapy improved AMP PC(20) and other surrogate inflammatory markers along with asthma diary outcomes in ICS-treated atopic asthmatic patients. Further studies are indicated to evaluate the long-term add-on effects of FEX on asthma exacerbations.
Lee
Daniel K C
DK
Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
Jackson
Catherine M
CM
Haggart
Kay
K
Lipworth
Brian J
BJ
D000085:Acetates / Q000008:administration & dosage*; D000249:Adenosine Monophosphate; D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D018926:Anti-Allergic Agents / Q000008:administration & dosage*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D011804:Quinolines / Q000008:administration & dosage*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy*; D013440:Sulfides; D016593:Terfenadine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D016896:Treatment Outcome
D000085:Acetates; D000305:Adrenal Cortex Hormones; D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; D000249:Adenosine Monophosphate; D016593:Terfenadine; C093230:fexofenadine; C093875:montelukast