Effect of a very late antigen-4 receptor antagonist on allergen-induced airway responses and inflammation in asthma.
BACKGROUND
Very late antigen-4 (VLA(4)) plays a key role in the recruitment of eosinophils in allergic responses in animal studies.


OBJECTIVE
We investigated whether pretreatment with multiple doses of a VLA(4) receptor antagonist, HMR 1031, protects against allergen-induced airway responses and airway inflammation in humans.


METHODS
Fourteen asthmatics (7F/7M), 18-49 years, PC(20) forced expiratory volume in 1 s (FEV(1)) methacholine (M) (<8 mg/mL; FEV(1) 82.3-116.1% predicted) with dual responses to inhaled allergen participated in a double-blind, placebo-controlled, cross-over study. Each treatment period consisted of 9 days, separated by >or=2 weeks. Exhaled nitric oxide (eNO), PC(20)FEV(1)(M) and hypertonic saline-induced sputum was obtained on Days 1, 7 and 9. Subjects inhaled HMR 1031 (20 mg b.i.d.) or placebo (P) on Days 1--8. On Day 8, an allergen bronchoprovocation test was performed, the airway response was measured by FEV(1), and expressed as %fall from baseline. Data from 12 evaluable subjects are presented here.


RESULTS
Both treatments were well tolerated. There was no significant difference between HMR 1031 and P in the early asthamatic response: mean AUC (0-3 h)+/-SEM (%fall h): 26.01+/-4.26 and 17.41+/-4.26, respectively (P=0.18), nor in the late response: mean AUC (3-9 h)+/-SEM (%fall h): 97.09+/-8.63 and 97.61+/-8.63, respectively, P=0.97. This corresponded to the absence of significant allergen-induced changes in PC(20)FEV(1)(M), eNO, sputum eosinophils and soluble inflammation markers between both treatment periods.


CONCLUSIONS
Treatment with multiple inhaled doses of the VLA(4) antagonist, HMR 1031, did not result in detectable protection against allergen-induced airway responses or airway inflammation in asthma.
Diamant
Z
Z
Erasmus University Medical Centre, Lung Function Lab, Rotterdam, The Netherlands. z.diamant@gems.demon.nl
Kuperus
J
J
Baan
R
R
Nietzmann
K
K
Millet
S
S
Mendes
P
P
Miller
B
B
Amin
D
D
Rohatagi
S
S
Sterk
P J
PJ
Hoogsteden
H C
HC
Prins
J-B
JB
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000276:immunology; D001985:Bronchial Provocation Tests / Q000379:methods; D002000:Bronchospirometry / Q000379:methods; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000276:immunology*; D039041:Integrin alpha4beta1 / Q000276:immunology*; D008297:Male; D016210:Methacholine Chloride / Q000276:immunology; D008875:Middle Aged; D009569:Nitric Oxide / Q000276:immunology; D011422:Propionates / Q000008:administration & dosage / Q000276:immunology*; D016029:Receptors, Very Late Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D013183:Sputum / Q000276:immunology
C483465:(3S)-3-(((2S)-2-(4,4-dimethyl-3-(4-((((2-methylphenyl)amino)carbonyl)amino)benzyl)-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoyl)amino)-3-phenylpropanoic acid; D000485:Allergens; D007093:Imidazoles; D039041:Integrin alpha4beta1; D011422:Propionates; D016029:Receptors, Very Late Antigen; D016210:Methacholine Chloride; D009569:Nitric Oxide