Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses.
BACKGROUND
Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%.


OBJECTIVE
To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only.


METHODS
Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge.


RESULTS
TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia.


CONCLUSIONS
We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.
Avila
P C
PC
Department of Medicine and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94143-0130, USA. avila@itsa.ucsf.edu
Boushey
H A
HA
Wong
H
H
Grundland
H
H
Liu
J
J
Fahy
J V
JV
D000328:Adult; D000485:Allergens; D000704:Analysis of Variance; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007262:Infusions, Intravenous; D016023:Integrins / Q000037:antagonists & inhibitors*; D008168:Lung / Q000503:physiopathology; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000627:therapeutic use*; D012882:Skin Tests; D017211:Treatment Failure
D000485:Allergens; D001713:Biphenyl Compounds; D016023:Integrins; D008362:Mannosides; C108700:bimosiamose disodium; D008358:Mannose