Impact of a soluble phospholipase A2 inhibitor on inhaled allergen challenge in subjects with asthma.
The possible roles of secretory phospholipases A2 (sPLA2) in asthma include the release of arachidonic acid from cellular membranes, generation of lysophospholipids, sPLA2-mediated activation of cPLA2 with increased leukotriene production, and surfactant degradation. LY333013 is a potent inhibitor of sPLA2. This study examined the impact of two doses of LY333013 vs. placebo on allergen-induced bronchoconstriction following inhaled allergen challenge in atopic asthmatics. Fifty subjects were randomly assigned to treatment, and 40 subjects completed the study. A double-blind, placebo-controlled, random order, crossover study design was used. LY333013 had no impact on the primary outcome variables of the areas under the FEV1 response curve early (0-3 hours) (AUC(early)) and late (3-8 hours) (AUC(Iate)) following inhaled allergen challenge. No significant drug-related adverse effects were observed. The response to inhaled allergen challenge was reproducible and confirms the utility of this technique as a model in which to screen compounds for further testing in asthmatic patients.
Bowton
David L
DL
Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA. dbowton@wfubmc.edu
Dmitrienko
Alexei A
AA
Israel
Elliot
E
Zeiher
Bernhardt G
BG
Sides
Gregory D
GD
D000085:Acetates / Q000627:therapeutic use*; D000280:Administration, Inhalation; D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D007651:Keto Acids; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D012882:Skin Tests
D000085:Acetates; D007211:Indoles; D007651:Keto Acids; C117948:varespladib; D010741:Phospholipases A; D054467:Phospholipases A2