Treatment with a peroxisomal proliferator activated receptor gamma agonist has a modest effect in the allergen challenge model in asthma: a randomised controlled trial.
OBJECTIVE
A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma.


METHODS
A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1 hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation.


RESULTS
The late asthmatic reaction (LAR) change from post saline FEV(1) from 4-10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects.


CONCLUSIONS
Treatment with a PPARgamma agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARgamma agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma. Registered with www.clinicaltrials.gov (NCT00318630).
Richards
Duncan B
DB
Drug Discovery, GlaxoSmithKline, Stevenage, UK. duncan.b.richards@gsk.com
Bareille
Philippe
P
Lindo
Emma L
EL
Quinn
Dean
D
Farrow
Stuart N
SN
D052242:Adiponectin / Q000097:blood; D000293:Adolescent; D000328:Adult; D000485:Allergens; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001944:Breath Tests; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D009569:Nitric Oxide / Q000032:analysis; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D052242:Adiponectin; D000485:Allergens; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016085:Bronchoconstrictor Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016210:Methacholine Chloride; D009569:Nitric Oxide