Effects of celecoxib on major prostaglandins in asthma.
BACKGROUND
Prostaglandin (PG) D(2) is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma.


OBJECTIVE
Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD(2) , monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE(2) , thromboxane A(2) and PGI(2) , also measured as major urinary metabolites.


METHODS
Eighteen subjects with asthma participated in a cross-over study where celecoxib 200mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV(1) and airway inflammation as fraction of exhaled nitric oxide (F(E) NO).


RESULTS
Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV(1) or F(E) NO.


CONCLUSIONS
Biosynthesis of PGD(2) was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE(2) . The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.
Daham
K
K
Department of Medicine, Division of Respiratory Medicine and Allergy, Karolinska University Hospital, Huddinge, Sweden.
Song
W-L
WL
Lawson
J A
JA
Kupczyk
M
M
Gülich
A
A
Dahlén
S-E
SE
FitzGerald
G A
GA
Dahlén
B
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D000068579:Celecoxib; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011453:Prostaglandins / Q000096:biosynthesis* / Q000378:metabolism / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D012129:Respiratory Function Tests; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D055815:Young Adult
D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib