The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo.
BACKGROUND
The 5-lipoxygenase metabolites of arachidonic acid are likely to be involved in the pathophysiology of atopic asthma. We investigated the effect of pretreatment with MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), and subsequent airway hyperresponsiveness to histamine.


METHODS
Eight atopic men with mild to moderate asthma aged 19 to 31 years, (forced expiratory volume in 1 second [FEV1] > or = 67% of predicted value, histamine provocative concentration causing a 20% fall in FEV1 [PC20] < 4 mg/ml) and documented EAR and LAR to house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. During each study period histamine PC20 was measured 2 days before and 1 day after a standardized allergen inhalation challenge test. MK-0591 was administered in 3 oral doses of 250 mg each at 24, 12, and 1.5 hours before inhalation of allergen. Biochemical activity of MK-0591 was determined by calcium ionophore A-23187-stimulated leukotriene (LT)B4 biosynthesis in whole blood ex vivo and by urinary LTE4 excretion. Airway response to allergen was measured by FEV1 (percent fall from baseline). The EAR (0 to 3 hours) and the LAR (3 to 8 hours) were expressed as corresponding areas under the time-response curves.


RESULTS
MK-0591 and placebo did not differ in their effects on prechallenge FEV1 (p = 0.10). As compared with the value before pretreatment, MK-0591 blocked LTB4 biosynthesis and LTE4 excretion by a mean of 98% (range, 96% to 99%; p < 0.002) and 87% (range, 84% to 96%; p < 0.046), respectively, from 0 to 24 hours after allergen challenge. Both the EAR and the LAR were significantly reduced after administration of MK-0591 as compared with placebo, with a mean inhibition of 79% (p = 0.011) and 39% (p = 0.040), respectively. Allergen-induced airway hyperresponsiveness was not significantly different between the two pretreatment periods (p = 0.37).


CONCLUSIONS
In this study oral MK-0591 prevented leukotriene biosynthesis after allergen challenge in patients with mild to moderate asthma. The results of our study indicate that 5-lipoxygenase products play an important role during the EAR, whereas their contribution to the pathophysiology of the LAR seems to be of less importance.
Diamant
Z
Z
Department of Pulmonology, University Hospital, Leiden, The Netherlands.
Timmers
M C
MC
van der Veen
H
H
Friedman
B S
BS
De Smet
M
M
Depré
M
M
Hilliard
D
D
Bel
E H
EH
Sterk
P J
PJ
D058927:5-Lipoxygenase-Activating Proteins; D000284:Administration, Oral; D000328:Adult; D000485:Allergens / Q000009:adverse effects*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003404:Creatinine / Q000652:urine; D004311:Double-Blind Method; D005541:Forced Expiratory Volume / Q000187:drug effects; D006632:Histamine; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000097:blood; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000485:Allergens; D002352:Carrier Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; D006632:Histamine; D003404:Creatinine