The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air.
BACKGROUND
The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction, then prevention of their formation should decrease the severity of an induced asthmatic response.


METHODS
In a randomized, double-blind, placebo-controlled, crossover study, we examined the effect of A-64077, a 5-lipoxygenase inhibitor, on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187.


RESULTS
A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4, a 5-lipoxygenase product, by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter, P less than 0.001), but it did not affect the ionophore-induced synthesis of thromboxane B2, a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077, the amount of cold, dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077, P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077, P less than 0.005).


CONCLUSIONS
Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold, dry air, suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.
Israel
E
E
Department of Medicine, Beth Israel Hospital, Boston, MA 02215.
Dermarkarian
R
R
Rosenberg
M
M
Sperling
R
R
Taylor
G
G
Rubin
P
P
Drazen
J M
JM
D001249:Asthma / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction; D000001:Calcimycin / Q000494:pharmacology; D003080:Cold Temperature / Q000009:adverse effects*; D004311:Double-Blind Method; D015777:Eicosanoids / Q000097:blood; D006801:Humans; D006813:Humidity; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors; D008297:Male
D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D000001:Calcimycin; C063449:zileuton; D006918:Hydroxyurea