Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor.
METHODS
The clinical importance of leukotrienes in human allergy has not been defined, in part because there have been no selective 5-lipoxygenase inhibitors that have been effective and safe for use in humans. To address the hypothesis that stimulated leukotriene synthesis causes symptoms of immediate-hypersensitivity reactions in vivo, I investigated the effects of a new 5-lipoxygenase inhibitor, A-64077, on provoked allergic nasal symptoms and mediator release in a double-blind, randomized, placebo-controlled study. Eight subjects with allergic rhinitis underwent nasal challenge on two occasions after an oral dose of 800 mg of A-64077 or an identical-appearing placebo.


RESULTS
Allergen-induced nasal congestion was significantly attenuated (P less than 0.02) by A-64077; peak levels of leukotriene B4 (median, 684 pg per milliliter) and 5-hydroxyeicosatetraenoic acid (median, 704 pg per milliliter) in nasal-rinse fluids were markedly reduced (to 67 and 185 pg per milliliter, respectively; P less than 0.01), whereas levels of prostaglandin D2 were not. Histamine release and sneezing were not reduced significantly by A-64077, but there was a significant correlation (P less than 0.01) between the changes in these variables within subjects. The mean (+/- SEM) stimulated synthesis of leukotriene B4 in whole blood ex vivo was markedly reduced by A-64077 (from 153 +/- 19 to 20 +/- 9 ng per milliliter, P less than 0.01), and the specificity of A-64077 for 5-lipoxygenase inhibition was verified by its lack of effect on the synthesis of serum thromboxane B2 or 12-hydroxyeicosatetraenoic acid.


CONCLUSIONS
These results provide direct evidence of an important role for the 5-lipoxygenase products of arachidonic acid in allergic rhinitis and support the notion that further experiments in this area may lead to new therapeutic approaches to allergic disorders.
Department of Medicine, Vanderbilt University, Nashville.
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Knapp
D004311:Double-Blind Method; D005260:Female; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D008297:Male; D015508:Nasal Obstruction / Q000503:physiopathology*; D009299:Nasal Provocation Tests; D015230:Prostaglandin D2 / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial / Q000188:drug therapy / Q000503:physiopathology*; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy / Q000503:physiopathology*; D012912:Sneezing / Q000187:drug effects
D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D015230:Prostaglandin D2; C063449:zileuton; D006918:Hydroxyurea