Disease relevance of Leutrol

• 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 [1].
• 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 [2].
• Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) concentrations were measured in rectal dialysis fluid from ten patients with active ulcerative colitis before and after oral administration of 800 mg of the 5-lipoxygenase inhibitor A-64077 [3].
• Standard antiinflammatory compounds including BW-755C, Abbott A-64077 (zileuton), dexamethasone-21-acetate, indomethacin, and naproxen did not affect LTB4-induced neutropenia [4].
• A selective and potent 5-LO inhibitor, zileuton (N-1(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea, A-64077) was evaluated in models of airway anaphylaxis, where leukotrienes are a major component [5].

High impact information on Leutrol

• 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 [1].
• 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) [2].
• In contrast, pretreatment with the leukotriene (LT) synthesis inhibitor, A-64077, completely blocked neutrophil but not eosinophil migration in response to SP [6].
• 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886 [7].
• Both indomethacin and pyrilamine reduced (7-10% of BaCl maximum; p <0.05) the contractile response of sensitized ureter to antigen, whereas A-64077 did not [8].

Biological context of Leutrol

• Both 5-LO inhibitors inhibited antigen-induced contraction, with IC50 values for BI-L-239 and A-64077 of 1.58 and 4.35 microM respectively [9].
• 4. In contrast to A-64077, the inhibitory effect of disulfiram on LTB4 production by isolated leukocytes from the pleural cavity was reduced by the addition of the cell-free pleural exudate, suggesting that protein binding or conversion of disulfiram to inactive species contributes to diminish the potency of the drug [10].

Anatomical context of Leutrol

• Glucuronidation of zileuton (A-64077) by human hepatic microsomes [11].
• 1. The effect of disulfiram and A-64077 on leukotriene B4 biosynthesis was investigated using human polymorphonuclear leukocyte preparations and an in vivo rat pleurisy assay [10].

Associations of Leutrol with other chemical compounds

• The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma [12].

Gene context of Leutrol

• An example of these is zileuton (Abbott-64077), a potent 5-lipoxygenase inhibitor now under clinical evaluation [13].

References