via-2291 and Asthma

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.

Topics: Alleles; Anti-Asthmatic Agents; Arachidonate 5-Lipoxygenase; Asthma; Gene Frequency; Genetic Variation; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Phenotype; Promoter Regions, Genetic; Treatment Outcome

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise- and adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 +/- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E4 (LTE4) excretion at exercise was + 18.1 +/- 10.9% on placebo and -44.8 +/- 6.2% after ABT-761 (p = 0.017); changes at adenosine were + 38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.

Topics: Adenosine; Adult; Asthma; Bronchi; Bronchial Provocation Tests; Bronchoconstriction; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Exercise; Female; Forced Expiratory Volume; Humans; Hydroxyurea; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Vasodilator Agents

Abbott's ABT-761 is a 5-lipoxygenase inhibitor with 8-fold increased potency over Bay-X-1005 and 150-fold over zileuton [171665]. It has a longer duration of action than its closest competitor, ZD-2138 (AstraZeneca), and has entered phase III trials for asthma [224216]. ABT-761 is the follow-up compound for zileuton and, due to its increased potency, requires only once-daily dosing [187700]. ABT-761 has shown excellent oral bioavailability and an extended duration of plasma levels in man, and initial results for a single 200 mg po dose have shown a significant protective effect against exercise- and adenosine-induced bronchoconstriction in asthmatics [215839]. The drug is well tolerated in healthy volunteers and shows linear pharmacokinetics. The pharmacokinetics in children are similar to that of adults.

Topics: Asthma; Clinical Trials, Phase III as Topic; Humans; Hydroxyurea; Lipoxygenase Inhibitors