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Background: GSK2190915, a potent 5-lipoxygenase-activating protein inhibitor, prevents the synthesis of leukotrienes and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE)., Objective: To assess the effect of GSK2190915 on the allergen-induced asthmatic responses., Methods: Nineteen eligible male subjects with mild asthma were enrolled in and completed this four-centre, double-blind, two-way crossover study (ClinicalTrials.gov NCT00748306). Subjects took GSK2190915 100 mg and placebo orally once daily for 5 days in randomized order. On Day 1 and 4 they had a methacholine challenge, on Day 3 they had an inhaled allergen challenge, and on Days 4 and 6 they had sputum induction., Results: GSK2190915 attenuated the early (0-2 h) and late (4-10 h) asthmatic responses to inhaled allergen compared with placebo. There was a statistically significant attenuation of the early asthmatic response (EAR) by GSK2190915; treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) EAR was 0.408 L (0.205, 0.611). There was a statistically significant attenuation of the late asthmatic response (LAR) by GSK2190915; the treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) LAR was 0.229 L (0.041, 0.417). There was a statistically significant attenuation of allergen-induced sputum eosinophil count on Day 4 following GSK2190915: mean treatment difference (95% CI) between GSK2190915 and placebo was -9.95% (-18.15%, -1.77%). Compared with placebo, GSK2190915 100 mg reduced median sputum LTB(4) by > 90% on Days 4 and 6. There was no effect on methacholine PC(20) post allergen. GSK2190915 was generally well tolerated., Conclusion and Clinical Relevance: GSK2190915 shows potential as a treatment for patients with asthma., (© 2012 Blackwell Publishing Ltd.)

Cysteinyl-leukotrienes are important pro-inflammatory mediators in bronchial asthma (BA) and are derived from arachidonic acid by the action of 5-lipoxygenase. We identified a novel polymorphism, c.760 G>A (E254K), in exon 6 of the 5-lipoxygenase gene (5-LO). This substitution was detected in 11 out of 180 patients with BA, but not in any of the 150 non-allergic subjects. The frequency of c.760 G>A showed a significant difference between BA and non-allergic subjects (P=0.0007). The c.760 G>A polymorphism existed at the surface edge of the C-terminal catalytic domain, and the E-to-K substitution changed the charge of the side chain from negative to positive. Thus, our results suggest that E254K in the 5-LO might be associated with BA.

Background: Aspirin challenge of aspirin-intolerant asthma (AIA) patients causes a significant increase in leukotriene E4 (LTE4) concentration in urine. However, knowledge on leukotriene B4 (LTB4) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB4 is excreted as glucuronide into the urine in human healthy subjects., Objective: The purpose of this study is to estimate urinary LTB4 glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge., Methods: A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by beta-glucuronidase, the fraction containing LTB4 was purified by high-performance liquid chromatography and LTB4 concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis., Results: (1) After hydrolysis, the presence of urinary LTB4 was verified by gas chromatography-mass spectrometry-selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine [range 1.2-13] vs. 3.32 pg/mg creatinine [range, 0.14-10.5], P = 0.0159). (3) The patients with AIA (n = 7), but not those with aspirin-tolerant asthma (n = 6), showed significant increases in LTBG and LTE4 excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE4 concentration in patients with AIA (Spearman's rank correlation test, r = 0.817, P = 0.0003)., Conclusion: LTBG is present in human urine, albeit at a concentration lower than urinary LTE4. In addition to a marked increase in cysteinyl-leukotriene production, aspirin challenge induced LTB4 production in AIA patients.

Sublingual immunotherapy has been suggested for the treatment of respiratory allergies. Many controversial studies have been reported on the efficacy of sublingual immunotherapy. The aim of this prospective study was to evaluate whether sublingual immunotherapy was effective according to clinical and laboratory results in pediatric allergies. Thirty-nine allergic, grass pollen sensitive children were admitted into the study. Sublingual immunotherapy was given over a 12-month period to 21 children (mean age 10.5 +/- 3.3 years), 10 of whom had seasonal allergic rhinitis and 11 seasonal allergic asthma. During the same period, 18 children (mean age 11.1 +/- 2.5 years), 10 with seasonal allergic rhinitis and eight with seasonal allergic asthma, received placebo. Symptom scores and drug requirements were recorded and urine samples were collected to detect urinary levels of leukotrienes (Uc-LTB4 and Uc-LTE4). In patients who received sublingual immunotherapy, the symptom scores of seasonal allergic rhinitis significantly decreased, but no statistically significant changes were observed in terms of symptoms of seasonal allergic asthma. Uc-LTE4 and Uc-LTB4 levels of seasonal allergic rhinitis, with a geometric mean and 95% confidence interval (CI), were significantly decreased from 216 (103-464) and 61 (22-198) pmol/mmol creatinine to 78 (29-159) and 35 (12-118) pmol/mmol creatinine, respectively (p < 0.05 and p < 0.05). On the other hand, Uc-LTE4 and Uc-LTB4 levels for seasonal allergic asthma were 180 (92-355) and 78 (44-258) pmol/mmol creatinine and decreased to 156 (72-402) and 69 (32-254) pmol/mmol creatinine, respectively. These changes were not statistically significant (p > 0.05). According to our clinical results and urinary levels of leukotrienes, which are mediators showing the severity of allergic inflammation, it can be suggested that sublingual immunotherapy may be useful in the treatment of seasonal allergic rhinitis but not of seasonal allergic asthma.

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.

Leukotrienes may mediate bronchoconstriction in asthma. Cysteinyl leukotriene production rises in vivo after allergen challenge, but few reports describe leukotriene concentrations in clinical asthma or in children. Using high performance liquid chromatography/radioimmunoassay, plasma and urinary leukotrienes in asthmatic children (aged 5-10 years) were measured during an acute exacerbation (peak expiratory flow (PEF) < 65%, n = 10) and one month later (PEF 74-169%, n = 9), and in non-atopic normal children (aged 1.3-13.2 years). In the asthmatics, geometric mean (95% confidence interval) plasma leukotriene B4 (LTB4) was 746 pg/ml (398 to 1403) acutely and 1026 pg/ml (662 to 1593) in remission, compared with 369 pg/ml (167 to 728) in the normal children (n = 14). Plasma cysteinyl leukotrienes were low or undetectable, but urinary leukotriene E4 (LTE4) was higher in the asthmatics during an acute episode (210 pmol/mmol creatinine, 101 to 454) and at follow up (179 pmol/mmol, 110 to 293), compared with the normal children (98 pmol/mmol, 81 to 118, n = 41). This persistent increase in plasma LTB4 and urinary LTE4 concentrations one month after a severe asthmatic episode suggests leukotriene production is related to chronic inflammation rather than to acute bronchoconstriction.

In order to investigate the possible contribution of leukotrienes to the airway hypersensitiveness and inducibility of asthmatic spells, the probable temporal correlation of the urinary leukotriene levels (U-LTB4 and U-LTC4) were estimated along with the peripheral neutrophil counts in two groups of asthmatic children with or without an inflammatory sign of the elevated CRP. The first group consisted of 6 asthmatic children possessing inflammatory signs and symptoms of fever and peripheral leukocytosis. They all were hospitalized. The second group of 6 patients of light asthmatic attack without any signs and symptoms of acute inflammation were studied in the Outpatient Department. In the first group, U-LTB4 was as high as 258.6 +/- 88.9 ng/mmol Cr. during the attacks while U-LTB4 levels of the second group was as low as 62.2 +/- 32.20 ng/mmol Cr. The difference was statistically significant at p less than 0.01. Further mathematical analysis revealed a positive correlation of U-LTB4 to the peripheral neutrophils counts at r = 0.71. Thus, it was concluded that the elevation of U-LTB4 levels in the first group was strongly related to infections, and their asthmatic spells were thought to represent an infection-induced type. On the contrary, U-LTC4 levels in the samples during the asthmatic attacks were increased in 2 of the 6 of the first group. They both represented grave asthmatic spells. In the remainder, U-LTC4 levels did not rise enough to induce spasmodic contractions of the bronchial smooth muscles. Thus, it was also discussed that the most appropriate timing for urine collection for the study of U-LTs is some time following an asthmatic attack.