leukotriene-e4 and montelukast

Twenty five years after the structure elucidation of slow reacting substance of anaphylaxis, antileukotrienes are established as a new therapeutic modality in asthma. The chapter reviews the biochemistry and pharmacology of leukotrienes and antileukotrienes with particular focus on the different usage of antileukotrienes for treatment of asthma and rhinitis in Europe and the US. Further research needs and new areas for leukotriene involvement in respiratory diseases are also discussed.

Topics: Acetates; Animals; Asthma; Clinical Trials as Topic; Cyclopropanes; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipoxygenase Inhibitors; Membrane Proteins; Quinolines; Receptors, Leukotriene; Respiratory System; Rhinitis; Sulfides

To observe the effect of montelukast treatment on levels of serum leukotriene B4 and urinary leukotriene E4 in infants with bronchiolitis.. Seventy-five children who were diagnosed with bronchiolitis between June 2014 and December 2014 were randomly assigned into two groups, one with thirty-eight cases as the montelukast treatment group and another thirty-seven cases as the control group. All of the children were given routine medical treatment. The children in the montelukast treatment group were additionally given montelukast daily (4 mg once a day, for 7 days). The serum leukotriene B4 and urinary leukotriene E4 levels were measured using ELISA before and after treatment. The relationship between serum leukotriene B4 and urinary leukotriene E4 levels was analyzed by Peason correlation analysis.. After 7 days of treatment, the serum leukotriene B4 and urinary leukotriene E4 levels in the montelukast treatment and control groups were significantly reduced compared with before treatment (P<0.05). The montelukast treatment group showed significantly lower serum leukotriene B4 and urinary leukotriene E4 levels than the control group (P<0.05). The remission time of cough, wheezing and lung wheezes and the length of hospital stay in the montelukast treatment group were significantly shortened compared with the control group (P<0.05). There was a positive correlation between serum leukotriene B4 and urinary leukotriene E4 levels (r=0.723, P<0.05).. Montelukast has a reliable clinical curative efficacy for bronchiolitis in infants, possibly by decreasing serum leukotriene D4 and urinary leukotriene E4 levels.

Topics: Acetates; Bronchiolitis; Cyclopropanes; Humans; Infant; Leukotriene B4; Leukotriene E4; Quinolines; Sulfides

Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness.. We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy.. A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting β₂-agonist (LABA step-up therapy).. In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV₁ response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E₄ levels were marginally (P = .053) related to a differential FEV₁ response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV₁ and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses.. Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E₄ levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.

Topics: Acetates; Adolescent; Adrenergic beta-Agonists; Albuterol; Androstadienes; Anti-Asthmatic Agents; Asthma; Biomarkers; Bronchodilator Agents; Child; Cross-Over Studies; Cyclopropanes; Eosinophils; Female; Fluticasone; Forced Expiratory Volume; Humans; Leukocyte Count; Leukotriene Antagonists; Leukotriene E4; Male; Quinolines; Salmeterol Xinafoate; Sulfides; Vital Capacity

A subset of children with asthma respond better to leukotriene receptor antagonists than to inhaled corticosteroids. Information is needed to identify children with these preferential responses.. We sought to determine whether the ratio of urinary leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) delineates children with preferential responsiveness to montelukast compared with fluticasone propionate (FP) therapy.. Data from 318 children with mild-to-moderate asthma enrolled in 2 National Heart, Lung, and Blood Institute Childhood Asthma Research and Education Network studies (Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid [CLIC] and the Pediatric Asthma Controller Trial [PACT]) were analyzed. The association between LTE(4)/FE(NO) ratios at baseline and improved lung function or asthma control days (ACDs) with montelukast and FP therapy was determined, and phenotypic characteristics related to high ratios were assessed.. LTE(4)/FE(NO) ratios were associated with a greater response to montelukast than FP therapy for FEV(1) measurements (2.1% increase per doubling of ratio, P = .001) and for ACDs per week (0.3-ACD increase, P = .009) in the CLIC study. In PACT the ratio was associated with greater ACD responsiveness to MT than FP therapy (0.6 ACD increase, P=.03) [corrected]. In a combined study analysis, LTE(4): FE(NO) ratios were associated with greater response to MT than FP therapy for FEV(1) (1.8% increase, P =.0005) and ACDs (0.4 increase, P =.001)[corrected].Children with LTE(4)/FE(NO) ratios at or above the 75th percentile were likely (P < .05) to be younger and female and exhibit lower levels of atopic markers and methacholine reactivity.. LTE(4)/FE(NO) ratios predict a better response to montelukast than FP therapy in children with mild-to-moderate asthma.

Topics: Acetates; Adolescent; Age of Onset; Asthma; Biomarkers; Child; Cyclopropanes; Female; Humans; Immunoglobulin E; Leukotriene Antagonists; Leukotriene E4; Male; Nitric Oxide; Predictive Value of Tests; Quinolines; Sulfides; Treatment Outcome

Cysteinyl leukotrienes (CysLTs) are important mediators of asthma in children. Predictors of susceptibility to CysLT effects have not been developed.. To identify susceptibility markers to CysLT effects and montelukast response.. Twenty-seven schoolchildren were followed for 5 months with measurements of urinary leukotriene E4 (LTE(4)), cotinine, fractional exhaled nitric oxide (FENO), and monitoring of albuterol use. After a baseline run-in, children were randomized to receive daily montelukast or placebo without change in their current controller medications.. At baseline, a significant (P = .003) positive association was observed between LTE(4) levels and albuterol use 2 days later. LTE(4)-related albuterol usage (ie, change per interquartile increase in LTE(4)) declined significantly after montelukast treatment (12% decline; P = .0005 for relative difference between intervals) but not placebo (2% increase; P = .80). Declines in LTE(4)-related albuterol usage between intervals tended to be greater in girls (P = .01 for girls; P = .21 for boys; P = .07 for interaction) and were greater among children with higher cotinine levels (P = .01 for high cotinine group; P = .17 for low cotinine group; P = .04 for interaction). Children with high LTE(4) levels relative to FENO demonstrated significant (P = .05) declines in LTE(4)-related albuterol usage between intervals (P = .89 for low ratio group; P = .25 for interaction).. Increased individual CysLT levels are associated with subsequent albuterol usage. CysLT-related albuterol usage and montelukast responsiveness are increased in children exposed to tobacco smoke and tend to be greater in girls than boys. Measurement of LTE(4) to FENO ratios may help predict susceptibility to montelukast.

Topics: Acetates; Adolescent; Albuterol; Anti-Asthmatic Agents; Asthma; Biomarkers; Breath Tests; Bronchodilator Agents; Child; Cotinine; Cyclopropanes; Female; Humans; Leukotriene Antagonists; Leukotriene E4; Male; Nitric Oxide; Quinolines; Sex Factors; Sulfides; Tobacco Smoke Pollution

Previous research has demonstrated that blood and urine concentrations of various leukotrienes are elevated with acute hypoxic exposure. Some of these studies have suggested that leukotrienes may be mediators in the pathogenesis of acute mountain sickness (AMS). We conducted a randomized, double-blind study to determine if AMS symptoms correlated with the increase in leukotriene synthesis and if prophylactic leukotriene receptor blockade would prevent the development of AMS in a simulated high altitude exposure. Three male and five female subjects completed two normobaric hypoxia chamber exposures (average F(IO2) 12.4 +/- 0.09%), receiving montelukast 10 mg daily for 4 days prior to one session and placebo for 4 days prior to the other session. There were no differences in Lake Louise AMS scores, time spent in the chamber, average oxygen saturation, and average heart rate during the montelukast and placebo sessions. Headache scores were higher during treatment with montelukast than during treatment with placebo. Compared to preexposure values, urinary leukotriene E4 concentrations were unchanged during the hypoxic chamber exposure following treatment with placebo or montelukast. Urinary leukotriene E4 excretion during the hypoxic exposure did not differ between the two sessions. A 4-day course of leukotriene receptor blockade does not prevent symptoms of AMS. These results suggest that leukotrienes do not play a causal role in the pathophysiology of AMS.

Topics: Acclimatization; Acetates; Administration, Oral; Adult; Altitude Sickness; Atmosphere Exposure Chambers; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Humans; Hypoxia; Leukotriene Antagonists; Leukotriene E4; Male; Premedication; Quinolines; Severity of Illness Index; Statistics, Nonparametric; Sulfides

Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown.. (1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide.. An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma.. Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast.. Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values.. Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.

Topics: Acetates; Allergens; Anti-Asthmatic Agents; Asthma; Biomarkers; Breath Tests; Child; Cross-Sectional Studies; Cyclopropanes; Dinoprost; Dinoprostone; Humans; Hypersensitivity; Leukotriene Antagonists; Leukotriene E4; Nitric Oxide; Quinolines; Skin Tests; Spirometry; Sulfides

To evaluate the effects on signs and symptoms of a coexisting vernal keratoconjunctivitis in patients treated with oral montelukast sodium for asthma.. Twelve patients with vernal keratoconjunctivitis and asthma were enrolled in this pilot study. Topical eyedrops or any systemic treatment was discontinued for at least 7 days before montelukast treatment. Patients were asked to grade their ocular discomfort daily. The following signs and symptoms were also recorded and graded through medical examination at baseline,after 15 days of treatment, and 15 days after treatment discontinuation: physician-evaluated tarsal and bulbar papillae, hyperemia, secretion, and chemosis; and patient-evaluated itching, burning, tearing, photophobia, foreign body sensation, secretion, and redness. Peak expiratory flow rate at 8 AM was also recorded. Samples were collected at the same time points for enzyme-linked immunosorbent assay measurement of leukotriene B4 in tears and leukotriene E4 in urine.. Eight of the 10 patients evaluated reported a reduction in symptoms at the end of treatment. Montelukast treatment significantly decreased physician-rated hyperemia, secretion, and chemosis as well as patient-rated burning, tearing, photophobia, secretion, and redness. Effects persisted 15 days after discontinuation of treatment. Clinical changes were associated with a significant increase in leukotriene B4 in tears and a significant decrease in leukotriene E4 in urine after 15 days of treatment.. The significant and persistent reduction of ocular signs and symptoms in asthmatic patients with vernal keratoconjunctivitis treated for 15 days with montelukast strongly suggests the need for double-masked placebo-controlled trials to confirm the potential of this new treatment in vernal keratoconjunctivitis.

Topics: Acetates; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Conjunctivitis, Allergic; Cyclopropanes; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leukotriene Antagonists; Leukotriene B4; Leukotriene E4; Male; Ophthalmic Solutions; Peak Expiratory Flow Rate; Pilot Projects; Quinolines; Sulfides; Tears

Montelukast, a cysteinyl-leukotriene receptor antagonist, was reported to have a protective effect against exercise-induced bronchoconstriction (EIB). Aspirin-induced asthma (AIA) is characterized by overproduction of cysteinyl-leukotrienes.. The aim of the study was to compare the response to exercise and the effect of montelukast on EIB in AIA as compared to aspirin-tolerant asthma (ATA).. A placebo-controlled, double blind, cross-over randomized study was performed in 19 AIA and 21 ATA patients with stable asthma. A single dose of montelukast (10 mg) or placebo (PL), was given orally one hour prior to exercise challenge. FEV1 was measured before and 5, 10, 15 min after exercise and then at 15-minute intervals for 4 h. Urinary LTE4 excretion and blood eosinophil count were measured at baseline, 2 h and 4 h following exercise challenge.. Positive bronchial response to exercise was observed in 47.5% of all patients studied. Exercise led to almost identical maximal fall in FEV1 in AIA and ATA patients (23.5% +/- 6.8% vs. 21.8% +/- 12.0%, respectively; P = 0.7). Montelukast, as compared to PL, significantly attenuated EIB in 63.2% of 19 patients with positive exercise test preceded by PL. The mean of maximum fall in FEV1 from the pre-exercise value was 10.2% +/- 13.8 after montelukast as compared to 22.5% +/- 10.2 after placebo (P < 0.001). No significant differences between protective effect of montelukast was observed in AIA as compared to ATA patients (P = 0.63, anova). Urinary LTE4 excretion showed no change following exercise, irrespective of the result of the test in all subjects.. Patients with AIA and ATA react similarly to exercise challenge and obtain similar protection against EIB by montelukast.

Topics: Acetates; Adult; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma, Exercise-Induced; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Drug Hypersensitivity; Exercise Test; Female; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotriene E4; Lung; Male; Middle Aged; Quinolines; Sulfides

Leukotriene antagonists block the proinflammatory actions of leukotrienes (LT) and have been introduced as new treatments for asthma. Conventional therapy with glucocorticosteroids does not inhibit the biosynthesis of leukotrienes. We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90% already were treated with moderate to high doses of glucocorticosteroids. Under double-blind conditions, 80 aspirin-intolerant patients with asthma were randomized to receive 4 wk oral treatment of either 10 mg of montelukast or placebo once daily at bedtime. Pulmonary function was measured as forced expiratory volume in 1 s (FEV(1)) once a week in the clinic and daily as morning and evening peak expiratory flow rate (PEFR). Asthma symptoms and use of rescue bronchodilator were also recorded daily. Asthma specific quality of life (QoL) was assessed before and after the treatments. The group receiving montelukast showed a remarkable improvement of their asthma, whereas the group given placebo showed no change. Thus, from equal baseline values, the mean difference between the groups over the 4-wk treatment period was 10.2% for FEV(1) and 28.0 L for morning PEFR (p for both < 0.001). The improved pulmonary function in the group receiving montelukast occurred at the same time as 27% less bronchodilator was used (p < 0.05), and it was associated with fewer asthma symptoms than in the group given placebo, including 1.3 nights more of sleep per week and 54% fewer asthma exacerbations (p < 0.05). There was also an improvement in asthma-specific QoL (p < 0.05). The therapeutic response to montelukast was consistent across patients with different baseline characteristics and did not correlate with baseline urinary LTE(4). Addition of a leukotriene receptor antagonist such as montelukast improves asthma in aspirin-intolerant patients over and above what can be achieved by glucocorticosteroids.

Topics: Acetates; Administration, Oral; Adult; Aged; Anti-Asthmatic Agents; Aspirin; Asthma; Cyclopropanes; Double-Blind Method; Drug Hypersensitivity; Drug Monitoring; Female; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Quality of Life; Quinolines; Sulfides; Treatment Outcome

Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast.. In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge.. Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo.. Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.

Topics: Acetates; Adenosine Monophosphate; Adult; Anti-Asthmatic Agents; Asthma; Bronchoconstriction; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Quinolines; Receptors, Leukotriene; Sulfides

A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated.. Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis.. The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction.. Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.

Topics: Acetates; Adolescent; Adult; Asthma, Exercise-Induced; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Exercise; Exercise Test; Forced Expiratory Volume; Humans; Leukotriene Antagonists; Leukotriene E4; Male; Middle Aged; Quinolines; Sulfides

The cysteinyl leukotrienes (CysLTs), i.e. LTC

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bile Acids and Salts; Colitis; Cyclopropanes; Disease Models, Animal; Gene Expression; Genes, Reporter; HEK293 Cells; Hep G2 Cells; Humans; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Luciferases; Mice; Mice, Knockout; Molecular Docking Simulation; Quinolines; RAW 264.7 Cells; Receptors, G-Protein-Coupled; Receptors, Leukotriene; Recombinant Fusion Proteins; Sulfides

Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis.. Determinants of the urinary excretion of LTE. IH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE

Topics: 5-Lipoxygenase-Activating Proteins; Acetates; Adult; Animals; Arachidonate 5-Lipoxygenase; Atherosclerosis; Case-Control Studies; Cyclopropanes; Cysteine; Disease Models, Animal; Disease Progression; Female; Humans; Leukotriene Antagonists; Leukotriene E4; Leukotrienes; Male; Mice, Knockout, ApoE; Middle Aged; Plaque, Atherosclerotic; Quinolines; Receptors, Leukotriene; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Sulfides

Antileukotriene has been used for alleviating disease severity in children with adenotonsillar hypertrophy (ATH) and mild obstructive sleep apnea (OSA). Previous study showed the relationship between urinary cysteinyl leukotriene E₄ (uLTE₄) level and therapeutic response to montelukast in asthmatic adults. However, this relationship has never been investigated in pediatric OSA.. To determine the relationship between uLTE₄ level and therapeutic response to montelukast in children with ATH and mild OSA.. Children aged 3-15 yrs who had ATH and mild OSA were enrolled. All had quality of life (assessed by Thai version OSA-18 QoL questionnaire) and uLTE₄ levels measured prior to start a 6-week course of montelukast treatment. Overnight polysomnography (PSG) and QoL reassessment were performed after completing the treatment. Those who demonstrated a large improvement of mean total QoL score or ≥ 50% decrease of obstructive apnea-hypopnea index (OAHI) after the treatment were defined as responders.. Twenty-six children were enrolled (mean age 7.5 ± 2.9 yrs, 38.5% male). After 6-week course of montelukast, nine (34.6%) children showed significant improvement. The mean uLTE₄ level from the responders was higher comparing to the non-responders (2,952.56 ± 966.9 vs. 978.6 ± 460.8 pg/mg creatinine; p < 0.001). uLTE₄ level of ≥ 1,457 pg/mg creatinine had 100% sensitivity and 88.2% specificity in identifying the responders.. We found the association between ULTE4 and therapeutic response to monteleukast. The uLTE₄ level of ≥ 1,457 pg/mg creatinine could predict the therapeutic response to montelukast in children who had ATH and mild OSA.

Topics: Acetates; Adolescent; Anti-Asthmatic Agents; Biomarkers, Pharmacological; Child; Child, Preschool; Creatinine; Cyclopropanes; Disease Progression; Female; Humans; Leukotriene E4; Male; Predictive Value of Tests; Prognosis; Quinolines; Sleep Apnea, Obstructive; Sulfides

The effects of low-level environmental tobacco smoke (ETS) exposure, on asthma control, lung function and inflammatory biomarkers in children with asthma have not been well studied. The objective of the study was to assess ETS exposure in school-age children with asthma whose parents either deny smoking or only smoke outside the home, and to assess the impact of low-level ETS exposure on asthma control, spirometry and inflammatory biomarkers.. Forty patients age 8-18 years with well-controlled, mild-to-moderate persistent asthma treated with either inhaled corticosteroids (ICS) or montelukast were enrolled. Subjects completed an age-appropriate Asthma Control Test and a smoke exposure questionnaire, and exhaled nitric oxide (FeNO), spirometry, urinary cotinine and leukotriene E(4) (LTE(4)) were measured. ETS-exposed and unexposed groups were compared.. Only one parent reported smoking in the home, yet 28 (70%) subjects had urinary cotinine levels ≥1 ng/ml, suggesting ETS exposure. Seven subjects (18%) had FeNO levels >25parts per billion, six of whom were in the ETS-exposed group. In the ICS-treated subjects, but not in the montelukast-treated subjects, ETS exposure was associated with higher urinary LTE(4), p = 0.04, but had no effect on asthma control, forced expiratory volume in 1 s or FeNO.. A majority of school-age children with persistent asthma may be exposed to ETS, as measured by urinary cotinine, even if their parents insist they don't smoke in the home. Urinary LTE(4) was higher in the ETS-exposed children treated with ICS, but not in children treated with montelukast.

Topics: Acetates; Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Anti-Asthmatic Agents; Asthma; Child; Cohort Studies; Cotinine; Cyclopropanes; Environmental Monitoring; Female; Follow-Up Studies; Humans; Inflammation Mediators; Leukotriene E4; Male; Prospective Studies; Quinolines; Risk Assessment; Severity of Illness Index; Spirometry; Sulfides; Tobacco Smoke Pollution; Treatment Outcome

Leukotriene D(4) (LTD(4)) causes contraction of the stomach through unclear receptors. The aim of the present study is to characterize the cysteinyl leukotriene receptor (CysLT) mediating leukotriene-induced muscle contraction in the stomach.. We measured contraction of gastric muscle strips isolated from the guinea pig fundus and antrum caused by cysteinyl leukotrienes, including LTC(4), LTD(4) and LTE(4), as well as the dihydroxy leukotriene LTB(4) in vitro.. In both fundic and antral muscle strips, LTC(4) and LTD(4) caused marked whereas LTE(4) caused moderate, concentration-dependent contractions. In contrast, LTB(4) caused only small contraction. The relative potencies for cysteinyl leukotrienes to cause contraction in both fundus and antrum were LTC(4)=LTD(4)>LTE(4). The LTD(4)-induced contraction was not affected by tetrodotoxin or atropine, suggesting that the action is not neurally mediated. The LTD(4)-induced contraction in the fundus was almost abolished by the CysLT(1) selective antagonist montelukast. In contrast, the LTD(4)-induced contraction in the antrum was only partially inhibited by montelukast or the dual CysLT(1) and CysLT(2) antagonist BAY u9773. This antral contraction was almost abolished by the combination of montelukast and BAY u9773, indicating enhancement of inhibition.. The results of the present study demonstrate that cysteinyl leukotrienes LTC(4), LTD(4) and LTE(4) cause moderate to marked whereas the dihydroxy leukotriene LTB(4) causes small muscle contraction in the stomach in vitro. The leukotriene-induced contraction is mediated by CysLT(1) in fundus but by CysLT(1) and CysLT(2) in antrum.

Topics: Acetates; Animals; Cyclopropanes; Dose-Response Relationship, Drug; Gastric Fundus; Guinea Pigs; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Muscle Contraction; Pyloric Antrum; Quinolines; Receptors, Leukotriene; SRS-A; Sulfides

Baseline level of the cysteinyl leukotriene (CysLT), leukotriene E4 (LTE4), is associated with an increased pain rate in children and adults with sickle cell disease (SCD). To provide additional evidence for a role of CysLTs in the pathogenesis of vaso-occlusion, we tested the hypothesis that LTE4 levels will increase within an individual during painful episodes compared to baseline. In a cohort of 19 children and adults with SCD, median LTE4 levels increased from 82.36 pg/mg creatinine at baseline to 162.81 pg/mg creatinine during a painful episode (P < 0.001). These data further support a contribution of CysLTs to the process of vaso-occlusion.

Topics: Acetates; Adolescent; Adult; Anemia, Sickle Cell; Anti-Asthmatic Agents; Asthma; beta-Thalassemia; Biomarkers; Child; Cohort Studies; Cyclopropanes; Female; Fetal Hemoglobin; Hemoglobin C Disease; Heterozygote; Hospitalization; Humans; Ischemia; Leukotriene Antagonists; Leukotriene E4; Male; Pain; Quinolines; Retrospective Studies; Sickle Cell Trait; Sulfides; Young Adult

Use of leukotriene receptor antagonists improves disease control in children and adults with asthma. However, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly.. We sought to assess the relationship between daily variability in urinary leukotriene E(4) (LTE(4)) levels and daily lung function in children primarily taking inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs).. Fifty children primarily with moderate-to-severe asthma were followed with measurements of urinary LTE(4), monitoring of FEV(1), and albuterol use.. Increasing urinary LTE(4) levels were associated with significant (P = .006) decreases in percent predicted FEV(1) (ppFEV(1)) averaging 4.7% per interquartile range increase in LTE(4) and accompanied by increased albuterol use (P = .03). Children with lower FEV(1)/forced vital capacity ratios demonstrated larger LTE(4)-related FEV(1) decreases (6.4%) compared to those with higher ratios (4.2%, P = .009). This association was blunted in children taking montelukast (1.4% ppFEV(1) decrease) compared with that in children not taking this medication (5.4% ppFEV(1) decrease, P = .05). Children with lower lung function ratios demonstrated greater blunting of the LTE(4) effect with montelukast (0.9% ppFEV(1) decrease) compared to those with higher ratios (3.6% ppFEV(1), P = .0002).. Daily variability in LTE(4) levels is associated with clinically significant decreases in pulmonary function. In children who demonstrate a response associated with an increase in urinary LTE(4) levels, leukotriene receptor antagonists protect against daily FEV(1) decreases. This protection might be greatest in those with persistent airway obstruction despite use of ICS and LABA therapy.. Therapies designed to block cysteinyl leukotriene production or function might benefit children receiving ICS and LABA therapy who continue to experience persistent disease.

Topics: Acetates; Adolescent; Airway Obstruction; Albuterol; Asthma; Child; Chronic Disease; Cyclopropanes; Disease Susceptibility; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Quinolines; Severity of Illness Index; Sulfides

Leukotrienes play a key role in the pathophysiology of chronic asthma. Activation of leukotriene pathways is accompanied by rises in detectable urinary levels of leukotriene E4 (LTE4). The relationship between urinary LTE4 levels and factors associated with acute asthma has not been determined.. Adults aged 15-54 years presenting with moderate to severe acute asthma were evaluated at emergency departments in 16 US sites. Forced expiratory volume in 1 second (FEV1) was measured during the first 60 minutes after arrival and at specified times until discharge or admission. Urine samples for measurement of LTE4 levels were obtained either on arrival at the study site and/or before discharge. Patients were seen 2 weeks later for follow up, at which time repeat FEV1 measurements and urine samples for LTE4 were obtained.. One hundred and eighty four patients were evaluated; LTE4 results from both the acute and follow up periods were available for analysis in 146. Urinary LTE4 levels were increased during asthma exacerbations compared with levels obtained 2 weeks later (geometric means 111.7 and 75.6 pg/mg creatinine, respectively, mean percentage change -32.3; 95% confidence interval (CI) for the mean percentage change -39.6 to -24.3, p<0.001). The correlation between improvement in FEV1 and decline in LTE4 over the 2 week interval was significant (p<0.001, r=0.43).. Activation of leukotriene pathways in acute asthma is correlated with the degree of airflow obstruction, and resolution of the asthma exacerbation is associated with a reduction in leukotriene levels.

Topics: Acetates; Acute Disease; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Cyclopropanes; Forced Expiratory Volume; Humans; Infusions, Intravenous; Leukotriene Antagonists; Leukotriene E4; Middle Aged; Quinolines; Sulfides

Evidence suggests that small airways contribute to clinically significant processes in asthma. Cysteinyl leukotrienes (CysLTs) are considered to be pivotal mediators in the pathogenesis of asthma. Montelukast (MK), a specific CysLT1 receptor antagonist, is metabolized in two main hydroxylated metabolites (termed M5 and M6, respectively).. The aims of this study were to compare the responsiveness of small and large human bronchi to the three CysLTs, to evaluate the antagonist activity of MK, M5 and M6 in these preparations of human bronchi, and to characterize the CysLT receptors involved in the contractile response.. In isolated small bronchus (i.d. 0.5-2 mm), the potencies (-log molar EC50) of LTC4, LTD4 and LTE4 were 9.3 (n=11), 9.1 (n=30) and 8.4 (n=14), respectively. The three CysLTs were about 30-fold more potent in small bronchi than in larger bronchi (i.d. 4-6 mm). In small bronchi, MK significantly shifted to the right the CysLT concentration-effect curves with pA2 values against LTC4, LTD4 and LTE4 of 9.1 (n=3), 9.0 (n=11) and 8.7 (n=5), respectively. The antagonist potencies of M6 and M5 were similar to MK and fivefold lower, respectively. A similar activity of MK against the three CysLTs suggested that CysLT1 receptors are involved in the contraction of human bronchus. Analysis by RT-PCR also indicated that human bronchus mainly expressed CysLT1 receptors.. MK exerts a potent antagonist activity against the particularly potent constricting effects of CysLTs in isolated human small bronchi, which only expressed the CysLT1 receptor subtype. The metabolites of MK are also potent in vitro antagonists, but may not participate in the therapeutic activity of MK due to their low plasma concentrations in patients treated with the recommended dose of MK.

Topics: Acetates; Adult; Aged; Aged, 80 and over; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cyclopropanes; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Male; Middle Aged; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; Sulfides

The accumulation of eosinophils into the peripheral blood and airways of asthmatic subjects is, in part, dependent on cysteinyl leukotrienes (cysLTs). However, the effect of cysLTs on peripheral blood and bone marrow eosinophil pro-genitor cells in allergic subjects is not known.. The purpose of this study was to evaluate the effects of leukotriene (LT) D(4) and LTE(4) and the cysLT(1) receptor antagonist montelukast on peripheral blood and bone marrow eosinophil-basophil progenitor growth and development in atopic subjects.. Semisolid methylcellulose cultures for peripheral blood and bone marrow eosinophil-basophil colonies were counted after incubation with or without addition of LTD(4), LTE(4), and montelukast in the presence of suboptimal concentrations of GM-CSF, IL-3, and IL-5.. Peripheral blood eosinophil-basophil colony-forming unit cultures grown in the presence of GM-CSF and bone marrow eosinophil-basophil colony-forming units grown in the presence of IL-5 were significantly increased by the addition of LTD(4) (0.1 micromol/L). This increase was suppressed by montelukast (1 micromol/L).. This study has demonstrated that the cysLT LTD(4) can stimulate proliferation of eosinophil hematopoietic progenitor cells in the presence of eosinophilopoietic cytokines. The suppressive effect by montelukast demonstrates that this is a cysLT(1) receptor-mediated effect.

Topics: Acetates; Adult; Cell Differentiation; Cells, Cultured; Cyclopropanes; Dose-Response Relationship, Drug; Eosinophils; Hematopoietic Stem Cells; Humans; Hypersensitivity, Immediate; Leukotriene Antagonists; Leukotriene D4; Leukotriene E4; Quinolines; Sulfides

Topics: Acetates; Anti-Asthmatic Agents; Aspirin; Asthma; Cyclopropanes; Humans; Leukotriene E4; Prednisone; Quinolines; Sulfides