Urinary Leukotriene E4 Levels Research Articles

Clinical studies of asthma phenotypes focusing on the role of leukotrienes

AbstractIntroduction: Inflammation in the airways in connection to asthma is complex and the mechanisms underlying the associated clinical symptoms involve the interaction of many different kinds of cells and mediators, giving rise to different phenotypes.Objective: The objective of the present thesis was to investigate the molecular and cellular mechanisms that result in two of these phenotypes, i.e. aspirin‐intolerant asthma (AIA) and allergic asthma. The main focus was on leukotrienes.Materials and Methods: (i) Thirty‐three subjects with diagnosed AIA were challenged with celecoxib, a selective inhibitor of cyclooxygenase (COX)‐2. (ii) With the ultimate objective of finding a marker that could be used to identify patients with leukotriene‐associated asthma, the capacity to produce leukotrienes and the responsiveness to inhaled leukotrienes were determined in 20 subjects with mild asthma and in 10 healthy control individuals. (iii) Eight individuals with mild allergic asthma were challenged repeatedly with low doses of allergen in an experimental model aimed at mimicking the natural exposure to allergen. Exhaled nitric oxide was measured throughout the study. (iv) Thirteen patients with allergic asthma were subjected to bronchial challenges with methacholine and leukotriene D4 (LTD4) prior to and after administration of 500‐µg fluticasone twice daily for 2 weeks, and their levels of exhaled nitric oxide and urinary leukotriene E4 (LTE4) were determined.Results: (i) Both escalating doses from 5–100 mg (administered in a blinded, placebo‐controlled study) and an open‐label challenge with 200 + 200 mg celecoxib were tolerated well by AIA individuals. (ii) Neither group exhibited a correlation between the formation of leukotriene B4 by their whole blood in response to ex vivo stimulation or urinary levels of LTE4 and airway responsiveness to LTD4. (iii) The level of nitric oxide in the air that they exhaled rose significantly. At the same time, these subjects did not report any symptoms of asthma, did not require rescue by bronchodilator medication, and did not display any change in the calibre of their airways. (iv) Inhalation of glucocorticoid attenuated the responsiveness to methacholine and reduced the level of exhaled nitric oxide, but neither the responsiveness to LTD4 nor urinary excretion of LTE4 was affected.Conclusions: (i) This finding indicates that the intolerance reaction leading to broncho‐constriction in patients with AIA is caused by inhibition of COX‐1 and, furthermore, provides a scientific basis for administration of selective inhibitors of COX‐2 to alleviate prostaglandin‐mediated pain and inflammation in these patients. (ii) In further attempts to predict which asthmatic patients will respond well to anti‐leukotriene treatment, investigations on the capacity for leukotriene synthesis, responsiveness to these agents and expression of their specific receptors in the lungs are being performed. (iii) Monitoring of exhaled nitric oxide on a daily basis may allow for early detection of exacerbation in subjects with allergic asthma. (iv) Neither the release nor the actions of leukotrienes appear to be sensitive to inhaled glucocorticoids, strengthening the rationale for using a combination of glucocorticosteroids and anti‐leukotrienes to treat allergic asthma.

Relationship Between Urinary Cysteinyl Leukotriene E4 Levels and Clinical Response to Antileukotriene Treatment in Patients with Asthma

The aim of this study was to investigate and identify the relationship between urinary cysteinyl leukotriene E(4) levels and clinical response to antileukotriene treatment in patients with asthma. Forty-eight patients with stable mild to moderate asthma were treated with montelukast in a four-week trail. Asthmatic symptom score, beta(2)-agonist usage, percentage of eosinophil, total serum IgE concentration, forced expiratory volume in the first second (FEV(1)), peak expiratory flow rate (PEFR), and urinary leukotriene E(4) (uLTE(4)) were measured before and after treatment. Clinical response was assessed by the improvement of asthma symptom scores, beta(2)-agonist usage, and FEV(1). Responders were defined as patients who had to fit the following three criteria: a reduction of more than 20% in mean symptom score; a reduction of more than 20% in beta(2)-agonist usage, and a mean improvement of FEV(1) of more than 10% from baseline value. Others were classified as nonresponders. Logistic analysis was used to access the various clinical factors correlated with the clinical response. There were 25 responders and 23 nonresponders. The mean uLTE(4) level from the responders was higher than that from the nonresponders (224.5 +/- 34.4 vs. 175.3 +/- 37.1 pg/mg creatinine, p < 0.05). There was a significant correlation between the clinical response and the uLTE(4) level but not demographic features, percentage of eosinophils, serum IgE concentration, or spirometry (p > 0.05). Subjects with a uLTE(4) level of >/= 200 pg/mg creatinine were 3.5 times more likely to respond to montelukast than those with less than 200 pg/mg creatinine (95% confidence interval [CI] = 1.7-15.8). The uLTE(4) level is closely correlated with antileukotriene treatment. uLTE(4) is a good biomarker for selecting this drug to treat asthma.

Particulate Levels Are Associated with Early Asthma Worsening in Children with Persistent Disease

Ambient particulate concentrations have been associated with variable physiologic effects in children with persistent asthma taking controller medications. To determine whether exposure to particulate matter has immediate effects on asthma control in children with persistent disease. In a school-based cohort, 73 children, primarily with moderate and severe asthma, were followed daily over one or two winters (2001-2002, 2002-2003) in Denver, Colorado. The association among ambient fine particulate, bronchodilator use, and urinary leukotriene E4 levels was assessed. Daily concentrations of fine particulate peaked in the morning hours when children were commuting to school. In a multivariable analysis that controlled for meteorology, time trends, and upper respiratory infections, an increase of one interquartile range in morning maximum fine particulate levels was related to an average increase of 3.8% in bronchodilator usage at school (95% confidence interval [CI], 0.2-7.4; p = 0.04). Children with severe asthma demonstrated significantly stronger associations (8.1% increase; 95% CI, 2.9-13.4; p = 0.003) than those with mild/moderate disease (1.6% increase; 95% CI, -2.2-5.4; p = 0.41; p = 0.03 for difference between groups). Morning maximum fine particulate levels were also associated with urinary leukotriene E4 measured during school hours (average increase of 6.2% per interquartile range increase; 95% CI, 1.9-10.5; p = 0.006). These associations were not discernable when 24-h averaged concentrations were used. Peak concentrations of ambient fine particulate are associated with early increases in bronchodilator use and urinary leukotriene E4 levels among children with persistent asthma, despite the use of controller medications.

Interferon-γ Up-regulates Expression of Cysteinyl Leukotriene Type 2 Receptors on Eosinophils in Asthmatic Patients

Cysteinyl leukotrienes (cysLTs) are strong bronchoconstrictive mediators that play a key role in asthma inflammation. They act through specific receptors including cysLT type 1 receptor (CysLT1R) and cysLT type 2 receptor (CysLT2R). Although these two receptors are co-expressed on inflammatory cells, little is known about CysLT2R in patients with asthma. The aims of this study were to investigate the changes in cysLT receptors (CysLTRs) during asthma exacerbations and to determine which cytokine modulates CysLTR expression on eosinophils. We assessed protein expression and messenger RNA of CysLT1R and CysLT2R in peripheral blood eosinophils and measured urinary leukotriene E(4) levels in 36 patients with stable asthma, 23 subjects with asthma exacerbation, and 15 healthy subjects. We also evaluated the modulation of these receptors by interleukin (IL)-1beta, IL-4, IL-5, IL-13, interferon (IFN)-gamma and tumor necrosis factor-alpha in cultured eosinophils. Expression of both CysLT1R and CysLT2R on eosinophils during asthma exacerbations was significantly higher (p < 0.05) than in stable asthma and healthy subjects. A greater expression of CysLT2R in exacerbation was found in nonatopic asthmatics. Only IFN-gamma up-regulated cell-surface expression of CysLT2R in a dose-dependent manner and enhanced messenger RNA levels. No cytokine affected CysLT1R expression or messenger RNA level. CysLT2R expression on eosinophils was increased in patients, especially in nonatopic subjects, during asthma exacerbation, and was up-regulated by IFN-gamma; therefore we speculate that a pathway through CysLT2R might modulate exacerbations of asthma.

Brief case series: Montelukast, at doses recommended for asthma treatment, reduces disease severity and increases soluble CD14 in children with atopic dermatitis

Background: The choice of oral therapeutic agents for the treatment of atopic dermatitis (AD) in children is limited. Montelukast, a specific cysteinyl leukotriene (LT) receptor antagonist, may be useful in alleviating AD symptoms. Objective: To evaluate the clinical and immunological effects of montelukast in children with AD. Methods: After a 2‐week run‐in, children with AD were started on oral montelukast 5 mg once‐daily for children <12 years of age and 10 mg for older children. The clinical severity of AD as indicated by the SCORing Atopic Dermatitis (SCORAD) score, and serum soluble CD14 and urinary leukotriene E4 (LTE4) concentrations were evaluated at baseline and the end of a 3‐month treatment period. Results: Four boys and three girls, with a median (range) age of 12 (3–16) years, participated in the study. The total SCORAD was reduced in five patients (by 30–84%) and remained similar in two patients. Their median (range) SCORAD scores before and after treatment were 34.7 (16.5–54.8) and 17.0 (6.9–36.9) (p = 0.046). The intensity component of SCORAD also decreased from 5 (2–10) to 3 (1–7) (p = 0.042). Serum sCD14 levels increased significantly from 5533 (4575–6452) ng/ml to 6259 (5617–8988) ng/ml (p = 0.028), whereas urinary LTE4 levels remained the same (p = 0.735). Conclusions: Montelukast, at doses recommended for asthma treatment, resulted in over 30% reduction in the total SCORAD in some children. Treatment with montelukast may also be associated with deviation of the immune system towards the Th1‐specific pathway.

Abstracts

Abstracts

Increased levels of urinary leukotriene E4 in children with severe atopic eczema/dermatitis syndrome

Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U-LTE4) is a marker of whole-body cysteinyl-leukotriene production. To evaluate the role of leukotrienes in children with AEDS by measuring levels of U-LTE4, and to evaluate whether levels of U-LTE4 may reflect disease activity and allergic sensitization in AEDS. U-LTE4 was measured by enzyme-linked immunosorbent assay in 87 children with mild (n=32), moderate (n=34) and severe (n=21) AEDS, as well as in 72 nonatopic healthy controls. Fifty-eight of the children with AEDS were sensitized to common allergens, and 29 were not. Levels of U-LTE4 were higher in children with severe AEDS (140; 66-166 microg/mmol creatinine, median; quartiles) than in controls (52; 30-90, P <0.05), whereas levels of U-LTE4 in moderate and mild disease were similar to controls. U-LTE4 levels were similar in children with or without sensitization to common allergens, but severe AEDS children with sensitization had higher levels of U-LTE4 than those without sensitization. The results suggest a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene-antagonists in the treatment of this disorder. Levels of U-LTE4 may reflect the disease severity and sensitization to allergens in AEDS.

Macrolides in the treatment of asthma and cystic fibrosis

Asthma and cystic fibrosis are two respiratory diseases characterized by chronic inflammation, leading to remodelling of the airways. Macrolides are widely used antibiotics, with a peculiar anti-inflammatory effect. On the basis of the methodologies used by the Cochrane collaboration, this review discusses the evidence for their long-term use as anti-inflammatory agents in these two diseases. Three randomized-controlled trials (RCTs) were identified for both asthma and cystic fibrosis. A positive effect of macrolides on reducing eosinophil numbers and markers of eosinophilic inflammation was demonstrated in patients with asthma. Data on cystic fibrosis demonstrated an effect on lung function with an increase of 5.4% in forced vital capacity (FVC) in patients treated with macrolide vs. placebo, but without a significant effect on FEV1. Side-effects were rare, mild and reversible on withdrawal of treatment. Although preliminary data from small studies are promising, the role of macrolides in the treatment of these chronic disorders needs to be more firmly established with larger, well-designed trials, targeted to investigate major clinical outcomes.

Urinary leukotriene E4 in Henoch-Schonlein purpura.

Children with Henoch-Schonlein purpura (HSP) occasionally have allergic disease. We have previously shown that pranlukast hydrate was effective for purpura in HSP. Pranlukast hydrate is a leukotriene (LT) receptor antagonist; therefore, it is likely that LTs take part in the cause of HSP. Urinary leukotriene E4 (LTE4u) levels are a useful index of whole-body cysteinyl LT production in vivo. In this study, LTE4u was examined in children with HSP. The purpose of this study was to examine the relation between the level of LTE4u and the cause of HSP. Eighteen HSP children (six boys and 12 girls) and six healthy children were enrolled. LTE4u levels in patients with HSP were significantly higher (P< 0.05) at the onset than those in healthy children. Four weeks therapy with pranlukast hydrate lowers LTE4u levels in patients with HSP (P< 0.05). There were no differences in LTE4u between the group of HSP patients with purpura nephritis and the group of HSP patients without purpura nephritis. These results indicate that csyteinyl LTs may play a role in the pathophysiology of purpura in HSP.

Airway eicosanoids in acute severe respiratory syncytial virus bronchiolitis

We prospectively studied the levels of eicosanoids in intubated patients with severe bronchiolitis and compared them to electively intubated non-infected infants. LeukotrieneE4 (LTE4), leukotrieneB4 (LTB4), and prostaglandinE2 (PGE2) levels were significantly increased (P <.01) from endotracheal (ET) aspirates of infants with bronchiolitis compared with controls, as were urinary LTE4 levels (P <.001). We conclude that eicosanoids are increased in the tracheal aspirates and urine of children with bronchiolitis.

Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis

Background The urinary leukotriene E4 (U-LTE4) concentration is significantly increased in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic factors of asthma and the U-LTE4 concentration remains undetermined. Objective We sought to examine the clinical features of asthmatic patients with increased excretion levels of U-LTE4 (hyperleukotrienuria). Methods We measured the U-LTE4 concentrations in 137 asthmatic patients (including 64 patients with AIA) who were in clinically stable condition. A U-LTE4 concentration of 150 pg/mg creatinine or greater (mean U-LTE4 + 3 SDs of normal healthy control subjects) was indicative of hyperleukotrienuria. Results The basal concentration of U-LTE4 was significantly higher in the patients with AIA than in those with aspirin-tolerant asthma (ATA; median, 227.2 vs 90.3 pg/mg creatinine; P < .01). Compared with normal leukotrienuria in the patients with AIA, hyperleukotrienuria in the patients with AIA was associated with older age and decrease in pulmonary function. On the other hand, compared with normal leukotrienuria in the patients with ATA, hyperleukotrienuria in the patients with ATA was associated with severe asthma and chronic hyperplastic rhinosinusitis with nasal polyposis (CHRS/NP), which are well-known symptoms of the aspirin triad, as well as hypereosinophilia and anosmia. The patients with ATA with CHRS/NP excreted U-LTE4 at significantly high concentrations. There were significant decreases in the U-LTE4 concentrations before and after the sinus surgery in both the AIA and ATA groups ( P < .05). Conclusion Cysteinyl leukotrienes are not strictly associated with aspirin intolerance itself but rather with clinical features, such as CHRS/NP, that are similar to those seen in AIA. CHRS/NP might be involved in cysteinyl leukotriene overproduction in asthmatic patients.

Evaluation of montelukast in 8 to 14 year old children with mild persistent asthma and compared with inhaled corticosteroids

ObjectivesTo determine the clinical effectiveness, tolerability and reliability of montelukast and to compare this drug with inhaled corticosteroids MethodsWe performed a randomized, 14-week, 2-period, prospective parallel group study. After a 2-week run-in period, patients received treatment for 12 weeks. Sixty-three clinically stable outpatients aged 8 to 14 years with a history of mild persistent asthma for at least 1 year and a forced expiratory volume in one second (FEV1) greater than 80 % of the predicted value were evaluated ResultsMontelukast produced improvement in airway obstruction, daily symptom scores, total daily as-needed β-agonist use, nocturnal awakenings, percentage of days and percentage of patients with asthma exacerbations, and urinary leukotriene E4 levels. These beneficial effects were similar to those produced by inhaled corticosteroids. There were no significant adverse effects requiring treatment discontinuation ConclusionsMontelukast may be a well-tolerated and effective therapeutic option in 8 to 14-year-old patients with mild persistent asthma

Strenuous exercise increases plasmatic and urinary leukotriene E4 in cyclists.

The purpose of this study was to investigate plasma and urinary levels of leukotriene (LT) and the changes in pulmonary function induced by strenuous exercise in highly trained cyclists (HT) with mild exercised-induced hypoxemia (EIH). Nine HT and five untrained subjects (UT) performed a 30-min exercise at 78% of their VO2peak. Leukotriene E4 (LTE4) was assayed in plasma and urine. Pulmonary function tests and pulmonary diffusion capacity (DLCO) were examined before and after exercising. Ear arterialized blood gases were assessed at rest and during exercise. The mean drop in partial oxygen pressure was 15 mmHg in HT during exercise; and the DLCO decreased by 7.5% following exercise. No significant changes were found in forced vital capacity or forced expiratory flows. LTE4 levels increased significantly in HT following exercise: urinary LTE4 was 42.9 +/- 6.3 ng.mmol-1 creatinine at rest and 66.3 +/- 11.9 ng.mmol-1 creatinine 2 hrs after exercise, and plasma LTE4 rose from 528 +/- 91 pg.mL-1 at rest to 897 +/- 123 pg.mL-1 after exercise. By contrast, urinary LTE4 level was unchanged in the UT group. Among the HT group, there was no significant correlation between urinary LTE4 changes and PO2, air flow rates, or DLCO changes. These results suggest that strenuous exercise induces an increase of LTE4 release in highly trained cyclists with mild EIH. These changes in LTE4 levels were not related to significant impairment of lung function.

High Dose of Inhaled Fluticasone Reduces High Levels of Urinary Leukotriene E4 in the Early Morning in Mild and Moderate Nocturnal Asthma

The circadian variation in urinary leukotriene E(4) (LTE(4)) excretion with a morning acrophase has recently been reported in nocturnal asthma (NA); however, the effects of inhaled corticosteroids (ICS) on this circadian rhythmicity of leukotriene (LT) in patients with NA are controversial. We first measured peak expiratory flow (PEF), urinary LTE(4), 11-dehydro-thromboxane B(2) (TXB(2)), and creatinine levels six times every 4 h for 24 h in two groups: patients with mild-to-moderate, steroid-naive NA (n = 10, group A), and patients with severe NA treated with high-dose ICS (n = 10, group B). Next, group A patients received 2 weeks of treatment with 800 microg/d of inhaled fluticasone propionate (FP), and we compared the measured parameters before and after treatment. In group A, a circadian rhythm in urinary LTE(4) with peak levels at approximately 4 AM associated with reduced PEF was observed. Group B had suppression of urinary LTE(4) excretion and had no circadian rhythmicity, as seen in group A, despite a dip in PEF at 4 AM. A high dose of FP in group A significantly (p < 0.05) reduced LTE(4) levels and abolished the circadian rhythm, as well as improving PEF. We found no significant difference in the circadian rhythm of urinary 11-dehydro-TXB(2) between groups A and B, and high-dose FP partially decreased urinary 11-dehydro-TXB(2) levels but not significantly. A high-dose of ICS reduced urinary LTE(4) levels and abolished their circadian variation in patients with asthma, suggesting that LT might contribute to the mechanism of NA.

Urinary leukotriene E4 levels in children with allergic rhinitis treated with specific immunotherapy and anti‐IgE (Omalizumab)

Recently, we were able to demonstrate that Omalizumab, a humanized monoclonal anti-IgE antibody, reduces in vitro leukotriene (LT) release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy. The aim of this study was to investigate the effect of anti-IgE in combination with specific immunotherapy (SIT) on urinary leukotriene E4 (LTE4) levels. Children and adolescents with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomized to receive SIT for either birch or grass pollen and to receive either subcutaneous anti-IgE or placebo for 24 weeks during the pollen season. From a total population of 225 children, we collected three urine samples in a subgroup of 19 children [n = 12 boys (63%); mean age 11.8 years; range 7.2-17.5 years; Group A (n = 10): SIT (grass or birch) + anti-IgE; Group B (n = 9): SIT (grass or birch) + placebo]. Urine samples were collected before, during and at the end of treatment. Endogenous urinary LTE4 was separated by high-performance liquid chromatography (HPLC) and determined by enzyme immunoassay with a specific antibody. No differences in urinary LTE4 concentrations were observed between the anti-IgE and the placebo groups before (A: 35.2; B: 36.5 nmol/mol creatinine), during (A: 27.0; B: 29.3) and after treatment (A: 28.9; B: 26.5 nmol/mol creatinine). We conclude that urinary LTE4 levels are not helpful in monitoring patients treated with anti-IgE and SIT.

Biochemical and clinical evidence that aspirin-intolerant asthmatic subjects tolerate the cyclooxygenase 2-selective analgetic drug celecoxib

Background: Subjects with aspirin-intolerant asthma (AIA) respond with bronchoconstriction and extrapulmonary adverse reactions to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit the cyclooxygenase (COX) step in the biosynthesis of prostaglandins. Recently, 2 isotypes of COX have been identified, and COX-2-selective NSAIDs have been developed for treatment of inflammatory disorders. Objective: We investigated whether 33 subjects with a typical history of AIA tolerated the new COX-2-selective NSAID celecoxib. Methods: All subjects displayed current aspirin sensitivity in oral or inhalation challenge tests. The subjects first underwent a double-blind, randomized, cross-over, increasing-dose challenge with placebo or celecoxib (10, 30, or 100 mg in suspension) on 2 occasions 7 days apart. Thereafter, all subjects were exposed to 400 mg of celecoxib administered during an open challenge session as two 200-mg doses 2 hours apart. Lung function, clinical symptoms, and urinary excretion of leukotriene E4 (LTE4) were monitored, with the latter being a sensitive biochemical marker of aspirin intolerance. Results: There were no changes in lung function or extrapulmonary symptoms during the double-blind sessions or in urinary excretion of LTE4. Also, the highest recommended daily dose of celecoxib was well tolerated, with no symptoms, lung function changes, or alterations in urinary LTE4 levels. Conclusions: A group of subjects with clinically well-documented AIA tolerated acute challenge with the selective COX-2 inhibitor celecoxib. The findings indicate that the intolerance reaction in AIA is due to inhibition of COX-1. Large long-term studies of COX-2 inhibitors in AIA should be undertaken. (J Allergy Clin Immunol 2003;111:1116-21.)

The role of L-carnitine in treatment of a murine model of asthma.

Leukotrienes, one of the mediators of inflammation in asthma, have a strong bronchoconstrictive effect. L-carnitine has been reported to influence respiratory functions. It has also been reported that L-carnitine inhibits leukotriene synthesis. To evaluate the effects of L-carnitine on oxygen saturation, urine leukotriene E4 levels and lung histopathology in a murine model of asthma, high IgE responder BALB/c mice (n = 24) were systemically sensitized to ovalbumin and chronically challenged with low particle mass concentrations of aerosolized ovalbumin, and then they were divided into 3 groups (study groups A, B, and C) each including eight mice. After methacholine-induced bronchoconstriction, the mice in groups A and B were given intraperitoneal L-carnitine (250 and 125 mg/kg, respectively), while the mice in group C were given placebo. Oxygen saturation of the mice was measured by pulse oxymeter before and after methacholine and after L-carnitine/ placebo application. In addition, urine leukotriene E4 levels were measured before asthma development, and 24-h after L-carnitine injection in asthmatic mice. Inflammation in the lung tissues of the sacrificed animals was scored histopathologically to determine the effect of L-carnitine on tissue level. A control group of non-sensitized mice (n = 8) treated with placebo only was used for comparison of urine leukotriene E4 levels and of histopathological parameters. Oxygen saturation of the mice in the study groups tended to decrease after methacholine and to improve after L-carnitine injection, although these changes were not significant at all time points. Urine leukotriene E4 levels of all 3 study groups increased significantly after asthma development. The rate of increment was smallest in the group given the highest L-carnitine dose (group A). Inflammation at the tissue level was also mildest in group A, and severest in the group that was not given carnitine (group C). All of the study groups and the control group differed significantly with respect to inflammation scores. In conclusion, L-carnitine improved oxygen saturation, and decreased urine leukotriene E4 levels and inflammation in lung tissues in the present murine model of asthma.

Beyond our pages

Beyond our pages

Safety of a specific COX‐2 inhibitor in aspirin‐induced asthma

In a subset of patients with asthma, aspirin and several other non-steroidal anti-inflammatory drugs (NSAID) that inhibit simultaneously cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) precipitate dangerous asthmatic attacks. We tested the hypothesis that in patients with aspirin-induced asthma the attacks are triggered by inhibition of COX-1 and not COX-2. In twelve asthmatic patients (seven men, five women, average age 39 years) oral aspirin challenge precipitated symptoms of bronchial obstruction with fall in FEV1 > 20%, and a rise in urinary leukotriene E4 (LTE4) excretion; also in five patients the stable metabolite of PGD2, 9alpha11betaPGF2, increased in urine. The patients then entered a double-blind, placebo-controlled, cross-over study in which they received either placebo or rofecoxib in increasing doses 1.5-25.0 mg for 5 consecutive days, separated by a 1-week wash-out period. No patient on rofecoxib developed dyspnoea or fall in FEV1 > 20%; mean urinary LTE4 and 9alpha11betaPGF2 urinary levels, measured on each study day for 6 h post-dosing, remained unchanged. Two patients on placebo experienced moderate dyspnoea without alterations in urinary metabolites excretion. At least 2 weeks after completion of the study, all patients received on an open basis 25 mg rofecoxib without any adverse effects. NSAID that inhibit COX-1, but not COX-2, trigger asthmatic attacks in patients with asthma and aspirin intolerance. Rofecoxib can be administered to patients with aspirin-induced asthma.

Difference in urinary LTE4 and 11-dehydro-TXB2 excretion in asthmatic patients

Bronchoconstrictor cysteinyl leukotrienes (LT) and thromboxane (TX) A2 have been implicated in the pathogenesis of asthma. Determination of urinary leukotriene E4 (LTE4) and 11-dehydro-TXB2 levels are often used to assess cysteinyl LT and TXA2 production in humans. To define the potential role in the pathogenesis of asthma, we investigated the urinary LTE4 and 11-dehydro-TXB2 levels. LTE4 and 11-dehydro-TXB2 levels were determined using liquid chromatography/tandem mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS), respectively. Urinary LTE4 levels in asthmatic patients (192 ± 122 pg/mg creatinine, n = 14) were significantly higher ( P < 0.005) than those in healthy volunteers (55 ± 16 pg/mg creatinine, n = 13), but no significant difference in 11-dehydro-TXB2 levels was observed. A significant inverse correlation (r = −0.821, P < 0.005) was found between urinary LTE4 levels and the forced expiratory volume in 1 s (FEV1) but no significant correlation was observed between urinary 11-dehydro-TXB2 levels and FEV1. The present findings suggest that cysteinyl LTs play a more important role in the pathogenesis of asthma than TXA2.