leukotriene-e4 and Drug-Hypersensitivity

Leukotriene (LT) E(4) mediates many of the principal features of bronchial asthma, such as bronchial constriction, hyperresponsiveness, eosinophilia, and increased vascular permeability. Furthermore, it is the most stable of the cysteinyl leukotrienes (CysLTs) and can be active at the site of release for a prolonged time after its synthesis. There might be several reasons why LTE(4) has been forgotten. LTE(4) demonstrated low affinity for CysLT(1) and CysLT(2) receptors in equilibrium competition assays. It was less potent than other CysLTs in functional assays, such as calcium flux, in cells transfected with CysLT(1) and CysLT(2). The introduction of CysLT(1) antagonists into clinical practice diverted interest into CysLT(1)-related mechanisms, which were mediated mainly by LTD(4). However, experiments with animal models and human studies have revealed that LTE(4) has unique characteristics that cannot be explained by the current knowledge of CysLT(1) and CysLT(2). These activities include its potency relative to other CysLTs to increase airway responsiveness to histamine, to enhance eosinophilic recruitment, and to increase vascular permeability. Asthmatic airways also demonstrate marked in vivo relative hyperresponsiveness to LTE(4), especially in patients with aspirin-sensitive respiratory disease. This has stimulated a search for additional LT receptors that would respond preferentially to LTE(4) stimulation.

Topics: Animals; Aspirin; Asthma; Bronchial Hyperreactivity; Drug Hypersensitivity; Histamine; Humans; Leukotriene C4; Leukotriene D4; Leukotriene E4; Methacholine Chloride; Receptors, Leukotriene; Skin

Cysteinyl leukotrienes (CysLTs: leukotrienes C(4), D(4), and E(4)) have long been implicated in the pathogenesis of asthma and several allergic diseases. LTE(4) has been identified as a major metabolite of LTC(4), and urinary LTE(4) (U-LTE(4)) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From recent studies on the U-LTE(4) associated with adult stable asthma we identified four factors for hyperleukotrieneuria, namely, aspirin intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP, there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin sensitivity, and ENP is the most important factor for the overproduction of CysLTs in asthmatics. We also demonstrated that anaphylaxis and eosinophilic pneumonia (EP) are associated with a marked increase in the U-LTE(4) concentration. Under these disease conditions, U-LTE(4) may be one of the candidate biomarkers. Moreover, the changes in U-LTE(4) concentrations may provide valuable information concerning therapeutic targets.

Topics: Aspirin; Asthma; Biomarkers; Cell Movement; Drug Hypersensitivity; Eosinophils; Gene Expression Regulation; Inflammation; Leukotriene E4; Nasal Polyps; Risk Factors; Vasculitis

Aspirin-exacerbated respiratory disease (AERD) is diagnosed through graded aspirin challenges that induce hypersensitivity reactions and eicosanoid level changes. It is not known whether diagnostically useful changes also occur after low-dose aspirin challenges that do not induce hypersensitivity reactions.. To investigate the utility of low-dose oral aspirin challenges for diagnosing AERD by measuring different clinical parameters and eicosanoid changes.. Sixteen patients with AERD and 13 patients with aspirin-tolerant asthma underwent oral challenges with low-dose (20 or 40 mg) aspirin and diagnostic oral graded aspirin challenges (up to 325 mg of aspirin). Forced expiratory volume in 1 second, nasal peak flow, the fraction of exhaled nitric oxide (FeNO), and eicosanoid levels in plasma and urine were analyzed.. In patients with AERD but not in those with aspirin-tolerant asthma, 40-mg aspirin challenges induced a significant mean (SEM) decrease from baseline in FeNO (19% [5.1%]; P = .001) without causing any hypersensitivity reaction. The FeNO decrease also occurred after higher-dose aspirin challenges (27.8% [4.9%]; P < .001). The sensitivity and specificity of 40-mg aspirin-induced FeNO changes for identifying AERD were 90% and 100% with an area under the curve of 0.98 (95% CI, 0.92-1.00). The low-dose challenge also induced a significant leukotriene E4 urine increase in patients with AERD (from 6.32 [0.08] to 6.91 [0.15] log-pg/mg creatinine; P < .001), but the sensitivity and specificity of these changes were less than for the FeNO changes.. The low-dose aspirin-induced decrease in FeNO in patients with AERD may be useful for the diagnosis of aspirin allergy without inducing a hypersensitivity reaction.. clinicaltrials.gov Identifier: NCT01320072.

Topics: Administration, Oral; Adult; Allergens; Aspirin; Asthma, Aspirin-Induced; Drug Hypersensitivity; Female; Humans; Immunization; Leukotriene E4; Male; Middle Aged; Nitric Oxide; Sensitivity and Specificity

Topics: Adolescent; Anaphylaxis; Anti-Inflammatory Agents, Non-Steroidal; Dinoprost; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Prostaglandin D2; Salicylamides

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate adverse reactions in two apparently different clinical conditions: bronchial asthma and chronic idiopathic urticaria (CIU). Recent evidence indicates that the reactions are triggered by the drugs that inhibit cyclooxygenase-1 but not cyclooxygenase-2.. To assess whether patients with CIU and aspirin sensitivity share common eicosanoid alterations with patients who have aspirin-sensitive asthma.. Seventy-four patients with CIU and a history of sensitivity to aspirin and NSAIDs underwent placebo-controlled oral aspirin challenge tests. Concentrations of urinary leukotriene E4 (uLTE4) were measured by ELISA and plasma stable prostaglandin D2 metabolite, 9alpha,11beta prostaglandin F(2) by GC/MS. All measurements were carried out at baseline and after aspirin dosing. Patients were genotyped for the leukotriene C4 synthase (LTC4S) promoter single nucleotide polymorphism.. In 30 of 74 patients, the aspirin challenge was positive, resulting in urticaria/angioedema. In these 30 patients, baseline uLTE4 levels were higher than in nonresponders and the healthy control subjects and increased further (significantly) after the onset of clinical reaction. No such increase occurred in subjects with negative aspirin challenge. Baseline uLTE4 levels correlated with severity of skin reactions. Plasma 9alpha,11beta prostaglandin F(2) levels rose significantly in both aspirin responders and nonresponders, although in the latter group the increase occurred later than in the former. In patients who reacted to aspirin, frequency of (-444)C allele of LTC4S was significantly higher than in patients who did not react.. CIU with aspirin sensitivity is characterized by the eicosanoid alterations, which are similar to those present in aspirin-induced asthma.

Topics: Adult; Alleles; Aspirin; Asthma; Dinoprost; Drug Hypersensitivity; Eicosanoids; Female; Genotype; Glutathione Transferase; Humans; Leukotriene E4; Male; Middle Aged; Polymorphism, Single Nucleotide; Single-Blind Method; Urticaria

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.. We investigated whether 33 subjects with a typical history of AIA tolerated the new COX-2-selective NSAID celecoxib.. 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 E(4) (LTE(4)) were monitored, with the latter being a sensitive biochemical marker of aspirin intolerance.. There were no changes in lung function or extrapulmonary symptoms during the double-blind sessions or in urinary excretion of LTE(4). Also, the highest recommended daily dose of celecoxib was well tolerated, with no symptoms, lung function changes, or alterations in urinary LTE(4) levels.. 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.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Celecoxib; Cross-Over Studies; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Drug Hypersensitivity; Female; Humans; Isoenzymes; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides

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

A subset of persons with asthma develop bronchospasm, naso-ocular, gastrointestinal, and/or dermal reactions after ingesting aspirin (ASA) or agents with the capacity to inhibit cyclooxygenase. The bronchopulmonary reactions have been associated with a rise in urinary LTE4. We examined the effects of an inhibitor of 5-lipoxygenase, zileuton, in a group of eight asthmatic patients with known sensitivity to ASA accompanied by LTE4 hyperexcretion. We first confirmed ASA sensitivity and an increase in urinary LTE4 after ASA ingestion in these patients using a placebo-controlled ASA challenge. Subjects were then randomized to a double-blind, crossover trial to examine the effects of zileuton versus placebo on the response to ASA. Zileuton treatment decreased baseline urinary LTE4 excretion from a mean of 469 +/- 141 pg/mg creatinine to 137 +/- 69 pg/mg creatinine (p < 0.02) and blunted the maximum increase in urinary LTE4 after ingestion of ASA (3,539 +/- 826 pg/mg creatinine versus 1,120 +/- 316 pg/mg creatinine [p < 0.01]). The pre-ASA challenge FEV1 was unchanged by zileuton (3.41 +/- 0.15 L versus 3.35 +/- 0.17 L, zileuton versus placebo). Zileuton prevented the fall in FEV1 in response to ingestion of ASA; post-ASA ingestion the mean of the minimal FEV1 fell to 2.72 +/- 0.18 L on the placebo day while there was no significant fall on the zileuton day (3.26 +/- 0.17 L; p < 0.014). Zileuton also prevented the development of the nasal, gastrointestinal (p < 0.006 and p < 0.025, respectively), and dermal symptoms which developed after ASA ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arachidonate 5-Lipoxygenase; Aspirin; Asthma; Bronchoconstriction; Double-Blind Method; Drug Hypersensitivity; Female; Forced Expiratory Volume; Humans; Hydroxyurea; Leukotriene E4; Lipoxygenase Inhibitors; Male; Middle Aged

The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison.. Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry.. No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11β-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups.. We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

Topics: Administration, Oral; Adolescent; Adult; Anaphylaxis; Angioedema; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprost; Drug Hypersensitivity; Eicosanoids; Female; Humans; Leukotriene E4; Male; Middle Aged; Phenotype; Young Adult

Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD).. The aim of the study was to validate a simple measurement of urinary leukotriene E4 (uLTE4) excretion for the diagnosis of AERD in patients with CRS and indication for surgery.. Subjects requiring functional endoscopic sinus surgery (FESS) were recruited from the Department of Otolaryngology (n = 24). Before surgery, a standard oral placebo-controlled aspirin challenge was performed to diagnose aspirin hypersensitivity. Urine samples were collected on the placebo day and both before and within 2 to 4 hours after aspirin challenge for uLTE4 measurement.. All patients with CRS had sinusitis confirmed by computed tomography. Previous ear, nose, and throat surgery was performed in 70% of the patients, NP was present in 86%, and asthma was diagnosed in 62.5%. AERD was diagnosed in 8 subjects (7 women and 1 man). Five of those patients had bronchoconstriction. At baseline, median uLTE4 was 7.5-times higher in AERD subjects than in the remaining patients. It increased almost 6-fold following the challenge, while remained unchanged in patients without aspirin hypersensitivity. Pretest uLTE4 had a sensitivity of 87.5% and specificity of 93.75% to diagnose aspirin hypersensitivity in patients with CRS. After the challenge, the values improved to 100% sensitivity and 93% specificity.. Among CRS subjects requiring FESS, as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4.

Topics: Adult; Aspirin; Asthma; Chronic Disease; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Male; Middle Aged; Rhinitis; Sinusitis

After in vitro allergen-specific stimulation, basophils become activated and release sulfidoleukotrienes LTC4, LTD4 and LTE4. This can be detected by means of the CAST assay. We assessed the positivity criteria and the reliability of antigen-specific sulfidoleukotriene production (CAST) in the in vitro diagnosis of betalactam (BL) allergic patients.. We studied a sample of 67 patients (age 48.94 +/- 15.76 years) who had presented with anaphylaxis or urticaria-angioedema within the first 60 minutes after administration of Amoxicillin (54/67), Penicillin G (7/67), Cefuroxime (5/67) or Cefazoline (1/67). All of them had a positive skin test to at least one of the antigenic determinants of Penicillin. As control group 30 adults with negative skin tests who tolerated BL were included. All of them underwent skin tests, oral provocation tests, specific IgE (CAP-FEIA, Pharmacia) and CAST.. Positivity criteria were established by means of ROC curves: a sLT release induced by Betalactams of at least 100 pg/ml and greater than or equal to 3 times the basal value. The overall sensitivity of CAST is 47.7% and specificity 83.3%. Sensitivity of specific IgE is 37.8% and specificity 83.3%.. We have established validated positivity criteria for the CAST technique in patients allergic to Betalactams. This technique is a useful in vitro diagnostic method in patients with IgE-mediated allergy to Betalactam antibiotics.

Topics: Amoxicillin; Anaphylaxis; Angioedema; Anti-Bacterial Agents; Cefazolin; Cefuroxime; Drug Hypersensitivity; Female; Humans; Immunoglobulin E; Lactams; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Middle Aged; Penicillin G; Skin Tests; Urticaria

Leukotrienes (LTC4, LTD4, LTE4) belong to eicosanoids and they play important role in allergic inflammation. Leukotrienes are 5-lipooxygenaze products of arachinoid acid. It is known that concentration of LTE4 increases in patients with bronchial asthma, after some allergy provocation and in patients with bronchial asthma and intolerance of on steroids anti-inflammatory drugs. The aim of the study was estimated the urinary concentration of LTE4 in patients with bronchial asthma and intolerance of no steroids anti-inflammatory drugs.. The study group consisted of 21 patients with asthma and intolerance of non steroids antiinflammatory drugs (F 19, M 2) in age from 21 to 72 years old (mean = 49 +/- 14), with middle time of asthma duration mean = 13.4 +/- 12.9 years In study group 11 person had positive skin test, 7 nasal polyps, and 8 person positive family history of bronchial asthma. After oral provocation aspirin challenge in 5 subjects' aspirin induced asthma was confirmed, 3 persons were not qualified to test. Urinary concentration of LTE4 before and 24 h after aspirin provocation was analyzed in all the patients. Leukotriene were detected by enzymatic Leukotriene E4, EIA Kit, Cayman Chemical test.. In group of patients with aspirin asthma basic concentration of LTE4 was 416.6 +/- 374.4 pg/mL, and after provocation 496.6 +/- 485.3 pg/mL, in the group without sensitivity to aspirin appropriate 262.9 +/- 404.0 vs 261.2 +/- 259.66 pg/mL, and in the group disqualified to test 181.6 +/- 55.75 pg/mL.. 1 Patients with aspirin asthma have higher concentration of LTE4. 2. Excretion of LTE4 in patients with aspirin induced asthma raised after oral aspirin provocation and higher level was detected is til 24 hours after challenge. 3. This results confirmed the role of cysteinic leukotrienes in pathogenesis of aspirin induced asthma.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Bronchial Provocation Tests; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Male; Middle Aged

Although many studies have assumed that the overproduction of cysteinyl- leukotrienes (cys-LTs) and an imbalance of arachidonic acid metabolism may be plausible causes for the pathogenesis of aspirin-intolerant asthma (AIA), there has been little experimental evidence to substantiate this notion in lower airways of patients with AIA.. The purpose of this study was to compare the eicosanoid concentrations in sputum and urine from patients with AIA.. The concentrations of sputum cys-LTs, prostaglandin E2 (PGE2), PGF2alpha, PGD2 and thromboxane B2 were measured to assess local concentrations of eicosanoids in patients with AIA and in those with aspirin-tolerant asthma (ATA). The concentrations of two urinary metabolites, leukotriene E4 (LTE4) and 9alpha11betaPGF2, were also measured to corroborate the relationship between the eicosanoid biosynthesis in the whole body and that in lower airways.. The concentration of PGD2 in sputum was significantly higher in patients with AIA than in those with ATA (median, 5.3 pg/mL vs. 3.1 pg/mL, P < 0.05), but there was no significant difference in the concentration of the corresponding metabolite, 9alpha11betaPGF2, between the two groups. No differences were noted in the concentrations of other prostanoids in sputum between the two groups. The sputum cys-LT concentrations showed no differences between the two groups, in spite of the observation that the concentration of urinary LTE4 was significantly higher in patients with AIA than in those with ATA (median, 195.2 pg/mg-cre vs. 122.1 pg/mg-cre, P < 0.05). There was a significant correlation among the concentration of cys-LTs, the number of eosinophils and the concentration of eosinophil-derived neurotoxin (EDN) in sputum.. The urinary concentration of LTE4 does not necessary reflect cys-LT biosynthesis in lower airways. A significantly higher concentration of PGD2 in sputum from patients with AIA suggests the possible ongoing mast cell activation in lower airways.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Case-Control Studies; Drug Hypersensitivity; Eicosanoids; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Humans; Leukocyte Count; Leukotriene E4; Male; Middle Aged; Prostaglandin D2; Rhinitis; Ribonucleases; Sinusitis; Sputum

The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU).. Twenty patients with CU were studied. They were selected on the basis of double-blind placebo-controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (five patients). We recruited 15 healthy volunteers as controls (group A). During a second challenge, groups B and C were challenged double-blind with a single dose of ASA, or a specific food additive, or placebo. The healthy group was challenged only with a placebo (talc capsule). Patients in groups B and C were challenged twice: with placebo (as groups B1 and C1) and with ASA (groups B2 and C2) or food additives (C2). Four samples of urine were collected; one during the night before the specific or sham challenge (baseline), and three at 2, 6 and 24 h after the challenge. Urinary methylhistamine (N-MH) and LTE4 were analyzed and normalized for urinary creatinine.. For urinary N-MH at baseline, there was a significant difference only between group A and groups B1, B2, C1 and C2 (A vs. B1, P < 0.0001; A vs. B2, P < 0.0001; A vs. C1, P < 0.0001; A vs. C2, P < 0.0001). We detected a significant variation in urinary methylhistamine excretion only in group C2 after 2 h, 6 h and 24 h (P < 0.0001). However, no variations were observed in N-MH excretion rate in the other groups (A, B1, C1) after challenge with placebo, and in B2 after challenge with ASA 20 mg. For urinary LTE4 at baseline no differences were found between the mean values for the different groups. After specific challenge, only C2 patients showed significantly increased excretion rates of urinary LTE4 compared with the other groups challenged with placebo (A, B1, C1), or ASA (B2) (P < 0.0001). No significant correlation was seen between urinary LTE4 and methylhistamine excretion rate in any patients.. Our results show that urinary excretion of N-MH and LTE4 is different for CU patients without ASA or food hypersensitivity, compared to those with CU with ASA or food additive hypersensitivity after specific challenge.

Topics: Administration, Oral; Adult; Aspirin; Biomarkers; Bronchoconstrictor Agents; Chronic Disease; Controlled Clinical Trials as Topic; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Hypersensitivity; Female; Food Additives; Humans; Italy; Leukotriene E4; Male; Methylhistamines; Middle Aged; Sodium Benzoate; Sodium Glutamate; Sulfites; Tartrazine; Time Factors; Urticaria

Leukotrienes (LTs) are important in asthma, and LT modifiers modulate antigen-induced asthma. Overproduction of LT by suppression of cyclooxygenase activity is involved in patients with aspirin-intolerant asthma (AIA).. House dust mite (HDM) inhalation provocation tests were performed in HDM-sensitive asthmatic inpatients without AIA (HDM group; n = 6), and aspirin oral provocation tests were performed in AIA patients (ASA group; n = 7). Tests were repeated using the same regimen after 7 days of treatment with pranlukast, an LT receptor antagonist (LTRA). The effects of pranlukast on changes in sputum LTC(4)-LTD(4), eosinophil cationic protein (ECP), eosinophil count, urinary LTE(4)/creatinine, 11-dehydrothromboxane B(2) (11-dhTXB(2))/creatinine, serum LTC(4)-LTD(4), ECP, and peripheral blood eosinophil count, during immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) in the HDM group and during IAR in the ASA group for each test, were compared in each group.. In the HDM group, IAR and LAR were observed. Sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine increased significantly both during IAR and LAR. Sputum ECP increased during IAR and further increased during LAR. Eosinophil count in the sputum did not increase during IAR but significantly increased during LAR. Pranlukast suppressed the fall in FEV(1) both during IAR and LAR (73.8% and 51.9%, respectively) and inhibited the increase in sputum eosinophil count during LAR and sputum ECP during IAR and LAR. In the ASA group, aspirin-induced IAR was associated with a fall in urinary 11-dhTXB(2)/creatinine, increased the levels of sputum LTC(4)-LTD(4) and ECP and urinary LTE(4)/creatinine. Pranlukast suppressed IAR and inhibited the increase of the level of sputum ECP, but failed to change aspirin-induced LT production in the sputum and urine. The levels of sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine in the stable phase in the ASA group were significantly greater than those in the HDM group.. Our results indicated that HDM-provoked asthma is associated with overproduction of LT with an antigen-antibody reaction, while AIA is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade. LTRA may be useful against both types of asthma through inhibition of LT activity and eosinophilic inflammation of the airways.

Topics: Adult; Anti-Asthmatic Agents; Aspirin; Asthma; Blood Proteins; Bronchial Provocation Tests; Chromones; Drug Hypersensitivity; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Leukotriene D4; Leukotriene E4; Male; Middle Aged; Ribonucleases; Thromboxane B2

The A to C transversion in the promoter region of the gene encoding leukotriene C4 synthase (LTC4S) is proposed to be associated with the development of aspirin-induced asthma (AIA).. We investigated the frequency of the polymorphism in Japanese population and its association with clinical characteristics and cysteinyl leukotriene production.. Genotyping of LTC4S gene promoter was performed on 60 patients with AIA, 100 patients with aspirin-tolerant asthma (ATA), and 110 control subjects. We assessed the basal levels of urinary LTE4, the increment of urinary LTE4 on venous aspirin challenge, and LTC4S activity in peripheral blood eosinophils.. The frequency of the variant C allele was significantly higher in patients with AIA (frequency of allele [q] = 0.192) than in patients with ATA (q = 0.110, P =.042). Variant C-allelic carriers experienced asthma at a significantly younger age (31.8 +/- 2.9 years [mean +/- SEM]) than wild-type A homozygotes (41.3 +/- 2.2 years, P =.007). Basal levels of LTE4 and the increment of urinary LTE4 on venous aspirin challenge did not show a difference between wild-type A homozygotes and variant C-allelic carriers. There was no relationship between the polymorphism and the LTC4S activity in eosinophils, although LTC4S activities were significantly higher in patients with AIA than in patients with ATA.. Our findings reveal the lack of functionality of the polymorphism in the LTC4S gene, whereas this polymorphism might have some effect on the development of AIA, probably in linkage disequilibrium with another causatively important mutation.

Topics: Aspirin; Asthma; Drug Hypersensitivity; Eosinophils; Female; Gene Frequency; Genotype; Glutathione Transferase; Humans; Japan; Leukotriene E4; Male; Middle Aged; Polymorphism, Genetic; Promoter Regions, Genetic

Topics: Aspirin; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Humans; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Rhinitis, Allergic, Perennial; Sensitivity and Specificity; Sinusitis

Asthmatics with aspirin- (ASA) sensitive respiratory disease (ASRD) have a spectrum of respiratory reactions during oral ASA challenge that vary in severity and are temporally associated with leukotriene (LT) formation.. This study investigates the relationship of the severity of ASA-induced respiratory reactions to urinary LTE(4) excretion.. Asthmatics with suspected ASRD underwent oral ASA challenges. Urinary LTE(4) levels were measured at baseline, during the reaction, and after acute ASA desensitization.. Asthmatics who had respiratory reactions during oral ASA challenges were divided into 3 groups: asthmatics with naso-ocular reactions and <15% decline from baseline FEV(1) values (group 1), asthmatics with a decline in FEV(1) of 20% to 30% (group 2), and asthmatics with a decline in FEV(1) of >30% (group 3). There were no significant differences in age, baseline FEV(1) values, use of inhaled corticosteroids, daily prednisone doses, prednisone bursts, duration of reactions, or average provoking doses of ASA among the groups. At baseline group 3 asthmatics had significantly higher urinary LTE(4) levels than those in groups 1 or 2. At the time of respiratory reaction to ASA, the urinary LTE(4) levels rose significantly in all groups but were significantly greater among group 3 asthmatics compared with those in groups 1 and 2.. The severity of the respiratory reactions during oral ASA challenges was associated with the degree of elevation of baseline LTE(4) synthesis. Our results suggest that asthmatics with ASRD have a spectrum of respiratory tract reactions in which leukotrienes play a distinguishing role.

Topics: Adult; Aspirin; Asthma; Drug Hypersensitivity; Humans; Leukotriene E4; Middle Aged

Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.

Topics: Adult; Anaphylaxis; Animals; Antineoplastic Agents; Asparaginase; Bleomycin; Calcimycin; Drug Hypersensitivity; Humans; In Vitro Techniques; Inflammation; Ionophores; Leukotriene C4; Leukotriene E4; Leukotrienes; Lymphoma, Non-Hodgkin; Mast Cells; Mice; Mice, Inbred BALB C; Respiratory Distress Syndrome

Post-anesthesia anaphylactic reactions or those seen during drug provocation tests with a systemic clinical reaction may be confirmed by the sequential release into blood of plasma histamine, tryptase and leukotriene C4 and into urine of urinary methylhistamine and leukotriene E4.

Topics: Acetaminophen; Anaphylaxis; Anesthetics; Aspirin; Biomarkers; Chymases; Drug Hypersensitivity; Histamine; Humans; Leukotriene C4; Leukotriene E4; Postoperative Complications; Serine Endopeptidases; Tryptases

A protocol has been produced for the study of anaphylactic accidents that occur post-operatively that allows definition of the anaphylactic origin, and so reactions that are mediated by IgE in post-operative accidents. This protocol occurs in two stages, the first is done in the minutes and hours that follow the anaphylactic accident, and the second a month or 6 weeks afterwards. At first, we evaluate the sequential study of the liberation of the mediators of anaphylaxis, plasma histamine, serum tryptase, urinary methylhistamine and, more recently, leucotriene E4. The second study is devoted to reactions that are mediated by IgE, essentially, specific serum IgE, tests of activation of basophils by flow cytometry, measurement of leucotriene C4 and skin tests. A study on 16 subjects has evaluated and validated the protocol and shown a significant level of correspondence of results between the sequential measurement of mediators on one hand and on the other the search for IgE-mediated reactions every time that there was an anaphylactic reaction.

Topics: Adolescent; Adult; Aged; Anaphylaxis; Anesthetics; Basophils; Child; Chymases; Clinical Protocols; Creatine; Drug Hypersensitivity; Female; Gelatin; Histamine Release; Humans; Immunoglobulin E; Leukotriene C4; Leukotriene E4; Male; Methylhistamines; Middle Aged; Muscle Relaxants, Central; Plasma Substitutes; Postoperative Complications; Serine Endopeptidases; Skin Tests; Succinates; Tryptases

The objective of this study was to define the participation of cysteinyl leukotrienes (LTs) or thromboxane A2 in the pathogenesis of aspirin-sensitive asthma (ASA). Leukotriene E4 (LTE4) and 11-dehydrothromboxane B2 (11DTXB2) values in spot urine were measured in 22 asthmatics with a history of aspirin sensitivity and in 17 without such a history (non-aspirin-sensitive asthma [NASA]) in the outpatient clinic. The urinary LTE4 value was significantly higher in ASA patients than in NASA (340 +/- 47 vs 65 +/- 15 pg/mg.cr, P < 0.001), but there was no significant difference in urinary 11DTXB2 between the two groups (891 +/- 77 vs 657 +/- 90 pg/mg.cr). A high value of LTE4 was not associated with type of asthma, severity of disease, oral prednisolone treatment, sex, or age. A higher value of 11DTXB2 was observed in the atopic type than the nonatopic type in ASA (1086 +/- 111 vs 697 +/- 147 pg/mg.cr, P < 0.05). No correlation was observed between urinary LTE4 and 11DTXB2 in either ASA or NASA. In conclusion, LTs may play an important role in the pathogenesis of ASA, and TXA2 in the pathogenesis of the atopic type in ASA.

Topics: Aspirin; Asthma; Case-Control Studies; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Male; Middle Aged; Severity of Illness Index; Thromboxane B2

To determine the role of leukotriene (LT)-degrading enzymes in allergic reactions, we studied the effects of inhibitors of gamma-glutamyl transpeptidase (gamma-GTP) and dipeptidases on increases in pulmonary insufflation pressure (PIP) and vascular permeability induced by ovalbumin (OA) antigen in guinea pigs sensitized to OA antigen in vivo. Vascular permeability was assessed by the amount of extravasated Evans blue dye from the trachea, main bronchi, and segmental bronchi. An intravenous (i.v.) administration of OA antigen (200 micrograms/kg) caused increases in PIP and extravasated Evans blue dye, and OA antigen-induced effects were potentiated by gamma-GTP inhibitor L-serine borate (3 x 10(-5) M/kg, i.v.) (P < 0.05) and an inhibitor of dipeptidases, L-cysteine (3 x 10(-5) M/kg, i.v.) (P < 0.01). OA antigen-induced increases in PIP and Evans blue dye extravasation were in part inhibited by LT-receptor antagonist ONO-1078 (10(-4) M/kg, i.v.). Guinea-pig tracheal tissues contained gamma-GTP and microsomal dipeptidase activities. Histochemical and immunohistochemical studies indicate that gamma-GTP-like activity existed in the epithelium and smooth muscle, and an activity of microsomal dipeptidase was observed in the endothelial cells of microvessels and epithelium. These results suggest that LT-degrading enzymes have an important role in regulating allergic reaction in the airway in vivo.

Topics: Animals; Capillary Permeability; Dipeptidases; Dose-Response Relationship, Drug; Drug Hypersensitivity; Evans Blue; gamma-Glutamyltransferase; Glycosylphosphatidylinositols; GPI-Linked Proteins; Guinea Pigs; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Lung; Male; Muscle, Smooth; Ovalbumin; Trachea

Patients with aspirin sensitive asthma (ASA) can be desensitized to aspirin but the mechanisms by which this happens are unknown. To test the hypothesis that there may be a reduction in aspirin-induced leukotriene release following aspirin desensitization, we studied nine patients with ASA, 37 +/- 2.3 yr of age (mean +/- SEM) with a baseline FEV1 of 94 +/- 3.5%. Urinary leukotriene E4 (LTE4) and FEV1 were measured before and after ingestion of a threshold dose of aspirin leading to a 15% decrease in FEV1, and then at intervals following desensitization, when a maintenance dose of 600 mg aspirin was ingested. Prior to desensitization, the maximum decrease in FEV1 following ingestion of a threshold dose of aspirin was 15.3 +/- 3.9%, and urinary LTE4 rose from a baseline value of 235 +/- 79.4 pg/mg creatinine to 1,714 +/- 783 pg/mg creatinine at 3 h. Immediately after acute desensitization, which was performed over several days, 600 mg aspirin provoked a maximum decrease in FEV1 of only 3.3 +/- 2.4%, and urinary LTE4 increased from a baseline of 645 +/- 223 pg/mg creatinine to 1,256 +/- 456 pg/mg creatinine. Following ingestion of 600 mg aspirin for 9 +/- 3.2 mo (n = 5; chronic desensitization), urinary LTE4 rose from a basal level of 432 +/- 127 pg/mg creatinine to 749 +/- 257 pg/mg creatinine at 3 h after 600 mg aspirin, and this was accompanied by a maximum decrease in FEV1 of 7.4 +/- 4.5%. Although there was significantly less aspirin-induced LTE4 excretion after acute desensitization, substantial amounts of LTE4 were still produced without any significant change in lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspirin; Asthma; Creatinine; Desensitization, Immunologic; Drug Hypersensitivity; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Middle Aged

Pseudo-allergic reactions (PAR) are caused by a variety of drugs, of particular interest by acetylsalicylic acid (ASA) and other nonsteroidal antiinflammatory drugs. The clinical symptoms often resemble immediate type hypersensitivity reactions and consist of bronchospasm, urticaria, angioedema and even anaphylactic shock. Antigen specific immune mechanisms, however, are not involved. In general, skin tests are not reliable and the diagnosis of PAR is based mainly on risky provocation tests. Therefore, the purpose of this study was to establish procedures for in vitro diagnosis of PAR to ASA. A controlled study was performed including patients with PAR to ASA based on history and positive oral provocation test and non-atopic as well as atopic controls. In this in vitro study the production of sulfidoleukotrienes (sLT) by isolated leukocytes was measured by cellular allergen stimulation test (CAST), which is based on detection of LTC4, LTD4 and LTE4 by a monoclonal antibody. Accordingly, the direct effect of ASA as well as the modulatory effect of ASA on C5a-induced production of sLT in leukocytes in vitro was investigated. In patients with PAR to ASA, C5a-induced generation of sLT was significantly increased as compared to normal controls. In contrast, there was no difference in the spontaneous release of sLT in vitro in patients and controls. Preincubation of leukocytes with ASA did not exert a significant modulatory effect on the spontaneous or the C5a-induced production of sLT in patients and controls. In summary, the present study provides a novel in vitro test system for the diagnosis of PAR to ASA by measurement of sLT release in leukocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antigen-Antibody Reactions; Aspirin; Drug Hypersensitivity; Enzyme-Linked Immunosorbent Assay; Female; Humans; In Vitro Techniques; Leukocytes; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Middle Aged

Leukotrienes constitute a class of potent biological mediators of inflammation and anaphylaxis. However, their routine assay in various biological fluids is restricted by the complexity of the methodology. Previously this could only be performed by research laboratories with high pressure liquid chromatography and radioimmunological capabilities. The recent availability of kits for immunoenzymatic assay of leukotrienes offers a new tool for clinical laboratories provided the limitations of the method are understood. We suggest a simplified methodology for direct urinary LTE4 detection and outline a number of areas of concern encountered with this method.

Topics: Adult; Allergens; Drug Hypersensitivity; Female; Humans; Immunoenzyme Techniques; Leukotriene E4; Male; Wasp Venoms

We undertook fundamental studies on the measurement of urinary leukotriene E4, a stable end-product of peptidoleukotrienes, and obtained the following results. 1) After addition of 3H-LTE4 to 2 ml of urine, LTE4 was extracted with a commercial C18 mini-column, and purified by high performance liquid chromatography and then LTE4 in the elute was measured with an enzyme immunoassay kit. 2) As total recovery of LTE4 was 35.3 +/- 0.9% (n = 76), the amount of LTE4 was calculated after correction of the recovery with 3H-LTE4. 3) Before extraction of LTE4 by C18 column, the column was washed by ethyl acetate to remove interfering substances. This procedure greatly facilitated the following high performance liquid chromatographic analysis. 4) The basal levels of urinary LTE4 of seven aspirin-sensitive asthmatics were elevated as compared with five asthmatics without aspirin sensitivity (358.9 +/- 114.0 versus 77.9 +/- 47.3 pg/mg.cr; p < 0.05). 5) In two asthmatic patients, improvement of their symptoms was accompanied with decrease in the LTE4 level in urine. This method enabled us to measure LTE4 concentrations in a small volume of urine (2 ml), and would be useful for evaluating the pathogenesis of bronchial asthma.

Topics: Aspirin; Asthma; Chromatography, High Pressure Liquid; Drug Hypersensitivity; Humans; Immunoenzyme Techniques; Leukotriene E4

Topics: Animals; Aspirin; Asthma; Bronchoconstriction; Drug Hypersensitivity; Guinea Pigs; Humans; Leukotriene E4; Prostaglandin-Endoperoxide Synthases

Leukotriene E4 (LTE4) is excreted into the urine in a relatively constant proportion of 4-7% when either leukotriene C4 (LTC4) or LTE4 is intravenously infused, regardless of the magnitude of the infused dose. Measurement of LTE4 in urine is, therefore, a convenient and non-invasive method for assessing changes in the rate of total body sulphidopeptide leukotriene production. We assayed urinary LTE4 in 17 normal subjects, 31 subjects with asthma without aspirin sensitivity, and 10 aspirin-sensitive subjects. The relationship between urinary LTE4 and nonspecific bronchial hyperresponsiveness, as assessed by the provocative dose producing a 20% fall in forced expiratory volume in one second (PD20) to inhaled histamine, was examined in 19 non-aspirin-sensitive asthmatic subjects. The urinary LTE4 values were log-normally distributed. Urinary LTE4 was detected in 28 of the 31 non-aspirin-sensitive asthmatic subjects, and the geometric mean (95% confidence interval (CI) of 43 (32-57) pg.mg-1 creatinine was no different to that of 34 (25-48) pg.mg-1 creatinine measured in the normal subjects. The geometric mean of 101 (55-186) pg.mg-1 creatinine measured in the aspirin-sensitive asthmatics was significantly higher than that measured in the normal subjects (p less than 0.005) and in the asthmatic subjects who were non-aspirin-sensitive (p less than 0.002), but there was considerable overlap between the three groups. There was no relationship between urinary LTE4 and PD20, or between urinary LTE4 and baseline forced expiratory volume in one second (FEV1) (% predicted). Thus, measurement of LTE4 in a single sample of urine will not predict the extent of bronchial hyperresponsiveness or degree of airflow obstruction.

Topics: Adult; Aspirin; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Drug Hypersensitivity; Female; Histamine; Humans; Leukotriene E4; Male; SRS-A

Intradermal injections of 1-50 pmol leukotriene B4, C4, D4 and E4, (LTB4, LTC4, LTD4 and LTE4) were performed in healthy subjects and patients with recurrent urticaria. A wheal and erythema were seen 15 minutes after injection and were most marked after LTC4 and LTD4. LTE4 also produced a wheal whereas the reaction to LTB4 did not significantly differ from the saline control. When mixed with histamine no potentiation of the wheals was noted and no significant difference in reaction was observed between the healthy controls and those with urticaria.

Topics: Drug Hypersensitivity; Erythema; Histamine; Humans; Intradermal Tests; Leukotriene B4; Leukotriene E4; Male; Skin; SRS-A; Urticaria