RESUMEN
BACKGROUND: Exercise-induced bronchoconstriction (EIB) reflects poor asthma control. Assessing noninvasive biomarkers associated with EIB could help to monitor patients in the pediatric age. AIMS: To test exhaled and urinary biomarkers for assessing EIB in atopic asthmatic children. METHODS: In 45 atopic patients (11.1 ± 1.8 years, 25 males) we measured the fractional exhaled nitric oxide (FENO ), its alveolar (CaNO), and bronchial (J'awNO) components corrected for the trumpet shape of the airways and axial NO diffusion (TMAD), concentrations of urinary adenosine and 8-hydroxy-2'-deoxyguanosine (8-OxodG), blood eosinophils count, total immunoglobulin E , skin prick tests, and baseline spirometry before a treadmill exercise challenge. Forty healthy control subjects participated solely to baseline measurements. RESULTS: Patients yielded higher FENO and urinary adenosine concentrations than healthy controls. After the challenge, 18 patients (40%) had EIB; these patients had higher levels of CaNO, CaNO TMAD, and urinary adenosine than patients without EIB. Baseline spirometry, FE NO , JawNO, JawNO TMAD, urinary 8-OxodG, allergy, and blood eosinophil counts were found similar in both groups. In multiple linear regression, the fall in FEV 1 was explained by CaNO TMAD, urinary adenosine and blood eosinophil count, whereas the fall in FEF 25-75 was explained by CaNO TMAD and blood eosinophil count. Both CaNO TMAD ≥10.5 ppb and urinary adenosine ≥406 nmol/mmol Cr predicted a fall in FEV 1 ≥10%, while only CaNO TMAD ≥10.5 ppb predicted a fall in FEF 25-75 ≥26%. CONCLUSION: Concentrations of peripheral airway NO are complementary with urinary adenosine for assessing EIB and promising tools of asthma control in pediatric patients with the atopic phenotype.
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Adenosina/orina , Asma/fisiopatología , Biomarcadores/análisis , Óxido Nítrico/análisis , Asma/inmunología , Asma/orina , Asma Inducida por Ejercicio/orina , Biomarcadores/orina , Pruebas de Provocación Bronquial , Broncoconstricción , Niño , Desoxiadenosinas/orina , Eosinófilos , Prueba de Esfuerzo , Espiración , Femenino , Humanos , Hipersensibilidad Inmediata , Inmunoglobulina E/análisis , Recuento de Leucocitos , Masculino , Pruebas Cutáneas , EspirometríaRESUMEN
Airway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways. We investigated whether osmotic stress alone causes airway epithelial perturbation in athletes with suspected EIB. Twenty-four recreational summer sports athletes who reported respiratory symptoms on exertion performed a standard eucapnic voluntary hyperpnoea test with dry air and a mannitol test (osmotic challenge) on separate days. Median urinary CC16 increased from 120 to 310 ρg µmol creatinine(-1) after dry air hyperpnoea (P = 0.002) and from 90 to 191 ρg µmol creatinine(-1) after mannitol (P = 0.021). There was no difference in urinary CC16 concentration between athletes who did or did not bronchoconstrict after dry air hyperpnoea or mannitol. We conclude that, in recreational summer sports athletes with respiratory symptoms, osmotic stress per se to the airway epithelium induces a rise in urinary excretion of CC16. This suggests that hyperosmolarity of the airway surface lining perturbs the airway epithelium in symptomatic athletes.
Asunto(s)
Aire , Asma Inducida por Ejercicio/orina , Diuréticos Osmóticos , Manitol , Deportes/fisiología , Uteroglobina/orina , Adulto , Asma Inducida por Ejercicio/fisiopatología , Biomarcadores/orina , Pruebas de Provocación Bronquial/métodos , Broncoconstricción/fisiología , Femenino , Humanos , Hipercapnia/fisiopatología , Hipercapnia/orina , Masculino , Concentración Osmolar , Recreación , Pruebas de Función Respiratoria , Estaciones del AñoRESUMEN
Repeated injury of the airway epithelium caused by hyperpnoea of poorly conditioned air has been proposed as a key factor in the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. In animals, the short-acting ß2-agonist terbutaline has been shown to reduce dry airflow-induced bronchoconstriction and the associated shedding of airway epithelial cells. Our aim was to test the efficacy of inhaled terbutaline in attenuating hyperpnoea-induced bronchoconstriction and airway epithelial injury in athletes. Twenty-seven athletes with EIB participated in a randomized, double-blind, placebo-controlled, crossover study. Athletes completed an 8-min eucapnic voluntary hyperpnoea (EVH) test with dry air on two separate days 15 min after inhaling 0.5 mg terbutaline or a matching placebo. Forced expiratory volume in 1 s (FEV1) and urinary concentration of the club cell (Clara cell) protein 16 (CC16, a marker of airway epithelial perturbation) were measured before and up to 60 min after EVH. The maximum fall in FEV1 of 17 ± 8% (SD) on placebo was reduced to 8 ± 5% following terbutaline (P < 0.001). Terbutaline gave bronchoprotection (i.e., post-EVH FEV1 fall <10%) to 22 (81%) athletes. EVH caused an increase in urinary excretion of CC16 in both conditions (P < 0.001), and terbutaline significantly reduced this rise (pre- to postchallenge CC16 increase 416 ± 495 pg/µmol creatinine after placebo vs. 315 ± 523 pg/µmol creatinine after terbutaline, P = 0.016). These results suggest that the inhalation of a single therapeutic dose of terbutaline offers significant protection against hyperpnoea-induced bronchoconstriction and attenuates acute airway epithelial perturbation in athletes.
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Asma Inducida por Ejercicio/prevención & control , Atletas , Broncoconstricción/efectos de los fármacos , Broncodilatadores/administración & dosificación , Hiperventilación/fisiopatología , Pulmón/efectos de los fármacos , Mucosa Respiratoria/efectos de los fármacos , Terbutalina/administración & dosificación , Uteroglobina/orina , Administración por Inhalación , Adolescente , Adulto , Asma Inducida por Ejercicio/fisiopatología , Asma Inducida por Ejercicio/orina , Estudios Cruzados , Método Doble Ciego , Inglaterra , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Ventilación Pulmonar , Mucosa Respiratoria/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Leukotrienes are among the most important mediators associated with inflammatory responses in patients with exercise induced asthma (EIA). The aim of this study was to investigate the impact of exercise on the urinary leukotriene profile. Hence, we compared post exercise changes of urinary leukotriene E4 (LTE4) concentration between children with EIA and healthy controls. METHODS: Ten children with EIA and 15 controls were enrolled. Both groups underwent a standardised exercise challenge test (ECT). LTE4 concentration was measured in urine samples obtained pre and post ECT, using enzyme immunoassay and adjusted by urinary creatinine concentrations. RESULTS: Median (minimum-maximum) pre ECT concentration of LTE4 was 17.82 (7.58-90.23 pg/ml) in EIA and 17.24 (4.64-64.02 pg/ml) in controls, p=0.86. LTE4 concentration post ECT were 23.37 (4.02-93.00 pg/ml) in EIA and 11.74 (0.13-25.09 pg/ml) in controls, p=0.02. Changes of LTE4 concentration post ECT were 2.54 (-31.98 to 43.31 pg/ml) in cases and -13.53 (-46.00 to 11.02 pg/ml) in controls, p=0.03. There was no significant correlation between basal predicted FEV(1) [%] and changes in LTE4 concentration in cases (i.e., r(s)=0.14) nor controls (i.e., r(s)=0.12). There was a tendency towards more pronounced changes in LTE4 concentration post ECT in children with moderate/mild persistent asthma compared to those with mild but intermittent asthma. CONCLUSIONS: Children with EIA had significantly higher changes of urinary LTE4 concentrations post ECT compared to healthy controls. Urinary measurement of LTE4 may be an interesting and non-invasive option to assess control of EIA in children.
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Asma Inducida por Ejercicio/orina , Leucotrienos/orina , Adolescente , Asma Inducida por Ejercicio/inmunología , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Prueba de Esfuerzo , Femenino , Humanos , Leucotrienos/inmunología , MasculinoRESUMEN
PURPOSE: Exercise-induced bronchoconstriction (EIB) is a common condition in both individuals with asthma and otherwise healthy elite athletes. Although excessive water loss by peripheral airways during hyperpnea is regarded as the initial trigger for EIB, the cascade of events that follows remains unclear. Our goal was to establish whether transient disruption of the airway epithelial barrier occurs after a short period of hyperpnea of dry air in athletes with EIB. METHODS: Urinary concentration of the pneumoprotein Clara cell (CC16) was used as an assumed biomarker of lung epithelial cell damage or dysfunction. Samples were collected at baseline and for 90 min after an 8-min eucapnic voluntary hyperpnea (EVH) test in 50 female individuals (28 athletes and 22 untrained). RESULTS: Nineteen subjects (10 athletes) demonstrated a sustained bronchoconstriction after EVH (mean±SE forced expiratory volume in the first second (FEV1) fall from baseline=23.4%±2.6%). The remaining subjects had a negative challenge result with an FEV1 fall of 5.9%±0.6%. An increase (P<0.001) in urinary CC16 concentration was noticed after EVH in all but one subject, with no group difference (median CC16 increase before to after challenge: athletes EVH 0.083 ng·µmol, athletes EVH 0.223 ng·µmol, untrained EVH 0.074 ng·µmol, untrained EVH 0.571 ng·µmol; P>0.05). CONCLUSIONS: Urinary levels of CC16 are increased after EVH in all individuals (trained and untrained, with and without EIB) suggestive of dehydration-induced perturbation of the distal respiratory epithelium during episodes of hyperventilation.
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Asma Inducida por Ejercicio/fisiopatología , Asma Inducida por Ejercicio/orina , Broncoconstricción/fisiología , Hiperventilación/fisiopatología , Hiperventilación/orina , Uteroglobina/orina , Adolescente , Adulto , Atletas , Prueba de Esfuerzo , Femenino , Humanos , Persona de Mediana Edad , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
Elite swimmers have an increased risk of developing asthma, and exposure to chloramine is believed to be an important trigger factor. The aim of the present study was to explore pathophysiological mechanisms behind induced bronchoconstriction in swimmers exposed to chloramine, before and after swim exercise provocation as well as mannitol provocation. Urinary Clara cell protein (CC16) was used as a possible marker for epithelial stress. 101 elite aspiring swim athletes were investigated and urinary samples were collected before and 1 h after completed exercise and mannitol challenge. CC16, 11ß-prostaglandin (PG)F(2α) and leukotriene E(4) (LTE(4)) were measured. Urinary levels of CC16 were clearly increased after exercise challenge, while no reaction was seen after mannitol challenge. Similar to CC16, the level of 11ß-PGF(2α) was increased after exercise challenge, but not after mannitol challenge, while LTE(4) was reduced after exercise. There was no significant difference in urinary response between those with a negative compared to positive challenge, but a tendency of increased baseline levels of 11ß-PGF(2α) and LTE(4) in individuals with a positive mannitol challenge. The uniform increase of CC16 after swim exercise indicates that CC16 is of importance in epithelial stress, and may as such be an important pathogenic factor behind asthma development in swimmers. The changes seen in urinary levels of 11ß-PGF(2α) and LTE(4) indicate a pathophysiological role in both mannitol and exercise challenge.
Asunto(s)
Asma Inducida por Ejercicio/orina , Cloro/orina , Leucotrieno E4/orina , Manitol/orina , Natación , Uteroglobina/orina , Adolescente , Asma Inducida por Ejercicio/etiología , Asma Inducida por Ejercicio/fisiopatología , Biomarcadores/orina , Pruebas de Provocación Bronquial/métodos , Broncoconstricción/fisiología , Cloraminas/efectos adversos , Cloro/efectos adversos , Dinoprost/orina , Femenino , Humanos , Masculino , Medición de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: To evaluate changes in cysteinyl leukotriene (LT) concentrations in urine and bronchoalveolar lavage fluid (BALF) in cats with experimentally induced asthma. ANIMALS: 19 cats with experimentally induced asthma and 5 control cats. PROCEDURE: Cats were sensitized to Bermuda grass or house dust mite allergen, and phenotypic features of asthma were confirmed with intradermal skin testing, evaluation of BALF eosinophil percentages, and pulmonary function testing. A competitive ELISA kit for LTC4, LTD4, and LTE4 was used for quantitative analysis of LTs. Urinary creatinine concentrations and BALF total protein (TP) concentrations were measured, and urinary LT-to-creatinine ratios and BALF LT-to-TP ratios were calculated. RESULTS: Mean urinary LT-to-creatinine ratios did not differ significantly between control cats and allergen-sensitized cats before or after sensitization and challenge exposure with saline (0.9% NaCl) solution or allergen, respectively. In BALF the mean LT-to-TP ratio of control cats did not differ significantly before or after sensitization and challenge exposure with saline. Asthmatic cats had BALF LT-to-TP ratios that were significantly lower than control cats at all time points, whereas ratios for asthmatic cats did not differ significantly among the various time points. CONCLUSIONS AND CLINICAL RELEVANCE: Although LTs were readily detectable in urine, no significant increases in urinary LT concentrations were detected after challenge in allergen-sensitized cats. Spot testing of urinary LT concentrations appears to have no clinical benefit for use in monitoring the inflammatory asthmatic state in cats. The possibility that cysteinyl LTs bind effectively to their target receptors in BALF and, thus, decrease free LT concentrations deserves further study.
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Asma Inducida por Ejercicio/veterinaria , Líquido del Lavado Bronquioalveolar/química , Enfermedades de los Gatos/fisiopatología , Cisteína , Leucotrienos/análisis , Animales , Asma Inducida por Ejercicio/fisiopatología , Asma Inducida por Ejercicio/orina , Enfermedades de los Gatos/orina , Gatos , Ensayo de Inmunoadsorción Enzimática , Leucotrieno C4/análisis , Leucotrieno D4/análisis , Leucotrieno E4/análisis , Leucotrienos/orinaRESUMEN
OBJECTIVE: To explore the relationship between leukotriene (LT) and exercise-induced asthma. METHODS: Twenty-two non-smoking asthmatic patients with a reproducible fall in FEV(1) after exercise by least 10% and 10 normal patients were enrolled. Urinary levels of leukotriene E4 were measured before and 2 hours after exercise. Twelve subjects received cysteinyl LT receptor antagonist Zafirlukast (Ancolate) 20 mg twice a day for three days. Standardized exercise challenge were performed after 72 hours. End points included (1) area under the percent fall in FEV(1) versus time curve (AUC 0-60 min), (2) time to recovery to within 5% of the pre-exercise baseline FEV(1) value, (3) and maximum percent fall in FEV(1) from pre-exercise baseline. RESULTS: To exercise-induced aothma (EIA) group, urinary LTE4 in 2 hours after exercise were higher than that of in before exercise, P < 0.01. Urinary leukotriene E4 concentration before and 2 hours after exercise were higher than normal subjects. Zafirlukast can caused a significant reduction in AUC(0 - 60 min) (Aera under the FEV(1)-time curve for 0 to 60 minutes after exercise); caused a significant reduction in the maximum percent fall in FEV(1); and Zafirlukast resulted in a shorter time to recovery of FEV(1) to preexercise baseline. CONCLUSIONS: There was an increase in urinary LTE4 during the 2 hours after exercise challenge; Zafirlukast can attenuate EIA. The results indicate that there is an important role of leukotriene in the pathogenesis of exercise-induced asthma.
Asunto(s)
Asma Inducida por Ejercicio/orina , Leucotrieno E4/orina , Leucotrienos/orina , Proteínas de la Membrana , Receptores de Leucotrienos , Adulto , Antiasmáticos/uso terapéutico , Asma Inducida por Ejercicio/prevención & control , Femenino , Humanos , Indoles , Antagonistas de Leucotrieno , Masculino , Persona de Mediana Edad , Fenilcarbamatos , Sulfonamidas , Compuestos de Tosilo/uso terapéuticoRESUMEN
OBJECTIVE: To explore the relationship between eosinophils, T lymphocyte, leukotreine (LT) and exercise-induced asthma (EIA). METHODS: In 32 asthmatic patients (13 with EIA and 19 asthmatic without EIA) and 8 normal persons, serum eosinophil cationic protein (ECP) and actived T lymphocyte (CD(25)(+)%) in peripheral blood were measured at the time before and 10, 60 minutes after exercise testing. The maximum minute ventilation (V(E)) were also measured. Another 22 non-smoking asthmatic patients with EIA and 10 normal subjects were enrolled for measuring urinary leukotriene E(4) levels before and 2 hours after exercise. EIA patients received zafirlukast 20 mg twice a day for three days. Standardized exercise challenge were performed after 72 hours of medication. RESULTS: There was a linear relationship between ECP, CD(25)(+)% and the forced expiratory volume in one second (FEV(1)) in asthmatic group (r = -0.79 and -0.61 all P < 0.01). Expressions of IL-4 mRNA, IL-5 mRNA CD(25)(+)% and serum ECP levels showed no significant difference at all testing points between two asthmatic groups, meanwhile, V(E) also showed no difference among three groups. Urinary LTE(4) levels in EIA group increased significantly two hours after exercise. Zafirlukast significantly reduced AUC(0 approximately 60 min) and the percentage of maximum fall in FEV(1) and accelerated the falling FEV(1) to return to pre-exercise baseline. CONCLUSIONS: Hyperventilation during exercise may not be the cause leading to EIA, neither did the activation of T lymphocytes, IL-4 and IL-5 gene expression nor ECP. Leukotriene may play an important role in the pathogenesis of EIA.
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Asma Inducida por Ejercicio/inmunología , Eosinófilos/inmunología , Leucotrieno E4/orina , Ribonucleasas , Células Th2/inmunología , Adulto , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Asma/inmunología , Asma/fisiopatología , Asma/orina , Asma Inducida por Ejercicio/tratamiento farmacológico , Asma Inducida por Ejercicio/fisiopatología , Asma Inducida por Ejercicio/orina , Biomarcadores , Proteínas Sanguíneas/análisis , Proteínas en los Gránulos del Eosinófilo , Eosinófilos/citología , Femenino , Volumen Espiratorio Forzado , Humanos , Indoles , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-5/genética , Interleucina-5/inmunología , Antagonistas de Leucotrieno/uso terapéutico , Pulmón/fisiopatología , Activación de Linfocitos , Masculino , Ventilación Voluntaria Máxima , Persona de Mediana Edad , Ápice del Flujo Espiratorio , Fenilcarbamatos , Receptores de Interleucina-2 , Sulfonamidas , Células Th2/citología , Compuestos de Tosilo/uso terapéuticoRESUMEN
UNLABELLED: This double-blind, randomised and cross-over study was designed to compare the preventive effect against exercise-induced bronchoconstriction (EIB), defined as the percentage decrease in FEV1 > or = 15% after 6 min of exercise, of 2 mg and 10 mg of sodium cromoglycate (SCG), administered through a metered dose inhaler via spacer, in asthmatic children. Each of the 30 subject (age 11.6 +/- 3.2 years) was tested on five occasions. For inclusion, EIB in test1 was required. In tests 2 to 5, all subjects inhaled 2 mg or 10 mg of SCG 20 min and 120 min before exercise in a randomised order. In order to assess excretion of eosinophil protein X (EPX) accompanying EIB, urine samples were collected before and after exercise. The mean percentage fall in FEV1 (+/- SD) in test 1 was 26.8 +/- 9.8%. Inhalation of 2 mg and 10 mg of SCG 20 min before exercise provided a significant preventive effect in 83% and 77% and inhalation 120 min before exercise provided a preventive effect in 63% and 70%, respectively (n = 30). Variance analysis did not reveal a statistically different absolute fall in FEV1 after exercise when both doses (120 min before exercise) were compared (P = 0.356). In an unselected subgroup of 12 children, urinary EPX increased after the challenge without SCG premedication (test 1) (mean change: +48.7 micrograms/mmol creatinine, P = 0.034), whereas no significant increase was found in case of SCG premedication (mean change in microgram/mmol creatinine): 2 mg/20 min: +12.1; 2 mg/120 min: +8.5; 10 mg/20 min: -10.4 and 10 mg/120 min: -23.5; P > 0.1). CONCLUSION: Administration of 10 mg of sodium cromoglycate is no more effective in preventing exercise-induced bronchoconstriction than 2 mg regardless of whether the medication is given 20 or 120 min before exercise. The preventive effect of sodium cromoglycate on exercise-induced bronchoconstriction in asthmatic children is associated with the inhibition of urinary eosinophil protein X excretion.
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Antiasmáticos/uso terapéutico , Asma Inducida por Ejercicio/prevención & control , Proteínas Sanguíneas/orina , Broncoconstricción/efectos de los fármacos , Cromolin Sódico/uso terapéutico , Ribonucleasas/orina , Administración por Inhalación , Adolescente , Antiasmáticos/administración & dosificación , Asma Inducida por Ejercicio/orina , Proteínas Sanguíneas/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Niño , Cromolin Sódico/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Neurotoxina Derivada del Eosinófilo , Prueba de Esfuerzo , Humanos , Ribonucleasas/efectos de los fármacos , Ribonucleasas/metabolismo , Pruebas Cutáneas , Resultado del TratamientoRESUMEN
Controversy remains about the causative mediators in the bronchoconstrictive response to exercise in asthma. This study examined whether mast cell activation is a feature of exercise-induced bronchoconstriction by measuring urinary metabolites of mast cell mediators. Twelve nonsmoking subjects with mild asthma and a history of exercise-induced bronchoconstriction exercised on a stationary bicycle ergometer for 5 min at 80% maximum work load. Pulmonary function was monitored and urine was collected before and 30 and 90 min after the provocation. The urinary concentrations of the mast cell markers 9alpha,11beta-prostaglandin (PG)F2 and Ntau-methylhistamine, as well as leukotriene E4 (LTE4) were determined by immunoassay. Seven of the 12 subjects (responders) experienced bronchoconstriction (>15% fall in the forced expiratory volume in one second) following exercise, whereas the pulmonary function of the remaining five subjects (nonresponders) remained stable. The urinary excretion (mean+/-SE) of 9alpha,11beta-PGF2 in the responders increased significantly compared with the nonresponders at 30 (77.1+/-14.4 versus 37.2+/-5.6; p<0.05) and 90 min (79.3+/-8.6 versus 40.4+/-8.5, p<0.05) after exercise challenge. The urinary excretion of Ntau-methylhistamine and LTE4 was not significantly different between the two groups at 30 or 90 min after exercise. The findings represent the first documentation of increased urinary levels of 9alpha,11beta-prostaglandin F2 in adults following exercise challenge and provides clear evidence for mast cell activation during exercise-induced bronchoconstriction in asthmatics.
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Asma Inducida por Ejercicio/fisiopatología , Dinoprost/orina , Mastocitos/fisiología , Metilhistaminas/orina , Adulto , Asma Inducida por Ejercicio/orina , Pruebas de Provocación Bronquial , Broncoconstricción/fisiología , Prueba de Esfuerzo , Femenino , Humanos , Técnicas para Inmunoenzimas , Leucotrieno E4/orina , Masculino , Mastocitos/metabolismo , Radioinmunoensayo , Factores de TiempoRESUMEN
The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated for its effect on exercise-induced bronchoconstriction in asthmatic subjects. The relationship between 5-LO inhibition and effects on the response of the airways to exercise was examined. In a double-blind, randomized, crossover clinical trial, 10 patients with mild to moderate persistent asthma (who exhibited a fall in forced expiratory volume in one second (FEV1) > or = 20% following standardized exercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung function, urinary leukotriene E4 (LTE4) and ex vivo calcium ionophore-stimulated LTB4 release in whole blood were measured prior to dosing, prior to exercise and at various time points up to 4 h post-exercise. The mean (SD) maximal percentage fall in FEV1 after exercise was 27.1 (12)% on placebo and 19.9 (10)% on ABT-761 days, respectively (p<0.05). Post-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 and 30 min after exercise and the mean area under curve, representing the overall effect of exercise from 0-45 min post-challenge, was also significantly attenuated by ABT-761 (p<0.001). Ex vivo LTB4 release was inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Urinary LTE4 in the post-exercise period was significantly lower after ABT-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg x mg creatinine(-1); p<0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise FEV1 decline (r=0.711; p<0.05). We conclude that ABT-761 is effective in suppressing exercise-induced bronchoconstriction and that this protection is related quantitatively to the degree of 5-lipoxygenase inhibition.
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Asma Inducida por Ejercicio/tratamiento farmacológico , Broncoconstricción/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Hidroxiurea/análogos & derivados , Leucotrieno E4/orina , Inhibidores de la Lipooxigenasa , Adulto , Asma Inducida por Ejercicio/fisiopatología , Asma Inducida por Ejercicio/orina , Estudios Cruzados , Método Doble Ciego , Prueba de Esfuerzo , Femenino , Humanos , Hidroxiurea/uso terapéutico , MasculinoRESUMEN
BACKGROUND: 9Alpha,11beta-prostaglandin (PG) F2 is an initial metabolite of PGD2 which has a potent bronchoconstrictive activity. OBJECTIVES: We measured the urinary levels of 9alpha,11beta-PGF2 in asthmatic children to investigate its role in not only acute asthmatic attack in a time course study but also in exercise-induced asthma (EIA). METHODS: In the acute asthma study, 30 asthmatic children were examined. Urine samples were collected on the first, third, and sixth days. Urinary levels of 9alpha,11beta-PGF2 were measured with gas chromatography mass spectrometry using the electron impact method. In the exercise challenge study, 14 children with EIA and 14 children without EIA were studied. Urine samples were collected before exercise challenge, and at 1 h, and 5 h after exercise challenge. Urinary levels of 9alpha,11beta-PGF2 were measured. RESULTS: Elevated urinary levels of 9alpha,11beta-PGF2, which were observed on the first day when treatment was started in the hospital, were gradually decreased on the third day (P < 0.05), and on the sixth day (P < 0.01). A significant correlation between urinary levels of 9alpha,11beta-PGF2 and symptom scores (P < 0.005) was observed on the first day. In EIA, there was a significant increase in urinary levels of 9alpha,11beta-PGF2 at 1 h (P < 0.01) and at 5 h (P < 0.01) after exercise challenge, but not in the children without EIA. CONCLUSION: 9Alpha,11beta-PGF2 may be involved in the pathogenesis of acute and exercise-induced asthma in children.
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Asma Inducida por Ejercicio/orina , Asma/orina , Dinoprost/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Enfermedad Aguda , Adolescente , Niño , Preescolar , Femenino , Cromatografía de Gases y Espectrometría de Masas/estadística & datos numéricos , Humanos , Masculino , Factores de TiempoRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Acetatos/uso terapéutico , Asma Inducida por Ejercicio/tratamiento farmacológico , Ejercicio Físico/fisiología , Antagonistas de Leucotrieno , Leucotrieno E4/orina , Quinolinas/uso terapéutico , Acetatos/sangre , Adolescente , Adulto , Asma Inducida por Ejercicio/sangre , Asma Inducida por Ejercicio/orina , Estudios Cruzados , Ciclopropanos , Método Doble Ciego , Prueba de Esfuerzo , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Quinolinas/sangre , SulfurosRESUMEN
Recent evidence suggests that the cysteinyl-leukotrienes (LTC4, LTD4, and LTE4) may be important in the pathogenesis of exercise-induced asthma. To evaluate the role of these mediators further, nine asthmatic subjects with exercise-induced bronchoconstriction were studied on two occasions. On visit 1, subjects performed 6 min of treadmill exercise; the mean maximal percent fall in FEV1 was 38.0 +/- 5.3%. On visit 2, maximal bronchoconstriction observed after exercise was matched with aerosolized methacholine. Urine was collected in two 90-min fractions (0-90 and 90-180 min) after challenges and analyzed by high-performance liquid chromatography-radioimmunoassay for LTE4. There were no significant differences in urinary LTE4 excretion between exercise and methacholine challenges for the periods 0-90 min (16.9 +/- 5.4 vs. 20.4 +/- 4.2 ng/mmol urinary creatinine), 90-180 min (24.9 +/- 8.2 vs. 20.1 +/- 5.5), or 0-180 min (21.5 +/- 6.5 vs. 18.8 +/- 4.1). Thus in contrast to allergen-induced bronchoconstriction, there is little evidence for enhanced cysteinyl-leukotriene generation in exercise-induced bronchoconstriction as assessed by urinary LTE4. If local release and subsequent participation of functionally active cysteinyl-leukotrienes in the pathways that ultimately lead to bronchoconstriction after exercise challenge do occur, these are of insufficient magnitude to perturb urinary LTE4 excretion.
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Asma Inducida por Ejercicio/orina , SRS-A/análogos & derivados , Adulto , Volumen Espiratorio Forzado/fisiología , Humanos , Leucotrieno E4 , Masculino , Compuestos de Metacolina , SRS-A/orinaRESUMEN
To assess the role of sulfidopeptide leukotrienes in the pathogenesis of exercise-induced asthma (EIA), the urinary levels of leukotriene E4 (LTE4), a metabolite of LTC4 and LTD4, were measured by RIA before and after exercise in 13 children with EIA and 10 healthy children. Mass spectrometry was used to confirm the presence of LTE4 in urine and the specificity of the RIA. There was no significant difference in the urinary LTE4 levels before exercise between the children with asthma and healthy children (109 [21 to 265] versus 122 [45 to 156] pg/mg of creatinine; median and range). Urinary LTE4 levels increased significantly after exercise in the children with EIA (from 109 [21 to 265] to 196 [40 to 655] pg/mg of creatinine; median and range; p less than 0.05) but not in the healthy children. The children with asthma demonstrated no significant correlation between the LTE4 level after exercise and the degree of bronchoconstriction, as revealed by the maximal percent fall in the peak expiratory flow rate. Taken together with a recent study that pretreatment with a potent and selective LTD4 antagonist markedly attenuated EIA, our findings suggest that sulfidopeptide leukotrienes may play some role in the pathogenesis of this type of asthma with other factors also being involved in determining the overall airway response.
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Asma Inducida por Ejercicio/orina , SRS-A/análogos & derivados , Asma Inducida por Ejercicio/epidemiología , Asma Inducida por Ejercicio/etiología , Niño , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Prueba de Esfuerzo , Humanos , Leucotrieno E4 , Espectrometría de Masas/instrumentación , Espectrometría de Masas/métodos , Radioinmunoensayo/instrumentación , Radioinmunoensayo/métodos , Análisis de Regresión , SRS-A/orina , Factores de TiempoRESUMEN
Histamine is partly metabolized to a stabile metabolite N-methyl-histamine and excreted in the urine. We analysed the degradation of infused histamine and the N-methyl-histamine-excretion in atopic and normal individuals as in patients with a bronchoconstriction due to allergen/exercise challenge. N-methyl-histamine was determined by a newly developed radioimmunoassay. 60 controls and 38 atopic individuals were investigated. There is a proportional increase of N-methyl-histamine in the urine in young children. However, no significant difference between allergic and non-allergic individuals was found. After parenteral administration of a standardized amount of histamine 12% of the applied amount was secreted in the urine as N-methylhistamine. The most significant increase of N-methylhistamine-excretion was observed in the first hour after application. Only an 0.1% rise of N-methyl-histamine was observed following an oral administration of histamine. Neither bronchial challenge with specific allergen nor physical exercise elicited significant changes of N-methylhistamine excretion. The secretion of N-methyl-histamine demonstrates the degradation of histamine in the circulation, the measurement oft this metabolite in the urine should be considered when analysing the cause of severe systemic allergic reaction as anaphylaxis but not asthma or atopic disposition.
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Asma Inducida por Ejercicio/orina , Asma/orina , Histamina/administración & dosificación , Metilhistaminas/orina , Hipersensibilidad Respiratoria/orina , Adolescente , Adulto , Pruebas de Provocación Bronquial , Niño , Preescolar , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
Urinary leukotriene E4 (LTE4) concentrations were measured in six asthmatic subjects after treadmill exercise, and in five asthmatic subjects after allergen challenge. Exercise and allergen challenge produced a 42 +/- 18% (mean +/- SD) and 22 +/- 8% fall in FEV1, respectively. The baseline concentration of urinary LTE4 in subjects challenged with exercise was 64 (27 to 150) pg/mg creatinine (geometric mean and 95% confidence interval), and in those challenged with allergen it was 36 (23 to 59) pg/mg creatinine. Urinary LTE4 concentrations did not change significantly in the 24 h after exercise. In contrast, there was a mean 4-fold increase in urinary LTE4 during the 3 h after allergen challenge.
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Asma Inducida por Ejercicio/orina , SRS-A/análogos & derivados , Adulto , Asma Inducida por Ejercicio/diagnóstico , Pruebas de Provocación Bronquial , Prueba de Esfuerzo , Femenino , Humanos , Leucotrieno E4 , Masculino , SRS-A/orina , Factores de TiempoRESUMEN
Urinary levels of leukotriene (LT) E4, a stable end-product of LTC4 and LTD4, were measured before and after exercise in 10 children with severe asthma and seven children with moderate asthma using HPLC and RIA to clarify the relationship of LT to the severity of asthma and to the degree of bronchospasm in exercise-induced asthma. The urinary LTE4 level significantly increased after exercise in the severe asthma group, but not in the moderate asthma group (14.3 +/- 14.5 to 24.3 +/- 20.6 versus 19.6 +/- 12.3 to 17.6 +/- 10.8 ng/mmol creatinine, p less than 0.05). The urinary LTE4 level increased in 10 patients (eight with severe asthma), and it decreased in seven patients (five with moderate asthma). A significant difference in the degree of bronchospasm after exercise (as shown by the maximal % fall in the peak expiratory flow rate), was seen when patients with increased urinary LTE4 excretion were compared with those with decreased excretion (60.4 +/- 17.3 versus 24.1 +/- 14.3%, p less than 0.01). Our findings suggest that exercise-induced asthma, or at least a subtype of exercise-induced asthma, may partly develop through the release of LTC4.