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Introduction: Periostin is a matricellular protein expressed by many tissues. Its release may be enhanced, among others, through mechanical stimulation of muscles and bones as well as by cytokines of allergic inflammation., Objectives: Our aim was to assess periostin levels in serum and exhaled breath condensate (EBC) of professional athletes, asthmatics and healthy controls. We also sought to determine whether acute treadmill exercise influences serum and EBC periostin., Methods: Study groups included 9 competitive swimmers, 10 mild-to-moderate asthmatics and 7 healthy controls. Athletes were assessed twice (in- and off-training period) while asthmatics and controls in one time-point. Data on demographics, allergy symptoms and exercise load were acquired through Allergy Questionnaire for Athletes (AQUA) and International Physical Activity Questionnaire (IPAQ). Serum and EBC were collected before and after treadmill exercise challenge., Results: Baseline serum periostin in swimmers during training period was significantly higher (5- to 7-fold) than in asthmatics (P = .01) and controls (P < .05). In EBC, lowest periostin levels were seen in athletes in-training as compared with off-training period (P < .01) and with asthmatics (P < .03). Acute bout of exercise did not induce significant changes neither in serum nor in EBC periostin in any group., Conclusion: Increased serum, but not EBC, periostin levels in competitive athletes are probably because of permanently increased exercise load leading to stimulation, injury and regeneration of musculoskeletal tissues. Periostin may be considered marker of long-term exercise overload after confirmation in larger groups., (© 2018 John Wiley & Sons Ltd.)

Background: The pathogenesis of exercise-induced bronchoconstriction (EIB) is poorly understood., Objective: To evaluate the biomarkers concentration in exhaled breath condensate (EBC) in schoolchildren with postexercise symptoms. We also evaluated changes in fractional exhaled nitric oxide (FeNO) value and the serum tryptase level after exercise., Methods: One hundred children with postexercise symptoms were included. Methacholine challenge testing (MCT) was performed at visit 2, and exercise challenge testing (ECT) was performed at visit 3. Before and after ECT serum tryptase levels and FeNO values were measured. EBC was collected after ECT from 10 randomly selected children from each group. The children were assigned to the following groups: ECT(+) MCT(+), ECT(+) MCT(-), ECT(-) MCT(+), ECT(-) MC(-). We measured the following molecules: eotaxin, interleukin (IL) 8, IL-1ra, IL-1 beta, IL-6, IL-1 alpha, IL-12(p40), IL-5, granulocyte-macrophage colony-stimulating factor, IL-7, IL-15, IL-4, IL-2, IL-10, tumor necrosis factor alpha, interferon gamma, IL-13, tumor necrosis factor beta, monocyte chemoattractant protein-1, IL-17A, macrophage inflammatory proteins-1 alpha, macrophage inflammatory proteins-1 beta, IL-12(p70), and regulated on activation, normal T-cell expressed and secreted by using a multiplex immunoassay. Prostaglandin E2 (PGE2), leukotriene B4, and cysteinyl leukotriene were analyzed by using separate enzyme-linked immunosorbent assay kits., Results: In the MCT(+) group, a detectable level of IL4 in EBC and detectible levels of eicosanoids were seen in the ECT(+) group. We observed the opposite direction of ECT-induced changes in FeNO and serum tryptase concentrations in patients with detectable compared with patients without detectable levels of cytokines in EBC. We showed ECT-induced reduction in the tryptase level in patients with a nondetectable PGE2 level in EBC and an increase in tryptase levels in patients who had detectable levels of PGE2 in EBC., Conclusions: EBC was a useful method to estimate inflammation but only in children with symptoms and with EIB shown by a positive ECT. Children with a positive ECT had detectable levels of eicosanoids in EBC; the opposite direction of ECT-induced changes in FeNO and serum tryptase concentrations was observed. The results of above study confirm the role of mast cells and eicosanoids in the pathogenesis of EIB in children.

Objective: To assess the effects of weight loss on adipokines, asthma-related symptoms, exercise-induced bronchospasm (EIB) and lung function, and to evaluate the role of leptin and adiponectin levels on lung function after treatment in obese adolescents., Methods: 84 postpubertal obese adolescents were enrolled and distributed in quartiles according to weight loss (low (<2.5 kg), low to moderate (>2.5 and <8 kg), moderate (<8 and <14 kg) and massive (<14 kg)). Body composition was measured by plethysmography, and visceral and subcutaneous fat were detected by ultrasound. Serum levels of adiponectin and leptin were analyzed. Lung function, asthma and EIB were evaluated according to the American Thoracic Society criteria. Patients were submitted to 1 year of interdisciplinary intervention consisting of physiotherapy, medical, nutritional, exercise, and psychological therapy., Results: After treatment the moderate and massive weight loss promoted an increase in adiponectin and adiponectin/leptin (A/L) ratio as well as a decrease in leptin levels and a reduction in EIB frequency and asthma-related symptoms. Furthermore, the reduction in leptin levels was a predictor factor to improvement in lung function., Conclusion: Interdisciplinary therapy was able to decrease EIB and asthma-related symptoms and to improve pro/anti-inflammatory adipokines. Additionally, the leptin concentration was a predictor factor to explain changes in lung function., (Copyright © 2012 S. Karger AG, Basel.)

Background: Exercise-induced bronchoconstriction (EIB), a form of bronchial hyperresponsiveness (BHR), is common in children with asthma or obesity. Epidemiological studies have shown that asthma and obesity are increasing in parallel, but obesity- and adipokine-related effects on inflammation and BHR have not yet been demonstrated in the human airway., Objective: To address the relationship between leptin and adiponectin and EIB in children with asthma., Methods: Eighty-five prepubertal children between the ages of 6 and 10 years were included in our study. They comprised obese with asthma (n = 19), normal weight with asthma (n = 23), obese without asthma (n = 23), and healthy (n = 20). We measured serum leptin and adiponectin levels. We also performed pulmonary function tests: baseline, postbronchodilator inhalation, methacholine inhalation, and exercise. The area under the forced expiratory volume in 1 second (FEV(1))-time curve quantified the severity of EIB over a 20-minute period after exercise (AUC(20))., Results: The obese children had significantly elevated levels of leptin and reduced levels of adiponectin. The maximum decreases in %FEV(1) and AUC(20) after exercise were positively correlated with leptin levels and negatively with serum adiponectin levels in children with asthma. The odds for having EIB were incrementally and significantly higher for children with higher levels of serum leptin., Conclusions: Levels of the adipocyte-derived hormones leptin and adiponectin are significantly correlated with BHR induced by exercise challenge in children with asthma. Further studies are needed to elucidate whether the changes in leptin and adiponectin levels bear a causal relationship to the EIB/BHR., (Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Epidemiological studies have established a relationship between low levels of serum vitamin D and reduced lung function in healthy adults, and asthma onset and severity in children. However, no study has examined the relationship between vitamin D levels and exercise-induced bronchoconstriction in asthmatic children. We evaluated the relationship between 25-hydroxyvitamin D concentrations and baseline forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and change in FEV1 (ΔFEV1) after a standardised exercise challenge in 45 children with intermittent asthma. Only 11% of the children had desirable serum vitamin D levels (at least 30-40 ng·mL(-1)). A positive correlation was found between serum 25-hydroxyvitamin D and both FVC (r=0.34; p=0.037) and FEV1 (r=0.32; p=0.037). Subjects with a positive response to the exercise challenge (ΔFEV1≥10%) presented lower serum levels of 25-hydroxyvitamin D than children with a negative challenge (mean±sd 16.2±5.2 versus 23.4±7.0 ng·mL(-1), respectively; p=0.001). Our results indicate that hypovitaminosis D is frequent in asthmatic children who live in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced lung function and increased reactivity to exercise.

Purpose of Review: This review describes the diverse clinical manifestations of IgE-mediated allergy to ingested wheat and summarizes recent advances in characterization of clinically significant allergens and diagnostic workup., Recent Findings: Recent population-based studies have shown the prevalence of wheat allergy and sensitization more precisely than past studies among small populations and in hospital settings. Intensive research has demonstrated the diverse profile of both water/salt-soluble and insoluble allergens involved in clinical types of wheat allergies determined depending on the patient age, the sensitization route, and the protein state during the exposure. Consequently, some new allergens, including nonspecific lipid transfer protein (Tri a 14), have been identified. For diagnosis, the role of water/salt-insoluble gliadins, particularly omega-5 gliadin, a major allergen of wheat-dependent, exercise-induced anaphylaxis, was assessed as compared with the results of oral challenges. The mechanisms of eliciting anaphylactic symptoms by exercise in wheat-dependent, exercise-induced anaphylaxis were speculated upon; one is the allergenicity strengthened by activated tissue transglutaminase and another is the increased absorption of allergens through the gastrointestinal tract., Summary: Findings of the recent studies show potential for more precise diagnosis in each clinical type of wheat allergies.

Wheat is not an uncommon cause of food-dependent, exercise-induced anaphylaxis. This study aims to describe common clinical characteristics and laboratory manifestations of the disease. Five children, aged 8-14 years were evaluated. An atopic history was found in 20% of the patients. All patients had symptoms which involved the skin and three had hypotension. Serum specific IgE for wheat was measured and showed a positive result in 2 patients. A three-day challenge protocol with an open challenge for wheat on day 1, an exercise challenge test on day 2 and another exercise challenge test on day 3 after a meal containing wheat was performed. Four patients completed the three-day challenge protocol. Anaphylaxis occurred in 2 out of 4 patients who consumed more than 100 grams of wheat prior to the exercise. The three-day challenge protocol is a definitive diagnostic tool to confirm the diagnosis of WDEIA. However, the amount of wheat used for challenging should be at least 100 grams.

Background: IL-13 is a pivotal cytokine in allergic inflammation and bronchial hyperresponsiveness, and is known to influence leukotriene levels., Objective: We investigated whether IL-13 polymorphisms may be associated with clinical phenotypes and drug responsiveness to the leukotriene receptor antagonist (LTRA) in Korean asthmatic children with exercise-induced bronchoconstriction (EIB)., Methods: We enrolled 242 normal controls and 374 patients with asthma. Of the asthmatic patients, 100 performed exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks and included 80 subjects in drug responsiveness analysis. We assessed IL-13 polymorphisms (-1512A/C, -1112C/T, +2044G/A) through PCR-restriction fragment length polymorphism analysis., Results: Significantly higher total IgE levels and maximum percent fall in forced expiratory volume in 1 s (FEV1) (%) after exercise challenge test were found in asthmatic patients carrying one or two copies of the IL-13 +2044A versus those homozygous for +2044G (P=0.011 and 0.040, respectively). We further noted a correlation of total IgE with maximum percent fall in FEV1 (%) in asthmatic patients, as well as a reverse correlation with improvement of maximum percent fall in FEV1 (%) after exercise challenge tests. Finally, we observed a significant association between responsiveness to montelukast and IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms., Conclusion: The IL-13 +2044G/A polymorphism may be associated with atopy and EIB severity in Korean children with EIB, and thus could potentially be considered as a disease-modifying gene. Moreover, the IL-13 -1112C/T polymorphism and the haplotype of IL-13 polymorphisms seem to be associated with LTRA drug responsiveness, and thus might prove useful as a target for modulation of LTRA drug responsiveness.

Background: The pathogenesis of exercise-induced bronchoconstriction in asthma is incompletely understood, and the role of lipoxin A4 has not been investigated., Objective: To investigate the involvement of lipoxin A4 in exercise-induced bronchoconstriction., Methods: Two groups of children were enrolled in the study: asthmatic children with positive (n = 12) and negative (n = 8) responses to exercise. Levels of lipoxin A4 were determined in plasma before and immediately after exercise challenge using enzyme-linked immunosorbent assay., Results: No significant difference was observed in the pre-exercise lipoxin A4 levels among the groups (p > 0.05). A significant difference was observed in the postexercise lipoxin A4 levels between the two groups (p = 0.041). We also observed significant decreases in plasma lipoxin A4 levels immediately after exercise challenge both in asthmatic children with positive responses to exercise (p = 0.013) and negative responses to exercise (p = 0.05). But these levels were significantly higher in asthmatic children with negative responses to exercise (p = 0.041). There was an inverse correlation between lipoxin A4 levels and a reduction in forced expiratory volume at one second percent after exercise (p = 0.045, r = -0.465)., Conclusion: Our results are the first demonstration of the lower levels of lipoxin A4 associated with exercise-induced bronchoconstriction in asthma. We hypothesize that the development of exercise-induced bronchoconstriction in asthmatic children may be in relation to a reduced endogenous lipoxin biosynthetic capability. Lipoxin mimetics and related compounds could provide novel therapeutic approaches to the treatment of exercise-induced bronchoconstriction in asthma.

In asthmatic patients, airway obstruction provoked by exercise challenge is accompanied by an increase in plasma adenosine level. In this study, the current authors investigated if exercise-induced bronchoconstriction was associated with local changes of adenosine concentration in the airways. Oral exhaled breath condensate (EBC) collection (5-min duration) and forced expiratory volume in one second (FEV1) measurements were performed at rest (baseline) and 4-8 times after treadmill exercise challenge in healthy and asthmatic subjects. Adenosine concentration in EBC was determined by HPLC. Observations indicated that physical exercise results in bronchoconstriction together with a significant increase of adenosine level in EBC in asthmatic patients (mean+/-sd maximal fall in FEV1 27+/-13%; associated increase in adenosine 110+/-76% as compared to baseline), but not in healthy control subjects. Exercise-induced changes in adenosine concentration correlated significantly with the fall in FEV1 values in asthmatic patients. In conclusion, the observed increase in adenosine concentration of oral exhaled breath condensate most probably reflects changes in the airways during exercise-induced bronchoconstriction. Due to its known bronchoconstrictor property in asthma, adenosine may contribute to the development of bronchospasm.

Purpose: Estimate influences of standard physical exercise on lactic acid concentration and acid-base equilibrium in patients with mild and moderate bronchial asthma compared with healthy trained persons and do not ones., Material and Methods: In 47 asthmatic patients and 20 healthy persons: 1) bronchial reactivity was investigated; 2) at rest and 1, 5 and 10 min after 8 min exercise (PWC85%max, bicycle ergometer): FEV1, lactic acid concentration (LAC), pH, pO2, pCO2 and HCO3 (in capillary blood) were investigated. Among asthmatic patients: 1) 21 experienced exercise-induced asthma (EIA), 2) 20 reacted to histamine in concentration of 0.125 mg/ml/3', 3) 6 reacted to histamine in concentration of 0.25 mg/ml/3'. In healthy persons, without EIA and reaction to histamine, were: 12 who did not train, and 8 athletes., Results: After exercise LAC increased in all groups (p<0.05); the increase was significantly higher in patients and persons who did not train, then athletes, and did not normalised, in opposite to athletes, however in persons who did not train was significantly lower then in asthmatics. pH and pCO2 did not change significantly in all examined persons, but HCO3 decreased significantly in patients with bronchial hyperactivity and in persons who did not train. Significant increase of pO2 appeared only in healthy persons., Conclusion: Physical effort caused significant greater metabolic changes in asthmatic patients then in healthy persons, especially athletes

Background: Exercise-induced asthma (EIA) is increasingly encountered among school children in Kuwait. Available evidence has shown that inflammatory mediators may be involved in the pathogenesis of EIA. Studies on release of inflammatory mediators have been carried out in adult patients with asthma in Kuwait, but no study on EIA involving children has taken place in this region., Objective: To investigate changes in the concentration of some of the mediators involved in EIA in adolescent school children, using exercise challenge., Design: Prospective, case control study., Setting: Respiratory and Cardiology units Mubarak Hospital, Kuwait, between January and June 2001., Subjects: Nine EIA and 14 non-EIA and 10 normal control subjects, designated as groups one, two and three aged between 13 and 17 years, who were non-smokers, were enrolled for the study., Main Outcome Measures: Blood eosinophils (EOS), eosinophil cationic protein (ECP) and tryptase were estimated pre-exercise, 5 and 30 minutes after exercise. Spirometry was measured at the same period., Results: In group one, ECP and tryptase levels fell after exercise, but significant difference in the levels were obtained only in tryptase between pre-exercise and 30 minutes after exercise (4.1 microg/L Vs 3.8 microg/L) P <0.05, while the difference for ECP was not significant (P=0.09). In group two, both tryptase (6.0 microg/L Vs 5.7 microg/L) P < 0.05, and ECP (21.8 microg/L Vs 12.1 microg/L) P<0.01, fell after exercise. However, in group three, no appreciable difference was observed between pre and post exercise. Correlation between tryptase and EOS (r=0.770; P<0.05) and between tryptase and ECP (r=0.850; p<0.05) was observed pre-exercise and after exercise in groups one and two., Conclusion: A fall in the level of the mediators was observed after exercise challenge, but the relevance of this finding in the pathogenesis of EIA remains unclear. Further studies are required to verify this finding.

Objective: To explore the role of eosinophil cationic protein (ECP) and T lymphocytes in exercise-induced asthma (EIA)., Methods: In 32 patients with asthma (13 patients with EIA) and 8 normal subjects, peripheral blood ECP, CD(25)(+)%, and IL-5 mRNA were measured before, 10 min and 60 min after exercise testing., Results: (1) There was a linear relationship between ECP, CD(25)(+)% and the forced expiratory volume in one second (FEV(1)) before exercise (r = -0.79, -0.61, P < 0.01). (2) In patients with EIA, FEV(1) and PEF decreased remarkably after exercise test, but in patients without EIA, FEV(1) and PEF did not change. The difference between the two groups was significant. (3) There was no significant difference between the two groups in terms of ECP, CD(25)(+)%, and IL-5 mRNA., Conclusion: T lymphocyte activation and ECP secreted by eosinophils do not seem to play a major role in EIA.

Background: Exercise-induced asthma is defined as the transient broncho-spasm, that occurs after 3 to 8 minutes of continuous exercise; one of two mechanisms are implicated: the first is given by a hyper-osmolar environment interchange with the warm respiratory air and the water loss, the second due to reactive hyperemia or bronchial blood vessels edema., Objectives: To determine the effectiveness and safety of Zafirlukast treatment in exercise induce asthma, and in mild and moderated persistent bronchial asthma. Evaluate the security with laboratory test IL-2, IL-4, INFg, and CD69, to determinate TH1 and Th2 cells, laboratory and thorax x-ray determinations before and after zafirlukast treatment in exercise induce asthma, plus the functional respiratory test, and assert the clinical and adverse reaction with Zafirlukast., Material and Methods: A open, prospective, longitudinal study. Challenge test on a treadmill for 8 minutes. Twenty patients from the Allergy Service at Lic. Adolfo López Mateos Hospital, ISSSTE, in México City, fifteen female and five males. Aged 15 to 35 years. There was a control group of ten healthy subjects with similar age and sex. The drug Zafirlukast was administered 20 mg twice a day for eight weeks, with patient's informed and signed consent. Laboratory test: Blood Cell count, transaminases, bilirubins A, G, M and E immunoglobulins thorax X-ray, electrocardiogram, functional respiratory test before and after treatment., Results: Zafirlukast blocked exercise induced asthma in the early and late phases. There was a statistically significant improvement of a VEF-1 after exercise with a p > 0.001; furthermore, there was significant improvement in the mid-spiratory speed before the exercise with a p > 0.05. The mid-spiratory speed after the exercise, improved (p > 0.01). There were no collateral reactions, such as Churg-Strauss, only transitory headache in six and nauseas in two. There were no statistically significant changes in the cytokines assessment., Conclusions: There were no statistically significant changes in the cytokines assessments, in four cases the IL-4 decreased after the treatment. The anti-leukotriene improved the bronchospastic answer during the early and late phases, reducing the FEV-1, decreasing the recovering phase.

We investigated whether the level of plasma adenosine (ADO) changed during exercise and whether this could be related to exercise-induced bronchoconstriction. Baseline levels of ADO did not differ, but exercise resulted in higher ADO in patients with asthma than in healthy subjects (86 +/- 35 vs 59 +/- 16 nmol/L; P <.001). In patients with asthma, the increase in ADO was related to decreases in FEV(1) (r (2) = 0.475; P <.05) and SaO(2) (r (2) = 0.693; P <.05). These data suggest that adenosine might be involved in the development of exercise-induced bronchoconstriction.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

It has been suggested that airway eosinophilic inflammation is associated with the severity of exercise-induced bronchospasm (EIB). Blood eosinophils are known to be an indirect marker of airway inflammation in asthma. The aim of this study is to investigate that a simple and easy blood test for blood eosinphil counts may predict the severity of EIB in asthma. Seventy-seven men with perennial asthma (age range 18-23 years) were included. Lung function test, skin prick test, and blood tests for eosinophils counts and total IgE levels were performed. Methacholine bronchial provocation test and, 24 h later, free running test were carried out. EIB was defined as a 15% reduction or more in post-exercise FEV1 compared with pre-exercise FEV1 value. Atopy score was defined as a sum of mean wheal diameters to allergens. EIB was observed in 60 (78%) of 77 subjects. Asthmatics with EIB showed significantly increased percentages of eosinophils (P<0.01), log eosinophil counts (P<0.001), and atopy scores (P<0.05) and decreased log PC20 values (P < 0.05) compared with asthmatics without EIB. Asthmatics with eosinophils of > 700 microl(-1) (36.9 +/- 12.7%) had significantly greater maximal % fall in FEV1 after exercise than asthmatics with eosinophils of < 350 microl(-1) (24.7 +/- 16.6%, P <0.05). Blood eosinophil counts > 350 microl(-1) yielded the specificity of 88% and positive predictive value of 93% for the presence of EIB. When a multiple regression analysis of maximal % fall in FEV1 according to log eosinophil counts, log PC20, log IgE and atopy score was performed, only blood eosinophil counts were significant factor contributing to the maximal % fall in FEV1 after exercise. These findings not only suggest that a simple blood test for eosinophils may be useful in the prediction of the severity of EIB, but also reinforce the view that airway eosinophilic inflammation may play a major role in EIB in asthma.

Background: Lycopene has previously been shown to have high antioxidative activity. In view of the controversy regarding the beneficial effect of antioxidants on asthma, the acute effects of lycopene (LYC-O-MATO) on airway hyperreactivity were assessed in patients with exercise-induced asthma (EIA)., Methods: Twenty patients with EIA participated in our study to verify the antioxidative effects. The test was based on the following sequence: measurement of baseline pulmonary function, 7-min exercise session on a motorized treadmill, 8-min rest and again measurement of pulmonary function, 1-week, oral, randomly administered, double-blind supplementation of placebo or 30 mg/day of lycopene (LYC-O-MATO), measurement of pulmonary function at rest, 7-min exercise session, and 8-min rest and again measurement of pulmonary function. A 4-week washout interval was allowed between each protocol., Results: All patients given placebo showed significant postexercise reduction of more than 15% in their forced expiratory volume in 1 s (FEV1). After receiving a daily dose of 30 mg of lycopene for 1 week, 11 (55%) patients were significantly protected against EIA. Serum analyses of the patients by high-pressure liquid chromatography detected in the lycopene-supplemented patients an elevated level of lycopene compared to the placebo group, with no change in retinol, tocopherols, or in the other carotenoids., Conclusions: Our results indicate that a daily dose of lycopene exerts a protective effect against EIA in some patients, most probably through an in vivo antioxidative effect.

beta-adrenaline receptors exist on peripheral mononuclear leukocytes as well as in lung tissue. We assessed the relationships of plasma catecholamine release by exercise to aerobic capacity and to exercise-induced asthma (EIA) in asthmatic children (Study 1). We then measured mononuclear leukocyte beta-adrenergic receptor densities at rest and assessed the relationships of the number of receptors to aerobic capacity, EIA, and bronchial responsiveness to acetylcholine (Study 2). Study 1: Eleven children (9 males, 2 females; 11-16 years old) with bronchial asthma participated in this study. The subjects underwent an incremental aerobic exercise test on a cycle ergometer to determine their aerobic capacity at the lactic threshold (LT) and VO2max. Each subject underwent an EIA test of which the intensity was 175% of LT, and plasma catecholamine concentrations were measured before and after exercise. A significant negative relationship was found between the degree of EIA and % change of plasma adrenaline concentrations to rest level (p < 0.05), and a significant positive relationship was found between VO2 max/wt and % change of plasma adrenaline concentrations (p < 0.05). Study 2: Twelve asthmatic children (10 males, 2 females; 11-16 years old) participated in this study. Aerobic capacity, and degree of EIA were also measured in each subject by the same method as that used in Study. 1. The number of mononuclear leukocyte beta-adrenergic receptors at rest was determined by (-) [125I]-iodocyanopindolol binding in each subject. A significant negative relationship was found between the number of adrenergic receptors and Max. % fall in FEV1.0 (p < 0.01), and a significant positive relationship was found between the number of adrenergic receptors and VO2max/kg (p < 0.001). These results suggested that a reduced adrenaline production and a reduced number of beta-receptors contributed to the pathogenesis of EIA.

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.

Objectives: The degree and duration of protection against exercise-induced bronchoconstriction afforded by three doses of a specific leukotriene D4 receptor antagonist, cinalukast, were assessed after an initial dosing and after 1 week of therapy., Methods: A placebo-controlled crossover study was performed in eight male patients who had mild, stable asthma and exercise-induced bronchoconstriction. Treatment consisted of four 7-day periods of placebo and three dose levels of the drug (10, 50, and 200 mg administered orally). Exercise challenge was performed at 2 hours and 8 hours after treatment on the first and seventh treatment days. The response was measured as the area under the FEV1-time effect curve (AUEC)., Results: On the first day of treatment, the mean (+/- SEM) AUEC at 2 hours was 24.2 +/- 3.3 L.min after placebo and was 5.5 +/- 2.2 L.min, 6.3 +/- 2.7 L.min, 3.3 +/- 3.8 L.min after 10 mg, 50 mg, and 200 mg, respectively (p < 0.05 for all values compared with placebo). The AUEC at 8 hours on the first day was 25.1 +/- 4.4 L.min after placebo and was 6.8 +/- 4.1 L.min, 11.2 +/- 2.5 L.min, and 5.0 +/- 2.8 L.min after 10 mg, 50 mg, and 200 mg, respectively (p < 0.05 for all values compared with placebo). The protection afforded by 10 mg of cinaluicast was lost after 7 days of treatment but persisted with 50 mg and 200 mg doses., Conclusion: Orally administered cinalukast provides at least 8 hours of protection against exercise-induced bronchoconstriction. This protection is lost with regular treatment for 1 week for the lowest dose studied.

We evaluated the effect of inhaled indomethacin, a nonsteroidal antiinflammatory drug (NSAID), on exercise-induced bronchoconstriction (EIB) in children with asthma. Nine asthmatic children (7 boys, 2 girls, with a mean +/- SEM age of 11.0 +/- 0.8 yr) with a history of EIB participated in this study. These subjects were pretreated with inhaled indomethacin (3 mg/m2 body surface area [BSA]) or placebo (0.9% saline) according to a double-blind, randomized, crossover design, and underwent an exercise challenge test 15 min after the pretreatment. Inhaled indomethacin significantly attenuated EIB. The mean maximal percent decrease in FEV1 following exercise was 36.1 +/- 5.7% after placebo and 18.0 +/- 4.6% after indomethacin pretreatment (p = 0.0310). Indomethacin also significantly reduced the mean maximal decrease in arterial oxygen saturation after exercise (p = 0.0378). The inhibition of local prostaglandin synthesis and/or ion transport in the airways may be a mechanism involved in the protective potency of inhaled indomethacin.

Thrombomodulin (TM) is a membrane protein present in the vascular endothelium. It has also been found in human plasma, within which, however, its pathological functions have not been clearly described. In this study, the plasma TM concentrations in 19 asthmatic patients were determined by sandwich enzyme immunoassay using two monoclonal antibodies for human TM. The concentration of plasma TM in exercise-induced asthma (EIA)-positive asthmatic patients was significantly increased by exercise challenge. In addition, for these patients a positive correlation was found between the severity of EIA and the degree of change in plasma TM induced by exercise challenge. These findings suggest that the increase in influx of TM into the plasma in EIA-positive asthmatics may be due to generalized pulmonary endothelial damage following exercise challenge.

Objective: To determine whether a generic slow-release theophylline tablet (manufactured by Sidmak Laboratories, Inc.) is therapeutically equivalent to a proprietary theophylline tablet, Theo-Dur, in children., Design: Prospective, randomized, double-blind, crossover trial., Setting: Multicenter clinics., Patients: 38 children, 6 to 16 years of age, with asthma., Interventions: Individualized doses of Theo-Dur or generic tablet every 12 hours for 5 days., Measurements and Main Results: During the last 24 hours of each regimen, theophylline serum concentrations were measured serially and a standardized exercise stress test was performed at 24 hours (trough serum concentration). Neither formulation effectively blocked the response to exercise; the maximum decrease in forced expiratory volume in the first second was 26.1% +/- 18.9% with Theo-Dur and 24.8% +/- 19.7% with the generic product (p = 0.68; beta = 0.08). The mean +/- SD peak serum concentrations were 18.0 +/- 3.0 micrograms/ml with Theo-Dur and 18.7 +/- 3.7 micrograms/ml with the generic tablet; the trough serum concentration was < 10 micrograms/ml in 15 subjects after administration of Theo-Dur and in 20 subjects after administration of the generic product. There were no significant differences in relative extent of absorption or the time to reach peak serum concentration., Conclusions: This generic formulation and Theo-Dur are bioequivalent in children. However, these results cannot be extrapolated to slow-release theophylline formulations that have not been approved by the U.S. Food and Drug Administration as equivalent to Theo-Dur.

The present study was designed to examine the effect of physical exercise on T-lymphocyte proliferation in patients with exercise-induced asthma (EIA). Indeed, a decrease in different immune functions is described in normal man after exercise. Thirty subjects (10 normal and 20 asthmatic subjects with or without EIA) underwent a submaximal exercise test on an electrically driven treadmill. Before and after this test, ventilatory variables were measured, and venous blood was taken to study plasma histamine (RIA) and spontaneous and phytohemagglutinin (PHA)-pulsed T-lymphocyte proliferation (mononuclear cells isolated on Ficoll-Hypaque; tritiated thymidine incorporation). Ten minutes after the end of the exercise, there was a significant FEV1 decrease only in asthmatic subjects with EIA (mean: 24 +/- 5%). In the same group, the mean plasma histamine level was 0.31 ng/ml-1 (+/- 0.06) before the challenge. It rose to 0.62 ng/ml-1 (+/- 0.14) 10 min after the end of the exercise (P < 0.05), and returned to normal limits 20 min after the test. In this group, there was also a significant decrease (by about 35%) of spontaneous and PHA-pulsed T-lymphocyte proliferation 2 and 4 h after the exercise. By contrast, exercise challenge had no effect on either plasma histamine level or T-lymphocyte proliferation in the normal group. Our results show a rapid and transient increase in plasma histamine in EIA. This was followed 2 and 4 h later by a significant decrease of T-lymphocyte proliferation. A possible relationship between these two phenomena is discussed.

The influence of different inspired air conditions on exercise-induced bronchoconstriction (EIB) is well appreciated. However, the mechanism by which this influence is exerted is uncertain. To determine if varied inspired air conditions during exercise could affect the catecholamine response to physical exercise, we had 13 asthmatic and 6 healthy children (aged 10-18 years) undergo two bouts of cycle ergometry tests under different air conditions. One test was done while breathing cold dry (CD) air (temperature, -20.2 degrees C; relative humidity, 0%) and the other while breathing warm humid (WH) air (temperature, 34.3 degrees C; relative humidity, 100%). Forced expiratory volume in 1 second (FEV1) and plasma catecholamine concentrations were recorded before and after exercise. Marked EIB (48 +/- 5% SEM fall in FEV1 from baseline) developed in all asthmatics after the CD exercise, but no EIB was noted after the WH exercise. Normal controls had no EIB under either test conditions. Plasma levels of catecholamines at rest, and the changes that occurred during and after exercise, were comparable within as well as between the groups in both tests. Catecholamines did not rise in asthmatics following development of EIB. These data demonstrate that inspired air conditions do not influence the sympathoadrenal response to exercise, at least as reflected in plasma catecholamine levels. In fact, this response did not differ between asthmatics and normals, irrespective of the development of EIB. These results are consistent with previous reports about impaired catecholamine response of asthmatics to bronchoconstriction.

To investigate the role of eosinophilis in the mechanisms of EIA we determined the changes in the density distribution profiles and ultrastructure of peripheral eosinophils from children with asthma after exercise. The subjects were 20 asthmatic children consisting of 12 EIA-positive patients and 8 EIA-negative patients and 6 normal children. Fifteen, 30 and 60 minutes after exercise, the number of hypodense eosinophils (< 1.0825 g/ml) in the EIA-positive group was significantly higher than in the EIA-positive group. In the ultrastructural findings, before exercise the ratio of the area of specific granules to the area of cytoplasm per cell (the ratio SG/C) was significantly higher in the EIA-negative patients than in the EIA-positive patients even before exercise, and the ratio of the degranulated area to the area of cytoplasm per cell (the ratio D/C) was significantly higher in the EIA-positive group than in the EIA-negative group. Thirty minutes after exercise, the ratio D/C had clearly increased in the EIA-positive group. These results suggested that eosinophils in the EIA-positive group were already activated before exercise. It will be necessary to further study the factors activating eosinophils which play some roles in EIA.

This study compared the protection provided by salbutamol and salmeterol against exercise-induced asthma. Asthmatic patients (n = 12) with exercise-induced asthma were exercised submaximally for 6 min on a treadmill 1, 6 and 12 h after inhalation of 200 micrograms salbutamol or 50 micrograms salmeterol. Each patient also took baseline exercise 1 h after two puffs of placebo. Two days later the drugs were administered in a double-blind trial of crossover design with an interval of 48 h between the two treatments. The main parameters measured were: air flow with a Wright flowmeter and mediator concentrations (histamine, leucotriene and prostaglandin D2 measured by radioimmunoassay) in venous blood, which was withdrawn before and 4 min after each exercise period. The maximum percentage bronchoconstriction recorded following placebo was 29 +/- 4% and following salbutamol inhalation it was 4 +/- 4%, 20 +/- 13%, 27 +/- 10%, respectively, for the exercise periods performed 1, 6 and 12 h after inhalation of the drug. Following salmeterol, the corresponding figures were 3 +/- 4%, 3 +/- 3% and 11 +/- 9%. The concentrations of mediator in plasma were significantly increased after exercise. Salbutamol and salmeterol intake reduced these concentrations both when the patients were at rest and following the exercise period. This effect of both drugs on the mediators corresponded with the protection they provided against exercise-induced asthma and was maintained for 12 h after salmeterol inhalation and for 6 h after salbutamol inhalation.

As many as 71 bronchial asthma (BA) patients and 12 patients suffering from chronic asthmatic bronchitis were examined in the stage of subsiding exacerbation. Before and 10 minutes after exercise measurements were made of the blood content of histamine (H), PGF2 alpha and PGE, adrenaline (A) and noradrenaline (NA), hydroperoxides (HP), and of the general and non-protein thiol groups. The initial level of H, PGF2 alpha, HP, A and NA was so much higher than the control value and the degree of its increase after exercise was so much more significant the more pronounced bronchospasm of effort (BE). The content of PGE after exercise rose to an approximately equal measure both in patients and in healthy subjects thereby pointing out to the relationship between the PGE increment and muscular work itself. The low level of thiol group in BA patients' blood determined by the pathological process was noticeably reduced after exercise, paralleled by an increase in the content of HP. Thus, muscular work in BA patients demonstrates high responsiveness of the systems that produce bronchoconstricting substances. It is likely that BE and its degree in BA patients may be predicted more significantly on the basis of the blood content of H, PGF2 alpha and HP rather than on the basis of the clinical and functional parameters.

The variations in serum levels of eosinophil cationic protein (ECP) have been measured after exercise challenge of 13 patients with asthma with exercise-induced asthma (EIA) and nine patients with asthma without EIA. The patients were treated before exercise in a randomized and blinded fashion with inhalation of one dose of either disodium chromoglycate, terbutaline, or budesonide and in an open study with 4 weeks of inhaled budesonide. In the group with EIA, there was, in some patients, an initial increase in serum levels of ECP after exercise, but 60 minutes after exercise, the levels were significantly reduced (p less than 0.001). Disodium chromoglycate and 4 weeks of budesonide treatment inhibited this reduction. Histamine challenge of the group with EIA produced a similar fall in serum ECP levels (p less than 0.001). The group without EIA had initially lower levels of ECP than the group with EIA (p less than 0.05 to p less than 0.01), and ECP stayed unaltered after exercise. The preexercise serum ECP levels correlated significantly to the maximal fall in peak expiratory flow in the untreated group (r = 0.91; p less than 0.001) and in the group receiving one dose of budesonide (r = 0.62; p less than 0.05). The blood eosinophil counts were unchanged after challenge and not related to lung function. The results suggest that the ECP content in serum reflects the degree of allergic inflammation in the lungs and thereby the degree of bronchial hyperreactivity.

Background: Intravenous infusion of atrial natriuretic peptide has been shown to cause bronchodilatation in patients with asthma and endogenous atrial natriuretic peptide is known to rise with exercise. Whether an aberration in release of atrial natriuretic peptide is concerned in the pathogenesis of exercise induced bronchoconstriction has not been studied., Methods: The atrial natriuretic peptide response to exercise was studied in eight men with exercise induced asthma and eight age matched non-asthmatic men. Subjects exercised to exhaustion on a treadmill, using the Bruce protocol. Atrial natriuretic peptide and catecholamines were measured at the end of each stage of exercise and oxygen consumption and heart rate were monitored throughout., Results: Both groups showed a 3.5 fold increase in plasma atrial natriuretic peptide during exercise (mean (SE): normal subjects 25 (4) pmol/l; asthmatic subjects 24 (5) pmol/l), with no difference between the two groups. There was a close correlation between plasma atrial natriuretic peptide concentrations and oxygen uptake, catecholamine release, and heart rate in both groups. The catecholamine response was similar in the asthmatic and normal subjects, both groups showing a four fold rise in plasma adrenaline and a 4-5 fold rise in plasma noradrenaline., Conclusion: A defect in the release of circulating atrial natriuretic peptide does not account for exercise induced asthma; the concentrations of the circulating peptide that were achieved may effect a small reduction in airway reactivity. Our data do not support the idea that asthmatic patients have abnormal sympathoadrenal activity.

Objective: To determine whether caffeine consumption affects bronchoprovocation challenge (BPC)., Design: A prospective, double-blind, placebo-controlled, randomized, crossover trial., Patients: Eleven nonsmoking men, aged 18 to 42 years, with normal baseline spirometry and evidence of exercise-induced bronchospasm., Intervention: On three separate test days, each individual received, in random order, either placebo, 5 mg/kg caffeine, or 10 mg/kg caffeine, and then underwent BPC with eucapnic voluntary hyperventilation (EVH)., Results: Caffeine (10 mg/kg) significantly reduced bronchoconstriction compared to placebo (p = 0.02). The reduction in bronchoconstriction correlated with the serum level of caffeine (p = 0.014)., Conclusions: Caffeine decreases bronchoconstriction due to EVH. Caffeine should be eliminated from diet prior to BPC.

In order to investigate the mechanism of exercise-induced asthma (EIA) from the aspect of eosinophil function, we determined the changes in the peripheral eosinophil count and the specific gravity of the eosinophils in EIA patients, and also as a parameter of endocrine function, we determined the serum cortisol level. All parameters were analyzed in respect to time before and after inducement of exercise. The subjects selected for this study were 14 asthmatic children, an EIA positive group consisting of 8 subjects and 6 subjects in an EIA negative group. Eosinophil counts with a specific gravity less than 1.0825 gm/ml were recorded in respect to the time sequence of 15, 30, and 60 minutes after inducement of exercise. The eosinophil counts recorded were significantly higher in the EIA positive group in comparison to the EIA negative group. With progression of time after inducement of exercise, the number of eosinophils observed with a specific gravity of less than 1.0825 gm/ml tended to increase in the EIA positive group when compared to the results recorded before inducement of exercise. In respect to the course of time, 15 minutes after inducement of exercise, the serum cortisol level tended to decrease. At the point of 7 hours after inducement of exercise, the serum cortisol levels in the EIA positive group were significantly lower than the EIA negative group. These findings suggest that eosinophils and the endocrine system play an important role in EIA.

Metabolic and cardio-respiratory responses of four asthmatic and four non-asthmatic athletes to two hours of treadmill running at 70 percent of maximal oxygen uptake are compared. The asthmatic group had pre-exercise airflow obstruction, as indicated by the lower forced expiratory volume in one second (FEV1) even after medication (2.90 +/- 0.661) compared to the non-asthmatic group (4.09 +/- 1.331). Changes in blood lactate, glucose and catecholamine concentrations as a result of the two hour run were similar for the two groups. However, the pattern of breathing was different. The asthmatics had a slower breathing frequency but a similar tidal volume to the non-asthmatics. Both groups had an increase in the ventilation rate over the two hour run. For the non-asthmatic group, this increase in ventilation was achieved by an increase in the breathing frequency (p less than 0.01), whereas tidal volume was reduced (p less than 0.05). The increase in the ventilation rate over the two hour run for the asthmatic group was brought about by a small increase in breathing frequency (p less than 0.05), whereas tidal volume was not changed. This maintenance of the tidal volume by the asthmatic athletes during endurance running may compensate for the airflow obstruction, and so allow successful participation in endurance running.

Maximal growth hormone (GH) increments following exercise were compared in asthmatic (n = 14) and normal (n = 8) children. Exercise, which consisted of 6 min ergometer cycling while breathing cold dry (CD) air, induced asthma in all asthmatic patients but not in normal subjects. Baseline plasma GH levels were similar in both groups. Following exercise, however, asthmatic patients had significantly higher mean GH increments than normal subjects (14.8 vs 4.9 ng/ml, P less than 0.025). To evaluate the possible role of bronchoconstriction in the GH response all subjects exercised again, this time while breathing warm humid (WH) air. Despite the absence of exercise-induced asthma (EIA) while breathing WH air, asthmatic patients still had significantly higher mean GH increments than normal subjects (9.2 vs 2.3 ng/ml, P less than 0.05). We conclude that some asthmatic children show excessive GH secretion after exercise regardless of inspired air conditions or the development of EIA.

We compared specific airway conductance (SGaw) and the FEV1 after repetitive exercise or repetitive eucapnic voluntary hyperventilation (EVH) challenges. Replicate challenges were matched in terms of inspired air conditions and minute ventilations (VE) in order to determine the degree of refractoriness after each type of challenge in patients with exercise-induced asthma. Ten patients exercised or hyperventilated dry, room temperature air at matched VE on two study days. When the patients FEV1 had returned to 90% of baseline or better, or at 3.75 h if FEV, had not returned to 90% of baseline, patients repeated the identical exercise or the EVH challenge. Minimum FEV1 values expressed as a percent of predicted FEV1 after the first and second exercise challenges were 52 +/- 16 and 58 +/- 17, respectively, which were statistically different (p less than 0.001; paired t test). Minimum FEV1 values after the first and second EVH challenges were 52 +/- 13 and 59 +/- 9% of predicted, respectively, which were also statistically different (p less than 0.01; paired t test). Seven of 10 subjects demonstrated higher SGaw values after the second exercise challenge compared with the first challenge, whereas eight of 10 subjects showed higher SGaw values after the second EVH challenge compared with the first challenge. Paired t test analysis indicated that percent protection, measured by FEV1, was similar after either type of challenge. We conclude that replicate exercise or EVH challenges with similarly matched inspired air conditions and VE induce similar degrees of refractoriness.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of a specific PAF acether antagonist (BN 52063) on the response to isocapnic hyperventilation with dry cold air (ISH study) and exercise (EIA study) were assessed in a single dose and short term treatment study in 10 patients with exercise induced asthma. 2. ISH challenge was performed twice within 1 h after administration of either placebo, 240 mg BN 52063 p.o. or inhalation of 2.4 mg BN 52063. Hyperventilation increased Raw from 0.30 +/- 0.02 to 0.89 kPa s l-1 (P less than 0.001) after the first challenge and from 0.28 +/- 0.04 to 0.84 +/- 0.06 kPa s l-1 (P less than 0.001) after the second challenge. Oral pretreatment with BN 52063 did not result in a reduction of bronchoconstriction during both challenges. A significant increase of Raw was noted immediately after inhalation of BN 52063. An inhibition of PAF induced platelet aggregation (by a factor of 2) occurred after oral administration of BN 52063 after both ISH challenges (P less than 0.05). No significant inhibition of PAF induced platelet aggregation was seen after inhalation of BN 52063. At concentrations up to 30 microM in vitro, BN 52063 inhibited PAF induced platelet aggregation in a dose dependent manner. The IC50 of BN 52063 against the aggregating effect of 1 microM PAF was 7.0 +/- 2.1 microM. 3. In the EIA study the patients were challenged on the third day of treatment with either placebo or 240 mg BN 52063 p.o. or 5 mg BN 52063 by inhalation. Peak expiratory flow rates (PEFR) fell by 155 +/- 37 1 min-1 after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of the plasma obtained before and after graded submaximal exercise was examined in 10 bronchial asthma patients with the syndrome of asthma of physical effort (APE) by means of fluorescent exploration using the cation probe 4-(p-demethylaminostyryl)-1-methylpyridinum and rat thymocytes as a test system. Four normal donors and five bronchial asthma patients without the APE syndrome were used as control. The plasma of patients with the APE syndrome, obtained after physical exercise, brought about a decrease of the number of fluorescent cells. In APE patients, the coefficient of the drop of thymocyte fluorescence amounted to 0.65 +/- 0.04, that in the control group to 1.1 +/- 0.08 (p less than 0.01). It is assumed that after physical exercise in the plasma of APE patients, there may occur factor depolarizing the membrane of thymocytes, which is likely to play a substantial role in the pathogenesis of the afterload bronchospasm.

The pathogenesis of bronchospasm of effort is not yet elucidated and it is probable that is determined by multiple factors. In this study we have tested the role of mastocytes in taking as an index of their activation the fluctuation of plasma histamine levels during repeated exercise tests. We will show that asthmatic subjects who develop bronchospasm on effort have a significant rise (times 3) in their level of serum histamine whilst normal subjects don't show much change. Furthermore in a repeated effort test we have observed a strict parallelism between the occurrence of bronchospasm of effort and a rise in plasma histamine levels. These different observations enable us to consider that the activation of mastocytes and the liberation of mediators which follow play an important role in the pathogenesis of bronchospasm of effort.

Elevated levels of the mast-cell-associated serum neutrophil chemotactic factor (NCF) and an increase in blood basophil counts were observed in 6 atopic asthmatics during exercise-induced asthma (EIA). These changes were not found when the same degree of airways obstruction was elicited in the same subjects by isocapnic hyperventilation (ISH) with cold air. The NCF was unlikely to be related to the basophilia alone, because asthmatics without EIA who underwent the same exercise task, produced a similar basophilia but significantly less NCF. These findings suggest that mast-cell-associated (as opposed to basophil-associated) mediators of hypersensitivity are detectable in the bloodstream during the bronchoconstriction induced by exercise, but not by ISH.

Plasma glucagon levels and peak expiratory flow rates (PEF) were determined before and after treadmill exercise test in 5 atopic patients with exercise-induced asthma (EIA) and in 10 non-atopic patients with EIA, and also in 14 controls without exercise-induced bronchoconstriction. In addition, changes in plasma glucagon were determined during an allergen-inhalation challenge test in 5 asthmatics. Plasma glucagon was determined by radioimmunoassay using antiserum and 125I-labelled glucagon. Plasma glucagon level of atopic asthmatics at rest was significantly lower (P less than 0.05) than in non-atopic EIA patients. In the atopic EIA patients the plasma glucagon level increased by 41 per cent 10 minutes after exercise, whereas in the nonatopic EIA patients it decreased by about 19 per cent. In the controls there were only insignificant exercise-induced changes in the plasma glucagon level. The exercise-induced changes of the plasma glucagon in the atopic EIA patients differed significantly from those in the non-atopic EIA patients (P less than 0.05). No change in plasma glucagon was observed in five asthmatics during inhalation challenge tests with a known positive allergen. The results suggest that the rise in glucagon is a defence mechanism against exercise-induced broncho-constriction.

M&B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one) is an orally absorbed mast cell stabilizer which is 30 times as potent as disodium cromoglycate in laboratory and animal studies. In a double-blind placebo-controlled cross-over trial we studied the protection afforded by a single oral dose of 10 mg of M&B 22,948 against asthma induced by histamine and exercise, each in 12 patients. Compared with placebo the drug had no significant effect on the response to inhaled histamine but significantly inhibited the fall in FEV1 induced by exercise on treadmill (P less than 0.005). The exercise-induced fall in FEV1 was less following M&B 22,948 than placebo in all patients and the fall was inhibited by more than 50% in five (42%) of 12 patients. The degree of inhibition was significantly correlated with the plasma drug concentration (r = 0.65, P less than 0.025). M&B 22,948 merits evaluation in the treatment of asthma.

Neutrophils demonstrate increased complement receptor activity, measured by rosetting of C3b-coated erythrocytes, after asthma that was provoked experimentally. However, it is not clear whether the increased rosetting is due simply to increase in receptor numbers or whether other factors, such as cell adhesiveness, are involved. We have therefore enumerated granulocyte complement receptors, after asthma provoked experimentally, with monoclonal antibodies against the receptors and flow cytometry. There was a maximal 28.2 +/- 7.5% and 33.4 +/- 9.5% (mean +/- SEM; n = 15) increase in granulocyte CR1 and CR3, respectively, at 3 hours after asthma induced by antigen. There was a maximal 32.0 +/- 7.3% (mean +/- SEM; n = 7) increase in granulocyte CR1, but no change in granulocyte CR3, at 1 hour after exercise-induced asthma. No significant changes in granulocyte CR1 or CR3 were observed up to 6 hours after methacholine challenge, or after exercise in subjects who did not develop exercise-induced asthma. There was a maximal 33 +/- 9% (mean +/- SEM; n = 8) increase in granulocyte CR1 at 30 minutes, but no increase in granulocyte CR3, after histamine challenge of subjects with asthma. Incubation of whole blood with histamine in vitro did not lead to any enhancement in expression of granulocyte CR1. This suggests that antigen- and exercise-induced release of histamine may augment granulocyte CR1 expression through an indirect mechanism. These data indicate that there is increase in the numerical expression of CR1 on granulocytes, after asthma provoked experimentally, which is accompanied by increases in granulocyte CR3 after bronchoprovocation with antigen, but not histamine or exercise.

The content of acetylcholine, histamine and the total amount of catecholamines were measured in blood of 33 patients with bronchial asthma, in 6 patients with preasthma and in 10 practically normal subjects before and after the use of graded exercise (bicycle ergometry). Subgroups of the patients with asthma of effort were singled out. In such patients, exercises resulted in a significant rise of histamine (p less than 0.05) or acetylcholine level (p less than 0.05). Histaminemia was mostly accompanied by an immediate obstructive response of the bronchi to exercise in the distal parts. In patients with a high acetylcholine content, obstruction of the large bronchi was mainly observed, with a slightly delayed response to exercise.