Title: Arterial Plasma Histamine Levels at Rest, and During and after Exercise in Patients with Asthma: Effects of Terbutaline Aerosol
Author: Anderson, S. D.; Bye, P. T.; Schoeffel, R. E.; Seale, J. P.; Taylor, K. M.; Ferris, L.; (Date: Apr, 1981)
Journal: Thorax; V. 36; Issue: 4; Pages: 259-67
Abstract: Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.
Notes: Clinical Trial
Controlled Clinical Trial
Journal Article
Title: Acute Effect of Sodium Cromoglycate on Airway Narrowing Induced by 4.5 Percent Saline Aerosol. Outcome before and During Treatment with Aerosol Corticosteroids in Patients with Asthma
Author: Anderson, S. D.; du Toit, J. I.; Rodwell, L. T.; Jenkins, C. R.; (Date: Mar, 1994)
Journal: Chest; V. 105; Issue: 3; Pages: 673-80
Abstract: STUDY OBJECTIVE: To investigate the acute effect of sodium cromoglycate on airway responses to 4.5 percent saline aerosol challenge, before and during treatment with inhaled budesonide–a corticosteroid. DESIGN: Open study, with a total of five visits, two before budesonide treatment, and three follow-up visits, two between 5 and 6 weeks and one at more than 11 weeks. SETTING: Referral-based Respiratory Investigation Unit at Royal Prince Alfred Hospital, a major Sydney-based teaching hospital. PATIENTS: Eleven patients with asthma (ten atopic), with a PD20 FEV1 to 4.5 percent saline aerosol challenge and about to commence inhaled budesonide for treatment of their asthma. INTERVENTIONS: The 40 mg of sodium cromoglycate was inhaled before a 4.5 percent NaCl challenge, both before and after regular (36 +/- 9 d) treatment with budesonide (1,000 micrograms/d). The final challenge was repeated in ten subjects after 11 weeks or more of treatment with budesonide. MEASUREMENTS AND RESULTS: Sensitivity to 4.5 percent saline aerosol was measured as the dose of saline aerosol required to induce a 20 percent fall in FEV1 (PD20). Reactivity was measured as the dose-response slope by taking the percent fall in FEV1 and dividing it by the dose required to induce the fall. On the control day the geometric mean PD20 (95 percent CI) for 4.5 percent saline aerosol was 2.8 (1.4 to 5.4) and the dose response slope (DRS) 5.6 (2.9-11.1). An acute dose of sodium cromoglycate reduced sensitivity (PD20) by 8-fold and reactivity (DRS) 12.3-fold. This effect was similar in magnitude to that measured after regular treatment with budesonide alone. When sodium cromoglycate was given during treatment with budesonide, the PD20 was reduced 16-fold and the DRS 42-fold, and this was greater than the reduction with budesonide taken for 3 months (p < 0.03, p < 0.05 respectively). CONCLUSIONS: Sodium cromoglycate inhibits responses to 4.5 percent saline aerosol and has additional benefits to those conferred by aerosol steroids. The mechanism for responsiveness to saline aerosol and efficacy of these drugs may relate to alteration in chloride ion channel regulation by inflammation.
Notes: Clinical Trial
Journal Article
Author Address: Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia.
Title: The Mechanism of Exercise-Induced Asthma Is
Author: Anderson, S. D.; Daviskas, E.; (Date: Sep, 2000)
Journal: J Allergy Clin Immunol; V. 106; Issue: 3; Pages: 453-9
Abstract: Exercise-induced asthma (EIA) refers to the transient narrowing of the airways that follows vigorous exercise. The mechanism whereby EIA occurs is thought to relate to the consequences of heating and humidifying large volumes of air during exercise. In 1978 airway cooling was identified as an important stimulus for EIA; however, severe EIA also occurred when hot dry air was inspired, and there was no abnormal cooling of the airways. In 1986 the thermal hypothesis proposed that cooling of the airways needed to be followed by rapid rewarming and that these two events caused a vasoconstriction and a reactive hyperemia of the bronchial microcirculation, together with edema of the airway wall, causing the airways to narrow after exercise. The osmotic, or airway-drying, hypothesis developed from 1982-1992 because neither airway cooling nor rewarming appeared to be necessary for EIA to occur. As water is evaporated from the airway surface liquid, it becomes hyperosmolar and provides an osmotic stimulus for water to move from any cell nearby, resulting in cell volume loss. It is proposed that the regulatory volume increase, after cell shrinkage, is the key event resulting in release of inflammatory mediators that cause airway smooth muscle to contract and the airways of asthmatic subjects to narrow. This event may or may not be associated with airway edema. The osmotic and thermal theories come together by considering that inspiration of cold air not only cools the airways but also increases the numbers of airway generations becoming dehydrated in the humidifying process.
Notes: Journal Article
Review
Review, Tutorial
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Author Address: Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia.
Title: Exercise-Induced Asthma: Is It the Right Diagnosis in Elite Athletes?
Author: Anderson, S. D.; Holzer, K.; (Date: Sep, 2000)
Journal: J Allergy Clin Immunol; V. 106; Issue: 3; Pages: 419-28
Abstract: Exercise-induced asthma, as recognized in asthmatic subjects, is an exaggerated airway response to airway dehydration in the presence of inflammatory cells and their mediators. The airway narrowing is primarily caused by contraction of bronchial smooth muscle. The milder airway narrowing documented in response to exercise in elite athletes and otherwise healthy subjects may simply be the result of the physiologic responses and pathologic changes in airway cells arising from dehydration injury. These changes, which include excessive mucus production and airway edema, would serve both to cause cough and to amplify the narrowing effects of normal bronchial smooth muscle contraction, resulting in symptoms. These changes are more likely to occur in healthy subjects who exercise intensely for long periods of time breathing cold air, dry air, or both. Under these conditions, the ability to humidify inspired air may be overwhelmed, causing significant dehydration of the airway mucosa and an increase in osmolarity, even in small airways. In addition to dehydration injury, airway narrowing to pharmacologic and physical agents may occur as a result of injury caused by large volumes of air containing irritant gases, particulate matter, or allergens being inspired during exercise. As a result, the airways may become inflamed, and the airway smooth muscle may become more sensitive. These events could result in the same exaggerated airway response to dehydration, as documented in asthmatic subjects.
Notes: Journal Article
Review
Review, Tutorial
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Author Address: Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, Australia.
Title: Decrease of T-Lymphocyte Proliferation in Exercise-Induced Asthma
Author: Bury, T. B.; Corhay, J. L.; Louis, R.; Radermecker, M. F.; (Date: Sep, 1994)
Journal: Allergy; V. 49; Issue: 8; Pages: 605-10
Abstract: 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.
Notes: Journal Article
Author Address: Department of Respiratory Medicine, CHU Sart Tilman, University of Liege, Belgium.
Title: Inhalation of Hypertonic Saline Aerosol Enhances Mucociliary Clearance in Asthmatic and Healthy Subjects
Author: Daviskas, E.; Anderson, S. D.; Gonda, I.; Eberl, S.; Meikle, S.; Seale, J. P.; Bautovich, G.; (Date: Apr, 1996)
Journal: Eur Respir J; V. 9; Issue: 4; Pages: 725-32
Abstract: Hyperosmolarity of the airway surface liquid (ASL) has been proposed as the stimulus for hyperpnoea-induced asthma. We found previously that mucociliary clearance (MCC) was increased after isocapnic hyperventilation (ISH) with dry air, and we proposed that the increase related to transient hyperosmolarity of the ASL. We investigated the effect of increasing the osmolarity of the ASL on MCC, by administering an aerosol of concentrated salt solution. MCC was measured using 99mTc-sulphur colloid, gamma camera and computer analysis in 12 asthmatic and 10 healthy subjects on three separate days, involving administration of each of the following: 1) ultrasonically nebulized 14.4% saline; 2) ultrasonically nebulized 0.9% saline; and 3) no aerosol intervention (control). The (mean +/- SD) volume of nebulized 14.4% saline was 2.2 +/- 1.2 mL for asthmatics and 3.2 +/- 0.7 mL for healthy subjects. This volume was delivered over a period of 5.4 +/- 1.3 and 6.4 +/- 0.7 min for asthmatic and healthy subjects, respectively. The airway response to 14.4% saline was assessed on a separate visit and the fall in forced expiratory volume in one second (FEV1) was 22 +/- 4% in the asthmatic and 3 +/- 2% in the healthy subjects. Compared to the MCC with the 0.9% saline and control, the hypertonic aerosol increased MCC in both groups. In asthmatic subjects, MCC of the whole right lung in 1 h was 68 +/- 10% with 14.4% saline vs 44 +/- 14% with 0.9% saline and 39 +/- 13% with control. In healthy subjects, MCC of the whole right lung in 1 h was 53 +/- 12% with 14.4% saline vs 41 +/- 15% with 0.9% saline and 36 +/- 13% with control. We conclude that an increase in osmolarity of the airway surface liquid increases mucociliary clearance both in asthmatic and healthy subjects. These findings are in keeping with our previous suggestion that the increase in mucociliary clearance after isotonic hyperventilation with dry air is due to a transient hyperosmolarity of the airway surface liquid.
Notes: Journal Article
Author Address: Dept of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
Title: Gc/Ms Analysis of Urinary Excretion of 9alpha,11beta-Pgf2 in Acute and Exercise-Induced Asthma in Children
Author: Nagakura, T.; Obata, T.; Shichijo, K.; Matsuda, S.; Sigimoto, H.; Yamashita, K.; Masaki, T.; Maekawa, K.; (Date: Feb, 1998)
Journal: Clin Exp Allergy; V. 28; Issue: 2; Pages: 181-6
Abstract: 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.
Notes: Journal Article
Author Address: Department of Paediatrics, Jikei University School of Medicine, Tokyo, Japan.
Title: Evidence for Mast Cell Activation During Exercise-Induced Bronchoconstriction
Author: O’Sullivan, S.; Roquet, A.; Dahlen, B.; Larsen, F.; Eklund, A.; Kumlin, M.; O’Byrne, P. M.; Dahlen, S. E.; (Date: Aug, 1998)
Journal: Eur Respir J; V. 12; Issue: 2; Pages: 345-50
Abstract: 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.
Notes: Journal Article
Author Address: Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Title: Increased Urinary Excretion of Lte4 after Exercise and Attenuation of Exercise-Induced Bronchospasm by Montelukast, a Cysteinyl Leukotriene Receptor Antagonist
Author: Reiss, T. F.; Hill, J. B.; Harman, E.; Zhang, J.; Tanaka, W. K.; Bronsky, E.; Guerreiro, D.; Hendeles, L.; (Date: Dec, 1997)
Journal: Thorax; V. 52; Issue: 12; Pages: 1030-5
Abstract: 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.
Notes: Clinical Trial
Journal Article
Randomized Controlled Trial
Author Address: Department of Pulmonary/Immunology and Biostatistics, Merck Research Laboratories, Rahway, New Jersey 07065, USA.