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Bronchoconstrictive responses to inhaled ultrasonically nebulized distilled water and airway inflammation in asthma.

Twenty-two asthmatic patients with a range of airway hyperresponsiveness to methacholine underwent a bronchial challenge with ultrasonically nebulized distilled water (UNDW). The presence of positive responses to this stimulus was related to the extent of airway inflammation, as assessed by histochemical and immunohistochemical evaluation of bronchial biopsy specimens. Twelve patients had airflow obstruction during distilled water inhalation and they showed more severe disease than subjects with no response, as demonstrated by the higher degree of nonspecific bronchial hyperresponsiveness (p < 0.01), higher variability of peak expiratory flow rates (p < 0.01), symptom scores (p < 0.01), and daily use of bronchodilators (p < 0.01). Those patients also had increased numbers of mast cells and eosinophils (p < 0.01) and increased percentage of bronchial epithelial cells expressing endothelin 1 immunoreactivity (p < 0.01). Thus, positive responses to inhaled UNDW reflect the bronchial hyperresponsiveness consistent with moderate to severe asthma and may be due to the release of mediators with bronchoconstrictive properties from inflammatory cells or activated resident cells or both.

Adult↗

Gastroesophageal reflux-induced bronchoconstriction. An intraesophageal acid infusion study using state-of-the-art technology.

STUDY OBJECTIVE: To study mechanisms of gastroesophageal reflux-induced bronchoconstriction during intraesophageal infusions. DESIGN: Prospective study blinded to the subject. SETTING: Outpatient pulmonary function laboratory at a 908-bed university hospital. PARTICIPANTS: Forty-seven adult subjects divided into four groups: asthmatics with reflux, 20; asthmatics, 7; gastroesophageal refluxers, 10; and normal controls, 10. Asthmatics were defined by American Thoracic Society criteria, and refluxers were defined by symptoms and 24-hour pH monitoring. INTERVENTIONS: Dual antimony esophageal pH probe placed just below the upper esophageal sphincter and 5 cm above the lower esophageal sphincter. Intraesophageal infusions of normal saline solution followed by 0.1N hydrochloric acid then normal saline solution were given for 15 to 18 min. Spirometry and specific airway resistance (SRaw) were performed after placement of pH probes, insertion of esophageal infusion tube, and after each infusion. Bernstein tests were assessed during esophageal infusions. MEASUREMENTS AND RESULTS: Peak expiratory flow rate (PEF) decreased with intraesophageal acid in all four groups (p < 0.014). Esophageal acid clearance improved PEF in all groups except the asthmatics with reflux group that had a further decrease in PEF. These effects were not dependent on a positive Bernstein test or evidence of proximal reflux. The asthmatics with reflux group also had an increase in SRaw with intraesophageal acid, which continued to increase despite acid clearance. CONCLUSIONS: Intraesophageal acid infusions caused a decrease in PEF in all groups without evidence of microaspiration, implying a vagally mediated reflex may be involved. Esophageal mucosal inflammation, assessed by a positive Bernstein test, was not required. Asthmatics with reflux also had further decline in PEF despite acid clearance.

Adult↗

Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma?

BACKGROUND: Some of the disagreements on the perception of dyspnea (PD) during bronchoconstriction in asthma patients could depend on the interrelationships among the following: (1) the influence of baseline airflow obstruction on the patient's ability to detect any further increase in airway resistance; (2) the effect of eosinophilic inflammation on the airway; (3) bronchial hyperresponsiveness (BHR); and (4) the effect of inhaled corticosteroids (ICSs). OBJECTIVE: We hypothesized that if the inflammation of the airway wall influences to some extent and in some way the PD in asthma patients, ICSs reverse the effect of airway inflammation on the PD. METHODS: We studied 100 asthma patients who were divided into the following four groups: patients with obstruction who were either ICS-naive (group I) or were treated with ICSs (group II); and nonobstructed patients who were either ICS-naive (group III) or were treated with ICSs (group IV). PD on the visual analog scale (VAS) was assessed during a methacholine-induced FEV(1) decrease and specifically was quantified as the VAS slope and score at an FEV(1) decrease of 5 to 20%. BHR was assessed in terms of the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)). Eosinophil counts in induced sputum samples also were performed. Regression analysis, univariate analysis of variance, and factor analysis were applied for statistical evaluation. RESULTS: For a 5 to 20% fall in FEV(1) from the lowest point after saline solution induction, VAS score was lowest in group II, slightly higher in group I, slightly higher still in group IV, and the highest in group III. In the patients as a whole, BHR related to PD, but age, clinical score, duration of the disease, and presence of baseline airway obstruction did not. In patients with obstruction who were treated with ICSs, eosinophil counts related to PD negatively. Factor analysis yielded the following four factors that accounted for 70% of the variance in the data: ICS; eosinophil counts; FEV(1); and PC(20) loaded on separated factors with PD loading on the same factors as PC(20). The post hoc analysis carried out dividing the patients into ICS-treated and ICS-naive, showed that in the former group eosinophil counts and BHR proved to be factors negatively associated with PD, while in the latter group eosinophil counts were positively associated with PD. CONCLUSIONS: We have shown that eosinophilic inflammation of the airway wall may increase PD and that the association of eosinophil counts with ICSs may result in lessening the PD.

Adolescent↗

Effects of montelukast and salmeterol on physical performance and exercise economy in adult asthmatics with exercise-induced bronchoconstriction.

STUDY OBJECTIVES: To compare the effect of montelukast and the long-acting beta(2)-agonist salmeterol on cardiopulmonary exercise economy and physical performance in adult patients with asthma during exercise. DESIGN AND PATIENTS: Asthmatic patients (n = 18), aged 18 to 35 years with exercise-induced bronchoconstriction (EIB), using a double-blind, double-dummy cross-over design. Montelukast, 10 mg/d, was compared to inhaled salmeterol, 50 microg bid. The study medication was administered for at least 5 days prior to testing, with a washout period of at least 5 days. Treadmill exercise tests (5.3% inclination, -15 degrees C ambient temperature) were performed at work loads of 80% of maximal oxygen uptake (Vo(2)max) [6 min], rest (4 min), 60% of Vo(2)max (6 min), and finally step increments until exhaustion. MEASUREMENTS AND RESULTS: We investigated parameters of gas exchange, physical performance, and lung function. After montelukast, the oxygen pulse was higher than after salmeterol, at 80% of Vo(2)max (p = 0.035), and 6 min at 60% of Vo(2)max (p = 0.011). Lung function during exercise, running time to exhaustion, Borg score, lactate levels, Vo(2)max, carbon dioxide elimination, minute ventilation, ventilatory equivalents, respiratory exchange ratio, and heart rate were not significantly different between the two treatments. The maximal postexercise fall in FEV(1) from baseline occurred 2 min after run to exhaustion, and was greater after salmeterol than after montelukast: mean, 16.2% (SD, 11.0) vs 10.0% (SD, 12.2) [p < 0.001]. CONCLUSIONS: In adult asthmatics with EIB, montelukast may have a more favorable effect on the oxygen pulse, thus suggesting improved gas exchange during exercise.

Acetates↗

Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is of particular importance in children with asthma. It is an important measure of asthma control and should be monitored by exercise testing. However, exercise testing puts a large demand on health-care resources and is therefore not widely used in routine monitoring of pediatric asthma control. The fractional concentration of exhaled nitric oxide (FeNO) also reflects uncontrolled asthma. We hypothesized that FeNO may be used for prescreening of asthmatic children to exclude those with good asthma control unlikely to have EIB, thereby reducing the need for exercise testing. OBJECTIVE: The aim of this study was to estimate the value of FeNO as a predictor of EIB in asthmatic children. METHODS: Stable outpatient asthmatic school children performed standard exercise challenge tests and measurement of FeNO. RESULTS: FeNO and response to a standardized submaximal exercise test on the treadmill were measured in 111 school children with asthma. EIB could be excluded with a probability of 90% in asthmatic children with FeNO levels < 20 parts per billion (ppb) without current inhaled corticosteroid treatment, and < 12 ppb in children with current inhaled corticosteroid treatment. CONCLUSION: Measurement of FeNO is a simple, and time- and resource-efficient tool that may be used to screen for EIB testing and therefore optimizes the resources for exercise testing in pediatric asthma monitoring.

Adolescent↗

Clinical role of rapid-incremental tests in the evaluation of exercise-induced bronchoconstriction.

STUDY OBJECTIVE: To determine whether rapid-incremental work rate (IWR) testing would be as useful as standard high-intensity constant work rate (CWR) protocols in eliciting exercise-induced bronchoconstriction (EIB) in susceptible subjects. DESIGN AND SETTING: A cross-sectional study performed in a clinical laboratory of a tertiary, university-based center. SUBJECTS AND MEASUREMENTS: Fifty-eight subjects (32 males, age range, 9 to 45 years) with suspected EIB were submitted to CWR testing (American Thoracic Society/European Respiratory Society guidelines) and IWR testing on different days; 21 subjects repeated both tests within 4 weeks. Spirometric measurements were obtained 5, 10, 15, and 20 min after exercise; a FEV1 decline > 10% defined EIB. RESULTS: Twenty-seven subjects presented with EIB either after CWR or IWR testing; 21 subjects had EIB in response to both protocols (kappa = 0.78, excellent agreement; p < 0.001). Of the six subjects in whom discordant results were found, two had EIB only after IWR. Assuming CWR as the criterion test, IWR combined high positive and negative predictive values for EIB detection (91.3% and 88.6%, respectively). Tests reproducibility in eliciting EIB were similar (kappa = 0.80 and 0.72 for CWR and IWR, respectively; p < 0.001). Total and intense (minute ventilation > 40% of maximum voluntary ventilation) ventilatory stresses did not differ between EIB-positive and EIB-negative subjects, independent of the test format. There were no significant between-test differences on FEV(1) decline in EIB-positive subjects (25.7 +/- 10.8% vs 23.7 +/- 10.0%, respectively; p > 0.05). Therefore, no correlation was found between exercise ventilatory response and the magnitude of EIB after either test (p > 0.05). CONCLUSIONS: Rapid-incremental protocols (8 to 12 min in duration) can be as useful as high-intensity CWR tests in diagnosing EIB in susceptible subjects. Postexercise spirometry should be performed after incremental cardiopulmonary exercise testing when EIB is clinically suspected.

Adolescent↗

Exercise-induced bronchoconstriction in athletes.

Exercise-induced bronchoconstriction (EIB) describes airway narrowing that occurs in association with exercise. EIB occurs in up to 90% of asthmatic patients and is estimated to occur in > 10% of the general population. Recent reviews have identified asthma as a risk factor for sudden death and have reported many deaths that have been attributed directly to EIB. We present a review of the literature related to EIB in athletes including sections discussing its pathogenesis, diagnosis, and treatment, and which athletes are most at risk for experiencing EIB.

Adolescent↗

Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma.

BACKGROUND: Previous research has demonstrated that fish oil supplementation has a protective effect on exercise-induced bronchoconstriction (EIB) in elite athletes, which may be attributed to its antiinflammatory properties. Since EIB in asthma involves proinflammatory mediator release, it is feasible that fish oil supplementation may reduce the severity of EIB in asthmatic subjects. STUDY OBJECTIVES: To determine the efficacy of fish oil supplementation on severity of EIB in subjects with asthma. DESIGN: Randomized, double-blind, crossover study. SETTING: Lung function and exercise testing in a university research laboratory. PATIENTS AND MEASUREMENTS: Sixteen asthmatic patients with documented EIB entered the study on their normal diet and then received either fish oil capsules containing 3.2 g of eicosapentaenoic acid and 2.0 g of docohexaenoic acid (fish oil diet, n = 8) or placebo capsules (placebo diet, n = 8) daily for 3 weeks. At the beginning of the study (normal diet) and at the end of each treatment phase, the following pre-exercise and postexercise measures were assessed: (1) pulmonary function; (2) induced sputum differential cell count percentage and proinflammatory eicosanoid metabolite (leukotriene C4 [LTC4]-leukotriene E4 [LTE4] and prostaglandin D2 [PGD2]) and cytokine (interleukin [IL]-1beta and tumor necrosis factor [TNF]-alpha) concentrations; and (3) eicosanoid metabolites leukotriene B4 (LTB4) and leukotriene B5 (LTB(5)) generation from activated polymorphonuclear leukocytes (PMNLs). RESULTS: On the normal and placebo diet, subjects exhibited EIB. However, the fish oil diet improved pulmonary function to below the diagnostic EIB threshold, with a concurrent reduction in bronchodilator use. Induced sputum differential cell count percentage and concentrations of LTC4-LTE4, PGD2, IL-1beta, and TNF-alpha were significantly reduced before and following exercise on the fish oil diet compared to the normal and placebo diets. There was a significant reduction in LTB4 and a significant increase in LTB5 generation from activated PMNLs on the fish oil diet compared to the normal and placebo diets. CONCLUSION: Our data suggest that fish oil supplementation may represent a potentially beneficial nonpharmacologic intervention for asthmatic subjects with EIB.

Adult↗

Protective effects of different doses of inhaled fenoterol on methacholine-induced bronchoconstriction in asthmatic children.

OBJECTIVE: To evaluate the protective effect of different doses of inhaled fenoterol (F) on bronchoconstriction induced by methacholine (M). DESIGN: Randomized double-blind study. SETTING: Referrence center. PARTICIPANTS: 9 children (aged from 7 to 15 years old), with mild or moderate asthma and allergic to D. pteronyssinus. INTERVENTION: On the first day, the M concentration necessary to induce a 20% fall in the forced expiratory volume in the first second (FEV1; PC20FEV1) was determined using closed circuit inhalation (De Vilbiss 646). On subsequent days, the children inhaled a dose of F (25 or 50 or 100 or 200 micrograms) through the same circuit and, after 15 minutes the FEV1 was measured, becoming the basal value. Bronchoprovocation was then initiated using the concentration prior to the PC20FEV1 of the first day and continuing until there was a 20% fall in the FEV1. This concentration was the "new" PC20FEV1. RESULTS: F in a dose of 25 micrograms protected 2 of the 9 children, in a dose of 50 mg protected 4 of the 9 and in doses of 100 and 200 micrograms protected all children. We did not observe any relationship between the magnitude of the bronchodilation and bronchoprotection induced by the inhalation of F. CONCLUSIONS: Our results suggest that a dose of 100 micrograms of F is capable of inducing bronchoprotection in children with mild/moderate asthma.

Administration, Inhalation↗

Enzymatic modulation of bronchoconstriction, gland secretion, plasma extravasation and cough.

This review describes novel aspects of enzymes in the pertinent tissues of the airway and those associated with inflammatory cells. These include neutral endopeptidase, histamine N-methyltransferase, mast cell and neutrophil enzymes which have a potentially important role in the modulation of several airway functions such as bronchoconstriction, gland secretion, plasma extravasation and cough. Thus, regulation of enzyme activities in the airways may have new therapeutic implications in inflammatory diseases of airways.

Animals↗

Exercise-induced bronchoconstriction.

Exercise-induced asthma, or more appropriately, exercise-induced bronchoconstriction (EIB), occurs in 80 to 90% of individuals with asthma and in approximately 11% of the general population without asthma. EIB is characterised by post-exercise airways obstruction resulting in reductions in forced expiratory volume in 1 second (FEV(1)) of greater than 10% compared with pre-exercise values. The mechanism of EIB remains elusive, although both cooling and drying of airways play prominent roles. Cold, dry inhaled air during exercise or voluntary hyperventilation is the most potent stimulus for EIB. Inflammatory mediators play central roles in causing the post-exercise airways obstruction. Diagnosis of EIB requires the use of an exercise test. The exercise can be a field or laboratory based test, but should be of relatively high intensity (80 to 90% of maximal heart rate) and duration (at least 5 to 8 minutes). Pre- and post-exercise pulmonary function should be compared, and post exercise pulmonary function determined over 20 to 30 minutes for characterisation of EIB. A pre- to post-exercise drop in FEV(1) of greater than 10% is abnormal. Approaches to treatment of EIB include both nonpharmacological and pharmacological strategies. A light exercise warm up prior to moderate to heavy exercise reduces the severity of EIB. More recently, studies have supported a role for dietary salt as a modifier of the severity of EIB, suggesting that salt restrictive diets should reduce symptoms of EIB. Short acting, inhaled beta(2)-agonists constitute the most used prophylactic treatment for EIB. However, antileukotriene agents are emerging as effective, well tolerated, long-term treatments for EIB.

Adrenergic beta-Agonists↗

Severe bronchoconstriction after bronchoalveolar lavage in a dog with eosinophilic airway disease.

Bronchoalveolar lavage (BAL) is considered to be a safe procedure in humans and other animals. However, in some instances, potentially life-threatening complications can arise. In this clinical report, a dog with eosinophilic airway disease that underwent a BAL and subsequently became profoundly dyspneic during the recovery period is described. The dyspnea was severe enough to warrant mechanical ventilation for almost 24 hours. Several anti-inflammatory and bronchodilatory medications were also used. The dog was successfully weaned off the ventilator and made a full recovery. On the basis of radiographic findings and clinical response to treatment, we believe the dog had acute exacerbation of eosinophilic airway disease and severe bronchoconstriction secondary to the BAL. Caution should be exercised when performing a BAL if there is suspicion of a reactive airway disease.

Animals↗

Retention of particles inhaled in boli with and without induced bronchoconstriction.

Large lung retentions (up to 50%) of particles < or = 4 microns inhaled with a bolus technique at a penetration depth less than dead space have been reported to occur after 24 h. This retention may be due to retarded clearance of particles deposited in the airways of the tracheobronchial tract; an alternative explanation could be that particles are deposited in the alveolar region. The purpose of the present study was to confirm the occurrence of retained fractions and to study the influence of a cholinergic drug, which is assumed to give a more central particle deposition, on these retentions in human lungs after shallow aerosol bolus inhalation. Twelve healthy subjects inhaled, with a bolus technique, monodisperse Teflon particles (2.4 microns geometric diameter, 3.5 microns aerodynamic diameter), labeled with 111In. The volumetric lung depth of the inspired bolus was around 60 mL and flow rate was about 300 mL/s. Six subjects inhaled the test particles after a provocation with a cholinergic aerosol, which induced a threefold increase in airway resistance. The other six subjects inhaled a cholinergic aerosol after inhalation of the test particles or inhaled no cholinergic aerosol at all. Radioactivity in the body was measured after 0.5, 24, 48, and 72 h with a whole-body scanner with three 127 x 101-mm Nal detectors. The investigation confirmed results obtained earlier by a group in Frankfurt claiming that great retentions occur after 24 h. The retentions tended to be lower in the group receiving a bronchoconstricting drug before the bolus inhalations. There was a significant lung clearance of particles between 24 and 72 h, in contrast to the findings in earlier studies in healthy subjects and asthmatics who inhaled Teflon particles in large volumes. On the other hand, the clearance agreed well with the clearance in healthy subjects with extensive deposition of Teflon particles in the small ciliated airways, obtained by means of an extremely low inhalation flow rate. The results suggest that a considerable fraction of the particles in the bolus inhalation have been deposited in small ciliated airways in which the mucociliary transport is less efficient or in the alveolar region.

Administration, Inhalation↗

Maximal airway narrowing on the dose-response curve to methacholine is increased after exercise-induced bronchoconstriction.

The changes in airway responsiveness between before and after exercise in asthma are not well defined. We investigated the effect of exercise on PC20 (bronchial sensitivity) and maximal airway narrowing (MAN) on the dose-response curve to methacholine in 56 mildly asthmatic children. High-dose methacholine inhalation tests were performed before and 7 hr after exercise challenge. Methacholine PC20 was not changed by exercise, irrespective of exercise-induced bronchoconstriction (EIB). However, the subjects with (+)EIB displayed increased MAN after exercise, whereas those with (+/-)EIB or (-)EIB did not. The results showed that EIB may be followed by increased MAN but not by the change of bronchial sensitivity.

Administration, Inhalation↗

Roxithromycin attenuates acid-induced cough and water-induced bronchoconstriction in children with asthma.

In the present study, we evaluated the effect of roxithromycin, a semisynthetic macrolide antibiotic, on the cough response to inhaled acetic acid (AA) and on the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with asthma. Ten hospitalized asthmatic children (8 boys and 2 girls, mean +/- SEM age 12.6 +/- 0.4 years) were enrolled in this study. They were treated with 150 mg of roxithromycin once a day orally for 8 weeks without any side effects. All the patients underwent AA inhalation challenge before and 2, 4, and 8 weeks after the administration of roxithromycin. Seven of the 10 patients, who had a fall in FEV1 of at least 20% after UNDW inhalation, underwent UNDW inhalation challege at the same time. The cough threshold values, the lowest concentrations of AA eliciting coughs, and UNDW provocative dose producing a 20% fall in FEV1 (UNDW PD20) values 4 or 8 weeks after the administration of roxithromycin increased significantly over the initial values (p < 0.05). No significant change was observed in baseline FEV1 or serum theophylline concentrations throughout the study. These results support the notion that administration of roxithromycin may have favorable results in the treatment of childhood asthma.

Acetic Acid↗

Bronchodilating effects of bambuterol on bronchoconstriction in guinea pigs.

AIM: To study the effects of bambuterol (Bam) on bronchoconstriction in guinea pigs. METHODS: Bronchospasm induced by histamine aerosol, lung resistance (RL) and dynamic lung compliance (Cdyn) changes induced by ovalbumin aerosol in vivo, isolated resting lung parenchyma strips, and carbamylcholine-induced tracheal constriction in vitro in guinea pig were investigated. RESULTS: Bam dose-dependently prolonged the time to histamine-induced collapse, ED50 values (95% confidence limits) of Bam intragastric gavage (i.g.) after 1 h, 4 h, and 24 h were 0.74 (0.60-0.91), 0.75 (0.61-0.91) and 1.00 (0.77-1.30) mg.kg-1, respectively. Bam 2 or 10 mg.kg-1 i.g. 2 h before ovalbumin aerosol partly or almost completely inhibited bronchial challenge of ovalbumin-induced change of RL and Cdyn. Bam 0.1-1.0 mumol.L-1 gave a weak relaxation on isolated tracheal strips induced by carbamylcholine and failed to relax the isolated resting lung parenchyma strips in guinea pig. CONCLUSION: Bam showed a long-acting bronchodilation by its slow metabolism in vivo.

Animals↗

Effects of BRL 55 834 on allergen-induced bronchoconstriction and airway inflammation in sensitized guinea pigs.

OBJECTIVE: To investigate the effects of potassium channel activator on allergen-induced bronchoconstriction and airway inflammation and to discuss which role it plays in asthma therapy. METHODS: Airway insufflation pressure, examination of inflammatory cells in bronchial alveolar lavage fluid, analysis of airway pathology and airway Evans blue dye extravasation measurement were employed to detect airway resistance and airway inflammatory responses. RESULTS: [(3s, 4R)-3, 4-dihydro-2, 2-dimethyl-4-(2-oxopiperidin-l-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol] (BRL) 55 834 (8 micrograms/kg) inhibited not only ovalbumin-induced airway insufflation pressure increase but also inflammatory cell infiltration (ICI) in sensitized guinea-pigs; moreover, it did not decrease blood pressure; in contrast to BRL 55 834, single dose of BRL 38 227 (200 micrograms/kg) and verapamil (0.5 mg/kg) had a little effect on ICI; single dose of aminophylline (25 mg/kg) and dexamethasone (1 mg/kg) could not inhibit ICI, but the former could inhibit airway insufflation increase; drugs, besides aminophylline, could reduce microvascular leakage; single dose of BRL 38 227, verapamil and dexamethasone had no inhibition of airway insufflation pressure; BRL 38 227 and verapamil decreased blood pressure markedly. CONCLUSIONS: Selective potassium channel activator BRL 55 834 not only decreases airway resistance, but also inhibit airway inflammation, and both of them are of benefit to asthma therapy.

Animals↗

[Effect of loratadine (LO), a selective H1 antagonist, on histamine-induced bronchoconstriction].

The influence of single and repeated LO (10 mg/day) doses on histamine-induced bronchoconstriction was studied in 11 patients with stabile bronchial asthma. Bronchial reactivity was estimated as histamine content potent to elicit a 20% FEV, fall, i.e. PC20H. A single dose gave a significant (5.5 fold) reduction in bronchial reactivity to inhaled histamine. Application of LO during 6 days gave a similar effect. Withdrawal of LO for 6 days yielded an increase in bronchial hyperreactivity.

Adult↗