Inosine-5''-monophosphate analogues as inhibitors of human IMP cyclohydrolase and cellular growth

The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated for its effect on exercise-induced bronchoconstriction in asthmatic subjects. The relationship between 5-LO inhibition and effects on the response of the airways to exercise was examined. In a double-blind, randomized, crossover clinical trial, 10 patients with mild to moderate persistent asthma (who exhibited a fall in forced expiratory volume in one second (FEV1) > or = 20% following standardized exercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung function, urinary leukotriene E4 (LTE4) and ex vivo calcium ionophore-stimulated LTB4 release in whole blood were measured prior to dosing, prior to exercise and at various time points up to 4 h post-exercise. The mean (SD) maximal percentage fall in FEV1 after exercise was 27.1 (12)% on placebo and 19.9 (10)% on ABT-761 days, respectively (p<0.05). Post-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 and 30 min after exercise and the mean area under curve, representing the overall effect of exercise from 0-45 min post-challenge, was also significantly attenuated by ABT-761 (p<0.001). Ex vivo LTB4 release was inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Urinary LTE4 in the post-exercise period was significantly lower after ABT-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg x mg creatinine(-1); p<0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise FEV1 decline (r=0.711; p<0.05). We conclude that ABT-761 is effective in suppressing exercise-induced bronchoconstriction and that this protection is related quantitatively to the degree of 5-lipoxygenase inhibition.     

Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids

The aim of the present study was to examine the efficacy of low-dose inhaled budesonide (BUD) administered via Turbuhaler once or twice daily on symptoms, lung function and bronchial hyperreactivity in children with mild asthma. One hundred and sixty-three children (mean age 9.9 yrs, 56 females/107 males) with mild asthma (forced expiratory volume in one second (FEV1) 103% of predicted, morning peak expiratory flow (PEF) 87% pred, reversibility in FEV1 3%, fall in FEV1 after exercise 10.4% from pre-exercise value) and not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. After a two-week run-in period, the children received inhaled BUD 100 microg or 200 microg once daily in the morning, 100 microg twice daily or placebo for 12 weeks. Exercise and methacholine challenges were performed before and at the end of treatment. After 12 weeks of therapy, the fall in FEV1 after an exercise test was significantly less in all three BUD groups (43-5.1%) than in the placebo group (8.6%). Bronchial hyperreactivity to methacholine with the provocative dose causing a 20% fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo (ratio at the end of treatment 156%). Changes in baseline lung function (FEV1 and PEF) were less marked than changes in bronchial responsiveness. In conclusion, low doses of inhaled budesonide, given once or twice daily, provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function.     

Response of the nose to exercise in healthy subjects and in patients with rhinitis and asthma

BACKGROUND: Although the nose and the bronchi are both involved in the process of regulating respiratory heat exchange, thermal changes may precipitate airway obstruction during exercise but rarely cause nasal obstruction in patients with rhinitis. The cause of the different response of the nose and bronchial tree has hardly been investigated. This study was performed to assess the response of the nose during exercise in the presence of rhinitis, asthma, and in normal controls. METHODS: Ten healthy subjects (group 1), 15 patients with asthma and rhinitis (group 2), 10 with rhinitis only (group 3), and 11 with asthma only (group 4) were included in the study. Exercise was performed on a bicycle ergometer for six minutes, reaching a heart rate of 80% of predicted. Bronchial and nasal responses were measured by forced expiratory volume in one second (FEV1) and posterior rhinomanometry, respectively. A drop in the FEV1 of 20% or more was considered a positive exercise induced asthma challenge test. RESULTS: Heart rate and ventilation increased by a similar proportion in the four groups. The FEV1 significantly decreased in asthmatic patients (groups 2 and 4) but it did not change in healthy subjects (group 1) or in those with rhinitis (group 3). Thirteen asthmatic patients developed exercise induced asthma. Nasal patency increased with exercise by a similar proportion in all groups, and no differences were detected between those with rhinitis (groups 2 and 3) and those without (groups 1 and 4). Nasal patency had returned to basal values at 25 minutes after completion of exercise in the four groups. The nose of patients with exercise induced asthma, however, remained significantly more patent than in patients without exercise induced asthma between 10 and 30 minutes after exercise. CONCLUSIONS: These results suggest that the nose responds differently from the bronchi during exercise induced airway obstruction: whereas the bronchial tree responds by becoming narrowed, the nose becomes more patent. These findings suggest that the mechanisms regulating the response of the nose to exercise are different from those involved in the response of the bronchial tree.     

Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

Comparison of bronchial challenge with ultrasonic nebulized distilled water and hypertonic saline in children with mild-to-moderate asthma

There is still controversy about the most suitable method to measure bronchial hyperresponsiveness in children. In epidemiological surveys, nonisotonic aerosols are being used increasingly for bronchial provocation testing. Our aim was to study the acceptability, safety and correlation between two published bronchial challenge tests. Two standardized protocols--the inhalation of hypertonic saline (HS) and ultrasonically-nebulized distilled water (UNDW)--were performed in 36 children: 19 patients with the clinical diagnosis of mild-to-moderate asthma (7-12 yrs of age), and 17 control subjects (8-18 yrs of age). HS challenge involved stepwise inhalation of 4.5% saline (for 0.5, 1, 2, 4 and 8 min), whereas challenge with UNDW was performed as a single step protocol with 10 min inhalation of cold UNDW. Asthma medication was withheld prior to challenge testing. Thirty five subjects completed both challenge tests (one asthmatic patient did not return after UNDW challenge) in random order within a 7 day time interval. For HS a > or = 15% reduction in forced expiratory volume in one second (FEV1) from baseline was considered a positive response, and for UNDW a > or = 10% decrease. In 13 of the 19 asthmatic patients, but in none of the controls, a positive response was observed for UNDW. Fifteen out of 18 patients and one control subject had a positive response to HS. Twelve out of 18 asthmatic children responded to both challenges, three responded only to HS and three had no response to either challenge. There was a negative correlation between log provocative dose causing a 15% reduction in FEV1 (PD15) after HS and the maximum fall in FEV1 after UNDW (rs = -0.63; p < 0.005). The HS challenge had a lower acceptability than challenge with UNDW due to the unpleasant salty taste of HS. However, this did not inhibit the completion of the tests in any subject. The results of this study suggest a good correlation between response to hypertonic saline and ultrasonically-nebulized distilled water in children with mild-to-moderate asthma. A multiple step protocol might be safer when applied in field studies involving children.     

The effect of inhaling a dry powder of sodium chloride on the airways of asthmatic subjects

Wet aerosols of 4.5% sodium chloride (NaCl) are often used to assess the bronchial responsiveness associated with asthma. We questioned whether dry NaCl could be used as an alternative. Dry powder NaCl was inhaled from capsules containing either 5, 10, 20 or 40 mg to a cumulative dose of 635 mg. The powder was delivered via an Inhalator or Halermatic. The airway sensitivity to the dry and wet NaCl was compared in 24 patients with asthma aged 19-39 yrs. All subjects responded to both preparations and the geometric mean (95% confidence intervals) for the provocative dose of NaCl causing forced expiratory volume in one second (FEV1) to fall 20% from baseline (PD[20,NaCl]) for dry NaCl was 103 mg (68-157) versus 172 mg (102-292), p<0.03 for the wet NaCl. The response to dry NaCl was reproducible and on repeat challenge the PD20 was 108 mg (75-153). The mean maximum fall in FEV1 was approximately 25% on each of the two test days. Spontaneous recovery occurred within 60 min after challenge with dry NaCl and within 5 min after bronchodilator. There were no serious side-effects requiring medical attention, however some patients coughed on inhalation of the 40 mg dose and three gagged. Arterial oxygen saturation remained within normal limits. We conclude that a suitably prepared dry powder of sodium chloride could potentially replace wet sodium chloride to assess bronchial responsiveness in patients with asthma, but further studies are required to establish the long-term stability of the dry powder preparation.     

Comparative influence of a single allergen exposure on the different components of airway response to methacholine

We compared the effects of an allergen challenge on airway responsiveness to methacholine, the slope of the dose-response curve (DRC) and post-methacholine fall in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1)/FVC, and determined whether any changes in these parameters were related to the presence and magnitude of the late asthmatic response (LAR) in mild stable asthma. Twenty-three allergic asthmatic subjects had an allergen challenge, preceded and followed 24 (n = 12) and/or 48 (n = 22) h later by a methacholine challenge. Sixteen subjects had a dual asthmatic response to the allergen. On the post-allergen methacholine challenge, as compared with the pre-allergen test, differences in mean fall in FVC or FEV1/FVC at 20% fall in FEV1 and the slope of the DRC did not achieve statistical significance, even in the group with LAR, which showed a significant increase in airway responsiveness at 24 h. There was, however, a correlation between allergen-induced changes in PC20 and (1) the change in post-methacholine FVC fall in the LAR group at 48 h, and (2) the change in the slope of the DRC in the early-asthmatic-response group at 24 h. In conclusion, allergen-challenge-induced changes in airway response to methacholine are heterogeneous among asthmatic subjects and although it may increase airway responsiveness (PC20), particularly in late responders, it minimally affects the other aspects of airway response to methacholine, suggesting that a more powerful or sustained allergic stimulus is required to modify the latter.     

Comparison of bronchial reactivity to ultrasonically nebulized distilled water, exercise and methacholine challenge test in asthmatic children

We studied the responses to ultrasonically nebulized distilled water (UNDW) challenge, exercise challenge and methacholine challenge in asthmatic children. Fifty-four asthmatic and fourteen nonasthmatic control children participated in this study. The UNDW inhalation test was by the methodology described by Anderson. The average output of water was approximately 3.0 mL/min (SD = .1) and inhalation times were 30 seconds, one minute, two minutes and four minutes. Some subjects performed exercise challenge on a bicycle ergometer and methacholine challenge by an Astrograph technique. Twenty-three of 54 asthmatic patients (42.6%) and none of the controls showed a fall in FEV1 greater than 20% with UNDW challenge. The fall in FEV1 with UNDW correlated with that induced by exercise challenge (r = .89) and Log Dmin, which may reflect bronchial sensitivity (r = .70). Our method is not sensitive enough for detecting bronchial hyperresponsiveness in all asthmatic children. Bronchoconstriction induced by UNDW has a similar mechanism of action as exercise and methacholine.     

Surface tension of blood

Buckwheat flour, mainly used for pancakes, may induce asthma following inhalation and anaphylactic reactions following ingestion. These allergic reactions are mediated by specific IgE and may be confirmed by skin test and radio-allergo-sorbent test. The occupational asthma of a patient working in pancake restaurant was confirmed by specific challenge test with a computerised device to generate particles. A very small amount of buckwheat flour (10 micrograms) induced an immediate fall of the FEV1 to 56% of the initial value. No bronchial reaction was observed with lactose nor with wheat flour. Specific bronchial challenge identifies the allergen responsible for asthma, measures the level of sensitization and thus can prevent the occupational exposure.     

Citric acid-induced cough thresholds in normal subjects, patients with bronchial asthma, and smokers

Several challenge procedures have been developed to characterize the cough reflex in patients with airway diseases. This study was performed to compare the interindividual range of cough sensitivity in asthmatic and normal subjects as well as smokers using an identical method. Sixteen normal subjects, 20 patients with mild bronchial asthma, 6 patients with moderate to severe bronchial asthma, 9 current smokers, and 7 occasional smokers were included. In all subjects, methacholine challenges and standardized citric acid challenges were performed. Sensitivity of the cough reflex was expressed as cough threshold, i.e., as concentration at which coughing occurred. Reproducibility was assessed in 23 subjects. Within a concentration range of 0.625-320.0 mg/ml, inhaled citric acid caused cough in all subjects. Geometric mean (range) cough threshold was 13 (2.5-160) in normal subjects, 14 (5-40) in patients with mild, and 32 (20-40) mg/ml in patients with moderate to severe asthma, 40 (20-80) in current smokers, and 119 (80-160) in occasional smokers. Cough thresholds were reproducible within one doubling concentration. In normal subjects and patients with mild bronchial asthma, thresholds were not significantly different from each other but lower than those of the other groups (p<0.05 each). Cough thresholds in smokers and patients with moderate to severe asthma did also not differ significantly and were lower than in occasional smokers (p<0.05). There was no significant correlation between cough threshold, baseline FEV subset1 , and methacholine responsiveness. Our data indicate that (1) subjects with mild asthma showed on average similar cough thresholds as normal subjects, (2) there was a large variation in cough thresholds within groups, (3) the reproducibility of cough thresholds was within one doubling concentration, (4) cough thresholds did not correlate with methacholine responsiveness or baseline airway tone. In view of the prevalence of cough as a symptom of bronchial asthma, it appears that the determination of citric acid-induced cough thresholds does not yield additional diagnostic information in these subjects.     

Effects of acute passive smoking on exercise-induced bronchoconstriction in asthmatic children

This study was designed to investigate the acute effects of environmental tobacco smoke (ETS) in children with mild asthma during rest and exercise. We studied 13 children [8 males, 5 females; mean age 10 (range 8-13) yr; mean forced expired volume in 1 s (FEV1) 93% (range 82-108%) of predicted] with exercise-induced bronchoconstriction [46 +/- 4% (SE) fall in FEV1 after exercise during cold air breathing]. Children were exposed to ETS (20 ppm carbon monoxide) or ambient air (AA) for 1 h. During the first 54 min of exposure, children were at rest, and during the last 6 min they exercised on a bicycle ergometer (2 W/kg body wt). Spirometry was performed before and during exposure and after exercise. Respiratory symptoms were recorded before and after exposures. In seven children the experiments with AA and ETS were done in duplicate. FEV1 between 5 and 54 min of exposure at rest decreased by 3.2 +/- 0.8% (SE) during AA and by 7.2 +/- 2.3% during ETS exposure compared with preexposure values; the difference between AA and ETS was statistically significant (P = 0.04). The drop in FEV1 was achieved within 5 min and did not change with ongoing exposure. Analysis of individual data revealed that the mean changes during ETS were mainly effected by three children with a significant fall and one child with a significant improvement in FEV1 (P < 0.05). Maximum postexercise fall of FEV1 was 25 +/- 4% after AA and 24 +/- 3% after ETS, which did not differ significantly. Upper and lower respiratory tract symptoms were not significantly different between exposures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of neutral endopeptidase in exercise-induced bronchoconstriction in asthmatic subjects

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator peptides within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thiorphan, a NEP inhibitor, as pretreatment to a 6-min standardized exercise challenge. Thirteen clinically stable asthmatic subjects participated in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by two inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40-50% of predicted maximal voluntary ventilation while inhaling dry air (20 degrees C, relative humidity 6%). The airway response to exercise was measured by forced expiratory volume in 1 s (FEV1) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV1 from baseline and as the area under the time-response curve (AUC) (0-30 min). The acute effects of both pretreatments on baseline FEV1 were not different (P > 0.2), neither was there any difference in maximal percent fall in FEV1 between thiorphan and placebo (P > 0.7). However, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUC (0-30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall.h (placebo); P = 0.047]. These data indicate that NEP inhibition by thiorphan reduces EIB during the recovery period. This suggests that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients with asthma.     

X-SCID B cell responses to interleukin-4 and interleukin-13 are mediated by a receptor complex that includes the interleukin-4 receptor alpha chain (p140) but not the gamma c chain

We previously reported that patients with mild to moderate airflow limitation have a lower exercise capacity than age-matched controls with normal lung function, but the mechanism of this reduction remains unclear (1). Although the reduced exercise capacity appeared consistent with deconditioning, the patients had altered breathing mechanics during exercise, which raised the possibility that the reduced exercise capacity and the altered breathing mechanics may have been causally related. Reversal of reduced exercise capacity by an adequate exercise training program is generally accepted as evidence of deconditioning as the cause of the reduced exercise capacity. We studied 11 asymptomatic volunteer subjects (58 +/- 8 yr of age [mean +/- SD]) selected to have a range of lung function (FEV1 from 61 to 114% predicted, with a mean of 90 +/- 18% predicted). Only one subject had an FEV1 of less than 70% predicted. Gas exchange and lung mechanics were measured during both steady-state and maximal exercise before and after training for 30 min/d on 3 d/wk for 10 wk, beginning at the steady-state workload previously determined to be the maximum steady-state exercise level that subjects could sustain for 30 min without exceeding 90% of their observed maximal heart rate (HR). The training workload was increased if the subject's HR decreased during the training period. After 10 wk, subjects performed another steady-state exercise test at the initial pretraining level, and another maximal exercise test. HR decreased significantly between the first and second steady-state exercise tests (p < 0.05), and maximal oxygen uptake (VO2max) and ventilation increased significantly (p < 0.05) during the incremental test, indicating a training effect. However, the training effect did not occur in all subjects. Relationships between exercise parameters and lung function were examined by regression against FEV1 expressed as percent predicted. There was a significant positive correlation between VO2max percent predicted and FEV1 percent predicted (p < 0.02), and a negative correlation between FEV1 and end-expiratory lung volume (EELV) at maximal exercise (p < 0.03). There was no significant correlation between FEV1 and maximal HR achieved during exercise; moreover, all subjects achieved a maximal HR in excess of 80% predicted, suggesting a cardiovascular limitation to exercise. These data do not support the hypothesis that the lower initial VO2max in the subjects with a reduced FEV1 was due to deconditioning. Although increased EELV at maximal exercise, reduced VO2max and a reduced VO2max response with training are all statistically associated with a reduced FEV1, there is no direct evidence of causality.     

Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study

Hyperosmolar aerosols are used to assess airway responsiveness in subjects with asthma. Using a 10% NaCl aerosol, we investigated airway responsiveness in 23 cystic fibrosis (CF) subjects (12 females, 11 males; 19.1 +/- 3.3 years) who had asthma-like symptoms. The pre-challenge predicted forced expiratory volume in 1 second (FEV1) was 74.7 +/- 21.5. The aerosol was generated by a MistO2gen 143A ultrasonic nebulizer and inhaled for 0.5, 1, 2, 4, 8, 8, and 8 minutes or part thereof. Spirometry was performed before and 1 minute after each inhalation period. The challenge was stopped when a > or = 20% fall from the baseline FEV1 was recorded, after the last inhalation period, or when requested by the subject. We recorded different responses to 10% NaCl among subjects. In 7, the FEV1 fell progressively throughout the challenge in a manner similar to asthmatics. By contrast, in 15 subjects the FEV1 was higher at the completion of challenge compared to during challenge, i.e., the fall in FEV1 was transient. In 7 of these subjects, the final FEV1 at the end of the challenge was higher than the pre-challenge FEV1. We conclude that inhaled 10% hyperosmolar saline causes either progressive and sustained or transient airway narrowing during challenge in the majority of CF subjects. The cause of the transient airway narrowing requires further investigation.     

Human granulocytic ehrlichiosis in Europe: clinical and laboratory findings for four patients from Slovenia

OBJECTIVE: To determine whether montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma. STUDY DESIGN: Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced expiratory volume in 1 second (FEV1) > or =70% of the predicted value and a fall in FEV1 > or =20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in each period. End points included area above the postexercise percent fall in FEV1 versus time curve (AAC0-60 min), maximum percent fall in FEV1 from pre-exercise baseline, and time to recovery of FEV1 to within 5% of pre-exercise baseline. RESULTS: Montelukast significantly reduced AAC0-60 min (265 vs 590% x min for montelukast and placebo, respectively, P < or = .05; approximately 59% protection relative to placebo) and the maximum percent fall (18% vs 26% for montelukast and placebo, respectively, P < or = .05). Montelukast treatment resulted in a shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively, P = .079). CONCLUSIONS: Montelukast attenuates EIB at the end of the dosing interval in 6- to 14-year-old children with asthma.     

Airways remodeling is a distinctive feature of asthma and is related to severity of disease

PURPOSE: Airways remodeling, evaluated as the subepithelial layer thickness, was compared in asthmatic patients with that of healthy subjects, and was related to clinical grading of disease, presence of atopy, and length of asthmatic history. SUBJECTS AND METHODS: Thirty-four patients with stable asthma (mean age+/-SD: 26.5+/-9.2 years; 10 female) treated with only inhaled beta2-agonists and eight healthy volunteers (mean age+/-SD: 24.6+/-2.5 years; four female) were recruited for the study. Twenty-seven of 34 asthmatics had atopy. Eleven patients had newly diagnosed conditions (duration of disease < or = 1 year), nine patients had long asthmatic history (> 1 year and < or = 10 years), and 14 had prolonged asthmatic history (> 10 years). Bronchial responsiveness to methacholine (M) was expressed as provocative concentration of M causing a 20% fall in FEV1 (PC20) (mg/mL). Degree of asthma severity was assessed using a 0- to 12-point score based on symptoms, bronchodilator use, and daily peak expiratory flow variability over a 3-week period. Bronchoscopy and bronchial biopsy were performed successfully for all subjects; the subepithelial layer thickness, in biopsy samples, was measured from the base of bronchial epithelium to the outer limit of reticular lamina. RESULTS: In asthmatics, baseline FEV1 values (percent of predicted) ranged from 75.7 to 137.0%, and PC20 M ranged from 0.15 to 14.4 mg/mL. According to the asthma severity score, 14 asthmatics were classified as having mild disease, 14 as having moderate disease, and six as having severe disease. The mean values of subepithelial layer thickness were 12.4+/-3.3 microm (range, 6.8 to 22.1 microm) in asthmatics, and 4.4+/-0.5 microm (range, 3.8 to 5.2 microm) in healthy subjects (p<0.001). Subepithelial layer thickness of those with severe asthma differed significantly from that of patients with moderate and mild asthma (16.7+/-3.1 microm vs 12.1+/-2.7 microm and 10.8+/-2.4 microm, p<0.01 and p<0.003, respectively). Moreover, in asthmatics, degree of thickening was positively correlated to asthma severity score (Spearman rank correlation coefficient [rs]=0.581; p<0.001), and negatively correlated with baseline FEV1 (rs=-0.553; p<0.001) and PC20 M (rs=-0.510; p<0.01). No difference was found between degree of thickening observed in atopic asthmatics, compared with that of nonatopic asthmatics, or between degree of thickening in patients with different lengths of asthmatic history. Lastly, multiple regression analysis revealed that asthma severity score was the significant predictive factor for thickness of subepithelial layer. CONCLUSIONS: We confirmed that airways remodeling is a very distinctive and characteristic pathologic finding of asthma. We also demonstrated that it is related to the clinical and functional severity of asthma, but not to atopy or length of asthmatic history.     

Incidence of exercise-induced asthma in children

The incidence of exercise-induced asthma (EIA) was studied in 134 asthmatic and 102 nonasthmatic atopic children and compared to that in 56 nonatopic children. Pulmonary function tests measuring forced vital capacity (FVC) and 1-sec forced expiratory volume (FEV1) were performed on each child prior to and serially for 20 min following free running exercise. The incidences of EIA among the asthmatic and atopic nonasthmatic children were 63% and 41%, respectively. This phenomenon is widespread among allergic children and cannot be accurately predicted from the history. A simple and easily performed outpatient procedure is described for the diagnosis of EIA.     

Evaluation of the inhaled glucocorticosteroid effects on non specific bronchial reactivity with particular reference to the late inflammatory phase in atopic asthma patients. II. The effect of regular administration of budesonide R on specific and non-specific bronchial reactivity

The purpose of the study was to determine whether regular administration of budesonide R decreases inflammation, specific and non-specific bronchial hyperreactivity in allergic asthma patients. The studies were carried out on 16 patients suffering from mild to moderate allergic asthma, sensitive to D. pteronyssinus allergen. After performance of the specific and non-specific bronchial provocation tests, collection of blood samples for an ECP evaluation, the patients were regularly treated with budesonide R, 2 x 320 micrograms for a period of 8 weeks. At the end of the study the BPTs and blood collection were repeated. BPTs with methacholine and D. pteronyssinus were performed according to Ryan's method. After the allergen challenge, early (EAR) and late asthmatic reaction (LAR) were to be observed. After the therapy non-specific BHR to methacholine expressed as PC20FEV1 and specific BHR to allergen (PD20FEV1D. pteronyssinus) and serum ECP concentrations decreased significantly. Although after the treatment with budesonide R, the patients had to inhale much larger amounts of allergen, in order to induce EAR, the number of LAR did not change significantly. After treatment the LAR appeared about 1 hour later and the decrease in FEV1 was less than previously. We conclude that budesonide R decreases the intensity of the inflammation and BHR.     

Leukotrienes and asthma. Clinical and experimental experiences with leukotriene receptor antagonists and leukotriene synthesis inhibitors]

Leucotrienes are synthesized from arachidonic acid. They are potent proinflammatory mediators that contribute to bronchial hyperreactivity. Antileukotrienes constitute a new group of antiasthmatic drugs. Zafirlucast, a leukotriene receptor antagonist, is now registered in Ireland and Finland for the treatment of mild to moderate asthma. We have studied the literature on antileukotrienes and have focused on their ability to prevent or inhibit symptoms in asthma. When patients with mild to moderate asthma are pretreated with an antileukotriene, the bronchoconstriction following provocation with cold, dry air, exercise or allergen is significantly reduced. ASA-sensitive asthmatics with adenoids and a lost sense of smell achieved a significant increase in FEV1s and regained their sense of smell after administration of an antileukotriene. Ongoing studies will tell us whether antileukotrienes have a significant steroid-sparing effect as compared with placebo, after which recommendations can be made concerning the future use of these interesting medicaments.