pulmicort and Bronchial-Hyperreactivity

The use of histamine and methacholine is well established for identifying airway hyperresponsiveness (AHR) but the AHR to these agents is not specific for asthma diagnosis. Further, these agents do not identify or exclude exercise-induced asthma (EIA) so they are inappropriate for some occupational and sporting assessments. Measurement of AHR by pharmacological agents has other limitations in that a positive response does not necessarily identify a person who will respond to inhaled steroids and responses do not differentiate between doses of steroids. As most asthmatics remain hyperresponsive to these agents after treatment they have not been useful for guiding steroid dose reduction. Bronchial provocation tests (BPTs) with physical stimuli such as exercise, eucapnic voluntary hyperpnea and hypertonic saline have provided useful information on presence and severity of asthma and EIA. These tests however, can be time consuming and require more resources compared with the pharmacological tests. To simplify testing, a challenge has been developed that uses a dry powder of mannitol administered from a simple hand-held device. The mannitol is given in increasing doses from capsules containing from 5 mg to 40 mg. Mannitol responsiveness identifies people with EIA and those who will respond to inhaled steroids. Mannitol responsiveness is reduced following treatment with inhaled steroids, and some subjects become unresponsive within 6 to 8 weeks. Responsiveness to mannitol can be used to predict risk of exacerbation during back titration of steroids. Should this BPT become more readily available it would be the first to provide a common operating standard for use in the laboratory, office, or field.

Topics: Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Forced Expiratory Volume; Humans; Mannitol; Saline Solution, Hypertonic

Topics: Administration, Inhalation; Adult; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Follow-Up Studies; Forced Expiratory Volume; Forecasting; Glucocorticoids; Humans; Lung Diseases, Obstructive; Peak Expiratory Flow Rate; Pregnenediones; Randomized Controlled Trials as Topic; Smoking; Vital Capacity

The use of inhaled corticosteroids in mild to moderate COPD is controversial. The aim of this study was to determine whether airway hyperresponsiveness to mannitol might identify patients who are likely to respond to add-on inhaled corticosteroids.. Ninety subjects with mild to moderate COPD were recruited and 68 subsequently randomized in a double-blind manner to receive inhaled budesonide (1,600 μg/d, n = 31) or placebo (n = 37) for 3 months. Thirty-eight subjects had airway hyperresponsiveness to mannitol (17 received budesonide, 21 placebo). All subjects received tiotropium throughout the study, including 4 weeks before randomization. Spirometry, quality of life (St. George Respiratory Questionnaire), degree of dyspnea, airway responsiveness to mannitol, and exhaled nitric oxide were assessed at week 0 (recruitment), week 4 (baseline prior to randomization), and week 16 (posttreatment).. Compared with placebo, budesonide was associated with improved quality of life in subjects showing airway hyperresponsiveness to mannitol (difference of changes in quality of life score between randomization and study completion, −9.1; 95% CI, −15.8 to −2.3; P < .01). Treatment with inhaled budesonide also led to a reduction in airway responsiveness to mannitol compared with placebo (difference in log10 response-dose ratio, −0.3; 95% CI, −0.6 to −0.04; P < .01). However, postrandomization changes in FEV1 % predicted, quality of life, and exhaled nitric oxide showed no difference between budesonide and placebo.. In subjects with mild to moderate COPD and airway hyperresponsiveness to mannitol, quality of life and airway responsiveness improved after treatment with inhaled corticosteroids added to long-acting bronchodilator therapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Bronchial Hyperreactivity; Budesonide; Diuretics, Osmotic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Mannitol; Middle Aged; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Treatment Outcome

Inhaled combined therapy improves the pulmonary function in asthmatic patients. The effect on the airway hyperresponsiveness (AHR) and the efficacy of different pharmacological schedules is not well clarified on adolescent asthmatics.. Evaluate the responses to different combined inhaled therapies in adolescent asthmatics and study its impact on exercise induced AHR.. Basal lung function tests (LFT) were performed in 30 adolescents (13 to 16 years old; 19 female) with allergic asthma. They were submitted to exercise challenge test (EC) followed by bronchodilator test (BD). During 4 weeks, 15 adolescents were submitted to inhaled fluticasone/salmeterol (group A) and other 15 to inhaled budesonide/formoterol (group B). After this period, they underwent another functional evaluation as previous.. Before treatment, pulmonary function was similar in both groups. After 4 weeks of treatment, these groups showed an improvement of the basal LFT (p = 0.001 for FEV1 in both), decrease on bronchoconstriction induced by exercise (NS for both) and less recovery on BD response (p = 0.001 and 0.002, for FEV1 respectively groups A and B). Group B showed a better performance, with higher improvement of basal FEF 25/75 (p = 0.001), reduced bronchoconstriction response to EC (p = 0.008 for FEV1) and fewer response to BD test (p < 0.0001 for FEV1 and 0.024 for FEF 25/75) No adverse events were observed.. After 4 weeks of inhaled combined therapy, these patients improved their pulmonary function and bronchomotricity. Those under budesonide/formoterol showed the highest improvement. These medications are a safe measure in controlling the asthma in these patients.

Topics: Adolescent; Albuterol; Androstadienes; Asthma; Asthma, Exercise-Induced; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Drug Combinations; Ethanolamines; Female; Fluticasone-Salmeterol Drug Combination; Formoterol Fumarate; Humans; Male; Respiratory Function Tests

Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).. 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.. Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.. IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.

Topics: Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Child; Double-Blind Method; Genetic Variation; Genotype; Haplotypes; Humans; Karyopherins; Linkage Disequilibrium; Nedocromil; Polymorphism, Genetic; Polymorphism, Single Nucleotide

Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation as a result of chronic inflammation of the airways and lung parenchyma. COPD patients always have airway hyperreactivity (AHR), so how to reduce AHR becomes the key purpose of clinical treatment. It is hypothesized that combined inhalation of corticosteroids and beta2-agonists can reduce the AHR in COPD. In this study, atomization inhalation of budesonide and terbutaline plus conventional therapies was applied to treat AECOPD (acute exacerbation of chronic obstructive pulmonary disease) patients for two weeks. The results showed that additional inhalation of budesonide and terbutaline could upregulate serum IL-2 levels, the percentages of CD3+ T and CD4+ T cells, and CD4/CD8 ratio, and decrease eosinophils and serum CRP level more efficiently than conventional treatment in patients with AECOPD. And the lung function of the atomization inhalation group was improved more obviously after the treatment compared with the conventional treatment group. Thus, atomization inhalation of terbutaline and budesonide can control AECOPD effectively, and has wide clinical perspective in controlling and preventing the exacerbation of COPD.

Topics: Administration, Inhalation; Aged; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; C-Reactive Protein; Eosinophils; Female; Humans; Interleukin-2; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; T-Lymphocyte Subsets; Terbutaline

Airway responsiveness is a prognostic marker for asthma symptoms in later life.. To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma.. A total of 1,041 children, initially aged 5-12 years, with mild to moderate persistent asthma enrolled in the Childhood Asthma Management Program (CAMP) were studied prospectively for 8.6 +/- 1.8 years with methacholine challenges yearly.. Least squares geometric mean models were fit to determine effects of sex and age on airway responsiveness (provocative concentration producing 20% decrease in FEV(1) [PC(20)]). Multiple linear regression analysis was performed to determine factors at baseline and over time, which were associated with PC(20) at end of follow-up. A total of 7,748 methacholine challenges were analyzed. PC(20) increased with age, with boys having greater increase after age 11 years than girls (P < 0.001). The divergence coincided with the mean age for Tanner stage 2. Postpubertal girls had greater airway responsiveness, even after adjustment for FEV(1) and other potential confounders. Although multivariable regression analyses noted a variety of factors that influenced airway responsivness in both sexes, a history of hay fever (beta= -0.30, P = 0.005), respiratory allergy (beta= -0.32, P = 0.006), or recent inhaled corticosteroid usage (beta= -0.18, P = 0.02) were associated with decrements in final log PC(20) only in girls.. Airway responsiveness (PC(20)) is more severe in the postpubertal female with asthma than in males. Although there are factors associated with airway responsiveness in both males and females, sex-specific factors may contribute to new insights into asthma pathogenesis.

Topics: Adolescent; Age Factors; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Bronchodilator Agents; Budesonide; Child; Child, Preschool; Cohort Studies; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Least-Squares Analysis; Male; Methacholine Chloride; Nedocromil; Prognosis; Prospective Studies; Puberty; Sex Ratio; Vital Capacity

The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma.. To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure.. In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 mug), formoterol (12 mug), budesonide (400 mug), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured.. All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV(1) fall: placebo, [mean +/- SEM] 21.2% +/- 3.1%; budesonide/formoterol, 4.2% +/- 1.4%; formoterol, 7.5% +/- 1.7%; budesonide, 10.4% +/- 1.6%). Allergen-induced change in methacholine PC(20) was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response.. A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen.. The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles.

Topics: Administration, Inhalation; Adolescent; Adult; Allergens; Asthma; Bronchial Hyperreactivity; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Female; Forced Expiratory Volume; Formoterol Fumarate; Humans; Male; Methacholine Chloride

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Topics: Acetates; Administration, Inhalation; Adult; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Cross-Over Studies; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Eosinophils; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Humans; Leukocyte Count; Lung Volume Measurements; Male; Methacholine Chloride; Middle Aged; Quinolines; Sputum; Sulfides

Montelukast has been shown to be effective in controlling the increase in exhaled NO in asthmatic children re-exposed to house dust mite (HDM). This study compared the effect of low dose inhaled budesonide and oral montelukast in preventing the expected relapse of airway inflammation and reactivity in a group of 24 mild asthmatic children allergic to HDM after a brief period of exposure to relevant allergens.. Lung function, bronchial hyperresponsiveness (BHR) to methacholine (PC(20)), fractional exhaled nitric oxide (FeNO) levels and sputum eosinophilia were evaluated.. Pulmonary function remained stable. The BHR was unchanged after exposure in the group treated with budesonide, whereas a significant increase (P = 0.028) was observed in the patients receiving montelukast. No significant difference was observed in FeNO levels after exposure to mite antigen in the two groups. In both the groups of asthmatic children we observed a significant increase in sputum eosinophil % after the exposure to mite antigen.. The significant increase in BHR level observed in the group of children receiving montelukast suggests a more comprehensive effect as disease controller by inhaled steroids than by leukotriene antagonist in allergic asthmatic children re-exposed to relevant allergens.

Topics: Acetates; Allergens; Anti-Asthmatic Agents; Antigens, Dermatophagoides; Asthma; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Child; Cyclopropanes; Eosinophils; Exhalation; Female; Humans; Lung; Male; Methacholine Chloride; Nitric Oxide; Quinolines; Respiratory Function Tests; Sputum; Sulfides

Treatment with inhaled steroids is an effective method of reducing bronchoconstriction and airway inflammation after allergen challenge. However, the duration of the protective effects of inhaled steroids after discontinuation of therapy has not been established.. We sought to evaluate the protective effect of 1 week of inhaled steroid therapy against inhaled allergen challenge 12 hours after discontinuation of therapy.. In this randomized, double-blind, placebo-controlled crossover trial, 26 asthmatic subjects (>18 years old) not using inhaled steroids were administered 200 microg of budesonide twice daily, 200 microg of fluticasone twice daily, or placebo twice daily for 1 week. Twelve hours after discontinuation of therapy, subjects were administered an inhaled allergen challenge. Each treatment period was separated by a 3-week washout period.. When compared with placebo (26% +/- 14%), there was a slight but significant protection against the allergen-induced early response after fluticasone treatment (19% +/- 10%, P = .001) but not after budesonide treatment (23% +/- 13%, P = .08). However, when the area under the curve for the early airway response was examined, there was no difference between the 2 drugs in the amount of protection ( P = .62). Partial protection was demonstrated against the late-response allergen-induced sputum eosinophilia with both treatments ( P = .001). By contrast, no protection was observed against allergen-induced airway hyperresponsiveness for either treatment.. The protective effects of inhaled steroids against allergen-induced early responses, airway eosinophilia, and allergen-induced airway hyperresponsiveness are partially or completely lost as early as 12 hours after discontinuation of therapy.

Topics: Adult; Allergens; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Eosinophils; Female; Fluticasone; Humans; Male; Middle Aged; Time Factors

To investigate the long term efficacy as well as the side-effects of small dose budesonide turbuhaler in mild bronchial asthma.. Fifty-two patients with mild asthma were randomly divided into groups A, B and C. Twenty-two cases in group A received 200 microg budesonide turbuhaler by inhalation every night. Fifteen cases in group B received oral prednisone 5 mg/d and theophyllin control release tablet 0.2 g twice daily, as well as ventolin aerosol inhalation 200 microg three times daily during asthmatic attack. Fifteen cases in group C received no glucocorticoids, but theophyllin control release tablet 0.2 g twice daily as well as ventolin aerosol inhalation (200 microg/d) were given during asthmatic attack. All three groups received treatment consecutively for 3 years, and followed for one year after stopping treatment. During the total 4 years, pulmonary function measurements (FEV1, Raw, Gaw), bronchial hyperreactivity (BHR), clinical effects, plasma cortisol level and the activated reaction of ACTH were evaluated.. (1) Before the treatment, BHR of the three groups were similar, with most cases graded III-IV, being 91% (20/22), 100% (15/15) and 93% (14/15) respectively. After the treatment, the BHR of 18 (82%) cases of group A was reduced to grades I-II. However, 13 cases (87%) of group B still remained at grades III-IV and 15 cases (100%) of group C were still at grades III-IV. The results of the three groups showed a significant difference (P < 0.01). (2) Compared to measurements before the treatment, Raw was (623 +/- 103)% vs (158 +/- 24)% in group A, (605 +/- 90)% vs (340 +/- 61)% in group B, and (638 +/- 108)% vs (420 +/- 81)% in group C, the difference among the three groups being significant (P < 0.01). (3) Compared to the measurements before the treatment, Gaw was (22 +/- 4)% vs (83 +/- 15)% in group A, (27 +/- 6)% vs (42 +/- 9)% in group B, and (27 +/- 5)% vs (31 +/- 6)% in group C, the difference among the three groups being significant (all P < 0.01 respectively). (4) Compared with the measurements before the treatment, FEV1 was (2.3 +/- 0.4) L vs (2.9 +/- 0.4) L in group A, (2.3 +/- 0.4) L vs (2.6 +/- 0.4) L in group B, and (2.3 +/- 0.4) L vs (2.7 +/- 0.4) L in group C, the difference among the three groups being significant (P < 0.01). (5) With asthmatic symptom control as the criteria of therapeutical effects, the effective rate of group A, B and C were 91%, 53% and 33% respectively, which showed significant difference among the three groups (all P < 0.01 respectively). (6) The plasma cortisol levels of group A and B were (326 +/- 103) nmol/L and (308 +/- 29) nmol/L before treatment, compared with (318 +/- 78) nmol/L and (299 +/- 98) nmol/L after treatment, the difference in group A or in group B was not significant (all P > 0.05). When the measurements before and after treatment were compared, the cortisol levels of group A and B were (365 +/- 102) nmol/L vs (373 +/- 102) nmol/L and (343 +/- 79) nmol/L vs (346 +/- 103) nmol/L respectively after the stimulation of ACTH, which showed no significant changes even after the stimulation of ACTH (all P > 0.05).. Long term small dose budesonide turbuhaler inhalation could effectively decrease BHR and the Raw, while increase the Gaw of asthmatic patients, hence improving the pulmonary function and preventing acute attack. In addition, it did not induce suppression of HPAA axis function in the patients.

Topics: Administration, Inhalation; Adolescent; Adult; Airway Resistance; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Child; Drug Administration Schedule; Female; Glucocorticoids; Humans; Hydrocortisone; Lung; Male; Middle Aged; Prednisone

Corticosteroids are the antiinflammatory treatment of choice in asthma. Treatment guidelines are mainly symptom-driven but symptoms are not closely related to airway inflammation. The fraction of nitric oxide in exhaled air (FENO) is a marker of airway inflammation in asthma.. We evaluated whether titrating steroids on FENO improved asthma management in children.. Eighty-five children with atopic asthma, using inhaled steroids, were allocated to a FENO group (n=39) in which treatment decisions were made on both FENO and symptoms, or to a symptom group (n=46) treated on symptoms only. Children were seen every 3 months over a 1-year period.. Symptoms were scored during 2 weeks before visits and 4 weeks before the final visit. FeNO was measured at all visits, and airway hyperresponsiveness and FEV1 were measured at the start and end of the study. Primary endpoint was cumulative steroid dose.. Changes in steroid dose from baseline did not differ between groups. In the FENO group, hyperresponsiveness improved more than in the symptom group (2.5 vs. 1.1 doubling dose, p=0.04). FEV1 in the FENO group improved, and the change in FEV1 was not significantly different between groups. The FENO group had 8 severe exacerbations versus 18 in the symptom group. The change in symptom scores did not differ between groups. FENO increased in the symptom group; the change in FENO from baseline differed between groups (p=0.02).. In children with asthma, 1 year of steroid titration on FENO did not result in higher steroid doses and did improve airway hyperresponsiveness and inflammation.

Topics: Adolescent; Anti-Inflammatory Agents; Asthma; Breath Tests; Bronchial Hyperreactivity; Budesonide; Child; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Nitric Oxide; Prednisone

Bronchial hyperresponsiveness to adenosine monophosphate, an indirect measure of airway inflammation, is a sensitive marker of inhaled corticosteroid efficacy.. To evaluate the relative therapeutic efficacy of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in patients with mild-to-moderate persistent asthma.. In a double-masked, dose-response crossover study, 27 patients received inhaled budesonide in cumulative sequential doubling dose increments, 2 weeks per dose, of 200, 400, and 800 microg/d. Each treatment block was preceded by 1- to 3-week placebo run-in and washout periods. End points were measured after each placebo (ie, baseline) and treatment period. Adenosine monophosphate bronchial challenge was the primary outcome, and exhaled nitric oxide, serum eosinophilic cationic protein, spirometry, domiciliary peak expiratory flow, symptoms, and rescue medication use were the secondary outcomes.. For the adenosine monophosphate provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20), a significant overall dose-response effect (P = .006) was found, and there was no significant difference between the devices (P = .8). The relative microgram dose potency ratio between Clickhaler and Turbuhaler was 1.11 (95% confidence interval [CI], 0.50-2.46). After administration of the highest dose of budesonide, the mean doubling dilution shift in adenosine monophosphate PC20 from placebo baseline was 3.46 (95% CI, 2.66-4.27) with the Clickhaler vs 3.41 (95% CI, 2.47-4.35) with the Turbuhaler. A significant overall dose-response effect was demonstrated for exhaled nitric oxide (P = .03) but not for any of the other secondary outcome measures. There were no significant differences between the devices for any of the outcome measures.. Inhaled budesonide exhibited overall dose-response effects on adenosine monophosphate PC20 delivered via Turbuhaler and Clickhaler, with no significant difference between the devices.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adolescent; Adult; Aged; Asthma; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Powders

The aim of this study was to determine the clinical effect of inhaled corticosteroid treatment for persistent cough, post upper respiratory tract infection (URTI) in previously healthy individuals, and on bronchial hyperresponsiveness (BHR).. This was a prospective, randomized, double-blinded, placebo-controlled study conducted at a university hospital. A total of 30 non-asthmatic, non-smoking patients who were >15 years old and who had persistent post-URTI cough for >3 weeks were assessed by a physical examination, CXR and spirometry, and were allocated to receive inhaled budesonide (400 microg/puff, twice daily) or placebo for 4 weeks. If a patient suffered from sinusitis, it was a requirement that it had been well treated. A symptom score (frequency of cough, frequency of coughing bouts, symptoms associated with cough, night-time cough, frequency of taking medications to relieve cough, and number of medications) was recorded at entry, and after 2 and 4 weeks of treatment. A methacholine challenge test was performed at entry and after 4 weeks of treatment.. The mean symptom scores for the treatment group (9.4) and the placebo group (9.8) at baseline were not significantly different (P=0.79), and no differences were found between the groups after week 2 and week 4 of treatment (3.93 and 4.27 vs 2.26 and 2.66, P=0.29). The mean change in symptom scores from baseline to week 2 and to week 4 of treatment were also not different between groups (5.93 and 5.6 vs 7.00 and 7.58, P=0.23). No difference between groups was found in the mean changes in FEV(1), FVC, and FEF(25--75%) after 4 weeks of treatment. A positive bronchial provocation test occurred in three patients (10%) but these were borderline.. Inhaled corticosteroid is ineffective in treating persistent post-URTI cough in previously healthy individuals.

Topics: Administration, Inhalation; Adult; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cough; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Respiratory Function Tests; Respiratory Tract Infections; Treatment Failure

There is a need for controlled trials among children with asthma to evaluate and compare different markers of inflammation.. Our goal was to investigate the effect of withdrawal of inhaled budesonide on repeated measurements of exhaled NO (ENO), peripheral blood eosinophils (PBE), sputum/NAL/serum-eosinophil cationic protein (ECP), bronchial hyperresponsiveness (BHR) and forced expiratory volume in 1 s (FEV(1)) in children with allergic asthma.. Eighteen asthmatic children were randomly allocated to continue or discontinue use of inhaled budesonide. They were followed up, at six visits for 4 months with regular blood, serum, sputum, and NAL samples. Sixteen age-matched healthy children served as controls.. ENO, PBE, and S-ECP increased significantly in the withdrawal group (p < 0.05) but not in the continuous treatment group. No trend could be observed during the study for markers in sputum or in NAL in either group.. The present data provide evidence for the clinical usefulness of measuring ENO, PBE, and S-ECP and when combined they could help to avoid over- and undertreatment with corticosteroids in the growing child.

Topics: Adolescent; Anti-Inflammatory Agents; Asthma; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Eosinophil Cationic Protein; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Nasal Lavage Fluid; Nitric Oxide; Sputum

Mild persistent asthma is most effectively controlled with inhaled corticosteroids. Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control. The additional effect of a leukotriene receptor antagonist, zafirlukast, was investigated in stable asthma patients under control with inhaled budesonide. We conducted a randomised, double-blind, placebo-controlled, single center trial to investigate the effects of add-on zafirlukast treatment to budesonide, on symptom score, pulmonary function, bronchial responsiveness, and serum levels of eosinophilic cationic protein (ECP) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide. The present study included 21 mild or moderate asthmatic patients (8 males and 13 females), who were stable at least for 6 weeks with inhaled budesonide (400 microg/day). Serum total antioxidant capacity (TAC) and ECP levels were measured, and symptom scoring, spirometry, and bronchial provocation with methacholine were performed. Then, the patients were randomised to use either placebo or oral zafirlukast (40 mg/day) in addition to budesonide for 6 weeks. At the 6th week, symptom scoring, spirometry, and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again. After add-on zafirlukast treatment to budesonide, forced expiratory volume in 1 second (FEV(1)), TAC and ECP values did not change significantly (p > 0.05) but bronchial hyperresponsiveness and symptom score decreased significantly (p = 0.022) compared to baseline. Thus, in stable asthmatic patients, add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness.

Topics: Adolescent; Adult; Antioxidants; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Double-Blind Method; Drug Therapy, Combination; Eosinophil Cationic Protein; Female; Humans; Indoles; Leukotriene Antagonists; Male; Middle Aged; Phenylcarbamates; Placebos; Respiratory Function Tests; Sulfonamides; Tosyl Compounds

Airway hyperresponsiveness (AHR) to pharmacologic stimuli and sputum eosinophils might be useful in the individual adjustment of long-term asthma management. However, it is not clear whether inhaled glucocorticosteroids (GCSs) provide greater protection against specific surrogate markers of airways inflammation than other means. In addition, detailed longitudinal assessment of changes in airway response with inhaled GCSs has never been carried out.. We compared changes in AHR to inhaled methacholine and adenosine 5'-monophosphate (AMP) after budesonide treatment in a randomized, double-blind, placebo-controlled, crossover study of patients with mild-to-moderate asthma. Subsequently, we undertook a separate study to examine the time course of the changes in AHR in more detail and the changes in sputum cell counts in relation to budesonide treatment.. In the phase 1 of the study, patients undertook bronchial provocation studies with increasing doubling concentrations of methacholine (0.06 to 16 mg/mL) and AMP (3.125 to 800 mg/mL) before and after budesonide 0.8 mg/daily for 3 weeks. The bronchial responses to the inhaled agonists were expressed as the provocative concentration causing a 20% decline in FEV(1) (PC(20)). In phase 2 of the study, patients attended the laboratory on 12 separate occasions to investigate changes in PC(20) methacholine, PC(20) AMP, and sputum cell counts before, during, and after withdrawal of therapy with inhaled budesonide 0.8 mg/daily for 6 weeks.. Budesonide treatment for 3 weeks significantly attenuated the constrictor response by 0.8 +/- 0.3 doubling doses for methacholine and by 2.6 +/- 0.5 doubling doses for AMP. These changes were significantly different from each other (P =.003). Significant variation in PC(20) methacholine (P <.05) value, PC(20) AMP (P <.001) value, percentage of sputum eosinophils (P <.001), and percentage of sputum epithelial cells (P <.001) were observed throughout the longitudinal assessment of changes in airway response to budesonide. Compared with the other surrogate markers, PC(20) AMP appears to be useful in promptly detecting early inflammatory changes of the asthmatic airways; a significant change of 1.6 +/- 0.3, 2.2 +/- 0.3, and 2.8 +/- 0.3 doubling doses of PC(20) AMP was observed at 1, 4, and 6 weeks, respectively, in the course of budesonide treatment.. The present findings underline the exquisite selectivity of diverse surrogate markers of airway inflammation in response to inhaled budesonide. When compared with that to the other markers, AHR to inhaled AMP is an early and sensitive indicator of the beneficial anti-inflammatory effects of topical GCSs.

Topics: Adenosine Monophosphate; Adult; Asthma; Bronchial Hyperreactivity; Budesonide; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Sputum

The perception of bronchoconstriction may be modulated by airway inflammation. However, the effect of inhaled corticosteroid (ICS) treatment on perception in subjects with asthma has received limited study. The aim of this study was to determine the effect of inhaled budesonide on the perception of breathlessness induced by histamine challenge. Thirty-five subjects with poorly controlled asthma were randomized to receive budesonide (1,600 or 3,200 microg/d) for 8 wk, followed by 8 wk at 1,600 microg/d and subsequent downtitration according to a clinical algorithm. Borg scores were recorded during histamine challenges performed at baseline and at 8, 16, 24, 48, and 72 wk. Perception was estimated as the slope of Borg/% fall FEV(1). The Borg/FEV(1) slope increased significantly after 8 wk of budesonide (0.09 [0.08-0.12] to 0.15 [0.11-0.19], p = 0.002), and remained increased compared with baseline values at all subsequent visits. There were no significant differences in Borg/ FEV(1) slope between subjects who were and were not taking ICS at study entry. The magnitude of change in the Borg/FEV(1) slope did not differ significantly between treatment groups and was not related to changes in baseline FEV(1), airway hyperresponsiveness, blood eosinophils, or serum eosinophil cationic protein (ECP). We conclude that treatment with budesonide enhances the perception of airway narrowing, but the effect is unrelated to budesonide dose, or to changes in circulating eosinophil markers.

Topics: Administration, Inhalation; Adolescent; Adult; Algorithms; Asthma; Attitude to Health; Blood Proteins; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Dyspnea; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Inflammation Mediators; Leukocyte Count; Male; Middle Aged; Regression Analysis; Ribonucleases; Severity of Illness Index; Treatment Outcome

Markers of airway inflammation are needed for prediction of asthma deterioration and evaluation of disease severity. Few studies have focused on the dynamics of airway inflammation as reflected by the activity of the eosinophils and their proteins after withdrawal of inhaled corticosteroids.. Our goal was to investigate the effect of withdrawal of inhaled budesonide on eosinophil count in blood and eosinophil proteins in serum and urine and to relate the levels of these markers to the risk of symptoms of asthma, increased bronchial hyperresponsiveness, and deterioration of lung function.. Thirty-three children were randomly selected to continue or discontinue use of inhaled budesonide in a double-blind, placebo-controlled study. They were followed up for 4 months with regular analysis of blood, serum, and urine samples; lung function; and methacholine challenges. Eosinophil activity markers were analyzed. Age-matched healthy children provided reference data for all parameters measured.. The eosinophil number in blood and eosinophil protein levels in serum (serum eosinophil cationic protein [ECP] and serum eosinophil peroxidase [EPO]) increased significantly in the withdrawal group, and the difference between the groups was significant (P =.02 for all). Twenty-nine percent of the children in the withdrawal group remained symptom free. This subgroup had eosinophil counts at baseline below 350/microL, a serum ECP level below 15 microg/L, and a serum EPO level below 25 microg/L, each of which was related to a low risk of exacerbation (relative risk = 0.37, 0.48, and 0.37 respectively; P <.05 for all). All eosinophil markers were lower in the healthy children than in the symptom-free children with asthma.. Our data indicate that eosinophil count and/or ECP and EPO levels can be used to estimate the short-term risk of deterioration and the need for corticosteroid treatment in cases of mild and moderate allergic asthma.

Topics: Adolescent; Anti-Asthmatic Agents; Antigens, CD; Asthma; Biomarkers; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Disease Progression; Double-Blind Method; Eosinophil Granule Proteins; Eosinophil Peroxidase; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Forced Expiratory Volume; Humans; Inflammation; Leukocyte Count; Male; Membrane Glycoproteins; Methacholine Chloride; Peroxidase; Peroxidases; Ribonucleases; Skin Tests; Spirometry; Tetraspanin 29

Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. The regular use of inhaled corticosteroids improves BHR in patients with symptomatic asthma. The aim of this study was to determine whether BHR in adolescents with asthma remission could be reduced by prolonged treatment with inhaled corticosteroids.. A randomized, double-blind, placebo-controlled, parallel study.. Thirty-seven adolescents with BHR and long-term remission of their asthma (neither symptoms nor any medication use during the previous 2 years).. Subjects received inhaled budesonide (two 200-microg puffs bid; budesonide group, n = 19) or identical placebo (placebo group, n = 18) for 9 months. A separate group of patients with symptomatic asthma (symptomatic group, n = 19), using the same regimen of budesonide, was also studied.. The provocative concentration of methacholine producing a 20% fall in FEV(1) (PC(20)) was measured before and every 3 months during treatment. There was no significant difference among the three groups for the baseline PC(20). In neither the placebo nor the budesonide group did the geometric mean of PC(20) change significantly over the 9-month period. In contrast, a significant increase in PC(20) was noted in the symptomatic group as a result of the budesonide treatment.. Our data have shown that budesonide inhaled regularly for 9 months did not cause a significant improvement in the BHR of adolescents with long-term asthma remission. This suggests that the mechanism underlying BHR in this clinical setting may be different from that in symptomatic asthma.

Topics: Administration, Inhalation; Adolescent; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male

Both specific immunotherapy (SIT) and nasal steroid (NS) have been shown to effectively reduce symptoms of allergic rhinitis. Although a number of investigators have convincingly shown anti-inflammatory effects of both treatments in separate studies, few comparative studies have been performed.. The purpose of this study was to compare the effects of preseason SIT with a standardized allergen extract and NS in seasonal allergic disease (rhinoconjunctivitis and asthma).. We examined 41 patients allergic to birch pollen, 21 with rhinoconjunctivitis and 20 with both rhinoconjunctivitis and asthma; they were treated in a randomized, double-blinded comparative study with birch SIT and NS (budesonide 400 microg daily). Bronchial hyperresponsiveness was measured before and during the season. Changes in eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity (ECA) in peripheral blood were investigated.. Symptoms of rhinoconjunctivitis increased significantly less in the NS-treated patients than in the SIT-treated patients during the final 2 weeks of the season (P = .03 and P = .04, respectively). Seasonal peak expiratory flow values decreased significantly only in the NS-treated patients (P = .01). In the NS-treated patients, bronchial hyperresponsiveness increased significantly during the season (P = .0001); however, SIT treatment prevented seasonal PC(20) increase in the asthmatic patients. Measurement of blood eosinophils, eosinophil cationic protein, and eosinophil chemotactic activity demonstrated significant seasonal increase only in the NS-treated asthmatic patients.. Treatment with NS was more effective than short-course preseason SIT in reducing symptoms of rhinoconjunctivitis; however, the 2 therapies were equivalent in terms of the need for rescue medication. SIT prevented seasonal increase in bronchial hyperresponsiveness, eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity only in asthmatic patients. The mechanisms underlying bronchial hyperresponsiveness developing during allergen exposure in rhinitis might be different from those operating in asthma.

Topics: Administration, Intranasal; Adult; Allergens; Asthma; Blood Proteins; Bronchial Hyperreactivity; Budesonide; Conjunctivitis, Allergic; Double-Blind Method; Eosinophil Granule Proteins; Female; Humans; Immunotherapy; Male; Rhinitis; Ribonucleases

Eosinophilic bronchitis is a common cause of chronic cough, characterized by sputum eosinophilia similar to that seen in asthma, but unlike asthma the patients have no objective evidence of variable airflow obstruction or airway hyperresponsiveness. The reason for the different functional associations is unclear. The authors have tested the hypothesis that in eosinophilic bronchitis the inflammation is mainly localized in the upper airway. In an open study the authors measured the lower (provocative concentration causing a 20% fall in forced expiratory volume in one second (PC20)) and upper (PC25 MIF50) airway responsiveness to histamine, lower and upper airway inflammation using induced sputum and nasal lavage, in II patients with eosinophilic bronchitis. The authors assessed changes in these measures and in cough reflex sensitivity to capsaicin and cough severity after 400 microg of inhaled budesonide for 4 weeks. A nasal eosinophilia was present in only three patients with one having upper airway hyperresponsiveness. Following treatment with inhaled corticosteroids the geometric mean sputum eosinophil count decreased from 12.8% to 2.9% (mean difference 4.4-fold, 95% confidence interval (CI) 2.14-10.02), the mean +/- sem cough visual analogue score on a 100 mm scale decreased from 27.2 +/- 6.6 mm to 12.6 +/- 5.7 mm (mean difference 14.6, 95% CI 9.1-20.1) and the cough sensitivity assessed as the capsaicin concentration required to cause two coughs (C2) and five coughs (C5) improved (C2 mean difference 0.75 doubling concentrations, 95% CI 0.36-1.1; C5 mean difference 1.3 doubling concentration, 95% CI 0.6-2.1). There was a significant positive correlation between the fold change in sputum eosinophil count and doubling dose change in C5 after inhaled budesonide (r=0.61). It is concluded that upper airway inflammation is not prominent in eosinophilic bronchitis and that inhaled budesonide improves the sputum eosinophilia, cough severity and sensitivity suggesting a causal link between the inflammation and cough.

Topics: Administration, Inhalation; Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchitis; Budesonide; Confidence Intervals; Cough; Dose-Response Relationship, Drug; Eosinophilia; Female; Glucocorticoids; Humans; Male; Middle Aged; Nasal Lavage Fluid; Reference Values; Treatment Outcome

Previous studies have shown that the regular administration of short acting beta-agonists can be associated with adverse effects on airway caliber and bronchial hyperresponsiveness (BHR) and that this may occur through a proinflammatory mechanism. The aim was to explore possible adverse effects of high-dose beta-agonist therapy and to assess any adverse interaction with corticosteroids. We undertook a randomized, crossover study to investigate the effects of 6 wk of treatment with regular terbutaline (1 mg four times a day), regular budesonide (400 microg twice a day), combined treatment, and placebo in subjects with mild to moderate asthma. Major endpoints were PD(15) saline, PD(20) methacholine, and induced sputum differential cell counts. Thirty-four subjects were randomized and 28 completed the study. PD(15) saline decreased on terbutaline alone compared with placebo treatment and on combined treatment compared with budesonide alone (mean fold decrease of 0.57 [95% CI = 0.36, 0.90] and 0.65 [95% CI = 0.43, 0.97], respectively). PD(20) methacholine was not affected by the use of terbutaline either alone or in combination with budesonide. The percentage of eosinophils in induced sputum increased during terbutaline treatment alone compared with placebo (median 8.3% versus 4.4%, p = 0.049). The addition of terbutaline to budesonide did not affect the percentage of eosinophils compared with budesonide treatment alone. These findings support the hypothesis that short-acting beta-agonists have a permissive effect on airway inflammation and that when used in high dose there may be an unfavorable interaction with inhaled corticosteroids.

Topics: Administration, Topical; Adolescent; Adrenergic beta-Agonists; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cell Count; Cross-Over Studies; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Male; Methacholine Chloride; Middle Aged; Peak Expiratory Flow Rate; Sodium Chloride; Sputum; Terbutaline

The importance of early initiation of inhaled steroids even in mild asthma has been documented in several studies. It is not, however, clear whether the treatment should be started with a high or a low dose of the inhaled steroid. We have compared the effects of high and low dose inhaled steroid, budesonide, in patients with newly detected asthma. We studied 101 adult patients with newly detected bronchial asthma who were without inhaled steroid or any regular pharmacological treatment for their asthma. The patients were randomly allocated to two treatment groups: one to receive 800 microg inhaled budesonide per day and the other to receive 200 microg inhaled budesonide per day. The drugs were given with a Turbuhaler dry powder inhaler. During the 3-month treatment period, no significant differences between the treatment groups were noted in morning or evening PEF values, in spirometric parameters, in asthmatic symptoms or in the use of rescue beta2-agonists. The decrease in bronchial hyperresponsiveness was, however, more marked in the high dose budesonide group, reaching a borderline significance (P=0.10 high vs. low dose budesonide). In addition, in serum markers of asthmatic inflammation significant differences were shown between the treatment groups. The decrease in the number of blood eosinophils during the treatment was more marked in the high dose budesonide group (P=0.02; high vs. low dose budesonide). In serum ECP no change was observed in the low dose budesonide group, but a marked decrease in the high-dose budesonide group (P=0.008; high vs. low dose budesonide). The change was even more marked with regard to serum EPX (P=0.005; high vs. low dose budesonide). Our results support the view that the treatment of newly detected asthma should be started with a high dose of inhaled steroid. The low dose may not be enough to suppress asthmatic inflammation despite good clinical primary response.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Patient Compliance; Vital Capacity

This study is an extended follow-up for 24 months of a 12-week trial to study the long-term clinical efficacy of low-dose inhaled budesonide (BUD) once or twice daily in children with mild asthma. A total of 122 children (mean age 9.7 years, girls/boys; 42/80) with mild asthma (FEV1 103.7% of predicted, reversibility in FEV1 3.5%, and fall in FEV1 after exercise 12.2%), not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. The children were treated with inhaled BUD 100 or 200 microg administered via Turbuhaler once daily in the morning, 100 microg twice daily, or placebo for 27 months. Exercise and methacholine challenges were performed at 3-month intervals the first year and at 6-month intervals the second year, in a total of seven visits. A significant dose-response effect favoring BUD 200 microg daily (vs 100 microg daily) was found when comparing changes in FEV1, FEF25%, and FEV50%; the fall in FEV1 after an exercise test; and the effect on blood eosinophils. Bronchial hyperreactivity to methacholine decreased significantly on three visits in patients treated with BUD 200 microg daily compared to placebo. Growth rate was not significantly affected except in children aged 7-11 years at baseline after 12 months of treatment. In conclusion, 100 or 200 microg daily of inhaled BUD for 27 months is safe and effective in protecting against exercise-induced asthma and achieving nearly normal lung function. Baseline lung function was not significantly affected in this group of children with mild asthma.

Topics: Administration, Inhalation; Adolescent; Anti-Inflammatory Agents; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Budesonide; Child; Double-Blind Method; Drug Administration Schedule; Eosinophil Granule Proteins; Eosinophils; Exercise Test; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Patient Compliance; Placebos; Pulmonary Eosinophilia; Ribonucleases

The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines. The study had a parallel-group design and included 61 subjects with poorly controlled asthma, randomized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks (double-blind), then 1,600 microg x day(-1) for 8 weeks (single-blind), followed by 14 months of open-label budesonide dose down-titration using a novel algorithm, with a written asthma crisis plan based on electronic peak expiratory flow monitoring. The primary outcome variable for weeks 1-16 was change in airway hyperresponsiveness (AHR), and, for the open-label phase, mean daily budesonide dose. By week 16, there were large changes from baseline in all outcomes, with no significant differences between the 3,200- and 1,600-microg x day(-1) starting dose groups (AHR increased by 3.2 versus 3.0 doubling doses, p=0.7; morning peak flow increased by 134 versus 127 L x min(-1), p=0.8). Subjects starting with 3,200 microg x day(-1) were 3.8 times more likely to achieve AHR within the normal range, as defined by a provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) of > or = 3.92 micromol by week 16 (p=0.03) [corrected]. During dose titration, there was no significant difference in mean budesonide dose (1,327 versus 1,325 microg x day(-1), p>0.3). Optimal asthma control was achieved in the majority of subjects (at completion/withdrawal: median symptoms 0.0 days x week(-1), beta2-agonist use 0.2 occasions x day(-1), and PD20 2.4 micromol). In subjects with poorly controlled asthma, a starting dose of 1,600 microg x day(-1) budesonide was sufficient to lead to optimal control in most subjects. The high degree of control achieved, compared with previous studies, warrants further investigation.

Topics: Administration, Inhalation; Adult; Aged; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Histamine; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Single-Blind Method; Treatment Outcome

Repeated low-dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics. Inhaled corticosteroids attenuate the airway responses to high-dose allergen challenge, but have not been evaluated against repeated low dose challenge.. This study evaluates the effects of once daily treatments of two doses of inhaled budesonide on airway responses to repeated low-dose allergen challenge.. Eight atopic asthmatics with a dual airway responses to inhaled allergen were recruited into a randomized, double-blind crossover, placebo-controlled study. In the mornings of four consecutive days (day 1-day 4), subjects inhaled budesonide 100 microg, 400 microg, or placebo, 30 min before inhaling a concentration of allergen causing a 5% early fall in FEV1. Airway hyperresponsiveness to methacholine and sputum eosinophils were measured at baseline, on the afternoon of day 2, day 4, and 24 h after the last challenge. There was a 1-week washout between each of the three treatment periods.. The repeated low-dose allergen challenge induced increases in the percentage sputum eosinophils from 2.0 +/- 0.7% at baseline to 16.6 +/- 7.1% on day 4 (P = 0.002), and this effect was reduced by once daily budesonide 100 microg to 5.6 +/- 1.8% (P = 0. 01) and by once daily budesonide 400 microg to 3.1 +/- 0.9% (P = 0. 004). Also, the allergen-induced methacholine airway hyperresponsiveness which occurred by day 4 (P = 0.03) of the repeated low dose challenge was inhibited by budesonide 400 microg (P = 0.017).. Both budesonide 100 microg and 400 microg inhaled once daily significantly reduces allergen-induced sputum eosinophilia after repeated low dose challenge; however, only the higher dose also attenuates the allergen-induced airway hyperresponsiveness.

Topics: Adult; Allergens; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cross-Over Studies; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Respiratory System

Inhaled corticosteroids have become the mainstay treatment of bronchial asthma. However, simultaneous evaluations of efficacy and side effects are few. This study aimed to compare the relative effect of fluticasone propionate (FP) and budesonide (BUD) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma. The study was double-blind and included 66 adults with asthma, who were randomized to FP (n = 33) or BUD (n = 33). Prestudy, all participants were clinically stable, using inhaled corticosteroids and hyperresponsive to methacholine. Eligible patients were randomized to three consecutive 2-wk periods with either FP 250 microg twice daily, FP 500 microg twice daily, and FP 1,000 microg twice daily, or BUD 400 microg twice daily, BUD 800 microg twice daily, and BUD 1,600 microg twice daily, delivered by Diskhaler and Turbuhaler, respectively. Before randomization and at the end of each treatment, bronchial methacholine PD(20), 24-h urinary cortisol excretion (24-h UC), plasma cortisol, serum osteocalcin, and blood eosinophils were determined. The relative PD(20) potency between FP and BUD was 2.51 (95% CI, 1.05-5.99; p < 0. 05), while the relative 24-h UC potency was 0.60 (95% CI, 0.44-0.83; p < 0.01). The differential therapeutic ratio (FP/BUD) based on PD(20) potency and 24-h UC was 4.18 (95% CI, 1.16-15.03; p < 0.05). The difference in systemic potency was also seen for plasma cortisol, serum osteocalcin, and blood eosinophils. Therapeutic ratio over a wide dose range, determined by impact on bronchial responsiveness and endogenous corticosteroid production, seems to favor FP.

Topics: Administration, Inhalation; Adrenal Cortex; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; Humans; Male; Time Factors

Immunotherapy has been shown to reduce allergen sensitivity to allergens such as cat and dust mite. The aim of this study was to investigate the effect of cat or dust mite immunotherapy on bronchial hyperreactivity and the need for inhaled corticosteroids in children with asthma, cat or dust mite allergy, and hay fever.. Twenty-nine children, 7 to 16 years old, completed the 3-year study. They were randomly allocated to receive cat/dust mite or placebo and birch/timothy immunotherapy.. Before immunotherapy was begun and then once each year, bronchial histamine challenges were performed. Bronchial allergen challenge with the perennial allergen was done before and after the 3-year study. Pharmacotherapy was given according to a standardized protocol.. PC20 allergen increased significantly in both the active immunotherapy group (P <.001) and in the placebo-pollen group (P <.05). PC20 histamine increased continuously in the active immunotherapy group (P <.05 and P =.002 after 1 and 3 years, respectively) and had also increased after 3 years in the placebo-pollen group (P <.05). The difference between the 2 groups was significant for PC20 allergen (P =.001) but not for PC20 histamine. There was no significant change in the dose of inhaled budesonide needed for symptom control in either of the groups.. Pollen immunotherapy combined with inhaled corticosteroids results in improvement of both cat/dust mite bronchial sensitivity and hyperresponsiveness to histamine. The combination of cat or dust mite, pollen immunotherapy, and inhaled budesonide enhances this improvement. Cat immunotherapy also induces cat allergen tolerance.

Topics: Adolescent; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cats; Child; Desensitization, Immunologic; Double-Blind Method; Dust; Histamine Release; Humans; Immunoglobulin E; Immunoglobulin G; Mites; Pollen; Rhinitis, Allergic, Seasonal

Guidelines for asthma management focus on treatment with inhaled corticosteroids and on home recording of peak expiratory flow (PEF). The effect of maintenance treatment with inhaled corticosteroids on PEF variation and its relation to other parameters of disease activity were examined in 102 asthmatic children aged 7-14 years.. During 20 months of treatment with inhaled salbutamol, with or without inhaled budesonide (600 micrograms daily), forced expiratory volume in one second (FEV1), the dose of histamine required to provoke a fall in FEV1 of more than 20% (PD20), the percentage of symptom free days, and PEF variation were assessed bimonthly. PEF variation was computed as the lowest PEF as a percentage of the highest PEF occurring over 14 days, the usual way of expressing PEF variation in asthma self-management plans. For each patient using inhaled corticosteroids within subject correlation coefficients (rho) were computed of PEF variation to the percentage of symptom free days, FEV1, and PD20.. PEF variation decreased significantly during the first two months of treatment with inhaled corticosteroids and then remained stable. The same pattern was observed for symptoms and FEV1. In contrast, PD20 histamine continued to improve throughout the whole follow up period. In individual patients predominantly positive associations of PEF variation with symptoms, FEV1, and PD20 were found, but the ranges of these associations were wide.. During treatment with inhaled corticosteroids the changes in PEF variation over time show poor concordance with changes in other parameters of asthma severity. When only PEF is monitored, clinically relevant deteriorations in symptoms, FEV1, or PD20 may be missed. This suggests that home recording of PEF alone may not be sufficient to monitor asthma severity reliably in children.

Topics: Administration, Inhalation; Administration, Topical; Adolescent; Airway Obstruction; Albuterol; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Child; Female; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Humans; Long-Term Care; Male; Peak Expiratory Flow Rate

Although many asthmatic patients are treated with a combination of beta2 agonist and corticosteroid inhalers, the clinical effects of combining the drugs are unknown. Studies on the early asthmatic response to allergen suggest that beta2 agonists may reduce the benefit of inhaled corticosteroids. A study of the effects of combining the drugs on asthma control was undertaken.. Sixty one subjects with mild to moderate asthma were randomised to a double blind crossover comparison of inhaled budesonide (200-400 microg twice daily), terbutaline (500-1000 microg four times daily), combined treatment, and placebo. Each treatment was given for six weeks following a four week washout period. Ipratropium was used for symptom relief. Treatments were ranked from worst (1) to best (4) based on need for oral steroid, mean morning peak flow, nocturnal awakening, ipratropium use, and asthma symptoms. Lung function and bronchial hyperresponsiveness were measured before and after each treatment.. Evaluable data for all four treatments were obtained from 47 subjects. The mean rank of each treatment was: placebo = 2.05; terbutaline = 2.13; budesonide = 2.48; combined treatment = 3.34. Combined treatment was ranked significantly better than any other treatment (p<0.01). Mean (95% CI) morning and evening peak flows were 14 (5 to 23) and 24 (15 to 34) l/min higher, respectively, during combined treatment than during budesonide, and 27 (17 to 37) and 15 (7 to 23) l/min higher than during terbutaline. Asthma symptoms tended to be least frequent during combined treatment but were not significantly different from budesonide alone. There was no significant difference between combined treatment and budesonide alone for lung function and bronchial hyperresponsiveness.. In this group of mild to moderate asthmatic subjects the combination of beta2 agonist and corticosteroid gave better asthma control than either treatment alone. There was no evidence that regular beta2 agonist treatment impaired the beneficial effect of inhaled corticosteroid.

Topics: Administration, Inhalation; Adolescent; Adrenergic beta-Agonists; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Child; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Patient Compliance; Peak Expiratory Flow Rate; Terbutaline; Treatment Outcome

Although some studies suggest that asthma deteriorates after reducing inhaled steroids, results of long-term studies indicate that this might not be true for all patients. The aim of this study was to determine the utility of the detection of a plateau on the concentration-response curves to inhaled methacholine as a marker for safely reducing the dose of inhaled budesonide in asthmatic patients who are well-controlled with a moderately high dose of this inhaled steroid. A total of 46 patients with moderate asthma, well-controlled for at least 6 months by treatment with 800 microg budesonide daily, were included in the study. Subjects were treated for a 2-week run-in period with their usual dose of budesonide. At the end of the run-in, all subjects were challenged with methacholine (0.095-200 mg x mL(-1)). Plateau responses, median effective concentration values, slopes and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) values were measured. For the subsequent 12 weeks, patients were treated in an open design with budesonide at a reduced dose (200 microg once daily), and were asked to record their peak expiratory flow (PEF) in the morning and in the evening. In addition, asthma symptoms and use of rescue terbutaline were recorded in diaries. Plateaus were present in 24 patients, whereas 22 subjects showed concentration-response curves without evidence of a plateau. Ten patients in the nonplateau group deteriorated after reducing inhaled budesonide, compared to one patient in the plateau group (p = 0.002). In the nonplateau group, FEV1 decreased from a baseline value of 3.28+/-0.19 L to 2.94+/-0.20 L at week 12 (p<0.0001). Likewise, morning PEF decreased from 419+/-19 L x min(-1) at baseline to 394+/-19 L x min(-1) at week 12 (p = 0.02). By contrast, these variables remained unchanged in the plateau group. In conclusion, in asthmatic patients, well-controlled with a moderately high dose of budesonide, the detection of a plateau on the concentration-response curve to inhaled methacholine may be used as a marker for safely reducing the corticosteroid dose.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Middle Aged; Peak Expiratory Flow Rate

The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) is unclear. We investigated the effects of budesonide on airway hyperresponsiveness (AHR) to methacholine (MCh) and adenosine 5'-monophosphate (AMP), to which we hypothesized the existence of greater sensitivity. Additionally, we studied the effects of budesonide on terfenadine and ipratropium bromide and on serum levels of interleukin-8 (IL-8) and histamine. Forty-four hyperresponsive smokers with moderate to severe COPD participated in the study. MCh and AMP challenges were given on three study days, after pretreatment with single doses of ipratropium bromide, terfenadine, or placebo. Thereafter, subjects were randomized to 6 wk treatment with either 1,600 microg budesonide or placebo, and the same three study days were repeated. Budesonide, as compared with placebo, did not significantly change PC20AMP, PC20MCh, or FEV1 after placebo pretreatment. Budesonide increased PC20MCh after ipratropium bromide pretreatment, from 5.05 to 10.20 mg/ml (p = 0.036). Budesonide decreased serum IL-8 from 9.2 +/- 3.7 to 6.2 +/- 2.1 pg/ml (p < 0.001). We conclude that AMP did not elicit greater sensitivity than MCh in assessing short-term effects of budesonide on AHR in smokers with COPD. We suggest that long-term treatment with inhaled corticosteroids might be beneficial, by reducing neutrophil load in the airways and improving the action of anticholinergic drugs.

Topics: Adenosine Monophosphate; Administration, Inhalation; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Female; Forced Expiratory Volume; Glucocorticoids; Histamine; Histamine H1 Antagonists; Humans; Interleukin-8; Ipratropium; Leukocyte Count; Longitudinal Studies; Lung Diseases, Obstructive; Male; Methacholine Chloride; Middle Aged; Neutrophils; Placebos; Smoking; Terfenadine; Time Factors

The effectiveness of inhaled corticosteroids in the control of daytime symptoms in asthma is well established, but the specific use against nocturnal asthma has not been systematically studied in Asian patients. This study examined the effect of treatment with inhaled budesonide on the nocturnal variation in measurements of airway calibre, bronchial hyperresponsiveness to inhaled histamine and circulating neutrophil chemotactic activity in Asian patients with nocturnal asthma. Thirty patients, with nocturnal asthma, were randomized into a 2-month, double-blind, parallel group study. Twice as many subjects were allocated to the group who received two consecutive months of inhaled budesonide 1600 microg daily as to the group who received placebo followed by budesonide. Spirometry, lung mechanics, bronchial hyperresponsiveness and serum neutrophil chemotactic factor (NCA) were measured at 16.00 h, 22.00 h and at 04.00 h on 3 days and nights, 4 weeks apart before and after either placebo or budesonide. The combined measurements for the two groups at 04.00 h before and after treatment with budesonide were: forced expiratory volume in 1 s (FEV1) mean (SEM) litres 1.34 (0.17) before, 2.00 (0.19) after; thoracic gas volume (TGV) litres 3.05 (0.32) before, 2.25 (0.14) after; specific airway conductance (sGaw) (cmH20.0 sec)(-1) 0.39 (0.07) before, 1.16 (0.17) after; PD20 microg geometric mean 1.16 before, 44.74 after; neutrophil chemotactic activity (NCA) in units of graduations of migration 98.8 (4.2) before, 101 (14.2) after. The data showed that short and intermediate term high dose inhaled budesonide is an effective specific treatment for nocturnal asthma in Asian patients, resulting in marked improvements in symptoms and in lung mechanics, and reductions in the diurnal variations in bronchial hyperresponsiveness, before any change could be demonstrated in a circulating marker of airway inflammation.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Analysis of Variance; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Chemotactic Factors; Circadian Rhythm; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Neutrophils; Respiratory Function Tests; Singapore

To determine if treatment with inhaled budesonide forte can diminish increased bronchial hyperreactivity and improve symptoms in patients with mitral valve stenosis.. The study was randomized, double blind, and placebo controlled.. Outpatient/university hospital.. Twelve subjects, 8 female and 4 male, who qualified for mitral valve replacement. All subjects presented with increased bronchial reactivity to histamine at the time of the study.. Patients received placebo or budesonide forte twice a day (1,200 mg/d) for 6 weeks. During the study, patients were treated with the same doses of diuretics and other medications that could affect bronchial reactivity.. Spirometry, provocative concentration of histamine causing a 20% fall in the FEV1 (PC20H), symptom scores.. In the treated group, the initial PC20H was 0.82+/-0.72 mg/mL; in the placebo group 1.39+/-1.3 mg/mL. After 6 weeks of treatment, PC20H was significantly higher (3.07+/-2.28 mg/mL; p > 0.01) in the budesonide-treated group and remained unchanged in the placebo group (1.49+/-0.91). Symptom scores were significantly lower after administration of budesonide forte (mean change, 4.0+/-2.6).. Six weeks of treatment with budesonide forte significantly decreased bronchial reactivity to histamine and improved symptoms in patients with mitral valve stenosis.

Topics: Administration, Inhalation; Administration, Topical; Anti-Inflammatory Agents; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Double-Blind Method; Female; Follow-Up Studies; Forced Expiratory Volume; Glucocorticoids; Histamine; Humans; Male; Middle Aged; Mitral Valve Stenosis; Treatment Outcome

Airways hyperresponsiveness (AHR) is an important feature of patients with chronic obstructive pulmonary disease (COPD). Little is known about factors that modulate AHR in COPD.. To study these factors, we performed a long-term, double-blind, parallel intervention study in 58 male, non-allergic patients with COPD.. During a period of 2 years, patients were treated with inhaled budesonide (1600 microg/day), inhaled budesonide (1600 microg/day) plus oral prednisolone (5 mg/day), or placebo. PC20 histamine was measured at 4-monthly intervals. The influence of treatment, smoking, age, level of lung function, initial serum IgE level and peripheral blood eosinophils on level and longitudinal change of PC20 histamine was analysed.. During follow-up, PC20 decreased in our group, and this decrease was not influenced by treatment. PC20 tended to decrease faster in current smokers than in ex-smokers. PC20 was significantly associated with pre-challenge FEV1 at each time point. Level nor decline of PC20 were significantly related to age. A higher initial serum IgE level was independently associated with a lower PC20. Moreover, a higher initial serum IgE level was associated with a slower annual decline of PC20, regardless of treatment, pre-challenge FEV1, and other modulating factors. No significant associations were found between initial blood eosinophils and level or decline of PC20.. We conclude that AHR increases over time in non-allergic patients with COPD. Treatment with an inhaled corticosteroid alone or in combination with oral prednisolone does not change this increase. Our study suggests an important role for IgE in the course of the disease, since a higher initial serum IgE level predicts a more favourable course with regard to annual decline of PC20 histamine.

Topics: Aged; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Double-Blind Method; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Immunoglobulin E; Longitudinal Studies; Lung Diseases, Obstructive; Male; Middle Aged; Prednisolone

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.

Topics: Administration, Inhalation; Adolescent; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Budesonide; Child; Double-Blind Method; Drug Administration Schedule; Exercise; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Pulmonary Ventilation

Bronchial hyperreactivity (BHR) is found in Sjögren's syndrome, as in a number of other conditions such as asthma. BHR associated with asthma can be effectively treated with corticosteroids or sodium cromoglycate. We treated 19 Sjögren's syndrome patients with BHR with inhaled budesonide and inhaled cromoglycate for 6 weeks each. None of the treatment had any significant effect on symptoms of hyperreactivity or lung function. There was no effect on BHR measured as methacholine reactivity. Primary Sjögren's syndrome is a disease with inflammation not only in the salivary and lacrimal glands but also in the pulmonary alveoli and the bronchi. The main inflammatory cell is the lymphocyte, whereas, in the bronchi in asthma, the eosinophil granulocyte is the characteristic inflammatory cell. The cause of the discrepancy with regard to treatability of BHR in asthma and in Sjögren's syndrome is not known. Possibly not all BHR is caused by inflammation. There is not a perfect correlation between inflammation and hyperreactivity even in asthma. Even in the bronchial inflammation and the asthma symptoms are easy to treat with anti-inflammatory medicines, a considerable component of BHR usually still remains, as measured with methacholine or histamine.

Topics: Adult; Aged; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Budesonide; Cromolyn Sodium; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Inflammation; Methacholine Chloride; Middle Aged; Pregnenediones; Prospective Studies; Sjogren's Syndrome

Inhaled corticosteroids are the most commonly used antiinflammatory agents for asthma. There is no simple way to compare objectively the relative potency of inhaled corticosteroids. The allergen-induced late asthmatic response (LAR) can be suppressed by a single dose of inhaled corticosteroid.. This study was undertaken to evaluate LAR as a model for the determination of the relative potency of single doses of inhaled corticosteroids.. We compared doses of 200 and 800 microg of a highly active inhaled corticosteroid (budesonide) with placebo and a marginally active investigational inhaled corticosteroid (D5159). Ten atopic patients with asthma completed a randomized, double-blind, double-dummy, multicenter, four-way, crossover trial. A standardized allergen challenge with the identical dose of allergen was performed 10 minutes after each of four blinded, single-dose treatments: 200 microg of budesonide, 800 microg of budesonide, 8 mg of D5159, and placebo, all administered from Turbuhaler. The LAR was recorded as the maximum percent fall in FEV1 between 4 and 7 hours, and the allergen-induced increase in methacholine airway responsiveness at 24 hours was recorded as the A log PC20 from the day before to the day after allergen challenge.. There were no significant differences in the early asthmatic responses during the 4 days; the mean maximum percent in FEV1 fall ranged between 19.5% and 22%. D5159 produced a slight inhibition of the LAR with maximum percent fall in FEV1 recorded as 28.8% +/- 5.0% for D5159 versus 34.1% +/- 4.8% for placebo (p < 0.05). There was a greater reduction recorded after administration of the two doses of budesonide. The mean LAR was 15.1% +/- 3.8% for 200 microg of budesonide and 11.2% +/- 2.3% for 800 microg of budesonide (p < 0.01 compared with placebo and D5159). The two doses of budesonide were not statistically different. Airway responsiveness to methacholine increased by 1.07 doubling doses 24 hours after allergen challenge. This increased airway responsiveness was slightly, but not significantly, reduced by the three active treatments (0.6 to 0.91 doubling doses).. The allergen-induced LAR model was able to differentiate a single dose of an active inhaled corticosteroid from placebo and a highly potent inhaled corticosteroid from a weak inhaled corticosteroid. The model did not differentiate between 2 fourfold doses of the highly active inhaled corticosteroid (at the doses used in this study), neither for the fall in FEV1 nor for the increase in airway hyperresponsiveness.

Topics: Administration, Inhalation; Administration, Topical; Adult; Allergens; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Hypersensitivity, Immediate; Male; Methacholine Chloride; Pregnenediones

The efficacy and safety of anti-inflammatory treatment with inhaled glucocorticosteroids in patients with cystic fibrosis (CF) and complicating chronic Pseudomonas aeruginosa (P.a.) lung infection was studied in a placebo-controlled, parallel, double-blind single center trial. Active treatment consisted of budesonide dry powder, 800 microg twice daily, delivered from a Turbuhaler. The study period covered two successive 3-mo intervals between elective courses of intravenous anti-Pseudomonas antibiotics. Fifty-five patients entered the study, with a mean age of 20 yr and a mean FEV1 of 63% of predicted. Analysis of all patients entered, irrespective of trial adherence ("intention to treat"), showed a decrease in FEV1 in the first period of -0.032 L in patients on budesonide versus -0.187 L in patients on placebo (p = 0.08). The corresponding figures for the patients adhering to the protocol during the first period were -0.017 L versus -0.198 L (p < 0.05, confidence interval of the difference: -0.035 to +0.327 L). For all patients entered, as well as for patients adhering to the trial, there was always a trend in favor of budesonide, as judged by changes in FEV1 and FVC in both 3-mo periods. None of the patients had asthma, but the patients on budesonide had a mean improvement in histamine reactivity of +1.15 dose steps over the entire 6-mo period, as opposed to +0.017 dose steps in patients on placebo (p < 0.05). There was also a significant (p = 0.01) correlation between pre-trial histamine reactivity and the change in FEV1 in the first period in patients on budesonide. We conclude that inhaled glucocorticosteroids can be of short-term benefit in patients with CF and chronic P.a. infection and that those patients most likely to benefit from this treatment are patients with hyperreactive airways. Prolonged studies in larger number of patients are necessary to determine the long-term efficacy of this treatment.

Topics: Administration, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchopneumonia; Budesonide; Child; Chronic Disease; Cystic Fibrosis; Double-Blind Method; Follow-Up Studies; Forced Expiratory Flow Rates; Histamine; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Sputum; Treatment Outcome

11 patients with severe bronchial asthma entered a randomized trial of glucocorticosteroid budesonide of Russian produce. Of them 6 patients received inhalations of budesonide (800 micrograms/day for 6 months), 5 control patients did not receive the drug. As shown by investigations of external respiration and bronchoalveolar lavage with estimation of cytogram, metacholine provocative tests, fiber bronchoscopy, budesonide inhalations relieved clinical symptoms of asthma, bronchial hyperreactivity and inflammation.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchitis; Bronchodilator Agents; Bronchoscopy; Budesonide; Female; Glucocorticoids; Humans; Male; Middle Aged; Pregnenediones

Inhaled steroids may control bronchial inflammation in asthmatics exposed to allergens. In this study we evaluated whether prophylactic budesonide would prevent relapse of asthma in children re-exposed to offending allergens at sea level, after a period of antigen avoidance at high altitude. Thirty children received either budesonide (200 micrograms b.i.d.) or placebo (double-blind). Following a 4-wk baseline period and 2 wk of treatment at high altitude, children were treated for 3 mo at sea level. Methacholine challenge and pulmonary function studies were performed before and after baseline period, after the 2 wk of treatment in the mountain environment, and at the end of treatment. ECP serum levels were evaluated after the baseline period and at the end of treatment. PEFR and symptoms were recorded in a diary card during the study. The increase in methacholine provocative dosage was greater, although not significant (p = 0.096), in the budesonide than in the placebo group after the treatment at high altitude and remained higher at the end of the treatment (p = 0.04). ECP levels increased in both the groups with no significant difference. Our results confirm that budesonide, in addition to its efficacy in treating pre-existent airway inflammation, is effective in preventing the increase of reactivity in asthmatic children re-exposed to allergens.

Topics: Adolescent; Altitude; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Double-Blind Method; Female; Humans; Male; Pregnenediones; Recurrence; Respiratory Function Tests; Treatment Outcome

Bronchial hyperresponsiveness is present in 40-60% of adult patients with cystic fibrosis (CF). Drugs which alter airway hyperresponsiveness have not yet been studied in CF. In this randomized placebo-controlled study, we investigated the effects of an inhaled corticosteroid, budesonide, on lung function and bronchial hyperresponsiveness in adult CF patients, with proven bronchial hyperresponsiveness to histamine. Twelve patients were treated with budesonide, 1600 micrograms day-1, and with placebo during two periods of 6 weeks in a randomized, double-blind, cross-over study. Drug effects were assessed with regard to bronchial hyperresponsiveness to histamine, spirometry and clinical symptom scores. After treatment with budesonide, no significant differences in spirometry were seen, however, bronchial hyperresponsiveness to histamine significantly improved as compared to baseline. Fifty-eight percent of the patients showed at least one doubling-dose increase in PC20 histamine. Daily symptom scores showed small, but statistically significant, improvements in dyspnoea and cough after budesonide treatment. There is increasing evidence suggesting that excessive inflammatory responses contribute to the pulmonary damage that characterizes CF. Treatment with oral corticosteroids improved the clinical course of selected CF patients, but was associated with unacceptable adverse effects. We conclude that daily inhalation of 1600 micrograms day-1 budesonide for 6 weeks induced a small, but significant, improvement in bronchial hyperresponsiveness to histamine, and symptoms of cough and dyspnoea in adult CF patients. Longer observations are needed to establish whether inhaled corticosteroids improve the long term outcome of CF.

Topics: Adolescent; Adult; Bronchial Hyperreactivity; Budesonide; Cystic Fibrosis; Double-Blind Method; Female; Glucocorticoids; Histamine; Humans; Male; Pregnenediones; Respiratory Function Tests

We studied the effect of inhaled budesonide on bronchial hyperresponsiveness (BHR) in twenty mild asthmatic patients. The study was conducted as a randomized, double-blind, placebo-controlled study. Before entering the study, the patients performed methacholine inhalation challenge (MIC) using a reservoir method to assess BHR. Then, they were randomly allocated to receive budesonide turbuhaler (200 micrograms/dose) or placebo turbuhaler two inhalations, twice daily for eight weeks. During the study, each patient recorded daily asthma score and daily number of puffs of beta 2 agonist and they were assessed at weeks 4 and 8. At the end of the treatment, MIC was repeated again. Patients receiving budesonide showed a significant improvement in airway responsiveness compared with those receiving placebo (p < 0.05). They also showed a significant improvement in asthma severity score and a significant decrease in beta 2 agonist bronchodilator use. This study also suggested that inhaled corticosteroids may be the primary treatment in patients, even with mild asthmatic and well-controlled symptoms.

Topics: Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Humans; Male; Methacholine Chloride; Pregnenediones; Pulmonary Ventilation

The phenotypically distinct low-density eosinophil, with its greater inflammatory potential, is increased in asthma. However, the role of hypodense eosinophils in the development of asthma is still unclear. We conducted a double-blind, placebo-controlled study to examine the effect of inhaled corticosteroids on the number of hypodense eosinophils in 27 asthmatic subjects and its relationship with clinical severity. The density profile of eosinophils in the peripheral blood was determined using Percoll density gradient fractionation. Eosinophils recovered from asthmatics were mainly in the lower density fractions (< 1.095 g.ml-1) (63 +/- 3%; n = 27), significantly different from those of normal subjects (27 +/- 2%; n = 7). The proportion of hypodense eosinophils was inversely related to the provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) value (r = -0.75). Patients with mild asthma had a lower percentage of hypodense eosinophils (45 +/- 4%; n = 14) than those with moderate asthma (67 +/- 3%; n = 13). Inhalation of budesonide (800 micrograms.day-1) (n = 15) for 4 weeks, but not placebo, significantly improved the PC20 values by 0.97 doubling dose, forced expiratory volume in one second (FEV1) % predicted by 17%, and peak expiratory flow rate (PEFR) by 15%, and decreased PEFR diurnal variability by 5.4%. The percentage of hypodense eosinophils was significantly decreased from 68 +/- 4 to 47 +/- 4% in the budesonide group (n = 15), but not in the placebo group (n = 12) (63 +/- 4 to 65 +/- 4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Cell Separation; Double-Blind Method; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Male; Methacholine Chloride; Middle Aged; Peak Expiratory Flow Rate; Pregnenediones; Ribonucleases

To determine whether inhaled budesonide given after allergen inhalation challenge inhibits the late asthmatic response (LAR) and/or the associated increase of airway responsiveness to methacholine, we performed a double-blind randomized cross-over study in 12 adult asthmatics (eight male, four female; mean age, 20.3 yr; range, 18 to 29 yr) sensitized to Dermatophagoides pteronyssinus (DP) previously shown to develop early and late asthmatic response to allergen challenge with DP. On different days each subject was randomized to receive budesonide 800 micrograms by Turbuhaler or placebo, given three times; (1) after allergen inhalation, after the onset of LAR, when FEV1 had fallen by > or = 15%; (2) 2 h later; (3) 4 h later. Airway responsiveness to methacholine was measured before allergen challenge at 8 to 10 h from allergen inhalation and 24 h after the allergen inhalation. Inhaled budesonide significantly reduced the LAR induced by allergen (maximal % fall in FEV1, delta FEV1%: -23 +/- 6% with budesonide versus -38 +/- 9% with placebo; p < 0.001) and inhibited the associated increase of airway responsiveness (geometric mean of PD20FEV1 methacholine: 0.047 mg after budesonide versus 0.033 mg after placebo at 8 to 10 h, p < 0.05; 0.119 mg after budesonide versus 0.062 mg after placebo at 24 h, p < 0.01). These results suggest that inhaled budesonide may not only prevent but also reduce the late asthmatic response induced by allergen and that it might also be considered in the treatment of exacerbation of asthma.

Topics: Administration, Inhalation; Adolescent; Adult; Allergens; Analysis of Variance; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Double-Blind Method; Dust; Female; Forced Expiratory Volume; Humans; Hypersensitivity, Delayed; Male; Methacholine Chloride; Mites; Pregnenediones; Severity of Illness Index; Skin Tests; Time Factors

In a previous study, we found that two years of treatment with an inhaled corticosteroid, budesonide, was more effective than treatment with an inhaled beta 2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from beta 2-agonist therapy to corticosteroid therapy would have.. A total of 37 patients treated for two years with inhaled budesonide at a dose of 1200 micrograms per day were randomly assigned to treatment with 400 micrograms of budesonide per day (19 patients) or placebo (18 patients) in a double-blind manner. Another 37 patients, who had received terbutaline during the first two years, were crossed over in an open-label manner to treatment with 1200 micrograms of budesonide per day during the third year.. Treatment with the reduced dose of budesonide was sufficiently effective in 74 percent of the patients to maintain bronchial responsiveness at a level similar to that achieved with the higher dose. In contrast, improvement was maintained in only 33 percent of the patients receiving placebo, and the differences in pulmonary function between the steroid and placebo groups were significant (for forced expiratory volume in one second, P = 0.007; for bronchial responsiveness to histamine, P = 0.025; and for peak expiratory flow in the morning, P = 0.040). The condition of patients who were crossed over from terbutaline therapy to treatment with 1200 micrograms of budesonide per day improved. However, the degree of improvement in these patients appeared to be less than in those who were treated with budesonide at the beginning of the three-year study.. Early treatment with inhaled budesonide results in long-lasting control of mild asthma. Maintenance therapy can usually be given at a reduced dose, but discontinuation of treatment is often accompanied by exacerbation of the disease.

Topics: Administration, Inhalation; Adult; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Pregnenediones; Terbutaline; Vital Capacity

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.. 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.. Referral-based Respiratory Investigation Unit at Royal Prince Alfred Hospital, a major Sydney-based teaching hospital.. 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.. 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.. 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).. 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.

Topics: Adolescent; Adult; Aerosols; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Chloride Channels; Cromolyn Sodium; Female; Forced Expiratory Volume; Humans; Male; Pregnenediones; Saline Solution, Hypertonic

Thirty-nine subjects were included in this double-blind, placebo-controlled study of bronchial hyperresponsiveness (BHR) in patients with mild to moderate asthma. The time-courses of change of FEV1, PEFR%, bronchial reactivity, and daily measures of asthma control were determined during 8 weeks of treatment after a run-in period of 2 weeks. Bronchial hyperresponsiveness was assessed by the methacholine provocation method, defined as the dose of methacholine causing a 20% fall of FEV1 compared with baseline values. The trends of FEV1 and the percentage change in PEFR from baseline were significantly different between groups, in favor of budesonide (P < .05). Patient assessments of the effect of treatment showed that PEF improved significantly in the budesonide group only. The budesonide group increased their tolerability for methacholine provocation by 1.8 DD (doubling dose), which tended to be higher compared with the 0.8 DD of the placebo group. It is evident from this study and previous studies that more data are needed to establish the dose-effect relationship with time and severity of the disease.

Topics: Adolescent; Adult; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Humans; Lung; Male; Pregnenediones; Respiratory Function Tests

Inhaled corticosteroid has been shown to be effective in the management of asthma. However, there is a lack of studies that assess the effect of cessation after long-term treatment with inhaled corticosteroid. This question was addressed in 28 children with stable asthma, aged 11 to 18 yr of age, who had completed 28 to 36 months of treatment with inhaled corticosteroid (budesonide 200 micrograms 3 times/day) and inhaled beta-2-agonist (salbutamol 200 micrograms 3 times/day). The children were randomized in a 1:2 ratio in a double-blind study either to continue budesonide (n = 8) during a period of 6 months or to decrease the dose of budesonide (n = 20) within 2 months, followed by placebo for 4 months. Treatment with salbutamol 600 micrograms daily was continued in both groups. Eight children from the tapering-off group withdrew, mainly due to symptoms of asthma, compared with none in the continuous treatment group. Five patients in the tapering-off group experienced exacerbations for which prednisolone was given, compared with none in the continuous treatment group. After tapering-off, symptoms of asthma and additional bronchodilator use increased, and both FEV1% predicted and PD20 histamine (provocation dose of histamine causing a 20% fall in FEV1) decreased, whereas these all remained unchanged in the group that continued treatment with inhaled corticosteroid. We conclude that in this study long-term treatment with 600 micrograms budesonide daily suppressed underlying mechanisms of asthma, but did not cure the disease.

Topics: Administration, Inhalation; Adolescent; Albuterol; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Child; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Peak Expiratory Flow Rate; Pregnenediones; Time Factors

A definition of asthma includes symptoms due to reversible airflow limitation and airway hyperresponsiveness. Characteristically, there is also airway inflammation. In children with methacholine airway hyperresponsiveness but no asthma symptoms, we examined whether there were features of asthmatic airway inflammation. Forty one children, aged 11-16 yrs, were studied. Thirteen asymptomatic children with methacholine airway hyperresponsiveness (provocative concentration producing a 20% fall in forced expiratory volume in one second (PC20) geometric mean of 3.35 (range 1.08-7.81) mg.ml-1) were compared with 13 currently symptomatic asthmatics with a similar PC20 of 1.91 (0.42-6.5) mg.ml-1 and 13 normal children with a normal PC20 of 52.4 (17.6 to > 64) mg.ml-1. Breathlessness experienced during a methacholine test was recognized to have occurred previously in 7 out of 13 asymptomatic children and all symptomatic children. Asymptomatic children had significantly more airway responses to hyperventilation with cold dry air (4 out of 13) than normal children (0 out of 13) but less than symptomatic children (11 out of 15). Sputum induced with hypertonic saline contained lower eosinophil counts in the asymptomatic children (median (interquartile range) 0.20 (0.59)%) than in the symptomatic children (1.70 (9.45)%), and not different from the normal children (0.15 (0.61)%). Budesonide, 400 micrograms b.i.d. improved respiratory symptoms, forced expiratory volume in one second (FEV1) and methacholine PC20 in symptomatic children, but this effect did not reach statistical significance in asymptomatic children. We conclude that symptomatic children are more likely to have evidence of asthmatic inflammation than asymptomatic children and this probably explains the symptom difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adolescent; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Eosinophils; Female; Humans; Leukocyte Count; Male; Methacholine Chloride; Pregnenediones

In a double blind crossover trial we compared the effect of a four week treatment with inhaled nedocromil (4 x 4 mg/d) or budesonide (2 x 400 micrograms/d by spacer) on non-specific bronchial hyperresponsiveness (BHR) to cold air hyperventilation (CHV) and carbachol. 15 persons with clinically mild asthma, who showed a more than 50% decrease in sG(aw) after CHV were randomly allocated to treatment groups. A double dummy technique was applied. Before and after both treatment periods, which were separated by an out wash period of four weeks, BHR to isocapnic cold air hyperventilation and carbachol was determined on two consecutive days. 13 persons completed the study. Maximum percentual drop of sG(aw-) and FEV1-values after CHV, the number of steps of carbachol-provocation carried out to reach a decrease in sGaw of at least 50% and the calculated cumulative breath units (CBU) of carbachol to cause a 50% (20%) decrease in sG(aw) (FEV1) were assessed. Peak-flow values were registered throughout the study. Data were compared by means of Wilcoxon's matched-pairs signed-ranks test. After budesonide most parameter showed a significant decrease of BHR (CHV: sG(aw) p < 0.1; FEV1 p < 0.05; Carbachol: provocation-steps: p < 0.05; CBU: PD50 sG(aw) p < 0.05; PD20 FEV1 p < 0.05). There was no evidence for an influence of nedocromil on BHR (p-values all > 0.2). Comparing both treatments there was a difference in favour of budesonide partly reaching significance at 5% level. Budesonide but not nedocromil treatment showed a significant increase in peak-flow values (morning p < 0.02, evening p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Carbachol; Cold Temperature; Double-Blind Method; Female; Humans; Male; Middle Aged; Nedocromil; Pregnenediones; Quinolones

Several studies have shown that long-term administration of inhaled corticosteroid reduces airway hyperresponsiveness. This study was performed in order to exclude an acute effect of inhaled corticosteroid. In a double-blind, randomized, cross-over study, children with asthma, who had never used inhaled or oral corticosteroid, received a single dose of 0.8 mg budesonide or placebo on two separate days, with an interval of at least 48 h. On each test day, baseline forced expiratory volume in one second (FEV1) and methacholine responsiveness (expressed as provocative dose producing a 20% fall in FEV1 (PD20) to methacholine, in doubling dose) were measured. Both measurements were repeated 2 and 5 h after administration of the drug. Twenty children were included in the study. FEV1 showed a mean increase of 1% at 5 h on the budesonide day, and a decrease of 2% on the placebo day (p = 0.01). PD20 increased by 0.1 doubling dose on the budesonide day, and decreased by 0.4 doubling dose on the placebo day. These changes are within the measurement variation (p = 0.06). We conclude that a single dose of 0.8 mg budesonide has a minor effect on methacholine responsiveness 5 h after administration in children with asthma. It is unlikely that such an effect interferes with the interpretation of data collected in long-term studies.

Topics: Aerosols; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Child; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Pregnenediones

The efficacy of budesonide (800 micrograms b.d.) and beclomethasone dipropionate (750 micrograms b.d.) in controlling the symptoms of asthma, pulmonary function, bronchial responsiveness to histamine, and adrenal function, was assessed in a double-blind, double-dummy cross-over study of 36 adult chronic asthmatic patients. The patients, the majority of whom were assessed to be affected to a severe degree, were insufficiently controlled in their current regimen of inhaled steroids and/or inhaled and oral bronchodilators. A 2 weeks baseline period preceded 6 weeks of treatment with each of the study drugs. Both treatment groups showed improvements from baseline in clinical assessment of lung function carried out after the first 6 weeks of treatment. No significant differences were seen throughout the entire 12 weeks study, when comparing the effects of the treatments on FEV1, FVC, PEF or the histamine PC20. Asthma severity, symptom score and inhaled bronchodilator use showed the same results after both treatments. It is concluded that inhalations of budesonide and beclomethasone dipropionate in high doses are equally potent in the treatment of severe asthma. There is no significant influence on the adrenal function and no significant side effects during a period equal to that of the present study.

Topics: Administration, Inhalation; Adolescent; Adrenal Glands; Adult; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Statistical; Pregnenediones; Respiratory Mechanics

We have investigated separate and interactive effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness. Twelve allergic subjects with asthma were treated in a double-blind, crossover, randomized study with budesonide, 1.6 mg daily for 3 weeks, prednisone, 40 mg daily, for 8 days, and placebo. After each period, dose-response curves were measured on 4 study days with doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo until a plateau in FEV1 was reached. A histamine challenge was then performed, and the provocation concentration causing a 20% fall in FEV1 (PC20) was calculated. The budesonide and prednisone regimens were equipotent. FEV1 was 81.2% of predicted after budesonide, 81.0% predicted after prednisone, and 67.5% predicted after placebo, bronchodilatation thus being 13.7% predicted (budesonide) and 13.5% predicted (prednisone). PC20 improved with 2.17 doubling concentrations (DCs) after budesonide, and 1.86 DCs after prednisone, compared with that of placebo. Salbutamol caused stronger bronchodilatation than ipratropium (26.2% versus 14.7% predicted) and a better protection against histamine challenge (3.95 versus 1.12 DC). The effects of corticosteroids and bronchodilators on FEV1 and PC20 were, in general, additive. This study emphasizes different modes of action on both airflow obstruction and airway hyperresponsiveness by corticosteroids and bronchodilators, and it demonstrates no enhancement of bronchodilator action by corticosteroids.

Topics: Adrenal Cortex Hormones; Adult; Airway Obstruction; Airway Resistance; Albuterol; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Ipratropium; Male; Prednisone; Pregnenediones

The effects of the topical steroid budesonide on bronchial hyperreactivity were evaluated in a patient group (A, n = 17) and a placebo-controlled patient group (B, n = 11). Group A was given budesonide 400 micrograms/12 h for 4 weeks and 200 micrograms/12 h for four more weeks. The drug proved efficient in controlling asthma clinically and improving the spirometric parameters: FVC (p < 0.05), FEF50 (p < 0.05) and FEV1 (p < 0.01). Bronchial hyperreactivity (PD20) decreased moderately in the treatment group (p < 0.1). On the contrary, basal spirometry and PD20 worsened in the control group. Some patients in group A showed peripheric eosinophilia (2/15) or in secretions (9/15), which persisted in one patient at end of treatment. Budesonide was effective in the clinical and spirometric control of asthma. We conclude that for a better assessment of the treatment of bronchial hyperreactivity with budesonide, the drug must be administered for a longer period of time. The differences between this study and previous ones is that the improvement in PD20 can be explained by the different characteristics of the patients selected for this study.

Topics: Administration, Topical; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Eosinophilia; Female; Glucocorticoids; Humans; Male; Pregnenediones; Respiratory Mechanics; Time Factors

In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion.. This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response.. RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC50 of 2.5 ± 0.7 nM and PGD2 production from mast cells with an IC50 of 8.3 ± 1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC50(RN983) = 59 μg/kg) than the β-agonist salbutamol (IC50(salbutamol) = 15 μg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC50(RN983) = <3 μg/kg) than the inhaled corticosteroid budesonide (IC50(budesonide) = 27 μg/kg) in the mouse model of the LAR.. Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and β-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Agammaglobulinaemia Tyrosine Kinase; Albuterol; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; B-Lymphocytes; Bronchial Hyperreactivity; Bronchoconstriction; Bronchodilator Agents; Budesonide; Cell Degranulation; Cells, Cultured; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Dry Powder Inhalers; Glucocorticoids; Humans; Immunoglobulin G; Lung; Male; Mast Cells; Mice, Inbred BALB C; Ovalbumin; Phthalazines; Pneumonia; Prostaglandin D2; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridazines

Allergic asthma is strongly associated with the exposure to house dust mite (HDM) and is characterized by eosinophilic pulmonary inflammation and airway hyperresponsiveness (AHR). Recently, there is an increased interest in using dietary oligosaccharides, also known as prebiotics, as a novel strategy to prevent the development of, or reduce, symptoms of allergy.. We investigated the preventive capacity of dietary galacto-oligosaccharides (GOS) compared to an intra-airway therapeutic treatment with budesonide on the development of HDM-induced allergic asthma in mice.. BALB/c mice were intranasally sensitized with 1 μg HDM on day 0 followed by daily intranasal challenge with PBS or 10 μg HDM on days 7 to 11. Two weeks prior to the first sensitization and throughout the experiment mice were fed a control diet or a diet containing 1% GOS. Reference mice were oropharyngeally instilled with budesonide (500 μg/kg) on days 7, 9, 11, and 13, while being fed the control diet. On day 14, AHR was measured by nebulizing increasing doses of methacholine into the airways. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lungs were collected.. Sensitization and challenge with HDM resulted in AHR. In contrast to budesonide, dietary intervention with 1% GOS prevented the development of AHR. HDM sensitization and challenge resulted in a significant increase in BALF leukocytes numbers, which was suppressed by budesonide treatment and dietary intervention with 1% GOS. Moreover, HDM sensitization and challenge resulted in significantly enhanced concentrations of IL-6, CCL17, IL-33, CCL5 and IL-13 in lung tissue. Both dietary intervention with 1% GOS or budesonide treatment significantly decreased the HDM-induced increased concentrations of CCL5 and IL-13 in lung tissue, while budesonide also reduced the HDM-enhanced concentrations of IL-6 and CCL17 in lung tissue.. Not only did dietary intervention with 1% GOS during sensitization and challenge prevent the induction of airway eosinophilia and Th2-related cytokine and chemokine concentrations in the lung equally effective as budesonide treatment, it also prevented AHR development in HDM-allergic mice. GOS might be useful for the prevention and/or treatment of symptoms in asthmatic disease.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchodilator Agents; Budesonide; Cytokines; Dietary Carbohydrates; Disease Models, Animal; Galactosides; Lung; Male; Mice, Inbred BALB C; Oligosaccharides; Prebiotics; Pulmonary Eosinophilia; Pyroglyphidae; Th2 Cells

TH2 cytokines are not responsible for the ongoing symptoms and pathology in children with severe therapy-resistant asthma (STRA). IL-33 induces airway hyperresponsiveness, but its role in airway remodeling and steroid resistance is unknown.. We sought to investigate the relationship between IL-33 and airway remodeling in pediatric patients with STRA.. IL-33 levels were quantified in neonatal mice given inhaled house dust mite (HDM), and the effect of blocking IL-13 on remodeling and IL-33 levels was assessed. HDM-induced allergic airways disease (AAD) in neonatal ST2(-/-) mice lacking the IL-33 receptor was assessed, together with collagen production after IL-33 administration. The effect of steroid therapy on IL-33 levels in patients with neonatal AAD was explored. IL-33 expression was quantified in endobronchial biopsy (EB) specimens from children with STRA and related to remodeling, and collagen production by airway fibroblasts from pediatric patients stimulated with IL-33 and budesonide was quantified.. Blocking IL-13 after AAD was established in neonatal mice and did not reduce remodeling or IL-33 levels; airway hyperresponsiveness was only partially reduced. IL-33 promoted collagen synthesis both from asthmatic fibroblasts from pediatric patients and after intranasal administration in mice. Increased cellular expression of IL-33, but not IL-13, was associated with increased reticular basement membrane thickness in EB specimens from children with STRA, whereas remodeling was absent in HDM-exposed ST2(-/-) mice. IL-33 levels were maintained, whereas IL-13 levels were abrogated by steroid treatment in neonatal HDM-exposed mice and in EB specimens from children with STRA.. IL-33 is a relatively steroid-resistant mediator that promotes airway remodeling in patients with STRA and is an important therapeutic target.

Topics: Adolescent; Airway Remodeling; Animals; Animals, Newborn; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Child; Collagen; Drug Resistance; Female; Glucocorticoids; Humans; Interleukin-13; Interleukin-33; Interleukins; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Pyroglyphidae

Capsaicin causes direct irritation of the eyes, mucous membranes, and respiratory tract. It is used in self-defense, in crowd control, and as a less lethal weapon in police work. Controlled trials suggest that capsaicin has minimal serious acute effects. Herein, we report a woman who had a 20-minute exposure to capsaicin during a jail riot. She subsequently developed episodic dyspnea and cough, and increased sensitivity to scents, perfumes, and cigarette smoke. She has not had wheezes on physical examination or abnormal pulmonary function tests. Her response to inhaled steroids and long-acting beta-agonists has been incomplete. She appears to have developed airway sensory hyperreactivity syndrome after the inhalation of capsaicin, which likely injured sensory nerves and/or caused persistent neurogenic inflammation.

Topics: Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Capsaicin; Cough; Dyspnea; Ethanolamines; Female; Formoterol Fumarate; Humans; Middle Aged; Respiratory Sounds

Triphala (TRP), a herbal extract from Tibetan medicine, has been shown to affect lymphocytes and natural killer T (NKT) cell function. We hypothesize that TRP could ameliorate bronchial hyperreactivity through immune-cell modulations.. Asthma mouse models were generated through intraperitoneal (IP) injections of ovalbumin (OVA)/2 weeks followed by repeated intranasal OVA challenges. Mice were then treated with normal saline (OVA/NS) or Triphala (OVA/TRP). Data were compared with mice treated with inhaled budesonide. All groups were assessed for allergen-induced hyperreactivity; lymphocytes from lungs, livers and spleens were analyzed for OVA-induced proliferation and their alterations were determined by flow cytometry. Oxidative reactivity using chemiluminescence, serum anti-OVA antibodies level and lung histology were assessed.. Both TRP and budesonide significantly ameliorated functional and histological OVA-induced bronchial hyperreactivity. TRP had no effect on serum anti-OVA antibodies as compared with decreased levels following budesonide treatment. Furthermore, a significant increase in lung and spleen CD4 counts and a decrease in the liver were noted after TRP treatments. Bronchoalveolar fluid from TRP-treated animals but not from the budesonide-treated animals showed anti-oxidative effects.. TRP and budesonide caused a significant decrease in bronchial reactivity. TRP treatment altered immune-cell distributions and showed anti-oxidative properties. These findings suggest that immune-cell modulation with TRP can ameliorate lung injury.

Topics: Administration, Inhalation; Alanine Transaminase; Animals; Anti-Asthmatic Agents; Antioxidants; Asthma; Biomarkers; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Budesonide; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Flow Cytometry; Immunity, Humoral; Liver; Lung; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Plant Extracts; Spleen

The cause-and-effect relationship between airway smooth muscle (ASM) remodeling and airway hyperresponsiveness (AHR) following allergen challenge is not well established. Using a rat model of allergen-induced ASM remodeling we explored the relationship between the site of ASM remodeling and AHR. Brown Norway rats, sensitized and challenged (3 times at 5-day intervals) with ovalbumin, were intranasally administered 0.1 mg/kg budesonide 24 and 1 h before challenge. Airway responses to aerosolized methacholine were assessed 48 h or 1 wk after three challenges. Airways were stained and analyzed for total airway wall area, area of smooth muscle-specific α-actin, and goblet cell hyperplasia, and the constant-phase model was used to resolve the changes in respiratory system mechanics into large airway and peripheral lung responses. After three ovalbumin challenges, there was a significant increase in ASM area and in the total wall area in all sized airways as well as an increase in goblet cells in the central airways. Budesonide inhibited ASM growth and central airway goblet cell hyperplasia following ovalbumin challenges. Budesonide also inhibited small but not large airway total wall area. AHR was attributable to excessive responses of the small airways, whereas responsiveness of the large airways was unchanged. Budesonide did not inhibit AHR after repeated challenge. We conclude that ASM remodeling induced by repeated allergen challenges involves the entire bronchial tree, whereas AHR reflects alterations in the lung periphery. Prevention of ASM remodeling by corticosteroid does not abrogate AHR.

Topics: Airway Remodeling; Animals; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Cell Proliferation; Chemokines; Cytokines; Disease Models, Animal; Goblet Cells; Hyperplasia; Inflammation Mediators; Lung; Male; Muscle, Smooth; Ovalbumin; Rats; Rats, Inbred BN; Time Factors

Allergic asthma is characterized by airway inflammation in response to chronic allergen exposure, resulting in remodeling of the airway wall accompanied by dysfunctional airway physiology. However, a link between the immune-inflammatory response to allergen and changes to airway structure and physiology has not yet been fully elucidated. Moreover, the impact of inhaled corticosteroids and beta(2)-agonists, the primary pharmacotherapy for asthma, on this process has not been completely evaluated. In this study, we employed a murine model of chronic exposure to a common environmental aeroallergen, house dust mite, to recapitulate the phenotype of clinical asthma. By examining the therapeutic effects of corticosteroid/beta(2)-agonist combination therapy with budesonide/formoterol (BUD/FORM) in this model of airway disease, we endeavored to determine the impact of BUD/FORM on lung inflammation, structure, and physiology. BUD/FORM was delivered either while allergen exposure was ongoing (concurrent therapy) or following the cessation of allergen exposure (postexposure therapy). Our results show that airway inflammation was substantially reduced in BUD/FORM-treated mice in the concurrent therapy group, whereas in the postexposure therapy group airway inflammation spontaneously resolved. In contrast, BUD/FORM was most effective in resolving several aspects of airway remodeling and bronchial hyperreactivity when delivered in conjunction with allergen withdrawal. This study demonstrates that although both BUD/FORM therapy and allergen avoidance independently reduce airway inflammation, only BUD/FORM therapy in conjunction with allergen avoidance can effectively reverse airway remodeling and bronchial hyperreactivity induced by chronic allergen exposure.

Topics: Actins; Allergens; Animals; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Collagen; Drug Therapy, Combination; Epithelial Cells; Epithelium; Ethanolamines; Female; Formoterol Fumarate; Methacholine Chloride; Mice; Mice, Inbred BALB C; Mucus; Pneumonia; Pyroglyphidae; Respiratory Tract Diseases

Corticosteroids are known to inhibit bronchial hyperresponsiveness (BHR) and allergic inflammation but there is little information on its dose-dependence. We examined the effect of different doses of the glucocorticosteroid budesonide in an allergic model. Brown-Norway rats were sensitised to ovalbumin (OVA) and pretreated with an intra-gastric dose of budesonide (0.1, 1.0, or 10 mgkg(-1)). Exposure to OVA induced BHR, accumulation of eosinophils in the bronchoalveolar lavage (BAL) fluid and in the airways submucosa. Budesonide dose-dependently inhibited BAL fluid influx of lymphocytes, eosinophils and neutrophils, tissue eosinophils and lymphocytes and BHR. At 0.1 mgkg(-1), budesonide did not inhibit these parameters but at 1 mgkg(-1), BAL fluid eosinophils and T-cells, and submucosal T-cells were significantly reduced. At 10 mgkg(-1), budesonide suppressed BHR, BAL fluid inflammatory cells numbers and tissue eosinophilia. T-cell numbers were more related to BHR than eosinophil numbers. Budesonide inhibited both airway inflammation and BHR, but BAL fluid eosinophil cell counts may be dissociated from BHR.

Topics: Acetylcholine; Animals; Blood Cell Count; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Dose-Response Relationship, Drug; Glucocorticoids; Hypersensitivity; Male; Ovalbumin; Rats

Previously, we found pulmonary gas trapping to be a rapid, simple and objective measure of methacholine-induced airway obstruction in naïve mice. In this study we extended that finding by using methacholine-induced pulmonary gas trapping to differentiate airway responses of ovalbumin-sensitized, ovalbumin-exposed (Positive Control) and ovalbumin-sensitized, sodium chloride-exposed (Negative Control) mice. Additionally, pulmonary gas trapping and enhanced pause were compared following methacholine exposure in sensitized and nonsensitized mice. Finally, we examined by nose-only inhalation the ability of the glucocorticosteroid budesonide and the peroxisome proliferator-activated receptor-gamma agonist ciglitazone to modify methacholine-induced airway responses in ovalbumin-sensitized mice. Positive Controls exhibited a 7.8-fold increase in sensitivity and a 2.4-fold enhancement in the maximal airway obstruction to methacholine versus Negative Controls. Following methacholine, individual Positive and Negative Control mouse enhanced pause values overlapped in 9 of 9 studies, whereas individual Positive and Negative Control mouse excised lung gas volume values overlapped in only 1 of 9 studies, and log[excised lung gas volume] correlated (P=0.023) with in vivo log[enhanced pause] in nonsensitized mice. Finally, budesonide (100.0 or 1000.0 microg/kg) reduced methacholine-mediated airway responses and eosinophils and neutrophils, whereas ciglitazone (1000.0 microg/kg) had no effect on methacholine-induced pulmonary gas trapping, but reduced eosinophils. In conclusion, pulmonary gas trapping is a more reproducible measure of methacholine-mediated airway responses in ovalbumin-sensitized mice than enhanced pause. Also, excised lung gas volume changes can be used to monitor drug interventions like budesonide. Finally, this study highlights the importance of running a positive comparator when examining novel treatments like ciglitazone.

Topics: Administration, Inhalation; Airway Obstruction; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Male; Methacholine Chloride; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; PPAR gamma; Thiazolidinediones

Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA)+ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA+ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Animals; Animals, Newborn; Antigens, Dermatophagoides; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Eosinophils; Leukocyte Count; Macaca mulatta; Mucins; Muscle, Smooth; Ozone; Respiratory Mucosa

Clara cells are nonciliated secretory cells implicated in lung homeostasis by the synthesis of immunomodulatory and host defense products, being one of the most important the CC16 protein. In this study, we compared the effects of budesonide (BUD), an inhaled corticoid, on Clara cell biology and its ability to reverse morphofunctional changes induced in an allergic airway hyper-responsiveness mouse model. In normal mice, exposure to BUD induced morphological changes compatible with a state of maximal differentiation on CC16 positive cells which developed a prominent cupola filled up with numerous mitochondria rich in CYP2E1, a member of the cytochrome P450 family. Consequently, CYP2E1 expression raised significantly. Exposure to OVA provoked hypertrophy of Clara cells and an increment in their number per millimeter of basal membrane. These cells acquired a mucous cell phenotype characterized by a notorious expansion of the secretory granular content. Synthesis of CC16 was greatly up-regulated concurrent to the finding of MUC5AC expression and the increment of epidermal growth factor receptor (EGFR). Mitochondrial content decreased significantly with a consequent reduction in CYP2E1 expression. After BUD treatment of OVA-challenged animals, the majority of Clara cells regained their normal morphology and functional characteristics; CYP2E1 levels raised when compared to the OVA exposed group. The BUD potential to differentiate Clara cells appeared to be important for the regression of the profound changes generated by the allergic injury. These results demonstrated the wide range of stimuli that can modify different aspects of Clara cell biology, and highlighted the effects of budesonide as a modulator of P450 enzymes, which probably contributes to a complementary antiinflamatory activity.

Topics: Animals; Anti-Inflammatory Agents; Bronchi; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cytochrome P-450 CYP2E1; Epithelial Cells; Glucocorticoids; Hypersensitivity; Inflammation; Mice; Up-Regulation; Uteroglobin

Asthma is characterized by airway hyperresponsiveness, chronic inflammation, and airway remodeling, which may lead to progressive, irreversible lung damage. Liposomes have been used for the delivery of aerosolized asthma medications into the lungs. This method could facilitate sustained action of steroids while using only a fraction of the dosage and a less frequent dosing interval than conventional therapy. We describe the evaluation of the effect of budesonide encapsulated in sterically stabilized liposomes on lung inflammation and airway hyperreactivity in a mouse model of asthma. We outline the determination of markers implicated in the progression of asthma, including histopathology, eosinophil peroxidase activity in bronchoalveolar lavage, and airway hyperresponsiveness to methacholine. Weekly administration of budesonide in sterically stabilized liposomes results in a significant reduction in the total lung inflammation score, peripheral blood eosinophil counts, and the total serum IgE level, similar to that obtained with daily budesonide. Airway hyperresponsiveness to methacholine challenge decreases significantly in the group treated with weekly budesonide in sterically stabilized liposomes, while it does not decrease in the daily budesonide group.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Bronchodilator Agents; Budesonide; Child; Eosinophil Peroxidase; Humans; Immunoglobulin E; Liposomes; Lung; Methacholine Chloride; Mice

Airway inflammation and remodelling are important pathophysiologic features of chronic asthma. Although current steroid use demonstrates anti-inflammatory activity, there are limited effects on the structural changes in the lung tissue.. We have used a mouse model of prolonged allergen challenge that exhibits many of the salient features of airway remodelling in order to investigate the anti-remodelling effects of Budesonide.. Treatment was administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation and hyper-reactivity.. Budesonide administration reduced airway hyper-reactivity and leukocyte infiltration in association with a decrease in production of the Th2 mediators, IL-4, IL-13 and eotaxin-1. A reduction in peribronchiolar collagen deposition and mucus production was observed. Moreover, our data show for the first time that, Budesonide treatment regulated active transforming growth factor (TGF)-beta signalling with a reduction in the expression of pSmad 2 and the concomitant up-regulation of Smad 7 in lung tissue sections.. Therefore, we have determined that administration of Budesonide modulates the progression of airway remodelling following prolonged allergen challenge via regulation of inflammation and active TGF-beta signalling.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchi; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Budesonide; Chemokine CCL11; Chemokines, CC; Collagen; Extracellular Matrix; Female; Image Processing, Computer-Assisted; Interleukin-13; Interleukin-4; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Models, Animal; Mucus; Signal Transduction; Time Factors; Transforming Growth Factor beta

To investigate the dynamic changes in airway hyperresponsiveness (AHR) in allergen-induced asthma in rats and the effects of budesonide.. Among 36 BALB/c female mice, 6 were randomized as negative control group (group C), the remaining mice were challenged with ovalbumin (OVA) to reproduce asthma. Kinetics of airway AHR of OVA-induced asthmatic mice was carried out as follows: on day 15, 18, 21 and 25 (A1, A2, A3, A4 groups), 6 mice were randomly chosen and sacrificed after measurement of airway AHR to investigate tidal volume (V(T)), airway resistance of expiring phase (R(A)), compliance of thorax and lung (C(T-L)) with different doses of methacholine chloride (MCH). In group B 6 mice were randomly chosen and treated with 1 mg budesonide aerosol once per day from day 15 to 17, then sacrificed on day 18. Their physiological and pathological changes were determined similarly to those of A2 group.. (1) The increase of R(A) in group A1, A2 and A3 were significantly higher than that in group C when MCH reached the dose of 200 ng/g. (2) The decrease of C(T-L) in group A1 and A2 was significant with 100 ng/g and 200 ng/g MCH. (3) The value of V(T) markedly decreased in group A2 with 100 ng/g MCH and in all asthma model groups with 200 ng/g MCH than that in group C. (4) There was an eosinophil-dominant inflammatory infiltration in the asthma lungs, and the degree of infiltration peaked on day 15, and then alleviated afterwards. (5) With the dose of 200 ng/g MCH, the increase of R(A) in group B was significantly alleviated when compared with that in group A2, but there was no significant difference between group B and C. With the dose of 100 and 200 ng/g MCH, the decrease of C(T-L) in group B was significantly less marked compared with that in group A2 but there was no significant difference between group B and group C; the decrease of V(T) in group B was significantly lessened in degree when compared with that in group A2, while there was no statistical difference between group B and group C. The infiltration of inflammatory cells was obviously alleviated and the repair of airway epithelium was better in budesonide group.. (1) Airway hyperresponsiveness increases greatly in mice challenged and sensitized with OVA, and it lasts for about 7 days and then declines afterwards. (2) Budesonide aerosol could effectively alleviate the eosinophil dominant inflammatory response and decrease AHR in the murine asthma model.

Topics: Allergens; Animals; Asthma; Bronchial Hyperreactivity; Budesonide; Disease Models, Animal; Female; Mice; Mice, Inbred BALB C; Random Allocation

Airway hyperresponsiveness (AHR) is one of the most important characteristics of asthma. This study investigated the parameters, by which assess the airway responsiveness under tidal ventilation.. Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) (group A), and part of them were treated with budesonide aerosol (group B). All the mice were anaesthetized and mechanically ventilated. The values of tidal volume (Vt), airway pressure (PA), airway flow (F), expiratory lung resistance (RL) and dynamic compliance of the thorax and lung (CT-L) were recorded by the AniRes2003 animal lung function system. In addition, the expiratory volume in the first 0.1 second after the start of expiration (EV0.1) was obtained according to the flow-volume (F-V) curve. The maximal or minimal values of EV0.1, RL and CT-L were documented after each dose of methacholine (MCH) and compared with values from negative control group (group C).. (1) When the dose of MCH reached 100 ng/g or 200 ng/g, the decrease of Vt in group A was much more significant than group C (P = 0.001, < 0.001 respectively), but not so between groups B and group C (P = 0.974, 0.362 respectively). (2) With the dose of 25, 50, 100 or 200 ng/g MCH, the decrease in percentage of EV0.1 in group A was much higher than group C (P = 0.012, 0.025, 0.001, 0.003 respectively), while that in group B showed no significant difference as compared with group C (P = 0.507, 0.896, 0.972, 0.785). (3) RL and CT-L: with the dose of 200 ng/g MCH, there was a statistically significant increase of RL in group A compared to group B or group C (P < 0.001, < 0.001 respectively), but no significant difference between groups B and C (P = 0.266). With doses of 100 ng/g and 200 ng/g MCH, there was a statistically significant decrease of CT-L in group A compared to group B (P = 0.001, = 0.001) and group C (P < 0.001, < 0.001 respectively), but no significant difference between groups B and C (P = 0.775, 0.310). (4) Histopathology: there were eosinophilic predominant peribronchial and perivascular inflammatory influx in murine lungs after OVA sensitizing and challenging, which could be counteracted by inhalation of budesonide in group B.. The decline in EV0.1 in response to MCH challenge correlated with simultaneous changes in Vt, RL and CT-L, but more sensitively than all the other parameters. The decline in EV0.1 and inflammation in murine lung could be significantly alleviated by inhalation of nebulized budesonide solution, which indicated that EV0.1 to MCH is a valid measure of AHR in mice.

Topics: Airway Resistance; Animals; Bronchial Hyperreactivity; Budesonide; Female; Lung Compliance; Methacholine Chloride; Mice; Mice, Inbred BALB C; Ovalbumin

Evidence suggests that gender differences exist in the severity of many immunological diseases and their response to glucocorticosteroid treatment. In this report, we have used a murine model of ovalbumin-induced lung inflammation to address whether gender could affect the systemic response, airway inflammation and hyperreactivity and their responses to budesonide.. Following an acute ovalbumin challenge, actively sensitised BALB/c mice developed a time-dependent increase in interleukin-4 and interleukin-5 production and inflammatory cell influx into bronchoalveolar lavage fluid. Apart from an increased number of lymphocytes in female mice at day 3 post-challenge, none of the above parameters were affected by gender. Blood leukocyte numbers were also unaffected, whereas a two-fold increase in total serum immunoglobulin E was observed in female mice. Budesonide, given intranasally, did not affect the blood parameters, but dose-dependently inhibited the pulmonary inflammation and airway hyperreactivity in both male and female mice. Female mice were slightly less sensitive to budesonide's inhibitory action on interleukin-5 production and the development of airway hyperreactivity.. Our results suggest that, apart from a 2-fold increase in serum immunoglobulin E levels observed in female mice, gender is not a major factor in the present murine model of ovalbumin-induced lung inflammation. In contrast, gender might slightly influence the potency of test compounds such as steroids.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Blood Cell Count; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Budesonide; Disease Models, Animal; Female; Gender Identity; Immunoglobulin E; Inflammation; Male; Mice; Mice, Inbred BALB C

Lipopolysaccharide (LPS) inhalation (30 microg ml(-1), 1 h) caused airway hypereactivity (AHR) to histamine (1 mM, 20 s) 1 h later in conscious guinea-pigs. Bronchoalveolar lavage fluid (BALF) levels of neutrophils, myeloperoxidase (MPO) and protein were elevated whereas nitric oxide (NO) metabolites were reduced 1 h after LPS compared with saline challenge. 24 h after LPS, there was no AHR, but BALF neutrophils, eosinophils, macrophages, MPO, protein and NO metabolites were all raised. Budesonide (0.7 mM) and a molar equivalent concentration of the NO-donating budesonide derivative, NCX 1020, were inhaled (15 min) at 24 h and 45 min before LPS. The only change produced by budesonide was to reduce eosinophil influx at 24 h after LPS, compared with vehicle treated animals. NCX 1020, however, blocked AHR and reduced neutrophils (1 and 24 h) and MPO (1 and 24 h), while NO levels were raised at 1 and reduced at 24 h after LPS. The combined inhalation before LPS of the NO donor, SNAP (1.4 mM), with budesonide (0.7 mM) blocked the AHR to histamine and significantly reduced neutrophils (1 and 24 h) and MPO (1 and 24 h), while NO levels were raised at 1 h after LPS. Thus, NO and a corticosteroid co-administered as NCX 1020 or budesonide with a NO donor, have an additive effect against LPS-induced inflammatory responses and may have value in the treatment of neutrophil-driven airways disease such as COPD.

Topics: Administration, Inhalation; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Chemotaxis, Leukocyte; Guinea Pigs; Lipopolysaccharides; Male; Neutrophils; Nitrates; Nitric Oxide Donors; Nitrites; S-Nitroso-N-Acetylpenicillamine; Time Factors

No current therapy is considered to be satisfactory for severe asthma, and alternative approaches are still required for what is a major unmet medical need. In this study, we compared the effect of a rapamycin derivative, SAR 943, with budesonide, using a murine model of lung inflammation and remodeling. Allergen challenge of ovalbumin-sensitized BALB/c mice induced an increase in the levels of interleukin-5 and interleukin-4; numbers of eosinophil, neutrophil, and lymphocyte; cellular fibronectin; lung epithelial cell proliferation and mucus hypersecretory phenotype; as well as hyperreactivity to methacholine. Both SAR 943 and budesonide, when given intranasally 1 hour before and 24 hours after the aerosol challenge, inhibited all of these parameters with a similar potency (effective dose 50% of 1 mg/kg). In primary cultured smooth muscle cells from human airways, SAR 943 dose dependently inhibited epidermal growth factor-induced proliferation but did not affect the basal cell proliferation. Neither the basal nor stimulated proliferation of a human bronchial epithelial cell line (16HBE14o-) was affected by SAR 943. In conclusion, SAR 943 is as effective as budesonide in inhibiting both lung inflammation and remodeling in a murine model of asthma. Hence, this class of compound could offer beneficial effects in patients with severe asthma.

Topics: Administration, Intranasal; Animals; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Cell Division; Cells, Cultured; Disease Models, Animal; Female; Immunohistochemistry; In Vitro Techniques; Mice; Mice, Inbred BALB C; Ovalbumin; Pneumonia; Probability; Random Allocation; Reference Values; Sensitivity and Specificity; Sirolimus; Statistics, Nonparametric

Topics: Adenosine Monophosphate; Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Diagnosis, Differential; Dose-Response Relationship, Drug; Fluticasone; Humans; Kinetics; Pulmonary Disease, Chronic Obstructive; Research

In the present study, the pharmacological effects of etiprednol dicloacetate (BNP-166; ethyl-17alpha-dichloroacetoxy-11beta-hydroxyandrosta-1,4-diene-3-one-17beta-carboxylate), a new soft steroid, intended to use for the treatment of asthma, were investigated in an animal model of allergen sensitized and challenged Brown Norway rats using local treatment. The examinations involved the determination of the effect of the compound on the extent of allergen induced broncho-alveolar fluid and lung tissue eosinophilia, goblet cell hyperplasia and mucus production, perivascular edema formation, and airways hyperresponsiveness. The activity of etiprednol dicloacetate was compared with that of budesonide. Using in vitro methods, the soft character of etiprednol dicloacetate was investigated together with its capability to dissociate transrepressing and transactivating properties. We found that combining all the examined parameters etiprednol dicloacetate was at least equipotent with budesonide in the animal model, but in several investigated variables it surpassed the activity of budesonide. The effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of the serum, present in the assay, it was also strongly affected by the incubation time and decreased significantly when it was preincubated with human plasma. These features are characteristics of a soft drug that is quickly inactivated in the systemic circulation. In addition, it was revealed that while the transrepressing potential of etiprednol dicloacetate remained high, its transactivating activity was greatly reduced. These data indicate that the strong local effect of the compound will very likely be accompanied with a significantly reduced systemic activity predicting favorable selectivity in the pharmacological action of etiprednol dicloacetate.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Edema; Epithelial Cells; Glucocorticoids; Humans; Male; Neutrophil Infiltration; Rats; Time Factors; Transcriptional Activation

We have previously demonstrated that allergen inhalation induces expansion of bone marrow eosinophil progenitors in sensitized mice and subjects with asthma and that the inhaled corticosteroid, budesonide, reduced baseline but not allergen-induced increase in bone marrow eosinophil/basophil progenitors (EoB-CFU) in subjects with asthma. Here, we evaluated the effects of intranasal budesonide on allergen-induced increases in interleukin (IL)-5 and eotaxin in the airway and peripheral blood, expansion of bone marrow Eo-CFU and eosinophilia in bone marrow, peripheral blood and airway, as well as airway hyperresponsiveness, in ovalbumin (OVA)-sensitized mice. Budesonide treatment attenuated allergen-induced eosinophilia in bone marrow, peripheral blood, and airways as well as allergen-induced increases in bone marrow eosinophil progenitors but not allergen-induced increases in IL-5 or eotaxin 12 h following the second of two daily exposures to allergen; at later time points treatment was associated with attenuation of IL-5, eosinophilia, Eo-CFU, and airway hyperresponsiveness. These results suggest that a component of the mechanism by which corticosteroid treatment attenuates allergen-induced airway inflammation is through suppression of bone marrow eosinophilopoiesis, and that this is likely not mediated simply through the blocking of IL-5 production at the airway.

Topics: Administration, Intranasal; Airway Resistance; Allergens; Animals; Anti-Inflammatory Agents; Bone Marrow; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Budesonide; Chemokine CCL11; Chemokines, CC; Chemotactic Factors, Eosinophil; Eosinophils; Female; Glucocorticoids; Hematopoietic Stem Cells; Immunization; Interleukin-5; Leukocyte Count; Lung; Mice; Mice, Inbred BALB C; Ovalbumin

The extent of improvement in bronchial hyperresponsiveness (BHR) with corticosteroids varies considerably among patients with asthma, although predictive factors for improvement are largely unknown. We tested the hypothesis that the improvement may vary according to family history of BHR. Children with atopic asthma (n = 121) received inhaled budesonide (800 micro g per day) regularly for 6 months. Methacholine provocative concentration causing a 20% fall in FEV(1) was measured before treatment and again after 3 and 6 months of treatment. A methacholine challenge test was also performed in each patient's parents, and the results were analyzed with regard to their children's response to corticosteroid therapy. When the children were classified into large (n = 40) and small (n = 40) improvement groups after 6 months of treatment, the prevalence of BHR and the bronchial responsiveness index were higher in parents of the small improvement group (28.8%, 1.145 +/- 0.104) than in parents of the large improvement group (6.3%, 1.095 +/- 0.064; both, p < 0.01). The magnitude of improvement in BHR at 6 months was lower in children with at least one parent with BHR (n = 45; 1.666 +/- 1.244 doubling doses) than in children with non-BHR parents (n = 76; 2.531 +/- 1.726, p < 0.01). Our results suggest that a family history of BHR may be an important factor in the sensitivity of BHR of individuals with asthma to inhaled corticosteroids.

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Child; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Treatment Outcome

Topics: Administration, Topical; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Glucocorticoids; Humans

Many children with asthma go into long-term clinical remission at adolescence, but bronchial hyperresponsiveness (BHR) persists in some of these subjects. BHR in asthma is characterized by an increase in sensitivity and in maximal airway response to bronchoconstrictor stimuli.. The aims of this study were to compare the profiles of maximal airway response between adolescents with asthma remission and adolescents with symptomatic asthma to a similar degree of airway hypersensitivity, and to determine whether maximal airway response in adolescents with asthma remission is reduced by prolonged treatment with inhaled corticosteroids.. A high-dose methacholine inhalation test was performed in 46 adolescents with long-term asthma remission (remission group) and 44 adolescents with symptomatic asthma (symptomatic group). Subjects exhibiting a maximal response plateau in the remission group were administered inhaled budesonide (400 microg bid, budesonide/remission group, n = 15) or identical placebo (placebo/remission group, n = 15) for 6 months, and the subjects in the symptomatic group were administered the same regimen of budesonide (budesonide/symptomatic group, n = 17). The plateau level was measured after 3 months and 6 months of treatment.. Thirty-four subjects (73.9%) in the remission group featured a maximal response plateau on the dose-response curve to methacholine, whereas 19 subjects (43.2%) in the symptomatic group had a plateau (p = 0.003). In neither the placebo/remission group nor the budesonide/remission group did the plateau level change significantly over the 6-month period, whereas budesonide markedly decreased the level in the budesonide/symptomatic group.. The difference in frequency of detection of a plateau between the remission group and the symptomatic group, as well as the difference in its response to treatment with budesonide between the two groups, suggests that inflammatory changes impact the maximal airway response in symptomatic asthmatic adolescents but not in adolescents with asthma remission.

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Airway Obstruction; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Case-Control Studies; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Probability; Prognosis; Reference Values; Remission, Spontaneous; Respiratory Function Tests; Sampling Studies; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Urinary eosinophil protein X (UEPX) concentration, lung function, and nonspecific bronchial hyperreactivity were determined in 40 asthmatic children (asymptomatic for 6.4 +/- 3.0 months) (mean age 9.8 +/- 2.9 years) receiving inhaled budesonide, in order to establish whether measurement of these parameters is useful in determining discontinuation of inhaled corticosteroid therapy. After the discontinuation of therapy, patients were asked to come to the Outpatient Clinic if symptoms recurred and did not respond to beta2 mimetic usage in 24 hr. Otherwise they were to be seen 2-3 months later for a follow-up visit. UEPX concentration was determined and spirometry was performed on this visit. While UEPX concentrations had increased (p < 0.0001), FEV1, FEF 25-75 and PEF had decreased significantly 2.3 +/- 0.53 months after the cessation of inhaled budesonide therapy in all children (p = 0.004, p = 0.02, p = 0.02, respectively). Due to clinical deterioration, inhaled corticosteroid therapy had to be restarted in 19 (48%) of the children (Group I), while the remaining 21 (52%) (Group II) continued to be asymptomatic during the 2.3 +/- 0.5 months follow-up period. Although the initial UEPX concentrations, spirometer variables, and methacholine PC20 values of these two groups were not statistically different, the duration of clinical remission before discontinuation of budesonide prophylaxis was significantly longer in group II (p = 0.0037). We concluded that, in determining discontinuation of inhaled corticosteroid prophylaxis, duration of clinical remission seems to be a more useful criterion than measurement of UEPX levels, lung function test, and assessment of bronchial hyperreactivity.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Child; Eosinophil-Derived Neurotoxin; Female; Follow-Up Studies; Humans; Male; Ribonucleases; Spirometry; Time Factors

Intratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4(+) T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the alphabeta-TCR caused 54% depletion of total (CD2(+)) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.

Topics: Acetylcholine; Animals; Antibodies, Monoclonal; Biomarkers; Bradykinin; Bronchial Hyperreactivity; Budesonide; Cell Movement; Cells, Cultured; Cyclosporine; Cytokines; Dextrans; Gene Expression Regulation; Inflammation; Interleukin-2; Intubation, Intratracheal; Lung; Lymphocyte Depletion; Male; Mast Cells; Pulmonary Eosinophilia; Rats; Rats, Sprague-Dawley; T-Lymphocyte Subsets; Time Factors

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.

Topics: Acetylcholine; Administration, Topical; Animals; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cyclosporins; Cytokines; Disease Models, Animal; Gene Expression Regulation; Immunosuppressive Agents; Inflammation; Male; Ovalbumin; Rats; Rats, Inbred BN; RNA, Messenger; Sirolimus; Specific Pathogen-Free Organisms; T-Lymphocytes; Vasodilator Agents

The aim of the study was to investigate whether treatment using inhaled corticosteroids decreases airway responsiveness to inhaled mannitol in asthmatic subjects.. Before treatment or a change in treatment with inhaled corticosteroids, 18 asthmatic subjects had measurements of lung function and airway sensitivity to mannitol taken and they completed a self-administered questionnaire on asthma symptoms. The procedure was repeated 6-9 weeks after taking 800-2400 microg/day of budesonide.. There were significant reductions in airway sensitivity (provoking dose to induce a 15% fall in FEV1 (PD15)) and airway reactivity measured by the response dose ratio (RDR; final percentage fall FEV1/total dose of mannitol administered). The PD15 (Gmean (95%CI)) increased from 78 mg (51, 117) before treatment to 289 mg (202, 414) following treatment (P < 0.001). All subjects had a significant increase beyond the repeatability of 0.9 doubling doses with seven subjects becoming unresponsive. There was a 4.2 (3.4, 4.9)-fold improvement in the RDR with the value before the treatment period 0.18 (0.12, 0.28) decreasing to 0.04 (0.03, 0.08) following treatment (P < 0.001). These improvements were associated with significant improvements in lung function and symptom severity.. Treatment with the inhaled corticosteroid budesonide caused a decrease in airway sensitivity and reactivity to inhaled mannitol and this was associated with expected improvements in lung function and symptoms.

Topics: Administration, Inhalation; Adult; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Budesonide; Female; Forced Expiratory Volume; Humans; Male; Mannitol; Middle Aged; Pilot Projects; Time Factors

Topics: Administration, Inhalation; Administration, Topical; Adrenal Cortex; Adult; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Dose-Response Relationship, Drug; Fluticasone; Glucocorticoids; Humans

In non-smokers the underlying causes for chronic persistent cough (CPC) e.g. chronic cough without diagnostic chest X-ray or pulmonary function test--are usually as follows: several common upper airways diseases, bronchial (cough type) asthma, gastrooesophageal reflux or treatment with an ACE (angiotensin converting enzyme)--inhibitor. In 10% of CPC however the cause remains uncertain. We report a 30 year old non-smoker with severe coughing and repeated vomiting for two months. No laboratory or technical data could be collected suggestive of a common cause of CPC: Upper airways disease, bronchial flow limitation or hyperresponsiveness, ACE inhibitor medication, B. pertussis infection, gastrooesophageal reflux disease (by 24 hours pH-probe) were ruled out. Fiberbronchoscopic findings remained unremarkable, except for the bronchial biopsy specimen, which showed moderate eosinophilic inflammation of the mucosa and marked thickening of the subepithelial layer. Since the cough was non-productive, sputum induction with 3 ml nebulised 3% NaCl solution was performed. 28% of the granulocytes were eosinophil stained. A low quality morning sputum (< 1 ml) showed 21% eosinophilia. Thus, the diagnosis of eosinophilic bronchitis was established. 400 micrograms budesonide dry powder inhalations b.i.d. for one week resolved the cough, treatment was stopped after three weeks. No recurrence was seen two months later. Both the cough type asthma and the eosinophilic bronchitis could represent a form fruste of classical bronchial asthma beyond wheezing or dyspnoea, but with the common main symptom: cough. Since hyperresponsiveness and cough are phenotypic hallmarks of cough variant asthma, in eosinophilic bronchitis--beside cough--another two features of asthma are present: eosinophilic inflammation of the mucosa along with sputum eosinophilia and subepithelial layer thickening. Not surprisingly, eosinophilic bronchial inflammation could be shown in patients with cough variant asthma as well, who--up to 56% during a four year-period--develop classic asthma. The long-term outcome of eosinophilic bronchitis is not known, however. Thus, asthma, cough variant asthma and cough due to eosinophilic bronchitis can mirror different phenotypes or phases of the same entity. CPC due to either the cough type asthma or the eosinophilic bronchitis is like asthma fast responding to inhalative steroids. (Induced) sputum staining should be added to the diagnostic armamentarium of CPC.

Topics: Adult; Asthma; Bronchial Hyperreactivity; Bronchitis; Bronchodilator Agents; Budesonide; Chronic Disease; Cough; Diagnosis, Differential; Eosinophilia; Humans; Male

Topics: Administration, Topical; Adrenergic beta-Agonists; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Ethanolamines; Formoterol Fumarate; Glucocorticoids; Humans

Topics: Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Budesonide; Confounding Factors, Epidemiologic; Cross-Over Studies; Dose-Response Relationship, Drug; Fluticasone; Humans; Metabolic Clearance Rate; Random Allocation; Research Design; Therapeutic Equivalency; Time Factors

To investigate correlations between quality of life, bronchial obstruction, nonspecific bronchial hyperreactivity (NSBH) and response of these parameters to treatment with inhalation steroids in patients with bronchial asthma (BA).. The study included 67 BA patients (47 women and 20 men) aged 18 to 62 years (mean age 43 years). 59 of them had the diagnosis of atopic BA, 8 had bacterial BA. Quality of life was assessed with the questionnaire AQLQ, bronchial obstruction was judged by forced expiratory volume per a second (FEV1). Bronchial hyperreactivity was studied with acetylcholine and histamine tests.. Quality of life strongly correlated with FEV1 and NSBH. Positive changes in the latter due to treatment with inhalation glucocorticoid budesonide (400 mcg/day) entailed improvement of life quality.. Bronchial obstruction and NSBH have a significant effect on BA patients' life quality which should be considered in monitoring of BA patients' condition.

Topics: Acetylcholine; Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Budesonide; Female; Humans; Male; Middle Aged; Quality of Life; Respiration

We studied the effect of the glucocorticoids, dexamethasone and budesonide, on the interleukin-1beta-induced increase of bradykinin B2 receptors in cultured human bronchial smooth muscle cells, a cellular model of bronchial hyperreactivity. Both compounds prevented the increase of the bradykinin B2 mRNA and the bradykinin-induced inositol phosphate accumulation. These results demonstrate a direct effect of glucocorticoids on airway smooth muscle hyperresponsiveness mediated through inhibition of the over-expression of receptors for contractile mediators induced by inflammatory mediators.

Topics: Anti-Inflammatory Agents; Bronchi; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cells, Cultured; Dexamethasone; Drug Interactions; Humans; Inositol Phosphates; Interleukin-1; Muscle, Smooth; Receptor, Bradykinin B2; Receptors, Bradykinin; RNA, Messenger

1. The effects of the inhaled corticosteroid budesonide and a novel PDE 4 inhibitor CDP840 given systematically, were evaluated in a model of antigen-induced airway inflammation in the rabbit. 2. Adult litter-matched NZW rabbits (2.4-3.5 kg) immunised within 24 h of birth with Alternaria tenuis antigen were pretreated with budesonide (total dose 100 micrograms, inhaled over 2 days) or CDP840 (total dose 7 mg kg-1, i.p. over 3 days), before antigen challenge. For each drug-treated group a parallel group of rabbits was pretreated with the appropriate vehicle. In all groups airway responsiveness to inhaled histamine was assessed and bronchoalveolar lavage (BAL) performed 24 h before and after antigen challenge. 3. Basal lung function in terms of total lung resistance (RL; cmH2O l 1s-1) and dynamic compliance (Cdyn; ml cmH2O-1) were unaltered by pretreatment with budesonide or CDP840 compared to their respective vehicles 24 h before or after antigen challenge. 4. The RL component of the acute bronchoconstriction induced by inhaled Alternaria tenuis aerosol was unaffected by pretreatment with budesonide. However, budesonide prevented the fall in Cdyn due to antigen. Treatment with CDP840 significantly reduced antigen-induced acute bronchoconstriction in terms of both RL and Cdyn. 5. Airway hyperresponsiveness (AHR) to inhaled histamine was indicated by reduced RL PC50 (2.4-4.5 fold) and Cdyn PC35 (2.1-3.9 fold) values 24 h after antigen challenge. Treatment with either budesonide or CDP840 abolished the antigen-induced increase in responsiveness to inhaled histamine. 6. Total cells recovered per ml of BAL fluid increased 24 h after antigen challenge. Antigen-induced pulmonary eosinophilia was reduced (93%) in budesonide and (85%) in CDP840 treated rabbits. Antigen-induced increases in neutrophil numbers were reduced (76%) with budesonide but not CDP840 pretreatment. 7. Inhalation of Alternaria tenuis aerosol elicited an acute bronchoconstriction, followed 24 hours later by an increased responsiveness to inhaled histamine and pulmonary neutrophil and eosinophil recruitment. CDP840 was more effective than budesonide in preventing the antigen-induced increase in total lung resistance (RL); however, both drugs prevented the antigen-induced reduction in dynamic compliance (Cdyn). CDP840 and budesonide also prevented antigen-induced AHR and eosinophilia in the immunised rabbit.

Topics: Administration, Inhalation; Airway Resistance; Analysis of Variance; Animals; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Budesonide; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Histamine Antagonists; Humans; In Vitro Techniques; Lung; Male; Neutrophils; Phosphodiesterase Inhibitors; Pregnenediones; Pyridines; Rabbits; Respiratory Hypersensitivity; Trachea

In the case reported, serial evaluation of sputum inflammatory cell counts made it possible to identify an unusual series of events in a man with eosinophilic bronchitis. The patient initially presented with a productive cough, which did not respond to treatment with antibiotics or high-dose inhaled corticosteroids. A diagnosis of eosinophilic bronchitis was made after demonstration of intense sputum eosinophilia. When inhaled corticosteroids were stopped, symptoms and sputum eosinophilia became worse and airway hyperresponsiveness developed. Both abnormalities were reversed by a course of prednisone. When the prednisone was stopped the productive cough recurred but on this occasion sputum examination suggested a different disease process and the symptoms resolved after a course of co-trimoxazole. The patient has subsequently remained well on no treatment with little or no sputum eosinophilia.

Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Bronchitis; Budesonide; Cough; Diagnosis, Differential; Eosinophilia; Eosinophils; Glucocorticoids; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Prednisone; Pregnenediones; Sputum; Trimethoprim, Sulfamethoxazole Drug Combination

Airway inflammation is implicated in the pathogenesis of the airway hyperresponsiveness in asthma. An increased production of inflammatory cell progenitors may contribute to asthmatic airway inflammation. Although the number of circulating inflammatory cell progenitors in asthmatic subjects increases after allergen inhalation, no direct evidence exists for increased bone marrow progenitor production. We examined the effect of allergen inhalation on bone marrow progenitor production in seven dogs that develop allergen-induced airway hyperresponsiveness. The effect of inhaled budesonide, a corticosteroid known to be effective in the treatment of asthma, on allergen-induced bone marrow progenitor production and airway hyperresponsiveness was also examined. Allergen inhalation increased airway responsiveness (P < 0.001) and the number of granulocyte-macrophage colony-forming units (CFU) when cultured with dog serum and either recombinant canine stem cell factor (rcSCF) (P < 0.001) or granulocyte colony-stimulating factor (rcG-CSF) (P = 0.035). Budesonide treatment reduced the allergen-induced increases in airway responsiveness (P = 0.005) and abolished the allergen-induced increases in the numbers of CFU cultured with dog serum and either rcSCF (P < 0.001) or rcG-CSF (P = 0.009). These findings provide the first direct evidence that allergen inhalation increases bone marrow progenitor production and suggest that such increases may contribute to the development of airway hyperresponsiveness in asthma. In addition, the effectiveness of inhaled corticosteroids in asthma may result, in part, from their ability to suppress bone marrow production of inflammatory cells.

Topics: Administration, Inhalation; Allergens; Animals; Ascaris suum; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Disease Models, Animal; Dogs; Hematopoietic Stem Cells; Inflammation; Pregnenediones; Respiratory Function Tests

Histamine challenge testing is used to measure airway responsiveness in asthma. Histamine tachyphylaxis has been demonstrated after repeated challenges in mild asthmatics not using inhaled corticosteroid. Other studies, using subjects with variable severity of asthma, have not demonstrated histamine tachyphylaxis. Forty patients with stable asthma were studied and stratified according to severity of airway hyperresponsiveness and use of inhaled corticosteroid, to examine the effects of these factors on histamine tachyphylaxis. Airway responsiveness was measured as the histamine provocative concentration causing a 20 percent fall in FEV1 (PC20). Twenty subjects had mildly increased airway hyperresponsiveness (PC20 > 1 mg/ml), of whom 10 were using inhaled corticosteroid. Twenty subjects had moderate to severely increased airway hyperresponsiveness (PC20 < 1 mg/ml), of whom 10 were using inhaled corticosteroid. On each of two study days, 1 week apart, two histamine challenges were performed 1 h apart. Histamine tachyphylaxis was found for the entire group on both study days. The geometric mean PC20 increased from 1.0 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 1 (p < 0.0005), and 1.1 mg/ml (percent SEM 1.2) to 1.3 mg/ml (percent SEM 1.2) 1 h later on day 2 p < 0.05). Subgroup analysis demonstrated that tachyphylaxis only occurred consistently in subjects with mildly increased airway hyperresponsiveness not receiving inhaled corticosteroid. In this group, the PC20 increased from 2.2 mg/ml (percent SEM 1.2) to 3.2 mg/ml (percent SEM 1.2) on day 1 (p < 0.001), and from 2.5 mg/ml (percent SEM 1.3) to 3.4 mg/ml (percent SEM 1.2) on day 2 (p < 0.05). This study confirms that histamine tachyphylaxis occurs in asthmatics, but is consistently present only in mild, noncorticosteroid-dependent asthmatics.

Topics: Administration, Inhalation; Administration, Topical; Adult; Anti-Inflammatory Agents; Asthma; Beclomethasone; Bronchial Hyperreactivity; Bronchial Provocation Tests; Budesonide; Female; Forced Expiratory Volume; Glucocorticoids; Histamine; Humans; Male; Pregnenediones; Tachyphylaxis

Topical corticosteroids are effective in the treatment of asthma by improving bronchial hyperresponsiveness and reducing airway inflammation.. We assessed the effect of a nebulized corticosteroid, budesonide, on airway hyperresponsiveness and inflammatory response provoked by inhalation of trimellitic anhydride (TMA) dust, a known cause of occupational asthma in human beings, in guinea pigs sensitized to the free hapten. Male Dunkin-Hartley guinea pigs (n = 24) were injected intradermally with 0.1 ml of 0.3% TMA in corn oil, followed by exposure 21 to 28 days later to five consecutive doses of budesonide aerosol (0.5 mg/ml) or saline solution, administered for 10 minutes every 12 hours. They were then exposed (noses only) to TMA dust (8 mg/m3) or air for 1 hour (four groups, n = 6 in each). Airway responsiveness to acetylcholine, defined as the concentration needed to cause a 200% increase in lung resistance (PC200), was measured 8 hours later.. In saline-treated guinea pigs exposed to TMA, mean PC200 was 0.094 mmol/L (geometric SEM, 1.4 mmol/L) compared with 0.31 mmol/L (geometric SEM, 1.3 mmol/L, p < 0.05) in those guinea pigs pretreated with budesonide. In sham-exposed sensitized guinea pigs, PC200 was 0.35 mmol/L (geometric SEM, 1.2 mmol/L), which was not significantly different from the budesonide-treated group (0.36 mmol/L; geometric SEM, 1.3 mmol/L). There was a significant increase in the number of eosinophils in the subepithelium of guinea pigs further exposed to TMA dust (71.5 +/- 6.8 cells/unit area [mean +/- SEM]) compared with those exposed to air (22.7 +/- 6.7, p < 0.01). Budesonide did not inhibit the number of subepithelial eosinophils of guinea pigs exposed to TMA dust (54.0 +/- 3.7 cells/unit area) or in those exposed to air (24.3 +/- 6.7 cells/unit area) and did not affect the increase in eosinophils found in bronchoalveolar fluid.. Budesonide significantly inhibited the increase in airway responsiveness but not the eosinophilic inflammation induced by exposure to TMA dust in sensitized guinea pigs.

Topics: Administration, Topical; Aerosols; Analysis of Variance; Animals; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Glucocorticoids; Guinea Pigs; Male; Phthalic Anhydrides; Pregnenediones; Pulmonary Eosinophilia; Respiratory Hypersensitivity