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Biomedical subjects

Paul M O'Byrne

Publications and source records attributed to Paul M O'Byrne.

At least 19 recordsLinked to original sources
PubMed2006

The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge.

BACKGROUND: The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL IMPLICATIONS: 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.

Administration, Inhalation↗
PubMed2006

Pharmacological management of mild or moderate persistent asthma.

Patients with mild persistent asthma rarely see their doctor with symptoms of the disease. Partly as a result of this situation, mild asthma is generally undertreated. Findings of several large randomised clinical trials have shown benefits for this population of regular treatment with low doses of inhaled corticosteroids. Additional drugs are rarely needed, and although leukotriene modifiers are effective, they are less so than inhaled corticosteroids. People with moderate persistent asthma are not well controlled on low doses of inhaled corticosteroids. A combination of this drug and long-acting inhaled beta2 agonists provides improved control compared with doubling of the maintenance dose of inhaled corticosteroids. The combination of budesonide and formoterol has been assessed as both maintenance and reliever treatment. This approach further reduces the risk for severe exacerbations. With these strategies, most individuals can achieve good control of their asthma. For patients who do not achieve asthma control despite taking drugs, measurement of the inflammatory response in the airway in induced sputum could provide further information to guide treatment.

Adrenal Cortex Hormones↗
PubMed2006

Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses.

RATIONALE: 1018 ISS is a synthetic oligonucleotide containing immunostimulatory CpG motifs. In animal studies, 1018 ISS effectively inhibited Th2-mediated lung inflammation, including eosinophil infiltration, and airway hyperresponsiveness. OBJECTIVES: To evaluate whether 1018 ISS has activity in subjects with allergic asthma. METHODS: Forty subjects (n = 21, 1018 ISS; n = 19, placebo) were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study to examine safety, pharmacologic activity, and efficacy of 1018 ISS on allergen-induced airway responses. Subjects received 36 mg of 1018 ISS or placebo by nebulization weekly for 4 wk. MEASUREMENTS: Allergen inhalation challenge was performed 24 h after the 2nd and 4th doses to measure the early and late fall in FEV(1). Sputum cells and peripheral blood mononuclear cells were collected before and after dosing, and gene expression was measured by quantitative polymerase chain reaction. MAIN RESULTS: Treatment with 1018 ISS significantly increased expression of interferon (IFN)-gamma and IFN-inducible genes, such as IFN-gamma-inducible 10 kD protein (IP10), monokine induced by IFN-gamma (MIG), IFN-stimulated gene (ISG)-54, monocyte chemotactic protein (MCP)-1, and MCP-2 from cells collected postdose (p < 0.05). There was no attenuation of the early or late decrease in FEV(1) after 1018 ISS compared with placebo, nor a reduction in allergen-induced sputum eosinophils or Th2-related gene expression measured in sputum cells. CONCLUSIONS: This study demonstrated that 1018 ISS is safe and pharmacologically active in the respiratory tract of asthmatics but, at this dose regimen, did not inhibit a fall in FEV(1) or other key features of the response to inhaled allergen challenge. This suggests that induction of IFN and IFN-inducible genes alone is not sufficient to inhibit allergen-induced responses in asthmatic subjects.

Adjuvants, Immunologic↗
PubMed2006

Effectiveness of early budesonide intervention in Caucasian versus Asian patients with asthma: 3-year results of the START study.

OBJECTIVE AND BACKGROUND: Few studies have assessed the effectiveness of inhaled corticosteroid therapy exclusively in Asian patients with asthma. The present analysis compared the efficacy of early intervention with inhaled budesonide in Caucasian and Asian patients over the first 3 years of the inhaled Steroid Treatment As Regular Therapy in early asthma study. METHODS: Patients aged 5-66 years with mild persistent asthma of <or=2 years' duration were randomized to 3 years of double-blind treatment with once-daily budesonide 200 microg (for patients aged<11 years) or 400 microg administered via Turbuhaler or placebo, plus usual asthma therapy. RESULTS: Budesonide significantly improved asthma outcomes in both Caucasian (n=4661) and Asian (n=1995) patients compared with reference therapy (placebo plus usual asthma therapy). Budesonide reduced the risk of a first severe asthma-related event by 42% and 49% in Caucasian and Asian patients, respectively, over the 3-year treatment period (P<0.001 for both). Moreover, budesonide significantly increased symptom-free days, decreased nights with sleeping problems, improved pre- and postbronchodilator FEV1 and reduced the need for additional asthma medications of particular drug classes compared with reference therapy. Except for differences in the patterns of use of additional asthma medications, outcomes with budesonide and overall adverse events were similar in the Caucasian and Asian patient populations. CONCLUSION: Inhaled budesonide administered once daily in Asian patients with recent-onset, mild persistent asthma significantly improved asthma control and pulmonary function compared with reference therapy. Moreover, this effectiveness paralleled that observed in Caucasian patients.

Administration, Inhalation↗
PubMed2006

Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regular Therapy in early asthma (START) trial.

Inhaled corticosteroids are known to be effective in persistent asthma, but their long-term effect in mild persistent disease of recent onset, which is particularly relevant in children, requires clarification. The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment. Children aged 5-10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200 microg or placebo via Turbuhaler in addition to usual clinical care and other asthma medication. The double-blind treatment phase continued for 3 yrs. Of the 1974 children, 1000 in the budesonide group and 974 in the placebo group, were analyzed for efficacy. Addition of once-daily budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) and significantly reduced risk of SARE over 3 yrs. The hazard ratio relative to usual care (placebo) was 0.60 (95% confidence interval: 0.40-0.90; p = 0.012), with a relative risk reduction of 40%. Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting beta2-agonists. Budesonide treatment also had a significant beneficial effect on lung function relative to placebo. In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone.

Administration, Inhalation↗
PubMed2006

Predictors of loss of asthma control induced by corticosteroid withdrawal.

BACKGROUND: Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control. OBJECTIVE: To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma. PATIENTS AND METHODS: In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20+/-2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV1 of at least 15% or a decrease in PC20 of at least fourfold. RESULTS: Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV1 and methacholine PC20 were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control. CONCLUSION: In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.

Administration, Inhalation↗
PubMed2006

Beta2 déjà vu.

Explore the source record for details and available documents.

Administration, Inhalation↗
PubMed2006

Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma.

STUDY OBJECTIVES: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease. DESIGN: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications. RESULTS: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents. CONCLUSIONS: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.

Administration, Inhalation↗
PubMed2006

Cytokines or their antagonists for the treatment of asthma.

T helper (Th) type 2 cytokines, particularly interleukin (IL)-4, IL-5, and IL-13, may be important in the development of allergic asthma. Humanized monoclonal antibodies (MoAbs) against IL-5 and a recombinant human soluble IL-4 receptor (sIL-4R) have been developed as possible treatments. These approaches have not yet proven to be successful in patients with persistent asthma. This may suggest that neither IL-4 nor IL-5 is important in asthma pathogenesis. There is, however, insufficient information about the efficacy of sIL-4R and the anti-IL-5 MoAbs in asthma to draw any firm conclusions about the importance of these Th2 cytokines. Also, the administration of the potentially antiinflammatory cytokines IL-12 and interferon-gamma has not shown benefit in asthmatic patients. By contrast, the treatment of severe oral steroid-dependent asthma with soluble tumor necrosis factor-alpha receptor has demonstrated very promising results, suggesting that this cytokine plays an important role in the persistence of severe asthma.

Animals↗
PubMed2006

Montelukast treatment attenuates the increase in myofibroblasts following low-dose allergen challenge.

RATIONALE: Airway remodeling is believed to be important in the pathophysiology of asthma, and myofibroblasts are increased in the airways of asthmatic individuals 24 h after allergen challenge. Leukotriene receptor antagonists exert antiinflammatory activity in asthma, but it is unknown whether they influence indices of airway remodeling. In the present study, we evaluated the effect of montelukast on airway myofibroblasts following low-dose allergen challenge (LDAC). METHODS: Stable subjects with mild asthma were included in a two-center, randomized, parallel-group study. A 2-week run-in period was followed by LDAC and endobronchial biopsy. Subjects were then randomized to receive either montelukast, 10 mg/d, or placebo (n = 10 in each group) for 8 weeks in a double-blind manner; at the end of the treatment period, subjects underwent a second LDAC and endobronchial biopsy. The effect of treatment on myofibroblasts, fibroblasts, and inflammatory cells was examined using electron microscopy techniques. RESULTS: Treatment with montelukast showed no significant difference by comparison with placebo but did show a significant within-group treatment-related decrease in airway wall myofibroblasts not seen in the placebo group. In addition, the montelukast-treated group also showed a significant within-group reduction in lymphomononuclear cells and increased neutrophils. CONCLUSIONS: The results suggest that montelukast has an inhibitory effect on airway structural cells that play a key role in airway remodeling in allergic airway inflammation, and that montelukast may be a useful therapy to attenuate airway remodeling in asthma.

Acetates↗
PubMed2005

Initiation, dose reduction, and duration of inhaled corticosteroid therapy.

Asthma is characterized by persistent airway inflammation, which is associated with airway hyperresponsiveness and variable airflow obstruction, which accounts for the majority of symptoms experienced by asthmatic patients. Allergen sensitization and inhalation causes airway inflammation, and is likely important in the initiation and persistence of asthma in more than 50% of patients, and while allergen avoidance (or avoidance of other initiating factors, such as occupational sensitizers) can help some patients, it is often difficult to achieve. For this reason, pharmacologic treatment to reduce airway inflammation is currently the cornerstone of therapy for most individuals who have asthma.

Administration, Inhalation↗
PubMed2005

Progenitor egress from the bone marrow after allergen challenge: role of stromal cell-derived factor 1alpha and eotaxin.

BACKGROUND: CCR3 expression on CD34+ cells mediates migration to eotaxin in vitro. CXCR4 and stromal cell-derived factor (SDF)-1alpha are important for stem cell homing to hemopoietic compartments. OBJECTIVE: To study chemokine-mediated progenitor cell traffic in allergic inflammation. METHODS: Bone marrow (BM) aspirates were obtained at baseline from normal subjects; atopic subjects without asthma; and subjects with asthma before, 5 hours after, and 24 hours after allergen inhalation (dual and early responders). Changes in chemokine receptor expression and migration were assessed. RESULTS: Expression of CXCR4, but not CCR3, on BM CD34+ cells was greater in normal subjects compared with atopic subjects with asthma. Likewise, SDF-1alpha, but not eotaxin, stimulated a greater migrational response by BM CD34+ cells from normal subjects compared with subjects with asthma. For all subjects, a positive correlation was found between intensity of CXCR4 expression and magnitude of CD34+ cell response to SDF-1alpha. Allergen inhalation attenuated both intensity of CXCR4 expression and SDF-1alpha levels in marrow from dual compared with early responders 24 hours postallergen. In contrast, the intensity of CCR3 expression on BM CD34+ cells increased in dual compared with early responders at 24 hours postallergen. In addition, an increase in migrational responsiveness of BM CD34+ cells to eotaxin and a decrease to SDF-1alpha 24 hours postallergen was found in dual responder subjects with asthma. CONCLUSION: After allergen inhalation in subjects with asthma, a downregulation in CXCR4 intensity on BM CD34+ cells and a reduction in BM SDF-1alpha levels may reduce progenitor retention to marrow stroma promoting peripheral egress, possibly mediated by the CCR3/eotaxin axis.

Antigens, CD34↗
PubMed2005

Protection by budesonide and fluticasone on allergen-induced airway responses after discontinuation of therapy.

BACKGROUND: 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. OBJECTIVE: We sought to evaluate the protective effect of 1 week of inhaled steroid therapy against inhaled allergen challenge 12 hours after discontinuation of therapy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2005

Different profiles of T-cell IFN-gamma and IL-12 in allergen-induced early and dual responders with asthma.

BACKGROUND: IFN-gamma and IL-12 are anti-inflammatory cytokines released from various cells, including T cells. Allergen inhalation by atopic subjects with asthma results in 2 bronchoconstrictor phenotypes, termed isolated early and dual responders . Persistence of allergen-induced airway response and inflammation is a distinctive feature of dual responders. OBJECTIVE: To evaluate the roles of IFN-gamma and IL-12 in resolving allergen-induced airway inflammation by comparing T lymphocytes (CD4 + and CD8 + cells) producing these cytokines in isolated early and dual responders. METHODS: Twenty-four subjects with asthma (12 isolated early and 12 dual responders) were challenged with inhaled allergen. Peripheral blood and induced sputum were taken before and 1 day, 3 days, and 7 days after challenge. Frequency of IFN-gamma, IL-12, IL-4, and IL-13 producing CD4 + and CD8 + cells was assessed by using flow cytometry. RESULTS: After allergen, both CD4 + and CD8 + IFN-gamma positive cells in peripheral blood significantly decreased in dual responders only, whereas CD4 + and CD8 + IFN-gamma positive cells in induced sputum significantly increased in isolated early responders only. By contrast, IL-12 positive cells in peripheral blood significantly increased after allergen challenge only in isolated early responders. The ratio of CD4 + and CD8 + IL-4/IFN-gamma positive cells in peripheral blood significantly decreased in isolated early responders by 3 days and had recovered by 7 days. CONCLUSION: These results suggest that contrasting profiles of IFN-gamma and IL-12 production may be responsible for different time courses of allergen-induced airway responses between isolated early and dual responders.

Allergens↗
PubMed2005

Effect of low-dose ciclesonide on allergen-induced responses in subjects with mild allergic asthma.

BACKGROUND: Inhalation of allergens by sensitized patients with asthma induces reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. Attenuation of allergen-induced bronchoconstriction and inflammation has been used to examine the efficacy of therapeutic agents such as inhaled corticosteroids in asthma. Ciclesonide, a nonhalogenated inhaled corticosteroid being developed for the treatment of persistent asthma, remains inactive until cleaved by esterases in the lung. OBJECTIVE: This study examined the effect of low doses of inhaled ciclesonide, 40 microg and 80 microg, on allergen-induced bronchoconstriction, serum eosinophil cationic protein, and eosinophilic airway inflammation. METHODS: Twenty-one nonsmokers with mild atopic asthma completed a multicenter, randomized, 3-way crossover study comparing the effects of 7-day treatment of ciclesonide or placebo. Allergen-induced responses, including the early and late fall in FEV1, peripheral blood eosinophils, serum eosinophil cationic protein levels, and eosinophils in induced sputum were measured. RESULTS: Ciclesonide 80 microg attenuated the early and late asthmatic responses, including the change in FEV1, serum eosinophil cationic protein, and sputum eosinophils measured at 24 hours postchallenge (P < .025). Ciclesonide 40 microg attenuated the late asthmatic responses and sputum eosinophils measured at 24 hours postchallenge (P < .025), with no effect on the early allergen-induced bronchoconstriction, 24-hour FEV1, or serum eosinophil cationic protein levels (P < .025). CONCLUSION: With the exception of 24-hour postchallenge peripheral blood eosinophils, a low dose of ciclesonide, 80 microg, was effective in blocking all allergen-induced responses measured.

Adult↗
PubMed2004

Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma.

Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens.

Adolescent↗