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The introduction of inhaled corticosteroids (ICSs) changed over a few decades the treatment focus of mild-to-moderate asthma from bronchodilation to reduction in inflammation. This was achieved by inhaling a suitable corticosteroid (CS), giving a high, protracted airway concentration at a low total dose, thereby better combining efficacy and tolerance than oral therapy. Successful trials with the potent, lipophilic "skin" CS beclomethasone dipropionate (BDP) paved the way, suggesting that ICSs require a very low water solubility, prolonging their intraluminal dissolution within airways. The subsequent ICS development, with resulting clinical landmarks, is exemplified here with budesonide (BUD), showing that a similar efficacy/safety relationship is achievable by partly alternative mechanisms. BUD is much less lipophilic, giving it a 100-fold higher water solubility than BDP and later developed ICSs, leading to its more rapid intraluminal dissolution and faster airway and systemic uptake rates. In airway tissue, a BUD fraction is reversibly esterified to intracellular fatty acids, a lipophilic conjugate, which prolongs airway efficacy. Another mechanism is that the rapidly absorbed bulk fraction, via short plasma peaks, adds anti-inflammatory activity at the blood and bone marrow levels. Importantly, these plasma peaks are too short to provoke systemic adverse actions. Controlled clinical trials with BUD changed the use of ICS from a last resort to first-line treatment. Starting ICS treatment immediately after diagnosis ("early intervention") became a landmark for BUD. An established dose response made BUD suitable for the treatment of patients with all degrees of asthma severity. With the development of the budesonide/formoterol combination inhaler (BUD/FORM), BUD contributed to the widely used BUD/FORM maintenance and reliever therapy (MART). Recent studies demonstrated the value of BUD/FORM as a generally recommended as-needed therapy for asthma ("anti-inflammatory reliever", AIR). These abovementioned qualities have all influenced international asthma management and treatment guidelines. [ABSTRACT FROM AUTHOR]

Abstract Background Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation. Methods This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 μg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 μg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30–60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home. A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' double-blind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 μg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined. Results Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified. Conclusion High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used. Clinical trial registration NCT00259779

Many sarcoidosis-associating immunological genes have been shown to be shared between other immune-mediated diseases. In Finnish sarcoidosis patients, good prognosis subjects more commonly have HLA-DRB1 * 03:01 and/or HLA-DRB1 * 04:01-DPB1 * 04:01 haplotype, but no marker for persistent disease have been found. The objective was to further pinpoint genetic differences between prognosis subgroups in relation to the HLA markers. Whole-exome sequencing was conducted for 72 patients selected based on disease activity (resolved disease, n = 36; persistent disease, n = 36). Both groups were further divided by the HLA markers (one/both markers, n = 18; neither of the markers, n = 18). The Finnish exome data from the Genome Aggregation Database was used as a control population in the WES sample. Statistical analyses included single-variant analysis for common variants and gene level analysis for rare variants. We attempted to replicate associated variants in 181 Finnish sarcoidosis patients and 150 controls. An association was found in chromosome 1p36.21 (AADACL3 and C1orf158), which has recently been associated with sarcoidosis in another WES study. In our study, variations in these genes were associated with resolved disease (AADACL3, p = 0.0001 and p = 0.0003; C1orf158, p = 7.03E-05). Another interesting chromosomal region also peaked, Leucocyte Receptor Complex in 19q13.42, but the association diminished in the replication sample. In conclusion, this WES study supports the previously found association in the region 1p36.21. Furthermore, a novel to sarcoidosis region was found, but additional studies are warranted to verify this association. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen--presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA--DRA with tag--SNPs and their relation to HLA--DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren's syndrome. In a joint analysis, seven SNPs were associated with non--Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E--07, OR = 1.9) and eight with Löfgren's syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E--12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA--DRB1 challenged the result interpretation. When the SNPs and HLA--DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA--DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA--DRB1 and/or HLA--DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA--DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA--DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi--population study demonstrates that at least a part of these associations are HLA--DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA--DRB1 associations acted as eQTL for HLA--DRB1 and/or --DRB5, suggesting a role in regulating gene expression. [ABSTRACT FROM AUTHOR]

The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever". [ABSTRACT FROM AUTHOR]

Objective: Baseline inhaled corticosteroid (ICS) dose may be a factor for prescribers to consider when they select a budesonide/formoterol maintenance and reliever therapy regimen for symptomatic asthmatics.Methods: A 6-month randomized study compared two maintenance doses of budesonide/formoterol 160/4.5 µg, 1 × 2 and 2 × 2, plus as needed, in 8424 asthma patients with symptoms when treated with ICS ± an inhaled long-acting β2-agonist (LABA). In the total study population, 1339 (17%) were high-dose ICS (HD) users (≥1600 µg/day budesonide). This HD stratum was compared with the rest of the study population, divided into low-dose (LD; 400 µg/day) and medium-dose strata (MD; 401–1599 µg/day) with regard to severe asthma exacerbations and mean changes in five-item Asthma Control Questionnaire (ACQ5) scores from baseline.Results: In all three strata there were fewer exacerbations in the 2 × 2 treatment groups (yearly rates 0.268, 0.172 and 0.094) than in the 1 × 2 treatment groups (yearly rates 0.232, 0.138 and 0.764). In no stratum was the difference between the treatment groups statistically significant. There was no statistically significant difference in time to the first severe exacerbation between the treatments 2 × 2 and 1 × 2 in the HD group (hazard ratio 0.944, p = 0.75). The adjusted mean changes in ACQ5 scores in the HD, MD and LD strata were −0.89, −0.61 and −0.65, respectively, with 1 × 2 treatment and −0.90, −0.74 and −0.76, respectively, with 2 × 2 treatment. In the MD and LD strata, the difference between doses was significant in favour of 2 × 2 (MD p < 0.0001; LD p = 0.004), but not in the HD stratum (p = 0.870). No difference in serious adverse events was seen.Conclusion: Compared with the LD and MD strata, the HD stratum patients had more exacerbations and a shorter time to first exacerbation. However, there were no differences in response between the 1 × 2 and 2 × 2 groups in any of the strata. This indicates that patients using budesonide/formoterol maintenance and reliever therapy, irrespective of baseline ICS dose, can be switched to 1 × 2 with its lower steroid load. ACQ5 scores improved more in the HD stratum than in the MD and LD strata indicating, among other things, that HD patients were not overtreated at baseline.ClinicalTrials.gov registration: NCT00463866 [ABSTRACT FROM PUBLISHER]

To investigate whether dry powder inhalers (DPIs) function in a constrained situation, a literature analysis was performed to evaluate the use of DPIs compared with established therapies in the treatment of acute asthma and COPD, irrespective of rapid-acting β2-agonist used. The external databases Medline, Embase, Biosis and Current Contents and AstraZeneca's internal literature database Planet were searched up to April 2008. Only publications or congress abstracts describing clinical trials in patients treated at EDs or hospitals were considered, and then only those in which exacerbation severity (measured as FEV1) were included. Fifteen clinical studies met these criteria; twelve in acute asthma and three in acute COPD. For acute asthma, eight studies were double-blind, randomised studies (six in adults and two in children), two were open-label studies (one in adults and one in children), and two were investigational (methacholine challenge) studies. For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label. This review found that administration of fast-acting bronchodilators via DPIs, the majority of which were Turbuhaler, is effective during an asthma or COPD worsening. Our literature review finds that DPIs function in patients with acute asthma or COPD equally well as established therapies with other inhaler devices. Patients can therefore rely upon DPIs in the same way that they rely upon other inhaler devices. [ABSTRACT FROM PUBLISHER]

Background: Oral corticosteroids and inhaled bronchodilators with or without antibiotics represent standard treatment of COPD exacerbations of moderate severity. Frequent courses of oral steroids may be a safety issue. We wanted to evaluate in an out-patient setting whether a 2-week course of inhaled budesonide/formoterol would be equally effective for treatment of acute COPD exacerbations as standard therapy in patients judged by the investigator not to require hospitalisation. Methods: This was a double-blind, randomised, non-inferiority, parallel-group, multicentre study comparing two treatment strategies; two weeks' treatment with inhaled budesonide/formoterol (320/9 μg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 μg bid) in patients with acute exacerbations of COPD attending a primary health care centre. Inclusion criteria were progressive dyspnoea for less than one week, FEV1 30-60% of predicted normal after acute treatment with a single dose of oral corticosteroid plus nebulised salbutamol/ipratropium bromide and no requirement for subsequent immediate hospitalisation, i.e the clinical status after the acute treatment allowed for sending the patient home. A total of 109 patients (mean age 67 years, 33 pack-years, mean FEV1 45% of predicted) were randomized to two weeks' doubleblind treatment with budesonide/formoterol or prednisolone plus formoterol and subsequent open-label budesonide/formoterol (320/9 μg bid) for another 12 weeks. Change in FEV1 was the primary efficacy variable. Non-inferiority was predefined. Results: Non-inferiority of budesonide/formoterol was proven because the lower limit of FEV1-change (97.5% CI) was above 90% of the efficacy of the alternative treatment. Symptoms, quality of life, treatment failures, need for reliever medication (and exacerbations during follow-up) did not differ between the groups. No safety concerns were identified. Conclusion: High dose budesonide/formoterol was as effective as prednisolone plus formoterol for the ambulatory treatment of acute exacerbations in non-hospitalized COPD patients. An early increase in budesonide/formoterol dose may therefore be tried before oral corticosteroids are used. [ABSTRACT FROM AUTHOR]

Summary: Background: Inhaled corticosteroids (ICS) represent first-line treatment in persistent asthma with clinical studies showing benefits of initiating therapy early. Whether treatment should be started with a high or low dose remains controversial. We investigated the importance of disease duration on the response to the starting dose of the ICS, budesonide, in asthma patients not previously treated with ICS. Methods: Forty patients with newly detected asthma (symptoms for <12 months) and 41 patients with established asthma (mean duration 5.2 years, range 2–11) were randomized (double-blind, parallel-group) to treatment with budesonide Turbuhaler® 100 or 400μg twice daily or placebo for 12 weeks. Results: For morning peak expiratory flow (mPEF), all four budesonide treatments resulted in statistically significant improvements from baseline and, after 12 weeks, the changes in all four groups were statistically significantly greater than placebo. In patients receiving early treatment, no significant differences were seen between budesonide doses. In patients with established symptoms, 800μg/day improved mPEF significantly more than 200μg/day. The 800μg/day dose in the early treatment group improved mPEF significantly more than in the delayed treatment group. Changes in forced expiratory volume in 1s (FEV1), the concentration of inhaled histamine causing a 20% drop in FEV1, and use of as-needed medication behaved in very similar ways to mPEF. Asthma symptoms were reduced in all budesonide groups without a difference between doses. Conclusion: In patients with newly detected asthma treated early the initial ICS dose is not important. In contrast, in patients with symptoms for a longer duration a high starting dose improves airway function and hyperresponsiveness significantly better than a low dose. [Copyright &y& Elsevier]

Background. Budesonide, a widely used inhaled corticosteroid(ICS) with a favorable therapeutic ratio, is available via a dry powder inhaler(Pulmicort Turbuhaler®) and as a suspension for nebulization(Pulmicort Respules®). METHODS: MEDLINE and an AstraZeneca database were searched to identify relevant controlled clinical trials published between 1986 and 2002 using the key words budesonide OR inhaled corticosteroid, AND once daily. RESULTS: Thirty-four controlled clinical studies involving once-daily administration of budesonide to asthmatic patients were identified. Excluding long-term studies, this review presents data from 23 controlled studies for 4466 adults or adolescents and 1532 children with asthma and demonstrates efficacy of budesonide in both corticosteroid-naïve patients and patients previously treated with ICS. Once-daily administration of budesonide achieves clinical efficacy comparable with that of twice-daily regimens in patients with mild-to-moderate asthma and is equally effective when given in the morning or evening. Once-daily administration simplifies treatment regimens and may improve patient compliance. The tolerability profiles of budesonide once-daily via Turbuhaler® or as budesonide inhalation suspension are good and comparable with those for twice-daily dosing. CONCLUSIONS: Once-daily budesonide is effective and well tolerated as initial treatment for adults and children with mild asthma and as maintenance therapy in patients with more severe asthma once asthma control has been achieved. [ABSTRACT FROM AUTHOR]

Compares the efficacy of budesonide Turbuhaler with that of beclomethasone dipropionate pMDI in Japanese patients with persistent asthma. Basis in comparing the outcomes; Approach for improving the efficacy of budesonide; Importance of a higher dose treatment when comparing two formulations.

Objective:The aim of this study was to evaluate the oral steroid-sparing capacity of budesonide Turbuhaler®. Methodology:One hundred and thirteen oral steroid-dependent patients were treated for 6 months with placebo or budesonide 800 μg or 1600 μg daily. Every second week the oral steroid dose was reduced if asthma control permitted. Results:The reductions in oral steroid doses were 9, 35 and 60% in the placebo and budesonide 800 μg and 1600 μg groups, respectively. Oral steroid treatment could be discontinued in 4% (placebo), 15% (800 μg) and 23% (1600 μg). Mean peak expiratory flow values increased by 21 and 24 L/min in the budesonide groups but decreased by 6 L/min in the placebo group. Asthma attack, activity and sleep scores remained unchanged showing maintained efficacy. Plasma cortisol levels increased and an adrenocorticotropic hormone test showed improved adrenocortical response in both budesonide groups, indicating improved safety. Adverse drug reactions were infrequent and mild in all study groups. Conclusion:Budesonide Turbuhaler, 800 μg and 1600 μg daily, resulted in a significant reduction in oral steroid usage in steroid-dependent patients. The effect was achieved with maintained asthma control together with improvements in lung and adrenal functions. [ABSTRACT FROM AUTHOR]

Objective:The aim of this study was to investigate the dose–response for inhaled budesonide via Turbuhaler® in Japanese patients with mild to moderate asthma. Methodology:Inhaled budesonide 100 μg, 200 μg, 400 μg or placebo was administered twice daily via Turbuhaler for 6 weeks, to 267 adult Japanese patients (mean age 51 years) with mild-to-moderate, non-steroid-dependent bronchial asthma, in a double-blind, placebo-controlled, randomized, parallel group study. The patients had to be symptomatic for more than 3 days/week and have an average morning peak expiratory flow (PEF) 50–80% of predicted normal value. Results:The response to budesonide was rapid, all treatments showing a significant improvement in morning PEF after 1 week (P < 0.05). During week 6, mean improvements of 15, 45, 53 and 71 L/min were observed for the placebo, 200 μg, 400 μg and 800 μg budesonide groups, respectively. Compared with placebo all improvements in the budesonide groups were statistically significant and a significant dose–response was demonstrated (P < 0.001). The difference between the 200 μg and 800 μg doses was significant. Also, for several secondary efficacy variables (e.g. evening PEF, symptom score, treatment score, daily activity score and sleep score) significant dose–responses were shown. Other variables included the investigators’ assessments of improvement and usefulness. They also showed statistically significant dose–response relationships and confirmed the rapid onset of action. Budesonide was well tolerated at all tested doses, with a low incidence of adverse events, all of which were minor in severity. Conclusions:Budesonide Turbuhaler in the doses 100 μg to 400 μg twice daily was effective, well tolerated and showed a rapid onset of action in patients with mild-to-moderate asthma. Dose–response was demonstrated for several variables of clinical efficacy. [ABSTRACT FROM AUTHOR]

The presence of ozone is to a large extent due to the emissions of hydrocarbons and nitrogen oxides over large areas. During periodic peak concentrations of ozone in the range of 0.1-0.2 ppm in the polluted air of big cities, people may suffer reactions such as eye discomfort, headache, chest discomfort, shortness of breath, and cough. Bronchoconstriction, with an increased airway resis tance resulting in reductions in lung function parameters, arises at concentra tions of ozone > 0.2 ppm. Asthmatics seem to be more sensitive than healthy individuals, but long-term effects in humans are to a large extent unknown since they are very difficult to evaluate. [ABSTRACT FROM PUBLISHER]

It is of great importance to investigate the role of air pollutants in causing and aggravating lung diseases. The levels of concentration of some of these com bustion products have shown a decreasing emission curve, but the emissions of nitrogen dioxide (NO2) are still increasing. Most of the NO2 emissions origi nate from road traffic. The installation of catalytic converters may well change this. It is established that low concentrations of NO2 affect the respiratory system; this is especially obvious in asthmatics. Regarding long-term effects, it is believed that high levels of NO2 may cause an increased frequency of respi ratory illness, but it is not possible to confirm this suspicion completely. [ABSTRACT FROM PUBLISHER]