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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]

Introduction: We compared in vitro drug delivery characteristics of two budesonide/formoterol dry powder inhalers, the Bufomix Easyhaler and the budesonide/formoterol Turbuhaler, at different patient air flow rates, and to test dose delivery from the Easyhaler in stressed conditions exposed to moisture, dropping, vibration and freezing/thawing. Methods: A total of 36 inhalers from two batches of both products (160/4.5 µg strength) were used when comparing the effect of flow rate; six inhalers for each of the three flow rates for uniformity of delivered dose (DD), fine particle dose (FPD), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Consistency of DD, FPD, MMAD and GSD were determined for each inhaler at three different flow rates: 10th, 50th and 90th percentile air flows. Dosing properties as a function of inhaler life were tested. The effects of moisture, dropping, vibration and freezing/thawing on DD and FPD were tested with two to four inhalers per test using all three strengths of Easyhaler: 80/4.5, 160/4.5 and 320/9 µg. Results: The Easyhaler, 160/4.5 µg, showed statistically significantly better dose consistency (expressed as percentage of labelled dose) at all three inhalation flows compared with the Turbuhaler, 160/4.5 µg, ( p < 0.001 for three flow rates). Exposure to moisture, dropping, vibration and freezing/thawing did not affect DD or FDP. These results were similar to all three tested Easyhaler strengths. Conclusion: In vitro performance of the Easyhaler indicates reliable dosing. Dose consistency was superior compared with the Turbuhaler at all tested flow rates. Environmental moisture, dropping, vibration and freezing/thawing did not affect the performance. Funding: Orion Corporation Orion Pharma. [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]

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]

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]

Clinical trials show that formoterol (Oxis®) Turbuhaler® 4.5 μg delivered dose (6 μg metered dose) has a rapid onset of bronchodilation similar to that of salbutamol and a 12-h duration of action. Maximum increase in FEV1 and duration of bronchodilation are dose-dependent, the 4.5 μg dose being the lowest dose tested giving both effects.Clinical studies investigating onset of bronchodilation show a significant increase in specific airway conductance occurring within 1 min after inhalation of formoterol Turbuhaler 4.5 μg. When measured from 3–20 min after inhalation, formoterol Turbuhaler 4.5 μg showed similar increases in FEV1 to salbutamol administered via pMDI. No difference in onset of bronchodilation was observed between the formoterol Turbuhaler 4.5 and 9 μg doses.Single-dose studies and studies of 1–12 weeks'' duration show that formoterol Turbuhaler 4.5 μg produces a significant and clinically important mean bronchodilating effect for ≥12 h after inhalation. In the cited studies no significant differences in duration of bronchodilation were observed between the formoterol Turbuhaler 4.5 and 9 μg doses.Conclusion: clinical data show that formoterol Turbuhaler 4.5 μg is an effective dose in patients with asthma, with a rapid onset of bronchodilation and a duration of at least 12 h. [Copyright &y& Elsevier]

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]

Abstract: The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed. [Copyright &y& Elsevier]

The author discusses a study related to the Helsinki Early Intervention Childhood Asthma Programme which is a program that highlights the benefits and safety aspects of intermittent treatment of asthma with budesonide. Several graphs depicting findings of the study are also presented. The author concludes that intermittent treatment using inhaled corticosteroids is an efficient alternative for treating mild persistent asthma in children.

Objective: The aim of this study was to investigate patients' inhaler competence and satisfaction with the Easyhaler dry powder inhaler. Design: Two open, uncontrolled, non-randomised studies. Setting: Real life based on patients attending 56 respiratory clinics in Hungary. Participants: Patients with asthma or chronic obstructive pulmonary disease (COPD) ( n = 1016). Intervention: In a 3-month study, adult patients (age range 18-88 years; n = 797) received twice-daily inhalations of formoterol via Easyhaler, and in a consequential study (from one visit to another, with 3-12 months in-between) children and adolescents (age range 4-17 years; n = 219) received salbutamol via Easyhaler as needed. Main Outcome Measures: Control of six Easyhaler handling steps and patients' satisfaction with Easyhaler based on questionnaires. Results: Correct performances (minimum and maximum of the six steps) were noticed after one demonstration in 92-98 % of the adults, 87-99 % of the elderly, 81-96 % of the children and 83-99 % of the adolescents. These figures had markedly increased at the last visit. Repeat instructions were necessary in 26 % of the cases. Investigators found Easyhaler easy to teach in 87 % of the patients and difficult in only 0.5 %. Patients found Easyhaler easy to learn and use, and the patients' (and parents') satisfaction with the inhaler was very high. Lung function values [forced expiratory volume in 1 s (FEV), forced vital capacity (FVC), peak expiratory flow (PEF)] improved statistically significantly during the studies, indicating good inhaler competence and treatment adherence. Conclusion: Investigators found Easyhaler easy to teach and patients found it easy to use, and their satisfaction with the device was high. [ABSTRACT FROM AUTHOR]

Abstract: Sarcoidosis is a multiorgan immune-mediated disease of unknown etiology with varying clinical pictures. We studied 3 genes in the major histocompatibility complex region (HLA-DRB1 and complement C4A and C4B) in patients with resolved disease after a 2-year follow-up (n = 90) and in patients whose disease was still active at that time point (n = 98) and compared them with controls (n = 150). Our primary aim was to detect genetic differences between the patient groups. We observed that the susceptibility allele for sarcoidosis was HLA-DRB1*15:01 (p = 0.011; odds ratio [OR] = 1.67) and the protective allele was HLA-DRB1*01:01 (p = 0.001; OR = 0.43). HLA-DRB1*03:01 was associated with resolving disease when compared with the persistent group (p = 0.011; OR = 2.22). The probability of having resolving disease was even greater if the patient had HLA-DRB1*03:01 and did not have extrapulmonary lesions (p = 0.001; OR = 3.39). By evaluating amino acid variants of the HLA-DRB1 gene, we determined that specific amino acids in pockets 4, 7, and 9 were associated with the prognosis of sarcoidosis. Our results support the importance of HLA-DRB1 as a predisposing gene for sarcoidosis. Particularly, HLA-DRB1*03:01 and polymorphisms of DRB1 pocket residues were associated with a favorable prognosis. Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis. [Copyright &y& Elsevier]

Study objective: To evaluate the 5-year prognosis of patients with stage I and stage II newly detected (< 3 months) pulmonary sarcoidosis treated immediately after diagnosis with prednisolone for 3 months followed by inhaled budesonide for 15 months. Design: Randomized, double-blind, placebo-controlled, parallel-group study for 18 months. Thereafter, open follow-up without treatment. Setting: Twenty pulmonary medicine departments in Finland. Patients: One hundred eighty-nine adult patients, most of them with normal lung function, were randomized to treatment. One hundred forty-nine patients were followed up for 5 years: 79 patients with initial stage I disease and 70 patients with stage II disease. Treatment: Oral prednisolone for 3 months followed by inhaled budesonide for 15 months (800 µg bid), or placebo tablets followed by placebo inhaler therapy. Thereafter, treatment only on an individual basis in the ease of clinical deterioration. Measurements: Yearly follow-up visits with chest radiographs, lung function tests (FEV[sub 1], FVC), diffusion capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and serum and urinary calcium measurements. Results: No initial differences were observed in chest radiographic findings between the active-treatment and placebo-treatment groups, either in patients with initial stage I or stage II(-III) disease. However, after the 5-year follow-up, 18 steroid-treated patients (26%) and 30 placebo-treated patients (38%) still had remaining chest radiographic changes. Placebo-treated patients more frequently required treatment with corticosteroids during the 5-year follow-up (p < 0.05). Steroid-treated patients with initial stage II(-III) disease improved more in FVC and DLCO (p < 0.05). No differences in reported adverse events or in SACE, serum calcium, or urinary calcium values were seen. Conclusion: Immediate treatment of pulmonary stage II(-III) sarcoidosis—but not stage I... [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.

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 microg, qid) was compared with prednisolone (30 mg once daily) plus inhaled formoterol (9 microg 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 microg 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. [ABSTRACT FROM AUTHOR]

Background: In a previous study, we found that two years of treatment with an inhaled corticosteroid, budesonide, was more effective than treatment with an inhaled β2-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 β2-agonist therapy to corticosteroid therapy would have. Methods: A total of 37 patients treated for two years with inhaled budesonide at a dose of 1200 μg per day were randomly assigned to treatment with 400 μg 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 μg of budesonide per day during the third year. Results: 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 μg 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. Conclusions: 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. (N Engl J Med 1994;331:700-5.) [ABSTRACT FROM AUTHOR]