Multidetector-row computed tomography assessment of adding budesonide/formoterol to tiotropium in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), multidetector-row computed tomography (MDCT) showed that tiotropium dilated the inner diameters in airways from the third to the sixth generation of the bronchi. Here we aimed to evaluate the morphological effect by adding a budesonide/formoterol combination to tiotropium in COPD patients using three-dimensional MDCT. METHODS: Pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ) and MDCT imaging studies were performed at the beginning and after budesonide/formoterol combination treatment for 12 weeks in 14 patients with COPD. RESULTS: The median age was 73.5 years and the mean forced expiratory volume in 1 s (FEV1) as a percentage of the predicted value was 57.2 ± 18.3%. The luminal area in the fifth generation bronchi and the emphysema volume/CT-derived total lung volume were significantly correlated with FEV1 at baseline (r = 0.682, p < 0.02 and r = -0.868, p < 0.001, respectively). The average luminal area and wall area percentage in the third, fourth and fifth generations were correlated with the SGRQ total score. Budesonide/formoterol induced insignificant pulmonary function changes and significant symptoms improvement. CT images showed an increased inner luminal area and decreased wall area after budesonide/formoterol treatment. Average luminal area was significantly increased from 24.3 ± 9.7 to 26.0 ± 9.9 mm(2) in the third generation, 13.0 ± 6.5 to 14.7 ± 7.3 mm(2) in the fourth generation, 8.0 ± 4.8 to 9.4 ± 4.9 mm(2) in the fifth generation and 5.6 ± 2.7 to 6.7 ± 3.6 mm(2) in the sixth generation (p < 0.01). The average increase of the third generation luminal area was correlated with the FEV1 increase (r = 0.632, p < 0.03). The wall area percentage significantly decreased from 51.5 ± 9.2 to 49.1 ± 9.7 in the third generation, 56.1 ± 9.7 to 53.0 ± 11.1 in the fourth generation, and 62.3 ± 9.9 to 57.6 ± 9.8 in the fifth generation (p < 0.05). Emphysema volume/CT-derived total lung volume was unchanged with treatment. CONCLUSION: MDCT demonstrated budesonide/formoterol induced bronchodilation in the non-small airway. CT imaging can evaluate drug therapeutic effect and may provide additional insights into pharmacotherapy for COPD.

Effects of budesonide inhalation on energy expenditure, somatic growth and salivary cortisol levels in preterm infants with chronic lung disease.

BACKGROUND: We hypothesized that the use of inhaled budesonide (BUD) would alter somatic growth by increasing energy expenditure (EE) in premature infants with chronic lung disease (CLD). METHODS: A prospective study was conducted of the effect of BUD on EE, growth and salivary cortisol excretion in infants with CLD who required supplemental oxygen and were treated with inhaled BUD for 4 weeks according the severity of their CLD, or without BUD treatment. Infants were compared with a healthy control group matched for gestational age. EE, anthropometric measures and salivary cortisol levels were examined before, during and after BUD treatment. RESULTS: A total of 30 spontaneously breathing premature infants were enrolled in the study. EE in CLD (BUD) and CLD (no BUD) patients were greater than EE in healthy preterm infants (p < 0.01) at the study time points. Growth did not differ between the groups. Salivary cortisol levels of treated infants were significantly lower when compared with the levels of nontreated infants. CONCLUSION: The administration of inhaled BUD in preterm infants with CLD was associated with an increase in EE, a suppression of endogenous cortisol production and with no effect on duration of supplemental oxygen, but did not compromise their somatic growth.

Budesonide/formoterol: a review of its use as maintenance and reliever inhalation therapy in asthma.

The use of combination budesonide/formoterol dry powder inhaler (Symbicort Turbuhaler) for both daily maintenance therapy and as-needed relief of breakthrough symptoms using a single inhaler is a new approach to asthma management that is indicated in patients with persistent asthma not adequately controlled by conventional regimens using reliever therapy with a short-acting beta(2)-adrenoceptor agonist alone. The administration of additional corticosteroid with each reliever inhalation in response to symptoms is expected to provide improved control of airway inflammation.Budesonide/formoterol maintenance and reliever therapy reduced the risk of severe asthma exacerbations compared with conventional regimens using a short-acting beta(2)-adrenoceptor agonist alone as reliever therapy in the majority of trials, while providing similar or better daily asthma control than higher fixed maintenance doses of budesonide or inhaled corticosteroid/long-acting beta(2)-adrenoceptor agonist combination therapy in patients with generally moderate to severe, uncontrolled, persistent asthma. The strategy offers the convenience of a single inhaler and simplifies treatment by providing immediate additional anti-inflammatory medication in response to asthma symptoms and immediate step-down when symptoms abate. The improved efficacy, with respect to exacerbation prevention, observed with budesonide/formoterol maintenance and reliever therapy in all double-blind comparative trials was achieved with a lower mean daily dose of inhaled corticosteroid or with fewer daily inhalations of reliever medication. Budesonide/formoterol maintenance and reliever therapy was well tolerated with an incidence of adverse events similar to that with conventional regimens. Therefore, it offers a new approach to therapy in patients with uncontrolled, persistent asthma; providing improved efficacy with a lower overall drug load.

Effects of oral administration of controlled-ileal-release budesonide and assessment of pituitary-adrenocortical axis suppression in clinically normal dogs.

OBJECTIVE: To evaluate the effects of oral administration of controlled-ileal-release (CIR) budesonide on the pituitary-adrenal axis in dogs with a normal gastrointestinal mucosal barrier. ANIMALS: 10 healthy dogs. PROCEDURES: 5 dogs received CIR budesonide orally once daily for days 1 through 28, and 5 dogs received placebo. Treatment group dogs that weighed < 18 kg received 2 mg of CIR budesonide; treatment group dogs that weighed > or = 18 kg received 3 mg of CIR budesonide. In the treatment and placebo groups, there were 3 and 2 dogs, respectively, that weighed > 18 kg. Plasma cortisol concentration before and after ACTH stimulation, basal plasma endogenous ACTH concentration, and body weight were measured on days 0, 7, 14, 21, 28, and 35. Serum biochemical analysis, CBC determination, and urinalysis were performed on days 0, 28, and 35. On days 7, 14, and 21, serum ALP and ALT activities, serum glucose concentration, and urine specific gravity were obtained in lieu of a full hematologic evaluation and urinalysis. RESULTS: Basal and post-ACTH stimulation plasma cortisol concentrations and plasma endogenous ACTH concentration were significantly suppressed by treatment. No other variables were altered over the course of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Budesonide suppresses pituitary-adrenal function in dogs with normal gastrointestinal integrity, whereas other variables often affected by glucocorticoids were not altered by a 4-week treatment course. Budesonide may be a good alternative to traditional cortico-steroids if used short-term for acute exacerbations of inflammatory bowel disease.

Corticosteroids and adrenoceptor agonists: the compliments for combination therapy in chronic airways diseases.

The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used as maintenance therapy in patients with moderate to severe asthma or chronic obstructive pulmonary disease (COPD). The main effect of inhaled corticosteroids is thought to be mediated through suppression of airway inflammation, while long-acting beta2-adrenoceptor agonists are thought to work by inducing bronchodilation. However, there is emerging data to indicate that these two classes of drugs interact positively with each other, leading to added or perhaps synergistic benefits for patients. Corticosteroids enhance the expression of beta2-adrenoceptor, thus providing protection against desensitization and development of tolerance to beta2-adrenoceptor agonists, which may occur with prolonged use of these medications. Long-acting beta2-adrenoceptor agonists, on the other hand, may amplify the anti-inflammatory effects of corticosteroids by accelerating nuclear translocation of the glucocorticoid receptor complex, and enhancing transcription and expression of steroid-inducible genes in pro-inflammatory cells. In clinical trials, corticosteroids in combination with long-acting beta2-adrenoceptor agonists reduce exacerbation rates, and improve lung function and health status of patients with moderate to severe asthma or COPD beyond that achieved by individual component therapy. Their effects on mortality are unknown. There is a large clinical trial currently underway, which will provide mortality data by the year 2006. On balance, clinical evidence supports the use of combination therapy in moderate to severe asthma and COPD.

Effect of steroids on energy expenditure and substrate oxidation in women with Crohn's disease.

OBJECTIVE: Patients with Crohn's disease (CD) have increased energy expenditure and fat oxidation. Steroids, commonly used to treat flare-up of CD, induce weight gain. This study was designed to evaluate the effects of prednisone and budesonide on energy expenditure and substrate oxidation in patients with CD. METHODS: Twenty-nine women with CD and 10 healthy controls were studied. Ten patients received prednisone (0.75-1.0 mg/kg/day), nine received budesonide (9 mg/ day), and 10 did not receive steroids. Resting energy expenditure and substrate oxidation were measured by indirect calorimetry in a fasting state and after a standard diet. RESULTS: In the fasting state, resting energy expenditure was higher in patients without steroids than in the controls. Lipid oxidation was lower (p < 0.01) in patients with prednisone (0.46 +/- 0.39 mg/kg/min) than in patients with budesonide (0.97 +/- 0.28 mg/kg/min) and without steroids (1.06 +/- 0.32 mg/kg/min), but was similar with control subjects (0.47 +/- 0.20 mg/kg/min). Postprandially, lipid oxidation was lower (p < 0.01) in patients with prednisone (0.32 +/- 0.23 mg/kg/min) than in patients with budesonide (0.75 +/- 0.20 mg/kg/min), without steroids (0.82 +/- 0.23 mg/kg/min), and controls (0.58 +/- 0.15 mg/kg/min). Protein oxidation was significantly higher in patients with prednisone than in the other subjects. CONCLUSIONS: In women with CD, prednisone decreases lipid oxidation and increases protein oxidation. These effects are not observed with budesonide and may contribute to the weight gain and side effects commonly observed with prednisone. A low-fat/high-protein diet could be proposed during a course of prednisone.

Assessment of the systemic effects of budesonide inhaled from Easyhaler and from Turbuhaler in healthy male volunteers.

The main objective of this study was to show dose-dependent equivalence in the systemic activity of budesonide 800 microg day(-1) and 1600 microg day(-1) delivered from either Easyhaler or Turbuhaler in healthy male subjects. This single-centre study was carried out according to a randomized, double-blind, double-dummy, five-way crossover design over a 9-week period. All subjects received 1 week of treatment with the following, in randomized order, with a washout week between each treatment: budesonide Easyhaler 800 microg day(-1) plus placebo Turbuhaler; budesonide Easyhaler 1600 microg day(-1) plus placebo Turbuhaler; placebo Easyhaler plus Pulmicort Turbuhaler 800 microg day(-1); placebo Easyhaler plus Pulmicort Turbuhaler 1600 microg day(-1); placebo Easyhaler plus placebo Turbuhaler. The final inhalation of study drug was performed at the study centre, where blood and urine samples were collected. Fifteen subjects were recruited and all completed the study. Mean serum cortisol AUC0-20 values (the primary outcome variable) were comparable for each device at the two dose levels, and met the defined criteria for equivalence (90% CI 0.8-1.25 for between-treatment difference). Budesonide 800 microg day(-1) caused minimal suppression of serum cortisol AUC0-20 values, Budesonide 1600 microg day(-1) statistically significantly suppressed serum cortisol AUC0-20 values compared with placebo. Mean morning serum cortisol values were within the reference range in al treatment groups. At a budesonide dose of 800 microg day(-1) mean urine cortisol/creatinine ratio was statistically significantly higher with Easyhaler than with Turbuhaler, but there was no significant difference between the devices at the 1600 microg day(-1) dose. Serum budesonide concentrations were equivalent for each device at both dose levels. Adverse drug reactions were infrequent and mild in nature and there were no clinically significant changes in laboratory safety variables. In conclusion, in healthy male volunteers, budesonide 800 microg day(-1) and 1600 microg day inhaled from Easyhaler had comparable systemic effects to the same doses inhaled via Turbuhaler.

A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA-axis in healthy subjects.

AIMS: To investigate the effect on the hypothalamo-pituitary-adrenal (HPA) axis of treatment with budesonide, 400 microg once daily, morning or evening, or 200 microg twice daily, and 800 microg twice daily via Turbuhaler in a randomized, placebo-controlled, double-blind, double-dummy crossover study. METHODS: Healthy men received budesonide, 400 microg in the morning (08.00-09.00 h) or evening (20.00-21.00 h), budesonide, 200 microg twice daily, 800 microg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty-five subjects completed all treatments, and 27 were included in the analysis. RESULTS: The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 microg in the morning, 92% (83, 100) for 400 microg in the evening, 95% (86, 104) for 200 microg twice daily, and 76% (70, 84) for 800 microg twice daily. CONCLUSIONS: Budesonide at a dose of 400 microg day-1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 microg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.

A randomized controlled assessment of the systemic activity of budesonide when given once or twice daily via Turbuhaler.

OBJECTIVE: To compare the effects on the hypothalamo-pituitary-adrenal (HPA) axis of budesonide, delivered via Turbuhaler at doses of 800 microg once daily in the morning or evening or 400 microg twice daily. METHODS: Healthy men (n = 24) received four treatments in random order: budesonide, 800 Fg in the morning and placebo in the evening; budesonide, 800 microg in the evening and placebo in the morning; budesonide, 400 microg in the morning and evening; placebo in the morning and evening. Each treatment was given for 1 week, with a 2-week washout period between treatments. Blood samples for measurement of plasma cortisol were obtained before the evening dose on day 6 of each treatment period and over the following 22 h. RESULTS: All three budesonide regimens produced a statistically significant reduction (mean 16-19%) in the area under the curve of plasma cortisol concentration versus time over 22 h (AUC0-22h) compared with placebo. There were no statistically significant differences among the three regimens. These reductions in plasma cortisol concentrations were not considered to be clinically significant. Analysis of the fractional AUCs measured 0-10 h and 10-22 h after dosing showed that evening dosing had a greater effect on nocturnal cortisol than morning dosing; daytime cortisol was reduced by all treatments. CONCLUSION: There was no significant difference between the effects on plasma cortisol of budesonide 400 microg twice daily and 800 microg once daily in the morning or evening.

An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy.

The objective of the study was to develop an algorithm based on a pharmacokinetic-pharmacodynamic (PK/PD) modeling approach to quantify and predict cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. Two Excel spreadsheets, one for single dose and another for steady-state multiple doses of inhaled steroids, were developed for predicting CCS. Four of the commonly used inhaled steroids were chosen for the purposes of simulation: fluticasone propionate (FP), budesonide (BUD), flunisolide (FLU), and triamcinolone acetonide (TAA). Drug-specific PK and PD parameters were obtained from previous single- and multiple-dose studies. In cases in which multiple-dose data were not available, the single-dose data were extrapolated. The algorithm was designed to calculate CCS based on 5 input parameters: name of drug, dose, dosing interval, time(s) of dosing, and type of inhaler device. In addition, a generalized algorithm was set up to calculate CCS based on clearance, volume of distribution, absorption rate, protein binding, pulmonary deposition, oral bioavailability, and unbound EC50 of the corticosteroid of interest. The spreadsheet allowed predictions of CCS for single doses as well as steady-state conditions. A simple method has been developed that facilitates comparisons between various drugs and dosing regimens and has the potential to significantly reduce the number of comparative clinical trials to be performed for evaluating the short-term systemic activity of inhaled corticosteroids.