Budesonide Concentrations Research Articles

Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats.

The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases.

Respiratory syncytial virus induces leukotriene C4 synthase expression in bronchial epithelial cells

Respiratory syncytial virus (RSV) results in acute wheezing in infants and is frequently associated with recurrent wheezing. Although RSV-induced wheezing clinically resembles that of asthma, corticosteroids are not equivalently effective in RSV-associated wheezing. The study sought to determine the mechanisms of RSV-induced wheezing by establishing an in vitro model of RSV-infected human bronchial epithelial cells (16-HBEC). Leukotriene C4 synthase (LTC4 S) messenger RNA (mRNA) expression in 16-HBEC was detected using fluorescence quantitative polymerase chain reaction, and the relative level of LTC4 S mRNA was expressed as quotient cycle threshold (qCt) based on the threshold cycle number value compared with that of β-actin. Cysteinyl leukotrienes (CysLT) in culture supernatant were measured by enzyme-linked immunosorbent assay. RSV-infected 16-HBEC was incubated with gradient concentration of budesonide (BUD) to assess its effects on LTC4 S expression and CysLT secretion. RSV infection resulted in increased LTC4 S mRNA expression between 48 and 96 h post-infection. High level of CysLT was detected in the supernatant of RSV-infected 16-HBEC. BUD at concentrations of 10(-10) to 10(-5) mol/L did not significantly alter LTC4 S mRNA expression. RSV infection upregulated LTC4 S expression in HBEC leading to increased CysLT secretion. Such induction was not attenuated by BUD, suggesting that CysLT might contribute to the pathogenesis of RSV-induced wheezing.

Plasma concentrations and therapeutic effects of budesonide in dogs with inflammatory bowel disease

To evaluate the pharmacokinetics and clinical efficacy of budesonide in dogs with inflammatory bowel disease (IBD). 11 dogs (mean ± SD age, 5.7 ± 3.9 years; various breeds and body weights) with moderate or severe IBD. Each dog received a controlled-release formulation of budesonide (3 mg/m(2), PO, q 24 h) for 30 days (first day of administration was day 1). The concentration of budesonide and its metabolite (16-α-hydroxyprednisolone) was measured via liquid chromatography-tandem mass spectrometry in plasma and urine samples obtained on days 1 and 8 of treatment. On those days, plasma samples were obtained before the daily budesonide administration and 0.5, 1, 2, 4, and 7 hours after drug administration, whereas urine samples were obtained after collection of the last blood sample. A clinical evaluation was performed on the dogs before onset of drug administration and on days 20 and 30 after start of drug administration. The highest plasma concentration of budesonide and 16-α-hydroxyprednisolone on day 1 was detected at 1 hour and at 2 hours after drug administration, respectively. After standardization on the basis of specific gravity, the ratio between urinary concentrations of budesonide and 16-α-hydroxyprednisolone was 0.006 and 0.012 on days 1 and 8, respectively. The clinical response was adequate in 8 of 11 dogs. Budesonide was rapidly absorbed and metabolized in dogs with IBD. The drug gradually accumulated, and there was an adequate therapeutic response and no adverse effects.

Biophysical interaction between corticosteroids and natural surfactant preparation: implications for pulmonary drug delivery using surfactant a a carrier.

Intratracheal administration of corticosteroids using a natural pulmonary surfactant as a delivery vehicle has recently received significant attention in hopes of treating premature newborns with or at high risk for chronic lung disease. As a new practice, both the surfactant preparation used as the carrier and the corticosteroid delivered as the anti-inflammatory agent, and their mixing ratios, have not been standardized and optimized. Given the concern that corticosteroids delivered via a pulmonary surfactant may compromise its surface activity and thus worsen lung mechanics, the present study was carried out to characterize the biophysical interaction between a natural surfactant preparation, Infasurf, and two commonly used inhaled corticosteroids, budesonide and beclomethasone dipropionate (BDP). Based on surface activity measurements by the Langmuir balance and lateral film structure studied by atomic force microscopy, our findings suggest that when Infasurf is used as a carrier, a budesonide concentration less than 1 wt% of surfactant or a BDP concentration up to 10 wt % should not significantly affect the biophysical properties of Infasurf, thus being feasible for pulmonary delivery. Increasing corticosteroid concentration beyond this range leads to early collapse of the surfactant film due to increased film fluidization. Our study further suggests that different affinities to the surfactant films are responsible for the different behavior of budesonide and BDP. In addition to the translational value in treating chronic lung disease, this study may also have implications in inhaled steroid therapy to treat asthma.

Inflammatory Stimuli Inhibit Glucocorticoid-Dependent Transactivation in Human Pulmonary Epithelial Cells: Rescue by Long-Acting β2-Adrenoceptor Agonists

By repressing inflammatory gene expression, glucocorticoids are the most effective treatment for chronic inflammatory diseases such as asthma. However, in some patients with severe disease, or who smoke or suffer from chronic obstructive pulmonary disease, glucocorticoids are poorly effective. Although many investigators focus on defects in the repression of inflammatory gene expression, glucocorticoids also induce (transactivate) the expression of numerous genes to elicit anti-inflammatory effects. Using human bronchial epithelial (BEAS-2B) and pulmonary (A549) cells, we show that cytokines [tumor necrosis factor α (TNFα) and interleukin 1β], mitogens [fetal calf serum (FCS) and phorbol ester], cigarette smoke, and a G(q)-linked G protein-coupled receptor agonist attenuate simple glucocorticoid response element (GRE)-dependent transcription. With TNFα and FCS, this effect was not overcome by increasing concentrations of dexamethasone, budesonide, or fluticasone propionate. Thus, the maximal ability of the glucocorticoid to promote GRE-dependent transcription was reduced, and this was shown additionally for the glucocorticoid-induced gene p57(KIP2). The long-acting β(2)-adrenoceptor agonists (LABAs) formoterol fumarate and salmeterol xinafoate enhanced simple GRE-dependent transcription to a level that could not be achieved by glucocorticoid alone. In the presence of TNFα or FCS, which repressed glucocorticoid responsiveness, these LABAs restored glucocorticoid-dependent transcription to levels that were achieved by glucocorticoid alone. Given the existence of genes, such as p57(KIP2), which may mediate anti-inflammatory actions of glucocorticoids, we propose that repression of transactivation represents a mechanism for glucocorticoid resistance and for understanding the clinical benefit of LABAs as an add-on therapy in asthma and chronic obstructive pulmonary disease.

Effect of budesonide on TGF‐β1‐enhanced VEGF production by lung fibroblasts

VEGF (vascular endothelial growth factor) is a potent proangiogenic cytokine, and vascular change is one of the characteristic features of airway remodelling. Since the glucocorticoids have shown antifibrosis properties, we sought to investigate whether budesonide, a widely used glucocorticoid in clinical practice, could attenuate TGF-beta1 (transforming growth factor-beta1)-induced VEGF production by HFL-1 (human lung fibroblasts). HFL-1 fibroblasts were treated with various concentrations of budesonide (10(-11) M, 10(-9) M and 10(-7) M) in the absence or presence of TGF-beta1. Postculture media were collected for ELISA of VEGF at the indicated times. The cell lysates were subjected to Western blotting analysis to test TGF-beta1/Smad and MAP (mitogen-activated protein) kinase signalling activation, respectively. The results suggested that budesonide pretreatment reduced the significant increase of VEGF release induced by TGF-beta1 in HFL-1 fibroblasts in a dose-dependent manner, and suppressed the increase of phospho-Smad3 and phosphor-ERK (extracellular signal-regulated kinase) protein levels. In conclusion, budesonide may reduce TGF-beta1-induced VEGF production in the lung, probably through the Smad/ERK signalling pathway and, thus, may provide new sight into the molecular mechanism underlying glucocorticoid therapy for airway inflammatory diseases.

The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial

BackgroundAirway absorption and bioavailability of inhaled corticosteroids (ICSs) may be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting β2-agonists, formoterol and salmeterol.MethodsThis was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 μg) and salmeterol/fluticasone (50/500 μg), separated by a 4–14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects.ResultsMean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 μM·hr versus 6.21 μM·hr) and fluticasone (0.84 μM·hr versus 1.50 μM·hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 μM versus 0.09 μM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated.ConclusionThe relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide.Trial registrationTrial registration number NCT00379028

Procaterol Potentiates the Anti-Inflammatory Activity of Budesonide on Eosinophil Adhesion to Lung Fibroblasts

Background: The interaction between leukocytes and various parenchymal cells is the first step of inflammation. Therefore, the adhesion of eosinophils to lung fibroblasts is thought to be a crucial step in the inflammatory process of asthma. Procaterol, a β₂-selective full agonist, is currently prescribed for patients with asthma. In addition to its potent bronchodilatory action, the agonist has been reported to have anti-inflammatory actions. In this study, to examine whether procaterol can potentiate the anti-inflammatory action of glucocorticoids, the effect of procaterol on eosinophil adhesion to normal human lung fibroblasts (NHLF) was assessed in the presence and absence of budesonide, one of the most potent glucocorticoids. Methods: Following pretreatment of NHLF with tumor necrosis factor-α (TNF-α) in the presence of various concentrations of procaterol and/or budesonide, the eotaxin-stimulated eosinophil adhesion was determined using the peroxidase activity of eosinophils. To investigate the mechanism of the inhibitory action of procaterol, TNF-α-induced expression of adhesion molecules, ICAM-1 and VCAM-1, in NHLF was also evaluated. Results: Pretreatment with procaterol inhibited the adhesion of eosinophils to NHLF in a concentration-dependent manner, and shifted the concentration-response curve of budesonide to the left. Both procaterol and budesonide resulted in concentration-dependent inhibition of expression of ICAM-1 and VCAM-1 in NHLF, and an additive inhibitory effect was found when the agents were combined. Conclusions: Given the results of this study which indicated that procaterol exerted an additive action on the anti-inflammatory effect of budesonide, procaterol and glucocorticoids may provide better control for asthma when used together than when used separately.

Budesonide/formoterol effects on metalloproteolytic balance in TGF β-activated human lung fibroblasts

In the airways of asthmatic patients, activated fibroblasts account for an excessive matrix production including proteoglycans (PGs). Transforming growth factor-beta (TGFbeta), metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in matrix turnover. It is unclear whether asthma therapy with combination of inhaled glucocorticoids and long-acting beta(2)-agonists affects metalloproteolytic equilibrium and by that counteracts airway fibrosis. The effects of the glucocorticoid, budesonide, and the long-acting beta(2)-agonist, formoterol, on the PG production and the activity of PGs' main regulators: MMP-3, MMP-9, MMP-2 and TIMP-1 were investigated in human lung fibroblasts (HFL-1) treated for 24h with TGFbeta1 (10 ng/ml) without/with budesonide (10(-9) to 10(-6)M) and/or formoterol (10(-11) to 10(-6)M). TGFbeta1 significantly increased production of PGs and TIMP-1, and the activity of MMP-3, MMP-9 and MMP-2. Concurrent budesonide/formoterol combination counteracted the enhanced: PG and TIMP-1 production, MMP-9 activity and MMP-9/TIMP-1 ratio, whereas MMP-2 and MMP-3 were not affected and so their ratios to TIMP-1 were significantly increased. Budesonide or formoterol alone achieved equal effects as budesonide/formoterol on MMP-9 and MMP-9/TIMP-1 ratio but had no effects on TIMP-1, MMP-2 or MMP-3. In the formoterol absence, higher budesonide concentrations were required to reduce the PG production, whereas formoterol alone had no effects. These results suggest that the budesonide/formoterol combination enhanced metalloproteolytic activity of human lung fibroblasts via a synergistic decrease of TIMP-1, and that this mechanism may be involved in the synergistic inhibition of the TGFbeta1-induced PG production. This implies that budesonide/formoterol combination therapy can counteract excessive matrix production and thus pathological airway fibrotic remodeling in asthma.

Pharmacokinetics of Budesonide and Formoterol Administered Via 1 Pressurized Metered‐Dose Inhaler in Patients With Asthma and COPD

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Effect of COPD treatments on MRP1-mediated transport in bronchial epithelial cells

Smoking is the principle risk factor for development of chronic obstructive pulmonary disease (COPD). Multidrug resistance-associated protein 1 (MRP1) is known to protect against toxic compounds and oxidative stress, and might play a role in protection against smoke-induced disease progression. We questioned whether MRP1-mediated transport is influenced by pulmonary drugs that are commonly prescribed in COPD. The immortalized human bronchial epithelial cell line 16HBE14o- was used to analyze direct in vitro effects of budesonide, formoterol, ipratropium bromide and N-acetylcysteine (NAC) on MRP1-mediated transport. Carboxyfluorescein (CF) was used as a model MRP1 substrate and was measured with functional flow cytometry. Formoterol had a minor effect, whereas budesonide concentration-dependently decreased CF transport by MRP1. Remarkably, addition of formoterol to the highest concentration of budesonide increased CF transport. Ipratropium bromide inhibited CF transport at low concentrations and tended to increase CF transport at higher levels. NAC increased CF transport by MRP1 in a concentration-dependent manner. Our data suggest that, besides their positive effects on respiratory symptoms, budesonide, formoterol, ipratropium bromide, and NAC modulate MRP1 activity in bronchial epithelial cells. Further studies are required to assess whether stimulation of MRP1 activity is beneficial for long-term treatment of COPD.

Influence of CYP3A4, CYP3A5, and ABCB1 Genotype and Expression on Budesonide Pharmacokinetics: A Possible Role of Intestinal CYP3A4 Expression

Budesonide treatment of chronic inflammatory bowel disease commonly leads to non-response or adverse reactions, possibly because of alterations in efflux transport mediated by the ABCB1 gene product P-glycoprotein or metabolism by CYP3A isoenzymes. Two groups, each consisting of nine healthy volunteers, one with the CYP3A5(*)1/(*)3 genotype (expressors) and the other with the CYP3A5(*)3/(*)3 genotype (non-expressors), were given a single oral dose of 9 mg budesonide. Plasma and urine concentrations of budesonide and its major metabolites were determined using liquid chromatography-tandem mass spectrometry. Subsequently, rectosigmoidal biopsies were taken for analysis of messenger RNA (mRNA) expression. Budesonide pharmacokinetics did not differ between genotype groups. However, intestinal CYP3A4 expression was shown to correlate directly with partial metabolic clearances of 16-hydroxy-prednisolone (r(2) = 0.30; P = 0.010) and 6-hydroxy-budesonide (r(2) = 0.25; P = 0.016), but inversely with budesonide AUC(0-24 h) (r(2) = 0.18; P = 0.040). Interestingly, a strong correlation was found between CYP3A5 and ABCB1 expression in CYP3A5 expressors (r(2) = 0.79; P = 0.001). This study suggests that intestinal CYP3A4 expression has an impact on budesonide pharmacokinetics. Moreover, CYP3A5 and ABCB1 expression appears to be coregulated.

Interactive effects of steroids and β-agonists on accumulation of type 2 T cells

Airway inflammation associated with asthma has been reported to be either unaffected or slightly increased by inhaled beta-agonist monotherapy, and concerns regarding disease exacerbations with continuous long-acting beta-agonist monotherapy have prompted the recommendation of concomitant steroid treatment. Using peripheral blood lymphocytes from asthmatic subjects, we aimed to determine (1) whether short- or long-acting beta-agonists increase IL-13-producing (IL-13+ or IFN-gamma-producing (IFN-gamma+ T-cell numbers and (2) the ability of the corticosteroid budesonide to reverse these effects. Peripheral blood lymphocytes from asthmatic subjects were cultured 6 days ex vivo with IL-2 and various concentrations of albuterol, formoterol, and budesonide. Numbers of IL-13+ and IFN-gamma+ T cells were determined by means of flow cytometric analysis. Both albuterol and formoterol increased IL-2-stimulated accumulation of IL-13+ T cells, and this increase was highest at concentrations approximating the dissociation constant of each beta-agonist for the beta(2)-adrenergic receptor. Budesonide at greater than 1 nmol/L reversed the augmenting effects of beta-agonists on IL-13+ T-cell accumulation, and budesonide at greater than 10 nmol/L inhibited increases in IL-13+ T cells stimulated by IL-2. Budesonide decreased, whereas beta-agonist did not affect, numbers of total and IFN-gamma+ T cells in IL-2-stimulated cultures. beta-Agonists at physiologically and clinically relevant concentrations stimulate increased antigen-independent, cytokine-stimulated accumulation, specifically of type 2 T cells from asthmatic subjects. The corticosteroid budesonide potently reverses this effect.

Effect of High‐Dose Metronidazole on Pharmacokinetics of Oral Budesonide and Vice Versa: A Double Drug Interaction Study

Recent case reports suggest that addition of high-dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients with fistulizing Crohn's disease benefit by using high doses of metronidazole for prolonged periods, this study's primary aim was to evaluate the effect of high-dose metronidazole on the pharmacokinetics of oral budesonide, a sensitive substrate of CYP3A commonly prescribed in acute inflammatory bowel disease. Twelve healthy adults received 1.5 g metronidazole per day over 1 week. The CYP3A-dependent metabolic profile of an oral dose of budesonide (3 mg) and that of endogenous cortisol were compared intraindividually before and after administration of metronidazole. There was neither a significant effect of high-dose metronidazole on the area under the plasma concentration-time curve (AUC) of budesonide (90% confidence interval, 79%-115%) nor on the AUC ratios of 6beta-hydroxybudesonide/budesonide and 16alpha-hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6beta-hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%-100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.

Exposure of infants to budesonide through breast milk of asthmatic mothers

Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. These data support continued use of inhaled budesonide during breast-feeding.

Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstriction.

To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. Twenty people with mild asthma inhaled 1000 microg fluticasone (Accuhaler) plus 800 microg budesonide (Turbohaler) on two visits. On one occasion, prior to drug inhalation, FEV(1) was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. The mean difference in FEV(1) prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36-75) and 29% (IQR 2-44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma.

A 12-week, multicenter, randomized, partially blinded, active-controlled, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaled corticosteroids with a metered-dose or dry powder inhaler

Nebulized budesonide inhalation suspension (BIS) is approved in the United States for children with asthma aged 1 to 8 years. The primary objective of this study was to compare the efficacy of BIS 0.5 mg QD and 2.0 mg BID in terms of the mean change from baseline to end of treatment in predose forced expiratory volume in 1 second (FEV1). In this 12-week, partially blinded, randomized study, subjects aged >or=12 years with moderate to severe persistent asthma previously receiving inhaled corticosteroids (ICSs) by dry powder inhaler (DPI) or metered-dose inhaler (MDI) continued therapy during a 2- to 3-week run-in period and then switched to BIS 0.5 mg QD, 1.0 mg QD, 1.0 mg BID, or 2.0 mg BID, or budesonide DPI 400 microg BID (active reference arm). Besides FEV1 (the primary variable), other outcome variables included changes in forced vital capacity (FVC) from baseline to weeks 4, 8, and 12 and to the average over the treatment period; as well as changes from baseline to the end of treatment in diary-collected daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings due to asthma, morning and evening peak expiratory flow (PEF), percentages of symptom-free and medication-free periods, and the incidence of predefined asthma events. Adverse events were recorded by subjects. Steady-state pharmacokinetics of budesonide were assessed in all treatment arms. Efficacy analyses included data in a modified intent-to-treat approach. Differences in the change from baseline to end of treatment in FEV1 were assessed using analysis of covariance (ANCOVA). For secondary variables, changes from baseline to each visit or to the treatmentperiod average were compared among groups using an ANCOVA model. P <or= 0.05 was considered statistically significant. The randomized population consisted of 758 subjects: 57 (7.5%) aged 12 to <17 years, 667 (88.0%) aged 17 to <65 years, and 34 (4.5%) aged >or=65 years. There was no significant difference in mean change in predose FEV1 between BIS 0.5 mg QD and BIS 2.0 mg BID (0.02 vs 0.01 L). On average, mean values for the BIS dosage groups did not indicate any deterioration from baseline to the treatment period for variables associated with asthma control such as FEV1, FVC, daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings, morning and evening PEF, percentages of symptom-free and rescue medication-free periods, and predefined asthma events. The BIS 1.0-mg BID treatment appeared to be closest to budesonide DPI in plasma budesonide concentrations and improvement in predose FEV1 (0.08 vs 0.12 L). All treatments were well tolerated. In this study, no difference in efficacy between BIS 2.0 mg BID and 0.5 mg QD was found in adolescents and adults with persistent asthma when transitioned from ICSs delivered with a DPI or MDI. Subjects taking all BIS dosages experienced similar responses for variables associated with asthma control.

An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers

Budesonide, a glucocorticosteroid, is used as a first-line treatment for asthma. The aim of the study was to develop a PK/PD model for the effect of budesonide on ACTH and cortisol. The modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 microg budesonide (Pulmicort Turbohaler), with a wash-out period of 7 days between treatments. Baseline concentrations of cortisol and ACTH were measured after placebo treatment and concentrations of cortisol, ACTH and budesonide were assessed after budesonide treatment. A one-compartment disposition model was used for budesonide disposition. Based on indirect response models, two types of models, distinguishing between production driven by a sum of cosine functions and production driven by surges, were used in parallel to describe the data. The surge-based approach was the most appropriate, based on goodness-of-fit, objective function values and number of parameters. The surge-based model that integrated both ACTH and cortisol data was chosen as the final model. The estimated half-lives of endogenous ACTH and cortisol were 9 and 113 min, respectively. The budesonide and ACTH concentrations producing 50% of the maximal response (IC(50) and A(50)) were 0.325 microg l(-1) and 4.96 pmol l(-1). The present PK/PD model of the effect of budesonide on ACTH and cortisol can serve as a tool for further understanding of the hypothalamic-pituitary-adrenal (HPA) axis and be useful in the development of drugs interacting with the axis.

Pharmacokinetics and bone effects of budesonide in primary biliary cirrhosis

To evaluate the safety of budesonide in primary biliary cirrhosis. 77 primary biliary cirrhosis patients, with stages I-III at entry, were randomized to use either budesonide 6 mg and ursodeoxycholic acid 15 mg/kg (group A), or ursodeoxycholic acid alone (group B) daily for 3 years. In 22 patients, budesonide pharmacokinetics was determined after 3 years. Bone mass density was measured in 62 patients at baseline and 3 years; in 57 patients also liver biopsies were performed. At 3 years, no significant differences in the pharmacokinetics of budesonide were found between the patients with stages 0-I, II and III primary biliary cirrhosis. In group A, bone mass density in femoral neck and lumbar spine were decreased by 3.6% (P = 0.0002) and 2.8% (P = 0.003) from the baseline. In group B, the corresponding decreases were 1.9% (P = 0.029) and 0.7% (P = 0.25), but the differences between the groups were not statistically significant (P = 0.16 for femoral neck and P = 0.08 for lumbar spine). The plasma concentrations of budesonide do not significantly differ within stages I-III primary biliary cirrhosis patients. The combination of budesonide and ursodeoxycholic acid may decrease bone mass density in the femoral neck and lumbar spine in some primary biliary cirrhosis patients, and bone mass density is recommended to be monitored during budesonide therapy.

Airborne occupational contact dermatitis caused by extremely low concentrations of budesonide

Airborne occupational contact dermatitis caused by extremely low concentrations of budesonide