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1.  In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices 
Respiratory Research  2007;8(1):65.
Background
The therapeutic effect of inhaled corticosteroids (ICS) may be affected by the metabolism of the drug in the target organ. We investigated the in vitro metabolism of beclomethasone dipropionate (BDP), budesonide (BUD), ciclesonide (CIC), and fluticasone propionate (FP) in human lung precision-cut tissue slices. CIC, a new generation ICS, is hydrolyzed by esterases in the upper and lower airways to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC).
Methods
Lung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 μM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection.
Results
BDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP.
Conclusion
The in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.
doi:10.1186/1465-9921-8-65
PMCID: PMC2071910  PMID: 17883839
2.  Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate 
Mediators of Inflammation  1996;5(5):362-369.
At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a β2-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.
doi:10.1155/S096293519600052X
PMCID: PMC2365803  PMID: 18475731
3.  Neurally Mediated Airway Constriction in Human and Other Species: A Comparative Study Using Precision-Cut Lung Slices (PCLS) 
PLoS ONE  2012;7(10):e47344.
The peripheral airway innervation of the lower respiratory tract of mammals is not completely functionally characterized. Recently, we have shown in rats that precision-cut lung slices (PCLS) respond to electric field stimulation (EFS) and provide a useful model to study neural airway responses in distal airways. Since airway responses are known to exhibit considerable species differences, here we examined the neural responses of PCLS prepared from mice, rats, guinea pigs, sheep, marmosets and humans. Peripheral neurons were activated either by EFS or by capsaicin. Bronchoconstriction in response to identical EFS conditions varied between species in magnitude. Frequency response curves did reveal further species-dependent differences of nerve activation in PCLS. Atropine antagonized the EFS-induced bronchoconstriction in human, guinea pig, sheep, rat and marmoset PCLS, showing cholinergic responses. Capsaicin (10 µM) caused bronchoconstriction in human (4 from 7) and guinea pig lungs only, indicating excitatory non-adrenergic non-cholinergic responses (eNANC). However, this effect was notably smaller in human responder (30±7.1%) than in guinea pig (79±5.1%) PCLS. The transient receptor potential (TRP) channel blockers SKF96365 and ruthenium red antagonized airway contractions after exposure to EFS or capsaicin in guinea pigs. In conclusion, the different species show distinct patterns of nerve-mediated bronchoconstriction. In the most common experimental animals, i.e. in mice and rats, these responses differ considerably from those in humans. On the other hand, guinea pig and marmoset monkey mimic human responses well and may thus serve as clinically relevant models to study neural airway responses.
doi:10.1371/journal.pone.0047344
PMCID: PMC3467211  PMID: 23056631
4.  Comparison of Airway Responses in Sheep of Different Age in Precision-Cut Lung Slices (PCLS) 
PLoS ONE  2014;9(9):e97610.
Background
Animal models should display important characteristics of the human disease. Sheep have been considered particularly useful to study allergic airway responses to common natural antigens causing human asthma. A rationale of this study was to establish a model of ovine precision-cut lung slices (PCLS) for the in vitro measurement of airway responses in newborn and adult animals. We hypothesized that differences in airway reactivity in sheep are present at different ages.
Methods
Lambs were delivered spontaneously at term (147d) and adult sheep lived till 18 months. Viability of PCLS was confirmed by the MTT-test. To study airway provocations cumulative concentration-response curves were performed with different allergic response mediators and biogenic amines. In addition, electric field stimulation, passive sensitization with house dust mite (HDM) and mast cells staining were evaluated.
Results
PCLS from sheep were viable for at least three days. PCLS of newborn and adult sheep responded equally strong to methacholine and endothelin-1. The responses to serotonin, leukotriene D4 and U46619 differed with age. No airway contraction was evoked by histamine, except after cimetidine pretreatment. In response to EFS, airways in PCLS from adult and newborn sheep strongly contracted and these contractions were atropine sensitive. Passive sensitization with HDM evoked a weak early allergic response in PCLS from adult and newborn sheep, which notably was prolonged in airways from adult sheep. Only few mast cells were found in the lungs of non-sensitized sheep at both ages.
Conclusion
PCLS from sheep lungs represent a useful tool to study pharmacological airway responses for at least three days. Sheep seem well suited to study mechanisms of cholinergic airway contraction. The notable differences between newborn and adult sheep demonstrate the importance of age in such studies.
doi:10.1371/journal.pone.0097610
PMCID: PMC4167544  PMID: 25229890
5.  Regulation of CYP3A genes by glucocorticoids in human lung cells 
F1000Research  2013;2:173.
Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma.  However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung.  CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes.  However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined.  In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7.  There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
doi:10.12688/f1000research.2-173.v1
PMCID: PMC3869485  PMID: 24555085
6.  Regulation of CYP3A genes by glucocorticoids in human lung cells 
F1000Research  2013;2:173.
Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma.  However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung.  CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes.  However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined.  In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7.  There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.
doi:10.12688/f1000research.2-173.v2
PMCID: PMC3869485  PMID: 24555085
7.  Neurokinin receptors in recurrent airway obstruction: A comparative study of affected and unaffected horses 
The purpose of the study was to compare in vitro airway responses to neurokinin A & B (NKA and NKB) and expression of NK-2 receptors in airways of horses affected and unaffected with recurrent airway obstruction (RAO). Neurokinin-A, an inflammatory mediator belonging to the tachykinin family of neuropeptides, causes bronchoconstriction by binding to NK-2 receptors. Neurokinin-B is a lesser-known neuropeptide that acts on NK-3 receptors. Horses were placed into RAO-affected and RAO-unaffected groups based on their history, clinical scoring, and pulmonary function testing. Lung tissue from each lobe was collected for immunohistochemical staining for NK-2 receptors. Cumulative concentration-response relationships were determined on bronchial rings (4-mm wide) collected and prepared from the right diaphragmatic lung lobe to graded concentrations (half log molar concentrations 10−7M to 10−4M) of NKA and NKB. The results showed that NKA caused significantly greater contraction than NKB in both groups. In RAO-affected horses, both agents produced significantly greater bronchial contractions than those in the RAO-unaffected horses. Immunohistochemical staining showed that the overall NK-2 receptor distribution was significantly increased in bronchial epithelium and smooth muscles of bronchi and pulmonary vessels of RAO-affected than RAO-unaffected horses. The findings indicate that NK-2 receptors are up-regulated in RAO, suggesting that NK-2 receptor antagonists may have some therapeutic value in controlling the progression of airway hyperreactivity in horses affected with RAO.
PMCID: PMC2613593  PMID: 19337392
8.  The effects of inhaled beclomethasone dipropionate on lung function and histamine responsiveness in recurrently wheezy infants. 
Archives of Disease in Childhood  1995;73(4):327-332.
Inhaled steroids improve pulmonary function and bronchial responsiveness in older asthmatics. Data from studies using subjective outcome measures to determine the effectiveness of inhaled steroids in infants with recurrent wheezing are equivocal. Therefore, this study tested the hypothesis that beclomethasone dipropionate improves pulmonary function, including bronchial responsiveness to histamine, in recurrently wheezy infants. The study was double blind, placebo controlled lasting nine weeks. After the first baseline week, pulmonary function was measured using the rapid thoracoabdominal compression technique and bronchial responsiveness assessed with a histamine challenge test. Infants were then randomly allocated to receive doses of placebo or beclomethasone dipropionate (100 micrograms/puff) from metered aerosols. Two puffs of test aerosol were administered twice daily for eight weeks via a large volume spacer fitted with a facemask. Symptoms were recorded daily and pulmonary function and bronchial responsiveness assessed at the end of the treatment period; 50 infants, median age 12 months (range 5 to 18 months), were recruited. Twenty three in the beclomethasone dipropionate group and 15 in the placebo group completed the study and had pairs of pulmonary function measurements. Three were probable treatment failures (one beclomethasone dipropionate, two placebo), three were possible treatment failures (placebo), and others were non-compliant with study protocol. Baseline variables were not significantly different between those infants who completed the study and those who did not. Beclomethasone dipropionate and placebo groups were similar in all respects at baseline. Lung function and symptoms improved for both groups of infants during the study. Bronchial responsiveness increased significantly in the placebo group but there were not statistically significant differences between groups for any of the other outcome measures. It is concluded that beclomethasone dipropionate (400 microgram daily) via a large volume spacer does not significantly improve lung function or symptoms in recurrently wheezy infants but might hav a beneficial effect on bronchial responsiveness.
PMCID: PMC1511345  PMID: 7492197
9.  Comparison of fluticasone propionate and beclomethasone dipropionate on direct and indirect measurements of bronchial hyperresponsiveness in patients with stable asthma. 
Thorax  1995;50(10):1044-1050.
BACKGROUND--Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores, without increased systemic activity. The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness, assessed by both a direct (histamine) and an indirect (ultrasonically nebulised distilled water (UNDW)) provocation test. METHODS--Fluticasone propionate, 750 micrograms/day, and beclomethasone dipropionate, 1500 micrograms/day, were compared in a randomised, double blind, crossover study consisting of two six week treatment periods, each preceded by a three week single blind placebo period. Twenty one non-smoking asthmatics (mean forced expiratory volume in one second (FEV1) 74.7% predicted, mean PC20histamine 0.36 mg/ml) completed the study. RESULTS--Fluticasone propionate and beclomethasone dipropionate improved FEV1, peak flow rates, asthma symptoms, and bronchial hyperresponsiveness to the same extent. Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine (mean 2.29 [95% confidence interval 1.45 to 3.13] and 1.95 [1.07 to 2.84] doubling doses, respectively) and in PD20UNDW (1.12 [0.55 to 1.70] and 1.28 [0.88 to 1.70] doubling doses, respectively). Neither treatment changed morning serum cortisol levels, but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate, indicating smaller systemic effects of fluticasone propionate. CONCLUSIONS--These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness, assessed by provocation with both histamine and UNDW, without increased systemic activity.
Images
PMCID: PMC475016  PMID: 7491551
10.  Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse 
Respiratory Research  2006;7(1):65.
Background
It has been proposed that serotonin (5-HT)-mediated constriction of the murine trachea is largely dependent on acetylcholine (ACh) released from the epithelium. We recently demonstrated that ACh can be released from non-neuronal cells by corticosteroid-sensitive polyspecific organic cation transporters (OCTs), which are also expressed by airway epithelial cells. Hence, the hypothesis emerged that 5-HT evokes bronchoconstriction by inducing release of ACh from epithelial cells via OCTs.
Methods
We tested this hypothesis by analysing bronchoconstriction in precision-cut murine lung slices using OCT and muscarinic ACh receptor knockout mouse strains. Epithelial ACh content was measured by HPLC, and the tissue distribution of OCT isoforms was determined by immunohistochemistry.
Results
Epithelial ACh content was significantly higher in OCT1/2 double-knockout mice (42 ± 10 % of the content of the epithelium-denuded trachea, n = 9) than in wild-type mice (16.8 ± 3.6 %, n = 11). In wild-type mice, 5-HT (1 μM) caused a bronchoconstriction that slightly exceeded that evoked by muscarine (1 μM) in intact bronchi but amounted to only 66% of the response to muscarine after epithelium removal. 5-HT-induced bronchoconstriction was undiminished in M2/M3 muscarinic ACh receptor double-knockout mice which were entirely unresponsive to muscarine. Corticosterone (1 μM) significantly reduced 5-HT-induced bronchoconstriction in wild-type and OCT1/2 double-knockout mice, but not in OCT3 knockout mice. This effect persisted after removal of the bronchial epithelium. Immunohistochemistry localized OCT3 to the bronchial smooth muscle.
Conclusion
The doubling of airway epithelial ACh content in OCT1/2-/- mice is consistent with the concept that OCT1 and/or 2 mediate ACh release from the respiratory epithelium. This effect, however, does not contribute to 5-HT-induced constriction of murine intrapulmonary bronchi. Instead, this activity involves 1) a non-cholinergic epithelium-dependent component, and 2) direct stimulation of bronchial smooth muscle cells, a response which is partly sensitive to acutely administered corticosterone acting on OCT3. These data provide new insights into the mechanisms involved in 5-HT-induced bronchoconstriction, including novel information about non-genomic, acute effects of corticosteroids on bronchoconstriction.
doi:10.1186/1465-9921-7-65
PMCID: PMC1468398  PMID: 16608531
11.  Trichostatin A Abrogates Airway Constriction, but Not Inflammation, in Murine and Human Asthma Models 
Histone deacetylase (HDAC) inhibitors may offer novel approaches in the treatment of asthma. We postulate that trichostatin A (TSA), a Class 1 and 2 inhibitor of HDAC, inhibits airway hyperresponsiveness in antigen-challenged mice. Mice were sensitized and challenged with Aspergillus fumigatus antigen (AF) and treated with TSA, dexamethasone, or vehicle. Lung resistance (RL) and dynamic compliance were measured, and bronchial alveolar lavage fluid (BALF) was analyzed for numbers of leukocytes and concentrations of cytokines. Human precision-cut lung slices (PCLS) were treated with TSA and their agonist-induced bronchoconstriction was measured, and TSA-treated human airway smooth muscle (ASM) cells were evaluated for the agonist-induced activation of Rho and intracellular release of Ca2+. The activity of HDAC in murine lungs was enhanced by antigen and abrogated by TSA. TSA also inhibited methacholine (Mch)-induced increases in RL and decreases in dynamic compliance in naive control mice and in AF-sensitized and -challenged mice. Total cell counts, concentrations of IL-4, and numbers of eosinophils in BALF were unchanged in mice treated with TSA or vehicle, whereas dexamethasone inhibited the numbers of eosinophils in BALF and concentrations of IL-4. TSA inhibited the carbachol-induced contraction of PCLS. Treatment with TSA inhibited the intracellular release of Ca2+ in ASM cells in response to histamine, without affecting the activation of Rho. The inhibition of HDAC abrogates airway hyperresponsiveness to Mch in both naive and antigen-challenged mice. TSA inhibits the agonist-induced contraction of PCLS and mobilization of Ca2+ in ASM cells. Thus, HDAC inhibitors demonstrate a mechanism of action distinct from that of anti-inflammatory agents such as steroids, and represent a promising therapeutic agent for airway disease.
doi:10.1165/rcmb.2010-0276OC
PMCID: PMC3297166  PMID: 22298527
HDAC; asthma; allergen; mice; trichostatin A
12.  Systemic activity of inhaled and swallowed beclomethasone dipropionate and the effect of different inhaler devices. 
Postgraduate Medical Journal  1998;74(877):675-677.
Inhaled glucocorticoids such as beclomethasone dipropionate, which are used in the treatment of asthma, may be associated with systemic adverse effects. To determine whether any systemic absorption following the inhalation of beclomethasone was a result of drug being absorbed from the lung (inhaled fraction) or the gastrointestinal tract (swallowed fraction), we studied normal subjects after the inhalation or swallowing of 2 mg beclomethasone dipropionate. Systemic activity was assessed using early morning cortisol suppression. Both inhaled and swallowed fractions produced significant systemic activity, the degree of which depended on the inhaler device used. Systemic activity was greater using a dry powder inhaler (52%) than using a metered dose inhaler with a large volume spacer (28%). These findings suggest that to limit potential adverse effects from high-dose beclomethasone dipropionate it is better to use a metered dose aerosol with large volume spacer than a dry powder.
PMCID: PMC2431615  PMID: 10197215
13.  Secretoglobin 1A1 and 1A1A Differentially Regulate Neutrophil Reactive Oxygen Species Production, Phagocytosis and Extracellular Trap Formation 
PLoS ONE  2014;9(4):e96217.
Secretoglobin family 1A member 1 (SCGB 1A1) is a small protein mainly secreted by mucosal epithelial cells of the lungs and uterus. SCGB 1A1, also known as club (Clara) cell secretory protein, represents a major constituent of airway surface fluid. The protein has anti-inflammatory properties, and its concentration is reduced in equine recurrent airway obstruction (RAO) and human asthma. RAO is characterized by reversible airway obstruction, bronchoconstriction and neutrophilic inflammation. Direct effects of SCGB 1A1 on neutrophil functions are unknown. We have recently identified that the SCGB1A1 gene is triplicated in equids and gives rise to two distinct proteins. In this study we produced the endogenously expressed forms of SCGBs (SCGB 1A1 and 1A1A) as recombinant proteins, and analyzed their effects on reactive oxygen species production, phagocytosis, chemotaxis and neutrophil extracellular trap (NET) formation ex vivo. We further evaluated whether NETs are present in vivo in control and inflamed lungs. Our data show that SCGB 1A1A but not SCGB 1A1 increase neutrophil oxidative burst and phagocytosis; and that both proteins markedly reduce neutrophil chemotaxis. SCGB 1A1A reduced chemotaxis significantly more than SCGB 1A1. NET formation was significantly reduced in a time- and concentration-dependent manner by SCGB 1A1 and 1A1A. SCGB mRNA in bronchial biopsies, and protein concentration in bronchoalveolar lavage fluid, was lower in horses with RAO. NETs were present in bronchoalveolar lavage fluid from horses with exacerbated RAO, but not in fluid from horses with RAO in remission or in challenged healthy horses. These findings indicate that SCGB 1A1 and 1A1A have overlapping and diverging functions. Considering disparities in the relative abundance of SCGB 1A1 and 1A1A in airway secretions of animals with RAO suggests that these functional differences may contribute to the pathogenesis of RAO and other neutrophilic inflammatory lung diseases.
doi:10.1371/journal.pone.0096217
PMCID: PMC4002474  PMID: 24777050
14.  The effects of long-acting β2-agonists plus inhaled corticosteroids for early reversibility in patients with airway obstruction 
Journal of Thoracic Disease  2013;5(4):461-465.
Background
Salbutamol, as a short-acting β2-agonist, was popularly used in the past for detection of reversibility in patients with airway obstruction when it was the only drug available in the treatment of airway obstruction. Today, the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids are the first choice of therapy, with or without the presence of reversibility, in patients with airway obstruction. We aimed to compare the efficacy of salbutamol and long acting β2-agonists plus inhaled glucocorticoids for early reversibility test in patients with airway obstruction.
Methods
Symptomatic patients (cough, dyspnea, and/or wheezing) with airway obstruction according to pulmonary function testing (FEV1/FVC value less than 70% of expected) who had never used bronchodilators before or had not received short- or long-acting inhaled bronchodilator therapy within the most recent 12 hours were evaluated. Reversibility measurements were made by administering the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids after 15 minutes.
Results
A total of 90 patients were evaluated. The mean age of patients was 57.3±17.7 (range, 8-88) years and the male-to-female ratio was 69/21. The baseline pulmonary function test results were mean FVC; 2,747±1,181 mL and 74.7%±21.4%, mean FEV1; 1,716±825 mL and 57.5%±19.0%, mean FEV1/FVC; 61.4%±7.4%. The bronchodilator drugs given before reversibility testing were as salmeterol/fluticasone (FTC/SAL), formoterol/budesonide (BUD/FOR), beclomethasone dipropionate/formoterol (BDP/FOR) and salbutamol (SLB) in 24, 22, 24 and 20 patients, respectively. The reversibility was positive in 33 (36.7%) patients. The absolute change and percentage of change in mean FEV1 were 206±252 mL, 13.2%±16.6% for FTC/SAL group, 273±201 mL, 14%±8% for BUD/FOR group, 240±151 mL, 18.7%±15.9% for BUD/FOR groupand 171±116 mL, 13.3%±11.8% for SLB group. There was no statistically significant for reversibilty results between LABAs/inhaledsteroids and SLB group. And the patients with positivere versibility test were significantly higher in both of BUD/FOR and BDP/FOR groups than SLB group.
Conclusions
We think that performance of an early reversibility test using the combination of a LABA and an inhaled corticosteroid for treatment would enhance both the education of the patient in using the device and the reliability of the drug. And, we suggest that: “you should make the reversibility test with Long-Acting β2-Agonists plus Inhaled Corticosteroids which used in treatment of obstructive lung diseases”.
doi:10.3978/j.issn.2072-1439.2013.08.22
PMCID: PMC3755673  PMID: 23991303
Salmeterol/fluticasone; formoterol/budesonide; beclomethasone dipropionat/formoterol; salbutamol; pulmonary function test; reversibility
15.  Lung Deposition of BDP/Formoterol HFA pMDI in Healthy Volunteers, Asthmatic, and COPD Patients 
Abstract
Background
When inhaling medication, it is essential that drug particles are delivered to all sites of lung inflammation, including the peripheral airways. The aim of this study was to assess the lung deposition and lung distribution of beclomethasone dipropionate (BDP)/formoterol (100/6 μg), both dissolved in hydrofluoroalkane (HFA) and delivered by pressurized metered dose inhaler (pMDI) in healthy subjects, asthmatic, and chronic obstructive pulmonary disease (COPD) patients, to investigate how the in vitro characteristics of the formulation translate into the in vivo performance in diseases with different airway obstruction.
Methods
Healthy volunteers (n = 8), persistent asthmatics (n = 8), and patients with stable COPD (n = 8) completed this open-label, single-dose parallel-group study. Each patient received one single treatment of four puffs of 99 mTc-labeled BDP/formoterol formulation. The correlation between particle size distribution of radioactivity and of the drugs in the radiolabeled formulation was validated. Intra- and extrapulmonary deposition, amount of exhaled drug, and the central to peripheral ratio (C/P) were calculated immediately after inhalation. Patients' lung function and pharmacokinetic parameters were also assessed up to 24 h post-dose.
Results
The average lung deposition of BDP/formoterol was 34.08 ± 9.30% (relative to nominal dose) in healthy subjects, 30.86 ± 8.89% in asthmatics, and 33.10 ± 8.90% in COPD patients. Extrathoracic deposition was 53.48% ± 8.95, 57.64% ± 9.92 and 54.98% ± 7.01, respectively. C/P ratios of 1.42 ± 0.32 in healthy subjects, 1.96 ± 0.43 in asthmatics, and 1.94 ± 0.69 for COPD patients confirmed drug distribution to all regions of the lungs. Forced expiratory volume in 1 sec (FEV1) increased in all groups after BDP/formoterol inhalation, but was more evident in the patient groups. No significant correlation between baseline lung function and drug deposition was observed. Formoterol, BDP, and beclomethasone 17 monopropionate (B17MP) plasma profiles were comparable between groups.
Conclusion
Inhalation of BDP/formoterol HFA (100/6 μg) produces high and homogeneous deposition of BDP and formoterol in the airways, regardless of pathophysiological condition.
doi:10.1089/jamp.2009.0772
PMCID: PMC3123836  PMID: 20109122
asthma; beclomethasone dipropionate; chronic obstructive pulmonary disease; extra fine; formoterol; hydrofluoroalkane; lung deposition; small airways
16.  Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients 
Thorax  2002;57(10):885-888.
Background: There is evidence that the bronchial microcirculation has the potential to contribute to the pathophysiological mechanisms of exercise induced bronchoconstriction (EIB) in asthmatic subjects. Vascular endothelial growth factor (VEGF), which is highly expressed in asthmatic airways, increases vascular permeability. The relationship between VEGF levels in induced sputum and the severity of EIB in asthmatic subjects was studied.
Methods: The concentration of VEGF in induced sputum was examined in 23 asthmatic subjects and 11 normal controls. The asthmatic subjects performed an exercise test and the % maximal fall in forced expiratory volume in 1 second (FEV1) was measured. Beclomethasone dipropionate (BDP) 400 µg twice daily was administered to the asthmatic subjects for 8 weeks and the exercise test and sputum induction were repeated.
Results: The concentration of VEGF in induced sputum was significantly higher in asthmatic subjects than in normal controls. There was a significant correlation between the concentration of VEGF and the % maximal fall in FEV1 (r=0.826, p=0.0001) and between the concentration of VEGF and airway vascular permeability index (r=0.621, p=0.0037). After treatment with inhaled BDP there was a significant decrease in the concentration of VEGF in the asthmatic subjects (before treatment: 7051 (2361) pg/ml, after treatment: 4498 (2135) pg/ml, p<0.0001). The change in the concentration of VEGF was significantly correlated with the change in the % maximal fall in FEV1 (r=0.463, p=0.031).
Conclusions: Excessive production of VEGF in asthmatic airways may contribute to the pathogenesis of EIB via increased airway vascular permeability.
doi:10.1136/thorax.57.10.885
PMCID: PMC1746203  PMID: 12324676
17.  Comparison of the efficacy and safety of inhaled fluticasone propionate 200 micrograms/day with inhaled beclomethasone dipropionate 400 micrograms/day in mild and moderate asthma. 
Archives of Disease in Childhood  1993;69(2):206-211.
This study was designed to compare the efficacy and safety of a new inhaled corticosteroid, fluticasone propionate at a total daily dose of 200 micrograms, with beclomethasone dipropionate 400 micrograms/day in childhood asthma. A total of 398 asthmatic children (aged 4-19 years) were randomised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler. During the study the patients recorded morning and evening peak expiratory flow rate (PEFR), symptom scores, and use of beta 2 agonist rescue medication. In addition, clinic visit PEFR and forced expiratory volume in one second were measured. Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment. For the purposes of analysis the diary card data were grouped into three periods: week 3 (days 15-21), week 6 (days 36-42), and weeks 1-6 (days 1-42). The results showed no significant difference between treatments on most efficacy parameters. However, there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 (fluticasone propionate 6.1%, beclomethasone dipropionate 3.9%) and at week 6 (fluticasone propionate 8.3%, beclomethasone dipropionate 5. 9%) and % predicted evening PEFR at week 6 (fluticasone propionate 7.3%, beclomethasone dipropionate 4.9% and over weeks 1-6 (fluticasone propionate 5.5%, beclomethasone dipropionate 3.6%. Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 81%) and % days without rescue medication at week 6 (fluticasone propionate 87%, beclomethasone dipropionate 80%) and over weeks 1-6 (fluticasone propionate 80%, beclomethasone dipropionate 73%). Except for a higher incidence of sore throat in the fluticasone propionate group, the two treatments did not differ with regard to safety. There was no evidence of adrenal suppression with either treatment. In conclusion, fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma.
PMCID: PMC1029458  PMID: 8215522
18.  Bronchoconstriction Induces TGF-β Release and Airway Remodelling in Guinea Pig Lung Slices 
PLoS ONE  2013;8(6):e65580.
Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin) after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A) or TGF-β receptor kinase (SB431542) prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl) mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.
doi:10.1371/journal.pone.0065580
PMCID: PMC3694103  PMID: 23840342
19.  Multiple secretoglobin 1A1 genes are differentially expressed in horses 
BMC Genomics  2012;13:712.
Background
Secretoglobin 1A1 (SCGB 1A1), also called Clara cell secretory protein, is the most abundantly secreted protein of the airway. The SCGB1A1 gene has been characterized in mammals as a single copy in the genome. However, analysis of the equine genome suggested that horses might have multiple SCGB1A1 gene copies. Non-ciliated lung epithelial cells produce SCGB 1A1 during inhalation of noxious substances to counter airway inflammation. Airway fluid and lung tissue of horses with recurrent airway obstruction (RAO), a chronic inflammatory lung disease affecting mature horses similar to environmentally induced asthma of humans, have reduced total SCGB 1A1 concentration. Herein, we investigated whether horses have distinct expressed SCGB1A1 genes; whether the transcripts are differentially expressed in tissues and in inflammatory lung disease; and whether there is cell specific protein expression in tissues.
Results
We identified three SCGB1A1 gene copies on equine chromosome 12, contained within a 512-kilobase region. Bioinformatic analysis showed that SCGB1A1 genes differ from each other by 8 to 10 nucleotides, and that they code for different proteins. Transcripts were detected for SCGB1A1 and SCGB1A1A, but not for SCGB1A1P. The SCGB1A1P gene had most inter-individual variability and contained a non-sense mutation in many animals, suggesting that SCGB1A1P has evolved into a pseudogene. Analysis of SCGB1A1 and SCGB1A1A sequences by endpoint-limiting dilution PCR identified a consistent difference affecting 3 bp within exon 2, which served as a gene-specific “signature”. Assessment of gene- and organ-specific expression by semiquantitative RT-PCR of 33 tissues showed strong expression of SCGB1A1 and SCGB1A1A in lung, uterus, Fallopian tube and mammary gland, which correlated with detection of SCGB 1A1 protein by immunohistochemistry. Significantly altered expression of the ratio of SCGB1A1A to SCGB1A1 was detected in RAO-affected animals compared to controls, suggesting different roles for SCGB 1A1 and SCGB 1A1A in this inflammatory condition.
Conclusions
This is the first report of three SCGB1A1 genes in a mammal. The two expressed genes code for proteins predicted to differ in function. Alterations in the gene expression ratio in RAO suggest cell and tissue specific regulation and functions. These findings may be important for understanding of lung and reproductive conditions.
doi:10.1186/1471-2164-13-712
PMCID: PMC3556144  PMID: 23253434
CC10; Clara cell; Clara cell secretory protein; End-point limiting dilution PCR; Horse; Immunohistochemistry; Long-range PCR; Recurrent airway obstruction; Uteroglobin
20.  Delivery of beclomethasone dipropionate from a spacer device: what dose is available for inhalation? 
Thorax  1994;49(10):961-964.
BACKGROUND--It is common for inhaled steroids to be delivered through a large volume spacer device. Comparatively little is known about how this practice affects the dose of drug received by patients compared with drug delivered directly from a metered dose inhaler. METHODS--The amount of beclomethasone dipropionate, contained in particles of various size, available for inhalation from a 750 ml polycarbonate spacer (Volumatic) was determined by impinger measurement and high performance liquid chromatography. Three strengths of metered dose inhalers were studied (50 micrograms, 100 micrograms, and 250 micrograms/actuation). The effect of multiple actuations of beclomethasone dipropionate into a Volumatic spacer, and increasing residence times of drug within the spacer before inhalation, on the amount of drug available to the patient for inhalation was determined. RESULTS--The amount of beclomethasone dipropionate in particles < 5 microns when delivered by a spacer device or directly from a metered dose inhaler was similar. The total amount of beclomethasone dipropionate available for inhalation per actuation decreased by 20 micrograms with the 50 micrograms inhaler, 48 micrograms with the 100 micrograms inhaler, and 161 micrograms with the 250 micrograms inhaler, when given via the spacer compared with delivery directly from a metered dose inhaler. There was a progressive decrease in drug available for inhalation per actuation as the number of actuations into the spacer increased, for all strengths of beclomethasone dipropionate tested. A progressive decrease in drug recovered per actuation was also seen with increasing residence times of drug within the spacer before inhalation. CONCLUSIONS--Use of the spacer device significantly reduced the amount of nonrespirable beclomethasone dipropionate available for inhalation. The amount of beclomethasone dipropionate within respirable particles decreased considerably following multiple actuations into the spacer and with increasing residence times within the spacer before inhalation. When given via a spacer device beclomethasone dipropionate should be inhaled immediately after actuation and multiple actuations into the device should be avoided.
PMCID: PMC475229  PMID: 7974311
21.  Monitoring the initial pulmonary absorption of two different beclomethasone dipropionate aerosols employing a human lung reperfusion model 
Respiratory Research  2005;6(1):21.
Background
The pulmonary residence time of inhaled glucocorticoids as well as their rate and extend of absorption into systemic circulation are important facets of their efficacy-safety profile. We evaluated a novel approach to elucidate the pulmonary absorption of an inhaled glucocorticoid. Our objective was to monitor and compare the combined process of drug particle dissolution, pro-drug activation and time course of initial distribution from human lung tissue into plasma for two different glucocorticoid formulations.
Methods
We chose beclomethasone dipropionate (BDP) delivered by two different commercially available HFA-propelled metered dose inhalers (Sanasthmax®/Becloforte™ and Ventolair®/Qvar™). Initially we developed a simple dialysis model to assess the transfer of BDP and its active metabolite from human lung homogenate into human plasma. In a novel experimental setting we then administered the aerosols into the bronchus of an extracorporally ventilated and reperfused human lung lobe and monitored the concentrations of BDP and its metabolites in the reperfusion fluid.
Results
Unexpectedly, we observed differences between the two aerosol formulations Sanasthmax®/Becloforte™ and Ventolair®/Qvar™ in both the dialysis as well as in the human reperfusion model. The HFA-BDP formulated as Ventolair®/Qvar™ displayed a more rapid release from lung tissue compared to Sanasthmax®/Becloforte™. We succeeded to explain and illustrate the observed differences between the two aerosols with their unique particle topology and divergent dissolution behaviour in human bronchial fluid.
Conclusion
We conclude that though the ultrafine particles of Ventolair®/Qvar™ are beneficial for high lung deposition, they also yield a less desired more rapid systemic drug delivery. While the differences between Sanasthmax®/Becloforte™ and Ventolair®/Qvar™ were obvious in both the dialysis and lung perfusion experiments, the latter allowed to record time courses of pro-drug activation and distribution that were more consistent with results of comparable clinical trials. Thus, the extracorporally reperfused and ventilated human lung is a highly valuable physiological model to explore the lung pharmacokinetics of inhaled drugs.
doi:10.1186/1465-9921-6-21
PMCID: PMC555845  PMID: 15727687
22.  Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or non-corticosteroid treatment for two years 
Thorax  2001;56(4):272-278.
BACKGROUND—Inhaled corticosteroids are clearly beneficial for patients with asthma of moderate severity, but the risks and benefits of using them in patients with milder asthma are less clear. We have compared the change in bone mineral density over 2 years in adults with mild asthma randomised to receive an inhaled corticosteroid or non-corticosteroid treatment.
METHODS—Subjects with mild asthma (mean forced expiratory volume in one second (FEV1) 86% predicted, mean age 35 years, taking β agonists only) were randomised to receive inhaled budesonide, inhaled beclomethasone dipropionate, or non-corticosteroid treatment for 2 years in a prospective randomised open study in 19 centres in France, New Zealand, Spain, and the UK. The corticosteroid dose was adjusted according to a written self-management plan. The main outcome measure—change in bone mineral density after 6, 12, and 24 months—was measured "blind". Secondary outcomes included lung function, the relation between change in bone density and inhaled steroid dose and change in biochemical markers of bone metabolism.
RESULTS—Of 374 subjects randomised, 239 (64%) completed the study and were included in the analysis. The median daily doses of inhaled budesonide (n=87) and beclomethasone (n=74) were 389 µg and 499 µg, respectively. Subjects treated with an inhaled corticosteroid had better asthma control than those in the reference group (n=78). Change in bone mineral density did not differ between the three groups over the 2 years, nor did it correlate with changes in markers of bone metabolism. The mean change in bone mineral density over 2 years in the budesonide, beclomethasone dipropionate, and reference groups was 0.1%, -0.4%, and 0.4% for the lumbar spine and -0.9%, -0.9%, and -0.4% for neck of the femur. Mean daily dose of inhaled steroid was related to reduction in bone mineral density at the lumbar spine but not at the femoral neck.
CONCLUSION—In subjects with mild asthma an inhaled corticosteroid provided better asthma control than alternative non-corticosteroid treatment with no difference in change in bone mineral density over 2 years. The relation between dose of inhaled corticosteroid and change in bone density at the lumbar spine may be due to a direct effect of inhaled corticosteroids on bone. Since inhaled steroid dose is also related inversely to lung function, an effect of asthma severity on bone density was also possible.


doi:10.1136/thorax.56.4.272
PMCID: PMC1746016  PMID: 11254817
23.  Effect of inhaled glucocorticoids on IL-1 beta and IL-1 receptor antagonist (IL-1 ra) expression in asthmatic bronchial epithelium 
Thorax  1997;52(5):407-410.
BACKGROUND: Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and the existence of naturally occurring cytokine antagonists has added to this complexity. Upregulation of both interleukin 1 beta (IL-1 beta) and its naturally occurring receptor antagonist, interleukin 1 receptor antagonist (IL- 1ra), has previously been observed on asthmatic bronchial epithelium compared with normal airways. METHODS: The effect of inhaled beclomethasone dipropionate (BDP) on asthmatic bronchial epithelial expression of IL-1 beta and IL-1ra was studied. Frozen bronchial biopsy specimens from nine asthmatic subjects receiving 1000 micrograms BDP daily for eight weeks and from six asthmatic subjects receiving matching placebo were stained with anti-IL-1 beta and anti-IL-1ra antibodies. Hue-saturation-intensity (HSI) colour image analysis was used to quantify the brown immunoperoxidase reaction colour present on the bronchial epithelium. RESULTS: There was a significant twofold decrease in the epithelial expression of IL-1 beta after treatment with BDP but no significant change was seen in IL-1ra (P = 0.175). CONCLUSION: The selective inhibition of IL-1 beta, without effect on IL- 1ra, provides a novel mechanism for the anti-inflammatory action of glucocorticosteroids. 



PMCID: PMC1758566  PMID: 9176529
24.  Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. International Study Group. 
Thorax  1993;48(8):817-823.
BACKGROUND--High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma. Although effective, they may cause systemic side effects. Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses. METHODS--Fluticasone propionate, 1.5 mg per day, was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate. The study was multicentre, double blind and of a parallel design. For the first three months patients attended the clinic every four weeks and completed daily diary cards. For the next nine months they were only seen at three monthly intervals in the clinic. RESULTS--During the first three months diary card peak expiratory flow (PEF) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate (difference in morning PEF 15 l/min (95% CI 6 to 25)), and these differences were apparent at the end of the first week. The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8% compared with those receiving beclomethasone dipropionate. No significant differences between the two groups were observed in morning plasma cortisol levels, urinary free cortisol levels, or response to synthetic ACTH stimulation. In addition, both the rates of withdrawal and of adverse events were low, and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate. CONCLUSIONS--This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate, with no increase in systemic or other side effects.
PMCID: PMC464708  PMID: 8211872
25.  Effects of high doses of inhaled corticosteroids on adrenal function in children with severe persistent asthma. 
Thorax  1993;48(6):599-602.
BACKGROUND--Childhood asthma generally responds well to inhaled corticosteroids within the dosage range recommended by the manufacturers, but it is sometimes necessary to use higher doses--that is, above 400 micrograms/day--a practice which has become more widespread recently. Whereas the lack of adrenal suppression in children given inhaled corticosteroids in normal doses is well documented, little is known about the effects of higher doses. METHODS--The effects on adrenal function of high dose (above 400 micrograms/day) inhaled corticosteroids were evaluated by measuring cortisol concentration in the morning and performing a short tetracosactrin test in 49 children taking budesonide (mean age 9.2 years (range 4 to 16 years) and 28 children taking beclomethasone dipropionate (10.2 years (5 to 13 years)). Twenty three non-asthmatic children (8.9 years (4.9 to 13 years)) who were under investigation for short stature served as controls for the study. RESULTS--Compared with controls mean basal cortisol concentration was lower in children taking budesonide and beclomethasone dipropionate (control 401 (26.8) nmol/l, budesonide 284 (22) nmol/l, beclomethasone dipropionate 279 (23.2) nmol/l). Sixteen of the 49 children taking budesonide had subnormal basal cortisol concentrations compared with seven of the 28 taking beclomethasone dipropionate. Mean stimulated cortisol concentrations were lower in children taking inhaled corticosteroids than in controls, with no difference between those taking budesonide or beclomethasone dipropionate. CONCLUSIONS--Adrenal suppression occurs in some children who are given inhaled corticosteroids in doses greater than 400 micrograms/day. It may therefore be advisable to try alternative treatments before such doses are used.
PMCID: PMC464574  PMID: 8346487

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