Differential effects of inhaled budesonide and oral prednisolone on serum osteocalcin

Inhaled glucocorticosteroids have been developed for the treatment of asthma in an attempt to minimize the suppression of endogenous adrenal function that complicates oral or injected steroid usage, but it is unclear whether this strategy leads to reduced systemic complications in other areas, such as the skeleton. In this study we evaluated serum osteocalcin levels as a marker of skeletal metabolism in healthy volunteers treated with oral and inhaled steroids alone and in response to an oral calcitriol stimulation test. Forty subjects, aged 33 +/- 9 (mean +/- SD) yr were randomized to receive either high or low dose oral prednisolone (40 vs. 10 mg/day) or inhaled budesonide (3.2 vs. 0.8 mg/day). Each dose of budesonide is known to have a greater antiasthmatic potency than the dose of prednisolone with which it was compared. In addition 10 control subjects received placebos containing no active steroid drugs. During the second week of treatment, half of the subjects in each of the 4 steroid-treated groups and all subjects in the control group received oral calcitriol (2.0 micrograms/day). There was a marked dose-dependent reduction in serum cortisol levels, but this reduction was significantly less pronounced during budesonide treatment, such that low dose budesonide was without effect. During the first week of steroid therapy there were significant dose-dependent reductions in serum osteocalcin (P = 0.003), but this reduction was not significantly different between budesonide and prednisolone treatments. In response to calcitriol, serum osteocalcin increased by 35% in the control group (P = 0.06). Osteocalcin levels increased by 56% and 50% in the low dose budesonide and prednisolone groups and by 106% in the high dose budesonide group, but did not change in the high dose prednisolone group. The osteocalcin response to calcitriol was significantly higher in the budesonide groups (P = 0.03, by analysis of variance). High dose prednisolone caused increases in serum 1,25-dihydroxyvitamin D3 (P less than 0.02), urinary calcium excretion (P = 0.07), and urinary hydroxyproline (P less than 0.01). None of these changes was seen during budesonide therapy. There are as yet no data for these variables after long term use of inhaled budesonide in asthmatic patients, but our acute studies suggest that this potent topical glucocorticoid may have considerably less impact on the skeleton than oral prednisolone, even if used at doses high enough to suppress endogenous adrenal function.     

Does vitamin D administered to children with asthma treated with inhaled glucocorticoids affect short‐term growth or bone turnover?

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily.     

The effect of montelukast and different doses of budesonide on IgE serum levels and clinical parameters in children with newly diagnosed asthma

BACKGROUND: Since IgE is considered to play a crucial role in allergic immune responses, the reduction of free IgE level has been an attractive target in the treatment of allergic diseases. The present study was conducted to determine the effects of a 6-month treatment with different doses of inhaled budesonide and montelukast sodium in children with newly diagnosed atopic asthma. METHODS: In this randomized, double-blind, double-dummy trial, 51 children with newly diagnosed asthma and sensitivity to house-dust mites were randomly allocated to receive budesonide (in two different doses 400 or 800 mcg) or montelukast for 6 months. The primary end point was the level of serum total and specific IgE before and after treatment. The secondary end points were clinical parameters and forced expiratory volume in 1s (FEV1). RESULTS: After 6 months of treatment, a high dose of inhaled corticosteroid and montelukast, significantly decreased levels of total and specific IgE. Medium dose of inhaled corticosteroid had no effect on total and specific IgE serum level. Clinical score and FEV1 significantly improved after 6 months of treatment with medium (P = 0.002) and high dose (P = 0.001) of inhaled budesonide and montelukast (P = 0.002). There were no differences between groups in changes of all clinical parameters after treatment. CONCLUSION: Only high doses of inhaled corticosteroids and montelukast decreased the serum IgE levels. Perhaps long-term treatment with montelukast will be beneficial to asthma patients by decreasing IgE levels.     

Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma

BACKGROUND: Neutrophils, in addition to eosinophils, are prominent in the airways of patients with severe asthma who are usually on long-term oral and inhaled corticosteroid treatment. We determined whether inhaled or oral corticosteroid therapy can induce airway neutrophilia. METHODS: We performed two separate placebo-controlled studies in which patients with mild asthma were treated with either prednisolone (30mg per day for 7 days; n = 9) or placebo tablets (n = 8), or with either inhaled budesonide (800 microg twice daily for 4 weeks; n = 6) or inhaled placebo (n = 6). Fiberoptic bronchoscopy was performed before treatment and at day 7 of oral treatment, and at day 28 of inhaled therapy. Bronchial sections were immunostained with an antibody to major basic protein for eosinophils, and with an antibody to neutrophil elastase for neutrophils. Induced sputum was obtained in the prednisolone study. RESULTS: Neutrophils in airway submucosa increased after prednisolone from median 76 to 140/mm2 (P = 0.05); this change was higher than that after placebo (P = 0.04). Eosinophils decreased from 24 to 9/mm2 (P = 0.03), but this was not significantly different from placebo. Eosinophils and neutrophils, and levels of IL-8 and myeloperoxidase in induced sputum did not change after prednisolone. There was no change in neutrophil counts after budesonide, but the reduction in eosinophils was greater than placebo (P = 0.05). Budesonide improved bronchial responsiveness, but prednisolone did not. CONCLUSION: Corticosteroid therapy by the oral but not inhaled route can induce neutrophil recruitment into the airways of patients with mild asthma. This could explain the increase in airway neutrophils observed in severe asthmatics treated with oral corticosteroids.     

Genetic factors in bone turnover

Genetic factors are major determinants of adult bone density, however, it is unknown how these effects may be mediated. Since bone mineral density is the net result of bone formation and bone resorption we studied biochemical indices of bone formation (serum osteocalcin) and resorption [fasting urinary calcium:creatinine (Ca/Crt) and hydroxyproline:creatinine (OH/Crt)] in adult female twins; 39 monozygotic (MZ) and 31 dizygotic (DZ) twin pairs (age, mean +/- SEM, MZ: 51.1 +/- 1.5 yrs; DZ: 46.5 +/- 1.5 yrs, P = NS). Of these subjects, 18 MZ twin pairs and 10 DZ twin pairs were postmenopausal. The MZ twin pair correlations (rMZ) for each index of bone turnover exceeded that between DZ pairs (rDZ), but this difference was only significant for osteocalcin (rMZ = 0.81, rDZ = 0.21, P less than 0.001). Similarly, in the postmenopausal group examined alone, the rMZ (r = 0.84) for serum osteocalcin was significantly greater than rDZ (r = -0.003, P less than 0.03). These osteocalcin data imply that 80% of the variance in serum osteocalcin could be explained by genetic factors. Although genetic effects on fasting urinary hydroxyproline:creatine and calcium:creatinine were not demonstrable, these indices may be less precise and specific. The data indicate that circulating osteocalcin, and therefore bone formation, is strongly genetically determined. These studies suggest at least one of the mechanisms of the genetic effect on bone mass relates to the regulation of bone turnover.     

High-Dose Inhaled Budesonide May Substitute for Oral Therapy After an Acute Asthma Attack

Patients attending the emergency room with acute asthma, participating in a study comparing salbutamol (albuterol in the United States) via a dry powder inhaler (Turbuhaler®) with pressurized metered-dose inhaler (pMDI), were included in this 1-week follow-up study with the aim of assessing whether inhaled budesonide via Turbuhaler may be an alternative to prednisolone tablets after an acute asthma attack. Eighty-one patients with a mean age of 38 years and forced expiratory volume in 1 sec (FEV₁) of 64% predicted normal value after treatment with salbutamol were randomized in this double-blind, double-dummy, parallel-group study. The doses given were budesonide 1600 μg b.i.d. or prednisolone in daily doses from 40 mg (day 1) decreased to 5 mg (day 7). FEV₁ was recorded before and after the 7-day treatments and peak expiratory flow (PEF) morning and evening, clinical symptoms (visual analogue scale 0-100), and doses of rescue medication (terbutalineTurbuhaler 0.25 mg/dose) were recorded daily. The mean increase in FEV, from baseline to day 7 was 1 7.3% in the budesonide Turbuhaler group and 1 7.6% in the prednisolone group. Mean values of morning PEF increased from day 1 to day 7 by 67 L/min in the budesonide Turbuhaler group and by 57 L/min in the prednisolone group (not significant). There were no statistically significant differences between the groups in clinical symptoms and in the number of doses of rescue medication. Because of disease deterioration, five patients in the Turbuhaler group and three in the prednisolone group needed additional symptomatic as well as corticosteroid treatment. Inhaled budesonide in high doses may be a substitute for oral therapy as follow-up treatment after an acute asthma attack.     

Once versus twice daily budesonide metered-dose inhaler in children with mild to moderate asthma: effect on symptoms and bronchial responsiveness

BackgroundSimplifying dosing regimens could improve both adherence and asthma-related morbidity. However, there is little information on the effectiveness of once-daily budesonide, administered through a metered dose inhaler (MDI) plus spacer, on asthma symptoms and pulmonary function in asthmatic children.MethodsThe aim of this study was to compare the effect of once-daily versus twice-daily doses of inhaled budesonide on symptoms, lung function and bronchial hyperresponsiveness (BHR) in asthmatic children. This study was a randomized, single-blind, parallel clinical trial. Patients received budesonide from an MDI either 800 μg as a daily dose or fractionated in 400 μg twice a day for 12 weeks. Statistical analysis was performed using tests for independent and paired samples.ResultsIn both groups, asthma symptoms significantly decreased. However, the improvement in asthma symptoms, decrease in BHR and treatment adherence were significantly greater in the once-daily group than in the twice-daily group (p < 0.05). No significant differences were found between the two groups in spirometric parameters, morning peak expiratory flow or plasma cortisol values.ConclusionsOnce-daily administration of 800 μg of inhaled budesonide administered by MDI plus spacer was more effective in controlling symptoms and improving BHR than fractionating the dose to 400 μg twice daily. The differences observed in this study could have been due to the greater adherence to treatment in patients in the once-daily group.     

Effect of high-dose fluticasone propionate on bone density and metabolism in children with asthma

Significant concern remains over the long-term side effects of inhaled steroids. This cross-sectional study evaluates the effect of high-dose inhaled fluticasone propionate (FP) on biochemical markers of bone metabolism and bone density in children with asthma. Children with chronic asthma using FP >/= 1,000 mcg daily for at least 6 months, and healthy controls, were entered in the study. No children had taken oral prednisolone within the previous month. Fasting morning serum was analyzed for bone formation markers, and spot urine for bone resorption markers. Dual-energy X-ray absorptiometry (DEXA) results were reviewed in a subgroup of patients. Forty-nine children with asthma and 32 controls were recruited. The mean FP dose was 771.2 +/- 253.35 mcg/m2/day. Unpaired t-test analysis revealed no significant difference in biochemical markers studied. In subjects with asthma; 13 of 37 (35.1%) had lumbar spine density more than one standard deviation below the mean (P = 0.001). This fell to 6/37 (16.2%) with bone age correction (NS). In conclusion, no significant reduction in bone metabolism or bone age-corrected bone mineral density was observed in children with asthma on prolonged high doses of inhaled FP.     

The Role of Budesonide in Adults and Children with Mild-to-Moderate Persistent Asthma

Asthma, a chronic and potentially life-threatening disease of the airways, affects patients of all ages. Inhaled corticosteroids (ICS) are the recommended first-line therapy for patients with persistent asthma. To review the clinical efficacy and tolerability data available on budesonide in the treatment of mild-to-moderate persistent asthma, a MEDLINE database search was performed for 1996-2003 using the following key words: budesonide, inhaled corticosteroid, efficacy, safety, systemic. When administered once or twice daily, budesonide effectively controls asthma in children, adolescents, and adults with mild-to-moderate asthma. Budesonide can be delivered effectively via a dry powder inhaler (Pulmicort Turbuhaler®) in patients aged ≥ 6 years or as an inhalation suspension (Pulmicort Respules®) in children as young as 12 months. With over 20 years' clinical exposure, budesonide has been demonstrated to be well tolerated in the treatment of chronic asthma in patients as young as 12 months. Specifically, at doses required to treat mild or moderate persistent asthma, budesonide does not affect hypothalamic-pituitary-adrenal axis function, bone mineral density, cataract formation, or final adult height. As Pulmicort Turbuhaler®, budesonide is the only ICS to achieve a Food and Drug Administration pregnancy category B rating. Early intervention with budesonide is recommended in asthma management: maximum benefit from therapy is reported in patients treated within 2 years of disease recognition. Budesonide is effective and well tolerated in the control of mild-to-moderate persistent asthma in patients aged 12 months and older. There is no evidence for variation in efficacy in population subgroups.     

Comparison of high and low dose of the inhaled steroid, budesonide, as an initial treatment in newly detected asthma

The importance of early initiation of inhaled steroids even in mild asthma has been documented in several studies. It is not, however, clear whether the treatment should be started with a high or a low dose of the inhaled steroid. We have compared the effects of high and low dose inhaled steroid, budesonide, in patients with newly detected asthma. We studied 101 adult patients with newly detected bronchial asthma who were without inhaled steroid or any regular pharmacological treatment for their asthma. The patients were randomly allocated to two treatment groups: one to receive 800 microg inhaled budesonide per day and the other to receive 200 microg inhaled budesonide per day. The drugs were given with a Turbuhaler dry powder inhaler. During the 3-month treatment period, no significant differences between the treatment groups were noted in morning or evening PEF values, in spirometric parameters, in asthmatic symptoms or in the use of rescue beta2-agonists. The decrease in bronchial hyperresponsiveness was, however, more marked in the high dose budesonide group, reaching a borderline significance (P=0.10 high vs. low dose budesonide). In addition, in serum markers of asthmatic inflammation significant differences were shown between the treatment groups. The decrease in the number of blood eosinophils during the treatment was more marked in the high dose budesonide group (P=0.02; high vs. low dose budesonide). In serum ECP no change was observed in the low dose budesonide group, but a marked decrease in the high-dose budesonide group (P=0.008; high vs. low dose budesonide). The change was even more marked with regard to serum EPX (P=0.005; high vs. low dose budesonide). Our results support the view that the treatment of newly detected asthma should be started with a high dose of inhaled steroid. The low dose may not be enough to suppress asthmatic inflammation despite good clinical primary response.     

Effect of salmeterol treatment on nitric oxide level in exhaled air and dose–response to terbutaline in children with mild asthma

The aim of this study was to investigate whether regular treatment with inhaled salmeterol modifies the dose–response curve to the inhaled short-acting β₂-agonist terbutaline or affects the concentration of nitric oxide (NO) in exhaled air of children with asthma. Twenty-two children aged 7 to 15 years (mean = 11.6 years) with mild asthma were treated with inhaled 50 μg salmeterol twice daily or placebo for 3 weeks in a randomized double-blind cross-over study. These treatments were followed by treatment with inhaled 200 μg budesonide twice daily for 3 weeks. On the last day of each period, NO level was measured in exhaled air and a cumulative dose–response experiment with terbutaline (cumulative dose: 1,475 μg) was performed. Baseline lung functions after salmeterol treatment were significantly higher than baseline after placebo (P + 0.05). Salmeterol treatment flattened out the dose–response curve to terbutaline such that higher doses of terbutaline were required to produce the same degree of bronchodilation (ED₅₀ for FEV₁ was increased by an estimated factor of 70 (95% CI: 0.8–6307) and ED₅₀ for FEF_25–75 by a factor of 41 (95% CI: 6.7–254); P < 0.05). NO levels were unaffected by salmeterol treatment (12.7 ppb; placebo = 10.7 ppb), but were significantly reduced during budesonide therapy (5.2 ppb; P < 0.001). The corresponding maximal NO levels were 19.5 (placebo), 22.9 (salmeterol), and 9.4 ppb (budesonide). We conclude that 3 weeks treatment with salmeterol does not affect NO levels in exhaled air, but it significantly changes the dose–response curve to terbutaline. Pediatr Pulmonol. 1998; 25:314–321. © 1998 Wiley-Liss, Inc.     

Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma

PURPOSE: Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function. SUBJECTS AND METHODS: After a 10-day placebo run-in, we evaluated the effects of 200 microg, 400 microg, and 800 microg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 years (mean +/- SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor. RESULTS: For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 microg (low dose) and 800 microg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 microg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose. CONCLUSIONS: In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.     

Effect of budesonide on bone density and metabolism in asthmatic children

OBJECTIVE: To assess the effect of inhaled budesonide on the mineral density, content and bone metabolism in children with asthma. MATERIAL AND METHODS: From September 1996 to July 1997, a cross-sectional study was conducted in 38 prepubertal children aged 6 to 11 years, selected from the pediatric chest outpatient clinic of the Instituto Autónomo Hospital Universitario de Los Andes, Mérida, Venezuela. Three study groups were assembled: 9 asthmatic children treated with inhaled budesonide (300 micrograms/day) for over 6 months (Group A); 14 asthmatic children not treated with inhaled corticosteroids (Group B); and 15 non-asthmatic children (Group C). All of them underwent testing of bone formation and resorption markers, and measurement of bone mineral density (DMO) and content (CMO). Statistical analysis consisted of central tendency and dispersion measures, analysis of variance, and Fisher and Scheffe tests for comparison of means. RESULTS: In the groups studied (A, B, and C) calcium serum levels were 9.1 +/- 0.3; 9.6 +/- 0.4; 9.3 +/- 0.6 mg/ml, respectively; osteocalcin levels were 14.8 +/- 4.6; 13.0 +/- 2.5; 11.9 +/- 3.4 ng/dl; the type I collagen carboxyterminal telopeptide (ICTP) levels were 19.6 +/- 16.5; 14.2 +/- 15.4; 13.0 +/- 18.3 micrograms/l; the DMO levels were 0.67 +/- 0.06; 0.68 +/- 0.06; 0.69 +/- 0.06 g/cm2; and the CMO levels were 1,158.8 +/- 217.4; 1,106.4 +/- 256.1; 1,176.5 +/- 240.5 g, respectively. No statistically significant differences were observed between the groups. CONCLUSIONS: The administration of 100-400 micrograms/day of inhaled budesonide for a period of six months, did not change the bone mineral density and metabolism of asthmatic children.     

High-Dose Inhaled Budesonide May Substitute for Oral Therapy After an Acute Asthma Attack

Patients attending the emergency room with acute asthma, participating in a study comparing salbutamol (albuterol in the United States) via a dry powder inhaler (Turbuhaler®) with pressurized metered-dose inhaler (pMDI), were included in this 1-week follow-up study with the aim of assessing whether inhaled budesonide via Turbuhaler may be an alternative to prednisolone tablets after an acute asthma attack. Eighty-one patients with a mean age of 38 years and forced expiratory volume in 1 sec (FEV₁) of 64% predicted normal value after treatment with salbutamol were randomized in this double-blind, double-dummy, parallel-group study. The doses given were budesonide 1600 μg b.i.d. or prednisolone in daily doses from 40 mg (day 1) decreased to 5 mg (day 7). FEV₁ was recorded before and after the 7-day treatments and peak expiratory flow (PEF) morning and evening, clinical symptoms (visual analogue scale 0–100), and doses of rescue medication (terbutalineTurbuhaler 0.25 mg/dose) were recorded daily. The mean increase in FEV, from baseline to day 7 was 1 7.3% in the budesonide Turbuhaler group and 1 7.6% in the prednisolone group. Mean values of morning PEF increased from day 1 to day 7 by 67 L/min in the budesonide Turbuhaler group and by 57 L/min in the prednisolone group (not significant). There were no statistically significant differences between the groups in clinical symptoms and in the number of doses of rescue medication. Because of disease deterioration, five patients in the Turbuhaler group and three in the prednisolone group needed additional symptomatic as well as corticosteroid treatment. Inhaled budesonide in high doses may be a substitute for oral therapy as follow-up treatment after an acute asthma attack.     

Serum leptin in children with asthma treated with inhaled budesonide.

Leptin, a 167-amino-acid peptide, is a recently discovered hormone which is believed to play a major role in the regulation of body weight. Systemic administration of exogenous glucocorticoids has been found to increase circulating leptin levels. In this study, we aimed to assess serum leptin in children with asthma treated with inhaled budesonide 800 micrograms day-1. Ten boys and three girls with asthma, all adolescents aged from 12.9 to 16.6 years, were studied in a randomized double-blind two-period cross-over trial with 4-week treatment periods and a 1-week wash out. Placebo was given during one period and 800 micrograms budesonide during the other via a 750 ml volume spacer (Nebuhaler, Astra Draco, Lund, Sweden). On the last day of the placebo and budesonide periods blood samples were taken and serum leptin was measured by a specific radioimmunoassay. The difference in mean (SEM) leptin concentration between the budesonide and placebo period was 0.2 (0.4) microgram l-1 (P = 0.71; t = -0.4; df = 12, 95% confidence interval -0.9-0.7 microgram l-1). Inhaled budesonide 800 micrograms per day from a Nebuhaler does not influence circulating leptin levels, suggesting that regulation of body weight is unaffected.     

Comparison of inhaled budesonide with oral prednisolone at two dose-levels commonly used for the treatment of moderate asthma

The purpose of the study was to compare the anti-asthmatic efficacy of two doses of inhaled budesonide with two doses of oral prednisolone commonly used in clinical practice. The patients studied had not been taking regular inhaled glucocorticosteroids and so there was minimal interference from previous medication. The study was conducted as two double-blind crossovers with a washout period between them - firstly, comparing 400 micrograms budesonide with 5 mg prednisolone per day and secondly, 800 micrograms budesonide with 10 mg prednisolone per day. Lung function and symptoms were improved significantly from run-in by all treatments and improvement on both drugs was dose-dependent. When low-dose treatments were compared, mean morning peak expiratory flow rate was higher during budesonide treatment and, as a result, diurnal variation was significantly less than that during prednisolone treatment. At the higher doses, differences between the drugs were not observed, but this may have been due to the fact that a "ceiling effect" had been reached.     

Effect of two doses of budesonide on exhaled nitric oxide and urinary EPX excretion in asthmatic children

The use of objective outcome measures that assess airway inflammation in pediatric asthma can provide a good evaluation of asthma severity and treatment response. In this double-blind and randomized study the effects of 200 micro g of budesonide and 800 micro g of budesonide on markers of inflammation (exhaled nitric oxide (eNO), eosinophil protein X (EPX) excretion in urine) and on lung function (FEV (1)) were prospectively investigated in 24 ICS-naive children with mild persistent to moderate persistent asthma over a period of eight weeks. After eight weeks of treatment 200 micro g and 800 micro g of budesonide led to a significant decrease (p < 0.025) in eNO [median (90 % interval): 200 micro g: - 17.2 ppb (- 54.6 to 0.9); 800 micro g: - 13.2 ppb (- 44.6 to - 1.7)]. A significant change in urinary EPX excretion was only observed in the high dose group [200 micro g: - 10.3 micro g/mmol creatinine (- 116.2 to 50.5), p = 0.9; 800 micro g: - 49.2 micro g/mmol creatinine (- 231.0 to 48.7), p = 0.02]. However, a significant difference between the change from baseline after 8 weeks of either group was found neither for eNO (p = 0.66) nor for EPX excretion (p = 0.04). In conclusion, our data demonstrate that 800 micro g budesonide per day did not show any advantage in reduction of airway inflammation, measured by eNO and urinary EPX excretion, in children with mild persistent to moderate persistent asthma.     

Effects of Inhaled Mometasone Furoate on Growth Velocity and Adrenal Function: A Placebo-Controlled Trial in Children 4–9 Years Old with Mild Persistent Asthma

Objective. To assess the effects of long-term mometasone furoate delivered via a dry powder inhaler (MF-DPI) on growth velocity and hypothalamic–pituitary–adrenal axis function in children with asthma. Study design. Children aged 4–9 years with asthma (n = 187) were randomized to MF-DPI 100 μg (delivered dose; actuated dose is 110 μg) once daily in the morning (QD AM), 100 μg twice daily (BID), 200 μg QD AM, or placebo for 52 weeks followed by a 3-month follow-up period. The primary outcome was growth velocity calculated from stadiometric heights recorded at each visit. Secondary outcomes included serum and 12-h urinary cortisol, serum osteocalcin, and urinary N-telopeptide. Results. MF-DPI 100 μg QD AM treatment did not significantly affect growth velocity compared with placebo (–0.10 ± 0.31 cm/y, p = 0.76). When the effect of a total daily dose of 200 μg MF-DPI on growth velocity was examined, no significant effect was demonstrated for MF-DPI 100 μg BID compared with placebo (–0.64 ± 0.39 cm/y, p = 0.10), although the change in mean growth velocity with MF-DPI 200 μg QD AM reached statistical significance (–0.70 ± 0.29 cm/y, p = 0.02). The effects of all examined doses of MF-DPI on mean plasma cortisol levels were similar to cortisol changes seen in the placebo group, suggesting an absence of drug-related effects. No differences in 12-h urinary cortisol or other outcomes were observed between groups. Conclusions. One year of treatment with a total daily dose of 100 μg of MF-DPI in the morning resulted in no significant difference, whereas a total daily dose of 200 μg of MF-DPI was associated with some changes in growth velocity when compared with placebo. The differences in growth velocity, and the absence of drug-related cortisol effects, support the use of a total daily dose of 100 μg of MF-DPI in children aged 4–9 years with mild persistent asthma.     

Serum leptin and adiponectin are positively associated with bone mineral density at the distal radius in patients with type 2 diabetes mellitus

There have been several reports about associations of serum leptin or adiponectin with bone mineral density and biochemical markers of bone turnover. However, the precise roles of adipocytokines in bone metabolism have not been fully elucidated. We investigated the associations of serum level of leptin or adiponectin with bone mineral density, serum osteocalcin, and urinary N-terminal telopeptide of type I collagen (NTX) in 40 Japanese patients with type 2 diabetes mellitus. Bone mineral density was measured by using dual-energy x-ray absorptiometry at different sites (distal radius, femoral neck, and lumbar spine) and was expressed as z score. Multiple regression analysis revealed that there were significant positive correlations between serum leptin or adiponectin level and z score at the distal radius, but not at the femoral neck or the lumbar spine. Although no correlation was observed between serum leptin and serum osteocalcin, there was a significant negative correlation between serum leptin and urinary NTX, a marker of bone resorption. No correlation was observed between serum adiponectin and serum osteocalcin or urinary NTX. These results indicate that leptin and adiponectin may have a protective effect on bone metabolism in patients with type 2 diabetes mellitus.