Adrenal suppression, evaluated by a low dose adrenocorticotropin test, and growth in asthmatic children treated with inhaled steroids

The aim of the present study was to evaluate the prevalence of adrenal suppression and growth retardation in children using moderate doses of budesonide or fluticasone propionate. Seventy-five asthmatic children were randomly divided into three treatment groups: 30 to the fluticasone propionate (FP), 30 to the budesonide (BUD), and 15 to the cromone (CROM) group. FP doses were 500 microg/day during the first 2 months and 200 microg/day thereafter. The respective BUD doses were 800 and 400 microg/day. A low dose ACTH (0.5 microg/1.73 m2) test was performed before treatment and 2, 4, and 6 months later. The test was considered abnormal if the stimulated serum cortisol concentration was more than 2 SD lower than the pretreatment mean (<330 nmol/L). The low dose ACTH test was abnormal after both the high and low steroid doses in 23% of the children. At the 4 month measurement there were more abnormal tests in the BUD (n = 9) than in the FP (n = 5) group (P < 0.05). At that time also the stimulated concentration of serum cortisol was lower in the BUD than in the CROM group (P < 0.01), whereas the difference between the FP and CROM groups was not significant. During the study year the mean decrease in height SD score was 0.23 in the children treated with BUD, 0.03 in the children treated with FP, and 0.09 in the children treated with CROM; the difference between the BUD and FP groups was significant (P < 0.05). In conclusion, the low dose ACTH test revealed mild adrenal suppression in a quarter of the children using moderate doses of inhaled steroids. A FP dose of 200 microg/day caused less adrenal and growth suppression than did a BUD dose of 400 microg/day.     

Growth deceleration of children on inhaled corticosteroids is compensated for after the first 12 months of treatment

Timing and duration of linear growth suppression in children on long-term inhaled corticosteroids (ICS) are not entirely clear; we undertook a "pragmatic" study to determine growth of asthmatic children on long-term ICS managed by a flexible dosing step-down approach. Standard deviation scores of height (HSDS), height velocity (HVSDS), and body mass index (BMISDS) of pre-pubertal asthmatic children on maintenance therapy with either budesonide (BUD) or fluticasone propionate (FP) were calculated in a prospective open-label non-randomized study. Outcomes were recorded at initiation of ICS, 6, 12, 24, and 36 months, as applicable, and 6 months after ICS treatment discontinuation. Three hundred twenty-two children on BUD and 319 on FP were enrolled after the completion of 6-month treatment. The median (range) daily dose at initiation was 400 mcg (400-1,200) and 200 mcg (200-500), the final maintenance 200 mcg (200-400) and 100 mcg (100-200), respectively. In the first 6-12 months, a decrease in HSDS of approximately 18% below baseline values was noted (P < 0.01) that was restored to almost baseline average levels by 24 months, and slightly increased to above baseline during the third year. HVSDS showed a linear increase in both treatment arms (P < 0.01). No differences were found between the two treatment arms regarding HSDS, HVSDS, and BMISDS at any time point over the course of the study. In conclusion, growth deceleration of asthmatic children on maintenance ICS is compensated for after the first 12 months of treatment. This effect does not differ between BUD and FP treatment, despite some variation in the pattern of linear growth.     

A comparison of the relative growth velocities with budesonide and fluticasone propionate in children with asthma

There have been no previous large, well-designed direct comparisons of the effects of fluticasone propionate (FP) and budesonide (BUD) on growth in children. This randomised, double-blind study compared the effects on growth of FP and BUD in children aged 6-9 years with persistent asthma. Following a 6-month run-in period (without inhaled corticosteroids), patients with normal growth velocity were randomised to 12 months' treatment with FP 100 micro g bd (n=114) or BUD 200 micro g bd (n=119). Growth velocity was determined by stadiometric height measurement. Lung function, asthma symptoms and use of relief medication were also assessed. Annualised mean growth velocity during run-in was comparable in the two groups (FP: 5.9 cm/yr; BUD: 6.0 cm/yr). During the treatment period, adjusted mean growth velocity was significantly higher in the FP than the BUD group (5.5 cm/yr vs 4.6 cm/yr; P<0.001). Asthma control improved similarly in both treatment groups. Bone mineral density and overnight urinary cortisol:creatinine ratios were similar in the two groups. Drug-related adverse events were reported among 3% of FP-treated children, compared with 2% for BUD. In conclusion, this study demonstrates that FP for childhood asthma has significantly less impact on childhood growth velocity than a therapeutically equivalent dose of BUD.     

Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children

Pharmacokinetic studies can be used to measure lung dose of inhaled drugs. The aim of this study was to compare the lung deposition of budesonide (BUD) inhaled from Turbuhaler (AstraZeneca, Lund, Sweden) and fluticasone propionate (FP) inhaled from Diskus (GlaxoSmithKline, London, UK) and to assess if the study design used for pharmacokinetic studies can be simplified. Plasma levels of BUD and FP were measured for 21 hours on five separate days in 15 patients aged 8 to 14 years: (1) Intravenous infusion of 200 microg BUD, (2) intravenous infusion of 200 microg fluticasone dipropionate, (3) inhalation of 800 microg BUD via Turbuhaler, (4) inhalation of 750 microg FP via Diskus, and (5) inhalation of BUD and FP on the same day. Charcoal was ingested to eliminate drug uptake from the gastrointestinal tract. The mean lung deposition of drug after Turbuhaler and Diskus inhalation was 30.8 and 8.0% when BUD and fluticasone were administered on separate days and 29.5% (BUD) and 7.6% (fluticasone) when the two drugs were inhaled on the same day. Lung deposition is four times higher in children after inhalation from Turbuhaler than after inhalation from Diskus. Pharmacokinetic studies with BUD and FP can be simplified because the two treatments can be administered on the same day.     

Therapeutic ratio of inhaled corticosteroids in adult asthma. A dose-range comparison between fluticasone propionate and budesonide, measuring their effect on bronchial hyperresponsiveness and adrenal cortex function

Inhaled corticosteroids have become the mainstay treatment of bronchial asthma. However, simultaneous evaluations of efficacy and side effects are few. This study aimed to compare the relative effect of fluticasone propionate (FP) and budesonide (BUD) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma. The study was double-blind and included 66 adults with asthma, who were randomized to FP (n = 33) or BUD (n = 33). Prestudy, all participants were clinically stable, using inhaled corticosteroids and hyperresponsive to methacholine. Eligible patients were randomized to three consecutive 2-wk periods with either FP 250 microg twice daily, FP 500 microg twice daily, and FP 1,000 microg twice daily, or BUD 400 microg twice daily, BUD 800 microg twice daily, and BUD 1,600 microg twice daily, delivered by Diskhaler and Turbuhaler, respectively. Before randomization and at the end of each treatment, bronchial methacholine PD(20), 24-h urinary cortisol excretion (24-h UC), plasma cortisol, serum osteocalcin, and blood eosinophils were determined. The relative PD(20) potency between FP and BUD was 2.51 (95% CI, 1.05-5.99; p < 0. 05), while the relative 24-h UC potency was 0.60 (95% CI, 0.44-0.83; p < 0.01). The differential therapeutic ratio (FP/BUD) based on PD(20) potency and 24-h UC was 4.18 (95% CI, 1.16-15.03; p < 0.05). The difference in systemic potency was also seen for plasma cortisol, serum osteocalcin, and blood eosinophils. Therapeutic ratio over a wide dose range, determined by impact on bronchial responsiveness and endogenous corticosteroid production, seems to favor FP.     

Improved safety with equivalent asthma control in adults with chronic severe asthma on high-dose fluticasone propionate

OBJECTIVE: High-dose inhaled corticosteroids (ICS) have been associated with the same side-effects as oral corticosteroids. Beclomethasone dipropionate (BDP) and budesonide (BUD) in doses greater than 2000 microg/day are used regularly in severe asthma, despite the fact that safety and efficacy data at such high doses are limited. Fluticasone propionate (FP) has been promoted as being twice as potent clinically as BDP or BUD at doses of 2000 microg/day or less with a similar safety profile. The aim of this study was to compare the efficacy and safety of FP with BDP and BUD in 133 symptomatic adult asthmatics requiring at least 1750 microg/day of BDP or BUD. METHODOLOGY: Patients fulfilling the entry criteria were randomized to receive either their regular ICS medication or FP at approximately half the microgram dose for 6 months in an open, parallel group study. The primary efficacy measure was based on morning peak expiratory flow measurements recorded by patients on daily record cards, while determination of safety was based on a number of endpoints including changes in bone turnover indices, the incidence of topical side-effects and assessments of quality of life. RESULTS: It was shown that patients who were switched to FP, but not those continuing with BDP or BUD, had significant increases in levels of morning serum cortisol and the urine cortisol:creatinine ratio while maintaining asthma control. Serum osteocalcin and the pyridinoline:creatinine ratio, as well as the deoxypyridinoline:creatinine ratio, were also shown to increase only in the FP group. Subjective assessments such as quality of life score, the incidence and ease of bruising, and reports of hoarseness also favoured the FP group. CONCLUSIONS: It is concluded that, at the doses studied and with the delivery devices used clinically, FP is at least as effective as BDP/BUD in the management of severe asthma and may offer clinical advantages with respect to steroid-related adverse effects.     

Addition of montelukast versus double dose of inhaled budesonide in moderate persistent asthma

BACKGROUND: Although current guidelines suggest the use of inhaled corticosteroids as the first line therapy in persistent asthma, the concerns about high-dose corticosteroids may limit their usage. We aimed to investigate the efficacy of inhaled budesonide plus oral montelukast versus a double dose of inhaled budesonide. METHODOLOGY: Thirty patients with moderate asthma took part in the study. Following a 2-week run in period, the patients were randomized into two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of montelukast (BUD + M group) or 800 microg/day of inhaled budesonide (high BUD group). The patients were evaluated at 2-week intervals (during a total treatment period of 6 weeks) for symptom scores, asthma exacerbations, lung function, use of short-acting beta2 agonist, blood eosinophil counts and adverse events. RESULTS: At the end of the study, morning and daytime symptom scores were significantly reduced within the groups. Although there was a significant decrease in the frequency of short-acting beta2 agonist use in the BUD + M group, the decrease in the high BUD group was not significant. During the study period, no patient in either group experienced an asthma exacerbation. Blood eosinophil levels significantly declined in both the BUD + M (0.87 +/- 0.31%) and high BUD groups (0.67 +/- 0.29%) as compared with baseline levels (BUD + M = 2.60 +/- 0.65%, high BUD group = 2.60 +/- 0.47%; P < 0.05). CONCLUSION: Our results suggest that the addition of montelukast to low-dose inhaled budesonide is as effective as a double dose of inhaled budesonide in asthma control.     

沙美特罗/丙酸氟替卡松干粉与布地奈德干粉吸入治疗成人支气管哮喘的临床疗效和安全性对照研究

目的比较低剂量的沙美特罗/丙酸氟替卡松干粉剂(SM/FP)与中等剂量的布地奈德干粉(BUD)吸入治疗成年轻、中度支气管哮喘(简称哮喘)患者的临床疗效和安全性。方法采用多中心、随机、开放、平行对照试验,389例18～70岁哮喘患者按随机数字表法分为试验组[199例,吸入SM/FP1泡/次(每泡SM50μg、FP100μg),每天2次]和对照组(193例,吸入BUD,每次400μg,每天2次)。结果试验组和对照组患者晨间呼气峰流速(PEFam)在治疗的第1周末较基线值分别提高(26±2)L/min和(7±5)L/min(P均<0.01);6周后两组的改善分别为(54±6)L/min和(31±8)L/min(P均<0.01);治疗期间试验组每周均改善更明显;晚间呼气峰流速(PEFpm)与PEFam结果相似;日间和夜间症状评分在试验组和对照组治疗第1周比较差异均有统计学意义(P<0.05);6周时试验组下降的程度与对照组比较差异有统计学意义(P<0.01);全天无症状天数的百分数试验组由治疗前的6.9%增加至治疗后的55.2%,对照组则由8.4%增加至36.1%。沙丁胺醇气雾剂的揿数在两组分别由治疗前的(3.32±3.15)揿和(3.21±3.23)揿下降至治疗结束时的(1.06±1.79)揿和(2.03±3.17)揿,两组比较差异有统计学意义(P<0.01),试验组的用药揿数显著少于对照组;无需沙丁胺醇的天数试验组与对照组比较差异有统计学意义(P<0     

Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma

This study was designed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate (FP) over 6 months, compared to a control group who remained on a lower dose of FP. The multi-centre, double-blind, parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500-800 micrograms (microg) inhaled corticosteroids (ICS) twice daily (b.d.) in a broadly representative group of 100 hospitals and general practices in six countries. Two doses of FP--250 microg b.d. (FP250) or 500 microg b.d. (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist, salmeterol 50 microg b.d. (SM/FP250). Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period. Over 6 months, SM/FP250 significantly improved mean morning peak expiratory flow rates (amPEF) by 42.1 l/min, more than twice the improvement achieved with either dose of FP alone. SM/FP250 also resulted in more symptom-free days and nights (P < 0.002) and days and nights with no relief medication (P < 0.001). The number of severe exacerbations was low: 3, 6 and 8% in the SM/FP250, low- and high-dose FP groups, respectively. This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP. Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250. There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups.     

Study on serum and urinary cortisol levels of asthmatic patients after treatment with high dose inhaled beclomethasone dipropionate or budesonide

BACKGROUND: The potential for long-term adverse effects from inhaled corticosteroids relates to their systemic absorption. With increasing use of high dose inhaled corticosteroids, there is need to establish whether similar doses of beclomethasone dipropionate (BDP) and budesonide (BUD) produce clinically important differences in untoward side effects specially hypothalamo-pituitary-adrenal (HPA) axis suppression. METHODS: Fifteen asthmatic patients were started on BDP or BUD (2000 microg/day) through spacer for six weeks. Serum cortisol (9 AM and 4 PM), 24-hour urinary steroid and pulmonary function testing parameters were performed. RESULTS: The serum cortisol levels were not found to be suppressed with either BDP or BUD. Similarly no significant changes were found in 24 hours urinary excretion of steroids with either of the drugs. Significant improvement was found in values of forced expiratory volume in the first second (FEV1) with BDP. With BUD the changes in forced vital capacity (FVC) and FEV1 were found to be significant. CONCLUSION: BDP or BUD in high doses of 2000 microg/day given upto six weeks through spacer are equally effective for treatment of bronchial asthma and do not cause any significant change in serum and urinary cortisol levels, and adrenal function/HPA axis.     

A randomized, double-blind study comparing the effects of beclomethasone and fluticasone on bone density over two years.

Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids have reduced bone mass. This prospective 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids. Patients (n = 33) (males aged 18-50 yrs, females aged 18-40 yrs) on inhaled corticosteroids 1,000-2,000 microg x day(-1), were randomized in a double-blind fashion to either fluticasone propionate (FP) 1,000 microg x day(-1) or beclomethasone dipropionate (BDP) 2,000 microg x day(-1). In parallel, three open control groups of the same age range were studied: asthmatics (n = 8) receiving low dose inhaled corticosteroids (< or =400 microg x day(-1)) (group A); chronic, severe asthmatics (n = 8) receiving oral corticosteroids (> or =10 mg x day(-1) (group B); and healthy untreated volunteers (n = 7) (group C). Bone densitometry scans (quantitative computed tomography (QCT) of spine; dual X-ray absorptiometry of spine, femoral neck, and single photon absorptiometry of forearm) were performed at baseline and after 6, 12 and 24 months of treatment. Biochemical bone marker measurements (serum osteocalcin, bone alkaline phosphatase, pro-collagen type 1 carboxy terminal propeptide, deoxypyridinoline and C-telopeptide of type 1 collagen) were collected every 3 months. Fifteen FP (mean age 36 yrs, six male) and 9 BDP patients (mean age 33 yrs, five male); completed the study. At 0 months, mean bone mineral density (BMD) was lower in patients receiving inhaled corticosteroids (both low dose and high dose) than in normal volunteers. In the FP-treated group, mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline, whereas there was some decline in the BDP-treated group. The treatment difference between FP and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months (p = 0.006) and 24 months (p = 0.004). This study suggests that over 24 months, changes in bone density are minimal in patients on high-dose inhaled corticosteroids.     

Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma

We studied the effect of inhaled corticosteroids on the increase in bone mineral content in prepubertal children with asthma. Forty-eight asthmatic, prepubertal children receiving either inhaled beclomethasone dipropionate or budesonide were evaluated. Nine children of similar age not receiving inhaled steroids served as controls. The average age of corticosteroid-treated children was 7.8 +/- 2.4 years, and of control children, 8.4 +/- 2.1 years (NS). The average dose of inhaled corticosteroids in the treated children was 0.67 +/- 0.48 mg/m(2)/day, and they were followed over a 9-20-month period. Total bone mineral content (TBMC) was measured at baseline and after 9-20 months. A derived value for 12 months' TBMC was calculated, assuming that changes in TBMC were linear with the passage of time. The change in TBMC over a 12-month period was 264 +/- 68 mg for the corticosteroid-treated children and 330 +/- 84 mg for control children (P < 0.025). In a multiple regression analysis in which adjustments were made for the effects of age, height, and weight, the change in TBMC in corticosteroid-treated children was inversely related to the inhaled steroid dose/m(2)/day (P = 0.016). The increase in the lumbar vertebral bone mineral density in control children was also significantly greater than in the corticosteroid-treated children (P < 0.025). We conclude that inhaled steroids, at an average dose of 0.67 mg/m(2)/day, when used in the treatment of asthma reduce the acquisition of bone mineral in prepubertal children.     

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.     

The effect of inhaled budesonide on adrenal and growth suppression in asthmatic children.

The present authors evaluated adrenal reserve in asthmatic children on long-term inhaled corticosteroids and whether possible adrenal suppression could be predicted by growth retardation. Low-dose synacthen test (0.5 microg x 1.73 m(-2)) was performed in 72 asthmatic children with a median age of 9.4 (range 4.2-15.7) yrs on long-term treatment (median 18 (range 6-84) months) with low-to-moderate doses (median 363 (range 127-1012) microg x m(-2)) of inhaled budesonide, as well as in 30 controls. Adrenal suppression was considered as a peak serum cortisol <495 nmol x L(-1). The current authors calculated height standard deviation score (HSDS) at the time of testing and height velocity SDS (HVSDS) in the preceding year. Mean HSDS was 0.06+/-1.3 and HVSDS was -0.9+/-2.3. Adrenal suppression was disclosed in 15 asthmatic children (20.8%). There were no differences in HSDS and HVSDS between children with and without adrenal suppression. There was no correlation between peak cortisol response and dose or duration of treatment. However, a positive relationship between HVSDS and duration of treatment was noted. These data suggest that long-term treatment of asthmatic children with low and moderate doses of inhaled budesonide may result in mild adrenal suppression that cannot be predicted by growth deceleration. The negative influence of inhaled corticosteroids on growth becomes less the longer the duration of treatment.     

Low- and high-dose fluticasone propionate in asthma; effects during and after treatment.

The dose dependency of the effects of inhaled corticosteroids on markers of asthmatic airway inflammation have not been well studied. There is a need to study the dose/response effects on this inflammation. In order to determine the dose/response effects of fluticasone propionate (FP), 24 asthmatic subjects were randomized to low- (100 microg x day(-1)) or high-dose (1,000 microg x day(-1)) FP for six weeks followed by placebo for 3 weeks. During treatment, the median increase in forced expiratory volume in one second (FEV1)was 12% in the high-dose group (p<0.05) and 10% in the low-dose group (p<0.05) (p>0.05 between groups); the median decrease in the percentage of sputum eosinophils was 93% in the high-dose group (p<0.05) and 46% in the low-dose group (p<0.05) (p>0.05 between groups). Symptoms, salbutamol use, morning peak flow, provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), sputum eosinophil cationic protein concentration and tryptase activity improved significantly in both groups (p<0.05), but only the improvement in salbutamol use was greater in the high-dose group (p<0.05). During the run-out, the improvements in FEV1 and PC20 were rapidly reversed in both groups, but the improvements in peak flow and tryptase activity persisted; the improvement in sputum eosinophil concentration persisted only in the high-dose group (p<0.05). It was concluded that dose/response effects for FP are not easily demonstrable because low-dose FP is quite effective. For most outcomes, the effects of high- and low-dose FP are relatively short-lived after treatment is stopped. This finding raises questions about the extent to which inhaled corticosteroids are disease-modifying in asthma.     

Inhaled corticosteroids reduce growth. Or do they?

The class label warning in the United States for inhaled corticosteroids (ICS's) states that these drugs may reduce growth velocity in children. In this paper, the evidence for this warning is reviewed from a clinical point of view. Children with asthma tend to grow slower than their healthy peers during the prepubertal years because they go into puberty at a later age. However, asthmatic children do achieve a (near) normal adult height. In randomized controlled clinical trials, the use of inhaled beclomethasone, budesonide and fluticasone is associated with a reduced growth during the first months of therapy, in the order of magnitude of approximately 0.5-1.5 cm x yr(-1). It is, however, unlikely that such an effect continues or persists because accumulating evidence shows that asthmatic children, even when they have been treated with ICS for years, attain normal adult height. Individual rare cases have been reported, however, where ICS use was associated with clinically relevant growth suppression. Inhaled corticosteroids are the most effective therapy available for maintenance treatment of childhood asthma. Fear of reduced growth velocity is based on exceptional cases and not on group data. It should, therefore, not be a reason to withhold or withdraw such highly effective treatment in children with asthma.     

Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients

STUDY OBJECTIVE: Adding inhaled long-acting beta2-agonists to a low dose of inhaled corticosteroids (ICSs) results in better asthma control than increasing the dose of ICSs. An important, but as yet unresolved, question is whether this is due to an additional reduction of airway inflammation. DESIGN: Double-blind, parallel-group trial. PATIENTS: Forty asthma patients (FEV1, 50 to 90% predicted; provocative concentration of a substance [methacholine] causing a 20% fall in FEV1 of < 8 mg/mL; no ICSs in the last 4 weeks). INTERVENTIONS: Randomization to 8 weeks of treatment with 100 microg of budesonide bid plus placebo (BUD200) or 100 microg of budesonide bid plus 12 microg of formoterol (BUD200 + F). Then the dose of budesonide (BUD) was increased to 400 microg bid in both groups for another 8 weeks. Bronchial biopsy specimens were collected before, and after 8 and 16 weeks of treatment. Eosinophils (major basic protein [MBP]) and mast cells (tryptase) were analyzed by immunohistochemistry. RESULTS: BUD200 reduced the MBP staining (p = 0.008) and tryptase staining (p = 0.048) in the epithelium compared to baseline levels. There were no significant differences between the BUD200 and BUD200 + F groups. In both groups, increasing the dosage of BUD to 800 microg had no significant additional antiinflammatory effect. CONCLUSIONS: Our results demonstrate that BUD administered at a low dose has significant antiinflammatory effects in patients with mild asthma. No significant additional antiinflammatory effects could be demonstrated either by adding formoterol or by increasing the dose of BUD.     

Oropharyngeal candidiasis with dry-powdered fluticasone propionate: 500 microg/day versus 200 microg/day

We aimed to determine the frequency of oropharyngeal candidiasis and its clinical correlates in the asthmatic patients who use fluticasone propionate (FP) as a dry powdered inhaler. We selected four groups of patients: 62 asthmatic patients who were taking 200 microg/d FP, 122 asthmatics who were taking 500 microg/d FP, 50 asthmatic patients who had not been on inhaled corticosteroid (ICS) treatment and 40 normal non-asthmatic subjects. The frequency of positive swabs for Candida colonization was higher in 500 microg/d FP group than asthmatics without ICS use (chi2 = 6.8, p < 0.05) and normal controls (chi2 = 4.9, p < 0.05), whereas it wasn't different in the 200 microg/day FP group when compared to controls. When we considered patients who used ICS, the most effective variables affecting the occurrence of Candida colonization were washing of the throat by the patients (OR = 9.4, 95 % Confidence Interval [CI] = 3.9-22.7, p < 0.0001) and duration of ICS use more than 12 months (OR = 2.5, 95 % CI = 1.1-2.6, p < 0.05). The present study showed that in the patients who use ICS, the most important determinants on colonization were not washing the throat regularly and duration of ICS use for more than 12 months.     

Cost analysis of the use of inhaled corticosteroids in the treatment of asthma: a 1-year follow-up

A retrospective cohort using pharmacy and medical claims was analysed to determine whether the differences in efficacy of various inhaled corticosteroids demonstrated in clinical trials lead to differences in costs of care observed in clinical practice. Subjects that had an ICD-9 (493.XX) code for asthma and a new pharmacy claim for inhaled fluticasone propionate 44 mcg (FP), beclomethasone dipropionate (BDP), triamcinolone acetonide (TAA), budesonide (BUD) or flunisolide (FLU) were identified and followed for 12 months. Annual asthma care charges (pharmacy and medical) over the 12-month observation period were significantly (P < 0.03) higher in patients treated with BDPTAA, BUD and FLU compared to FP, 24%, 27%, 34% and 45% respectively In addition, patients treated with BDPTAA, and FLU were associated with significantly (P < 0.005) higher total healthcare (asthma + non-asthma) charges compared to patients on FP, 53%, 46% and 39% respectively Asthma care and total healthcare charges remained lower for FP after including FP110 mcg and excluding patients who were extreme cost outliers (+/- 2 SD from the mean) in a univariate sensitivity analysis. This analysis supports recent randomized control trials that FP offers a superior efficacy profile at lower asthma care as well as total healthcare charges compared to other inhaled corticosteroids.     

Children with mild asthma: do they benefit from inhaled corticosteroids?

In children with mild asthma, who show hardly any abnormalities in pulmonary function, objective measurement of the effect of inhaled corticosteroids is difficult. The short term effect of fluticasone propionate (FP) in these children was evaluated, using both subjective and objective parameters. A total of 68 children (5-10 yrs old) were randomly assigned to either FP 250 microg or placebo twice daily as metered-dose inhaler via spacer during 12 weeks. Symptom scores, use of rescue medication, wheezing, parent global evaluation and pulmonary function tests including forced expiratory volume in one second (FEV1), peak expiratory flow (PEF) and bronchial responsiveness (provocation dose of methacholine causing a 20% fall in FEV1 (PD20)) were evaluated. FP-treated versus placebo-treated children showed significant changes in percentage symptom-free days, use of beta2-mimetics, morning and evening PEF, FEV1 % pred and wheezing. No significant improvements were found in parent global evaluation, absolute values of FEV1 nor PD20. These findings show that inhaled corticosteroids are effective in children with mild asthma. This effect can be assessed by both objective and subjective parameters. Early start of inhaled corticosteroids should be considered even when pulmonary function is normal.