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Background: Therapy with inhaled corticosteroids (ICS) is beneficial in patients with asthma. However, in preschool children with symptoms like cough, wheeze, or shortness of breath diagnosing asthma is difficult. Therefore, the role of ICS in the management of preschool children with recurrent respiratory symptoms is unclear. We assessed the effectiveness of ICS in preschool children with recurrent respiratory symptoms in general practice., Methods: In this multicenter, randomized, double blind, placebo controlled trial, 96 children aged 1-5 years consulting their general practitioners for recurrent respiratory symptoms and in whom treatment with ICS was considered by the general practitioner were randomly allocated to receive ICS (fluticasone propionate 200 mcg/day by metered dose inhaler/spacer combination) or placebo for 6 months. Outcome assessments were carried out 1, 3, and 6 months after randomization. The primary outcome measure was the symptom score (cough, shortness of breath and wheeze during day and night) as measured by a symptom diary card. Secondary endpoints were symptom-free days, use of rescue medication, adverse events, and lung function variables as measured by the interrupter technique and forced oscillation technique., Results: During the 6 months treatment period, symptoms improved in both groups, with no differences between ICS and placebo. In addition, none of the secondary outcome parameters showed differences between both treatment groups., Conclusion: ICS treatment has no beneficial effect in preschool children with recurrent respiratory symptoms in general practice. We therefore recommend a watchful waiting policy with only symptomatic treatment in these children. General practitioners and pediatricians should be aware of the high probability of overtreatment when prescribing ICS in these children.

Study Objectives: Subjects with atopic asthma often experience a disappearance of symptoms around puberty. However, airway inflammation and remodeling may persist. It is unknown whether those findings warrant prolonged anti-inflammatory treatment despite the absence of symptoms. In this study, we investigated whether a short course of combined anti-inflammatory treatment would, also in this specific patient population, diminish airway inflammation and/or remodeling., Design: A double-blind, randomized placebo-controlled trial was conducted in 28 asymptomatic subjects with a history of atopic asthma, with established bronchial hyperresponsiveness to methacholine (MCh) as non-invasive indicator of ongoing airway pathology., Interventions: Intervention consisted of the salmeterol/fluticasone propionate combination (SFC) product (50/250 microg bid via the Diskus inhaler) or placebo for 3 months., Measurements: The change in lung function (FEV1), bronchial response to MCh and adenosine monophosphate (AMP), the fraction of nitric oxide in exhaled air (FENO) and quality of life (QOL) scores were measured. Also, bronchial biopsies were taken and cryo sections immunostained for eosinophils (major basic protein, MBP) and mast cells (tryptase and chymase) before and after treatment. The change in reticular basement membrane (RBM) thickness, one of the parameters of airway remodeling, was also determined., Results: SFC treatment improved hyperresponsiveness to MCh (P = 0.014) as well as AMP (P = 0.011), and reduced FENO (P < 0.001) significantly as compared with placebo. Lung function tended to improve (NS). Furthermore, SFC treatment reduced tryptase in the subepithelium of bronchial biopsy specimens (P = 0.01), and slightly reduced RBM thickness (P = 0.05). However, eosinophils in (sub)epithelium were not significantly affected; neither were chymase levels, blood eosinophils or QOL scores., Conclusions: We found that 3 months of treatment with fluticasone propionate and salmeterol reduced airway hyperresponsiveness, FENO and tryptase density in the airway mucosa as markers of airway inflammation. MBP density in the airway mucosa and QOL were, however, unchanged. The clinical relevance of these findings, especially with respect to the long-term outcome, has not been determined yet.

Background: Inhaled corticosteroids are currently regarded as the gold standard in anti-inflammatory therapy, however, leukotriene receptor antagonists have been ascribed anti-inflammatory properties., Objective: We directly compared the anti-inflammatory effects of inhaled fluticasone propionate (FP, 100 microg Diskus, twice daily) and oral montelukast (MON 10 mg, nocte) in bronchial biopsies of patients with asthma in a double-blind, double-dummy, parallel-group design., Methods: Bronchial biopsies, serum and urine samples were collected from 36 atopic asthmatics before and after 8 weeks of treatment. Activated T cells (CD25+), eosinophils (MBP+) and mast cells (tryptase+) were analysed by immunohistochemistry. Serum eosinophil cationic protein (ECP) and IL-5 were analysed by radio and enzyme immunoassay (EIA), respectively. Urinary 9alpha-11beta-PGF2 and leukotriene E4 (LTE4) were measured by EIA., Results: A comparison of changes from baseline [FP/MON ratio (95% confidence interval)] of activated T cells was not different when subjects were treated with FP compared to treatment with MON [1.00 (0.18-4.86); P=0.924]. Following treatment, mast cells in the FP group were significantly lower than in the group treated with MON [0.39 (0.16-0.97); P=0.041]. There was no difference in the number of eosinophils in the lamina propria following either treatment [0.54 (0.05-2.57); P=0.263]. However, treatment with FP resulted in a significantly greater decrease in serum ECP, compared to treatment with MON [0.37 (0.25-0.71); P=0.002]., Conclusions: FP appears to be superior to MON as an anti-inflammatory therapy in mild asthmatics.

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.

Background: The wet-wrap treatment involves emollients or corticosteroid dilutions under occlusive wet dressings, and has been reported to be highly effective in severe refractory atopic dermatitis (AD)., Objectives: To investigate the influence of different corticosteroid dilutions on the efficacy and hypothalamic-pituitary-adrenal (HPA) axis suppression in children with severe refractory AD having wet-wrap dressings., Methods: Eighteen children were treated with a 50% dilution of fluticasone propionate (FP) 0.05% cream for 2 weeks. In another five children a side-to-side comparison was conducted with 10%, 25% and 50% dilutions of FP cream under wet wrap. A third group of eight children was treated with 0% (= emollient), 5%, 10% or 25% dilutions of FP cream applied on the whole body under wet wrap., Results: After 1 week, a major improvement averaging 74% was observed, without apparent differences between 5%, 10% or 25% dilutions of FP cream under wet wrap, with less improvement in the second week of treatment. The first and second group of children showed HPA axis suppression in only three of 23 children using measurements of 09.00 h serum cortisol after 2 weeks. The third group of children showed HPA axis suppression, as indicated by 06.00 h serum cortisol levels, which was related to the absolute amount of FP applied., Conclusions: This suggests that weaker corticosteroid dilutions had comparable high efficacy, but lower risk of HPA axis suppression.

Background: The local production and release of a number of cytokines regulate allergic upper airway inflammation. Medication is usually used at the presentation of the first symptoms. There are, however, clues that it is advisable to start taking the corticosteroid before the grass pollen season begins., Methods: This single allergen provocation study was conducted in autumn, out of the hay fever season. Nasal mucosa biopsies were taken twice before provocation (before and after 4 weeks of preventive treatment) and three times after allergen provocation (1 h, 24 h and 1 week). The preventive treatment used was fluticasone propionate aqueous nasal spray (FPANS) (n = 10) or a placebo (n = 9). Eosinophils and mRNA positive cells (in situ hybridization for IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IFNgamma, RANTES and TNFalpha) were counted in the biopsies., Results: Preventive treatment with FPANS out of season resulted in a decrease in eosinophils and mRNA positive cells for IL-5 and IL-6. After allergen provocation, levels of most of the measured cytokines (IL-3, IL-5, IL-6, IL-13, IFNgamma, RANTES and TNFalpha) and eosinophils were reduced using corticosteroids. The numbers of cells (eosinophils, IL-3, IL-6 and IL-8) correlated with nasal symptoms. Significant correlations in the early and late allergic phase were found between eosinophils and cytokines (IL-3, IL-10 and IL-13)., Conclusion: These results indicate that preventive treatment with FPANS prior to contact with grass pollen is effective in reducing the increase of cytokine mRNA positive cells in reaction to grass pollen contact.

Objective: To compare the efficacy and safety of using a combination of fluticasone propionate (FP) and UV-A with that of either drug used alone in the long-term treatment of vitiligo., Design: Prospective, randomized, controlled, left-right comparison study. Repigmentation was judged by a single dermatologist (L.N.-K.) and skin thickness was scored by a pathologist (using biopsy samples), a dermatologist (L.N.-K.) (visually), and patients (using a standard questionnaire)., Setting: Netherlands Institute for Pigmentary Disorders, Amsterdam., Patients: Patients with lesions on arms, legs, and trunk were treated on 2 symmetrical lesions for 9 months with FP alone and a combination of FP and UV-A (FP group) or with UV-A alone and a combination of FP and UV-A (UV-A group). Fluticasone propionate cream was applied once daily at about bedtime, and UV-A (10 J/cm2) exposure was twice a week. Patients attended the clinic at 3-month intervals., Results: One hundred thirty-five patients were included, 96 of whom were evaluable after 9 months. Patients not reaching the end point withdrew because of insufficient repigmentation (n = 23), decreased motivation (n = 11), or protocol violations (n = 5). No patient (irrespective of whether they withdrew) experienced any adverse effects. The FP and UV-A groups were comparable with respect to sex, age, and location of lesions. On average, combination treatment was 3 times more effective than either UV-A or FP treatment alone. In the FP group, no atrophy was seen after 9 months with either treatment. In the UV-A group, a little atrophy was detected twice: as well during UV-A treatment alone as during combination treatment., Conclusions: Combination treatment with FP and UV-A is much more effective in reaching complete repigmentation than are FP and UV-A used alone, but large inter-individual differences occur. Fluticasone propionate, UV-A, and a combination of FP and UV-A seem to be safe for long-term treatment of vitiligo.

This study was designed to investigate a long-term therapeutic strategy for the management of recurring atopic dermatitis (AD) in adults using fluticasone propionate (FP) ointment (CutivateTM) whereby FP could help to prevent a relapse of AD once symptoms were under control. Adult patients with chronic, moderate to severe AD entered this multicentre study. All patients were initially treated with FP 0.005% (g/g) ointment in two different regimens. Patients whose AD had been completely healed by these treatments then entered a long-term treatment phase applying FP or placebo ointment once daily, two times per week for 16 weeks to 'known' healed lesions. By the end of the initial treatment period, mean SCORAD values had significantly (P < 0.0005) improved from baseline. Patients who entered the maintenance phase and were treated with intermittent FP for up to 16 weeks, demonstrated its superior efficacy (P = 0.018) over placebo, maintaining the improvements achieved after the initial treatment phase, reducing risk of relapse and delaying time to relapse (P = 0.013). No significant changes were detected in either treatment group in serum cortisol levels or in skin thickness measurements. Intermittent FP applied two times per week maintained a significant level of control, and delayed relapse of AD by comparison with placebo.

Current guidelines on asthma management recommend the early use of inhaled corticosteroids. Recent studies of patients with moderate to severe asthma show that the addition of salmeterol is superior to a further increase of the steroids. In this study with adult, mild persistent asthma patients, we compared the effects of adding salmeterol 50 microg b.i.d. versus beclomethasone dipropionate (BDP) 200 microg b.i.d. (both via Diskhaler dry powder inhaler) to the low-dose inhaled steroids. A double-blind, randomized, parallel-group study was conducted with a run-in period of 2 weeks and a treatment period of 12 weeks. Patients (n = 233) were randomized with a peak expiratory flow (PEF) reversibility of 22 +/- 10% (mean +/- SD) in the run-in period. The morning PEF was 84 +/- 17% predicted and the age was 42 +/- 14 years (45% males). The average prestudy inhaled steroid dose was 361 microg daily. Within a week of salmeterol treatment the daily PEF recordings reached maximal levels. At the end of the treatment period the evening PEF remained significantly better in the salmeterol group than in the BDP group (p = 0.036). The PEFs, measured at the general practitioners' (GPs') office, were at least 95% of the predicted values and the post-salbutamol values at the end of both treatments. However, the salmeterol group had already obtained this level after 2 weeks and differed significantly from the beclomethasone group (p = 0.003 for percent predicted and p = 0.0007 for post-salbutamol PEF values). The symptom scores and the use of rescue medication showed a similar profile. Quality of life improved with both treatments, but without significant statistical differences between the groups. The frequency of adverse events, typical for beta2-agonists, was low and showed no differences between the groups. These results showed that the addition of salmeterol is at least as effective as adding beclomethasone in normalizing peak flows and improving asthma control in mild persistent asthma patients. Furthermore, salmeterol has a much faster onset of action.

Background: Fluticasone propionate is a novel and potent corticosteroid. It seems to have an improved therapeutic index on the basis of studies on skin thinning and suppression of hypothalamic-pituitary-adrenal axis., Objective: We assessed the efficacy and safety of fluticasone propionate (FP) 0.05% cream once daily as compared with clobetasone butyrate (CB) 0.05% cream twice daily in children with atopic dermatitis (AD)., Methods: Twenty-two children (3 to 8 years old) with moderately active AD received either FP once daily or CB twice daily. Severity of AD was scored weekly by means of the modified Scoring of Atopic Dermatitis system (SCORAD) and treatment was either stopped when skin lesions were almost cleared (SCORAD < 9) or after 4 weeks. Cortisol excretion was determined by means of 24-hour urine before and after treatment., Results: Twenty-one children completed the study. After 1 week of treatment, mean SCORAD significantly decreased in both treatment groups. After 2, 3, and 4 weeks cumulatively, 8, 12, and 16 children, respectively, were clinically healed (SCORAD < 9). No significant differences in efficacy were observed between the two treatments. Urinary cortisol excretion was not altered by either of the treatments. Two weeks after discontinuation of active treatment, mean SCORAD had increased to 22, but still was significantly lower than that at the beginning of the study., Conclusion: Once-daily treatment with FP is as safe and effective as twice-daily treatment with CB in children with AD. All children experienced an exacerbation of AD within 2 weeks after treatment was withdrawn, indicating the need for long-term "intermittent" treatment.

In a 1-year, placebo-controlled, double-blind, randomized study the long-term effect of Fluticasone Propionate Aqueous Nasal Spray (FPANS) in 42 patients with a perennial allergic rhinitis was studied with regard to safety and efficacy. Twenty-nine patients completed the entire treatment period. After 1 year of treatment no deleterious changes consequent on therapy were observed in nasal mucosal biopsies. The appearance of the epithelial layer, the degree of cellular infiltration, the extent to which the sinusoids were dilated and the degree of tissue oedema improved or remained unchanged in 93% of the patients of the FPANS group, versus 75% of the placebo group, and worsened in 7% of the FPANS group versus 25% of the placebo group. Assessment of the changes in haematological, biochemical, urinary, plasma cortisol levels, and in the findings during nasal examination revealed no significant differences between the two treatment groups. After 1 year of treatment symptom scores for sneezing, nasal itching, and total symptom score were significantly better in the FPANS treated group (P < 0.05, P < 0.05, P < 0.01). An initial reduction in total symptom score was found after 4 weeks FPANS treatment with a further reduction after 8 months of FPANS treatment. These findings suggest that the maximum efficacy of topical intranasal steroids is reached after long-term treatment, and thus advocates longer usage before treatment is stopped because of presumed inefficacy.

Topical corticosteroids are the therapy of choice for nonallergic, noninfectious perennial rhinitis (NANIPER). However, the efficacy of steroid therapy in NANIPER is controversial, as is its mode of action. To our surprise, of 300 patients initially diagnosed as having NANIPER, only 65 reached threshold nasal symptom scores. Patients were randomized into four different treatment regimens: placebo administered twice daily (BD) for 8 weeks, fluticasone propionate aqueous nasal spray (FPANS) (200 microg) once daily (OD) and placebo OD for 8 weeks, FPANS (200 microg) OD and placebo OD for 4 weeks followed by FPANS (200 microg) BD for 4 weeks, and FPANS (200 microg) BD for 8 weeks. A small decrease in nasal symptoms was found, which only reached significance for sneezing in the FPANS 200 microg BD group. A significant dose-dependent decrease in immunocompetent cells was found in nasal biopsy specimens obtained before, after 4 weeks, and after 8 weeks of treatment. We conclude that FPANS did not significantly reduce nasal symptoms in this group of selected NANIPER patients, even though a significant effect on cells in the nasal mucosa was seen.

Background: The reduction of symptoms due to treatment with corticosteroids varies among patients with perennial rhinitis. Most patients will respond but a few patients respond less to these drugs., Objective: To investigate the association in reduction of symptoms due to glucocorticoids and glucocorticoid receptor characteristics in patients with perennial allergic rhinitis, in vitro glucocorticoid receptor binding studies were performed with peripheral blood mononuclear cells using dexamethasone and in vitro production of mediators were measured., Methods: During a double-blind placebo-controlled crossover study, 200 micrograms fluticasone propionate aqueous nasal spray (in the active treatment period) and placebo (in the placebo treatment period) were administered twice daily for 2 weeks to 22 patients allergic to house dust mite. At the end of both treatment periods symptoms were scored after allergen provocation (100, 1000, 10000 BU/mL) and during the 9.5 hours after this challenge. Receptor binding studies with dexamethasone were performed with peripheral blood mononuclear cells. Leukotriene B4 produced by monocytes in vitro and soluble interleukin-2 receptor released by lymphocytes in vitro and cortisol levels in plasma were determined., Results: No significant partial correlations of the number of the peripheral blood mononuclear cell glucocorticoid receptors (6821 +/- 5669 binding sites per cell) and the affinity (Kd: 16.5 +/- 13.51 nmol/L) for the glucocorticoid receptors with the symptom score (placebo: 4.3 +/- 2.45 pts; fluticasone: 2.4 +/- 1.55 pts) after active treatment were found. Also no significant partial correlations of the levels of leukotriene B4 (45.6 +/- 105.3 ng/10(6) cells) produced by monocytes in vitro, soluble interleukin-2 receptor (734 +/- 237 ng/10(6) cells) released by lymphocytes in vitro and cortisol levels (571 +/- 236 ng/mL) in plasma with the symptom score after active treatment were found., Conclusions: The reduction of symptoms due to topical fluticasone propionate in patients with rhinitis and allergy to house dust mite is not correlated with the characteristics of the glucocorticoid receptor.

Methacholine is frequently used to determine bronchial hyperresponsiveness (BHR) and to generate dose-response curves. These curves are characterized by a threshold (provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20) = sensitivity), slope (reactivity) and maximal response (plateau). We investigated the efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate in a double-blind, placebo-controlled study in 33 atopic asthmatics. The outcome measures used were the influence on BHR and the different indices of the methacholine dose-response (MDR) curve. After 2 weeks run-in, baseline lung function data were obtained and a MDR curve was measured with doubling concentrations of the methacholine from 0.03 to 256 mg x mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently developed, sigmoid cumulative Gaussian distribution function was fitted to the data. Although sensitivity was obtained by linear interpolation of two successive log2 concentrations, reactivity, plateau and the effective concentration at 50% of the plateau value (EC50) were obtained as best fit parameters. In the fluticasone group, significant changes occurred after 6 weeks with respect to means of PC20 (an increase of 3.4 doubling doses), plateau value fall in forced expiratory volume in one second (FEV1) (from 58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to 3.75 L) in contrast to the placebo group. Stabilization occurred after 12 weeks. Changes for reactivity were less marked, whereas changes in log, EC50 were not significantly different between the groups. We conclude that fluticasone is very effective in decreasing the maximal airway narrowing response and in increasing PC20. However, it is likely that part of this increase is related to the decrease of the plateau of maximal response.

Inhaled corticosteroids (ICS) in dosages above 1,000 micrograms/d may influence parameters of bone metabolism. Fluticasone propionate (FP) is a new ICS with a higher clinical potency than beclomethasone dipropionate (BDP) combined with negligible oral bioavailability. The aim of this study was to evaluate the effects of FP and BDP in clinically equipotent dosages on indices of bone metabolism and morning cortisol. FP 750 micrograms/d and BDP 1,500 micrograms/d were compared in a randomized, double-blind, crossover study consisting of two 6-wk treatment periods, each preceded by a 3-wk single-blind placebo period. Twenty-one nonsmoking asthmatic completed the study. FP had the same effect on FEV1 and peak expiratory flow as the double dose of BDP. Both treatments did not change morning cortisol. BDP decreased both osteocalcin and procollagen type 1 carboxyterminal propeptide, indices of bone formation, significantly by 18.5 and 21.9%, respectively. In contrast, FP did not change any variable of bone formation. FP and BDP did not increase type 1 collagen carboxyterminal telopeptide and deoxypyridinoline crosslinks, both markers of bone resorption. In changes in parameters of bone metabolism indicate adverse effects on bone quality in the long term, FP may offer an advantage over BDP.

The effect of nasal corticosteroid therapy on allergic rhinitis is uncertain. In a double-blind, placebo-controlled study over 3 months, we investigated the influence of a new corticosteroid spray, fluticasone propionate aqueous nasal spray (FPANS), on Langerhans cells (CD1a+ cells), HLA-DR+ cells, and T cells in nasal mucosa. Efficacy was evaluated by nasal symptom score. This treatment significantly decreased the number of CD1a+ cells and HLA-DR+ cells in the nasal mucosa. Furthermore, a clear trend of decreasing numbers of T cells in nasal epithelium was found. No change in nasal symptom score was found after the treatment period. These findings suggest that fluticasone propionate aqueous nasal spray decreases the antigen presentation in nasal allergy.