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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Inhaled corticosteroids decrease airway responsiveness in asthma partly through suppression of airway inflammation. We have previously demonstrated that inhaled budesonide reduced airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) to a threefold greater extent than to methacholine and sodium metabisulfite, suggesting that AMP responsiveness may be a
more sensitive marker of airway inflammation and steroid action in order to assess a dose-response
relationship. To investigate this, we studied the effects of three doses of the novel corticosteroid ciclesonide (50 µg, 200 µg, and 800 µg) inhaled as a dry powder twice daily on airway responsiveness
to AMP and inflammatory parameters in induced sputum. In a three-parallel-dose group, double-blind, placebo-controlled, randomized, crossover study, with a washout period of 3 to 8 wk, a total of
29 patients with mild to moderate allergic asthma underwent AMP challenge and sputum induction
before and after 14 d of treatment with ciclesonide or matched placebo. Compared with placebo,
ciclesonide 100 µg, 400 µg, and 1,600 µg daily reduced airway responsiveness to AMP by 1.6 (95%
confidence interval [CI], 
0.1 to 3.4, not significant [NS]), 2.0 (95% CI, 0.4 to 3.6, p < 0.05), and 3.4 (95% CI, 2.3 to 4.4, p < 0.05) doubling doses, respectively, and this reduction in airway responsiveness was dose-dependent (p = 0.039). A significant reduction in the percentage of eosinophils in induced
sputum was observed after 400 µg and 1,600 µg daily ciclesonide (p < 0.05), but this was not dose-dependent. Sputum eosinophil cationic protein (ECP) was significantly reduced after 400 µg daily
ciclesonide only (p < 0.05). Thus, in patients with mild to moderate asthma, assessment of airway responsiveness to AMP, rather than inflammatory parameters in induced sputum, represents a sensitive
method to evaluate a dose-response relationship of an inhaled corticosteroid and may have applications in evaluating other novel inhaled corticosteroids.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Inhaled corticosteroids are the most effective prophylactic agents available for the treatment of asthma, particularly in patients with mild to moderate asthma and persistent symptoms (1). They exert their effect principally through attenuation of airway inflammation. Regular treatment with inhaled corticosteroids reduces asthma exacerbations, improves asthma control and lung function (1), and attenuates surrogate markers of airway inflammation such as increased airway responsiveness and inflammatory parameters in induced sputum (2).
For any drug it is important to assess the relationship between dose and response so as to define the minimal effective dose and avoid exposing patients to potentially dangerous side effects with doses higher than those achieving the maximal therapeutic effect. Studies investigating dose-response relationships of inhaled corticosteroids in terms of clinical parameters of asthma control have produced conflicting results (3). In part this reflects differences in study design, but an important factor is also the heterogeneity of patients studied with differing degrees of asthma severity, concomitant medication, and duration of asthma symptoms, all of which may influence the effectiveness of anti-inflammatory medications. In addition, different dose-response relationships may exist for different efficacy outcomes, suggesting that some outcome parameters may be more sensitive at defining dose-response relationships than others. There is recent evidence that increased airway responsiveness, as assessed by bronchoprovocation with adenosine-5'-monophosphate (AMP) (4), may be one such parameter, but no study has demonstrated a dose-response relationship between this and an inhaled corticosteroid.
Airway inflammation underlies increased airway responsiveness in asthma (5), and inhaled corticosteroids reduce airway responsiveness to a variety of direct and indirect stimuli in patients with mild asthma (4, 6). We have previously demonstrated that budesonide 800 µg, inhaled twice daily for 2 wk, reduced airway responsiveness to the indirect spasmogen AMP by almost threefold more than to the neural stimulus sodium metabisulfite and the direct smooth muscle stimulus methacholine in patients with mild asthma (4). Because AMP exerts its effect principally through the release of spasmogenic mediators from immunologically primed mast cells (9), we interpreted this as an additional action of budesonide to reduce mast cell numbers and or function. With the observation that a high dose of inhaled corticosteroid reduced airway responsiveness to AMP to such a great extent, we hypothesized that lower doses would reduce airway responsiveness to a lesser extent in a dose-dependent manner. We therefore wished to determine whether this was a sensitive method to assess the dose-response relationship of an inhaled corticosteroid in asthmatic patients.
Ciclesonide is a novel inhaled corticosteroid currently under development for the treatment of asthma, and this is the first study to address the efficacy of ciclesonide in asthmatic patients. The study aimed to examine the effects of three doses of ciclesonide (50 µg, 200 µg, and 800 µg) inhaled twice daily for 2 wk on airway responsiveness to AMP in patients with mild to moderate asthma. In addition, we assessed the effect of each dose on eosinophils and eosinophil cationic protein (ECP) in induced sputum.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
Thirty-seven patients, age 18 to 45 yr, took part in the study. All patients had mild to moderate asthma with a forced expiratory volume
in one second (FEV1) 
60% of predicted, demonstrated a positive
skin test in response to common airborne allergens (Dermatophagoides pteronyssinus, mixed grass pollen, or cat fur), and documented sensitivity to AMP (provocative concentration of AMP producing a
20% reduction in FEV1 [PC20] 
60 mg/ml). All were nonsmokers and
none had an exacerbation of asthma or a respiratory tract infection in
the preceding 8 wk. Patients were steroid-naive and took no regular
medications for their asthma apart from treating occasional symptoms
with intermittent short-acting 
2-agonists. Written informed consent
was obtained from each patient, and the study was approved by the
ethics committee of the Royal Brompton Hospital.
Study Protocol
For each of three parallel-dose groups, a randomized, double-blind, placebo-controlled, crossover study was performed, consisting of two 14-d treatment periods separated by a washout period of between 3 and 8 wk. In each group patients inhaled one of three doses of ciclesonide as a dry powder through a Cyclohaler giving a total daily dose of 100 µg, 400 µg and 1,600 µg, respectively, during one treatment period and matched placebo during the other. Prior to the study, patients attended the unit for a screening visit to assess entry criteria and pulmonary function and to undergo physical examination, safety blood profile (hematology and biochemistry), and electrocardiogram (ECG). They then attended on the first (Day 0) and last (Day 14) day of both treatment periods. Patients withheld from the use of rescue medication and caffeinated beverages for at least 12 h prior to each visit and attended the laboratory at the same time in the morning. After baseline lung function and serum cortisol measurements, each patient was challenged with AMP followed by sputum induction when lung function had returned to baseline values. Treatment was commenced immediately after completion of the first sputum induction on Day 0 and continued up to the AMP challenge on Day 14. After the washout period, AMP airway responsiveness (PC20) at the beginning of the second treatment period had to be within ± 1.5 doubling doses of that obtained at the beginning of the first treatment period. If this was not achieved, the second treatment was delayed a further week and patients withdrawn from the study if at that time the PC20 had not returned to within the stated ± 1.5 doubling doses.
AMP Challenges
Fresh solutions of AMP (Sigma, Poole, UK) were made up in 0.9% saline in a range of concentrations from 0.39 to 800 mg/ml. Each solution was administered from a nebulizer attached to a breath-activated dosimeter (Mefar, Brescia, Italy). The nebulizer delivers particles with an aerodynamic mass median diameter of 3.5 to 4.0 µm at an output of 9 µl per breath.
Pulmonary function was assessed by measurement of FEV1 with a
dry wedge spirometer (Vitalograph, Buckingham, UK). A standard challenge protocol was used for all provocation tests. Three measurements of FEV1 were taken at 1-min intervals, the best of which was
taken as the baseline. The patients then inhaled a series of five breaths of saline as control, followed by a series of five breaths of doubling
concentrations of AMP at 3-min intervals (i.e., during each sequential
inhalation, the concentration of AMP administered was doubled).
FEV1 was measured 90 and 150 s after each inhalation and the highest
value recorded for analysis. The challenges were terminated when a
20% decrease in FEV1 from the postsaline value was recorded. A
log dose-response curve was constructed and AMP PC20 was calculated by linear interpolation.
Induction of Sputum
Before induction patients were pretreated with inhaled salbutamol 200 µg. Subjects then inhaled 3.5% saline at 5-min intervals for 15 min in total via an ultrasonic nebulizer (DeVilbiss 2000; DeVilbiss, Heston, UK) with an output of 6 ml/min. After each 5-min interval subjects discarded excess saliva into a separate bowl and after thorough mouthwashing were then encouraged to expectorate airway secretions. Secretions expectorated over the first 5 min were discarded to minimize squamous epithelial cell contamination and the rest saved for analysis once an adequate sample between 2 and 4 ml was obtained. All sputum samples were kept at 4° C for not more than 2 h prior to processing.
Processing of Sputum
The whole sputum sample was diluted with 2 ml Hanks' balanced salt
solution (HBSS) containing 1% dithiothreitol (DTT) (Sigma Chemicals, Poole, UK) and after gentle agitation left to homogenize at room
temperature. The volume was recorded and the sample further diluted with HBSS and centrifuged at 300 × g for 10 min. The supernatant was then separated and stored at 70° C for subsequent ECP
analysis and the cell pellet resuspended in 1 ml of HBSS. A total cell count was determined on a hemocytometer using Kimura stain. Slides were then prepared using a cytospin (Shandon, Runcorn, UK) and stained with May-Grunwald-Giemsa. Differential cell counts were performed on 400 nonsquamous cells by a blinded observer (D.A.T.) and expressed as a percentage of airway inflammatory cells, excluding epithelial cells. Slides containing > 50% squamous cells were not included in the analysis.
ECP Analysis
The concentration of ECP in the sputum supernatant was measured
by radioimmunoassay (Pharmacia and Upjohn Diagnostics, Uppsala, Sweden). The detection limit of the assay is 2 µg/ml.
Statistical Analysis
Within each dose group, the AMP PC20 ratios (post/pretreatment) were compared by analysis of variance for a two-way, two-period crossover design after logarithmic transformation. Geometric mean and two-sided 95% confidence intervals (CI) were given for the ratio ciclesonide/placebo and these values expressed as doubling doses. Comparison between the three dose levels was based on the AMP PC20 ratios for ciclesonide/placebo. The distribution-free Jonckheere-Terpstra test (10) was used to test for a monotone dose-response relationship. Differences in FEV1 (post- versus pretreatment) were analyzed similarly without logarithmic transformation. Sputum parameters were compared pre- and post-treatment by the Wilcoxon signed rank test followed by similar analysis to assess dose-response. Statistical significance was taken as p < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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After screening, 37 patients were randomized into the study. Eight patients were withdrawn during the course of the study: four failed to achieve an AMP PC20 at the beginning of the second treatment period within ± 1.5 doubling doses of that obtained before the first treatment period, one had an FEV1 < 60% of predicted before commencing the second treatment period, one was excluded due to noncompliance with the study medication, and two patients withdrew for personal reasons. Thus 29 patients completed the study; nine in the 100-µg, and 10 in the 400-µg and 1,600-µg daily ciclesonide study groups, respectively. Demographic and baseline data of these patients are given in Table 1.
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Effect of Ciclesonide on FEV1
Mean FEV1 values before and after treatment with ciclesonide
and placebo are given in Table 2. The mean difference between the effect of ciclesonide and placebo treatment on
FEV1 was 0.12 L (95% CI, 0.34 to 0.55, not significant [NS])
for ciclesonide 100 µg daily, 0.26 L (95% CI, 0.01 to 0.44, p < 0.05) for ciclesonide 400 µg daily, and 0.20 L (95% CI, 0.37
to 0.78, NS) for ciclesonide 800 µg daily.
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Effect of Ciclesonide on Airway Responsiveness to AMP
All three doses of ciclesonide reduced airway responsiveness
to AMP in a dose-dependent manner (Figure 1, Table 3).
Ciclesonide 100 µg daily increased the geometric mean PC20
for AMP from 7.6 mg/ml (95% CI, 2.6 to 22.3) pretreatment to
15.6 mg/ml (95% CI, 5.1 to 48.1) post-treatment (post/pre ratio
2.0). In this group the corresponding values for placebo pre-
and post-treatment were 9.2 mg/ml (95% CI, 3.8 to 22.6) and
6.2 mg/ml (95% CI, 2.6 to 15.0), respectively (post/pre ratio
0.7). This increase in AMP PC20, adjusted for the respective
pretreatment value, was higher for ciclesonide than placebo
by a factor of 3.0, corresponding to a shift in the AMP dose-
response curve of 1.6 (95% CI, 0.1 to 3.4) doubling doses (NS).
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Ciclesonide 400 µg daily increased the geometric mean PC20 for AMP from 8.0 mg/ml (95% CI, 3.6 to 18.2) pretreatment to 32.6 mg/ml (95% CI, 14.5 to 73.5) post-treatment (post/pre ratio 4.1). In this group the corresponding values for placebo pre- and post-treatment were 8.7 mg/ml (95% CI, 4.0 to 19.0) and 8.9 mg/ml (95% CI, 3.5 to 22.8), respectively (post/ pre ratio 1.0). This increase in AMP PC20, adjusted for the respective pretreatment value, was higher for ciclesonide than placebo by a factor of 3.9, corresponding to a shift in the AMP dose-response curve of 2.0 (95% CI, 0.4 to 3.6) doubling doses (p < 0.05).
Ciclesonide 1,600 µg daily increased the geometric mean PC20 for AMP from 6.3 mg/ml (95% CI, 2.4 to 16.6) pretreatment to 54.9 mg/ml (95% CI, 29.6 to 101.8) post-treatment (post/pre ratio 8.7). In this group the corresponding values for placebo pre- and post-treatment were 6.6 mg/ml (95% CI, 2.2 to 18.5) and 5.5 mg/ml (95% CI, 2.4 to 12.6), respectively (post/pre ratio 0.8). This increase in AMP PC20, adjusted for the respective pretreatment value, was higher for ciclesonide than placebo by a factor of 10.4, corresponding to a shift in the AMP dose-response curve of 3.4 mg/ml (95% CI, 2.3 to 4.4) doubling doses (p < 0.05).
The trend in reduction in airway responsiveness after the three doses of ciclesonide as assessed by the increase in PC20 for AMP was dose-dependent (p = 0.039).
Effect of Ciclesonide on Parameters in Induced Sputum
Four patients (two in each of the 400 µg daily and 1,600 µg daily ciclesonide groups) produced sputum specimens at one or more visits with > 50% squamous cells. These patients were excluded from analysis of differential cell counts, but were included in measurements of ECP from the fluid phase of the induced sputum.
Ciclesonide 100 µg daily had no significant effect on the percentage of eosinophils or ECP in induced sputum (Figures 2 and 3). Ciclesonide 400 µg and 1,600 µg daily significantly reduced the percentage of eosinophils in induced sputum from pretreatment levels, but only in the 400 µg daily group was a significant reduction in sputum ECP observed (Figures 2 and 3). No effect on the percentage of eosinophils or ECP in induced sputum was observed after placebo treatment (Figures 2 and 3).
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No dose-related effect of ciclesonide was observed on the percentage of eosinophils in induced sputum.
Safety
Ciclesonide at all three doses was well tolerated, there being no differences in adverse event profile or alterations in hematological and biochemical parameters between ciclesonide and placebo treatment. No changes in morning serum cortisol levels were observed after ciclesonide or placebo treatment in any of the three groups (Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study has demonstrated that three doses of ciclesonide, 100 µg, 400 µg, and 1,600 µg daily, reduce airway responsiveness to AMP in a dose-dependent manner by 1.6, 2.0, and 3.4 doubling doses, respectively. In contrast, we did not observe a dose-dependent reduction of either eosinophils or ECP in induced sputum following ciclesonide.
We chose to study patients with mild to moderate asthma and few asthma symptoms as this represented a more homogeneous group to study a dose-response relationship of an inhaled corticosteroid. This was aimed at avoiding some of the confounding factors associated with a heterogeneous population of patients that may have contributed to the conflicting results in previous inhaled steroid dose-response studies (3). One problem with this approach, however, is that patients in our study represented a group who are unlikely to require treatment with high doses of inhaled steroids, and it is not surprising that we observed only small changes in lung function after each active treatment period. Despite this we did see a clear dose- response relationship of ciclesonide on airway responsiveness to AMP in this group of patients. This brings into question the clinical relevance of our study and requires some explanation.
Inhaled steroids improve the clinical parameters of asthma control and this is accompanied by reductions in airway responsiveness to both direct (11) and indirect spasmogens, including AMP (12). Although studies have demonstrated dose-dependent improvements in asthma control after regular inhalation of steroids (13, 14), this has not been mirrored by similar changes in airway responsiveness to direct spasmogens, possibly because neither methacholine nor histamine is sensitive enough to generate a dose-response relationship. There has been increasing interest recently in the role of AMP bronchoprovocation in asthma (9). This stems from observations suggesting that AMP may be a more specific marker of asthmatic inflammation than the direct smooth muscle spasmogens. Studies suggest that AMP-induced bronchoconstriction results from a direct action of AMP on immunologically primed airway mast cells to release histamine and other preformed spasmogenic mediators (15, 16). In addition AMP may also stimulate sensory neural pathways that also contribute to the contractile airway response (17). Thus it is likely that AMP produces bronchoconstriction through two pathways that play an important role in the pathogenesis of asthma. This suggests that assessment of airway responsiveness to AMP may be clinically relevant in asthma. In support of this, patients with chronic obstructive pulmonary disease are much less responsive to AMP than nonsmoking asthmatics, whereas the sensitivity to methacholine is similar (18). Furthermore, Van Velzen and coworkers recently demonstrated that when allergic asthmatic children are admitted to a hypoallergenic high-altitude clinic, reductions in peak flow variability are accompanied by significant reductions in airway responsiveness to AMP but not to methacholine (19). In addition, the greater reduction in airway responsiveness to AMP than to other spasmogens after regular inhaled steroids in mild asthmatic patients supports the view that AMP bronchoprovocation is a more sensitive marker of steroid action in asthma than histamine or methacholine. The 3.6 doubling-dose reduction in airway responsiveness to AMP after ciclesonide 1,600 µg daily by Cyclohaler is compatible with our previous observations with the same dose of budesonide by Turbohaler (4). It is likely this property of inhaled steroids on the mechanisms of AMP bronchoprovocation reflects a dual action, first by reducing airway mast cell numbers and/or function, and second by inhibiting airway smooth muscle responsiveness. In keeping with this, regular treatment with inhaled steroids reduces mast cell numbers in the bronchial mucosa of asthmatic patients (20, 21) and inhibits the early response to inhaled allergen (22), a potent mast cell stimulus. It was not possible to determine directly the effect of ciclesonide on mast cell numbers and mediator release in our study as the AMP challenge immediately prior to sputum induction may have adversely affected these parameters, making interpretation of any changes difficult.
The evidence that AMP bronchoprovocation is a sensitive marker of steroid action and acts through pathways involved in asthmatic inflammation may help explain the clinical relevance of the findings of our study. First, all three doses of ciclesonide attenuated airway responsiveness to AMP, suggesting that a significant degree of airway inflammation is still present in this group of mild to moderate asthmatics despite near-normal lung function. Second, the fact that the highest dose of ciclesonide was able to attenuate airway responsiveness to AMP by 3.6 doubling doses implies the degree of inflammation is not trivial. Third, if airway responsiveness to AMP is sensitive enough to differentiate the effects of three doses of an inhaled steroid on airway inflammation in relatively mild asthmatics, it is interesting to speculate that it may also be a sensitive method to monitor changes in asthma control and disease activity that are not detectable either by lung function or other surrogate markers of airway inflammation. This will need to be assessed in future studies. Finally, with relevance to the clinical development of ciclesonide and other novel inhaled steroids, dose-response information generated in this group of patients will help define appropriate doses and duration of action for efficacy studies in later clinical development.
We did not observe any dose-related effect of ciclesonide on the percentage of eosinophils in induced sputum despite significant but similar reductions after the two higher doses. In comparison to AMP airway responsiveness, the degree of variability in sputum eosinophil percentage was large between, as well as within, each group. In addition, the degree of airway eosinophilia was low in all three groups, consistent with mild asthma, and thus any effect of an inhaled steroid was likely to be small. This, combined with the smaller number of patients studied owing to excessive squamous cell contamination of the sputum in some subjects, is likely to account for the lack of dose-response relationship observed with this parameter. Furthermore, it is important to emphasize that patients in this study were not selected on their ability to produce analyzable sputum, with eosinophils above a given percentage, but on the basis of other criteria including a high degree of airway responsiveness to AMP. This by definition would tend to reduce between-group variability for AMP responsiveness. In a similar manner, ECP measurements in the fluid phase of the induced sputum were even more variable than sputum eosinophils, with a significant reduction after the middle dose of ciclesonide only. Although we minimized salivary contamination of the sputum sample by thorough mouth-washing this could have contributed to the more variable ECP results observed. It is possible that had we studied a larger group of patients, we may have observed a similar dose-response relationship for induced sputum parameters as for AMP responsiveness.
Previous studies have investigated the dose-response relationship of inhaled steroids on surrogate markers of airway inflammation in patients with mild asthma. In keeping with our observations, Jatakanon and colleagues (23) demonstrated that budesonide administered over 4 wk via a Turbohaler at the same doses used in our study significantly reduced sputum eosinophils after the 400 µg and 1,600 µg daily doses but not after the 100 µg daily dose. Interestingly methacholine airway responsiveness was significantly attenuated only after the 1,600 µg daily dose, there being no alteration after the lower two doses, highlighting further the sensitivity of AMP airway responsiveness in our study to low doses of inhaled steroids. In addition, budesonide at all three doses reduced exhaled nitric oxide levels in a dose-dependent manner, suggesting this inflammatory parameter may also be a sensitive marker of steroid action.
This is the first study to evaluate the efficacy of ciclesonide in asthmatic patients; the results suggest that ciclesonide is efficacious. The data also suggest that the effects of ciclesonide on AMP airway responsiveness and sputum eosinophilia in this group of patients with mild to moderate asthma are comparable with budesonide (4), a well-established inhaled steroid. Although this study was not designed to address the issue of endogenous steroid suppression, it is interesting to note that no significant changes in morning plasma cortisol levels were observed after 2 wk of treatment with all three doses.
In conclusion, this study has demonstrated that the novel inhaled steroid ciclesonide reduces airway responsiveness to AMP in a dose-dependent manner in a small group of patients with mild to moderate asthma. In this setting, assessment of airway responsiveness to AMP appears to be a more sensitive marker of steroid action than attenuation of inflammatory parameters in induced sputum. This study has been instrumental in defining the appropriate doses of ciclesonide currently under evaluation in ongoing clinical trials, and we believe assessment of AMP airway responsiveness may have a significant impact on the early-phase clinical evaluation of other novel inhaled steroids.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. D. A. Taylor, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.
(Received in original form September 11, 1998 and in revised form February 16, 1999).
Acknowledgments: Supported by a grant from Byk Gulden Pharmaceuticals.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Barnes, P. J., and S. Pederson. 1993. Efficacy and safety of inhaled corticosteroids in asthma. Am. Rev. Respir. Dis. 148: S1-S26 .
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 J. Cohen, W. R. Douma, N. H. T. ten Hacken, J. M. Vonk, M. Oudkerk, and D. S. Postma Ciclesonide improves measures of small airway involvement in asthma Eur. Respir. J., June 1, 2008; 31(6): 1213 - 1220. [Abstract] [Full Text] [PDF]
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M. Duong, P. Subbarao, E. Adelroth, G. Obminski, T. Strinich, M. Inman, S. Pedersen, and P. M. O'Byrne Sputum Eosinophils and the Response of Exercise-Induced Bronchoconstriction to Corticosteroid in Asthma Chest, February 1, 2008; 133(2): 404 - 411. [Abstract] [Full Text] [PDF]
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P. J. Barnes Scientific rationale for using a single inhaler for asthma control Eur. Respir. J., March 1, 2007; 29(3): 587 - 595. [Abstract] [Full Text] [PDF]
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F. Cerasoli Jr Developing the Ideal Inhaled Corticosteroid Chest, July 1, 2006; 130(1_suppl): 54S - 64S. [Abstract] [Full Text] [PDF]
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E. Bateman, J. Karpel, T. Casale, S. Wenzel, and D. Banerji Ciclesonide Reduces the Need for Oral Steroid Use in Adult Patients With Severe, Persistent Asthma Chest, May 1, 2006; 129(5): 1176 - 1187. [Abstract] [Full Text] [PDF]
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S. Szefler, S. Rohatagi, J. Williams, M. Lloyd, S. Kundu, and D. Banerji Ciclesonide, a Novel Inhaled Steroid, Does Not Affect Hypothalamic-Pituitary-Adrenal Axis Function in Patients With Moderate-to-Severe Persistent Asthma Chest, September 1, 2005; 128(3): 1104 - 1114. [Abstract] [Full Text] [PDF]
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 M. G. Belvisi, D. S. Bundschuh, M. Stoeck, S. Wicks, S. Underwood, C. H. Battram, E.-B. Haddad, S. E. Webber, and M. L. Foster Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 568 - 574. [Abstract] [Full Text] [PDF]
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A. Foresi, B. Mastropasqua, A. Chetta, R. D'Ippolito, R. Testi, D. Olivieri, and A. Pelucchi Step-Down Compared to Fixed-Dose Treatment With Inhaled Fluticasone Propionate in Asthma Chest, January 1, 2005; 127(1): 117 - 124. [Abstract] [Full Text] [PDF]
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L. Proietti, A. Di Maria, and R. Polosa Monitoring the Adjustment of Antiasthma Medications With Adenosine Monophosphate Bronchoprovocation Chest, October 1, 2004; 126(4): 1384 - 1385. [Full Text] [PDF]
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 D. C. Grootendorst and K. F. Rabe Mechanisms of Bronchial Hyperreactivity in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2004; 1(2): 77 - 87. [Abstract] [Full Text] [PDF]
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S. Rohatagi, S. Appajosyula, H. Derendorf, S. Szefler, R. Nave, K. Zech, and D. Banerji Risk-Benefit Value of Inhaled Glucocorticoids: A Pharmacokinetic/Pharmacodynamic Perspective J. Clin. Pharmacol., January 1, 2004; 44(1): 37 - 47. [Abstract] [Full Text] [PDF]
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L. Prieto, L. Bruno, V. Gutierrez, S. Uixera, C. Perez-Frances, A. Lanuza, and A. Ferrer Airway Responsiveness to Adenosine 5'-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects Chest, October 1, 2003; 124(4): 1325 - 1333. [Abstract] [Full Text] [PDF]
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G.F. Joos and B. O'Connor Indirect airway challenges Eur. Respir. J., June 1, 2003; 21(6): 1050 - 1068. [Abstract] [Full Text] [PDF]
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N.J. Vanacker, E. Palmans, R.A. Pauwels, and J.C. Kips Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats Eur. Respir. J., October 1, 2002; 20(4): 873 - 879. [Abstract] [Full Text] [PDF]
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S.L. Jones, P. Herbison, J.O. Cowan, E.M. Flannery, R.J. Hancox, C.R. McLachlan, and D.R. Taylor Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose-response relationship Eur. Respir. J., September 1, 2002; 20(3): 601 - 608. [Abstract] [Full Text] [PDF]
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G. P. Currie and B. J. Lipworth Bronchoprotective Effects of Leukotriene Receptor Antagonists in Asthma* : A Meta-analysis Chest, July 1, 2002; 122(1): 146 - 150. [Abstract] [Full Text] [PDF]
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R Polosa, S Rorke, and S T Holgate Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease Thorax, July 1, 2002; 57(7): 649 - 654. [Abstract] [Full Text] [PDF]
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Leader of the Working Group:, J.C. Kips, Members of the Working Group:, M.D. Inman, L. Jayaram, E.H. Bel, K. Parameswaran, M.M.M. Pizzichini, I.D. Pavord, R. Djukanovic, et al. The use of induced sputum in clinical trials Eur. Respir. J., July 1, 2002; 20(37_suppl): 47S - 50s. [Full Text] [PDF]
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 A. Weinbrenner, D. Huneke, M. Zschiesche, G. Engel, W. Timmer, V. W. Steinijans, T. Bethke, W. Wurst, A. Drollmann, H. J. Kaatz, et al. Circadian Rhythm of Serum Cortisol after Repeated Inhalation of the New Topical Steroid Ciclesonide J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2160 - 2163. [Abstract] [Full Text] [PDF]
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K.F. Rabe and D.T. Schmidt Pharmacological treatment of asthma today Eur. Respir. J., July 2, 2001; 18(34_suppl): 34S - 40s. [Abstract] [Full Text] [PDF]
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D.S. Postma, C. Sevette, Y. Martinat, N. Schlosser, J. Aumann, and H. Kafe Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening Eur. Respir. J., June 1, 2001; 17(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
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P. E. Silkoff, P. McClean, M. Spino, L. Erlich, A. S. Slutsky, and N. Zamel Dose-Response Relationship and Reproducibility of the Fall in Exhaled Nitric Oxide After Inhaled Beclomethasone Dipropionate Therapy in Asthma Patients Chest, May 1, 2001; 119(5): 1322 - 1328. [Abstract] [Full Text] [PDF]
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