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CLINICAL STUDIES |
From the Pulmonary Research Institute at Hospital Grosshansdorf Center for Pneumology and Thoracic Surgery, Grosshansdorf, Germany (K. Richter, F. Kanniess, H. Magnussen), and ALTANA Pharma AG, Konstanz, Germany (C. Biberger, R. Nave).
Address for reprints: Dr Kai Richter, Pulmonary Research Institute at Hospital Grosshansdorf, Center for Pneumology and Thoracic Surgery, Woehrendamm 80, 22927 Grosshansdorf, Germany.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Ciclesonide • inhaled corticosteroids • fluticasone propionate • desisobutyryl-ciclesonide • asthma
Ciclesonide is a novel inhaled corticosteroid intended for the treatment of persistent asthma. Preclinical studies have demonstrated that ciclesonide has very low glucocorticoid receptor-binding affinity and requires activation by esterases in the lung to increase its affinity for the glucocorticoid receptor by 100-fold.2 Ciclesonide is formulated as a hydrofluoroalkane-propelled metered-dose inhaler (HFA-MDI). Studies in asthmatics with disease across the entire severity spectrum have shown that ciclesonide improves lung function and asthma symptoms and decreases the use of rescue medication at daily doses between 100 and 800 µg (ex-valve HFA-MDI, equivalent to 80-640 µg exactuator).3-5 Furthermore, studies investigating the effect of acute repeated inhalation of daily doses of ciclesonide 800 µg over three 7-day periods in healthy volunteers6 and 200 to 800 µg/d for 52 weeks in asthmatic patients7 suggested that it has a good systemic safety profile, as indicated by the absence of any clinically relevant effects on the hypothalamic-pituitaryadrenal axis or the suppression of cortisol levels.
Ciclesonide, administered via HFA-MDI, results in a relatively high proportion of drug being deposited in the lungs: 52% compared to 38% being deposited in the mouth and oropharynx.8 To date, however, there is little or no information on the conversion of ciclesonide to its active metabolite, desisobutyrylciclesonide (des-CIC), in the oropharynx, which may possibly lead to adverse effects at the site of deposition following inhalation of a comparatively high dose of ciclesonide. Therefore, the aims of this study were to investigate the oropharyngeal deposition and the degree of activation of an inhaled therapeutic dose of ciclesonide 800 µg in the oropharynx, compared with that of a well-established therapeutic dose of fluticasone propionate (FP) 1000 µg.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1 week before the study. In addition, all were in stable clinical states (no recent exacerbation or relevant respiratory tract infection) and were able to inhale 8 puffs of all study medication via an HFA-MDI within 3 minutes. Heavy smokers (current or ex-smokers) with 10 pack-years and patients suffering from acute or chronic oropharyngeal disorders (eg, gingivitis, current dental therapy) were excluded.
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Study Design
The study (code BY9010/FK1 112) was approved by an independent ethics committee (Medical Association, Bad Segeberg, Germany), and all patients gave informed written consent to participate. It was conducted according to an open, 2-treatment, 2-sequence design with repeated measurements at 5 time points. In general, it consisted of a screening (1-7 days) and a treatment (5-14 days) period. Eighteen patients were randomized to 1 of 2 treatment sequences: patients inhaled either (1) 4 puffs of ciclesonide (total 800 µg, ex-valve), followed by 4 puffs of FP (total 1000 µg, ex-valve), or (2) 4 puffs of FP (total 1000 µg, ex-valve), followed by 4 puffs of ciclesonide (total 800 µg, ex-valve).
At the first treatment visit, each patient was randomly assigned to a specific inhalation treatment sequence and inhaled ciclesonide and FP within a maximum of 3 minutes. Immediately after inhalation of the last puff, the patient performed an oropharyngeal wash, as described below, to obtain a sample for analysis. After a minimum 1-day washout period, patients returned to the investigator's site for 4 subsequent visits. At each subsequent visit, they inhaled the study medications in the same sequence within 2 hours of the time noted at first visit. Oropharyngeal wash and sampling were performed at 15, 30, 45, and 60 minutes after the first puff of the study medication. Only 1 sampling time was performed at each visit.
Laboratory Investigations
Pulmonary Function Tests
Forced vital capacity (FVC), FEV1, and peak expiratory flow (PEF) were recorded at screening using an electronic Pneumotachograph MasterScope Model 4.1 spirometer (Fa. Jaeger, Hoechberg, Germany), according to the recommendations of the American Thoracic Society.9
Oropharyngeal Washing
All patients performed an oropharyngeal wash with 50% (v/v) ethanol solution at each scheduled time point, as noted above, to recover the study drug deposited in the oropharynx. Briefly, each patient rinsed his or her mouth with 30 mL 50% (v/v) ethanol solution for 5 seconds, followed by gargling for 2 to 3 seconds, with his or her neck flexed backward to increase the efficiency of the washing procedure and to maximize drug recovery. The wash solution was collected by spitting back into its container before repeating the entire procedure with a 30-mL aliquot of fresh washing solution. At the end, the subjects washed their mouths with 100 mL mineral water and drank 100 mL mineral water to remove any residual ethanol from the mucous membrane in the mouth. The mineral water was not collected for analysis.
After measuring the volumes of the first and the second rinsing solution obtained from 1 patient, both solutions were pooled. If the total volume of wash recovered was greater than 80% of the original washes, which applied for all samples in the study, aliquots were withdrawn and stored at –20 °C before analysis.
Measurement of Ciclesonide, des-CIC, and FP in the Oropharyngeal Wash
Samples were analyzed by an independent laboratory (MDS Pharma Services, Fehraltorf, Switzerland). Two assays with sample volumes of 0.2 mL using liquid chromatography with tandem mass-spectrometric detection (LC/MS/MS) were developed and validated. The internal standard was an analog of des-CIC carrying a deuterium label.
Fluticasone propionate and ciclesonide concentrations were determined simultaneously after addition of the internal standard and dilution with the mobile phase, without further sample cleanup by a flow injection LC/MS/MS system (PE-Sciex API 3000; MDS Sciex, Concord, Ontario, Canada). Briefly, 0.2-mL aliquots of study samples were mixed with 0.2 mL of the internal standard solution and 1 mL of the mobile phase (1.25 mM ammonium acetate in 85% methanol/15% water, v/v). Following centrifugation, an aliquot was transferred into an autosampler vial, and 10 µLof the solution was injected into the LC/MS apparatus using the mobile phase at a flow rate of 0.2 mL/min. Mouth-rinsing solution samples with des-CIC were spiked with the internal standard, and 5 µL was injected into a reversed-phase LC/MS/MS system (Waters Symmetry C18, 3.5 µm, 2.1 x 50 mm; Waters Corporation, Milford, MA) at a flow rate of 0.2 mL/min.
Detection of the analytes of interest was accomplished by a PE-Sciex API 3000 MS/MS in negative ion daughter mode. Monitoring was at mass 356.5, 356.5, 338.8, and 413 (atomic mass units) for the internal standard, des-CIC, ciclesonide, and FP, respectively. The concentrations were determined by linear least squares regression in plotting the peak area ratios of the analytes over the internal standard against the nominal concentrations. Calibration ranges were 1.0 to 50 ng/mL, 5.0 to 1000 ng/mL, and 4.8 to 1000 ng/mL for des-CIC, ciclesonide, and FP, respectively.
Statistical Analysis
Because this was primarily an analytical investigation, the sample size (N = 18) was selected purely on the basis of feasibility. The primary study variables assessed were the respective AUC0-60 min of ciclesonide, its active metabolite des-CIC, and FP in the oropharyngeal washes. AUC0-60 min was calculated on molar concentrations by the trapezoidal rule using the value zero for samples with a concentration below the limit of quantification (BLQ). Point estimate and 95% confidence limits were calculated for the ratio of the molar AUC population medians adjusted for the molar dose, with 800 µg ciclesonide corresponding to 1.48 µmol and 1000 µg FP corresponding to 1.99 µmol. A multiplicative model reflecting the 2 treatment sequences and a parametric analysis after logarithmic transformation were used for calculation of the point estimates for (1) des-CIC and FP (primary analysis), (2) des-CIC + ciclesonide and FP (secondary analysis), and (3) des-CIC and ciclesonide (secondary analysis with regard to metabolite formation). All statistical evaluations and analyses, except for P values, were performed using an inhouse validated program (BIOQPC, version 1.2.2; ALTANA Pharma; Konstanz, Germany), which has been published previously.10 P values were calculated using 2-tailed t tests.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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LC/MS/MS Analysis
Calibration data, quality control data, and chromatograms indicated that the methods performed acceptably during analysis of the study samples. Between-batch precision values based on the coefficient of variation of quality control samples were better than 8.0% (FP), 7.8% (ciclesonide), and 6.0% (des-CIC). Between-batch accuracy values based on the coefficient of variation of quality control samples for all compounds were in the range of 94.7% to 104.8% of the nominal concentration.
Concentrations of Drugs Detected in Oropharyngeal Washes
Maximum concentrations of ciclesonide and FP were detected immediately after inhalation (mean 2.4 minutes after start of inhalation). The mean Cmax value for ciclesonide was 1336.7 nmol/L (2798 µg/L), with a total mean recovery of 43.5 µg, corresponding to 5.4% of the nominal inhaled dose of 800 µg. Analysis of ciclesonide over a period of 60 minutes after inhalation indicated that the amounts present within the oropharynx decreased sharply over a period of 15 minutes following inhalation, and little residual ciclesonide was detected after 30 minutes (Figure 1). des-CIC was detected in very low levels with comparable concentrations in the wash samples after 15 to 60 minutes following inhalation of ciclesonide, with a mean tmax of 0.53 hours (Figure 1). The mean and the maximal individual concentration of des-CIC detected were 62.2 nmol/L (29.3 µg/L) and 173.8 nmol/L (81.8 µg/L).
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Similar to ciclesonide, maximum concentrations of FP were also detected in the wash samples immediately after inhalation and decreased sharply within 15 minutes after inhalation (Figure 2). However, the mean Cmax value for FP immediately after inhalation was nearly 3-fold higher (1752 µg/L; 3501.3 nmol/L), and the mean total amount recovered was approximately 2-fold higher (105.4 µg, corresponding to 10.5% of the nominal inhaled dose of 1000 µg) than that detected for ciclesonide.
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The mean AUC0-60 min (± SEM) for ciclesonide, des-CIC, and FP was calculated to be 250.4 ± 62.5, 37.8 ± 8.0, and 636.2 ± 118.2 nmol·h/L, respectively. Point estimate and 95% confidence limits were calculated for the ratio of the standardized AUC population medians using a molar dose value of 1.48 µmol for ciclesonide and 1.99 µmol for FP (Table II). Differences in the oropharyngeal deposition of des-CIC or ciclesonide compared with FP were statistically significant (P < .001). A point estimate of 0.08 was obtained for the ratio of the AUC0-60 min population medians for des-CIC, with reference to FP (P < .00001), suggesting that when only both active study medications are compared, des-CIC was present in the oropharynx within the first hour following inhalation in an amount that was only 8% relative to FP. Comparison between des-CIC and its parent compound, ciclesonide, demonstrated that less than 20% (point estimate of 0.17; P < .00001; Table II) of ciclesonide was converted to des-CIC within the first hour following inhalation.
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Figure 2 illustrates the time course of the concentrations of the sum of both ciclesonide and its active metabolite, des-CIC, compared to FP. A point estimate of 0.53 was obtained for the ratio of the AUC0-60min population medians for ciclesonide + des-CIC, with reference to FP (P < .001), suggesting that approximately 50% less ciclesonide and des-CIC were present in the oropharynx within the first hour following inhalation compared with FP (Table II).
Half of the patients inhaled ciclesonide first, followed by FP, whereas the others received the medication vice versa. Based on the analytical results, there was no sequence effect.
Adverse Events
Seven patients reported 1 or more adverse events (AEs) during some stage of the study. A total of 13 AEs were observed (1 occurred before randomization and first intake of study medication), of which coughing (n = 3) was the most common, and none was serious enough to warrant premature withdrawal of any patient from the study. All the AEs were mild to moderate in intensity.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study demonstrates that there are significant differences in the oropharyngeal deposition of ciclesonide and FP administered via HFA-MDI in patients with asthma. A comparison of the AUC0-60 min for the 2 drugs showed that oropharyngeal deposition of ciclesonide and des-CIC was only half that of FP at therapeutic doses of 800 µg ciclesonide and 1000 µgFP. For the data analyses, doses were adjusted on a molar basis. In addition, only 17% of the ciclesonide that was deposited into the oropharyngeal cavity was converted to the biologically active des-CIC, suggesting that the activation of the parent compound, ciclesonide, within the upper oropharynx was low. Different esterases are involved in the activation of ciclesonide, including mainly cytosolic carboxylesterases, as demonstrated previously.11 The concentration of des-CIC in the oropharynx was only 8% of the FP concentration. Therefore, there was 12.5-fold less des-CIC than FP in the oropharynx within 1 hour after inhalation.
A previous study investigating the pulmonary deposition of ciclesonide using 2-D and 3-D scintigraphy demonstrated that about 52% of the inhaled drug is deposited in the lung with even distribution.8 In comparison, 16% pulmonary deposition has been reported in the literature for FP using MDI.12 Low deposition in the lung can be associated with a higher deposition in the oropharynx.
Clinically relevant side effects result from oropharyngeal deposition of inhaled corticosteroids. The incidence and severity of these side effects depend on the dose, the frequency of administration, and the delivery system used. Hoarseness of the voice (dysphonia), which may be due to myopathy of laryngeal muscles, is the most commonly reported local side effect of inhaled corticosteroids and is alleviated on treatment withdrawal. Oropharyngeal candidiasis can be a problem in some patients, particularly in the elderly on concomitant oral steroids and in more severe asthmatics at higher doses.13 In most studies, reporting local side effects has only been a small part of the study, and the focus most often has been on systemic side effects. Few studies have investigated the local side effects of inhaled corticosteroids systematically. Williamson et al14 found that 58% of outpatients receiving an inhaled corticosteroid reported throat symptoms or dysphonia compared with 13% of control subjects. Local side effects were equally prevalent with both beclomethasone dipropionate and budesonide aerosol inhalers. A recent study by Kanda et al15 showed a significantly higher prevalence of esophageal candidiasis in patients treated with FP (37%) compared to those in the control group (0.3%; P < .001). Furthermore, the prevalence was significantly higher in patients receiving 1200 µg/d FP than in those receiving 
800 µg/d (P < .05).15 This dose-dependent effect of FP was also reported by Adams et al,16 who showed that hoarseness and oral candidiasis were significantly higher with 800 to 1000 µg/d than 50 to 100 µg/d. The results from the current study indicate a significant potency of ciclesonide to cause a lower incidence of local side effects than FP. It could be speculated whether the low concentration of des-CIC, considering its glucocorticoid receptor affinity, results in sufficient occupancy of receptors to cause local side effects in the same frequency as other inhaled steroids. However, this is refuted by clinical findings: a recent clinical study confirmed that the incidence of local side effects with ciclesonide is dose independent, comparable with placebo, and less than that with FP.17 This was confirmed by a pooled analysis of more than 6800 patients, in which the incidence of local AEs/patient year under ciclesonide was found to be equal to placebo and less than other inhaled glucocorticosteroids investigated, including FP.18
The systemic effects—which could possibly arise as a consequence of oropharyngeal deposition—and subsequent gastrointestinal absorption and first-pass metabolism of the swallowed fraction of the dose of ciclesonide are also likely to be greatly reduced. This might have contributed to findings of a recent study on cortisol secretion in asthma patients that showed that ciclesonide therapy results in significantly less cortisol suppression than FP.19 Whereas the degree of cortisol suppression increased with higher doses of FP, there was no evidence of a dose-dependent increase in cortisol suppression with ciclesonide.19
Besides its unique pharmacologic and pharmacokinetic profile with conversion of the parent compound to the active metabolite des-CIC by esterases, ciclesonide has been shown to be clinically effective in several studies. A study on the effect of inhaled ciclesonide (100, 400, and 1600 µg/day) on airway responsiveness to inhaled adenosine-5'-monophosphate (AMP) showed a dose-dependent reduction in airway responsiveness to AMP.20 Furthermore, a study by Kanniess et al21 showed that ciclesonide is equieffective to budesonide with regard to its potency to reduce the airway responsiveness to inhaled AMP and airway inflammation in patients with mild asthma. Ciclesonide has also been shown to provide significant reduction in early and late-phase reactions to allergen challenge in mild asthmatics.22 In clinical studies, ciclesonide—administered at 100 to 800 µg once daily—has been shown to provide significant improvement in pulmonary function, asthma symptom control, and rescue medication use when compared with placebo.3,4 Hence, ciclesonide has demonstrated effectiveness in the treatment of asthma. From a clinical point of view, ciclesonide has a useful pharmacology that delivers potent anti-inflammatory activity close to its site of action while potentially reducing the risk for local or systemic side effects.
In conclusion, the present study demonstrates that oropharyngeal deposition of ciclesonide is much lower (approximately 50%) than that for FP following inhalation from an HFA-MDI. Furthermore, there is little activation of ciclesonide to its active metabolite, des-CIC, in the oropharynx, suggesting a decreased likelihood of local or oropharyngeal side effects compared with FP. More clinical trials directly comparing the safety of ciclesonide with FP or other inhaled corticosteroids used for asthma treatment should confirm the lower incidence of local side effects with ciclesonide.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication May 20, 2004; Revised version accepted September 15, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. National Institutes of Health, National Heart, Lung, and Blood Institute. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention (revised 2002). Available at: www.ginasthma.com/workshop.pdf. Accessed May 4, 2004.
2. Dietzel K, Engelstätter R, Keller A. Ciclesonide: an on-site-activated steroid. In: Hansel TT, Barnes PJ, eds. New Drugs for Asthma, Allergy and COPD. Vol 31. Basel, Switzerland: Karger; 2001: 91-93.
3. Engelstätter R, Langdon C, Bethke T, Rathgeb F, Steinijans VW, Wurst W. Efficacy of ciclesonide after twelve-week treatment of bronchial asthma [abstract]. Paper presented at: 98th International Conference of the American Thoracic Society; May 17-22, 2002; Atlanta, Ga. Abstract G 70.
4. Chapman KR, D'Urzo AD, Oedekoven C, Steinijans VW, Wurst W. Effects of ciclesonide versus placebo on lung function after 12 weeks of treatment in patients with asthma [abstract]. Paper presented at: 98th International Conference of the American Thoracic Society; May 17-22, 2002; Atlanta, Ga. Abstract G 74.
5. Postma DS, Sevette C, Martinat Y, Schlösser N, Aumann J, Kafé H. Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Eur Respir J. 2001;17: 1083-1088.
6. Weinbrenner A, Hüneke D, Zschiesche M, et al. Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. J Clin Endocrinol Metab. 2002;87: 2160-2163.
7. Chapman KR, Patel P, Boulet LP, et al. Efficacy and long-term safety of ciclesonide in asthmatic patients as demonstrated in a 52 week long study [abstract]. Paper presented at: 12th Annual Congress of the European Respiratory Society; September 14-18, 2002; Stockholm, Sweden. Abstract 2328.
8. Bethke TD, Boudreau RJ, Hasselquist BE. High lung deposition of ciclesonide in 2D-and 3D-imaging [abstract]. Paper presented at: 12th Annual Congress of the European Respiratory Society; September 14-18, 2002; Stockholm, Sweden. Abstract P746.
9. American Thoracic Society. Standardization of spirometry, 1994 update. Am JRespir Crit Care Med. 1995;152: 1107-1136.[Web of Science][Medline] [Order article via Infotrieve]
10. Sauter R, Steinijans VW, Diletti E, Bohm A, Schulz HU. Presentation of results from bioequivalence studies. Int J Clin Pharmacol Ther Toxicol. 1992;30: 233-256.[Medline] [Order article via Infotrieve]
11. Mutch E, Nave R, Zech K, Williams FM. Esterases involved in the hydrolysis of ciclesonide in human tissues [abstract]. Paper presented at: 13th Annual Congress of European Respiratory Society; September 25–Oct 1, 2003; Vienna, Austria. Abstract 267s.
12. Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety. Respir Med. 1997;91(suppl A): 22-28.
13. Toogood JH, Jennings B, Greenway RW, Chuang L. Candidiasis and dysphonia complicating beclomethasone treatment of asthma. J Allergy Clin Immunol. 1980;65: 145-153.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Williamson IJ, Matusiewicz SP, Brown PH, Greening AP, Crompton GK. Frequency of voice problems and cough in patients using pressurized aerosol inhaled steroid preparations. Eur Respir J. 1995;8: 590-592.[Abstract]
15. Kanda N, Yasuba H, Takahashi T, et al. Prevalence of esophageal candidiasis among patients treated with inhaled fluticasone propionate. Am J Gastroenterol. 2003;98: 2146-2148.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Adams N, Bestall JM, Jones PW. Inhaled fluticasone at different doses for chronic asthma. Cochrane Database Syst Rev. 2002;(1): CD003534.
17. Bernstein JA, Noonan MJ, Rim C, et al. Ciclesonide has minimal oropharyngeal side effects in the treatment of patients with moderate-to-severe asthma [abstract]. Paper presented at: 60th Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI); March 19-23, 2004; San Francisco. Abstract 349.
18. Engelstätter R, Banerji D, Steinijans VW, Wurst W. Low incidence of oropharyngeal adverse events in asthma patients treated with ciclesonide: results from a pooled analysis [abstract]. Paper presented at: 100th International Conference of the American Thoracic Society; May 21-26, 2004; Orlando, Fla. Abstract A 92.
19. Pauwels RA, Derom E, Van De Velde V, Marissens S, Vincken W. Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and PC20 for adenosine in asthma patients [abstract]. Paper presented at: 98th International Conference of the American Thoracic Society; May 17-22, 2002; Atlanta, Ga.
20. Taylor DA, Jensen MW, Kanabar V, et al. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients. Am J Respir Crit Care Med. 1999;160: 237-243.
21. Kanniess F, Richter K, Böhme S, Jörres RA, Magnussen H. Effect of inhaled ciclesonide on airway responsiveness to inhaled AMP, the composition of induced sputum and exhaled nitric oxide in patients with mild asthma. Pulm Pharmacol Ther. 2001;14: 141-147.[Medline] [Order article via Infotrieve]
22. Larsen BB, Nielsen LP, Engelstätter R, Steinijans V, Dahl R. Effect of ciclesonide on allergen challenge in subjects with bronchial asthma. Allergy. 2003;58: 207-212.[CrossRef][Medline]
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