Mometasone furoate antagonizes AMPinduced bronchoconstriction in patients with mild asthma

Transcription

1 Mometasone furoate antagonizes AMPinduced bronchoconstriction in patients with mild asthma Stephen T. Holgate, MD, DSc, a Hasan Arshad, DM, MRCP, a Paul Stryszak, PhD, b and Judy E. Harrison, BM, BCh b Southampton, United Kingdom Background: Mometasone furoate (MF) is a new potent corticosteroid for use in treating asthma. Objective: To test the lower range of the dose-response curve, effects of MF delivered by dry powder inhaler (DPI) on AMPinduced bronchoconstriction were compared with those of placebo. Methods: In a placebo-controlled, 3-phase cross-over, singlecenter, double-blind study, 15 patients with mild asthma were randomized to three 2-week treatment phases (separated by 4- week washout phases) with MF DPI 50 µg twice daily, MF DPI 100 µg twice daily, or placebo. AMP challenge was performed before and at the end of each treatment phase. Results: Thirteen patients completed all 3 phases and were included in the primary efficacy analysis. Treatment with MF DPI 50 µg twice daily or with MF DPI 100 µg twice daily significantly reduced the bronchoconstrictor response to AMP, displacing the dose-response curve to the right by 2.81 and 3.11 doubling dilutions, respectively, compared with placebo (P <.001). The improvement in FEV 1 over the 2-week treatment phase was significantly (P.033) greater during treatment with MF DPI 50 µg or 100 µg twice daily than with placebo. Peak expiratory flow rate, wheezing scores, difficulty breathing scores, nocturnal awakenings requiring salbutamol, and puffs of salbutamol per day also indicated a greater improvement in respiratory function and symptoms of asthma with MF DPI 50 or 100 µg twice daily than with placebo. Both doses of MF DPI were well tolerated. Conclusions: Treatment with low doses of MF DPI decreased airway responsiveness to AMP challenge and improved secondary measures of pulmonary function and asthma symptoms. (J Allergy Clin Immunol 2000;105: ) Key words: Asthma, mometasone furoate, bronchoconstriction, adenosine challenge, placebo Inhaled corticosteroids are the most important drugs used in the management of mild to moderately severe asthma. 1,2 They decrease the frequency of asthma attacks and may have disease-modifying properties. 1,2 Many of From the a Southampton General Hospital, Southampton, United Kingdom, and the b Schering-Plough Research Institute, NJ. Received for publication Sept 20, 1999; revised Jan 14, 2000; accepted for publication Jan 14, Reprint requests: Stephen T. Holgate, MD, DSc, Southampton General Hospital, Southampton University, Med I, Level D, Southampton, S016 6YD United Kingdom. Copyright 2000 by Mosby, Inc /2000 $ /1/ doi: /mai Abbreviations used BID: Twice-daily dosing DPI: Dry powder inhaler FVC: Forced vital capacity MF: Mometasone furoate PC 20 : Provocative concentration producing a 20% fall in FEV 1 PEFR: Peak expiratory flow rate the currently available inhaled corticosteroids have high topical potency in the lungs, as well as rapid first-pass hepatic metabolism when absorbed from the gastrointestinal tract, thus greatly reducing their systemic bioavailability relative to oral corticosteroids. 2 Mometasone furoate (MF) is a highly potent topical steroid. MF has been used extensively in topical dermatologic formulations since 1987 for treating corticosteroid-responsive skin diseases. 3-5 MF is also available in an aqueous nasal spray formulation for the treatment of allergic rhinitis. 6 A new dry powder inhaler (DPI) formulation of MF is under investigation for use in treating asthma. 7,8 Much of the current knowledge concerning the antiinflammatory effects of inhaled glucocorticoids is based on in vitro studies. Administration of MF has been shown in vitro to reduce the mediators involved in the inflammatory response associated with asthma MF has an affinity for the glucocorticoid receptor in the human lung that is higher than that of fluticasone, budesonide, or triamcinolone acetonide, which relates to its potency in inhibiting inflammation. 12 This study was designed to evaluate the efficacy of low doses of MF DPI for antagonizing AMP-induced bronchoconstriction compared with placebo. When inhaled, AMP causes dose-related bronchoconstriction in patients with atopic and nonatopic asthma. AMP is thought to cause bronchoconstriction indirectly by activating airway mast cells. 13 The anti-inflammatory properties of inhaled corticosteroids are thought to lead to a reduction in the number of inflammatory cells, such as mast cells, in the airway. Hence response to AMP provocation, as assessed by the effect on FEV 1 after dosing with increasing concentrations of AMP, may provide a useful and sensitive method for assessing the effect of treatment with low doses of corticosteroids in patients with asthma. 14

2 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 5 Holgate et al 907 METHODS This randomized, placebo-controlled, single-center, 3-phase cross-over, double-blind study was designed to evaluate the effect of 2 low doses of MF DPI on AMP-induced bronchoconstriction compared with placebo in patients previously maintained on inhaled β- agonists alone. Patients This study enrolled 15 nonsmoking patients with a history of asthma of at least 6 months duration. Patients must have had a baseline FEV 1 60% of predicted screening and baseline visits when all restricted medications (see below) were withheld for the specified intervals. At screening patients had to demonstrate an increase in absolute FEV 1 of 12%, with an absolute volume increase of at least 200 ml after reversibility testing. Patients must have demonstrated sensitivity to inhaled AMP at screening; the provocative concentration causing a 20% fall in FEV 1 (PC 20 ) must have been 100 mg/ml. Patients were to be using only short-acting inhaled β 2 -agonists to control their asthma for the 2 weeks before screening. Women of childbearing potential were to be using acceptable methods of birth control. Patients were free of any clinically significant disease other than asthma. Patients were excluded from the study if they received treatment with inhaled corticosteroids for asthma within 1 month before screening, required daily or alternate day oral corticosteroid treatment for more than a total of 14 days during the 6 months before the screening visit, required a burst of systemic steroids within the previous 3 months, had been hospitalized for asthma control within the previous 3 months, or received emergency hospital treatment for management of airway obstruction on 2 or more occasions within the previous 6 months. Women who were pregnant, breast-feeding, or premenarchial were excluded. Additionally, patients were excluded whose clinical condition required daily use of nebulized β 2 -agonists, who had used any investigational drug in the last 30 days or who had ever been treated with any investigational antibody for asthma, who were allergic to corticosteroids or β 2 -agonists or who were allergic to more than 2 different classes of medications, who required ventilator support for respiratory failure as a result of asthma within the last 5 years, who had clinical evidence of chronic obstructive pulmonary disease, who had evidence of clinically significant oropharyngeal candidiasis, who demonstrated an increase or decrease in FEV 1 of 20% between screening and baseline visits, who required the use of >12 puffs of salbutamol per day on any 2 consecutive days between screening and baseline, and who had clinically significant abnormal laboratory tests or electrocardiogram at the screening visit. The study was conducted in accordance with applicable law, regulations, and the principles of good clinical practice. Written informed consent was obtained for each patient and the protocol and informed consent form were reviewed by the Southampton General Hospital Ethics Committee. Drug administration There were three 2-week treatment phases with MF DPI 50 µg given twice daily (BID), MF DPI 100 µg BID, and placebo BID, separated by a wash-out phase of 4 weeks. After randomization patients were assigned to 1 of the 6 possible treatment sequences beginning with placebo, MF DPI 50 µg BID, or MF DPI 100 µg BID. Patients were administered test medications once in the morning and once in the evening; doses were separated by approximately 12 hours. All patients received a salbutamol metered-dose inhaler (Ventolin, Allen and Hanbury, Uxbridge, UK) at visit 1. Salbutamol was used for symptom relief as needed. Salbutamol use more than 12 puffs per day on any 2 consecutive days was reported to the investigator. Salbutamol was to be withheld 6 hours before each visit but could be used during the two 4-week wash-out periods. Nebulized β 2 -agonists (where 1 nebulization treatment was regarded as equivalent to 6 puffs of salbutamol) were permitted during the study, with a 6-hour withhold before study visits. No other asthma medications were allowed, including oral or inhaled β 2 -agonists, anticholinergics, theophylline, cromolyn, nedocromil, or corticosteroids. Other permitted medications included over-the-counter pain relievers, antibiotics for indications other than lower respiratory tract infections, topical antimicrobials, topical nasal or ocular decongestants, nasal or ocular cromolyn, ocular antihistamines, intranasal anticholinergics, short-acting pseudoephedrine, oral antihistamines, and dermatologic topical corticosteroids. Study Design After the completion of a 1-week run-in period and all specified baseline evaluations, patients took the first medication specified by the randomization code for the first 2-week treatment phase (phase I). Phase I was followed by a 4-week wash-out period. Patients returned at the end of the wash-out period for evaluation. They then had all phase II pretreatment procedures performed and received the second drug specified by the randomization code. They entered the second 2-week treatment phase (phase II). Another 4-week washout period followed, after which patients returned for evaluation and phase III pretreatment procedures. Patients then received the third drug specified by the randomization code and entered the last 2- week treatment phase (phase III). The patients then returned for the final visit at the end of phase III. AMP challenge was performed at each study visit. Before AMP challenge, spirometry was performed at all visits to measure FEV 1 and forced vital capacity (FVC) and compared with the European Community Steel and Coal reference ranges. 15 Patients recorded peak expiratory flow rate (PEFR) (in liters per minute), asthma symptom scores, and use of rescue medication twice daily throughout the study. Investigators assessed response to therapy at the posttreatment visit of each phase. Each patient received diary cards and a Personal Best Peak Flow meter (Clement Clarke, Harlow, UK) for measuring PEFR and instructions regarding its proper use. Patients recorded morning and evening PEFR, total number of salbutamol inhalations, asthma symptoms (wheezing, difficulty breathing, cough), number of nocturnal awakenings asthma requiring salbutamol use, adverse events, and use of study drug and concomitant medications. Efficacy assessments The primary efficacy variable was the change in log 10 PC 20 (postttreatment pretreatment). Secondary efficacy variables included FEV 1, FVC, PEFR, asthma symptoms, response to therapy, salbutamol use, and the number of nocturnal awakenings requiring salbutamol use. Asthma symptoms were scored as 0 = none; 1 = noticeable; 2 = annoying, some interference with my normal daily activities/sleep; and 3 = very uncomfortable, interfered with most or all of my normal daily activities/ sleep. Investigators assessed the patient s response to therapy at the posttreatment visits of each phase by comparing the patient s current level of symptoms with those noted at the start of each pretreatment phase with use of the following scale: 1 = much improved, 2 = improved, 3 = no change, 4 = worse, 5 = much worse. AMP challenge Before AMP challenge patients were instructed to withhold medications for the following intervals: salbutamol, 6 hours; oral antihistamines, 48 hours; nasal cromolyn, 24 hours; intranasal anticholinergics and topical nasal decongestants, 48 hours. Patients were to avoid exercise or cold air exposures for at least 2 hours before the challenge and were to refrain from ingestion of coffee, tea, cola, and chocolate for at least 6 hours before the challenge. AMP challenge

3 908 Holgate et al J ALLERGY CLIN IMMUNOL MAY 2000 was not to be performed if patients had a prechallenge FEV 1 of less than 60% predicted, had clinically significant symptoms of asthma, or had upper or lower respiratory tract infections. Patients were rested for 15 minutes and the prechallenge spirometry performed. The highest FEV 1 was recorded as the prechallenge (presaline) value. Patients then inhaled a control aerosol of 0.9% wt/vol sodium chloride in 5 breaths from end-tidal volume to maximum inspiratory capacity. The aerosol was nebulized with a Medic-Aid (Pagham, UK) or equivalent nebulizer, driven by compressed air at 8 L/min. Under these conditions the mass median particle diameter was <5.0 µm at a delivery rate of 0.25 to 0.5 ml/min. FEV 1 was measured at 1 and 3 minutes after inhalation and the lower of the best readings was recorded. Provided the postsaline FEV 1 value did not fall by >10% from the presaline value, an AMP dose-response challenge was performed. Investigators prepared a fresh mixture of AMP in 0.9% wt/vol sodium chloride to produce a range of concentrations of 0.39 to 400 mg/ml. Each concentration was administered to the patient as a nebulized aerosol in doubling increments at 5-minute intervals. Two measurements of FEV 1 were taken at both 1 and 3 minutes after each concentration of AMP. The best of the 2 measurements at each time point were taken, with the lower of the 2 best readings recorded. Dosing ceased when the postdose FEV 1 fell by >20% of the postsaline value or when the maximum concentration of AMP was reached. The PC 20 was calulated by linear interpolation of the last 2 points on either side of the PC 20 line of the dose-response curve. If required, residual bronchoconstriction was reversed by inhalation of 200 µg of salbutamol. At the start of each treatment phase the PC 20 was required to be within 1.2 doubling dilutions of the screening value for the patient to receive study treatment in that phase. 16 If this criterion was not met, the challenge was repeated within the next 3 days, but on no more than 2 occasions. If, on the second rechallenge, the criterion was still not met, the patient was removed from the study. Safety evaluations Medical histories were taken at screening. The primary safety variables included adverse events (all visits), vital signs (all visits), and the results of physical (screening and final visits) and oropharyngeal examinations (all visits). Laboratory tests and a 12-lead electrocardiogram were conducted at the screening visit only. Patients could withdraw at any time. Patients were to be removed from the study if they had a clinically significant worsening of asthma, defined as 20% or greater decrease in FEV 1 (absolute value) from the baseline value; clinical asthma exacerbation requiring emergency treatment, hospital admission or treatment with additional asthma medication (other than short-acting inhaled β 2 -agonists); 25% or greater decrease in morning PEFR from the mean baseline morning value on any 2 consecutive days; or a clinically significant increase in the use of bronchodilators (eg, use of 12 puffs of salbutamol or >2 treatments with nebulized β 2 -agonists on any 2 consecutive days). Statistical methods All randomized patients who received study medication and had data from at least 2 treatment phases were included in the primary efficacy analysis data set. ANOVA was used to analyze the response for the primary and some secondary variables (eg, FEV 1 and FVC) allowing for the sources of variability resulting from sequence, patients within sequences, period, and treatment. Statistical tests of significance were not performed for the other secondary variables. The primary comparison was based on a pairwise comparison between the MF DPI 100 µg BID and placebo with use of the least-square means from the ANOVA model. If the comparison of MF DPI 100 µg BID and placebo was statistically significant at the 5% level (2-sided), the comparison of the MF DPI 50 µg BID with placebo and the MF DPI 50 µg BID with MF DPI 100 µg BID were made at the 5% significance level with no adjustments for multiple comparisons. Pairwise treatment mean differences were estimated with use of linear contrasts of the least-squares means from the ANOVA, and 95% confidence intervals were calculated. Changes in log 10 PC 20 were expressed in terms of doubling dilutions: ([Posttreatment Pretreatment]log 10 PC 20 [Posttreatment Pretreatment]log 10 PC 20 )/log Demographic information, adverse events, vital signs, physical examination findings, and diary data (eg, symptom scores) were summarized by treatment group and sequence. These summaries were based on all randomized patients. RESULTS Demographics This study included 7 female and 8 male patients between the ages of 21 and 49 years. All patients were white. There was a wide variation in patient PC 20 before treatment. At the beginning of phase I, before the administration of any study medication, PC 20 values ranged from 1.02 mg/ml to mg/ml with a median of 3.15 mg/ml. One patient discontinued the study during the first treatment phase and one during the second treatment phase (see Safety). Thirteen patients completed all 3 treatment phases and were included in the primary analysis data set. AMP challenge Treatment with MF DPI 50 µg BID or MF DPI 100 µg BID significantly decreased the bronchoconstrictor response to AMP compared with treatment with placebo. With use of the least-squares means, these increases in log 10 PC 20 during treatment with MF DPI 50 µg BID or MF DPI 100 µg BID were significantly greater (P <.001) than increases during treatment with placebo (Table I). Although there were no significant differences between doses, treatment response based on AMP challenge was numerically greater during treatment with MF DPI 100 µg BID than with MF DPI 50 µg BID (Table I). The numbers of doubling dilutions of AMP concentrations were 3.11 and 2.81, for MF DPI 100 µg BID and MF DPI 50 µg BID, respectively. AMP challenge data were plotted as the slope of the least-squares line fitted to the scatterplot of FEV 1 (expressed as percent decrease from the postsaline value) against log 10 AMP concentration. The slope of the least squares increased during treatment with both doses but was essentially unchanged during treatment with placebo (Table I). These results indicate that after treatment with MF DPI patients were less responsive to increases in AMP than after treatment with placebo. The differences in response seen during treatment with MF DPI 50 µg BID and placebo (P.001) as well as during treatment with MF DPI 100 µg BID and placebo (P.001) were statistically significant. There was no significant difference between treatment with MF DPI 50 µg BID and with MF DPI 100 µg BID.

4 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 5 Holgate et al 909 TABLE I. Effects of MF DPI on AMP-induced bronchoconstriction Placebo MF DPI 50 µg BID MF DPI 100 µg BID Change in AMP concentration (mean log 10 PC 20 ) Pretreatment (raw mean) Posttreatment (raw mean) Change (raw mean) Change (least-squares mean ± SE) ± ± ± Slope of percent change in FEV 1 plotted against AMP concentration Pretreatment Posttreatment Difference in least-square means MF DPI 50 µg BID vs placebo ± (P.001) MF DPI 100 µg BID vs placebo ± (P.001) MF DPI 50 µg BID vs 100 µg BID ± (P =.57) FEV 1 was recorded before and after challenge with AMP ( mg/ml). TABLE II. Effects of MF DPI treatment on pulmonary function and asthma Placebo MF DPI 50 µg BID MF DPI 100 µg BID No. Mean No. Mean No. Mean Pulmonary function FEV 1 (L) Pretreatment Change ± ± 0.070* ± 0.070* FVC (L) Pretreatment Change ± ± ± Diary data Morning PEFR (L/min) Washout Change Morning wheeze Washout Change Morning difficulty breathing Washout Change Morning cough Washout Change Nocturnal awakenings requiring salbutamol (per night) Washout Change Salbutamol (puffs/d) Washout Change For measures of pulmonary function, the change is the difference between treatment for 2 weeks and the pretreatment period. Only FEV 1 and FVC were statistically analyzed. For the diary data, the change is the difference between the values obtained during each treatment phase and the washout period. *P < 0.05 compared with placebo. FEV 1 and FVC Results of pulmonary function testing indicated that improvements in FEV 1 during treatment with MF DPI 50 µg BID or MF DPI 100 µg BID were significantly greater (P.033) than those observed during treatment with placebo (Table II, Fig 1). There was no statistically significant difference in response between treatment with MF DPI 50 µg BID and MF DPI 100 µg BID (P =.258). Mean increases in FVC were not statistically significant (P =.850, Table II). PEFR, asthma symptoms, and response to therapy Improvements based on patient recorded changes in PEFR, morning wheezing scores, morning difficulty breathing scores, number of asthma-related nocturnal awakenings, and use of salbutamol were numerically better during treatment with MF DPI than during treatment with placebo (Table II) but were not analyzed for statistical significance. Evening wheezing, coughing, and difficulty breathing scores showed results similar to the

5 910 Holgate et al J ALLERGY CLIN IMMUNOL MAY 2000 FIG 1. Effects of MF DPI treatment on FEV 1. Bars represent change in mean between pretreatment and 2 weeks of treatment. TABLE III. Summary of adverse events reported by at least 10% of the patients Placebo MF DPI 50 µg MF DPI 100 µg Event (n = 15) BID (n = 13) BID (n = 14) Headache 1 (7) 0 (0) 4 (29) Pharyngitis 2 (13) 1 (8) 2 (14) Infection, viral 4 (27) 2 (15) 2 (14) Allergy 2 (13) 2 (15) 1 (7) Menstrual disorder* 2 (29) 1 (14) 1 (14) Values are number of patients (%). *Percent calculated based on total female population. morning scores (data not shown). Investigators assessed the response to therapy by comparing each subject s level of symptoms at the beginning and end of each treatment phase. The response to treatment scores were also numerically better during treatment with MF DPI 50 µg BID (mean 2.0) and MF DPI 100 µg BID (mean 2.4) than during treatment with placebo (mean 3.1). Safety All 15 patients were included in the safety evaluation. MF DPI was well tolerated. All reported adverse events were mild or moderate in severity at both doses during the 2 weeks or more of patient exposure. The overall incidence of adverse events was similar in patients receiving MF DPI 50 µg BID (54%), MF DPI 100 µg BID (64%), and placebo (67%). The most frequently reported adverse events included viral infection, headache, pharyngitis, allergy, and menstrual disorder. Headache was more common during treatment with MF DPI 100 µg BID than with MF DPI 50 µg BID or placebo; otherwise there were no notable differences in incidence of adverse events between treatment groups. Adverse events reported by at least 10% of patients during treatment are summarized in Table III. No patients reported oral candidiasis. In addition, no patients had an FEV 1 of less than 60% predicted, which would have precluded participation in the AMP challenge. Adverse events related to study drug were seen in 2 patients receiving MF DPI 50 µg BID and included nasal congestion, pharyngitis, and sinusitis in one patient and pharyngitis in the other. One patient, receiving placebo, was removed from the study because of viral infection in the first phase of the trial. A second patient, also receiving placebo, discontinued the study for treatment failure after completing phase I. No patients reported any serious adverse events. No unexpected changes in vital signs or physical examination were noted. DISCUSSION Treatment with MF DPI at 2 low doses (50 and 100 µg BID) for 2 weeks successfully antagonized AMPinduced bronchoconstriction. The PC 20 (expressed as doubling dilutions) increased by approximately 3-fold relative to placebo for both doses of MF DPI. Treatment with both doses also resulted in improvement in pulmonary function, patient-reported symptoms, and investigator assessments of response to therapy.

6 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 5 Holgate et al 911 Airway inflammation is a major factor contributing to disease severity and bronchial hyperresponsiveness in asthma 17 and the therapeutic effect of inhaled glucocorticosteroids is linked to their anti-inflammatory actions In in vitro studies, MF was shown to be overall the most potent inhibitor of inflammatory mediators among the glucocorticoids tested MF has also been shown to effectively inhibit the influx of inflammatory cells, particularly mast cells and eosinophils, to the nasal mucosa in patients with allergic rhinitis. 21 Mast cells are one of the primary effector cells involved in the inflammatory response associated with asthma. 2,22 The ability to attenuate this response therefore is likely to correlate with clinical efficacy. AMP primarily activates mast cells, and the response to AMPinduced bronchoconstriction can provide a sensitive method to assess the effect of low-dose corticosteroid treatment and the potential for anti-inflammatory activity in patients with asthma. A previous study showed that inhaled budesonide (800 µg BID) significantly decreased airway responsiveness to AMP challenge by 2.92 doubling dilutions compared with placebo and with both methacholine and sodium metabisulfite challenges. The authors suggested that budesonide may therefore confer an additional effect on reducing mast cell activity. 14 The results of the current study indicate that MF is also very effective in reducing bronchial responsiveness. In addition to the reduced bronchial hyperresponsiveness, both MF DPI 50 and 100 µg BID treatment significantly improved FEV 1 compared with placebo. This study was conducted using patients with mild asthma whose mean baseline FEV 1 value was 90% of predicted. Furthermore, the treatment was short term, and very low doses of MF DPI were used. Although the study involved only a small number of patients, this additional therapeutic benefit suggests clinical relevance. Improvements in PEFR, asthma symptoms, nocturnal awakenings requiring salbutamol use, and response to therapy supported the results based on the AMP challenge and showed a greater improvement in these variables after MF DPI treatment compared with placebo. There were no statistically significant differences between the MF DPI doses. Increases in PC 20 and FEV 1 were numerically larger, however, during treatment with MF DPI 100 µg BID than during treatment with MF DPI 50 µg BID. This suggests a trend toward a greater effectiveness of MF DPI 100 µg BID compared with 50 µg BID. Both doses of MF DPI were well tolerated, and no unusual or unexpected adverse events were reported. The most frequently reported adverse events were viral infection, headache, pharyngitis, allergy, and menstrual disorders. No patients reported oral candidiasis in this study. Otherwise, the adverse events reported in this study were similar to those reported in other studies investigating the effects of inhaled glucocorticosteroids. 2 In conclusion, both doses of MF DPI reduced responsiveness to AMP-induced bronchoconstriction and alleviated the signs and symptoms of asthma in this placebocontrolled study of patients with mild asthma. REFERENCES 1. Pedersen S, O Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997;52: Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids: new developments. Am J Respir Crit Care Med 1998;157:S Medansky RS, Bressinck R, Cole GW, Deeken JH, Ellis CN, Guin JD, et al. Mometasone furoate ointment and cream 0.1 percent in treatment of psoriasis: comparison with ointment and cream formulations of fluocinolone acetonide percent and triamcinolone acetonide 0.1 percent. Cutis 1988;42: Bronsky EA, Aaronson DW, Berkowitz RB, Chervinsky P, Graft D, Kaiser HB, et al. Dose ranging study of mometasone furoate (Nasonex) in seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1997;79: Prakash A, Benfield P. Topical mometasone: a review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs 1998;55: Onrust SV, Lamb HM. Mometasone furoate: a review of its intranasal use in allergic rhinitis. Drugs 1998;56: Bernstein DI, Berkowitz RB, Chervinsky P, Dvorin DJ, Finn AF, Gross GN, et al. Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler. Respir Med 1999;93: Nayak AS, Banov C, Corren J, Feinstein BK, Floreani A, Friedman BF, et al. Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma. Ann Allergy Asthma Immunol In press. 9. Barton BE, Jakway JP, Smith SR, Siegel MI. Cytokine inhibition by a novel steroid, mometasone furoate. Immunopharmacol Immunotoxicol 1991;13: Umland SP, Nahrebne DK, Razac S, Beavis A, Pennline KJ, Egan RW, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL- 5, and interferon-gamma production by cultured primary CD4+ T cells. J Allergy Clin Immunol 1997;100: Crocker IC, Church MK, Newton S, Townley RG. Glucocorticoids inhibit proliferation and interleukin-4 and interleukin- 5 secretion by aeroallergen-specific T-helper type 2 cell lines. Ann Allergy Asthma Immunol 1998;80: Smith CL, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Arzneimittelforschung 1998;48: Aziz I, Tan KS, Hall IP, Devlin MM, Lipworth BJ. Subsensitivity to bronchoprotection against adenosine monophosphate challenge following regular once-daily formoterol. Eur Respir J 1998;12: O Connor BJ, Ridge SM, Barnes PJ, Fuller RW. Greater effect of inhaled budesonide on adenosine 5 -monophosphate- induced than on sodiummetabisulfite induced bronchoconstriction in asthma. Am Rev Respir Dis 1992;146: Quanger PH. Standardized lung function testing: report of Working Party for the European Community for Steel and Coal. Bull Eur Physiopathol Respir 1983;19(5 Supp): Polosa R, Rajakulasingam K, Prosperini G, Church MK, Holgate ST. Relative potencies and time course of changes in adenosine 5 monophosphate airway responsiveness with inhaled furosemide and bumetanide in asthma. J Allergy Clin Immunol 1993;92: Holgate ST. Asthma: a dynamic disease of inflammation and repair. In: Chadwick D, Cardew G, editors. The rising trends in asthma. Chichester (UK): John Wiley; p Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 1992;145: Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, doubleblind, parallel-group controlled trial. J Allergy Clin Immunol 1992;90: Olivieri D, Chetta A, Del Donno M, Bertorelli G, Casalini A, Pesci A, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study. Am J Respir Crit Care Med 1997;155: Minshall E, Ghaffar O, Cameron L, O Brien F, Quinn H, Rowe-Jones J, et al. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (Nasonex) in the treatment of perennial rhinitis. Otolaryngol Head Neck Surg 1998;118: Busse WW. Inflammation in asthma: the cornerstone of the disease and target of therapy. J Allergy Clin Immunol 1998;102:S17-22.