Publications by authors named "David S Pearlman"

28 Publications

  • Page 1 of 1

Long-term safety and efficacy studies of epinephrine HFA metered-dose inhaler (Primatene Mist): a two-stage randomized controlled trial.

J Asthma 2020 Jan 20:1-12. Epub 2020 Jan 20.

Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA, USA.

: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI.: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline.: The primary efficacy endpoint (AUC of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant.: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.
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http://dx.doi.org/10.1080/02770903.2020.1713147DOI Listing
January 2020

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6-<12 years).

Ann Allergy Asthma Immunol 2017 04 1;118(4):489-499.e1. Epub 2017 Mar 1.

Allergy, Asthma & Immunology, AAADRS Clinical Research Center, Coral Gables, Florida.

Background: The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old.

Objective: To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma.

Methods: This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β-agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks.

Results: Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments.

Conclusion: Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone.

Trial Registration: ClinicalTrials.gov Identifier: NCT02091986.
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http://dx.doi.org/10.1016/j.anai.2017.01.020DOI Listing
April 2017

Novel albuterol multidose dry powder inhaler in patients with exercise-induced bronchoconstriction: A single-dose, double-blind, randomized, 2-way crossover study.

Respir Med 2015 Nov 8;109(11):1410-5. Epub 2015 Sep 8.

Colorado Allergy & Asthma Centers, 125 Rampart Way, Suite 150, Denver, CO 80230, USA. Electronic address:

Background: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) was developed that eliminates the need to coordinate device actuation with inhalation as is required with conventional metered-dose inhalers.

Objective: To evaluate albuterol MDPI efficacy and safety in patients with exercise-induced bronchoconstriction (EIB).

Methods: This single-dose, double-blind, 2-way crossover study randomized adolescents and adults with EIB (≥20% fall from pre-exercise challenge FEV(1)) to treatment sequences of albuterol MDPI (180 μg [2 inhalations of 90 μg each])/placebo MDPI (n = 19) or the reverse sequence (n = 19). FEV(1) was measured 30 and 5 min predose, 30 min postdose (ie, 5 min before treadmill exercise challenge; baseline) and 5, 10, 15, 30, and 60 min after exercise challenge. The primary efficacy endpoint was maximum percentage fall from baseline in FEV(1) up to 60 min post-exercise challenge.

Results: Mean maximum percentage fall in FEV(1) within 60 min post-exercise challenge was 6.2 ± 1.4% for albuterol MDPI versus 22.4 ± 1.4% for placebo MDPI (between-treatment difference: -16.2%; 95% CI: -20.2% to -12.1%; P < 0.0001). A significantly higher percentage of albuterol MDPI-treated patients were protected against EIB (<10% maximum FEV(1) fall post-exercise challenge) versus placebo MDPI (84.2% vs 15.8%; P < 0.0001). Protection with albuterol MDPI was evident within 5 min and maintained through 30 min; recovery was complete for both groups at 60 min. Treatment with a single dose of albuterol MDPI was generally well tolerated.

Conclusions: Albuterol MDPI provides clinically significant protection from EIB in adolescents and adults with EIB; no new safety issues were observed with short-term albuterol MDPI use. ClinicalTrials.gov identifier NCT01791972.
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http://dx.doi.org/10.1016/j.rmed.2015.09.004DOI Listing
November 2015

Efficacy and safety of budesonide administered by pressurized metered-dose inhaler in children with asthma.

Ann Allergy Asthma Immunol 2015 Dec 13;115(6):516-22. Epub 2015 Oct 13.

T-STAT, LLC Statistical Consulting and Contracting, Downingtown, Pennsylvania.

Background: Budesonide is approved for delivery using a nebulized solution and dry-powder inhaler, but its use through a pressurized metered-dose inhaler (pMDI) in pediatric patients with asthma has not been determined.

Objective: To examine the efficacy and safety of 160 μg twice daily of budesonide through a pMDI vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.

Methods: A 6-week, international, multicenter, double-blinded, parallel-group, phase 2 study randomized 304 pediatric patients (mean age, 9 years; 21.7% <8 years) 1:1 to 160 μg (80 μg × 2 inhalations) twice daily of budesonide through a pMDI or placebo after a 7- to 21-day run-in period. The primary efficacy end point was change from baseline in morning peak expiratory flow (PEF); safety end points included adverse events, vital signs, and discontinuations.

Results: Budesonide treatment significantly improved morning PEF vs placebo; mean treatment effect (budesonide vs placebo) was 13.6 L/min (P < .0001). Budesonide also showed significant improvements vs placebo for forced expiratory volume in 1 second, evening PEF, forced expiratory flow at 25% to 75% of pulmonary volume, reliever medication use, nighttime awakenings, awakenings with reliever use, and percentage of patients with at least 15- and at least 30-L/min increase in morning PEF from baseline. The numbers of patients experiencing adverse events and discontinuations were smaller in the budesonide than in the placebo group. No serious adverse events were reported.

Conclusion: Budesonide at 160 μg twice daily through a pMDI was generally well tolerated and significantly improved lung function, symptoms, rescue medication use, and nighttime awakenings vs placebo in children 6 to younger than 12 years with asthma and a demonstrated need for inhaled corticosteroids.
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http://dx.doi.org/10.1016/j.anai.2015.09.007DOI Listing
December 2015

The effect of GSK2190915, a 5-lipoxygenase-activating protein inhibitor, on exercise-induced bronchoconstriction.

Allergy Asthma Proc 2014 Mar-Apr;35(2):126-33

GlaxoSmithKline, London, UK.

Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.
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http://dx.doi.org/10.2500/aap.2014.35.3723DOI Listing
December 2014

Fluticasone/Formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma.

Clin Ther 2013 Jul;35(7):950-66

Colorado Allergy & Asthma Centers, Denver, CO 80230, USA.

Objectives: This study investigated the efficacy and tolerability of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol)*, administered twice daily (BID) via a single aerosol inhaler, compared with fluticasone propionate (fluticasone) or formoterol fumarate (formoterol) administered alone, in patients with mild to moderate asthma.

Methods: Patients aged ≥12 years were evenly randomized to 12 weeks of treatment with fluticasone/formoterol (100/10 µg BID), fluticasone (100 µg BID), or formoterol (10 µg BID), in this multicenter, double-blind, parallel-group, study. The 2 coprimary end points were: (1) change in forced expiratory volume in 1 second (FEV(1)) from morning predose at baseline to predose at week 12 for the comparison of the combination product with formoterol alone; and (2) change in FEV(1) from morning predose at baseline to 2 hours postdose at week 12 for the comparison of the combination product with fluticasone alone. The secondary objective was to demonstrate the efficacy of fluticasone/formoterol using other pulmonary function tests and clinical end points. Tolerability was assessed based on adverse events, clinical laboratory tests and vital sign evaluations.

Results: Statistically significant differences were demonstrated for the 2 coprimary end points. Fluticasone/formoterol combination therapy showed significantly greater improvements from baseline to end of study in the change in predose FEV(1) compared with formoterol (least squares [LS] mean treatment difference, 0.118 L [95% CI, 0.034-0.201; P = 0.006]) and the change in predose compared with 2 hours postdose FEV(1) versus fluticasone (LS mean treatment difference, 0.122 L [95% CI, 0.040-0.204; P = 0.004]). Statistical analyses of the secondary efficacy endpoints revealed that evaluations of lung function, asthma exacerbations, asthma symptoms, rescue medication use and asthma control were supportive overall of the superior efficacy of fluticasone/formoterol combination therapy compared with its individual components; were supportive overall of the efficacy of fluticasone/formoterol combination therapy compared with its individual components. Since the secondary endpoints were analyzed using the sequential gatekeeper approach, only the mean change from baseline to final week in morning peak expiratory flow rate between the combination-therapy and formoterol groups returned statistically significant results (least squares mean difference, 20.05 [95% CI, 7.631-32.472; P = 0.002]). The fluticasone/formoterol combination therapy had a good tolerability profile over the 12-week treatment period.

Conclusions: Fluticasone/formoterol had a good tolerability profile and showed statistically superior efficacy for the two co-primary endpoints compared to fluticasone or formoterol, in adolescents and adults with mild to moderate asthma. ClinicalTrials.gov identifier: NCT00394199.
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http://dx.doi.org/10.1016/j.clinthera.2013.05.012DOI Listing
July 2013

Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma.

BMC Pulm Med 2011 Feb 28;11:14. Epub 2011 Feb 28.

MedImmune LLC, Gaithersburg, MD, USA.

Background: Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics.

Methods: Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both.

Results: In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation.

Conclusions: In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.
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http://dx.doi.org/10.1186/1471-2466-11-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058114PMC
February 2011

Baseline predictors of placebo response in exercise-induced bronchoconstriction (EIB): pooled regression analysis >from three studies of montelukast in EIB.

J Asthma 2010 Oct;47(8):935-41

Merck Research Laboratories, North Wales, Pennsylvania 19454, USA.

Background: Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient-related factors driving placebo response could facilitate more efficient clinical trials for EIB.

Methods: Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15-45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV₁) ≥20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5-12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV₁ while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the "best" model.

Results: Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV₁ % predicted (p <.001), smaller maximum % fall in FEV₁ in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011).

Conclusion: Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients.
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http://dx.doi.org/10.3109/02770903.2010.498541DOI Listing
October 2010

Reproducibility of the airway response to an exercise protocol standardized for intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of asthma.

Respir Res 2010 Sep 1;11:120. Epub 2010 Sep 1.

Department of Respiratory & Sleep Medicine, 11 West, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.

Background: Exercise testing to aid diagnosis of exercise-induced bronchoconstriction (EIB) is commonly performed. Reproducibility of the airway response to a standardized exercise protocol has not been reported in subjects being evaluated with mild symptoms suggestive of asthma but without a definite diagnosis. This study examined reproducibility of % fall in FEV1 and area under the FEV1 time curve for 30 minutes in response to two exercise tests performed with the same intensity and duration of exercise, and inspired air conditions.

Methods: Subjects with mild symptoms of asthma exercised twice within approximately 4 days by running for 8 minutes on a motorized treadmill breathing dry air at an intensity to induce a heart rate between 80-90% predicted maximum; reproducibility of the airway response was expressed as the 95% probability interval.

Results: Of 373 subjects challenged twice 161 were positive (≥ 10% fall FEV1 on at least one challenge). The EIB was mild and 77% of subjects had <15% fall on both challenges. Agreement between results was 76.1% with 56.8% (212) negative (< 10% fall FEV1) and 19.3% (72) positive on both challenges. The remaining 23.9% of subjects had only one positive test. The 95% probability interval for reproducibility of the % fall in FEV1 and AUC0-30 min was ± 9.7% and ± 251% for all 278 adults and ± 13.4% and ± 279% for all 95 children. The 95% probability interval for reproducibility of % fall in FEV1 and AUC0-30 min for the 72 subjects with two tests ≥ 10% fall FEV1 was ± 14.6% and ± 373% and for the 34 subjects with two tests ≥ 15% fall FEV1 it was ± 12.2% and ± 411%. Heart rate and estimated ventilation achieved were not significantly different either on the two test days or when one test result was positive and one was negative.

Conclusions: Under standardized, well controlled conditions for exercise challenge, the majority of subjects with mild symptoms of asthma demonstrated agreement in test results. Performing two tests may need to be considered when using exercise to exclude or diagnose EIB, when prescribing prophylactic treatment to prevent EIB and when designing protocols for clinical trials.
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http://dx.doi.org/10.1186/1465-9921-11-120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939602PMC
September 2010

Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids.

Allergy Asthma Proc 2010 Jul-Aug;31(4):269-79. Epub 2010 Jul 30.

Asthma and Allergy Associates and Research Center, Colorado Springs, Colorado 80907, USA.

Asthma is a heterogeneous condition characterized by reduced lung function, chronic inflammation, and periodic asthma deteriorations. This study was performed to evaluate the effect of mometasone furoate (MF)/formoterol (F) combination, 200/10 microg, administered twice daily (b.i.d.) on asthma deteriorations and pulmonary function in patients with asthma uncontrolled on medium-dose inhaled corticosteroid (ICS). After 2- to 3-week open-label run-in with MF 200 microg b.i.d., patients (>or=12 years) were randomized to 26 weeks of treatment with MF/F 200/10 microg, MF 200 microg, F 10 microg, or placebo b.i.d. Coprimary end points were time to first asthma deterioration (MF/F versus F) and bronchodilation, assessed by the area under the curve of the change in forced expiratory volume in 1 second 0-12 hours (FEV(1) AUC(0-12h); MF/F versus MF). A total of 781 patients were randomized. Treatment with MF/F 200/10 microg reduced asthma deteriorations and clinically judged deteriorations (i.e., deterioration resulting in emergency treatment, hospitalization, or treatment with additional excluded asthma medication [i.e., systemic corticosteroids]). The proportion of patients experiencing asthma deteriorations was MF/F, 30.4%; MF, 33.9%; F, 54.0%; placebo, 55.6% (p < 0.001, MF/F versus F and placebo). There was a sixfold reduction in clinically judged deteriorations with MF/F versus F and placebo (p < 0.001). Lung function improved more rapidly with MF/F than MF and placebo. Mean change from baseline FEV(1) AUC(0-12h) at week 12 was MF/F, 11.7% versus MF, 5.7%; F, 8.5%; and placebo, 3.9% (p < 0.001). Treatment-related AEs were rare and similar across groups. Treatment with MF/F 200/10 microg was effective in reducing the risk of asthma deteriorations. MF/F was safe and provided rapid and sustained bronchodilation in patients with asthma.
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http://dx.doi.org/10.2500/aap.2010.31.3364DOI Listing
June 2011

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma.

Respir Res 2009 Jan 23;10. Epub 2009 Jan 23.

Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.

Background: Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.

Methods: 509 people (6-50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a > or = 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 < or = 16 mg/ml and to mannitol a 15% fall in FEV1 at < or = 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.

Results: Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6) mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.

Conclusion: In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.

Trial Registration: This was a multi-center trial comprising 25 sites across the United States of America.
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http://dx.doi.org/10.1186/1465-9921-10-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644668PMC
January 2009

Bronchodilator efficacy of indacaterol, a novel once-daily beta2-agonist, in patients with persistent asthma.

Ann Allergy Asthma Immunol 2008 Jul;101(1):90-5

Colorado Allergy and Asthma Centers PC, Denver, USA.

Background: Indacaterol is a novel once-daily inhaled beta2-agonist in development for the treatment of patients with asthma or chronic obstructive pulmonary disease.

Objective: To investigate the bronchodilator efficacy of indacaterol in patients with persistent asthma.

Methods: Patients received a randomized sequence of single doses of indacaterol, 400 microg, via single-dose dry powder inhaler (SDDPI); indacaterol, 200 microg, via multidose dry powder inhaler (MDDPI); and placebo. At each visit, the forced expiratory volume in 1 second (FEV1) was recorded at a series of time points during a 24-hour period.

Results: Of 33 patients screened, 25 were randomized to treatment. Adjusted mean FEV1 was significantly higher (P < or = .005) for both indacaterol doses vs placebo at most time points. The first time points at which statistically significant treatment differences were observed for indacaterol and placebo in FEV1 were 0.17 L at 5 minutes after dosing for 400 microg of indacaterol (SDDPI) and 0.21 L at 10 minutes for 200 microg of indacaterol (MDDPI) (both P < .001 vs placebo). Differences relative to placebo at the final time point, 24 hours after dosing, were 0.29 L and 0.15 L for indacaterol, 400 microg and 200 microg, respectively (both P < or = .003 vs placebo). Overall, FEV1 was significantly higher for the 400-microg dose compared with the 200-microg dose from 15 minutes to 2 hours after dosing (P < or = .013) and from 5 hours onward (P < or = .022). Indacaterol was associated with good tolerability and safety.

Conclusions: Indacaterol demonstrates sustained bronchodilator efficacy throughout the full 24-hour period, with a rapid onset of action and a good overall safety profile.
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http://dx.doi.org/10.1016/S1081-1206(10)60840-XDOI Listing
July 2008

Evaluation of efficacy and safety of budesonide delivered via two dry powder inhalers.

Curr Med Res Opin 2008 May 16;24(5):1497-510. Epub 2008 Apr 16.

Clinical Research Institute of Southern Oregon, Medford, OR 97504, USA.

Background: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 microg (DPI-A) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 microg and 180 microg; DPI-B).

Objective: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device.

Methods: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6-17 years with mild asthma (N = 516) received budesonide DPI-B 360 microg or DPI-A 400 microg twice-daily (total daily dose 720 microg or 800 microg), budesonide DPI-B 180 microg or DPI-A 200 microg once daily (total daily dose 180 microg or 200 microg), or matching placebo. Change in forced expiratory volume in 1 second (FEV(1)) and secondary variables (asthma symptoms, beta(2)-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured.

Results: In both studies, FEV(1) significantly (p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI-B 180 mug in adults. In the adult study, significantly (p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p
Conclusions: The efficacy and safety of budesonide DPI-A and DPI-B versus placebo were demonstrated across the low to medium inhaled corticosteroid dose range in children >or= 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.
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http://dx.doi.org/10.1185/030079908x297240DOI Listing
May 2008

Single-dose montelukast or salmeterol as protection against exercise-induced bronchoconstriction.

Chest 2007 Sep 15;132(3):875-83. Epub 2007 Jun 15.

Merck Research Laboratories, Respiratory & Allergy Department, Mail code RY34B-348, 126 East Lincoln Ave, Rahway, NJ 07065, USA.

Background And Objective: It has been previously established that montelukast provides protection against exercise-induced bronchoconstriction (EIB) after a single dose. The present objective was to assess the onset and duration of this protective action in a trial that included both positive and negative controls.

Methods: A randomized, active-controlled and placebo-controlled, double-blind, double-dummy, three-way crossover study was conducted in 47 patients (age range, 15 to 44 years) in whom there was a 20 to 40% fall in FEV(1) following exercise (DeltaFEV(1)). In randomized sequence, patients received oral montelukast (10 mg), placebo, or inhaled salmeterol (50 microg) as a positive control. Dosing was followed by exercise challenges at 2, 8.5, and 24 h. The primary end point was maximum DeltaFEV(1) at 2 h postdose. Secondary end points included maximum DeltaFEV(1) at the two later time points, and other measures (including recovery time and need for beta-agonist rescue) at all time points.

Results: The maximum DeltaFEV(1) magnitudes at 2, 8.5, and 24 h were significantly smaller after montelukast administration than after placebo administration (least squares mean [+/- SE], 13.2 +/- 1.2%, 11.7 +/- 1.2%, and 10.0 +/- 1.1% vs 21.8 +/- 1.2%, 16.8 +/- 1.3%, and 14.0 +/- 1.1%, respectively; p
Conclusion: Montelukast provided significant protection against EIB having an onset within 2 h following a single oral dose and lasting for at least 24 h.
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http://dx.doi.org/10.1378/chest.07-0550DOI Listing
September 2007

Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast.

J Asthma 2007 Apr;44(3):213-7

Merck Research Laboratories. Rahway, NJ 07065, USA.

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV(1)) > or = 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV(1) (from pre-exercise FEV(1)) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean +/- SD = 11.7% +/- 10.8) versus placebo (17.5% +/- 13.8) (p < or = 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p < or = 0.001) and a smaller area under the curve for percent-fall in FEV(1) during 60 minutes after challenge (p < or = 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.
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http://dx.doi.org/10.1080/02770900701209806DOI Listing
April 2007

Efficacy of desloratadine, 5 mg, compared with fexofenadine, 180 mg, in patients with symptomatic seasonal allergic rhinitis.

Allergy Asthma Proc 2006 May-Jun;27(3):214-23

Allergy and Asthma Associates of Southern California, Mission Viejo, California 92691, USA.

This is the first U.S.-based study to compare efficacy and safety of desloratadine with fexofenadine in subjects with symptomatic seasonal allergic rhinitis (SAR). In this double-blind study, subjects were randomized to desloratadine, 5 mg (n = 290),fexofenadine, 180 mg (n = 288), or placebo (n = 144) once daily for 15 days. Primary end point was mean change from baseline to study end in morning instantaneous total symptom score (AM NOW TSS) excluding congestion. Secondary measures included change from baseline in the morning/evening reflective TSS (AM/PM PRIOR TSS) excluding congestion, AM NOW individual symptom score (AM NOW ISS) including congestion, and the AM/PM PRIOR ISS including congestion. Subjects self-evaluated their symptoms on a five-point scale. Mean AM NOW TSSs were significantly reduced from baseline at day 15 with desloratadine (p = 0.006) and fexofenadine (p = 0.024) versus placebo. Desloratadine and fexofenadine were not statistically different (p = 0.491); the upper limit of the 95% CI for desloratadine to fexofenadine (0.259) was within the prespecified noninferiority margin of 0.7 U. Decrease in mean AM/PM PRIOR TSS excluding congestion was comparable between desloratadine and fexofenadine (p = 0.405; CI = 0.221) but was significantly greater with both active treatments versus placebo (desloratadine, p < 0.001;fexofenadine, p = 0.003). Desloratadine and fexofenadine provided greater reduction in the AM NOW ISS and AM/PM PRIOR ISS (both including congestion) versus placebo; reductions were comparable between active treatments. All treatments were well tolerated. Desloratadine, 5 mg, and fexofenadine, 180 mg, provide comparable efficacy and tolerability in the treatment of SAR. Both treatments are significantly more effective than placebo.
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http://dx.doi.org/10.2500/aap.2006.27.2851DOI Listing
October 2006

Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukast.

Ann Allergy Asthma Immunol 2006 Jul;97(1):98-104

Colorado Allergy and Asthma Centers, PC, Denver, Colorado 80230, USA.

Background: Leukotriene modifiers have been shown to protect against exercise-induced bronchoconstriction (EIB) with repeated, chronic dosing.

Objective: To study the onset and duration of protection against EIB after a single dose of montelukast, a leukotriene receptor antagonist.

Methods: In this randomized, crossover, double-blind study, 51 adult asthma patients with EIB (> or = 20% postexercise decrease in forced expiratory volume in 1 second [FEV1]) received a single oral dose of montelukast (10 mg), or placebo followed by exercise challenge 2, 12, and 24 hours after dosing. The primary end point was maximum percentage decrease in FEV1 from preexercise baseline during 60 minutes after the 2-hour challenge.

Results: At 2, 12, and 24 hours after dosing, the maximum decrease in FEV1 was 10.8% +/- 7.9%, 8.4% +/- 7.5%, and 8.3% +/- 7.3% for montelukast and 22.3% +/- 13.1%, 16.1% +/- 10.2%, and 16.9% +/- 11.7% for placebo, respectively (P < or = .001 at each time point). Postexercise recovery was quicker with montelukast than with placebo (P < or = .001); mean (95% confidence interval) differences were -26.8 minutes (-35.1 to -18.4 minutes), -16.0 minutes (-22.9 to -9.2 minutes), and -17.4 minutes (-24.9 to -9.9 minutes) at the 3 time points, respectively. At all time points, area under the curve for percentage decrease in FEV1 during 60 minutes after exercise was smaller after montelukast (P < or = .001); montelukast protected more patients against EIB (P < or = .001). Fewer patients required postexercise beta-agonist rescue at 2 hours after dosing with montelukast (P = .03).

Conclusion: Montelukast provided significant protection against EIB as soon as 2 hours after a single oral dose, with persistent benefit up to 24 hours.
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http://dx.doi.org/10.1016/S1081-1206(10)61377-4DOI Listing
July 2006

Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroids.

Ann Allergy Asthma Immunol 2006 Jan;96(1):51-9

AARA Research Center, Dallas, TX 75231, USA.

Background: Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants.

Objective: To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS.

Methods: Randomized, double-blind, parallel-group, 12-week study.

Results: Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups.

Conclusions: Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.
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http://dx.doi.org/10.1016/S1081-1206(10)61040-XDOI Listing
January 2006

Primum non nocere and "black box" warnings.

Authors:
David S Pearlman

J Allergy Clin Immunol 2006 Jan 2;117(1):30-1. Epub 2005 Dec 2.

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http://dx.doi.org/10.1016/j.jaci.2005.09.030DOI Listing
January 2006

Once-daily ciclesonide improves lung function and is well tolerated by patients with mild-to-moderate persistent asthma.

J Allergy Clin Immunol 2005 Dec 10;116(6):1206-12. Epub 2005 Oct 10.

Colorado Allergy and Asthma Centers, PC, Denver 80230, USA.

Background: Inhaled corticosteroids are recommended as first-line therapy for persistent asthma.

Objective: We sought to assess the efficacy and safety of ciclesonide once daily in patients with mild-to-moderate persistent asthma.

Methods: An integrated analysis of 2 identical, multicenter, double-blind, randomized, parallel-group, placebo-controlled trials was conducted. Patients (n = 1015; aged > or =12 years) with mild-to-moderate asthma (FEV1 of 60% to 85% of predicted value) were randomized to ciclesonide 80 microg (CIC80), 160 microg (CIC160), or 320 microg (CIC320), once daily (exactuator doses) in the morning or placebo for 12 weeks.

Results: All ciclesonide groups showed significant improvements from baseline to week 12 in FEV1 compared with the placebo group (CIC80, 0.12 L [P = .0007]; CIC160, 0.13 L [P = .0004]; and CIC320, 0.14 L [P < .0001]). Likewise, FEV1 percent predicted, morning and evening peak expiratory flow, 24-hour asthma symptom score, daily albuterol use, and nighttime awakenings were significantly improved in all ciclesonide groups compared with the placebo group. Overall ciclesonide safety profile and rates of oropharyngeal adverse events for all groups were low and similar to those of the placebo group. Fewer ciclesonide-treated patients exhibited asthma-aggravated adverse events, and fewer ciclesonide-treated patients discontinued the study for any reason or because of a lack of efficacy compared with those in the placebo group. No suppression of hypothalamic-pituitary-adrenal-axis function (as assessed by means of 24-hour urinary cortisol levels corrected for creatinine and peak serum cortisol levels after stimulation with low-dose [1 microg] cosyntropin) was observed with any dose of ciclesonide.

Conclusions: In this integrated analysis, ciclesonide once daily administered in the morning is effective and well tolerated.
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http://dx.doi.org/10.1016/j.jaci.2005.08.037DOI Listing
December 2005

Short-term and long-term asthma control in patients with mild persistent asthma receiving montelukast or fluticasone: a randomized controlled trial.

Am J Med 2005 Jun;118(6):649-57

Department of Allergy-Immunology, Kaiser Permanente Medical Center, Los Angeles, California, USA.

Purpose: To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescue-free days.

Subjects And Methods: Participants aged 15 to 85 years with mild persistent asthma (n = 400) were randomized to oral montelukast (10 mg once nightly) or inhaled fluticasone (88 mug twice daily) in a year-long, parallel-group, multicenter study with a 12-week, double-blind period, followed by a 36-week, open-label period.

Results: The mean percentage of rescue-free days was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference = 1.8%, 95% confidence interval [CI]: -3.2% to 6.8%) but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference = 6.2%, 95% CI: 0.8% to 11.7%). Although both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, greater improvements occurred with fluticasone in lung function during both periods and in asthma control during open-label treatment. Post hoc analyses revealed a difference in rescue-free days favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline.

Conclusion: In patients with mild persistent asthma, rescue-free days and most asthma control measures improved similarly with fluticasone or montelukast over the short term, but with prolonged open-label treatment, asthma control improved more with fluticasone. Improved asthma control with fluticasone appeared to occur in those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that classification criteria for mild persistent asthma may need to be re-evaluated.
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http://dx.doi.org/10.1016/j.amjmed.2005.03.003DOI Listing
June 2005

Efficacy and safety of fluticasone propionate/salmeterol HFA 134A MDI in patients with mild-to-moderate persistent asthma.

J Asthma 2004 ;41(8):797-806

Colorado Allergy and Asthma Centers, P.C., Denver, Colorado 80230, USA.

The objective of this study was to compare the efficacy and safety of fluticasone propionate (FP) (44 microg)/salmeterol (21 microg) delivered as two inhalations twice daily via a single hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) (FSC) with that of placebo HFA 134a (PLA), fluticasone propionate 44 microg chlorofluorocarbon (CFC) alone and salmeterol 21 microg CFC alone (S) in patients (n=360) with persistent asthma previously treated with beta2-agonists (short- or long-acting) or inhaled corticosteroids (ICS). After 12 weeks of treatment, patients treated with FSC had a significantly greater increase (p < or = 0.006) in mean FEV1 AUC(bl) compared with PLA, FP, or S. At end point, mean change from baseline in morning predose FEV1 for FSC (0.58 L) was significantly (p < or = 0.004) greater than PLA (0.14 L), FP (0.36 L), and S (0.25 L). Patients treated with FSC also had a significantly higher probability of remaining in the study without being withdrawn due to worsening asthma (2%) compared with those in the PLA (29%) and S (25%) groups (p < 0.001). Finally, treatment with FSC resulted in significantly (p < or = 0.007) greater improvements in morning and evening peak expiratory flow, need for rescue albuterol, and asthma symptom scores compared with FP, S, and PLA. The safety profile of FSC was also similar to FP or S alone. Initial maintenance treatment of the two main components of asthma, inflammation, and smooth muscle dysfunction (e.g., bronchoconstriction), with FSC results in greater overall improvements in asthma control compared with treatment of either individual component alone.
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http://dx.doi.org/10.1081/jas-200038368DOI Listing
January 2005

Variability of symptoms in mild persistent asthma: baseline data from the MIAMI study.

Respir Med 2004 Sep;98(9):898-905

Department of Allergy-Immunology, Kaiser Permanente Medical Center, 7060 Clairemont Mesa Boulevard, San Diego, CA 92111, USA.

Objective: To describe the variability of the asthma phenotype in patients with mild persistent asthma enrolled in the Mild Asthma Montelukast versus Inhaled Corticosteroid (MIAMI) study.

Methods: The variability of asthma rescue-free days, asthma symptoms, albuterol use, medical resource use, and exercise Limitations among patients with documented mild persistent asthma was compared between the month before study enrollment and the last 2 weeks of the run-in period.

Results: Patients eligible for randomization (n = 400), aged 15-85 years, exhibited symptoms (mean +/- SD) 3.6 +/- 1.3 days/week, beta-agonist use 3.5 +/- 1.3 days/week, and normal FEV1 (94.0 +/- 9.9% predicted) during the last 2 weeks of the run-in period. In the year before enrollment, medical intervention for asthma flares was common: 38.5% made office visits, 15.8% had oral corticosteroids, and 8.3% required emergency room or hospitalized care. In the month before enrollment, 11.8% experienced daily symptoms, and 28.3% had limitations of normal activity. Patients with daily symptoms in the month before study enrollment, compared with those having less-than-daily symptoms, experienced fewer rescue-free days (P = 0.024) and had more days per week with symptoms (P = 0.008) and requiring albuterol (P = 0.048) during the run-in; FEV1 was similar for both groups (93.1% vs. 94.2% predicted, respectively).

Conclusion: Patients with mild persistent asthma reported a substantial disease burden in the year before enrollment. The asthma burden experienced by these patients both before and during the run-in period was of sufficient severity to support the recommendation that mild persistent asthma should be managed with daily controller therapy.
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http://dx.doi.org/10.1016/j.rmed.2004.02.016DOI Listing
September 2004

Preclinical properties of budesonide: translation to the clinical setting.

Authors:
David S Pearlman

Clin Ther 2003 ;25 Suppl C:C75-91

Colorado Allergy and Asthma Centers, PC, Denver, Colorado 80230, USA.

Background: Since the introduction of inhaled corticosteroids (ICSs) nearly 30 years ago, the management of asthma has been transformed. It is now understood that asthma is primarily a disease of chronic inflammation, even in its milder forms, and that to delay treatment may lead to deterioration in lung function. International treatment guidelines for asthma recommend early intervention with a potent ICS, with the greatest benefit observed when treatment is started within 2 years of the onset of symptoms. Each of the currently available ICSs has distinct physical and pharmacokinetic properties and is delivered via different devices.

Objective: This article brings together the findings and concepts presented in this supplement. It provides an overview of budesonide's predicted clinical efficacy and tolerability in patients with asthma based on its physical properties and pharmacokinetic and pharmacodynamic characteristics.

Conclusions: Budesonide's physical properties and pharmacokinetic and pharmacodynamic profiles help predict its clinical efficacy and tolerability when used as early intervention in asthma. Study results indicate that lung deposition of budesonide is increased by delivery via dry-powder inhaler, enhancing the drug's efficacy in patients with newly diagnosed mild persistent asthma. The preclinical, clinical, and safety data support budesonide's predicted performance in the clinical setting.
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http://dx.doi.org/10.1016/s0149-2918(03)80307-7DOI Listing
March 2004

Histamine skin test reactivity following single and multiple doses of azelastine nasal spray in patients with seasonal allergic rhinitis.

Ann Allergy Asthma Immunol 2003 Sep;91(3):258-62

Colorado Allergy & Asthma Centers, PC, Denver, Colorado 80230, USA.

Objective: To determine whether azelastine nasal spray suppresses the dermal response to epicutaneous histamine in allergic patients and the duration of suppression after azelastine use is discontinued.

Methods: Seventy-eight patients with seasonal allergic rhinitis were entered into this randomized, double-blind, parallel-group, placebo-controlled study. Patients received either azelastine nasal spray (2 sprays per nostril twice daily) or placebo nasal spray for 14 days. Skin tests were performed 5 hours after the first dose of study drugs to determine the effect of a single dose of azelastine nasal spray on the wheal-and-flare response to histamine. At the end of the 14-day treatment period, skin tests were performed 5 hours after the last dose of study drugs and at 24-hour intervals thereafter, until each patient's wheal-and-flare response to histamine (1.0 and 5.0 mg/mL) returned to within 20% of baseline values.

Results: A single dose of azelastine nasal spray did not significantly alter the wheal-and-flare response to histamine. The wheal response was within 20% of the baseline value in 82% and 88% (1.0 and 5.0 mg/mL of histamine, respectively) of the patients 5 hours after discontinuing 14 days of treatment with azelastine nasal spray. Wheal responses were within 20% of baseline values 48 hours after treatment was discontinued, whereas flare responses returned to within 20% of baseline within 48 hours in 92% of the patients.

Conclusions: Azelastine nasal spray should be discontinued for at least 48 hours before beginning allergy skin test procedures.
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http://dx.doi.org/10.1016/S1081-1206(10)63527-2DOI Listing
September 2003

Formoterol delivered via a dry powder inhaler (Aerolizer): results from long-term clinical trials in children.

Curr Med Res Opin 2002 ;18(8):445-55

University of Colorado Health Sciences Center, Denver, Colorado, USA.

Over 500 children with asthma, aged 5-12 years, have been treated with formoterol fumarate (Foradil) delivered via the Aerolizer dry powder inhaler in clinical trials, with treatment periods of up to 15 months. In pivotal double-blind trials, two dose levels, 12 and 24 microg taken twice daily, provided significant benefit in terms of lung function measurements and symptom control (a lower dose of 6 microg twice daily appeared insufficient with this formulation). The higher, 24 microg dose appeared to provide an additional margin of benefit in a subgroup of children with more unstable/severe disease when the results from long-term follow-up (12-15 months) were analysed. Formoterol was shown to have a good safety profile when taken as regular maintenance treatment and when used as rescue medication by patients already receiving formoterol as regular maintenance treatment. In this flexible regimen, with formoterol used for rescue and maintenance, the overall daily intake of formoterol was low, with 96.1% of all treatment days (n = 2452) covered by a total daily dose (regular + rescue) of 48 microg (four doses) or less. There was no increase in the average daily intake of rescue formoterol over time. The clinical efficacy associated with this regimen was maintained over time and, in the case of morning peak expiratory flow rate, steadily improved over time. The Foradil Aerolizer inhalation system is simple to use and has a low resistance to inspiratory airflow that maximises the patient's control over dosing, while minimising the risk of under- and overdosing. These features may be especially valuable in a young patient population.
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http://dx.doi.org/10.1185/030079902125001254DOI Listing
April 2003

Fluticasone propionate/salmeterol combination compared with montelukast for the treatment of persistent asthma.

Ann Allergy Asthma Immunol 2002 Feb;88(2):227-35

Colorado Allergy and Asthma Centers, PC, Denver 80230, USA.

Background: Asthma is a chronic disease characterized by inflammation and bronchoconstriction. Medications that are able to effectively treat both components are advantageous.

Objective: To compare the efficacy of an inhaled corticosteroid and a long-acting beta2-agonist combination product with a leukotriene antagonist for initial maintenance therapy in patients who were symptomatic while receiving short-acting beta2-agonists alone.

Methods: A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 432 patients 15 years of age and older with persistent asthma who were symptomatic on short-acting beta2-agonists alone. Fluticasone propionate 100 microg and salmeterol 50 microg combination product (FSC) twice daily or montelukast 10 mg once daily was administered.

Results: At endpoint, compared with montelukast, FSC significantly increased morning predose forced expiratory volume in 1 second (0.61 +/- 0.03 L vs 0.32 +/- 0.03 L), morning peak expiratory flow rate (peak expiratory flow rate; 81.4 +/- 5.9 L/minute vs 41.9 +/- 4.8 L/minute), evening peak expiratory flow rate (64.6 +/- 5.3 L/minute vs 38.8 +/- 4.7 L/minute), the percentage of symptom-free days (40.3 +/- 2.9% vs 27.0 +/- 2.7%), the percentage of rescue-free days (53.4 +/- 2.8% vs 26.7 +/- 2.5%), and the percentage of nights with no awakenings (29.8 +/- 2.5% vs 19.6 +/- 2.1%) (P < or = 0.011, all comparisons). At endpoint, FSC significantly reduced asthma symptom scores (-1.0 +/- 0.1 vs -0.7 +/- 0.1) and rescue albuterol use (-3.6 +/- 0.2 puffs/day vs -2.2 +/- 0.2 puffs/day) compared with montelukast (P < 0.001). At endpoint, patients treated with FSC also had a significantly greater improvement in quality of life scores and were more satisfied with their treatment compared with montelukast-treated patients (P < or = 0.001). Both treatments were well tolerated.

Conclusions: Initial maintenance therapy with FSC provides greater improvement in asthma control and patient satisfaction than montelukast.
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http://dx.doi.org/10.1016/S1081-1206(10)62001-7DOI Listing
February 2002