Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions.

Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force.

Patient Satisfaction and Clinical Outcomes with Budesonide plus Formoterol Spiromax for Asthma and Chronic Obstructive Pulmonary Disease: A Real-World, Observational Trial.

BACKGROUND: The fixed-dose combination of budesonide/formoterol (B/F) has been available in the Spiromax® dry powder inhaler since 2014. OBJECTIVES: To assess patient satisfaction, inhaler use errors, and disease control in patients with asthma or chronic obstructive pulmonary disease (COPD) treated with B/F Spiromax. METHODS: This non-interventional, prospective, 12-week study enrolled consecutive asthma or COPD patients who had recently begun treatment with B/F Spiromax or were switched from another inhaled corticosteroid/long-acting ß2-agonist combination to B/F Spiromax in routine clinical practice. Patients recruited from 243 specialist respiratory clinics or general practices in Germany were assessed for patient satisfaction (Satisfaction with Inhalers and Preference questionnaire), inhaler application errors (modified Easy Low Instruction over Time checklist), disease control, and safety. RESULTS: The population included 3,943 patients: asthma n = 2,707 (68.7%); COPD n = 1,236 (31.3%). At baseline, 60.1% of patients were "satisfied" or "very satisfied" with their previous inhaler, and this increased to 88.8% at week 12 of B/F Spiromax use. Overall, 62.1% of pre-treated patients preferred B/F Spiromax to their old inhaler. The frequency of any handling error observed with B/F Spiromax at week 12 was lower than at baseline (11.9 vs. 25.5% of patients, respectively). After 12 weeks, 77.4% were assessed as having improved (minimally, much, or very much) overall health status versus baseline. Guideline-defined disease severity (as rated by physicians) and patient-reported symptom severity improved during the study in both asthma and COPD patients. B/F Spiromax was well tolerated. CONCLUSION: B/F Spiromax was associated with high patient satisfaction, low device handling error rate, and improvements in clinical outcomes in real-world clinical practice.

Effects of low- versus high-dose fluticasone propionate/formoterol fumarate combination therapy on AMP challenge in asthmatic patients: A double-blind, randomised clinical trial.

BACKGROUND: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform(®), 100/10 µg and 500/20 µg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). METHODS: Patients aged ≥18 years with forced expiratory volume in 1 s (FEV1) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV1 (AMP PD20) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 µg (high dose), 100/10 µg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2-3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD20 data for both treatments ("fluticasone/formoterol subgroup"). Changes in AMP PD20 FEV1, percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA). RESULTS: Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol (post hoc subgroup). The difference in AMP PD20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol. CONCLUSIONS: A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP.

CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease.

RATIONALE: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. METHODS: This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1. MEASUREMENTS AND MAIN RESULTS: A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups. CONCLUSIONS: Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).

Extrafine beclomethasone/formoterol combination via a dry powder inhaler (NEXThaler(®)) or pMDI and beclomethasone monotherapy for maintenance of asthma control in adult patients: A randomised, double-blind trial.

BACKGROUND: The fixed combination of extrafine beclomethasone dipropionate and formoterol fumarate (BDP/FF) pMDI (Foster(®)) is approved for treatment of adult asthmatic patients. In order to provide an alternative drug delivery system for BDP/FF to physicians and patients, a dry powder inhaler (NEXThaler(®)) has been developed, capable to deliver extrafine particles to the lungs and therefore improve the dosing of the drugs, especially in patients with poor hand-breath coordination. OBJECTIVE: This trial was performed to compare efficacy and safety of extrafine BDP/FF NEXThaler(®) with extrafine BDP/FF pMDI or non-extrafine BDP DPI alone in adult patients with controlled asthma. METHODS: In this 8-week randomised, double-blind, parallel-group trial, patients were randomized to receive either extrafine BDP/FF NEXThaler(®) 100/6 µg bid, extrafine BDP/FF 100/6 µg pMDI bid or non-extrafine BDP DPI 100 µg bid. The primary efficacy variable was change from baseline to the entire 8-week randomised treatment period in average pre-dose morning PEF. RESULTS: The ITT population comprised 754 patients. Extrafine BDP/FF NEXThaler(®) was non-inferior (pre-defined margin: -15 L/min) relative to extrafine BDP/FF pMDI (mean difference: -1.84; 95% CI: -6.73, 3.05) in terms of the primary efficacy variable, change from baseline in average pre-dose morning PEF. Statistical superiority of both extrafine BDP/FF formulations over non-extrafine BDP DPI was demonstrated for the primary efficacy variable (providing evidence of assays sensitivity of the trial), ACQ score and percentage of rescue medication use-free days. No significant safety signals were observed. CONCLUSION: NEXThaler(®) is an effective and well-tolerated delivery device for treatment of patients with asthma who need a regular treatment.

The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma.

BACKGROUND: Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response. OBJECTIVE: We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinical outcome parameters in patients with mild-to-moderate persistent allergic asthma. METHODS: In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734). RESULTS: All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n = 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n = 30, P < .05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10 administration. CONCLUSION: Treatment with QbG10 may contribute to continued asthma control during steroid reduction in patients on moderate or high-dose inhaled steroids.

Detection of exacerbations in asthma based on electronic diary data: results from the 1-year prospective BIOAIR study.

BACKGROUND: Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. METHODS: In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. RESULTS: Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥ 3%, body mass index >25 and low quality of life (St George's Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p<0.05). CONCLUSIONS: Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.

Remote consultations in primary care across low-, middle- and high-income countries: Implications for policy and care delivery.

The COVID-19 pandemic mandated a substantial switch in primary health care delivery from an in-person to a mainly remote telephone or video service. As the COVID-19 pandemic approaches its third year, limited progress appears to have been made in terms of policy development around consultation methods for the post-acute phase of the pandemic. In September 2020, the International Primary Care Respiratory Group convened a global panel of primary care clinicians - including family physicians, paediatricians, pharmacists, academics and patients - to consider the policy and health management implications of the move to remote consultations in the primary care setting. The group gave special consideration to how and how far remote consultations should be integrated into routine primary health care delivery. Remote consultations can be a useful alternative to in-person consultations in primary care not only in situations where there is a need for viral infection control but also for the routine delivery of chronic disease management. However, they may not be more time efficient for the clinician, and they can add to the workload and work-related stress for primary care practitioners if they remain the dominant consultation mode. Remote consultations are also less appropriate than in-person consultations for new disease diagnosis, dealing with multiple issues and providing complex care. Ensuring health care professionals have the appropriate skill set to effectively deliver remote consultations, administrative and/or IT support and appropriate reimbursement will be key to achieving optimal integration of remote consultations into routine clinical practice. Addressing digital access and digital literacy issues at a societal level will also be essential to ensure individuals have fair and equitable access to the internet and sufficient security for exchange of personal and health-related data.

[Efficacy of Disease Management Programs Asthma and COPD? Results of a Cross-Sectional Study]. / Wirksamkeit von Disease-Management-Programmen für Asthma und COPD? Ergebnisse einer Querschnittstudie.

BACKGROUND: The efficacy of the German disease management programs (DMP) asthma and chronic obstructive pulmonary disease (COPD) cannot be shown with the legally bound documentations. Studies with control groups are rare. Aim of this work was to investigate in a cross-sectional study whether the disease control differs in participants (DMP+) and non-participants (DMP-) of the DMPs asthma and COPD. METHODS: The study was a prospective multicenter cross-sectional study. Primary endpoints were the Asthma Control Test™ (ACT) in the asthma part of the study and the COPD Assessment Test™ (CAT) for the COPD part. RESULTS: A total of 1038 asthma patients and 846 COPD patients were included, of whom about 70 % participated in the corresponding DMP. The ACT total score was higher in asthma DMP+ patients than in DMP- patients (mean difference 0.86; 95 %CI:0.29 - 1.43;p = 0.003), but not clinically relevant. For COPD there was no clinically relevant difference in COPD disease impact (0.52; 95 %CI:-0.71 - 1.75;p = 0.405). Although DMP patients had to be enrolled in the respective DMP for at least one year, only 60 % of these patients had participated in a structured education. We did not observe a difference in disease control in DMP patients who respectively participated and did not participate in a structured education. DISCUSSION: There was no clinically relevant difference in disease control between DMP+ and DMP- patients. The efficacy of DMPs has been demonstrated internationally in randomized controlled trials. Randomized controlled trials should be conducted in Germany for demonstrating efficacy of DMPs asthma and COPD. REGISTRATION: drks.de, DRKS00007664, Registration date: Jan 15, 2015.

Stress effects on lung function in asthma are mediated by changes in airway inflammation.

OBJECTIVE: To examine the association of changes in current negative mood and long-term daily hassles with changes in lung function and airway inflammation in patients suffering from asthma and in healthy controls. Associations between psychological factors and asthma symptoms have been documented, but the relationship between airway inflammation and psychological factors has been largely unexplored. METHOD: Data were analyzed from 46 asthma patients and 25 controls who completed questionnaires on current mood and daily hassles at two assessments 3 months apart. Lung function was measured by spirometry (forced expiratory volume in the first second (FEV(1))) and airway inflammation by the fraction of nitric oxide in exhaled air (FeNO). Regression analyses controlling for allergen load and air pollution (ozone) were calculated to study the association between changes in psychological factors and changes in lung function and airway inflammation, and to examine the mediational role of airway inflammation in the stress-lung function association. RESULTS: In patients with asthma, increases in negative affect were associated with decreases in FEV(1) and increases in FeNO. For daily hassles, a reverse pattern of associations was found, with decreases in daily hassles linked to decreases in FEV(1) and increases in FeNO. Mediation analyses showed that FeNO was a significant mediator of the association of both negative affect and daily hassles with lung function changes. No significant associations were found for healthy controls. CONCLUSION: Psychological variables are consistently associated with spirometric lung function and airway inflammation in asthma patients. For asthma patients, effects of acute negative affect must be distinguished from more chronic distress due to daily hassles.

Perceived triggers of asthma: evaluation of a German version of the Asthma Trigger Inventory.

BACKGROUND AND OBJECTIVE: Patients' perception of asthma triggers has been explored in a largely unstructured fashion in the past. Therefore, we developed the Asthma Trigger Inventory (ATI), a questionnaire that allows for a psychometrically valid measurement of patients' perceived asthma triggers. Here we evaluate a German language version of the ATI and studied the relationship of subscales with self-reported health status, health care use, psychopathology, and results of allergy skin testing. METHOD: Data were obtained from 370 asthma patients recruited from the community, primary care, and in-patient asthma treatment and education. RESULTS: Analysis revealed a five-factor structure that largely confirmed results with the English original. Reliability was good to satisfactory (Cronbach's alpha=0.77-0.89) for allergy, exercise, air pollution/irritants, infection, and psychological trigger subscales. In hierarchical regression analysis adjusting for demographics and asthma severity, asthma patients with stronger non-allergic triggers showed less physical and mental well-being and more asthma-related health care use. Psychological triggers showed unique associations with anxious and depressed mood. Pollen and animal allergen scores of the ATI were significantly related to skin test results for relevant allergens. Non-allergic but not allergic triggers showed substantial associations with asthma control. CONCLUSION: The German version of the ATI reliably measures asthma patients' trigger perceptions. Non-specific asthma triggers exert a greater burden on patients' well-being and primary health care use.

Efficacy and safety of indacaterol, a new 24-hour beta2-agonist, in patients with asthma: a dose-ranging study.

BACKGROUND: Indacaterol is a new once-daily inhaled beta(2)-agonist in clinical development for asthma as a component of a fixed-dose combination with an inhaled corticosteroid. OBJECTIVES: To investigate the efficacy and safety of indacaterol in patients with chronic persistent asthma. METHODS: A total of 115 patients were randomized in a double-blind, incomplete-block cross-over design to sequences of four 7-day treatment periods (separated by 7-day washouts) with indacaterol 100, 200, 300, 400, or 600 micro g or placebo, once daily, via single-dose dry-powder inhaler. After the fourth washout, patients received 1 day of open-label formoterol 12 mu g twice daily. Forced expiratory volume in 1 second (FEV(1)) was measured for 24 hours post-dose on days 1 and 7. RESULTS: For standardized (with respect to time) FEV(1) area under the curve at 22 to 24 hours (AUC(22-24h)) on day 1, indacaterol doses >or=200 micro g were superior to placebo (p < 0.05) and similar or greater than formoterol 12 micro g twice daily. By day 7, mean differences from placebo in FEV(1) standardized AUC(22-24h) were 0.08, 0.16, 0.15, 0.11, and 0.16 L for indacaterol 100, 200, 300, 400, and 600 micro g, respectively (all p < 0.05 vs. placebo). Mean FEV(1) for indacaterol doses >or= 200 micro g on day 7 was higher than placebo (p < 0.05) pre-dose and at all post-dose time points. AEs were generally mild in severity; no serious AEs occurred. No clinically meaningful differences were observed between treatments in any safety assessments. CONCLUSIONS: Once-daily indacaterol demonstrated sustained 24-hour bronchodilator efficacy, with similar efficacy on days 1 and 7, and was generally well tolerated.

The influence of corticosteroids on the perception of dyspnea in asthma.

Corticosteroids are effective anti-inflammatory medications that are recommended for the control of persistent asthma. Little, however, is known about their influence on the perception of dyspnea, which, in turn, is important to the successful self-management of asthma. This paper provides a synopsis of available studies examining the impact of corticosteroids on the sensitivity to perceive dyspnea and presents possible mechanisms underlying this relationship. The results of these investigations are conflicting with some studies showing improved perception and other studies showing worsened perception of dyspnea after corticosteroid treatment. Thus, firm conclusions cannot be derived from the currently available data. Implications for future research, which is required to increase our understanding of potential influences of corticosteroids on the perception of dyspnea, are provided.

Association of depression and anxiety with health care use and quality of life in asthma patients.

INTRODUCTION: Demographic factors, symptom severity, and psychopathology, in particular anxiety and depression, are known to influence health care use and quality of life in asthma. Because depression and anxiety are typically correlated, we sought to explore whether depression specifically is associated with health care utilization and quality of life when effects of anxiety are controlled for. METHOD: In a cross-sectional questionnaire study, 88 asthma patients (46 women; age range 27-70 years) reported on symptoms and treatment of their disease, as well as anxiety and depression (Hospital Anxiety and Depression Scale, HADS), general quality of life (Short Form 12 Health Survey Questionnaire, SF-12) and asthmatic-specific quality of life (Living with Asthma, LAQ). RESULTS: While no considerable associations between anxiety and health care use were found, the associations between higher scores in depression and hospital visits as well as days of corticosteroid intake were significant. Furthermore, considerable variance in all subscales of quality of life questionnaires was explained by higher scores in depression, even when controlling for anxiety. For anxiety scores these associations were comparable, except for physical well-being. CONCLUSION: Depression is an important issue in asthma, as it is substantially related to quality of life and intake of corticosteroids, and marginally to hospitalization. Routine screening for depression should be considered in hospital and primary care.

[Pharmacological treatment of COPD and future of anti-inflammatory therapy]. / COPD-pharmakologische Basisbehandlung und Zukunft der antiinflammatorischen Therapie.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible. It is caused by chronic inflammation of the airways and the lung parenchyma. Symptomatic treatment is based on bronchodilatation, which leads to a reduction of hyperinflation and relief of dyspnea. Smoking cessation is the only known causative treatment option. Inhaled corticosteroids (ICS) reduce exacerbations and, potentially, mortality. Future therapies should ameliorate chronic inflammation and thus stop the annual decline of lung function. In face of increasing mortality and morbidity more research is needed.

Comparison of the oropharyngeal deposition of inhaled ciclesonide and fluticasone propionate in patients with asthma.

Ciclesonide is a novel inhaled corticosteroid that is converted in the lungs to its active metabolite, desisobutyryl-ciclesonide (des-CIC). The aim of this study was to compare the deposition of ciclesonide, as well as its conversion to des-CIC, in the oropharyngeal cavity with fluticasone propionate (FP) following inhalation via hydrofluoroalkane-propelled metered-dose inhalers (HFA-MDIs). Eighteen asthmatics inhaled ciclesonide 800 microg followed by FP 1000 microg or vice versa in an open, randomized, 2-treatment, 2-sequence study design. The oropharynx was washed out immediately and at 15, 30, 45, and 60 minutes after inhalation. Samples were analyzed for ciclesonide, des-CIC, and FP using liquid chromatography with tandem mass-spectrometric detection. Concentration-time curves and area under the concentration-time curve (AUC) were calculated for each drug. Ciclesonide and FP were recovered in almost all samples. Within 60 minutes after inhalation, the amounts of both ciclesonide and FP decreased sharply, and low residual levels were detected after 30 minutes. des-CIC was detected in relatively low concentrations, with maximum concentration 30 minutes following inhalation. The AUC(0-60 min) for ciclesonide (250.4 nmol x h/L) and des-CIC (37.8 nmol x h/L) were found to be significantly lower compared with FP (636.2 nmol.h/L, P < .001). Approximately 50% less ciclesonide and 90% less metabolite were present in the oropharynx compared with FP. Less than 20% of the residual ciclesonide in the oropharynx was metabolized to des-CIC. These findings indicate that oropharyngeal deposition of ciclesonide is only half that of FP following inhalation from an HFA-MDI. Furthermore, there is little activation of ciclesonide to its active metabolite in the oropharynx, suggesting a decreased likelihood of inhaled ciclesonide-associated oropharyngeal side effects.

Validation of the human ozone challenge model as a tool for assessing anti-inflammatory drugs in early development.

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double-dummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development.

Effect of beclomethasone dipropionate (BDP) as extrafine aerosol on bronchoalveolar lavage (BAL) lymphocytes in chronic sarcoidosis.

BACKGROUND AND AIM OF THE STUDY: Patients with pulmonary sarcoidosis can benefit from inhaled corticosteroids. In this study we assessed the effect of beclomethasone dipropionate (BDP), administered as extrafine, HFA(hydrofluoroalkane)-driven aerosol with high peripheral deposition, on bronchoalveolar lavage (BAL) lymphocyte numbers, as a marker of the disease. METHODS: Fifteen patients with newly-diagnosed pulmonary sarcoidosis (Stages I-III) received either BDP 800 microg daily (n = 6) or placebo (n = 9) for 6 months in a parallel-group design. Before and after treatment, clinical and radiological states were assessed, bronchoalveolar lavage (BAL) performed, and the cellular composition of BAL fluid as well as cytokine production by BAL lymphocytes determined. RESULTS: BDP caused a decrease in the percentage of BAL lymphocytes in the BDP (p < 0.05) but not the placebo group. HLA-DR expression on lymphocytes was diminished after BDP (p < 0.05), while intracellular cytokine production by lymphocytes was not altered. Chest radiography suggested an improvement in the BDP group. There was also a rise (p < 0.05) in the diffusing capacity for carbon monoxide. CONCLUSIONS: Though based on a small group of patients, the present findings suggest that in patients with pulmonary sarcoidosis of stage II and minor functional impairment, inhalation of high doses of BDP as extrafine, peripherally deposited aerosol is associated with a reduction in the number of BAL lymphocytes, in parallel with improvements in other markers of the disease.