The burden of systemic corticosteroid use in asthma management in Asia.

For most patients, asthma can be effectively managed using inhaled medications. However, patients who have severe and/or uncontrolled asthma, or who experience exacerbations, may require systemic corticosteroids (SCSs) to maintain asthma control. Although SCS are highly effective in this regard, even modest exposure to these medications can increase the risk for long-term, adverse health outcomes, such as type 2 diabetes, renal impairment, cardiovascular disease and overall mortality. Clinical and real-world data from studies investigating asthma severity, control and treatment practices around the globe have suggested that SCS are overused in asthma management, adding to the already substantial healthcare burden experienced by patients. Throughout Asia, although data on asthma severity, control and SCS usage are limited and vary widely among countries, available data strongly suggest a pattern of overuse consistent with the broader global trend. Coordinated changes at the patient, provider, institutional and policy levels, such as increasing disease awareness, promoting better adherence to treatment guidelines and increasing availability of safe and effective alternatives to SCS, are likely necessary to reduce the SCS burden for patients with asthma in Asia.

Long-term effectiveness of omalizumab treatment in Thai severe asthmatic patients: A real-life experience.

BACKGROUND: To evaluate long-term effectiveness of omalizumab in 'real-life' setting of Thai asthmatic patients. METHODS: We conducted multi-center, observational study in severe asthma patients who received omalizumab in Thailand. Outcomes were asthma exacerbation (hospitalization and ER visit), asthma control test (ACT), and daily ICS dose. Data were evaluated at baseline, 16 Week, and 52 Week. RESULTS: A total of 78 patients received omalizumab treatment (average duration 16.9 months with range 16 weeks-2 years). The mean annualized rate of exacerbations was reduced from baseline (3.79) at Week 16 (3.54) and Week 52 (1.16), (p<0.05), respectively. The mean hospitalization rate was reduced from 0.49 in previous year to 0.15 at Week 16 and 0.19 at Week 52. A reduction in ER visit rates was observed at Week 16 (0.15) and Week 52 (0.97) respectively from baseline (1.44) (p<0.05). The ACT score increased from 15.4 at baseline to 20.6 at Week 16 (p<0.001) and increased to 21.5 at Week 52 (p<0.001). The number of patients with controlled asthma (ACT≥20) increased from 16 of 51 at baseline to 32 of 45 at Week 16 and 25 of 32 at week 52, respectively. The median daily dose of ICS equivalent to fluticasone was reduced from baseline 680 mcg to 500 mcg at Week 52. In all, 22 patients discontinued omalizumab after 1 year. Six patients who discontinued omalizumab were restarted due to relapse of symptoms. CONCLUSIONS: These data confirms the effectiveness of one-year duration of omalizumab treatment in Thai severe asthmatic patients. Furthermore, 27% of patients who discontinued treatment required restarting due to relapse of symptoms.

Evaluation of Proinflammatory Cytokines and Adverse Events in Healthy Volunteers upon Inhalation of Antituberculosis Drugs.

Inhalation therapy is a promising drug delivery approach for tuberculosis treatment. However, there is always concern about the safety of the dosage form by inhalation as it may induce inflammation. Developing a new dosage form for inhalation must include tests for its safety especially for the tumor necrosis factor (TNF)-α and interleukine (IL)-1ß. The safety of four anti-tuberculosis (anti-TB) drugs administered via inhalation was assessed in healthy volunteers. Four anti-TB drugs; isoniazid, rifampicin, pyrazinamide and levofloxacin were prepared as dry powder and evaluated for uniformity of delivered dose and in vitro drug deposition. These four anti-TB dry powder formulations for inhalation met the criteria of uniformity of delivered dose and exhibited suitable size for lung delivery. Forty healthy volunteers were recruited and each was sequentially challenged with isoniazid, rifampicin, pyrazinamide and levofloxacin in different orders. Safety was monitored by measuring the pro-inflammatory cytokines in their sputum, lung function test, blood chemistry and adverse events. This study proves that all four anti-TB dry powders did not provoke inflammatory cytokines and are safe to healthy volunteers.

Blood Eosinophil Count Stability and Clinical Outcomes in Patients With Chronic Obstructive Pulmonary Disease in a High Endemic Area of Parasitic Infection: A Prospective Study.

Background: The blood eosinophil count (BEC) is an effective biomarker for predicting inhaled corticosteroid responsiveness in patients with chronic obstructive pulmonary disease (COPD). Methods: A 12-month prospective observational study was conducted in patients with COPD. BEC was measured at enrolment, and after 6 and 12 months. Patients were classified into three groups according to their baseline BEC: <100, 100 - 299, and ≥300 cells/µL. We aimed to describe the patterns of blood eosinophil stability in patients with stable COPD and compare the exacerbation rates and other clinical outcomes at 6 and 12 months. Results: A total of 252 patients with COPD were included. The <100, 100 - 299, and ≥ 300 cells/µL groups consisted of 14.7, 38.9, and 46.4% of patients, respectively. BEC stability was highest (85%) in the ≥300 cells/µL group for both durations. The lowest stability was observed in the <100 cells/µL group at 57 and 46% after 6 and 12 months, respectively. The persistent ≥ 300 cells/µL group had a higher incidence of moderate-to-severe exacerbation (IRR 2.44, 95% confidence interval (CI): 1.13-5.27, p value 0.023, as well as severe exacerbation (IRR 2.19, 95%CI: 1.39-3.45, p value 0.001). Other patient-reported outcomes did not differ significantly between groups. Conclusion: Blood eosinophil levels had good stability in patients with COPD with BEC ≥300 cells/µL and was associated with a high risk of exacerbation in the persistent ≥300 cells/µL group. The variability of BEC was higher in patients with COPD with BEC <300 cells/µL.

Association between Increased Risk of Pneumonia with ICS in COPD: A Continuous Variable Analysis of Patient Factors from the IMPACT Study.

INTRODUCTION: Despite the proven benefits of inhaled corticosteroid (ICS)-containing triple therapy for chronic obstructive pulmonary disease (COPD), clinicians limit patient exposure to ICS due to the risk of pneumonia. However, there are multiple factors associated with the risk of pneumonia in patients with COPD. This post hoc analysis of IMPACT trial data aims to set the risks associated with ICS into a context of specific patient-related factors that contribute to the risk of pneumonia. METHODS: The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI), FF/VI or UMEC/VI. Annual rate of on-treatment pneumonias in the intent-to-treat population associated with age, body mass index (BMI), percent predicted forced expiratory volume in 1 s (FEV1) and blood eosinophil count (BEC) was evaluated. RESULTS: This analysis revealed that the annual rate of pneumonia showed the lowest risk at the age of 50 years. The 95% confidence intervals (CI) between ICS-containing and non-ICS containing treatments diverged in ages > 63 years, suggesting a significantly increased ICS-related risk in older patients. In contrast, the annual rate of pneumonia rose in both groups below BMI of 22.5 kg/m2, but above that, there was no relationship to pneumonia rate and no differential effect between the two groups. The relationship between BEC and pneumonia was flat up to > 300/µL cells with ICS-containing treatment and then rose. In contrast, the rate of pneumonia with non-ICS containing treatment appeared to increase at a lower level of BEC (~ 200/µL). CONCLUSIONS: There was little evidence of a differential effect of older age, lower BMI, lower FEV1 and BEC on the pneumonia rate between ICS-containing and non-ICS containing treatments. This analysis points to the need for a balanced approach to risk versus benefit in the use of ICS-containing treatments in COPD. CLINICAL TRIAL REGISTRATION: IMPACT ClinicalTrials.gov number, NCT02164513.

Clinical Concepts for Triple Therapy Use in Patients with COPD: A Delphi Consensus.

Purpose: Role of triple therapy in chronic obstructive pulmonary disease (COPD) management is supported by growing evidence, but consensus is lacking on various aspects. We conducted a Delphi survey in respiratory experts on the effects of triple therapy on exacerbation reduction, early optimization, pneumonia risk, and mortality benefits in COPD management. Methods: The study comprised 2-round online surveys and a participant meeting with 21 respiratory experts from 10 countries. The 31-statement questionnaire was prepared using Decipher software after literature review. Responses were recorded using Likert scale ranging from 1 (disagreement) to 9 (agreement) with a consensus threshold of 75%. Results: All experts participated in both surveys and 14/21 attended participant meeting. Consensus was reached on 13/31 questions in first survey and 4/14 in second survey on: mortality benefits of triple therapy; comparable pneumonia risk between single inhaler triple therapy (SITT) and multiple inhaler triple therapy (81%); preference of SITT for patients with high eosinophil count (95%); exacerbation risk reduction and healthcare cost benefits with early initiation of SITT post exacerbation-related hospitalization (<30 days) (86%). No consensus was reached on first line SITT use after first exacerbation resulting in COPD diagnosis (62%). Conclusion: This study demonstrated that there is consensus among experts regarding many of the key concepts about appropriate clinical use and benefits of triple therapy in COPD. More evidence is required for evaluating the benefits of early optimisation of triple therapy.

Efficacy of Roflumilast in Bronchiectasis Patients with Frequent Exacerbations: A Double-Blinded, Randomized, Placebo-Controlled Pilot Clinical Trial.

BACKGROUND: Bronchiectasis patients with neutrophilic airway inflammation develop symptoms of chronic cough, sputum production, and recurrent exacerbations. Roflumilast has anti-inflammatory actions via decreased neutrophilic airway inflammation. The effectiveness of roflumilast to reduce bronchiectasis exacerbation has never been evaluated. METHODS: We conducted a double-blinded, randomized, placebo-controlled trial. Our primary objective was to assess the effect of roflumilast compared with that of a placebo in reducing exacerbation rates in bronchiectasis patients. The secondary objectives were the changes in forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ). Bronchiectasis patients older than 18 years who had had two exacerbations during the previous 12 months were randomly assigned to receive either 500 µg of either roflumilast or a placebo once daily for 6 months in a 1:1 ratio. RESULTS: Forty bronchiectasis patients who had experienced exacerbations were screened. Thirty patients completed the study after 6 months of treatment: roflumilast group (n=15) and placebo group (n=15). The rates of exacerbations were 0.57 and 0.59 per patient in the roflumilast and placebo groups, respectively. Prebronchodilator FEV1 increased by 0.07 L from baseline in the roflumilast group and decreased by 0.015 L in the placebo group, but the difference was not significant. No significant differences were observed in the change of SGRQ scores between the roflumilast and placebo groups. Roflumilast had significant side effects, including loss of appetite and headache. CONCLUSION: Roflumilast did not significantly affect the rate of exacerbations or quality of life. However, FEV1 tended to improve more in the roflumilast group than in the placebo group.

Association between blood eosinophils with exacerbation and patient-reported outcomes in chronic obstructive pulmonary disease patients in an endemic area for parasitic infections: a prospective study.

BACKGROUND: Eosinophilic chronic obstructive pulmonary disease (COPD) patients have eosinophilic airway inflammation. No prospective study has reported blood eosinophil counts in an endemic area for parasitic infection. The primary objective was to compare exacerbation rates. The secondary objectives were patient-reported outcomes between eosinophilic and non-eosinophilic COPD. METHODS: A prospective study was conducted in COPD patients for 52 weeks. COPD was diagnosed according to GOLD criteria. Blood eosinophil counts were recorded at study entry. Exacerbations were recorded during the entire study period whereas COPD Assessment Test (CAT) and spirometry were recorded at 12 months. The eosinophilic and non-eosinophilic groups were defined by blood eosinophil counts ≥300 and <300 cells/µL, respectively. RESULTS: A total of 145 COPD patients were included. Fifty-eight (40%) and 87 (60%) patients were eosinophilic and non-eosinophilic COPD and the median [interquartile range (IQR)] eosinophil counts were 481 [378.5, 675] and 149 [101.2, 208] cells/µL, respectively. The median (IQR) annual exacerbation rates were 3 [2, 4] and 2 [2, 2.5] times/year in the eosinophilic and non-eosinophilic groups, respectively (P=0.024). The eosinophilic group had higher admissions (P=0.007) but lower mortality (P=0.041). The patient-reported outcomes were not statistically significantly different between the two groups. Eosinophil counts ≥300 cells/µL identified exacerbation in COPD patients with sensitivity and specificity of 0.71 and 0.64, respectively. CONCLUSIONS: COPD patients with blood eosinophil counts ≥300 cells/µL had more exacerbations and admissions but lower mortality than the non-eosinophilic patients. Blood eosinophil count is an effective biomarker to predict exacerbation risk in endemic parasitic areas. TRIAL REGISTRATION: NCT04123028 at ClinicalTrials.gov.

Clinical manifestation and survival of patients with small-cell lung cancer.

OBJECTIVE: To assess the clinical manifestation, diagnostic investigation, treatment, and survival of patients with small-cell lung cancer (SCLC). DESIGN: Retrospective study. MATERIAL AND METHOD: Patients with histologically and/or cytologically proven SCLC, adequate medical record for clinical history, and survival between January 1, 1999 and December 31, 2003, were reviewed. The stage of disease at presentation was based on the Veterans' Administration Lung Cancer Study Group (VALSG) staging system of limited-stage and extensive-stage disease. RESULTS: One hundred and sixteen evaluative SCLC patients were enrolled in the present study. SCLC was common in elderly men who smoked. Major symptoms were cough 81%, weight loss 72%, and dyspnea 67%. Hoarseness and superior vena cava syndrome (SVC syndrome) were present in 18% and 17% respectively. Forty-nine patients (42%) presented with limited-stage disease and 67 (58%) with extensive-stage disease. Thirty patients (26%) received chemotherapy alone, 23 patients (20%) received radiotherapy alone, 33 patients (28%) received combined chemoradiotherapy, and 30 patients (26%) received supportive treatment. A chemotherapy regimen of cisplatin combined with etoposide was used in 61 of 63 patients (97%). The overall response to chemotherapy was complete remission in 12 cases (19%), and partial response in 20 cases (32%). The median survival of limited-stage disease was significantly better than those with extensive-stage disease (44 weeks vs. 22 weeks). Patients with chemotherapy treatment had significantly improved median survival in both limited-stage and extensive-stage disease. CONCLUSION: More than half of the SCLC patients presented in extensive-stage disease. The majority of the patients were treated with systemic chemotherapy. Patients with limited-stage disease had better response to chemotherapy and better survival than those with extensive-stage disease.

Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler.

INTRODUCTION: A delivery device is the most important factor that determines the local/systemic bioavailability of inhaled corticosteroids. Dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs) are the most commonly used delivery devices for localized drug delivery to the airways. OBJECTIVE: This study was to compare the clinical equivalence of budesonide delivered by the Pulmicort Turbuhaler (DPI) and the Aeronide inhaler (pMDI). MATERIALS AND METHODS: The two inhalers were compared for their pharmaceutical equivalence and clinical equivalence. The in vitro test included the uniformity of the delivered dose and determination of the aerodynamic particle size of budesonide. The in vivo test was carried out in 36 patients with mild to moderate asthma. This was a randomized, single-blinded study conducted for a period of 3 months. This included assessment of the spirometric parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 25-75% (FEF25-75)], the severity of asthma symptoms, adverse events, frequency of short-acting inhaled bronchodilator usage and measurement of urinary cortisol levels. RESULTS: The aerodynamic particle size was slightly different between the two inhalers (2.3 ± 0.2 µm for Pulmicort Turbuhaler and 2.2 ± 0.2 µm for Aeronide inhaler). Both inhalers passed the uniformity of delivered dose (95.4% and 97.4%) specified in the British Pharmacopoeia. There was no statistically significant difference observed between the two inhalers in terms of the spirometric parameters, symptom-free days, frequency of bronchodilator usage and the level of urinary cortisol. CONCLUSION: In addition to pharmaceutical equivalence, no clinical difference observed between the two budesonide inhalers.

Ambroxol lozenge bioavailability : an open-label, two-way crossover study of the comparative bioavailability of ambroxol lozenges and commercial tablets in healthy thai volunteers.

OBJECTIVE: To compare the bioavailability of two 15mg ambroxol lozenges with a commercial 30mg ambroxol tablet. DESIGN: Open-label, two-way crossover study. METHOD: Each formulation was randomly administered to 20 healthy Thai volunteers (ten male and ten female) with a 1-week washout period between formulations. After administration, serial blood samples were collected over a 24-hour period and the plasma concentration of ambroxol was subsequently measured using high performance liquid chromatography with ultraviolet detection after liquid-liquid extraction. Pharmacokinetic parameters were analysed by a noncompartmental pharmacokinetic model and compared between formulations using analysis of variance with a significance level of 0.05. RESULTS: The point estimates (90% CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) ratios between lozenge and commercial tablet were 1.07 (0.89 to 1.28) and 1.20 (1.04 to 1.40), respectively. The point estimate (90% CI) of the difference between formulations for time to C(max) was 0.40 (-0.20 to 1.00). CONCLUSION: The two formulations under test were not bioequivalent based on the stipulated bioequivalence criteria. The bioavailability from the ambroxol lozenge might be better, since the 90% CI of the AUC(0-infinity) fell outside the bioequivalence range, and its range was narrower. The difference in rate of absorption was not conclusive because ambroxol was delivered from the lozenge by two parallel processes, namely absorption via oral and gastrointestinal mucosa. The additional oral mucosal absorption might not only contribute more absorption but also introduce variability compared with that of tablet administration. The relative importance of oral versus gastrointestinal mucosal absorption of ambroxol from the lozenge formulation, and the clinical significance of this, requires further study.