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1.  A study to assess COPD Symptom-based Management and to Optimise treatment Strategy in Japan (COSMOS-J) based on GOLD 2011 
Background and objective
The Global initiative for chronic Obstructive Lung Disease (GOLD) Committee has proposed a chronic obstructive pulmonary disease (COPD) assessment framework focused on symptoms and on exacerbation risk. This study will evaluate a symptom and exacerbation risk-based treatment strategy based on GOLD in a real-world setting in Japan. Optimal management of COPD will be determined by assessing symptoms using the COPD Assessment Test (CAT) and by assessing the frequency of exacerbations.
Methods
This study (ClinicalTrials.gov identifier: NCT01762800) is a 24-week, multicenter, randomized, double-blind, double-dummy, parallel-group study. It aims to recruit 400 patients with moderate-to-severe COPD. Patients will be randomized to receive treatment with either salmeterol/fluticasone propionate (SFC) 50/250 μg twice daily or with tiotropium bromide 18 μg once daily. Optimal management of patients will be assessed at four-weekly intervals and, if patients remain symptomatic, as measured using the CAT, or experience an exacerbation, they have the option to step up to treatment with both drugs, ie, SFC twice daily and tiotropium once daily (TRIPLE therapy). The primary endpoint of the study will be the proportion of patients who are able to remain on the randomized therapy.
Results
No data are available. This paper summarizes the methodology of the study in advance of the study starting.
Conclusion
The results of this study will help physicians to understand whether TRIPLE therapy is more effective than either treatment strategy alone in controlling symptoms and exacerbations in patients with moderate-to-severe COPD. It will also help physicians to understand the GOLD recommendation work in Japan.
doi:10.2147/COPD.S48298
PMCID: PMC3795054  PMID: 24124358
COPD; GOLD; symptom; exacerbation risk; TRIPLE therapy
2.  Increased human Ca2+-activated Cl- channel 1 expression and mucus overproduction in airway epithelia of smokers and chronic obstructive pulmonary disease patients 
Respiratory Research  2012;13(1):55.
Background
The mechanisms underlying the association between smoking and mucus overproduction remain unknown. Because of its involvement in other airway diseases, such as asthma, we hypothesized that Ca2+-activated Cl- channel 1 (CLCA1) was associated with overproduction of mucus in the airways of smokers and COPD patients.
Methods
Using real-time quantitative PCR analyses, we compared the CLCA1 mRNA expression levels in induced-sputum cells from COPD patients (n = 20), smokers without COPD (n = 5), and non-smokers (n =13). We also examined the relationship between CLCA1 protein expression and mucus production in lung airway epithelia of COPD patients (n = 6), smokers without COPD (n = 7), and non-smokers (n = 7).
Results
CLCA1 mRNA expression was significantly up-regulated in the induced-sputum cells of COPD patients compared with cells of non-smokers (p = 0.02), but there was no significant difference compared with cells of smokers without COPD. Using immunostaining with an anti-CLCA1 antibody, semi-quantitative image analyses of airway epithelium demonstrated significantly increased CLCA1 expression in smokers without COPD (p = 0.02) and in COPD patients (p = 0.002) compared with non-smokers. There were significant negative correlations between CLCA1 protein expression and FEV1/FVC (r = −0.57, p = 0.01) and %predicted FEV1 (r = −0.56, p = 0.01). PAS staining for mucus showed that there was a significant positive correlation between CLCA1 protein expression and mucus production (r = 0.67, p = 0.001). These markers were significantly increased in smokers without COPD (p = 0.04) and in COPD patients (p = 0.003) compared with non-smokers (non-smokers < smokers ≤ COPD).
Conclusions
CLCA1 expression is significantly related to mucus production in the airway epithelia of smokers and COPD patients, and may contribute to the development and pathogenesis of COPD by inducing mucus production.
doi:10.1186/1465-9921-13-55
PMCID: PMC3489697  PMID: 22731784
Ca2+-activated Cl- channel 1 (CLCA1); Chronic obstructive pulmonary disease (COPD); Smoking; Mucus production; Airway epithelia
3.  Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma 
Background
Chronic obstructive pulmonary disease (COPD) and asthma may overlap and converge in older people (overlap syndrome). It was hypothesized that patients with overlap syndrome may have different clinical characteristics such as sputum eosinophilia, and better responsiveness to treatment with inhaled corticosteroid (ICS).
Methods
Sixty-three patients with stable COPD (forced expiratory volume in 1 second [FEV1] ≤80%) underwent pulmonary function tests, including reversibility of airflow limitation, arterial blood gas analysis, analysis of inflammatory cells in induced sputum, and chest high-resolution computed tomography. The inclusion criteria for COPD patients with asthmatic symptoms included having asthmatic symptoms such as episodic breathlessness, wheezing, cough, and chest tightness worsening at night or in the early morning (COPD with asthma group). The clinical features of COPD patients with asthmatic symptoms were compared with those of COPD patients without asthmatic symptoms (COPD without asthma group).
Results
The increases in FEV1 in response to treatment with ICS were significantly higher in the COPD with asthma group. The peripheral eosinophil counts and sputum eosinophil counts were significantly higher. The prevalence of patients with bronchial wall thickening on chest high-resolution computed tomography was significantly higher. A significant correlation was observed between the increases in FEV1 in response to treatment with ICS and sputum eosinophil counts, and between the increases in FEV1 in response to treatment with ICS and the grade of bronchial wall thickening. Receiver operating characteristic curve analysis revealed 82.4% sensitivity and 84.8% specificity of sputum eosinophil count for detecting COPD with asthma, using 2.5% as the cutoff value.
Conclusion
COPD patients with asthmatic symptoms had some clinical features. ICS should be considered earlier as a potential treatment in such patients. High sputum eosinophil counts and bronchial wall thickening on chest high-resolution computed tomography might therefore be a good predictor of response to ICS.
doi:10.2147/COPD.S30651
PMCID: PMC3346210  PMID: 22589579
COPD; asthma; HRCT; inhaled corticosteroid; pulmonary function
4.  Accuracy of ECG-based screening for sleep-disordered breathing: a survey of all male workers in a transport company 
Purpose
Sleep-disordered breathing (SDB) is associated with increased risk for cardiovascular morbidity and mortality and for sleepiness-related accidents, but >75 % of the patients remain undiagnosed. We sought to determine the diagnostic accuracy of ECG-based detection of SDB when used for population-based screening.
Methods
All male workers, mostly truck drivers, of a transport company (n = 165; age, 43 ± 12 years) underwent standard attended overnight polysomnography. Cyclic variation of heart rate (CVHR), a characteristic pattern of heart rate associated with SDB, was detected from single-lead ECG signals during the polysomnography by a newly developed automated algorithm of autocorrelated wave detection with adaptive threshold (ACAT).
Results
Among 165 subjects, the apnea–hypopnea index (AHI) was ≥5 in 62 (38 %), ≥15 in 26 (16 %), and ≥30 in 16 (10 %). The number of CVHR per hour (CVHR index) closely correlated with AHI [r = 0.868 (95 % CI, 0.825–0.901)]. The areas under the receiver operating characteristic curves for detecting subjects with AHI ≥5, ≥15, and ≥30 were 0.796 (95 % CI, 0.727–0.855), 0.974 (0.937–0.993), and 0.997 (0.971–0.999), respectively. With a predetermined criterion of CVHR index ≥15, subjects with AHI ≥15 were identified with 88 % sensitivity and 97 % specificity (likelihood ratios for positive and negative test, 30.7 and 0.12). The classification performance was retained in subgroups of subjects with obesity, hypertension, diabetes mellitus, dyslipidemia, and decreased autonomic function.
Conclusions
The CVHR obtained by the ACAT algorithm may provide a useful marker for screening for moderate-to-severe SDB among apparently healthy male workers.
doi:10.1007/s11325-012-0681-7
PMCID: PMC3575561  PMID: 22430527
Apnea–hypopnea index; Cyclic variation of heart rate; Electrocardiogram; Sleep apnea; Sleep-disordered breathing; Population
5.  Comparison of efficacy of long-acting bronchodilators in emphysema dominant and emphysema nondominant chronic obstructive pulmonary disease 
Background:
The purpose of this study was to clarify the association between morphological phenotypes according to the predominance of emphysema and efficacy of long-acting muscarinic antagonist and β2 agonist bronchodilators in patients with chronic obstructive pulmonary disease (COPD).
Methods:
Seventy-two patients with stable COPD treated with tiotropium (n = 41) or salmeterol (n = 31) were evaluated for pulmonary function, dynamic hyperinflation following metronome-paced incremental hyperventilation, six-minute walking distance, and St George’s Respiratory Questionnaire (SGRQ) before and 2–3 months following treatment with tiotropium or salmeterol. They were then visually divided into an emphysema dominant phenotype (n = 25 in the tiotropium-treated group and n = 22 in the salmeterol-treated group) and an emphysema nondominant phenotype on high-resolution computed tomography, and the efficacy of the two drugs in each phenotype was retrospectively analyzed.
Results:
Tiotropium significantly improved airflow limitation, oxygenation, and respiratory impedance in both the emphysema dominant and emphysema nondominant phenotypes, and improved dynamic hyperinflation, exercise capacity, and SGRQ in the emphysema dominant phenotype but not in the emphysema nondominant phenotype. Salmeterol significantly improved total score for SGRQ in the emphysema phenotype, but no significant effects on other parameters were found for either of the phenotypes.
Conclusion:
These findings suggest that tiotropium is more effective than salmeterol for airflow limitation regardless of emphysema dominance, and also can improve dynamic hyperinflation in the emphysema dominant phenotype, which results in further improvement of exercise capacity and health-related quality of life.
doi:10.2147/COPD.S18461
PMCID: PMC3107698  PMID: 21660299
emphysema; dynamic hyperinflation; long-acting β2 agonist; long-acting muscarinic antagonist; exercise capacity; quality of life
6.  Survey on negative impact of chironomid midges (Diptera) on bronchial asthmatic patients in a hyper-eutrophic lake area in Japan 
Chironomid midges have been revealed to be a hazardous inhalant antigen of bronchial asthma. To determine the awareness of the negative impact of chironomid midges (Chironomus plumosus and Propsilocerus akamusi) among patients, a questionnaire survey of 118 patients in the Lake Suwa area and in the Matsumoto area was conducted from early September to mid-November of 1993. The life style was almost the same among the asthmatic patients in the Lake Suwa area and in the Matsumoto area, but the reactions to the nuisance differed significantly from each other. Although “Flight density” was higher in the Lake Suwa area (p < 0.01) than that in the Matsumoto area, 25.5% of the patients in the Lake Suwa area and 9.1% of those in the Matsumoto area answered “Endurable” (p < 0.01). Further follow-up studies including prick tests, intradermal tests and provocation tests should be conducted for patients who complained a strong allergic reaction.
doi:10.1007/BF02931237
PMCID: PMC2723270  PMID: 21432506
Bronchial asthmatic patients; Chironomid midges; Lake Suwa; Nuisance; Questionnaire
7.  Pharmacokinetic Evaluation of Amphotericin B in Lung Tissue: Lung Lymph Distribution after Intravenous Injection and Airspace Distribution after Aerosolization and Inhalation of Amphotericin B 
We have studied the pharmacokinetics of amphotericin B (AmB) in lung lymph circulation and bronchial-wash fluid after intravenous infusion and inhalation, respectively. For two experiments with awake sheep, we used lung lymph fistulas and tracheotomy. In experiment 1, AmB concentrations in plasma and lung lymph after intravenous infusion of AmB (1 mg/kg of body weight) over 1.5 h were measured. The mean peak in plasma level was 756.0 ± 188.8 ng/ml at 3 h after the start of infusion, and the level then decreased gradually to 194.8 ± 28.9 ng/ml at 24 h. The stable and maximal levels in lung lymph last 5 to 9 h after the start of AmB infusion. The concentrations in lung lymph after 9 h were slightly higher than those in plasma. Thus, the lung lymph-to-plasma ratio of AmB concentrations increased gradually during infusion, and the ratio was more than 1.0 after the end of infusion, suggesting that AmB could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. In another experiment, 5 or 30 mg of aerosol AmB was inhaled, and the concentration of AmB in the bronchial-wash fluid was determined by bronchoalveolar lavage. The peak AmB concentration in the fluid was observed at 0.5 h. After that, AmB was slowly eliminated over 24 h. The area under the concentration-time curve for 30 mg of inhaled AmB was higher than that for 5 mg, but maximum concentrations of AmB in serum for 5 and 30 mg were almost similar. These observations identify the pharmacokinetic characteristics of AmB in the lung and may provide a new insight into the strategy for clinical treatment of fungal pneumonia.
PMCID: PMC105652  PMID: 9660990

Results 1-7 (7)