Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand.

BACKGROUND: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. METHODS: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. RESULTS: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). CONCLUSIONS: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).

Prevalence of Uncontrolled Asthma despite Treatment with Medium- or High-Dose ICS/LABA Using Patient-Reported Outcomes in Japan: The KOCU (KnOwing the Controlled statUs of Asthma in Japan) Study.

INTRODUCTION: Evidence on the prevalence of uncontrolled asthma upon the standard of care in Japan is scarce and inconsistent. We report the prevalence of uncontrolled asthma using the Japanese Guidelines for Asthma (JGL) 2018 and Global Initiative for Asthma (GINA) 2019 classifications in patients who are currently receiving standard-of-care treatment in a real-life setting. METHODS: In this prospective, 12-week, noninterventional study, patients with asthma aged 20-75 years and continuously treated with medium- or high-dose inhaled corticosteroid (ICS)/LABA, with or without other controller(s), were assessed for their asthma control status. The demographics, clinical characteristics, treatment patterns, health care resource utilization, patient-reported outcomes (PROs), and adherence to prescribed treatments were assessed for patients classified as either controlled or uncontrolled. RESULTS: Of 454 patients, 53.7% and 36.3% of the patients reported their asthma as uncontrolled based on the JGL and GINA criteria, respectively. Uncontrolled asthma was even higher (JGL, 75.0%; GINA, 63.5%) within the subpopulation of 52 patients receiving long-acting muscarinic antagonists (LAMAs; i.e., ICS/LABA/LAMA subpopulation). Sensitivity analysis by propensity matching identified significant odds ratios of controlled versus uncontrolled asthma for several demographics and clinical characteristics: male; sensitization to animals, fungi, or birch; comorbidities including food allergy or diabetes; and history of exacerbation were associated with the risk of uncontrolled asthma. No significant changes in PROs were observed. CONCLUSION: The frequency of uncontrolled asthma in the study population was high, as per JGL and GINA guidelines, despite good adherence to ICS/LABA treatment and other prescribed treatments over 12 weeks.

[CHARACTERISTICS OF BUDEFORU® FOR BUDESONIDE AND FORMOTEROL MIXTURE].

BACKGROUND: Recently, BudeForu® (BF), a generic of Symbicort Turbuhaler® (SMB), is widely used in Japan. Although appearance of BF resembles to SMB, several differences in length, weight, and side-hole sizes are seen with precise inspection. As particle releases from the inhalation device is strongly influenced by its mechanical characteristics, we compared their particle release patterns. METHODS: An inhalation simulator generated either ramp-up or triangular (time to reach peak inhaling flow (PIF) = 0.42 s) inhalation pattern. Time trajectories of inhaled flow and released particles from either device were depicted with a photo-reflection method. Internal resistances of them were also measured. RESULTS: Particle release patterns of both dry powder inhalers resembled each other. Immediately after release from the inhaler, they reached the peak value and then completed in 0.5 s. In either ramp-up or triangular inspiration pattern, a single burst developed at early inhalation. There were linear relationships between PIFs and emitted doses. The regression lines using ramp-up patters were: Y = 0.00241 X - 0.039, r2 = 0.700, p ＜ 0.0001 (BF), Y = 0.00210 X - 0.038, r2 = 0.654, p ＜ 0.0001 (SMB), and those using triangular patterns were: Y = 0.00223X － 0.0015, r2 = 0.445, p ＜ 0.0001 (BF), and Y = 0.00229X － 0.0023, r2 = 0.687, p ＜ 0.0001 (SMB). Internal resistances of the BF and SMB were 0.105±0.004 and 0.119±0.105 cmH2O0.5/L/min respectively. CONCLUSIONS: Present experimental study suggested that aerodynamic characteristics of BF were quite similar to those of SMB.

[IS IT NECESSARY TO PROHIBIT SIDE-HOLE CLOSURE IN USE OF THE DRY POWDER INHALERS?]

BACKGROUND: In use of Ellipta (EPT), Diskus (DKS) or Turbuhaler (TBH), an instruction not to close side holes is sometimes given, but validity of such instruction has not been proved. METHOD: Using an inhalation simulator we measured peak inhaled flow (PIF), peak inhaled pressure (PIP) and amount of the drug release from these DPIs before and after closure of side holes (SHC). In the case of EPT, incomplete obstruction was also assessed. RESULTS: SHC increased internal resistance by 2.8 times in TBH, 1.0 in DKS, and 1.28 (incomplete obstruction) and 1.86 (complete) in EPT. Inhaled flows at pressure of -15cmH2O were 14L/min in TBH, 47 in DKS and 34 in EPT (incomplete obstruction). SHC suppressed drug release from TBH but statistical significance was not obtained. Drug release was not suppressed by SHC in DKS, while it was almost half during SHC in EPT. The level of PIF decreased by SHC was serious since fine particles generation is not expected. Such severe decreases were not found in DKS and EPT. CONCLUSION: SHC severely inhibited drug release from TBH, but almost no effects on DKS. Such negative effect was limited in usual use of EPT.

Pharmacological effects of lysozyme on COPD and bronchial asthma with sputum: A randomized, placebo-controlled, small cohort, cross-over study.

BACKGROUND: Mucolytic agents are often used in Japan to ease excessive mucus production in patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma (BA); the treatment ameliorates dyspnea and improves quality of life (QOL). AIM: Efficacy and safety of lysozyme hydrochloride (LYS), an oral mucolytic enzyme preparation, for patients with COPD or BA were investigated. PATIENTS AND METHODS: This study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-four patients with COPD and twenty-four patients with BA were enrolled. LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods. The results of spirometry, impulse oscillometry system (IOS) examination, fractional exhaled nitric oxide (FeNO) measurement, as well as the changes in the subjective symptoms, were evaluated after the treatment period. RESULTS: On spirometry, airway function (FEV1) improved in patients with COPD after administration of LYS (LYS vs placebo: 0.08 L vs 0.029 L, p = 0.030). Similar trends were also found in %FEV1 in COPD patients. On IOS examination, resistance of the respiratory system at 5 Hz levels was significantly improved only in patients with COPD (LYS vs placebo: -0.455 cm H2O/L/s vs 0.095 cmH2O/L/s, p = 0.012). Similar trends were found in terms of the resistance of the respiratory system at 20 Hz, and of the reactance area. In the COPD assessment test, subjective symptoms also significantly improved in patients with COPD during the LYS treatment period (improvement rates-LYS vs. placebo: 69.6% vs. 39.1%; p = 0.022). A similar effect of LYS was not seen in BA patients. CONCLUSION: LYS, a mucolytic agent, has capability to improve the function of peripheral airways in patients with COPD, which leads to improvements of the patients' symptoms and QOL.

Effects of Ninjin'yoeito on Patients with Chronic Obstructive Pulmonary Disease and Comorbid Frailty and Sarcopenia: A Preliminary Open-Label Randomized Controlled Trial.

Purpose: To present the preliminarily findings regarding the effects of a herbal medicine, Ninjin'yoeito, on comorbid frailty and sarcopenia in patients with chronic obstructive pulmonary disease (COPD). Patients and Methods: Patients with COPD (GOLD II or higher) and fatigue were randomly assigned to Group A (n = 28; no medication for 12 weeks, followed by 12-week administration) or B (n= 25; 24-week continuous administration). Visual analog scale (VAS) symptoms of fatigue, the COPD assessment test (CAT), and the modified Medical Research Council (mMRC) Dyspnea Scale were examined. Physical indices such asknee extension leg strength and walking speed, skeletal muscle mass index (SMI), and respiratory function test were also measured. Results: VAS fatigue scales in Group B significantly improved after 4, 8, and 12 weeks compared to those in Group A (each p<0.001, respectively). Right and left knee extension leg strength in Group B significantly improved after 12 weeks compared to that in Group A (p=0.042 and p=0.037, respectively). The 1-s walking speed for continued to increase significantly over 24 weeks in Group B (p=0.016, p<0.001, p<0.001, p=0.004, p<0.001, and p<0.001 after 4, 8, 12, 16, 20, and 24 weeks, respectively); it also significantly increased after the administration of Ninjin'yoeito in Group A. In Group B, the SMI significantly increased at 12 weeks in patients with sarcopenia (p=0.025). The CAT scores in Group B significantly improved after 12 weeks compared to those in Group A (p=0.006). The mMRC scores in Group B also significantly improved after 8 and 12 weeks compared to those in Group A (p= 0.045 and p <0.001, respectively). The changes in %FEV1.0 in Group B were significantly improved at 12 and 24 weeks (p=0.039 and p=0.036, respectively). Conclusion: Overall, Ninjin'yoeito significantly improved patients' quality of life, physical activity, muscle mass, and possibly lung function, suggesting that Ninjin'yoeito may improve frailty and sarcopenia in patients with COPD.

Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan.

OBJECTIVE: Persistent cough is a frequent cause of doctor and hospital visits, and its incidence may be increasing. However, diagnosis of the cause of cough remains difficult. Because different causes of cough have different treatments, accurate diagnosis of the cause of cough is critical. To gain a better understanding of the causes of cough in Japan, we performed a multicenter epidemiological study of Japanese patients. METHODS: The study involved seven institutions in five different areas of Japan, and was conducted over 1 year from March 2009. Patients aged ≥16 years attending the participating centers for the first time complaining of cough persisting for ≥3 weeks were eligible. Patients with chest X-ray abnormalities responsible for cough, fever or blood-stained sputum were excluded, while those with wheeze or shortness of breath were included. Frequency and severity of cough were assessed using questionnaires, and laboratory tests were performed to enable differential diagnoses. RESULTS: Among the 313 patients evaluated, mean duration of cough symptoms was 192.1 ± 558.4 days. Cough variant asthma (CVA) was the most common cause of prolonged/chronic cough (42.2%), followed by cough-predominant asthma (CPA) (28.4%), atopic cough (7.3%) and chronic obstructive pulmonary disease (6.7%). Patients with an unclear diagnosis were treated with tulobuterol, a transdermal ß2-agonist preparation, for 1-2 weeks. Transdermal tulobuterol improved assessments of cough in patients with CVA or CPA, enabling rapid diagnosis of these diseases. CONCLUSIONS: These findings show that CVA and CPA are the main causes of cough persisting for ≥3 weeks.

Analysis of the impact on efficacy of lubiprostone dose reduction to manage adverse events in the treatment of chronic constipation in Japan.

OBJECTIVE: To compare outcomes between two doses of lubiprostone in patients with chronic constipation (CC), to assess whether dose reduction affects efficacy. METHODS: This open-label exploratory study involved 146 patients with CC treated initially with lubiprostone 24 mcg twice daily for a planned duration of 4 weeks. Patients who experienced adverse events (AEs) had their dose reduced to 12 mcg twice daily (for 4 weeks). RESULTS: Lubiprostone dose was unchanged in 104 patients and reduced due to AEs in 42 patients. Significant differences in the mean number of bowel movements per week favored the dose-reduced group at Week 1 and end of follow-up. No between-group differences were observed over time for mean number of days per week with bowel movements or mean Bristol Stool Form Scale scores. Symptoms of abdominal bloating, strained defecation, and sensation of incomplete evacuation improved in both groups. Before dose reduction, nausea was reported by 64.3% and diarrhea by 45.2% of patients in the dose-reduced group; after dose reduction, no patients reported nausea and one patient reported diarrhea. CONCLUSION: Dose reduction of lubiprostone reduced the incidence of AEs, with no compromise to efficacy, and may be a suitable approach for patients who develop AEs during treatment.

[Examination of the inspiratory flow rates of COPD patients in Japanese medical facilities].

UNLABELLED: Chronic obstructive pulmonary disease (COPD) is treated primarily with inhalation therapy. However, as many COPD patients are elderly, whether or not patients inhale dry powder at an adequate inspiratory flow rate requires investigation. We therefore conducted a multicenter investigation of the effects of height, body weight, age, disease severity, and other factors on inspiratory flow rate in COPD patients. METHODS: We measured inspiratory flow rates and forced expiratory volume in the first second (FEV1) with the In-Check Dial (Clement Clarke) fitted with a discus adapter in 175 COPD patients of 40 years old and over (mean age 71.3, men 89.1%, women 10.9%). RESULTS: A total of 98.9% of the patients had an inspiratory flow rate exceeding 30L/minute. Two patients had a rate of 30L/minute or less. The mean inspiratory flow rate was 98 +/- 30L/minute overall, 104 +/- 27L/minute in mild COPD, 109 +/- 28L/minute in moderate COPD, 91 +/- 26L/minute in severe COPD, 71 +/- 24L/minute in very severe COPD, and 83 +/- 28L/minute in patients 75 years and older. Inspiratory flow rates significantly correlated with body mass index and FEV1. CONCLUSION: Most elderly patients with COPD maintained a sufficient inspiratory flow rate when inhaling dry powder.

Comparison of User Satisfaction and Preference with Inhalant Devices Between a Pressurized Metered-Dose Inhaler and Ellipta in Stable Asthma Patients: A Randomized, Crossover Study.

INTRODUCTION: Inhalation therapy involves two types of adherence: adherence to the drug and adherence to the procedures for the inhalation device. User satisfaction and preference are key factors for maintaining good adherence of both types, and they should be evaluated based on three conditions being well maintained: asthma control level (ACL), adherence, and adequate device operability during usage duration. We compared user satisfaction and preference between a pressurized metered-dose inhaler (pMDI) and a dry powder inhaler (Ellipta), while maintaining the three conditions during usage in stable asthma patients. METHODS: In this open-label, randomized, two-way crossover study, patients with stable asthma [Asthma Control Questionnaire (ACQ) scores < 0.75] were classified into a 20-64-year age group (G1) and a ≥ 65-year age group (G2) and randomly assigned to either a formoterol/fluticasone combination (FFC) as the pMDI group or a vilanterol/fluticasone combination (VFC) as the Ellipta group. Satisfaction and preference levels were evaluated at week 4. ACL was measured using the ACQ and Japan Asthma Control Survey questionnaires at weeks 0 and 4. Device operability and respiratory resistance were also examined. RESULTS: Forty-four patients (23 G1, age 45.8 ± 1.9 years; 21 G2, 74.1 ± 1.3 years) were enrolled and maintained good ACL during the study. Adherence to FFC pMDI and VFC Ellipta was > 97% in all groups. Device operability did not differ significantly between FFC pMDI and VFC Ellipta in the G1 (p = 0.189) or G2 (p = 0.506) group. Overall satisfaction was marginally higher with the FFC pMDI than with the VFC Ellipta in G2 (p = 0.012) but non-significantly different in G1 (p = 0.733). Factors affecting overall satisfaction in G2 were difference of inhalation device and body mass index. Respiratory resistance did not change significantly over the study in G2. CONCLUSION: Based on maintaining good ACL, adherence, and device operability, FFC pMDI showed significantly higher satisfaction and preference levels than VFC Ellipta in elderly persons. TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier, jRCTs041180001 (registered 21 August 2018).

Open-label study to evaluate the treatment continuation rate after a dose reduction of lubiprostone due to onset of adverse events.

OBJECTIVE: To investigate the continuation rate with a reduced lubiprostone dose (12 mcg twice daily, BD) after the onset of adverse events (AEs) in patients with chronic constipation (CC). METHODS: In this exploratory, open-label, multicenter study, patients with CC received lubiprostone 24 mcg BD and the dose was reduced to 12 mcg BD in subjects experiencing AEs. The primary objective was the continuation rate after dose reduction due to nausea/vomiting. Secondary objectives included the continuation rate after dose reduction due to diarrhea/any AE and efficacy, including changes in number of weekly bowel movements and Bristol Stool Form Scale. RESULTS: Of the 146 patients included in the study, 42 (28.8%) received lubiprostone 12 mcg BD (dose-reduced group) due to any AE. Thirty-six (85.7%) subjects in the dose-reduced group continued treatment and completed the study. 22/27 (81.5%) and 17/19 (89.5%) patients in whom the dose was reduced due to nausea/vomiting or diarrhea, respectively, continued treatment. There was no clinically relevant difference in efficacy after dose reduction. CONCLUSION: These results suggest that treatment withdrawal due to AEs associated with lubiprostone 24 mcg BD could be minimized in patients with CC after dose reduction to 12 mcg BD, thus resulting in improved long-term outcomes. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials (https://jrct.niph.go.jp/latest-detail/jRCTs031180069).

Safety of Once-Daily Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol in Japanese Patients with Asthma: A Long-Term (52-Week) Phase III Open-Label Study.

PURPOSE: The pivotal CAPTAIN study reported a favorable safety profile with once-daily inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in patients with inadequately controlled asthma, some of whom were Japanese. Here, we evaluate the long-term (52 weeks) safety of FF/UMEC/VI in Japanese patients with asthma. PATIENTS AND METHODS: This was a Phase III, 52-week, multicenter, non-comparator, non-randomized, open-label study (NCT03184987) in Japanese adults receiving maintenance therapy with ICS/LABA, with or without LAMA. At enrollment, patients were allocated to either FF/UMEC/VI 100/62.5/25mcg (Group 1) or 200/62.5/25mcg (Group 2). Patients in Group 1 could have their treatment stepped up to 200/62.5/25mcg at Week 24 if their Asthma Control Questionnaire (ACQ)-7 score was >0.75. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included vital signs, electrocardiogram measurements, and clinical laboratory tests (biochemistry, hematology, urinalysis). Efficacy was assessed as "other" endpoints. RESULTS: A total of 111 Japanese patients were included in the intention-to-treat (ITT) population. Overall, 77 (69%) patients reported ≥1 AE (Group 1: n=30 [64%]; step-up group: n=7 [78%]; Group 2: n=40 [73%]). SAEs were reported for 1 (2.1%) and 2 (3.6%) patients in Groups 1 and 2, respectively. All SAEs were considered unrelated to study treatment. One AE and one SAE led to study withdrawal: oropharyngeal discomfort (Group 1); eosinophilic granulomatosis with polyangiitis (Group 2). No new safety concerns were identified throughout the 52-week treatment period. CONCLUSION: In this uncontrolled open-label study, no new safety concerns were observed with long-term (52 weeks) treatment with once-daily FF/UMEC/VI among 111 Japanese patients with asthma.

Efficacy and safety of once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol in Japanese patients with inadequately controlled asthma: the CAPTAIN study.

OBJECTIVE: In CAPTAIN, a double-blind, parallel-group, Phase IIIA study, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) improved lung function, symptoms and asthma control versus FF/VI in patients with inadequately controlled asthma. Here, we report efficacy and safety from a Japanese cohort in CAPTAIN. METHODS: Adults with inadequately controlled asthma despite inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) were randomized (1:1:1:1:1:1) to once-daily FF/VI (100/25 mcg or 200/25 mcg) or FF/UMEC/VI (100/31.25/25 mcg, 100/62.5/25 mcg, 200/31.25/25 mcg, or 200/62.5/25 mcg) for ≥24 weeks. Endpoints included change from baseline in clinic trough FEV1 (primary), annualized rate of moderate/severe asthma exacerbations (key secondary), clinic FEV1 3 h post-dose, and Asthma Control Questionnaire (ACQ)-7, St George's Respiratory Questionnaire (SGRQ) (all Week 24), Evaluating Respiratory Symptoms (E-RS): Asthma total scores (Weeks 21-24) (all secondary). Adverse events and adverse events of special interest were monitored. Clinical trials.gov registry no: NCT02924688. RESULTS: Overall, 229 of 2436 patients in the intention-to-treat (ITT) population were from Japan. In this cohort, change from baseline in trough FEV1 for FF/UMEC/VI 100/62.5/25 mcg versus FF/VI 100/25 mcg was 105 mL (95% confidence interval -5, 216) and 69 mL (-42, 179) for 200/62.5/25 mcg versus 200/25 mcg. These observations were supported by clinic FEV1 at 3 h post-dose. Moderate/severe exacerbation incidence was low and similar across pooled treatment groups (FF/VI, FF/UMEC 31.25 mcg/VI, FF/UMEC 62.5 mcg/VI). All pooled groups demonstrated clinically important improvements from baseline in ACQ-7, SGRQ and E-RS: Asthma total scores. Safety profiles were consistent with the overall ITT population, with no new safety concerns. CONCLUSION: FF/UMEC/VI is an effective option with a favorable risk-benefit profile in Japanese patients with uncontrolled moderate or severe asthma on ICS/LABA.

Current situation of asthma therapy by allergists in primary medical facilities in Japan.

BACKGROUND: To reduce deaths from asthma, further use of inhaled corticosteroids (ICS) in accordance with the guidelines is required. The present study was conducted because specialists are responsible for increasing the use of guidelines, but the current state of asthma care provided by specialists in primary clinical settings has not been clarified. METHODS: In collaboration with five primary medical facilities throughout Japan, severity of asthma, contents of asthma therapy, and the implementation rate of pulmonary function testing and peak flow measurements were analyzed for 1007 outpatients ≥40 years old with stable bronchial asthma. In all patients, peak inspiratory flow (PIF) was measured during examination. RESULTS: Either ICS or ICS/long-acting beta 2 agonist (LABA) was used in almost all patients with at least mild persistent asthma. Although treatments adhered to the guidelines, therapeutic steps did not match asthma severity in many patients with mild intermittent asthma. Large gaps existed between facilities that measure pulmonary function and PEF in daily clinical practice and those that do not. While mean PIF value for all subjects was well maintained at 102.0 ± 29.1L/min, some patients may not have been able to inhale efficiently in terms of PIF (5.1% of Turbuhaler® users and 5.7% of Diskhaler® users). CONCLUSIONS: When stepping down asthma therapy, some confusion in policy may exist, leading to guideline mismatches. Differences in the implementation of pulmonary function and PEF measurements, as indicators for long-term management, need to be minimized among specialists. For maintaining effective inhalation, inspiratory flow should be periodically checked.

Serum periostin reflects dynamic hyperinflation in patients with asthma.

INTRODUCTION: Dynamic hyperinflation (DH) is sometimes observed and is associated with impaired daily life activities of asthma. We assessed the relationship between DH and asthma biomarkers (blood eosinophil, fractional exhaled nitric oxide (F eNO) and serum periostin) in patients with asthma. METHODS: Fifty patients with stable asthma were prospectively recruited and underwent blood test, F eNO measurement, spirometry and metronome-paced tachypnoea (MPT) test to assess DH. In MPT tests, inspiratory capacity (IC) was measured at baseline and after 30 s of MPT with breathing frequencies of 20, 30 and 40 breaths·min-1. DH was assessed by the decline of IC from baseline, and maximal IC reduction ≥10% was considered as positive DH. RESULTS: Thirty patients (60%) showed positive DH. Patients with positive DH showed higher serum periostin levels (107.0±30.7 ng·mL-1) than patients with negative DH (89.7±23.7) (p=0.04). Patients in Global Initiative for Asthma treatment steps 4-5 (n=19) showed higher serum periostin levels (p=0.01) and more severe IC reduction after MPT (p<0.0001) than patients in steps 1-3 (n=31). Maximal IC reduction after MPT was significantly correlated with asthma control test score (r=-0.28, p=0.05), forced expiratory volume in 1 s (r=-0.56, p<0.0001), and serum periostin levels (r=0.41, p=0.003). CONCLUSION: Serum periostin may have the possibility to reflect DH in patients with stable asthma.

Additional effects of pranlukast in salmeterol/fluticasone combination therapy for the asthmatic distal airway in a randomized crossover study.

BACKGROUND: Salmeterol/fluticasone combination (SFC) therapy is used to control inflammation in the distal airway of patients with well-controlled asthma, but the efficacy of this approach is unclear. OBJECTIVES: The goal of the study was to evaluate the effect of pranlukast, a leukotriene receptor antagonist (LTRA), on distal airway inflammation and pulmonary resistance in patients with asthma that was well-controlled using SFC therapy alone. METHODS: The subjects were 32 patients with well-controlled asthma (age 61.1+/-17.8 years old, Step 3 in the GINA guidelines, Asthma Control Test score 23.2+/-1.8 points) based on use of SFC therapy alone for more than 3 months. These subjects were randomly assigned to groups receiving SFC alone or SFC+LTRA (pranlukast 450 mg daily) and then switched to the opposite group after 4 weeks in a crossover manner. Eosinophilic inflammation in induced sputum samples was assessed after each treatment period. Sputum was induced by inhalation of 10% hypertonic saline for 15 min. Impulse oscillometry parameters (R5, R20, X5 and AX) and spirometry were examined during each period. The Asthma-related Quality of Life Questionnaire (AQLQ) was also administered in each period. RESULTS: The ECP levels in late-phase sputum were significantly higher than those in early-phase sputum with SFC therapy alone (178.3+/-166.0 vs. 65.5+/-68.9 microg/l, p<0.001), whereas these values did not differ significantly with SFC+LTRA treatment (70.9+/-95.1 vs. 54.6+/-65.7, p=0.554). ECP levels in late-phase sputum with SFC therapy were also significantly higher than those with SFC+LTRA (p=0.045). The values of R5, R20, R5-R20 (kPa/(L/s)), and AX (kPa/L) all significantly improved during with SFC+LTRA treatment compared with SFC alone (median (25-75 percentile)): 0.350 (0.283-0.440) vs. 0.340 (0.280-0.378), p=0.036; 0.280 (0.233-0.365) vs. 0.270 (0.240-0.318), p=0.019; 0.050 (0.030-0.110) vs. 0.500 (0.030-0.073), p=0.032; and 0.570 (0.308-1.045) vs. 0.410 (0.263-0.820), p=0.014; respectively. Pulmonary function indexes did not differ significantly between the two treatments, but the symptom and activity limitation domains of the AQLQ were significantly improved by SFC+LTRA treatment. CONCLUSION: This study suggests that the combination of SFC and LTRA may give better control of residual eosinophilic inflammation in the distal airway compared with SFC therapy alone.

[Examination of beneficial effects of risedronate in improving quality of life during long-term treatment of primary osteoporosis].

BACKGROUND AND AIMS: Risedronate is a first-line medication in the therapy of osteoporosis and a substantial amount of evidence has already established the clinical efficacy of risedronate in the treatment of osteoporosis. However, studies addressing its long-term efficacy in improving patients' quality of life (QOL) are rare. The aim of this study was to evaluate the therapeutic effect of long-term treatment with risedronate on the time-course of changes in patients' QOL. METHODS: Fourteen Japanese outpatients with primary osteoporosis (mean age: 69.4 +/- 10.1 yr, 7 men and 7 women), who had continued treatment with oral risedronate alone (2.5 mg, daily) for more than 3 years as of July 2008, were the subjects of this study. We investigated the time-course of changes in patients' QOL using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL) of the Japanese Society for Bone and Mineral Research, together with measurement of bone mineral density and bone metabolic markers over 3 years. RESULTS: Risedronate significantly improved the total JOQOL score from 119.0 (103.0-127.0) points at entry to 128.0 (119.0-142.0) points at 12 months into the study (p=0.029) and this improvement was maintained during the study period. In addition, the pain score and the falls and anxiety score of the JOQOL continued to show significant improvements over 12 and 24 months, respectively. Serum BAP and NTX levels were significantly decreased at 6 months and continued to improve significantly during the study. We found no new bone fractures during the three study years and bone mineral density was maintained at good levels during the study period. The usage of cold or hot packs gradually decreased during the study period and was significantly reduced after 24 months (p=0.018). CONCLUSION: This study showed that long-term treatment with risedronate significantly improved and favorably maintained the QOL of patients with primary osteoporosis, particularly pain-related scores.

Pitavastatin improves serum resistin levels in patients with hypercholesterolemia.

AIM: Resistin in serum is associated with high risk in patients with atherosclerosis. This clinical study aimed to investigate whether pitavastatin can regulate the serum level of resistin, together with levels of other inflammatory cytokines and adipocytokines. METHODS: Forty two outpatients (mean age 65.2 +/- 12.6 yr, M/F: 21/21) with hypercholesterolemia were administered 2 mg of pitavastatin and serum levels of resistin, together with serum levels of adiponectin, leptin, TNF-alpha and hsCRP, were measured before, and 12 weeks after enrollment. RESULTS: There was no significant gender-related difference in initial serum resistin levels. Pitavastatin significantly decreased LDL-cholesterol after 12 weeks. Initial levels of resistin showed a significant correlation with those of hsCRP (r=0.38, p=0.013), but not TNF-alpha or HOMA-R. Serum resistin, but not adiponectin and leptin, levels were significantly decreased, dropping from 17.1 +/- 9.9 ng/ dL to 15.2+/-10.0 (p=0.001) after 12 weeks of administration. The patient group with a baseline hsCRP > or = 0.1 at enrollment (n=17) had decreased levels of both resistin and hsCRP (p=0.011 and p=0.022, respectively). CONCLUSION: This study showed the pleiotropic effect of pitavastatin on the serum resistin concentration, suggesting that it may assist in the prevention of atherosclerosis.

[The evaluation of the distal airway inflammation of well controlled asthmatic patients using sputum induction by inhalation of 10% hypertonic saline for 15 minutes].

BACKGROUND: As the clinical importance of treatment to asthmatic distal airway has been recognized, this study aimed to evaluate the efficacy of the 10% hypertonic saline-induced 15 minutes long-inhaled method to assess the inflammatory situation in the distal airways. METHODS: The subjects were 16 healthy volunteers and 29 patients with well controlled asthma. They inhaled 5% or 10% hypertonic saline for 15 minutes and the sputum induction rates and induced times were measured. We also investigated the values of surfactant protein D (SP-D) and eosinophil cationic protein (ECP) both in early- and late-phase induced sputum, together with pulmonary function indexes, and the patients' impressions of the method. RESULTS: The sputum induction rates with 10% hypertonic saline inhalation in both healthy volunteer group and well controlled asthmatic patients group were significantly high compared with those with 5% hypertonic saline inhalation; 75.0% (p=0.004) and 75.9% (p=0.007), respectively. The SP-D levels in late-phase sputum in both healthy volunteer group and well controlled asthmatic patients group significantly elevated compared with those in the early-phase: p=0.045 and p=0.007, respectively. The SP-D levels in late-phase sputum significantly correlated to those of ECP in the well controlled asthmatic patients group (r=0.527, p=0.017). The pulmonary function index FEV1.0% of 18 well controlled asthmatic patients (62.1%) attenuated 2.9+/-2.5% soon after finishing the 10% hypertonic saline inhalation, and recovered after an additional 15 minutes rest. 70 approximately 80% of the subjects in both groups answered that they felt no strain in using the inhaled method. CONCLUSION: The late-phase sputum obtained by the 10% hypertonic saline-induced 15 minutes long-inhaled method may be useful in evaluating the inflammatory situation in the distal airways.