Ho Joo Yoon

Preparation of budesonide-loaded porous PLGA microparticles and their therapeutic efficacy in a murine asthma model

Inhaling corticosteroids, such as budesonide (BD), is the most common treatment for asthma. However, frequent steroid administration is associated with many side effects. We hypothesized that porous microparticles containing BD could provide an effective treatment method for asthma, as the sustained delivery of corticosteroid and a reduced number of doses could be achieved using porous polymeric microparticles. Porous microparticles were prepared from poly(lactic-co-glycolic acid) (PLGA) by a water-in-oil-in-water double emulsion method with ammonium bicarbonate as the porogen. Varying the porogen concentration controlled the morphology, particle size, and pore size of the PLGA microparticles, with particle size and pore size increasing as the porogen concentration increased. The BD loading efficiency in the porous PLGA microparticles was about 60%, and BD was released from the porous microparticles in a sustained manner for 24h in vitro. Lung uptake efficiency of the porous PLGA microparticles in mice was significantly higher than that of non-porous PLGA microparticles. Budesonide-loaded porous PLGA microparticles were delivered to asthmatic mice, and the numbers of inflammatory cells in bronchoalveolar lavage (BAL) fluid and tissue sections were significantly reduced when the drug was administrated every 3days. We also found significantly reduced bronchial hyperresponsiveness of asthmatic mice after treatment with budesonide-loaded porous PLGA microparticles. This approach to controlling the porous structure of polymeric microparticles, as well as the release behavior of drugs from the microparticles, could have useful applications in the pulmonary delivery of many therapeutic drugs.

Inappropriate techniques used by internal medicine residents with three kinds of inhalers (a metered dose inhaler, Diskus, and Turbuhaler): changes after a single teaching session.

Background. While initial education and regular evaluation of inhaler technique in patients are emphasized in the management of asthma and chronic obstructive pulmonary disease, health care professionals are not experienced in using inhalers. This study assessed whether internal medicine residents used common inhalers correctly and whether a single teaching session successfully improved their performance. Methods. We evaluated 142 internal medicine residents from six university hospitals in Korea for their techniques with three different inhaler devices: a metered dose inhaler (MDI), Diskus, and Turbuhaler. We assessed whether participants completed each step in using the three inhalers and classified overall performance as good, adequate, or inadequate for each inhaler type. To estimate the effect of a single teaching session, reassessment was performed 2 months after education. Results. Performance grade was inadequate for 50.7% of participants with a MDI, 43.0% for Diskus, and 51.4% for Turbuhaler. An early year of residency was associated significantly with inappropriate technique for Diskus (p = 0.003), but not for MDI and Turbuhaler. After a single teaching session, overall skills improved significantly for all three inhalers. The proportion of subjects with good or adequate skill changed notably from 39.7% to 83.8% for MDI (p = 0.001), from 50.0% to 86.8% for Diskus (p = 0.001), and from 44.1% to 88.2% for Turbuhaler (p = 0.001). Conclusions. These findings demonstrate that a high proportion of internal medicine residents cannot use inhalers correctly and just a single teaching can effectively enhance their inhaler technique.

Reference values and determinants of exhaled nitric oxide in healthy Korean adults.

Background: Measuring fractional exhaled nitric oxide (FeNO) provides an indication of airway inflammation and is used as an inflammatory marker for asthma management. However, reference values and determinants of FeNO levels are not well defined in healthy Asian adults. This study aimed to establish FeNO reference values in nonsmoking, healthy Asian adults and to determine the factors related to FeNO levels. Methods. The authors measured FeNO in 166 nonsmoking, healthy Korean adults and collected data regarding factors possibly associated with FeNO, including age, height, weight, and respiratory symptoms. Lung function was measured using spirometry, and atopic status was determined based on the skin-prick test. Results. In a multivariate linear regression analysis, FeNO levels were positively associated with male gender (p = .008) and atopy (p = .044) after adjusting for age, height, weight, forced expiratory volume in one second (FEV1), and chronic rhinitis. Reference values were presented according to gender and atopic status, and the mean FeNO value was highest in male atopic subjects (37.3 ± 12.1 ppb), followed by nonatopic males (33.9 ± 14.3 ppb), atopic females (28.6 ± 17.7 ppb), and nonatopic females (24.1 ± 10.6 ppb). In healthy Korean adults, FeNO levels showed a significant and independent association with male gender and atopy. Conclusions. We believe that the presented FeNO reference values and the determining factors could be useful for research and clinical practice in the adult Asian population.

Comparison of two exhaled nitric oxide analyzers: The NIOX MINO hand‐held electrochemical analyzer and the NOA280i stationary chemiluminescence analyzer

Background and objective:  Measurement of the fraction of nitric oxide (FeNO) in exhaled air is useful in the management of asthma. A new hand‐held nitric oxide (NO) analyzer, the NIOX MINO, is simple and easy to use in clinical practice. In this study, FeNO values measured using the NIOX MINO were compared with those obtained using a stationary chemiluminescence analyzer, the Sievers NOA280i.

Classification and implementation of asthma phenotypes in elderly patients

BACKGROUND No attempt has yet been made to classify asthma phenotypes in the elderly population. It is essential to clearly identify clinical phenotypes to achieve optimal treatment of elderly patients with asthma. OBJECTIVES To classify elderly patients with asthma by cluster analysis and developed a way to use the resulting cluster in practice. METHODS We applied k-means cluster to 872 elderly patients with asthma (aged ≥ 65 years) in a prospective, observational, and multicentered cohort. Acute asthma exacerbation data collected during the prospective follow-up of 2 years was used to evaluate clinical trajectories of these clusters. Subsequently, a decision-tree algorithm was developed to facilitate implementation of these classifications. RESULTS Four clusters of elderly patients with asthma were identified: (1) long symptom duration and marked airway obstruction, (2) female dominance and normal lung function, (3) smoking male dominance and reduced lung function, and (4) high body mass index and borderline lung function. Cluster grouping was strongly predictive of time to first acute asthma exacerbation (log-rank P = .01). The developed decision-tree algorithm included 2 variables (percentage of predicted forced expiratory volume in 1 second and smoking pack-years), and its efficiency in proper classification was confirmed in the secondary cohort of elderly patients with asthma. CONCLUSIONS We defined 4 elderly asthma phenotypic clusters with distinct probabilities of future acute exacerbation of asthma. Our simplified decision-tree algorithm can be easily administered in practice to better understand elderly asthma and to identify an exacerbation-prone subgroup of elderly patients with asthma.

Nasal and exhaled nitric oxide in allergic rhinitis.

Objectives The primary aim of this study was to assess whether one can use levels of nasal nitric oxide (nNO) and exhaled nitric oxide (eNO) as a means of evaluation in allergic rhinitis. Methods We used a chemiluminescence analyzer to measure nNO and eNO in normal controls (n=34) and allergic rhinitis patients (n=35), and compared these measurements with various parameters of clinical symptoms and laboratory data. Results Mean nNO (389±119 ppb) in allergic rhinitis patients was significantly higher than normal controls (276±88 ppb). Without asthma, mean eNO (64.8±55.9 ppb) in allergic rhinitis patients was significantly higher than normal controls (33.0±24.0 ppb). In the persistent allergic rhinitis group, eNO concentration was significantly higher, while nNO concentration was significantly lower than the intermittent group. Conclusion We can use nNO and eNO levels for evaluation of allergic rhinitis. However, we should consider the fact that nNO levels can be reduced, when symptoms are severe and long-lasting. Additionally, in allergic rhinitis, eNO can be elevated without asthma.

GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans.

Adverse reactions induced by antituberculosis drugs (ATD) often result in serious morbidities, impeding scheduled treatment and cure. In the development of ATD-induced adverse reactions, glutathione S-transferase has been suggested to play a protective role as an intracellular scavenger by conjugating toxic reactive metabolites of ATD. This study examined the association of null mutations in GST enzyme genes (GSTT1 and GSTM1) with the development of ATD-induced hepatitis and cutaneous reactions. We compared the frequencies of GSTT1 and GSTM1 null mutations in 57 patients with hepatitis, 94 patients with cutaneous adverse reactions, and 190 ATD-tolerant controls. The frequency of null mutations in GSTT1 and GSTM1 in patients with ATD-induced hepatitis was not significantly different from that of controls (59.6% vs. 54.2% and 45.6% vs. 54.7%, respectively). Additionally, no significant difference was observed in the frequency of either null mutation in patients with ATD-induced cutaneous reactions, including maculopapular eruption, compared with controls (58.5% vs. 54.1% for GSTT1 and 59.6% vs. 54.6% for GSTM1). These findings indicate that GSTT1 and GSTM1 null mutations are not associated with the development of ATD-induced hepatitis or cutaneous reactions in this Korean population, and suggest that glutathione S-transferase enzymes do not play important roles in the pathogenesis of these conditions.

The Wnt/β-catenin signaling pathway regulates the development of airway remodeling in patients with asthma

Airway remodeling is a key characteristic of chronic asthma, particularly in patients with a fixed airflow limitation. The mechanisms underlying airway remodeling are poorly understood, and no therapeutic option is available. The Wnt/β-catenin signaling pathway is involved in various physiological and pathological processes, including fibrosis and smooth muscle hypertrophy. In this study, we investigated the roles of Wnt/β-catenin signaling in airway remodeling in patients with asthma. Wnt7a mRNA expression was prominent in induced sputum from patients with asthma compared with that from healthy controls. Next, we induced a chronic asthma mouse model with airway remodeling features, including subepithelial fibrosis and airway smooth muscle hyperplasia. Higher expression of Wnt family proteins and β-catenin was detected in the lung tissue of mice with chronic asthma compared to control mice. Blocking β-catenin expression with a specific siRNA attenuated airway inflammation and airway remodeling. Decreased subepithelial fibrosis and collagen accumulation in the β-catenin siRNA-treated mice was accompanied by reduced expression of transforming growth factor-β. We further showed that suppressing β-catenin in the chronic asthma model inhibited smooth muscle hyperplasia by downregulating the tenascin C/platelet-derived growth factor receptor pathway. Taken together, these findings demonstrate that the Wnt/β-catenin signaling pathway is highly expressed and regulates the development of airway remodeling in chronic asthma.

Adiposity, adipokines, and exhaled nitric oxide in healthy adults without asthma.

Background. Epidemiological studies have shown that obesity/adiposity is closely associated with asthma in terms of development, severity, and control of asthma. However, effects of obesity/adiposity on airway inflammation are not well known in subjects without asthma. We assessed whether fractional exhaled nitric oxide (FeNO), a marker of eosinophilic airway inflammation, was associated with obesity/adiposity in nonasthmatic healthy adults. Methods. We measured FeNO and serum levels of adipose-derived hormones and adipokines in 117 adult subjects without a previous diagnosis of asthma or current asthmatic symptoms. Associations between FeNO and measures of obesity/adiposity [body mass index (BMI), body fat mass, and body fat percentages] were examined by correlation analyses and uni- and multivariate linear regression analyses. Results. FeNO was not significantly associated with BMI, body fat mass, or body fat percentage by a multivariate linear regression model, adjusting for age, gender, chronic rhinitis, atopy, and lung function. No significant association of FeNO with serum levels of leptin, adiponectin, tumor necrosis factor (TNF)-α, or interleukin (IL)-6 was observed. Conclusions. These findings suggest that in healthy subjects without asthma, obesity/adiposity has no significant effect on eosinophilic airway inflammation and that hormones and systemic inflammation derived from adipose tissue do not affect eosinophilic airway inflammation.

Airway Hyperresponsiveness Is Negatively Associated with Obesity or Overweight Status in Patients with Asthma

Background: Obesity is a risk factor for asthma in the general population, but the effect of obesity on airway hyperresponsiveness (AFHR) or airway inflammation in asthma is not clear. This study evaluated the relationship between obesity and asthma, assessing aspects of symptoms, AHR, and severity. Methods: In total, 852 patients with asthma diagnosed by asthma specialists based on AHR as confirmed by a methacholine bronchial provocation test, were enrolled from the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) adult asthma cohort. The intensity of AHR was assessed by the concentration of methacholine needed to cause a 20% decrease in FEV1 (PC20). Patients were classified into four categories based on body mass index (BMI): underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), and obese (≥30). Results: BMI was negatively correlated with FEV1 (l), FVC (l), and FEV1/FVC (%) in lung function tests. The prevalence of wheezing increased with higher BMI after adjustment for age, sex, smoking, medication history, and PC20 (p < 0.0001). logPC20 was lower in the normal weight group compared with the overweight group (p = 0.003). The risk of moderate or severe AHR (PC20 ≤ 4 mg/ml) decreased with increased BMI after adjustment for age, sex, smoking, and medication history (p = 0.035). Conclusions: Obesity is a risk factor for asthma in the general population, but obesity in asthmatic patients is negatively correlated with the intensity of AHR and is not related to asthma severity. Obesity is positively related with the prevalence of wheezing but negatively related to AHR in asthmatic patients.