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Transforming growth factor beta 1 (TGF-β1) induces pulmonary fibrosis by enhancing epithelial apoptosis and affects the enzymatic activity of transglutaminase 2 (TG2). The aim of this study was to determine the role of TG2 in TGF-β1-induced lung remodeling and alveolar macrophage modulation. We characterized the in vivo effects of TGF-β1 and TG2 on lung inflammation, fibrosis, and macrophage activity using transgenic C57BL/6 mice with wild and null TG2 loci. The effect of TG2 inhibition on in vitro TGF-β1-stimulated alveolar macrophages was assessed through mRNA analysis. TG2 was remarkably upregulated in the lungs of TGF-β1 transgenic (TGF-β1 Tg) mice, especially in alveolar macrophages and epithelial cells. In the absence of TG2, TGF-β1-induced inflammation was suppressed, decreasing the number of macrophages in the bronchoalveolar lavage fluid. In addition, the alveolar destruction and peribronchial fibrosis induced by TGF-β1 overexpression were significantly reduced, which correlated with decreases in the expression of fibroblast growth factor and matrix metallopeptidase 12, respectively. However, TG2 deficiency did not compromise the phagocytic activity of alveolar macrophages in TGF-β1 Tg mice. At the same time, TG2 contributed to the regulation of TGF-β1-induced macrophage activation. Inhibition of TG2 did not affect the TGF-β1-induced expression of CD86, an M1 marker, in macrophages, but it did reverse the TGF-β1-induced expression of CD206. This result suggests that TG2 mediates TGF-β1-induced M2-like polarization but does not contribute to TGF-β1-induced M1 polarization. In conclusion, TG2 regulates macrophage modulation and plays an important role in TGF-β1-induced lung inflammation, destruction, and fibrosis.

Background/Aims: Tuberculosis has incidence and mortality rates that are among the highest for all communicable diseases. Adverse drug reactions (ADRs) to anti-tubercular drugs are common, and have a major impact on treatment maintenance and prognosis. It is important to understand the characteristics of ADRs and establish a suitable management plan. Methods: We retrospectively reviewed patients with ADRs during treatment with first-line antitubercular drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide from 2009 to 2018. Age, sex, and total treatment period, and the onset, severity, seriousness, and system organ class of ADRs, were analyzed to understand the characteristics of first-line anti-tubercular drug-related ADRs. Results: A total of 1,606 of 5,482 patients (29.3%) experienced ADRs after administration of first-line anti-tubercular drugs. The incidence of ADRs related to isoniazid, rifampicin, ethambutol, and pyrazinamide was 22.2%, 21.3%, 24.5%, and 29.6%, respectively. A total of 2,098 ADR reports were made (mean of 1.3 ± 0.6 per patient). The rates of mild, moderate, and severe ADRs were 32.4%, 61.1%, and 6.5%, respectively. There were 127 reports (6.1%) of serious ADRs. Skin and appendage disorders were most frequently reported (27.5%), followed by gastrointestinal disorders (17.5%), and liver and biliary system disorders (13.1%). The total treatment period was longer in patients who experienced ADRs (224.0 ± 3.1 days vs. 247.0 ± 4.7 days, p = 0.009). Conclusions: The incidence of ADRs to first-line anti-tuberculosis drugs was 29.3%, and 6.5% were severe ADRS. ADRs prolonged the overall treatment duration, indicating the importance of their detection and management.

Background/Aims: Despite proper use of pharmaceuticals, adverse drug reactions (ADRs) can lead to problems related to patient safety. We analyzed the characteristics of ADRs, particularly serious adverse events (SAEs), in a single tertiary medical institution. Methods: Spontaneous ADR report data collected from 2010 to 2019 in Seoul National University Hospital were assessed. Causality was evaluated according to the World Health Organization-Uppsala Monitoring Centre criteria. Age, sex, onset, severity, seriousness, and system organ class (SOC) of ADRs and SAEs were analyzed. Results: During the study period, a total of 49,955 individual case safety reports were assessed as possible, probable, or certain. Although the number of gastrointestinal ADR reports was high (25.9%), severe cases were uncommon (2.6%). By contrast, the number of hematologic disorders was low (6.6%) but 39.2% of them were severe. Among ADRs, 10.2% were assessed as SAEs, the proportion of which was high at extreme ages and in males. Body as a whole-general disorders were the most frequently reported SOC for SAEs, followed by skin and appendage disorders. Antineoplastic agents and antibiotics were the most common causative agents of SAEs and ADRs. Anaphylactic reaction was the most frequent SAE (6.5%). Conclusions: The proportion of SAE differs according to SOC and drug. Attention should be paid to SAEs in children and older adults because the rate of SAEs is significantly higher at extreme ages.

Background There is very limited evidence regarding long-term prognosis of chronic cough. We examined longitudinal outcomes among patients with chronic cough, and explored predictors of cough persistence. Methods A retrospective cohort was constructed of adults who had newly visited a specialist cough clinic in 2012–2013. All had undergone systematic investigation for chronic cough. The Hull Airway Reflux Questionnaire (HARQ) was administered to assess reflux cough symptoms. A follow-up survey was conducted in 2016–2017 to assess cough persistence. Results From 418 candidates, 323 participated in the follow-up study; main analyses focused on patients with chronic persistent cough (n = 64; 19.8%) and remitted cough (n = 193; 59.8%). Compared with remitted cough group, chronic persistent cough group had more family history of chronic cough (17.2% vs. 4.7%, p = 0.001) and cold air-sensitive cough (62.5% vs. 44.6%, p = 0.013). The total HARQ score did not differ; however, two items (cough with eating and cough with certain foods) scored significantly higher in chronic persistent cough. In multivariate analyses, a family history of chronic cough (adjusted odds ratio 4.27 [95% confidence interval 1.35–9.89]), cold air-sensitive cough (2.01 [1.09–3.73]), and cough with eating (1.22 [1.02–1.45]) were associated with chronic persistent cough at 4 years. Conclusions Cough persists in about 20% of patients after 4 years following systematic assessment and treatments. Several cough characteristics, such as family history, cold air-sensitivity, or reflux cough, may be associated with cough persistence. Larger cohort studies are warranted to further understand long-term prognosis and confirm predictors of persistence in patients with chronic cough.

Background The effect of novel tobacco products, such as electronic cigarettes (EC) and heated tobacco products (HTP), on allergic rhinitis (AR) and asthma is not well known. Objective To evaluate the health effect of novel tobacco products on asthma and AR. Methods This study was conducted using large survey data on Korean middle and high school students. The relationship between current asthma/AR and novel tobacco products user status was evaluated. In order to compare the combined effects of conventional cigarette (CC), EC, and HTP use on current allergic diseases, the participants were classified into 18 groups based on CC (current, former, and never), EC (current, former, and never), and HTP (ever and never) status. Results A total of 60,040 participants representing 2,850,118 Korean adolescents were analyzed. Of all participants, 6.7%, 2.7%, and 2.9% were current CC, current EC, and ever HTP users, respectively. Current CC and ever HTP use was significantly associated with current asthma and AR in adjusted models. Current EC showed association with current AR but the association with asthma disappeared in the adjusted model. Among 18 groups, the groups including current CC use showed higher risk of current AR and asthma than never HTP-never EC-never CC group. The odds ratio of current asthma especially increased more in those who used EC and/or HTP with CC concurrently than those in the never HTP-never EC-current CC user group. Conclusion Using EC and/or HTP in adolescents might enhance the adverse effect of CC on AR and asthma.

Background: Asthma is a heterogeneous inflammatory airway disorder with various phenotypes. Quantitative computed tomography (QCT) methods can differentiate among lung diseases through accurate assessment of the location, extent, and severity of the disease. The purpose of this study was to identify asthma clusters using QCT metrics of airway and parenchymal structure, and to identify associations with visual analyses conducted by radiologists. Methods: This prospective study used input from QCT-based metrics including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph) to perform a cluster analysis and made comparisons with the visual grouping analysis conducted by radiologists based on site of airway involvement and remodeling evaluated. Results: A total of 61 asthmatics of varying severities were grouped into 4 clusters. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbations were observed in the 5-year follow-up period. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthmatics, and showed bronchodilator responses limited to the proximal airways. C3 and C4 included severe asthmatics that showed a reduced Dh of the proximal airway and diminished bronchodilator responses. While C3 was characterized by severe allergic asthma without fSAD, C4 included ex-smokers with high fSAD% and Emph%. These clusters correlated well with the grouping done by radiologists and clinical outcomes. Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and can be a complementary tool to predict clinical outcomes.

Background Delayed hypersensitivity reactions (DHRs) to radiocontrast media (RCM) occur in approximately 0.5–23.0% of patients and are thought to be caused by T cell-mediated mechanisms. However, an optimal pharmacological preventive strategy is not yet established in patients with histories of delayed reactions to RCM. Objective We aimed to evaluate the efficacy of pharmacological prevention in patients with histories of delayed reactions to non-ionic low-osmolar RCM when re-exposed to RCM. Methods A retrospective review of electronic medical records of 117 patients with previous histories of DHRs to RCM who visited an allergy clinic for the prevention of reactions after the re-exposure to RCM was conducted. The effects of pharmacological prevention were compared according to the symptom scores of previous reactions based on their intensities and durations with electronic medical records (EMRs). Results Of the 117 patients who experienced DHRs after RCM injection, we confirmed the outcomes of RCM re-exposure in 101 patients. For pharmacological prevention, 92 patients (91.1%) received steroids before RCM injection and among them, 50 patients (49.5%) received additional steroids after RCM injection. With this pharmacological prevention, patients of symptoms improved or no recurrence, recurrence of similar previous symptoms, and recurrence of worse symptoms were 98 (97.0%), 2 (2.0%), and 1 (1.0%), respectively. The proportions of no recurrence after pharmacological prevention were lower in patients with severe reactions and higher symptom scores. Conclusion Pharmacological prevention showed a beneficial effect in most patients with delayed hypersensitivity to RCM. Further investigations are needed to establish an effective protocol for the prevention of delayed reactions to RCM.

Asthma is a heterogeneous disease whose development is shaped by a variety of environmental and genetic factors. While several recent studies suggest that microbial dysbiosis in the gut may promote asthma, little is known about the relationship between the recently discovered lung microbiome and asthma. Innate lymphoid cells (ILCs) have also been shown recently to participate in asthma. To investigate the relationship between the lung microbiome, ILCs, and asthma, we recruited 23 healthy controls (HC), 42 patients with non-severe asthma, and 32 patients with severe asthma. Flow cytometry analysis showed severe asthma associated with fewer natural cytotoxicity receptor (NCR)+ILC3s in the lung. Similar changes in other ILC subsets, macrophages, and monocytes were not observed. The asthma patients did not differ from the HC in terms of the alpha and beta-diversity of the lung and gut microbiomes. However, lung function correlated positively with both NCR+ILC3 frequencies and microbial diversity in the lung. Sputum NCR+ILC3 frequencies correlated positively with lung microbiome diversity in the HC, but this relationship was inversed in severe asthma. Together, these data suggest that airway NCR+ILC3s may contribute to a healthy commensal diversity and normal lung function.

OBJECTIVES We investigated the incidence of immediate hypersensitivity reaction (HSR) caused by different types of low-osmolar contrast media (LOCM) and cumulative exposure to LOCM. METHODS This cohort study included all consecutive patients who underwent LOCM-enhanced computed tomography from 2012 through 2014. We assessed 5 LOCM (iobitridol, iohexol, iomeprol, iopamidol, and iopromide). All patients were monitored for adverse events, and new symptoms and signs were recorded in real time using the Contrast Safety Monitoring and Management System (CoSM2oS). RESULTS The overall incidence of immediate HSR to LOCM was 0.97% (2004 events resulting from 205 726 exposures). Incidence differed significantly depending on whether the patient had a previous history of HSR to LOCM (0.80% in patients with no history and 16.99% in patients with a positive history of HSR to LOCM, P=.001). The incidence of HSR to individual LOCM ranged from 0.72% (iohexol) to 1.34% (iomeprol), although there were no significant differences across the 5 LOCM. A longitudinal analysis demonstrated that the incidence of HSR increased gradually with more frequent previous exposure to LOCM (HR=2.006 [95%CI, 1.517-2.653], P

Chronic cough is a common problem in various populations. The present study assessed the impact of cough and unmet needs in Korean patients with chronic cough. This cross-sectional multi-center study enrolled adult patients newly referred to clinic for assessment of chronic cough. A second group of patients with unexplained chronic cough following detailed assessment were recruited for comparison. Patients completed self-reported questionnaires, including cough characteristics, impact of cough on daily life, and unmet needs. A total of 447 subjects were recruited from six referral clinics, including 408 with chronic cough and 39 with unexplained chronic cough. Almost all patients reported that cough impacted their daily lives. Psychosocial impacts were more evident in unexplained cough patients compared to newly referred patients. Approximately 75% of newly referred patients had previously sought medical care for cough on multiple occasions, but the effectiveness of treatment was limited (70.3%) or absent (17.3%). The most frequent unmet need was the ineffectiveness of treatment (49.3%), followed by unclear diagnosis (30.1%). The majority of participants ( > 80%) expressed the need for further information on accessing cough specialists and disease management. The main problem faced by unexplained cough patients was poor cough control despite treatment (64%). Chronic cough has a substantial impact on daily life and is worst in those whose cough remains unexplained following assessment. Ineffectiveness of treatment and unclear diagnosis were major unmet needs. Medical information about chronic cough was also lacking. Improvements in the management of chronic cough patients in Korea are necessary.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

Patient education is important for successful management of atopic dermatitis; however, due to limited time and resources, patient education remains insufficient. This study aimed to investigate the current state of education provided by Korean dermatologists, pediatric allergists, and allergists to patients with atopic dermatitis. A questionnaire survey consisting of items regarding educational programs for patients with atopic dermatitis was conducted via e-mail. In total, 153 participants responded to the questionnaires, and 26.8% indicated that they have had separate educational programs. The workforce involved in the educational program included nurses, residents or fellows, dieticians, pharmacists, and clinical psychologists. Most education protocols addressed the characteristics and natural course of atopic dermatitis and environmental management. Overall, 96.7% of the participants replied that an additional charge is needed for education; moreover, additional assistance from an academic society or association, in the form of medical staff, organized data, and advertisement, is required to develop and provide a well-structured educational program. A standardized education protocol will effectively provide appropriate education for patients with atopic dermatitis. Arrangement of education fees, covered by the National Health Insurance Service, will lead to the establishment of a structured educational program and participation of an additional medical workforce.

It has been recently reported that cigarette smoke exposure during allergen sensitization facilitates the development of allergic asthma; however, the underlying mechanisms remain elusive. We evaluated the role of interleukin (IL-23) in a cigarette smoke extract (CSE)-induced Dermatophagoides pteronyssinus (Dp)-allergic asthma mouse model. BALB/c mice were exposed to CSE during allergen sensitization period. Anti-IL-23p19 or IL-23R antibody was administered during the sensitization period. And we evaluated several immunological responses. The expression of IL-23 and IL-23 receptor (IL-23R) was examined in lung tissue. IL-23 and IL-23R expression was increased in the airway epithelium of Dp/CSE co-administered mice. CSE administration during the sensitization promoted Dp-allergic sensitization and the development of asthma phenotypes. Additionally, the proportion of innate lymphoid type 2 cells (ILC2) was also increased by CSE and Dp co-instillation. Anti-IL-23 or IL-23R antibody treatment during allergen sensitization significantly diminished phenotypes of allergic asthma and the ILC2 population. The levels of IL-33 and thymic stromal lymphopoietin (TSLP) were also significantly reduced by anti-IL-23 or IL-23R antibody treatment. IL-23 may thus play a significant role in cigarette smoke-induced allergic sensitization and asthma development. Clinically, the increase in allergen sensitization due to cigarette exposure causes onset of asthma, and IL-23 may be important in this mechanism. KEY MESSAGES: IL-23 and IL-23R expression was increased in the lung epithelium of Dp and CSE co-exposed mice during sensitization period. The population of ILC2s was increased in Dp and CSE co-exposed mice during sensitization period. Anti-IL23 or IL-23R antibody treatment with co-administration of CSE and HDM during sensitization period significantly suppresses ILC2. In vitro, IL-23 blockade in Dp and CSE-stimulated epithelial cells suppressed IL-13 expression in ILC2.

While hypersensitivity reactions (HSR) to intravenously administered iodinated contrast media (ICM) have been well studied, not much is known about HSR to intra-arterially administered ICM.A prospective observational study was performed to evaluate coronary angiography (CAG)-induced ICM hypersensitivity in patients who underwent CAG using ICM including ioversol, a low-osmolar non-ionic monomer, and iodixanol, an iso-osmolar non-ionic dimer. The HSR were investigated through in-patient monitoring after CAG and telephone interview after discharge.A total of 714 patients were enrolled during the observation period, of whom 26 (3.6%) showed immediate HSR and 108 (15.1%) showed delayed HSR. With regard to severity, proportion of immediate HSR grades 1, 2, and 3 was 57.7%, 38.5%, and 3.8%, respectively, whereas that of delayed HSR grades 1, 2, and 3 was 85.2%, 13.9%, and 0.9%, respectively. Multivariate analysis revealed that previous intra-arterial exposure to ICM was an independent risk factor for immediate HSR (odds ratio (OR) 2.92, 95% confidence interval (CI) 1.22-6.96; p = 0.015). Iodixanol was a significant risk factor for delayed HSR (OR 1.61, 95% CI 1.07-2.43; p = 0.024) and correlated with a higher incidence of delayed HSR within 24-h post-ICM administration compared to ioversol.The incidence rate of immediate and delayed HSR in intra-arterially administered ICM was 3.6% and 15.1%, respectively. Previous exposure to intra-arterially administered contrast media was a significant risk factor for immediate HSR. Compared to ioversol, iodixanol was associated with relatively earlier and more frequent delayed HSR.• In this prospective study, the incidence of immediate and delayed hypersensitivity in intra-arterial injection of contrast media during coronary angiography was 3.6% and 15.1%, respectively. • Delayed hypersensitivity reactions were more common but less severe than immediate hypersensitivity reactions during coronary angiography. • Previous exposure to ICM via intra-arterial route was a significant risk factor for immediate hypersensitivity to intra-arterial contrast medium.

Background: We conducted a meta-analysis to determine a practical observation time for detecting a biphasic reaction after resolution of the initial anaphylactic reaction. Methods: A systematic literature search identified studies on adult patients with anaphylaxis and a subsequent biphasic reaction due to various causes that contained sufficient data to extract outcomes. The outcomes were pooled using a random-effects model. Results: Twelve studies with a total of 2,890 adult patients with anaphylaxis and 143 patients with a biphasic reaction were included. In terms of the pooled negative predictive value, 1 h of observation achieved a 95.0% negative predictive value and ≥6 h of observation provided a 97.3% negative predictive value (95% CI: 95.0–98.5). The negative predictive value for a biphasic reaction increased with a longer observation time after initial anaphylaxis, and the increasing trend slowed down from 6 h of observation time. The pooled additional incidence rates of biphasic reactions per 100 person-hours after 1- and 4-h observations were 0.45 (95% CI: 0.20–1.04) and 0.41 (95% CI: 0.19–0.87), respectively. After > 8–12 h of postanaphylactic observation, the negative predictive value reached > 98%, while the additional incidence per 100 person-hours was < 0.10. Conclusions: An observation time of ≥6 h after resolution of an initial anaphylaxis symptom can exclude recurrence of a secondary reaction in > 95% of patients. Although longer observation periods resulted in the detection of more biphasic reactions, 6–12 h of observation time would be practical, supporting current relevant guidelines.

Background Transglutaminase 2 (TG2), a multifunctional calcium‐dependent acyltransferase, is upregulated in asthmatic airways and reported to play a role in the pathogenesis of allergic asthma. However, the underlying mechanism is not fully understood. Objective To investigate the role of TG2 in alternative activation of alveolar macrophages by using murine asthma model. Methods TG2 expression was assessed in induced sputum of 21 asthma patients and 19 healthy controls, and lung tissue of ovalbumin (OVA)‐induced murine asthma model. To evaluate the role of TG2 in asthma, we developed an OVA asthma model in both TG2 null and wild‐type mice. The expression of M2 macrophage markers was measured by fluorescence‐activated cell sorting (FACS) after OVA sensitization and challenge. To evaluate the effect of TG2 inhibition in vitro, interleukin 4 (IL‐4) or IL‐13‐stimulated expression of M2 macrophage markers was measured in CRL‐2456 cells in the presence and absence of a TG2 inhibitor. Results The expression of both TG2 and M2 markers was increased in the sputum of asthmatics compared with that of healthy controls. The expression of TG2 was increased in macrophages of OVA mice. Airway hyperresponsiveness, and the number of inflammatory cells, including eosinophils, was significantly reduced in TG2 null mice compared with wild‐type mice. Enhanced expression of M2 markers in OVA mice was normalized by TG2 knockout. IL‐4 or IL‐13‐stimulated expression of M2 markers in alveolar macrophages was also attenuated by TG2 inhibitor treatment in vitro. Conclusion Our results suggest that TG2‐mediated modulation of alveolar macrophage polarization plays important roles in the pathogenesis of asthma., Transglutaminase 2 (TG2) is crucial in the development of asthma by alternatively activating alveolar macrophage as well as augmentation of Th2 response. TG2 inhibitor directly suppresses Th2 cytokine‐driven alternative activation of alveolar macrophage.

Cough is a protective mechanism against aspiration, but it becomes pathologic when cough reflex is impaired or hypersensitive. Chronic cough is a clinical syndrome in adults, commonly characterized by hypersensitivity in the cough reflex, and is more prevalent and difficult to manage in older adults (≥65 years). The reason for the age-related increase in prevalence is unknown but may be related to comorbidities that are more frequent with aging. Adverse drug reactions can be also problematic in the aged patients, as they are prone to cognitive dysfunction, injurious fall, or pneumonia. In this chapter, we describe the characteristics of chronic cough in older adults and discuss clinical approaches including safety issues of therapeutic options.

Background: Recent attempts to develop more efficacious treatments for asthma, a TH2-dominant disease, have incorporated mesenchymal stem cell (MSC)-based cell therapies. Despite numerous previous studies, the full action mechanism of the pathogenesis of asthma remains undiscovered, and the need for further investigation is increasing in order to identify more effective target molecules. Objective: This study aimed to evaluate the anti-asthmatic effects of intratracheally administered MSCs primed with Liproxstatin-1, a potent ferroptosis inhibitor. In addition, we sought to examine the changes within macrophage populations and their characteristics in asthmatic conditions to explain the pathogenesis of asthma. Methods: Seven-week-old transgenic (TG) mice, constitutively overexpressing lung-specific interleukin (IL)-13, were used to simulate chronic asthma. Human umbilical cord-derived MSCs (hUC-MSCs) primed with Liproxstatin-1 were intratracheally administered four days prior to sampling. Bronchoalveolar lavage fluid and lung tissues were then evaluated. Results: IL-13 TG mice demonstrated phenotypes of chronic asthma, including severe inflammation in the respiratory organs, goblet cell hyperplasia, and subepithelial fibrosis. The ratio of Ly6C+M2 macrophages, found within the pro-inflammatory CD11c+CD11b+ macrophages, was also upregulated, and showed a strong correlation with lung eosinophil counts. Upon intratracheal administration of Liproxstatin-1-primed hUC-MSCs, which showed enhanced ability to downregulate the activation of TH2 cells compared to naive MSCs in vitro, the IL-13 TG mice showed reduced airway inflammation and fibrosis, in addition to a decreased ratio of Ly6C+M2 macrophages. Conclusions: Intratracheal administration is an effective method of MSC delivery, and macrophages hold great potential as an additional therapeutic target for asthma.

Background Although some respiratory virus infections are known to contribute to the development and exacerbation of asthma, commensal viromes in airway have not been extensively studied due to technical challenges. Objectives This study investigated the characteristics of the virome in asthmatic airways. Methods Both the bacteriome and virome profiles in sputum from 12 healthy individuals, 15 patients with nonsevere asthma, and 15 patients with severe asthma were analyzed and assessed for the association with clinical characteristics such as severity, exacerbation, Asthma Control Test (ACT), and lung function. Results While analysis of the 16S ribosomal RNA bacteriome in the airway showed no differences, clear contrasts in the diversity and composition of airway viromes were observed between healthy controls and patients with asthma. Herpesviruses were the most abundant type of virus in the asthma group (44.6 ± 4.6%), mainly with cytomegalovirus (CMV) and EBV accounting for 24.5 ± 3.3% and 16.9 ± 3.5%, respectively, in contrast to those in the healthy controls (5.4 ± 2.5% and 7.1 ± 3.0%, respectively). CMV and EBV were more abundant in patients with asthma who experienced exacerbation, and their abundance showed correlation with more severe asthma, lower ACT score, and lower lung function. On the contrary, bacteriophage that is abundant in healthy controls was severely reduced in patients with asthma in the order of nonsevere and severe asthma and presented significant positive correlation with ACT and FEV1/forced vital capacity. Conclusions Lung viromes, especially, CMV, EBV, and bacteriophage may be potential biomarkers of asthma severity and exacerbation.

OBJECTIVE The lung function changes presenting before and after asthma treatment in obese people remain largely unknown. This study aimed to investigate the association between obesity and lung function changes before and after treatment in adults with asthma. METHODS We enrolled 937 newly diagnosed asthma patients from Cohort for Reality and Evolution of Adult Asthma in Korea cohort in 2015-2017, who performed follow-up spirometry after three months of asthma treatment. The percentage changes (Δ) between the spirometry results before and after treatment were calculated. Patients were categorized into four body mass index (BMI) groups; underweight (

BackgroundMesenchymal stem cells (MSCs) possess immunomodulatory properties that provide therapeutic potential for the treatment of inflammatory diseases. While the therapeutic and clinical effects of MSCs are partially known, the effects of its administration to the airway in asthma, a chronic airway inflammatory disease, remain unclear.MethodsSix-week-old female BALB/c mice were sensitized and challenged with ovalbumin. The effects of intratracheally administered umbilical cord MSCs were evaluated by measuring airway hyperresponsiveness, airway inflammatory cell analysis, histological analysis, flow cytometry, and quantitative real-time PCR. Furthermore, ex vivo experiments confirmed the effect of MSC treatment on macrophages that originated from bronchoalveolar lavage fluid and were treated with interleukin (IL)-4 to induce M2 activation. Additionally, an in vitro transwell assay confirmed the effect of MSCs on macrophage activation through direct or indirect treatment using the CRL-2019 alveolar macrophage (AM) cell line.ResultsIntratracheal administration of MSCs significantly decreased the elevated levels of inflammatory cells and airway resistance in the murine asthma model. MSC administration also significantly decreased the numbers of Th2 cells, ILC2, and macrophages in the lungs of asthmatic mice. In particular, MHCII and CD86 expression was prominently reduced in dendritic cells and AMs following MSC treatment. Suppressed SiglecF+CD11c+CD11b- resident AMs, presenting strong negative correlation with type II inflammatory cells such as Th2 cells, ILC2, and eosinophils, were restored by intratracheal MSC treatment. Typical macrophage polarization to M2, particularly M2a, was significantly diminished. Expression levels of markers presenting M2 polarization and Th2 inflammation were decreased in the asthma model upon MSC administration. Ex vivo experiments of IL-4 treated AMs confirmed that MSC treatment reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla. In vitro experiments of IL-4 treated AMs confirmed that both direct and indirect MSC treatments through transwells significantly reduced Il-5 and Il-13 expression. No difference between the two treatment methods was found.ConclusionsUmbilical cord MSCs appear to regulate pulmonary macrophages, suppress Th2 inflammation, and mediate anti-asthmatic effects via soluble mediators.

Objective To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TU2670, a novel orally active, nonpeptide gonadotropin-releasing hormone (GnRH) antagonist administered to healthy female participants. Methods This was a first-in-human, multicenter, phase 1, randomized, double-blind, placebo-controlled, single-dose ascending trial that took place in multiple medical centers. A total of 16 healthy premenopausal women (23 to 45 years of age) were randomized and received 20, 40, 80, and 160 mg TU2670 (GnRH antagonist) or placebo 7 days (±1 day) after the onset of menstrual bleeding. We performed a noncompartmental analysis for pharmacokinetic parameters and calculated relative minimum concentration values (Cmin, % Baseline) of serum pharmacodynamic (PD) markers (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and estradiol). Results There were no significant differences among treatments with respect to vital signs, electrocardiography, adverse events, ovulation test results, and ultrasonography. The median Tmax of TU2670 occurred 0.75 to 1.00 hours after dosing, and concentrations then declined, with a mean apparent half-life (t1/2) of 3.0 to 5.9 hours. AUClast (17.7-417.9 ng·h/mL) and Cmax (8.1-95.4 ng/mL) increased in a dose-dependent manner. The PD analysis after a single administration of TU2670 revealed dose-dependent suppression of LH, FSH, and estradiol. Maximal suppression of the pre-dose baseline (%) was 58% to 82% at 6 to 8 hours for LH, 28% to 39% at 6 to 12 hours for FSH, and 34% to 82% at 12 to 24 hours for estradiol. Conclusion The single administration of TU2670 in healthy premenopausal women was well tolerated and resulted in the dose-dependent suppression of LH, FSH, and estradiol, suggesting rapid and significant inhibition of pituitary and ovarian hormones.

The original version of this article, published on 01 April 2019, unfortunately contained a mistake. The presentation of Fig. 1 was incorrect. The corrected figure is given below.

Background There could be a gap between asthma management guidelines and current practice. We evaluated the awareness of and compliance with asthma management guidelines, and the internal and external barriers to compliance, for the first time in Korea. Methods From March to September of 2012, 364 physicians treating asthma patients at primary, secondary, and tertiary teaching hospitals were enrolled. They completed a questionnaire on the awareness of and compliance with asthma management guidelines, and the barriers and alternatives to their implementation. Results Of the 364 physicians, 79.1% were men and 56.9% were primary care physicians. The mean age was 40.5 ± 11.2 years. Most of them were aware of asthma management guidelines (89.3%). However, only a portion (11.0%) of them complied with the guidelines for asthma. Pulmonary function tests for diagnosis of asthma were performed by 20.1% of all physicians and 9.2% of primary care physicians, and by 9.9% of all physicians and 5.8% of primary care physicians for monitoring. Physicians stated that ‘asthma monitoring’ was the most difficult part of the guidelines, followed by ‘environmental control and risk factors.’ Only 39.6% (31.9% of the primary care physicians) prescribed an inhaled corticosteroid (ICS) as the first-line treatment for persistent asthma. The internal barriers were physician's preference for oral medications, difficulty in use even with inhaler training, and concern over ICS side effects. The external barriers were possible rejection of medical reimbursement by health insurance, refusal by the patient, cost, and a poor environment for teaching the patient how to use the inhaler. Alternatives proposed by physicians to implement asthma management guidelines were to improve medical reimbursement policies and the level of awareness of such guidelines. Conclusion Compliance with the asthma management guidelines, including ICS prescription, is low despite the awareness of the guidelines. It is necessary to develop a strategy to overcome the internal and external barriers., Graphical Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction involving various internal organs. Flare-ups after recovery from the initial presentation of DRESS are caused by relapse of drug-induced T-cell-mediated reactions. However, the specific underlying mechanism is unclear. Here, we report a case of a 60-year-old man with allopurinol-induced DRESS who suffered recurrent episodes of generalized rash with eosinophilia, which mimicked immune reconstitution inflammatory syndrome. Analysis of immunological profiles revealed that the percentages of T lymphocytes and regulatory T cells in the patient with DRESS were higher than those in healthy controls. In addition, there was a notable change in the subtype of monocytes in the patient with DRESS; the percentage of nonclassical monocytes increased, whereas that of classical monocytes decreased. Upon viral infection, nonclassical monocytes exhibited strong pro-inflammatory properties that skewed the immune response toward a Th2 profile, which was associated with persistent flare-ups of DRESS. Taken together, the results increase our understanding of the pathogenesis of DRESS as they suggest that expansion of nonclassical monocytes and Th2 cells drives disease pathogenesis.

Objectives This study aimed to establish a system that can classify severe asthma on the basis of airway remodeling patterns visualizedusing computed tomography (CT) images and to evaluate the clinical characteristics of individual image-based subtypes. Methods Chest CT images from severe asthma patients were retrospectively evaluated to classify phenotypes by site of airway involvement and remodeling. The association between radiologic subtypes and clinical characteristics was assessed. Results Of 91 patients with severe asthma, 74 (81.3%) exhibited abnormal radiologic findings, including bronchial wall thickening (BT), mucus plugging (MP), and bronchiectasis (BE). The severity of BT and the extent of MP were independently associated with peripheral blood eosinophil count (P=.012, r2=0.112) and sputum eosinophil count (P=.022, r2=0.090), respectively. The large-to-medium airway remodeling type, which showed diffuse BT combined with MP and BE, accounted for 44% of patients and revealed higher peripheral blood eosinophil counts than other types. In the small airway remodeling type, which accounted for 6.6% of patients, we observed a higher rate of fixed airflow obstruction, along with a predominance of males and smokers and more frequent use of controller medication than other phenotypes. In 26% of patients with severe asthma, no prominent airway remodeling was observed (near-normal type); the near-normal type required oral corticosteroids less frequently than the large-to-medium airway and small airway remodeling types. Conclusions Depending on the site of airway involvement and remodeling pattern, 3 different structural types can be distinguished in chest CT findings from patients with severe asthma. Remodeling in large-to-medium sized airways revealed an association with systemic eosinophilic inflammation in patients with severe asthma.

Background: Asthma and allergic diseases account for school absenteeism and may limit academic and social opportunities for a substantial number of students, because they are common chronic disorde...

Purpose To evaluate premedication protocols involving administration of antihistamine and multidose corticosteroid that have been widely used in prevention of recurrent hypersensitivity reactions (HSRs) to iodinated contrast media (ICM); an evidence-based optimal preventive strategy customized for patients with mild cases has not yet been established. Materials and Methods The outcomes of patients with mild HSR who subsequently underwent contrast material-enhanced computed tomography (CT) between January 2012 and December 2015 were analyzed. For premedication, 4 mg of chlorpheniramine was intravenously administered 30 minutes prior to reexposure to ICM. Logistic regression with generalized estimating equations was used to determine the relationship between premedication and recurrence rate. Results A total of 1178 patients with mild immediate HSR were reexposed to ICM 3533 times. Among these patients, 1056 patients experienced allergylike reactions and 122 patients developed gastrointestinal reactions. With reexposure to the culprit agent without premedication, the recurrence rate was 31.1% (85 of 273 examinations). The recurrence rate decreased to 12% (105 of 872 examinations; P.001) by only changing the culprit agent and to 7.6% (148 of 1947 examinations; P.001) by using the combination of changing the ICM and antihistamine premedication. Changing the ICM plus antihistamine premedication was also helpful in reducing the recurrence of gastrointestinal symptoms from 16.1% to 1.8% (P = .020). However, despite changing of the ICM, some combinations of ICM did not show a prophylactic effect. Conclusion A combination of changing the culprit agent and antihistamine premedication resulted in the best preventive outcome for patients with mild immediate HSR. The optimal choice of substitute ICM could be individualized according to the culprit agent.

It is well known that depression is associated with asthma symptoms. We assessed the combined effects of genetic factors and depression on asthma symptom severity using Bayesian network (BN) analysis. The common 100 top-ranked single-nucleotide polymorphisms (SNPs) were obtained from two genome-wide association studies of symptom severity in two childhood asthmatics trials (CAMP (Childhood Asthma Management Program) and CARE (Childhood Asthma Research and Education)). Using SNPs plus five discretized variables (depression, anxiety, age, sex, and race), we performed BN analysis in 529 CAMP subjects. We identified two nodes (depression and rs4672619 mapping to ERBB4 (Erb-B2 receptor tyrosine kinase 4)) that were within the Markov neighborhood of the symptom node in the network and then evaluated the interactive effects of depressive status and rs4672619 genotypes on asthma symptom severity. In childhood asthmatics with homozygous reference alleles, severe depression was related to less severe symptoms. However, in childhood asthmatics with heterozygous alleles and homozygous variant alleles, depression and symptom severity showed a positive correlation (interaction permutation P value = 0.019). We then tried to evaluate whether the interactive effects that we found were sustained in another independent cohort of elderly asthmatics. Contrary to the findings from childhood asthmatics, elderly asthmatics with homozygous reference alleles showed a positive correlation between depression and symptom severity, and elderly asthmatics with heterozygous alleles and homozygous variant alleles showed a negative correlation (interaction permutation P value = 0.003). In conclusion, we have identified a novel SNP, rs4672619, that shows interactive effects with depression on asthma symptom severity in childhood and elderly asthmatics in opposite directions., Asthma: How genetic factors and depression affect symptom severity A novel mutation affects how depression influences the severity of asthma symptoms, with opposite effects in children and the elderly. Depression is known to affect the severity of symptoms experienced by patients with chronic disorders, such as asthma. Heung-Woo Park at Seoul National University College of Medicine in South Korea and coworkers investigated how genetic factors might influence the interaction between depression and asthma. Using previously collected genetic data, the researchers identified a mutation linked with both asthma and depression. In children with the mutation, depression was linked to severe asthma symptoms; children with depression but without the mutation experienced milder symptoms. The researchers observed the opposite relationship in a group of elderly patients with asthma. They conclude that further study of this mutation could illuminate ways to improve asthma management strategies.

Background/aims Effective educational tools are important for increasing adherence to asthma guidelines and clinical improvement of asthma patients. We developed a computer-based interactive education program for asthma guideline named the Virtual Learning Center for Asthma Management (VLCAM). We evaluated the usefulness of program in terms of its effects on user awareness of asthma guideline and level of satisfaction. Methods Physicians-in-training at tertiary hospitals in Korea were enrolled in a cross-sectional questionnaire survey. The e-learning program on asthma guideline was conducted over a 2-week period. We investigated changes in the awareness of asthma guideline using 35-item self-administered questionnaire aiming at assessing physicians' knowledge, attitude, and practice. Satisfaction with the program was scored on 4-point Likert scales. Results A total of 158 physicians-in-training at six tertiary hospitals completed the survey. Compared with baseline, the overall awareness obtained from the scores of knowledge, attitude, and practice was improved significantly. Participants were satisfied with the VLCAM program in the following aspects: helpfulness, convenience, motivation, effectiveness, physicians' confidence, improvement of asthma management, and willingness to recommend. All items in user satisfaction questionnaires received high scores over 3 points. Moreover, the problem-based learning with a virtual patient received the highest user satisfaction among all parts of the program. Conclusions Our computer-based e-learning program is useful for improving awareness of asthma management. It could improve adherence to asthma guidelines and enhance the quality of asthma care.

Udenafil is a phosphodiesterase-5 inhibitor used to treat erectile dysfunction. Although udenafil is not predominantly eliminated by the kidney, renal impairment can alter its secretion/transport pathways. Drug pharmacokinetics and safety must therefore be assessed in subjects with a renal impairment. We investigated the effects of impaired renal function on the pharmacokinetics and safety of a single 100-mg oral dose of udenafil in a single-dose, open-label, parallel-group study of 31 subjects. Cockcroft-Gault creatinine clearance was used to stratify these subjects into healthy controls (>80 mL·min-1 ) and individuals with mild (50 to ≤80 mL·min-1 ), moderate (30 to ≤50 mL·min-1 ), and severe (

Background: Allergic rhinitis (AR), asthma, chronic obstructive pulmonary disease (COPD), and rhinosinusitis are common and little studied in the Asia-Pacific region. Objectives: We sought to investigate real-world practice patterns for these respiratory diseases in India, Korea, Malaysia, Singapore, Taiwan, and Thailand. Methods: This cross-sectional observational study enrolled adults (age ≥18 years) presenting to general practitioners (GP) or specialists for physician-diagnosed AR, asthma, COPD, or rhinosinusitis. Physicians and patients completed study-specific surveys at one visit, recording patient characteristics, health-related quality of life (QoL), work impairment, and healthcare resource use. Findings by country and physician category (GP or specialist) were summarized. Results: Of the 13,902 patients screened, 7,243 (52%) presented with AR (18%), asthma (18%), COPD (7%), or rhinosinusitis (9%); 5,250 of the 7,243 (72%) patients were eligible for this study. Most eligible patients (70–100%) in India, Korea, Malaysia, and Singapore attended GP, while most (83–85%) in Taiwan and Thailand attended specialists. From 42% (rhinosinusitis) to 67% (AR) of new diagnoses were made by GP. On average, patients with COPD reported the worst health-related QoL, particularly to GP. Median losses of work productivity for each condition and activity impairment, except for asthma, were numerically greater for patients presenting to GP vs. specialists. GP prescribed more antibiotics for AR and asthma, and fewer intranasal corticosteroids for AR, than specialists (p < 0.001 for all comparisons). Conclusions: Our findings, albeit mostly descriptive and influenced by between-country differences, suggest that practice patterns differ between physician types, and the disease burden may be substantial for patients presenting in general practice.

Background Although inhaled corticosteroids (ICSs) are the recommended first-line therapy for asthma, determining whether to continue or discontinue ICS treatment in patients with mild asthma remains challenging for clinicians. Several studies have revealed that patients with mild-persistent asthma maintained a well-controlled state after ICS withdrawal. However, the long-term outcomes of ICS withdrawal have not yet been determined. Objective To determine the possible clinical outcomes of the discontinuation of ICS in patients with well-controlled mild asthma. Methods We investigated the clinical outcomes of discontinuing ICSs in patients with well-controlled mild asthma and compared the time to loss of control (LOC) between patients who stopped ICS treatment (ICS withdrawal group, IWG) and those who continued treatment for 3 years (continuous ICS group, CIG). Results A significant difference in the time to LOC was observed between the IWG and CIG (hazard ratio, 2.56; 95% confidence interval, 1.52-4.33; P Conclusion Our results suggest that the maintenance of ICS treatment may help keep patients’ asthma under control. Furthermore, patients with LOC had significantly higher sputum eosinophil counts in the CIG than those in the non-LOC group. Therefore, continuous ICS use by patients with mild, well-controlled asthma could be associated with good clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: KCT0002234.

Background Epidemiology and risk factors of drug-induced anaphylaxis are difficult to estimate due to lack of confirmative diagnosis and under reporting. Here we report the current state of drug-induced anaphylaxis in Korea based on an in-hospital pharmacovigilance database in a tertiary hospital. Methods This study is a retrospective analysis of drug-induced anaphylaxis, reported to an in-hospital pharmacovigilance center in Seoul National University Hospital from June 2009 to May 2013. Anaphylaxis occurred in patients under 18 years of age or developed by medications administered from outside pharmacies or hospitals were excluded. We assessed causative drug, incidence per use of each drug and risk factors of fatal anaphylactic shock. Results A total of 152 in-hospital drug-induced anaphylaxis cases were reported during the study period. The single most frequently reported drug was platinum compound and the incidence of anaphylaxis and anaphylactic shock in platinum compounds users was 2.84 and 1.39 per 1000 patients use. Risk factors of anaphylactic shock among total anaphylaxis cases were identified as older age ≥70 years [Odd's ratio (OR), 5.86; 95% confidence interval (CI), 1.70–20.14]. The use of iodinated contrast media (OR, 6.19; 95% CI, 1.87–20.53) and aminosteroid neuromuscular blocking agent (NMBA) (OR, 12.82; 95% CI, 1.50–109.92) were also a risk factor for the development of anaphylactic shock. Conclusions Platinum compounds are the most commonly reported causative agents of in-hospital drug-induced anaphylaxis. Older age ≥70 years and drugs such as iodinated contrast media and aminosteroid NMBA are related with high risk of anaphylactic shock.

To investigate the prevalence of biphasic and protracted anaphylaxis to iodinated contrast media (ICM), their risk factors and practical observation duration for detecting biphasic reaction. 145 patients with ICM anaphylaxis from January 2005–February 2016 were retrospectively categorised into uniphasic, biphasic (anaphylaxis recurrence within 72 h after resolution of initial anaphylaxis) and protracted (anaphylaxis >5 h) reaction groups. Multivariate regression analyses of potential risk factors were performed. We calculated negative predictive value (NPV) for biphasic reactions and additional person-hours required to detect one case during post-anaphylaxis observation. Fifteen patients had biphasic reactions with secondary reactions with similar or milder severity and six had protracted reactions. Most significant risk factors were anaphylaxis duration >40 min for biphasic reactions (odds ratio (OR), 8.65 [95 % CI, 1.05–70.71]; P=0.044), and additional epinephrine administration within 1 h of initial dosing for protracted reactions (OR, 102.0 [95 % CI, 3.40–3057.25]; P=0.008). A 6-h post-anaphylaxis observation produced NPV of 96.4 %, while requiring a minimum of 65.5 additional person-hours to detect one additional case. Biphasic and protracted ICM anaphylaxis developed in 10.3 % and 4.1 %, respectively, with revealing risk factors. Six hours could be practical for post-anaphylaxis observation to detect biphasic reaction. • Incidence of biphasic anaphylaxis in iodinated contrast media anaphylaxis is 10.3 %. • Incidence of protracted anaphylaxis in iodinated contrast media anaphylaxis is 4.1 %. • Initial anaphylaxis >40 min can predict for biphasic anaphylaxis development. • A 6-h post-anaphylactic observation in ICM-related anaphylaxis seems practical.

As an essential part of patient safety, pharmacovigilance is of worldwide interest and should expand its scope and focus on new emerging issues. South Korea has been making continuous efforts in the field of pharmacovigilance for the last 3 decades since voluntary adverse drug reaction (ADR) reporting system was first launched in 1988. Korea joined the World Health Organization Program for International Drug Monitoring in 1992, and the activities of Pharmacovigilance Research Network, Korean Society for Pharmacoepidemiology and Risk Management, and Regional Pharmacovigilance Center (RPVC) have contributed to the remarkable progress in the pharmacovigilance area and global status. RPVCs have played pivotal roles in establishment of pharmacovigilance system in Korea by monitoring voluntary ADR reports. RPVCs started with 3 hospitals in 2006 and have now expanded to 27 hospitals nationwide. The Korea Institute of Drug Safety & Risk Management was established in 2012 and in charge of operating the decentralized national pharmacovigilance system. The voluntary report of ADR, which is the basis of current pharmacovigilance system, has various limitations and an active surveillance system can be the overarching alternative. This change in pharmacovigilance paradigm is a global trend and Korea has excellent infrastructure such as broad distribution of electronic medical recording systems and a nationwide single healthcare insurance. As a result, the pharmacovigilance in Korea is now expected to progress to a new active surveillance system from traditional spontaneous reporting system.

목적: 노화에 따라 약물의 분포와 약동학적 반응에 변화가 생기며 사용하는 약제의 수도 늘어나게 되면서 노인에서 약제에 관련한 여러 문제점이 야기될 위험성이 높다. 타 연령대에 비하여 노인에서의 약물유해반응 특성을 확인하고자 하였다. 방법: 2010년 2월부터 2013년 9월까지 서울대학교병원 지역약물감시센터로 보고된 모든 약물유해반응 사례들을 대상으로 원인 약물의 성분명 및 ATC 상위 코드에 따른 보고 빈도, WHO-ART 기관계별 분류에 따른 유해사례 분포, 중증도 등을 분석하였다. 결과: 18세 이상 환자에서 총 15,541개의 사례가 보고되었다. ATC 코드에 따라 원인 약물을 분석해본 결과 신경계 약물, 항종양제 및 면역조절제, 전신 항감염제가 4,696건(30.2%), 3,490건(22.5%), 3,185건(20.5%)으로 가장 많이 보고 되었다. 60세 이상 군에서는 호흡기계 약물 363건(6.1%), 심혈관계 약물 183건(3.1%)으로 다른 연령군에 비해 비교적 높은 비중을 차지하였다. 유해사례를 WHO-ART 기관계별 분류 코드에 따라 살펴볼 때 소화기 질환이 3,961건(25.5%), 피부 및 부속기 질환이 3,427건(24.1%)으로 가장 빈번하게 보고되었다. 60세 이상 군에서는 다른 연령군에 비해 정신 질환, 심혈관계 질환, 혈액 질환, 요로계 질환의 비중이 높은 경향을 보였다. 보고된 약물들의 중증도를 분류해보았을 때 경증은 10,025건(64.5%), 중등증은 4,703건(30.3%), 중증은 775건(5.0%)을 나타냈다. 60세 이상 군에서는 중증으로 분류 된 사례가 358건(6.1%)으로 다른 연령군에 비해 상대적으로 높은 비율을 나타냈다. 여성에 비해 남성에서 상대적으로 중증도의 비중이 높았다. 결론: 노인에서는 ATC 분류 코드에 따른 약물군 중 호흡기계 약물과 심혈관계 약물에 의한 약물유해반응이 다른 연령대에 비해 비교적 빈번하였다. 약물유해반응에 의한 증상은 정신 질환, 심혈관계 질환, 혈액 질환, 요로계 질환의 비중이 다른 연령대에 비해 높은 비중을 차지하였다. 약물유해반응에 더욱 취약한 노인에 있어서 약물유해반응의 특성을 이해하고 예방 및 대처에 대한 더 많은 노력이 필요하다.

Aims A novel necrosis inhibitor, LC28-0126, is expected to have a cellular protective effect from ischaemic reperfusion injury in acute myocardial infarction. The objective of this study was to investigate the safety, tolerability and pharmacokinetics of LC28-0126 after a single intravenous administration in healthy male subjects. Methods The study was a dose-block-randomized, double-blind, placebo-controlled, single ascending dose, first-in-human trial. Subjects were randomly assigned to receive 0.3, 1, 3, 10, 25, 50, 100 or 200 mg of LC28-0126. LC28-0126 was infused for 30 min and 5 min in cohorts 1 and 2, respectively. An interim analysis to assess the tolerability and pharmacokinetics was conducted in each dose group. Blood samples were taken to determine plasma LC28-0126 concentrations from predose to 48 or 144 h postdose, and urine samples were taken from predose to 48 or 72 h postdose. Results Overall, 89 subjects were randomly assigned to the dose groups of the two cohorts. LC28-0126 was well tolerated, and no serious adverse events were reported. LC28-0126 showed rapid disposition in the distribution phase. Overall, the fraction of unchanged LC28-0126 excreted during the 48 or 72 h after administration was below 5%. The systemic exposure of LC28-0126 tends to be increased in a dose-proportional manner in the dose range of 0.3-200 mg. Conclusions A single intravenous dose of LC28-0126 was safe and well tolerated up to 200 mg. Furthermore, LC28-0126 demonstrated a predictable pharmacokinetic profile after a single intravenous infusion of doses ranging from 0.3 to 200 mg.