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Yul Hee Kim,1 Han-Seul Kim,1 Hyeung Kyoo Kim,2 Soo Young Kim,2 Jeonghun Lee,2 You Chan Kim,1 Young Joon Park1 1Department of Dermatology, Ajou University School of Medicine, Suwon, Republic of Korea; 2Department of Surgery, Ajou University School of Medicine, Suwon, Republic of KoreaCorrespondence: Young Joon Park, Department of Dermatology, Ajou University Hospital, 164, World Cup-ro, Yeongtong-gu, Suwon-si, Gyeonggi-Do, Suwon, Republic of Korea, Tel +82-31-219-5187, Email aro@ajou.ac.krPurpose: Early intervention of surgical scars with a pulsed dye laser is known to effectively prevent pathologic scars. Despite multiple reports on the effectiveness of the treatment, very few studies have demonstrated its appropriate initiation timing. In this study, our objective was to determine the optimal timing for initiating laser treatment following thyroidectomy.Methods: This study retrospectively analyzed 91 patients undergoing pulsed dye laser treatment post-thyroidectomy, grouping them by treatment initiation timing. The patients underwent treatment at intervals of 3– 4 weeks with at least five sessions. Those with a high pliability score were injected with intralesional corticosteroids. The Antera 3D® skin imaging analyzer was used to assess biophysical parameters.Results: The total Vancouver Scar Scale score significantly reduced after treatment in all groups. The Vancouver Scar Scale score reduction rate was significantly higher after treatment in the group for which the treatment was initiated within 3 weeks of surgery. The pigmentation and erythema score analyzed by Antera 3D® was also lower in this group.Conclusion: Early intervention using a pulsed dye laser within 3 weeks of thyroidectomy can substantially inhibit pathological scar development, providing physicians with a guide for optimal treatment commencement.Keywords: hypertrophic scars, laser treatment of scar, scar, pulsed dye laser

Jae-Kwang Lim,1 Byunggeon Park,1 Jongmin Park,1 Keum-Ju Choi,2 Chi-Young Jung,2 Young Hwan Kim,3 Jin Young Kim,4 Sungjun Moon,5 Yong Hoon Lee,6 Jaehee Lee6 1Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 3Department of Radiology, Daegu Catholic University School of Medicine, Daegu, Republic of Korea; 4Department of Radiology, Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea; 5Department of Radiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea; 6Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaCorrespondence: Jaehee LeeDepartment of Internal Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, 41944, Daegu, Republic of KoreaTel +82-53-420-5536Fax +82-53-426-2046Email jaelee@knu.ac.krBackground: Chronic obstructive pulmonary disease (COPD) is considered a risk factor for poor outcomes in patients with coronavirus disease 2019 (COVID-19). However, data on the prognostic impact of radiological emphysema extent on patients with COVID-19 are limited. Thus, this study aimed to examine whether computed tomography (CT)-quantified emphysema score is associated with a worse clinical outcome in patients with COVID-19.Methods: Volumetric quantitative analyses of CT images were performed to obtain emphysema scores in COVID-19 patients admitted to four tertiary referral hospitals in Daegu, South Korea, between February 18 and March 25, 2020. Patients were divided into three groups according to emphysema score (emphysema score ≤ 1%, 1%< emphysema score ≤ 5%, and emphysema score > 5%).Results: A total of 146 patients with confirmed SARS-CoV-2 infection were included. The median emphysema score was 1.0% (interquartile range, 0.5– 1.8%). Eight patients (6%) had a previous COPD diagnosis. Eighty (55%), 55 (38%), and 11 (8%) patients had emphysema scores ≤ 1%, between 1% and 5%, and > 5%, respectively. The number of patients who received oxygen therapy two weeks after admission was significantly higher in the group with emphysema scores > 5% than in other groups (p=0.025). The frequency of deaths was three (27%) in the group with emphysema scores > 5% and tended to be higher than that in other groups. Multivariate analysis revealed that age, COPD, and serum lactate dehydrogenase levels were associated with a greater risk of in-hospital mortality in patients with COVID-19.Conclusion: The current study demonstrated that patients with CT-quantified emphysema scores > 5% tended to progress to severe disease over time; however, they did not exhibit an increased risk of mortality in our COVID-19 cohort. Further studies with consideration of both emphysema extent and airflow limitation degree are warranted.Keywords: COVID-19, emphysema, computed tomography, COPD, mortality

Jeong Uk Lim,1 Hye Seon Kang,2 Chang Dong Yeo,3 Ju Sang Kim,4 Chan Kwon Park,1 Yong Hyun Kim,2 Jin Woo Kim,5 Seung Joon Kim,6,7 Sang Haak Lee3,7 1Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea; 3Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 4Division of Pulmonary, Critical Care and Sleep Allergy, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 5Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 6Division of Pulmonary, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 7Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Yong Hyun KimDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327, Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of KoreaTel +82-32-340-7039Fax +82-32-340-2669Email kyh30med@catholic.ac.krBackground: In patients with non-small cell lung cancer (NSCLC), both chronic obstructive pulmonary disease (COPD) and systemic inflammatory biomarkers, such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), have significant association with prognosis. NLR and PLR also predict mortality in patients with COPD alone. A combination of the two parameters may be helpful in a more individualized approach for predicting prognosis in NSCLC.Methods: Medical records of patients with stage IIIB and IV NSCLC from January 2012 to January 2018 in seven university hospitals were reviewed. Patients were categorized into four subgroups based on pulmonary function test results and cutoffs for NLR or PLR.Results: A total of 277 patients were evaluated and categorized into non-COPD and COPD groups; 194 patients were in the non-COPD group and 83 patients were in the COPD group. The non-COPD group showed significantly longer overall survival (OS) compared with the COPD group (P = 0.019). Median survival was significantly different between high/low PLR groups (P < 0.001), between high/low NLR groups (P = 0.001), and between high/low c-reactive protein (CRP) groups (P < 0.001). PLR, NLR and CRP showed significant correlations with each other. PLR showed a significant negative linear correlation with FVC (absolute) (r = − 0.149, P = 0.015), FVC (%) (r = − 0.192, P = 0.002), DLCO (absolute) (r = − 0.271, P < 0.001), DLCO (%) (r = − 0.139, P = 0.032), and NLR (r = 0.718, P < 0.001). In the multivariate analysis, the high PLR, COPD sub-group showed significantly higher risk for mortality (HR 2.066 (1.175– 3.633), P = 0.012) compared with the low-PLR non-COPD group. However, COPD-NLR subtype was not an independent predictor for OS.Conclusion: A combination of COPD status and PLR may be a cost-effective and readily available prognostic marker in patients with advanced NSCLC.Keywords: chronic obstructive pulmonary disease, non-small cell lung cancer, survival, platelet, lymphocyte, inflammation, biomarker

Joon Young Choi,1,* Shin Young Kim,2,* Jae Ha Lee,3 Yong Bum Park,4 Yee Hyung Kim,5 Soo-Jung Um,6 Ki Suck Jung,7 Kwang Ha Yoo,8 Seoung Ju Park,9 Hyoung Kyu Yoon10 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 3Division of Pulmonology, Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Republic of Korea; 4Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul 134-701, Republic of Korea; 5Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 6Division of Respiratory Medicine, Department of Internal Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea; 7Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang, Republic of Korea; 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Republic of Korea; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea*These authors contributed equally to this work.Correspondence: Hyoung Kyu YoonDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, #62 Youido-Dong Yeongdeungpo-Gu, Seoul, Republic of KoreaTel +82 2 3779 2213Fax +82 2 780 3132Email cmcyhg@gmail.comPurpose: The prevalence of chronic obstructive pulmonary disease (COPD) in females has increased, changing the concept of COPD as a disease mostly limited to males. In this study, the clinical characteristics of COPD in females were investigated.Patients and Methods: The study was based on a multicenter cohort of COPD patients recruited from 54 medical centers in South Korea. Sex-based differences in general characteristics, exposure risk factors, depression scores, results of pulmonary function tests, COPD exacerbation, symptom scores, and radiologic findings were evaluated. Sex-related differences in the annual FEV1 change over 5 years were analyzed in a linear mixed model.Results: Of the 2515 patients enrolled in this study, 8.1% were female. Female patients who had a higher BMI and a lower level of education were less likely to be smokers, were more exposed to passive smoking/biomass, and were more depressed compared to males. The rates of bronchiectasis, previous childhood respiratory infection, and asthma were higher in females. Female patients also had more symptoms and a poorer exercise capacity than males, but no significant differences were observed in terms of exacerbations. Radiologic findings revealed that male patients had worse emphysema, and female patients had worse bronchiectasis, as determined based on chest X-ray and computed tomography findings. On pulmonary function tests, female patients had less obstruction and less annual FEV1 loss over 5 years.Conclusion: This study revealed differences in the clinical parameters between male and female patients with COPD, including general characteristics, disease characteristics, and clinical outcomes.Keywords: COPD, gender difference, KOCOSS database, cohort study

Jinhui Ser1 ,* Ji Yeon Lee2 ,* Yong Ho Kim,3 Hoonsung Cho1 1School of Materials Science & Engineering, Chonnam National University, Gwangju 61186, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Gachon University, Gil Medical Center, Incheon 21565, Republic of Korea; 3Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea*These authors contributed equally to this workCorrespondence: Yong Ho KimGachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of KoreaTel +82-32-899-6691Fax +82-32-724-9071Email euro16@gachon.ac.krHoonsung ChoSchool of Materials Science & Engineering, Chonnam National University, Gwangju 61186, Republic of KoreaTel +82-62-530-1717Fax +82-62-530-1699Email cho.hoonsung@jnu.ac.krIntroduction: Photodynamic therapy (PDT), which induces tissue damage by exposing tissue to a specific wavelength of light in the presence of a photosensitizer and oxygen, is a promising alternative treatment that could be used as an adjunct to chemotherapy and surgery in oncology. Cell-penetrating peptides (CPPs) with high arginine content, such as protamine, have membrane translocation and lysosome localization activities. They have been used in an extensive range of drug delivery applications.Methods: We conjugated cell-penetrating peptides (CPPs) with methylene blue (MB) and then purification by FPLC. Synthesis structure was characterized by the absorbance spectrum, FPLC, Maldi-TOF, and then evaluated cell viability by cytotoxicity assay after photodynamic therapy (PDT) assay. An uptake imaging assay was used to determine the sites of MB and MB-Pro in subcellular compartments.Results: In vitro assays showed that MB-Pro has more efficient photodynamic activities than MB alone for the colon cancer cells, owing to lysosome rupture causing the rapid necrotic cell death. In this study, we coupled protamine with MB for high efficacy PDT. The conjugates localized in the lysosomes and enhanced the efficiency of PDT by inducing necrotic cell death, whereas PDT with non-coupled MB resulted in only apoptotic processes.Discussion: Our research aimed to enhance PDT by engineering the photosensitizers using CPPs coupled with methylene blue (MB). MB alone permeates through the cell membrane and distributes into the cytoplasm, whereas coupling of MB dye with CPPs localizes the MB through an endocytic mechanism to a specific organelle where the localized conjugates enhance the generation of reactive oxygen species (ROS) and induce cell damage.Keywords: methylene blue, protamine, CPP, photodynamic therapy, bioconjugation, anticancer, fluorescent

Sungpil Han,1 Yo Han Kim,1 Hee Youn Choi,1 Dong-Jun Soh,2 Jeongmin Kim,2 Joonwoo Nam,2 Jong-Woo Kim,2 Kyun-Seop Bae,1 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Clinical Development Team, Jeil Pharmaceutical Co. Ltd, Seoul, Republic of KoreaCorrespondence: Hyeong-Seok LimDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of KoreaTel +82-2-3010-4623Fax +82-2-3010-4622Email mdlhs@amc.seoul.krBackground: Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor has therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. In this first-in-human study, we investigate the safety, tolerability and pharmacokinetics (PK) of JPI-289 in healthy male volunteers.Subjects and Methods: In single ascending dose (SAD) study, 35, 75, 150, 300, 600 mg JPI-289 or placebo was infused intravenously over 30 minutes to 40 subjects. In multiple ascending dose (MAD) study, 150, 300, 450 mg JPI-289 or placebo was infused over 1 hour every 12 hours to each of 24 subjects for 3.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined.Results: In the SAD study, AUClast and Cmax tended to increase supra-proportionally especially at higher doses in SAD study. However, Cmax showed dose-proportionality in the range of 75– 600mg. JPI-289 reached a mean Tmax within 0.50 hour after dosing and a mean elimination half-life (t1/2) was 2.18 to 3.21 hours. In the MAD study, observed accumulation index ranged from 1.52 to 1.76. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that the plasma JPI-289 concentration rapidly reaches steady state. % recovered of JPI-289 measured in urine was 1.59– 9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Adverse events reported in the study were all mild in intensity and resolved without any sequelae.Conclusion: The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.Keywords: stroke, pharmacokinetics, pharmacodynamics, healthy subject, PARP-1 inhibitor

Tae Sik Goh,1,* Mihyang Ha,2,* Jung Sub Lee,1 Dae Cheon Jeong,3 Eun Sang Jung,4 Myoung-Eun Han,2 Yun Hak Kim,5,6 Sae-Ock Oh2 1Department of Orthopaedic Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea; 2Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea; 3Deloitte Analytics Group, Deloitte Consulting LLC, Seoul, Republic of Korea; 4Department of Bioenvironmental Energy, College of Life & Resources Science, Pusan National University, Miryang, Republic of Korea; 5Department of Anatomy and Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea; 6Biomedical Research Institute, Pusan National University, Busan, Republic of Korea *These authors contributed equally to this work Background: Advances in genomics have greatly improved the survival rate in cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early, and its survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients using independent cohort data. Materials and methods: To develop a novel prognostic biomarker, we used the gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan–Meier survival curve using median values of genes as cutoff showed that EIF4G1 was the only statistically significant gene in the 3 cohorts. We analyzed the prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of Uno’s C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate Cox analysis. We also compared EIF4G1 levels between tumors and matched non-tumor tissues. Results: EIF4G1 is the only prognostic gene in patients with PDAC, which was selected by Kaplan–Meier survival analysis. The survival curve showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with a good discriminative ability in 3 independent cohorts. The risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate Cox regression confirmed its prognostic significance. EIF4G1 expression was significantly higher in PDAC tissues than in the matched normal tissues. Conclusion: EIF4G1 could be used as a novel prognostic marker for PDAC and to determine suitable treatment options. Keywords: EIF4GI, pancreatic ductal adenocarcinoma, prognosis, GEO, TCGA

Ho-Jin Lee,1 Eunjoo Choi,1 Francis Sahngun Nahm,1 Seong-Soo Choi,2 Young-Hoon Kim,3 Jee Youn Moon,4 Shin Hyung Kim,5 Chan-Woo Cho,6 Pyung Bok Lee1,7 1Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Asan Medical Center, Seoul, Republic of Korea; 3Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, Seoul, Republic of Korea; 4Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 5Department of Anesthesiology and Pain Medicine, Severance Hospital, Seoul, Republic of Korea; 6Seoul Chan Pain Clinic, Seoul, Republic of Korea; 7Department of Anesthesiology and Pain Medicine, Seoul National University, Seoul, Republic of Korea Purpose: We aimed to investigate the prevalence of fibromyalgia (FM) in patients who visited outpatient pain clinics in Korea, using the modified 2010 American College of Rheumatology (ACR) criteria and to evaluate comorbid conditions that may be associated with FM.Patients and methods: Outpatients, aged ≥18 years, who first visited pain clinics at any of the 14 tertiary care university hospitals, were recruited for this study. Modified 2010 ACR criteria were used to diagnose FM. Participants’ demographic information and eleven comorbid measures (sleep disturbance, fatigue, irritable bowel syndrome, amnesia, hypothyroidism, headache, anxiety, depression, rheumatism, low back pain, and history of traffic accident) were also investigated via additional questionnaires.Results: We recruited 1,233 outpatients (754 men and 479 women). Based on the modified 2010 ACR criteria, 13.38% (165/1,233 patients, 95% CI: 11.48–15.28) of patients had FM. As participants with a history of FM were excluded, the prevalence of FM was 11.0% (123/1,118 patients). Patients with FM were more likely to have one or more of the eleven predetermined comorbid conditions. Patients who were female and who had a previous history of FM, sleep disturbance, headache, or a history of traffic accident were more likely to have FM.Conclusion: FM, according to the modified 2010 ACR criteria, appears to be a common disorder among chronic pain patients referred to tertiary care university hospital pain clinics. Therefore, physicians treating pain should consider this prevalence of FM among pain clinic patients. Keywords: tertiary care centers, chronic pain, diagnosis, fibromyalgia

Yong Suk Jo,1 Yee Hyung Kim,2 Jung Yeon Lee,3 Kyungjoo Kim,4 Ki-Suck Jung,5 Kwang Ha Yoo,6 Chin Kook Rhee4 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Chungju Hospital, Chungju, Republic of Korea; 4Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea; 5Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Republic of Korea; 6Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea Background and objective: The rate of obesity is increasing in Asia, but the clinical impact of body mass index (BMI) on the outcome of chronic obstructive pulmonary disease (COPD) remains unknown. We aimed to assess this impact while focusing on the risk of exacerbation, health-care utilization, and medical costs. Methods: We examined 43,864 subjects registered in the Korean National Health and Nutrition Examination Survey (KNHANES) database from 2007 to 2012, and linked the data of COPD patients who had mild to moderate airflow obstruction (n = 1,320) to National Health Insurance (NHI) data. COPD was confirmed by spirometry. BMI was used to stratify patients into four categories: underweight (BMI

Jeong Uk Lim, Chang Dong Yeo, Chin Kook Rhee, Yong Hyun Kim, Chan Kwon Park, Ju Sang Kim, Jin Woo Kim, Seung Joon Kim, Hyoung Kyu Yoon, Sang Haak Lee Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Objectives: Focusing on the advanced non-small cell lung cancer (NSCLC) patients without driver mutations can elucidate the clinical impact of COPD on treatment outcomes. The present study evaluated the effects of COPD on the overall survival of driver mutation-negative NSCLC patients undergoing conventional chemotherapy as the first-line treatment. Patients and methods: Medical records of stage IIIB and IV NSCLC patients from January 2008 to December 2015 from six university hospitals were reviewed. Results: The total study population consisted of 197 patients; 92 (46.7%) were COPD patients and 105 (53.3%) were non-COPD patients. The median survival in the non-COPD group was 11.5 months, compared to 9.2 months in the COPD group. Univariate analysis showed that old age (>70 years), high Eastern Cooperative Oncology Group status score (2–3), squamous cell histology, and COPD were risk factors for mortality. The presence of COPD was a significant prognostic factor in univariate analysis (hazard ratio [HR], 1.402; p=0.037), but not in multivariate analysis (HR, 1.275; p=0.144). Subgroup analysis of 143 smokers showed that COPD was a significant prognostic factor on multivariate analysis (HR, 1.726; p=0.006). In 154 stage IV patients, COPD was also a prognostic factor in multivariate analysis (HR, 1.479; p=0.039). Conclusion: COPD had a negative impact on overall survival in the stage IV NSCLC and smoker NSCLC patients who underwent conventional chemotherapy. Keywords: non-small cell lung cancer, chronic obstructive pulmonary disease, smoker, overall survival

Min-Hye Kim,1 Chin Kook Rhee,2 Kyungjoo Kim,2 Sang Hyun Kim,3 Jung Yeon Lee,4 Yee Hyung Kim,5 Kwang Ha Yoo,6 Young-Joo Cho,1 Ki-Suck Jung,7 Jin Hwa Lee1 1Department of Internal Medicine, College of Medicine, Ewha Womans University, 2Department of Internal Medicine, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, 3Big Data Division, Health Insurance Review and Assessment Service, Wonju, 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Chungju Hospital, Chungju, 5Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, 6Department of Internal Medicine, Konkuk University College of Medicine, Seoul, 7Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Republic of Korea Background: Asthma and COPD are heterogeneous diseases. Patients with both disease features (asthma–COPD overlap [ACO]) are common. However, clinical characteristics and socio-economic burden of ACO are still controversial. The aim of this study was to identify the heterogeneity of ACO and to find out the subtypes with clinical impact among ACO subtypes. Methods: In the Korean National Health and Nutrition Examination Survey (KNHANES) conducted between 2007 and 2012, subjects who were ≥40 years and had prebronchodilator FEV1/FVC

Hyungsub Kim,1 Hee Youn Choi,1 Yo-Han Kim,1 Kyun-Seop Bae,1 Jina Jung,2 Hankil Son,2 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea; 2Clinical Research Team, Hanmi Pharmaceutical Co. Ltd., Seoul, Republic of Korea Purpose: Rosuvastatin is a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that effectively reduces low-density lipoprotein cholesterol levels. However, statin monotherapy does not always achieve acceptable low-density lipoprotein cholesterol levels in patients with severe hypercholesterolemia. Ezetimibe, a selective cholesterol-absorption inhibitor, is approved for use as a monotherapy or combination therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for patients with hypercholesterolemia. The aim of this study was to examine the pharmacokinetics (PKs) of drug interactions between rosuvastatin and ezetimibe, and the tolerability of combined administration in healthy Korean male volunteers.Subjects and methods: Healthy subjects (n=24) were randomly allocated to 3 treatment groups: rosuvastatin (20 mg) alone, ezetimibe (10 mg) alone, and rosuvastatin (20 mg) plus ezetimibe (10 mg). The drugs were taken once every 24 hours over a period of 10 days. Blood samples were collected to analyze steady-state PKs.Results: All adverse events observed during the study were mild, and the frequency was no higher for combined administration than for mono administration. For rosuvastatin, the steady-state mean ratios (90% CI) of the combined over the single dose were 1.076 (1.019–1.136) for AUCτ,ss and 1.099 (1.003–1.204) for concentration at steady-state, respectively. In the case of free and total ezetimibe, the steady-state ratios of AUCτ,ss and concentration at steady-state were 1.131 (1.051–1.218) and 1.182 (1.038–1.346), and 1.055 (0.969–1.148) and 0.996 (0.873–1.135), respectively.Conclusion: Combined administration of rosuvastatin and ezetimibe was well tolerated. No clinically significant PK interactions between rosuvastatin and ezetimibe were observed when the 2 drugs were administered concomitantly. Keywords: rosuvastatin, ezetimibe, pharmacokinetics, DDI, tolerability

Chul-Kyu Park,1,* Yong Ho Kim,1,* Suhyun Hwangbo,2 Hoonsung Cho2 1Department of Physiology, College of Medicine, Gachon University, Incheon, 2School of Materials Science & Engineering, Chonnam National University, Gwangju, South Korea *These authors contributed equally to this work Abstract: Photodynamic therapy (PDT) is a promising alternative therapy that could be used as an adjunct to chemotherapy and surgery for cancer, and works by destroying tissue with visible light in the presence of a photosensitizer (PS) and oxygen. The PS should restrict tissue destruction only to the tumor and be activated by light of a specific wavelength; both of these properties are required. Arginine-rich peptides, such as cell-penetrating peptides, have membrane-translocating and nuclear-localizing activities, which have led to their application in various drug delivery modalities. Protamine (Pro) is an arginine-rich peptide with membrane-translocating and nuclear-localizing properties. The reaction of an N-hydroxysuccinimide (NHS) ester of rhodamine (Rho) and clinical Pro was carried out in this study to yield RhoPro, and a demonstration of its phototoxicity, wherein clinical Pro improved the effect of PDT, was performed. The reaction between Pro and the NHS ester of Rho is a solution-phase reaction that results in the complete modification of the Pro peptides, which feature a single reactive amine at the N-terminal proline and a single carboxyl group at the C-terminal arginine. This study aimed to identify a new type of PS for PDT by in vitro and in vivo experiments and to assess the antitumor effects of PDT, using the Pro-conjugated PS, on a cancer cell line. Photodynamic cell death studies showed that the RhoPro produced has more efficient photodynamic activities than Rho alone, causing rapid light-induced cell death. The attachment of clinical Pro to Rho, yielding RhoPro, confers the membrane-internalizing activity of its arginine-rich content on the fluorochrome Rho and can induce rapid photodynamic cell death, presumably owing to light-induced cell membrane rupture. PDT using RhoPro for HT-29 cells was very effective and these findings suggest that RhoPro is a suitable candidate as a PS for solid tumors. Keywords: photodynamic therapy, rhodamine, protamine, endocytosis, cell-penetrating peptide

Hye Seon Kang, Chin Kook Rhee, Sung Kyoung Kim, Jin Woo Kim, Sang Haak Lee, Hyung Kyu Yoon, Joong Hyun Ahn, Yong Hyun Kim Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Bucheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Purpose: We compared the clinical characteristics and treatment outcomes of patients with eosinophilic and neutrophilic COPD exacerbations requiring hospital admission. Patients and methods: This was a retrospective multicenter study performed between January 2010 and December 2014. In all, 1,688 COPD patients admitted via the outpatient clinics or emergency departments of six university hospitals were enrolled. The patients were grouped by complete blood counts: eosinophilic group, >2% peripheral blood eosinophils, and neutrophilic group, >65% peripheral blood neutrophils or >11,000 leukocytes/mL. The patients with radiographic evidence of pneumonia at the time of admission, those with lung cancer, those admitted for treatment of other medical problems, and those who chronically used steroids were excluded. Results: A total of 605 patients hospitalized with COPD exacerbations (177 eosinophilic and 380 neutrophilic) were included. Pulmonary functions, including the forced expiratory volume in 1 second and forced vital capacity, were better in patients with eosinophilic exacerbations. Treatment outcomes, including the rate of admission to the intensive care unit and mortality, were poorer in patients with neutrophilic exacerbations (4.5% vs 12.4%, P=0.004; 1.1% vs 4.5%, P=0.043, respectively). Congestive heart failure (odds ratio [OR] =3.40, 95% confidence interval [CI]: 1.28–9.01) and neutrophilic exacerbation (OR =2.81, 95% CI: 1.21–6.52) were independent risk factors for intensive care unit admission. Conclusion: COPD patients with neutrophilic exacerbations experienced worse clinical outcomes than did those with eosinophilic exacerbations. The peripheral blood eosinophil count may be a useful predictor of clinical progress during hospitalization of COPD patients with acute exacerbations. Keywords: eosinophilia, neutrophilia, pulmonary disease, chronic obstructive, exacerbations, intensive care unit

Hyekyung Jin,1 Yeonhee Kim,2 Sandy Jeong Rhie1,3 1College of Pharmacy, 2Center for Excellence in Teaching & Learning, 3Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea Background: Little is known about the functional health literacy (FHL) associated with medication adherence in elderly patients. The aim of this study was to examine the FHL among older adults and identify influencing factors that can predict medication adherence. Methods: This was a cross-sectional survey. Participants (n=160) aged 65 years and older were selected from outpatient clinics of 3 tertiary care hospitals, 6 community pharmacies, and 2 senior centers between November 1 and 30, 2014. The participants’ FHL was measured using the Korean Functional Health Literacy Test, which consists of 15 items including 8 numeracy and 7 reading comprehension items. Medication adherence was measured by the Adherence to Refills and Medication Scale. Descriptive statistics, chi-square or Fisher’s exact test, and multiple regression analyses were used to analyze the data. Results: The mean score of the total FHL was 7.72±3.51 (range 0–15). The percentage of the total number of correct answers for the reading comprehension subtest and numeracy subtest were 48.1% and 54.4%, respectively. Among 160 participants, 52.5% showed low adherence to medication. The factors affecting medication adherence included the patient’s degree of satisfaction with the service (β=-0.215, P=0.022), sufficient explanation of medication counseling (β=-0.335, P=0.000), education level (β=-0.153, P=0.045), health-related problems (β=-0.239, P=0.004), and dosing frequency (β=0.189, P=0.018). Conclusion: In this study, we found medication adherence of elderly patients was associated with education level, health-related problems, dosing frequency, satisfaction with patient counseling, and explanation of medication, but no association was found with FHL. Pharmacists should consider elderly patients’ individual characteristics such as educational background and specific patient-related health problems, provide sufficient information and explanation of medication, and ensure patient satisfaction with the counseling. Keywords: ARMS, elderly, health literacy, medication adherence

Jin-Sun Park,1,* Joon-Han Shin,1,* Taek-Jong Hong,2 Hong-Seog Seo,3 Wan-Joo Shim,4 Sang-Hong Baek,5 Jin-Ok Jeong,6 Youngkeun Ahn,7 Woong-Chol Kang,8 Young-Hak Kim,9 Sang-Hyun Kim,10 Min-Su Hyon,11 Dong-Hoon Choi,12 Chang-Wook Nam,13 Tae-Ho Park,14 Sang-Chol Lee,15 Hyo-Soo Kim16 1Department of Cardiology, Ajou University School of Medicine, Suwon, 2Division of Cardiology, Pusan National University Hospital, Busan, 3Division of Cardiology, Korea University Guro Hospital, Korea University College of Medicine, 4Division of Cardiology, Korea University Anam Hospital, 5Cardiovascular Division, Catholic University of Korea, Seoul St Mary’s Hospital, Seoul, 6Division of Cardiology, Chungnam National University Hospital, Daejeon, 7Division of Cardiology, Chonnam National University Hospital, Gwangju, 8Division of Cardiology, Gachon University Gil Hospital, Incheon, 9Division of Cardiology, Asan Medical Center, College of Medicine, University of Ulsan, 10Division of Cardiology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, 11Division of Cardiology, Soonchunhyang University Hospital, 12Division of Cardiology, Yonsei University Severance Hospital, Seoul, 13Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, 14Division of Cardiology, Dong-A University Hospital, Busan, 15Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 16Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul, Korea *These authors contributed equally to this work Abstract: The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of fixed-dose combination (FDC) therapy with olmesartan medoxomil (40 mg) and rosuvastatin (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. This multicenter, randomized, double-blind, factorial-design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia. Patients were randomly assigned to receive FDC therapy (40 mg olmesartan medoxomil, 20 mg rosuvastatin), 40 mg olmesartan medoxomil, 20 mg rosuvastatin, or a placebo. The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil, and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment. A total of 162 patients were included. The least square mean percentage change (standard error) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group (–52.3% [2.8%] vs –0.6% [3.5%], P

Yoon Ji Choi,1 Won Jin Chang,1 Sang Won Shin,1 Kyong Hwa Park,1 Seung Tae Kim,2 Yeul Hong Kim11Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, 2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaBackground: C-X-C chemokine receptor type 4 (CXCR4) is involved in tumor progression including angiogenesis, metastasis, and survival. However, whether serum CXCR4 levels in metastatic or recurrent colorectal cancer have a prognostic role, have not been evaluated.Methods: We analyzed serum samples from 55 patients with advanced colorectal cancer diagnosed between March 2008 and July 2011. Serum CXCR4 levels were quantified by a commercially available enzyme-linked immunosorbent assay (ELISA) kit.Results: The median age of the patients was 62 years, and all patients received systemic chemotherapy of two or more lines. The median serum CXCR4 level was 283.47 pg/mL (range: 77.48–846.52). Patients with two or more metastatic sites, liver metastasis, or higher CA 19-9 level (>37 IU/mL) showed significantly higher levels of serum CXCR4 than patients without. The median overall survival (OS) of all patients was 19.53 months. OS was significantly longer in patients with lower CXCR4 levels (≤240.45 pg/mL) compared with those having higher CXCR4 levels (>240.45 pg/mL) (median OS: 26.50 vs 17.03 months, P=0.046). Univariate analysis showed that liver metastasis, no palliative surgery, and higher levels of CXCR4 (>240.45 pg/mL) had a significantly poor prognostic value with regard to OS (P

Yo Han Kim,1 Jong-Lyul Ghim,2 Jin Ah Jung,2 Sang-Heon Cho,3 Sangmin Choe,4 Hee Youn Choi,1 Kyun-Seop Bae,1 Hyeong-Seok Lim1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, 2Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, 3Department of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon, 4Clinical Trials Center, Pusan National University Hospital, Busan, Republic of Korea Background: A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers.Methods: This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results: A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (96–120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) Cmax,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4'-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated. Conclusion: At steady state, the AUCT of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well tolerated. Keywords: cilostazol, bioavailability, sustained release, immediate release, pharmacokinetics, healthy subjects

Amal Kumar Ghimeray,1 Un Sun Jung,1,2 Ha Youn Lee,1 Young Hoon Kim,1 Eun Kyung Ryu,1 Moon Sik Chang11R&D Center, Natural Solution Co., Ltd, Gojan-dong, Namdong-gu, Incheon, Republic of Korea; 2Department of Horticultural Biotechnology, Kyung Hee University, Yongin, Republic of KoreaBackground: In phytotherapy, the therapeutic potential is based on the combined action of different herbal drugs. Our objective was to evaluate the antioxidant, anti-collagenase (in vitro), and anti-wrinkle (in vivo) effect of combined formulation containing Ginkgo biloba, Punica granatum, Ficus carica, and Morus alba fruits extract.Methods: Antioxidant evaluation was based on the scavenging activity of free radicals (1,1-diphenyl-2-picrylhydrazyl, H2O2, and O2-) and the anti-collagenase activity was based on the reduction of collagenase enzyme in vitro. In an in vivo study, 21 female subjects were examined in a placebo-controlled trail. Facial wrinkle, especially the crow's feet region of eyes, was treated with topical formulated 2% cream for 56 days and compared with the placebo.Results: In the in vitro study, the combination of fruits extract showed a higher antioxidant activity which was comparable with the positive standard (ascorbic acid, butylated hydroxyanisole, and Trolox). The data also showed a dose-dependent inhibition of collagenase. In the in vivo study, treatment with 2% formulated cream for 56 days significantly reduced the percentage of wrinkle depth, length, and area with 11.5, 10.07, and 29.55, respectively.Conclusion: The combined formulation of fruit extracts showed excellent antioxidative and anti-collagenase activity as well as a significant effect on anti-wrinkle activity on human skin.Keywords: antioxidant, anti-collagenase, anti-wrinkle, fruits, topical formulation

Yo Han Kim,1 Hee Youn Choi,1 Yook-Hwan Noh,1 Shi Hyang Lee,1 Hyeong-Seok Lim,1 Chin Kim,2 Kyun-Seop Bae11Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, 2Chong Kun Dang Clinical Research and Clinical Epidemiology and Medical Information, CKD Pharmaceuticals, Seoul, Republic of KoreaBackground: Carvedilol is a third-generation β-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects.Methods: An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formulations (8, 16, 32, 64, or 128 mg once). The treatment periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 h after dosing. The plasma concentrations of carvedilol were determined by using validated liquid chromatography–tandem mass spectrometry. Pharmacokinetic parameters including the area under the plasma concentration–time curve (AUC) from time 0 to the last measurable time (AUClast), AUC extrapolated to infinity (AUCinf), and the measured peak plasma concentration (Cmax) were obtained by noncompartmental analysis. Dose proportionality was evaluated if the ln–ln plots of AUClast, AUCinf, and Cmax versus dose were linear and the 90% confidence intervals (CIs) of the slopes were within 0.9195 and 1.0805. Tolerability was assessed by vital signs, electrocardiogram, clinical laboratory tests, and monitoring of adverse events (AEs) throughout the study.Results: A total of 31 subjects were enrolled, and 30 completed the study. The assessment of dose proportionality meets the statistical criteria; the point estimates of slope were 1.0104 (90% CI: 0.9849–1.0359) for AUClast, 1.0003 (90% CI: 0.9748–1.0258) for AUCinf, and 0.9901 (90% CI: 0.9524–1.0277) for Cmax, respectively. All AEs were mild, and none of the subjects dropped out due to AEs.Conclusion: In this study, exposure to carvedilol was proportional over the therapeutic dose range of 8–128 mg. The carvedilol SR formulation was well tolerated. Keywords: dose linearity, carvedilol, sustained release, healthy subjects

Yo Han Kim,1 Hee Youn Choi,1 Hyeong-Seok Lim,1 Shi Hyang Lee,1 Hae Sun Jeon,1 Donghyun Hong,2 Seong Su Kim,2 Young Kweon Choi,2 Kyun-Seop Bae1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2iCure Pharmaceutical lncorporated, Anseong, Gyeonggi-do, Republic of Korea Background: Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods: Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results: The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2ß was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion: The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. Keywords: donepezil, transdermal patch, pharmacokinetics, healthy subjects

Yo Han Kim,1 Hee Youn Choi,1 Shi Hyang Lee,1 Hyeong-Seok Lim,1 Tokutaro Miki,2 Jong-Koo Kang,3 Kyoung-Goo Han,4 Kyun-Seop Bae1 1Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; 2Nippon Hypox Laboratories Inc., Yamanashi, Japan; 3College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea; 4Biotoxtech Co., Ltd, Cheongju, Republic of Korea Background: HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. Methods: A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results: Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63–1.50 hours and slowly eliminated with a terminal half-life of 21.12–40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. Conclusion: HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing. Keywords: HX-1171, antioxidant, pharmacokinetics, tolerability, healthy subjects

Yo Han Kim,1 Hee Youn Choi,1 Shi Hyang Lee,1 Hae Sun Jeon,1 Hyeong-Seok Lim,1 Mi Young Bahng,2 Kyun-Seop Bae1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, College of Medicine, University of Ulsan, 2Clinical Development Department, Dong-A ST Co, Ltd, Seoul, Republic of Korea Background: “Udenafil” is a phosphodiesterase-5 inhibitor indicated for erectile dysfunction. “Dapoxetine” is a serotonin transport inhibitor indicated for premature ejaculation. The aim of the study reported here was to investigate the pharmacokinetic drug interaction between udenafil and dapoxetine in healthy male subjects. Methods: An open-label, three-treatment, six-sequence, three-period crossover study was performed in healthy male subjects. In varying sequences, each subjects received single oral doses of udenafil 200 mg, dapoxetine 60 mg, and both treatments. The periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 hours after dosing. The plasma concentrations of udenafil and dapoxetine were determined using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed throughout the study. Results: Twenty-three healthy subjects completed the study. The geometric mean ratios of the area under the plasma concentration–time curve from time 0 to last measurable time point and measured peak plasma concentration for udenafil were 0.923 (90% confidence interval [CI]: 0.863–0.987) and 0.864 (90% CI: 0.789–0.947), respectively. The geometric mean ratios of the area under the plasma concentration–time curve from time 0 to last measurable time point and measured peak plasma concentration for dapoxetine were 1.125 (90% CI: 1.044–1.213) and 0.837 (90% CI: 0.758–0.925), respectively. There were no serious adverse events reported, and none of the subjects dropped out due to adverse events. Conclusion: Udenafil was found to have no clinically significant pharmacokinetic interactions with dapoxetine. The concurrent administration of udenafil and dapoxetine was generally well tolerated. Keywords: drug interaction, pharmacokinetics, erectile dysfunction, premature ejaculation

Young Il Jeong,1,* Kyu Don Chung,2,* Da Hye Kim,3 Yoon Hyuk Kim,4 Yeon Soo Lee,5 Ki Choon Choi31Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea; 2Department of Anesthesiology and Pain Medicine, Catholic University, Seoul, South Korea; 3Grassland and Forage Research Center, Rural Development Administration, Cheonan, South Korea; 4Department of Mechanical Engineering, Kyung Hee University, Seoul, South Korea; 5Department of Biomedical Engineering, Catholic University of Daegu, Daegu, South Korea*These authors equally contributed to this workPurpose: All-trans retinoic acid (RA)-incorporated nanoparticles were prepared using deoxycholic acid-conjugated dextran (DexDA). Anticancer activity of RA-incorporated DexDA nanoparticles were tested in vitro and in vivo.Methods: RA-incorporated nanoparticles were prepared by dialysis. Antiproliferative and anti-invasive potential of RA-incorporated nanoparticles were studied using CT26 colorectal carcinoma cells.Results: RA-incorporated nanoparticles have small particle sizes of around 70–300 nm and spherical shapes. The higher drug-feeding ratio and higher substitution degree of deoxycholic acid in the conjugates resulted in higher drug contents, lower loading efficiency, and larger particle size. RA release rate became slower at higher drug contents and higher substitution degree of deoxycholic acid in the DexDA conjugates. The antiproliferation activity, anti-invasive activity, and matrix metalloproteinase 2 expression of RA-incorporated nanoparticles against CT26 cells in vitro was similar to RA. However, RA-incorporated nanoparticles had superior antimetastatic activity in an animal pulmonary metastatic model of CT26 cells compared to RA itself.Conclusion: RA-incorporated nanoparticles showed similar anticancer activity in vitro and superior antimetastatic activity in vivo in a pulmonary metastatic model of CT26 cells. We suggest that RA-incorporated nanoparticles are promising vehicles for efficient delivery of RA.Keywords: nanoparticle, dextran, deoxycholic acid, retinoic acid, cancer cell invasion

Rishi Agarwal,1,2 Paramveer Saluja,1 Angela Pham,3 Karen Ledbetter,3 Sukhveer Bains,3 Seema Varghese,3 John Clements,1 Young H Kim41Synergy Medical Education Alliance, Michigan State University College of Human Medicine, Saginaw, Michigan, USA; 2MD Anderson Cancer Center, Houston, Texas, USA; 3Michigan State University, Saginaw, Michigan, USA; 4Seton Cancer Institute, Saginaw, Michigan, USAIntroduction: The current standard for treating operable early stage non-small cell lung cancer is surgical resection and for inoperable cases it is external beam radiotherapy. Lung functions are adversely affected with both the above treatments. CyberKnife treatment limits radiation damage by tracking targets moving with each breath. The effect of CyberKnife treatment on pulmonary function tests has not been well documented.Methods: Lung cancer patients who underwent CyberKnife treatment and had pre- and post-treatment pulmonary function tests were included. Paired t-tests were conducted. We also conducted subgroup analysis.Results : Thirty-seven patients were included. Median age was 73 years. No statistical difference between mean pre- and post-CyberKnife pulmonary function tests was found.Discussion: We observed that CyberKnife better preserves lung function status compared to current standards of care. It has shown to have very minimal side effects.Keywords: non-small cell lung cancer, radiation pneumonitis, radiotherapy, pulmonary function tests

Kang HS, Rhee CK, Kim SK, Kim JW, Lee SH, Yoon HK, Ahn JH, Kim YH. Int J Chron Obstruct Pulmon Dis. 2016;11:2467–2473.Page 2467, Abstract, Results section, line 1, the text “COPD exacerbations (177 eosinophilic and 380 neutrophilic) were included” should read “COPD exacerbations (177 eosinophilic, 380 neutrophilic and 48 paucigranulocytic) were included. Of these, we compared patients with eosinophilic and neutrophilic COPD exacerbations”.Read the original article

Farnoosh Fazlollahi1,8, Arnold Sipos1,2, Yong Ho Kim1,2, Sarah F Hamm-Alvarez6, Zea Borok1–3, Kwang-Jin Kim1,2,5–7, Edward D Crandall1,2,4,8 1Will Rogers Institute Pulmonary Research Center, 2Department of Medicine, 3Department of Biochemistry and Molecular Biology, 4Department of Pathology, 5Department of Physiology and Biophysics, 6Department of Pharmacology and Pharmaceutical Sciences, 7Department of Biomedical Engineering, 8Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA Background: In this study, primary rat alveolar epithelial cell monolayers (RAECM) were used to investigate transalveolar epithelial quantum dot trafficking rates and underlying transport mechanisms. Methods: Trafficking rates of quantum dots (PEGylated CdSe/ZnS, core size 5.3 nm, hydrodynamic size 25 nm) in the apical-to-basolateral direction across RAECM were determined. Changes in bioelectric properties (ie, transmonolayer resistance and equivalent active ion transport rate) of RAECM in the presence or absence of quantum dots were measured. Involvement of endocytic pathways in quantum dot trafficking across RAECM was assessed using specific inhibitors (eg, methyl-ß-cyclodextrin, chlorpromazine, and dynasore for caveolin-, clathrin-, and dynamin-mediated endocytosis, respectively). The effects of lowering tight junctional resistance on quantum dot trafficking were determined by depleting Ca2+ in apical and basolateral bathing fluids of RAECM using 2 mM EGTA. Effects of temperature on quantum dot trafficking were studied by lowering temperature from 37°C to 4°C. Results: Apical exposure of RAECM to quantum dots did not elicit changes in transmonolayer resistance or ion transport rate for up to 24 hours; quantum dot trafficking rates were not surface charge-dependent; methyl-ß-cyclodextrin, chlorpromazine, and dynasore did not decrease quantum dot trafficking rates; lowering of temperature decreased transmonolayer resistance by approximately 90% with a concomitant increase in quantum dot trafficking by about 80%; and 24 hours of treatment of RAECM with EGTA decreased transmonolayer resistance by about 95%, with increased quantum dot trafficking of up to approximately 130%. Conclusion: These data indicate that quantum dots do not injure RAECM and that quantum dot trafficking does not appear to take place via endocytic pathways involving caveolin, clathrin, or dynamin. We conclude that quantum dot translocation across RAECM takes place via both transcellular and paracellular pathways and, based on comparison with our prior studies, interactions of nanoparticles with RAECM are strongly dependent on nanoparticle composition and surface properties. Keywords: alveolar epithelial barrier, transport, paracellular pathways, endocytosis

The purpose of this paper is to give some properties of several Bernstein type polynomials to represent the fermionic -adic integral on . From these properties, we derive some interesting identities on the Euler numbers and polynomials.

Abstract We give a new construction of the -Euler numbers and polynomials of higher order attached to Dirichlet's character . We derive some theoretic identities involving the generalized -Euler numbers and polynomials of higher order.

We define the twisted -Bernoulli polynomials and the twisted generalized -Bernoulli polynomials attached to of higher order and investigate some symmetric properties of them. Furthermore, using these symmetric properties of them, we can obtain some relationships between twisted -Bernoulli numbers and polynomials and between twisted generalized -Bernoulli numbers and polynomials.

Human exposure to wildfire-derived particulate matter (PM) is linked to adverse health outcomes; however, little is known regarding the influence of biomass fuel type and burn conditions on toxicity. The aim of this study was to assess the irritant potential of extractable organic material (EOM) of biomass smoke condensates from five fuels (eucalyptus, pine, pine needle, peat, or red oak), representing various fire-prone regions of the USA, burned at two temperatures each [flaming (approximately 640°C) or (smoldering approximately 500°C)] using a locomotor assay in zebrafish (Danio rerio) larvae. It was postulated that locomotor responses, as measures of irritant effects, might be dependent upon fuel type and burn conditions and that these differences relate to combustion byproduct chemistry. To test this, locomotor activity was tracked for 60 min in 6-day-old zebrafish larvae (25–32/group) immediately after exposure to 0.4% dimethyl sulfoxide (DMSO) vehicle or EOM from the biomass smoke condensates (0.3–30 µg EOM/ml; half-log intervals). All EOM samples produced concentration-dependent irritant responses. Linear regression analysis to derive rank-order potency indicated that on a µg PM basis, flaming pine and eucalyptus were the most irritating. In contrast, on an emission-factor basis, which normalizes responses to the amount of PM produced/kg of fuel burned, smoldering smoke condensates induced greater irritant responses (>100-fold) than flaming smoke condensates, with smoldering pine being the most potent. Importantly, irritant responses significantly correlated with polycyclic aromatic hydrocarbon (PAH) content, but not with organic carbon or methoxyphenols. Data indicate that fuel type and burn condition influence the quantity and chemical composition of PM as well as toxicity. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. Design: A multicentre, randomised, open‐label, equivalence trial and a meta‐analysis. Setting: Tertiary referral hospitals in South Korea. Population: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). Methods: Eligible women were screened and randomised at 16‒22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α‐hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). Main outcome measure: Preterm birth (PTB) before 37 weeks of gestation. Results: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention‐to‐treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI −7.6 to 13.8%), which was within the equivalence margin of 15%. The meta‐analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. Conclusion: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation. Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate central nervous system (CNS) strategies for controlling multifinger forces during a circle-drawing task. Subjects drew 30 concentric, discontinuous clockwise and counter clockwise circles, at self and experimenter-set paces. The three-dimensional trajectory of the pen's center of mass and the three-dimensional forces and moments of force at each contact between the hand and the pen were recorded. Uncontrolled Manifold Analysis was used to quantify the synergies between pen-hand contact forces in radial, tangential and vertical directions. Results showed that synergies in the radial and tangential components were significantly stronger than in the vertical component. Synergies in the clockwise direction were significantly stronger than the counterclockwise direction in the radial and vertical components. Pace was found to be insignificant under any condition. [ABSTRACT FROM AUTHOR]

GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution. Relevant PD markers generally changed in a dose-dependent manner and were described well with sigmoid, simple maximum effect, or linear models. GCC-4401C was absorbed more rapidly than rivaroxaban. Comparisons based on simulations of PD marker changes over time suggest that 20 mg and 40 mg of GCC-4401C administered under fasted status are comparable to 10 mg and 20 mg of rivaroxaban under fed status. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia and is characterized by deposition of amyloid beta (A[beta]) in the brain. The components of the herb Magnolia officinalis are known to have antiinflammatory, antioxidative and neuroprotective activities. In this study we investigated the effects of ethanol extract of M. officinalis on memory dysfunction and amyloidogenesis in a transgenic mouse model of AD. Oral pretreatment of ethanol extract of M. officinalis (10 mg/kg in 0.05% ethanol) into drinking water for 3 months inhibited memory impairment and A[beta] deposition in the brain of Tg2576 mice. Ethanol extract of M. officinalis also decreased activity of [beta]-secretase, cleaving A[beta] from amyloid precursor protein (APP), and expression of [beta]-site APP cleaving enzyme 1 (BACE1), APP and its product, C99. Our results showed that ethanol extract of M. officinalis effectively prevented memory impairment via down-regulating [beta]-secretase activity. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The literature lacks studies that confirm whether the improved radiographic alignment that can be achieved with computer-navigated total knee arthroplasty improves patients’ activities of daily living or the durability of total knee prostheses. The purpose of this study was to determine whether computer-navigated total knee arthroplasty improves the clinical function, alignment, and survivorship of the components.Methods: We prospectively compared the results of 520 patients with osteoarthritis who underwent computer-navigated total knee arthroplasty for one knee and conventional total knee arthroplasty for the other. The assignment of the knee to navigation or not was done randomly. There were 452 women (904 knees) and sixty-eight men (136 knees) with a mean age of sixty-eight years (range, forty-nine to eighty-eight years) at the time of the index arthroplasty. The mean follow-up period was 10.8 years (range, ten to twelve years). The patients were assessed clinically and radiographically with the rating system of the Knee Society and with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at three months, one year, and annually thereafter.Results: Total knee scores, knee function scores, pain scores, WOMAC scores, knee motion, and activity scores did not show statistically significant differences between the two groups preoperatively or at the time of the final follow-up. Alignment and the survivorship of the components were not significantly different between the two groups. The Kaplan-Meier survivorship with revision as the end point at 10.8 years was 98.8% (95% confidence interval [CI], 0.96 to 1.00) in the computernavigated total knee arthroplasty group and 99.2% (95% CI, 0.96 to 1.00) in the conventional total knee arthroplasty group.Conclusions: Our data demonstrated no difference in clinical function or alignment and survivorship of the components between the knees that underwent computer-navigated total knee arthroplasty and those that underwent conventional total knee arthroplasty. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway. [ABSTRACT FROM AUTHOR]