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This study aimed to analyze pharyngeal reflux episodes in patients with suspected LPR versus healthy subjects using 24-h MII-pH monitoring. One hundred twenty-one patients who visited our clinic with a chief complaint of LPR-related symptoms and underwent 24-h MII-pH monitoring were enrolled prospectively. Also, 27 healthy subjects were enrolled and underwent 24-h MII-pH monitoring during the same period. We analyzed sensitivity, specificity, and accuracy comprehensively to determine appropriate cut-off values of pharyngeal reflux episodes in 24-h MII-pH monitoring to diagnose patients with LPR. Twenty-nine of 121 patients with suspected LPR showed no pharyngeal reflux episodes, while 92 showed more than one pharyngeal reflux event. In contrast, the 22 healthy subjects showed no pharyngeal reflux episodes, three showed one reflux event, and two showed two reflux events. A cut-off value of ≥ 1 showed best accuracy reflected by combined sensitivity and specificity values, while ≥ 2 demonstrated better specificity with slight loss of sensitivity and slightly lower overall accuracy, suggesting cut-off value of ≥ 1 pharyngeal reflux episodes is a good clinical indicator. A cut-off value of ≥ 1 in pharyngeal reflux episodes on 24-h MII-pH monitoring in patients with suspected LPR might be an acceptable diagnostic tool for LPR.

There is a lack of studies on the effects of Korean ginseng (

Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OC

BACKGROUND/AIM Cancer stem cells (CSCs) and ABC transporters are associated with treatment resistance and outcomes of cancer patients. We aimed to investigate the prognostic implications of CSC markers and ABC transporters in colorectal cancer (CRC) patients. MATERIALS AND METHODS We collected 331 CRC samples and evaluated 3 CSC markers (SOX2, LGR5, and ALDH1) and 3 ABC transporters (ABCC2, ABCC3, and ABCG2) by immunohistochemistry. The association between the expression of these protein and patients' prognoses was statistically analyzed. RESULTS SOX2 was associated with longer overall survival (OS) (p

The statistical procedures as outlined by the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) guidelines for bioequivalence testing of highly variable drugs (HVDs) are complex. Additionally, the sample size is affected by clinical study designs or practical real-world problems, such as dropout rate or study budget. To overcome these difficulties, we propose a model-based approach for the selection of a study design with a sample size that satisfies the bioequivalence criteria using simulation studies based on a pharmacokinetic (PK) model. The designed approach was implemented using a simulation procedure considering some conventionally measured factors, such as geometric mean ratio and within-subject coefficient of variation, with various PK information important in determining bioequivalence. All simulation results were assessed according to the EMA and FDA guidelines. Furthermore, power calculations from simulation results were interpreted with regard to PK characteristics and compared among 2 × 2, 3 × 3, and 2 × 4 crossover designs to determine the efficient design considering appropriate sample size and duration of the clinical study. The proposed approach can be applied to bioequivalence studies of all drugs. However, the current study was targeted at HVDs, which are highly likely to require detailed decision making for sample size and study design.

Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.

Objective Metabolic side effects of antipsychotics significantly affect adherence to medication. We aimed to identify factors associated with the occurrence of metabolic diseases among Korean patients with schizophrenia (SCZ) from the national health insurance system database. We evaluated the frequency of antidiabetic and antihyperlipidemic use after diagnosis of SCZ according to typical or atypical antipsychotic use. Materials and methods Among the 43,800 patients diagnosed with SCZ between 2008 and 2012, 29,591 patients who had no metabolic diseases before the diagnosis were included in the analysis to investigate the occurrence of metabolic diseases associated with antipsychotic use. The associations between the development of metabolic diseases and patient characteristics were evaluated using logistic regression analysis. Results Use of both typical and atypical antipsychotics (multivariate-adjusted odds ratio (OR), 1.2513; 95% confidence interval (CI), 1.0953 - 1.4294) was associated with higher incidence of metabolic diseases than without their use. Among the atypical antipsychotics, use of clozapine (multivariate-adjusted OR, 1.1959; 95% CI, 1.0086 - 1.4179) and quetiapine (multivariate-adjusted OR, 1.1284; 95% CI, 1.0446 - 1.2189) showed higher incidence of metabolic diseases compared to that without their use. Among the patients using ≥ 1 type of antidiabetic or antihyperlipidemic agents within 6 years after diagnosis of SCZ, the proportion of patients using only atypical antipsychotics was greater than those using only typical antipsychotics. Conclusion The use of both typical and atypical antipsychotics, and clozapine and quetiapine treatment, may be associated with the occurrence of metabolic diseases in patients with SCZ. Additional prospective studies with accurate dosage information are needed to validate our findings.

Previously, we reported that the hot water extract of Hydrangea serrata leaves (WHS) and its active component, hydrangenol, possess in vitro and in vivo effects on skin wrinkles and moisturization. We conducted a randomized, double-blind, placebo-controlled trial to clinically evaluate the effect of WHS on human skin. Participants (n = 151) were randomly assigned to receive either WHS 300 mg, WHS 600 mg, or placebo, once daily for 12 weeks. Skin wrinkle, hydration, elasticity, texture, and roughness parameters were assessed at baseline and after 4, 8, and 12 weeks. Compared to the placebo, skin wrinkles were significantly reduced in both WHS groups after 8 and 12 weeks. In both WHS groups, five parameters (R1&ndash, R5) of skin wrinkles significantly improved and skin hydration was significantly enhanced when compared to the placebo group after 12 weeks. Compared with the placebo, three parameters of skin elasticity, including overall elasticity (R2), net elasticity (R5), and ratio of elastic recovery to total deformation (R7), improved after 12 weeks of oral WHS (600 mg) administration. Changes in skin texture and roughness were significantly reduced in both WHS groups. No WHS-related adverse reactions were reported. Hence, WHS could be used as a health supplement for skin anti-aging.

Background: Preoperative chemoradiotherapy (CRT) has been established as a treatment of choice for locally advanced rectal cancer. However, the responses to CRT range very widely and there is no specific molecular marker definitively proven to be predictive of responses to CRT. We aimed to investigate the relationship between the expression of ATP-binding cassette (ABC) transporters and cancer stem cell (CSC) markers in pretreatment biopsy samples and pathological response to CRT in rectal cancer. Methods: The immunohistochemical expression of three ABC transporters (ABCG2, ABCC2, and ABCC3) and two CSC markers (SOX2 and LGR5) was determined in 76 biopsy specimens from rectal cancer patients who underwent preoperative CRT. The association between protein expression and pathologic tumor regression grade was statistically analyzed. Results: Fifty-eight (76.3%) cases were classified as chemoradio-resistant group and 18 (23.7%) cases as chemoradio-sensitive group and pathological complete remission was found in 8 (10.5%) cases. ABCG2 was frequently expressed in chemoradio-sensitive group (P=0.042), while expression of ABCC2 was found in chemoradio-resistant group (P=0.014). Low expression of ABCC2 was associated with pathologic complete remission (P=0.008). Conclusions: Immunohistochemical expression of ABCC2 and ABCG2 was associated with tumor regression after preoperative CRT in rectal cancer. In particular, ABCC2 was associated with resistance to CRT of rectal cancer. These markers might be used as biomarkers for predicting response against CRT in rectal cancer.

Programmed cell death ligand‐1 (PD‐L1) detection assays have not been standardized for patients with colorectal cancer, and the prognostic value of PD‐L1 expression is unclear. We compared the PD‐L1 expression patterns in colorectal cancer samples using various immunohistochemical assays using 3 primary PD‐L1 antibodies (assay 1, MIH1; assay 2, E1L3; and assay 3, 22C3) and investigated the prognostic implication of PD‐L1 expression using each. Additionally, PD‐L1 gene amplification was evaluated using FISH. The percentage scorings and positivity rates of the 3 assays differed; the degrees of correlation and concordance between assays 2 and 3 were relatively high, whereas assay 1 was an outlier. Multivariate analyses indicated that PD‐L1 positivity in tumor cells and its negativity in tumor‐infiltrating lymphocytes were independent predictors of poorer overall and disease‐free survival in patients with colorectal cancer. PD‐L1 gene amplification was found in 2 patients (PD‐L1/CEP ratio, 5.60 and 5.84, respectively); both had strong PD‐L1 expression according to immunohistochemistry. Overall, our study showed that PD‐L1 expression status in tumor and immune cells is an independent prognostic factor in patients with colorectal cancer. Standardizations of both PD‐L1 detection using immunohistochemistry and the cut‐off for positivity are necessary. Finally, PD‐L1 gene amplification was found in a small fraction of samples, suggesting the possibility of an ancillary test for PD‐L1 evaluation.

Obesity is caused by excessive fat cells and the overgrowth of adipocytes and is a major risk factor for several chronic illnesses. Aronia melanocarpa fruit is rich in anthocyanins and polyphenols and has protective effects against various diseases. In this study, we examined the effect of Aronia extract (Aronia bioactive fraction, ABF®) on the biomarkers of the adipogenic pathway during adipocyte differentiation of 3T3-L1 cells. Lipid accumulation was verified by Oil Red O staining. mRNA and protein expression of lipoprotein lipase (LPL), CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 2 (FABP2), and fatty acid synthase (FAS) were assayed by RT-qPCR and Western blot analyses. Adiponectin and leptin secretion were measured using enzyme-linked immunosorbent assays. ABF® treatment downregulated lipid accumulation based on Oil Red O staining. ABF®-treated cells exhibited decreased mRNA and protein expression of LPL, C/EBPα, PPARγ, FABP2, and FAS. Moreover, ABF® treatment significantly increased adiponectin secretion and decreased leptin secretion. In conclusion, ABF® has anti-adipogenic effects on the differentiation of 3T3-L1 cells and may be used as an anti-obesity nutraceutical.

Jieon Lee,1 Bo-Hyung Kim,2 Kyung-Sang Yu,1 Hee Sun Kim,3 Ji Duck Kim,4 Joo-Youn Cho,1 SeungHwan Lee,1 Namyi Gu5 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 2Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul, 3Life Science Research Institute, Daewoong Pharmaceutical Co. Ltd., Yongin, 4Clinical Development Team, Daewoong Pharmaceutical Co. Ltd., Seoul, 5Department of Clinical Pharmacology and Therapeutics, Dongguk University College of Medicine and Ilsan Hospital, Goyang,Republic of Korea Objectives: DWP05195 is a transient receptor potential vanilloid 1 (TRPV1) antagonist developed for managing pain. The purpose of this study was to evaluate the pharmacodynamics pharmacokinetics, safety, and tolerability of DWP05195 in healthy subjects. This was a first-in-human randomized, double-blinded, placebo-controlled, dose escalation study.Subjects and methods: DWP05195 or placebo was administered as a single dose of 10–600mg in the single-dose study and as 100–400mg once daily for 8days in the multiple-dose studies. Each study group consisted of 10 subjects (study drug-to-placebo ratio was 8:2). For pharmacodynamics assessment, the heat pain threshold (HPtr), heat pain tolerance (HPtol), perfusion intensity, and flare area ratio of cutaneous blood flow were measured. Safety and tolerability were evaluated throughout the study.Results: The maximum plasma concentrations and area under the plasma concentration–time curve from zero to the last measurable time dose-dependently increased. HPtr and HPtol tended to increase more after DWP05195 administration than after placebo administration. HPtr and HPtol tended to dose-dependently increase after administration of DWP05195. Cutaneous blood flow was reduced as the dose of DWP05195 increased during the multiple-dose study. DWP05195 was well tolerated up to 600 and 400 mg single- and multiple-dose administrations, respectively.Conclusion: The pharmacological activity of DWP05195, measured using HPtr and HPtol, increased as expected in a dose-dependent manner owing to increased systemic exposure, indicating that DWP05195 can be used as a TRPV1 antagonist for pain management. Keywords: DWP05195, TRPV1 antagonist, pain tolerance, pain threshold, capsaicin

BACKGROUNDS Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients. It depresses the transmission of monosynaptic and polysynaptic reflex by stimulating GABAβ (gamma-aminobutyric acid) receptors. OBJECTIVES The aim of this study was to compare the pharmacokinetic characteristics of two 10-mg baclofen formulations and to assess bioequivalence. METHODS A randomized, single-dose, two-period, two-sequence crossover study was conducted in healthy male subjects. Each subject received the test or reference formulations. After washout period, all subjects received the alternative formulation. Blood samples were collected for up to 24 hours after the dose in each period. Pharmacokinetic (PK) parameters, including tmax, Cmax, and AUClast were calculated by noncompartmental methods. The geometric mean ratio (GMR) of the test to the reference formulation and its 90% confidence interval (CI) for Cmax and AUClast were calculated for assessment of bioequivalence. RESULTS A total of 22 subjects completed the study. The median tmax of the test and the reference formulation were 1.50 and 1.25 hours, respectively. The mean (± SD) Cmax of the test and the reference formulation were 141.401 ± 29.447 ng/mL and 138.837 ± 31.392 ng/mL, respectively. The mean (± SD) AUClast of the two formulations were 702.404 ± 82.149 ng×h/mL and 726.803 ± 90.638 ng×h/mL, respectively. The GMR (90% CI) of the test to the reference formulation for the Cmax and AUClast were 1.0306 (0.9564 - 1.1106) and 0.9674 (0.9437 - 0.9916), respectively. CONCLUSIONS The two different baclofen 10-mg formulations had similar PK profiles and were bioequivalent based on Cmax and AUClast. .

Background Pregabalin binds to the α2δ auxiliary subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). Objective The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. Methods This bioequivalence study was based on an open-label, single-dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 - 1.25). Results The extent of exposure in terms of AUClast amounted to 26,018.3 - 3,580.8 µg×h/L for the test formulation and 25,680.2 ± 3,083.6 µg×h/L for the reference formulation. Cmax reached values of 4,782.7 ± 1,124.2 µg/L and 4,654.0 ± 911.4 µg/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 - 1.0351) for AUClast and 1.0153 (0.9351 - 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 - 1.25). Conclusions The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption. .

SOX11 is a transcription factor that is normally expressed in the fetal brain and has also been detected in some malignant tumors, including mantle cell lymphoma (MCL). MCL is a mature B-cell lymphoma that characteristically expresses cyclin D1, which has been used as a diagnostic tumor marker. SOX11 has also recently emerged as a tumor marker for MCL, particularly in cyclin D1-negative MCLs and to distinguish between MCLs and other cyclin D1-positive lymphomas. In this study, we evaluated the diagnostic accuracy of SOX11 immunohistochemistry for the diagnosis of MCL using a meta-analysis. A comprehensive literature search was performed using the PubMED, EMBASE, and Cochrane library through May 9, 2018. In total, 14 studies were included in our meta-analysis. The sensitivity, specificity, and area under the curve calculated from the summary receiver operator characteristic were 0.9, 0.95, and 0.934, respectively. Effect sizes of log positive likelihood ratios, log negative likelihood ratios, and log diagnostic odds ratios were 2.67, -2.12, and 5.27, respectively. Statistically significant substantial heterogeneity was observed for specificity (I2 = 95%), but not for sensitivity. Subgroup analysis and meta-regression were performed to explain the heterogeneity in specificity and showed that the proportions of Burkitt's lymphoma, lymphoblastic lymphoma, and hairy cell leukemia were significant covariates among studies using rabbit polyclonal antibodies. Overall, this meta-analysis showed that SOX11 was a useful diagnostic marker for MCL, with the clone MRQ-58 mouse monoclonal antibody showing particularly robust performance.

Background/objective The aim of this study was to evaluate the usefulness of simultaneous middle and inferior meatal antrostomies (SMIAs) as a treatment modality in patients with maxillary fungal sinusitis and to compare the efficacy of SMIA with that of conventional middle meatal antrostomy (MMA). Methods A retrospective study was performed on consecutive patients with noninvasive fungal maxillary sinusitis. Twenty-one patients underwent endoscopic sinus surgery with SMIA group and the remaining 24 patients were treated with the conventional MMA group. Medical records were reviewed for history, clinical presentation, radiographic findings, surgical intervention, complications, and outcomes. Outcomes consisted of the visual analog scale (VAS) for the main symptoms and maxillary sinus endoscopic scores. The stenosis or obstruction of the antrostomy site and postoperative mucociliary function was also evaluated. Results VAS scores for facial pain and nasal discharge/postnasal drip were significantly improved in the SMIA group. The maxillary endoscopic score was also significantly reduced in the SMIA group. There were no significant differences between 2 groups with respect to the preoperative Lund–Mackay score, VAS score of nasal obstruction, nasal bleeding, postoperative mucociliary function, and MMA patency. Conclusions The SMIA technique is useful for identifying and removing fungal debris that cannot be reached through the MMA and could bring better surgical outcomes.

The genetic alterations (GAs) in two specific histological subtypes of colorectal cancer (CRC), signet ring cell colorectal carcinoma (SRC) and mucinous colorectal carcinoma (MC), are not well known. In the present study, we employed next-generation sequencing to perform genetic profiling of SRC and MC, and compared the spectrum of GAs with the alterations found in conventional type colorectal cancer (CON).We selected 46 CRCs comprising 17 SRCs and mucinous carcinoma with signet ring cell component (SRCCs), 17 MCs, and 12 CONs with microsatellite stability or microsatellite instability-low. Deep sequencing was performed using a targeted cancer panel composed of 171 cancer-related genes. SMAD4 protein expression was evaluated by immunohistochemical staining.We detected 108 mutations in 18 different genes. Overall, 2.34 GAs were detected per tumor (range, 0-14). The overall frequency of GA and alteration in targetable genes was less prevalent in SRC/SRCC compared to the frequency of alteration in MC/CON (p = 0.040 and p 0.001, respectively). The GA profile of SRC/SRCC included TP53 (8/17, 47.1%), SMAD4 (5/17, 29.4%), KRAS (4/17.23.5%), APC (4/17.23.5%), PIK3CA, ATM, BRAF, and PIK3R1 (1/17, 5.9%, each). KRAS mutation was significantly less prevalent in SRC/SRCC compared to the number of KRAS mutations in MC (12/17, 70.6%) and CON (9/12, 75.0%) (p = 0.015 and 0.01, respectively). Compared to the 152 non-hypermutated CONs from TCGA database, SMAD4 alteration was predominant in SRC/SRCC (p = 0.045) with aberrant loss of SMAD4 expression (13/17, 76.5%) compared to the SMAD4 alterations in CON (5/15, 33.3%) (p = 0.031). Accordingly, KRAS (12/17, 70.6%), APC (6/17, 35.3%), SMAD4, TP53 (4/17, 23.5%, each), PIK3CA (3/17, 17.6%), AKT1, ATM, BRAF, EGFR, and EZH2 (1/17, 5.9%, each) were altered in MC. APC and TP53 mutations were less frequent in MC compared to those in TCGA-CON (p 0.001 and 0.003, respectively) whereas KRAS mutation was prevalent (p = 0.041).Alterations of known cancer associated genes and targetable genes in SRC/SRCC are infrequent. The profile of GAs in SRC/SRCC and MC differs from the GA profile of CON. Specifically, SMAD4 mutation and loss of SMAD4 expression is frequently found in SRC/SRCC. The genetic profiles revealed in the present study may aid in developing precision medicine for CRC treatment based on histological subtype.

TPS12134 Background: Cancer Cachexia (CC) is a multi-factorial process characterized by progressive weight loss, muscle mass and fat tissue wasting, and adversely affecting the quality of life and survival in patients with advanced stage of cancer. CC has a complex and multi-factorial pathophysiology, and there is no established standard treatment. Once it occurs, it is often irreversible and also difficult to suppress the its progression with any single treatment modality. We are conducting an open-label, parallel, randomized phase 2 trial to investigate the effect on preventing or alleviating cancer cachexia and safety of a multi-modal intervention including anti-inflammation, omega-3-fatty acids, nutritional supplement with counselling, physical exercise, psychiatric intervention as well as bojungikki-tang, which mediates immune-modulation and reverse inflammation-related chronic consumptive wasting condition as a complementary and alternative medicine compared to patients receiving best supportive care. Methods: Eligible criteria included patients with recurrent or metastatic gastrointestinal (gastric, colorectal and pancreaticobiliary) as well as lung cancer undergoing active palliative chemotherapy. Patients who have already developed refractory cachexia (ie, low performance status, difficult to take medications orally or visit the hospital to exercise) are excluded. Patients are randomized into experimental arm (Multi-modal intervention care: MIC) versus control arm (Conventional Palliative Care, CPC). MIC are comprised of 1) daily oral medications; ibuprofen 400 mg three times a day, omega-3-fatty acid 1 g twice a day, Bojungikki-tang 3.75g twice a day, oral nutritional supplement (HAMONILAN SOLN) 200 ml twice a day, and 2) clinical interventions; weekly physical exercise (60 minutes per visit), psychiatric assessment on every other week, and nutritional counselling total four times during the study period. CPC included basic nutritional counselling for two times provided by National Health Insurance Service, and megestrol acetate as needed (ie, anorexia ≥ Grade 2). All interventions were provided during 12 weeks per subject. Co-primary outcomes are change of total lean body mass and handgrip strength from the baseline. Secondary outcomes included change of fat mass and total body mass, lean body mass, Functional Assessment of Anorexia/Cachexia Treatment (FAACT) score, quality of life assessed by EORTC QLQ-C30, Spleen Qi Deficiency questionnaire (SQDQ), and overall survival. Total 112 patients will be assigned in the two arms (56 in each group). We have started the study in October 2020. At the time of submission, 26 patients were enrolled. Planned period of enrollment is 18 months. Clinical trial information: Clinical Research information Service, CRIS (KCT0004967). Clinical trial information: KCT0004967.

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

Background Talniflumate, a prodrug of niflumic acid, is a potent analgesic and anti-inflammatory drug that has been widely used for the treatment of rheumatoid diseases. Objective The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two formulations of talniflumate 370 mg tablets (test formulation: Flumagen® 370 mg tablet; reference formulation: Somalgen® 370 mg tablet). Methods A randomized, open-label, single dose, two-sequence, two-period crossover clinical study was conducted. After oral administration of the study drug in each period, blood samples were collected up to 15 hours post-dose. The plasma concentration of niflumic acid, a metabolite of talniflumate, was determined using HPLC-MS/MS. The pharmacokinetic parameters were estimated by non-compartmental method. Results The maximum plasma concentration (Cmax) and area under the concentration-time curve from zero to the time point with the last measurable concentration (AUClast) for the test formulation were 290.7 ± 199 µg/L and 1,154 ± 643 µg×h/L, respectively, and the corresponding values for the reference formulation were 286.8 ± 193 µg/L and 1,151 ± 577 µg×h/L, respectively. The geometric mean ratio and 90% confidence intervals (CI) of the test formulation to the reference formulation for the Cmax and -AUClast were 0.983 (0.829 - 1.166) and 0.979 (0.856 - 1.121), respectively. Conclusions The pharmacokinetic profiles of the test and reference formulations were found not to be significantly different, meeting the Korean regulatory criteria for bioequivalence. .

Objective This study had a single-dose, randomized, open-label, 2-period, and 2-sequence crossover design to evaluate pharmacokinetic (PK) bioequivalence between the test and reference formulations. Methods and materials Of the 34 healthy male volunteers enrolled, 4 were excluded owing to consent withdrawal before drug administration and the remaining 30 subjects were administered 20 mg each of the test and reference formulations of omeprazole. The blood samples for PK analysis were collected at the scheduled time-points, prior to dosing to 10 hours after dosing. Plasma concentrations of omeprazole were quantified by a liquid chromatography-tandem mass spectrometry method. Bioequivalence was assessed according to current guidelines issued by regulatory authorities. Results The plasma concentration-time profiles of omeprazole were similar between the reference and test drugs. The geometric mean ratios (90% confidence interval: CI) of test to reference were 0.9104 (0.8538 - 0.9708) for peak plasma concentration (Cmax) and 0.9304 (0.8836 - 0.9796) for area under the plasma concentration-time curve from time zero to time of last measureable concentration (AUC0-t). Conclusion The results from the PK analysis suggested that the reference and test formulations of 20 mg omeprazole capsules were bioequivalent in healthy male subjects.

To explore potential biomarkers for amoxicillin/clavulanate-induced liver injury (AC-DILI), we conducted a clinical trial in 32 healthy subjects based on multi-omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver-specific microRNA-122 (miR-122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC-DILI. We also identified urinary metabolites, such as azelaic acid and 7-methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC-DILI, including metabolic changes, increased miR-122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC-DILI based on currently known mechanisms using comprehensive multi-omics approaches.

Background and objective Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose–SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by currently approved doses.

The study aimed to identify single nucleotide polymorphisms (SNPs) that significantly influenced the level of improvement of two kinds of training responses, including maximal O2 uptake (VʹO2max) and knee peak torque of healthy adults participating in the high intensity training (HIT) program. The study also aimed to use these SNPs to develop prediction models for individual training responses. 79 Healthy volunteers participated in the HIT program. A genome-wide association study, based on 2,391,739 SNPs, was performed to identify SNPs that were significantly associated with gains in VʹO2max and knee peak torque, following 9 weeks of the HIT program. To predict two training responses, two independent SNPs sets were determined using linear regression and iterative binary logistic regression analysis. False discovery rate analysis and permutation tests were performed to avoid false-positive findings. To predict gains in VʹO2max, 7 SNPs were identified. These SNPs accounted for 26.0 % of the variance in the increment of VʹO2max, and discriminated the subjects into three subgroups, non-responders, medium responders, and high responders, with prediction accuracy of 86.1 %. For the knee peak torque, 6 SNPs were identified, and accounted for 27.5 % of the variance in the increment of knee peak torque. The prediction accuracy discriminating the subjects into the three subgroups was estimated as 77.2 %. Novel SNPs found in this study could explain, and predict inter-individual variability in gains of VʹO2max, and knee peak torque. Furthermore, with these genetic markers, a methodology suggested in this study provides a sound approach for the personalized training program.

While many disperse dyes have been studied in a variety of scientific fields, from textiles to biochemistry, most studies have been conducted on individual dyes having specific chromogens. However, bearing in mind that dyes are often used in combinations, in order to produce target colors for outdoor environments, an understanding of the photophysics of mixed system of dyes is important. As an extension of our previous work pertaining to scarlet and blue disperse dyes developed for use in outdoor applications, we investigated the photophysics of two commercial colorants and their various components (azo and anthraquinone red disperse dyes) to help account for their photostability when used in combinations. In this regard, experimental and modeling studies were performed to get insight into excited-state properties following light absorption. Transient absorption spectroscopy (TAS) showed that the dye mixtures dissipated excited-state energy much faster than the main component (an anthraquinone disperse red dye), which emphasized the benefit of multiple components in a commercial dye. The reduced excited-state lifetime clearly showed that the presence of additional dyes can play an important role in the photophysics and improving photostability.

Acetaminophen and Ojeok-san are both frequently used analgesics. In this study, we evaluated acetaminophen pharmacokinetics (PK) and changes in microRNA-122 (miR-122) levels after multiple dosing of acetaminophen with or without Ojeok-san. An open-label, 1-sequence, 2-period, 2-treatment crossover study was conducted in 18 subjects. In period 1, 500 mg of acetaminophen was administered 3 times on day 1 and once on day 2. In period 2, after the administration of 14.47 g of Ojeok-san twice on day 2 and 3 times daily on days 3 to 7, Ojeok-san and acetaminophen were coadministered 3 times each on day 8 and once each on day 9. The geometric mean ratios (90% confidence intervals) of acetaminophen with Ojeok-san to acetaminophen alone were 0.98 (0.87 to 1.10) and 1.02 (0.98 to 1.05) for the maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve during the dosing interval (AUC0-τ ), respectively, of acetaminophen at steady state. The alanine aminotransferase (ALT) levels were within the reference range in all the participants throughout the study period, although the mean fold changes in both serum miR-122 and ALT levels from baseline tended to increase on days 2 to 5. In conclusion, the PK properties of acetaminophen were not significantly affected by Ojeok-san coadministration. For osteoarthritis patients taking acetaminophen with or without Ojeok-san, monitoring potential liver toxicity using miR-122 as a biomarker may be useful.

Recently, lead-tin-based alloyed halide perovskite quantum dots (QDs) with improved stability and less toxicity have been introduced. However, the perovskite QDs containing tin are still unstable and exhibit low photoluminescence quantum yields (PLQYs), owing to the presence of defects in the alloyed system. Here, we have attempted to introduce sulfur anions (S2-) into the host lattice (MAPb0.75Sn0.25Br3) as a promising route to stable alloyed perovskite QDs with improved stability and PLQY. In this study, we used elemental sulfur as a sulfur precursor. The successful incorporation of sulfur anions into the host lattice resulted in a highly improved PLQY (>75% at room temperature), which is believed to be due to a reduction in the defect-related non-radiative recombination centers present in the host lattice. Furthermore, we found that the emission property could be tuned between the bright green and cyan-bluish regions without compromising on color quality. This work invigorates the perovskite research community to prepare stable, bright, and color-tunable alloyed inorganic-organic perovskite QDs without compromising on their phases and color quality, which can lead to considerable advances in display technology.

Objective The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics of two 2-mg tulobuterol transdermal delivery systems (TDSs) in healthy subjects. Materials and methods The pharmacokinetic (PK) analysis was performed using data from a randomized, open-label, single-dose, two-way, two-period, crossover study. Eligible subjects received either the Bretol®patch (test drug) or Hokunalin®patch (reference drug) in sequence according to their allocated group. Serial blood samples for PK analyses were collected for up to 48 hours after tulobuterol TDS application. The PK parameters, including the maximum concentration (Cmax) and area under the curve from time zero to the last quantifiable concentration time (AUClast), were estimated by using noncompartmental analysis. The geometric mean ratios (GMRs) of the Cmax and AUClast and their 90% confidence intervals (CIs) were estimated. Results A total of 27 subjects completed the study as planned. The concentration-time profiles of tulobuterol were similar in both formulations. The GMRs (90% CIs) of Cmax and AUClast were 0.9443 (0.8790 - 1.0144) and 0.9600 (0.8660 - 1.0642), respectively. Conclusion The PK profiles of both tulobuterol TDSs were comparable. In addition, the 90% CIs of the GMR were within the bioequivalence criteria of 0.800 - 1.250. Therefore, the Bretol®patch can be used as an alternative to the Hokunalin®patch for the treatment of patients with asthma and chronic obstructive pulmonary disease. .

Background and Objective Radiofrequency (RF) turbinoplasty may be effective in treating nonallergic rhinitis in elderly patients. The present study evaluated the efficacy of nasal turbinate surgery with RF for the treatment of nonallergic rhinitis in elderly patients refractory to medical therapy. Methods A total of 35 consecutive patients older than 65 years of age (mean subject age, 75.5 ± 9.6 [standard deviation] years) with nonallergic rhinitis refractory to medical therapy who underwent RF turbinate surgery were enrolled in this study. The efficacy of RF turbinoplasty in treating nonallergic rhinitis in elderly patients was evaluated by using rhinoscopy and a visual analog scale score of nasal symptoms. Results The response rate of primary RF turbinate surgery for nonallergic rhinitis refractory to medical therapy was 68.6%. Postoperative symptom scores for rhinorrhea and nasal obstruction were significantly improved. Persistent crust formation developed in seven patients (20.0%). No patient experienced major complications (e.g., septal hematoma, abscess, septal perforation), but partial bone necrosis was observed in one patient. Conclusion RF turbinoplasty appeared to be effective for treating some nonallergic rhinitis symptoms in elderly patients, including rhinorrhea and nasal obstruction. These preliminary results are encouraging and warrant further investigation.

The prevalence of obesity is increasing worldwide and has become a serious epidemic health problem. We developed the ‘Change 10 Habits’ educational program based on obesity treatment and dietary guidelines and examined its effects on customized nutrition education in mildly obese adults. The study was approved by the Institutional Review Board. Study subjects were excluded if they had several major diseases, if had consumed an anti-obesity drug, or if they practiced an obesity-related program within 30 days. The subjects (n=87, 25≤BMI＜30) were each exposed to the customized nutrition education program with four lessons according to the stage of the transtheoretical model (TTM). The stage-matched program was administered for 12 weeks and was run by a clinical dietitian. Overall, subjects who were in the precontemplation/contemplation stage at baseline made progress in the preparation and action/maintenance stage after 12 weeks (P＜0.05). For ‘Alcohol is consumed, up to 2 drinks per day’, the proportion of subjects who belonged in the action/main-tenance stage increased from 34.5% to 49.4% at 12 weeks. In addition, scores of all items significantly in-creased after the program (P＜0.05). ‘Chew more than 10 times and eat slowly’ score significantly increased from 3.9±2.4 to 5.8±2.3 (P＜0.05). In conclusion, behavioral stage-matched nutrition education using the ‘Change 10 Habits’ program was effective in improving eating behaviors and enhancing healthy lifestyles in mildly obese adults.

Demethylsuberosin isolated from the roots of Cudrania tricuspidata demonstrated a potent proteasome activator by enhancing all three chymotrypsin-like, trypsin-like, and caspase-like proteasome activities in a 20S proteasome activity assay. It also attenuated the 1-methyl-4-phenylpyridinium-induced dysfunction of the chymotrypsin-like and caspase-like activities of proteasome in SH-SY5Y cells with EC 50 values of 0.76 µM and 0.82 µM, respectively. Additionally, demethylsuberosin protected neuronal cells against 1-methyl-4-phenylpyridinium-induced cell death with an EC 50 value of 0.17 µM, while the EC 50 value of betulinic acid was 4.29 µM. We are reporting that demethylsuberosin is a potent proteasome activator with a neuroprotective effect, suggesting a possible candidate for the protection or treatment of neurodegenerative diseases such as Parkinsonʼs disease.