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Prothionamide, a second-line drug for multidrug-resistant tuberculosis (MDR-TB), has been in use for a few decades. However, its pharmacokinetic (PK) profile remains unclear. This study aimed to develop a population PK model for prothionamide and then apply the model to determine the optimal dosing regimen for MDR-TB patients. Multiple plasma samples were collected from 27 MDR-TB patients who had been treated with prothionamide at 2 different study hospitals. Prothionamide was administered according to the weight-band dose regimen (500 mg/day for weight 50 kg) recommended by the World Health Organization. The population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment, based on systemic exposure and MIC, was used as a response target. Fixed-dose regimens (500 or 750 mg/day) were simulated to compare the efficacies of various dosing regimens. PK profiles adequately described the two-compartment model with first-order elimination and the transit absorption compartment model with allometric scaling on clearance. All dosing regimens had effectiveness >90% for MIC values

Yu-Jin Kwon,1– 3 Hyangkyu Lee,4 Chung Mo Nam,5 Hyuk-Jae Chang,6 Young-Ran Yoon,7 Hye Sun Lee,8 Ji-Won Lee1 1Department of Family Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea; 2Department of Medicine, Graduate School of Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea; 4 Yonsei University College of Nursing, Mo-Im Kim Nursing Research Institute, Seoul, Republic of Korea; 5Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 6Department of Internal Medicine, Division of Cardiology, Severance Cardiovascular Hosp, Yonsei University College of Medicine, Seoul, Republic of Korea; 7Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 8Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Ji-Won LeeDepartment of Family Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju‐ro, Gangnam‐gu, 06273, Seoul, 135-720, Republic of KoreaTel +82 2 2019 3480Fax +82 3462 8209Email indi5645@yuhs.acBackground: In clinical practice, concomitant treatment of orlistat with phentermine is commonly used off-label. However, clinical trials have not been performed to evaluate whether their combination improves metabolic parameters and cardiovascular risk factors other than weight loss. Therefore, we aimed to compare the efficacy of concomitant administration of orlistat and phentermine versus phentermine alone on the endothelial cell function in overweight and obese adults with back pain.Methods: We conducted a 12-week, double-blinded, placebo-controlled clinical trial involving 114 patients with a body mass index of ≥ 30 (obese) or ≥ 27 (overweight) with weight-related comorbidities. We randomly assigned patients in a 1:1 ratio to receive orlistat (120mg) three times daily and phentermine (37.5mg) once daily, or a placebo three times daily and phentermine (37.5mg) once daily. Primary endpoint was changes in endothelium-dependent vasodilatation measured using ultrasound assessment of flow-mediated dilatation (FMD). Differences within groups after intervention were compared using the paired t-test or Wilcoxon signed-rank test. Differences in changes between the groups were calculated using an analysis of covariance after adjusting for each baseline value.Results: Mean weight loss during the 12-week study period was 6.1kg in the orlistat/phentermine group and in the placebo/phentermine group. Adjusted mean changes in total and non-high-density lipoprotein cholesterol were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group. Adjusted mean changes in endothelium-dependent FMD were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group (4.97± 0.98% vs 2.05± 0.99%, respectively; p=0.038). Changes in endothelium-independent nitroglycerin-mediated dilatation were not significantly different between the groups.Conclusion: Orlistat/phentermine significantly improved the vascular endothelial cell function compared with phentermine alone. Orlistat might have beneficial effects on the decrease of the risk of cardiovascular disease, especially in overweight and obese patients with comorbidities.Trial Registration: ClinicalTrails.gov number, NCT03675191.Keywords: obesity, orlistat, phentermine, endothelial cell function

Characterizing potential interactions between red ginseng, an herb with desirable health effects, and metformin, a commonly used drug for the treatment of type 2 diabetes mellitus, is of high clinical importance. In this study, we evaluate the effects of Korean red ginseng on the pharmacokinetic and pharmacodynamic properties of metformin in healthy subjects. The study was conducted in an open-label, two-period and single-sequence design. A total of 11 subjects received multiple doses of metformin in the first study period followed by multiple doses of metformin and red ginseng in the second study period. The Geometric Mean Ratio (GMR) (90% Confidence Interval (CI)) between the groups for area under the plasma drug concentration-time curve within a dosing interval (tau) at steady state (AUCtau,ss) of metformin was out of the range of bioequivalence, indicating that the systemic exposure of metformin when combined with red ginseng was reduced compared with administration of metformin alone. However, the pharmacodynamic analysis showed that the GMR (90% CI) between the groups for area under the blood glucose values–time curve from time zero to the time of the last measurable value (AUClast) and maximum blood glucose value (Gmax) were within the range of bioequivalence. We concluded that the observed reduction in the systemic exposure of metformin when administered with red ginseng is clinically insignificant. This study demonstrated that Korean red ginseng did not have clinically significant pharmacokinetic or pharmacodynamic herb–drug interactions with metformin in healthy subjects.

Objective Fimasartan, an angiotensin II type 1 receptor blocker, and linagliptin, a dipeptidyl-peptidase-4 inhibitor, are frequently coadministered to treat patients with hypertension and diabetes, respectively. This study sought to evaluate the pharmacokinetic interactions between fimasartan and linagliptin after co-administration in healthy Korean subjects. Methods The overall study was divided into two separate parts, with each part designed as an open-label, multiple-dose, two-period, and single-sequence study. In Part A, to investigate the effect of linagliptin on fimasartan, 25 subjects received 120 mg fimasartan alone once daily for seven days during Period I, and 120 mg fimasartan with 20 mg linagliptin for seven days during Period II. In Part B, to examine the effect of fimasartan on linagliptin, 12 subjects received only linagliptin once daily for seven days during Period I, followed by concomitant administration of fimasartan for seven days during Period II, at the same doses used in Part A. Serial blood samples were collected at scheduled intervals for up to 24 h after the last dose to determine the steady-state pharmacokinetics of both drugs. Results Thirty-six subjects completed the study. The geometric mean ratio and 90% confidence intervals for maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve at steady state (AUCτ,ss) of fimasartan with or without linagliptin were 1.2633 (0.9175-1.7396) and 1.1740 (1.0499-1.3126), respectively. The corresponding values for Cmax,ss and AUCτ,ss of linagliptin with or without fimasartan were 0.9804 (0.8480-1.1336) and 0.9950 (0.9322-1.0619), respectively. A total of eight adverse events (AEs) were reported and the incidence of AEs did not increase significantly with co-administration of the drugs. Conclusion Our results suggest that there are no clinically significant pharmacokinetic interactions between fimasartan and linagliptin when co-administered. Treatments were well tolerated during the study, with no serious adverse effects. Clinical trial registry http://clinicaltrials.gov, NCT03250052.

A new fixed-dose combination (FDC) formulation of raloxifene 60 mg and cholecalciferol 800 IU was developed to improve the medication compliance and overall efficacy of raloxifene treatment in postmenopausal osteoporosis patients. The aim of this study was to compare the pharmacokinetics between two tablets of FDC formulation of raloxifene/cholecalciferol and the two products administered concomitantly at respective doses. This randomized, open-label, single-dose, two-treatment, two-way crossover study included 46 volunteers. During each treatment period, subjects received the test formulation (FDC formulation containing raloxifene and cholecalciferol) or the reference formulation (co-administration of raloxifene and cholecalciferol), with a 14-d washout period. Serial blood samples were collected periodically over 96 hours after drug intake. In total, 46 subjects completed the study. The geometric mean ratios and its 90% confidence intervals of the FDC to the single agents for the area under the concentration-time curve from zero to the last quantifiable time point and the maximum plasma concentration met the regulatory criteria for bioequivalence: 1.1364 (1.0584-1.2201) and 1.1010 (0.9945-1.2188) for raloxifene and 1.0266 (0.9591-1.0989) and 1.0354 (0.9816-1.0921) for baseline-corrected cholecalciferol, respectively. Both formulations were well tolerated. No significant differences was observed in the incidence of adverse events between the two treatments. It was concluded that two tablets of the newly developed FDC formulation of raloxifene and cholecalciferol and the corresponding two agents administered concomitantly at respective doses were bioequivalent.ClinicalTrials.gov Identifier: NCT03010267.

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.ClinicalTrials.gov Identifier: NCT05182684.

Hae Won Lee,1,2 Woo Youl Kang,1,2 Wookjae Jung,1,2 Mi-Ri Gwon,1,2 Kyunghee Cho,3 Young-Ran Yoon,1,2 Sook Jin Seong1,2 1Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; 2Department of Clinical Pharmacology, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea; 3Analytical Research Division, Biocore Co. Ltd., Seoul, 08511, Republic of KoreaCorrespondence: Young-Ran Yoon, Department of Molecular Medicine, School of Medicine, Kyungpook National University, 130 Dongdeok-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82 53-420-4950, Fax +82 53-420-5218, Email yry@knu.ac.kr Sook Jin Seong, Department of Clinical Pharmacology, School of Medicine, Kyungpook National University, 130 Dongduk-Ro, Jung-gu, Daegu, 41944, Republic of Korea, Tel +82 53-200-6351, Fax +82 53-420-5218, Email wintersj@knu.ac.krBackground: YYD601 was developed as a novel dual delayed release (DDR) formulation of esomeprazole to prolong the plasma esomeprazole concentration and extend the duration of acid suppression.Purpose: The pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of YYD601 after single and multiple oral administrations were investigated in healthy Korean adults under fasting and fed conditions, and compared with the original esomeprazole capsule.Methods: In the single-center, randomized, open-label, parallel-design, two-period study, thirty two volunteers were enrolled into four dosing groups, including esomeprazole 40-mg (group A), YYD60130-mg (group B), YYD601 40-mg (group C), and YYD601 60-mg (group D) once daily for 5 days. Blood samples were collected for PK analysis, before and up to 24 h after dosing. For PD characteristics of YYD601, the percentages of time with intragastric pH > 4 over a 24-h period and during night-time following multiple oral administrations were evaluated.Results: A total of 27 subjects completed the study. YYD601 showed a dual-peak PK profile under fasting condition, with delayed Tmax, compared with conventional formulation. There were no significant differences in the AUC values adjusted for dose between the three YYD601 dosage groups and the conventional esomeprazole 40 mg. The esomeprazole AUC following single and multiple administration decreased with food intake by approximately 33%. YYD601 showed a linear pharmacokinetic profile in the dose range studied. There was no statistically significant difference in increase in mean percentage of time with intragastric pH > 4 for 24-hour and during night-time between the three different doses of YYD601 and the conventional formulation. The treatments were well-tolerated during the study and no serious adverse events were observed.Conclusion: YYD601 30 mg has a comparable effect on gastric acid inhibition as conventional esomeprazole 40 mg following once daily oral administration. Single and multiple oral dosing of YYD601 up to 60 mg were safe and well-tolerated throughout the study.Clinical Trial Registry: http://clinicaltrials.gov, NCT03558477 (date of registration: June 15, 2018; study period: between October 2017 and February 2018).Keywords: esomeprazole, dual delayed release, pharmacokinetics, pharmacodynamics

The Clinical Research Information Service (CRIS) in South Korea provides a clinical trial registry platform in which all clinical trials should be mandatorily and prospectively registered. However, to date, the registration status of clinical trials in the field of dentistry has not been investigated. Therefore, this study aimed to provide an overview of the methodological design and trends of the registered clinical trials over a period of nine years. Information about registered clinical trials in the field of dentistry from the CRIS was comprehensively collected from 2013 to 2021. The details assessed from the collected trials include: type of sponsors, recruitment status, study design, randomization, allocation concealment, single or multi-centric, retrospective or prospective registration, and publication status. A total of 65 registered clinical trials were identified. The number of clinical trials in dentistry in South Korea was found to be less; however, an increasing trend was observed in the recent three years. A majority of the trials were interventional (81.5%), single-centered (86.2%), and conducted on patients (81.5%) and in private hospitals (55.4%). A considerable number of trials had an unclear phase, were retrospectively registered, and rarely published. Regarding the quality, most trials have inadequately reported the method of randomization and allocation concealment. The number of clinical trials in dentistry is still low in South Korea, and most of them were registered retrospectively. A poor-quality reporting of methods at several specific areas was observed. It is necessary for dental investigators to raise awareness of the need to register clinical trials.

Purpose S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. Methods This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. Results In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. Conclusion The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.

To improve early renal allograft function, it is important to develop a noninvasive diagnostic method for acute T cell-mediated rejection (TCMR). This study aims to explore potential noninvasive urinary biomarkers to screen for acute TCMR in kidney transplant recipients (KTRs) using untargeted metabolomic profiling. Urinary metabolites, collected from KTRs with stable graft function (STA) or acute TCMR episodes, were analyzed using liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analyses were performed to discriminate differences in urinary metabolites between the two groups. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of potential urinary biomarkers. Statistical analysis revealed the differences in urinary metabolites between the two groups and indicated several statistically significant metabolic features suitable for potential biomarkers. By comparing the retention times and mass fragmentation patterns of the chemicals in metabolite databases, samples, and standards, six of these features were clearly identified. ROC curve analysis showed the best performance of the training set (area under the curve value, 0.926; sensitivity, 90.0%; specificity, 84.6%) using a panel of five potential biomarkers: guanidoacetic acid, methylimidazoleacetic acid, dopamine, 4-guanidinobutyric acid, and L-tryptophan. The diagnostic accuracy of this model was 62.5% for an independent test dataset. LC-MS-based untargeted metabolomic profiling is a promising method to discriminate between acute TCMR and STA groups. Our model, based on a panel of five potential biomarkers, needs to be further validated in larger scale studies.

Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug–drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10 mg/160 mg alone for 10 consecutive days in period I, and the same FDC for 10 days with concomitant 7-day administration of 20 mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7 days in period I, and the FDC for 10 days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72 h for amlodipine and rosuvastatin, and for up to 48 h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography–tandem mass spectrometry. Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration–time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029–0.9763) and 0.9316 (0.8970–0.9675) for amlodipine, 0.7698 (0.6503–0.9114) and 0.7888 (0.6943–0.8962) for valsartan, and 0.9737 (0.8312–1.1407) and 0.9596 (0.8826–1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. https://cris.nih.go.kr CRIS KCT0001660. KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.

Osteoporosis is a common skeletal disorder, often leading to fragility fracture. Combination therapy with raloxifene, a selective estrogen receptor modulator, and cholecalciferol (vitamin D

Background: Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells.Methods: Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, β-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells.Results: The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/μg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/μg according to the PCB quintiles of summary measure (P trend

A rapid analytical method developed for the analysis of β-lapachone in in vitro samples could not be directly applied to the analysis of clinical samples because of interference from unknown substances. Here, we developed and validated a rapid interference-free analytical method to accurately determine β-lapachone levels in human plasma using liquid chromatography-tandem mass spectrometry. First, we achieved the baseline-separation of β-lapachone from any interfering substances within a total run time of 4 min by adjusting the eluent strength of the mobile phase. Second, precursor-ion scanning revealed the identity of the interfering substances. Sulfonate- or glucuronide-conjugated metabolites were converted to β-lapachone in an electrospray ion source, causing interference. In a method validation study, calibration curves for β-lapachone in human plasma were linear over a concentration range from 0.5 to 200 ng/mL (r > 0.999), and the lower limit of quantification was 0.5 ng/mL. The other validation parameters, including intra- and interday accuracy and precision, were acceptable with a coefficient of variation less than 10% (n = 5). The validated analytical method was successfully applied to a pharmacokinetic study of a single, oral dose of 100 mg MB12066 (a clinical form of β-lapachone) in healthy volunteers.

Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors &alpha, agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A reductase inhibitor, in healthy Korean subjects. The study design was an open-label, randomized, multiple-dose, three-period, and six-sequence crossover study with a 10-day washout in 24 healthy volunteers. It had three treatments: 160 mg of micronized fenofibrate once daily for 5 days, 2 mg of pitavastatin once daily for 5 days, and 160 mg of micronized fenofibrate with 2 mg of pitavastatin for 5 days. Serial blood samples were collected at scheduled intervals for up to 48 h after the last dose in each period to determine the steady-state pharmacokinetics of both drugs. Plasma concentrations of fenofibric acid and pitavastatin were measured using a validated high-performance liquid chromatography with the tandem mass spectrometry method. A total of 24 subjects completed the study. Pitavastatin, when co-administered with micronized fenofibrate, had no effect on the Cmax,ss and AUC&tau, ss of fenofibric acid. The Cmax,ss and AUC&tau, ss of pitavastatin were increased by 36% and 12%, respectively, when co-administered with fenofibrate. Combined treatment with pitavastatin and micronized fenofibrate was generally well tolerated without serious adverse events. Our results demonstrated no clinically significant pharmacokinetic interactions between micronized fenofibrate and pitavastatin when 160 mg of micronized fenofibrate and 2 mg of pitavastatin are co-administered. The treatments were well tolerated during the study, with no serious adverse events.

Background and Aims Innovative strategies to promote adherence to immunosuppressants in kidney transplant recipients (KTRs) is imperative. This study aimed to evaluate the efficacy and stability of the information and communication technology (ICT)-based centralized monitoring system in increasing medication adherence in Korean KTRs. Method A prospective, multicenter, randomized controlled study was conducted (ClinicalTrials.gov Identifier: NCT03136588). All KTRs were randomized into the ICT-based centralized monitoring or the control group and had follow-up visits every 4 weeks during 6 months. The ICT-based centralized monitoring system alerted both patients and medical staff with texts and pill box alarms if there was a dosage/dosing time error or a missed dose. Medication adherence and transplant outcomes were compared between the two groups, and patient satisfaction on the ICT-based monitoring system was evaluated. Results Among enrolled 114 KTRs, 57 patients were assigned to the ICT-based centralized monitoring group and 57 patients to the control group. Mean adherence at each follow-up visit was not significantly different between groups. No differences in intrapatient variability of tacrolimus and mycophenolic acid levels, renal function, and adverse transplant outcomes were observed between the intervention and control groups, as well as between the intervention group with feedback generation and the intervention group without feedback generation. Overall patient satisfaction with the ICT-based centralized monitoring system was high and significantly improved during the study period (P = 0.012). Conclusion Although the ICT-based centralized monitoring system did not maximize mediation adherence or enhance transplant outcomes in Korean KTRs due to high baseline adherence, patient satisfaction with the system was high. We identified the future possibility that the ICT-based centralized monitoring system could be successfully applied in clinical trials targeting other disease groups with impaired adherence.

Background: T-cell immunosenescence, a hallmark of an aging immune system, is potentially linked to the risk of developing cancer and other aging-related diseases. Chronic infection by cytomegalovirus (CMV) has been widely studied as a risk factor for T-cell immunosenescence, but the role of persistent chemicals has never been examined. As a typical example of persistent chemicals, we evaluated whether organochlorine pesticides (OCPs) are related to T-cell immunosenescence in the general population. Methods: Serum concentrations of β-hexachlorocyclohexane, p,p′-DDT, p,p′-DDE, and trans-nonachlor were measured in 95 Korean adults ages 30 to 64 years. T-cell immunosenescence was assessed by the frequencies of CD8+CD57+, CD8+CD28−, CD4+CD57+, and CD4+CD28− T lymphocytes in 20 mL of fresh peripheral blood. Results: The senescence of CD8+ T lymphocytes was the most consistently associated with OCPs. For quartiles of measurements of OCPs, adjusted mean percentages of CD8+CD57+ and CD8+CD28− T lymphocytes in the CD8+ T lymphocyte population were 23.9, 27.6, 31.0, and 38.7 (Ptrend < 0.01) and 25.6, 27.3, 28.0, and 35.5 (Ptrend = 0.02), respectively. When we compared the strength of the associations among OCPs, CMV IgG titer, and age, OCPs showed the strongest association with markers of immunosenescence. Importantly, the association between OCPs and immunosenescence markers was more prominent among participants without known risk factors, such as a young age or low CMV immunoglobulin G titer. Conclusions: Chronic exposure to low-dose OCPs may be a new risk factor for T-cell immunosenescence. Impact: T-cell immunosenescence may be one possible mechanism linking low-dose OCPs and many chronic diseases. Cancer Epidemiol Biomarkers Prev; 27(10); 1159–67. ©2018 AACR.

Background: We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Methods: Red ginseng extract (dried ginseng > 60%) was administered once and repeatedly for 15 days to 15 healthy Korean people. After single and repeated administration of red ginsengextract, blood sample collection, measurement of blood pressure and body temperature, and routine laboratory test were conducted over 48-h test periods. Results: Repeated administration of high-dose red ginseng for 15 days was well tolerated and did not produce significant changes in body temperature or blood pressure. The plasma concentrations of Rb1, Rb2, and Rc were stable and showed similar area under the plasma concentration-time curve (AUC) values after 15 days of repeated administration. Their AUC values after repeated administration of red ginseng extract for 15 days accumulated 4.5- to 6.7-fold compared with single-dose AUC. However, the plasma concentrations of Rd and compound K showed large interindividual variations but correlated well between AUC of Rd and compound K. Compound K did not accumulate after 15 days of repeated administration of red ginseng extract. Conclusion: A good correlation between the AUC values of Rd and compound K might be the result of intestinal biotransformation of Rb1, Rb2, and Rc to Rd and subsequently to compound K, rather than the intestinal permeability of these ginsenosides. A strategy to increase biotransformation or reduce metabolic intersubject variability may increase the plasma concentrations of Rd and compound K. Keywords: ginsenosides, pharmacokinetics, red ginseng, single and repeated administration, tolerability

Purpose: Red ginseng is one of the world's most popular herbal medicines; it exhibits a wide range of pharmacologic activities and is often co-ingested with other herbal and conventional medicines. This open-label, randomized, 3-period study investigated the in vivo herb–drug interaction potential for red ginseng extract with cytochrome P-450 (CYP) enzymes and organic anion-transporting polypeptide (OATP) 1B1. Methods: Fifteen healthy male volunteers (22-28 years; 57.1-80.8 kg) were administered a single dose of cocktail probe substrates (caffeine 100 mg, losartan 50 mg, omeprazole 20 mg, dextromethorphan 30 mg, midazolam 2 mg, and pitavastatin 2 mg) and single or multiple doses of red ginseng extract for 15 days. Findings: The pharmacokinetic profiles of the probe substrates and metabolites after single- or multiple-dose administration of red ginseng extracts were comparable to the corresponding profiles of the control group. The geometric mean ratio of AUC0–t and 90% CIs for the probe substrate drugs between the control and multiple doses of red ginseng for 15 days were within 0.8 to 1.25 (CYP2C9, CYP3A4, and OATP1B1 probe substrates) or slightly higher (CYP1A2, CYP2C19, and CYP2D6 probe substrates). Additional assessments of the in vitro drug interaction potential of red ginseng extracts and the ginsenoside Rb1 on drug-metabolizing enzymes and transporters using human liver microsomes, cryopreserved human hepatocytes, and transporter-overexpressed cells were negative. Implications: Red ginseng poses minimal risks for clinically relevant CYP- or OATP-mediated drug interactions and is well tolerated. Clinical Research Information Service registry no.

Identification of the factors influencing energy consumption in buildings is crucial for energy efficient control in the operation stage. By using a multi-variate approach in energy performance prediction, we can characterize the building energy usage with a few available variables. However, very few studies have applied the variables related to building operation for energy consumption in buildings. Especially, the importance of the use factor, which affects the energy consumption, varies depending on the usage of tenants. However, there is a lack of sufficient research on the energy consumption based on energy use factors of each tenant in a building. Therefore, in this study we propose an energy consumption model using data on the energy use factors, such as occupant schedule, operation, and equipment, especially with a focus on the tenants in buildings. In this study, we analyzed the ranking of variable importance using the Random Forest algorithm and verified the energy consumption results of individual, office, and retail tenants in commercial buildings using a Gaussian process regression model. The main contribution of this study is the identification of the influence of energy use factors on the energy consumption of each tenant, both office and retail, thereby developing an energy model. This study established a method to identify the combination of variables that could estimate the energy consumption. Moreover, it can be seen that the significant variables to consider for developing an energy model differ depending on the tenant use class, i.e., office or retail.