Development of an External Control Arm Using Electronic Health Record-Based Real-World Data to Evaluate the Efficacy of COVID-19 Treatment.

To protect people from severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, tremendous research efforts have been made toward coronavirus disease 19 (COVID-19) treatment development. Externally controlled trials (ECTs) may help reduce their development time. To evaluate whether ECT using real-world data (RWD) of patients with COVID-19 is feasible enough to be used for regulatory decision making, we built an external control arm (ECA) based on RWD as a control arm of a previously conducted randomized controlled trial (RCT), and compared it to the control arm of the RCT. The electronic health record (EHR)-based COVID-19 cohort dataset was used as RWD, and three Adaptive COVID-19 Treatment Trial (ACTT) datasets were used as RCTs. Among the RWD datasets, eligible patients were evaluated as a pool of external control subjects of the ACTT-1, ACTT-2, and ACTT-3 trials, respectively. The ECAs were built using propensity score matching, and the balance of age, sex, and baseline clinical status ordinal scale as covariates between the treatment arms of Asian patients in each ACTT and the pools of external control subjects was assessed before and after 1:1 matching. There was no statistically significant difference in time to recovery between ECAs and the control arms of each ACTT. Among the covariates, the baseline status ordinal score had the greatest influence on the building of ECA. This study demonstrates that ECA based on EHR data of COVID-19 patients could sufficiently replace the control arm of an RCT, and it is expected to help develop new treatments faster in emergency situations, such as the COVID-19 pandemic.

Long-term taxonomic and functional stability of the gut microbiome from human fecal samples.

Appropriate storage of fecal samples is a critical step for unbiased analysis in human microbiome studies. The purpose of this study was to evaluate the stability of the fecal microbial community for up to 18 months. Ten healthy volunteers provided fecal samples at the Jeonbuk National University Hospital. Stool samples were stored under the following six conditions: four different storage temperatures (- 70 °C, - 20 °C, 4 °C, and room temperature [20-25 °C]) and two different collection tubes (OMNIgene-Gut and DNA/RNA shield-fecal collection tubes). The gut microbiome was analyzed with 16S rRNA sequencing. We compared the taxonomic composition, alpha diversity, beta diversity and inferred pathway abundance between the baseline and 18 months after storage. Samples collected in the DNA/RNA Shield-fecal collection tubes showed the best performance in preservation of the taxonomic composition at 18 months. Pairwise differences in alpha diversity metrics showed the least deviation from zero. The PERMANOVA test showed non-significant change of beta diversity metrics (Unweighted Unifrac: q-value 0.268; Weighted Unifrac: q-value 0.848). The functional stability was significantly well preserved in the DNA/RNA Shield-fecal collection tubes (adjusted p value < 0.05). Our results demonstrate the use of the DNA/RNA Shield-fecal collection tube as an alternative storage method for fecal samples to preserve the taxonomic and functional stability of the microbiome over a long term.

Treatment outcomes of oral doxycycline versus intravenous azithromycin in adults hospitalized with scrub typhus: A retrospective study using inverse probability treatment weighting (IPTW) propensity analysis.

OBJECTIVE: Only a few well-designed studies that have investigated the effectiveness of azithromycin in treating adult patients hospitalized with scrub typhus are currently available. The purpose of our study was to compare the effects of intravenous azithromycin administration with those of oral doxycycline, and to evaluate cardiovascular death associated with intravenous azithromycin in adult patients hospitalized with scrub typhus. METHODS: This retrospective study investigated Korean National Infectious Disease Cohort Collaborative-registered scrub typhus-infected patients who were hospitalized between January 1, 2013, and December 31, 2021, and who were ≥18 years old. The primary outcome was time to fever clearance and the secondary outcomes were treatment failure, relapse, scrub typhus-related death, or azithromycin-related cardiovascular death. To address any indication bias, inverse probability of treatment weighting (IPTW) analysis was performed. Times to fever clearance between the doxycycline and azithromycin groups were compared using log-rank tests and Kaplan-Meier curves. RESULTS: A total of 326 consecutive patients with laboratory-confirmed scrub typhus were included in this study of whom 109 were treated with azithromycin and 217 with doxycycline. Using IPTW, there were no statistically significant differences in the following end points between the azithromycin and doxycycline groups: median time to fever clearance (3 days vs. 3 days, P = 0.649), treatment failure (0.71% vs. 0.42%, P = 0.702), relapse (0.0% vs. 0.0%), and scrub typhus-related death (5.12% vs. 0.0%, P = 0.155). No azithromycin-related cardiovascular deaths occurred. In the sensitivity analyses, there were no significant changes in effect size. CONCLUSIONS: Our study showed that the therapeutic effects and safety of intravenous azithromycin are comparable to those of oral doxycycline administration in patients hospitalized with scrub typhus. A well-designed randomized controlled trial may help further evaluate the most adequate route of administration, dose and duration of treatment with azithromycin.

Occlusion type and posterior communicating artery patency may predict favorable outcome after endovascular thrombectomy in selective basilar top occlusion.

Introduction: The top of the basilar artery is a five-branched junction, consisting of two superior cerebellar arteries (SCAs), two posterior cerebellar arteries (PCAs), and the basilar artery itself. This study aimed to investigate prognostic factors in patients with selective acute basilar top occlusion managed with mechanical thrombectomy, focusing on occlusion type and posterior communicating artery (PCoA) patency. Methods: Eligible patients who underwent endovascular treatment (EVT) for acute basilar top occlusion were reviewed. Patterns of basilar top occlusion were categorized as types I-III according to whether the SCA and PCA were visible on angiography. The PCoA was categorized as hypoplastic or non-visible (type I), normal patency but non-visible PCA through PCoA flow (type II), and fetal type (type III). Results: Good outcomes were observed in 50% (21/42) and mortality in 11.9% (5/42) of the cases at 90 days. Patients with good outcomes showed lower baseline National Institutes of Health Stroke Scale (NIHSS) score (P = 0.001) and a higher proportion of type III basilar top occlusion (P = 0.004) and type III PCoA (P = 0.001). Multivariable logistic analysis showed that baseline NIHSS score [odds ratio (OR), 0.84; 95% confidence interval (CI), 0.73-0.97; P = 0.017) and type III PCoA (OR, 21.54, 95% CI, 1.33-347.97; P = 0.031) were independent predictors of good functional outcomes. Conclusion: A low initial NIHSS score and good PCoA patency were independent predictors of favorable clinical outcomes after EVT in patients with acute basilar top occlusion. Furthermore, the favorable outcome group showed a high proportion of type III basilar top occlusions.

Changes of Atherosclerotic Plaque in Cerebral Artery Stenosis According to High-Resolution MR Imaging.

Atherosclerosis can affect multiple arteries, and result in stroke and heart disease. Clinical and conventional imaging is insufficient to predict the progression of atherosclerosis. This study investigates risk factors that rely on high-resolution magnetic resonance imaging (HR-MRI). Patients with cerebral artery stenosis who had undergone HR-MRI at least twice were included. The demographics, risk factors, and proportion of patients with cerebral artery stenosis were investigated. The association between atherosclerotic plaque characteristics and the progression or regression of artery stenosis was also analyzed. A total of 42 patients were analyzed, with a median follow-up of 16.88 ± 12.53 months. The mean age of all subjects was 63.1 ± 9.15 years, and 83.3% of them were male. The incidences of stenosis of the basilar, proximal internal carotid, and middle cerebral arteries were 21.4%, 61.9%, and 16.7%, respectively. Intraplaque hemorrhage (IPH) was detected in 20 (47.6%) patients. Multivariate analysis showed that age (odds ratio (OR), 0.87; p = 0.014), smoking (OR, 0.11; p = 0.033), and IPH regression (OR, 10.13; p = 0.027) were associated with stenosis regression. The progression of IPH (OR, 115.80; p = 0.007) was associated with stenosis progression. Results suggest that IPH on HR-MRI is associated with changes in cerebral atherosclerotic stenosis.

Clinical characteristics of medication-overuse headache according to the class of acute medication: A cross-sectional multicenter study.

OBJECTIVE: To characterize the clinical features of patients with medication-overuse headache (MOH) according to the class of acute medications being overused. BACKGROUND: MOH is a common global health problem, severely disabling the majority of the patients affected. Although various medications can cause MOH, whether clinical features differ according to the overused medication type remains unclear. METHODS: We analyzed data from a multicenter cross-sectional study in neurology clinics in Korea from April 2020 to June 2021. RESULTS: Among 229 eligible patients, MOH was documented in patients who overused multiple drug classes (69/229, 30.1%; most frequent occurrence), triptans (50/229, 21.8%), non-opioid analgesics (48/229, 21.0%), and combination-analgesics (40/229, 17.4%). Patients who overused multiple drug classes reported more frequent use of acute medications (median [25th-75th percentiles]: 25.0 [15.0-30.0] vs. 17.5 [10.0-25.5] days/month, p = 0.029) and fewer crystal-clear days (0.0 [0.0-9.5] vs. 9.0 [0.0-10.0] days/month, p = 0.048) than those who overused triptans. Patients who overused multiple drug classes also reported shorter intervals from chronic daily headache to the onset of MOH than patients who overused combination-analgesics (0.6 [0.2-1.9] vs. 2.4 [0.7-5.4] years, p = 0.001) or non-opioid analgesics (1.5 [0.6-4.3] years, p = 0.004). Patients who overused multiple drug classes reported more emergency room visits (1.0 [0.0-1.0] visits/year) than those who overused combination-analgesics (0.0 [0.0-1.0], p = 0.024) or non-opioid analgesics (0.0 [0.0-1.0], p = 0.030). Patients who overused triptans reported fewer headache days (21.0 [20.0-30.0] vs. 30.0 [20.5-30.0] days/month, p = 0.008) and fewer severe headache days (7.0 [4.0-10.0] vs. 10.0 [5.0-15.0] days/month, p = 0.017) than those who overused non-opioid analgesics. CONCLUSIONS: Some clinical characteristics of MOH significantly differed according to the class of overused medications. The findings from this study may contribute to the understanding of the clinical characteristics and pathophysiology of MOH.

Comparison of hepatotoxicity of tegoprazan, a novel potassium-competitive acid blocker, with proton pump inhibitors using real-world data: A nationwide cohort study.

Background: Proton pump inhibitors (PPIs) are acid suppressants that are frequently prescribed in many countries to reduce heartburn. A potassium-competitive acid blocker (P-CAB; tegoprazan) was launched relatively recently that also inhibits gastric acid secretion. This study aimed to compare the hepatotoxicity of the six existing PPIs with P-CAB. Methods: This retrospective cohort study was conducted between January 2019 and December 2020 and included data from the total population of 50 million inhabitants in Korea. Propensity score (PS) matching was performed using 10 variables, and the differences in hepatotoxicity between P-CAB and the six PPIs were compared in a similar distribution. The primary endpoint was hepatotoxicity which included toxic liver disease, hepatitis, hepatic failure, liver transplantation, and other liver diseases. Results: The risk ratios (RR) of tegoprazan vs. the six PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) were all significant [RR: 0.70 (95% CI: 0.69-0.72), 0.81 (95% CI: 0.79-0.83), 0.61 (95% CI: 0.59-0.63), 1.17 (95% CI: 1.13-1.20), 0.61 (95% CI: 0.59-0.62), and 0.73 (95% CI: 0.71-0.75), respectively]. The risk ratio of tegoprazan vs. the six existing PPIs was 0.73 (95% CI: 0.72-0.75). The hazard ratios (HRs) of hepatotoxicity of the six PPIs to tegoprazan showed significantly higher values apart from omeprazole (HR: dexlansoprazole, 1.13; esomeprazole, 1.04; lansoprazole, 1.25; omeprazole, 0.77; pantoprazole, 1.26; rabeprazole, 1.15, respectively, and the six existing PPIs, 1.10). Conclusion: Using a large-scale data cohort analysis consisting of 50 million Koreans, tegoprazan did not induce higher hepatotoxicity compared with the six conventional PPIs.

Treatment Patterns of Type 2 Diabetes Assessed Using a Common Data Model Based on Electronic Health Records of 2000-2019.

BACKGROUND: Real-world data analysis is useful for identifying treatment patterns. Understanding drug prescription patterns of type 2 diabetes mellitus may facilitate diabetes management. We aimed to analyze treatment patterns of type 2 diabetes mellitus using Observational Medical Outcomes Partnership Common Data Model based on electronic health records. METHODS: This retrospective, observational study employed electronic health records of patients who visited Jeonbuk National University Hospital in Korea during January 2000-December 2019. Data were transformed into the Observational Medical Outcomes Partnership Common Data Model and analyzed using R version 4.0.3 and ATLAS ver. 2.7.6. Prescription frequency for each anti-diabetic drug, combination therapy pattern, and prescription pattern according to age, renal function, and glycated hemoglobin were analyzed. RESULTS: The number of adults treated for type 2 diabetes mellitus increased from 1,867 (2.0%) in 2000 to 9,972 (5.9%) in 2019. In the early 2000s, sulfonylurea was most commonly prescribed (73%), and in the recent years, metformin has been most commonly prescribed (64%). Prescription rates for DPP4 and SGLT2 inhibitors have increased gradually over the past few years. Monotherapy prescription rates decreased, whereas triple and quadruple combination prescription rates increased steadily. Different drug prescription patterns according to age, renal function, and glycated hemoglobin were observed. The proportion of patients with HbA1c ≤ 7% increased from 31.1% in 2000 to 45.6% in 2019, but that of patients visiting the emergency room for severe hypoglycemia did not change over time. CONCLUSION: Medication utilization patterns have changed significantly over the past 20 years with an increase in the use of newer drugs and a shift to combination therapies. In addition, various prescription patterns were demonstrated according to the patient characteristics in actual practice. Although glycemic control has improved, the proportion within the target is still low, underscoring the need to improve diabetes management.

A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy: Results of the Korean South West Oncology Group (KSWOG) Study.

PURPOSE: Data on the efficacy of olanzapine in patients receiving moderately emetogenic chemotherapy (MEC) are limited. This study aimed to evaluate and compare the efficacy of olanzapine versus placebo in controlling nausea and vomiting in patients receiving MEC. MATERIALS AND METHODS: We conducted a randomized, double-blind, placebo-controlled study to determine whether olanzapine can reduce the frequency of chemotherapy-induced nausea and vomiting (CINV) and improve the quality of life (QOL) in patients receiving palonosetron and dexamethasone as prophylaxis for MEC-induced nausea and vomiting. The primary end point was complete response for the acute phase (0-24 hours after chemotherapy). The secondary end points were complete response for the delayed (24-120 hours) and overall phase (0-120 hours), proportion of significant nausea (visual analogue scale ≥ 25 mm), use ofrescue medications, and effect on QOL. RESULTS: Fifty-six patients were randomized to the olanzapine (n=29) and placebo (n=27) groups. Complete response rates were not significantly different between the olanzapine and placebo groups in the acute (96.5% vs. 88.0%, p=0.326), delayed (69.0% vs. 48.0%, p=0.118), and overall phases (69.0% vs. 48.0%, p=0.118). However, the percentage of patients with significant nausea (17.2% vs. 44.0%, p=0.032) and the use of rescue medications (0.03±0.19 vs. 1.88±2.88, p=0.002) were lower in the olanzapine group than in the placebo. Furthermore, the olanzapine group demonstrated better QOL (p=0.015). CONCLUSION: Olanzapine combined with palonosetron and dexamethasone significantly improved QOL and vomiting control among previously untreated patients receiving MEC, although the efficacy was limited to the reduction of the frequency of CINV.

Clinical Phenotype of Diabetic Peripheral Neuropathy and Relation to Symptom Patterns: Cluster and Factor Analysis in Patients with Type 2 Diabetes in Korea.

OBJECTIVES: Patients with diabetic peripheral neuropathy (DPN) is the most common complication. However, patients are usually suffering from not only diverse sensory deficit but also neuropathy-related discomforts. The aim of this study is to identify distinct groups of patients with DPN with respect to its clinical impacts on symptom patterns and comorbidities. METHODS: A hierarchical cluster analysis and factor analysis were performed to identify relevant subgroups of patients with DPN (n = 1338) and symptom patterns. RESULTS: Patients with DPN were divided into three clusters: asymptomatic (cluster 1, n = 448, 33.5%), moderate symptoms with disturbed sleep (cluster 2, n = 562, 42.0%), and severe symptoms with decreased quality of life (cluster 3, n = 328, 24.5%). Patients in cluster 3, compared with clusters 1 and 2, were characterized by higher levels of HbA1c and more severe pain and physical impairments. Patients in cluster 2 had moderate pain levels but disturbed sleep patterns comparable to those in cluster 3. The frequency of symptoms on each item of MNSI by "painful" symptom pattern showed a similar distribution pattern with increasing intensities along the three clusters. CONCLUSIONS: Cluster and factor analysis endorsed the use of comprehensive and symptomatic subgrouping to individualize the evaluation of patients with DPN.

An assessment of the pharmacokinetics of a sustained-release formulation of a tramadol/acetaminophen combination in healthy subjects.

PURPOSE: To provide consistent pain relief and improve convenient sustained release (SR), a fixed-dose combination tramadol/acetaminophen tablet was formulated. This study aimed to evaluate the pharmacokinetic profiles of an SR 75-mg tramadol/650-mg acetaminophen formulation after a single dose compared with an immediate release (IR) 37.5-mg tramadol/325-mg acetaminophen formulation after 2 doses and at steady state and to assess the effect of food on the pharmacokinetic SR formulation profile after a single dose. METHODS: Two clinical trials were conducted: (1) an open-label, randomized, 3-period, 3-treatment, crossover study to assess the pharmacokinetic SR (one 75-mg tramadol/650-mg acetaminophen combination tablet) formulation profiles after a single dose and IR (one 37.5-mg tramadol/325-mg acetaminophen combination tablet q6h for 2 doses) formulation profiles after 2 doses and the effect of food intake on healthy male subjects and (2) an open, randomized, 2-period, 2-treatment multiple dose crossover study to evaluate the steady-state pharmacokinetic SR and IR formulation profiles. Safety assessments were performed. FINDINGS: Forty-three subjects completed each study protocol. The SR combination tramadol/acetaminophen formulation was clinically and statistically equivalent to the IR combination formulation in the fasting state. When tramadol and acetaminophen tablets were administered with food, the time to peak plasma concentrations and the tramadol/acetaminophen absorption were unaffected. There was no serious adverse event reported. IMPLICATIONS: The SR combination tramadol/acetaminophen tablet exhibited similar exposure and absorption rates compared with those of the IR formulation of tramadol, O-desmethyltramadol, and acetaminophen. The SR formulation may be more convenient for patients and has the potential to enhance compliance and pain control. ClinicalTrials.gov identifier: NCT01880125.

Improvement in the Electrical Performance of Ge-Doped InZnO Thin-Film Transistor.

We fabricated amorphous oxide semiconductor thin-film transistors (TFTs) using Ge-doped InZnO (Ge-IZO) thin films as active-channel layers. The Ge-IZO thin films were deposited at room temperature by radio-frequency (RF) magnetron co-sputtering system, and then annealed in air for 1 h at 300 °C. Some processing parameters such as sputtering oxygen partial pressure [O2/(Ar + O2)] and sputtering power for GeO2 target were changed to investigate what was the optimal amount of Ge in the Ge-IZO active layer. A small concentration of Ge added to IZO by co-sputtering enhanced the carrier concentration, mobility, and conductivity; but further increase in Ge concentration degraded the device performance. In order to optimize the electrical properties of Ge-IZO TFTs, we tried to adjust the processing parameters and the best Ge-IZO TFT was obtained at a co-sputtering oxygen partial pressure of 2% and GeO2 target power of 10 W. The fabricated Ge-IZO TFT exhibited an on/off ratio of 3.0 x 10(7), a saturation mobility of 13.05 cm2/V·s, a subthreshold swing of 0.95 V/dec, and a threshold voltage of 0 V. XPS and XRD analyses of Ge-IZO films were performed to investigate the binding energies of atoms in Ge-IZO films and the crystallinity of the films. 90% transmittance of visible light was achieved, which makes the technology useful for transparent devices.

Effects of Double Active Layer and Acetic Acid Stabilizer on the Electrical Properties of a Solution-Processed Zinc Tin Oxide Thin-Film Transistor.

We investigated the effects of a double active layer (DAL) and acetic acid stabilizer on zinc tin oxide (ZTO) thin-film transistors (TFTs) fabricated using a solution process. The DAL was composed of two layers created by a ZTO solution doped with the same or different percentiles of an atomic Sn concentration (30 at.%, 60 at.%). The electrical performance of the ZTO TFTs significantly was improved after we added acetic acid (AA) instead of monoethanolamine (MEA). This was accomplished by applying a type 2 DAL (bottom layer: Sn 60 at.%, top layer: Sn 30 at.%, 60/30) instead of other types (30/30 or 60/60). It was demonstrated that AA plays a role in lowering the decomposition temperature, enhancing the metal-oxygen bridge, and decreasing hydroxyl groups in the film. In addition, the type 2 DAL structure (60/30) lowered the Ioff of the ZTO TFT and controlled the carrier concentration in the channel. The best performances were obtained at a Sn concentration of 60 at.% in the bottom ZTO layer and 30 at.% in the top ZTO layer, with AA added as a stabilizer. The ZTO TFT exhibited an on/off ratio of 1.1 x 10(9), a saturation mobility of 5.04 cm2/V·s, a subthreshold slope of 0.11 V/decade, and a threshold voltage of 1.6 V.

Pharmacokinetic properties of two erlotinib 150 mg formulations with a genetic effect evaluation in healthy Korean subjects.

BACKGROUND AND OBJECTIVE: Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor that acts on the epidermal growth factor receptor and inhibits cell proliferation, growth, migration, invasion and survival. This study was performed for the subsequent marketing of a test erlotinib formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy adult volunteers. METHODS: A total of 46 healthy male subjects were enrolled in a single-dose, randomized, open-label, two-period, two-sequence, crossover, bioequivalence study. During each treatment period, subjects received 150 mg of erlotinib in either the test or reference formulation. There was a 2-week washout period between each period. Blood samples were obtained 15 times during each period, before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral administration. Plasma concentrations of erlotinib were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C(max)), area under the plasma concentration-time curve to the last sampling time (AUC(t)), AUC from time zero to infinity (AUC(∞)), and time to reach C(max) (t(max)), were measured, and all treatment-emergent adverse events and their relationships with the study medications were recorded throughout the study. An additional analysis was performed to characterize the association between the cytochrome P450 (CYP) 1A1, CYP1A2 and CYP3A4 genotypes and the erlotinib pharmacokinetic parameters. RESULTS: A total of 41 subjects completed the study. There were no significant differences in the prevalence of adverse events between the two formulations, and there were no serious or unexpected adverse events during the study. Both formulations had very similar C(max), AUC, terminal half-life (t ½) and t(max) values. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 1.09 (0.98-1.22) for C(max) and 1.10 (1.01-1.21) for AUCt. Statistical significance was observed between the CYP1A2*1M genotype and the erlotinib pharmacokinetic parameter, particularly C(max) (p = 0.015). CONCLUSIONS: This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.

Pharmacokinetic properties of isosorbide-5-mononitrate under fasting and fed conditions in healthy male subjects.

OBJECTIVE: This study was performed to compare the pharmacokinetic properties and relative bioavailability of two isosorbide-5-mononitrate (5-ISMN) sustained-release drugs in healthy Korean subjects under fasting and fed conditions. METHODS: A total of 60 healthy volunteers (30 each in the fasting and fed arms of the study) were enrolled in the study and were randomized to treatment. After the administration of a single dose of one of the investigational products, blood samples were collected at specific time intervals from 0 to 36 hours. The plasma concentrations of 5-ISMN were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance on logarithmically transformed data. RESULTS: The corresponding 90% CIs of AUClast and Cmax for the test/reference geometric mean ratio were 90.75 - 98.44% and 92.28 - 98.33%, respectively, under fasting conditions. In the fed state study, the 90% CIs for the geometric mean ratio of test to reference drugs were 94.79 - 103.33% for AUClast and 99.86 - 108.02% for Cmax. CONCLUSION: The test product is equivalent to the reference product in subjects under fasting and fed conditions within the Korean regulatory bioequivalence criteria. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles between the test and reference drugs.

Pharmacokinetic comparison study of a combination containing 500 mg of Naproxen and 20 mg of Esomeprazole: a randomized, single-dose, 2-way crossover, open-label study in healthy Korean men.

PURPOSE: Nonsteroidal anti-inflammatory drugs have been used for analgesic, anti-inflammatory, and antithrombotic effects, but they carry a risk of major gastrointestinal damage. This risk can be greatly reduced by the coadministration of inhibitors of gastric acid secretion, such as proton pump inhibitors. This study was performed for the subsequent marketing of a combination drug that contained 500 mg of naproxen and 20 mg of esomeprazole in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy men. METHODS: A total of 60 healthy men were enrolled in this single-dose, randomized, open-label, 2-period, 2-sequence, crossover study. During each period, men received a combination of 500 mg of naproxen and 20 mg of esomeprazole for test or reference, and between each period, there was a 1-week washout period. Blood samples were obtained 21 times throughout each period before dosing and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, and 72 hours after oral administration. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic parameters, including Cmax, AUC0-t, AUC0-∞, and Tmax, were measured, and all treatment-emergent adverse events and their associations with the study medications were recorded throughout the entire study. FINDINGS: A total of 59 men completed the study. No significant differences were found in the prevalence of AEs between the 2 formulations. In addition, there were no serious or unexpected AEs during the study. Both formulations had very similar Cmax, AUC, and t½ values, but the Tmax of naproxen appeared earlier in the test formulation than in the reference formulation and that of esomeprazole appeared later in the test formulation than in the reference formulation. IMPLICATIONS: This study suggests that the test and reference formulations of a combination of 500 mg of naproxen and 20 mg of esomeprazole are bioequivalent in the extent of absorption and peak concentration. We anticipate that the test formulation will treat those who need relief from pain and inflammation and will decrease the risk of developing gastric ulcers. cris.nih.go.kr identifier: KCT0001117.

The validities and efficiencies of korean ADHD rating scale and korean child behavior checklist for screening children with ADHD in the community.

OBJECTIVE: The purpose of this study is to examine the validity of primary screening tools for attention deficit hyperactivity disorder (ADHD) in a community-based sample of children using the Korean version of the Child Behavior Checklist (K-CBCL) and the Korean version of the ADHD Rating Scale (K-ARS). METHODS: A large-scale community-based study for ADHD screening was conducted in the Jeollabuk province in the Republic of Korea. In 2010-2011, we surveyed a total of 49,088 first- and fourth-grade elementary school students. All of the participants in this study were assessed by the K-ARS-Parent version (K-ARS-P) and the K-ARS-Teacher version (K-ARS-T) as the primary screening instruments. The Diagnostic Interview Schedule for Children Version IV (DISC-IV) was used for confirming the diagnosis of ADHD. DISC-IV was administered to subjects who received top 10% scores in the K-ARS-P or K-ARS-T tests. RESULTS: Of the 3,085 subjects who completed the DISC-IV, 1,215 were diagnosed as having ADHD. A reasonable level of sensitivity, specificity, and negative predictive value were obtained when the total K-ARS-P scores were ≥90th percentile. The positive predictive value and specificity increased significantly when the total K-ARS-P scores were ≥90th percentile, T scores were ≥60 in the attention problems of K-CBCL, and T scores were ≥63 in the total problems of K-CBCL. CONCLUSION: These results suggested that the K-ARS-P could effectively serve as a primary screening tool to identify elementary school children with ADHD in the community. Also, there might be some increment in the effectiveness of K-ARS-P when combined with K-CBCL-A and K-CBCL-T as a secondary screening tool.

Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water.

OBJECTIVE: To compare the pharmacokinetic profiles and to assess bioequivalence of a newly developed orally soluble film formulation of sildenafil, taken without water, with those of a conventional formulation of sildenafil. METHODS: This study was conducted in a population of healthy subjects as an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to 1 of 2 sequences of the two formulations: an orally soluble film (OSF) of 50 mg sildenafil as the test drug and a film-coated tablet (FCT) of 50 mg sildenafil as the reference drug. Blood samples were collected at intervals from 0 to 24 hours after administration. Plasma concentrations of sildenafil and its active metabolite N-desmethyl sildenafil were analyzed using a liquid chromatography/tandem mass spectrometry method. RESULTS: 48 healthy male subjects completed the study. The geometric mean (CV%) for Cmax in the OSF and FCT formulations were 267.21 (4.68%) ng/mL and 285.97 (5.32%) ng/mL, respectively. The geometric mean for AUClast in the OSF and FCT formulations were 664.48 (4.40%) ng x h/mL and 647.96 (4.63%) ng x h/mL, respectively. The geometric mean for AUCinf in the OSF and FCT formulations were 685.65 (4.37%) ng x h/mL and 666.28 (4.60%) ng x h/ mL, respectively. The 90% confidence intervals of the ratios of the geometric means of the Cmax, AUClast, and AUCinf were 0.844 - 1.030, 0.961 - 1.091, and 0.965 - 1.093, respectively. CONCLUSIONS: The OSF sildenafil formulation exhibited no significant differences in its pharmacokinetics compared with those of the FCT formulation. Therefore this convenient OSF sildenafil formulation, which can be taken without the need for water or chewing, offers physicians a novel and attractive treatment option for men with erectile dysfunction. *These authors contributed equally to this work.

Comparison of the pharmacokinetics, safety, and tolerability of vitamin D3 in DP-R206 (150-mg ibandronate/24,000-IU vitamin D3 tablet) and as monotherapy (24,000 iu) in healthy male Korean adults.

BACKGROUND: Combined treatment with a bisphosphonate and vitamin D has been proposed for postmenopausal osteoporosis. A new, fixed-dose combination tablet of ibandronate plus vitamin D3 has been developed for monthly administration to treat postmenopausal osteoporosis. OBJECTIVES: The main objective of the present study was to compare the pharmacokinetics of vitamin D3 administered in 2 forms: a newly developed ibandronate 150-mg/vitamin D3 24,000-IU tablet (DP-R206, test drug) and a stand-alone vitamin D3 24,000-IU tablet (reference drug). A secondary objective was to evaluate the safety and tolerability of DP-R206 in healthy adult male Korean volunteers. METHODS: This study was a single-dose, open-label, randomized-sequence, 2-treatment, 2-way crossover trial. Blood samples were collected from 24 hours' predose to 120 hours' postdose. The plasma concentrations of vitamin D3 were analyzed by using a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated, and the 90% CIs of the ratios of the geometric means of the parameters were determined from the logarithmically transformed data by using ANOVA. RESULTS: Thirty-sex healthy adult male Korean volunteers with a mean (SD) age of 25.8 (2.7) years, a mean height of 174.0 (5.9) cm, and a mean weight of 69.1 (6.2) kg were enrolled; 29 participants completed the study. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-corrected Cmax, AUC0-last, and AUC0-∞ values were 0.93 to 1.24, 0.89 to 1.19, and 0.87 to 1.18, respectively. The 90% CIs of the ratios of the geometric means (test drug/reference drug) of the baseline-uncorrected Cmax, AUC0-last, and AUC0-∞ values were 0.93 to 1.24, 0.88 to 1.19, and 0.87 to 1.18, respectively. Eighty-four adverse events (AEs) were reported in 24 of 32 subjects receiving DP-R206, and 14 AEs were reported in 8 of 29 subjects receiving the vitamin D3 24,000-IU tablet. All of the subjects who experienced AEs recovered without sequelae, and no serious AEs were observed. CONCLUSIONS: The vitamin D3 pharmacokinetics were similar for DP-R206 and the 24,000-IU vitamin D3 tablet. DP-R206 was well tolerated.

Pharmacokinetic properties and bioequivalence of olmesartan medoxomil/hydrochlorothiazide in healthy Korean male subjects.

UNLABELLED: Olmesartan medoxomil inhibits the vasoconstrictor effects of angiotensin II. Hydrochlorothiazide (HCTZ) promotes sodium excretion, resulting in a reduction of plasma volume and peripheral resistance. A combination of these agents is known to have a greater effect for the treatment of hypertension than monotherapy with either one of these components. OBJECTIVE: To assess bioequivalence between fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide (HCTZ) in healthy Korean subjects. METHODS: 40 healthy Korean volunteers were randomized into two groups. After administration of a single dose of investigational products, blood samples were collected before study drug administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 36 hours after study drug administration. The plasma concentrations of olmesartan and HCTZ were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance (ANOVA) on logarithmically transformed data. RESULTS: The corresponding 90% CIs for the geometric mean ratio of the test to reference drugs were 0.93 - 1.04, 0.93 - 1.04, and 0.95 - 1.10. For HCTZ treatments, the 90% CIs for the geometric mean ratio of test to reference drugs were 0.95 - 1.03 for AUClast, 0.96 - 1.03 for AUC∞, and 0.89 - 1.04 for Cmax. CONCLUSION: This study demonstrated that the test and reference products met the regulatory criteria assuming bioequivalence. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles of the test and reference drugs.