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Hypertension and hyperlipidemia are often comorbid, requiring combination therapies of antihypertensive drugs and antihyperlipidemia drugs. Taking 1 fixed-dose combination (FDC) may increase patient compliance rather than taking each of the drugs separately. This study aimed to evaluate the pharmacokinetic bioequivalence between an FDC of pitavastatin/valsartan 4/160 mg and the corresponding individual components. Considering that valsartan is a highly variable drug for maximum plasma concentration (C

PURPOSE: Neutralizing antibodies can reduce SARS-CoV-2 cellular entry, viral titers, and pathologic damage. CT-P59 (regdanvimab), a SARS-CoV-2 neutralizing monoclonal antibody, was examined in 2 randomized, double-blind, placebo-controlled, single ascending dose, Phase I studies. METHODS: In study 1.1, healthy adults were sequentially enrolled to receive CT-P59 10, 20, 40, or 80 mg/kg or placebo. In study 1.2, adult patients with mild SARS-CoV-2 infection were enrolled to receive CT-P59 20, 40, or 80 mg/kg or placebo. Primary objectives of both studies were safety and tolerability up to day 14 after infusion. Secondary end points included pharmacokinetic properties. Study 1.2 also measured virology and clinical efficacy. FINDINGS: Thirty-two individuals were randomized to study 1.1 (6 per CT-P59 dose cohort and 8 in the placebo cohort). By day 14 after infusion, adverse events (AEs) were reported in 2 individuals receiving CT-P59 20 mg/kg (headache and elevated C-reactive protein levels) and 1 receiving CT-P59 40 mg/kg (pyrexia) (all Common Terminology Criteria for Adverse Events grade 1). In study 1.2, 18 patients were randomized (5 per dose cohort and 3 in the placebo cohort). Sixteen AEs were reported in 10 patients receiving CT-P59. No AEs in either study led to study discontinuation. Greater reductions in viral titers were reported with CT-P59 than placebo in those with maximum titers >105 copies/mL. Mean time to recovery was 3.39 versus 5.25 days. IMPLICATIONS: CT-P59 exhibited a promising safety profile in healthy individuals and patients with mild SARS-CoV-2 infection, with potential antiviral and clinical efficacy in patients with mild SARS-CoV-2 infection. ClinicalTrials.gov identifier: NCT04525079 (study 1.1) and NCT04593641 (study 1.2).

The activation of receptor-interacting protein kinase 1 (RIPK1) by death-inducing signaling complex (DISC) formation is essential for triggering the necroptotic mode of cell death under apoptosis-deficient conditions. Thus, targeting the induction of necroptosis by modulating RIPK1 activity could be an effective strategy to bypass apoptosis resistance in certain types of cancer. In this study, we screened a series of arborinane triterpenoids purified from Rubia philippinesis, and identified rubiarbonol B (Ru-B) as a potent DISC-mediated caspase-8 activator. Ru-B elicited both the apoptotic and necroptotic modes of cell death, depending on the cellular expression of RIPK3. In RIPK3-expressing human colorectal cancer (CRC) cells, and the pharmacological or genetic inhibition of caspase-8 was sufficient to cause a switch in cell death mode from apoptosis to necroptosis following Ru-B treatment by necrosome formation which accompanied by the upregulation of RIPK1 phosphorylation. Conversely, Ru-B-induced cell death was almost completely abrogated by RIPK1 deficiency. The enhanced RIPK1 phosphorylation and necroptosis triggered by Ru-B treatment occurred independently of tumor necrosis factor receptor signaling, and was mediated by the production of reactive oxygen species via NADPH oxidase 1 in CRC cells. Thus, we propose Ru-B as a novel anticancer agent that enhances the cytotoxic potential of RIPK1, prompting the further development of Ru-B as a necroptosis-targeting compound in apoptosis-resistant CRC.

This study aimed to demonstrate pharmacokinetic (PK) equivalence of a single dose of the proposed adalimumab biosimilar CT‐P17 to United States‐licensed adalimumab (US‐adalimumab) and European Union‐approved adalimumab (EU‐adalimumab). This double‐blind, parallel‐group, phase I trial (clinicaltrials.gov NCT03970824) was conducted at 10 hospitals (Republic of Korea), in which healthy subjects (1:1:1) were randomized to receive a single 40 mg (100 mg/ml) subcutaneous injection of CT‐P17, US‐adalimumab, or EU‐adalimumab. Primary end points were PK equivalence in terms of: area under the concentration–time curve from time zero to infinity (AUC0–inf); AUC from time zero to the last quantifiable concentration (AUC0–last); and maximum serum concentration (Cmax). PK equivalence was concluded if 90% confidence intervals (CIs) for percent ratios of geometric least squares means (GLSMs) for pairwise comparisons were within the equivalence margin of 80–125%. Additional PK end points, safety, and immunogenicity were evaluated. Of the 312 subjects who were randomized (103 CT‐P17; 103 US‐adalimumab; 106 EU‐adalimumab), 308 subjects received study drug. AUC0–inf, AUC0–last, and Cmax were equivalent among CT‐P17, US‐adalimumab, and EU‐adalimumab, because 90% CIs for the ratios of GLSMs were within the 80–125% equivalence margin for each pairwise comparison. Secondary PK end points, safety, and immunogenicity were similar between treatment groups. In conclusion, PK equivalence for single‐dose administration of CT‐P17, EU‐adalimumab, and US‐adalimumab was demonstrated in healthy adults. Safety and immunogenicity profiles were comparable between treatment groups and consistent with previous reports for adalimumab biosimilars.

Histamine acts by binding to four histamine receptors (H1 to H4), of which the H1 is known to participate in dilate blood vessels, bronchoconstriction, and pruritus. Olopatadine hydrochloride blocks the release of histamine from mast cells and it inhibits H1 receptor activation. Olopatadine hydrochloride is anti-allergic agent that is effectively used. The object of this study had conducted to compare the pharmacokinetics (PKs) and safety characteristics between olopatadine hydrochloride 5 mg (test formulation) and olopatadine hydrochloride 5 mg (reference formulation; Alerac ®) in Korean subjects. This study had conducted an open-label, randomized, fasting condition, single-dose, 2-treatment, 2-period, 2-way crossover. Subjects received single-dosing of reference formulation or test formulation in each period and blood samples were collected over 24 hours after administration for PK analysis. A wash-out period of 7 days was placed between the doses. Plasma concentration of olopatadine were determined using liquid chromatography-tandem spectrometry mass (LC-MS/MS). A total of 32 subjects were enrolled and 28 subjects completed. There were not clinical significantly different in the safety between two treatment groups for 32 subjects who administered the study drug more than once. The geometric mean ratio of test formulation to reference formulation and its 90% confidence intervals for The peak plasma concentration (Cmax) and the areas under the plasma concentration-time curve from 0 to the last concentration (AUClast) were 1.0845 (1.0107-1.1637) and 1.0220 (1.0005-1.0439), respectively. Therefore, the test formulation was bioequivalent in PK characteristics and was equally safe as the reference formulation. Trial registration Clinical Research Information Service Identifier: KCT0005943.

Purpose Gastric cancer (GC) is one of the most common cancers in the world. Recently, several studies have suggested that single-nucleotide polymorphisms (SNPs) of long noncoding RNA (lncRNA) are associated with GC risk. However, the association of the lncRNA highly upregulated in liver cancer (HULC) SNP with GC risk is not yet known. The aims of this study were to evaluate the association between HULC rs7763881 SNP and the risk of GC and GC subgroups via a case-control study. Patients and methods rs7763881 was genotyped using TaqMan genotyping assay with 459 GC patients and 379 controls. Results A significant association between HULC rs7763881 SNP and GC risk was not found. However, after adjustment for age and gender, the rs7763881 recessive model (CC) showed a significant association with an increased GC risk in the undifferentiated (odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17-2.94, P = 0.009), diffuse-type GC (OR = 1.72, 95% CI = 1.05-2.82, P = 0.033), LNM-positive (OR = 2.02, 95% CI = 1.24-3.27, P = 0.004), T3/T4 (OR = 1.75, 95% CI = 1.05-2.91, P = 0.032), and tumor stage III (OR = 2.01, 95% CI = 1.17-3.45, P = 0.011) subgroups when compared to the rs7763881 combined genotypes (AA+AC). Furthermore, after adjusting for age and gender, the rs7763881 additive model (CC) indicated a significantly higher GC risk than rs7763881 AA genotype in the undifferentiated (OR = 1.96, 95% CI = 1.15-3.32, P = 0.013), diffuse-type GC (OR = 2.08, 95% CI = 1.23-3.52, P = 0.004), and LNM-positive (OR = 2.00, 95% CI = 1.14-3.49, P = 0.016) subgroups. Conclusion Our findings suggest that the HULC rs7763881 SNP is associated with increased susceptibility to GC. However, further studies are required to validate our results in large populations as well as different ethnic groups.

UI026 is an expectorant and antitussive agent which is a new combination ofClinical Research Information Service Identifier: KCT0003451.

Genetic polymorphisms of plasmacytoma variant translocation 1 can affect various tumors including gastro-intestinal, sexual hormone sensitive cancers and lymphoma. Accumulated evidence have shown that plasmacytoma variant translocation 1 acts as an oncogene and tumor suppressor in various cancers. In fact, the rs13255292 and rs2608053 single nucleotide polymorphisms of plasmacytoma variant translocation 1are known to affect lymphoma; however, their effects on gastric cancer are primarily unknown. In this study, we evaluated the association between these plasmacytoma variant translocation 1 polymorphisms and the risk of gastric cancer.In the present study, 462 patients diagnosed with gastric cancer and 377 cancer-free controls were enrolled. The TaqMan genotyping assay was used to analyze the association between rs13255292 and rs2608053 single nucleotide polymorphisms and the risk of gastric cancer.The rs2608053 dominant model (CT + TT) was associated with a decreased risk of gastric cancer in T3 + T4 (odds ratio [OR] = 0.61, confidence interval (CI) = 0.41 - 0.92, P = .019), and stage III Gastric cancer subgroups (OR = 0.59, 95% CI = 0.38 - 0.91, P = .017) compared to the CC genotype. When stratified analysis by sex was carried out, the rs13255292 dominant model (CT + TT) had a significant association with an increased risk of gastric cancer in the female negative lymph node metastasis gastric cancer subgroup, compared to the CC genotype (OR = 1.96, 95% CI = 1.16 - 3.30, P = .012). The recessive model (TT) of rs13255292 was associated with an increased risk of gastric cancer in the male T3 + T4 gastric cancer subgroups compared to the CC + CT genotype (OR = 3.82, 95% CI = 1.02 - 14.33, P = .047). The dominant model (CT + TT) of rs2608053 was related to a decreased risk of gastric cancer in male T3 + T4 (OR = 0.57, 95% CI = 0.33 - 0.98, P = .042) and stage III gastric cancer subgroups (OR = 0.49, 95% CI = 0.27 - 0.89, P = .020) compared to the CC genotype.The rs13255292 and rs2608053 single nucleotide polymorphisms in plasmacytoma variant translocation 1 may contribute to susceptibility of gastric cancer. Further studies with more subjects and different ethnic groups are needed to validate our results.

Purpose This study was performed to compare the pharmacokinetic properties and assess bioequivalence for the test formulation (HUG116 tablet; tenofovir disoproxil) and reference formulation (Viread tablet; tenofovir disoproxil fumarate). Materials and methods A randomized, open-label, single-dosing, two-treatment, two-period, two-sequence cross-over study was conducted in 50 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for pharmacokinetic evaluation were collected up to 72 hours post dose, and the pharmacokinetic parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. Results The test formulation showed similar pharmacokinetic profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (Cmax) was 0.93 (0.87 - 0.99), and the corresponding value for the area under the concentration-time curve from time zero to time of last quantifiable concentration (AUCt) was 0.94 (0.89 - 0.99). Both CIs were within the conventional bioequivalence range of 0.8 - 1.25. The tolerability profile was not significantly different between the test and reference formulations. Conclusion This study found that the PKs of the test formulation (HUG116 tablet; tenofovir disoproxil) and reference formulation (Viread tablet; tenofovir disoproxil fumarate) were similar, and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation.

Background Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) drives tumorigenesis of various human cancers. However, the association between MALAT1 variants and gastric cancer (GC) risk is unknown. We performed a case‐control study to evaluate the possible association between rs619586 and rs3200401 SNPs in MALAT and GC risk. Methods Samples from 458 patients with GC and 381 controls were genotyped using the TaqMan genotyping assay. Results In stratified analyses, we observed that rs3200401 CT in the codominant model and CT+TT in the dominant model were associated with increased GC risk in male patients (CT: odds ratio [OR] = 1.81, 95% confidence interval [CI] = 1.09–3.01, p = 0.022; CT+TT: OR = 1.74, 95% CI = 1.07–2.83, p = 0.026), and the differentiated (CT: OR =1.79, 95% CI = 1.18–2.73, p = 0.007; CT+TT: OR = 1.76, 95% CI = 1.17–2.64, p = 0.007), and intestinal (CT: OR = 1.67, 95% CI = 1.11–2.49, p = 0.013; CT+TT: OR = 1.68, 95% CI = 1.14–2.47, p = 0.009) GC subgroups. Conclusion MALAT1 rs3200401 increases GC susceptibility and might affect GC development. Further studies are needed to validate our results in large populations and different ethnic groups., Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) drives tumorigenesis of various human cancers. We performed a case‐control study with 458 patients with GC and 381 controls. we found that rs3200401 CT in the codominant model and CT+TT in the dominant model were associated with increased GC risk in male patients, and the differentiated and intestinal GC subgroups.

A fixed-dose combination (FDC) formulation of bazedoxifene 20 mg and cholecalciferol 8 mg was developed to increase medication compliance and convenience for osteoporosis patients. This study was conducted to demonstrate bioequivalence by comparing the pharmacokinetic (PK) profiles and tolerability of an FDC tablet and the individual component tablets. A randomized, open-label, single-dosing, 2-treatment, 2-period, 2-sequence crossover study was conducted in 52 healthy subjects. All subjects were randomly assigned to 2 sequences, and they received FDC tablets of bazedoxifene and cholecalciferol and individual component tablets. Serial blood samples for PK evaluation were collected up to 24 hours predose and 120 hours postdose, and the PK parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. Of the enrolled 52 subjects, 47 subjects completed the study. The results, the geometric mean ratios (GMRs) and 90% confidence intervals (90%CIs), of bazedoxifene Cmax and AUC0-t for FDC to single entities given together were 0.98 (0.91-1.05) and 1.02 (0.97-1.07), respectively. The GMRs (90%CIs) of cholecalciferol Cmax and AUC0-t for FDC to single entities given together were 0.96 (0.91-1.00) and 0.94 (0.90-0.99), respectively. Overall, the GMRs (90%CIs) of the PK parameter of bazedoxifene and cholecalciferol fell within the conventional bioequivalence range of 0.8-1.25. There were no clinically significant differences in the safety profile between the 2 treatments. In conclusion, this study confirmed the development of a new FDC drug by demonstrating that the FDC formulation of bazedoxifene and cholecalciferol is biologically equivalent to the coadministered individual formulations.

Gastric cancer is one of the leading causes of cancer-associated death; however, analysis of its molecular and clinical characteristics has been complicated by its histological and etiological heterogeneity. The present study aimed to estimate somatic mutation profiling in gastric cancer. To do so, targeted next-generation sequencing (NGS) was performed with the Oncomine Focus Assay to compare the clinicopathological characteristics with the mutation profiles in 50 patients with advanced gastric cancer (AGC). Among the 35 hotspot genes and 19 genes for copy number variations (CNVs), 18 single nucleotide variants (SNVs) or small insertions and deletions (14 missense and four frameshift mutations), and 10 amplifications were identified. To examine the association between mutation profiles and clinicopathological characteristics, each element of the clinicopathological characteristics was categorized into three groups: No alteration, PI3K catalytic subunit α (PIK3CA) alterations and alterations other than PIK3CA. Fisher's exact test identified no statistical differences between the clinicopathological characteristics, with the exception of the Tumor-Node-Metastasis (TNM) T stage between the three groups. Cases of AGC with somatic alterations but no PIK3CA exhibited a significant difference in the TNM T stage compared with those with no alterations or PIK3CA alterations (P=0.044). In addition, AGC with PIK3CA alterations was categorized by Lauren's classification to the intestinal type only. The distribution of Lauren's classification in AGC with PIK3CA alterations was statistically different compared with AGC with alterations other than PIK3CA (P=0.028), but not compared with AGC with no alterations (P=0.076). In conclusion, the present study demonstrated a molecular profiling approach that identified potential molecular classifications for gastric cancer and suggested a framework for precision medicine in AGC.

Bazedoxifene, used as bazedoxifene acetate, is a selective estrogen receptor modulator that selectively affects the uterus, breast tissue, bone metabolism, and lipid metabolism by antagonizing or enhancing estrogens in the estrogen receptor in the tissue. This study was conducted as an open, randomized, two-period, two-treatment, crossover design to compare the pharmacokinetic (PK) characteristics and tolerability of two bazedoxifene tablets when administered to 50 healthy Korean male volunteers. Enrolled subjects were randomly allocated to 2 sequences of a single oral administration of a test drug and a reference drug, or vice versa with a 14-day washout period between the two doses. Serial blood samples were collected over 96 h for PK analysis. Plasma concentration of bazedoxifene was assayed using liquid chromatography-tandem spectrometry mass. Forty-five participants completed the study with no clinically relevant safety issues. The peak concentrations (Cmax, mean ± strandard deviation) of reference drug and test drug were 3.191 ± 1.080 and 3.231 ± 1.346 ng/mL, respectively, and the areas under the plasma concentration-time curve from 0 to the last measurable concentration (AUClast) were 44.697 ± 21.168 ng∙h/mL and 45.902 ± 23.130 ng∙h/mL, respectively. The geometric mean ratios of test drug to reference drug and their 90% confidence intervals for Cmax and AUClast were 0.9913 (0.8828-1.1132) and 1.0106 (0.9345-1.0929), respectively. The incidence of adverse events between the two formulations was similar. The present study showed that PK and tolerability of two bazedoxifene tablet formulations were comparable when administered to healthy Korean male volunteers. Trial registration Clinical Research Information Service Identifier: KCT0003978.

Purpose Gastric cancer (GC) is one of the most common cancers in the world. Recently, several studies have suggested that single-nucleotide polymorphisms (SNPs) of long noncoding RNA (lncRNA) are associated with GC risk. However, the association of the lncRNA highly upregulated in liver cancer (HULC) SNP with GC risk is not yet known. The aims of this study were to evaluate the association between HULC rs7763881 SNP and the risk of GC and GC subgroups via a case–control study. Patients and Methods rs7763881 was genotyped using TaqMan genotyping assay with 459 GC patients and 379 controls. Results A significant association between HULC rs7763881 SNP and GC risk was not found. However, after adjustment for age and gender, the rs7763881 recessive model (CC) showed a significant association with an increased GC risk in the undifferentiated (odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17–2.94, P = 0.009), diffuse-type GC (OR = 1.72, 95% CI = 1.05–2.82, P = 0.033), LNM-positive (OR = 2.02, 95% CI = 1.24–3.27, P = 0.004), T3/T4 (OR = 1.75, 95% CI = 1.05–2.91, P = 0.032), and tumor stage III (OR = 2.01, 95% CI = 1.17–3.45, P = 0.011) subgroups when compared to the rs7763881 combined genotypes (AA+AC). Furthermore, after adjusting for age and gender, the rs7763881 additive model (CC) indicated a significantly higher GC risk than rs7763881 AA genotype in the undifferentiated (OR = 1.96, 95% CI = 1.15–3.32, P = 0.013), diffuse-type GC (OR = 2.08, 95% CI = 1.23–3.52, P = 0.004), and LNM-positive (OR = 2.00, 95% CI = 1.14–3.49, P = 0.016) subgroups. Conclusion Our findings suggest that the HULC rs7763881 SNP is associated with increased susceptibility to GC. However, further studies are required to validate our results in large populations as well as different ethnic groups.

An extended-release (ER) fixed-dose combination (FDC) of tramadol 37.5 mg/acetaminophen 325 mg was developed due to the demand for varying dosages. This study aimed to evaluate the pharmacokinetics (PKs) for two tablets of the new developed tramadol 37.5 mg/acetaminophen 325 mg ER FDC (DW-0920, Wontran Semi ERClinicalTrials.gov Identifier: NCT01606059.

The most common therapy for estrogen receptor–positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G2–M phase of the cell cycle. We assessed Plk1 expression in five chemoresistant cancer cell types and found that Plk1 and its downstream phosphatase Cdc25c were selectively overexpressed in tamoxifen-resistant MCF-7 (TAMR-MCF-7) breast cancer cells. Real-time monitoring of cell proliferation also showed that TAMR-MCF-7 cells were more sensitive to inhibition of cell proliferation by the ATP-competitive Plk1 inhibitor BI2536 than were the parent MCF-7 cells. Moreover, BI2536 suppressed expression of epithelial–mesenchymal transition marker proteins and 3D spheroid formation in TAMR-MCF-7 cells. Using TAMR-MCF-7 cell–implanted xenograft and spleen–liver metastasis models, we showed that BI2536 inhibited tumor growth and metastasis in vivo. Our results suggest that Plk1 could be a novel target for the treatment of tamoxifen-resistant breast cancer. Mol Cancer Ther; 17(4); 825–37. ©2018 AACR.

Soyoung Lee,1,* Kyu-Yeol Nam,2,3,* Jaeseong Oh,1 SeungHwan Lee,1 Sang-Min Cho,3 Youn-Woong Choi,3 Joo-Youn Cho,1 Beom-Jin Lee,2,4,* Jang Hee Hong5,* 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2College of Pharmacy, Ajou University, Suwon, Republic of Korea; 3Korea United Pharm Inc., Seoul, Republic of Korea; 4Institute of Pharmaceutical Science and Technology, Ajou University, Suwon, Republic of Korea; 5Department of Pharmacology, Chungnam National University Hospital and College of Medicine, Daejeon, Republic of Korea *These authors contributed equally to this work Background: Levodropropizine is a non-opioid antitussive agent that inhibits cough reflex by reducing the release of sensory peptide in the peripheral region. To improve patients’ compliance, a controlled-release (CR) tablet is under development. The aim of this study was to compare the pharmacokinetic (PK) profiles of the CR and immediate-release (IR) tablets of levodropropizine. In addition, the effect of food on the PK properties of levodropropizine CR tablet in healthy subjects was evaluated.Subjects and methods: A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence, crossover study was conducted on 47 healthy subjects. All subjects were randomly assigned to one of the six sequences, which involve combinations of the following three treatments: levodropropizine IR 60mg three times in the fasted state (R), levodropropizine CR 90mg two times in the fasted state (T), and levodropropizine CR 90mg two times in the fed state (TF). Serial blood samples were collected up to 24h after the first dose. Tolerability was assessed based on the vital signs, adverse events (AEs), and clinical laboratory tests.Results: Levodropropizine CR showed lower maximum drug concentration (Cmax) and similar total exposure compared to levodropropizine IR. The geometric mean ratios (GMRs) (90% confidence intervals [CIs]) of T to R for the Cmax and area under the concentration–time curve from the 0 to 24h time points (AUC0–24h) were 0.80 (0.75–0.85) and 0.89 (0.86–0.93), respectively. In the fed group, levodropropizine CR showed exposure similar to that in the fasted group. The GMRs (90% CIs) of TF to T for the Cmax and AUC0–24h were 0.90 (0.85–0.97) and 1.10 (1.05–1.14), respectively. No serious AEs occurred with both levodropropizine CR and IR tablets.Conclusion: Total systemic exposure for levodropropizine was similar in subjects receiving the CR and IR formulations in terms of the AUC. Although food delayed the absorption of levodropropizine CR, systemic exposure was not affected. Keywords: pharmacokinetics, controlled-release, immediate-release, food effect

Sang-In Park,1,* Su-Hak Heo,2,3,* Gihwan Kim,2 Seokhoon Chang,2 Keon-Hyoung Song,3 Min-Gul Kim,4 Eun-Heui Jin,5 JaeWoo Kim,5 SeungHwan Lee,1 Jang Hee Hong5,6 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2R&D Center, C.L. Pharm Co., Ltd, Seoul, Republic of Korea; 3Department of Pharmaceutical Engineering, College of Medical Science, Soonchunhyang University, Asan, Republic of Korea; 4Department of Pharmacology, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea; 5Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea; 6Department of Pharmacology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea *These authors contributed equally to this work Background: An orodispersible film (ODF) of tadalafil may provide increased convenience for erectile dysfunction (ED) patients as compared to conventional tablet formulations. In this study, we aimed to compare the pharmacokinetic, safety, and tolerability profiles of a newly developed ODF formulation of tadalafil to those of a film-coated tablet (FCT) of tadalafil.Materials and methods: This study was conducted in healthy male subjects using an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to one of two sequences of the two formulations: both the test drug (ODF) and the reference drug (FCT) contained 20 mg of tadalafil. Blood samples were collected up to 72 h after administration. Plasma concentrations of tadalafil were analyzed using liquid chromatography–tandem mass spectrometry. Geometric mean ratios (GMRs) of the ODF to FCT formulations and their 90% CIs for the pharmacokinetic parameters were estimated. Safety and tolerability were assessed throughout the study.Results: Forty healthy male subjects were enrolled, and 36 of these completed the study. The GMRs (90% CIs) of the maximum plasma concentration and the area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration for tadalafil were 0.927 (0.882–0.974) and 0.972 (0.918–1.029), respectively. Both ODF and FCT formulations were well tolerated, and no clinically significant changes from the baseline were observed after dosing.Conclusion: The pharmacokinetics of the tadalafil ODF formulation did not differ significantly from those of the FCT formulation. Furthermore, the safety and tolerability profiles of the ODF formulation were comparable to those of the FCT formulation. Therefore, this tadalafil ODF formulation offers a convenient treatment option for patients with erectile dysfunction. Keywords: erectile dysfunction, orodispersible film, tadalafil, pharmacokinetics

Accumulating evidence indicates that mitochondrial DNA alterations contribute to cancer development and progression. In this study, we evaluated the relationship between polymorphisms of mitochondrial NADH dehydrogenase subunit 3 (MTND3) and the risk of gastric cancer (GC). Five single nucleotide polymorphisms (SNPs; rs28358278, rs2853826, rs201397417, rs41467651, and rs28358275) were identified and genotyped in 377 patients with GC patients and 363 controls by direct sequencing. The rs41467651 T allele was significantly associated with GC risk [adjusted odds ratio (OR) = 2.11, 95% confidence interval (CI) = 1.25-3.55, P = 0.005). In stratified analysis, rs28358278, rs2853826, and rs41467651 were associated with subgroups of GC, with the rs28358278 G, rs2853826 T, and rs41467651 T alleles associated with an increased GC risk in females (adjusted OR = 1.70, 95% CI = 1.08-2.69, P = 0.023; adjusted OR = 1.78, 95% CI = 1.11-2.85, P = 0.016; adjusted OR = 2.07, 95% CI = 1.04-4.12, P = 0.038, respectively). The rs441467651 T allele was also related with GC risk in diffuse-type subjects compared to that of controls (adjusted OR = 2.61, 95% CI = 1.43-4.89, P = 0.002). In addition, The rs441467651 T allele was significantly related with increased GC risk regardless of lymph node metastasis (LNM), T classification, and tumor stage compared to that of controls (adjusted OR = 2.00, 95% CI = 1.12-3.55, P = 0.019 in LNM-negative subjects; adjusted OR = 2.10, 95% CI = 1.05-4.22, P = 0.0379 in LNM-positive subjects; adjusted OR = 1.82, 95% CI = 1.02-3.24, P = 0.042 in T1/T2 subjects; adjusted OR = 2.60, 95% CI = 1.29-5.24, P = 0.007 in T3/T4 subjects; adjusted OR = 1.91, 95% CI = 1.09-3.34, P = 0.025 in tumor stage I (A+B)/II (A+B+C) subjects; adjusted OR = 2.36, 95% CI = 1.12-5.13, P = 0.025 in tumor stage III (A+B+C) subjects) compared to that of controls. Our findings suggest that the rs28358278, rs2853826, and rs41467651 polymorphisms of MTND3 increase the susceptibility to GC development.

DNA methylation is an important epigenetic modification that alters gene expression; DNA hypomethylation contributes to tumorigenesis through multiple processes. In the present study, the methylation of long interspersed element-1 (LINE-1) in 95 gastric cancer (GC) tissues and matched adjacent normal tissues was investigated by pyrosequencing. LINE-1 methylation was compared with the expression of ubiquitin-like with PHD and ring-finger protein 1 (UHRF1), an essential regulator of DNA methylation, using reverse transcription-quantitative polymerase chain reaction. Significant hypomethylation of LINE-1 and overexpression of UHRF1 were observed in GC tissues compared with the matched controls (P

The root of Asparagus cochinchinensis (Lour.) Merr. has been utilized as mucoregulators and expectorants for controlling the airway inflammatory diseases in folk medicine.We investigated whether dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis (Lour.) Merr. suppress the gene expression and production of airway MUC5AC mucin induced by phorbol ester and growth factor.Confluent NCI-H292 cells were pretreated with dioscin or methylprotodioscin for 30 min and then stimulated with EGF or PMA for 24 h. The MUC5AC mucin gene expression was measured by RT-PCR. Production of MUC5AC mucin protein was measured by ELISA.(1) Dioscin and methylprotodioscin suppressed the expression of MUC5AC mucin gene induced by EGF or PMA; (2) dioscin suppressed the production of MUC5AC mucin induced by either EGF at 10(-5) M (p0.05) and 10(-6) M (p0.05) or PMA at 10(-4) M (p0.05), 10(-5) M (p0.05) and 10(-6) M (p0.05); (3) methylprotodioscin also suppressed the production of MUC5AC mucin induced by either EGF at 10(-4) M (p0.05) or PMA at 10(-4) M (p0.05).These results suggest that dioscin and methylprotodioscin isolated from the root of Asparagus cochinchinensis suppress the gene expression and production of MUC5AC mucin, by directly acting on airway epithelial cells, and the results are consistent with the traditional use of Asparagus cochinchinensis as remedy for diverse inflammatory pulmonary diseases.

In this study, we investigated whether natural products including coixol derived from Coix Lachryma-Jobi var. ma-yuen affect MUC5AC mucin gene expression, production and secretion from airway epithelial cells. Confluent NCI-H292 cells were pretreated with oleic acid, linoleic acid, glyceryl trilinoleate, beta-stigmasterol or coixol for 30 min and then stimulated with PMA (phorbol 12-myristate 13-acetate), EGF (epidermal growth factor) or TNF-α (tumor necrosis factor-α) for 24 h. The MUC5AC mucin gene expression, mucin protein production and secretion were measured by RT-PCR and ELISA. The results were as follows: (1) Oleic acid, linoleic acid, glyceryl trilinoleate, beta-stigmasterol and coixol inhibited the expression of MUC5AC mucin gene induced by PMA from NCI-H292 cells; (2) Oleic acid, linoleic acid, glyceryl trilinoleate, beta-stigmasterol and coixol also inhibited the production of MUC5AC mucin protein induced by the same inducers from NCI-H292 cells; (3) Coixol inhibited the expression of MUC5AC mucin gene and production of MUC5AC mucin protein, induced by EGF or TNF-α from NCI-H292 cells; (4) Coixol decreased PMA-induced MUC5AC mucin secretion from NCI-H292 cells. This result suggests that coixol, the characteristic component among the examined five natural products derived from C. Lachryma-Jobi var. ma-yuen, can regulate gene expression, production and secretion of mucin, by directly acting on airway epithelial cells.

We investigated whether aqueous extract of the root of Platycodon grandiflorum A. de Candolle (APG), platycodinD(3) and deapi-platycodin significantly affect the production and secretion of airway mucin using in vivo and in vitro experimental models. Effect of APG was checked on hypersecretion of pulmonary mucin in sulfur dioxide-induced bronchitis in rats. Confluent NCI-H292 cells were pretreated with platycodinD(3) or deapi-platycodin for 30min and then stimulated with PMA (phorbol 12-myristate 13-acetate) for 24h. The MUC5AC mucin production and secretion were measured by ELISA. The results were as follows: (1) APG stimulated the secretion of airway mucin in sulfur dioxide-induced bronchitis rat model; (2) platycodinD(3) and deapi-platycodin inhibited the production of MUC5AC mucin induced by PMA from NCI-H292 cells, respectively; (3) however, platycodinD(3) and deapi-platycodin did not inhibit but stimulated the secretion of MUC5AC mucin induced by PMA from NCI-H292 cells, respectively. This result suggests that aqueous extract of P. grandiflorum A. de Candolle and the two natural products derived from it, platycodinD(3) and deapi-platycodin, can regulate the production and secretion of airway mucin and, at least in part, explains the traditional use of aqueous extract of P. grandiflorum A. de Candolle as expectorants in diverse inflammatory pulmonary diseases.

Aims The 3-phosphoinositide-dependent protein kinase-1 (PDK1) activates a number of protein kinases of the AGC subfamily, including protein kinase B and ribosomal S6 protein kinase by phosphorylating these kinases at the activation-loop. PDK1 activity is regulated by auto-phosphorylation and is further increased by stimulation of cells. PDK1 has been shown to have several phosphorylation sites including 5 serine and 3 tyrosine residues. However, Ser241 and Tyr373/376 are only involved in the regulation of PDK1 activity. Main methods In this study, we found the putative fragments of PDK1 by using anti-Myc and anti-PDK1 antibodies. Furthermore, the existence of four different sizes of PDK1 were confirmed with other phosphosite specific antibodies. Key findings Taken together, the catalytic domain of PDK1 (42 kDa and 37 kDa) is separately existed in the cells and might be important for the regulation of subset of PDK1 substrate. Because the crystal structural studies suggested that PIF-pocket is located at the catalytic domain and plays a critical role on substrate recognition. Significance These suggested importance and roles of this fragment are needed to be determined. Further study on these fragments of PDK1 will provide new insight on the regulatory mechanism of PDK1 in patho-physiological condition.

A simple, robust, and rapid LC-MS/MS method has been developed and validated for the simultaneous quantitation of clopidogrel and its active metabolite (AM) in human plasma. Tris(2-carboxyethyl)phosphine (TCEP) was used as a reducing agent to detect the AM as a disulfide-bonded complex with plasma proteins. Mixtures of TCEP and human plasma were deproteinized with acetonitrile containing 10 ng/mL of clopidogrel-d4 as an internal standard (IS). The mixtures were separated on a C18 RP column with an isocratic mobile phase consisting of 0.1% formic acid in acetonitrile and water (90:10, v/v) at a flow rate of 0.3 mL/min. Detection and quantification were performed using ESI-MS. The detector was operated in selected reaction-monitoring mode at m/z 322.0→211.9 for clopidogrel, m/z 356.1→155.2 for the AM, and m/z 326.0→216.0 for the IS. The linear dynamic range for clopidogrel and its AM were 0.05-20 and 0.5-200 ng/mL, respectively, with correlation coefficients (r) greater than 0.9976. Precision, both intra- and interday, was less than 8.26% with an accuracy of 87.6-106%. The validated method was successfully applied to simultaneously analyze clinical samples for clopidogrel and its AM.

In this study, we investigated whether wogonin significantly affects MUC5AC mucin gene expression and production in human airway epithelial cells. Confluent NCI-H292 cells were pretreated with wogonin for 30 min and then stimulated with tumor necrosis factor-α (TNF-α) for 24 h or the indicated periods. The MUC5AC mucin gene expression and mucin protein production were measured by RT-PCR and ELISA, respectively. We found that incubation of NCI-H292 cells with wogonin significantly inhibited mucin production and down-regulated MUC5AC gene expression induced by TNF-α in a dose-dependent fashion. To elucidate the action mechanism of wogonin, effect of wogonin on TNF-α-induced NF-κB signaling pathway was investigated by western blot analysis. Wogonin inhibited NF-κB activation induced by TNF-α. Inhibition of IKK by wogonin led to the suppression of IκB phosphorylation and degradation, p65 nuclear translocation and NF-κB-regulated gene expression. This, in turn, led to the down-regulation of MUC5AC protein production in NCI-H292 cells. Wogonin also inhibited the gene products involved in cell survival (Bcl-2) and proliferation (cyclooxygenase-2). These results suggest that wogonin inhibits the NF-κB signaling pathway, which may explain its role in the inhibition of MUC5AC mucin gene expression and production.

Objective Aberrant splicing is one of the most significant components generating functional diversity in many pathological conditions. The objective of this study was to analyse the mutations or aberrant splicing of A20 transcript, the region encompassing the ovarian tumour (OTU) domain [which is functionally important as an inhibitor of nuclear factor (NF)-κB activation] in fibroblast-like synoviocytes (FLSs) from RA patients. Methods Alterations in A20 transcripts were determined through sequence analysis of 10 clones of A20 cDNA in FLSs from each of the five RA patients. The levels of aberrant A20 transcript were measured by quantitative real-time RT-PCR with primers to specifically recognize the inserted introns. The functional role of A20 and its aberrant variants were examined by analysing NF-κB luciferase reporter activity and NF-κB-dependent target gene expression. Results In RA FLSs, we discovered four novel aberrant A20 transcripts, most of which resulted from insertion of partial intron 2, intron 4 and/or deletion of exon 4. In each of these FLSs, sequence analysis revealed that these aberrant insertional sequences were flanked by consensus splice donor and acceptor sequences without nucleotide substitution, suggesting alternative splicing as the likely mutational mechanism. These variants elicited a codon frame shift by creating a premature translational stop codon, and eventually, disruption of the OTU domain (which is functionally important as an inhibitor of NF-κB activation) of A20. The expression level of aberrant A20 transcript was correlated well with persisitently enhanced status of NF-κB signalling, as evident by the phosphorylation of inhibitor of NF-κB (IκB)-α and transcription of NF-κB target genes. Conclusion The results suggest that A20 inactivation by the novel aberrant splicing may contribute to RA progression by inducing persistent NF-κB activation.

This study aimed to investigate the effect of combined interventions composed of both quiz/feedback and information sheet format change performed after the standard informed consent process on the understanding of clinical study participants. The participants were 117 healthy volunteers: group A (n = 50) receiving a standard information sheet, group B (n = 50) receiving the photo-novella, and the control group (n = 17). The subjective understanding level increased from 82.5 to 90.0 out of 100 points (P < 0.001) and objective understanding level from 13.9 to 16.1 out of 20 points (P < 0.001) for the choice type and 14.0 to 15.7 points out of 20 points (P < 0.001) for the short-answer type after providing quiz/feedback with any type of information sheets. However, photo-novella information sheet did not increase understanding levels more than the standard one. In conclusion, quiz/feedback with any type of information sheet can enhance the understanding in the informed consent of research.

Background: We investigated whether chrysin affected MUC5AC mucin production and gene expression induced by phorbol ester (phorbol 12-myristate 13-acetate, PMA) or epidermal growth factor (EGF) from human airway epithelial cells. Methods: Confluent NCI-H292 cells were pretreated with varying concentrations of chrysin for 30 minutes, and were then stimulated with PMA and EGF for 24 hours, respectively. MUC5AC mucin gene expression and mucin protein production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Results: Concentrations of 10μM and 100μM chrysin were found to inhibit the production of MUC5AC mucin protein induced by PMA; A concentration of 100μM chrysin also inhibited the production of MUC5AC mucin protein induced by EGF; 100μM chrysin inhibited the expression of MUC5AC mucin gene induced by PMA or EGF. The cytotoxicity of chrysin was checked by lactate dehydrogenase assay, and there was no cytotoxic effect observed for chrysin.Conclusion: These results suggest that chrysin can inhibit mucin gene expression and the production of mucin protein by directly acting on airway epithelial cells.Key Words: Epithelial Cells; Mucins; Chrysin

Purpose To evaluate the degree of biological healing response that occurs between the anterior horn of the medial meniscus (MM) and the tibial plateau and investigate the biological healing response after injection of human bone marrow stem cells (hBMSCs) in a rabbit model. Materials and methods Twenty-five rabbits with a mean body weight of 2.5 kg were chosen for this study. On the left knee, a complete radial tear was made at the anterior tibial attachment site of MM and after removal of tibial cartilage, pullout repair of the torn MM was performed on the tibial plateau. On the right knee, the same procedure was performed, and a scaff old (matrix gel) that contained human bone marrow stem cell was implanted between MM and the tibial plateau. A biopsy was performed at 2 (group 1), 4 (group 2), and 8 (group 3) weeks postoperatively. The authors compared the differences in the degree of biological healing of each group and investigated the degree of biologic healing after hBMSC implantation by comparing the left knee with the right knee. Results On the biopsy of 40 knees of 20 rabbits that survived after operation, all groups did not show the healing response between the undersurface of MM and the tibial plateau. There was no significant difference in terms of the pathological criteria such as fibroblasts and fibrochondrocytes etc., with and without hBMSC implantation. Conclusions There was no attachment between the repaired MM and the tibial plateau after complete radial tear on MM and the authors could not identify the effect of hBMSC.

Ethnopharmacological relevance Cynanchi atrati Radix has been traditionally used as an anti-inflammatory agent to treat febrile diseases, acute urinary infection or subcutaneous pyogenic infection with invasion of the pathogenic factors. Aim of study Nuclear factor (NF)-κB is a pleiotropic transcriptional factor of many genes involved in inflammatory and anti-apoptotic responses. To identify a novel, potent inhibitor of NF-κB signaling pathway, a plant extract library of traditional oriental medicine was screened for the capability to block the NF-κB activity in cells overexpressing toll-like receptor 4 (TLR4), and then evaluated the anti-inflammatory and pro-apoptotic functions of water extract of Cynanchi atrati Radix (WECR) in macrophages and cancer cells, respectively. Materials and methods The effect of WECR on the proinflammatory mediators (inducible NO synthase [iNOS], cyclooxygenase [COX]-2), IκB-α degradation, RelA/p65 phosphorylation and caspase cleavages were measured by immunblotting. NF-κB transcriptional activity, IκB kinase (IKK) activity and nitric oxide (NO) production was measured using the luciferase assay, in vitro kinase assay and Griess reaction. Results WECR efficiently inhibited LPS-induced expression of proinflammatory mediators including iNOS and COX-2. IKK kinase activity, IκB-α degradation, nuclear translocation of RelA/p65 and NF-κB transcriptional activity induced by LPS were suppressed by WECR. Furthermore, WECR dramatically enhances the apoptotic response, as evident by the combination with tumor necrosis factor (TNF) was able to induce the cytotoxic action through caspase-dependent pathway. Conclusion These results indicate that WECR has a potential to inhibit IKK-mediated NF-κB activation, and is a valuable compound for modulating inflammatory or cancerous conditions.

Three kinds of herbal medicines, commonly used in Korea, Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix were studied to evaluate their effect on cytochrome P450 (CYP) activities in healthy volunteers. A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05-0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54-0.94). In addition, S. radix showed a 1.42-fold (1.03-1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings.

Background/Aims Based on the observation of biphasic induction of SGK1 expression in the regenerating liver, we investigated the role of SGK1 in the regulation of MEK/ERK signaling pathway which plays a crucial role in regulating growth and survival signaling. Methods To determine the role of SGK1 in the activation of MEK/ERK signaling cascade, we infected primary hepatocytes with recombinant adenoviral vector encoding SGK1, and assessed its effect on the MEK/ERK signaling pathway. Results Partial hepatectomy resulted in the biphasic transcriptional induction of SGK1 in regenerating liver tissues. Infection of primary hepatocytes with an adenoviral vector encoding SGK1 enhanced the ERK phosphorylation under serum-starved conditions and this was blocked by the expression of kinase-dead SGK1. SGK1 was found to physically interact with ERK1/2 as well as MEK1/2. Furthermore, SGK1 mediated the phosphorylation of ERK2 on Ser29 in a serum-dependent manner. Replacement of Ser29 to aspartic acid, which mimics the phosphorylation of Ser29, enhanced the ERK2 activity as well as the MEK/ERK complexes formation. Conclusions SGK1 expression during liver regeneration is a part of a signaling pathway that is necessary for enhancing ERK signaling activation through modulating the MEK/ERK complex formation.