A randomized, open-label, crossover study to compare the safety and pharmacokinetics of two tablet formulations of tenofovir (tenofovir disoproxil and tenofovir disoproxil fumarate) in healthy subjects.

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.

A study of the development of the Korean version of PedsQL(TM) 3.0 cerebral palsy module and reliability and validity.

[Purpose] The purpose of this study was to develop the Korean version of the PedsQL(TM) 3.0 Cerebral Palsy Module to evaluate the health-related quality of life of children with cerebral palsy and to test the reliability and validity. [Subjects and Methods] The study included 108 caregivers of children with cerebral palsy aged 2 to 4 years and 72 caregivers of children aged 5 to 7 years, who visited multiple sites between February and August 2015. The Translation Commission performed the first translation with the approval of the Mapi Research Trust Company to create a Korean-version of the PedsQL(TM). Afterwards, back-translation was performed by one translator specializing in health and medical treatment who was a native English-speaker fluent in Korean, and one native Korean-speaker fluent in English. The consistency of each question was confirmed and a translation-integrated version was created. Test components were explained to caregivers during a one-on-one interview; caregivers then completed the PedsQL(TM) questionnaire and a Pediatric Evaluation Disability Inventory (PEDI) questionnaire. Subjects contributing to test-retest measures were asked to repeat the PedsQL questionnaire one week later and return it by mail. To assess data quality for the survey question results, non-response rate, ceiling effect, and floor effect were analyzed. Test-retest reliability and internal consistency reliability were assessed. For test-retest reliability, an intraclass correlation coefficient (ICC) was calculated, and for internal consistency reliability, Cronbach's alpha was used. To test criterion-related validity, Pearson's correlation coefficient was used. [Results] The content validity of the PedsQL 3.0 Cerebral Palsy Module was high for both age groups, and demonstrated significant internal consistency (>0.7) in all areas. For test-retest reliability, both groups demonstrated a significant ICC (>0.61). Correlation with the PEDI was statistically significant in all areas except pain and hurt. [Conclusion] The Korean version of the PedsQL(TM) 3.0 Cerebral Palsy Module was found to be reliable and valid, and is expected to contribute greatly to the evaluation of the quality of life of children with cerebral palsy.

The effects of eupatilin (stillen®) on motility of human lower gastrointestinal tracts.

Gastrointestinal motility consists of phasic slow-wave contractions and the migrating motor complex (MMC). Eupatilin (Stillen®) has been widely used to treat gastritis and peptic ulcers, and various cytokines and neuropeptides are thought to be involved, which can affect gastrointestinal motility. We performed a study to identify the effects of eupatilin on lower gastrointestinal motility with electromechanical recordings of smooth muscles in the human ileum and colon. Ileum and colon samples were obtained from patients undergoing bowel resection. The tissues were immediately stored in oxygenated Krebs-Ringer's bicarbonate solution, and conventional microelectrode recordings from muscle cells and tension recordings from muscle strips and ileal or colonic segments were performed. Eupatilin was perfused into the tissue chamber, and changes in membrane potentials and contractions were measured. Hyperpolarization of resting membrane potential (RMP) was observed after administration of eupatilin. The amplitude, AUC, and frequency of tension recordings from circular and longitudinal smooth muscle strips and bowel segments of the ileum and colon were significantly decreased after admission of eupatilin. Eupatilin elicited dose-dependent decreases during segmental tension recordings. In conclusion, eupatilin (Stillen®) showed inhibitory effects on the human ileum and colon. We propose that this drug may be useful for treating diseases that increase bowel motility, but further studies are necessary.

The Effects of Visual Field Conditions on Electromyography of the Lower Extremities during Reaching Tasks in Healthy Adults.

[Purpose] The purpose of this study was to identify the effects of visual field condition on electromyography of the lower extremities during arm reaching in healthy adults, and to compare differences in electromyography of the lower extremities between young and old adults according to visual fields condition. [Subjects and Methods] Twenty-nine young persons in their 20s and 19 elderly persons in their 60s, a total of 48 persons, participated in this study. Prior to participation in the study, each subject signed an informed consent form to comply with ethics guidelines dictated by the ethics committee for research at Silla University, Korea. We collected the muscle activation data for both of tibialis anterior and gastrocnemius muscle during reaching by subjects using electromyography. Data analysis with SPSS for Window Version 20.0 was performed using repeated one-way analysis of variance according to visual fields and age. [Results] There were no significantly differences between subjects in their 20s and 60s to visual field conditions except for left tibialis anterior muscle activation during left-side reaching. Left tibialis anterior muscle activation in subjects in their 60s was higher than in subjects in their 20s during left-side reaching. [Conclusion] We determined that tibialis anterior muscle activation in subjects in their 60s was higher than in subjects in their 20s. We suggest that visual field conditions are the important factor for physical therapy interventions to improve balance and priority of intervention .

Comparison of pharmacokinetics and safety characteristics between two olopatadine hydrochloride 5 mg tablet formulations in healthy Korean subjects.

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.

Bioequivalence for a Fixed-Dose Combination Formulation of Bazedoxifene and Cholecalciferol Compared With the Corresponding Single Entities Given Together.

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.

Eupatilin exhibits a novel anti-tumor activity through the induction of cell cycle arrest and differentiation of gastric carcinoma AGS cells.

In many cases, the process of cancer cell differentiation is associated with the programmed cell death. In the present study, interestingly, we found that eupatilin, one of the pharmacologically active ingredients of Artemisia asiatica that has been reported to induce apoptosis in human gastric cancer AGS cells, also triggers differentiation of these cells. Treatment of AGS cells with eupatilin induced cell cycle arrest at the G(1) phase with the concomitant induction of p21(cip1), a cell cycle inhibitor. This led us to test whether eupatilin may trigger AGS cells to differentiate into the matured phenotypes of epithelial cells and this phenomenon may be coupled to the apoptosis. Eupatilin induced changes of AGS cells to a more flattened morphology with increased cell size, granularity, and mitochondrial mass. It also markedly induced trefoil factor 1 (TFF1), a gene responsible for the gastrointestinal cell differentiation. Eupatilin dramatically induced redistribution of tight junction proteins such as occludin and ZO-1, and F-actin at the junctional region between cells. It also induced phosphorylation of extracellular signal-regulated kinase 2 and p38 kinase. Blockade of ERK signaling by PD098059 or the dominant-negative ERK2 significantly reduced eupatilin-induced TFF1 and p21 expression as well as ZO-1 redistribution, indicating that ERK cascades may mediate eupatilin-induced AGS cell differentiation. Collectively, our results suggest that eupatilin acts as a novel anti-tumor agent by inducing differentiation of gastrointestinal cancer cells rather than its direct role in inducing apoptotic cell death.

Pharmacokinetic comparison of two bazedoxifene acetate 20 mg tablet formulations in healthy Korean male volunteers.

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.

Eupatilin inhibits T-cell activation by modulation of intracellular calcium flux and NF-kappaB and NF-AT activity.

Eupatilin, one of the pharmacologically active ingredients of Artemisia princeps, exhibits a potent anti-ulcer activity, but its effects on T-cell immunity have not been investigated. Here, we show that eupatilin has a profound inhibitory effect on IL-2 production in Jurkat T cells as well as in human peripheral blood leukocytes. Eupatilin neither influenced clustering of CD3 and LFA-1 to the immunological synapse nor inhibited conjugate formation between T cells and B cells in the presence or absence of superantigen (SEE). Eupatilin also failed to inhibit T-cell receptor (TCR) internalization, thereby, suggesting that eupatilin does not interfere with TCR-mediated signals on the membrane proximal region. In unstimulated T cells, eupatilin significantly induced apoptotic cell death, as evidenced by an increased population of annexin V(+)/PI(+) cells and cleavage of caspase-3 and PARP. To our surprise, however, once cells were activated, eupatilin had little effect on apoptosis, and instead slightly protected cells from activation-induced cell death, suggesting that apoptosis also is not a mechanism for eupatilin-induced T-cell suppression. On the contrary, eupatilin dramatically inhibited I-kappaBalpha degradation and NF-AT dephosphorylation and, consequently, inhibited NF-kappaB and NF-AT promoter activities in PMA/A23187-stimulated T cells. Interestingly, intracellular calcium flux was significantly perturbed in cells pre-treated with eupatilin, suggesting that calcium-dependent cascades might be targets for eupatilin action. Collectively, our results provide evidence for dual regulatory functions of eupatilin: (1) a pro-apoptotic effect on resting T cells and (2) an immunosuppressive effect on activated T cells, presumably through modulation of Ca(2+) flux.

Chemopreventive effects of the standardized extract (DA-9601) of Artemisia asiatica on azoxymethane-initiated and dextran sulfate sodium-promoted mouse colon carcinogenesis.

Dextran sulfate sodium (DSS) administration has been reported to cause inflammation in mouse colonic mucosa, which promotes colon carcinogenesis. When male ICR mice were treated with a single intraperitoneal dose (10 mg/kg body weight) of azoxymethane (AOM) followed by 2.5% DSS in drinking water for 7 consecutive days, all developed tumors at the 16th wk, mostly in the distal colon. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were markedly upregulated in the AOM-initiated and DSS-promoted colon tumors. The DNA binding activity of nuclear factor-kappaB (NF-kappa B) was also elevated in the colon tumors. In this study, we examined the chemopreventive effects of the standardized extract (DA-9601) of Artemisia asiatica that has been used in the traditional herbal medicine for the treatment of inflammatory disorders. Mice fed the chow diet containing 10% DA-9601 for 15 wk following DSS treatment displayed the significantly lower multiplicity of colon tumors. DA-9601 treatment suppressed the expression of COX-2 and iNOS as well as NF-kappa B DNA binding in the colonic tissues. It also downregulated the phosphorylation of extracellular, signal-regulated protein kinase and p38 mitogen-activated protein kinase that are upstream of NF-kappa B. Furthermore, DA-9601 reduced expression of beta-catenin in colonic mucosa of mice challenged with AOM plus DSS.

Artemisia asiatica extracts protect against ethanol-induced injury in gastric mucosa of rats.

BACKGROUND AND AIM: Based on our previous studies that Artemisia asiatica extracts exert either antioxidative or cytoprotective actions against non-steroidal anti-inflammatory drugs or Helicobacter pylori-induced gastric mucosal injury, or imposes qualified ulcer healing in an acetic acid-induced gastric ulcer model, we investigated the protective effects of Artemisia asiatica extracts against ethanol-induced gastric mucosal injury. METHODS: Sprague-Dawley rats received 4 g/kg body weight (BW) of absolute ethanol intragastrically, which produced visible hemorrhagic gastric lesions 60 min later. RESULTS: In this animal setting, the pretreatment of Artemisia extracts (30 or 100 mg/kg BW), 1 h before ethanol administration, significantly attenuated the source of gastric injury, which was assessed with gross and microscopic analysis (P < 0.01). Protection from alcohol-induced damage with Artemisia pretreatment was associated with significantly decreased lipid peroxidation, protecting gastric mucosa from glutathione depletion, as well as the inhibition of the cytochrome 2E1 ethanol-metabolizing enzyme. It attenuated the expressions of ethanol-induced pro-inflammatory cytokines, including interleukin (IL)-1beta and interferon-gamma, a weak activation of IL-10, the inhibition of the alcohol-induced overexpression of intercellular adhesion molecule-1, and the considerable induction of heat shock protein-72 expression in gastric mucosal homogenates. CONCLUSION: The data suggest that the ethanol extracts of Artemisia asiatica exerted significant protection from alcohol-induced gastric mucosal injury through bio-regulation, which is essential for cytoprotection and anti-inflammation.

The protective effect of eupatilin on indomethacin-induced cell damage in cultured feline ileal smooth muscle cells: involvement of HO-1 and ERK.

Chronic users of non-steroidal anti-inflammatory drugs frequently develop ulcerative lesions in their intestines. The purpose of the present study was to investigate whether eupatilin, an active ingredient derived from Artemisia plants, prevents this side effect in vitro. Extracts of the whole herb of Artemisia asiatica Nakai have been used in oriental medicine for the treatment of inflammation. As measured by the MTT assay, the treatment of cultured feline ileal smooth muscle cells (ISMCs) with 2.5mM indomethacin for 2h decreased the cell viability to 43%. Pretreatment with eupatilin resulted in dose-dependent inhibition on indomethacin-induced cell damage. This cytoprotective effect of eupatilin required concentrations of more than 150 microM and incubation periods of longer than 16 h. Pretreatment of ISMC with cycloheximide, an inhibitor of protein synthesis, attenuated the cytoprotective effect of eupatilin, suggesting that eupatilin induces proteins that are responsible for the cytoprotection. Heme oxygenase-1 (HO-1), which is known as a cytoprotective enzyme due to its anti-inflammatory actions, is a candidate protein since ZnPP, an HO-1 inhibitor, repressed the protective effect of eupatilin on indomethacin-induced cell damage in a concentration-dependent manner. Western blot analysis revealed that eupatilin-mediated HO-1 induction occurred in a concentration- and time-dependent manner. We also found that PD98059, a MEK (MAPK/ERK kinase) inhibitor, attenuated the eupatilin-induced HO-1 expression and nuclear translocation of transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Taken together, the data imply that eupatilin protects ISMC from cell damage caused by indomethacin, and that its cytoprotective action could be attributed to eupatilin-mediated HO-1 induction via ERK and Nrf2 signaling in ISMC.

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects.

A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread®) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration-time curve to the last quantifiable concentration (AUC0-t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration-time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815-0.990) for Cmax and 0.904 (0.836-0.978) for AUC0-t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF.

Comparable pharmacokinetics and pharmacodynamics of two epoetin alfa formulations Eporon® and Eprex® following a single subcutaneous administration in healthy male volunteers.

PURPOSE: This study aimed to assess and compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties following a single subcutaneous injection of epoetin alfa (Eporon®) with those of the comparator (Eprex®) in healthy male subjects. SUBJECTS AND METHODS: A randomized, double-blind, two-sequence, crossover study was conducted. Subjects were randomly assigned to receive a single dose, that is, 4,000 IU, of the test or comparator epoetin alfa. After 4 weeks, all subjects received the alternative formulation. The primary PK parameters, maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUCinf), were calculated with the serum erythropoietin (EPO) concentrations from blood samples collected for 144 h after dosing. The reticulocyte, hematocrit, hemoglobin and red blood cell counts were measured up to 312 h as PD markers. The primary PD parameters, maximum observed effect (Emax) and area under the effect curve (AUEC), were obtained from the baseline-corrected reticulocyte count. The serum EPO concentration and the reticulocyte count were used to assess the concentration-response relationship. The tolerability and immunogenicity profiles were assessed together. RESULTS: Forty-two subjects completed the study. The mean EPO concentration-time profiles were comparable between the two formulations. The geometric mean ratios (90% CI) of the Cmax and AUCinf were 0.908 (0.843-0.978) and 1.049 (0.999-1.101), respectively, both of which were within the regulatory range of 0.80-1.25. Additionally, the PD and tolerability profiles were similar between the two formulations. The time-matched serum EPO concentration and PD markers presented a counterclockwise hysteresis, suggesting a time delay between the measured concentration and the response. Both formulations were well tolerated, and production of anti-drug antibodies was not observed. CONCLUSION: The two epoetin alfa formulations had similar PK, PD and tolerability profiles. Furthermore, both formulations had a similar time-matched serum EPO concentration and erythropoietic response profile. Thus, the two formulations are expected to be used interchangeably in clinical settings.

DA-9601, a standardized extract of Artemisia asiatica, blocks TNF-alpha-induced IL-8 and CCL20 production by inhibiting p38 kinase and NF-kappaB pathways in human gastric epithelial cells.

AIM: To investigate whether, or how, DA-9601, which is a new gastroprotective agent, inhibits TNF-alpha-induced inflammatory signals in gastric epithelial AGS cells. METHODS: Cell viability was determined by MTT assay. IL-8 and CCL20 promoter activities were determined by a luciferase reporter gene assay. NF-kappaB-dependent transcriptional activity was determined by I-kappaB alpha degradation, NF-kappaB p65 nuclear translocation and a luciferase activity assay. IL-8 and CCL20 gene expression and protein secretion were determined by RT-PCR and an enzyme-linked immunosorbent assay (ELISA). Total and phosphorylated forms of mitogen-activated protein kinases (MAPKs) were determined by Western blot. RESULTS: Treatment of AGS cells with DA-9601 reduced TNF-alpha-induced IL-8 and CCL20 promoter activities, as well as their gene expression and protein release. TNF-alpha also induced NF-kappaB-dependent transcriptional activity in AGS cells. In contrast, in cells treated with DA-9601, TNF-alpha-induced NF-kappaB activity was significantly blocked. Although all three MAP kinase family members were phosphorylated in response to TNF-alpha, a selective inhibitor of p38 kinase SB203580 only could inhibit both NF-kappaB-dependent transcriptional activity and IL-8 and CCL20 production, suggesting a potential link between p38 kinase and NF-kappaB-dependent pathways in AGS cells. Interestingly, DA-9601 also selectively inhibited p38 kinase phosphorylation induced by TNF-alpha. CONCLUSION: DA-9601 blocked TNF-alpha-mediated inflammatory signals by potentially modulating the p38 kinase pathway and/or a signal leading to NF-kappaB-dependent pathways in gastric epithelial cells.

Is there an agreement among the items of the Korean physical therapist licensing examination, learning objectives of class subjects, and physical therapists' job descriptions?

PURPOSE: To determine the agreement among the items of the Korean physical therapist licensing examination, learning objectives of class subjects, and physical therapists' job descriptions. METHODS: The main tasks of physical therapists were classified, and university courses related to the main tasks were also classified. Frequency analysis was used to determine the proportions of credits for the classified courses out of the total credits of major subjects, exam items related to the classified courses out of the total number of exam items, and universities that offer courses related to the Korean physical therapist licensing examination among the surveyed universities. RESULTS: The proportions of credits for clinical decision making and physical therapy diagnosis-related courses out of the total number credits for major subjects at universities were relatively low (2.06% and 2.58%, respectively). Although the main tasks of physical therapists are related to diagnosis and evaluation, the proportion of physiotherapy intervention-related items (35%) was higher than that of examination and evaluation-related items (25%) on the Korean physical therapist licensing examination. The percentages of universities that offer physical therapy diagnosis and clinical decision making-related courses were 58.62% and 68.97%, respectively. CONCLUSION: Both the proportion of physiotherapy diagnosis and evaluation-related items on the Korean physical therapist licensing examination, and the number of subjects related to clinical decision making and physical therapy diagnosis in the physical therapy curriculum, should be increased to ensure that the examination items and physical therapy curriculum reflect the practical tasks of physical therapists.

Synergism of Helicobacter pylori infection and stress on the augmentation of gastric mucosal damage and its prevention with alpha-tocopherol.

Despite evidence that Helicobacter pylori (H. pylori) infection is closely associated with stress in gastric ulcer patients, the underlying mechanism why ulcer recurrence after stress is augmented especially in patients with H. pylori remains unknown. In this study, we found that oxidative stress played a critical role in the augmented mucosal damage provoked by water immersion restraint stress (WIRS) in H. pylori infection and that an antioxidant, alpha-tocopherol, could ameliorate the aggravation of stress-associated gastric mucosal damage. Two hundred forty SD rats were divided into two groups according to H. pylori inoculation, and after 24 weeks of H. pylori infection, the water immersion restraint stress was imposed for 30, 120, or 480 min, respectively. To evaluate the therapeutic effects of an antioxidant, alpha-tocopherol was administrated 40 mg/kg daily prior to imposing WIRS. Remarkably increased hemorrhagic lesions and bleeding indexes were noted in the H. pylori-infected group with statistical significance (P < 0.05) compared to the noninfected group at the same duration of WIRS. Significantly higher oxidative stress documented by iNOS, lipid peroxides, and GSH level was detected in gastric homogenates of the H. pylori-infected group. Proteomic analysis using 2-dimensional electrophoresis showed a decrease of HSP27 and other chaperone proteins. alpha-Tocopherol pretreatment significantly prevented the gastric mucosal damage, caused by WIRS in the presence of H. pylori. alpha-Tocopherol induced HSP27 expression, which was well correlated with downregulation of iNOS mRNA. Conclusively, the presence of H. pylori caused significant deterioration of stress-induced gastric mucosal lesions through increased oxidative stress and thus antioxidant treatment such as alpha-tocopherol protected the gastric injuries.

Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells.

PURPOSE: To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Gastric H+/K(+)-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. On the basis of the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that pantoprazole (PPZ), one of gastric H+/K(+)-ATPase inhibitors used frequently to treat acid-related diseases, could inhibit growth of tumor cells. EXPERIMENTAL DESIGN: Genomic DNA fragmentation, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay, and annexin V staining were performed to detect PPZ-induced apoptosis. Mitogen-activated protein kinase activation and heat shock proteins expression were determined by immunoblot with specific antibodies. The antitumor effect of PPZ was evaluated in vivo by a xenograft model of nude mice. RESULTS: After PPZ treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with extracellular signal-regulated kinase deactivation. By contrast, normal gastric mucosal cells showed the resistance to PPZ-induced apoptosis through the overexpression of antiapoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPZ significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells. CONCLUSIONS: PPZ selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors could be used for selective anticancer effects.

Increased susceptibility of ethanol-treated gastric mucosa to naproxen and its inhibition by DA-9601, an Artemisia asiatica extract.

AIM: To examine the effect of DA-9601, a new gastroprotective agent, on the vulnerability of ethanol-treated rat's stomach to naproxen (NAP). METHODS: Male Sprague-Dawley rats were pretreated with 1 mL of 50% ethanol twice a day for 5 d and then NAP (50 mg/kg) was administered. DA-9601 was administered 1 h before NAP. Four hours after NAP, the rats were killed to examine gross injury index (mm2), histologic change and to determine mucosal levels of malondialdehyde (MDA), prostaglandin E2 (PGE2), glutathione (GSH) and myeloperoxidase (MPO). RESULTS: Pretreatment of ethanol significantly increased NAP-induced gastric lesions, as well as an increase in MDA and MPO. On the contrary, mucosal PGE2 and GSH contents were decreased dramatically by ethanol pretreatment, which were aggravated by NAP. DA-9601 significantly reduced NAP-induced gastric injury grossly and microscopically, regardless of pretreatment with ethanol. DA-9601 preserved, or rather, increased mucosal PGE2 and GSH in NAP-treated rats (P<0.05), with reduction in mucosal MDA and MPO levels. CONCLUSION: These results suggest that repeated alcohol consumption renders gastric mucosa more susceptible to NSAIDs though, at least in part, reduction of endogenous cytoprotectants including PGE2 and GSH, and increase in MPO activation, and that DA-9601, a new gastroprotectant, can reduce the increased vulnerability of ethanol consumers to NSAIDs-induced gastric damage via the mechanism in which PGE2 and GSH are involved.

Protective effects of green tea polyphenol extracts against ethanol-induced gastric mucosal damages in rats: stress-responsive transcription factors and MAP kinases as potential targets.

There are multiple lines of compelling evidence from epidemiologic and laboratory studies supporting that frequent consumption of green tea is inversely associated with the risk of chronic human diseases including cancer. The chemopreventive and chemoprotective effects of green tea have been largely attributed to antioxidative and anti-inflammatory activities of its polyphenolic constituents, such as epigallocatechin gallate. The present study was designed to evaluate the efficacy of green tea polyphenols in protecting against alcohol-induced gastric damage and to elucidate the underlying mechanisms. Intragastric administration of ethanol to male Sprague-Dawley rats caused significant gastric mucosal damage, which was accompanied by elevated expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as well as transient activation of redox-sensitive transcription factors, such as NF-kappaB and AP-1, and mitogen-activated protein kinases (MAPKs). Oral administration of the green tea polyphenolic extract (GTE) significantly ameliorated mucosal damages induced by ethanol and also attenuated the ethanol-induced expression of COX-2 and iNOS. Inactivation of MAPKs, especially p38 and ERKl/2, by GTE might be responsible for inhibition of ethanol-induced expression of COX-2 and iNOS.