Apple juice greatly reduces systemic exposure to atenolol.

AIM: Fruit juice reduces the plasma concentrations of several ß-adrenoceptor blockers, likely by inhibiting OATP2B1-mediated intestinal absorption. The aim of this study was to investigate the effects of apple juice on the pharmacokinetics of atenolol. METHODS: Twelve healthy Korean volunteers with genotypes of SLCO2B1 c.1457C> T (*1/*1 (n = 6) and *3/*3 (n = 6)) were enrolled in this study. In a three-phase, one-sequence crossover study, the pharmacokinetics (PK) of atenolol was evaluated after administration of 50 mg atenolol. Subjects received atenolol with either 300 ml water, 1200 ml apple juice or 600 ml apple juice. RESULTS: Apple juice markedly reduced the systemic exposure to atenolol. The geometric mean ratios (95% confidence intervals) of apple juice : water were 0.18 (0.13, 0.25, 1200 ml) and 0.42 (0.30, 0.59, 600 ml) for the AUC(0,t(last)). In this study, the PK parameters of atenolol responded in a dose-dependent manner to apple juice. CONCLUSIONS: Apple juice markedly reduced systemic exposure to atenolol. The genetic variation of SLCO2B1 c.1457C>T had a minimal effect on the pharmacokinetics of atenolol when the drug was administered with water or apple juice.

The effects of bridge exercise on an unstable base of support on lumbar stability and the thickness of the transversus abdominis.

[Purpose] We examined the effects of an abdominal drawing-in bridge exercise using a pressure biofeedback unit on different bases on the thickness of trunk and abdominal muscles, and lumbar stability. [Subjects] Thirty healthy young adults (2 males, 28 females) took part in this study. The subjects were randomly and equally assigned to a stable bridge exercise group and an unstable bridge exercise group. [Methods] The subjects performed bridge exercises using an abdominal drawing-in method on a stable base and on an unstable base, and changes in their abdominal muscle thickness and on the stable and on unstable bases lumbar stability were evaluated. [Results] After the intervention, the stable bridge exercise group showed a statistically significantly increased muscle thickness in the transversus abdominis, and the unstable bridge exercise group showed significantly increased muscle thicknesses of the transversus abdominis and internal obliques in static and dynamic lumbar stability. The unstable bridge exercise group showed significant increase after performing the exercise. [Conclusion] Lumbar stability exercise, with the compensation of the lumbar spine minimized, using an abdominal drawing-in method on an unstable support of base is effective and efforts to prevent the compensation may induce a greater exercise effect.

Risk Assessment and Determination of Arsenic and Heavy Metals in Fishery Products in Korea.

The purpose of this study is to quantify several heavy metals (Pb, Cd, Hg, Me-Hg, and metalloid arsenic) contained in Korean fishery products (seven categories, 1186 samples) and assess their health risk. Heavy metals quantification was conducted using inductively coupled plasma mass spectrometry (ICP-MS) and a direct mercury analysis (DMA). The good linearity (R2 > 0.999), limits of detection (1.0-3.2 µg/kg), limits of quantification (3.1-9.6 µg/kg), accuracy (88.14-113.80%), and precision (0.07-6.02%) of the five heavy metals were obtained, and these results meet the criteria recommended by the AOAC. The average heavy metal concentrations of fishery products were in the following order: As > Cd > Pb > Hg > Me-Hg for sea algae, crustaceans, mollusks, and echinoderms, As > Hg > Me-Hg > Pb > Cd for freshwater fish and marine fish, and As > Pb > Cd > Hg > Me-Hg for tunicates. Heavy metal concentrations were lower than MFDS, EU, CODEX, and CFDA standards. In addition, the exposure, non-carcinogenic, and carcinogenic evaluation results, considering the intake of aquatic products for Koreans, were very low. It was concluded that this study will provide basic data for food safety and risk assessment.

Development and characterization of pH-responsive nanocarriers for chemo-photothermal combination therapy of acidic tumors.

The combination of photothermal therapy and chemotherapy has been considered a promising strategy for improving the excellent antitumor activities of these treatments. In this study, we developed a new simple type of pH-sensitive chemo-photothermal combination agent capable of repeated exposures to a near-infrared (NIR) laser and evaluated its anticancer efficacy in vitro and in vivo. Doxorubicin (Dox) and gold nanoclusters (GNCs) were successfully co-loaded into pH-sensitive nanoparticles (poly(ethylene glycol)-poly[(benzyl-l-aspartate)-co-(N-(3-aminopropyl)imidazole-L-aspartamide)] (PEG-PABI)), resulting in a particle size of approximately120 nm with a narrow size distribution. The dual drug-loaded nanoparticles (Dox/GNC-loaded PEG-PABI micelles (Dox/GNC-Ms)) showed consistent pH-sensitive properties and heat generation efficiency after repeated NIR laser exposure. In particular, GNC-M has improved photothermal stability while maintaining high photothermal conversion efficiency, addressing the shortcomings of previous gold nanoparticles. As the concentration of GNC-Ms, irradiation light exposure time, and light source intensity increased, the amount of heat generated and the anticancer effect increased. When Dox was encapsulated with GNCs (Dox/GNC-Ms), a faster drug release rate under acidic pH conditions and a strong synergistic effect against U87MG cells were observed. When the Dox/GNC-M system was extended to in vivo studies, it effectively increased the temperature of the tumor tissue under near-infrared irradiation and showed excellent anticancer efficacy. Therefore, the Dox/GNC-M system could be a simple but promising strategy for chemo-photothermal combination treatment capable of targeting acidic tumors.

Pharmacokinetics and pharmacodynamics of oral tolvaptan administered in 15- to 60-mg single doses to healthy Korean men.

Tolvaptan is a selective arginine vasopressin V2-receptor antagonist that is used as an aquaretic agent. This trial investigated the pharmacokinetics and pharmacodynamics of 15- to 60-mg single oral doses of tolvaptan in healthy Korean men. A dose block-randomized, placebo-controlled, double-blind, single ascending dose trial was conducted with 46 subjects receiving tolvaptan (15, 30, or 60 mg) or placebo. To determine pharmacokinetics and pharmacodynamics, blood and urine samples were collected at baseline and up to 48 hours after drug administration. Urine volume and fluid intake were measured for 24 hours starting the day before dosing (day -1) as baseline, and on the day of drug administration (day 1). Tolvaptan showed dose-linear pharmacokinetic characteristics regarding area under the concentration-time curve. Changes from baseline in 24-hour urine volume and 24-hour fluid balance correlated significantly with area under the concentration-time curve from time 0 to the last measurable time. Dose-dependent increases were observed in serum osmolality, serum sodium concentration, and free water clearance in the 4- to 8-hour interval after dosing, and these increases were maintained for at least 24 hours. Single 15- to 60-mg doses of tolvaptan exhibited linear pharmacokinetics and resulted in substantial, dose-dependent aquaresis in healthy Korean men.

Assessment of the drug-drug interactions between fimasartan and hydrochlorothiazide in healthy volunteers.

AIM: Fimasartan is a selective angiotensin II receptor blocker. Hydrochlorothiazide (HCTZ), which is used to treat hypertension and edematous conditions, is coadministered with many antihypertensive agents. METHODS: An open-label, randomized, multiple-dosing, 2-arm, 1-sequence, 2-period study was conducted to assess the effects of fimasartan (240 mg) on HCTZ (25 mg) or vice versa in 18 and 14 healthy male volunteers, respectively. During each drug administration period, drugs were given once daily for 7 days, with a 7-day washout period between the 2 administration periods. RESULTS: The respective geometric mean ratios of fimasartan for AUC τ,ss and C max,ss with HCTZ were 1.30 [90% confidence interval (CI), 0.84-2.01] and 1.17 (90% CI, 0.93-1.47) compared with fimasartan alone. The respective geometric mean ratios of HCTZ for AUC τ,ss and C max,ss with fimasartan were 0.94 (90% CI, 0.84-1.04) and 0.88 (90% CI, 0.80-0.97) compared with HCTZ alone. Plasma renin activity indicated no significant differences between fimasartan monotherapy and coadministered treatment. CONCLUSIONS: Fimasartan administered alone or in combination with HCTZ was well tolerated at the described dosages. Coadministration of fimasartan increased the urinary excretion of HCTZ and urine volume, but these observations are unlikely to have any clinical relevance.

Comparison of projected rice blast epidemics in the Korean Peninsula between the CMIP5 and CMIP6 scenarios.

Recently, the International Panel for Climate Change released the 6th Coupled Model Intercomparison Project (CMIP6) climate change scenarios with shared socioeconomic pathways (SSPs). The SSP scenarios result in significant changes to climate variables in climate projections compared to their predecessor, the representative concentration pathways from the CMIP5. Therefore, it is necessary to examine whether the CMIP6 scenarios differentially impact plant-disease ecosystems compared to the CMIP5 scenarios. In this study, we used the EPIRICE-LB model to simulate and compare projected rice blast disease epidemics in the Korean Peninsula using five selected family global climate models (GCMs) of the CMIP5 and CMIP6 for two forcing scenarios. We found a similar decrease in rice blast epidemics in both CMIP scenarios; however, this decrease was greater in the CMIP6 scenarios. In addition, distinctive epidemic trends were found in North Korea, where the rice blast epidemics increase until the mid-2040s but decrease thereafter until 2100, with different spatial patterns of varying magnitudes. Controlling devastating rice blast diseases will remain important during the next decades in North Korea, where appropriate chemical controls are unavailable due to chronic economic and political issues. Overall, our analyses using the new CMIP6 scenarios reemphasized the importance of developing effective control measures against rice blast for specific high-risk areas and the need for a universal impact and vulnerability assessment platform for plant-disease ecosystems that can be used with new climate change scenarios in the future. Supplementary information: The online version contains supplementary material available at 10.1007/s10584-022-03410-2.

The prevalence and risk factors of female sexual dysfunction in young korean women: an internet-based survey.

INTRODUCTION: In Korea, although male sexual problems have been relatively well addressed, few surveys have been conducted on female sexual dysfunction (FSD) in the general population. In the present study, we investigated the prevalence and identified the risk factors of sexual dysfunction in young Korean women. AIM: To evaluate the prevalence and to identify the risk factors of FSD in young Korean women. METHODS: A total of 47,000 women were initially approached. All received an e-mail requesting that they participate in a Web-based survey. The participants were asked to complete a questionnaire requesting detailed medical and sexual histories, which included the questions contained in the Korean version of the Female Sexual Function Index questionnaire. MAIN OUTCOME MEASURES: The prevalence of FSD in young Korean women in the different age groups and risk factors for developing FSD. RESULTS: A total of 504 women of average age 28.5 years (18-52 years) were evaluated during this survey. Setting the cutoff score for FSD using a receiver operating characteristic curve of our data as 25.0 points, 43.1% of women under 40 years old reported FSD. FSD was detected as a desire problem in 44.0% of women, an arousal problem in 49.0%, a lubrication problem in 37.0%, an orgasm problem in 32.0%, a satisfaction problem in 37.0%, and a pain problem in 34.6%. Risk factors for FSD as determined by logistic regression analysis were increasing age, a low frequency of sex, depression, a sexually abused history, and voiding dysfunction. CONCLUSIONS: The prevalence of FSD in Korean young women was common and comparable to those reported worldwide.

[The subjectivity of attitudes toward life support care].

PURPOSE: The purpose of this study was to categorize adult's subjectivity of their attitudes towards life sustaining treatment, and thereby understand the differences among these life sustaining treatment types using Q methodology. METHODS: Q-methodology, which provides a method of analyzing the subjectivity of each item, was used. Thirty selected Q-statements received from 52 adults were classified into a shape of normal distribution using a 7 point scale. The collected data was analyzed using a QUANL pc program. RESULT: Four types of attitudes toward life sustaining treatment were identified. Type I is called one's autonomy type. Type II is called potentiality of resuscitation type. Type III is called DNR (Do not resuscitation) type. Type IV is calledone's effort type. CONCLUSION: The results of the study indicate that different approaches of life support care programs are recommended based on the four types of life sustaining treatment attitudes among Korean adults.

Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells.

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (TH9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-κB-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting TH9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.

Uterine infarction in a patient with uterine adenomyosis following biochemical pregnancy.

Adenomyosis is a common gynecological disorder characterized by the presence of endometrial glands and stroma deep within the myometrium associated with myometrial hypertrophy and hyperplasia. Focal uterine infarction after IVF-ET in a patient with adenomyosis following biochemical pregnancy has not been previously reported, although it occurs after uterine artery embolization in order to control symptoms caused by fibroids or adenomyosis. We report a case of a nulliparous woman who had uterine adenomyosis presenting with fever, pelvic pain and biochemical abortion after undergoing an IVF-ET procedure and the detection of a slightly elevated serum hCG. Focal uterine infarction was suspected after a pelvic magnetic resonance imaging demonstrated preserved myometrium between the endometrial cavity and inner margin of the necrotic myometrium. This case demonstrates that focal uterine infarction should be considered in the differential diagnosis of acute abdominal pain, vaginal bleeding and infectious signs in women experiencing biochemical abortion after an IVF-ET procedure.

High-risk human papillomavirus load and biomarkers in cervical intraepithelial neoplasia and cancer.

The purpose of this study was to examine the implication of high-risk human papillomavirus (HPV) load in cervical intraepithelial neoplasia (CIN) and cancer, and to detect biomarkers in cervical disease. We conducted high-risk HPV DNA load and cervical cytology tests in 343 women, cervical tissue biopsy in 143 women, and immunohistochemistry for p16(INK4A), cyclin D1, p53, cyclooxygenase-2, Ki-67, GLUT1, hPygopus2, and beta-catenin. As a result, HPV load [relative light units (RLU) value] was correlated with the histological severity of cervical disease (p < 0.05). In the 'atypical squamous cells of undetermined significance' cytology group, 2.385 of HPV load seemed to be the cut-off value at which 'benign' or CIN I can be differentiated from 'CIN II or more severe' (AUC = 0.712), but not statistically significant. The relative risk (odds ratio) of p16(INK4A) and GLUT1 overexpression increased gradually according to the histological severity of cervical disease. The p16(INK4A) showed statistically significant odds ratios in CIN II, CIN III, and cancer; GLUT1, in CIN II and CIN III; hPygopus2, in CIN III; and beta-catenin, in CIN III and cancer. Conclusively, HPV load, p16(INK4A) , and GLUT1 can be instrumental in predicting the severity of HPV-related cervical disease. The beta-catenin/hPygopus2 signaling may be involved in proceeding to CIN III.

Pharmacodynamics, pharmacokinetics, and tolerability of intravenous or subcutaneous GC1113, a novel erythropoiesis-stimulating agent.

BACKGROUND AND OBJECTIVES: GC1113, a hybrid Fc-fused erythropoietin, is a novel erythropoiesis-stimulating agent that is expected to have an extended duration of action. The preclinical data showed that the hemoglobin increase lasted longer following GC1113 administration than it did following the administration of darbepoetin alfa (NESP®). This study aimed to investigate the pharmacodynamic and pharmacokinetic characteristics and tolerability profiles of GC1113 in humans after single intravenous or subcutaneous administration and to compare the results with those for darbepoetin alfa. METHODS: A dose-block randomized, placebo- and active-controlled, dose-escalation phase I clinical trial was conducted in 96 healthy volunteers. Blood samples were collected before and up to 672 h after drug administration and the serum erythropoietin concentration following the GC1113 or darbepoetin alfa administration was measured by an ELISA. The reticulocyte counts were measured for pharmacodynamic assessments. Pharmacokinetic and pharmacodynamic parameters were determined using non-compartmental methods. RESULTS: The reticulocyte count-time profiles in the intravenous GC1113 3-5 µg/kg groups were comparable with those of the darbepoetin alfa 30 µg group. After subcutaneous administration of GC1113, reticulocyte count peaked later and decreased more slowly than it did following darbepoetin alfa administration. GC1113 (0.3-5 µg/kg intravenous, 1-8 µg/kg subcutaneous) was well-tolerated in the volunteers, and no immunogenicity was observed. CONCLUSION: GC1113 was tolerated and effective in the studied dose range; these findings could be applied to further clinical studies with patients.

Relationship between absolute neutrophil count profiles and pharmacokinetics of DA-3031, a pegylated granulocyte colony-stimulating factor (pegylated-G-CSF): a dose block-randomized, double-blind, dose-escalation study in healthy subjects.

BACKGROUND: DA-3031 is a newly developed pegylated filgrastim, a recombinant human granulocyte colony-stimulating factor, that is expected to have an extended duration of action compared with non-modified filgrastim. OBJECTIVE: This study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of DA-3031 in humans, and compared them with filgrastim. METHODS: The study was conducted in 48 healthy male Korean subjects. Forty subjects received subcutaneous single doses of 1.8, 3.6, 6, or 18 mg of DA-3031 or placebo in a dose block-randomized, double-blind, dose-escalation design. The remaining eight subjects were given subcutaneous doses of 100 µg/m² of filgrastim daily for 5 days. Serial blood samples were collected for pharmacokinetic and pharmacodynamic analyses up to 312 h after the administration of DA-3031 and up to 264 h following the first administration of filgrastim. RESULTS: DA-3031 reached its peak plasma concentration at 6.0-48.0 h and was eliminated mono-exponentially. The pharmacokinetic parameters of DA-3031 increased with dose in a non-linear fashion. Absolute neutrophil count (ANC) levels increased with the dose of DA-3031, although the extent of the increase in ANC decreased at higher dose levels. DA-3031 resulted in similar ANC changes in the 3.6 to 6 mg dose range as 100 µg/m² of filgrastim. The most frequent adverse event was back pain, which was observed after both DA-3031 and filgrastim administration. CONCLUSIONS: DA-3031 showed non-linear pharmacodynamic and pharmacokinetic profiles and an extended duration of action compared with non-modified filgrastim, without unexpected toxicities in healthy subjects.