Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations.

Increased cardiovascular risk in Korean patients with systemic lupus erythematosus: a population-based cohort study.

To determine the increased risk of major adverse cardiovascular events (MACE) in patients with systemic lupus erythematosus (SLE) compared to the general population in Korea. Using data from the National Health Insurance Service database spanning 2008 to 2018, incident SLE patients aged 18 years and above were selected along with a 1:4 age- and sex-matched control group. The crude incidence rate (IR) of MACE was calculated as the number of events per 1000 person-years and the IR ratio (IRR) for MACE was adjusted using generalized estimating equations. Subgroup analysis was conducted to evaluate the risk differences of overall MACE and its composites based on age and sex stratification. The study included 8568 SLE patients and 34,272 controls. The cumulative IR of MACE per 1000 person-years in SLE patients and controls were 4.08 and 1.30, respectively. After adjusting for confounders, SLE patients had a higher risk of MACE compared to the general population (adjusted IRR of 2.40 [95% confidence interval [CI] 1.88-3.05]), with no gender differences observed. The increased risk of MACE in SLE patients was highest in the 18-39 age group (IRR 11.70, 95% CI 5.95-23.01) and gradually decreased with age. The increased risk of ischemic stroke (IRR 2.41, 95% CI 1.84-3.15) and myocardial infarction (IRR 2.19, 95% CI 1.30-3.68) in SLE patients was comparable. The risk of MACE in SLE patients is 2.40 times higher than that of the general population, with a higher relative risk observed in younger individuals.

PSME4 Degrades Acetylated YAP1 in the Nucleus of Mesenchymal Stem Cells.

Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group previously elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly accelerates the cardiac commitment of naïve mesenchymal stem cells (MSCs) through acute loss of YAP1. Here, we propose the novel regulation of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteasomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteasomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed the subcellular localization of YAP1. Apicidin successfully induced acetylation and subsequent dissociation of YAP1 from 14-3-3, an essential molecule for cytoplasmic restriction. HDAC6 regulated both acetylation and subcellular localization of YAP1. An acetylation-dead mutant of YAP1 retarded nuclear redistribution upon apicidin treatment. We failed to acquire convincing evidence for polyubiquitination-dependent degradation of YAP1, suggesting that a polyubiquitination-independent regulator determined YAP1 fate. Nuclear PSME4, a subunit of the 26 S proteasome, recognized and degraded acetyl YAP1 in the nucleus. MSCs from PSME4-null mice were injected into infarcted heart, and aberrant sudden death was observed. Injection of immortalized human MSCs after knocking down PSME4 failed to improve either cardiac function or the fibrotic scar area. Our data suggest that acetylation-dependent proteasome subunit PSME4 clears acetyl-YAP1 in response to apicidin treatment in the nucleus of MSCs.

Pharmacokinetic Model Based on Stochastic Simulation and Estimation for Therapeutic Drug Monitoring of Tacrolimus in Korean Adult Transplant Recipients.

BACKGROUND: Tacrolimus shows high variability in inter- and intraindividual pharmacokinetics (PK); therefore, it is important to develop an appropriate model for accurate therapeutic drug monitoring (TDM) procedures. This study aimed to develop a pharmacokinetic model for tacrolimus that can be used for TDM procedures in Korean adult transplant recipients by integrating published models with acquired real-world TDM data and evaluating clinically meaningful covariates. METHODS: Clinical data of 1829 trough blood samples from 269 subjects were merged with simulated data sets from published models and analyzed using a nonlinear mixed-effect model. The stochastic simulation and estimation (SSE) method was used to obtain the final parameter estimates. RESULTS: The final estimated values for apparent clearance, the volume of distribution, and absorption rate were 21.2 L/h, 510 L, and 3.1/h, respectively. The number of postoperative days, age, body weight, and type of transplant organs were the major clinical factors affecting tacrolimus PK. CONCLUSIONS: A tacrolimus PK model that can incorporate published PK models and newly collected data from the Korean population was developed using the SSE method. Despite the limitations in model development owing to the nature of TDM data, the SSE method was useful in retrieving complete information from the TDM data by integrating published PK models while maintaining the variability of the model.

Nitrosative Stress and Human Disease: Therapeutic Potential of Denitrosylation.

Proteins dynamically contribute towards maintaining cellular homeostasis. Posttranslational modification regulates the function of target proteins through their immediate activation, sudden inhibition, or permanent degradation. Among numerous protein modifications, protein nitrosation and its functional relevance have emerged. Nitrosation generally initiates nitric oxide (NO) production in association with NO synthase. NO is conjugated to free thiol in the cysteine side chain (S-nitrosylation) and is propagated via the transnitrosylation mechanism. S-nitrosylation is a signaling pathway frequently involved in physiologic regulation. NO forms peroxynitrite in excessive oxidation conditions and induces tyrosine nitration, which is quite stable and is considered irreversible. Two main reducing systems are attributed to denitrosylation: glutathione and thioredoxin (TRX). Glutathione captures NO from S-nitrosylated protein and forms S-nitrosoglutathione (GSNO). The intracellular reducing system catalyzes GSNO into GSH again. TRX can remove NO-like glutathione and break down the disulfide bridge. Although NO is usually beneficial in the basal context, cumulative stress from chronic inflammation or oxidative insult produces a large amount of NO, which induces atypical protein nitrosation. Herein, we (1) provide a brief introduction to the nitrosation and denitrosylation processes, (2) discuss nitrosation-associated human diseases, and (3) discuss a possible denitrosylation strategy and its therapeutic applications.

S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction.

BACKGROUND: Although the clinical importance of heart failure with preserved ejection fraction has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit. Although the clinical characteristics of heart failure with preserved ejection fraction are somewhat heterogeneous, diastolic dysfunction (DD) is one of the most important features. Here we report that neuronal NO synthase (nNOS) induces DD by S-nitrosylation of HDAC2 (histone deacetylase 2). METHODS: Two animal models of DD-SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) and mild transverse aortic constriction mice-as well as human heart samples from patients with left ventricular hypertrophy were used. Genetically modified mice that were either nNOS-ablated or HDAC2 S-nitrosylation-resistant were also challenged. N(ω)-propyl-L-arginine, an nNOS selective inhibitor, and dimethyl fumarate, an NRF2 (nuclear factor erythroid 2-related factor 2) inducer, were used. Molecular events were further checked in human left ventricle specimens. RESULTS: SAUNA or mild transverse aortic constriction stress impaired diastolic function and exercise tolerance without overt systolic failure. Among the posttranslational modifications tested, S-nitrosylation was most dramatically increased in both models. Utilizing heart samples from both mice and humans, we observed increases in nNOS expression and NO production. N(ω)-propyl-L-arginine alleviated the development of DD in vivo. Similarly, nNOS knockout mice were resistant to SAUNA stress. nNOS-induced S-nitrosylation of HDAC2 was relayed by transnitrosylation of GAPDH. HDAC2 S-nitrosylation was confirmed in both DD mouse and human left ventricular hypertrophy. S-nitrosylation of HDAC2 took place at C262 and C274. When DD was induced, HDAC2 S-nitrosylation was detected in wild-type mouse, but not in HDAC2 knock-in mouse heart that expressed HDAC2 C262A/C274A. In addition, HDAC2 C262A/C274A mice maintained normal diastolic function under DD stimuli. Gene delivery with adenovirus-associated virus 9 (AAV9)-NRF2, a putative denitrosylase of HDAC2, or pharmacological intervention by dimethyl fumarate successfully induced HDAC2 denitrosylation and mitigated DD in vivo. CONCLUSIONS: Our observations are the first to demonstrate a new mechanism underlying DD pathophysiology. Our results provide theoretical and experimental evidence to explain the ineffectiveness of conventional NO enhancement trials for improving DD with heart failure symptoms. More important, our results suggest that reduction of NO or denitrosylation of HDAC2 may provide a new therapeutic platform for the treatment of refractory heart failure with preserved ejection fraction.

Serum Ferritin as a Diagnostic Biomarker for Kawasaki Disease.

Diagnosis of Kawasaki disease (KD) is occasionally delayed because it is solely based on clinical symptoms. Previous studies have attempted to identify diagnostic biomarkers for KD. Recently, patients with KD were reported to have elevated serum ferritin levels. We investigated the usefulness of the serum ferritin level as a diagnostic biomarker for distinguishing KD from other acute febrile illnesses. Blood samples were obtained from pediatric patients with KD (N=77) and those with other acute febrile illnesses (N=32) between December 2007 and June 2011 for measuring various laboratory parameters, including serum ferritin levels. In patients with KD, laboratory tests were performed at diagnosis and repeated at 2, 14, and 56 days after intravenous immunoglobulin treatment. At the time of diagnosis, serum ferritin levels in patients with KD (188.8 µg/L) were significantly higher than those in patients with other acute febrile illnesses (106.8 µg/L, P=0.003). The serum ferritin cut-off value of 120.8 µg/L effectively distinguished patients with KD from those with other acute febrile illnesses, with a sensitivity and specificity of 74.5% and 83.3%, respectively. Serum ferritin may be a useful biomarker to distinguish KD from other acute febrile illnesses.

Comparison of In Vivo Pharmacokinetics and Pharmacodynamics of Vancomycin Products Available in Korea.

PURPOSE: Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator. MATERIALS AND METHODS: The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice. RESULTS: Generic products had a lower proportion of vancomycin B (range: 90.3-93.8%) and a higher proportion of impurities (range: 6.2-9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (Cmax) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p<0.1). In the thigh-infection model, the maximum efficacies of generic products reflected in maximal effect (Emax) values were not significantly different from the innovator. However, the PD profile curves of some generic products differed significantly from that of the innovator in mice injected with a high level of Mu3 (all p≤0.05). CONCLUSION: Some generic vancomycin products available in Korea showed inferior PK and PD profiles, especially in mice infected with hetero-vancomycin-resistant Staphylococcus aureus.

A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis.

RATIONALE: Glecaprevir/pibrentasvir, a pan-genotypic and ribavirin-free direct acting antiviral agent regimen, has shown significant efficacy and very few serious complications. However, as the drug metabolizes in the liver, it is not recommended in patients with decompensated liver cirrhosis. Herein, we report the case of a patient with compensated liver cirrhosis who developed severe jaundice after glecaprevir/pibrentasvir medication. PATIENT CONCERNS: A 77-year-old man diagnosed with chronic hepatitis C-related compensated liver cirrhosis visited hospital due to severe jaundice after 12 weeks of glecaprevir/pibrentasvir medication. DIAGNOSES: On the laboratory work-up, the total/direct bilirubin level was markedly elevated to 21.56/11.68 from 1.81 mg/dL; the alanine aminotransferase and aspartate aminotransferase levels were within the normal range. We checked the plasma drug concentration level of glecaprevir, and 18,500 ng/mL was detected, which was more than 15 times higher than the drug concentration level verified in normal healthy adults. INTERVENTIONS: Glecaprevir/pibrentasvir was abruptly stopped and after 6 days, the drug concentration level decreased to 35 ng/mL and the serum total/direct bilirubin decreased to 7.49/4.06 mg/dL. OUTCOMES: Three months after drug cessation, the serum total bilirubin level normalized to 1.21 mg/dL and HCV RNA was not detected. LESSONS: We report what is likely the first known case of severe jaundice after medication with glecaprevir/pibrentasvir in a patient with compensated liver cirrhosis. Clinicians should bear potential hyperbilirubinemia in mind when treating chronic hepatitis C with this regimen and should monitor the patient closely during follow-up laboratory exams, especially in elderly cirrhotic patients.

In Vitro Synergy and In Vivo Activity of Tigecycline-Ciprofloxacin Combination Therapy against Vibrio vulnificus Sepsis.

The mortality rate associated with Vibrio vulnificus sepsis remains high. An in vitro time-kill assay revealed synergism between tigecycline and ciprofloxacin. The survival rate was significantly higher in mice treated with tigecycline plus ciprofloxacin than in mice treated with cefotaxime plus minocycline. Thus, combination treatment with tigecycline-ciprofloxacin may be an effective novel antibiotic regimen for V. vulnificus sepsis.

Author Correction: PP2A negatively regulates the hypertrophic response by dephosphorylating HDAC2 S394 in the heart.

After the publication of this article, the authors noticed an error in one of the grant numbers (2015R1A2A1A05001708) in the Acknowledgements section.

HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases.

Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.

PP2A negatively regulates the hypertrophic response by dephosphorylating HDAC2 S394 in the heart.

Cardiac hypertrophy occurs in response to increased hemodynamic demand and can progress to heart failure. Identifying the key regulators of this process is clinically important. Though it is thought that the phosphorylation of histone deacetylase (HDAC) 2 plays a crucial role in the development of pathological cardiac hypertrophy, the detailed mechanism by which this occurs remains unclear. Here, we performed immunoprecipitation and peptide pull-down assays to characterize the functional complex of HDAC2. Protein phosphatase (PP) 2 A was confirmed as a binding partner of HDAC2. PPP2CA, the catalytic subunit of PP2A, bound to HDAC2 and prevented its phosphorylation. Transient overexpression of PPP2CA specifically regulated both the phosphorylation of HDAC2 S394 and hypertrophy-associated HDAC2 activation. HDAC2 S394 phosphorylation was increased in a dose-dependent manner by PP2A inhibitors. Hypertrophic stresses, such as phenylephrine in vitro or pressure overload in vivo, caused PPP2CA to dissociate from HDAC2. Forced expression of PPP2CA negatively regulated the hypertrophic response, but PP2A inhibitors provoked hypertrophy. Adenoviral delivery of a phosphomimic HDAC2 mutant, adenovirus HDAC2 S394E, successfully blocked the anti-hypertrophic effect of adenovirus-PPP2CA, implicating HDAC2 S394 phosphorylation as a critical event for the anti-hypertrophic response. PPP2CA transgenic mice were protected against isoproterenol-induced cardiac hypertrophy and subsequent cardiac fibrosis, whereas simultaneous expression of HDAC2 S394E in the heart did induce hypertrophy. Taken together, our results suggest that PP2A is a critical regulator of HDAC2 activity and pathological cardiac hypertrophy and is a promising target for future therapeutic interventions.

Usefulness of Age-Stratified N-Terminal Prohormone of Brain Natriuretic Peptide for Diagnosing Kawasaki Disease.

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was recently reported as a biomarker for diagnosing Kawasaki disease (KD). The basal NT-proBNP level, however, gradually decreases with age. We investigated the usefulness of an age-stratified cutoff value of NT-proBNP for diagnosing KD. All the patients enrolled in this study visited Chonnam National University Hospital between December 2007 and March 2016. The KD groups consisted of 214 patients with complete KD and 129 patients with incomplete KD. The control group included 62 children with simple febrile illness but without heart disease. Laboratory data including NT-proBNP level were evaluated. Each group was divided into subgroups according to patient age (<6 months, 6-12 months, 12-24 months, and >24 months), and different cutoff values of NT-proBNP were calculated. The cutoff values of NT-proBNP used to diagnose total KD and incomplete KD were 762 and 762 pg/mL (<6 months), 310 and 310 pg/mL (6-12 months), 326 and 326 pg/mL (12-24 months), and 208 and 137 pg/mL (>24 months), respectively. In conclusion, age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of KD in patients with a simple febrile illness.

Effect of the allelic variants of ABCB1, CYP2D6 and HTR3B on response of ramosetron to prevent chemotherapy-induced nausea and vomiting in Korean cancer patients.

AIM: Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT3 receptor antagonist in a dose escalation clinical trial. METHODS: We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA. RESULTS: There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B-100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy. CONCLUSION: These results suggest that the -AAG deletion variant of the 5-HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis.

Associations between sleep duration and abnormal serum lipid levels: data from the Korean National Health and Nutrition Examination Survey (KNHANES).

BACKGROUND: Shorter or longer sleep duration has been reported to be associated with abnormal serum lipid levels, but the findings have been inconsistent. This study examined associations between sleep duration and abnormal serum lipid levels in a Korean adult population. METHODS: This study used the data of 13,609 people aged ≥20 years from the Korean National Health and Nutrition Examination Survey (KNHANES) in 2010-2012. Sleep duration was classified into five groups: ≤5, 6, 7 (reference category), 8, and ≥9 hours. The serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride were measured and defined in terms of abnormal serum lipid levels. Multiple logistic regressions were performed to determine the associations between sleep duration and abnormal serum lipid levels. The covariates included age, sex, education, marital status, current smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, depressive symptoms, and stress level. RESULTS: Self-reported sleep duration of ≤5 hours was significantly associated with high TC and high LDL-C levels in unadjusted models, but after adjusting for age and sex, the statistical significance disappeared. On the other hand, after adjusting for covariates, self-reported sleep duration of ≥9 h was significantly associated with low HDL-C levels (odds ratio = 1.30; 95% confidence interval = 1.09-1.54). CONCLUSIONS: These findings suggest that longer sleep duration is associated with low HDL-C levels among Korean adults.

Relationships between high-density lipoprotein cholesterol and depressive symptoms: Findings of the Korean National Health and Nutrition Examination Survey (KNHANES).

Although serum cholesterol has been associated with late-life depression, few studies on the associations between lipids and depression among middle-aged adults have been performed. This study examined associations between serum lipid levels and depressive symptoms in Korean middle-aged adults. We used data from 8207 participants aged 40-64 years who completed a questionnaire about their experience of depressive symptoms over the last year as part of the 2010-2012 Korean National Health and Nutrition Examination Survey. Higher HDL-C levels were significantly associated with an elevated risk of depressive symptoms (OR=1.32; 95% CI=1.09-1.60) after adjusting for other covariates.

Associations between serum lipid levels and suicidal ideation among Korean older people.

INTRODUCTION: There have been inconsistent reports on the relationships between lipids and suicidality, and studies conducted in older adults are rare. This study examined associations between serum lipid levels and suicidal ideation in an older population. METHODS: This study used data obtained from a representative Korean sample of 4265 people age 65 years or older who completed a self-administered questionnaire about suicidal ideation over the last year. The fasting serum concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured and categorized into lower, intermediate (reference), and upper quartiles. A complex sample logistic regression stratified by gender was performed to determine the associations between serum lipid levels and suicidal ideation after controlling for covariates including age, education, marital status, current smoking, alcohol drinking, body mass index, hypertension, diabetes, diagnosed depression, antidepressant use, and lipid-lowering therapies. RESULTS: In this study, the prevalence of suicidal ideation in an older Korean population was 22.9% (SE=0.9%). The prevalence was significantly higher in women than in men, 27.7% (1.2%) vs. 15.9% (1.1%) respectively. After adjusting for covariates, lower triglyceride levels were significantly associated with a decreased risk of suicidal ideation (OR=0.65; 95% CI=0.43-0.99) among men but no significant associations were observed among women. Additionally, there were no significant associations between any other measure of cholesterol levels and suicidal ideation in either men or women. LIMITATIONS: Cross-sectional design cannot infer temporality or the effects of changes in variables. CONCLUSIONS: These results support the association between lower triglyceride levels and a reduced risk of suicidal ideation among Korean men over 65. Further studies are necessary to investigate gender difference and the biological mechanism.