Soo-Han Lee

Ulsan College, Urusan, Ulsan, South Korea

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Publications (13)51.27 Total impact

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    ABSTRACT: Hepatitis C virus (HCV) is the major cause of progressive liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Previously, we reported that a 29 nucleotide-long 2'-F pyrimidine modified RNA aptamer against the HCV nonstructural protein 5B efficiently inhibited HCV replication and suppressed HCV infectious virus particle formation in a cell culture system. In this study, we modified this aptamer through conjugation of cholesterol for in vivo availability. This cholesterol-conjugated aptamer (chol-aptamer) efficiently entered the cell and inhibited HCV RNA replication, without any alteration in gene expression profiling including innate immune response-related genes. Moreover, systemic administration of the chol-aptamer was well tolerated without any abnormalities in mice. To evaluate the pharmacokinetics of the chol-aptamer in vivo, dose proportionality, bioavailability, and pharmacokinetic parameters were evaluated by noncompartmental analyses in normal BALB/c mice. Population analysis was performed using nonlinear mixed effects modeling. Moreover, the pharmacokinetics of two different routes (intravenous, IV, versus intraperitoneal, IP) were compared. Cholesterol conjugation showed dose proportionality, extended the time that the aptamer was in the plasma, and enhanced aptamer exposure to the body. Noticeably, the IV route was more suitable than the IP route due to the chol-aptamer remaining in the plasma for a longer period of time.
    Full-text · Article · Oct 2015 · Molecular Therapy - Nucleic Acids
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    ABSTRACT: Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at pre-set intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics were analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg, and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration, than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single- to multiple-dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each doses. Additionally, the memantine patch formulation displayed a smaller inter-individual variability and lower accumulation than the oral formulation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015 · Basic & Clinical Pharmacology & Toxicology
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    ABSTRACT: There have been no pharmacokinetic parameters and blood-brain equilibration rate constant (k e0) of propofol obtained in a single population of children, by which propofol can be administered using a target effect-site concentration controlled infusion. Thirty-nine, American Society of Anesthesiologists Physical Status 1-2 children aged 2-12 years were given an intravenous bolus of propofol (3 mg kg(-1)), followed by infusion (200 µg kg(-1) min(-1)). Arterial drug concentrations and bispectral index (BIS) values were measured. Population pharmacokinetic and pharmacodynamic analysis was performed using nonlinear mixed effects modeling. External model validation was performed in a separate population of children. A two-compartment model and a sigmoid E max model directly linked by an effect compartment well described the time courses of propofol concentration and BIS. The estimates of parameters were: V 1 (L) = 1.69, V 2 (L) = 27.2 + 0.929 × (weight - 25), Cl (L min(-1)) = 0.893 × (weight/23.6)(0.966), Q (L min(-1)) = 1.3; E 0 = 76.9; E max = 35.4, Ce 50 (μg mL(-1)) = 3.47 - (0.095 × age) - (1.63 × mean infusion rate of remifentanil in µg kg(-1) min(-1)); γ = 2.1; and k e0 (min(-1)) = 0.371. Pooled biases (95 % CI) of the target effect-site concentration controlled infusion system of propofol was -20.2 % (-23.3 to -18.1 %) and pooled inaccuracy was 30.4 % (28.6-32.7 %). Pooled biases of BIS prediction was -6.8 % (-9.1 to -4.1 %) and pooled inaccuracies was 19.1 % (17.5-20.9 %).The altered weight-based dose requirements of propofol are well described pharmacokinetically, and pharmacodynamically. Predictive performances of the TCI system in this study were clinically acceptable.
    No preview · Article · Feb 2015 · Journal of Pharmacokinetics and Pharmacodynamics
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    ABSTRACT: This study aimed to characterize pharmacodynamic interaction between propofol and aminophylline. Nine beagle dogs were randomly allocated at the propofol rates of 0.75 (group A), 1.00 (group B), and 1.25 (group C) mg/kg/min. During period 1, propofol only was infused, while during period 2, aminophylline only, at the rate of 0.69 (group A), 1.37 (group B), and 2.62 (group C) mg/kg/h. During periods 3-5, the two drugs were co-administered. The aminophylline infusion rate was 0.69 (period 3), 1.37 (period 4), and 2.62 (period 5) mg/kg/h. The aminophylline was infused from 0 to 30 h, and the propofol was infused at 24 h for 20 min. Blood samples and electroencephalograms were obtained at preset intervals. In the linear regression between log-transformed doses of aminophylline and AUC inf , the slope was 0.6976 (95 % CI 0.5242-0.8710). Pharmacokinetics of aminophylline was best described by a one-compartment, with enzyme auto-induction, model. Pharmacokinetics and pharmacodynamics of propofol were best described by a three-compartment model and a sigmoid E max model, respectively. Pharmacodynamic parameter estimates of propofol were: k e0 = 0.805/min, E 0 = 0.76, E max = 0.398, Ce 50 na = 2.38 μg/mL (without aminophylline-exposure), Ce 50 wa = 4.49 μg/mL (with aminophylline-exposure), and γ = 2.21. Propofol becomes less potent when exposed to aminophylline. Pharmacodynamic antagonistic interaction of aminophylline with propofol sedation, may occur, not in a dose-dependent manner, but in an all-or-none response.
    No preview · Article · Aug 2014 · Journal of Pharmacokinetics and Pharmacodynamics
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    ABSTRACT: This study was carried out to investigate the effects of pycnogenol (PYC) on the cutaneous wound healing of the mice. The wounds were extracted on days 1, 3, 5, and 7 post-injury for histomorphometrical analysis including wound area, infiltrating inflammatory cells, wound contracture including collagen deposition. As the result, the wound area of PYC-treated group was larger than the control group on days 1 to 7. Inflammatory cells in the PYC-treated wounds were decreased at day 1 compared to the control wound tissue. From day 3 to 7, there was no significant difference between the control and the PYC-treated skin wounds. Though the degree of contraction in the PYC-treated group was lower than that of the control group from days 1 to 5, but appeared significantly higher on day 7. Compared to the control group, collagen accumulation in the PYC-treated group was higher than that of the control group from days 5 to 7. From this result, it may support the possibility that PYC would be useful agent for early inflammatory response and matrix remodeling phase of the skin wounds.
    Full-text · Article · Dec 2013
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    ABSTRACT: This study identified specific and avid RNA aptamers consisting of 2′-hydroxyl- or 2′-fluoropyrimidines against hepatitis C virus (HCV) NS5B replicase, an enzyme that is essential for HCV replication. These aptamers acted as potent decoys to competitively impede replicase-catalyzed RNA synthesis activity. Cytoplasmic expression of the 2′-hydroxyl aptamer efficiently inhibited HCV replicon replication in human liver cells through specific interaction with, and sequestration of, the target protein without either off-target effects or escape mutant generation. A selected 2′-fluoro aptamer could be truncated to a chemically manufacturable length of 29 nucleotides (nt), with increase in the affinity to HCV NS5B. Noticeably, transfection of the truncated aptamer efficiently suppressed HCV replication in cells without escape mutant appearance. The aptamer was further modified through conjugation of a cholesterol or galactose-polyethylene glycol ligand for in vivo availability and liver-specific delivery. The conjugated aptamer efficiently entered cells and inhibited genotype 1b subgenomic and genotype 2a full-length HCV JFH-1 RNA replication without toxicity and innate immunity induction. Importantly, a therapeutically feasible amount of the conjugated aptamer was delivered in vivo to liver tissue in mice. Therefore, cytoplasmic expression of 2′-hydroxyl aptamer or direct administration of chemically synthesized and ligand-conjugated 2′-fluoro aptamer against HCV NS5B could be a potent anti-HCV approach.
    Full-text · Article · Apr 2013 · Journal of Virology
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    ABSTRACT: Carcinoembryonic antigen (CEA) is expressed by many types of cancer cells; its overexpression induces cell adhesion, increases resistance to anoikis, and promotes hepatic metastasis of colon cancer cells. The amino acid sequence PELPK in its hinge region, between the N and A1 domains, is required for migration of cancer cells to the liver. We sought to identify ligands of this domain for use in diagnosis and therapy. We screened for RNA aptamers against the domain of CEA required for metastasis using systematic evolution of ligands by exponential enrichment. The specificity and affinity of the aptamer for CEA protein were characterized by mobility shift, uptake, and surface plasmon resonance assays. We analyzed the effects of the aptamer on metastatic properties of cells, as well as metastasis of colon cancer cells in mice. Using systematic evolution of ligands by exponential enrichment, we identified an RNA aptamer that bound to the PELPK sequence in CEA with high affinity and specificity. The isolated aptamer bound specifically to CEA-positive cells and inhibited interactions between CEA and heterogeneous nuclear ribonucleoprotein M4. The aptamer inhibited homotypic aggregation, migration, and invasion by CEA-positive cancer cells, but did not affect adhesion of endothelial cells. The aptamer induced colon cancer cell anoikis by interrupting the interaction between death receptor 5 and CEA. The aptamer prevented metastasis of human colon cancer cells to the livers of mice. An RNA aptamer that binds to the PELPK sequence in CEA inhibits its interactions with heterogeneous nuclear ribonucleoprotein M4 and death receptor 5, migration and invasion by colon cancer cells, and hepatic metastasis of colon cancer cells in mice. It promoted cancer cell anoikis and might be used to identify CEA-positive tumors in patients or be developed as an anti-cancer reagent.
    Full-text · Article · Mar 2012 · Gastroenterology
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    ABSTRACT: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Remifentanil, an intravenous ultra short-acting opioid, depresses central nervous system activity with an increase in the delta band power, and causes beta activation after discontinuation, resulting in a rebound of the processed electroencephalographic parameters, including 95% spectral edge frequency, the canonical univariate parameter and electroencephalographic approximate entropy. • A sigmoid Emax model, in which the highest predicted values of processed electroencephalographic parameters are restricted to the baseline value, cannot describe a rebound of these parameters. • Electroencephalographic approximate entropy correlated well with the remifentanil blood concentration and demonstrated high baseline stability. WHAT THIS STUDY ADDS • A combined effect and tolerance model effectively characterized the time course of the remifentanil effect on the central nervous system, including the rebound which occurred during recovery from the remifentanil effect. • Temporal linear mode complexity was comparable with approximate entropy as a univariate electroencephalographic descriptor of the effect of remifentanil on the central nervous system. AIMS Previously, electroencephalographic approximate entropy (ApEn) effectively described both depression of central nervous system (CNS) activity and rebound during and after remifentanil infusion. ApEn is heavily dependent on the record length. Linear mode complexity, which is algorithmatically independent of the record length, was investigated to characterize the effect of remifentanil on the CNS using the combined effect and tolerance, feedback and sigmoid Emax models. METHODS The remifentanil blood concentrations and electroencephalographic data obtained in our previous study were used. With the recording of the electroencephalogram, remifentanil was infused at a rate of 1, 2, 3, 4, 5, 6, 7 or 8 µg kg−1 min−1 for 15–20 min. The areas below (AUCeffect) or above (AACrebound) the effect vs. time curve of temporal linear mode complexity (TLMC) and ApEn were calculated to quantitate the decrease of the CNS activity and rebound. The coefficients of variation (CV) of median baseline (E0), maximal (Emax), and individual median E0 minus Emax values of TLMC were compared with those of ApEn. The concentration–TLMC relationship was characterized by population analysis using non-linear mixed effects modelling. RESULTS Median AUCeffect and AACrebound were 1016 and 5.3 (TLMC), 787 and 4.5 (ApEn). The CVs of individual median E0 minus Emax were 35.6, 32.5% (TLMC, ApEn). The combined effect and tolerance model demonstrated the lowest Akaike information criteria value and the highest positive predictive value of rebound in tolerance. CONCLUSIONS The combined effect and tolerance model effectively characterized the time course of TLMC as a surrogate measure of the effect of remifentanil on the CNS.
    Full-text · Article · Jun 2011 · British Journal of Clinical Pharmacology
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    ABSTRACT: Polycystic ovary syndrome (PCOS) is hormonal imbalance condition as the endocrine and metabolic disorder that induces the infertility and various complications in reproductive age women. Estradiol valerate (EV) is used hormone replacement therapy in menopausal women and is reported that excessive administration of EV induces the PCOS. Nerve growth factor (NGF) is the factor to regulate the survival and maturation of developing neuronal cell and is also synthesized in ovary. And NGF is overexpressed in EV-induced polycystic ovary (PCO) as previously reported. Therefore, this study examined the possibility of NGF as can be used the biological marker in diagnosis of PCOS, the hormonal imbalance condition, using PCO and CHO (chinese hamster ovarian) cell lines. The concentration of EV treatment is optimized a 1 mg as not influence on the proliferation of CHO cell but 2 mg and 3 mg of EV treatment have the inhibition effect at initial stage. The morphological change was not observed in CHO cell after dose dependent manner treatment of EV. Expression of NGF mRNA and protein is significantly increased at 30 min after EV treatment in CHO cells compared to that of control. And NGF protein expression is strongly increased in PCO tissue, which observed many follicular cysts compared to normal ovary tissue. Taken together, overexpression of NGF may be act as a molecule to induce an abnormal development of follicle, suggesting that NGF can be used as a biological marker in diagnosis of PCOS.
    Full-text · Article · Jan 2011
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    ABSTRACT: To evaluate the incidence and severity of injection pain caused by microemulsion propofol and lipid emulsion propofol in relation to plasma bradykinin generation and aqueous free propofol concentrations. Injection pain was evaluated in 147 patients. Aqueous free propofol concentrations in each formulation, and in formulation mixtures containing agents that reduce propofol-induced pain, were measured by high-performance liquid chromatography. Plasma bradykinin concentrations in both formulations and in their components mixed with blood sampled from six volunteers were measured by radioimmunoassays. Injection pain caused by 8% polyethylene glycol 660 hydroxystearate (PEG660 HS) was evaluated in another 10 volunteers. The incidence of injection pain [visual analogue scale (VAS) >30 mm] caused by microemulsion and lipid emulsion propofol was 69.7 and 42.3% (P < 0.001), respectively. The median VAS scores for microemulsion and lipid emulsion propofol were 59 and 24 mm, respectively (95% confidence interval for the difference 12.5, 40.0). The aqueous free propofol concentration of microemulsion propofol was seven times higher than that of lipid emulsion propofol. Agents that reduce injection pain did not affect aqueous free propofol concentrations. Microemulsion propofol and 8% PEG660 HS enhanced plasma bradykinin generation, whereas lipid emulsion propofol and lipid solvent did not. PEG660 HS did not cause injection pain. Higher aqueous free propofol concentrations of microemulsion propofol produce more frequent and severe pain. The plasma kallikrein-kinin system may not be involved, and the agents that reduce injection pain may not act by decreasing aqueous free propofol concentrations.
    Preview · Article · Dec 2008 · British Journal of Clinical Pharmacology
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    ABSTRACT: A newly developed microemulsion propofol consisted of 10% purified poloxamer 188 and 0.7% polyethylene glycol 660 hydroxystearate. The authors studied the physicochemical properties, aqueous free propofol concentration, and plasma bradykinin generation. Pharmacokinetics and pharmacodynamics were also evaluated in rats. The pH, particle size, and osmolarity of microemulsion propofol were measured using a pH meter, particle size analyzer, and cryoscopic osmometer, respectively. The aqueous free propofol and plasma bradykinin were measured by a dialysis method and radioimmunoassay, respectively. Microemulsion propofol was administered by zero-order infusion of 0.5, 1.0, and 1.5 mg . kg . min for 20 min in 30 rats. The electroencephalographic approximate entropy was used as a surrogate measure of propofol effect. The pH, osmolarity, and particle size of microemulsion propofol are 7.5, 280 mOsm/l, and 67.0 +/- 28.5 nm, respectively. The aqueous free propofol concentration in microemulsion propofol was 63.3 +/- 1.2 mug/ml. When mixed with human blood, microemulsion propofol did not generate bradykinin in plasma. Although microemulsion propofol had nonlinear pharmacokinetics, a two-compartment model with linear pharmacokinetics best described the time course of the propofol concentration as follows: V1 = 0.143 l/kg, k10 = 0.175 min, k12 = 0.126 min, k21 = 0.043 min. The pharmacodynamic parameters in a sigmoid Emax model were as follows: E0 = 1.18, Emax = 0.636, Ce50 = 1.87 mug/ml, gamma = 1.28, ke0 = 1.02 min. Microemulsion propofol produced a high concentration of free propofol in the aqueous phase. For the applied dose range, microemulsion propofol showed nonlinear pharmacokinetics.
    No preview · Article · Oct 2008 · Anesthesiology
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    ABSTRACT: The aim of this trial was to evaluate the induction and recovery characteristics of microemulsion propofol (Aquafol; Daewon Pharmaceutical Co., Ltd., Seoul, Korea). Pharmacokinetics, pharmacodynamics, and safety profile were investigated. Lipid emulsion propofol (Diprivan; AstraZeneca, London, United Kingdom) was used as a comparator. Thirty-one healthy volunteers aged 20-79 yr were given an intravenous bolus of propofol 2 mg/kg, followed by variable rate infusion for 60 min. Each volunteer was studied twice with different formulations at an interval of 1 week. Arterial concentrations of propofol were measured, and Bispectral Index was used as a surrogate measure of propofol effect. The induction and recovery characteristics including bioequivalence were evaluated by noncompartmental analysis. The pharmacokinetics and pharmacodynamics were investigated using a population approach with mixed effects modeling. The rate, severity, and causal relation of adverse events were analyzed. Both formulations were bioequivalent. The observed time to peak effect after a bolus of both formulations was 1.5 min. Plasma concentration of propofol at loss of consciousness, time to loss of consciousness after a bolus, and time to recovery of consciousness after discontinuation of infusion did not show significant differences. The population pharmacokinetics and pharmacodynamics revealed a variety of differences between two formulations. Aquafol showed similar safety profile to Diprivan. The efficacy and safety of Aquafol were not different from those of Diprivan within the dose range in this study.
    No preview · Article · Jun 2007 · Anesthesiology
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    ABSTRACT: Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent that exhibits potent activity against most Gram-negative and Gram-positive organisms, and has a comparatively low chondrotoxic potential in immature animals. This study examined the effects of gemifloxacin on the Achilles tendons in immature Sprague-Dawley rats treated by oral intubation once daily for 5 consecutive days from postnatal week 4 onward at doses of 0 (vehicle), and 600mg/kg body weight Ofloxacin was used for comparison. The Achilles tendon sperimens were examined by electron microscopy. In comparison with the vehicle-treated controls, there were ultrastructural changes in all samples from the gemifloxacin- and ofloxacin-treated rats. Degenerative changes were observed in the tenocytes, and the cells that detached from the extracellular matrix were recognizable. The degree of degenerative changes and the number of degenerated cells in the Achilles tendon were significantly higher in the treated group than in the control group. Moreover, among the quinolone treated groups, these findings were more significant in the ofloxacin treated group, and less significant in the gemifloxacin treated group. It is unclear what these findings mean with respect to the possible risk ill juvenile patients treated with gemifloxacin or other quinolones. However, these results show that gemifloxacin causes fewer changes in the connective tissue structures.
    Full-text · Article · Jan 2006

Publication Stats

135 Citations
51.27 Total Impact Points

Institutions

  • 2015
    • Ulsan College
      Urusan, Ulsan, South Korea
  • 2011-2015
    • Konkuk University
      • College of Veterinary Medicine
      Sŏul, Seoul, South Korea
  • 2011-2012
    • University of Ulsan
      Urusan, Ulsan, South Korea
  • 2008
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea