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Relationship between <i>CES2</i> genetic variations and rifampicin metabolism
Song, Sang Hoon,Chang, Ho Eun,Jun, Sun Hee,Park, Kyoung Un,Lee, Jae Ho,Lee, Eun-Mi,Song, Young-Han,Song, Junghan Oxford University Press 2013 The Journal of antimicrobial chemotherapy Vol.68 No.6
<P><B>Objectives</B></P><P>Rifampicin is known to be deacetylated <I>in vivo</I>, resulting in its metabolite 25-desacetyl rifampicin, but the enzyme metabolizing rifampicin and the association of this process with any genetic variation have not yet been elucidated. In this study, genetic variations of a surrogate enzyme, carboxylesterase 2 (CES2), and their association with the metabolism of this drug, were investigated.</P><P><B>Methods</B></P><P>Plasma concentrations of rifampicin and 25-desacetyl rifampicin were measured in 35 patients with tuberculosis receiving a first-line antituberculosis treatment. Direct PCR-based sequencing of the <I>CES2</I> gene, covering all 12 exons, the 5′-untranslated region (UTR), the 3′-UTR and intronic and promoter regions, was performed. A dual luciferase reporter assay was carried out to assess whether variations in the promoter region affected the transcription of this gene.</P><P><B>Results</B></P><P>Ten variations were detected, of which two were in the candidate promoter region, five in introns and three in the 3′-UTR. One of the variations in the 3′-UTR was a novel variation. Genotypes at three closely linked variations (c.−2263A > G, c.269-965A > G and c.1612 + 136G > A) and c.1872*302_304delGAA were associated with significantly different plasma rifampicin concentrations. The mean plasma rifampicin concentration significantly increased with the number of risk alleles at the three closely linked variations, while the plasma concentration decreased along with an increase in the number of risk alleles at c.1872*302_304delGAA. When HepG2 cells were transfected with a luciferase reporter construct bearing the c.−2263G allele, luciferase activities were consistently decreased (by 5%–10%) compared with those harbouring the c.−2263A sequence.</P><P><B>Conclusions</B></P><P>Variations in <I>CES2</I>, especially c.−2263A > G in the promoter region, may alter rifampicin metabolism by affecting expression of the gene.</P>
Song, Sang Hoon,Jun, Sun Hee,Park, Kyoung Un,Yoon, Yeomin,Lee, Jae Ho,Kim, Jin Q,Song, Junghan John Wiley Sons, Ltd. 2007 Rapid communications in mass spectrometry Vol.21 No.7
<P>Monitoring of anti-tuberculosis drug concentrations and dose adjustment can be helpful in cases that show poor response to treatment. Here, we describe a method that can rapidly and simultaneously measure the blood concentrations of four anti-tuberculosis drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) and two major metabolic ratios (acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin) using high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A C18 reversed-phase column and gradients of methanol in 0.3% formic acid and water were used for HPLC separation. The drug concentrations were determined by multiple reaction monitoring in positive ion mode and the assay performance was evaluated. We determined peak concentration ranges for each drug and acetylisoniazid/isoniazid and 25-desacetylrifampicin/rifampicin ratios by analyzing 2-h post-dose samples in patients treated with standard dosing as a first-line treatment. The preparation of 20 samples including two steps of deproteinization with 50% and 100% methanol was performed within 20 min and chromatographic separation was achieved within 4 min/sample. Interassay calibration variability data obtained over concentrations of 0–8 µg/mL for isoniazid and ethambutol and 0–80 µg/mL for rifampicin and pyrazinamide showed a linear and reproducible curve. Within-run and between-run imprecision (CVs) were 1.9–5.5% and 3.5–10.5% and the lower limits of detection and quantification were 0.01–0.5 µg/mL and 0.05–1.0 µg/mL, respectively. The isoniazid concentration was found to be inversely correlated to the acetylisoniazid/isoniazid ratio (R = −0.739, P < 0.001). The devised method allows for the simple, rapid, sensitive and reproducible quantification of isoniazid, rifampicin, pyrazinamide, ethambutol and their two metabolic ratios and should be helpful for therapeutic drug monitoring in tuberculosis patients. Copyright © 2007 John Wiley & Sons, Ltd.</P>
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송정한(Junghan Song),허훈(Hoon Huh),김세호(Seho Kim),박성호(Sungho Park) 한국자동차공학회 2005 한국자동차공학회 춘 추계 학술대회 논문집 Vol.2005 No.11_3
Springback is a common phenomenon in sheet metal forming since the elastic recovery of the internal stresses is induced after removal of the tooling. The numerical analysis of spring back is a complicated time-consuming job and its result is greatly effected by a type of the yield function, finite elements used and the constraint condition for eliminating a rigid body motion. In this paper, optimization of the draw-bead force is carried out utilizing the response surface method in order to reduce springback and improve shape accuracy of a deep drawn product. In the optimization process, the tendency of springback is evaluated qualitatively without springback simulation usually done with the implicit solving scheme. Instead of springback simulation, the amount of stress deviation along the thickness direction in the deep drawn product is used as an indicator of springback. The stamping process is analyzed for a front side member formed with advanced high strength steel (AHSS) sheets such as DP60. The analysis procedure fully covers the binder-wrap, stamping, trimming and springback processes with the commercial elasto-plastic finite element code LS-DYNA 3D. The effect of the restraining force of draw-beads is con finned with the decreased stress deviation. The analysis result shown in the final springback simulation demonstrates that the present analysis provides a guideline for controlling the evolution of spring back based on the finite element simulation of complicated auto-body members.
송정한(Junghan Song),허훈(Hoon Huh),김홍기(Honggee Kim),박성호(Sungho Park) 한국자동차공학회 2004 한국자동차공학회 춘 추계 학술대회 논문집 Vol.- No.-
Simulation of vehicle crashes using the finite element method has made major advances in the last several years. Every major automotive company now uses CAE to perform virtual crash tests. Designers can mow quickly adjust the structural performance before performing a physical crash test. Compared to physical crash tests, the virtual simulation is less costly and faster which allows manufactures to reduce costs and vehicle development time. In order to produce more efficient and precise simulations, it is needed to adopt the dynamic property of materials and the failure modeling of resistance spot weld. The resistance spot weld in most current finite element crash models are characterized as a rigid beam at the location of the weld. The role of this rigid beam is simply to transfer the load across the welded component. The spot weld elements is design to be failed by some failure criteria which is function of axial and shear load at the rigid beam. For this reason, the calculation of the load at the rigid beam is important to predict the failure of the spot weld. In this paper, the numerical simulations are carried out to evaluate the calculation of the load at the rigid beam. The first study conducted is to examine the effect of mesh size on the load at the rigid beam. The effect of element shape on the welded components is, then, investigated. Finally, the location and the number of welded constrains is changed for the correct prediction of the load on the spot weld element. The analysis results demonstrate that the correct prediction of the load on the spot weld element is achieved by the change of the element shape on the welded component s and the location of welded constrains.
송정한(Junghan Song),허훈(Hoon Huh),임지호(Jiho Lim),박성호(Sungho Park) 한국자동차공학회 2008 한국자동차공학회 춘 추계 학술대회 논문집 Vol.- No.-
This paper is concerned with the evaluation of the dynamic failure load of the spot weld under combined axial and shear loading conditions. The testing fixture are designed to impose the combined axial and shear load on the spot weld. Using the proposed testing fixtures and specimens, quasi-static and dynamic failure tests of the spot weld are conducted with seven different combined loading conditions. The failure load and failure behavior of the spot weld are investigated with different loading conditions. Dynamic effects on the failure load of the spot weld, which is critical for structural crash worthiness, are also examined based on the experimental data. In order to evaluate the effect of the strain rate on the failure contour of the spot weld under combined axial and shear loads, the failure loads measured from the experiment are decomposed into the two components along the axial and shear directions. Experimental results indicate that the failure contour is expanded with increasing strain rates according to the rate sensitivity of the ultimate stress for welded material.