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Lee, Ji-Sook,Son, Hee-Sook,Song, Chang-Hwa,Kim, Hwa-Jung,Park, Jeong-Kyu,Paik, Tae-Hyun,Suhr, Ji-Won,Kim, Chul-Hee,Kong, Suck-Jun,Shon, Mal-Hyun,Jo, Eun-Kyeong The Korean Society for Microbiology 2002 Journal of Bacteriology and Virology Vol.32 No.2
In this study, we investigated profiles of the cytokines IFN-${\gamma}$, IL-12, and IL-10 in active pulmonary tuberculosis (EAPTB) patients, HIV-negative patients with multidrug-resistant tuberculosis (MDR-TB) and in healthy tuberculin reactors (HTR). We studied the responses of peripheral blood mononuclear cells (PBMC) from 12 EAPTB patients and 15 MDR-TB patients to stimulation with a purified protein derivatives (PPD) antigen (Ag), and compared them with those from 14 HTR. Using ELISA, IFN-${\gamma}$ production was found to be significantly depressed, while IL-10 was significantly elevated in both MDR-TB and EAPTB after in vitro stimulation with PPD, compared with those in HTR. Although there was no significant difference in IL-12 production among the three groups, mean IL-12 production was highest in patients with MDR-TB. In these patients, IL-12 production was significantly correlated with IL-10 expression, but not IFN-${\gamma}$ production. In addition, neutralization of endogenous IL-10 led to enhanced IFN-${\gamma}$ and IL-$12R{\beta}2$ mRNA expression in TB patients. Our findings suggest that both groups of TB patients may have a similar disregulated pattern of IL-12, IL-10, and IFN-${\gamma}$ production during M. tuberculosis infection. Furthermore, the results suggest a potentially pathogenic role for IL-10 in impaired Th1 immune responses in TB patients.
Kim, Ho-Sook,Sunwoo, Yu Eun,Ryu, Ji Young,Kang, Ho-Jin,Jung, Hye-Eun,Song, Im-Sook,Kim, Eun-Young,Shim, Joo-Cheol,Shon, Ji-Hong,Shin, Jae-Gook Blackwell Publishing Ltd 2007 British journal of clinical pharmacology Vol.64 No.5
<P>Aims</P><P>To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties <I>in vitro</I>, on the disposition of lamivudine in healthy subjects.</P><P>Methods</P><P>To evaluate whether lamivudine is a substrate of ABCG2, intracellular accumulation and vectorial transport of <SUP>3</SUP>H-lamivudine were determined in MDCK-ABCG2 cells. The pharmacokinetic parameters of lamivudine were compared among subjects with four different ABCG2 genotypes, including wild type (seven subjects), K141/K141 (six subjects), Q126/Stop126 (four subjects) and M12/M12 (five subjects) after a single oral dose of 100 mg lamivudine.</P><P>Results</P><P>The intracellular accumulation of lamivudine in MDCK-ABCG2 cells was significantly lower than that in MDCK-mock cells, but fumitremorgin C reversed the intracellular lamivudine concentration to that of MDCK-mock cells. The ABCG2-mediated transport of lamivudine was saturable and the values of <I>K</I><SUB><I>m</I></SUB> and <I>V</I><SUB>max</SUB> were 216.5 ± 58 µ<SMALL>M</SMALL> and 20.42 ± 2.9 nmol h<SUP>−1</SUP> per 10<SUP>6</SUP> cells, respectively. After lamivudine administration to healthy subjects, the AUC of lamivudine showed no difference among subjects with different ABCG2 genotypes; 2480 ± 502, 2207 ± 1019, 2422 ± 239, 2552 ± 698 ng h<SUP>−1</SUP> ml<SUP>−1</SUP> for wild type, K141/K141, Q126/Stop126 and M12/M12 genotype, respectively (<I>P </I>= 0.85). The estimated 95% confidence intervals for the mean difference between K141/K141, Q126/Stop126, M12/M12 and wild as reference were (−1053, 507), (−555, 439) and (−552, 696), respectively. No other pharmacokinetic parameters were estimated to be significantly different among four different ABCG2 genotypes tested.</P><P>Conclusions</P><P>Lamivudine appeared to be a substrate of ABCG2 <I>in vitro</I>, but the disposition of lamivudine was not significantly influenced by known <I>in vitro</I> functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects.</P>
Lee, Ji-Sook,Lee, So-Hyun,Song, Chang-Hwa,Lim, Jae-Hyun,Kim, Hwa-Jung,Park, Jeong-Kyu,Paik, Tae-Hyun,Kim, Chul-Hee,Kong, Suck-Jun,Shon, Mal-Hyun,Jo, Eun-Kyeong The Korean Society for Microbiology 2002 Journal of Bacteriology and Virology Vol.32 No.4
Understanding human immune responses in chronic refractory tuberculosis (CRTB) is important for developing immunotherapy against the disease. the aim of this study was to examine cytokine responses [interferon (IFN)-$\gamma$, tumor necrosis factor (TNF)-$\alpha$, interleukirl (IL)-6, and IL-10] by peripheral blood mononuclear cells (PBMCs) in CRTB patients after in vitro stimulation with the 30-kDa or purified protein derivative (PPD) antigen (Ag). Most of the CRTB cases were multidrug-resistant (MDR) TB. The results were compared with those from early TB (E-TB) patients and healthy tuberculin reactors (HTR). IFN-$\gamma$ production was significantly depressed in both CRTB and E-TB groups compared with HTR. In response to the 30-kDa Ag, TNF-$\alpha$ levels were significantly depressed only in CRTB patients, while greatly increased in E-TB patients. In addition, IL-10 production was significantly increased in E-TB patients, and PBMC from both E-TB and CRTB patients secreted more IL-6 than HTR. IL-10 neutralization significantly increased TNF-$\alpha$ levels, whereas anti-TNF-$\alpha$ did not alter IL-10 induction significantly in PBMC from HTR and CRTB patients. Our findings suggest that CRTB patients have depression in both IFN-$\gamma$ and TNF-$\alpha$ reponses, which might play important roles during chronic M. tuberculosis infection.
Kim, Ho-Sook,Chang, Kiyuk,Koh, Yoon-Seok,Park, Mahn-Won,Choi, Yun-Seok,Park, Chul-Soo,Oh, Minkyung,Kim, Eun-Young,Shon, Ji-Hong,Shin, Jae-Gook,Seung, Ki-Bae American Heart Association, Inc. 2013 Circulation. Cardiovascular genetics Vol.6 No.5
<P><B>Background—</B></P><P>More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina.</P><P><B>Methods and Results—</B></P><P>Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27–6.53; <I>P</I>=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction <I>P</I>=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group.</P><P><B>Conclusions—</B></P><P>CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina.</P><P><B>Clinical Trial Registration Information—</B></P><P>URL: clinicaltrials.gov. Identifier: NCTO1239914.</P>
Jiang, Fen,Desta, Zeruesenay,Shon, Ji‐,Hong,Yeo, Chang‐,Woo,Kim, Ho‐,Sook,Liu, Kwang‐,Hyeon,Bae, Soo‐,Kyung,Lee, Sang‐,Seop,Flockhart, David A.,Shin, Jae‐,Goo Blackwell Publishing Ltd 2013 British journal of clinical pharmacology Vol.75 No.1
<P><B>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT</B></P><P>• Cytochrome P450 (CYP) 2B6 is the enzyme primarily responsible for the metabolism of many clinically important drugs, including efavirenz, which it converts to 8‐hydroxyefavirenz and then to 8,14‐hydroxyefavirenz.</P><P>• The CYP2B6*6 polymorphism influences efavirenz pharmacokinetics, but a validated phenotyping method for predicting CYP2B6 activity in human subjects is not yet available.</P><P>• The disposition of 8,14‐dihydroxyefavirenz in humans <I>in vivo</I> is unknown.</P><P><B>WHAT THIS STUDY ADDS</B></P><P>• This study is the first quantitative examination of 8,14‐dihydroxyefavirenz pharmacokinetics in human subjects.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio correlates with efavirenz oral clearance and is sensitive and specific to CYP2B6 activity alterations.</P><P>• The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio may be a useful phenotyping index for CYP2B6 activity <I>in vivo</I>.</P><P><B>AIMS</B> To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the <I>CYP2B6</I>*<I>6</I> genotype and explore potential phenotyping indices for CYP2B6 activity <I>in vivo</I> using a low dose of oral efavirenz.</P><P><B>METHODS</B> We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre‐genotyped for the <I>CYP2B6</I>*<I>6</I> allele (<I>CYP2B6</I>*<I>1</I>/*<I>1</I>, <I>n</I>= 6; *<I>1</I>/*<I>6</I>, <I>n</I>= 6; *<I>6</I>/*<I>6</I>, <I>n</I>= 5). Subjects were pretreated with clopidogrel (75 mg day<SUP>−1</SUP> for 4 days), itraconazole (200 mg day<SUP>−1</SUP> for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0–120 h) and urine (0–24 h) concentrations of efavirenz and its metabolites (7‐ and 8‐hydroxyefavirenz and 8,14‐dihydroxyefavirenz) were determined by LC/MS/MS.</P><P><B>RESULTS</B> This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), <I>C</I><SUB>max</SUB> and Ae(0,24 h) for 8,14‐dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14‐dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight‐adjusted CL/<I>F</I> of efavirenz (<I>r</I><SUP>2</SUP>≈ 0.4, <I>P</I> < 0.05), differed with <I>CYP2B6</I>*<I>6</I> genotype and was affected by clopidogrel pretreatment (<I>P</I> < 0.05) but not by itraconazole pretreatment.</P><P><B>CONCLUSIONS</B> The disposition of 8,14‐dihydroxy‐EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14‐dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity <I>in vivo</I>.</P>
한정아(Jeong A Han),추지은(Ji Eun Choo),손지원(Jee Won Shon),김윤숙(Youn Sook Kim),서수연(Su Yeon Suh),안원근(Won Gun An) 한국생명과학회 2019 생명과학회지 Vol.29 No.2
시스템 약리학적 분석을 통해 대회향(Anisi Stellati Fructus)의 활성성분 스크리닝, 표적유전자 확보 및 관련 질병과의 네트워크를 구축한 후 대회향의 항균작용을 중점적으로 분석하였다. Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database 와 Analysis Platform을 통해 대회향의 잠재적 활성성분 49개를 확보하였으며, 그 중 설정한 조건에 부합하는 9개 활성성분을 스크리닝 하였다. TCMSP Database는 활성성분의 약물 동태학적 특성 및 약물-표적-질병 간의 관련성을 네트워크 수준에서 파악할 수 있는 획기적인 in silico적 접근을 가능하게 해준다. 활성성분과 반응하는 201개의 유전자 정보를 UniProt database를 통해 확인하고, 취합한 유전자들이 관여하는 348개의 생물학적 과정을 David 6.8 Gene Functional Classification Tool에서 확보하였다. Chemokine ligand 2, Interleukin-10, Interleukin-6, Tumor Necrosis Factor를 포함한 총 47개의 유전자가 항균작용에 관여하였고 이들을 표적으로 하는 luteolin, kaempferol, quercetin 등이 대표적 항균 관련 활성성분이었다. 이와 같이 확보된 데이터는 연구 재료 선정에 정확성과 시간, 노력, 비용 절감의 효과를 제공함과 더불어 추후 실험적 증명으로 이어져 감염병의 예방과 치료 전략에 과학적인 근거를 제시할 수 있을 것이다. The purpose of this study was to acquire the active compounds of Anisi stellati fructus (ASF) and to analyze the genes and diseases it targets, focusing on its antibacterial effects using a system pharmacological analysis approach. Active compounds of ASF were obtained through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform. This contains the pharmacokinetic properties of active compounds and related drug–target–disease networks, which is a breakthrough in silico approach possible at the network level. Gene information of targets was gathered from the UnitProt Database, and gene ontology analysis was performed using the David 6.8 Gene Functional Classification Tool. A total of 201 target genes were collected, which corresponded to the nine screened active compounds, and 47 genes were found to act on biological processes related to antimicrobial activity. The representative active compounds involved in antibacterial action were luteolin, kaempferol, and quercetin. Among their targets, Chemokine ligand2, Interleukin-10, Interleukin-6, and Tumor Necrosis Factor were associated with more than three antimicrobial biological processes. This study has provided accurate evidence while saving time and effort to select future laboratory research materials. The data obtained has provided important data for infection prevention and treatment strategies.