선인장 양심실 보조장치의 설계 및 임상적용을 위한 평가

민병구,박찬영,최재순,이혁수,황창모,김삼성,윤걸중,김종원,선경,이경갑,정종태,김원곤 제주대학교 인공심장이식연구소 2001 인공심장 연구 Vol.2 No.1

현재 개발되고 있는 맥동형 이식형 인공심장은 완전이식형 인공심장과 좌심실보조장치 뿐이다. 좌심실보조장치를 장착한 환자의 10~15%가 우심실의 보조를 필요로하고 완전이식형 인공심장의 장착을 위해서는 자연심장을 제거해야하는 상황에서 이식형 양심실보조장치에 대한 필요성이 대두되고 있다. 본 연구진은 완전이식형 인공심장으로 개발된 한국형 인공심장을 개선하여 양심 실 보조장치를 개발하였다. 양심실보조장치는 이동형 작동기식 미케니즘을 이용하고 있으며 에너지 변환장치와 감속기로 구성된 작동기와 혈액주머니, 그리고 내장형 제어기로 구성되어 있다. 선인장 펌프로 명명된 KAH350은 캐뉼라의 연결을 위한 커넥터를 포함하여 길이 177mm, 폭 164mm, 높이 67 이고 무게 780g이며 최대 심박출량은 5L/min 이다. 양심실보조장치로 개발된 선인장펌프는 좌심실보조장치로도 응용이 가능하다. 이식적합성과 생체적합성을 평가하기 위하여 좌심실보조장치로 5회, 양싱실보조장치로 6회의 동물실험을 수행하였다. 각각 최장 28일간 생존하였으며 11회의 동물실험중 장치의 결함에 의한 것이 3회 있었는데 이들은 모두 전자장치의 결함과 방수처리문제였다. 현재 이식적합성과 일박출량을 향상시킨 KAH400모델이 개발중이다. The types of pulsatile implantable artificial hearts that are on the way of development and have been developed are totally implantable artificial heart and implantable left ventricular assist device (LVAD). Approximately 10% to 15% of all patients Implanted with wearable VADs have required right heart support with another device. And it is reluctant to patient who should remove his or her own heart to be implanted with total artificial heart. These situations drive the development of implantable bi-ventricular assist device (BVAD). The Korean BVAD was develophed by modifying the moving actuator type Korean artificial heart. This electro-mechanical BVAD comprises actuator including energy converter and reduction gear train, blood sacs, and internal motor and energy controllers. The KAH350 which is named as 'Cactus Pump' is 177mm in length, 164mm in width, and 67mm in thickness including connectors and nuts. The weight and maximum cardiac output of Cactus Pump is 780g and 5L/min, respectively. The Cactus Pump that was developed as BVAD could be used as LVAD by attaching compliance caps on the 2 ports of one ventricle. The animal experiments were undergone 5 times for LVAD, and 6 times for BVAD. The best records were 28 days survival in both applications. There were 3 times of device failure and they were all associated with electrical connection and hermetic sealing. The KAH400 that has improved anatomical fitting characterisitcs and stroke volume is on development.

Profiling of endogenous metabolites and changes in intestinal microbiota distribution after GEN-001 (Lactococcus lactis) administration

Kim Min-Gul,Kim Suin,Jeon Ji-Young,Moon Seol Ju,Kwak Yong-Geun,Na Joo Young,Lee SeungHwan,Park Kyung-Mi,Kim Hyo-Jin,Lee Sang-Min,Choi Seo-Yeon,Shin Kwang-Hee 대한약리학회 2024 The Korean Journal of Physiology & Pharmacology Vol.28 No.2

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 1011 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5–6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus, and higher levels of the metabolites that have immunogenic properties.

Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers

Kim, Tae-Eun,Ha, Na,Kim, Yunjeong,Kim, Hyunsook,Lee, Jae Wook,Jeon, Ji-Young,Kim, Min-Gul Dove Medical Press 2017 Drug design, development and therapy Vol.11 No.-

<P>Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration–time curve from time 0 to the last measurable time (AUC<SUB>last</SUB>) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67–0.97) and the peak plasma concentration (<I>C</I><SUB>max</SUB>) by 15% (geometric mean ratio 0.85, 90% CI 0.70–1.04). AUC<SUB>last</SUB> or <I>C</I><SUB>max</SUB> of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG.</P>

Comparative Pharmacokinetics of a Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and an Immediate-release Pregabalin Capsule in Healthy Male Volunteers

Kim, Tae-Eun,Jeon, Ji-Young,Gu, Namyi,Chang Kwon, Min,Kim, Min-Gul Elsevier 2018 Clinical therapeutics Vol.40 No.12

<P><B>Abstract</B></P> <P><B>Purpose</B></P> <P>Pregabalin is a widely used drug for the management of neuropathic pain. This study compared the pharmacokinetics of the GLA5PR GLARS-NF1 tablet, a 150-mg controlled-release formulation of pregabalin taken once daily, with those of a 75-mg immediate-release (IR) capsule formulation of pregabalin taken twice daily with a 12-h interval between doses.</P> <P><B>Methods</B></P> <P>Two separate studies, single dose and multiple dose, were conducted with a sequence-randomized, open-label crossover design. In the single-dose study, 30 participants each received 3 treatments: two 75-mg IR capsules taken 12 h apart, each after a high-fat meal (SRF treatment); a single 150-mg GLA5PR GLARS-NF1 tablet taken after a high-fat meal (STF treatment); and a single 150-mg GLAR5PR GLARS-NF1 tablet taken in an overnight-fasted state (ST treatment). In the multiple-dose study, 24 participants each received 2 treatments, both of which occurred over 3 days: one 75-mg IR capsule in the evening after a standardized meal and a second 75-mg IR capsule the following morning after a standardized meal, for 3 days (MRF treatment); and a single 150-mg GLA5PR GLARS-NF1 tablet in the evening after a standardized meal, for 3 days (MTF treatment). Blood samples for pharmacokinetic assessments were collected over the 36 h following drug administration in each treatment period.</P> <P><B>Findings</B></P> <P>In the single-dose study, the geometric mean ratios (GMRs) of the Cmax and the AUC<SUB>last</SUB> values of the GLA5PR GLARS-NF1 tablet to those of the IR capsules (STF/SRF) were 1.047 (90% CI, 0.971–1.129) and 0.757 (90% CI, 0.694–0.826), respectively. In the multiple-dose study, the GMRs (MTF/MRF) of the Cmax and the AUC values over the dosing interval were 1.277 (90% CI, 1.210–1.348) and 0.974 (90% CI, 0.933–1.017), respectively. The systemic pregabalin exposure from the GLA5PR GLARS-NF1 tablet was higher in the fed state than in the fasted state; GMRs (STF/ST): <I>C</I> <SUB>max</SUB>, 1.458 (90% CI, 1.353–1.573) and AUC<SUB>last</SUB>, 1.655 (90% CI, 1.518–1.804).</P> <P><B>Implications</B></P> <P>The overall pregabalin exposure after multiple administrations of GLA5PR GLARS-NF1 tablets was comparable to that after multiple administrations of the IR capsules. A single administration of the GLA5PR GLARS-NF1 tablet produced lower overall pregabalin exposure than that of the same dose administered in 2 IR capsules taken every 12 h. A high-fat diet significantly increased the bioavailability of the GLA5PR GLARS-NF1 tablet. ClinicalTrials.gov identifiers: NCT01638273 and NCT02326987.</P>

Effect of Red Ginseng on cytochrome P450 and P-glycoprotein activities in healthy volunteers

Kim, Dal-Sik,Kim, Yunjeong,Jeon, Ji-Young,Kim, Min-Gul The Korean Society of Ginseng 2016 Journal of Ginseng Research Vol.40 No.4

Background: We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. Methods: This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data using analysis of variance after RG administration versus before RG administration. Results: Fourteen healthy male participants were evaluated, none of whom were genetically defined as poor CYP2C9, 2C19, and CYP2D6 metabolizers based on genotyping. Before and after RG administration, the geometric least-square mean metabolic ratio (90% CI) was 0.870 (0.805-0.940) for caffeine to paraxanthine (CYP1A2), 0.871 (0.800-0.947) for losartan (CYP2C9) to EXP3174, 1.027 (0.938-1.123) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.373 (0.864-2.180) for dextromethorphan to dextrorphan (CYP2D6), and 0.824 (0.658-1.032) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time ($AUC_{last}$) for fexofenadine (P-gp) was 0.963 (0.845-1.098). Administration of concentrated RG for 2 wk weakly inhibited CYP2C9 and CYP3A4 and weakly induced CYP2D6. However, no clinically significant drug interactions were observed between RG and CYP and P-gp probe substrates. Conclusion: RG has no relevant potential to cause CYP enzyme- or P-gp-related interactions.

Mechanotransduction of human pluripotent stem cells cultivated on tunable cell-derived extracellular matrix

Kim, In Gul,Gil, Chang-Hyun,Seo, Joseph,Park, Soon-Jung,Subbiah, Ramesh,Jung, Taek-Hee,Kim, Jong Soo,Jeong, Young-Hoon,Chung, Hyung-Min,Lee, Jong Ho,Lee, Man Ryul,Moon, Sung-Hwan,Park, Kwideok Elsevier 2018 Biomaterials Vol.150 No.-

<P><B>Abstract</B></P> <P>Cell-derived matrices (CDM) are becoming an attractive alternative to conventional biological scaffolding platforms due to its unique ability to closely recapitulate a native extracellular matrix (ECM) de novo. Although cell-substrate interactions are recognized to be principal in regulating stem cell behavior, very few studies have documented the acclimation of human pluripotent stem cells (hPSCs) on pristine and altered cell-derived matrices. Here, we investigate crosslink-induced mechanotransduction of hPSCs cultivated on decellularized fibroblast-derived matrices (FDM) to explore cell adhesion, growth, migration, and pluripotency in various biological landscapes. The results showed either substrate-mediated induction or inhibition of the Epithelial-Mesenchymal-Transition (EMT) program, strongly suggesting that FDM stiffness can be a dominant factor in mediating hPSC plasticity. We further propose an optimal FDM substratum intended for long-term hPSC cultivation in a feeder-free niche-like microenvironment. This study carries significant implications for hPSC cultivation and encourages more in-depth studies towards the fundamentals of hPSC-CDM interactions.</P>

No Association between PAWR Gene Polymorphisms and Tardive Dyskinesia in Schizophrenia Patients

Kim, Il-Soo,Yoon, Ho-Kyoung,Kang, Seung-Gul,Park, Young-Min,Kim, Yong-Ku,Kim, Seung-Hyun,Choi, Jung-Eun,Kim, Leen,Lee, Heon-Jeong Korean Neuropsychiatric Association 2012 PSYCHIATRY INVESTIGATION Vol.9 No.2

<P>Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD.</P>

Effect of green tea catechins on the pharmacokinetics of digoxin in humans

Kim, Tae-Eun,Shin, Kwang-Hee,Park, Jeong-Eun,Kim, Min-Gul,Yun, Yeo-Min,Choi, Dong-Hee,Kwon, Kyoung Ja,Lee, Jongmin Dove Medical Press 2018 Drug design, development and therapy Vol.12 No.-

<P><B>Background</B></P><P>Previous in vitro studies have reported the inhibitory effect of green tea on p-glycoprotein (p-gp) encoded by <I>ABCB1</I>. This study aimed to investigate the effect of green tea on the pharmacokinetics of digoxin, a typical probe drug of p-gp.</P><P><B>Methods</B></P><P>Sixteen healthy volunteers participated in this study. At Day 1, 0.5 mg of digoxin was administered via oral route. After a 14-day washout period, 630 mg of green tea catechins (GTC) was administered via oral route, followed by 0.5 mg of digoxin 1 hour later. From Day 16 through Day 28, 630 mg of GTC was administered alone. At Day 29, 630 mg of GTC and 0.5 mg of digoxin were administered in the same way as Day 15. Blood samples for the pharmacokinetic assessments of digoxin were collected up to 8 hours after each dose. Pharmacokinetic parameters were estimated by noncompartmental analysis. Area under the curve (AUC) and peak plasma concentration (<I>C</I><SUB>max</SUB>) were compared using mixed effect model between digoxin alone and digoxin with GTC. <I>ABCB1</I> was genotyped to determine whether its polymorphism affects digoxin–GTC interaction.</P><P><B>Results</B></P><P>Fifteen subjects completed the study. Compared to digoxin alone, the concomitant administration of digoxin and GTC significantly reduced the systemic exposure of digoxin: geometric mean ratios (GMR) and 90% confidence intervals (CI) of area under the concentration–time curve from time 0 to the last measurable time (AUC<SUB>last</SUB>) and <I>C</I><SUB>max</SUB> were 0.69 (0.62–0.75) and 0.72 (0.61–0.85), respectively. The concomitant administration of digoxin and GTC following pretreatment of GTC (Day 29) similarly reduced the AUC<SUB>last</SUB> (GMR [90% CI]: 0.67 [0.61–0.74]) and <I>C</I><SUB>max</SUB> (GMR [90% CI]: 0.74 [0.63–0.87]). In the comparison of the percentage changes from Day 1 (digoxin single administration) of AUC<SUB>last</SUB> between genotypes, C1236T variant type showed a significant difference to wild-type on Day 15 (concomitant administration of digoxin and GTC) (<I>P</I>=0.005).</P><P><B>Conclusion</B></P><P>This study demonstrates that the coadministration of GTC reduces the systemic exposure of digoxin regardless of pretreatment of GTC.</P>

Development and validation of an LC-MS/MS method for determination of compound K in human plasma and clinical application

Kim, Jung Soo,Kim, Yunjeong,Han, Song-Hee,Jeon, Ji-Young,Hwang, Minho,Im, Yong-Jin,Kim, Jung Hyun,Lee, Sun Young,Chae, Soo-Wan,Kim, Min-Gul The Korean Society of Ginseng 2013 Journal of Ginseng Research Vol.37 No.1

A rapid, sensitive and selective analytical method was developed and validated for the determination of compound K, a major intestinal bacterial metabolite of ginsenosides in human plasma. Liquid-liquid extraction was used for sample preparation and analysis, followed by liquid chromatography tandem spectrometric analysis and an electrospray-ionization interface. Compound K was analyzed on a Phenomenex Luna C18 column ($100{\times}2.00$ mm, 3 ${\mu}m$) with the mobile phase run isocratically with 10 mM ammonium acetate-methanol-acetonitrile (5:47.5:47.5, v/v/v) at a flow rate of 0.5 mL/min. The method was validated for accuracy (relative error <12.63%), precision (coefficient of variation <9.14%), linearity, and recovery. The assay was linear over the entire range of calibration standards i.e., a concentration range of 1 ng/mL to 1,000 ng/mL ($r^2$ >0.9968). The recoveries of compound K after liquid-liquid extraction at 1, 2, 400, and 800 ng/mL were $106.00{\pm}0.08%$, $103.50{\pm}0.19%$, $111.45{\pm}5.21%$, and $89.62{\pm}34.46%$ for intra-day and $85.40{\pm}0.08%$, $94.50{\pm}0.09%$, $112.50{\pm}5.21%$, and $95.87{\pm}34.46%$ for inter-day, respectively. The lower limit of quantification of the analytical method of compound K was 1 ng/mL in human plasma. The developed method was successfully applied to a pharmacokinetic study of compound K after oral administration in ten of healthy human subjects.

Effect of fermented red ginseng on cytochrome P450 and P‐glycoprotein activity in healthy subjects, as evaluated using the cocktail approach

Kim, Min‐,Gul,Kim, Yunjeong,Jeon, Ji‐,Young,Kim, Dal‐,Sik John Wiley and Sons Inc. 2016 British journal of clinical pharmacology Vol.82 No.6

<P><B>Aims</B></P><P>We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P‐glycoprotein (P‐gp), in healthy volunteers.</P><P><B>Methods</B></P><P>This study was an open‐label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (<SMALL>ANOVA</SMALL>).</P><P><B>Results</B></P><P>Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least‐square mean metabolic ratio (90% CI) was 0.901 (0.830–0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720–0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925–1.197) for omeprazole (CYP2C19) to 5‐hydroxyomeprazole, 1.150 (0.860–1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673–0.990) for midazolam (CYP3A4) to 1‐hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUC<SUB>last</SUB>) for fexofenadine (P‐gp) was 1.322 (1.112–1.571).</P><P><B>Conclusion</B></P><P>No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two‐week administration of concentrated fermented red ginseng. However, the inhibition of P‐gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P‐gp substrate drugs.</P>