• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.248-254
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• 2011

Biotransformation of pharmacologically inactive lactone prodrug simvastatin (SV) into pharmacologically active simvastatin ${\beta}$-hydroxy acid (SVA) exhibits inter-species differences due to variations in amount and activity of esterase enzymes. In this study, we investigated the pharmacokinetics (PK) of SV and its metabolite SVA following oral doses of SV from controlled-release (CR) tablets and immediate-release (IR) tablets in rodent and canine animal models that features different esterase activity. In rat PK study, no SV was detected in plasma for both formulations due to rapid hydrolysis of SV into SVA by plasma esterase. Besides, no significant differences in PK parameters of SV or SVA were observed between both species. In dog PK study, the relative oral bioavailability of CR tablets in terms of SV was 72.3% compared to IR tablets. Regarding formulation differences in dogs, CR tablets exhibited significantly lower $C_{max}$ (p<0.05), and higher $T_{max}$ (p<0.01) and MRT (p<0.01) for both SV and SVA compared to IR tablets. Accordingly, CR tablets of SV with prolonged drug release profiles in both species might be a potential candidate for a more effective delivery of SV with reduced side effects. Besides, similar PK parameters of SV and SVA in both species despite variation in enzyme activities suggested involvement of equally potent biotransformation pathways in these animal species.

• Preventive Nutrition and Food Science
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• v.13 no.4
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• pp.259-265
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• 2008

This study was designed to investigate the protective effect of fucoidan against AAPH-induced oxidative stress in LLC-PK1 cells (porcine kidney epithelial cells). Oxidative stress was induced by exposing of LLC-PK1 cells to the 1 mM 2,2'-azobis(2-amidino propane) dihydrochloride (AAPH) for 24 hr. Exposure of LLC-PK1 cells to 1 mM AAPH for 24 hr resulted in a significant (p<0.05) decrease in cell viability, but fucoidan treatment protected LLC-PK1 cells from AAPH-induced cell damage in a dose dependant manner. To investigate the protective action of fucoidan against AAPH-induced damage of LLC-PK1 cells, we measured the effects of fucoidan on lipid peroxidation and antioxidant enzymes activities of AAPH treated cells as well as scavenging activities on superoxide anion radical and hydroxyl radical. Fucoidan had protective effect against the AAPH-induced LLC-PK1 cellular damage and decreased lipid peroxidation and increased activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Furthermore, fucoidan showed strong scavenging activity against superoxide anion radical. The $IC_{50}$ value of fucoidan was $48.37{\pm}1.54\;{\mu}g/mL$ for superoxide anion radical scavenging activity. The fucoidan also had high hydroxyl radical scavenging activity ($IC_{50}=32.03\;{\mu}g/mL$). These results indicate that fucoidan protects against AAPH-induced LLC-PK1 cell damage by inhibiting lipid peroxidation, increasing antioxidant enzyme activities and scavenging offree radicals.

• Communications for Statistical Applications and Methods
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• v.10 no.2
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• pp.399-422
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• 2003

In actual manufacturing industries, process capability analysis often entails characterizing or assessing processes or products based on more than one engineering specification or quality characteristic. Since these characteristics are related, it is a risky undertaking to represent variation of even a univariate characteristic by a single index. Therefore, the desirability of using vector-valued process capability index(PCI) arises quite naturally. In this paper, some vector-valued ${PCI}_p$ ${C}_p$=(${C}_{px}$, ${C}_{py}$),${C}_{pk}$=(${C}_{pkx}$, ${C}_{pky}$) and ${C}_{pm}$=(${C}_{pmx}$, ${C}_{pmy}$) considering univariate PCIs ${C}_p$,${C}_{pk}$ and ${C}_{pm}$ are studied. First, we propose some asymptotic confidence regions of our vector-valued PCIs with bootstrap. And we examine the performance of asymptotic confidence regions of our vector-valued PCIs ${C}_p$ and ${C}_{pk}$ under the assumption of bivariate normal distribution BN($\mu_{x}$, $\mu_{y}$, $\sigma_{x}^{2}$, $\sigma_{y}^{2}$, $\rho$) and bivariate chi-square distribution Bivariate $x^2$(5,5,$\rho$).

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.199-205
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• 2016

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration ($2-75{\mu}M$) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was $1.9{\mu}L/min$ while passive diffusion clearance was $0.31{\mu}L/min$. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as $C_{max}$ and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level.

• Journal of Sericultural and Entomological Science
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• v.45 no.1
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• pp.46-57
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• 2003

This study was carried out to investigate the characteristics of the soluble sericins after degumming and after hydrolysis of insoluble sericin with various enzymes. Especially, the hydrolysis characteristics were examined in terms of molecular weight of the soluble sericin. Amino acid composition and molecular weight characteristics of the soluble sericins were also studied. When the insoluble sericin was hydrolyzed with kojizyme and flavourzyme, the solubility was highest at pH 7 and 50$^{\circ}C$. On the other hand, in the cases of protamex and alcalase, the highest solubility was obtained at 60$^{\circ}C$. In these cases, solubility increased with pH. In enzymatic hydrolysis, the solubility was increased with concentration of enzymes until 4 hours. After then, a slight difference was found along with treatment times. In enzymatic hydrolysis, the absorbance of the soluble sericin was increased with concentration of enzymes and treatment times. Average degree of polymerization was decreased with treatment time and concentration. The amino acid compositions were similar in low(low molecular weight by degumming) and high (high molecular weight by degumming). Those of PK (soluble sericin hydrolyzed with kojizyme), PP (soluble sericin hydrolyzed with protamex), and PA(soluble sericin hydrolyzed with alcalase) were similar to each other. Serine and tyrosine compositions were higher in low and high than those of PK, PP, and PA. However proline was absent in low and high. Molecular weights of the various sericins became higher as KP>high>PP>low>PA and those of KP and PA were 9,800 and 905 respectively.

• Journal of the Institute of Electronics Engineers of Korea SC
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• v.46 no.2
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• pp.72-77
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• 2009

In this paper, a 3.2Gb/s clock and data recovery (CDR) circuit for a high-speed serial data communication without the reference clock is described This CDR circuit consists of 5 parts as Phase and frequency detector(PD and FD), multi-phase Voltage Controlled-Oscillator(VCO), Charge-pumps (CP) and external Loop-Filter(KF). It is adapted the PD and FD, which incorporates a half-rate bang-bang type oversampling PD and a half-rate FD that can improve pull-in range. The VCO consists of four fully differential delay cells with rail-to-rail current bias scheme that can increase the tuning range and tuning linearity. Each delay cell has output buffers as a full-swing generator and a duty-cycle mismatch compensation. This materialized CDR can achieve wide pull-in range without an extra reference clock and it can be also reduced chip area and power consumption effectively because there is no additional Phase Locked- Loop(PLL) for generating reference clock. The CDR circuit was designed for fabrication using 0.18um 1P6M CMOS process and total chip area excepted LF is $1{\times}1mm^2$. The pk-pk jitter of recovered clock is 26ps at 3.2Gb/s input data rate and total power consumes 63mW from 1.8V supply voltage according to simulation results. According to test result, the pk-pk jitter of recovered clock is 55ps at the same input data-rate and the reliable range of input data-rate is about from 2.4Gb/s to 3.4Gb/s.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.3
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• pp.395-401
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• 1998

We have synthesized new platinum(II) analogs containing 1,2-diaminocyclohexane (dach) as a carrier ligand, 1,3-bis(diphenylphosphino) propane (DPPP) /1,2-bis(diphenylphosphino)ethane (DPPE) as a leaving group and nitrates to improve solubility. In the present study, the cytotoxicity of $[Pt(trans-l-dach)(DPPP)]\;2NO_3$ (KHPC-001) and $[Pt(trans-l-dach)(DPPE)]\;2NO_3$ (KHPC-002) was evaluated and compared on various P-388 cancer cell lines and porcine kidney cell line ($LLC-PK_1$). The new platinum complexes demonstrated high efficacy on P-388 mouse leukemia cell line as well as cisplatin-resistant (P-388/CDDP) and adriamycin-resistant (P-388/ADR) P-388 cell lines. The intracellular platinum content was measured by a flame atomic absorption spectrophotometer (FAAS), and it was comparable to the results of $IC_{50}$ of the three complexes on $LLC-PK_1$ and P-388/S cells, while only DPPE compound was accumulated in high volume in P-388/ADR and P-388/CDDP cells. While the DNA-interstrand cross-links of KHPC-001, KHPC-002 and cisplatin were similar on P-388/S leukemia cells, these new platinum complexes were much less DNA cross-linking to a kidney derived cell line, $LLC-PK_1$. These results indicate that KHPC-001 and KHPC-002 are a third-generation platinum complexes with potent antitumor activity and low nephrotoxicity.

• The Journal of Internal Korean Medicine
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• v.32 no.1
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• pp.56-67
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• 2011

Objectives : Recent etiological studies show that oxidative stress might play a major role in the diabetes and its complications. Mori Ramulus (MR) has been known to have antioxidative, anti-inflammatory and antidiabetic effects. The methanol extract of MR was tested for its effectiveness in LLC-PK1 cells exposed to high glucose. Methods : The cytoprotective effect of MR was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The antioxidative effect was measured in terms of generation amount of ${\cdot}O_2^-$ by 2',7'-dichlorodihydrofluorescein diacetate (DCFDA), NO by 4,5-diaminofluorescein (DAF-2), $ONOO^-$ by dihydrorhodamine 123 (DHR 123) in the high glucose -treated LLC-$PK_1$ cells. Western blotting was performed using anti-AGE, anti-RAGE, anti-MAPKs(ERK1/2, JNK, p38), anti-PI3K, anti-Akt, and anti-NF-${\kappa}$B (p50, p65) respectively. Results : MR extract reduced cell death and inhibited the generation of ${\cdot}O_2^-$, NO, $ONOO^-$ in the high glucose-treated LLC-$PK_1$ cells. MR inhibited the expression of AGE, RAGE, MAPKs, PI3K, and Akt by means of decreasing NF-${\kappa}$B activation. MR also inhibited NF-${\kappa}$B activation itself. Conclusions : These results indicate MR has cytoprotective, antioxidative, and anti-inflammatory effects. Therefore it is suggested that MR might prevent and cure diabetes and its complications.

• Nuclear Medicine and Molecular Imaging
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• v.43 no.4
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• pp.337-343
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• 2009

Purpose: ((R)-1-(2-chlorophenyl)-N-1-[$^{11}$C]methyl-N(1-propyl)-3-isoquinoline carboxamide ((R)-PK11195) is a specific ligand for the peripheral type benzodiazepine receptor and a marker of activated microglia, used to measure inflammation in neurologic disorders. We report here that a direct and simple radiosynthesis of [$^{11}$C](R)-PK11195 in mild condition using NaH suspension in DMF and one-step loop method. Materials and Methods: (R)-N-Desmethyl-PK11195 (1 mg) in DMSO (0.1 mL) and NaH suspension in DMF (0.1 mL) were injected into a semi-prep HPLC loop. [$^{11}$C]methyl iodide was passed through HPLC loop at room temperature. Purification was performed using semi-preparative HPLC. Aliquots eluted at 11.3 min were collected and analyzed by analytical HPLC and mass spectrometer. Results: The labeling efficiency of [$^{11}$C](R)-PK11195 was 71.8$\pm$8.5%. The specific activity was 11.8:$\pm$6.4 GBq/$\mu$mol and radiochemical purity was higher than 99.2%. The mass spectrum of the product eluted at 11.3 min showed m/z peaks at 353.1 (M+1), indicating the mass and structure of (R)-PK11195. Conclusion: By the one-step loop method with the [$^{11}$C]CH3l automated synthesis module, [$^{11}C$](R)-PK11195 could be easily prepared in high radiochemical yield using NaH suspension in DMF.

• The Journal of Internal Korean Medicine
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• v.30 no.1
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• pp.36-50
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• 2009

Objectives : This study was aimed to verify the cytoprotective function, antioxidative effect and inflammation genes inhibitory effects of Lycium chinense Milie. Therefore the generation of superoxide anion radical ( $O_2\;^-$), peroxynitrite ($ONOO^-$), nitric oxide (NO) and prostaglandin $E_2$ $(PGE_2)$ was investigated in the renal epithelial cells of mouse. Effects of Lycium chinense Milie on the expression of inflammation-related proteins, $IKK-{\alpha}$. $p-IKK-\alpha\beta$, $p-I{\kappa}B-\alpha$, $NF-{\kappa}B$ (p50, p65), COX-2 and iNOS, were examined by western blotting. Methods : For this study, the fluorescent probes were used, namely dihydrorhodamine 123 (DHR 123), 4.5-diaminofluorescein (DAF-2) and 2',7'-dichlorodihydrofluorescein diacetate (DCFDA). Western blotting was performed using anti-$IKK-\alpha$, anti-phospho $IKK-\alpha\beta$, anti-phospho $I{\kappa}B-\alpha$, anti-$NF-{\kappa}B$ (p50, p65), anti-COX-2 and anti-iNOS, respectively. Results : Lyciutn chinense Milie reduced $H_{2}O_{2}$-induced cell death dose-dependently. It inhibited the generation of $O_2\;^-$, $ONOO^-$, NO and $PGE_2$ in the $H_{2}O_{2}$-treated renal epithelial cells of mouse in vitro. Lycium chinense Milie inhibited the expression of $IKK-\alpha$, $p-IKK-\alpha\beta,\;p-I{\kappa}B-\alpha$, COX-2 and iNOS genes by means of decreasing activation of $NF-{\kappa}B$. Conclusions : According to above results. Lycium chinense Milie recommended to be applied in treatment for the inflammatory process and inflammation-related diseases.