• Journal of Korean Society for Quality Management
• /
• v.49 no.2
• /
• pp.145-159
• /
• 2021

Purpose: A statistical similarity evaluation to compare pharmacokinetics(PK) profile data between nonclinical and clinical experiments has become a significant issue on many drug development processes. This study proposes a new similarity index by considering important parameters, such as the area under the curve(AUC) and the time-series profile of various PK data. Methods: In this study, a new profile similarity index(PSI) by using the concept of a process capability index(Cp) is proposed in order to investigate the most similar animal PK profile compared to the target(i.e., Human PK profile). The proposed PSI can be calculated geometric and arithmetic means of all short term similarity indices at all time points on time-series both animal and human PK data. Designed simulation approaches are demonstrated for a verification purpose. Results: Two different simulation studies are conducted by considering three variances(i.e., small, medium, and large variances) as well as three different characteristic types(smaller the better, larger the better, nominal the best). By using the proposed PSI, the most similar animal PK profile compare to the target human PK profile can be obtained in the simulation studies. In addition, a case study represents differentiated results compare to existing simple statistical analysis methods(i.e., root mean squared error and quality loss). Conclusion: The proposed PSI can effectively estimate the level of similarity between animal, human PK profiles. By using these PSI results, we can reduce the number of animal experiments because we only focus on the significant animal representing a high PSI value.

• Journal of the Korea Safety Management & Science
• /
• v.15 no.1
• /
• pp.293-301
• /
• 2013

The purpose of this study is to introduce the limit of previously used six sigma quality process evaluation metrics, $Z_{st}$ and $P_{pk}$, and a solution to overcome this drawback by using a metric based on performance evaluation of Z-factor quality innovation. Case analysis on projects from national six sigma contest from 2011 to 2012 is performed and literature review on new drug development HTS (High Throughput Screening) is used to propose innovative performance evaluation metrics. This research shows that experimental study on six sigma evaluation metric, $Z_{st}$ and $P_{pk}$, have no significance difference between industrial type (Manufacturing, Semi-Public Institute, Public Institute) and CTQ type (Product Technology Type CTQ, Process Technology Type CTQ). Following discovery characterize this quality improvement as fixed target type project. As newly developed moving target type of quality innovation performance metric Z-Factor is used for evaluating experimental study, hypothetical analysis suggests that $Z_{st}$ and $P_{pk}$ share different relationship or even show reciprocal relationship. Constraints of the study are relatively small sample size of only 37 projects from past 2 years and conflict on having interview and communication with six sigma quality practitioner for qualitative experimental study. Both moving target type six sigma innovation project and fixed target type improvement project or quality circle enables efficient ways for a better understanding and quality practitioner use by applying quality innovation performance metric. Downside of fixed target type quality performance evaluation metric, $Z_{st}$ and $P_{pk}$, is presented through experimental study. In contrast, advantage of this study is that high throughput requiring product technology, process technology and quantum leap typed innovation effect is evaluated based on precision and accuracy and Z-Factor that enables relative comparison between enterprises is proposed and implemented.

• Analytical Science and Technology
• /
• v.33 no.4
• /
• pp.197-207
• /
• 2020

The current comparison methods with scoring systems that are used to compare visualized latent fingerprints (LF) have disadvantages. Evaluators using these methods are prone to make errors and fail to discriminate LFs correctly to notice the differences among those LFs. Therefore, a comparative and quantitative evaluation method that is capable of obtaining more objective and quantitative results is needed. Densitometric image analysis (DIA) is used in other fields as a reliable semi-quantitative comparison method. To apply DIA to LFs, the potential variables that can occur during the DIA process were tested. The visualized ridges of LFs can be compared using the concentration of dots against the background to make it possible to analyze the ridges with DIA. The variables that can be present during the DIA process include the thickness of the analysis line, the number of ridges to be taken, the number of divided zones within each of the fingerprints, and the angles of the analysis line against the ridge lines that were selected. From the analysis of the inked fingerprints and circular lines that are similar to fingerprints, the angle of the analysis lines with the ridge line was the most significant variable. The preliminary test result was applied to the comparison of LFs that were developed with the powder method and then compared with the AFIS analysis. A similar trend was found, and a more detailed and semi-quantitative comparison of the visualized LFs was possible. In the future, it is necessary to check the evaluative ability of the DIA method by analyzing the visualized LFs with other various development methods. However, DIA is currently an option that can be used as an objective comparative evaluation method during fingerprint studies with supplementary role.

• Molecular & Cellular Toxicology
• /
• v.1 no.3
• /
• pp.179-188
• /
• 2005

To develop the novel anti-allergic drug, many sophoricoside derivatives were synthesized. Among these derivatives, JSH-II-3, VI-3, VII-3, VIII-3, VII-20 and VII-20 (sodium salt) were selected and subjected to high throughput toxicity screening (HTTS) because they revealed strong IL-5 inhibitory activity and limitation of quantity. Single cell gel electrophoresis (Comet) assay, mouse lymphoma thymidine kinase ($tk^{+/-}$) gene assay (MOLY), chromosomal aberration assay in mammalian cells and Ames reverse mutation assay in bacterial system were used as simplified, inexpensive, short-term in vitro screening tests in our laboratory. Through the primary screening using the comet assay, we could choose the first candidates of sophoricoside derivatives with no genotoxic potentials as JSH-VI-3, VII-3, VII-20 and VII-20 (sodium salt). Also JSH-VII-3, VII-20 and VII-20 (sodium salt) are non-mutagenic in MOLY assay, while JSH-II-3 is mutagenic at high concentration with the presence of metabolic activation system in both comet assay and MOLY assay. The selected derivatives (JSH-VI-3, VII-3, VII-20 and VII-20 (sodium salt) are not mutagenic in S. typhimurium TA98 and TA100 strains both in the presence and absence of metabolic activation. From results of chromosomal aberration assay, 6 h treatment of JSH-VI-3, VII-3 and VII-20 (sodium salt) were not revealed clastogenicity both in the presence and absence of S-9 mixture. Therefore, we suggests that JSH-VI-3, VII-3, VII-20 and VII-20 (sodium salt), as the optimal candidates with both no genotoxic potential and IL-5 inhibitory effects must be chosen. To process the development into new anti-inflammatory drug of these derivatives, further investigation will need.

• Biomolecules & Therapeutics
• /
• v.29 no.5
• /
• pp.498-505
• /
• 2021

Amyotrophic lateral sclerosis (ALS) is a lethal neurological disorder characterized by the deterioration of motor neurons. The aim of this study was to investigate alteration of cationic amino acid transporter (CAT-1) activity in the transport of lysine and the pretreatment effect of lysine on pro-inflammatory states in an amyotrophic lateral sclerosis cell line. The mRNA expression of cationic amino acid transporter 1 was lower in NSC-34/hSOD1^G93A (MT) than the control cell line (WT), lysine transport is mediated by CAT-1 in NSC-34 cell lines. The uptake of [³H]L-lysine was Na⁺-independent, voltage-sensitive, and strongly inhibited by inhibitors and substrates of cationic amino acid transporter 1 (system y⁺). The transport process involved two saturable processes in both cell lines. In the MT cell line, at a high-affinity site, the affinity was 9.4-fold higher and capacity 24-fold lower than that in the WT; at a low-affinity site, the capacity was 2.3-fold lower than that in the WT cell line. Donepezil and verapamil competitively inhibited [³H]L-lysine uptake in the NSC-34 cell lines. Pretreatment with pro-inflammatory cytokines decreased the uptake of [³H]L-lysine and mRNA expression levels in both cell lines; however, the addition of L-lysine restored the transport activity in the MT cell lines. L-Lysine exhibited neuroprotective effects against pro-inflammatory states in the ALS disease model cell lines. In conclusion, studying the alteration in the expression of transporters and characteristics of lysine transport in ALS can lead to the development of new therapies for neurodegenerative diseases.

• 대한예방의학회:학술대회논문집
• /
• 1994.02a
• /
• pp.23-56
• /
• 1994

Recent criticisms of the conduct and use of risk assessment by regulatory agencies have led to a wide range of proposed remedies, including changes in regulatory statutes and the development of new methods for assessing risk. The mandate to this Committee was more limited. Our objective was to examine whether alterations in institutional arrangements or procedures, particularly the organizational separation of risk assessment from regulatory decision-making and the use of uniform guidelines for inferring risk from available scientific information, can improve federal risk assessment activities. Before undertaking to determine whether organizational and procedural reforms could improve the performance and use of risk assessment in the federal government, the Committee examined the state of risk assessment and the regulatory environment in which it is performed. In this chapter, we define risk assessment and differentiate it from other elements in the regulatory process, analyze the types of judgments made in risk assessment, and examine its current government context. Because one chronic health hazard, cancer, was highlighted in the Committee's congressional mandate and has dominated public concern about public health risks in recent years, most of our report focuses on it. Furthermore, because activities in four agencies--the Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), the Occupational Safety and Health Administration (OSHA), and the Consumer Product Safety Commission (CPSC)--have given rise to many of the proposals for changes in risk assessment practices, our review focuses on these four agencies. The conclusions of this report, although directed primarily at risk assessment of potential carcinogens as performed by these four agencies, may be applicable to other federal programs to reduce health risks.

• Proceedings of the Ginseng society Conference
• /
• 1993.09a
• /
• pp.127-131
• /
• 1993

The effects of total ginseng saponin. extracts of Panax ginseng C.A. Meyer, on the differentiation of F9 teratocarcinoma stem cells were studied. F9 stem cells cultured in the presence of ginseng saponin together with dibutyric cAMP became parietal endoderm - like cells. Moreover, the expressions of differentiation marker genes. laminin. type IV collagen. and retinoic acid $receptor-{\beta}(RAR{\beta})$ were increased after treatment of ginseng saponin. Among various ginsenosides purified from crude ginseng saponin, $Rh_1\;and\;Rh_2$ caused the differentiation of F9 cells most effectively. Since ginsenosides and steroid hormone show resemblance in chemical structure. we studied the possibility of the involvement of a steroid receptor in the differentiation process induced by ginsenosides. According to Southwestern blot analysis, a 94 kDa protein regarding as a steroid receptor was detected in F9 cells cultured in the medium containing ginseng saponin. Based on these data, we suggest that ginseng saponin, especially ginsenosides $Rh_1\;and\;Rh_2$ cause the differentiation of F9 cells and the effects of ginsenosides might be exerted via binding with a steroid receptor or its analogous nuclear receptor.

• Journal of Plant Biotechnology
• /
• v.37 no.1
• /
• pp.57-66
• /
• 2010

Programmed cell death systems are important for an active type of cell deaths. Among them, a type of programmed cell death, autophagy is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance. Thus, in the area of cancer, over the time frame form around the 1940s to date, of the 155 small molecules, 73% are other than "synthetic", with 47% actually being either "natural products" or "directly derived therefrom". Autophagy has multiple physiological functions in multicellular organisms, including protein degradation and organelle turnover. Genes and proteins that constitute the basic machinery of the autophagic process were first identified in the yeast system and some of their mammalian orthologues have been characterized as well. Numerous oncogenes, including Akt1, Bcl-2, NF1, PDPK1, class I PI3K, PTEN, and Ras and oncosuppressors, inculuding Bec-1, Bif-1, DAPK-1, p53 and UVRAG suppress or promote the autophagy pathway. Regulation of autophagy in tumors is governed by similar principles of the normal cells, only in a much more complicated manner, given the frequently observed abnormal PI3K activation in cancer and the multitude of interactions between the PI3K/AKT/mTOR pathway and other cell signaling cascades, often also deregulated in tumor cells. Autophagy induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality of development for natural medicines.

• Archives of Pharmacal Research
• /
• v.28 no.8
• /
• pp.988-994
• /
• 2005

The purpose of the present study was to prepare multivesicular liposomes with a high drug loading capacity and to investigate its potential applicability in the oral delivery of a peptide, human epidermal growth factor (rhEGF). The multivesicular liposomes containing rhEGF was prepared by a two-step water-in-oil-in-water double emulsification process. The loading efficiency was increased as rhEGF concentration increased from 1 to 5mg/mL, reaching approximately $60\%$ at 5 mg/mL. Approximately $47\%$ and $35\%$ of rhEGF was released from the multivesicular liposomes within 6 h in simulated intra-gastric fluid (pH 1.2) and intra-intestinal fluid (pH 7.4), respectively. rhEGF-loaded multivesicular liposomes markedly suppressed the enzymatic degradation of the peptide in an incubation with the Caco-2 cell homogenate. However, the transport of rhEGF from the multivesicular liposomes to the basolateral side of Caco­2 cells was two times lower than that of the rhEGF in aqueous solution. The gastric ulcer healing effect of rhEGF-loaded multivesicular liposomes was significantly enhanced compared with that of rhEGF in aqueous solution; the healing effect of the liposomes was comparable to that of the cimetidine in rats. Collectively, these results indicate that rhEGF-loaded multivesicular liposomes may be used as a new strategy for the development of an oral delivery system in the treatment of peptic ulcer diseases.

• Proceedings of the Plant Resources Society of Korea Conference
• /
• 2021.04a
• /
• pp.5-5
• /
• 2021

Alcoholic and nonalcoholic steaohepatitis is a leading form of chronic liver disease with few biomakers ad treatment options currently available. a progressive disease of NAFLD may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Recently, we extracted HIMH0021, which is an active flavonoid component in the Acer tegmentosum extract, has been shown to protect against liver damage caused by hepatic dysfunction. Therefore, in this study, we aimed to investigate whether HIMH0021 could regulate steatohepatitis and liver fibrosis during alcoholic or nonalcoholic metabolic process. HIMH0021, which was isolated from the active methanol extract of A. tegmentosum, inhibited alcohol-induced steatosis and attenuated the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during hepatocellular alcohol metabolism, both of which promote lipogenesis as well as liver inflammation. Treatment with HIMH0021 conferred protection against lipogenesis and liver injury, inhibited the expression of cytochrome P4502E1, and increased serum adiponectin levels in the mice subjected to chronic-plus-binge feeding. Furthermore, in hepatocytes, HIMH0021 activated fatty acid oxidation by activating pAMPK, which comprises pACC and CPT1a. These findings suggested that HIMH0021 could be used to target a TNFα-related pathway for treating patients with alcoholic hepatitis.