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한국동물실험대체법학회> 한국동물실험대체법학회지 (jaae)> Comprehensive in vitro Proarrhythmia Assay (CiPA) 기반 Torsade Metric Score (TMS)를 이용한 TdP 발생 약물의 위험군 분류 성능 평가

KCI등재

Comprehensive in vitro Proarrhythmia Assay (CiPA) 기반 Torsade Metric Score (TMS)를 이용한 TdP 발생 약물의 위험군 분류 성능 평가

Evaluation of Risk Classification Performance of TdP Incidence Drugs Using Torsade Metric Score (TMS) based on Comprehensive in vitro Proarrhythmia Assay (CiPA)

윤승현 ( Seung-hyun Yoon ) , 남유리 ( Yu Ri Nam ) , 강현수 ( Hyun-su Kang ) , 정다운 ( Da Un Jeong ) , 유예담 ( Ye Dam Yoo ) , 임기무 ( Ki-moo Lim ) , 박성준 ( Seong-jun Park ) , 김배환 ( Bae-hwan Kim ) , 김기석 ( Ki-suk Kim )
  • : 한국동물실험대체법학회
  • : 한국동물실험대체법학회지 (jaae) 15권1호
  • : 연속간행물
  • : 2021년 12월
  • : 23-43(21pages)
한국동물실험대체법학회지 (jaae)

DOI


목차

Introduction
Materials and Methods
Results
Discussion
Acknowledgements
References

키워드 보기


초록 보기

For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG block, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. In this study, based on the CiPA project and previous studies, the nine drugs were tested using in vitro multiple ion channel screening on both temperature conditions (room temperature and 37℃). Using the in vitro results, in silico computer simulation was performed based on the O'Hara-Rudy human ventricular myocyte model, and same as the CiPA project obtained a new biomarker, qNet. The in silico computer simulation was performed using 2000 samples of IC50 values extracted by R code. The nine test drugs were associated with cardiotoxicity and TdP, and were selected by the CiPA project and previous studies. Furthermore, as in previous studies, Torsade Metic Score (TMS), the mean qNet value averaged across 1-4 × Cmax, and the threshold was calculated. As a result, the nine tested drugs using the TMS were well plotted by the risk categories and the threshold was able to well classify the risk categories by grade on both temperature conditions. In particular, the threshold 2 value confirmed to significant difference depending on the temperature conditions. The range of threshold narrowed at 37℃, which can be considered as having the ability to distinguish more finely. It shows the correlation with the CiPA project’s validity that a study should be tested at a physiological temperature of 3 7℃. In this study, using the method proposed by the CiPA project, it was possible to predict the risk groups of drugs more accurately, which could be presented as a new paradigm in the cardiotoxicity assessment.

UCI(KEPA)

I410-ECN-0102-2022-500-000960620

간행물정보

  • : 의약학분야  > 기타(의약학)
  • : KCI등재
  • :
  • : 연간
  • : 1975-9657
  • :
  • : 학술지
  • : 연속간행물
  • : 2007-2021
  • : 110


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1면역독성평가 대체시험법 개발을 위한 참조 시험물질 선정 방안

저자 : 김창열 ( Changyul Kim ) , 허용 ( Yong Heo )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 5-14 (10 pages)

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Alternative test method for screening immunotoxic substances has not been actively challenged and no test guideline has been officialized internationally. Preparation of master list on reference chemicals is a critical process for decision on positive or negative immunotoxicity of test substances through alternative test method. The reference master list is recommended to include various scopes of immuntoxic xenobiotics including medicinal products, cosmetic ingredients, and industrial or environmental agents. Data bases or research results on human or animal immunotoxicity of chemicals were collected and analyzed for preparing the list of reference chemicals. Twenty eight chemicals were selected as non-immunotoxicants, which could be used as negative controls for immunotoxicity and 10 immunosuppressive drugs were chosen for classifying immunosuppressive toxicity of test substances. Considering chemicals used as positive controls for immunotoxicity, 38 substances with aberrant immune regulatory capacity were listed, which are categorized into 23 industrial or environmental agents, 12 medicinal products, and 3 agrochemicals. The list of reference test substances could contribute to development of in vitro alternative assay method for immunotoxicity evaluation.

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2피부감작성 동물대체시험법인 ARE-Nrf2 루시퍼라아제 LuSens 시험법(OECD TG 442D)의 국내 확립 연구

저자 : 홍미혜 ( Mi Hye Hong ) , 조인숙 ( In-suk Joe ) , 방서영 ( Seo Young Bang ) , 이정선 ( Jung-sun Yi ) , 김광진 ( Kwang Jin Kim ) , 윤혜성 ( Hae Seong Yoon ) , 김태성 ( Tae Sung Kim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 15-22 (8 pages)

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This study aimed to establish the LuSens test method for identification of skin sensitisers in our laboratory and to facilitate the domestic use of the method. We utilized 10 recommended proficiency substances in OECD TG 442D consisting of 6 skin sensitisers (UN GHS category 1A and 1B: Eugenol, Cinnamyl alcohol, 2-Mercaptobenzo-thiazole, 4-Methylaminophenol sulfate, Methyl dibromo glutaronitrile and 2,4-Dinitro-chlorobenzene) and 4 non-sensitisers (No category: Salicylic acid, Glycerol, Isopropanol and Sulfanilamide). We measured the activity of luciferase induced by the test substances based on the CV75 that was determined by cytotoxicity dose-finding test. While the maximal luciferase fold induction values for each skin non-sensitisers ranged from 0.95 to 1.28, those for each skin sensitisers ranged from 1.96 to 5.66. We predicted sensitivity of the test substances on the basis of the luciferase fold induction values. Our results were within the range of acceptance criteria and accord with in vivo and in vitro references in OECD TG 442D. We found that the LuSens test method correctly identified proficiency substances into sensitisers and non-sensitisers. Therefore, the results obtained from the proficiency test demonstrated that we successfully introduced the LuSens test method in our laboratory. Furthermore, we have prepared a new in vitro skin sensitization test (ARE-Nrf2 luciferase LuSens) guideline for the safety evaluation of cosmetics and contributed to the dissemination of the method via technical transfer in Korea.

KCI등재

3Comprehensive in vitro Proarrhythmia Assay (CiPA) 기반 Torsade Metric Score (TMS)를 이용한 TdP 발생 약물의 위험군 분류 성능 평가

저자 : 윤승현 ( Seung-hyun Yoon ) , 남유리 ( Yu Ri Nam ) , 강현수 ( Hyun-su Kang ) , 정다운 ( Da Un Jeong ) , 유예담 ( Ye Dam Yoo ) , 임기무 ( Ki-moo Lim ) , 박성준 ( Seong-jun Park ) , 김배환 ( Bae-hwan Kim ) , 김기석 ( Ki-suk Kim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 23-43 (21 pages)

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For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG block, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. In this study, based on the CiPA project and previous studies, the nine drugs were tested using in vitro multiple ion channel screening on both temperature conditions (room temperature and 37℃). Using the in vitro results, in silico computer simulation was performed based on the O'Hara-Rudy human ventricular myocyte model, and same as the CiPA project obtained a new biomarker, qNet. The in silico computer simulation was performed using 2000 samples of IC50 values extracted by R code. The nine test drugs were associated with cardiotoxicity and TdP, and were selected by the CiPA project and previous studies. Furthermore, as in previous studies, Torsade Metic Score (TMS), the mean qNet value averaged across 1-4 × Cmax, and the threshold was calculated. As a result, the nine tested drugs using the TMS were well plotted by the risk categories and the threshold was able to well classify the risk categories by grade on both temperature conditions. In particular, the threshold 2 value confirmed to significant difference depending on the temperature conditions. The range of threshold narrowed at 37℃, which can be considered as having the ability to distinguish more finely. It shows the correlation with the CiPA project's validity that a study should be tested at a physiological temperature of 3 7℃. In this study, using the method proposed by the CiPA project, it was possible to predict the risk groups of drugs more accurately, which could be presented as a new paradigm in the cardiotoxicity assessment.

KCI등재

4마이크로플레이트를 이용한 8종 화학물질의 복귀돌연변이 평가

저자 : 김명준 ( Myoung Jun Kim ) , 허성무 ( Seongmoo Heo ) , 남수현 ( Suhyun Nam ) , 백승민 ( Seng-min Back ) , 박성훈 ( Seong Hoon Park ) , 오정자 ( Jeong Ja Oh ) , 정영신 ( Young-shin Chung )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 45-55 (11 pages)

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This study was conducted to establish the technology for bacterial reverse mutation test using 384-well microplates and liquid media instead of solid agar in order to evaluate the mutagenicity of test articles with limited amounts. The important advantage of this test method was considered that the usage of S9 fraction prepared from rat liver was smaller in comparison with the Ames test using solid agar. Five bacterial strains (S. typhimurium TA98, TA100, TA1535, TA1537 and E. coli WP2 uvrA) recommended in OECD TG 471 were used to evaluate 8 chemicals including 6 mutagens (Allyl chloride, 4-amino-2-nitrophenol, ethylene glycol dimethyl ether, benzo[α]pyrene, 7,12-dimethylbenzanthracene, 8-hydroxyquinoline) and 2 non-mutagens (dioctyl phthalate, sulfisoxazole). All experiments were performed using Ames MPFTM Penta II kits (Xenometrix, Switzerland). Three independent laboratories participated in the intra-laboratory and inter-laboratory studies. Results from this study were compared with reference mutagenicity data (NTP or published data). In results of this study, five out of six mutagens were evaluated to be positive, and the one mutagen (ethylene glycol dimethyl ether) to be negative. Two non-mutagens were determined to be negative in microplate tests. Both the intra-laboratory and the inter-laboratory study showed the 87.5% concordance in the overall results. It was concluded that a microplated reverse mutation test may be a compatible test method for the animal welfare as well as for the limited amount of substances.

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53D 인공 피부모델을 이용한 화장품 안전성 및 효능 평가 연구

저자 : 김규리 ( Kyuri Kim ) , 황지현 ( Jee-hyun Hwang ) , 임경민 ( Kyung-min Lim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 57-63 (7 pages)

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Cosmetics and their raw materials must be safe for consumers under the conditions of use. Safety assessments for some toxicological endpoints and efficacy evaluation of raw materials have relied on animal studies for a long time. However, in addition to animal welfare concerns and regulatory measures, more human-relevant data without animal testing have led to a new approach to safety assessment. As animal testing for safety evaluation of cosmetics and its raw materials is prohibited, various alternative test methods have been developed and used. Recently, interest in efficacy evaluation and safety confirmation systems using artificial skin models as alternative for animal testing is increasing. In this study, latest research trends for alternative animal testing methods for cosmetic safety evaluation were reviewed, and the limitations and directions for improvement of the current alternative animal testing methods were investigated. In addition, the current status of cosmetic efficacy evaluation research using artificial skin model and guidelines for evaluating the functional efficacy of existing cosmetics were investigated.

KCI등재

6장내세균에 의한 crocin 대사가 사염화탄소로 유발한 in vitro 지질과산화에 미치는 영향

저자 : 라지나샤키아 ( Rajina Shakya ) , 정태천 ( Tae Cheon Jeong )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 65-72 (8 pages)

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Role of intestinal microbiota in drug metabolism has not widely been considered yet, despite of its importance in the biotransformation of xenobiotics. Crocin and its aglycone, crocetin, originally isolated from the fruit of Gardenia jasminoides, are used in treatment of inflammation, cancer, metabolic disorders, cardiovascular and neurological diseases. In this study, in vitro metabolism of crocin to crocetin by intestinal contents from antibiotic-treated rats were investigated by using HPLC. As consistent with the in vivo results reported previously, in vitro results also showed better metabolism of crocin to crocetin in intestinal contents isolated from normal rats than those from antibiotic-treated rats. Moreover, anti-oxidant effects of crocin and crocetin were compared to specify which compound would be pharmacologically more active in rat liver S-9 fractions that contain metabolic activation system. The results showed protective effects by both compounds against CCl4-induced depletion of glutathione and/or elevation of malondialdehyde. Overall, the results suggested that intestinal microbiota might be responsible for pharmacological actions of crocin, and that the present in vitro metabolic activation system would be a useful tool for studying the role of xenobiotic metabolism in pharmacology and toxicology, which can reduce the number of animals used.

KCI등재

7자외선에 의한 피부손상 및 염증반응에서 크랜베리 에탄올 추출물의 억제효과

저자 : 정민지 ( Min-ji Jung ) , 김배환 ( Bae-hwan Kim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 73-82 (10 pages)

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This research was conducted to examine the usability of Cranberry Ethanol Extract (CEE) as an anti-inflmmatory ingredient. The total content of polyphenol and flavonoid as well as DPPH electron-donation and ABTS+ radical scavenging abilities were measured to check anti-oxidation activity. To verify anti-inflammatory effect, the nitric oxide (NO) inhibition assay in Raw 264.7 cell were conducted. The anti-inflammatory effect of CEE in UVB (160 mJ/cm2) irradiated HaCaT cell was evaluated by checking tumor necrosis factor (TNF)-α expression. The cell migration assay was peformed to confirm the wound healing effect of test material. In addition, the safety related to irritation was verified by Bovine Corneal Opacity and Permeability (BCOP) assay. The antioxidant abilities increased in concentration dependent manner in all tests, which confirmed CEE had a good anti-oxidation activity. In anti-inflammatory test, LPS-induced NO secretion was inhibited by CEE treatment, confirming anti-inflammatory effect of CEE. In UVB irradiated HaCaT cell, TNF-α expression, main cytokine in inflammation induced by UVB, also decreased in CEE treatment group in western blot assay. In migration assay of HaCaT cells, the remaining area of wound decreased significantly in CEE treated group, indicating CEE showed the wound healing effect. As for BCOP assay, CEE was classified as a non-irritant according to the OECD guideline 437. In conclusion, the results of this study showed that CEE has high anti-oxidation and anti-inflammation effects, and inhibits irritation from an external irritant such as UVB, which indicated it can be used as an anti-inflmmatory ingredient.

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Alternative test method for screening immunotoxic substances has not been actively challenged and no test guideline has been officialized internationally. Preparation of master list on reference chemicals is a critical process for decision on positive or negative immunotoxicity of test substances through alternative test method. The reference master list is recommended to include various scopes of immuntoxic xenobiotics including medicinal products, cosmetic ingredients, and industrial or environmental agents. Data bases or research results on human or animal immunotoxicity of chemicals were collected and analyzed for preparing the list of reference chemicals. Twenty eight chemicals were selected as non-immunotoxicants, which could be used as negative controls for immunotoxicity and 10 immunosuppressive drugs were chosen for classifying immunosuppressive toxicity of test substances. Considering chemicals used as positive controls for immunotoxicity, 38 substances with aberrant immune regulatory capacity were listed, which are categorized into 23 industrial or environmental agents, 12 medicinal products, and 3 agrochemicals. The list of reference test substances could contribute to development of in vitro alternative assay method for immunotoxicity evaluation.

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발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 15-22 (8 pages)

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This study aimed to establish the LuSens test method for identification of skin sensitisers in our laboratory and to facilitate the domestic use of the method. We utilized 10 recommended proficiency substances in OECD TG 442D consisting of 6 skin sensitisers (UN GHS category 1A and 1B: Eugenol, Cinnamyl alcohol, 2-Mercaptobenzo-thiazole, 4-Methylaminophenol sulfate, Methyl dibromo glutaronitrile and 2,4-Dinitro-chlorobenzene) and 4 non-sensitisers (No category: Salicylic acid, Glycerol, Isopropanol and Sulfanilamide). We measured the activity of luciferase induced by the test substances based on the CV75 that was determined by cytotoxicity dose-finding test. While the maximal luciferase fold induction values for each skin non-sensitisers ranged from 0.95 to 1.28, those for each skin sensitisers ranged from 1.96 to 5.66. We predicted sensitivity of the test substances on the basis of the luciferase fold induction values. Our results were within the range of acceptance criteria and accord with in vivo and in vitro references in OECD TG 442D. We found that the LuSens test method correctly identified proficiency substances into sensitisers and non-sensitisers. Therefore, the results obtained from the proficiency test demonstrated that we successfully introduced the LuSens test method in our laboratory. Furthermore, we have prepared a new in vitro skin sensitization test (ARE-Nrf2 luciferase LuSens) guideline for the safety evaluation of cosmetics and contributed to the dissemination of the method via technical transfer in Korea.

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3Comprehensive in vitro Proarrhythmia Assay (CiPA) 기반 Torsade Metric Score (TMS)를 이용한 TdP 발생 약물의 위험군 분류 성능 평가

저자 : 윤승현 ( Seung-hyun Yoon ) , 남유리 ( Yu Ri Nam ) , 강현수 ( Hyun-su Kang ) , 정다운 ( Da Un Jeong ) , 유예담 ( Ye Dam Yoo ) , 임기무 ( Ki-moo Lim ) , 박성준 ( Seong-jun Park ) , 김배환 ( Bae-hwan Kim ) , 김기석 ( Ki-suk Kim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 23-43 (21 pages)

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For the assessment of cardiotoxicity and Torsade de Pointes (TdP), a fatal arrhythmic symptom, ICH S7B and E14 guidelines were presented. However, focusing on hERG block, which are essential determinants of arrhythmic risk, may unexpectedly limit drug development by increasing the risk of drugs that are actually non-toxic. To compensate for these problems, the Comprehensive in vitro Proarrhythmic Assay (CiPA) project was proposed. In this study, based on the CiPA project and previous studies, the nine drugs were tested using in vitro multiple ion channel screening on both temperature conditions (room temperature and 37℃). Using the in vitro results, in silico computer simulation was performed based on the O'Hara-Rudy human ventricular myocyte model, and same as the CiPA project obtained a new biomarker, qNet. The in silico computer simulation was performed using 2000 samples of IC50 values extracted by R code. The nine test drugs were associated with cardiotoxicity and TdP, and were selected by the CiPA project and previous studies. Furthermore, as in previous studies, Torsade Metic Score (TMS), the mean qNet value averaged across 1-4 × Cmax, and the threshold was calculated. As a result, the nine tested drugs using the TMS were well plotted by the risk categories and the threshold was able to well classify the risk categories by grade on both temperature conditions. In particular, the threshold 2 value confirmed to significant difference depending on the temperature conditions. The range of threshold narrowed at 37℃, which can be considered as having the ability to distinguish more finely. It shows the correlation with the CiPA project's validity that a study should be tested at a physiological temperature of 3 7℃. In this study, using the method proposed by the CiPA project, it was possible to predict the risk groups of drugs more accurately, which could be presented as a new paradigm in the cardiotoxicity assessment.

KCI등재

4마이크로플레이트를 이용한 8종 화학물질의 복귀돌연변이 평가

저자 : 김명준 ( Myoung Jun Kim ) , 허성무 ( Seongmoo Heo ) , 남수현 ( Suhyun Nam ) , 백승민 ( Seng-min Back ) , 박성훈 ( Seong Hoon Park ) , 오정자 ( Jeong Ja Oh ) , 정영신 ( Young-shin Chung )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 45-55 (11 pages)

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This study was conducted to establish the technology for bacterial reverse mutation test using 384-well microplates and liquid media instead of solid agar in order to evaluate the mutagenicity of test articles with limited amounts. The important advantage of this test method was considered that the usage of S9 fraction prepared from rat liver was smaller in comparison with the Ames test using solid agar. Five bacterial strains (S. typhimurium TA98, TA100, TA1535, TA1537 and E. coli WP2 uvrA) recommended in OECD TG 471 were used to evaluate 8 chemicals including 6 mutagens (Allyl chloride, 4-amino-2-nitrophenol, ethylene glycol dimethyl ether, benzo[α]pyrene, 7,12-dimethylbenzanthracene, 8-hydroxyquinoline) and 2 non-mutagens (dioctyl phthalate, sulfisoxazole). All experiments were performed using Ames MPFTM Penta II kits (Xenometrix, Switzerland). Three independent laboratories participated in the intra-laboratory and inter-laboratory studies. Results from this study were compared with reference mutagenicity data (NTP or published data). In results of this study, five out of six mutagens were evaluated to be positive, and the one mutagen (ethylene glycol dimethyl ether) to be negative. Two non-mutagens were determined to be negative in microplate tests. Both the intra-laboratory and the inter-laboratory study showed the 87.5% concordance in the overall results. It was concluded that a microplated reverse mutation test may be a compatible test method for the animal welfare as well as for the limited amount of substances.

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53D 인공 피부모델을 이용한 화장품 안전성 및 효능 평가 연구

저자 : 김규리 ( Kyuri Kim ) , 황지현 ( Jee-hyun Hwang ) , 임경민 ( Kyung-min Lim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 57-63 (7 pages)

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Cosmetics and their raw materials must be safe for consumers under the conditions of use. Safety assessments for some toxicological endpoints and efficacy evaluation of raw materials have relied on animal studies for a long time. However, in addition to animal welfare concerns and regulatory measures, more human-relevant data without animal testing have led to a new approach to safety assessment. As animal testing for safety evaluation of cosmetics and its raw materials is prohibited, various alternative test methods have been developed and used. Recently, interest in efficacy evaluation and safety confirmation systems using artificial skin models as alternative for animal testing is increasing. In this study, latest research trends for alternative animal testing methods for cosmetic safety evaluation were reviewed, and the limitations and directions for improvement of the current alternative animal testing methods were investigated. In addition, the current status of cosmetic efficacy evaluation research using artificial skin model and guidelines for evaluating the functional efficacy of existing cosmetics were investigated.

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6장내세균에 의한 crocin 대사가 사염화탄소로 유발한 in vitro 지질과산화에 미치는 영향

저자 : 라지나샤키아 ( Rajina Shakya ) , 정태천 ( Tae Cheon Jeong )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 65-72 (8 pages)

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Role of intestinal microbiota in drug metabolism has not widely been considered yet, despite of its importance in the biotransformation of xenobiotics. Crocin and its aglycone, crocetin, originally isolated from the fruit of Gardenia jasminoides, are used in treatment of inflammation, cancer, metabolic disorders, cardiovascular and neurological diseases. In this study, in vitro metabolism of crocin to crocetin by intestinal contents from antibiotic-treated rats were investigated by using HPLC. As consistent with the in vivo results reported previously, in vitro results also showed better metabolism of crocin to crocetin in intestinal contents isolated from normal rats than those from antibiotic-treated rats. Moreover, anti-oxidant effects of crocin and crocetin were compared to specify which compound would be pharmacologically more active in rat liver S-9 fractions that contain metabolic activation system. The results showed protective effects by both compounds against CCl4-induced depletion of glutathione and/or elevation of malondialdehyde. Overall, the results suggested that intestinal microbiota might be responsible for pharmacological actions of crocin, and that the present in vitro metabolic activation system would be a useful tool for studying the role of xenobiotic metabolism in pharmacology and toxicology, which can reduce the number of animals used.

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7자외선에 의한 피부손상 및 염증반응에서 크랜베리 에탄올 추출물의 억제효과

저자 : 정민지 ( Min-ji Jung ) , 김배환 ( Bae-hwan Kim )

발행기관 : 한국동물실험대체법학회 간행물 : 한국동물실험대체법학회지 (jaae) 15권 1호 발행 연도 : 2021 페이지 : pp. 73-82 (10 pages)

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This research was conducted to examine the usability of Cranberry Ethanol Extract (CEE) as an anti-inflmmatory ingredient. The total content of polyphenol and flavonoid as well as DPPH electron-donation and ABTS+ radical scavenging abilities were measured to check anti-oxidation activity. To verify anti-inflammatory effect, the nitric oxide (NO) inhibition assay in Raw 264.7 cell were conducted. The anti-inflammatory effect of CEE in UVB (160 mJ/cm2) irradiated HaCaT cell was evaluated by checking tumor necrosis factor (TNF)-α expression. The cell migration assay was peformed to confirm the wound healing effect of test material. In addition, the safety related to irritation was verified by Bovine Corneal Opacity and Permeability (BCOP) assay. The antioxidant abilities increased in concentration dependent manner in all tests, which confirmed CEE had a good anti-oxidation activity. In anti-inflammatory test, LPS-induced NO secretion was inhibited by CEE treatment, confirming anti-inflammatory effect of CEE. In UVB irradiated HaCaT cell, TNF-α expression, main cytokine in inflammation induced by UVB, also decreased in CEE treatment group in western blot assay. In migration assay of HaCaT cells, the remaining area of wound decreased significantly in CEE treated group, indicating CEE showed the wound healing effect. As for BCOP assay, CEE was classified as a non-irritant according to the OECD guideline 437. In conclusion, the results of this study showed that CEE has high anti-oxidation and anti-inflammation effects, and inhibits irritation from an external irritant such as UVB, which indicated it can be used as an anti-inflmmatory ingredient.

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