• 한국산업보건학회지
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• 제23권1호
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• pp.1-10
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• 2013

Objectives: The present study investigated the potential subacute toxicity of 1,4-dichlorobutane (1,4-DCB) by a 2-week repeated oral dose in male Sprague-Dawley rats. Materials and Methods: The test chemical was administered once daily by gavage to male rats at dose levels of 0, 74, 222, 667, and 2000 mg/kg/day for 2 weeks. All rats were sacrificed at the end of treatment period. During the test period, clinical signs, mortality, body weights, food and water consumption, urinalysis, hematology, serum biochemistry, gross findings, and organ weights were examined. Results: At 2000 mg/kg/day, treatment-related clinical signs, as evidenced by hypothermia, decreased locomotor activity, piloerection, lying on side, and prone position were observed. All the rats were found dead on test day 2. At 667 mg/kg/day, polyuria, suppressed body weight gain, food consumption, and spleen and thymus weights, and increased adrenal gland and liver weights were observed.Hematological and serum biochemical investigations revealed increases in the alanine aminotransferase, alkaline phosphataseand total bilirubinand decreases in the serum $Na^+$ level, white blood cell count and lymphocyte ratio. There were no treatment-related adverse effects in the 74 and 222 mg/kg/day groups. Conclusions: In the present experimental conditions, target organs were determined to be spleen, thymus,and liver. The no-observed-adverse-effect level was considered to be 222 mg/kg/day in male rats.

• 동의신경정신과학회지
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• 제32권2호
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• pp.95-109
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• 2021

Objectives: The coronavirus disease 2019 (COVID-19) has become a global pandemic. Mental sequelae occurring in patients with COVID-19 and the general population are important concerns. In Korea, herbal medicine is used nationwide to respond to this pandemic. It can be prescribed by COVID-19 telemedicine center of Korean medicine (KM). Among some herbal medicines, Gamiguibi-tang is the only herbal medicine prescribed for individuals with mental health, especially for those with insomnia. In this mini-review, the objective of this study was to summarize the evidence of some promising herbal medicines available for treating primary insomnia based on existing clinical and preclinical studies. Methods: A research team was formed for KM clinical practice guidelines for insomnia (version 1.0). Team members were provided with a list of references of relevant herbal medicines for insomnia. To gather evidence from clinical studies with appropriate sample sizes, among the list of references, randomized controlled trials for primary insomnia that included 50 subjects or more per arm and used herbal medicine were included in the final analysis. Moreover, pre-clinical studies examining the mechanism of action of each herbal medicine and studies on herb-drug interactions, were searched and summarized. Results: Four herbal medicines (Ondam-tang, Sanjoin-tang, Guibi-tang, and Hyeolbuchugeo-tang) were reviewed based on existing clinical and preclinical studies. Based on findings of existing studies, some suggestions of herbal medicines for insomnia in the COVID-19 era in Korea were suggested. Conclusions: Data of this study could be used to prepare a future revision of the manual of COVID-19 telemedicine center of KM.

• 대한방사성의약품학회지
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• 제7권2호
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• pp.93-98
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• 2021

meta-iodobenzylguanidine is one of the norepinephrine analogs and reuptakes together with norepinephrine with norepinephrine transporter. The radioiodinated ligand, ¹²³I-meta-iodobenzylguanidine, is the most widely used for single photon emission computed tomography imaging to diagnose functional abnormalities and tumors of the sympathetic nervous system. In this study, we performed cellular uptake studies of ¹²³I-meta-iodobenzylguanidine in positive- and negative-norepinephrine transporter cells in vitro to verify the uptake activity for norepinephrine transporter. After ¹²³I-meta-iodobenzylguanidine was injected via a tail vein into normal mice, Single photon emission computed tomography/computed tomography images were acquired at 1 h, 4 h, and 24 h post-injection, and quantified the distribution in each organ including the adrenal medulla as a norepinephrine transporter expressing organ. In vitro cell study showed that ¹²³I-meta-iodobenzylguanidine specifically uptaked via norepinephrine transporter, and significant uptake of ¹²³I-meta-iodobenzylguanidine in the adrenal medulla in vivo single photon emission computed tomography images. These results demonstrated that single photon emission computed tomography imaging with ¹²³I-meta-iodobenzylguanidine were able to quantify the biodistribution in vivo in the adrenal medulla in normal mice.

• Journal of Periodontal and Implant Science
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• 제53권1호
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• pp.20-37
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• 2023

Purpose: Our pilot study showed that a 3-dimensional dual drug delivery scaffold (DDDS) loaded with Chinese herbs significantly increased the regenerated bone volume fraction. This study aimed to confirm the synergistic anti-inflammatory and osteogenic preclinical effects of this system. Methods: The targets and pathways of parthenolide and naringin were predicted. Three cell models were used to assess the anti-inflammatory effects of parthenolide and the osteogenic effects of naringin. First, the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) and the bone mineral density (BMD) of surgical defects were measured in a rat model of periodontitis with periodontal fenestration defects. Additionally, the mRNA expression levels of matrix metallopeptidase 9 (MMP9) and alkaline phosphatase (ALP) were measured. Furthermore, the number of inflammatory cells and osteoclasts, as well as the protein expression levels of tumor necrosis factor-alpha (TNF-α) and levels of ALP were determined. Results: Target prediction suggested prostaglandin peroxidase synthase (PTGS2) as a potential target of parthenolide, while cytochrome P450 family 19 subfamily A1 (CYP19A1) and taste 2 receptor member 31 (TAS2R31) were potential targets of naringin. Parthenolide mainly targeted inflammation-related pathways, while naringin participated in steroid hormone synthesis and taste transduction. In vitro experiments revealed significant antiinflammatory effects of parthenolide on RAW264.7 cells, and significant osteogenic effects of naringin on bone marrow mesenchymal stem cells and MC3T3-E1 cells. DDDS loaded with parthenolide and naringin decreased the CEJ-ABC distance and increased BMD and ALP levels in a time-dependent manner. Inflammation was significantly alleviated after 14 days of DDDS treatment. Additionally, after 56 days, the DDDS group exhibited the highest BMD and ALP levels. Conclusions: DDDS loaded with parthenolide and naringin in a rat model achieved significant synergistic anti-inflammatory and osteogenic effects, providing powerful preclinical evidence.

• Asian Pacific Journal of Cancer Prevention
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• 제15권6호
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• pp.2863-2868
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• 2014

Background: The 765G>C polymorphism in cyclooxygenase-2 (COX-2) gene has been extensively investigated for association with gastric cancer (GC). However, the results of different studies have been inconsistent. The aim of this study is to comprehensively evaluate the genetic risk of -765G>C polymorphism in the COX-2 gene for GC. Materials and Methods: We searched Pubmed, Embase, Medline, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on Jan 10, 2014). Statistical analyses were performed using Revman 5.2 and STATA 10.0 software. Results: A total of 1,874 cases and 3,005 controls in 10 case-control studies were included in this meta-analysis. The results indicated that the variant C allele carriers (GC+CC) had a 69% increased risk of GC when compared with the homozygote GG (odds ratio (OR)=1.69, 95% confidence interval (CI), 1.10-2.61 for GC+CC vs GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with C allele carriers in Asians (OR=1.75, 95%CI=1.40-2.18, and p<0.00001) and in Indians (OR=8.38, 95%CI=4.34-16.16, and p<0.00001) but not in Caucasians (OR=1.07, 95%CI=0.81-1.42, and p=0.62) or in Dutch (OR=0.53, 95%CI= 0.33-0.87, and p= 0.01).In the subgroup analysis by Helicobacter pylori (H. pylori) status, a significantly increased risk was identified among H. pylori (+) (OR=3.58, 95%CI=2.33-3.50, and p<0.00001) and H. pylori (-) (OR=2.32, 95%CI=1.46-3.69, and p=0.0004). Conclusions: This meta-analysis suggested that the -765G>C polymorphism in the COX-2 gene could be a risk factor for GC in Asians and Indians.

• Journal of Gastric Cancer
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• 제20권1호
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• pp.60-71
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• 2020

Purpose: The utility of 18-fluordesoxyglucose positron emission tomography ([¹⁸F]-FDG-PET) combined with computer tomography or magnetic resonance imaging (MRI) in gastric cancer remains controversial and a rationale for patient selection is desired. This study aims to establish a preclinical patient-derived xenograft (PDX) based [¹⁸F]-FDG-PET/MRI protocol for gastric cancer and compare different PDX models regarding tumor growth and FDG uptake. Materials and Methods: Female BALB/c nu/nu mice were implanted orthotopically and subcutaneously with gastric cancer PDX. [¹⁸F]-FDG-PET/MRI scanning protocol evaluation included different tumor sizes, FDG doses, scanning intervals, and organ-specific uptake. FDG avidity of similar PDX cases were compared between ortho- and heterotopic tumor implantation methods. Microscopic and immunohistochemical investigations were performed to confirm tumor growth and correlate the glycolysis markers glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) with FDG uptake. Results: Organ-specific uptake analysis showed specific FDG avidity of the tumor tissue. Standard scanning protocol was determined to include 150 μCi FDG injection dose and scanning after one hour. Comparison of heterotopic and orthotopic implanted mice revealed a long growth interval for orthotopic models with a high uptake in similar PDX tissues. The H-score of GLUT1 and HK2 expression in tumor cells correlated with the measured maximal standardized uptake value values (GLUT1: Pearson r=0.743, P=0.009; HK2: Pearson r=0.605, P=0.049). Conclusions: This preclinical gastric cancer PDX based [¹⁸F]-FDG-PET/MRI protocol reveals tumor specific FDG uptake and shows correlation to glucose metabolic proteins. Our findings provide a PET/MRI PDX model that can be applicable for translational gastric cancer research.

• 한국방사선학회논문지
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• 제17권1호
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• pp.11-16
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• 2023

전임상용 양전자방출단층촬영기기는 관심 시야 외곽에서의 공간분해능 저하현상이 발생한다. 이를 해결하기 위해 감마선과 섬광체가 상호작용한 위치를 측정하는 반응 깊이 측정(depth of interaction, DOI) 검출기가 개발되었다. 여러 층으로 섬광 픽셀 배열을 구성한 방법, 하나의 층의 양단에 광센서를 배치한 방법, 여러 층으로 섬광 픽셀 배열을 구성하고 각 층마다 광센서를 배치한 방법 등이 있다. 본 연구에서는 기존에 개발된 검출기들의 특징을 분석하여 새로운 형태의 DOI 검출기를 설계하였다. 두층으로 구성된 검출기는 각 층마다 서로 다른 크기의 섬광 픽셀을 사용하여, 배열의 크기를 다르게 구성하였다. 이러한 형태로 구성할 경우 층별 섬광 픽셀의 위치는 서로 어긋나게 배열되어 평면 영상에서 서로 다른 위치에 영상화된다. 설계한 검출기의 반응 깊이 측정 가능성을 확인하기위해 DETECT2000 시뮬레이션을 수행하였다. 각 섬광 픽셀의 중심에서 발생된 감마선 이벤트로 획득한 빛의 신호로 평면 영상을 재구성하였다. 그 결과 각 층별 모든 섬광 픽셀이 재구성된 평면 영상에서 분리되어 영상화되어, 반응 깊이를 측정할 수 있음을 확인할 수 있었다. 본 검출기를 전임상용 PET에 적용할 경우 공간분해능의 향상을 이루어 우수한 영상을 획득할 수 있을 것으로 사료된다.

• 대한임상검사과학회지
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• 제54권4호
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• pp.249-255
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• 2022

알츠하이머병은 주요한 공중보건 문제로 나타나며 연구분야에서도 최우선적인 과제이다. 알츠하이머병(AD)에서 뇌척수액(CSF)을 활용한 바이오마커인 아밀로이드-β(Aβ42), 총 타우(T-tau) 및 인산화 타우(P-tau)가 알츠하이머병 병태생리학의 핵심 요소를 반영한다. 임상 연구 및 새로운 측정법을 통한 임상적으로 활용되는 진단은 전임상 알츠하이머병에 대해 민감적이고 특이적이며 신뢰할 수 있는 바이오마커의 발굴, 뿐만 아니라 치매의 조기 발견 및 감별 진단과 질병 진행 모니터링에 도움이 되는 검사법의 개발에도 중요할 것이다. 증상 전 단계에서 AD의 조기 발견은 시냅스 손상 및 신경 손실이 확장되기 전에 개입이 수행되기 때문에 치료 개입을 조기에 가능하게 하고 치료 성공을 위한 가능성이 더 큰 좋은 기회로 이어진다. 따라서 새롭고 접근하기 쉽고 비용이 적게 드는 바이오마커를 임상 진단에 활용하는 것이 매우 유익할 것이다. 치매의 초기단계에 일어나는 병리학적 변화나, 질병의 진행정도를 추적할 수 있는 다양한 바이오마커들의 진단방법을 찾는 일은 치료제 개발처럼 중요한 연구 분야이다. 조기진단을 위해 임상증상을 대변하거나(surrogate marker), 증상이 나타나기 이전 상태를 측정할 수 있는 새로운 진단마커가 필요한 상황이다. 이러한 이유로 인지기능 저하정도를 측정하여 정상, 경도인지장애(mild cognition impairment, MCI) 및 전임상(preclinical) 상태의 사람을 판별할 수 있는 바이오마커(biomarker)를 활용한 조기진단법 개발의 중요성이 강조되고 있다.

• 벤처창업연구
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• 제14권1호
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• pp.151-166
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• 2019

신약개발은 기초연구${\rightarrow}$전임상${\rightarrow}$임상${\rightarrow}$품목허가${\rightarrow}$판매에 이르기까지 10~15년의 긴 시간과 10억불 이상의 막대한 자금을 필요로 한다. 많은 신약개발 바이오벤처기업은 증권시장 상장을 통해 확보한 자금으로 신약개발을 지속적으로 추진하고자 한다. 본 연구는 증권시장 상장이 신약개발 바이오벤처기업에 미치는 영향에 주목하여, 상장 시점(D) 및 상장 후 2년 시점(D+2년)에서 등록특허, 전임상, 임상, 기술이 전계약의 증가 여부로 증권시장 상장에 의한 신약개발 바이오벤처기업의 기술사업화 성과를 분석하였다. 또한 상장 및 상장 후 2년 시점에서 등록특허, 전임상 및 임상이 기술이전계약에 유의미한 영향을 미치는지 분석하였다. 분석결과는 다음과 같다. 첫째, 한국의 신약개발 바이오벤처기업은 상장 시점과 상장 후 2년 시점을 비교하면, 등록특허는 증가했으나 전임상, 임상 및 기술이전계약은 증가하지 않았다. 둘째, 상장 시점과 상장 후 2년 시점에 전임상은 한국기술이전계약에 유의한 영향을 주고 있고 해외기술이전계약에 부분적으로 유의한 영향을 주고 있지만, 등록특허 및 임상은 기술이전계약에 유의한 영향을 주지 않았다. 한국의 신약개발 바이오벤처기업은 증권시장 상장에도 불구하고 특허는 증가했지만, 전임상, 임상 및 기술이전계약은 증가하지 못했음을 알 수 있다. 향후 신약개발 바이오벤처기업의 기술사업화를 강화하기 위해서는 IPO 공모자금의 효율적 사용을 위한 R&D전략 수립, 산 학 연 연계 강화를 통한 오픈 이노베이션, 보다 정교한 전임상 및 임상 전략 수립 등이 요청되고 있다.

• Biomolecules & Therapeutics
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• 제23권3호
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• pp.296-300
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• 2015

${\beta}$-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of ${\beta}$-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of ${\beta}$-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of ${\beta}$-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of ${\beta}$-lapachone was 15.5%. The considerable degradation of ${\beta}$-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of ${\beta}$-lapachone may be resulted from the first-pass metabolic degradation of ${\beta}$-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.