• 대한한의학회지
• /
• 제31권3호
• /
• pp.1-7
• /
• 2010

Objectives: To introduce to TKM scientific dose conversion methods of human to animal or animal to human for new drug investigations. Methods: We searched guidelines of the FDA and KFDA, and compared them with references for drug-dose conversion from various databases such as PubMed and Google. Then, we analyzed the potential issues and problems related to dose conversion in safety documentation of new herbal drugs based on our experiences during Investigational New Drug (IND) applications of TKM. Results: Dose conversion from human to animal or animal to human must be appropriately translated during new drug development. From time to time, investigators have some difficulty in determining the appropriate dose, because of misunderstandings of dose conversion, especially when they estimate starting dose in clinical or animal studies to investigate efficacy, toxicology and mechanisms. Therefore, education of appropriate dose calculation is crucial for investigators. The animal dose should not be extrapolated to humans by a simple conversion method based only on body weight, because many studies suggest the normalization method is based mainly on body surface area (BSA). In general, the body surface area seems to have good correlation among species with several parameters including oxygen utilization, caloric expenditure, basal metabolism, blood volume and circulating plasma protein. Likewise, a safety factor should be taken into consideration when deciding high dose in animal toxicology study. Conclusion: Herein, we explain the significance of dose conversion based on body surface area and starting dose estimation for clinical trials with safety factor.

• 대한한의학회지
• /
• 제24권1호
• /
• pp.41-53
• /
• 2003

The effect of Banhasasim-tang extracts on the hepatic, splenic and cardiac toxicity induced by doxorubicin administration (three injection protocol) were monitored using male ICR mice. Changes of body weight, clinical signs, necropsy findings and organ weights of liver, spleen and heart were observed with blood GOT and GPT levels. The results were as follows: 1. Decrease of body weight after doxorubicin treatment was dose-dependently inhibited by Banhasasim-tang extracts. 2. The degrees of anorexia, ataxia and dehydration that were observed in doxombicin treatment groups were dose-dependently inhibited by Banhasasim-rang extracts. 3. Increase of absolute and relative liver weight observed in the doxorubicin treatment group were dose-dependently inhibited by Banhasasim-tang extracts. In addition, the degrees of liver congestion and necrotic spot were significantly and dose-dependently decreased in the Banhasasim-rang extracts dosing group compared to that of the doxorubicin-only treatment group. It is also demonstrated that elevated serum GOT and GPT levels in the doxorubicin treatment group were significantly decreased in the Banhasasim-rang extracts dosing group. 4. Decrease of absolute and relative spleen weight observed in doxorubicin treatment groups were dose-dependently inhibited by Banhasasim-rang extracts. In addition, the degrees of splenic atrophy were significantly and dose-dependently decreased in the Banhasasim-rang extracts dosing group compared to that of doxorubicin-only treatment group. 5. Increase of absolute and relative heart weight observed in doxorubicin treatment groups were dose-dependently inhibited by Banhasasim-rang extracts. In addition, the degrees of heart congestion and enlargement were significantly and dose-dependently decreased in the Banhasasim-rang extracts dosing group compared to that of the doxorubicin-only treatment group. In conclusion, the toxicity of doxorubicin treatment (decrease of body weight, clinical signs such as anorexia, ataxia and dehydration, changes of organ weights of liver, spleen and heart, elevation of serum GOT and GPT levels) was inhibited and/or prevented by Banhasasim-rang extracts. According to these results, it is considered that Banhasasim-rang has some preventive effect against the toxicity induced by doxorubicin.

• Nutritional Sciences
• /
• 제9권3호
• /
• pp.167-172
• /
• 2006

This study investigated the effects of Platycodon grandiflorum aqueous extract on lipid concentration of serum and liver in rats fed high cholesterol diet Male Sprague-Dawley rats were assigned to three groups (control, low dose of extract, high dose of extract) for four weeks. The serum total cholesterol concentration was significantly lower in the low and high doses of extract groups than in the control group. There was a significant decrease in the free cholesterol, cholesterol ester, LDL-cholesterol, and triglycerides concentrations in serum, and the total cholesterol and the triglycerides contentin liver in the low and high doses of extract groups compared to the control group. When the serum phospholipid concentration was compared among the groups, it was significantly lower in high dose of extract group than in control and low dose of extract group. It can be postulated that Platycodon grandiflorum aqueous extract may possess substantial hypolipidemic properties in rats.

• 대한한의학회지
• /
• 제23권3호
• /
• pp.174-187
• /
• 2002

Objectives : This study was carried out to determine whether Kamihaengche-tang plus Yulanijihwang-tang (KCYH) exerts a protective effect against oxidant-induced liver cell injury. Methods : Cell injury was estimated by measuring lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) release, and lipid peroxidation was estimated by measuring malondialdehyde, a product of lipid peroxidation in rabbit liver slices. Results : Oxidants (tBHP and $H_2O_2$) increased dose-dependently LDH release which was significantly prevented by 1% KCYH. The protective effect of KCYH against oxidant-induced cell injury was dose-dependent in the range of 0.05-1 % concentrations. Similarly, KCYH inhibited oxidant-induced lipid peroxidation in a dose-dependent manner. When liver tissues were exposed to Hg (0.5 mM), ALT activity in the medium and lipid peroxidation in tissues were markedly increased. These changes were prevented by 1% KCYH, KCYH restored toxicant-induced inhibition of cellular GSH content. KCYH increased the activities of catalase and glutathion peroxidase in oxidant-treated tissues. Conclusions : These results indicate that KCYH exerts a protective effect against oxidant-induced liver cell injury, and this effect is attributed to prevention of lipid peroxidation. These effects may be due to an increase in concentration of endogenous antioxidants.

• Journal of Nutrition and Health
• /
• 제31권4호
• /
• pp.687-696
• /
• 1998

This study was performed to investigate effects of hesperidin and naringin on linpid peroxide formation and antioxidative enzyme activities in rats. Thiobarbituric acid reactive substance (TBARS) concentrations were measured in plasma and liver. Catalase, superoxide dismutase, and glutathione peroxidase activities were measured in erythrocyte and liver. Forty-nine male Sprague-Dauley rats weighing 275.3$\pm$3.3g were blocked into seven groups according to body weight and were raised fro four weeks on diets containing 0.25, 0.50 or 1.00%(w/w) hesperidin or naringin . Food intake, weight gain , food efficiency ratio, and weights of liver, kidney, spleen ,and epididymal fat pad were not significantly different among groups. In 0.50 and 1.00% naringin groups , plasma TBARS concentrations were significantly decreased with a dose response patter. In 0.25, 0.50 and 1.00% hesperidin groups, liver TBARS concentrations were significantly decreased without a dose dependent patter. Antiosidative enzyme activities in erythrocyte and liver were not significantly affected by type and amountof dietary bioflavonoid, but in the 1.00% hesperidin group, catalase, superoxide dismutase, and glutahione perosidase activities in linver showed a tendency to increase. In conclusion, naringin inhibited lipid peroxide formation with a dose response pattern in plasma without changing the activities of antioxidative enzymes. Hesperidin adminstration, regardless of the level in the diet, inhibited lipid peroxide formation in liver.

• Nutrition Research and Practice
• /
• 제12권6호
• /
• pp.535-540
• /
• 2018

BACKGROUND/OBJECTIVES: Propolis has a rich source of bioactive compounds and has renal and hepatic protective properties. The purpose of this study was to investigate the beneficial effect of hydro-ethanolic extract of propolis against paracetamol-induced liver damage and impairment of kidney function, as well as hematological changes in rats. MATERIALS/METHODS: Six groups of rats were used; the first group was served as a control; the second and third groups were treated by propolis extract at a dose of 50 and 100 mg/kg.B.WT. respectively; the fourth group was treated by paracetamol (200 mg/kg.B.WT.); the fifth group was treated by propolis (50 mg/kg.B.WT.) for eight days and then received similar dose of propolis for following seven days with paracetamol at a dose of 200 mg/kg.B.WT. daily for the seven days; and the sixth group was treated with propolis (100 mg/kg.B.WT.) for eight days and then received similar dose of propolis for following seven days with paracetamol at a dose of 200 mg/kg.B.WT. daily for the seven days. All the animals were treated for a period of 15 days. At the end of the experimental period, blood samples were collected for measurement of the liver enzymes, serum albumin, protein and creatinine, blood urea nitrogen, hematological parameters, and urine volume, protein and albumin. RESULTS: Paracetamol over dose significantly lowered hemoglobin, serum total protein, albumin, and uric acid, while it significantly increased blood creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities, white blood cells, and platelet count as compared to the control. However, these alterations were significantly attenuated by the use of propolis extract and the effect was dose dependent. Interestingly, propolis prevented paracetamol induced proteinuria, low hemoglobin and body weight loss. CONCLUSIONS: Propolis significantly prevented paracetamol induced renal, hepatic and hematological toxicity and might be useful in the management of liver and renal diseases particularly proteinuria.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권23호
• /
• pp.10413-10420
• /
• 2015

Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place. The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) against the hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel (DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups ($DTX_L$, $CTX_L$, $EPI_L$ or $DTX_H$, $CTX_H$, $EPI_H$), and low or high dose chemotherapeutics+APS groups ($DTX_L$+APS, $CTX_L$+APS, $EPI_L$+APS or $DTX_H$+APS, $CTX_H$+APS, $EPI_H$+APS). Controls were treated with equivalent normal saline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or high doses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group were separately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS (100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructure morphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points. With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and AST were significantly increased. Sections of liver tissue showed massive hepatotoxicity in $CTX_H$ group compared to the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis in hepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatin aggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that the protein levels of caspase-3 increased in $CTX_H$ group. The low dose groups exhibited trivial hepatotoxicity. More interestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities (low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes and the protein levels of caspase-3 ($CTX_H$+APS group). In conclusion, DTX, CTX and EPI induce liver damage in a dose dependent manner, whereas APS exerted protective effects.

• 한국환경성돌연변이발암원학회지
• /
• 제22권4호
• /
• pp.266-273
• /
• 2002

The dose dependence of the severity of radiation-induced thymic lymphoma in C57BL/6J mice was studied. Mice were exposed to fractionated irradiation at the total doses of 4.0, 6.0 and 8.0 Gy (four irradiations at 8-day intervals) starting from 33 days after birth. Pathological and histological changes of each mouse were observed after periodical sacrifice at day 75, 100, 125, 150, 175, 200, 250, 300 after the first irradiation. The severity of cancers were classified into 4 stages by clinical signs with respect to the enlargement of the thymus, spleen, liver, the progression of the cancer in the thymus, and the metastasis to the spleen, liver, lung and the lymphatic nodes. Among the 490 mice observed, 146 mice had thymic lymphoma. A clear dose-effect relationship was observed as well as the dose-response relationship. Also, periodical observation showed that thymic lymphoma was first induced in mice sacrificed at day 100 (130days old), and metastasize in the order of spleen, lung, liver and then the lymphatic nodes. The results suggest that radiation may be involved not only as a tumor initiator but also as a tumor promoter, and a tumor progression-enhancing agent.

• Journal of the Korean Physical Society
• /
• 제73권9호
• /
• pp.1289-1294
• /
• 2018

The present study aims to investigate experimentally and theoretically thermal ablation in soft tissues by using high intensity focused ultrasound (HIFU) to assess tissue damage during HIFU thermotherapy. The HIFU field was calculated by solving the axisymmetric Khokhlov-Zabolotskaya-Kuznetsov equation from the frequency-domain perspective. The temperature field was calculated by solving Pennes' bioheat transfer equation, and the thermal dose required to create a thermal lesion was calculated by using the thermal dose formula based on the thermal dose of a 240-min exposure at $43^{\circ}C$. In order to validate the simulation results, we performed thermal ablation experiments in a tissue-mimicking phantom and ex-vivo porcine liver for two different HIFU source conditions by using a 1.1-MHz, single-element, spherically focused HIFU transducer. The small difference between the measured and the predicted lesion sizes suggests that the implementation of the numerical model used here should be modified to iteratively allow for temperature-dependent changes in the physical properties of tissues.

• 핵의학기술
• /
• 제14권1호
• /
• pp.115-121
• /
• 2010

방사성핵종과 방사능을 측정하는 dose calibrator의 서로 다른 두개의 기기에서 F-18 FDG을 각각 측정하고, 이 측정값에 의한 인체 내 SUV (Standard Uptake Value)에 미치는 영향은 없는지에 대하여 알아보고자 하였다. 이 연구에서 두개의 다른 dose calibrator는 CRC-15 Dual PET, CRC-15R을 사용하였다. 각 dose calibrator에서 F-18 FDG를 2 mL 주사기 3개에 볼륨 1 mL, 2 mL, 3 mL를 만들어 각각 초기 radio activity를 측정한 후 4시간 30분(270분)까지 30분 간격으로 radio activity를 각각 측정하고 기록한다. 초기 radio activity 값을 기준으로 방사선붕괴 공식으로 산출된 값(decay factor)과 dose calibrator로 측정된 값 간의 직선성을 단순선형을 통하여 분석하였다. CRC-15 Dual PET에서 가장 이상적인 값에 가까운 측정값을 볼륨을 기준으로 하여, CRC-15R에서 측정된 값을 최적화하기 위한 선형회귀식을 회귀분석을 통하여 구한다. 선형회귀식의 산출값을 적용하여 PET/CT 검사를 시행한 50명을 대상으로 lung, liver, region 부위에 ROI을 그려 SUV를 구한다. CRC-15 Dual PET, CRC-15R에서 측정한 radio activity와 그 값을 이용한 SUV를 paired t-test로 통계적으로 유의한 차이가 있는지 알아보았다. CRC-15 Dual PET과 CRC-15R에서 측정한 radio activity의 상관분석결과 1 mL의 경우 상관성을 보여주는 r값은 r=0.999이었으며, 회귀분석에 위한 선형식은 y=1.0345x+ 0.2601이었다. 2 mL의 경우 r=0.999이며, 선형회귀식은 y=1.0226x+0.1669이었다. 3 mL의 경우 r=0.999이며, 선형회귀식은 y=1.0094x+0.1577이었다. 각 세 가지 볼륨에서 얻어진 선형회귀식의 산출 값을 이용하여 구한 lung, liver, region 부위에 ROI의 SUV에서의 차이는 1 mL의 경우, lung, liver, region은 (p<0.0001)로 t-test 결과 모두 유의한 차이가 있었다. 2mL의 경우, lung (p<0.002), liver, region은 ROI의 SUV에서 유의한 차이(p<0.0001)를 보였다. 또한 3 mL의 경우, lung(p<0.044), liver, region의 유의한 차이(p<0.0001)가 있었다. F-18 FDG 검사에서 사용되는 두 개의 dose calibrator CRC-15 Dual PET, CRC-15R의 radioactivity에 대한 측정치에서는 상관관계의 차이가 없다는 것을 알 수 있었다. 그러나 이 두 값을 통해 SUV는 인체 내의 uptake 정도에 있어서는 유의한 차이를 보인다는 것을 알 수 있었다. 따라서 이 두개의 dose calibrator를 사용함에 있어서, 이 두 값이 인체 내 SUV의 차이를 고려하여 사용하여야 할 필요성이 요구된다.