• 대한예방한의학회지
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• 제17권3호
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• pp.19-30
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• 2013

This study was aimed to develop a new formula for herbal medicine-safety classification in terms of evidence-based medicine. Recently, human equivalent dose(HED)-based therapeutic index was developed for herbal medicine-safety classification by transforming $LD_{50}$ to HED. However, the use of the $ED_{50}$ and $LD_{50}$ to derive the therapeutic index may be misleading as to safety, depending on the slope of the dose-response curves for therapeutic and lethal effects. To overcome this deficiency, HED-based MOS(Margin of Safety)was developed and suggested in this study. The HED-based MOS developed by using $LD_1$, changing to ALD(approximate lethal dose), and $ED_{99}$. The HED-based MOS seems to be more useful and safer than HED-based therapeutic index since its values for several herbal medicines are basically two times less than the values from HED-based therapeutic index. Thus, HED-based MOS can be a good example of Evidence-based approach for herbal medicine-safety classification.

• 대한예방한의학회지
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• 제19권2호
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• pp.123-133
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• 2015

The new formular for herbal medicine-safety classification in terms of evidence-based medicine was developed and applied to evaluate various herbal medicines in the previous study. This study is aimed to evaluate the frequently-used herbal medicines inducing toxic metabolites or reactive intermediates(RI), such as Ligusticum wallichii Franch, Angelica sinensis, Glycyrrhizae Radix, Rehmanniae Radix, based on 6 safety grades calculated from human equivalent dose(HED)-based MOS(margin of safety). HED-based MOS can be explained as the ratio of theoretical ALD(approximate lethal dose) of human as $LD_1$(lethal dose of 1%)/ clinical maximum dose as $ED_{99}$(Effective dose of 99%). The herbal medicine showing the ratio less than 1 belongs to Class 1, but the herbal medicine showing the ratio more than 500 belongs to Class 6 with the lowest toxicity. As a result, they were evaluated as class 2 for Angelica sinensis and Glycyrrhizae Radix, class 3 for Ligusticum wallichii Franch and Rehmanniae Radix. These resultant grades for 4 herbal medicines were lower than the grade expected under consideration that these herbal medicines are used very frequently in oriental clinics. These low grades would be due to their ingredients which is biotransformed to toxic metabolites.

• Journal of Acupuncture Research
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• 제39권4호
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• pp.310-316
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• 2022

Background: Verbenalin is an iridoid glucoside, which is among the active components of some medicinal herbs such as Verbena officinalis Linn, and Cornus officinalis Siebold and Zucc. Previous studies have confirmed the antioxidant activity and neuroprotective potential of verbenalin. To confirm the safety of verbenalin, an approximate lethal dose was determined based on a single oral dose toxicity study. Methods: Institute of Cancer Research mice were randomly assigned to three verbenalin exposure groups (250, 500, and 1,000 mg/kg) and a control group (5% methylcellulose solution). There were (5 male and 5 female mice per group). Mortality, clinical signs, and body weight were monitored for 14 days, and necropsies were conducted. Results: No mortalities were observed in the control group or the verbenalin 250 mg/kg group, whereas mortalities were observed in the 500 mg/kg and 1,000 mg/kg verbenalin groups. During the observation period, stool abnormalities such as mucous stools were observed. Clinical signs such as loss of locomotor activity were observed in the 500 mg/kg and 1,000 mg/kg verbenalin groups. During the study period, significant changes in body weight were observed in the 500 mg/kg and 1,000 mg/kg verbenalin groups; however, no gross abnormalities were observed at necropsy. Overall, no toxicity was found in the 250 mg/kg group. Conclusion: The approximate lethal dose of verbenalin was estimated to be 500 mg/kg. For a more accurate assessment of the safety of verbenalin, other types of studies such as repeated-dose toxicity studies should also be conducted.

• 대한약침학회지
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• 제26권1호
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• pp.86-93
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• 2023

Objectives: This study aimed to evaluate the potential toxicity of a recently developed and clinically used No-Pain pharmacopuncture (NPP) solution. We also assessed the lethal dose of the NPP agent following a single intramuscular injection in Sprague-Dawley (SD) rats. Methods: Animals were divided into two groups: the NPP test material group and the normal saline control group. A single intramuscular injection of the NPP agent (1.0 mL/animal) was administered to rats of the NPP test material group. The control group rats received the same volume of normal saline. Both female and male rats were included in each group. All rats were monitored for clinical signs and body weight changes for 14 days after administration of the test substance or saline. At the end of the observation period, a gross necropsy was conducted and localized tolerance at the injection site was analyzed. Results: No mortality was observed in the NPP test material and control groups. Moreover, no test substance-related effects were observed on clinical signs, body weight, necropsy findings, and localized tolerance at the injection site. Conclusion: The approximate lethal dose of the NPP agent is greater than 1.0 mL/animal under the conditions used in this study. Additional toxicity evaluations and clinical studies are needed to confirm the safety of NPP use in clinical practice.

• 동의생리병리학회지
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• 제28권2호
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• pp.186-194
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• 2014

The object of this study was to obtain acute toxicity information (single-dose oral toxicity) of Woohwangchungshim-won (WHCSW), a pill type herbal medicine used in Korean Medicine (KM) for treating stroke. In order to obtain the 50% lethal dose (LD50), approximate lethal dosage (ALD) and target organs, WHCSW powders were once orally administered to female and male ICR mice at dose levels of 2,000, 1,000, 500 and 0 (control) mg/kg (body weight.) according to the recommendation of Korea Food and Drug Administration (KFDA) Guidelines (Notification No. 2009-116). The mortality and changes in the body weight, clinical signs and gross observation were monitored for 14 days after single-dose oral administration of WHCSW according to KFDA Guidelines with organ weights and histopathological changes were observed in 12 principle organs. After single-dose oral administration of WHCSW, we could not find any mortality and toxicological evidences up to 2,000 mg/kg-administered group, except for some accidental findings and dose-independent increases of body weight gains in female 1,000 and 500 mg/kg-administered female mice. The results obtained in this study suggest that the LD50 and ALD of WHCSW in both female and male mice after single-dose oral administration were considered as over 2,000 mg/kg because no mortalities were detected up to 2,000 mg/kg that was the highest dose recommended by KFDA and Organization for Economic Co-Operation and Development (OECD), and can be safely used in clinics.

• 대한약침학회지
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• 제18권3호
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• pp.42-48
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• 2015

Objectives: The aim of the study is to investigate both the single-dose intramuscular injection toxicity and the approximate lethal dose of water-soluble Carthami-flos and Cervi cornu parvum pharmacopuncture (WCFC) in male and female Sprague-Dawley (SD) rats. Methods: The study was conducted at Biotoxtech Co. according to the Good Laboratory Practice (GLP) regulation and the toxicity test guidelines of the Ministry of Food and Drug Safety (MFDS) after approval of the Institutional Animal Care and Use Committee. Dosages for the control, high dose, middle dose and low dose groups were 0.5 mL/animal of saline and 0.5, 0.25 and 0.125 mL/animal of WCFC, respectively. WCFC was injected into the muscle of the left femoral region by using a disposable syringe (1 mL, 26 gauge). The general symptoms and mortality were observed 30 minutes, 1, 2, 4, and 6 hours after the first injection and then daily for 14 days after the injection. The body weights of the SD rats were measured on the day of the injection (before injection) and on the third, seventh, and fourteenth days after the injection. Serum biochemical and hematologic tests, necropsy examinations, and histopathologic examinations at the injection site were performed after the observation period. Results: No deaths, abnormal clinical symptoms, or significant weight changes were observed in either male or female SD rats in the control or the test (0.125, 0.25, and 0.5 mL/animal) groups during the observation period. No significant differences in hematology and serum biochemistry and no macroscopic abnormalities at necropsy were found. No abnormal reactions at injection sites were noted on the topical tolerance tests. Conclusion: The results of this single-dose toxicity study show that WCFC is safe, its lethal doses in male and female SD rats being estimated to be higher than 0.5 mL/animal.

• 대한약침학회지
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• 제21권2호
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• pp.104-111
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• 2018

Objective:This study is to evaluate both the single-dose intravenous injection toxicity and the approximate lethal dose of Water-soluble Danggui Pharmacopuncture (WDP) in Sprague-Dawley (SD) rats. Methods: Toxicity experiments were conducted at Good Laboratory Practice (GLP) laboratory in Biotoxtech Co., according to the regulations of GLP. WDP injection of dose 0.125, 0.25, and 0.5 mL/animal were experimental groups and normal saline injection group was control group. WDP and normal saline were injected once to 6- week old 5 male and 5 female SD rats at the tail veins at approximately 2 mL/min. During 14 days after the injection, general symptoms were observed and weight were measured. After the observation period, hematological and blood biochemical examination, macroscopic autopsy, topical resistance test at the injection area were performed. Results: RThe WDP 0.5 mL/animal injection group in 4 cases of male rats and all cases of female rats showed hematuria 30 minutes after the administration. However, after 1 hour, no more abnormal general symptoms were observed. The WDP did not affect weight, hematological and blood biochemical examination, macroscopic autopsy, and topical resistance test at the injection area. Conclusion: WDP single dose intravenous injection results showed that WDP have no toxic effects and a lethal dose of WDP should be over 0.5 mL/animal in male and female rats under the study condition. So WDP may be safe.

• 한방재활의학과학회지
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• 제25권2호
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• pp.73-80
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• 2015

Objectives To assess the safety of Shinbaro3 Pharmacopuncture by analyzing the potential single-dose intramuscular toxicity of Shinbaro3 Pharmacopuncture at various dose levels in SD (Spraque-Dawley) rats and Beagle dogs. Methods For evaluation of single-dose intramuscular toxicity of Shinbaro3 Pharmacopuncture, 40 SD rats (20 male and 20 famale) and 4 Beagle dogs (2 male and 2 female) were used. The rats were divided in four groups of 10 each, and treated intramuscularly with Shinbaro3 Pharmacopuncture at doses of 0.3, 0.6 and 1.2 mg/kg in distilled water, and distilled water as a vehicle control group, respectively. The Beagle dogs were divided into two groups of 2 each, and treated intramuscularly with Shinbaro3 Pharmacopuncture at doses of 0.15, and 0.3 mg/kg in distilled water, respectively, and signs of toxicity were observed. After a wash-out period of 3 days, the procedure was repeated with Shinbaro3 Pharmacopuncture at doses of 0.6, and 1.2 mg/kg in distilled water, respectively. Mortality, body weight changes, and necropsy findings were examined during the study period. Results There were no mortalities in either the SD rats or Beagle dogs. There were also no significant differences in adverse effects, body weight, or necropsy findings between the Shinbaro3 Pharmacopuncture and control groups. Conclusions There results suggest that the lethal dose 50 ($LD_{50}$) and approximate lethal dose (ALD) value of the test substance Shinbaro3 Pharmacopuncture are higher than 1.2 mg/kg in SD rats and Beagle dogs.

• 동의생리병리학회지
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• 제23권5호
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• pp.993-1002
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• 2009

The object of this study was to evaluate the single dose toxicity of Taeumjowui-tang(TUJWT), a polyherbal formula have been traditionally used as prevention or treatment agent for obesity, in male and female mice. Aqueous extracts of TUJWT (Yield = 10.5%) was administered to female and male ICR mice as an oral dose of 2000, 1000 and 500 mg/kg (body wt.) according to the recommendation of KFDA Guidelines. Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after dosing, upon necropsy, organ weight and histopathology of 12 principle organs were examined. As results, we could not find any mortality, clinical signs, and changes in the body and organ weight except for diarrhea restricted in TUJWT 2000 mg/kg treated one male mouse at 1 day after administration, and increases of popliteal lymph node weights in all TUJWT administered groups. In addition, no TUJWT-treatment related abnormal gross findings and changes in histopathology of principle organs were detected except for increases of the frequency of hypertrophy and hyperplasia of lymphoid cells in the popliteal lymph nodes in all TUJWT treatment groups with some sporadic accidental findings. These increases of popliteal lymph node weights with hypertrophy and hyperplasia of lymphoid cells were considered that related to the immune modulate effect of TUJWT not toxicological signs. The results obtained in this study suggest that the TUJWT does not cause any toxicological signs. The 50% lethal dose and approximate lethal dose of TUJWT aqueous extracts in both female and male mice were considered as over 2000 mg/kg.

• 동의생리병리학회지
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• 제23권5호
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• pp.1145-1153
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• 2009

The object of this study was to obtain acute information single oral dose toxicity of Mahwangbujaseshin-tang extracts, with mouse bone marrow cell micronucleus test for detecting possible genotoxicity. In order to observe the 50% lethal dose, approximate lethal dosage, maximum tolerance dosage and target organs, test articles were once orally administered to ICR mice at dose levels of 2000, 1000, 50 mg/kg according to the recommendation of KFDA Guidelines. The mortality and changes on body weight, clinical signs and gross observation were monitored during 14 days after dosing according to KFDA Guidelines with organ weights of 12 types of principle organs. In addition, after twice oral treatment of Mahwangbujaseshin-tang extracts 2000, 1000 and 500 mg/kg, we checked the changes on the number of MNPCE. We could not find any mortality, clinical signs, changes in the body weight and gross findings upto 2000 mg/kg treated group. The limited dosages in rodents except for increases of lymphoid organ weights and hypertrophy encounted as results from pharmacological effects of Mahwangbujaseshin-tang extracts, immune modulator effects with some sporadic accidental findings not toxicological signs. No evidence of increases of MNPCE numbers were also detected in all three different dosages of Mahwangbujaseshin-tang extracts treated mice. The results obtained in this study suggest that the LD50 and ALD of Mahwangbujaseshin-tang extracts in mice were considered as over 2000 mg/kg because no mortalities were detected upto 2000 mg/kg that was the highest dose recommended by KFDA and OECD. And the results of mouse bone marrow micronucleus test of Mahwangbujaseshin-tang extracts is negative results.