Rat 13-Week Repeated Oral Dose Toxicity Test of Palmul-tang - OECD Guideline 408 based KFDA Guideline 2015-082

( Kim Joo-ik ) 대구한의대학교 제한동의학술원 2022 제한동의학술원논문집 Vol.20 No.1

The objective of this study was to obtain 13 weeks repeated oral dose toxicity information of Palmul-tang (PMT), a representative Korean gi-tonifying polyherbal formula, consisted of eight herbs, has been employed in the treatment of qi deficiency and blood problems caused by consumptive diseases, in female and male Sprague-Dawley rats as a process to develop of natural origin medicinal ingredient or food itself, according to Organization for Economic Co-Operation and Development (OECD) Guideline 408 (1998) based Korea Food and Drug Administration (KFDA) Guideline (KFDA2015-082, 2015). In order to investigate the toxicity and identify target organs, PMT were orally administered to female and male Sprague-Dawley rats at dose levels of 2,000, 1,000, 500 and 0 (vehicle control) mg/kg (body weights), in a volume of 10 ml/kg, dissolved in distilled water, once a day for 91 days, and the mortality and changes on the body weight, food and water consumption, fecal and urine excretion, clinical signs were monitored during 91 days of treatment with gross observation, changes on the organ weights, hematology and serum biochemistry, and histopathology of principle organs based on the recommendation of OECD Guideline 408 (1998) based KFDA Guideline (KFDA2015-082, 2015), as compared with those of equal genders of vehicle control rats. Because LD50 and approximate LD of PMT, which were extracted and standardized by Aribio (Seungnam, Korea) in the both female and male Sprague-Dawley rats after single oral dose were considered over 2,000 mg/kg - the limited dosage of rodents with no specific target or clinical sings in our previous single oral dose toxicity test of PMT in Sprague-Dawley rats, the highest dosage used in the present study were also selected as 2,000 mg/kg in a volume of 10 ml of distilled water - the limit dosages of rodents, and 1,000 and 500 mg/kg were selected as middle and lower dosage groups using common ratio 2, according to OECD Guideline 408 (1998) based KFDA Guideline (KFDA2015-082, 2015). As the results of 13 weeks (91 days) repeated oral treatment of PMT, once a day in female and male Sprague-Dawley rats, no treatment related mortalities were observed within 91 days after end of treatment up to 2,000 mg/kg, the limited dosage of rodents in the both genders, and also no PMT treatment related changes on the body and organ weights, clinical signs, food and water consumption, fecal and urine excretion, hematology and serum biochemistrical analysis, necropsy and histopathological findings were observed in all test dose levels - 2,000, 1,000 and 500 mg/kg of both female and male rats, at least in a condition of the current experiment. The results obtained in this study suggest that the PMT, which were extracted and standardized by Aribio (Seungnam, Korea), is non-toxic in rats and is therefore, likely to be safe for clinical use (Table 24). The maximum tolerated dose (MTD) and No-observed-adverse-effect level (NQAEL) in rats after 13 weeks repeated oral dose of PMT were considered over 2,000 mg/kg, the limited dosage of rodents in both female and male Sprague-Dawley rats, respectively. In addition, no specific target or clinical sings were detected, at least in a condition of the present study, as same as previous oral dose toxicity tests of natural products in rats.

보중익기탕의 랫트 단회 경구투여 독성실험

김주익 ( Joo-ik Kim ),송창현 ( Chang-hyun Song ),박수진 ( Soo-jin Park ),최성훈 ( Seong-hun Choi ),구세광 ( Sae-kwang Ku ) 대구한의대학교 제한동의학술원 2021 제한동의학술원논문집 Vol.19 No.1

Objectives : The objective of this study was to obtain acute (single) oral dose toxicity information of Bojungikki-tang (BJIKT), prepared and standardized by Aribio Ltd. (Seungnam, Korea), in female and male Sprague-Dawley rats as a process to develop of natural origin medicinal ingredient or food itself. Materials and methods : In order to investigate the toxicity and identify target organs, BJIKT were once orally administered to female and male Sprague-Dawley rats at dose levels of 2000, 1000, 500 and 0 (vehicle control) mg/kg (body weights) in a volume of 10 ml/kg, dissolved in distilled water, and the mortality and changes on the body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs based on the recommendation of Organization for Economic Co-Operation and Development (OECD) Guideline 423 based Korea Food and Drug Administration (KFDA) Guideline (2015-082, 2015), as compared with those of equal genders of vehicle control rats. Because there are no available toxicological data after oral treatment in female and male rats of BJIKT, the highest dosage used in the present study were selected as 2,000 mg/kg in a volume of 10 ml of distilled water - the limited dosages of rodents, and 1,000 and 500 mg/kg were selected as middle and lower dosage groups according to OECD Guideline 423 based KFDA Guidelines (Notification No. 2015-082, 2015). In addition each female and male vehicle controls were added in this experiment. Principal organs for weighing : Lung, Heart, Thymus, Liver, Left Kidney, Left Adrenal Gland, Spleen, Left Testis/Ovary, Splenic lobe of Pancreas, Brain, Urinary bladder, Left Epididymis/total Uterus, Prostate and Left Submandibular Lymph node [Total 16 organs] Specific target organs for histopathology : Brain (Cerebrum, Cerebellum and Medulla oblongata), Heart, Thymus, Lung, Testis, Epididymis (head parts), Uterus, Ovary, Left-kidney, Left-adrenal glands, Spleen, Liver-left lateral lobe, Pancreas-splenic part, Digestive tracts (Esophagus, Fundus, Pylorus, Duodenum, Jejunum, Ileum, Cecum, Colon and Rectum), Left-submandibular lymph nodes, Urinary bladder and Prostate [Total 27 organs]. Results : As the results of single oral treatment of BJIKT on the female and male Sprague-Dawley rats, no treatment related mortalities were observed within 14 days after end of treatment up to 2,000 mg/kg, the limited dosage of rodents in the both genders, and also no BJIKT treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected, in this experiment. Conclusion : The results obtained in this study suggest that the BJIKT, prepared and standardized by Aribio Ltd. (Seungnam, Korea), is non-toxic in rats and is therefore, likely to be safe for clinical use. The 50% lethal dose (LD50) and approximate LD in rats after single oral dose of BJIKT were considered over 2,000 mg/kg, the limited dosage of rodents in both female and male Sprague-Dawley rats, respectively. In addition, no specific target or clinical sings were detected in the present study.

White Matter Damage and Hippocampal Neurodegeneration Induced by Permanent Bilateral Occlusion of Common Carotid Artery in the Rat: Comparison between Wistar and Sprague-Dawley Strain

김슬기,조경옥,김성윤 대한약리학회 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.3

In order to reproduce chronic cerebral hypoperfusion as it occurs in human aging and Alzheimer's disease, we introduced permanent, bilateral occlusion of the common carotid arteries (BCCAO) in rats (Farkas et al, 2007). Here, we induced BCCAO in two different rat strains in order to determine whether there was a strain difference in the pathogenic response to BCCAO. Male Wistar and Sprague-Dawley (SD) rats (250-270 g) were subjected to BCCAO for three weeks. Klüver-Barrera and cresyl violet staining were used to evaluate white matter and gray matter damage, respectively. Wistar rats had a considerably higher mortality rate (four of 14 rats) as compared to SD rats (one of 15 rats) following BCCAO. Complete loss of pupillary light reflex occurred in all Wistar rats that survived, but loss of pupillary light reflex did not occur at all in SD rats. Moreover, BCCAO induced marked vacuolation in the optic tract of Wistar rats as compared to SD rats. In contrast, SD rats showed fewer CA1 hippocampal neurons than Wistar rats following BCCAO. These results suggest that the neuropathological process induced by BCCAO takes place in a region-specific pattern that varies according to the strain of rat involved.

White Matter Damage and Hippocampal Neurodegeneration Induced by Permanent Bilateral Occlusion of Common Carotid Artery in the Rat: Comparison between Wistar and Sprague-Dawley Strain

Kim, Seul-Ki,Cho, Kyung-Ok,Kim, Seong-Yun The Korean Society of Pharmacology 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.3

In order to reproduce chronic cerebral hypoperfusion as it occurs in human aging and Alzheimer's disease, we introduced permanent, bilateral occlusion of the common carotid arteries (BCCAO) in rats (Farkas et al, 2007). Here, we induced BCCAO in two different rat strains in order to determine whether there was a strain difference in the pathogenic response to BCCAO. Male Wistar and Sprague-Dawley (SD) rats (250-270 g) were subjected to BCCAO for three weeks. Kluver-Barrera and cresyl violet staining were used to evaluate white matter and gray matter damage, respectively. Wistar rats had a considerably higher mortality rate (four of 14 rats) as compared to SD rats (one of 15 rats) following BCCAO. Complete loss of pupillary light reflex occurred in all Wistar rats that survived, but loss of pupillary light reflex did not occur at all in SD rats. Moreover, BCCAO induced marked vacuolation in the optic tract of Wistar rats as compared to SD rats. In contrast, SD rats showed fewer CA1 hippocampal neurons than Wistar rats following BCCAO. These results suggest that the neuropathological process induced by BCCAO takes place in a region-specific pattern that varies according to the strain of rat involved.

White Matter Damage and Hippocampal Neurodegeneration Induced by Permanent Bilateral Occlusion of Common Carotid Artery in the Rat: Comparison between Wistar and Sprague-Dawley Strain

Seul-Ki Kim,Kyung-Ok Cho,Seong Yun Kim 대한생리학회-대한약리학회 2008 The Korean Journal of Physiology & Pharmacology Vol.12 No.3

In order to reproduce chronic cerebral hypoperfusion as it occurs in human aging and Alzheimer s disease, we introduced permanent, bilateral occlusion of the common carotid arteries (BCCAO) in rats (Farkas et al, 2007). Here, we induced BCCAO in two different rat strains in order to determine whether there was a strain difference in the pathogenic response to BCCAO. Male Wistar and Sprague-Dawley (SD) rats (250-270 g) were subjected to BCCAO for three weeks. Klüver-Barrera and cresyl violet staining were used to evaluate white matter and gray matter damage, respectively. Wistar rats had a considerably higher mortality rate (four of 14 rats) as compared to SD rats (one of 15 rats) following BCCAO. Complete loss of pupillary light reflex occurred in all Wistar rats that survived, but loss of pupillary light reflex did not occur at all in SD rats. Moreover, BCCAO induced marked vacuolation in the optic tract of Wistar rats as compared to SD rats. In contrast, SD rats showed fewer CA1 hippocampal neurons than Wistar rats following BCCAO. These results suggest that the neuropathological process induced by BCCAO takes place in a region-specific pattern that varies according to the strain of rat involved.

부분방광출구폐색 후 비마취하 흰쥐의 요역동학검사 결과에서 폐색과 과민성방광 모델로서의 적용과 한계점

박수환,김룡호,권용현,윤상민,류지간,이택 대한비뇨의학회 2009 Investigative and Clinical Urology Vol.50 No.5

Purpose: Partial bladder outlet obstruction (PBOO) in rats leads to changes in bladder function, such as obstruction and detrusor overactivity (DO). The aim of our study was to observe factors essential for the objective descriptions of PBOO rats as an overactive bladder model as well as an obstruction model under awake cystometry. We also aimed to investigate the urodynamic effects of PBOO objectively in view of DO-related parameters as well as conventional pressure and volume-related parameters. Materials and Methods: PBOO was produced in 10 female Sprague- Dawley rats by ligating the proximal urethra over a 0.9 mm metal rod; 10 sham-operated rats were used as controls. Intravesical pressure (IVP) was recorded via an open catheter in the bladder, and intraabdominal pressure (IAP) via an intraabdominal balloon catheter. Continuous cystometry was performed 2 weeks after the PBOO procedure. Conventional and newly developed DO-related urodynamic parameters were investigated. Results: PBOO led to a significant increase in bladder weight. Three rats showed the picture of decompensated bladder and were excluded from the analysis. The obstructed group showed some increased pressure- and volume-related parameters. They showed a DO frequency of 1.5±0.3/min, but the sham group did not. Conclusions: Our results showed that bladder decompensation can happen after PBOO, and we need to describe those exclusions accurately in reports. In conscious PBOO rats, simultaneous registration of IAP and IVP is needed for accurate investigations of DO, because PBOO can lead to DO as well as bladder hypertrophy. Purpose: Partial bladder outlet obstruction (PBOO) in rats leads to changes in bladder function, such as obstruction and detrusor overactivity (DO). The aim of our study was to observe factors essential for the objective descriptions of PBOO rats as an overactive bladder model as well as an obstruction model under awake cystometry. We also aimed to investigate the urodynamic effects of PBOO objectively in view of DO-related parameters as well as conventional pressure and volume-related parameters. Materials and Methods: PBOO was produced in 10 female Sprague- Dawley rats by ligating the proximal urethra over a 0.9 mm metal rod; 10 sham-operated rats were used as controls. Intravesical pressure (IVP) was recorded via an open catheter in the bladder, and intraabdominal pressure (IAP) via an intraabdominal balloon catheter. Continuous cystometry was performed 2 weeks after the PBOO procedure. Conventional and newly developed DO-related urodynamic parameters were investigated. Results: PBOO led to a significant increase in bladder weight. Three rats showed the picture of decompensated bladder and were excluded from the analysis. The obstructed group showed some increased pressure- and volume-related parameters. They showed a DO frequency of 1.5±0.3/min, but the sham group did not. Conclusions: Our results showed that bladder decompensation can happen after PBOO, and we need to describe those exclusions accurately in reports. In conscious PBOO rats, simultaneous registration of IAP and IVP is needed for accurate investigations of DO, because PBOO can lead to DO as well as bladder hypertrophy.

Streptozotocin으로 유도된 당뇨 랫드에서 황칠나무 잎 열수추출물의 항당뇨 효과

김민재,강예진,이동언,김석,임세훈,이후장,Kim, Min-Jae,Kang, Ye-Jin,Lee, Dong-Eon,Kim, Suk,Lim, Se-Hun,Lee, Hu-Jang 대한수의학회 2021 大韓獸醫學會誌 Vol.61 No.4

This study examined the anti-diabetic effects of aqueous extracts of Dendropanax morbifera leaves (DMWEs) in streptozotocin-induced diabetic Sprague-Dawley (SD) rats. Thirty male SD rats (body weight [BW], 250.4 ± 19.7 g) were divided into the following six groups: normal control rats (NC), diabetic control rats (DC), diabetic rats treated with metformin HCl 100 mg/kg BW (DT), diabetic rats treated with DMWEs 50 mg/kg BW (DM-50), diabetic rats treated with DMWEs 100 mg/kg BW (DM-100), and diabetic rats treated with DMWEs 200 mg/kg BW (DM-200). From two weeks of administration of DMWEs, the BW of all groups treated with DMWEs increased significantly compared to DC (p < 0.05). At four weeks after treatment, the blood glucose levels in DT, DM-100, and DM-200 decreased below 200 mg/dL, while the glycated hemoglobin concentrations in all groups administered DMWEs were similar to those of NC and DT. Regarding the blood biochemical parameters, the levels of aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine in DM-100 and DM-200 were similar to those in NC and DT. Overall, these results highlight the effectiveness of DM-100 in the treatment of diabetes.

Sprague Dawley Rats을 이용한 현사시나무 추출물의 항산화 효능 평가

최선일,이옥환,김종대 강원대학교 농업생명과학연구원 2020 강원 농업생명환경연구 Vol.32 No.3

This study aimed to investigate the antioxidant potential and free radical generation ability of Populus tomentiglandulosa (PT) extract in Sprague-Dawley (SD) rats. Male SD rats were fed a diet supplemented with 0.5% PT extract, as recommended by American Institute of Nutrition (AIN) for 4 weeks. Free radical generation and antioxidant potentials in the blood were measured at 2-week intervals. After 4 weeks, weight gain in the PT extract-fed group was significantly higher than that in the negative control group. However, food intake, food efficiency ratio, and weight index were not significantly different between the groups. The blood antioxidative potentials in the PT extract-fed group were higher than those in the negative control group. Free radical generation in the blood in the ascorbic acid-fed group was higher than that in the negative control group. These results suggest that supplementation with Populus tomentiglandulosa extract had beneficial effects on antioxidant potential.

Sprague-Dawley Rat에서 RK3E-ras Cell의 주입에 의한 악성 종양의 유도

김현우,김수아,안상건,윤정훈 대한구강악안면병리학회 2006 대한구강악안면병리학회지 Vol.30 No.2

Several tumor animal models have been provided as a tool for developing cancer therapy. Here, we developed rapid, easy-to use, and cost-effective new rat animal model for invasion and metastasis of cancer using genetically k-ras-induced rat kidney cells(RK3E-ras). We observed tumor as early as 3 days after injection of RK3E-ras cells in subcutaneous of Sprague-Dawley rats. Tumor size and volume were increased exponentially for 2 weeks. The tail vein injected rats obtained the lethal infiltration in the lung within 2 weeks. This tumor animal model has great potential for studying cancer processes and short-term screening of variable cancer therapy strategy.

줄무늬체 및 운동신경계에서 노화에 따른 Neuropeptide Y 신경세포의 변화에 관한 연구

차중익,홍진주,이영일,이병란,조사선,백상호 대한해부학회 1997 Anatomy & Cell Biology Vol.30 No.3