• 제목/요약/키워드: Subacute toxicity

검색결과 166건 처리시간 0.023초

속단(續斷) 추출물의 C57BL/6 마우스를 이용한 2주 경구투여 독성시험 (Two-weeks Oral Dose Toxicity Study of Dipsacus asperoides Extracts in C57BL/6 Mice)

  • 허혜윤;신동호;이지혜;서윤수;김용범;신인식;강소희;손미경;김중선
    • 대한본초학회지
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    • 제36권5호
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    • pp.101-108
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    • 2021
  • Objectives : A root of Dipsacus asperoides C. Y. Cheng et T. M. Ai (D. asperoides) has been traditionally used as a medicinal resource in several Asian countries, including Korean and traditional Chinese medicine that has been traditionally used for treating several medical conditions including pain, arthritis, and bone fractures in Korea. In the present study, we investigated potential subacute toxicities of D. asperoides extract. Methods : C57BL/6 mice (male, 7weeks) were randomly divided into 4 groups of 5 mice. Except for the control group, the mice were orally administrated D. asperoides extract at doses of 50, 150, or 450 mg/kg/day for 2 weeks. At the end of the treatment period, all mice were euthanized, and the following parameters were examined: mortality, body weight, clinical signs, gross findings, hematology, serum biochemistry, organ weight, and histopathology. Results : There were no abnormalities in mortality, clinical signs, body weight, gross findings, or organ weight after repeated administration of D. asperoides extract for 2 weeks, compared with the control group. In addition, there were no significant changes in hematological, serum biochemical, and histopathological parameters between the control group and D. asperoides extract administrated groups with doses of up to 450 mg/kg/day. Conclusion : In this study, D. asperoides extract showed no significant toxicities at a dose of up to 450 mg/kg/day in mice. Although we could not confirm the toxic dose of D. asperoides extract, it can be considered safe for further pharmacological use.

혼합(混合)된 식품첨가물(食品添加物)이 흰쥐의 생리(生理)에 미치는 상승적(相乘的) 독성(毒性) 효과(效果)에 관(關)한 연구(硏究) (A Study of the Additional Toxicity of Mixed Food Additives to Rat)

  • 정호권
    • Applied Biological Chemistry
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    • 제18권2호
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    • pp.71-97
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    • 1975
  • To improve the food qualities in Korea, two hundred and fourtynine kinds of food additives have been allowed in food processing, of which one hundred and nineteen kinds could be used under the limitted conditions. Hence, in practical uses in food processing, many kinds of them are mixed at random within the permitted amounts for their special purposes. For last several years, many kinds of the food additives were prohibited because they have been proved to be toxic even with the single dose. Until recently a few studies on the toxicity in the mixture of food additives were reported, however, they were shown to be no severe additional effect on the animal. This study was performed to see if any elevation of chronic or subacute toxicity of food additives occur especially when they are mixed with each other, using three kinds of food additives (DHA, AF-2, BHT) most widely used as food preservatives, antiseptics and antioxidants. One hundred and fifty young male rats were taken and divided into ten feeding groups, one first control group (food additives blank), three second control groups (DHA 0.1%, AF-2 0.1%, BHT 0.5%), three mixture groups of low level (mixture of each 60% of two second control level) and three mixture groups of high level (mixture of each 90% of two second control level). As the methods of biological and clinical tests, the change of body weight (growth rate), daily intake of diets, organ to body weight ratio, histopathological findings of organs, hematological observation, liver and kidney function tests were checked three times during the periods of 24 weeks. The following results were obtained. 1. The low level group of DHA, AF-2 mixture and DHA, BHT mixture revealed a little retardation in growth rate than the first control group, however, they were similar to the second controls, while all the mixture groups of high level showed a more remarkable retardation than the first and second controls. 2. Average daily intake of the diets was the same in each group, showing a similar decreasing tendency (70-100g/kg of body weight) in accordance with the growth rate. It was observed that there are no differences in the taste and appetite in each group of rats. 3. Abnormal enlargements of kidney and lung were not seen in all the mixture groups compared with the controls, while a slight hepatomegaly was observed in all mixture groups of low level as in the second controls. Significant differences (almost 1% level) were observed between the high level groups and the first control group. 4. Histopathological effects of the food additives on lung, kidney and liver tissues were found in all mixture group of high level. The less frequencies of the same effects were also seen in the low level groups. 5. The esterified cholesterol to total cholesterol ratio in the mixture groups of high level showed a little lower values, and the activities of serum glutamate oxaloacetate transaminase and alkaline phosphatase decreased almost with significance of 5% level compared with the first control group. The serum A/G ratio in the mixture groups also decreased. The results demonstrated that the liver function was decreased in the mixture groups compared with the controls. 6. In all groups throughout the test period, kidney functions (concentration of protein and creatinine excreated per hour in urine and renal filtration rate) were shown almost as normal as the first control. 7. Average values of hematocrit, erythrocytes and leucocytes in the mixture groups were in the normal ranges as in the controls, which denotes that the production of blood cells in bone marrow were also normal in all groups. With the above results, it is concluded that when the food additives (DHA, AF-2, BHT) were given together to the rats in several combinations even in less amount, they showed more toxic signs than the single doses.

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다양(多樣)한 황금약침제제(黃芩藥鍼製劑)의 안전성(安定性) 및 효능(效能)에 관한 연구(硏究) (Studies on effect and Safety of various Aqua-acupunctures from Scutellariae Radix)

  • 김호경;마진열;전원경;윤수영;강은정;주혜정;고병섭
    • 한국한의학연구원논문집
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    • 제3권1호
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    • pp.183-197
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    • 1997
  • 황금약침제제(黃芩藥鍼製劑)의 안정성(安定性) 및 효능(效能)에 관한 연구(硏究)하기 위해, 약침제제(藥鍼製劑)들은 황금(黃芩)을 원료(原料)로 하여 전탕(煎蕩) 여과(濾過) 희석(稀釋)의 방법으로 제조(製造)하였다. 황금약침제제(黃芩藥鍼製劑)들은 랫트의 족삼리 근육에 반복투여(反復投與)하여 아급성(亞急性) 독성(毒性) 및 효능(效能)을 조사(調査)하였고, 대조군(對照群) 주사용(注射用) 생리식염수(生理食鹽水)와 연유수(燕溜水)의 매체대조군(媒體對照郡) 침자재군(鍼刺栽郡)을 설정하여 비교(比較)하였다. 1. 랫트에 황금약침제제(黃芩藥鍼製劑)들을 0.2cc 근육투여(筋肉投與)한 결과(結果) 대조군(對照群)과 시험군(試驗群)에서 1마리도 사망하지않았고, 일반증상(一般症狀) 및 부검소견(剖檢所見)에서도 특별한 이상이 발견(發見)되지 않았다. 또한 검액(檢液) 황금약침제제(黃芩藥鍼製劑)들 각각을 랫트에 반복 약침(藥鍼) 시술(施術)하여 체중변화(體重變化) 장기중량(臟器重量) 및 혈액생화학적(血液生化學的) 검사등(檢査等)을 실험(實驗)한 결과(結果), 검액(檢液)에 기인한 독성증상(毒性症狀)은 나타나지 않았다. 따라서 시험군(試驗群)에 사용한 황금약침제제(黃芩藥鍼製劑)은 안전성(安全性)에는 문제가 없는 것으로 사료되었다. 2. 경시적(輕視的) 체중변화(體重變化)의 결과(結果)에서 침자재군(鍼刺栽郡)(acupuncture)은 시술(施術) 3일후(日後)부터 p-value가 <0.05, 7일(日)부터는 p-value가 <0.001로 유의성(有意性)이 있는 체중감소(體重減少)가 나타났고, 9일후(日後)에는 모든 시험군(試驗群)이 체중(體重) 증가(增加)가 억제되었다. 3. 장기중량(臟器重量)에 대한 결과(結果)에서 D-2군(群)과 생리식염수군군(生理食鹽水群)은 간장중량(肝臟重量)이 통계적(統計的) 유의성(有意性)을 보이고 있는데 침자재(鍼刺栽)의 경우 간장(肝臟)과 비장(脾臟)에서 유의(有意)한 결과(結果)를 얻었다. 이러한 결과(結果) 효능면(效能面)에서 약침(藥鍼)의 침(鍼)과 약(藥)이 효과(效果)에서 침(鍼)의 효과(效果)가 우선하고 있다고 추측되어진다. 4. 약침(藥鍼) 시술군(施術群)에 대한 혈액생화학적(血液生化學的) 검사(檢査)는 GLU, T.G., CHOL에 대해 조사하였는데, glucose에 대한 영향(影響)은 황금약침제제(黃芩藥鍼製劑) ${\times}$10군(群)에서 대조군(對照群)에 비해 유의성(有意性) 있는 감소를 확인할 수 있었고, 황금약침제제(黃芩藥鍼製劑) ${\times}$100군(群), Distillation-2군(群), 생리식염수군군(生理食鹽水群)에서는 대조군(對照群)에 비해 유의성(有意性) 있는 증가(增加)를 확인할 수 있었고, 모든 시술군(施術群)에서 CHOL의 유의성(有意性)있는 감소(減少)를 보였고, T.G는 황금약침제제(黃芩藥鍼製劑)와 복합주사제군(複合注射劑群)를 제외한 모든 시술군(施術群)에서 통계학적(統計學的) 유의성(有意性)이 있었는데, 황금약침제제(黃芩藥鍼製劑)를 희석(稀釋)한 황금수액희석제제군(黃芩水液稀釋製劑群)에서 유의성(有意性)있는 감소가 일어나는 것을 확인(確認)할 수 있었다. 농도와는 관계없이 황금약침제제(黃芩藥鍼製劑)들이 함유하고 있는 성분상호간(成分相互間)의 작용에 의해서 T.G.가 감소(減少)된다고 생각되어진다. 또한 침자재군(鍼刺栽群)에서도 T.G.를 감소시키는 유의성있는 흥미로운 결과(結果)를 얻을수 있었다. 5. 혈액학적(血液學的) 검사결과(檢査結果)는 과립구(顆粒球)에서 황금수액제제(黃芩水液製劑)만을 제외한 모든 시술군(施術群)에서 유의성(有意性)있는 증가(增加)를 보였으며, 황금수액희석제제군(黃芩水液稀釋製劑群)들에서의 과립구(顆粒球)는 매우 유의적(有意的)인 증가(增加)(p-value가 <0.001)를 보였다. 침자재군(鍼刺栽群)은 과립구(顆粒球)와 평균혈구용적(平均血球容積)에서 통계적(統計的) 유의성(有意性)이 인정되었다.

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Preoperative short course radiotherapy with concurrent and consolidation chemotherapies followed by delayed surgery in locally advanced rectal cancer: preliminary results

  • Aghili, Mahdi;Sotoudeh, Sarvazad;Ghalehtaki, Reza;Babaei, Mohammad;Farazmand, Borna;Fazeli, Mohammad-Sadegh;Keshvari, Amir;Haddad, Peiman;Farhan, Farshid
    • Radiation Oncology Journal
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    • 제36권1호
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    • pp.17-24
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    • 2018
  • Purpose: This study aimed to assess complications and outcomes of a new approach, that is, combining short course radiotherapy (SRT), concurrent and consolidative chemotherapies, and delayed surgery. Materials and Methods: In this single arm phase II prospective clinical trial, patients with T3-4 or N+ M0 rectal adenocarcinoma were enrolled. Patients who received induction chemotherapy or previous pelvic radiotherapy were excluded. Study protocol consisted of three-dimensional conformal SRT (25 Gy in 5 fractions in 1 week) with concurrent and consolidation chemotherapies including capecitabine and oxaliplatin. Total mesorectal excision was done at least 8 weeks after the last fraction of radiotherapy. Primary outcome was complete pathologic response and secondary outcomes were treatment related complications. Results: Thirty-three patients completed the planned preoperative chemoradiation and 26 of them underwent surgery (24 low anterior resection and 2 abdominoperineal resection). Acute proctitis grades 2 and 3 were seen in 11 (33.3%) and 7 (21.2%) patients, respectively. There were no grades 3 and 4 subacute hematologic and non-hematologic (genitourinary and peripheral neuropathy) toxicities and perioperative morbidities such as anastomose leakage. Grade 2 or higher late toxicities were observed among 29.6% of the patients. Complete pathologic response was achieved in 8 (30.8%) patients who underwent surgery. The 3-year overall survival and local control rates were 65% and 94%, respectively. Conclusion: This study showed that SRT combined with concurrent and consolidation chemotherapies followed by delayed surgery is not only feasible and tolerable without significant toxicity but also, associated with promising complete pathologic response rates.

절제 불가능한 원발성 간암의 입체조형 방사선치료의 초기 임상 결과 (Preliminary Results of 3-Dimensional Conformal Radiotherapy for Primary Unresectable Hepatocellular Carcinoma)

  • 금기창;박희철;성진실;장세경;한광협;전재윤;문영명;김귀언;서창옥
    • Radiation Oncology Journal
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    • 제20권2호
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    • pp.123-129
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    • 2002
  • 목적 : 수술적 절제가 불가능한 원발성 간암 환자들을 대상으로 삼차원적인 방사선치료계획 시스템을 이용한 입체조형 방사선치료를 전향적으로 실시하고 조기 임상 결과를 분석하였다. 또한, 이를 통해 원발성 간암의 비수술적 치료에서 입체조형 방사선치료의 잠재적인 역할과 가능성을 판단해 보고자 하였다. 대상 및 방법 : 1995년 1월부터 1997년 6월까지 원발성 간암으로 진단 후 입체조형 방사선치료의 기법을 적용하여 치료를 받은 17명의 환자가 본 연구 대상에 포함되었다. 대상 환자의 선정 기준은 방사선치료의 과거력이 없는 경우, 간외 전이가 없는 경우, 간경변증의 정도가 Child-Pugh classification A또는 B군인 경우, 종양이 전체 간 용적의 2/3를 넘지 않는 경우, 전신수행도가 European Cooperative Oncology Group (ECOG) 3기 이상으로 악화되지 않은 경우이었다. 15명의 환자에서 경동맥화학색전술과 입체조형 방사선치료의 병용요법이 시행되었다. 대상 환자는 In-ternational Union Against Cancer (UICC) 병기별로 II기 1명, III기 8명, IVA기 8명이었다. 4명의 환자에서 간문맥 혈전증이 동반되었으며, 종양의 평균 직경은 8 cm이었다. 조사영역은 종양과 주변 1.5 cm이었고 조사선량의 분포는 $36\~60\;Gy$로 중앙값은 59.4 Gy이었다. 종양의 반응은 치료 후 $4\~8$주에 시행한 영상 진단을 기준으로 평가하였다. 추적관찰기간의 중앙값은 15개월이었다. 결과 : 2년 생존율은 $21.2\%$였고 평균 생존 기간은 19개월이었다. 완전 반응과 부분 반응을 포함하여 11명의 환자에서 치료에 대한 반응을 보여 반응률은 $64.7\%$였다. 종양의 진행을 보인 환자는 3명으로 이 중 2명의 환자가 조사영역 밖에서 종양의 진행을 보였다. 추적 기간 중 6명의 환자에서 원격 전이가 나타났고 폐 전이와 뼈 전이가 각각 5명과 1명이었다. 삼차원 입체 조형 치료와 관련된 것으로 판단되는 방사선 간염은 발생하지 않았으며 Grade 2의 위염과 십이지장염이 각각 1명씩 발생했다. 치료로 인해 사망하였던 경우는 없었다. 결론 : 절제 불가능한 원발성 간암의 치료에 입체조형 방사선치료를 적용할 것은 비교적 안전하였고 실제적인 치료 효과를 나타내었다. 향후 원발성 간암의 비수술적 치료에 입체조형 방사선치료의 역할이 기대되며 이 치료법의 우수성을 입증하기 위한 제 3상 연구가 뒤따라야 할 것으로 사료된다.

Cefoperazone(T-1551)의 약리학적 연구 (Pharmacological Studies of Cefoperazone(T-1551))

  • 임정규;홍사악;박찬웅;김명석;서유헌;신상구;김용식;김혜원;이정수;장기철;이상국;장우현;김익상
    • 대한약리학회지
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    • 제16권2호
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    • pp.55-70
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    • 1980
  • The pharmacological and microbiological studies of Cefoperazone (T-1551, Toyama Chemical Co., Japan) were conducted in vitro and in vivo. The studies included stability and physicochemical characteristics, antimicrobial activity, animal and human pharmacokinetics, animal pharmacodynamics and safety evaluation of Cefoperazone sodium for injection. 1) Stability and physicochemical characteristics. Sodium salt of cefoperazone for injection had a general appearance of white crystalline powder which contained 0.5% water, and of which melting point was $187.2^{\circ}C$. The pH's of 10% and 25% aqueous solutions were 5.03 ana 5.16 at $25^{\circ}C$. The preparations of cefoperazone did not contain any pyrogenic substances and did not liberate histamine in cats. The drug was highly compatible with common infusion solutions including 5% Dextrose solution and no significant potency decrease was observed in 5 hours after mixing. Powdered cefoperazone sodium contained in hermetically sealed and ligt-shielded container was highly stable at $4^circ}C{\sim}37^{\circ}C$ for 12 weeks. When stored at $4^{\circ}C$ the potency was retained almost completely for up to one year. 2) Antimicrobial activity against clinical isolates. Among the 230 clinical isolates included, Salmonella typhi was the most susceptible to cefoperazone, with 100% inhibition at MIC of ${\leq}0.5{\mu}g/ml$. Cefoperazone was also highly active against Streptococcus pyogenes(group A), Kletsiella pneumoniae, Staphylococcus aureus and Shigella flexneri, with 100% inhibition at $16{\mu}g/ml$ or less. More than 80% of Escherichia coli, Enterobacter aerogenes and Salmonella paratyphi was inhibited at ${\leq}16{\mu}/ml$, while Enterobacter cloaceae, Serratia marcescens and Pseudomonas aerogenosa were somewhat less sensitive to cefoperagone, with inhibitions of 60%, 55% and 35% respectively at the same MIC. 3) Animal pharmacokinetics Serum concentration, organ distritution and excretion of cefoperazone in rats were observed after single intramuscular injections at doses of 20 mg/kg and 50 mg/kg. The extent of protein binding to human plasma protein was also measured in vitro br equilibrium dialysis method. The mean Peak serum concentrations of $7.4{\mu}g/ml$ and $16.4{\mu}/ml$ were obtained at 30 min. after administration of cefoperazone at doses of 20 mg/kg and 50 mg/kg respectively. The tissue concentrations of cefoperazone measured at 30 and 60 min. were highest in kidney. And the concentrations of the drug in kidney, liver and small intestine were much higher than in blood. Urinary and fecal excretion over 24 hours after injetcion ranged form 12.5% to 15.0% in urine and from 19.6% to 25.0% in feces, indicating that the gastrointestinal system is more important than renal system for the excretion of cefoperazone. The extent of binding to human plasma protein measured by equilibrium dialysis was $76.3%{\sim}76.9%$, which was somewhat lower than the others utilizing centrifugal ultrafiltration method. 4) Animal pharmacodynamics Central nervous system : Effects of cefoperazone on the spontaneous movement and general behavioral patterns of rats, the pentobarbital sleeping time in mice and the body temperature in rabbits were observed. Single intraperitoneal injections at doses of $500{\sim}2,000mg/kg$ in rats did not affect the spontaneous movement ana the general behavioral patterns of the animal. Doses of $125{\sim}500mg/kg$ of cefoperazone injected intraperitonealy in mice neither increased nor decreased the pentobarbital-induced sleeping time. In rabbits the normal body temperature was maintained following the single intravenous injections of $125{\sim}2,000mg/kg$ dose. Respiratory and circulatory system: Respiration rate, blood pressure, heart rate and ECG of anesthetized rabbits were monitored for 3 hours following single intravenous injections of cefoperazone at doses of $125{\sim}2,000mg/kg$. The respiration rate decreased by $3{\sim}l7%$ at all the doses of cefoperazone administered. Blood pressure did not show any changes but slight decrease from 130/113 to 125/107 by the highest dose(2,000 mg/kg) injected in this experiment. The dosages of 1,000 and 2,000 mg/kg seemed to slightly decrease the heart rate, but it was not significantly different from the normal control. All the doses of cefoperazone injected were not associated with any abnormal changes in ECG findings throughout the monitering period. Autonomic nervous system and smooth muscle: Effects of cefoperazone on the automatic movement of rabbit isolated small intestine, large intestine, stomach and uterus were observed in vitro. The autonomic movement and tonus of intestinal smooth muscle increased at dose of $40{\mu}g/ml$ in small intestine and at 0.4 mg/ml in large intestine. However, in stomach and uterine smooth muscle the autonomic movement was slightly increased by the much higher doses of 5-10 mg/ml. Blood: In vitro osmotic fragility of rabbit RBC suspension was not affected by cefoperazone of $1{\sim}10mg/ml$. Doses of 7.5 and 10 mg/ml were associated with 11.8% and 15.3% prolongation of whole blood coagulation time. Liver and kidney function: When measured at 3 hours after single intravenous injections of cefoperaonze in rabbits, the values of serum GOT, GPT, Bilirubin, TTT, BUN and creatine were not significantly different from the normal control. 5) Safety evaluation Acute toxicity: The acute toxicity of cefoperazone was studied following intraperitoneal and intravenous injections to mice(A strain, 4 week old) and rats(Sprague-Dawler, 6 week old). The LD_(50)'s of intraperitonealy injected cefoperazone were 9.7g/kg in male mice, 9.6g/kg in female mice and over 15g/kg in both male and female rats. And when administered intravenously in rats, LD_(50)'s were 5.1g/kg in male and 5.0g/kg in female. Administrations of the high doses of the drug were associated with slight inhibition of spontaneous movement and convulsion. Atdominal transudate and intestinal hyperemia were observed in animals administered intraperitonealy. In rats receiving high doses of the drug intravenously rhinorrhea and pulmonary congestion and edema were also observed. Renal proximal tubular epithelial degeneration was found in animals dosing in high concentrations of cefoperazone. Subacute toxicity: Rats(Sprague-Dawley, 6 week old) dosing 0.5, 1.0 and 2.0 g/kg/day of cefoperazone intraperitonealy were observed for one month and sacrificed at 24 hours after the last dose. In animals with a high dose, slight inhibition of spontaneous movement was observed during the experimental period. Soft stool or diarrhea appeared at first or second week of the administration in rats receiving 2.0g/kg. Daily food consumption and weekly weight gain were similar to control during the administration. Urinalysis, blood chemistry and hematology after one month administration were not different from control either. Cecal enlargement, which is an expected effect of broad spectrum antibiotic altering the normal intestinal microbial flora, was observed. Intestinal or peritoneal congestion and peritonitis were found. These findings seemed to be attributed to the local irritation following prolonged intraperitoneal injections of hypertonic and acidic cefoperazone solution. Among the histopathologic findings renal proximal tubular epithelial degeneration was characteristic in rats receiving 1 and 2g/kg/day, which were 10 and 20 times higher than the maximal clinical dose (100 mg/kg) of the drug. 6) Human pharmacokinetics Serum concentrations and urinary excretion were determined following a single intravenous injection of 1g cefoperazone in eight healthy, male volunteers. Mean serum concentrations of 89.3, 61.3, 26.6, 12.3, 2.3, and $1.8{\mu}g/ml$ occured at 1,2,4,6,8 and 12 hours after injection respectively, and the biological half-life was 108 minutes. Urinary excretion over 24 hours after injection was up to 43.5% of administered dose.

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