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랫드에서 고환독성의 정색을 위한 정량적 평가법의 확립: 2-bromopropane의 예
차신우,배주현,손우찬,신진영,신동호,김성호,박승춘,김종춘,Cha Shin-Woo,Bae Joo-Hyun,Son Woo-Chan,Shin Jin-Young,Shin Dong-Ho,Kim Sung-Ho,Park Seung-Chun,Kim Jong-Choon 한국생명과학회 2005 생명과학회지 Vol.15 No.3
The aims of the study were to establish a short-term screening test for detecting testicular toxicity of chemicals in rats and to determine whether a 2-week administration period is sufficient to detect testicular toxicity of 2-bromopropane (2-BP) as an example. Male Sprague-Dawley rats were subcutaneously administered with 1000 mg/kg/day of 2-BP or its vehicle for 2 weeks. Ten male rats each were sacrificed on days 3, 7 and 14 after the initiation of treatment. Parameters of testicular toxicity included genital organ weights, testicular sperm head counts, epididymal sperm counts, motility and morphology, and qualitative and quantitative histopathologic examinations. The early histopathological changes observed on day 3 of treatment included degeneration of spermatogonia and spermatocytes, multinuclear giant cells, mature spermatid retention, vacuolization of Sertoli cells, and decreased number of spermatogonia in stages II and V. On day 7 of treatment, atrophy of seminiferous tubules, exfoliation of germ cells, degeneration of spermatogonia and spermatocytes, multinuclear giant cells, mature spermatid retention, vacuolization of Sertoli cells, decreased number of spermatogonia in stages II and V, and decreased number of spermatocytes in stages VII and XII. On day 14 after treatment, a significant decrease in the weights of testes and seminal vesicles was found. Atrophy of seminiferous tubules, exfoliation of germ cells, degeneration of spermatogonia and spermatocytes, mature spermatid retention, vacuolization of Sertoli cells, decreased number of spermatogonia in stages II and V, and decreased number of spermatocytes in all spermatogenic stages were also observed. In addition, a slight non-significant decrease in testicular sperm head counts, daily sperm production rate and epididymal sperm counts was found. The results showed that 2 weeks of treatment is sufficient to detect the adverse effects of 2-BP on male reproductive organs. It is considered that the short-term testicular toxicity study established in this study can be a useful tool for screening the testicular toxic potential of new drug candidates in rats.
Type IV phosphodiesterase inhibitor ( CJ-10882 ) 의 개에 대한 2 주간 경구반복투여 독성시험
차신우(Shin Woo Cha),배주현(Ju Hyun Bae),김종춘(Jong Choon Kim),김달현(Dal Hyun Kim),이근호(Koun Ho Lee),한정희(Jung Hee Han),송석범(Seog Beom Song) 한국응용약물학회 2002 Biomolecules & Therapeutics(구 응용약물학회지) Vol.10 No.2
N/A CJ-10882, (E)-[(3-Cyclopentyloxy-4methoxyphenyl)methylene]hydrazine-carboxamide, is a newly developed type IV phosphodiesterase isozyme (PDE IV) inhibitor. To investigate the subacute toxic effects of CJ-10882, it was administered to both male and female dogs at 0, 25, 50, 100 or 200 ㎎/㎏/day orally for up to 2 weeks. During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross finding, organ weight, and histopathology were evaluated. Several clinical signs were observed in treated dogs at above 25 ㎎/㎏, including salivation and vomiting. A reduction in the body weight was observed in both sexes at above 50 ㎎/㎏. There were no treatment-related effects on mortality, ophthalmoscopy, urinalysis, hematology, serum biochemistry, necropsy findings, and histopathology in any treatment group. The results of this study demonstrate that CJ-10882, a selective inhibitor of the type IV class of PDE, may cause effects on gastrointestinal tract and salivary glands. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors.
비글견에 있어서 새로운 안트라싸이클린계 항암제 DA-125의 정소독성연구
김종춘,차신우,송시환,정문구,Kim, Jong-choon,Cha, Shin-woo,Song, Si-whan,Chung, Moon-koo 대한수의학회 1997 大韓獸醫學會誌 Vol.37 No.2
To assess the testicular toxicity induced by DA-125, a new anthracycline anticancer agent, the test substance was intraveneously administered to male beagle dogs at dose levels of 0, 0.0023, 0.0375, 0.15, and 0.6 mg/kg/day, 6 days a week for 26 weeks. At 0.6 mg/kg/day, 1 out of 3 dogs had died on day 42 of treatment and the other dogs were sacrificed on days 46 and 122 of treatment due to the increasingly severe clinical condition. Clinical signs considered to be related to treatment were included anorexia, vomiting, salivation, decreased activity, mucous and/or dark faeces, diarrhea, and swelling, abscess and/or ulceration of injection sites. Suppression in body weight gain, reduction in food intake, decreases in testicular weight and size, and hemorrhage of epididymis were also observed in male dogs. Microscopically, severe degenerative changes such as atrophy of seminiferous tubules, loss of germ cells, degeneration of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed in all dogs. Azoospermia in epididymal tubules, atrophy of epithelia in the cauda epididymis, and prostate atrophy were also found. At 0.15 mg/kg/day, anorexia, vomiting, salivation, diarrhea, and swelling of injection sites were observed. In addition, suppression in body weight gain and decreases in testicular weight and size were found in male dogs. Atrophy of seminiferous tubules, decrease of germ cells, degeneration, exfoliation and retention of germ cells, vacuolization of Sertoli cells, and hyperplasia of Leydig cells were observed by histopathological examination. Azoospermia in epididymal tubules and prostate atrophy were also found. At 0.0375 mg/kg/day, there were no clinical signs considered to be indicative of a reaction to treatment, but testicular size was significantly reduced. Microscopically, decreases in the number of spermatogonia and epidydimal speramtozoa were found. There were no evidences of general or testicular toxicity at 0.0023 mg/kg/day. These results indicate that DA-125 produces significant and persistent damage to the spermatogenic compartments of the testes in male beagle dogs.
신호철,차신우,배주현,김현주,정태천,박종일,윤종만,김계웅,김진석,한상섭,Shin, Ho-chul,Cha, Shin-woo,Bae, Ju-hyun,Kim, Hyun-ju,Jeong, Tae-cheon,Park, Jong-il,Yoon, Jong-man,Kim, Gye-woong,Kim, Jin-suk,Han, Sang-seop The Korean Society of Veterinary Science 1996 大韓獸醫學會誌 Vol.36 No.1
Dihydrofolate reductase(DHFR) 억제제는 혈중활성엽산유도체의 농도저하를 초래하는데 이에 대한 기전을 밝히고자 DHFR 억제제의 대표적 약물로서 항암치료에 널리 사용되고 있는 methotrexate를 0.3 및 10mg/kg의 용량으로 랫드에 정맥주사한 후 활성엽산유도체의 담즙배설동태를 검토하였다. 임상적용 용량을 상회하는 용량임에도 불구하고 methotrexate에 의한 환원형엽산유도체의 담즙배설은 유의적 감소를 나타내지 않았다. 이러한 결과는 methotrexate에 의한 엽산유도체의 혈중농도저하가 활성엽산유도체의 담즙배설저하에 직접 관련되지 않는 것을 나타낸다. 따라서 장간순환계가 체내 엽산대사 및 항상성 유지에 중심기구임을 고려해 볼 때 DHFR 억제제에 의한 활성엽산유도체의 혈중농도저하는 담즙배설의 변화에 의한 것 보다는 소화관에 배설된 후 재흡수의 저하에 의해 초래될 가능성이 높은 것으로 사료된다. The biliary excretion kinetics of the active folate derivatives were examined after an intravenous injection of methotrexate at doses of 0.3 and 10mg/kg to clarify the mechanism of the acute decrease in the plasma folate by the dihydrofolate reductase inhibitors. Even at a higher dose than used in the clinical therapy, methotrexate did not cause any acute depletion of folate denvatives in the excreted bile. Therefore, the decrease in the plasma folate appeared not to be related with the biliary excretion process of folates. A factor responsible for the plasma folate depletion by DHFR inhibitors may be due to the malabsorption of folate derivatives excreted into the small intestine.
고우석(Woo Suk Koh),김종춘(Jong Choon Kim),차신우(Shin Woo Cha),김영민(Young Min Kim),정성엽(Sung Youb Jung),권세창(Se Chang Kwon),이관순(Gwan Sun Lee) 한국응용약물학회 2002 Biomolecules & Therapeutics(구 응용약물학회지) Vol.10 No.2
N/A HM10411 is a recombinant granulocyte-colony stimulating factor (rG-CSF) that has been developing as a drug for neutropenia. In this study, antigenic potential of HM 10411 was examined by active systemic anaphylaxis (ASA) in guinea pigs and passive cutaneous anaphylaxis (PCA) in guinea pig-guinea pig system. HM10411 was subcutaneously administered at 0, 5, and 50 ㎎/㎏ and also as a suspension with adjuvant (50 ㎎/㎏+FCA). Ovalbumin (OVA) as a suspension with adjuvant was used to induce positive control responses. In the ASA test, no symptoms except urination and evacuation that were considered as physiological phenomena were observed at 0 and 5 ㎎/㎏. Two of 5 animals at 50 ㎎/㎏ showed sneezing, dyspnea, or cyanosis. All animals in the adjuvant mixture group showed severe symptoms of anaphylatic shock and 3 of them died. In the PCA test, no antibody against HM10411 was detected in the sera from the animals sensitized with 0 or 5 ㎎/㎏. Only 1 serum sample from the animals immunized with 50 ㎎/㎏ showed positive reaction against HM10411, while all 5 sera collected from the HM10411 and FCA mixture group contained the HM10411 -specific antibodies. These results suggest HM10411 is considered to have antigenicity in guinea pig.
김성훈,황화선,차신우,한상섭,노정구,Kim, Sung-hoon,Hwang, Hwa-seon,Cha, Shin-woo,Han, Sang-seop,Roh, Jung-koo The Korean Society of Veterinary Science 1993 大韓獸醫學會誌 Vol.33 No.3
Captafol은 phthalimide계통의 항진균제로써 difolatan이란 상품명으로 개발되어 과일, 채소의 탄저병 및 원목 등의 곰팡이 구제에 널리 사용되고 있는 것으로 국내에서도 두번째로 많이 생산, 사용되는 품목이나 독성실험에 관한 보고는 거의 없는 상태이다. 이에 본 연구에서는 captafol 자체에 대한 독성기전의 일부를 확인하고자 동물체내에서 일어나는 여러가지 대사작용이 배제된 시험관내에서 실험을 수행하였다. 랫트 혈액을 후대정맥으로 부터 채혈하여 4개의 시험관에 $2.5m{\ell}$씩 분주한 후 captafol 농도가 $0.1{\times}10^{-4}M$, $1{\times}10^{-3}M$, $1{\times}10^{-2}M$이 되도록 한 ethanol용액 $25{\mu}{\ell}$씩 넣고 $CO_2$ incubator에서 2시간 동안 부드럽게 혼합하여 혈액학적 성상 및 적혈구 취약성 시험을 수행하였다. 또한 원심분리하여 얻어진 혈장에서 생화학적 성상 등을 조사한 결과 다음과 같은 성적을 얻었다. 1. 적혈구수 및 hematocrit치는 captafol 투여량에 비례적으로 유의한(p<0.05) 감소를 나타내었다. 2. 적혈구막 취약성 실험에서 $1{\times}10^{-3}M$ 및 $1{\times}10^{-2}M$ 농도에서 대조군에 비하여 유의한(p<0.01) 증가를 나타내었다. 3. 혈장내 potassium이온의 농도는 captafol의 투여량에 비례적으로 증가하였다. 4. Total bilirubin 및 creatine kinase가 대조군에 비하여 각각 증가 및 감소하였다. The effect of captafol on the hematological value, erythrocyte membrane and plasma biochemical value was investigated using blood of SPF Sprague-Dawley male rats in vitro. For the anticoagulations, we used 0.5mg of heparin per $10m{\ell}$ of blood from vena cava. Three con-centrations($0.1{\times}10^{-4}M$, $1{\times}10^{-3}M$ and $1{\times}10^{-2}M$) captafol in ethanol were added to the each $2.5m{\ell}$ blood so that the linal concentration of ethanol was 1%. The blood contained with each concentration of captafol was incubated at $37^{\circ}C$ C for 2 hours under 5% $CO_2$ gas The whole blood and plasma were examined for hematological vaJues, erythrocyte membrane damage and biochemical values, respectively. The results obtained were summarized as follows ; 1. The number of RBC in $1{\times}10^{-2}M$ group and the concentration of MCHC in $1{\times}10^{-3}M$ group were significantly (p<0.05) decreased and increased from that of control values, respectively. The percentage of Hct was significantly (p<0.05) decreased with dose-response. 2. Erythrocyte fragility rate of $1{\times}10^{-3}M$ and $1{\times}10^{-2}M$ group were significantly (p<0.01) increased from that control with dose response. 3. Potassium ion level of $1{\times}10^{-2}M$ was significantly (p<0.05) increased from that of control. 4. The concentration of total bilirubin in the $1{\times}10^{-3}M$ and $1{\times}10^{-2}M$ groups were significantly increased from that of control. The enzyme level of creatine kinase in $1{\times}10^{-2}M$ group was significanlty (p<0.05) decreased from control value.