Azinphos-methyl이 랫트 태아에 미치는 기형학적 연구

조명행,이창업,이영순,Cho, Myung-Haing,Lee, Chang-Eop,Lee, Yong-Soon 한국독성학회 1988 Toxicological Research Vol.4 No.1

azinphos-methyl을 S.D.랫트에 투여하여 기형이 유발되는지의 여부와 태아의 기관형성 및 자궁내에서 태아의 발달에 미치는 영향을 알아보기 위하여 무처치의 negative control군, 수도물을 경구투여한 sham control군, 이미 기형효과가 있는 것으로 알려진 aspirin투여의 positive control군, 그리고 azinphosmethyl 0.094 mg/kg, 0.4 mg/kg 및 1.5mg/kg 투여군으로 나누어 각군 30마리씩으로, 임신 6~15일 사이에 경구투여한 결과는 다음과 같다. 즉, 모체의 체중증가율은 임신 7~14일, 즉 약물투여기에 aspirin 투여군과 azinphos-methyl 1.5mg/kg 투여군에서 현저한 감소를 보였다(p<0.01). 모체의 장기무게는 azinphos-methyl 1.5mg/kg 투여군에서 간장의 절대무게비가 유의성(p<0.05) 있는 감소를 보였으며, 신장의 절대 및 상대무게비는 aspirin군에서 (p<0.05, p<0.01), 또 난소의 절대 및 상대무게비는 aspirin 투여군(p<0.01)과 azinphos-methyl 전처치군(p<0.05)에서 유의성 있게 증가하였다. 모체 간장의 단백질량은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 현저히 감소되었다(p<0.01). 모체의 배아와 태자에 대한 관찰 결과 azinphos-methyl 1.5mg/kg 투여군에서 암수의 비율에 있어 현저하게 증가(p<0.01) 했으며, 체중은 aspirin과 azinphos-methyl 1.5mg/kg 투여군에서 고도의 유의성(p<0.01) 있게 감소하였고, azinphos-methyl 0.4 mg/kg 투여군에서도 현저하게 감소하였다(p<0.05). 그리고 미숙태자와 흡수태자는 aspirin군에서, 죽은 태자수는 azinphos-methyl 1.5mg/kg 투여군에서 유의성 있게 증가하였다(p<0.05, p<0.01). 태자의 장기에서 나타난 기형은 aspirin과 azinphos-methyl 1.5mg/kg 투여군 공히 횡경막에서 횡격막 천공, 두부에서 무안구증, olfactory bulb의 확장, 수두뇌, 그리고 3뇌실과 측뇌실의 결손, 심장에서 좌심실벽 위축, 심첨확장 등이 유의성(P<0.01, P<0.05) 있게 관찰되었으며, 특히 횡경막, 심장 및 안구등에 높은 기형발생율을 보였다. 또 태자의 골화지연은 두개골에서 후두골, 접형골, 구개, 흉골에서 4번째 흉골편, 검상돌기, 척추에서 경추, 흉추, 미추, 전${\cdot}$후지골, 중족골에서 관찰되었다. 한편, 자연 분만시킨 태자의 사망율은 azinphos-methyl 1.5mg/kg 투여군에서 negative control군에 비해 고도의 유의성(p<0.01) 있게 높음을 알 수 있었으며, 체중도 역시 현저하게(p<0.01) 감소하였고, 발육지표중 pivoting, 체모형성, 청각능력, 시각능력, 사지근육 발달정도 및 고환하강시기 등에서 고도의 유의성(p<0.01)이 관찰되었다. This study was carried out to investigate the teratological potential of azinphos-methyl in the rat fetuses and to establish the nature of the effects on organogenesis and intrauterine development. The Sprague-Dawley female rats (180-210g) without previous litter were used in this study. Azinphos-methyl dosages of 0.094mg/kg, 0.4mg/kg, 1.5mg/kg were selected based on the acute intragastric $LD_{50}$ of 15mg/kg in the rat. Azinphos-methyl in water (Treatment Group), non-treatment control (Negative Control), water control (Sham Control), were administered by oral route and aqueous solution of acetyl salicylic acid (Positive Control) was administered by gavage at rate of 10 ml/kg of body weight from day 6 through 15. The results obtained were summarized as follows. 1. Decreased body weight of dams was observed in animals treated with aspirin and azinphos-methyl 1.5 mg/kg from day 7 through 14. (P<0.01) 2. There was an apparent decrement in the absolute liver weight in the azinphos-methyl 1.5 mg/kg treated group (P<0.05). However, the absolute and relative kidney weight in aspirin group (P<0.05, P<0.01) and the absolute and relative ovary weight in aspirin, azinphos-methyl treatment groups (P<0.01, P<0.05) were increased. 3. Decreased protein contents of dam's liver was observed in the aspirin and high dose azinphos-methyl treated group of animals (P<0.01). 4. The number of male-female ratio per dam increased in azinphos-methyl 1.5 mg/kg group but there was an apparent decrement in the body weight of fetuses in aspirin and high dose azinphos-methyl group (P<0.01, P<0.05). Total immature and resorbed fetuses were increased in aspirin group and the number of dead fetuses were also increased in azinphos-methyl 1.5mg/kg treated group of animals. (P<0.01, P<0.05). 5. In soft tissue defects, diaphragmatic hernia in diaphragm, anophthalmia, enlarged olfactory bulb, hydrocephalus, absence of third and lateral ventricle in skull, hydronephrosis in kidney, atrophy of left ventricle wall, enlarged apex in heart were observed. Especially, defects of diaphragm, heart and eye ball showed peak incidences in the high dose azinphosmethyl and aspirin group. (P<0.01). 6. Variations in the ossification patterns of skull, sternebrae, tail, forelimbs and hindlimbs showed peak incidences in the aspirin and high dose azinphos-methyl group. (P<0.01). 7. In the developmental indices of offspring, the mortality of aspirin and azinphos-methyl 1.5mg/kg treated group was higher than that of negative control. And, there was an apparent decrement in the body weight of fetuses (P<0.01) and considerable differences were obtained in pivoting, development of fur, auditory function, vision, quadrupled muscle development and testes descent in aspirin and azinphos-methyl 1.5mg/kg group. (P<0.01).

비글개에서 인체 재조합 적혈구 조혈인자, rHu-EPO의 급성독성에 관한 연구

조명행,성하정,김형식,곽승준,천선아,임소영,김원배,김병문,안병옥,이병무,Cho, Myung-Hang,Seong, Ha-Jung,Kim, Hyung-Sik,Kwack, Seung-Jun,Chun, Sun-Ah,Lim, So-Young,Kim, Won-Bae,Kim, Byoung-Moon,Ahn, Byoung-Ok,Lee, Byung-Mu 한국독성학회 1996 Toxicological Research Vol.12 No.2

The acute toxicity of rHu-EPO, newly developed recombinant erythropoietin, was tested in beagle dogs. rHu-EPO, when administered intravenously at 25, 000 IU/kg, did not cause any death. Also, rHu-EPO did not induce any change of body weight, food intake and clinical signs compared to controls. There were no significant changes in hematological, urine analysis and pathological examination. These results showed that rHu-EPO did not induce any remarkable toxic response and the $LD_50$ was greater than 25, 000 IU/kg in beagle dogs.

비글개에서 인체 재조합 적혈구 조혈인자 , rHuEPO 의 아만성 정맥독성에 관한 연구

조명행(Myung Haing Cho),성하정(Ha Jung Seong),김형식(Hyung Sik Kim),곽승준(Seung Jun Kwack),천선아(Sun Ah Chun),한하수(Ha Su Han),임소영(So Young Lim),안미영(Mi Young Ahn),김원배(Won Bae Kim),김병문(Byoung Moon Kim),안병옥(Byoung Ok 한국응용약물학회 1998 Biomolecules & Therapeutics(구 응용약물학회지) Vol.6 No.3

The subchronic toxicity study of rHuEPO, a newly developed recombinant erythropoietin, was investigated for 13 weeks in Beagle dogs intravenously treated with doses of 100, 500 and 2,500 IU/㎏/day. There were no significant changes in body weight, food intake, physical and opthalmic examination, urine analysis, etc. Any toxic response was not observed except for enlarged spleen and extramedullary hematopoiesis. These results indicate that the no-observed adverse effect level (NOAEL) of rHuEPO is 100 IU/㎏ in Beagle dogs.

개에서 Oleic acid 로 유발시킨 급성췌장염에 대한 Trypsin inhibitor 의 투여효과

조명행(Myung Haing Cho),윤영민(Young Min Yun),최희인(Hee In Choi) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.2

To investigate the effects of trypsin inhibitors, aprotinin and urinary trypsin inhibitor (UTl), on the acute pancreatitis, this study was carried out in dogs of acute pancreatitis induced by oleic acid (0.28 mg/kg). Administration with aprotinin and UTI seemed to have a therapeutic effect on the clinical sign, ultrasonographic finding, histopathologic finding. But in amylase and lipase activity, there were no significant differences among three groups.

오줌유래 Trypsin 효소 억제제가 췌장염에 미치는 영향에 관한 연구

조명행(Myung Haing Cho),권오경(Oh Kyung Kweon),정요찬(Yo Chan Jeong),유아선(Ah Sun You),김종민(Jong Min Kim),박수진(Soo Jin Park),송동호(Dong Ho Song) 한국응용약물학회 1996 Biomolecules & Therapeutics(구 응용약물학회지) Vol.4 No.3

The metabolism of carbinoxamine, 2-[(4-chlorophenyl)-2-pyridinyl-methoxy]-N, N-dimethylethaneamine, was studied in adult male volunteers after an oral dose of 15 mg. Solvent extracts of urine obtained with or without enzyme hydrolysis were analyzed by gas chromatography-mass spectrometry after derivatization with MSTFA/TMSCl (N-methyl-N-trimethylsilyltrifluoroacetamide/trimethyl chlorosilane). The structures of metabolites were determined based on the electron impact (EI) and chemical ionization (CI) mass spectra. Nonconjugated metabolites identified in the urine were carbinoxamine, nor-carbinoxamine, and bis-nor-carbinoxamine. Parent drug, nor-carbinoxamine, and bis-nor-carbinoxamine were also detected as conjugated forms. These metabolites observed in human urine were different from those previously reported in the rat. Urinary excretions of carbinoxamine were reached to maxima in 4 hours after drug administration with 4.9%-8.1% and 2.5-4.2% of the dose excreted during 24 h as carbinoxamine and its glucuronide, respectively.

호중구 감소증을 유도한 마우스에서의 유전자 재조합 인과립구 콜로니자극인자의 효과

조명행(Myung Haing Cho),유아선(Ah Sun Yu),방명주(Ming Zhu Fang),곽형일(Hyung Il Kwak),성하정(Ha Jung Seong),강관엽(Koan Yeob Kang),최승진(Seung Jin Choi),정경환(Kyung Hwan Jung),박두홍(Doo Hong Park),안길환(Gil Hwan Ahn) 한국응용약물학회 1998 Biomolecules & Therapeutics(구 응용약물학회지) Vol.6 No.2

Administration of 3 type KGCs [recombinant human granulocyte colony-stimulating factor (rhGCSF)] to mice with cyclophosphamide (CPA)-induced neutropenia for 4 consecutive days from the day after the CPA dosing (100 mg/kg) resulted in a dose dependent increase in the peripheral blood neutrophil count 6 hours after the final KGC injection. Within the KGC dose range of 0.1 to 40 ㎍ per mouse per day, there was a sigmoidal relationship between the logarithm of the dose and the peripheral blood neutrophil count (relative value for neutrophil count of the basal dose) in the treated mice. The sigmoidal relationship of test KGC preparations shows that there is a saturation point in terms of efficacy. Compared with effect of KGC-Orange, Green, and Blue, KGC-Orange recovers neutrophils more effectively than the others do.

비글개에서 인체 재조합 적혈구 조혈인자 , rHu-EPO 의 아급성정맥독성시험

조명행(Myung Hang Cho),성하정(Ha Jung Seong),김형식(Hyung Sik Kim),곽승준(Seung Jun Kwack),임소영(So Young Lim),천선아(Sun Ah Chun),김원배(Won Bae Kim),김병문(Byoung Moon Kim),안병옥(Byoung Ok Ahn),이병무(Byung Mu Lee) 한국응용약물학회 1996 Biomolecules & Therapeutics(구 응용약물학회지) Vol.4 No.4

The subacute toxicity was investigated in Sprague-Dawley rats orally treated with KDRD-010 at the doses of 0.056, 0.28, and 1.4 g/㎏ for one month. There were no clinical signs and pathological changes compared with control group. Body weights were not significantly changed between control and treatment groups. In hematological and biochemical serum parameters, all mean values appear to be within the normal range. In pathological examinations, hemorrhages of lung was observed in one male rat at low dose group and one female rat at high dose group of KDRD-010, but it was not considered to be caused by KDRD-010. These results suggest that KDRD-010 dose not induce any significant subacute oral toxicities in Sprague-Dawley rats.

닭에서 ciprofloxacin의 체내 동태에 관한 연구

강환구,조명행,이항,한명국,손성완,김재학,이재진,Kang, Hwan-goo,Cho, Myung-haing,Lee, Hang,Han, Myung-guk,Son, Seong-wan,Kim, Jae-hak,Lee, Jae-jin 대한수의학회 1995 大韓獸醫學會誌 Vol.35 No.3

The purpose of this experiment was to develop a simple and reliable HPLC method for the detection of ciprofloxacin in chicken serum and to provide a basic data on pharmacokinetic parameters after oral and intramuscular administration. The results obtained were as follows: 1. 0.2% meta-phosphoric acid: acetonitrile(7:3, v/v) solution had a high and regular recovery rates and was selected as an extraction solution. 2. The recovery rates of ciprofloxacin were 83-97% with the selected solution in chicken serum and the detection limit was 50ng/ml in serum. 3. Ka(abosorption rate constant) were 3.652 1/h in fasted group and 0.880 1/h in non-fasted group, and Ke (elimination rate constant) were 0.061 1/h and 0.133 1/h, respectively. 4. The highest concentration in serum after intramuscular injection was 840ng/ml within 15-30min and 160-324ng/ml in 1.1-3.2 hours after oral administration. 5. The time course of blood concentration fits well into a 2 compartment model. 6. On oral administration of ciprofloxacin with feed, ciprofloxacin was absorbed more slowly and the amount of absorbed was smaller than that of in fasted chickens. 7. Blood concentration of ciprofloxacin increased in a dose-dependent manner after intramusclular and oral administraiton.

Cyclopiazonic acid 및 aflatoxin B₁이 토끼의 혈소판 응집 및 ATP 방출에 미치는 영향

홍충만,조명행,Hong, Choong-man,Cho, Myung-haing 대한수의학회 1996 大韓獸醫學會誌 Vol.36 No.4

Cyclopiazonic acid(CPA) known as stimulating the release of intracellular calcium, aflatoxin $B_1(AFB_1)$ causing gastrointestinal hemorrhage frequently were used as model toxic mycotoxins in these studies. First of all, the effects of various mycotoxins on the platelet aggregation response were determined. The effects of mycotoxins on the ATP release from platelet by aggregating factors were investigated. The results and conclusions obtained from these studies are : 1) CPA promoted ADP, collagen, thrombin, A.A. and PAF-induced rabbit platelet aggregation. $AFB_1$ inhibited collagen, A.A. and PAF-induced rabbit platelet aggregation only. 2) CPA increased both aggregation and disaggregation time, whereas $AFB_1$ decreased in a dose dependent manner. 3) CPA increased ADP, thrombin, A.A. and PAF-induced ATP release. $AFB_1$ increased A.A.-induced ATP release and decreased PAF-induced release in a dose dependent manner. In conclusion, CPA promoted platelet aggregation by the increase of ATP. Antiaggregating effects of AFB1 may be due to decreases of ATP. These data provide the basis for the future study of roles of ATP release in platelet aggregation.

카드뮴의 Salmonella typhimurium 변이균주 및 랫드 간장 상피세포에서의 유전독성

정상희,조명행,조준형,Jeong, Sang-hee,Cho, Myung-haing,Cho, Joon-hyoung 대한수의학회 1998 大韓獸醫學會誌 Vol.38 No.3

Cadmium is one of the well-known environmental toxicants and induces cancer in rodents and human, but its carcinogenic mechanism has not been well demonstrated until now. Genotoxic effects of cadmium in Salmonella typhimurium TA98, TA100 and TA1535/pSK1002 or in WB-F344 rat liver epithelial cells were investigated to elucidate the tumor initiating effects of cadmium. TA98, TA100 and TA1535/pSK1002 tester strains were used to detect frameshift mutation, base-pair mutation and SOS repair response, respectively, in Salmonella mutation test. Reverse mutations from histidine to $histidin^+$ of Salmonella typhimurium TA98 and TA100 by $CdCl_2$ were not significantly different from control up to the maximum doses ($100{\mu}M$ and $200{\mu}M$ in TA98 and TA100, respectively) at which non-cytotoxicity was observed. DNA SOS repair responses(${\beta}$-galactosidase activity) generally did not show significant increases compared to control in both of the conditions with or without metabolic activation in Salmonella typhimurium TA1535/pSK1002 by $CdCl_2$. But the activities of ${\beta}$-galactosidase by $400{\mu}M$ of $CdCl_2$ in metabolic activation condition and by 130 and $400{\mu}M$ of $CdCl_2$ in non-metabolic activation condition were more decreased than those of control. DNA single strand breaks for 4hrs were observed only in WB-F344 rat liver epithelial cells treated with $200{\mu}M$ of $CdCl_2$. As a conclusion, $CdCl_2$ did not induce gene mutation in microbials but induce DNA single strand breaks in rat liver epithelial cells.