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CJ-11555의 Sprague-Dawely 랫드를 이용한 단회 및 4주 반복경구투여 독성시험
김일환(Il-Hwan Kim),이성학(Sung-Hak Lee),최재묵(Jae-Mook Choi),박지은(Jie-Eun Park),김덕열(Deog-Yeor Kim),노현정(Hyun-Jung Noh),김택로(Taek-Rho Kim),이상호(Sang-Ho Lee),김영훈(Young-Hoon Kim),김진완(Jin-Wan Kim),장준환(Jun-Hwan Chang 한국독성학회 2004 Toxicological Research Vol.20 No.2
This study was to investigate single and repeated-dose toxicities of CJ-11555, an anticirrhotic agent, in Sprague-Dawley (SD) rats. In single-dose oral toxicity study, the test article were<br/> administered once by gavage to males and females at dose levels of 0 and 2,000 mg/kg. No dead animals and abnormal necropsy findings were found in control and CJ-11555 treated group. Therefore, the approximate lethal dose of CJ-11555 was considered to be higher than 2,000 mg/kg in rats. In the 4-week repeated oral toxicity study, the test article was administered once daily by gavage to<br/> male and female rats at dose levels of 0, 10, 50 and 200 mg/kg/day for 4-weeks. In clinical signs, yellow-colored urine and yellow hair coat were observed in the 50 and 200 mg/kg male and female<br/> groups. In hematology, erythrocyte count and hemoglobin were significantly decreased in the 200mg/kg male and female groups. In serum biochemistry, total cholesterol was significantly increased and aspartate aminotransferase (AST) was significantly decreased in the 50 or 200 mg/kg male and female groups. In histopathological examinations, centrilobular hepatocellular hypertrophy in the liver, congestion and pigmentation in the spleen, hyaline droplets in the kidney were observed in the 50 and 200 mg/kg male and female groups. In toxicokinetic study, CJ-11555 was dose-dependent in systemic exposure and showed better absorption in female with minimum accumulation after multidosing. Based on these results, it was concluded that the 4-week repeated oral dose of CJ-11555<br/> resulted in the suppression of AST activity and centrilobular hepatocellular hypertrophy in both sexes at a dose level of 50 or 200 mg/kg/day. The target organ was estimated to be liver, spleen and male's kidney. The no-observed-adverse-effect level (NOAEL) for CJ-11555 in rats following gavage for at least 4-week is 10 mg/kg/day.
CJ-11555의 Sprague-Dawely 랫드를 이용한 단회 및 4주 반복경구투여 독성시험
김일환(Il-Hwan Kim),이성학(Sung-Hak Lee),최재묵(Jae-Mook Choi),박지은(Jie-Eun Park),김덕열(Deog-Yeor Kim),노현정(Hyun-Jung Noh),김택로(Taek-Rho Kim),이상호(Sang-Ho Lee),김영훈(Young-Hoon Kim),김진완(Jin-Wan Kim),장준환(Jun-Hwan Chang 한국독성학회 2004 Toxicological Research Vol.20 No.1
This study was to investigate single and repeated-dose toxicities of CJ-11555, an anticirrhotic agent, in Sprague-Dawley (SD) rats. In single-dose oral toxicity study, the test article were administered once by gavage to males and females at dose levels of 0 and 2,000 mg/kg. No dead animals and abnormal necropsy findings were found in control and CJ-11555 treated group. Therefore, the approximate lethal dose of CJ-11555 was considered to be higher than 2,000 mg/kg in rats. In the 4-week repeated oral toxicity study, the test article was administered once daily by gavage to<br/> male and female rats at dose levels of 0, 10, 50 and 200 mg/kg/day for 4-weeks. In clinical signs, yellow-colored urine and yellow hair coat were observed in the 50 and 200 mg/kg male and female<br/> groups. In hematology, erythrocyte count and hemoglobin were significantly decreased in the 200mg/kg male and female groups. In serum biochemistry, total cholesterol was significantly increased and aspartate aminotransferase (AST) was significantly decreased in the 50 or 200 mg/kg male and female groups. In histopathological examinations, centrilobular hepatocellular hypertrophy in the liver, congestion and pigmentation in the spleen, hyaline droplets in the kidney were observed in the 50 and 200 mg/kg male and female groups. In toxicokinetic study, CJ-11555 was dose-dependent in systemic exposure and showed better absorption in female with minimum accumulation after multidosing. Based on these results, it was concluded that the 4-week repeated oral dose of CJ-11555 resulted in the suppression of AST activity and centrilobular hepatocellular hypertrophy in both sexes at a dose level of 50 or 200 mg/kg/day. The target organ was estimated to be liver, spleen and male's kidney. The no-observed-adverse-effect level (NOAEL) for CJ-11555 in rats following gavage for at least 4-week is 10 mg/kg/day.
최재묵(Jae-Mook Choi),이성학(Sung-Hak Lee),김일환(Il-Hwan Kim),박지은(Jie-Eun Park),김덕열(Deog-Yeor Kim),노현정(Hyun-Jung Noh),김택로(Taekrho Kim),최광도(Do-Gwang Choi),김영훈(Young-Hoon Kim),김진완(Jin-Wan Kim),장준환(Joon-Hwan Jan 한국독성학회 2004 Toxicological Research Vol.20 No.1
Safety pharmacological properties of CJ-11555, an anti-cirrhotic agent, were investigated in experimental animals and in vitro test system. CJ-11555 had no effects on normal body temperature in rats, motor coordination, chemoshock induced by pentetrazol, electric shock induced by electric shocker and writhing syndromes in mice at dose levels of 100, 300 and 1,000 mg/kg. CJ-11555 inhibited intestinal activity and prolonged hexobarbital-induced sleeping time in mice at the dose level of 1,000 mg/kg. CJ-11555 affected on general activity and behaviour tests in SD rats, such as lacrimation, ptosis, piloerection, decreased body tone, abnormal dispersion within the cage, diarrhoea, red colored faeces, slight hypothermia and decreased grooming, at the dose level of 1,000<br/> mg/kg in rats. CJ-11555 was effected on cardiovascular and respiratory system in anesthetized beagle dogs, such as tachycardia, increase of mean blood pressure and decrease of PR interval, decrease of respiratory rate and minute volume, at dose levels of 10 and 30 mg/kg. However, these effects were also observed in vehicle treated anesthetized beagle dogs. In in vitro experiments, CJ-11555 inhibited agonists (histamine, acetyl-choline or BaCl2) induced contraction of isolated guinea-pig at the concentration of 30×10-6 M. CJ-11555 was weekly inhibited hERG channel current at concentrations of 10 and 30×10-6 M, and IC50 was estimated to be higher than 30×10-6 M. Based on these results, it was concluded that CJ-11555 affected on cardiovascular and respiratory system, general activity and behaviour and hexobarbital-induced sleeping time at the dose level of 1,000 mg/kg and contraction of the smooth muscle and hERG channel current at the concentration of 30×10-6 M.
최재묵(Jae Mook Choi),이성학(Sung Hak Lee),김일환(Il Hwan Kim),박지은(Jie Eun Park),김덕열(Deog Yeor Kim),노현정(Hyun Jung Noh),김택로(Taekrho Kim),최광도(Do-Gwang Choi),김영훈(Young Hoon Kim),김진완(Jin Wan Kim),장준환(Joon Hwan Jan 한국독성학회 2004 Toxicological Research Vol.20 No.2
Safety pharmacological properties of CJ-11555, an anti-cirrhotic agent, were investigated in experimental animals and in vitro test system. CJ-11555 had no effects on normal body temperature in rats, motor coordination, chemoshock induced by pentetrazol, electric shock induced by electric shocker and writhing syndromes in mice at dose levels of 100, 300 and 1,000 mg/kg. CJ-11555 inhibited intestinal activity and prolonged hexobarbital-induced sleeping time in mice at the dose level of 1,000 mg/kg. CJ-11555 affected on general activity and behaviour tests in SD rats, such as<br/> lacrimation, ptosis, piloerection, decreased body tone, abnormal dispersion within the cage, diarrhoea, red colored faeces, slight hypothermia and decreased grooming, at the dose level of 1,000mg/kg in rats. CJ-11555 was effected on cardiovascular and respiratory system in anesthetized beagle dogs, such as tachycardia, increase of mean blood pressure and decrease of PR interval, decrease of respiratory rate and minute volume, at dose levels of 10 and <br/> 30mg/kg. However, these effects were also observed in vehicle treated anesthetized beagle dogs. In in vitro experiments, CJ-<br/> 11555 inhibited agonists (histamine, acetyl-choline or BaCl2) induced contraction of isolated guinea-pig at the concentration of 30x10-6 M. CJ-11555 was weekly inhibited hERG channel current at concentrations of 10 and 30x10-6 M, and IC50 was estimated to be higher than 30x10-6 M. Based on these results, it was concluded that CJ-11555 affected on cardiovascular and respiratory system, general activity and behaviour and hexobarbital-induced sleeping time at the dose level of 1,000 mg/kg and contraction of the smooth muscle and hERG channel current at the concentration of 30x10-6 M.
박지은(Jie-Eun Park),이성학(Sung-Hak Lee),최재묵(Jae-Mook Choi),김일환(Il-Hwan Kim),김덕열(Deog-Yeor Kim),노현정(Hyun-Jung Noh),김택로(Taekrho Kim),김영훈(Young-Hoon Kim),임지웅(Lim Jee Woong),김진환(Jin-Wan Kim),장준환(Jun-Hwan Chan 한국독성학회 2004 Toxicological Research Vol.20 No.2
To evaluate the genotoxicity of CJ-11555, an anti-cirrhotic agent, the reverse mutation test, chromosomal aberration test and in vivo micronucleus test in rats were performed. In the reverse mutation test, the treatment of CJ-11555 at doses of 33.3, 100, 333, 1000, 3330 and 5000 mg/plate with and without S9 did not induce mutagenicity in Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli ( E. coli) WP2 uvrA. In chromosomal aberration test, CJ-11555 did not induce structural a chromosomal aberration in Chinese hamster ovary (CHO) cells with and without metabolic activation at all doses. In micronucleus test, CJ-11555 did not induce any statistically significant increases in micronucleated polychromatic erythrocyte (MNPCE) at doses of 500, 1000, and<br/> 2000 mg/kg. These results suggest that CJ-11555 might not have a mutagenic potential under the conditions in this study.
박지은(Jie-Eun Park),이성학(Sung-Hak Lee),최재묵(Jae-Mook Choi),김일환(Il-Hwan Kim),김덕열(Deog-Yeor Kim),노현정(Hyun-Jung Noh),김택로(Taekrho Kim),김영훈(Young-Hoon Kim),임지웅(Lim Jee Woong),김진완(Jin-Wan Kim),장준환(Jun-Hwan Chan 한국독성학회 2004 Toxicological Research Vol.20 No.1
To evaluate the genotoxicity of CJ-11555, an anti-cirrhotic agent, the reverse mutation test, chromosomal aberration test and in vivo micronucleus test in rats were performed. In the reverse mutation test, the treatment of CJ-11555 at doses of 33.3, 100, 333, 1000, 3330 and 5000 mg/plate with and without S9 did not induce mutagenicity in Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli ( E. coli) WP2 uvrA. In chromosomal aberration test, CJ-11555 did not induce structural a chromosomal aberration in Chinese hamster ovary (CHO) cells with and without metabolic activation at all doses. In micronucleus test, CJ-11555 did not induce any statistically significant increases in micronucleated polychromatic erythrocyte (MNPCE) at doses of 500, 1000, and 2000 mg/kg. These results suggest that CJ-11555 might not have a mutagenic potential under the conditions in this study.