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비 마약성 진통제 DA-5018 의 랫드에 대한 4 주 경구투여 아급성독성
백남기(Nam Gi Baik),안병옥(Byoung Ok Ahn),김원배(Won Bae Kim),양중익(Junn Ick Yang),김옥진(Ok Jin Kim),강경구(Kyung Koo Kang) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.2
4-week repeated dose toxicity of DA-5O18, a new capsaicin analogue analgesic agent, was examined in SD rats at dosage levels of 0, 0.4, 2, 10 and 50 mg/kg/day. DA-5018 was administered orally to 17 males and 17 females per group at doses of 0, 10 and 50 mg/kg and to 12 males and 12 females per group at doses of 0.4 and 2 mg/kg. After the administration period, 5 males and 5 females at the 0, 10 and 50 mg/kg were placed on withdrawal for 2 weeks. Treatment-related clinical signs were observed at 10 and 50 mg/kg. Clinical signs observed immediately after the administration of DA-5018 were grooming, sedation or depression, lacrimation, ataxia, reddening of extremities and ears, ventral or lateral recumbency, respiratory distress, cyanosis and convulsion. Delayed-type clinical signs including focal scabbing and depilation around nose were also observed 1 or 2 weeks after the start of administrarion of DA-5018. Only at the 50 mg/kg group, corneal opacities, reduced body weight gain (male) and death (male 6/17, female 3/17) were noted. In blood biochemical analysis, serum levels of glucose and triglyceride decreased at 10 and 50 mg/kg. In hematological examination, there were increases in the number of red blood cell, hemoglobin content and percent of hematocrit at 10 and 50 mg/kg. Pulmonary enlargement and hemorrhagic spot, focal scabbing and depilation around nose and corneal opacities were seen at the necropsy of the animals died during the dosing of DA-5018 50 mg/kg. Focal scabbing and depilation arowtd nose were observed in the animals terminally necropsied at doses of 10 and 50 mg/kg. Histopathological examination revealed pulmonary hemorrhage, focal necrosis in the scabbed area, corneal necrosis, fibrosis and neovasculization in the stroma. At 0.4 and 2 mg/kg, there were no significant toxic changes attributable to the administration of DA-5018. In conclusion, target organs following to 4-week repeated dose of DA-5018 in the rat were determined to be lung, skin and eyes. Definite toxic dose and no-observed-adverse-effect-level (NOAEL) were estimated to be 50 and 2 mg/kg/day, respectively.