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目的观察SD大鼠静脉注射AN200801重复给药4周的毒性病理学表现,了解受试物毒性作用及其靶器官,确定无毒反应剂量;描述受试物在实验动物体内的系统暴露以及这种暴露与给药剂量和给药期限的关系。从而预测受试物可能对人体产生的不良反应,降低临床受试者和药品上市后使用人群的用药风险。方法 SD大鼠80只分组雌雄分别静脉注射AN200801 0,0.45,0.9,1.8和0,0.75,1.5,3.0 mg·kg-1.d-1,连续给药4周,每组1/2存活动物给药结束后和恢复期结束后解剖取材进行病理检查。死亡动物当时解剖,其余全部动物按预定时间麻醉放血处死,称量并计算心、肺、肝、脾、肾、胸腺、肾上腺、睾丸或卵巢、附睾或子宫和脑等器官的脏器重量和脏器系数,解剖后肉眼检查,取材石蜡包埋制片后显微镜检查。结果 AN200801可以引起雌性大鼠(0.45 mg·kg-1.d-1)肝细胞坏死,恢复期完全恢复;雌(0.45 mg·kg.d-1)、雄(0.75 mg·kg.d-1)动物肾脏肾小管或集合管细胞核固缩,恢复期雌性动物未完全恢复,雄性动物完全恢复;雌(0.45 mg·kg.d-1)、雄(0.75 mg·kg.d-1)动物近段小肠局部粘膜坏死、脱落,恢复期完全恢复;雌(1.8 mg·kg.d-1)、雄(0.75 mg·kg.d-1)动物脾脏红髓及边缘区淋巴细胞核固缩,部分淋巴细胞核碎裂,恢复期完全恢复;雌(0.9 mg·kg.d-1)、雄(1.5 mg·kg.d-1)动物胸腺皮质内淋巴细胞核固缩,部分核碎裂,恢复期完全恢复;雌(0.45 mg·kg.d-1)、雄(0.75 mg·kg.d-1)动物骨髓原始及幼稚造血细胞减少,恢复期完全恢复,但中、高剂量组未完全恢复;雄性动物(0.75 mg·kg.d-1)睾丸生精上皮萎缩,脱落,生精细胞及精子减少,附睾管内精子减少、凝固体增多,恢复期未恢复。无法排除给药动物雌性高剂量组肺脏局灶坏死,雄性高剂量肝细胞团块状浊肿、气球样变,与AN200801相关。结论 SD大鼠静脉注射AN200801重复给药4周,雌、雄性动物的无毒反应剂量分别小于0.45和0.75 mg·kg.d-1,其毒性靶器官为肝、肾、小肠、脾、胸腺、骨髓、睾丸及附睾等,临床试验时,应重点监测上述脏器功能改变及采取相应防护措施。
OBJECTIVE To observe the toxicological pathology of ANOVA in SD rats after repeated administration of AN200801 for 4 weeks to understand the toxic effects of target substance and its target organs and determine the dose of non-toxic reaction. Describe the systematic exposure of test substance in experimental animals Exposure to dose and duration of administration. Thereby predicting the possible adverse effects of the test substance on the human body and reducing the risk of drug use of the clinical subjects and the drugs after the drug is put on the market. Methods 80 male and female SD rats were injected intravenously with AN200801,0,0.45,0.9,1.8 and0,0.75,1.5,3.0 mg · kg-1.d-1, After administration and recovery period after the end of anatomical material for pathological examination. The dead animals were dissected at that time, and all the remaining animals were anesthetized and blood was sacrificed at a predetermined time to weigh and calculate the organ weights and organs of heart, lung, liver, spleen, kidney, thymus, adrenal, testis or ovary, epididymis or uterus and brain Coefficients, anatomical visual examination, paraffin-embedded paraffin microscopy. Results AN200801 could induce hepatocellular necrosis in female rats (0.45 mg · kg-1.d-1) and complete recovery in convalescent period. Female (0.45 mg · kg-1) and male ), Animal kidney tubules or collecting tube nucleus pyknosis, the recovery of female animals did not fully recover, the male animals completely restored; female (0.45 mg · kg.d-1) and male (0.75 mg · kg · d -1) animal near The intestinal mucosa necrosis, shedding and complete recovery during the recovery stage were observed. The nuclei of the spleen red pulp and marginal zone of the female (1.8 mg · kg.d-1) and the male (0.75 mg · kg · d-1) The nuclear fragmentation and complete recovery in convalescent stage were observed. Nuclear condensation, partial nuclear fragmentation and complete recovery of condylar lymphocytes were observed in the female (0.9 mg · kg.d-1) and male (1.5 mg · kg.d-1) (0.45 mg · kg.d-1) and male (0.75 mg · kg · d-1), respectively. The original and naive hematopoietic cells in the bone marrow of the animals were reduced and recovered completely in the recovery period, but not in the medium and high dose groups. (0.75 mg · kg.d-1) testicular spermatogenic epithelium atrophy, loss, spermatogenic cells and sperm decreased, sperm in the epididymis decreased, coagulation increased, the recovery did not resume. It can not be ruled out that the high-dose group of female animals with high-dose lung tissue focal necrosis, massive male high-dose hepatocyte mass turbidity, balloon-like changes, and AN200801 related. Conclusion The non-toxic dose of AN200801 is less than 0.45 and 0.75 mg · kg-1 in female and male animals, respectively. The toxic target organs are liver, kidney, small intestine, spleen, thymus, Bone marrow, testis and epididymis, clinical trials, should focus on monitoring the changes in organ function and take appropriate protective measures.