复方蒿甲醚对Beagle犬的长期毒性

Long-term toxicity of co-artemether in beagle dogs

给 Beagle犬 po复方蒿甲醚 (蒿甲醚∶本芴醇 1∶ 6,W/W) 1 1 2 ,556,1 0 0 0 mg· kg-1· d-1,每天 1次 ,连服 1 4d.给药结束后 ,各组活杀 2 /3,留 1 /3继续观察 2 8d.观测了临床症状和生理指标 ,血液学 ,血生化 ,尿 ,心电图 ,眼底及病理组织学 .主要毒性反应为 1 0 0 0 mg·kg-1·d-1组给药早期出现网织红细胞降低 ,骨髓红系细胞的中幼红与早幼红比值降低 ,心电图 Q- T间期延长 ,生化检查谷草转氨酶 ,碱性磷酸酶轻度升高 .组织学检查可见肝 ,肾轻度损伤 .所有上述变化停药后均可恢复正常 . 556mg· kg-1· d-1及以下剂量组未见明显毒副作用 ,可视为基本安全剂量 .

Co-artemether is a fixed combination tablet comprising one part of artemether and six parts of benflumetol (1∶6, W/W). Experiments were carried out in beagle dogs. The dogs were divided randomly into groups of defferent dose (112, 556, 1000 mg·kg -1·d -1) and blank control group. Each group consisted of 3 males and 3 females. The drug was given once daily for 14 successive days. Manifestations and behaviors of the dogs, hematology, blood chemistry, urinalysis, electrocardiogram(ECG), ophthalmoscopy, necropsy and histopathology were examined. Twenty-four hours after the last dose, 4 dogs of each group were sacnificed and the others in each group were remained to be further observed for four weeks. The experiment suggested that the most sensitive tissue in the toxic effects induced by oral administration of co-artemether be still the erythrocytic system of bone marrow as was the case for injection of artemisinin derivatives. The reticulocyte count and the ratio of polychromatic normoblast/basophilic normoblast of erythrocytic series of bone marrow tended to decrease in 1000 mg·kg -1·d -1 group. In addition, prolongation of Q-T interval of ECG and transient increase in GOT and alkaline phosphatase activity were also observed. Histological examination revealed mild tissue damage of liver and kidney. All of these changes were reversible after stopping treatment. The dose 556 mg·kg -1·d -1 (50 times as large as the dose to be used in man) was considered as practically safe dose.