摘要
目的 进行重组人粒细胞／巨噬细胞集落刺激因子（ｒｈＧＭ－ＣＳＦ）的临床前研究和Ⅰ期临床试验。方法在动物模型上进行ｒｈＧＭ－ＣＳＦ的药理、毒理、药代和药效研究，并在人体上进行安全性评价和初步疗效观察。结果体外实验证明ｒｈＧＭ－ＣＳＦ对骨髓造血祖细胞有促增殖作用；在６０Ｃｏｒ射线照射造成的白细胞低下动物（狗和猴），显示了明显的升白细胞作用；急性毒性试验显示，ＬＤ５０大于５０００μｇ／ｋｇ；小鼠的药代动力学研究表明，注入的ＧＭ－ＣＳＦ主要从尿中排出，并不在体内蓄积；狗的慢性毒性试验表明在高于临床用量３倍时，无明显毒性反应。Ⅰ期临床试验证明，每天在２．５－７．５μｇ／ｋｇ的剂量下使用是安全的，并能升高白细胞。结论ｒｈＧＭ－ＣＳＦ可用于治疗放疗与化疗引起的白细胞减少症。
Obiective To:Conduct preclinical studies and phase I trial of the recombinant human granulocyte- macrophage colony-stimulating factor (rhGM-CSF ) . Methods Pharmacodynamics, pharmacokinetic and toxicology of the rhGM-CSF were studied in animal models , and the safety was also evaluated in humans. Results The human bone marrow cells could be stimulated by purified rhGM-CSF to form multilineage colonies (CFU-GM and BFU-E) . The rhGM-CSF administered for 7 days to Beagle dogs and monkeys subjected to 60Co r-ray irradiation was shown to induce both rapid and sustained increase in circulating leukocyte counts. Toxicology testing showed that the LD50 (i. v ) was over 5000μg/kg , and LD50 (i. p) over 10000μg/kg in mice. Administration of the rhGM-GSF in excess of four times as much as clinical dosages was not associated with severe chronic toxicities. Most injected rhGM-GSF was ex- creted from urine , and did not accumulate in the body. In the phase I clinical trial , injecting 2. 5-7. 5 μg/day of rhGM-CSF was safe. Conclusion It is effective and safe to use rhGM-GSF in the treatment of leukocytopenia.
出处
《中华医学杂志》
CAS
CSCD
北大核心
1996年第9期654-657,共4页
National Medical Journal of China
基金
中国人民解放军总后勤部卫生部"八五"攻关课题资助项目
