注射用GMDTC驱镉作用制剂起始剂量与安全性

Initial dose and safety of cadmium-antidote GMDTC for intravenous infusion

目的探讨注射用N-(2,3,4,5,6五羟基己基)-(N-二取代甲酸钠基)-L-甲硫氨酸钠(GMDTC)制剂静脉输注时的驱镉作用起始剂量与安全性。方法(1)有效性试验。雄性新西兰兔经2.5水合氯化镉制备镉中毒模型后,随机分为模型组、依地酸钠钙(EDTA)组和低、中、高剂量组。EDTA组兔静脉输注剂量为93.5 mg/kg体质量的EDTA二钾,3个剂量组兔依次予静脉输注剂量为12.0、36.0和108.0 mg/kg体质量的GMDTC,对照组(另设)和模型组兔均静脉输注等体积0.9%氯化钠溶液,每周连续给药5 d,分别给药1、2和4周。(2)毒性试验。将无特定病原体级SD大鼠随机分为溶剂对照组和低、中、高剂量组。急性毒性试验中,3个剂量组大鼠依次予一次性静脉输注剂量为200.0、800.0和3000.0 mg/kg体质量的GMDTC;长期毒性试验中,3个剂量组大鼠依次予静脉输注剂量为100.0、500.0、2000.0 mg/kg体质量的GMDTC,1次/d,连续4周,恢复期为4周;溶剂对照组大鼠同期静脉输注等体积0.9%氯化钠溶液。分别确定最大耐受剂量(MTD)和无可见有害作用水平(NOAEL)。结果(1)给药1周实验中,3个剂量组兔24 h尿镉水平均高于模型组(P值均<0.05)。给药2周实验中,中、高剂量组兔3个时间点24 h尿镉水平均高于同时间点的模型组(P值均<0.05)。给药4周实验中,低剂量组兔第19天24 h尿镉水平高于同时间点的模型组(P<0.05);除中剂量组第5天外,中、高剂量组兔5个时间点24 h尿镉水平均高于同时间点的模型组(P值均<0.05)。与模型组比较,给药4周的低剂量组和给药1、2和4周的中、高剂量组兔肾镉水平均下降(P值均<0.05)。给药期间均未观察到明显不良作用。(2)大鼠静脉注射GMDTC单次给药MTD为3000.0 mg/kg体质量。大鼠连续4周静脉输注GMDTC时,首次和末次给药结束时(8 min)血药浓度均达到峰浓度,期间未观察到临床不良反应,且未见明显蓄积;大鼠连续4周静脉输注的NOAEL为500.0 mg/kg体质量。结论注射用GMDTC制剂对镉模型兔的起始剂量为36.0 mg/kg体质量,推荐人用起始剂量为480.0 mg/人。注射用GMDTC制剂具有吸收迅速、快速消除、不蓄积的安全特性。

Objective To investigate the initial dose and safety of intravenous infusion of sodium(s)-2-(dithiocarboxylato((2R,3R,4R,5R,6R)-2,3,4,5,6-pentahydroxyhexyl)amino)-4-(methylthio)butanoate(GMDTC)for the displacement of cadmium.Methods i)Efficacy test.The New Zealand male rabbits were randomly divided into model group,calcium disodium edetate(EDTA)group and GMDTC low-,medium-and high-dose groups after cadmium poisoning using 2.5 cadmium chloride dihydrate.Rabbits in EDTA group were intravenously injected with EDTA dipotassium at a dose of 93.5 mg/kg body weight,rabbits in the three doses groups were intravenously injected of GMDTC at doses of 12.0,36.0,and 108.0 mg/kg body weight,respectively.The rabbits in the control group(separate set)and model group were intravenously injected with equal volumes of 0.9%sodium chloride solution,administered for five consecutive days per week for 1,2,and 4 weeks.ii)Toxicity test.Specific pathogen free SD rats were randomly divided into solvent control group and low-,medium-and high-dose groups.In the acute toxicity test,the rats in the three-dose groups were intravenously injected of GMDTC at doses of 200.0,800.0 and 3000.0 mg/kg body weight,respectively.In the long-term toxicity test,the rats in the three-dose groups were intravenously injected GMDTC at doses of 100.0,500.0 and 2000.0 mg/kg body weight,respectively,once a day for four consecutive weeks,with a recovery period of four weeks.The rats in the solvent control group were given an equal volume 0.9%sodium chloride solution intravenously at the same time.The maximum tolerated dose(MTD)and no observable adverse effect level(NOAEL)were detected.Results i)In the one week treatment experiment,the 24 hours urinary cadmium levels of rabbits in the three doses groups were higher than those in the model group at the same time point(all P<0.05).In the two weeks treatment experiment,the 24 hours urinary cadmium levels of rabbits in medium-dose and high-dose groups at the three time points were higher than those in the model group at the same time point(all P<0.05).In the four weeks treatment experiment,the 24 hours urinary cadmium level on the 19th day of rabbits in the low-dose group was higher than that in the model group at the same time point(P<0.05),and the 24 hours urinary cadmium levels of rabbits in medium-and high-dose groups at the five time points were higher than those in the model group at the same time point(all P<0.05),except for the rabbits of fifth day of the medium-dose group.The kidney cadmium levels of rabbits in the low-dose group after four week of treatment and in the medium-and high-dose groups after one,two,and four weeks of treatment decreased compared with the model group(all P<0.05).No obvious adverse effects were observed during the treatment.ii)The MTD of GMDTC in rats administered intravenously in a single dose was 3000.0 mg/kg body weight.During the period of intravenous infuseion with GMDTC for four consecutive weeks,the blood drug level reached the peak at the end of the first and last administrations(eight min),and no clinical adverse reactions were observed during this period of time,nor was there any apparent accumulation.The NOAEL for intravenous infusion of GMDTC for four consecutive weeks in rats was 500.0 mg/kg body weight.Conclusion The initial dose of the GMDTC injection in the cadmium poisoning rabbit was 36.0 mg/kg body weight,and the recommended initial dose for human is 480.0 mg/person.Intravenous infusion of GMDTC is characterized by rapid absorption,rapid elimination,and no accumulation.