GMDTC驱镉剂量研究

Study on the dosage of GMDTC for removing cadmium

目的探讨静脉滴注驱镉剂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)不同剂量下的驱镉效果。方法雄性新西兰兔随机分为空白对照组、GMDTC高剂量对照组、模型对照组、依地酸钠钙(EDTA)对照组和GMDTC低、中、高剂量组,每组5只。空白对照组和GMDTC高剂量对照组新西兰兔分别经耳缘静脉予0.90%氯化钠注射液,模型对照组、EDTA对照组和3个GMDTC剂量组新西兰兔分别经耳缘静脉予浓度为2μmol/kg氯化镉及浓度为40μmol/kg的β-巯基乙醇的混合溶液,给药量为5.0 mL/kg体质量,1次/d,连续5 d。于造模第41天即治疗第1天,空白对照组和模型对照组新西兰兔均经耳缘静脉予0.90%氯化钠注射液250 mL,EDTA对照组新西兰兔予剂量为93.5 mg/kg体质量的EDTA溶液,GMDTC高剂量对照组和3个GMDTC剂量组新西兰兔分别予剂量为108.0、12.0、36.0、108.0 mg/kg体质量的GMDTC溶液,1次/d,6次/周,连续4周。检测各组新西兰兔治疗前后尿β_2-微球蛋白(β_2-MG)、肾镉、血镉和尿镉水平。结果实验期间,新西兰兔体质量随饲养时间的增加而增加(P<0.01)。模型对照组、EDTA对照组和3个GMDTC剂量组新西兰兔治疗前尿β_2-MG水平均高于空白对照组(P<0.05)。GMDTC中、高剂量组新西兰兔治疗后肾镉水平均低于模型对照组和EDTA对照组(P<0.05)。EDTA对照组和3个GMDTC剂量组新西兰兔治疗后的血镉水平均低于同组治疗前(P<0.05),且均低于治疗后的模型对照组(P<0.05);GMDTC中、高剂量组和EDTA对照组新西兰兔治疗后血镉水平两两比较,差异均无统计学意义(P>0.05)。治疗后各时间点(治疗后第1、6、8、13、15、20、22和28天)的新西兰兔尿镉水平,在EDTA对照组和3个GMDTC剂量组均低于同时间点模型对照组(P<0.05);治疗后除第20和22天外,其余6个时间点新西兰兔尿镉水平均随GMDTC剂量的增加而增加(P<0.05)。GMDTC低、中、高剂量组新西兰兔治疗后血镉驱除率分别为70.06%、74.86%和78.05%,肾镉驱除率分别为14.27%、27.95%和61.24%。结论 GMDTC静脉滴注剂量为108.0 mg/kg体质量对镉中毒兔模型(相当于人用剂量36.0 mg/kg体质量)的驱镉效果显著,未见明显毒性反应,具备成药性基本要求。

Objective To explore different doses of sodium（s）-2-（dithiocarboxylato（（2R,3R,4R,5R,6R）-2,3,4,5,6-pentahydroxyhexyl） amino）-4-（methylthio） butanoate （GMDTC） for removing cadmium.Methods Thirty-five male New Zealand rabbits were randomly divided into blank control group,GMDTC high dose control group,model control group,ethylene diamine tetraacetic acid （EDTA） control group and GMDTC low,medium and high dose groups,five rabbits in each group.The blank control group and GMDTC high dose control group were given 0.90% normal saline solution intravenously;model control group,EDTA control group and GMDTC low,medium and high dose group were given 2 μmol/kg of cadmium chloride （CdCl2） and 40 μmol/kg of β-mercaptoethanol mixed solution intravenously,5.0 mL/kg body weight （bw）,once a day for five days.On the forty-one day of the experiment （the fist day of GMDTC treatment）,the control group and the model control group were injected 0.90% normal saline solution 250 mL via ear vein,the EDTA control group was given EDTA solution at the dose of 93.5 mg/kg bw with 250 mL 0.90% normal saline solution,also via ear vein;the GMDTC high dose control group,and the GMDTC low,medium and high dose groups were given 250 mL GMDTC solution at the concentration of 108.0,12.0,36.0 and 108.0 mg/kg bw with 0.90% normal saline by intravenous infusion,once a day,6 times a week for four consecutive weeks.The urine β2-microglobulin （MG）,renal cadmium,blood cadmium,and urinary cadmium before and after the treatment were detected.Results The body weight of New Zealand rabbits increased with the increasing feed time （P〈0.01）.The levels of β2-MG before treatment increased in model control group,EDTA control group,GMDTC low,medium and high dose groups than that in the blank control group （P〈0.01）.The levels of renal cadmium after treatment in GMDTC medium and high dose groups decreased compared with those in the blank control group and EDTA control group respectively （P〈0.05）.The blood cadmium after treatment in EDTA control group,GMDTC low,medium and high dose groups were decreased compared with those before treatment in the same group respectively （P〈0.05）,meanwhile decreased than the blood cadmium after treatment in the model control group respectively （P〈0.05）.The blood cadmium after treatment had not a statistically significant difference among the EDTA control group,GMDTC medium and high dose groups （P〈0.05）.At all the time points （1,6,8,13,15,20,22 and 28 days after treatment）,the urinary cadmium after treatment in EDTA control group and the three GMDTC dose groups increased compared to the model control group at the same time （P〈0.05）.The urinary cadmium after treatment increased with GMDTC dose increased at the other six time points,expect on 20 and 22 days after treatment （P〈0.05）.The blood cadmium removal rates after treatment were 70.06%,74.86% and 78.05% and the renal cadmium removal rates were 14.27%,27.95% and 61.24% in GMDTC low,medium and high dose groups,respectively.Conclusion The intravenous infusion of GMDTC at the dose of 108.0 mg/kg bw effectively removed cadmium in cadmium poisoning rabbit.This dose had no obvious toxic effect and was equivalent to human dose of 36.0 mg/kg bw which meets the requirement of new drug property.