SUCCIMER REDUCTION OF TISSUE PB AND TOXICITY

迫切需要验证螯合剂的功效， 作为琥珀酰（二巯基琥珀酸，DMSA），不仅可以减少体内铅 商店在幼儿，而且还减轻神经行为和目标 器官毒性这一多学科的提案检验了以下假设： 琥珀酰亚胺治疗将减弱铅对神经行为和 器官系统毒性，因为它减少了身体铅负荷。拟议 研究，这些研究与最近启动的儿科人类临床试验平行 (RFP NIH-ES 92-32），将使用恒河猴作为一个完善的， 非人类灵长类动物儿童期铅暴露模型。治疗组将 分为不接触铅（对照组）、一年每日接触铅 每日摄入量和两年的铅摄入量。电极导线给药将开始 在出生时。接受铅的猴子将维持在目标血 在铅摄入期间，铅浓度为35微克铅/天福尔斯 接近计划中的琥珀酰亚胺临床试验的中等水平。政权 对于琥珀酰亚胺治疗将遵循为人类选择的治疗 临床试验猴子将接受三种琥珀酰亚胺治疗方案 在大约12、16和18个月大时开始。药组 导致直到两岁将平行的情况下，一个孩子是 在螯合治疗后回到铅污染的环境中。 琥珀酰亚胺在逆转神经行为缺陷方面的疗效将被评估。 使用广泛的行为测试进行监测， 三种螯合疗法的过程和完成所有 螯合作用，后者用于评估琥珀酰亚胺的长期疗效 神经行为过程的治疗。铅诱导的血红素变化 生物合成途径将被用作系统性的敏感生物标志物。 器官铅中毒。一种已建立的稳定铅同位素技术将是 用于测定骨骼和软组织中铅的清除量 店K-X射线荧光技术将用于评估长期 青少年铅螯合治疗后骨铅减少的变化 猴子猴子研究将利用严格控制的环境 条件研究结果应提供有价值的解释 关于琥珀酰亚胺缓解 儿童神经行为学和靶器官毒性。

There is a pressing need to validate the efficacy of chelation agents such as succimer (dimercaptosuccinic acid, DMSA) not only to reduce body lead stores in young children but also to alleviate neurobehavioral and target organ toxicity. This multidisciplinary proposal tests the hypothesis that succimer therapy will attenuate the effects of lead on neurobehavioral and organ system toxicity as it reduces the body lead burden. The proposed studies, which parallel recently initiated pediatric human clinical trials (RFP NIH-ES 92-32), will use the rhesus monkey as a well-established, nonhuman primate model of childhood lead exposure. Treatment groups will be divided into no lead exposure (controls), one year of daily lead intake, and two years of daily lead intake. Lead administration will begin at birth. The monkeys receiving lead will be maintained at a target blood lead concentration of 35 micrograms Pb/d during lead intake, which falls near the midrange of the planned clinical trials of succimer. The regime for succimer treatment will follow the treatment chosen for the human clinical-trials. Monkeys will receive three treatment regimes of succimer beginning at approximately 12, 16, and 18 months of age. The groups given lead until two years of age will parallel cases in which a child is returned to a lead contaminated environment following chelation therapy. The efficacy of succimer in reversing neurobehavioral deficits will be monitored using a broad range of behavioral tests administered over the course of the three chelation therapies and after completion of all chelations, the latter to evaluate the long term efficacy of succimer therapy on neurobehavioral processes. Lead-induced alterations in the heme biosynthetic pathway will be used as a sensitive biomarker of systemic organ lead toxicity. An established stable-lead isotope technique will be used to determine the removal of lead from skeletal and soft tissue stores. K-X-ray fluorescence techniques will be used to assess long-term changes in reduction of skeletal lead due to chelation in adolescent monkeys. The monkey studies will utilize tightly controlled environmental conditions. Results of the studies should provide valuable interpretive scientific data concerning the efficacy of succimer to alleviate neurobehavioraI and target organ toxicity in children.