SUCCIMER REDUCTION OF TISSUE PB AND TOXICITY

迫切需要验证螯合剂的有效性，如 作为琥珀酸(二硫代丁二酸，DMSA)不仅能降低体内铅含量 存储在幼儿身上，也是为了缓解神经行为和靶向 器官毒性。这一多学科的提议检验了这样一个假设 琥珀酸治疗将减弱铅对神经行为和神经功能的影响 器官系统毒性，因为它减少了身体的铅负担。建议数 与最近启动的儿科人类临床试验平行的研究 (RFP NIH-ES 92-32)，将使用恒河猴作为一种成熟的， 儿童铅暴露的非人灵长类动物模型。治疗小组将 分为无铅暴露(对照)、一年每日含铅量 摄入量，以及两年的每日铅摄入量。领导行政将开始 在出生的时候。接受铅的猴子将维持在目标血液中 铅摄入期间，铅浓度为35微克/天，这将导致 接近计划中的琥珀酸临床试验的中档。该政权 继发治疗将遵循为人类选择的治疗方法 临床试验。猴子将接受三种琥珀酸治疗方案 从大约12个月、16个月和18个月开始。给出的组 直到两岁前的铅将平行于儿童 经过螯合治疗后，回到了铅污染的环境中。 琥珀酸单抗逆转神经行为缺陷的疗效将是 使用一系列在 三种螯合疗法的疗程及全部完成后 螯合作用，后者用于评价琥珀酸类药物的长期疗效 神经行为过程的治疗。铅引起的血红素改变 生物合成途径将作为系统性疾病的敏感生物标志物 器官铅中毒。一项成熟的稳定铅同位素技术将是 用于测定骨骼和软组织中铅的排除量 商店。将使用K-X-射线荧光技术评估长期 青春期因螯合作用引起的骨铅还原变化 猴子。猴子研究将利用严格控制的环境 条件。研究的结果应该提供有价值的解释 关于琥珀酸类药物疗效的科学数据 儿童的神经行为和靶器官毒性。

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.