DMSA--EFFICACY IN REDUCING NEUROBEHAVIORAL TOXICITY

DMSA--减少神经行为毒性的功效

• 批准号: 2391621
• 负责人: BARBARA J STRUPP
• 金额: $ 17.08万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2391621
• 关键词: behavior test; chelation therapy; cognition disorders; detoxification; developmental neurobiology; disease /disorder model; dosage; laboratory rat; lead poisoning; mature animal; neurotoxins; nonhuman therapy evaluation; pharmacokinetics; statistics /biometry; succinates; teratogens

There is increasing evidence that low-level lead (Pb) exposure is associated with significant neurobehavioral deficits. Of particular concern is the recent finding that even slight elevations in blood lead (BPb) level in early childhood are associated with enduring cognitive deficits. This evidence creates a pressing need to both reduce exposure to Pb and develop more effective means of treating children with even slightly elevated BPb levels. One promising new therapy is the chelating agent, dimercaptosuccinic acid (DMSA). This drug is highly effective in acutely reducing BPb and tissue Pb levels. Moreover, it can be administered orally, on an outpatient basis, and does not cause the many side effects (e.g. zinc diuresis, painful administration) associated with currently available chelators. To data, no studies have examined either the efficacy of this compound in alleviating the neurobehavioral toxicity of Pb, or the possible behavioral teratogenicity of DMSA itself. Such studies are essential before the drug can be approved for widespread use. The major purpose of the proposed studies is to determine if chelation with DMSA lessens the neurobehavioral deficits associated with Pb exposure in rodent models of both childhood and adult Pb exposure. Separate groups of analyzed will be euthanized before and after the three DMSA regimens so that changes in the neurobehavioral measures can be correlated with changes in Pb level in both brain and blood. The proposed study of developmental Pb exposure is designed to parallel two studies recently funded by NIEHS to examine the efficacy of DMSA in alleviating the neurobehavioral toxicity of Pb: a multicenter pediatric trial (REP NIH-ES 92-93) and a similar study using a non-human primate model. The proposed project will provide important information about the efficacy of DMSA in alleviating Pb-induced cognitive dysfunction that will not be provided by either of these ongoing studies and that should aid in interpreting their results. Briefly, the novel contributions of this project, relative to these two recently funded studies, include (1) dose response information about DMSA in alleviating Pb-induced cognitive dysfunction; (2) examination of DMSA efficacy as a function of BPb level under conditions in which pb and DMSA treatment can be carefully controlled and monitored, and sociodemographic factors affecting cognition can be controlled; (3) the opportunity to relate changes in neurobehavioral function to changes in brain Pb; and (4) assessment of DMSA efficacy in alleviating neurobehavioral deficits in cases of adult Pb exposure.

越来越多的证据表明，低浓度的铅 (Pb) 暴露 与显着的神经行为缺陷有关。 特别是 令人担忧的是最近发现即使血铅轻微升高 幼儿期 (BPb) 水平与持久认知能力相关 赤字。 这一证据表明迫切需要减少接触 并开发更有效的方法来治疗儿童，即使是轻微的铅 BPb 水平升高。 一种有前途的新疗法是螯合剂， 二巯基丁二酸（DMSA）。 这种药对于急性发作非常有效 降低 BPb 和组织 Pb 水平。 此外，还可以管理 口服，门诊治疗，不会引起许多副作用 （例如锌利尿、痛苦的给药）与当前相关 可用的螯合剂。 就数据而言，没有研究检验过其功效 该化合物减轻铅的神经行为毒性，或 DMSA 本身可能具有行为致畸性。 此类研究是 在药物被批准广泛使用之前至关重要。 主要 拟议研究的目的是确定是否与 DMSA 螯合 减轻啮齿动物与铅暴露相关的神经行为缺陷 儿童和成人铅暴露模型。 分开的组 分析者将在三种 DMSA 方案之前和之后被安乐死，因此 神经行为测量的变化可能与变化相关 大脑和血液中的铅含量。 拟议的发展研究 铅暴露旨在与 NIEHS 最近资助的两项研究并行 检查 DMSA 在减轻神经行为毒性方面的功效 Pb：一项多中心儿科试验 (REP NIH-ES 92-93) 和一项类似研究 使用非人类灵长类动物模型。 拟议的项目将提供 有关 DMSA 缓解 Pb 诱导的功效的重要信息 认知功能障碍不会由这些持续的任何一个提供 研究，这应该有助于解释他们的结果。 简而言之， 相对于最近资助的这两个项目，该项目的新颖贡献 研究，包括 (1) 有关 DMSA 缓解的剂量反应信息 铅引起的认知功能障碍； (2) DMSA功效检验 在 pb 和 DMSA 处理可以的条件下 BPb 水平的函数 受到仔细控制和监测，以及社会人口因素 影响认知是可以控制的； (3) 交往的机会 神经行为功能的变化导致脑铅的变化；和（4） DMSA 缓解神经行为缺陷的功效评估 成人铅暴露案例。