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，低水平的铅（Pb）暴露 与严重的神经行为缺陷有关 特别 令人担忧的是，最近发现，即使是轻微的血铅升高， (BPb)儿童早期的认知水平与 赤字 这一证据表明，迫切需要减少暴露于 铅和发展更有效的手段，治疗儿童，即使是轻微的 BPb水平升高。 一种有希望的新疗法是螯合剂， 二巯基丁二酸（DMSA）。 这种药对急性 降低BPb和组织Pb水平。 此外，它可以被管理 口服，在门诊的基础上，并不会引起许多副作用， (e.g.锌利尿，疼痛管理）与目前 可用的螯合剂。 根据数据，没有研究检查过 这种化合物在减轻铅的神经行为毒性，或 DMSA本身可能的行为致畸性。 此类研究 在药物被批准广泛使用之前是必不可少的。 主要 拟议研究的目的是确定是否与DMSA螯合 减轻了啮齿动物铅暴露相关的神经行为缺陷 儿童和成人铅暴露模型。 组独立的 将在三种DMSA方案之前和之后实施安乐死， 神经行为指标的变化可能与 大脑和血液中铅含量的变化。 拟议的发展研究 铅暴露的目的是平行的两项研究最近资助的NIEHS， 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。 拟议项目将提供 有关DMSA缓解铅诱导的功效的重要信息 认知功能障碍，将不会提供任何这些正在进行的 研究，这应该有助于解释他们的结果。 采用离体垂体碎片 新的贡献，这个项目，相对于这两个最近资助 研究，包括（1）关于DMSA在减轻 铅诱导的认知功能障碍;（2）检查DMSA的疗效， 在铅和DMSA处理可以 仔细控制和监测，社会人口因素 影响认知是可以控制的;（3）联系的机会 神经行为功能的变化对脑铅的变化;（4） 评估DMSA在缓解神经行为缺陷方面的疗效 成人铅暴露病例。