DMSA--EFFICACY IN REDUCING NEUROBEHAVIORAL TOXICITY

DMSA--减少神经行为毒性的功效

• 批准号: 2684440
• 负责人: BARBARA J STRUPP
• 金额: $ 38万
• 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/2684440
• 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，低水平的铅暴露是 与严重的神经行为缺陷有关。特别的 令人担忧的是，最近的研究发现，即使血铅水平略有上升 儿童早期(BPB)水平与持久认知有关 赤字。这一证据产生了一种迫切的需要，既要减少对 PB并开发更有效的方法来治疗即使是轻微的儿童 血铅水平升高。一种很有希望的新疗法是螯合剂， 二硫代丁二酸(DMSA)。这种药对急性发作非常有效。 降低血铅和组织铅水平。此外，它还可以用来管理 口服，在门诊的基础上，不会引起许多副作用 (例如，锌利尿，痛苦的服药)与目前 可用的螯合剂。就数据而言，还没有研究检验这两种药物的疗效 这种化合物在减轻铅的神经行为毒性方面的作用，或 DMSA本身可能具有行为致畸作用。这类研究是 在该药物被批准广泛使用之前是必不可少的。少校 拟议研究的目的是确定与DMSA的螯合作用 减轻与铅暴露相关的啮齿动物神经行为缺陷 儿童和成人铅暴露的模型。不同的组 分析将安乐死前后的三种DMSA方案 神经行为测量的变化可以与变化相关联 脑组织和血液中的铅含量。关于发展性学习的建议研究 铅暴露的设计是为了与NIEHS最近资助的两项研究平行进行 观察DMSA对大鼠神经行为毒性的影响 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 关于DMSA缓解铅中毒疗效的重要信息 认知功能障碍不会由这两个正在进行的 这应该有助于解释他们的研究结果。简而言之， 这个项目的新贡献，相对于这两个最近资助的项目 研究，包括(1)关于DMSA缓解的剂量反应信息 铅诱导的认知功能障碍；(2)DMSA疗效的检测 PB和DMSA处理条件下血铅水平的作用 被仔细控制和监测，以及社会人口因素 影响认知是可以控制的；(3)联系的机会 神经行为功能随脑铅变化的变化；以及(4) DMSA对改善精神分裂症患者神经行为缺陷的疗效评价 成人铅暴露6例。