ANTIDOTES TO HEAVY METAL POISONING

重金属中毒的解毒剂

基本信息

批准号：
3272944
负责人：
THOMAS W CLARKSON
金额：
$ 14.96万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-03-01 至 1986-06-30
项目状态：
已结题

项目摘要

Most metal poisonings present a formidable challenge to the physician whose arsenal of antidotal procedures has changed little over the last several decades. This proposal is a broad based approach to antidotes for metal poisoning which is geared at the overall increase in elimination of the metal from the body thereby decreasing the incidence and severity of toxic effects. We have taken a three-pronged new approach using two promising agents, DMSA and unithiol. In one approach, the time honored approach use of complexing agents will be studied in animal models which will provide simultaneous kinetic and toxicity data. The excretion of metals by the enteric route will be enhanced using non-absorbable resins with a variety of functional groups designed to bind specific metals in the gastrointestinal tract and speed their elimination. Specific chelating agents designed to be rapidly excreted in the bile will be utilized both alone and in combination with the resins to enhance metal excretion. Finally, since renal and hepatic function may be compromised in metal intoxication, or when rapid removal of the metal is critical the alternate pathway of extracorporeal complexing hemodialysis will be utilized to enhance metal excretion directly from the blood. The choice of a particular approach to detoxification for a specific metal is based both on information gained in illucidating the mechanisms of distribution and excretion of the metal and on the probability of using that particular therapeutic approach in poisoned humans.

大多数金属中毒对医生来说都是一个巨大的挑战过去几年中，解毒程序的武器库几乎没有变化几十年。该提案是一种基础广泛的金属解毒剂方法与金属消除总体增加有关的中毒从体内排出，从而降低毒性作用的发生率和严重程度。我们采取了三管齐下的新方法，使用两种有前途的药物：DMSA 和单位硫醇。在一种方法中，历史悠久的方法是使用络合剂将在动物模型中进行研究，该模型将提供同时的动力学和毒性数据。通过肠道途径的金属排泄将会增强使用具有多种旨在结合的官能团的不可吸收树脂胃肠道中的特定金属并加速其消除。设计用于在胆汁中快速排泄的特定螯合剂将是单独使用或与树脂结合使用以增强金属排泄。最后，由于肾功能和肝功能可能会受到损害金属中毒，或者当快速去除金属至关重要时，替代方法将利用体外复合血液透析途径来增强金属直接从血液中排出。特定方法的选择特定金属的解毒基于以下信息：阐明金属的分布和排泄机制以及在中毒者中使用特定治疗方法的可能性人类。