ALUMINUM TOXICITY--CHELATOR IDENTIFICATION AND SAFETY

长期目标是确定口服有效的铝螯合剂， 在动物中对Al和安全性有足够的选择性，以保证在 人类用于预防和治疗铝积累障碍。 一个 理想的铝螯合剂将克服去铁胺的局限性，即 口服疗效差，成本高，毒性大。 Al 药物的肠胃外给药导致积累， 肾功能受损患者长期使用铝基磷酸盐结合剂 以及工业工人暴露在铝烟雾中。 Al的作用 阿尔茨海默氏症和其他痴呆症正在调查中 并且是有争议的。 一个安全的铝螯合剂与持续的疗效可能有助于 确定铝在这些疾病中的作用。 的具体目标 本申请是为了检验系统可用性， Al螯合剂的功效和安全性与其亲脂性有关。 螯合剂和Al-螯合剂络合物导致Al从 储存地点，以安全地诱导铝消除和减少铝毒性。 口服有效金属化合物3-羟基吡啶-4-酮的8个类似物 将研究螯合剂。 它们的亲脂性从低到高不等 假设的理想范围。 每种类似物的口服生物利用度将 在家兔中定量，以确定 亲脂性和吸收。 类似物将以单剂量进行测试 iv研究，以测定体内铝螯合活性， 其表现为血清铝和胆汁或尿铝排出量增加。 选择 增加铝消除的口服吸收类似物将被反复地 给铝负荷兔，以确定其持续口服铝 螯合功效，如通过在重复施用后增加的Al消除所证明的 安全性和逆转铝诱导的细胞凋亡的能力 毒性将通过组织病理学、血液学和骨 组织学和组织形态测量。 Al的特异性 螯合作用将通过对所选液体的多元素分析进行评估 和纸巾。 有效性和安全性结果将与 亲脂性，以确定最佳的亲脂性 3-羟基吡啶-4-酮。 这些结果可能会识别出那些 在人类中进行测试，并将有力地指导未来的设计和选择 结构不同的化合物作为潜在的铝螯合剂。

The long-term goal is to identify orally effective aluminum chelators with sufficient selectivity for Al and safety in animals to warrant testing in humans for the prevention and treatment of Al accumulation disorders. An ideal Al chelator will overcome the limitations of desferrioxamine, namely lack of oral efficacy, its relatively high cost and toxicity. Al accumulation results from parenteral administration of pharmaceuticals, prolonged consumption of Al-based phosphate binders by the renally impaired and exposure of industrial workers to Al fumes. The role of Al in Alzheimer's disease and other dementing disorders is under investigation and is controversial. A safe Al chelator with continued efficacy may help determine the role of Al in these diseases. The specific aim of the present application is to test the hypothesis that systemic availability, efficacy and safety of Al chelators relates to the lipophilicity of the chelator and the Al-chelator complex results in Al mobilization from storage sites to safely induce Al elimination and reduce Al toxicity. Eight analogs of 3-hydroxypyridin-4-one, a family of orally effective metal chelators, will be studied. Their lipophilicity ranges from below to above the hypothesized ideal range. The oral bioavailability of each analog will be quantitated in rabbits to determine the relationship between lipophilicity and absorption. The analogs will be tested in a single dose iv study in Al-loaded rabbits to determine in vivo Al chelation activity, evidenced by increased serum Al and biliary or urinary Al output. Selected orally absorbed analogs that increase Al elimination will be repeatedly administered to Al-loaded rabbits to ascertain their continued oral Al chelation efficacy as evidenced by increased Al elimination after repeated treatment and decreased tissue Al. Safety and ability to reverse Al-induced toxicity will be assessed by histopathological, hematological and bone histological and histomorphometric measurements. Specificity of Al chelation will be assessed by multiple element analysis of selected fluids and tissues. Efficacy and safety results will be correlated to lipophilicity to identify the optimal lipophilicity of the 3-hydroxypyridin-4-ones. The results may identify compounds that warrant testing in humans and will strongly guide the future design and selection of structurally dissimilar compounds as potential Al chelators.