MECHANISMS FOR ALTERING PARAQUAT TOXICITY

这项拟议的研究的目的是调查这些机制。 通过这种方法可以防止百草枯的促氧化毒性 使用新型化学制剂进行预防性治疗。尽管 超氧化物歧化酶的使用已在 文献中，几乎没有研究过其他相互作用，除了 饮食习惯改变或营养不足。虽然涉及面广 现有关于百草枯的出版物，没有解药疗法 血液透析或血液置换似乎是有效的。 在鸡和老鼠身上的实验表明是阴性的。 关节炎药物与促氧化剂的相互作用 化学物质，如百草枯。预防百草枯中毒是 通过在饮食中添加Ebselen，一种新型的抗肿瘤药物 具有谷胱甘肽过氧化物酶活性的炎性物质或 同时注射青霉胺。初步实验 提示1)小剂量预防百草枯中毒 青霉胺和大剂量增强致命性，2)意想不到的 肌肉注射玉米油的实质保护作用 口服百草枯，以及3)逆转玉米油的保护作用 在玉米油中肌肉注射高剂量的依布硒。目前的研究 将集中在最后两个因素上来确定 注射用和口服依布塞林对百草枯毒性的影响 在鼠标中理解定义其 解毒剂与百草枯的毒性相互作用。预期 实验是1)玉米油和其他亚油酸的效果- 多不饱和油脂对百草枯毒性的影响2)口服的影响 与注射依贝塞林相比，百草枯毒性，3)改变 百草枯在Ebselen和玉米油中的药代动力学 肠/血浆和血浆/肺；4)百草枯的修饰 环氧合酶和脂氧合酶的毒性 不含玉米油的两种脂肪氧合酶抑制 使用和不使用玉米油都可以作为脂肪氧合酶的对照 依布硒的灭活作用及注射后可能的影响 玉米油对肺前列腺素和白三烯的影响。

The purpose of the proposed study is to investigate the mechanisms by which paraquat's prooxidant toxicity can be prevented through prophylactic treatment with novel chemical agents. Although the use of superoxide dismutase has been widely reviewed in the literature, few other interactions have been examined except for diet modification or nutritional deficiencies. Although extensive publications on paraquat exist, no antidotal therapies short of hemodialysis or blood replacement appear to be effective. Experiments in the chicken and the mouse have indicated negative interactions between arthritis medications and prooxidant chemicals, such as paraquat. Prevention of paraquat toxicity is accomplished through dietary addition of Ebselen, a novel anti- inflammatory agent with glutathione peroxidase activity or simultaneously administered penicillamine. Preliminary experiments in the mouse indicate 1) Low dose prevention of paraquat toxicity by penicillamine and high dose enhanced lethality, 2) an unexpected substantial protection of intramuscularly injected corn oil against oral paraquat, and 3) reversal of corn oil's protective effect by high intramuscular doses of Ebselen in corn oil. The present study will concentrate on the last two factors to determine the role of injected oils and injected versus oral Ebselen on paraquat toxicity in the mouse to understand the mechanisms which define their antidotal versus toxic interactions with paraquat. Expected experiments are 1) effects of corn oil and other linoleic- polyunsaturated oils on paraquat toxicity, 2) influence of oral versus injected Ebselen on paraquat toxicity, 3) alterations in paraquat pharmacokinetics by Ebselen and corn oil, especially in intestine/plasm and plasma/lung, and 4) modification of paraquat toxicity by cyclooxygenase and lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inhibition with and without corn oil both as a control for the lipoxygenase inactivation effects of Ebselen and possible effects of injected corn oil on lung prostaglandins and leukotrienes.