PREVENTION OR REVERSAL OF PARAQUAT TOXICITY IN ANIMALS

预防或逆转百草枯对动物的毒性

• 批准号: 3251511
• 负责人: SUSAN M POND
• 金额: $ 15.56万
• 依托单位: QUEENSLAND UNIVERSITY OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-05-01 至 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251511
• 关键词: affinity chromatography; antibody formation; antibody specificity; antidotes; biological models; brain; detoxification; electrofocusing; gel electrophoresis; hemodialysis; histopathology; human therapy evaluation; hybridomas; immunization; immunoglobulins; immunological substance; immunotherapy; insecticide biological effect; kidney function; liver function; model design /development; monoclonal antibody; paraquat; pulmonary fibrosis /granuloma; scintillation counter; statistics /biometry

Paraquat, a widely used herbicide, has caused hundreds of fatalities from pulmonary fibrosis in patients who have ingested as little as a mouthful of the concentrated solution that is marketed commercially. Many antidotes proposed as therapeutic modalities have failed to alter the course and clinical management rests largely on intensive supportive care. However, one therapeutic modality recently employed but not tested adequately in controlled human studies is that of repeated daily hemoperfusion done until paraquat has been removed from the body. Its efficacy probably depends on its removing paraquat from the body and keeping plasma concentration of the compound below those that allow active uptake of paraquat by the pneumocytes leading to their ultimate destruction and replacement by fibrous tissue. This research plan has been designed to determine under controlled conditions whether or not repeated charcoal hemoperfusion alters the course of paraquat toxicity in the Beagle. Clinical signs of pulmonary toxicity will be evaluated as well as laboratory test manifestations and changes on post-mortem examination in pulmonary, renal, hepatic and cerebral function and structure. Complications of hemoperfusion will be assessed and the cost benefit of the procedure in paraquat poisoning determined. In the second set of experiments, a novel approach to the rapid removal of large amounts of paraquat from paraquat-poisoned mice will be developed and tested. This will be effected by producing murine hybridomas that produce monoclonal antibodies of high specificity and affinity for paraquat. These antibodies will be reduced in size by papain digestion to produce Fab fragments which can be eliminated by the kidney. The efficacy of the antiparaquat Fab fragments in preventing lethality or the pulmonary fibrosis, and on paraquat tissue distribution will be determined in mice given a lethal intravenous injection of paraquat. The ultimate significance of this research extends beyond examination of the ability of these two techniques to remove paraquat from the body to many other intoxicants.

广泛使用的除草剂百草枯已导致数百人死亡 仅摄入一口水的患者的肺纤维化 商业销售的浓缩溶液。许多解毒剂 所提出的治疗方法未能改变这一进程， 临床管理在很大程度上取决于强化的支持性护理。然而， 最近使用的一种治疗方式，但没有在 受控人体研究是指每天重复进行血液灌流，直到 百草枯已被从体内移除。它的疗效可能取决于 它能清除体内的百草枯，并保持血浆中的药物浓度 下面的化合物允许主动摄取百草枯 导致肺泡细胞的最终破坏和替换 纤维组织。这项研究计划旨在确定 反复木炭血液灌流是否改变受控条件 百草枯在小猎犬体内的中毒过程。肺部疾病的临床体征 将评估毒性以及实验室测试表现和 肺、肾、肝和肺的尸检变化 大脑的功能和结构。血液灌流的并发症将是 百草枯中毒救治方法的评估及成本效益 下定决心。在第二组实验中，一种新的方法 从百草枯中毒小鼠体内快速清除大量百草枯将 需要开发和测试。这将通过生产小鼠来实现 产生高度特异性和特异性的单抗的杂交瘤 对百草枯的亲和力。这些抗体会被木瓜酶缩小。 消化产生可被肾脏清除的Fab片段。 抗百草枯Fab片段预防致死性肺炎的效果 肺纤维化，并对百草枯组织分布有影响 在静脉注射致死百草枯的小鼠身上测定。这个 这项研究的终极意义超越了对 这两种技术能够将百草枯从体内清除到许多 其他麻醉剂。