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: 3251509
• 负责人: SUSAN M POND
• 金额: $ 13.44万
• 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/3251509
• 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.

百草枯是一种广泛使用的除草剂，已造成数百人死亡 只摄入一口的患者就会出现肺纤维化 市售的浓缩溶液。 许多解药 提出的治疗方式未能改变病程并且 临床管理主要依靠重症支持护理。 然而， 最近采用的一种治疗方式，但尚未在 对照人体研究是每天重复进行血液灌流，直到 百草枯已从体内清除。 其功效大概取决于 它将百草枯从体内清除并保持血浆浓度 低于允许百草枯被人体主动吸收的化合物 肺细胞最终被破坏并被替换 纤维组织。 该研究计划旨在确定 控制条件，无论重复的木炭血液灌流是否改变 百草枯对小猎犬的毒性过程。 肺部疾病的临床症状 将评估毒性以及实验室测试表现和 死后检查肺、肾、肝等指标的变化 脑功能和结构。 血液灌流的并发症是 百草枯中毒处理程序的评估和成本效益 决定。 在第二组实验中，一种新颖的方法 从百草枯中毒小鼠体内快速清除大量百草枯将 进行开发和测试。 这将通过产生小鼠来实现 产生高特异性单克隆抗体的杂交瘤 对百草枯的亲和力。 这些抗体会被木瓜蛋白酶缩小 消化产生可被肾脏消除的 Fab 片段。 抗百草枯 Fab 片段在预防致死或死亡方面的功效 肺纤维化，以及百草枯组织分布 在静脉注射百草枯致死的小鼠中进行测定。 这 这项研究的最终意义超出了对 这两种技术能够将百草枯从许多人体内清除 其他麻醉品。