PREVENTION OR REVERSAL OF PARAQUAT TOXICITY IN ANIMALS

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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.