DMSA, DMPS AND OTHER ORALLY ACTIVE DITHIOL CHELATORS

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The water soluble dithiol chelating agent, DMSA, DMPS and DMPA are receiving increasing acceptance and therapeutic use in the Western world. DMSA has been classified by the FDA as an orphan drug for treating lead intoxication. DMSA and DMPS are now undergoing clinical evaluation for treating children with elevated blood levels of lead. According to NHANES II, the number of such children is not small. DMPA appears to be very effective in preventing 210polonium accumulation in the kidney. 210po is a decay daughter of radon. Analytical procedures have been developed to allow the study of these dithiols and their biotransformants. It is planned to isolate the biotransformants and determine their structure. The urinary metal chelates of these dithiols will be isolated and their structure determined. Using direct current plasma emission spectrometry, the metals and metalloids that are excreted after dithoils are given will be determined sequentially. This is an interdisciplinary project in which a Professor of Molecular Biology, Cell Biology and Pharmacology will interact with a Professor of Chemistry to obtain as much metabolic and physico-chemical information about these unusual agents used to treat metal intoxicaton. A new hghly sensitive and selective analytical assay using monobromo bimane, HPLC and fluorescence is the foundation of these studies. A new approach to the use of these dithiols will be investigated. The dithiol chelate of an essential metal will be sought which is less stable than the Pb, Hg or As dithiol chelate. Thus when the essential metal chelate is given, the essential metal might be replaced by the heavy metal and the heavy metal chelate will be excreted. In addition the influence of these dithiols on the metabolci pools of endogenous thiols such as glutathione and cysteine will be investigated. These dithiols may indirectly influence the biosynthesis of endogenous thiols and may have a protective effect in preventing their oxidation.