DMSA--A NEW ORAL ANTIDOTE FOR CHILDHOOD LEAD POISONING

The treatment of childhood lead (Pb) poisoning currently involves hospitalization and the parenteral administration of calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) and dimercaprol (BAL), drugs with potentially serious adverse effects. 2,3-Dimercaptosuccinic acid (DMSA) is an orally (p.o.) active orphan drug which is potentially useful for treating childhood and occupational Pb intoxication. Of the 42 subjects with elevated blood lead (BPb) who have been treated with DMSA at this institution, 39 have received DMSA for only 5 days. While safe and effective, a rebound in BPb has occurred in each case, indicating a need for more prolonged treatment. The proposed studies will extend the DMSA treatment period to three weeks in children with BPb's of 50-69 ug/dl, and will describe the kinetics of the rebound in BPb as compared to those which follow conventional therapy. Furthermore, DMSA metabolism has never been studied in humans with lead intoxication. Through a collaboration with Dr. Vasken Aposhian at the University of Arizona, DMSA metabolism and elimination will be studied in 12 children with BPb's of 50-69 ug/dl and 6 children with BPb's of 70 ug/dl or more. Thus, these studies will expand the pediatric clinical experience with DMSA so as to evaluate safety, metabolism and efficacy in the type of subjects who are most likely to receive the drug if and when it is approved by the FDA. Specifically we propose: 1. To evaluate, in the Clinical Research Center, the metabolism, elimination, pharmacokinetics, safety, and efficacy of DMSA in children with high BPb's. 12 children with BPb's of 50-69 ug/dl, and 6 children with BPb's of 70 ug/dl or more, will receive five- day courses with 1050 mg/m2/day p.o. DMSA in three divided doses daily. Two comparable control groups will receive standard in- hospital therapy with i.v. CaNa2EDTA or i.m. BAL + i.v. CaNa2EDTA, respectively. 2. To evaluate the safety and efficacy of out-patient p.o. DMSA in preventing the rebound in BPb which typically follows treatment in-hospital. The 12 above-mentioned children with initial BPb's of 50-69 ug/dl will, upon discharge from the hospital, be randomized to receive either 350 mg/m2/day p.o. DMSA once daily, or no drug, for 14 days. These children will be seen weekly as out-patients until two weeks after the last dose of DMSA.