Succimer is currently FDA approved for the treatment of children with blood lead concentrations >45 mcg/dL, but it is also commonly used in adults. The typical dosage is 10 mg/kg orally three times a day. Oral administration of succimer is comparable to parenteral EDTA in reducing blood lead concentration and has supplanted EDTA in outpatient treatment of patients who are capable of absorbing the oral drug. However, despite the demonstrated capacity of both succimer and EDTA to enhance lead elimination, their value in reversing established lead toxicity or in otherwise improving therapeutic outcome has yet to be established by a placebo-controlled clinical trial. In a recent study in lead-exposed juvenile rats, high-dose succimer did reduce lead-induced neurocognitive impairment when administered to animals with moderateand high-dose lead exposure. Conversely, when administered to the control group that was not lead exposed, succimer was associated with a decrement in neurocognitive performance. Based on its protective effects against arsenic in animals and its ability to mobilize mercury from the kidney, succimer has also been used in the treatment of arsenic and mercury poisoning.
In limited clinical trials, succimer has been well tolerated. It has a negligible impact on body stores of calcium, iron, and magnesium. It induces a mild increase in urinary excretion of zinc and, less consistently, copper. This effect on trace metal balance has not been associated with overt adverse effects, but its longterm impact on neurodevelopment is uncertain. Gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea, are the most common side effects, occurring in <10% of patients. Rashes, sometimes requiring discontinuation of the medication, have been reported in <5% of patients. Mild, reversible increases in liver aminotransferases have been noted in <5% of patients, and isolated cases of mild to moderate neutropenia have been reported.
EDETATE CALCIUM DISODIUM (ETHYLENEDIAMINETETRAACETIC ACID, EDTA)
Ethylenediaminetetraacetic acid (Figure 57–2) is an efficient chelator of many divalent and trivalent metals in vitro. To prevent potentially life-threatening depletion of calcium, treatment of metal intoxication should only be performed with the calcium disodium salt form of EDTA (edetate calcium disodium).
EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular metal ions much more effectively than intracellular ions.
The highly polar ionic character of EDTA limits its oral absorption. Moreover, oral administration may increase lead absorption from the gut. Consequently, EDTA should be administered by intravenous infusion. In patients with normal renal function, EDTA is rapidly excreted by glomerular filtration, with 50% of an injected dose appearing in the urine within 1 hour. EDTA mobilizes lead from soft tissues, causing a marked increase in urinary lead excretion and a corresponding decline in blood lead concentration. In patients with renal insufficiency, excretion of the drug—and its metal-mobilizing effects—may be delayed.
Edetate calcium disodium is indicated chiefly for the chelation of lead, but it may also have usefulness in poisoning by zinc, manganese, and certain heavy radionuclides. A recent randomized, double-blind, placebo-controlled prospective trial of edetate disodium (not edetate calcium disodium) observed a significant decrease in cardiovascular events in a subgroup consisting of diabetic patients with a prior history of myocardial infarction. Further study is indicated to replicate the findings and explore potential mechanisms of benefit.