In addition to precise analysis of metal elimination kinetics, measures of clinical outcome are essential for an understanding of the utility of this chelator. The Treatment of Lead-Exposed Children (TLC) trial was a step in that direction.102 The TLC trial was a randomized, multicenter, double-blind, placebo-controlled study to examine the effects of succimer on cognitive development, behavior, stature, and blood pressure in children 1 to 3 years of age with blood lead concentrations between 20 and 44 µg/dL and 780 children were enrolled.86 The children received up to three courses of 26 days each of succimer compared to placebo. For the first 7 days the children received 350 mg/m2 three times a day and for the remaining 19 days they received 350 mg/m2 twice a day. The largest drop in blood lead occurred within the first week of therapy with succimer and then rebounded somewhat. This pattern was repeated with repeated courses. However, at the end of one year, no difference was seen in the blood lead concentrations between the succimer and the placebo groups. There was also no difference in test scores on cognition, behavior, or neuropsychological function.86 A follow-up study conducted on those children at age 7 confirmed the lack of benefit in chelating children with succimer whose blood lead concentrations were 20 to 44 μg/dL, at ages 1 to 3 years.35 A case study showed similar results. Similarly, succimer showed no benefit on growth in children aged 12 to 33 months with blood lead concentrations of 20 to 44 µg/dL.82
Several groups are studying the efficacy of succimer in reducing blood, brain, and tissue lead by using rat and nonhuman primate models of childhood and adult lead poisoning.91,92,94 Although monkeys most closely resemble humans in their lead-associated toxicity, using them in studies is costly77; the rat model is economical but limited because of species differences in lead and succimer metabolism and efficacy.
The validity of using blood lead concentrations as a marker of brain lead was studied in the adult rhesus monkey. Lead was administered orally for 5 weeks to achieve a target blood lead concentration of 35 to 40 µg/dL.32 Five days after the cessation of lead exposure, succimer chelation was initiated in the currently approved dosage regimen. Two IV doses of radioactive lead tracer were administered prior to succimer chelation to study the kinetics of recent versus chronic lead uptake and distribution. Four areas of the brain, as well as blood and bone, were assayed for lead. Merely stopping further lead exposure significantly reduced blood lead concentrations by 63% and brain lead concentrations by 34% compared with pretreatment concentrations, a finding that was not statistically different from succimer administration after halting exposure. However, when an integrated area under the serum lead concentration versus time curve (AUC) blood analysis was used over the 19-day succimer treatment course, instead of a single blood lead concentration, the differences between succimer and control were statistically significant. The clinical significance of these differences is unclear. Succimer-treated animals showed the greatest drop in blood lead concentrations over the first 5 days, while a similar end point was gradually achieved in the control. The lead from both the recent exposure (radioactive tracer lead) and chronic exposure declined to the same extent, independent of treatment with succimer. A better correlation was found between brain prefrontal cortex lead concentrations and an integrated blood lead analysis than with a single blood lead measurement.
Similarly, a study in neonatal rats demonstrated that increasing the duration of succimer chelation from 7 to 21 days decreased brain lead concentrations without a corresponding decrease in blood lead concentrations.91 The authors proposed that a slow rate of egress of brain lead to the blood was responsible for the demonstrable benefit of prolonging therapy to 21 days. In this study, succimer decreased blood lead concentration by approximately 50% when compared with the vehicle as the control, and this difference persisted for the 21 days of treatment. With succimer treatment, brain lead concentration decreased by 38% at 7 days and by 68% at 21 days. This same group also demonstrated that rats exposed to lead from postnatal days 1 to 30, then treated with succimer, demonstrated reductions in blood and brain lead concentrations and an improvement in cognitive deficits.95 Previous animal studies demonstrated the ability of succimer to enhance urinary lead elimination41,49,94 and to reduce blood,16,30,38,39,54,80,92,94,96,98 brain,16,30,80,97,98 liver,94 and kidney lead concentrations,16,30,38,54,80,98 while either reducing16,54,80,98 or demonstrating no effect on bone lead concentrations.30,94 These studies differ in the amounts and duration of lead administration prior to chelation, as well as in route, dose, and duration of chelation; however, several months after a course of succimer chelation, tissue lead concentrations had returned to concentrations found in the pretreatment stage.30 Given the limited absolute amount of lead that is actually eliminated by chelation in comparison to the total body burden, particularly bone, these transient effects are not surprising.
Under a variety of experimental conditions in animals, succimer prevents the deleterious effect of lead on heme synthesis,16,49,80 blood pressure,58 and behavior.96
The use of succimer in both children and adults with chronic lead poisoning demonstrated consistent findings.18,27,50, 51, and 52,64,76 During the first 5 days of succimer chelation (1050 mg/m2/d in children, 30 mg/kg/d in adults both in three divided doses), the blood lead concentration dropped precipitously by approximately 60% to 70%. This blood lead concentration remained unchanged during the next 14 to 23 days of continued therapy. Increases in urinary lead excretion are concurrent with the drop in blood lead concentration, with maximal excretion occurring on day 1.27,51 Urinary lead excretion exceeds estimated blood content which suggests that some lead is being removed from soft tissues as a concentration gradient is established from tissue to blood to urine.27,52 Typically, 2 weeks after the completion of succimer, blood lead concentration rebounds to values 20% to 40% lower than pretreatment values. In the one randomized, double-blind, placebo-controlled trial of succimer use in children with pretreatment blood lead concentrations of 30 to 45 µg/dL, follow-up at 1 month and at 6 months showed no differences between succimer-treated children and controls.76 Succimer restores red blood cell D-aminolevulinic acid dehydratase activity, decreases erythrocyte protoporphyrin, and decreases urinary excretion of D-aminolevulinic acid and coproporphyrin.18,27,51,52,76
There is a large body of evidence reporting on the usage and safety profile of succimer in adults with chronic lead poisoning.13,17,27,40,43,44,47,48,59,61,69,83,100,103 The published experience outside the United States with the use of oral succimer for metal poisoning includes nearly 100 adult cases and contributes considerably to the supporting evidence. At least 74 additional individuals have been successfully treated parenterally (IM or IV) with the sodium salt of succimer.13,17,40,43