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Introduction

  1. Pharmacology
    1. Succimer (meso-2,3-dimercaptosuccinic acid [DMSA]) is a chelating agent that is used in the treatment of intoxication from several heavy metals. A water-soluble analog of BAL (dimercaprol), succimer enhances the urinary excretion of lead and mercury. Its effect on the elimination of the endogenous minerals calcium, iron, and magnesium is insignificant. Minor increases in zinc and copper excretion may occur. In an animal model, oral succimer was not associated with a significant increase in the GI absorption of lead or inorganic mercury (as mercuric chloride); the effect of oral succimer on the GI absorption of arsenic is not known.
    2. After oral administration, peak blood concentrations occur in approximately 3 hours. Distribution is predominantly extracellular, and in the blood, succimer is extensively bound (>90%) to plasma proteins. Succimer is eliminated primarily in the urine, where 80-90% appears as mixed disulfides, mainly 2:1 or 1:1 cysteine-succimer adducts. Studies suggest that these adducts, rather than the parent drug, may be responsible for metal-chelating activity in vivo. Renal elimination of the metal chelates appears to be mediated in part by the multidrug resistance protein 2 (Mrp2). The elimination half-life of transformed succimer is approximately 2-4 hours. Renal clearance may be diminished in the setting of pediatric lead intoxication.
  2. Indications
    1. Succimer is approved for the treatment of lead intoxication, where it is associated with increased urinary excretion of the metal and concurrent reversal of metal-induced enzyme inhibition. At moderately elevated blood lead concentrations, oral succimer is comparable with parenteral calcium EDTA in decreasing blood lead concentrations. The efficiency of succimer in eliminating lead from the blood and tissues may somewhat decline at very high blood concentrations of lead (eg, >100 mcg/dL). Although succimer treatment has been associated with subjective clinical improvement, controlled clinical trials demonstrating therapeutic efficacy have not been reported. A large, randomized, double-blind placebo-controlled trial of succimer in children with blood lead concentrations between 25 and 44 mcg/dL found no evidence of benefit in clinical outcome or long-term blood lead reduction.
    2. Succimer is protective against the acute lethal and nephrotoxic effects of mercuric salts in animal models and increases urinary mercury excretion in animals and humans. It, therefore, may have clinical utility in the treatment of human poisoning by inorganic mercury. In a recent animal model of methylmercury exposure during pregnancy, succimer was effective in reducing the maternal and fetal mercury burden; however, unithiol appeared to be somewhat more potent in that setting.
    3. Succimer is protective against the acute lethal effects of arsenic in animal models and may have potential utility in acute human arsenic poisoning.
  3. Contraindications. History of allergy to the drug. Because succimer and its transformation products undergo renal elimination, safety and efficacy in patients with severe renal insufficiency are uncertain. There is no available evidence that succimer increases the hemodialysis clearance of toxic metals in patients with anuria.
  4. Adverse effects
    1. Gastrointestinal disturbances including anorexia, nausea, vomiting, and diarrhea are the most common side effects and occur in fewer than 10% of patients. There may be a mercaptan-like odor to the urine; this has no clinical significance.
    2. Mild, reversible increases in liver transaminases have been observed in less than 5% of patients.
    3. Rashes, some requiring discontinuation of treatment, may occur in fewer than 5% of patients. Isolated cases of mucocutaneous reactions have been reported.
    4. Isolated cases of mild to moderate neutropenia have been reported.
    5. Small increases (approximately two- to fivefold) in urinary excretion of zinc and copper have been observed.
    6. When administered to juvenile rats in the absence of antecedent lead exposure or elevated blood lead levels, succimer was associated with persistent deficits in learning, attention, and arousal. The mechanism of this effect is uncertain but might involve detrimental succimer-induced changes in zinc and/or copper status during neurodevelopment.
    7. Use in pregnancy. FDA Category C (indeterminate). Succimer has produced adverse fetal effects when administered to pregnant animals in amounts one to two orders of magnitude greater than recommended human doses. However, succimer has also diminished the adverse effects of several heavy metals in animal studies. Its effect on human pregnancy has not been determined (Introduction).
  5. Drug or laboratory interactions. No known interactions. Concurrent administration with other chelating agents has not been studied adequately.
  6. Dosage and method of administration (adults and children)
    1. Lead poisoning. Availability in the United States is limited to an oral formulation (100-mg capsules) officially approved by the FDA for use in children with blood lead levels of 45 mcg/dL or higher. DMSA can also lower blood lead concentrations in adults. Note: Administration of DMSA should never be a substitute for removal from lead exposure. In adults, the federal Occupational Safety and Health Administration (OSHA) lead standard requires removal from occupational lead exposure of any worker with a single blood lead concentration in excess of 60 mcg/dL or an average of three successive values in excess of 50 mcg/dL; however, recent data suggest that removal at lower blood lead levels may be warranted. Prophylactic chelation, defined as the routine use of chelation to prevent elevated blood lead concentrations or lower blood lead levels below the standard in asymptomatic workers, is not permitted. Consult the local or state health department or OSHA for more detailed information.
      1. Give 10 mg/kg (children: 350 mg/m2) orally every 8 hours for 5 days and then give the same dose every 12 hours for 2 weeks.
      2. An additional course of treatment may be considered on the basis of posttreatment blood lead levels and the persistence or recurrence of symptoms. Although blood lead levels may decline by more than 50% during treatment, patients with high body lead burdens may experience rebound to within 20% of pretreatment levels as bone stores equilibrate with tissue levels. Check blood lead levels 1 and 7-21 days after chelation to assess the extent of rebound and/or the possibility of reexposure.
      3. Experience with oral succimer for severe lead intoxications (ie, lead encephalopathy) is limited. In such cases, consideration should be given to parenteral therapy with calcium EDTA. In resource limited settings where parenteral calcium EDTA was unavailable, oral succimer has been successfully administered to encephalopathic children via nasogastric tube.
    2. Mercury and arsenic poisoning
      1. Intoxication by inorganic mercury compounds and arsenic compounds may result in severe gastroenteritis and shock. In such circumstances, the capacity of the gut to absorb orally administered succimer may be impaired severely, and use of an available parenteral agent such as unithiol or BAL may be preferable.
      2. Give 10 mg/kg (or 350 mg/m2) orally every 8 hours for 5 days and then give the same dose every 12 hours for 2 weeks. Extending the duration of treatment in the presence of continuing symptoms or high levels of urinary metal excretion should be considered but is of undetermined value.