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SUCCIMER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Succimer (2,3-dimercaptosuccinic acid, DMSA) is a relatively selective, orally active, water-soluble chelating agent for the treatment of lead, arsenic, and organic and inorganic mercury poisoning. As a dithiol chelating agent, it forms water-soluble chelates with heavy metals. It is approved for the treatment of childhood lead poisoning with blood lead levels above 45 mcg/dL. Succimer is a hydrophilic, less toxic analog of dimercaptopropanol (dimercaprol; BAL), and offers the advantage of not forming a toxic chelate with iron, thus allowing simultaneous iron and succimer therapy in anemic patients.

Specific Substances

    1) (R*,S*)-2,3-Dimercaptobutanedioic acid
    2) Butanedioic acid, 2,3-dimercapto-,(R*,S*)
    3) Dimercaptosuccinic acid
    4) DIM-SA
    5) DMS
    6) DMSA
    7) meso-2,3-Dimercaptosuccinic acid
    8) meso-2,3-Dithiosuccinic acid
    9) meso-Dimercaptosuccinic acid
    10) Ro 1-7977
    11) Succimer
    12) Succinic acid, 2,3-dimercapto-,meso-
    13) Molecular Formula: C4-H6-O4-S2
    14) CAS: 304-55-2
    1.2.1) MOLECULAR FORMULA
    1) C4H6O4S2 (Prod Info CHEMET(R) oral capsules, 2013)

Available Forms Sources

    A) FORMS
    1) Succimer (Chemet(R)) is available as microspheres in 100 mg hard gelatin capsules. Each capsule contains beads coated with 100 mg of succimer. Inactive ingredients in the beads include povidone, sodium starch glycolate, starch and sucrose. Inactive ingredients in the capsule include gelatin, iron oxide, titanium dioxide and other agents (Prod Info CHEMET(R) oral capsules, 2013).
    B) USES
    1) Succimer (2,3-dimercaptosuccinic acid, DMSA) is approved for the treatment of childhood lead poisoning with blood lead levels above 45 mcg/dL (Prod Info CHEMET(R) oral capsules, 2013). It is also widely used in the treatment of lead poisoning in adults and in children with blood lead levels less than 45 mcg/dL. It has also been effective in arsenic and mercury poisoning (Fournier et al, 1988).
    2) Succimer has been designated an orphan product for use in the treatment of lead or mercury poisoning and prevention of cystine kidney stone formation.
    3) LEAD POISONING
    a) ADULT
    1) SUMMARY: Succimer in doses of 30 mg/kg/day has been effective in reducing blood lead levels and reversing plumbism in adults.
    a) CASE SERIES: Graziano et al (1985) studied the effects of succimer in 18 adult patients with toxic blood lead levels (range: 44 to 99 mcg/dL) and clinical symptoms of lead toxicity. Oral doses of either 30, 20, or 10 mg/kg/day in 3 divided daily doses were administered for 5 days. A linear decline in blood lead levels was observed over the 5-day period. The mean blood lead levels had decreased by 72.5%, 58.3%, and 35.5%, respectively, at the end of the 5-day interval. The mean 24-hour urinary lead excretion in the initial 24 hours increased by 28.6, 18.6, and 12.3 times the pretreatment level. A mean 19 mg of lead was excreted during the 5-day course of succimer 30 mg/kg/day; this dose was found to be significantly superior to either 10 or 20 mg/kg/day. Biochemical indices of hematologic toxicity also improved, as measured by decreases in urinary coproporphyrin excretion and increases in erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) activity. Clinical improvement was noted during this period (Graziano et al, 1985a).
    2) CASE REPORTS: Three adults presenting with lead encephalopathy have been reported to improve with succimer therapy; however, data is limited concerning succimer therapy in cases of encephalopathy (Prod Info CHEMET(R) oral capsules, 2013).
    b) PEDIATRIC
    1) LEAD POISONING: CHILDREN with blood lead levels above 45 mcg/dL should be given oral succimer, 10 mg/kg or 350 mg/m(2), every 8 hours for 5 days, followed by 10 mg/kg or 350 mg/m(2) every 12 hours for an additional 14 days; a course of therapy lasts a total of 19 days (Prod Info CHEMET(R) oral capsules, 2013).
    a) Courses of therapy may be repeated if indicated by weekly monitoring of blood lead concentrations; lead concentrations should be stabilized below 15 mcg/dL. A minimum of 2 weeks between courses is recommended, unless lead levels indicate a need for more frequent treatment (Prod Info CHEMET(R) oral capsules, 2013). Maintain adequate hydration throughout therapy.
    c) ANIMAL DATA
    1) Pappas et al (1992) demonstrated in rats pretreated with 550 ppm lead in water for 4 weeks, then fed lead in water with succimer, that use of succimer with ongoing lead exposures not only enhanced lead elimination, but also reduced total blood lead concentration and ALA-D levels as compared to rats given ongoing lead with no succimer (Pappas et al, 1992). It was not determined in this study of ongoing lead exposure whether total body burden of lead was impacted.
    2) Oral succimer was shown in rat studies to decrease whole-body lead retention and gastrointestinal lead absorption (Kapoor et al, 1989).
    4) MERCURY POISONING
    a) ADULT
    1) CASE REPORT: Succimer has been used for mercury poisoning. Bluhm et al (1992) described an outbreak of mercury vapor toxicity in 53 construction workers, 11 of whom received succimer or N-acetyl-DL-penicillamine (NAP) in a cross-over study (Bluhm et al, 1992). Succimer (30 mg/kg every 8 hr) or NAP (250 mg every 6 hr) was given for 2 weeks, followed by several weeks of no chelator therapy, then repeated therapy in a comparative 4 day study of Succimer and NAP.
    a) Chelation therapy with both drugs resulted in mobilization of a small fraction of the total estimated body mercury, with succimer increasing mercury excretion to a greater extent than NAP. A mean increase in mercury excretion, above the baseline estimate of mercury excretion, for the 4 days was 46 +/-9%, with a range of 26% to 61%. Excretion over a 4 day period represented 2.4 +/-0.9% of the estimated total mercury excreted. Following both succimer and NAP, there was a significant association between excretion rates before and during chelation (r=0.96 for succimer, P<0.001; r=0.97 for NAP, P<0.01). Difference in rates was smaller at lower initial rates of mercury excretion, and succimer caused a 3-fold increase at the higher baseline mercury excretion rates.
    b) Due to the large volume of distribution of mercury, prolonged therapy would be required to influence the excretion profile. During the chelation therapy, no increases in blood mercury were observed. It is unclear whether chelation therapy is mobilizing mercury only from the kidney compartment or enhancing the ability of the kidney to concentrate and excrete mercury.
    2) Zhang (1984) reported chelation therapy with succimer and DMPS for alkyl mercury intoxication to be an effective indicator for diagnosis and assessment of the degree of intoxication. The author also reported therapy to be useful as long as urinary mercury level was elevated (Zhang, 1984).
    b) PEDIATRIC
    1) Mercury (Hg) toxicity in 2 children was treated with oral succimer, 30 mg/kg/day for 5 days, followed by 20 mg/kg/day for 16 days. A second course was repeated after a 22-day drug-free period. Urinary mercury excretion ranged from 0% to 355% relative to pretreatment levels. Succimer appeared to be safe and efficacious for increasing urinary Hg excretion (Mortensen & Valenzuela, 1990).
    2) Pretherapy urinary Hg level in a 15-year-old boy was 1314 mcg/L. Following the second course of succimer therapy, the level dropped to 159 mcg/L. In the same patient, blood Hg fell from 2.3 to less than 1.0 mcg percent, with no rebound after the second course of therapy.
    c) ANIMAL DATA
    1) Graziano (1986) reported the effect of succimer (30 mg/kg/day for 5 days) administered to mice chronically poisoned with methylmercury (organic mercury). Succimer was equally effective as equivalent dosing with DMPS in inducing urinary mercury excretion (approximately 400 mcg mercury in 5 days) (Graziano, 1986a).
    5) ARSENIC POISONING
    a) ADULT
    1) CASE REPORT: A 46-year-old, chronic alcoholic, man presented to the ED after intentionally ingesting 2000 mg of arsenic. Succimer, 300 mg every 6 hours orally for 3 days, was started 21 hours following the arsenic ingestion. The patient eliminated 27.03 mg of arsenic via his urine. An increase of arsenic output on the first day of 7.38 mg, which increased to 12.6 mg on the third day of succimer therapy was reported. The urine arsenic elimination dropped to 0.7 mg/day 4 days after succimer was stopped. Despite the potentiation of arsenic elimination, the patient developed polyneuropathy 3 weeks later, which may be due to the fact the antidote was started 21 hours after the ingestion and because of chronic alcoholism (Lenz et al, 1981).
    2) CASE REPORT: Fournier et al (1988) reported an accidental ingestion of a mouthful of Fowler's solution in an adult. Arsenic was not detectable in the hair or nails. During succimer therapy (10 mg/kg/day 3 times daily for 5 days), mean daily urinary excretion of arsenic was 32 mcmol/day, with plasma concentrations declining from 0.24 to 0.10 mcmol/L. Clinical symptoms improved within several days (Fournier et al, 1988b).
    6) GOLD POISONING
    a) ANIMAL DATA
    1) Aaseth (1983) compared the effect of succimer (1 mmol/kg/day for 7 days) in mice and D-penicillamine (1 nmol/kg/day for 7 days) in another group of mice, both groups previously injected with 35 mcmol/kg of aurothiomalate. D-penicillamine increased significantly urinary excretion of gold the first day after the aurothiomalate injection, but on subsequent days the gold excretion was unaffected. Blood and kidney levels of gold were reduced to 30% to 50% of the controls by both succimer and D-penicillamine. (Aaseth, 1983).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Succimer is a lead chelator used in the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. It is not indicated for prophylactic treatment of lead poisoning in an environment known to contain elevated levels of lead. It has also been used to treat arsenic and mercury poisoning.
    B) PHARMACOLOGY: Succimer, an analog of dimercaprol, is an orally active heavy metal chelator that forms water soluble chelates and results in urinary excretion of lead.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: The following adverse effects have occurred following therapeutic use: a transient rise in serum transaminase levels, gastrointestinal symptoms including nausea, vomiting, diarrhea, cramping, mucocutaneous reactions, and metallic taste. Mild to moderate neutropenia has occurred in some patients. Back pain, flank pain, chills, flu-like symptoms, headache, and moniliasis can also develop.
    2) UNCOMMON: Drowsiness, dizziness, neuropathies, sleepiness and paresthesias are potential adverse effects of succimer therapy, but may be difficult to distinguish from the underlying metal intoxication being treated.
    3) RARE: Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency has rarely been reported. Other rare events may include: cardiac dysrhythmias and hyperthermia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Acute overdose of succimer was reported in one pediatric patient, with no acute toxicity, laboratory abnormalities, or short-term sequelae noted. Succimer is much less toxic than dimercaprol. The anticipated events following an overdose may be similar to adverse events observed with therapeutic use.
    2) MILD TO MODERATE TOXICITY: Clinical events may include elevations in serum transaminase levels, gastrointestinal symptoms, and mucocutaneous reactions.
    3) SEVERE TOXICITY: Limited data. Potentially severe events that may develop: cardiac dysrhythmias, hyperthermia, liver or hematologic toxicity may develop.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal complaints are among the most commonly reported adverse effects associated with succimer therapy. Halitosis, due to sulfhydryl groups, may occur.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Transient elevations in serum transaminases may occur during succimer therapy.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Urine may have a sulfurous odor, which is clinically insignificant.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Hemolysis has been rarely reported as an adverse effect occurring in patients with glucose-6-phosphate dehydrogenase deficiency.
    2) Mild to moderate neutropenia has occurred in some patients following therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Mucocutaneous reactions may occur as adverse effects during or after succimer therapy.
    0.2.20) REPRODUCTIVE
    A) There are no adequate and well controlled studies in pregnant women. Succimer is classified as FDA Pregnancy category C. In animal studies, succimer was shown to be teratogenic and fetotoxic.
    B) Data is lacking concerning excretion of succimer into breast milk. Because heavy metals and many drugs are excreted in human milk, it is recommended that mothers be discouraged from nursing their infants.

Laboratory Monitoring

    A) Monitor blood lead levels prior to initiation of therapy and during succimer therapy. Due to redistribution from bone stores, rebound increases in blood lead levels may occur following treatment. Monitor blood lead levels at least once per week after therapy until stable.
    B) Monitor CBC and liver enzymes during therapy with succimer.
    C) Succimer therapy may interfere with some laboratory tests, causing falsely decreased measurements for serum CPK and serum uric acid, and causing false positive results for urinary ketones.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited reports of human overdose with succimer. Monitor fluids and electrolytes in patients that develop significant gastrointestinal loss. Monitor liver enzymes. Seizures have been reported in animal studies. Treat with benzodiazepines, barbiturates.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Limited data. Treatment is symptomatic and supportive. Potentially significant events may include dysrhythmias; obtain a baseline ECG and continuous cardiac monitoring. Monitor CBC with differential following a significant overdose; neutropenia may develop. Monitor vital signs, including temperature.
    C) DECONTAMINATION
    1) PREHOSPITAL: Limited data. Consider activated charcoal after a recent significant overdose if the patient is alert and able to protect the airway.
    2) HOSPITAL: Activated charcoal may be considered following a recent significant ingestion if the patient is alert and can protect the airway.
    D) ENHANCED ELIMINATION
    1) Based on limited data, succimer is dialyzable, but this is unlikely to be necessary due to limited toxicity.
    E) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with a minor exposure (a few capsules) can likely be monitored at home with adult supervision. An asymptomatic adult with an inadvertent minor exposure (not exceeding a daily dose) can be monitored at home with telephone support.
    2) OBSERVATION CRITERIA: A patient that develops more than minor symptoms (ie, more than a few episodes of vomiting in a child) should be observed in a healthcare setting until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with persistent symptoms should be admitted and treated until symptoms resolve.
    4) CONSULT CRITERIA: Consult with a medical toxicologist or Poison control center to assist with diagnosis and therapy; contact public health personnel to assist with identifying the source of lead exposure and possible remediation measures in cases of lead poisoning in a child.
    F) PHARMACOKINETICS
    1) Oral absorption is rapid, but variable; bioavailability is good. Time to peak concentration is 1 to 2 h. Following a single oral dose of 10 mg/kg, succimer was rapidly and extensively metabolized. Of the total succimer eliminated in the urine, 90% is eliminated as mixed succimer-cysteine disulfide conjugates, with the remaining 10% being eliminated unchanged. Approximately, 10% to 25% of a dose is excreted in the urine, with peak urinary excretion occurring between 2 and 4 hours. Elimination half-life is reported to be about 2 days in healthy volunteers. In one study, elimination half-life of total succimer (parent drug plus oxidized metabolites) in 3 children with lead poisoning, 3 adults with lead poisoning, and 5 healthy adult volunteers half-lives were 3 +/- 0.2 hours in the children, 1.9 +/- 0.4 hours in the adults with lead poisoning, and 2 +/- 0.2 hours for the healthy volunteers, respectively.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. PEDIATRIC: An oral overdose of 2400 mg produced no acute toxicity, laboratory abnormalities, or short-term sequelae in a 13 kg child. ADULT: An adult intentionally ingested, at a minimum, an estimated 4000 mg (43 mg/kg) up to 8000 mg (87 mg/kg) of DMSA and fexofenadine with only minor symptoms reported.
    B) THERAPEUTIC: LEAD POISONING: Treatment is most often indicated for children; however it has been used in adults. ADULT: Start dosage at 10 mg/kg/day or 350 mg/m(2) every 8 hours for 5 days. PEDIATRIC: For lead blood levels above 45 mcg/dL, give 10 mg/kg or 350 mg/m(2) every 8 hours for 5 days, then 10 mg/kg or 350 mg/m(2) every 12 hours for 14 days.

Clinical Effects

Summary Of Exposure

    A) USES: Succimer is a lead chelator used in the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL. It is not indicated for prophylactic treatment of lead poisoning in an environment known to contain elevated levels of lead. It has also been used to treat arsenic and mercury poisoning.
    B) PHARMACOLOGY: Succimer, an analog of dimercaprol, is an orally active heavy metal chelator that forms water soluble chelates and results in urinary excretion of lead.
    C) EPIDEMIOLOGY: Exposure is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: The following adverse effects have occurred following therapeutic use: a transient rise in serum transaminase levels, gastrointestinal symptoms including nausea, vomiting, diarrhea, cramping, mucocutaneous reactions, and metallic taste. Mild to moderate neutropenia has occurred in some patients. Back pain, flank pain, chills, flu-like symptoms, headache, and moniliasis can also develop.
    2) UNCOMMON: Drowsiness, dizziness, neuropathies, sleepiness and paresthesias are potential adverse effects of succimer therapy, but may be difficult to distinguish from the underlying metal intoxication being treated.
    3) RARE: Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency has rarely been reported. Other rare events may include: cardiac dysrhythmias and hyperthermia.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Acute overdose of succimer was reported in one pediatric patient, with no acute toxicity, laboratory abnormalities, or short-term sequelae noted. Succimer is much less toxic than dimercaprol. The anticipated events following an overdose may be similar to adverse events observed with therapeutic use.
    2) MILD TO MODERATE TOXICITY: Clinical events may include elevations in serum transaminase levels, gastrointestinal symptoms, and mucocutaneous reactions.
    3) SEVERE TOXICITY: Limited data. Potentially severe events that may develop: cardiac dysrhythmias, hyperthermia, liver or hematologic toxicity may develop.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPERTHERMIA
    a) One adult developed acute severe hyperthermia associated with hypotension; rechallenge resulted in hyperthermia with shaking chills and hypertension (Marcus et al, 1991).

Heent

    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Pharyngitis, rhinorrhea, nasal congestion, sore throat, and cough have been reported as adverse effects of succimer therapy (Prod Info CHEMET(R) oral capsules, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In clinical studies, various dysrhythmias have been reported in 1.8% of adults and no reports in children receiving therapeutic succimer (Prod Info CHEMET(R) oral capsules, 2013).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) DYSPNEA
    a) Labored respirations occurred in rats given acute oral succimer doses of 2300 mg/kg and in mice given 2400 mg/kg (Prod Info CHEMET(R) oral capsules, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Drowsiness, dizziness, neuropathies, headache, and paresthesias are potential adverse effects of succimer therapy, but may be difficult to distinguish from the underlying metal intoxication being treated. Central nervous system effects have been reported in 1% of children and 12.7% of adults (Prod Info CHEMET(R) oral capsules, 2013).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures and ataxia were reported in rats given succimer, 2300 mg/kg, and in mice given succimer, 2400 mg/kg (Prod Info CHEMET(R) oral capsules, 2013).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Gastrointestinal complaints are among the most commonly reported adverse effects associated with succimer therapy. Halitosis, due to sulfhydryl groups, may occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Commonly occurring symptoms following succimer therapy include abdominal cramps, nausea, vomiting, diarrhea, anorexia, hemorrhoidal symptoms, and metallic taste. Digestive complaints occur in 12% of children and 20.9% of adults (Prod Info CHEMET(R) oral capsules, 2013).
    B) BREATH SMELLS UNPLEASANT
    1) WITH THERAPEUTIC USE
    a) Succimer may impart an unpleasant sulfurous odor to the breath due to the sulfhydryl groups on the compound; however, this is of no clinical significance (Prod Info CHEMET(R) oral capsules, 2005).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Transient elevations in serum transaminases may occur during succimer therapy.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Mild, asymptomatic elevations of SGOT, SGPT, serum cholesterol, and alkaline phosphatase have occurred with succimer therapy (Prod Info CHEMET(R) oral capsules, 2013; Graziano et al, 1985).
    b) INCIDENCE: Mild, transient elevations in serum SGPT occurred in 2 of 18 adult patients receiving oral succimer (doses of 10 to 30 mg/kg/day for 5 days) for treatment of lead intoxication (Graziano et al, 1985).
    c) INCIDENCE: Significant elevations in serum SGPT (greater than 2 times baseline) occurred in 5 out of 41 (12%) children over the first 5 days of succimer therapy (Marcus et al, 1991).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Urine may have a sulfurous odor, which is clinically insignificant.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) WITH THERAPEUTIC USE
    a) Succimer may impart an offensive sulfurous odor to the urine; although unpleasant, this is of no clinical significance (Prod Info Chemet(R), succimer, 2000).
    B) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Voiding difficulty and decreased urination have occasionally been reported as adverse effects of oral succimer therapy (Prod Info CHEMET(R) oral capsules, 2013).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hemolysis has been rarely reported as an adverse effect occurring in patients with glucose-6-phosphate dehydrogenase deficiency.
    2) Mild to moderate neutropenia has occurred in some patients following therapeutic use.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) WITH THERAPEUTIC USE
    a) Rarely, hemolysis may occur in patients with glucose-6-phosphate dehydrogenase deficiency. Hemolytic anemia was reported in a 45-year-old man with glucose-6-phosphate dehydrogenase deficiency (G6PD). After a 5 day course of succimer, 800 mg 3 times daily, the patient's hemoglobin and hematocrit had dropped from 15 g/dL and 43.5% prior to therapy to 11.7 g/dL and 34.1%. The risk of hemolytic anemia from succimer given to patients with G6PD deficiency is unknown (Gerr et al, 1994).
    b) Graziano et al (1992) reported giving succimer to 2 children with G6PD deficiency without evidence of hemolysis (Graziano et al, 1985).
    c) Marcus et al (1991) reported that 12 children out of 41 (29%) developed a drop in hemoglobin (greater than 1 g) over the first 5 days of succimer therapy. Four of 22 adults (18%) showed decreases in hemoglobin in the same study (Marcus et al, 1991).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Mild to moderate neutropenia has occurred in some patients that have been treated with succimer. A causal relationship has not been determined, but neutropenia has been observed in patients receiving agents from the same chemical class. A complete blood count is recommended prior to the start of therapy and repeated weekly during therapy (Prod Info CHEMET(R) oral capsules, 2013).
    C) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) Intermittent eosinophilia are infrequent adverse effects of succimer therapy, occurring in 0.5% of children and 1.5% of adults (Prod Info CHEMET(R) oral capsules, 2013).
    D) INCREASED PLATELET COUNT
    1) WITH THERAPEUTIC USE
    a) An increased platelet count may develop with succimer therapy (Prod Info CHEMET(R) oral capsules, 2013).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mucocutaneous reactions may occur as adverse effects during or after succimer therapy.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash, papular rash, herpetic rash, pruritus, and mucocutaneous eruptions have occurred during succimer therapy. These events occurred in 2.6% of children and 11.2% of adults during therapeutic use (Prod Info CHEMET(R) oral capsules, 2013).
    b) CASE REPORT: A 54-year-old man developed a mucocutaneous vesicular flare during succimer treatment, which faded after cessation of therapy (Grandjean et al, 1991).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate and well controlled studies in pregnant women. Succimer is classified as FDA Pregnancy category C. In animal studies, succimer was shown to be teratogenic and fetotoxic.
    B) Data is lacking concerning excretion of succimer into breast milk. Because heavy metals and many drugs are excreted in human milk, it is recommended that mothers be discouraged from nursing their infants.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) FETOTOXICITY
    a) In mouse studies, succimer was shown to be teratogenic and fetotoxic when injected subcutaneously into the pregnant mice at doses of 410 to 1640 mg/kg/day during the period of organogenesis (Prod Info CHEMET(R) oral capsules, 2013).
    b) Fetotoxic effects were observed in Sprague-Dawley rats at succimer doses less than one order of magnitude above standard human doses. The NOEL for maternal and developmental toxicity was less 100 mg DMSA/kg/day. Significant fetotoxicity was reported at doses of 100, 300, and 1000 mg/kg/day (Domingo et al, 1990).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Succimer is classified as FDA Pregnancy Category C (Prod Info CHEMET(R) oral capsules, 2013).
    B) RISK SUMMARY
    1) There are no adequate and well controlled studies in pregnant women. In animal studies, doses up to 510 mg/kg/day were tolerated in pregnant animals. However, impaired development of reflexes occurred in pups of 720 mg/kg/day group dam (Prod Info CHEMET(R) oral capsules, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Data is lacking concerning excretion of succimer into human breast milk. Because heavy metals and many drugs are excreted in human milk, it is recommended that mothers be discouraged from nursing their infants during succimer therapy (Prod Info CHEMET(R) oral capsules, 2013).
    3.20.5) FERTILITY
    A) LACK OF EFFECT
    1) In animal studies, doses of succimer up to 510 mg/kg/day in males and 100 mg/kg/day in females did not produce any adverse events or alterations in reproductive performance (Prod Info CHEMET(R) oral capsules, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood lead levels prior to initiation of therapy and during succimer therapy. Due to redistribution from bone stores, rebound increases in blood lead levels may occur following treatment. Monitor blood lead levels at least once per week after therapy until stable.
    B) Monitor CBC and liver enzymes during therapy with succimer.
    C) Succimer therapy may interfere with some laboratory tests, causing falsely decreased measurements for serum CPK and serum uric acid, and causing false positive results for urinary ketones.
    4.1.2) SERUM/BLOOD
    A) LEAD CONCENTRATIONS
    1) LEAD: Monitoring of blood lead levels should be performed prior to initiation of succimer therapy. Due to redistribution from bone stores, patients should be monitored for reduction of blood lead levels as well as for rebound increases in blood lead levels after discontinuation of therapy.
    a) After therapy, blood levels should be monitored at least weekly (or as clinically indicated) until stable; the degree of lead intoxication should be assessed by measurement of initial blood lead level and the rate and degree of rebound in lead levels and used as a guide for more frequent monitoring of blood lead levels (Prod Info CHEMET(R) oral capsules, 2013).
    B) OTHER HEAVY METALS
    1) A decrease in blood copper level from 86 mcg/dL before succimer therapy to 64 mcg/dL after a 5 day treatment period (total 8.37 g succimer) was reported. Two weeks after discontinuation of succimer, blood copper levels rose to 78 mcg/dL (normal 80 to 155 mcg/dL) (Bentur et al, 1987a).
    C) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes before starting succimer therapy and weekly during therapy, as mild and transient elevations in serum transaminases have been reported.
    D) HEMATOLOGIC
    1) Obtain a baseline CBC and repeat as indicated. Neutropenia has been reported in some patients receiving succimer therapy.
    2) Other parameters of lead-induced hematologic toxicity should be monitored as clinically indicated for improvements, such as an increase in erythrocyte delta-aminolevulinic acid (ALA) dehydratase activity or decreases in urinary delta-aminolevulinic acid and coproporphyrin excretion (Prod Info CHEMET(R) oral capsules, 2013).
    E) LABORATORY INTERFERENCE
    1) SERUM CPK: Succimer may cause falsely decreased measurements for serum creatine phosphokinase (CPK) (Prod Info CHEMET(R) oral capsules, 2013).
    2) SERUM URIC ACID: Succimer may cause falsely decreased measurements for serum uric acid (Prod Info CHEMET(R) oral capsules, 2013).
    3) In vitro tests have shown succimer to result in false-positive results for ketones in urine using nitroprusside reagents such as Ketostix(R) (Prod Info CHEMET(R) oral capsules, 2013).
    4.1.3) URINE
    A) URINALYSIS
    1) URINE KETONES: Succimer may cause false-positive results for urinary ketones using nitroprusside reagents such as Ketostix(R) (Prod Info CHEMET(R) oral capsules, 2013).
    B) OTHER
    1) Other parameters of lead-induced hematologic toxicity should be monitored as clinically indicated for improvements such as an increase in erythrocyte delta-aminolevulinic acid (ALA) dehydratase activity or decreases in urinary delta-aminolevulinic acid and coproporphyrin excretion (Prod Info CHEMET(R) oral capsules, 2013).
    2) Urinary heavy metal concentration (in 24 hour samples or in random samples corrected for urinary creatinine) collected before and during succimer therapy may help to evaluate the extent of metal excretion induced by succimer.
    C) HEAVY METALS
    1) Succimer influences the urinary elimination of many metals. Oral doses used for chelation of lead, arsenic and mercury have been similar. Oral succimer does not have a clinically significant effect on the excretion of essential minerals, including calcium, magnesium, iron, copper and zinc. It has induced less than a 2-fold increase in urinary zinc and copper excretion, which is statistically significant, but clinically not relevant (Graziano et al, 1992; Graziano, 1986).

Methods

    A) SPECTROSCOPY/SPECTROMETRY
    1) Blood and urine lead levels, before and during succimer therapy, have been measured by means of atomic absorption spectrophotometry (Bentur et al, 1987).
    B) MULTIPLE ANALYTICAL METHODS
    1) Urine samples of healthy subjects given succimer have been analyzed by HPLC, ion exchange and TLC techniques for quantification of succimer and its metabolites in pharmacokinetic studies (HSDB , 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms should be admitted and treated until symptoms resolve.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with a minor exposure (a few capsules) can likely be monitored at home with adult supervision. An asymptomatic adult with an inadvertent minor exposure (not exceeding a daily dose) can be monitored at home with telephone support.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with a medical toxicologist or Poison control center to assist with diagnosis and therapy; contact public health personnel to assist with identifying the source of lead exposure and possible remediation measures in cases of lead poisoning in a child.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) A patient that develops more than minor symptoms (ie, more than a few episodes of vomiting in a child) should be observed in a healthcare setting until symptoms resolve.

Monitoring

    A) Monitor blood lead levels prior to initiation of therapy and during succimer therapy. Due to redistribution from bone stores, rebound increases in blood lead levels may occur following treatment. Monitor blood lead levels at least once per week after therapy until stable.
    B) Monitor CBC and liver enzymes during therapy with succimer.
    C) Succimer therapy may interfere with some laboratory tests, causing falsely decreased measurements for serum CPK and serum uric acid, and causing false positive results for urinary ketones.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Activated charcoal may be considered after a recent, significant overdose if the patient is alert and can protect the airway.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There are limited reports of overdose with succimer.
    2) Succimer is not to be used for prophylaxis of lead toxicity in the presence of continued exposure. Clinical experience with prolonged administration is limited and uninterrupted treatment for more than 3 weeks is not recommended.
    B) MONITORING OF PATIENT
    1) Monitor liver enzymes following as indicated; elevations in serum transaminases have been reported during therapeutic use. Patients with a history of hepatic disease who receive succimer therapy should be closely monitored.
    2) Monitor CBC with differential following a significant exposure; neutropenia has been observed with therapeutic use.
    3) Monitor vital signs.
    4) Succimer is primarily eliminated renally and should be administered with caution in patients with renal impairment. Adequate hydration should be maintained in patients receiving succimer.
    C) FLUID BALANCE
    1) Monitor fluids and electrolytes in patients that develop significant gastrointestinal loss. Treat with IV fluids and antiemetics following persistent nausea and vomiting.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Based on limited data, succimer is dialyzable (Prod Info CHEMET(R) oral capsules, 2011). This is unlikely to be necessary as toxicity is limited.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. PEDIATRIC: An oral overdose of 2400 mg produced no acute toxicity, laboratory abnormalities, or short-term sequelae in a 13 kg child. ADULT: An adult intentionally ingested, at a minimum, an estimated 4000 mg (43 mg/kg) up to 8000 mg (87 mg/kg) of DMSA and fexofenadine with only minor symptoms reported.
    B) THERAPEUTIC: LEAD POISONING: Treatment is most often indicated for children; however it has been used in adults. ADULT: Start dosage at 10 mg/kg/day or 350 mg/m(2) every 8 hours for 5 days. PEDIATRIC: For lead blood levels above 45 mcg/dL, give 10 mg/kg or 350 mg/m(2) every 8 hours for 5 days, then 10 mg/kg or 350 mg/m(2) every 12 hours for 14 days.

Therapeutic Dose

    7.2.1) ADULT
    A) LEAD POISONING
    1) SUMMARY
    a) LEAD POISONING: ADULTS have been successfully treated with oral succimer in doses of 10 to 30 mg/kg/day (in 3 divided doses daily); 30 mg/kg/day (in 3 divided doses daily) for 5 days appears to be the optimal dose in adults (Graziano et al, 1985).
    b) CASE SERIES: Graziano et al (1985) studied the effects of succimer in 18 adult patients with toxic blood lead levels (range: 44 to 99 mcg/dL) and clinical symptoms of lead toxicity. Oral doses of either 30, 20, or 10 mg/kg/day in 3 divided daily doses were administered for 5 days.
    1) A linear decline in blood lead levels was observed over the 5-day period. The mean blood lead levels had decreased by 72.5%, 58.3%, and 35.5%, respectively, at the end of the 5-day interval. The mean 24-hour urinary lead excretion in the initial 24 hours increased by 28.6, 18.6, and 12.3 times the pretreatment level. A mean 19 mg of lead was excreted during the 5-day course of succimer 30 mg/kg/day; this dose was found to be significantly superior to either 10 or 20 mg/kg/day.
    2) Biochemical indices of hematologic toxicity also improved, as measured by decreases in urinary coproporphyrin excretion and increases in erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) activity. Clinical improvement was noted during this period (Graziano et al, 1985a).
    c) CASE REPORTS: Three adults presenting with lead encephalopathy have been reported to improve with succimer therapy; however, data are limited concerning succimer therapy in cases of encephalopathy (Prod Info CHEMET(R) oral capsules, 2013).
    d) CASE REPORT: A 54-year-old man, with chronic occupational lead poisoning, was treated with succimer, 30 mg/kg/day for 3 days, then 20 mg/kg/day for 4 days. During the first 7 days, total urinary excretion of lead was 75 mcmol. Therapy resulted in a decrease in blood lead concentration from 4.1 to 0.7 mcmol/L. A rebound of blood lead concentration up to 3.3 mcmol/L occurred over the next 7 months, and succimer therapy was repeated.
    1) The second course of succimer, 30 mg/kg/day for 6 days followed by 10 mg/kg/day for 10 days, was given. Blood lead concentration dropped to 0.5 mcmol/L. A gradual rebound to 3.5 mcmol/L occurred over the next 3 months.
    2) A third course of succimer, 30 mg/kg/day for 6 days was initiated. Due to adverse effects (mucocutaneous eruptions and elevated serum ALT), the drug was discontinued. His blood lead concentration rapidly declined to 0.5 mcmol/L with no rebound (Grandjean et al, 1991).
    e) CASE REPORT: A 45-year-old man, with chronic lead toxicity, was treated first with IV sodium calcium edetate 2.8 g twice daily for 5 days. Following a week with no chelation therapy, he was started on oral succimer, 660 mg 3 times daily for 5 days. Succimer was found to be equally as effective as sodium calcium edetate in reducing blood levels and increasing urinary lead excretion (Thomas & Ashton, 1991).
    B) MERCURY POISONING
    1) ADULT
    a) CASE REPORT: Succimer has been used for mercury poisoning. Bluhm et al (1992) described an outbreak of mercury vapor toxicity in 53 construction workers, 11 of whom received succimer or N-acetyl-DL-penicillamine (NAP) in a cross-over study. Succimer (30 mg/kg every 8 hr) or NAP (250 mg every 6 hr) was given for 2 weeks, followed by several weeks of no chelator therapy, then repeated therapy in a comparative 4 day study of succimer and NAP (Bluhm et al, 1992).
    1) Chelation therapy with both drugs resulted in mobilization of a small fraction of the total estimated body mercury, with succimer increasing mercury excretion to a greater extent than NAP. A mean increase in mercury excretion, above the baseline estimate of mercury excretion, for the 4 days was 46 +/-9%, with a range of 26% to 61%. Excretion over a 4 day period represented 2.4 +/-0.9% of the estimated total mercury excreted. Following both succimer and NAP, there was a significant association between excretion rates before and during chelation (r=0.96 for succimer, P less than 0.001; r=0.97 for NAP, P less than 0.01). Difference in rates was smaller at lower initial rates of mercury excretion, and succimer caused a 3-fold increase at the higher baseline mercury excretion rates.
    2) Due to the large volume of distribution of mercury, prolonged therapy would be required to influence the excretion profile. During the chelation therapy, no increases in blood mercury were observed. It is unclear whether chelation therapy is mobilizing mercury only from the kidney compartment or enhancing the ability of the kidney to concentrate and excrete mercury.
    b) Zhang (1984) reported chelation therapy with succimer and DMPS for alkyl mercury intoxication to be an effective indicator for diagnosis and assessment of the degree of intoxication. The author also reported therapy to be useful as long as urinary mercury level was elevated (Zhang, 1984).
    C) ARSENIC POISONING
    1) ADULT
    a) CASE REPORT: A 46-year-old, chronic alcoholic, man presented to the ED after intentionally ingesting 2000 mg of arsenic. Succimer, 300 mg every 6 hours orally for 3 days, was started 21 hours following the arsenic ingestion. The patient eliminated 27.03 mg of arsenic via his urine. An increase of arsenic output on the first day of 7.38 mg, which increased to 12.6 mg on the third day of succimer therapy was reported. The urine arsenic elimination dropped to 0.7 mg/day 4 days after succimer was stopped. Despite the potentiation of arsenic elimination, the patient developed polyneuropathy 3 weeks later, which may be due to the fact the antidote was started 21 hours after the ingestion and because of chronic alcoholism (Lenz et al, 1981).
    b) CASE REPORT: Fournier et al (1988) reported an accidental ingestion of a mouthful of Fowler's solution in an adult. Arsenic was not detectable in the hair or nails. During succimer therapy (10 mg/kg/day 3 times daily for 5 days), mean daily urinary excretion of arsenic was 32 mcmol/day, with plasma concentrations declining from 0.24 to 0.10 mcmol/L. Clinical symptoms improved within several days (Fournier et al, 1988a).
    7.2.2) PEDIATRIC
    A) SUMMARY
    1) LEAD POISONING: CHILDREN with blood lead levels above 45 mcg/dL should be given oral succimer, 10 mg/kg or 350 mg/m(2), every 8 hours for 5 days, followed by 10 mg/kg or 350 mg/m(2) every 12 hours for an additional 14 days; a course of therapy lasts a total of 19 days (Prod Info CHEMET(R) oral capsules, 2013).
    a) Courses of therapy may be repeated if indicated by weekly monitoring of blood lead concentrations; lead concentrations should be stabilized below 15 mcg/dL. A minimum of 2 weeks between courses is recommended, unless lead levels indicate a need for more frequent treatment (Prod Info CHEMET(R) oral capsules, 2013). Maintain adequate hydration throughout therapy.
    b) Succimer capsules may be separated and sprinkled onto a small amount of soft food for children unable to swallow capsules (Prod Info CHEMET(R) oral capsules, 2013).
    c) Succimer is primarily eliminated renally; caution should be observed when administering to patients with renal impairment (Prod Info CHEMET(R) oral capsules, 2013).
    d) Succimer is not known to interact with other drugs including iron supplementation; however, interactions have not been studied (Prod Info CHEMET(R) oral capsules, 2013).
    B) LEAD POISONING
    1) SUMMARY
    a) See the following dosing information for pediatric dose recommendations (Prod Info CHEMET(R) oral capsules, 2013):
    1) 8 to 15 KG: Dose: 100 mg (1 capsule)
    2) 16 to 23 KG: Dose: 200 mg (2 capsules)
    3) 24 to 34 KG: Dose: 300 mg (3 capsules)
    4) 35 to 44 KG: Dose: 400 mg (4 capsules)
    5) Greater than 45 KG: Dose: 500 mg (5 capsules)
    b) Three adults presenting with lead encephalopathy have been reported to improve with succimer therapy; however, data are incomplete concerning the use of succimer for the treatment of lead encephalopathy in children (Prod Info CHEMET(R) oral capsules, 2013).
    c) Because the prevalence of lead toxicity and iron deficiency is highest among poor, inner-city children, it appears to be clinically prudent to provide iron supplementation during chelation therapy with succimer, when the heme pathway is freed of the inhibitory effects of lead. Succimer can be safely administered to patients receiving supplemental iron, offering an advantage over BAL therapy. Intramuscular iron has been administered during succimer therapy with no adverse effects and with an associated therapeutic benefit (Haust et al, 1989).
    C) MERCURY POISONING
    1) SUMMARY
    a) Mercury (Hg) toxicity in 2 children was treated with oral succimer, 30 mg/kg/day for 5 days, followed by 20 mg/kg/day for 16 days. A second course was repeated after a 22-day drug-free period. Urinary mercury excretion ranged from 0% to 355% relative to pretreatment levels. Succimer appeared to be safe and efficacious for increasing urinary Hg excretion (Mortensen & Valenzuela, 1990).
    b) Pretherapy urinary Hg level in a 15-year-old boy was 1314 mcg/L. Following the second course of succimer therapy, the level dropped to 159 mcg/L. In the same patient, blood Hg fell from 2.3 to less than 1.0 mcg percent, with no rebound after the second course of therapy.

Maximum Tolerated Exposure

    A) ADULT
    1) An adult with a history of intentional arsenic trioxide exposure was treated with 1500 mg/day of DMSA and was discharged to home after several days to continue on a tapered dose of DMSA at home (a total of 150 capsules were dispensed). Five days after discharge, the patient intentionally ingested, at a minimum, an estimated 4000 mg (43 mg/kg) up to 8000 mg (87 mg/kg) of DMSA and fexofenadine with only minor symptoms reported. Laboratory studies were normal with only a slight increase in liver enzymes. The patient was discharged to home on day 17, and within 4 weeks all signs and symptoms had resolved (Buchwald, 2001).
    B) PEDIATRIC
    1) A 3-year-old girl, 13 kg, presented to the ED an hour after ingesting 2400 mg of succimer. No abnormalities, seizures, or CNS depression were observed. She remained asymptomatic during a 24 hour observation period. Electrolytes, CBC, and liver enzymes remained within normal limits. No short-term sequelae were noted (Sigg et al, 1998).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 500 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) Greater than 5011 mg/kg (RTECS, 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 1725 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Succimer, an analog of dimercaprol, forms water soluble chelates with heavy metals, which are subsequently excreted renally (Prod Info CHEMET(R) oral capsules, 2013). This drug is mainly used for the treatment of lead intoxication, but data have shown encouraging results in the treatment of mercury and arsenic poisoning (Graziano, 1994; Graziano, 1986).
    B) Succimer binds heavy metals; however, the chemical form of these chelates is not known. Rats given long-term DMSA were sacrificed after 4 months. Tissue analyses showed that DMSA mobilized lead only from soft tissue; no loss was reported from femur and there was no observable redistribution of lead to brain. Significant decrements in blood, brain and kidney lead concentrations were observed, with delayed loss from the liver. Effects were not sustained when assessed 4 months later (Cory-Slechta, 1988).
    1) Succimer appears to have little effect on the urinary excretion of the essential trace metals calcium, copper, iron, and magnesium (Mann & Travers, 1991).

Physicochemical

Physical Characteristics

    A) Succimer is a white crystalline powder, from aqueous methanol, with an unpleasant and characteristic mercaptan odor and taste (Prod Info CHEMET(R) oral capsules, 2013).

Molecular Weight

    A) 182.22 (Prod Info CHEMET(R) oral capsules, 2013)

References

General Bibliography

    1) Aaseth J: Recent advance in the therapy of metal poisonings with chelating agents. Human Toxicol 1983; 2:257-272.
    2) Bentur Y, Brook G, & Behar R: Meso-2,3-dimercaptosuccinic acid in the diagnosis and treatment of lead poisoning. Clin Toxicol 1987a; 25:39-51.
    3) Bentur Y, Brook J, & Behar R: Meso-2,3-dimercaptosuccinic acid in the diagnosis and treatment of lead poisoning. Clin Toxicol 1987; 25:39-51.
    4) Bluhm RE, Breyer JA, & Bobbitt RG: Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part II: hyperchloraemia and genitourinary symptoms. Hum Exp Toxicol 1992; 11:211-215.
    5) Buchwald AL: Intentional overdose of dimercaptosuccinic acid in the course of treatment for arsenic poisoning. J Toxicol Clin Toxicol 2001; 39(1):113-114.
    6) Cory-Slechta DA: Mobilization of lead over the course of DMSA chelation therapy and long-term efficacy. J Pharmacol Exp Ther 1988; 246:84-91.
    7) Dart RC, Hurlbut KM, & Maiorino RM: Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults. J Pediatr 1994; 125:309-316.
    8) Domingo JL, Ortega A, & Paternain JL: Oral meso-2,3-dimercaptosuccinic acid in pregnant Sprague-Dawley rats: teratogenicity and alterations in mineral metabolism. I. Teratological evaluation. J Toxicol Environ Health 1990; 30:181-190.
    9) Fournier L, Thomas G, & Garnier R: 2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Med Toxicol 1988; 3:499-504.
    10) Fournier L, Thomas G, & Garnier R: 2,3-dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Med Toxicol 1988b; 3:499-504.
    11) Fournier L, Thomas G, Garnier R, et al: 2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans.. Med Toxicol 1988a; 3:499-504.
    12) Gerr F, Frumkin H, & Hodgins P: Hemolytic anemia following succimer administration in a glucose-6-phosphate dehydrogenase deficient patient. Clin Toxicol 1994; 32:569-575.
    13) Grandjean P, Jacobsen IA, & Jorgensen PJ: Chronic lead poisoning treated with dimercaptosuccinic acid. Pharmcol Toxicol 1991; 68:266-269.
    14) Graziano JH, Lolacono NJ, & Moulton T: Controlled study of meso-2,3- dimercaptosuccinic acid for the management of childhood lead intoxication. J Pediatr 1992; 120:133-139.
    15) Graziano JH, Siris ES, & LoIacono N: 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985; 37:431-438.
    16) Graziano JH, Siris ES, & LoIacono N: 2,3-Dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985a; 37:431-439.
    17) Graziano JH: 2,3-Dimercaptosuccinic acid (DMSA, Succimer), in Goldfrank LR, Flomenbaum NE, Lewin NA et al (eds): Toxicologic Emergencies, 5'th ed, Appleton & Lange, Norwalk, CT, 1994, pp 1045-1047.
    18) Graziano JH: Role of 2,3-Dimercaptosuccinic acid in the treatment of heavy metal poisoning. Med Toxicol 1986a; 1:155-162.
    19) Graziano JH: Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisoning. Med Toxicol 1986; 1:155-162.
    20) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    21) Haust HL, Inwood M, & Spence JD: Intramuscular administration of iron during long-term chelation therapy with 2,3-dimercaptosuccinic acid in a man with severe lead poisoning. Clin Biochem 1989; 22:189-196.
    22) Kapoor SC, Wielopolski L, & Graziano JH: Influence of 2,3- dimercaptosuccinic acid on gastrointestinal lead absorption and whole-body lead retention. Toxicol App Pharmacol 1989; 97:525-529.
    23) Lenz K, Hruby K, & Druml W: 2,3-Dimercaptosuccinic acid in human arsenic poisoning. Arch Toxicol 1981; 47:241-243.
    24) Maiorino RM, Bruce DC, & Aposhian HV: Determination and metabolism of dithiol chelating agents. Toxicol Applied Pharmacol 1989; 97:338-349.
    25) Mann KV & Travers JD: Succimer, an oral lead chelator. Clin Pharm 1991; 10:914-922.
    26) Marcus S, Okose P, & Jennis T: Untoward effects of oral dimercaptosuccinic acid in the treatment of lead poisoning (abstract). Vet Hum Toxicol 1991; 33:376.
    27) Mortensen ME & Valenzuela PM: 2,3-Dimercaptosuccinic acid (DMSA) chelation in mercury (Hg) vapor poisoning (abstract). Vet Hum Toxicol 1990; 32:361.
    28) Pappas JB, Ahlquist JT, & Winn P: The effect of oral succimer (SUCC) on ongoing exposure to lead (Pb) (abstract). Vet Hum Toxicol 1992; 34:361.
    29) Product Information: CHEMET(R) oral capsules, succimer oral capsules. Ovation Pharmaceuticals,Inc, Deerfield, IL, 2005.
    30) Product Information: CHEMET(R) oral capsules, succimer oral capsules. Lundbeck Inc. (per Manufacturer), Deerfield, IL, 2011.
    31) Product Information: CHEMET(R) oral capsules, succimer oral capsules. Recordati Rare Diseases Inc. (per DailyMed), Lebanon, NJ, 2013.
    32) Product Information: Chemet(R), succimer. Sanofi-Synthelabo Inc, Fort Washington, PA, 2000.
    33) Sigg T, Burda A, & Leikin JB: A report of pediatric succimer overdose. Vet Human Toxicol 1998; 40:90-91.
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    35) Zhang J: Clinical observations in ethyl mercury chloride poisoning. Am J Ind Med 1984; 5:251-258.