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Introduction

  1. Pharmacology. Unithiol (DMPS; 2,3-dimercaptopropanol-sulfonic acid), a dimercapto chelating agent that is a water-soluble analog of BAL, is used in the treatment of poisoning by several heavy metals, principally mercury, arsenic, and lead. Available on the official formularies of Russia and former Soviet countries since 1958 and in Germany since 1976, unithiol has been legally available from compounding pharmacists in the United States since 1999. The drug can be administered orally and parenterally. Oral bioavailability is approximately 50%, with peak blood concentrations occurring in approximately 3.7 hours. It is bound extensively to plasma proteins, mainly albumin. More than 80% of an intravenous dose is excreted in the urine, 10% as unaltered unithiol, and 90% as transformed products, predominantly cyclic DMPS sulfides. The elimination half-life for total unithiol is approximately 20 hours. Unithiol and/or its in vivo biotransformation products form complexes with a variety of inorganic and organic metal compounds, increasing excretion of the metal in the urine and decreasing its concentration in various organs, particularly the kidneys. Renal elimination of the metal chelates appears to be mediated in part by the multidrug resistance protein 2 (Mrp2). Unlike BAL, unithiol does not redistribute mercury to the brain.
  2. Indications
    1. Unithiol has been used primarily in the treatment of intoxication by mercury, arsenic, and lead. In animal models, unithiol has averted or reduced the acute toxic effects of inorganic mercury salts and inorganic arsenic when administered promptly (minutes to hours) after exposure. Unithiol is associated with a reduction in tissue levels of mercury, arsenic, and lead in experimental animals, and it increases the excretion of those metals in humans. However, randomized, double-blind, placebo-controlled clinical trials demonstrating therapeutic efficacy in acute or chronic heavy metal poisoning have not been reported.
    2. Animal studies and a few case reports suggest that unithiol may have utility in the treatment of poisoning by bismuth compounds. Animal studies suggest that unithiol may increase survival after acute exposure to polonium 210; however, redistribution to the kidneys may occur.
  3. Contraindications
    1. History of allergy to the drug.
    2. Because renal excretion is the predominant route of elimination of unithiol and its metal complexes, caution is warranted in administering unithiol to patients with severe renal insufficiency. Published reports support the use of unithiol as an adjunct to high flux hemodialysis or hemodiafiltration in patients with anuric renal failure caused by mercury salts and bismuth.
  4. Adverse effects
    1. The German manufacturer (Heyl) notes a low overall incidence (<4%) of adverse side effects.
    2. Self-limited, reversible allergic dermatologic reactions such as exanthems and urticaria have been the most commonly reported adverse effect. Isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported.
    3. Because rapid intravenous administration may be associated with vasodilation and transient hypotension, intravenous injections of unithiol should be administered slowly, over a 15- to 20-minute interval.
    4. Unithiol increases the urinary excretion of copper and zinc, an effect that is not anticipated to be clinically significant in standard courses of treatment in patients without preexisting deficiency of these trace elements.
    5. Use in pregnancy. Unithiol did not exhibit teratogenicity or other developmental toxicity in animal studies. Although protection against the adverse reproductive effects of selected toxic metals has been demonstrated in pregnant animals, there is insufficient clinical experience with the use of unithiol in human pregnancy.
  5. Drug or laboratory interactions
    1. Aqueous solutions of unithiol for intravenous injection should not be mixed with other drugs or minerals. Oral preparations should not be consumed simultaneously with mineral supplements.
    2. Unithiol has been shown to form a complex with an arsenic metabolite, monomethylarsonous acid (MMAIII), which then is excreted in the urine. Laboratory techniques that use hydride reduction to measure urinary arsenic and its metabolites (“speciation”) may not detect this complex. However, the complex will contribute to measurement of “total urinary arsenic.”
  6. Dosage and method of administration. Unithiol may be administered by the oral, intramuscular, and intravenous routes. The intravenous route should be reserved for the treatment of severe acute intoxication by inorganic mercury salts or arsenic when compromised GI or cardiovascular status may interfere with rapid or efficient absorption from the GI tract. In animal models, oral unithiol did not increase the GI absorption of mercuric chloride. In the United States, compounding pharmacists (including those in hospital inpatient pharmacies) may obtain bulk quantities of pharmaceutical-grade unithiol and dispense it as an injection solution for infusion (usually 50 mg/mL in sterile water). Capsules (typically in 100- or 300-mg sizes) may also be prepared in an oral dose form. Note: Bulk unithiol must be obtained outside the United States, and such supplies should have a certificate of analysis to ensure product purity.
    1. Severe acute poisoning by inorganic mercury or arsenic. Administer 3-5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes. If, after several days, the patient's GI and cardiovascular status has stabilized, consider changing to oral unithiol, 4-8 mg/kg every 6-8 hours.
    2. Symptomatic poisoning by lead (without encephalopathy). Oral unithiol, 4-8 mg/kg orally every 6-8 hours, may be considered an alternative to succimer. Note: Parenteral therapy with EDTA is preferable for the treatment of patients with severe lead intoxication (lead encephalopathy or lead colic) and for patients with extremely high blood lead concentrations (eg, blood lead >150 mcg/dL).
    3. Mobilization or “chelation challenge” tests measuring an increase in urinary excretion of mercury and arsenic after a single dose of unithiol have been described, but their diagnostic or prognostic value has not been established.