A26: Antidotes in Depth

INTRODUCTION

Succimer (meso-2,3-dimercaptosuccinic acid, DMSA) is an orally active metal chelator that is approved by the US Food and Drug Administration (FDA) for the treatment of lead poisoning in children with blood lead concentrations higher than 45 µg/dL. Succimer is also used to treat patients poisoned with arsenic and organic and inorganic mercury. Succimer has a wider therapeutic index and exhibits many advantages over dimercaprol and edetate calcium disodium (CaNa₂EDTA), the two other chelators used for the same clinical problems. Animal studies suggest that succimer does not redistribute lead or arsenic to the central nervous system. The role of succimer alone and in conjunction with other chelators to treat lead encephalopathy continues to be defined.^60,73

HISTORY

Succimer was initially synthesized in 1949 in England.⁷¹ In 1954, antimony-a,a′-dimercaptopotassium succinate (TWSb) was developed to treat schistosomiasis.⁴² TWSb is antimony bound to the potassium salt of succimer in a 2:3 ratio, forming a water-soluble xenobiotic with 50 times less toxicity than the previously used antimony compound, tartar emetic. Several years later, a group from Shanghai demonstrated the ability of the sodium salt of succimer to increase the LD₅₀ of tartar emetic 16-fold in mice.¹⁰⁹ An early review of the Chinese experience with intravenous (IV) succimer in the treatment of occupational lead and mercury poisoning suggested efficacy similar to IV CaNa₂EDTA in increasing urinary lead and to intramuscular (IM) DMPS (racemic-2,3-dimercapto-1-propanesulfonic acid, unithiol) for mercury, with little observed toxicity.¹⁰⁵ This experience, the subsequent widespread use in Asia^{75,78,90,105,106,112} and Europe,^{17,34,40,43,63,99} and the realization that succimer could be used orally,^7,49 led to US-based animal experiments, human trials, and FDA approval in 1991 for the treatment of lead-poisoned children.

PHARMACOLOGY

Chemistry

Succimer is a white crystalline powder with a molecular weight of 182 Da and a characteristic sulfur odor and taste.⁶ Succimer is the meso form of 2,3-dimercaptosuccinic acid. It is highly polar and water soluble.

Related Agents

DMPS (racemic-2,3-dimercapto-1-propanesulfonic acid, Na salt) is a chelator that, like succimer, is a water-soluble analog of British anti-Lewisite (BAL).^7,9,23 A dose of 15 mg/kg of DMPS is equimolar to 12 mg/kg of succimer. DMPS has been used in the Soviet Union since the late 1950s and continues to be used in Russia and other former Soviet countries. DMPS, which is an investigational drug in the United States, is marketed in both oral and parenteral forms in Germany as Dimaval. DMPS seems promising in mercury and arsenic poisoning.^{3,5,7,9,11,14,23,45} DMPS is associated with an increase in the urinary ...