Therapeutic Applications of Succimer in Lead Poisoning and Its Potential Effects on Development

Applications of Succimer in the Treatment of Heavy Metal Poisoning

Succimer is an orally active, heavy-metal chelating agent that forms stable, water-soluble complexes with lead; it also chelates other toxic heavy metals, such as arsenic and mercury. It is a designated orphan drug that is indicated for the treatment of lead poisoning, specifically in children with blood lead concentrations higher than 45 micrograms/dL. Succimer reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output without adversely affecting essential mineral excretion at the recommended dosage regimen. The rebound in lead concentrations that can occur after short courses of chelating therapies (caused by redistribution of lead from bone stores) may require frequent and multiple courses of chelation therapy. The most common adverse effects reported in clinical trials of succimer in children and adults were nausea, vomiting, diarrhea, appetite loss, and loose stools; these effects may be related to the drug's unpleasant mercaptan odor. There are no known drug interactions between succimer and other drugs, including iron supplements, although data are limited. The recommended initial dosage in children is 10 mg/kg or 350 mg/sq m every eight hours for five days. The dosage is then reduced to 10 mg/kg or 350 mg/sq m every 12 hours for an additional two weeks. Clinical studies indicate that succimer is relatively selective for lead and effectively lowers blood lead concentrations. Although clinical experience is limited, an oral lead chelator may offer advantages over currently available agents. [1]

Absorption of Succimer in the Human Body

Sucimmer is absorbed rapidly but incompletely after oral administration, probably through an active transporter. There is evidence that enterohepatic circulation occurs. Most sucimmer in plasma is protein (mainly albumin)-bound through a disulfide bond with cysteine; only a very small amount is present as free drug, which is filtered at the glomerulus then extensively reabsorbed into proximal tubule cells. Nonfiltered protein-bound sucimmer in peritubular capillaries is also available for uptake into proximal tubule cells by active anion transport at the basolateral membrane. DMSA therefore accumulates in the kidney where it is extensively metabolized in humans to mixed disulfides of cysteine. Some 10–25% of an orally administered dose of DMSA is excreted in urine, the majority within 24 h and most (>90%) as DMSA–cysteine disulfide conjugates. It is not known whether protein-bound DMSA can chelate lead; there is evidence that the mixed disulfides of cysteine are the active chelating moiety in humans. [2]

Physiological Changes after Succimer Treatment

Effects on Body Functions

This study investigated the influence of succimer chelation therapy in eliminating and/or minimizing lead-associated impairments of motor functions such as postural balance and locomotion or gait activities. In this study, postural balance and functional locomotion or gait were quantitated in 161 children in Cincinnati enrolled in a randomized, placebo-controlled, double blind clinical trial. In comparison to the placebo group, the succimer therapy group showed significantly decreased postural sway during dynamic task performance implying improved postural balance. The results from locomotion tests demonstrated significant improvements in functional tasks of obstacle crossing and normal walking in the succimer treated group. While some beneficial neuromotor effects of succimer therapy were observed in the present study there remains several unanswered questions such as how long these effects will persist and how succimer therapy modifies lead-associated cerebellar deficits manifesting as perturbations in vestibular and/or proprioception systems for postural balance and functional locomotion. [3]

Impacts on Cognition and Brain Development

The present study provides clear evidence that administration of succimer, using a regimen sufficient to reduce brain Pb levels, can lessen Pb-induced impairments in learning ability, attention, and regulation of arousal and/or emotion. In conclusion, this study demonstrates that it is possible for chelation therapy to alleviate certain types of Pb-induced behavioral/cognitive dysfunction in rats. This is an important demonstration because Pb-induced behavioral dysfunction is generally considered to be irreversiblehe present findings thus suggest that if a succimer treatment protocol that produced a substantial removal of Pb from the brain could be identified for humans, a functional benefit might be derived. In addition, the finding that succimer produced lasting adverse effects when administered to non-Pb–exposed rats highlights the potential risks of administering succimer or other metal chelating agents to children who do not have elevated tissue Pb levels. It is of significant concern that this type of therapy is being widely advocated as safe and effective for treating autism. [4]

References：

[1] Mann KV, Travers JD. Succimer, an oral lead chelator. Clinical Pharmacy. 1991 Dec;10(12):914-922. PMID: 1663439.

[2] Bradberry, S., & Vale, A. (2009). Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning. Clinical Toxicology, 47(7), 617–631. https://doi.org/10.1080/15563650903174828

[3] Bhattacharya, A., Shukla, R., Auyang, E. D., Dietrich, K. N., & Bornschein, R. (2007). Effect of succimer chelation therapy on postural balance and gait outcomes in children with early exposure to environmental lead. Neurotoxicology, 28(3), 686-695.

[4] Stangle, D. E., Smith, D. R., Beaudin, S. A., Strawderman, M. S., Levitsky, D. A., & Strupp, B. J. (2007). Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure. Environmental Health Perspectives, 115(2), 201-209.