Succimer (meso-2,3-Dimercaptosuccinic Acid): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary

1.1 Overview of Succimer as a Chelating Agent

Succimer is an orally active, small molecule dithiol compound that functions as a heavy metal chelating agent.[1] Structurally, it is a water-soluble analog of dimercaprol (BAL) and is classified as a sulfur-containing dicarboxylic acid.[1] Its primary therapeutic role is as an antidote in the management of heavy metal poisoning. The molecule's efficacy stems from its ability to form stable, water-soluble complexes, or chelates, with toxic metal ions. These complexes are subsequently eliminated from the body, primarily through renal excretion, thereby reducing the overall metal burden and mitigating toxicity.[4]

1.2 Key Therapeutic Indications and Mechanism of Action

The United States Food and Drug Administration (FDA) has approved succimer for the treatment of lead poisoning in pediatric patients who present with blood lead levels (BLL) exceeding 45 µg/dL.[6] It is important to note that the drug is not indicated for the prophylaxis of lead poisoning in individuals who may be exposed to a lead-containing environment.[1] The mechanism of action is centered on the two sulfhydryl (mercapto) groups within the succimer molecule. These groups exhibit a high affinity for divalent and trivalent metal cations, binding to them to form a stable heterocyclic ring structure. This sequestration prevents the metal ions from interacting with and damaging essential biological macromolecules, such as enzymes.[6] While its primary indication is for lead poisoning, succimer is also used off-label for the treatment of mercury and arsenic poisoning.[1]

1.3 Summary of Pharmacokinetic Profile and Clinical Efficacy

Succimer exhibits rapid but variable oral absorption.[4] Following absorption, it undergoes extensive biotransformation into mixed disulfides with endogenous cysteine; these metabolites are now understood to be the primary active chelating moieties, suggesting that succimer functions as a prodrug.[3] The elimination half-life of these active transformed metabolites is approximately 2 to 4 hours, which dictates the recommended dosing frequency.[3] Clinically, succimer has demonstrated high efficacy in increasing the urinary excretion of lead and significantly reducing circulating BLLs.[13] However, a significant clinical limitation is the phenomenon of post-treatment rebound, where BLLs rise again after therapy is discontinued. This occurs due to the redistribution of lead from deep tissue compartments, particularly bone, back into the bloodstream.[7]

1.4 Synopsis of Safety, Tolerability, and Major Precautions

Succimer is generally considered to be well-tolerated, with a more favorable safety profile than older parenteral chelators.[9] The most frequently reported adverse effects are gastrointestinal in nature, including nausea, vomiting, and diarrhea, along with the potential for a skin rash.[6] Key clinical precautions include ensuring the patient remains adequately hydrated throughout the treatment course and performing regular monitoring of hematologic and hepatic function due to risks of transient neutropenia and elevated liver transaminases.[10] The only absolute contraindication to its use is a known history of hypersensitivity to the drug.[14]

2.0 Chemical Identity and Physicochemical Properties

2.1 Nomenclature and Identification Codes

Precise identification of a pharmaceutical substance is paramount for research, clinical practice, and regulatory affairs. Succimer is known by a variety of names and is cataloged under several international coding systems.

• Generic Name: Succimer [4]
• English Name: Succimer [User Query]
• Brand Names: The most common brand name in the United States is Chemet®.[6] International brand names include Succicaptal.[17]
• Synonyms/Other Names: The compound is widely known by the abbreviation DMSA, which stands for dimercaptosuccinic acid. It is also referred to as meso-2,3-dimercaptosuccinic acid to specify the clinically relevant stereoisomer.[6]
• IUPAC Name: The systematic name according to the International Union of Pure and Applied Chemistry is (2R,3S)-2,3-disulfanylbutanedioic acid, which may also be written as (2S,3R)-2,3-bis(sulfanyl)butanedioic acid.[1]
• Identification Codes:
• DrugBank ID: DB00566 [User Query]
• CAS Number: 304-55-2 [6]
• PubChem CID: 2724354 [6]
• ChEBI ID: CHEBI:63623 [6]
• InChI: InChI=1S/C4H6O4S2/c5-3(6)1(9)2(10)4(7)8/h1-2,9-10H,(H,5,6)(H,7,8)/t1-,2+ [1]
• InChIKey: ACTRVOBWPAIOHC-XIXRPRMCSA-N [1]
• SMILES: O=C(O)C@@HC(O)=O

2.2 Molecular Structure and Stereochemistry

Succimer's therapeutic activity is intrinsically linked to its specific three-dimensional structure.

• Molecular Formula: $C_{4}H_{6}O_{4}S_{2}$
• Molecular Weight: 182.21 g·mol⁻¹
• Structural Class: Succimer is a derivative of succinic acid, a four-carbon dicarboxylic acid. It is distinguished by the presence of two mercapto (thiol, -SH) groups attached to the second and third carbon atoms of the chain. It can also be classified within the broader group of thia fatty acids.
• Stereoisomerism: The succimer molecule contains two chiral centers at positions C2 and C3. This stereochemistry gives rise to three possible stereoisomers: a pair of enantiomers (the 2S,3S and 2R,3R forms) and a meso compound (the 2R,3S form). The clinically utilized drug, succimer, is specifically the meso isomer, which is achiral and thus optically inactive due to an internal plane of symmetry. The selection of this specific isomer is a critical aspect of its development. Manufacturing processes often favor single isomers to ensure predictable pharmacology and avoid the complexities of racemic mixtures. For succimer, the meso form is noted to be easier to synthesize and purify. This practical advantage, combined with a well-established therapeutic index, solidifies its use over the other isomers. Therefore, in a clinical and pharmaceutical context, the name "succimer" is synonymous with "meso-2,3-dimercaptosuccinic acid".

2.3 Physical and Chemical Properties

The bulk properties of the active pharmaceutical ingredient define its formulation, handling, and stability.

• Physical Description: Succimer is a white to off-white crystalline powder or solid.
• Odor and Taste: The molecule's two thiol groups are responsible for a potent and unpleasant mercaptan-like odor and taste, often described as a stench. This characteristic is inherent to the drug and is noticeable upon opening the capsule packaging; it does not signify product degradation. The strong odor presents a significant challenge for patient compliance, particularly in the pediatric population for which the drug is primarily indicated. This has driven specific efforts in manufacturing to mitigate this issue.
• Solubility: It is characterized as a water-soluble chelating agent, with a measured water solubility of 2.43 mg/mL. It is also soluble in organic solvents such as dimethyl sulfoxide (DMSO).
• Melting Point: The melting point is reported as 125 °C.
• pKa: The strongest acidic pKa value is 3.37, corresponding to the dissociation of a proton from one of the two carboxylic acid groups.

2.4 Synthesis and Purification

The manufacturing process for succimer aims to produce the correct stereoisomer with high purity.

• Synthesis: A common synthetic route involves the reaction of acetylenedicarboxylic acid with a sulfur-containing nucleophile, such as sodium thiosulfate or thioacetic acid. This addition reaction across the carbon-carbon triple bond is followed by a hydrolysis step to liberate the free thiol groups, yielding dimercaptosuccinic acid.
• Purification: Standard purification techniques include precipitation and recrystallization from solvents like methanol. Given the significant issue of the drug's odor, specific purification processes have been developed. One patented method focuses on producing a "low odor" product by washing the crude crystalline DMSA with an aqueous medium, preferably substantially pure water, and subsequently drying the material at a low temperature (below 40 °C) to minimize volatile impurities that may contribute to the odor. This highlights how a fundamental physicochemical property can directly influence industrial-scale manufacturing and final product formulation to improve patient acceptability.

Table 2.1: Summary of Succimer Identification and Physicochemical Properties

Property	Value	Source(s)
Generic Name	Succimer
Brand Name (US)	Chemet
Chemical Class	Dithiol, Dicarboxylic Acid
IUPAC Name	(2R,3S)-2,3-disulfanylbutanedioic acid
CAS Number	304-55-2	[User Query]
DrugBank ID	DB00566	[User Query]
Molecular Formula	$C_{4}H_{6}O_{4}S_{2}$
Molecular Weight	182.21 g·mol⁻¹
Physical Appearance	White or off-white crystalline powder
Odor/Taste	Unpleasant, characteristic mercaptan odor and taste
Water Solubility	2.43 mg/mL
pKa (Strongest Acidic)	3.37

3.0 Pharmacology

3.1 Mechanism of Action: Heavy Metal Chelation

Succimer's therapeutic effect is derived from its function as a heavy metal chelator. The core of this mechanism lies in the molecular structure, which features two vicinal sulfhydryl (thiol) groups. These groups have a strong chemical affinity for "soft" heavy metal ions, such as lead ($Pb^{2+}$), mercury ($Hg^{2+}$), and arsenic ($As^{3+}$).

Upon administration, succimer circulates and encounters these metal ions. The two thiol groups donate lone pairs of electrons to form strong covalent bonds with the metal ion, creating a stable, five-membered ring structure known as a chelate. This process effectively sequesters the toxic metal, preventing it from binding to the sulfhydryl groups of critical endogenous proteins and enzymes, thereby neutralizing its biological toxicity. The resulting succimer-metal complex is significantly more water-soluble than the free metal ion. This increased polarity facilitates its clearance from the body, as the complex is readily filtered by the glomeruli of the kidneys and excreted in the urine. This enhanced renal elimination is the ultimate goal of therapy, leading to a reduction in the total body burden of the heavy metal.

3.2 Pharmacodynamics: Effects on Metal Excretion and Endogenous Systems

The pharmacodynamic effects of succimer are a direct consequence of its chelating action.

• Increased Metal Excretion: The primary and most measurable effect of succimer administration is a dramatic increase in the urinary excretion of the target heavy metal. In clinical studies involving adults with lead poisoning, treatment with succimer at 30 mg/kg/day resulted in a median 12-fold increase in daily urine lead excretion compared to baseline levels. The peak effect on lead elimination is typically observed after the very first dose of the treatment course.
• Reduction in Blood Metal Concentrations: As a direct result of enhanced renal clearance, succimer therapy leads to a significant and rapid reduction in the concentration of lead in the blood.
• Reversal of Enzyme Inhibition: Lead is known to be a potent inhibitor of several enzymes, particularly those involved in the heme synthesis pathway. By chelating and removing lead, succimer can help reverse this enzyme inhibition, contributing to the resolution of some of the pathophysiological effects of lead toxicity.
• Effects on Essential Minerals: A crucial pharmacodynamic advantage of succimer is its relative selectivity for toxic heavy metals over essential endogenous minerals. At recommended therapeutic doses, it does not cause clinically significant depletion of iron, calcium, or magnesium. While it does cause minor increases in the urinary excretion of copper and zinc, this effect is generally not considered to be clinically important. This selectivity provides a superior safety profile compared to less specific chelating agents.

3.3 Target Selectivity and Binding Affinity

Succimer's clinical utility is defined by its affinity for specific metal ions.

• Primary Targets: The primary clinical targets for succimer chelation are lead, mercury, and arsenic. It demonstrates a particularly high specificity for lead ions circulating in the blood.
• Other Potential Targets: In principle, succimer can also form chelates with other heavy metals, including cadmium. This potential is reflected in its listing as a cadmium chelator in several pharmacological databases. However, it is critical to distinguish this theoretical capability from proven clinical effectiveness. A randomized trial in children with background environmental exposures found that while succimer effectively lowered blood lead levels, it did not produce a significant reduction in blood cadmium concentrations. This discrepancy underscores the important distinction between in-vitro binding potential and in-vivo therapeutic efficacy. The lack of effect on cadmium in a clinical setting could be due to several factors, including a lower binding affinity for cadmium compared to lead in a complex biological environment, differences in the pharmacokinetics of the succimer-cadmium chelate, or insufficient baseline levels of cadmium to demonstrate a measurable reduction. This finding serves as a crucial reminder that clinical application must be guided by robust in-vivo evidence rather than solely by chemical potential.

4.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

4.1 Oral Absorption and Bioavailability

Following oral administration, succimer's absorption from the gastrointestinal tract is characterized as rapid but both variable and incomplete. Peak blood concentrations are typically reached within 1 to 3 hours post-dose. There is evidence suggesting the involvement of an active transport mechanism for its absorption. Furthermore, pharmacokinetic studies indicate the presence of an enterohepatic circulation loop, where a metabolite of succimer is excreted into the bile, re-enters the intestine, and is subsequently reabsorbed. This reabsorption process appears to be dependent on the activity of the gut microflora. While there have been concerns that a chelating agent might increase the absorption of concurrently ingested metals, a study in a juvenile primate model demonstrated that oral succimer actually decreased the gastrointestinal absorption of lead.

4.2 Distribution and Protein Binding

Once absorbed, succimer's distribution is predominantly confined to the extracellular fluid compartment. In the bloodstream, it is extensively bound to plasma proteins, with binding reported to be greater than 95%. The primary binding protein is albumin, and the linkage occurs via the formation of a disulfide bond with a cysteine residue on the protein. The ability of succimer to cross the blood-brain barrier (BBB) in humans has not been definitively established. While studies in mice have shown that it can enter the central nervous system (CNS), its clinical use is not indicated for the treatment of lead encephalopathy, implying that its penetration into the human brain is either limited or not sufficient to be therapeutically effective for this severe condition.

4.3 Biotransformation: Succimer as a Prodrug

Succimer undergoes rapid and extensive biotransformation in the body, a process so central to its activity that it is now considered a prodrug. The parent molecule is metabolized into mixed disulfides, formed by creating a disulfide bridge between one or both of succimer's thiol groups and the thiol group of the amino acid L-cysteine.

This metabolic conversion is not merely a step in the drug's elimination but is fundamental to its therapeutic action. Pharmacokinetic studies have revealed that the time course of urinary lead excretion does not correlate with the concentration of the parent succimer molecule. Instead, it closely follows the concentration and excretion of its "altered" or metabolized forms—the succimer-cysteine disulfides. This observation leads to the conclusion that these metabolites are the primary active chelating species in vivo. This refined understanding of its mechanism shifts the conceptual model of its action. Rather than acting as a simple chelator that binds lead throughout the bloodstream, succimer appears to function as a delivery system. The parent drug is absorbed and distributed, accumulating in the kidneys where it is metabolized. The active chelating metabolites are thus generated at high concentration at the primary site of excretion, which may enhance the efficiency of capturing and eliminating lead from the body.

4.4 Elimination Pathways and Half-Life

The elimination of succimer and its metabolites occurs through two main routes. The unabsorbed fraction of the oral dose is excreted unchanged in the feces. The absorbed portion is primarily eliminated by the kidneys into the urine. The urinary excretion products consist of approximately 90% mixed succimer-cysteine disulfide metabolites and only about 10% unchanged parent drug.

The elimination half-life of succimer can be described by several different values, and it is crucial to distinguish what each represents:

• The most clinically relevant value is the elimination half-life of the transformed succimer (the active metabolites), which is approximately 2 to 4 hours. This relatively short half-life justifies the need for multiple daily doses (every 8 or 12 hours) to maintain effective therapeutic concentrations.
• In contrast, studies using radiolabeled ($^{14}C$) succimer have reported an apparent elimination half-life of the total radiolabeled material of about two days. This much longer value does not represent the active drug but rather the slow clearance of all carbon-14 containing fragments, some of which may be incorporated into endogenous pools.
• Studies comparing different populations have found that the half-life of total DMSA (parent drug plus its oxidized metabolites) is longer in children with lead poisoning (approximately 3.0 hours) than in healthy adults (approximately 2.0 hours). This suggests that lead poisoning itself may impair the renal clearance of the drug and its metabolites, a key pharmacodynamic interaction that highlights the stress placed on the kidneys during both poisoning and treatment.

5.0 Clinical Applications and Efficacy

5.1 Approved Indication: Treatment of Pediatric Lead Poisoning

The primary, FDA-approved indication for succimer is for the treatment of lead poisoning in pediatric patients aged one year and older who have a blood lead level (BLL) measured above 45 micrograms per deciliter (µg/dL). The use of succimer is strictly therapeutic and is not indicated for the prophylaxis or prevention of lead poisoning in individuals who anticipate exposure to a lead-contaminated environment. A foundational principle of treatment is that chelation therapy must always be accompanied by the identification and complete removal of the source of lead exposure from the patient's environment. Chelation therapy is an adjunct to, not a substitute for, environmental abatement.

5.2 Investigational and Off-Label Uses

Beyond its approved indication, succimer has been utilized and investigated for other conditions:

• Mercury and Arsenic Poisoning: Although not an approved indication on the US product label, succimer is widely used as a chelator for poisoning with inorganic mercury and arsenic. Clinical experience, though limited to small numbers of patients, has shown that succimer increases the urinary excretion of these metals and can lead to symptomatic improvement.
• Orphan Drug Designation: Succimer has been proposed as an orphan drug for two distinct conditions: the prevention of cystine kidney stone formation in individuals with homozygous cystinuria, and for the treatment of mercury intoxication.
• Cancer Therapy: The role of heavy metals in carcinogenesis has prompted new research. A Phase I clinical trial (NCT03630991) is currently investigating the use of succimer in combination with edetate calcium disodium (Ca-EDTA) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The hypothesis is that chelating and removing toxic metals from the bone marrow and blood may improve the patient's response to standard chemotherapy.
• Autism Spectrum Disorder: A completed Phase 1/2 trial (NCT00811083) explored the use of DMSA in children with autism, based on a theory that some individuals with autism have an impaired ability to excrete heavy metals. However, this use is considered anecdotal, and the practice is not supported by robust evidence of safety or efficacy.

5.3 Analysis of Clinical Trial Data and Therapeutic Outcomes

Clinical studies have provided a clear picture of both the strengths and limitations of succimer therapy.

• Efficacy in Reducing BLL: Succimer is unequivocally effective at mobilizing lead from the body. It significantly increases urinary lead excretion and produces a rapid and substantial decrease in BLLs. Patients often report symptomatic improvement, such as resolution of headache and lethargy, within the first 48 hours of treatment.
• Lack of Cognitive Benefit in Mild Poisoning: A landmark large, randomized, double-blind, placebo-controlled study known as the Treatment of Lead-exposed Children (TLC) trial provided a critical, albeit sobering, finding. In children with moderately elevated BLLs (in the range of 25 to 44 µg/dL), treatment with succimer, despite lowering BLLs, showed no evidence of benefit on long-term neurocognitive or behavioral outcomes. This finding strongly suggests that the neurotoxic effects of lead, particularly on the developing brain, can be irreversible. By the time lead exposure is detected and chelation is initiated, the structural and functional damage to the central nervous system may have already occurred. This positions chelation therapy not as a restorative cure, but as an intervention to prevent further damage from ongoing lead exposure. This reality underscores that the absolute priority in managing lead toxicity is the primary prevention of exposure in the first place.

5.4 Limitations of Therapy and Post-Treatment Rebound Phenomenon

A major limitation of chelation therapy is the post-treatment rebound of BLLs.

• Rebound Effect: After a course of succimer is completed, BLLs often rise again, sometimes rapidly. This is not a failure of the drug but a predictable physiological event. Succimer primarily chelates lead from the blood and soft tissues, which represent only a small fraction of the total body lead burden. The vast majority of lead is stored in deep tissue compartments, with the skeleton serving as the largest reservoir. When the circulating lead is removed by chelation, a concentration gradient is established, causing lead to leach back out of these bone stores and redistribute into the bloodstream.
• Clinical Implication of Rebound: This rebound phenomenon necessitates careful post-treatment management. Blood lead levels must be monitored at least weekly until they stabilize to assess the extent of the rebound. Often, the rebound is significant enough to require one or more repeated courses of chelation therapy. A treatment-free interval of at least two weeks between courses is generally recommended. This allows time for the lead to redistribute from bone to the blood, effectively "refilling" the chelatable pool and making the subsequent course of therapy more efficient.

6.0 Dosage, Administration, and Clinical Monitoring

6.1 Recommended Dosing Regimens in Pediatric and Adult Populations

The standard dosing for succimer follows a 19-day course designed to maximize initial lead removal and then manage the redistribution phase.

• Pediatric (FDA-Approved): For children aged 1 year and older, the total treatment course is 19 days.
• Days 1-5 (Initial Phase): The recommended dose is 10 mg/kg or 350 mg/m² administered orally every 8 hours.
• Days 6-19 (Maintenance Phase): The dosing frequency is reduced to 10 mg/kg or 350 mg/m² administered orally every 12 hours.
• Adults: Although not an FDA-approved indication, similar weight-based dosing is used in adults. A common regimen is 10 mg/kg orally every 8 hours for 5 days, followed by the same dose every 12 hours for an additional 14 days.
• Repeated Courses: If BLLs rebound to a clinically significant level after a course is completed, treatment may be repeated. A minimum interval of two weeks between courses is recommended to allow for lead redistribution, unless the BLL is high enough to warrant more immediate intervention.

6.2 Administration Guidelines and Patient Counseling

Proper administration is key to ensuring efficacy and tolerability.

• Succimer capsules can be taken with or without food.
• For young children or any patient unable to swallow capsules, the capsule can be opened and the medicated beads inside can be sprinkled onto a small amount of soft food (e.g., applesauce) or placed on a spoon and immediately followed by a fruit drink to ensure the full dose is ingested.
• Patients and caregivers should be counseled on the critical importance of maintaining adequate fluid intake throughout the treatment period to support renal function and the excretion of the metal chelates.
• Patients should be informed that the drug's mercaptan nature may cause a noticeable and unpleasant odor in their urine, sweat, and feces. This is a normal and expected effect of the medication.

6.3 Essential Pre-Treatment and On-Treatment Monitoring Protocols

Close clinical monitoring is required to ensure safety and efficacy.

• Pre-Treatment Evaluation: Before initiating therapy, a baseline assessment must be performed, including:
• Confirmation of blood lead concentration.
• Complete blood count (CBC) with differential and platelet count, ensuring the absolute neutrophil count (ANC) is above 1,500/mcL.
• Liver function tests (serum transaminases AST and ALT).
• Renal function tests (BUN and serum creatinine).
• On-Treatment Monitoring:
• Hematologic: A CBC with differential should be monitored weekly throughout the course of therapy to detect any signs of neutropenia.
• Hepatic: Serum transaminases should also be monitored weekly to assess for hepatotoxicity.
• Lead Levels: Following the completion of the 19-day course, BLL should be monitored at least weekly until stable to quantify the rebound effect and determine the need for subsequent courses of therapy.

Table 6.1: Weight-Based Pediatric Dosing Chart for Succimer

This chart simplifies dosing based on the available 100 mg capsule strength. The prescribed dose is administered every 8 hours for the first 5 days, then every 12 hours for the next 14 days.

7.0 Safety and Toxicology Profile

7.1 Adverse Drug Reactions and Side Effect Profile

Succimer is generally well-tolerated, especially in comparison to older, parenteral chelating agents. Adverse effects are typically mild and manageable.

• Common (>10%): The most frequently reported adverse reactions are gastrointestinal in nature and may be related to the drug's unpleasant mercaptan odor and taste. These include nausea, vomiting, diarrhea, loose stools, and decreased appetite. A metallic taste in the mouth is also common.
• Less Common (1-10%): Dermatologic reactions, primarily rash, occur in approximately 4% of patients. Other less common effects include pruritus, drowsiness, dizziness, and paresthesia. Transient, mild-to-moderate elevations in serum aminotransferases (ALT, AST) are also observed in 6-10% of patients during therapy.
• Rare but Serious:
• Hematologic Effects: Mild-to-moderate neutropenia has been reported. While a causal relationship is not definitively established, it is a known risk with this class of drugs. It is recommended that therapy be withheld if the absolute neutrophil count (ANC) falls below 1,200/mm³ and cautiously resumed only after the count recovers. Other hematologic changes noted include eosinophilia and thrombocytosis.
• Hypersensitivity and Dermatologic Reactions: Potentially severe allergic reactions can occur, including urticaria and angioedema. A rare but serious adverse event is the development of a mucocutaneous vesicular eruption. If a significant rash or any sign of a hypersensitivity reaction occurs, treatment should be interrupted immediately.

Table 7.1: Summary of Adverse Reactions Associated with Succimer Therapy

System Organ Class	Common (>10%) Reactions	Less Common (1-10%) Reactions	Rare / Frequency Not Defined Reactions
Gastrointestinal	Nausea, vomiting, diarrhea, loose stools, decreased appetite, metallic taste	Abdominal cramps, flatus	Hemorrhoidal symptoms
Dermatologic	-	Rash (including papular and herpetic), pruritus	Severe mucocutaneous eruptions, urticaria, angioedema
Hematologic	-	-	Neutropenia, eosinophilia, thrombocytosis
Hepatic	-	Transient elevations in serum transaminases (ALT, AST)	-
Nervous System	-	Drowsiness, dizziness	Paresthesia, sensorimotor neuropathy, headache
General/Other	-	-	Fever, chills, flu-like symptoms, unpleasant body odor (urine, sweat)

7.2 Warnings, Precautions, and Contraindications

• Contraindication: The only absolute contraindication is a history of a hypersensitivity reaction to succimer or any of the excipients in the formulation.
• Warnings and Precautions:
• Hydration: It is imperative that all patients undergoing treatment maintain adequate hydration to support renal function and facilitate the urinary excretion of the metal-chelate complexes.
• Renal Impairment: Succimer should be used with caution in patients with compromised renal function, as the drug and its metabolites are cleared by the kidneys. The safety and efficacy in patients with severe renal insufficiency are uncertain.
• Hepatic Impairment: Given that transient elevations in liver enzymes are common, the drug should be used with caution in patients with a pre-existing history of liver disease. Weekly monitoring of liver function tests is recommended for all patients.

7.3 Use in Special Populations

• Pregnancy: The safety of succimer use during pregnancy has not been established in humans. Animal reproduction studies at high doses have shown evidence of maternal toxicity and fetotoxicity. In cases of severe lead poisoning during pregnancy where chelation is deemed necessary, other agents such as sodium calcium edetate are generally preferred.
• Lactation: It is unknown whether succimer or its metabolites are excreted into human milk. Due to the potential for adverse effects in the nursing infant, breastfeeding is generally discouraged for mothers requiring succimer therapy.
• Pediatrics: While the drug is approved for use in children aged 1 year and older, its safety and efficacy have not been established in infants less than 12 months of age.

7.4 Preclinical Toxicology and Overdose Management

• Preclinical Toxicology: Succimer demonstrates a low acute oral toxicity, with a median lethal dose ($LD_{50}$) in rodents exceeding 3.6 g/kg. Chronic high-dose studies in dogs revealed renal toxicity and an autoimmune-mediated thrombocytopenia, a finding common in dogs but not other species.
• Overdose Management: There have been no cases of acute overdose reported in humans. Consequently, there is no established protocol for managing an overdose. Supportive care would be the mainstay of treatment. It is important to consider the drug's properties in the context of overdose management. Limited data suggest that the parent drug, succimer, is dialyzable. However, the lead-succimer chelates are not. This distinction is clinically critical. While hemodialysis might help remove the drug itself in a pure overdose scenario, it would be ineffective at enhancing the elimination of the toxic metal in a poisoned patient with renal failure. This means that for a patient with anuria, succimer therapy is not a viable option, as dialysis cannot substitute for the necessary renal excretion of the metal complexes.

8.0 Drug and Laboratory Test Interactions

8.1 Known and Potential Drug-Drug Interactions

The available data on drug-drug interactions with succimer are limited.

• Other Chelating Agents: Concurrent administration of succimer with other chelating agents, such as edetate calcium disodium (CaNa2EDTA) or dimercaprol (BAL), is not recommended due to a lack of data on safety and efficacy. If a patient has previously been treated with EDTA or BAL, a washout period of at least four weeks is recommended before initiating therapy with succimer.
• Diagnostic Agents: Succimer may interfere with certain diagnostic imaging agents. Specifically, it may decrease the effectiveness of Technetium Tc-99m oxidronate, which is used in bone scans.
• Nutritional Supplements: There are no known significant interactions with iron supplements, though data are limited.

8.2 Interference with Clinical Laboratory Assays

Succimer's chemical properties can lead to interference with certain laboratory tests.

• Urine Ketones: The presence of thiol groups in the succimer molecule can cause a false-positive result for ketones in the urine when using tests that rely on the nitroprusside reaction (e.g., dipstick tests).
• Serum Analytes: Succimer may also cause falsely decreased measurements of serum uric acid and creatine phosphokinase (CPK).

9.0 Historical Development and Global Regulatory Status

9.1 Discovery and Evolution as a Therapeutic Agent

Succimer, or dimercaptosuccinic acid (DMSA), has a history of use as an antidote that predates its formal FDA approval by several decades.

• Initial Synthesis and Purpose: The compound was first synthesized in the 1950s by V. L. Nirenburg at the Urals Polytechnic Institute in the former Soviet Union. The research was commissioned by an industrial enterprise that used large quantities of mercury and was seeking a prophylactic agent to protect its workers from mercury poisoning.
• Early Clinical Discoveries: In 1957, scientists in China discovered its effectiveness in treating poisoning from antimony, a complication of treatment with tartar emetic. In 1962, further research from the Soviet Union by I. E. Okonishnikova demonstrated its protective effects against arsenic and mercury poisoning in animal models.

9.2 Regulatory Approvals and Brand Formulations (U.S. FDA)

The formal regulatory journey of succimer in the United States began in the 1980s.

• Orphan Drug Status: In 1984, Bock Pharmaceutical Company successfully applied to the FDA for orphan drug status for succimer, which was intended to be marketed under the brand name Chemet.
• FDA Approval: The FDA granted marketing approval for Chemet in 1991, specifically for the treatment of lead poisoning in pediatric patients.
• Formulation: The approved product in the United States is an oral capsule containing 100 mg of succimer as coated beads.

9.3 International Status: Australia (TGA) and Europe (EMA)

The regulatory status of succimer varies globally, which reflects different national health priorities and pharmaceutical market dynamics.

• Australia (TGA): There does not appear to be a full marketing authorisation for an oral formulation of succimer in Australia. However, the drug is available to clinicians through the Therapeutic Goods Administration's (TGA) Special Access Scheme (SAS). The SAS is a regulatory pathway that allows health practitioners to access unapproved therapeutic goods for individual patients on a case-by-case basis when it is deemed clinically necessary. This status suggests that while succimer is recognized as an essential antidote for rare cases of heavy metal poisoning, the market size is not sufficient to incentivize a commercial sponsor to pursue a full registration.
• Europe (EMA): The provided information contains no evidence of a centralized marketing authorisation for succimer granted by the European Medicines Agency (EMA). While medicines can be authorized at the national level by individual member states, information on such authorizations is not available. The lack of a centralized EMA approval may be due to similar market dynamics as in Australia, where the drug is an essential but low-volume agent.
• Global Recognition: Despite the varied regulatory landscape, succimer's importance as an antidote is globally recognized, as evidenced by its inclusion on the World Health Organization's List of Essential Medicines.

10.0 Conclusion and Expert Recommendations

10.1 Synthesis of Succimer's Role in Modern Toxicology

Succimer (meso-2,3-dimercaptosuccinic acid) holds a firm and well-defined place in modern clinical toxicology. It is the preferred oral chelating agent for the treatment of significant lead poisoning in children, largely due to its efficacy and superior safety profile compared to older, more toxic parenteral agents like dimercaprol (BAL) and edetate calcium disodium (CaNa2EDTA). Its mechanism as a prodrug, with biotransformation to active cysteine-disulfide metabolites that likely act primarily within the kidney, represents a sophisticated understanding of its pharmacology. However, its clinical utility is sharply defined. It is a secondary intervention whose success is wholly dependent on the primary, and most critical, intervention: the complete and permanent abatement of the source of environmental lead exposure. Furthermore, clinical evidence has established that while succimer effectively reduces blood lead levels, it does not reverse established neurocognitive deficits, reinforcing its role in preventing further damage rather than curing past injury.

10.2 Gaps in Knowledge and Recommendations for Future Research

Despite its established use, several gaps in the understanding of succimer remain, which should guide future research efforts:

• CNS Penetration: There is a need for definitive studies to quantify the extent to which succimer and its active metabolites cross the human blood-brain barrier. This knowledge is critical for understanding its potential, or lack thereof, in mitigating CNS toxicity.
• Off-Label Indications: While used for arsenic and mercury poisoning, this is based on limited data. Robust, controlled clinical trials are needed to establish definitive evidence-based guidelines for its efficacy and dosing in these poisonings.
• Chronic Chelation: The long-term safety and efficacy of repeated or maintenance chelation courses are not well understood. This is particularly relevant for patients with retained lead sources, such as embedded shotgun pellets, who face chronic endogenous exposure.
• Special Populations: Pharmacokinetic and safety data are lacking for patients with severe renal or hepatic impairment, populations in whom the drug must be used with extreme caution.
• Novel Applications: The ongoing investigation of succimer in hematologic malignancies is an intriguing new frontier, exploring the broader role of metal homeostasis in cancer biology and treatment.

10.3 Final Recommendations for Clinical Practice

Based on a comprehensive review of the available evidence, the following recommendations are provided for clinicians:

1. Adhere to Approved Indications: Succimer should be used strictly for its approved indication—treatment of pediatric lead poisoning with BLL >45 µg/dL. Its use for lower BLLs is not supported by evidence of clinical benefit on neurocognitive outcomes. It must never be used for prophylaxis.
2. Prioritize Environmental Abatement: Chelation therapy is not a substitute for a safe environment. The identification and removal of the source of lead exposure is the most critical step in management and must precede or occur concurrently with treatment.
3. Manage Rebound Phenomenon: Clinicians must anticipate the post-treatment rebound in BLL. Patients and caregivers should be counseled on this predictable event. A full 19-day course should be completed, followed by at least weekly BLL monitoring until levels are stable to determine the need for further courses.
4. Maintain Vigilant Monitoring: Strict adherence to weekly monitoring of CBC with differential and liver transaminases is essential to promptly identify and manage potential hematologic and hepatic adverse effects.
5. Consult Toxicology Experts: The management of any significant heavy metal poisoning is complex. It is strongly recommended that clinicians consult with a regional poison control center or a clinical toxicologist when considering chelation therapy to ensure optimal patient management.

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