二巯基丁二酸

Target of Action

Succimer, also known as meso-2,3-Dimercaptosuccinic acid, primarily targets heavy metals in the body . It has a high specificity for ions of lead, mercury, cadmium, and arsenic .

Mode of Action

Succimer acts as a heavy metal chelator . It binds with high specificity to ions of lead in the blood to form a water-soluble complex . This complex is subsequently excreted by the kidneys . Succimer can also chelate mercury, cadmium, and arsenic in this manner .

Biochemical Pathways

The biochemical pathways affected by Succimer primarily involve the detoxification and excretion of heavy metals. By forming water-soluble complexes with heavy metals, Succimer facilitates their removal from the body, thereby reducing the toxic effects of these metals .

Pharmacokinetics

Succimer is orally active and is rapidly but variably absorbed . It forms water-soluble chelates and, consequently, increases the urinary excretion of lead . Chemical analysis of succimer and its metabolites (primarily mixed disulfides of L-cysteine) in the urine showed that succimer was rapidly and extensively metabolized .

Result of Action

The primary result of Succimer’s action is the reduction of heavy metal toxicity in the body. By binding to heavy metals and facilitating their excretion, Succimer helps to decrease the concentration of these toxic substances in the body . This can help to alleviate the symptoms of heavy metal poisoning and prevent further damage to the body’s tissues and organs .

Succimer, also known as dimercaptosuccinic acid (DMSA), is an orally active lead chelator that has been licensed by the U.S. Food and Drug Administration for the treatment of lead poisoning in children . Succimer's ability to lower blood lead levels has been well-documented, and the structure of succimer chelates of lead and cadmium are similar .

Chelation Therapy for Lead Poisoning

Succimer is primarily used in chelation therapy to reduce blood lead levels, particularly in children . A randomized, placebo-controlled trial involving 780 children with blood lead levels between 20–44 μg/dL showed that succimer treatment led to a more significant drop in blood lead levels compared to the placebo group. The succimer-treated group's mean blood lead level was 4.5 μg/dL lower than the placebo group during the six months after treatment initiation .

Modeling Succimer's Effects on Blood Lead Concentrations

Researchers have developed models to predict the impact of succimer chelation therapy on blood lead concentrations. A Chelation Lead Therapy (CLT) model was created by integrating a two-compartment kinetic succimer model into an existing PBPK (physiologically based pharmacokinetic) lead model. This model accurately simulated blood lead concentrations during and after succimer treatment in patients exposed to lead. The CLT model considers factors such as background exposure, additional exposure from sources like traditional remedies or occupational exposure, and chelation with succimer .

The CLT model calculates the effect of orally administered succimer during and after therapeutic sessions, considering multiple routes of lead exposure over days to years. It solves a system of ordinary differential equations that define the relationship between blood or urine lead concentration and its rate of change .

Impact on Postural Balance

Succimer therapy's effects extend beyond just reducing lead levels; it can also modify gross neuromotor function. A case study involving a nine-year-old boy with high lead levels used postural balance testing to measure therapy's effect. Following treatment with Ca EDTA and succimer, the patient's postural sway responses improved, becoming comparable to a low-lead comparison group in tests that rely less on higher centers for balance .

Case Studies

Patient A: A 44-year-old male ingested a traditional remedy for diarrhea during a visit to India for three days. He was admitted to the hospital with a blood lead concentration of 90 μg/dL after experiencing increasing lethargy and abdominal pain over two weeks. He was administered two successive courses of succimer at 30 mg/kg, one lasting eight days and the other five days, with a 23-day interval between them. The CLT model accurately simulated his blood lead concentrations during and after succimer treatment .

Patient B: A 57-year-old male was exposed to lead on two occasions through inhalation over several months due to occupational exposure. Data on blood and urine lead concentrations were available. The CLT model was used to predict the patient's blood lead concentrations after succimer therapy .

Data Table

Safety and Efficacy

Biochemical Properties

Succimer interacts with heavy metals in the body, forming strong chelates with them . This interaction is highly specific, particularly with ions of lead, mercury, cadmium, and arsenic . The nature of these interactions involves the binding of Succimer to these heavy metal ions, forming a water-soluble complex that can be excreted by the kidneys .

Cellular Effects

Succimer has a significant impact on various types of cells and cellular processes. Its primary function is to increase the urinary excretion of heavy metals, thereby reducing their concentration in the body . This can influence cell function by reducing the toxic effects of these heavy metals on cellular metabolism and gene expression .

Molecular Mechanism

The molecular mechanism of Succimer involves its role as a heavy metal chelator. It binds with high specificity to ions of lead in the blood, forming a water-soluble complex that is subsequently excreted by the kidneys . Similarly, Succimer can chelate mercury, cadmium, and arsenic in the same manner .

Temporal Effects in Laboratory Settings

The effects of Succimer can change over time in laboratory settings. For instance, it has been shown that Succimer treatment can produce lasting cognitive benefits if chelation sufficiently reduces brain lead levels .

Dosage Effects in Animal Models

In animal models, the effects of Succimer can vary with different dosages. For instance, studies have shown that doses of 2300 mg/kg in rats and 2400 mg/kg in mice produced ataxia, convulsions, labored respiration, and frequently death . No case of overdosage has been reported in humans .

Metabolic Pathways

Succimer is rapidly and extensively metabolized in the body, primarily to mixed disulfides of L-cysteine . This metabolic process occurs in the urine, where chemical analysis has shown that Succimer and its metabolites are rapidly and extensively metabolized .

Transport and Distribution

Succimer is primarily distributed extracellularly . After oral administration, absorption of Succimer is rapid but variable . It is then distributed throughout the body, where it binds to heavy metal ions and forms water-soluble chelates .

Succimer, chemically known as dimercaptosuccinic acid (DMSA), is an orally active chelating agent primarily used in the treatment of lead poisoning. Its biological activity is characterized by its ability to form stable complexes with heavy metals, facilitating their excretion from the body. This article delves into the biological mechanisms, efficacy, safety profile, and notable case studies associated with succimer.

Succimer operates through the following mechanisms:

• Chelation : Succimer binds to heavy metals such as lead, mercury, cadmium, and arsenic, forming water-soluble complexes that are excreted through urine .
• Increased Urinary Excretion : By enhancing the solubility of these metals, succimer significantly increases their urinary excretion rate, thereby reducing their toxic burden in the body .

Pharmacokinetics

The pharmacokinetic profile of succimer includes:

• Absorption : Rapid but variable absorption occurs after oral administration.
• Metabolism : Succimer is extensively metabolized into mixed disulfides of L-cysteine.
• Half-life : Approximately 48 hours, allowing for sustained action in chelation therapy .

Lead Poisoning Treatment

Succimer has been extensively studied for its efficacy in treating lead poisoning. A notable randomized controlled trial involving 780 children demonstrated that succimer reduced blood lead levels more effectively than placebo. The results indicated:

• Mean Blood Lead Level Reduction : A decrease of 4.5 μg/dL compared to placebo-treated children over six months post-treatment .
• Safety Profile : While succimer was generally well-tolerated, there was a noted increase in scalp rashes among treated children (3.5% vs. 1.3% in placebo) .

Case Study 1: Congenital Lead Poisoning

An infant with congenital lead poisoning due to maternal petrol sniffing was treated with succimer. The treatment resulted in:

• Initial Blood Lead Level : 3.98 μmol/L.
• Treatment Regimen : Oral succimer at a dose of 10 mg/kg three times daily for five days, followed by a reduced dose.
• Outcome : Significant reduction in blood lead levels and improvement in alertness without adverse effects noted .

Case Study 2: Occupational Lead Exposure

A 51-year-old decorator exposed to lead paint presented with symptoms indicative of lead poisoning. He received:

• Initial Blood Lead Level : 84.2 μg/dL.
• Treatment : Intravenous sodium calcium edetate followed by oral succimer.
• Outcome : Resolution of symptoms after 14 days of treatment despite developing a urticarial reaction to succimer .

Cognitive and Behavioral Outcomes

Research indicates that succimer not only reduces blood lead levels but may also have implications for cognitive function:

• In animal studies, succimer improved learning and attention in lead-exposed rats but raised concerns about potential cognitive impairments when administered without prior lead exposure .
• Long-term follow-up studies have shown mixed results regarding cognitive benefits in children treated with succimer for elevated blood lead levels .

Summary of Findings