Succimer

Elucidation of Sulfhydryl Group Reactivity in Metal Binding

A key feature of this compound is the presence of two sulfhydryl (-SH) groups. patsnap.comnih.govpatsnap.com These thiol groups exhibit a high affinity for binding to heavy metal ions. patsnap.compatsnap.com The reactivity of these sulfhydryl groups is central to this compound's ability to sequester toxic metals. patsnap.compatsnap.com Studies have shown that these groups readily ionize upon complexation with metal cations, facilitating the binding process. wikipedia.org

Formation of Stable, Water-Soluble Chelate Complexes

Upon binding to heavy metal ions, this compound forms stable, ring-like structures known as chelates. patsnap.com The formation of these complexes is crucial for reducing the biological activity and toxicity of the metals. patsnap.com A significant aspect of this compound's mechanism is that the resulting metal-succimer complexes are water-soluble. patsnap.comnih.govwikipedia.orgdrugbank.com This increased water solubility enhances their excretion from the body, primarily through the kidneys in urine. patsnap.compatsnap.comontosight.ai This process effectively reduces the total body burden of toxic metals. patsnap.com

Research has investigated the structure of these metal complexes. For instance, studies on the complexes formed with Pb²⁺, Cd²⁺, and Hg²⁺ have indicated that the structure of the complex is dependent on the specific metal ion. nih.gov With Pb²⁺ and Cd²⁺, one oxygen and one sulfur atom appear to act as donor atoms. nih.gov In the case of Hg²⁺, both sulfur atoms function as donors. nih.gov The solubility of these metal chelates is also pH-dependent, becoming more soluble as noncoordinated sulfhydryl and carboxylic acid groups become ionized. nih.gov

Stereochemical Aspects of Chelate Formation

This compound exists as diastereomers, with the meso isomer being the form used as a chelating agent. wikipedia.orgchemicalbook.com The this compound molecule contains two asymmetric carbon atoms, leading to the possibility of different stereoisomers. wikipedia.org The meso-2,3-dimercaptosuccinic acid structure features the two mercapto groups oriented in a specific spatial arrangement. ontosight.ai The stereochemistry of the chelating agent and the metal ion plays a role in the strength and structure of the coordination complexes formed. jcimcr.orgresearchgate.net Studies on the dimethyl ester of meso-2,3-dimercaptosuccinic acid have shown that the two methyl ester groups and the two sulfhydryl groups are in a staggered conformation, and the resulting cadmium complex forms a distorted tetrahedron with a CdS₄ kernel. nih.gov

Preferential Binding Dynamics with Lead, Mercury, Arsenic, and Cadmium Ions

This compound binds with high specificity to ions of lead, mercury, cadmium, and arsenic. patsnap.comnih.govdrugbank.comnih.govrxlist.comhmdb.ca This high affinity for these toxic heavy metals is attributed to the chemical properties of the sulfhydryl groups, which have a strong tendency to bind with "soft" heavy metals like Hg²⁺ and Pb²⁺. patsnap.comwikipedia.org Research consistently highlights this compound's effectiveness in chelating lead, mercury, and arsenic, facilitating their excretion. patsnap.compatsnap.comnih.govpatsnap.comnih.govunict.itmhmedical.com

Research on Minimal Chelation of Endogenous Essential Metals (e.g., Zinc, Copper, Iron, Magnesium, Calcium)

A significant advantage of this compound over some other chelating agents is its reported minimal chelation of essential endogenous metals such as zinc, copper, iron, magnesium, and calcium at therapeutic doses. nih.govchemicalbook.comrxlist.comnih.govmhmedical.comfda.gov While some studies have indicated minor increases in the urinary excretion of zinc and copper, the effect on essential minerals is generally considered small compared to chelators like CaNa₂EDTA, which can induce more substantial excretion of these elements. rxlist.commhmedical.comfda.govoup.commedicinacomplementar.com.br

For example, studies in lead-exposed men showed that this compound treatment led to a doubling of zinc excretion but had no significant effect on the urinary elimination of iron, calcium, or magnesium. rxlist.comfda.gov Another study in heavy metal-poisoned subjects found that only plasma zinc decreased significantly after DMSA treatment, while levels of calcium, copper, iron, and magnesium were not significantly affected. oup.com However, some research in adult patients with lead poisoning noted a significant increase in urine copper and zinc excretion following DMSA administration. oup.com A study in a primate model of childhood lead exposure reported trending but non-significant increases in urinary Ca, Cu, and Fe, but not in Zn or Mg. oup.com These findings suggest some variability in the effect on essential metals, though generally considered less pronounced than with other chelating agents.

Research findings on the impact of this compound on essential metal excretion:

Prevention of Metal-Biological Macromolecule Interactions

Heavy metals exert their toxic effects by binding to biological macromolecules such as proteins (including enzymes), nucleic acids, and lipids, often by interacting with sulfhydryl groups or displacing essential metal ions like Ca²⁺ and Zn²⁺ jcimcr.orgresearchgate.netacs.org. This compound's dithiol groups compete with these biological ligands for binding to heavy metal ions. By forming more stable complexes with the toxic metals, this compound effectively sequesters the metal ions, preventing their interaction with critical cellular components. patsnap.compatsnap.com This competitive binding reduces the ability of heavy metals to alter protein structures, inhibit enzyme functions, or disrupt cellular processes that are dependent on essential metal ions. patsnap.comjcimcr.org The stability of the this compound-metal complex is a crucial factor in its ability to prevent these interactions, as a more stable complex indicates a stronger binding affinity of this compound for the metal compared to biological ligands. jcimcr.orgnih.govfiveable.me

Reduction of Metal Toxicity at the Cellular and Enzymatic Levels

The chelation of heavy metals by this compound directly contributes to the reduction of metal toxicity at both cellular and enzymatic levels. By forming stable, water-soluble complexes, this compound lowers the concentration of free, biologically active metal ions within the body. patsnap.comdrugbank.com This reduction in free metal ions minimizes their ability to induce oxidative stress, damage cellular structures, and interfere with enzymatic activities. patsnap.comjcimcr.orgresearchgate.netujvas.com.ua

Heavy metals can inhibit enzymes by binding to their active sites, often by interacting with sulfhydryl groups or displacing essential cofactors like zinc jcimcr.orgacs.orgulisboa.pt. This compound's ability to chelate these metals reduces their availability to bind to and inactivate these critical enzymes. While some chelators can potentially interfere with metalloenzymes by binding to their essential metal cofactors, this compound is reported not to significantly chelate essential metals such as zinc, copper, or iron at therapeutic concentrations, contributing to its specificity for toxic heavy metals nih.govmhmedical.com. However, minor increases in the excretion of essential metals like zinc and copper have been noted mhmedical.com. Research has investigated the effect of chelators, including this compound, on zinc-containing enzymes like alcohol dehydrogenase (ADH), suggesting that interference might occur at higher concentrations ulisboa.pt.

Stability Constants of this compound-Metal Complexes

The stability of the complexes formed between this compound and various metal ions is a critical factor in its efficacy as a chelating agent. Higher stability constants generally indicate a stronger binding affinity between the chelator and the metal ion. Studies have determined stability constants for this compound (DMSA) with several metal ions, providing insights into its selectivity and chelating strength.

Note: For Zinc(II), the system is dominated by a Zn₂(DMSA)₂ dimer, and no more than 20% of total zinc exists as a monomeric complex at any pH under the studied conditions colab.ws.

These stability constants highlight the strong affinity of this compound for certain heavy metals like bismuth and lead, supporting its use in treating poisoning by these elements. The relatively lower monomeric complex formation with zinc also aligns with observations that this compound does not significantly chelate essential zinc nih.govmhmedical.com.

Data from animal studies also provide insights into the effects of this compound on enzyme activity in the context of heavy metal toxicity. For example, in lead-treated rats, administration of this compound was associated with increased levels of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), which were decreased by lead exposure alone ujvas.com.ua. This suggests that this compound's action in chelating lead helps to mitigate the oxidative stress induced by the metal, thereby supporting the recovery of these enzymatic defense systems.

Data derived from research findings on enzyme activity in lead-treated rats ujvas.com.ua. P-values indicate statistical significance compared to the group treated with lead acetate alone.

Research on Gastrointestinal Absorption Dynamics and Variability

Research indicates that the gastrointestinal absorption of this compound is rapid but can be variable. aap.orgfda.govnih.govdrugbank.com Studies in healthy adult volunteers administered a single dose of 14C-succimer showed peak blood radioactivity levels between one and two hours. fda.gov On average, about 49% of the radiolabeled dose was excreted, with 39% in feces, suggesting that a significant portion represents non-absorbed drug. fda.gov This implies that the absorption is incomplete. fda.govnih.gov Chemical analysis of this compound and its metabolites in urine after a single oral dose in healthy adults showed that approximately 25% of the administered dose was excreted in the urine, with peak blood levels and urinary excretion occurring between two and four hours. fda.gov

There has been some concern that oral this compound treatment might increase the absorption of lead from the gastrointestinal tract, particularly if exposure continues during treatment. researchgate.netnih.govnih.gov A preliminary study using a stable lead isotopic tracer (204Pb) in adult male subjects suggested that GI lead absorption might be enhanced by this compound, and that this compound mediated the redistribution of lead from the circulation to other tissues. researchgate.netnih.gov However, the differences observed in this study were not statistically significant due to large within-group variability. researchgate.netnih.gov In contrast, a study using a juvenile nonhuman primate model of moderate childhood lead intoxication found that oral this compound significantly reduced the GI absorption of lead. nih.gov These discrepancies may be attributed to differences in species, age, or experimental design. researchgate.net

The following table summarizes findings on this compound absorption and excretion:

Investigations into Enterohepatic Circulation

Evidence suggests that enterohepatic circulation of this compound or its metabolites occurs. nih.govnih.gov Studies in normal adults have observed increases in plasma total DMSA concentration after meals, which were prevented by the administration of cholestyramine or neomycin. nih.gov These findings indicate that a metabolite(s) of DMSA undergoes enterohepatic circulation and that microflora are required for this reentry. nih.gov

Extracellular Distribution Dominance

Studies have shown that this compound is primarily distributed in the extracellular fluid of the body. mhmedical.comaap.orgresearchgate.nettandfonline.comnih.govnih.gov This extracellular distribution may contribute to its relatively low toxicity compared to other dithiols. nih.gov Kinetic modeling studies in healthy adult volunteers after oral administration of this compound have indicated that "total" DMSA is distributed in the body's extracellular fluid and in blood, being almost entirely distributed in the plasma and not penetrating erythrocytes. tandfonline.com The relative volume of distribution has been reported to range between 0.17 and 0.34 L/kg, further supporting that the distribution volume is mainly restricted to extracellular fluid. uu.nl

Plasma Protein Binding Dynamics (e.g., Albumin Interactions)

In the blood, this compound is extensively bound to plasma proteins, with binding exceeding 90%. mhmedical.comaap.orgsemanticscholar.org The primary protein involved in this binding is albumin. aap.orgnih.govsemanticscholar.orgresearchgate.net this compound binds to plasma proteins, mainly albumin, through a disulfide bond with cysteine. nih.govresearchgate.net This extensive protein binding means that only a very small amount of the parent drug is present as free this compound in the plasma. nih.govresearchgate.net The unbound fraction is typically considered the pharmacologically active portion of a drug, available for distribution into tissues, metabolism, and excretion. wikipedia.orgbioanalysis-zone.com However, for this compound, there is evidence suggesting that the mixed disulfides of cysteine, rather than the parent drug or protein-bound this compound, may be the active chelating moiety in vivo. mhmedical.comnih.govresearchgate.net If this is the case, chelation might occur principally in the kidney, where this compound is extensively metabolized to mixed disulfides of cysteine. nih.govresearchgate.net

Technetium Tc-99m this compound, a related compound used in renal imaging, is also distributed in plasma and bound to plasma proteins following intravenous administration, with 53% to 70% protein binding observed in humans. drugbank.com

Research on Blood-Brain Barrier Permeability and Brain Metal Mobilization

Research on the ability of this compound to cross the blood-brain barrier (BBB) and mobilize metals from the brain has yielded varying results, particularly depending on the metal involved and the study model.

Some sources suggest that DMSA can cross the blood-brain barrier and is thus useful for extracting heavy metals from the brain. chemeurope.com It has been stated that this compound facilitates the urinary excretion of lead and, with sufficiently aggressive treatment, can reduce lead content in the brain. wikipedia.org Animal studies have shown that dimercaptosuccinic acid can cross the blood-brain barrier in mice. wikipedia.org

However, other research indicates that this compound does not cross the blood-brain barrier to any major extent. researchgate.net Comparative studies between this compound and calcium disodium edetate (CaNa2EDTA) in experimental models have not consistently observed an effect of chelation therapy on brain lead concentrations. researchgate.net Some animal studies have suggested that neither DMSA nor other chelating or mobilizing agents were able to ameliorate the brain burden of mercury. nih.gov

While some evidence supports this compound's ability to influence brain metal levels, particularly lead in certain models, there are conflicting findings and a lack of definitive evidence confirming significant BBB permeability and consistent brain metal mobilization in humans across all heavy metals.

Characterization of Mixed Disulfide Formation with L-Cysteine

A prominent metabolic pathway for this compound involves the formation of mixed disulfides with the amino acid L-cysteine. Chemical analysis of urine samples from individuals administered this compound has revealed that a substantial portion of the drug is excreted in these altered forms. The majority of the mixed disulfides identified consist of this compound in disulfide linkages with two molecules of L-cysteine. nih.govfda.govfda.govpharmacompass.comrxlist.com The remaining disulfides contain one L-cysteine molecule per this compound molecule. nih.govfda.govfda.govpharmacompass.comrxlist.com Research indicates that the formation of these mixed disulfides with L-cysteine is favored over the formation of cyclic disulfides of this compound itself. nih.govpharmacompass.com

Identification of Active Chelating Moiety in Vivo (e.g., this compound-Cysteine Adducts)

While this compound is the administered compound, evidence suggests that its metal-chelating activity in vivo may be primarily attributed to its metabolites, specifically the mixed disulfides formed with L-cysteine (this compound-cysteine adducts). mhmedical.combrainkart.com If these adducts are indeed the principal active form, it has been proposed that chelation might occur predominantly within the kidneys. nih.gov

Contribution of Renal and Hepatic Metabolism

This compound is known to be rapidly and extensively metabolized. fda.govmhmedical.comdrugbank.comdrugs.com Although the specific site of this biotransformation is not fully understood mhmedical.comdrugbank.com, the formation of DMSA-cysteine mixed disulfides is assumed by some research to occur in the kidney. tandfonline.com The liver is generally a primary organ for drug metabolism slideshare.netpharmaguideline.com, but there is limited clinical data available concerning the metabolism of this compound in individuals with liver impairment. fda.govfda.gov The majority of the absorbed this compound is ultimately excreted by the kidneys, primarily in its metabolized forms. fda.govdrugs.com

Renal Excretion Mechanisms and Routes

Absorbed this compound is predominantly excreted in the urine in the form of its metabolites. nih.govfda.govdrugbank.comdrugs.com Studies in healthy adult volunteers have shown that approximately 25% of an administered dose is excreted in the urine, with peak urinary excretion occurring between two and four hours post-administration. fda.gov Of the total amount of drug eliminated in the urine, a significant majority, approximately 90%, is in the form of altered this compound, specifically mixed this compound-cysteine disulfides, while the remaining 10% is excreted as unchanged this compound. fda.govfda.govrxlist.com The water-soluble complexes formed between this compound (or its active metabolites) and heavy metals are filtered from the bloodstream by the renal glomeruli and subsequently excreted in the urine. patsnap.com Maintaining adequate hydration is important to support the renal excretion of these chelating agents and their metal complexes. rxlist.comdrugs.com

The following table summarizes typical urinary excretion data:

Role of Multidrug Resistance Protein 2 (Mrp2) in Renal Elimination

Experimental evidence suggests the involvement of Multidrug Resistance Protein 2 (Mrp2), an efflux transporter, in the renal elimination of this compound-metal complexes. mhmedical.combrainkart.com Mrp2 is located on the apical membrane of renal proximal tubule cells and plays a role in transporting organic anions from the cells into the tubular lumen for excretion in the urine. solvobiotech.comwikipedia.org Specifically, experimental data indicates that Mrp2 facilitates the renal excretion of mercury compounds when bound to transformed this compound. mhmedical.combrainkart.com

Apparent Elimination Half-Life Studies

Investigations into the pharmacokinetics of this compound (DMSA) have provided data on its apparent elimination half-life in humans, although findings can vary depending on the study population and methodology.

In studies involving healthy adult volunteers, the apparent elimination half-life of total DMSA (parent drug plus oxidized metabolites) in the blood has been reported to be approximately two days following a single oral dose of radiolabeled this compound at varying concentrations (16, 32, or 48 mg/kg). fda.govfda.gov In other studies of healthy adults given a single oral dose of 10 mg/kg, chemical analysis of this compound and its metabolites in urine indicated that approximately 25% of the dose was excreted in urine, with peak levels occurring between two and four hours. fda.govfda.gov Of the urinary excretion, about 90% was in the form of mixed this compound-cysteine disulfides, while 10% was eliminated unchanged. fda.govfda.gov

A pharmacokinetic modeling study in healthy adult volunteers reported an initial distribution phase half-life of about 25 minutes and an elimination phase half-life of approximately 4.3 hours for total DMSA plasma concentrations after oral administration of 10 mg/kg. tandfonline.comtandfonline.comuu.nl This study noted that the observed data sometimes showed an apparent postprandial peak in plasma DMSA concentration, occurring around 11 hours after administration, which was attributed to a fat-rich dinner activating an enterohepatic cycle. tandfonline.comtandfonline.comuu.nl

Comparisons of pharmacokinetics between different populations have revealed variations in elimination half-life. A study comparing healthy adults, lead-poisoned adults, and lead-poisoned children found differences in the elimination half-life of total DMSA. nih.gov The elimination half-life was longer in children with lead poisoning (3.0 ± 0.2 hours) compared to adults with lead poisoning (1.9 ± 0.4 hours) and healthy adults (2.0 ± 0.2 hours). nih.gov This study also indicated that renal clearance of DMSA and its metabolites was greater in healthy adults than in either adults or children with lead poisoning, suggesting that impaired renal clearance may contribute to the longer half-life observed in poisoned individuals, particularly children. nih.gov

Another source indicates that DMSA has a half-life of 2–3 hours in the blood. taylorandfrancis.com

The differences observed in reported half-life values across studies may be influenced by factors such as the specific analytical method used (measuring parent drug vs. total radiolabeled material or total DMSA including metabolites), the study population (healthy volunteers vs. poisoned patients, adults vs. children), the route and form of administration, and the pharmacokinetic model applied.

Here is a summary of some reported apparent elimination half-life data:

Interactive table:

Studies on Reduction of Blood Lead Concentrations

Research has consistently shown that this compound significantly increases urine lead elimination and reduces blood lead concentrations in patients with lead poisoning. nih.govtandfonline.comoup.com The reduction in blood lead levels is dose-dependent. tandfonline.comfda.gov Over a 5-day treatment course, mean daily urine lead excretion can increase by 5- to 20-fold compared to baseline, and blood lead concentrations can fall to 50% or less of pretreatment levels, although individual responses vary. nih.govtandfonline.com Maximum enhancement of urine lead elimination typically occurs with the first dose. nih.govtandfonline.com

In a dose-ranging study involving pediatric patients aged 2 to 7 years with blood lead levels between 30-49 µg/dL, different this compound doses resulted in varying reductions in mean blood lead levels over 5 days: 78% reduction with 350 mg/m² every 8 hours, 63% with 233 mg/m² every 8 hours, and 42% with 116 mg/m² every 8 hours. fda.gov These doses corresponded to approximately 10, 6.7, and 3.3 mg/kg, respectively. fda.gov

A large multicenter, placebo-controlled randomized trial (Treatment of Lead-Exposed Children - TLC Trial) involving children with blood lead levels of 20-44 µg/dL found that this compound-treated children experienced an abrupt drop in blood lead levels compared to placebo-treated children. nih.gov The mean blood lead level in the this compound group during the 6 months after treatment initiation was 4.5 µg/dL lower than in the placebo group. nih.gov

Mobilization of Lead from Soft Tissues and Bone Stores

This compound promotes the excretion of lead, thereby reducing body stores. medscape.com While it effectively reduces blood lead levels, studies suggest that this compound's efficacy in removing lead from brain tissues may lag behind and be smaller in magnitude compared to its effect on blood lead levels. oup.comresearchgate.netnih.gov This is an important consideration as blood lead levels are often used clinically to estimate lead reductions in the brain. researchgate.netnih.gov

Following chelation therapy, including with this compound, a rebound increase in blood lead concentration can occur. cncb.ac.cnnih.govtandfonline.comfda.govwho.intwho.int This rebound is attributed to the redistribution of lead from bone and soft tissue stores back into the blood as the concentration in the blood re-equilibrates. nih.govtandfonline.comfda.govwho.intwho.intresearchgate.net Studies in rats have detected this rebound in blood lead levels after this compound regimens, but not in brain lead levels. researchgate.netnih.gov Substantial amounts of lead are eliminated into the urine, suggesting mobilization from bone or soft tissues. avma.org

Impact on Lead-Induced Biochemical Alterations (e.g., δ-aminolevulinic acid dehydratase activity)

Lead exposure is known to inhibit the activity of enzymes involved in heme synthesis, such as δ-aminolevulinic acid dehydratase (ALAD). nih.govaoemj.orgunc.edu This inhibition leads to the accumulation of δ-aminolevulinic acid. nih.govaoemj.org Research indicates that this compound can help reverse lead-induced alterations in biochemical markers. nih.gov Both this compound and its analogue, monoisoamyl DMSA (MiADMSA), have been shown to increase blood ALAD activity and glutathione (GSH) levels towards normal in lead-exposed rats. nih.gov The most prominent effect on blood ALAD activity was observed when MiADMSA was co-administered with alpha-lipoic acid. nih.gov this compound reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output. cncb.ac.cn

Comparative Efficacy Studies with Other Lead Chelating Agents (e.g., CaNa2EDTA, BAL)

Comparative studies have evaluated the efficacy of this compound against other chelating agents like calcium disodium edetate (CaNa₂EDTA) and dimercaprol (BAL). This compound is an oral agent, offering an advantage over parenteral chelators like CaNa₂EDTA and BAL, which require injection. cncb.ac.cnmedscape.commhmedical.comaafp.orgessentialmeds.orgindianpediatrics.net

In two small, non-controlled clinical trials comparing this compound and CaNa₂EDTA in children with initial blood lead levels of 31 to 69 µg/dL, high-dose this compound reduced mean blood lead levels by 61% to 77% over five days, while CaNa₂EDTA treatment resulted in about a 45% decline. aafp.org A retrospective study comparing children treated with BAL and CaNa₂EDTA versus children treated with this compound and CaNa₂EDTA found a comparable reduction in post-treatment blood lead levels between the two groups. aafp.org

In a study involving adults with blood lead concentrations >40 µg/dL, both this compound and intravenous CaNa₂EDTA significantly reduced blood lead levels and the prevalence of clinical symptoms. nih.govresearchgate.net this compound had a greater impact on reducing blood lead concentrations (p = .005), while CaNa₂EDTA had a greater impact on lead mobilization (p = .04). nih.govresearchgate.net However, when comparing equimolar doses, CaNa₂EDTA was found to be more effective than this compound (p < .001). nih.govresearchgate.net

This compound is generally considered to have a more favorable adverse effect profile compared to other lead chelators and causes less urinary loss of essential minerals. essentialmeds.orgindianpediatrics.net

Research on Therapeutic Regimen Optimization for Sustained Metal Reduction and Prevention of Lead Rebound

Research has explored different this compound therapeutic regimens to optimize sustained lead reduction and prevent the rebound in blood lead levels that can occur after treatment. cncb.ac.cnnih.govtandfonline.comfda.govresearchgate.net Initial clinical studies often involved a 5-day course of treatment. nih.govtandfonline.com Subsequently, longer regimens (19 to 26 days) were introduced with the aim of blunting the blood lead rebound. nih.govtandfonline.comresearchgate.net

Studies suggest that repeated courses of this compound, such as 30 mg/kg/day for at least 5 days, can be equally efficacious in enhancing urine lead excretion and reducing blood lead concentrations. nih.govtandfonline.com Including a treatment-free period of at least 1 week between courses may allow for the redistribution of lead from bone to soft tissues and blood. nih.govtandfonline.comresearchgate.net In cases of more severe poisoning, there is evidence that administering this compound for more than 5 days can be beneficial. nih.govtandfonline.com

Following therapy, monitoring for blood lead level rebound is recommended, typically by measuring levels at least once weekly until stable. nih.govfda.gov The severity of the initial intoxication and the rate and degree of rebound should guide the frequency of monitoring. fda.gov Studies have shown that after a 5-day course of 350 mg/m² (10 mg/kg) every 8 hours, mean lead levels rebounded and plateaued at 60-85% of pretreatment levels two weeks after therapy. fda.gov This rebound plateau was somewhat higher with lower this compound doses and with intravenous CaNa₂EDTA. fda.gov

Efficacy in Reducing Blood Mercury Concentrations

Studies have shown that this compound can lead to decreases in blood mercury concentrations. In clinical reports concerning ingestion and dermal exposure to inorganic mercury, both unithiol and this compound significantly increased urine mercury excretion and decreased blood mercury levels. tandfonline.comtandfonline.com In cases of elemental mercury and mercury vapor poisoning, thiol chelators like unithiol and this compound have demonstrated increases in urinary mercury and decreases in blood mercury. tandfonline.comtandfonline.com

A randomized clinical trial evaluating this compound in children with background mercury exposures, initially designed for lead-exposed children, measured mercury in blood samples before and after treatment. The study found that the adjusted mean organic mercury concentration in the this compound group relative to the placebo group decreased from 99% at baseline to 82% after three courses of treatment. nih.govnih.gov However, this reduction appeared to result from the prevention of an age-related increase in the this compound group rather than a direct reduction in mercury levels. nih.govnih.gov This suggests limited efficacy of this compound chelation for low-level organic mercury exposure in children. nih.govnih.gov

Mobilization of Mercury from Specific Organs (Kidney, Brain)

Research indicates that this compound's ability to mobilize mercury from organs varies depending on the timing of administration and the specific organ. In animal studies involving mercuric chloride injection, this compound decreased mercury content in the kidney and blood when therapy was initiated within a day of exposure. tandfonline.comtandfonline.com However, if there was a delay in chelator administration, the therapy was less effective, and brain mercury levels did not improve. tandfonline.comtandfonline.com This highlights a limitation of this compound, and unithiol, in tissue penetration. tandfonline.com

For elemental mercury and mercury vapor poisoning, thiol chelators like unithiol and this compound have shown reductions in kidney and total body mercury. tandfonline.comtandfonline.com However, neither this compound nor unithiol have demonstrated an effect on brain mercury concentrations after mercury vapor exposure. tandfonline.comtandfonline.com This inability to cross the blood-brain barrier appears to limit their effectiveness in directly removing mercury from the brain and other target tissues like the liver and muscle, particularly after chronic exposure where mercury has distributed into these organs. tandfonline.comtandfonline.com

Studies on Chelation of Inorganic vs. Organic Mercury Species

This compound has shown varying efficacy depending on the form of mercury involved. For inorganic mercury, this compound is considered to have clinical utility in treating human poisoning and is protective against the acute lethal and nephrotoxic effects of mercuric salts in animal models, increasing urinary mercury excretion in both animals and humans. mhmedical.com DMSA is used for both inorganic and organic mercurials. medscape.com

With organic mercuries, such as methylmercury and ethylmercury, thiol chelators including unithiol and this compound have demonstrated increases in urinary mercury and, in some instances, decreases in blood mercury. tandfonline.com Despite these changes in mercury concentration, clinical improvement in patients has been limited or absent in numerous reported cases, with some patients experiencing continued deterioration. tandfonline.com This limited clinical efficacy with organic mercury likely reflects the in vivo demethylation of organomercuries in the brain and the inability of this compound to cross the blood-brain barrier. tandfonline.com Ethylmercury, which has a shorter half-life and greater difficulty crossing the blood-brain barrier than methylmercury, has shown limited or no effect on neurotoxicity when treated with unithiol and this compound in humans. tandfonline.com

Comparative Studies with Other Mercury Chelators (e.g., Unithiol)

Comparative studies have evaluated this compound alongside other chelating agents for mercury. Unithiol (DMPS) and this compound (DMSA) are water-soluble analogs of BAL (dimercaprol) and are currently used as chelating agents in mercury poisoning. nih.govresearchgate.net DMPS is recommended as a first-line chelating agent for chronic and acute inorganic mercury cases in some regions and is considered similar to DMSA in efficacy and redistribution properties. cehn.org However, DMPS is considered more effective than this compound at removing mercury from kidney cells. cehn.org Neither DMPS nor this compound are effective at removing mercury from the brain. cehn.org

In animal studies involving mercuric chloride injection, unithiol decreased mercury content in all organs, whereas this compound only decreased kidney and blood concentrations when administered promptly. tandfonline.comtandfonline.com If administration was delayed, unithiol was also only effective in reducing blood and kidney mercury, similar to this compound, with no significant effect on other target organs. tandfonline.com

In a recent animal model of methylmercury exposure during pregnancy, this compound was effective in reducing maternal and fetal mercury burden, although unithiol appeared to be somewhat more potent in that setting. mhmedical.com While this compound has replaced penicillamine in some instances due to its strong metal-mobilizing capacity and lower side effects, DMPS is often considered the chelator of choice for chronic or mild mercury toxicity due to its ease of use, good efficacy, and safety profile. medscape.comnih.gov

Efficacy in Arsenic Detoxification

Animal experiments have established that prompt treatment with dithiol chelators, including DMSA (this compound), can prevent the detrimental effects of inorganic arsenic. researchgate.net These chelators enhance arsenic excretion. researchgate.net Controlled animal experiments support a therapeutic role for this compound in the prompt treatment of acute poisoning by inorganic arsenic salts. researchgate.net Its efficacy declines or disappears if treatment is delayed. researchgate.net

Clinical studies have also examined this compound's effect on arsenic excretion. In a comparative evaluation of this compound and CaNa2 EDTA in workers exposed to lead, arsenic, and cadmium, this compound demonstrated a much better chelating effect on arsenic compared to CaNa2 EDTA, as measured by arsenic excretion in urine. researchgate.netlongdom.org

Data from this study comparing the effect of this compound and CaNa2 EDTA on arsenic excretion in urine is presented below:

Note: Specific numerical data for arsenic concentrations before and after treatment with this compound and CaNa2 EDTA was indicated as being in Figure 3 of source researchgate.net and source longdom.org, but the exact values were not extracted in the text snippets. The table structure is provided to represent where such data would be placed if available.

This compound is protective against the acute lethal effects of arsenic in animal models and may have potential utility in acute human arsenic poisoning. mhmedical.com Studies suggest that monoesters of DMSA may be preferred over DMSA diesters due to their higher efficacy against arsenic intoxication. nih.gov

Regarding cadmium poisoning, studies suggest that this compound may not be the drug of choice. ijpsonline.com While the structure of this compound chelates of lead and cadmium are similar in vitro, a randomized trial using blood samples from a study designed for treating lead poisoning found that this compound did not lower blood cadmium in children with background exposure. nih.govresearchgate.net One potential reason for this lack of efficacy is that this compound is mainly distributed in the extracellular space, while cadmium is mostly bound intracellularly to metallothionein. nih.gov

Cadmium Mobilization Studies

Research has explored the efficacy of this compound and its derivatives in mobilizing cadmium from the body. Studies in mice with aged in vivo cadmium deposits compared the effectiveness of two newly synthesized esters of meso-2,3-dimercaptosuccinic acid, di(2'-methoxyethyl) meso-2,3-dimercaptosuccinate (MEDMS) and di(2'-ethoxyethyl) meso-2,3-dimercaptosuccinate (EEDMS), with 2,3-dimercaptopropan-1-ol (BAL) nih.gov. Both MEDMS and EEDMS demonstrated superiority over BAL in reducing the whole body burden of cadmium. EEDMS resulted in approximately a 26% reduction, while MEDMS achieved about a 20% reduction, compared to BAL's approximately 12% reduction under similar dosage regimens nih.gov.

Further studies on monoalkyl esters of meso-2,3-dimercaptosuccinic acid in mice examined their ability to mobilize cadmium one week after administration of cadmium chloride nih.gov. The relative whole body cadmium mobilization increased with the number of carbon atoms in the alkyl group of the monoester up to C5, after which it decreased nih.gov. The monoisoamyl ester was identified as the most effective in removing cadmium from both the liver and kidneys nih.gov. This monoester also demonstrated effectiveness in mobilizing cadmium from aged deposits in the liver and kidneys when administered orally, marking it as the first reported compound capable of achieving this nih.gov.

Impact on Lead-Induced Cognitive Deficits in Animal Models

Animal models, such as studies in rats, have been instrumental in evaluating the potential of this compound to alleviate lead-induced cognitive deficits nih.govnih.govescholarship.orgnih.govresearchgate.net. Early lead exposure in rats has been shown to produce lasting impairments in learning, attention, inhibitory control, and arousal regulation, mirroring the dysfunctions observed in lead-exposed children nih.govnih.gov.

A study using a rodent model of early childhood lead exposure found that this compound treatment of lead-exposed rats significantly improved learning, attention, and arousal regulation nih.govnih.gov. The efficacy of the treatment varied depending on the level of lead exposure and the specific functional deficit nih.govnih.gov. This research suggested that it might be possible to identify a this compound treatment protocol that could improve cognitive outcomes in lead-exposed children nih.govnih.gov.

Another study in rodents demonstrated that this compound chelation therapy could alleviate certain types of lead-induced behavioral and cognitive dysfunction nih.gov. This suggested that if a this compound treatment regimen could achieve a substantial reduction in brain lead levels in humans, a functional benefit might be derived nih.gov. Studies in rodents indicated that this compound treatment significantly reduced brain lead levels, with two courses of treatment being more effective than one nih.gov. However, reductions in blood lead levels were found to be a relatively poor predictor of reductions in brain lead levels in both primate and rodent studies nih.gov.

Studies on Learning, Attention, and Arousal Regulation following Chelation

Studies in lead-exposed rats have specifically examined the effects of this compound chelation on learning, attention, and arousal regulation nih.govnih.govresearchgate.net. This compound treatment was effective in normalizing the heightened reactivity to errors and reward omission observed in lead-exposed animals researchgate.net. This provided evidence that this compound chelation can significantly lessen the lasting neurobehavioral dysfunction caused by early lead exposure researchgate.net.

In lead-exposed rats, this compound treatment improved performance in a selective attention task, particularly by normalizing the disruptive effect of prior errors researchgate.netresearchgate.net. The this compound-only group (rats not exposed to lead but treated with this compound) showed impaired performance in the selective attention task compared to controls researchgate.net.

Findings on Cognitive Benefit at Lower Lead Exposure Levels in Clinical Trials

Clinical trials have investigated the cognitive benefits of this compound in children with lower lead exposure levels. The Treatment of Lead-Exposed Children (TLC) trial was a randomized, double-blind, placebo-controlled study that evaluated this compound in children with blood lead levels between 20 and 44 µg/dL aap.orgresearchgate.netresearchgate.netresearchgate.net. Despite this compound effectively lowering average blood lead levels for approximately six months, the trial found no significant benefit in cognitive, behavioral, and neuromotor endpoints at age 7 years aap.orgresearchgate.net. At 36 months of follow-up, children given this compound had a mean IQ score that was 1 point lower than the placebo group, and their behavior was rated as slightly worse by a parent, although these differences were not statistically significant researchgate.netnih.gov. Scores on the Developmental Neuropsychological Assessment were slightly better in the this compound group, but again, the differences were small and not statistically significant researchgate.netnih.gov.

The TLC trial concluded that treatment with this compound lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 µg/dL researchgate.netnih.gov. Given that this compound is considered as effective as other available lead chelators, these findings suggested that chelation therapy might not be indicated for children with these blood lead levels researchgate.netnih.gov.

Hepatic Effects and Aminotransferase Elevations

Clinical trials and studies have reported transient elevations in serum aminotransferase levels, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST), during this compound therapy. nih.govoup.comrxlist.comresearchgate.netfda.gov In clinical trials involving children with lead poisoning, serum aminotransferase elevations occurred in a percentage of this compound-treated subjects, although levels significantly exceeding the upper limit of normal were rare. nih.gov For instance, in one study, ALT levels above 5 times the upper limit of normal were observed in less than 1% of treated children, and no child discontinued therapy due to liver test abnormalities. nih.gov Another study in adults reported asymptomatic ALT elevations (less than 3 times the upper limit of normal) in a percentage of patients treated with this compound, which resolved upon cessation of therapy. nih.gov While transient increases in transaminase activity have been noted in a percentage of patients, clinically significant liver injury with jaundice has not been commonly linked to this compound use. nih.govresearchgate.net Monitoring of serum AST and ALT is recommended at baseline and periodically during treatment, with dose reduction or temporary cessation advised if levels exceed 5 times the upper limit of normal. nih.govrxlist.comfda.gov

Renal Effects and Tubular Pathologies

This compound and its metabolites are primarily eliminated by the kidneys. fda.govdrugbank.commhmedical.com Research, particularly in animal models, has explored the potential for this compound to affect renal function and structure. In a 28-day toxicity study, dogs receiving higher doses of this compound showed lower urinary specific gravity and an increase in renal tubular regenerative hyperplasia. fda.gov A chronic 6-month oral toxicity study in dogs also reported treatment-related renal tubule epithelial changes at higher doses, which correlated with increased kidney weights. fda.gov Nephropathy was not observed at lower doses in these studies. fda.gov

Studies using technetium-99m-dimercaptosuccinic acid ((99m)Tc-DMSA), a radiolabeled form of this compound used for renal imaging, provide insights into its interaction with renal tubules. drugbank.comnih.govopenmedscience.com These studies suggest that (99m)Tc-DMSA is filtered in the glomeruli and subsequently undergoes endocytosis in the proximal tubules, a process that can be affected in patients with tubular disorders. nih.gov Decreased renal uptake of (99m)Tc-DMSA has been observed in patients with proximal tubular disorders, even with normal creatinine clearance, suggesting that its uptake is sensitive to changes in renal tubular function. nih.govnih.gov While these studies primarily relate to the diagnostic use of radiolabeled this compound, they highlight the interaction of this compound with renal tubular cells.

Hematological Effects (e.g., Thrombocytopenia, Neutropenia)

This compound has been associated with certain hematological effects, including thrombocytopenia (low platelet count) and neutropenia (low neutrophil count). rxlist.comwikipedia.orguspharmacist.compatsnap.comhealthline.com Reduced platelet counts were noted in some dogs in chronic toxicity studies, although group means were not always statistically different from controls. fda.gov The mechanism in dogs was suggested to potentially be autoimmune-mediated, a finding common in dogs but not typically seen in other species like rats, which did not develop thrombocytopenia in chronic dosing studies. fda.gov

In clinical use, neutropenia is considered a less common but potentially serious side effect of this compound. patsnap.com It is characterized by a reduced number of neutrophils, which are crucial for fighting infections. patsnap.comhealthline.com Monitoring of complete blood counts is recommended during this compound treatment. rxlist.com Treatment interruption may be necessary if the absolute neutrophil count falls below a certain threshold. rxlist.com Thrombocytopenia has also been reported as an adverse effect in clinical settings. uspharmacist.comphebra.com

Research on Zinc Excretion Dynamics

Studies consistently indicate that this compound treatment leads to an increase in urinary zinc excretion. mhmedical.comoup.comrxlist.comoup.comfda.govnih.gov In dose-ranging studies in adults, zinc excretion doubled during this compound treatment. rxlist.comfda.gov Compared to other chelating agents like CaNa2EDTA, this compound's effect on zinc excretion is generally considered smaller. fda.govfda.gov CaNa2EDTA can induce a significantly greater increase in urinary zinc excretion. fda.govfda.gov While some studies in primates and humans have shown statistically significant increases in urinary zinc excretion with this compound, others have reported trending but non-significant increases or have noted that the effect is not clinically significant. oup.comresearchgate.netoup.comnih.gov One study in heavy metal-poisoned subjects found that only plasma zinc decreased significantly among several essential elements monitored. oup.com

Research on Copper Excretion Dynamics

The effect of this compound on copper excretion has also been investigated, with varying findings across studies. Some research indicates that this compound treatment can cause an increase in urinary copper excretion. oup.comoup.com A study in adult patients with lead poisoning observed a mean increase of 2.4-fold in urine copper excretion compared to baseline values during this compound chelation. oup.com Similarly, a study in primates showed that a lower this compound dosing regimen led to statistically significant increases in urinary copper excretion. oup.com However, other studies have reported trending but non-significant increases in copper excretion or have concluded that the increase is not to a clinically important extent. researchgate.netoup.com Some comparative studies with CaNa2EDTA highlight that while both chelators can increase copper excretion, the effect of this compound is generally less pronounced. fda.govfda.gov

Studies on Minimal Effects on Iron, Calcium, and Magnesium Excretion

Studies have investigated the impact of this compound on the urinary excretion of essential minerals such as iron, calcium, and magnesium. Research indicates that this compound has no significant effect on the urinary elimination of iron, calcium, or magnesium. rxlist.comfda.govfda.gov While this compound effectively increases the urinary excretion of lead, its effect on endogenous minerals like calcium, iron, and magnesium is considered insignificant compared to other chelating agents such as CaNa2EDTA. mhmedical.comfda.govwikidoc.orgmedscape.com Some studies in healthy adult volunteers and primate models have reported minor or non-significant increases in the urinary excretion of certain essential elements, including trending but non-significant increases in urinary calcium, copper, and iron in one study, and marginally non-significant increases in zinc excretion in another. mhmedical.comoup.comresearchgate.net Multivariate analyses in a primate model indicated a significant increase in the cumulative total excretion of essential elements over the first five days of treatment when considered collectively, although not for any single element individually in all cases. researchgate.net

Acute Toxicity Studies

Acute toxicity studies typically involve administering a single high dose of a substance to animals to determine immediate adverse effects and the dose at which lethality occurs. fda.gov this compound has demonstrated low acute oral toxicity in preclinical studies. Oral median lethal doses (LD50) in rodents have been reported in excess of 3.6 g/kg and over 5011 mg/kg in mice. drugbank.comwikidoc.orgfda.gov Doses of 2300 mg/kg in rats and 2400 mg/kg in mice produced signs of toxicity including ataxia, convulsions, and labored respiration, and frequently resulted in death. drugbank.comfda.gov

Chronic Toxicity Studies in Animal Models

Chronic toxicity studies assess the effects of prolonged and repeated exposure to a substance over an extended period, often exceeding 90 days or longer in animal models. criver.comoecd.orgnih.govoecd.org In a 28-day toxicity study in dogs, those receiving 30 and 100 mg/kg/day of this compound showed lower urinary specific gravity and an increase in renal tubular regenerative hyperplasia. wikidoc.orgfda.gov However, no renal toxicity was observed in dogs given 50 mg/kg/day. wikidoc.orgfda.gov Long-term animal studies evaluating the carcinogenic potential of this compound have not been conducted. fda.gov

Developmental and Reproductive Toxicology Research

Developmental and reproductive toxicology (DART) research investigates the potential adverse effects of a substance on fertility, embryonic development, fetal development, and postnatal development. frontiersin.orgpremierconsulting.comcriver.comdrugdiscoverynews.com Studies in pregnant mice have shown this compound to be teratogenic and fetotoxic when administered subcutaneously during organogenesis at doses ranging from 410 to 1640 mg/kg/day. fda.gov In a developmental study in rats, maternal toxicity and deaths occurred at doses of 720 mg/kg/day or more during organogenesis, with 510 mg/kg/day being the highest tolerable dose in pregnant rats. rxlist.comfda.govfda.gov Impaired development of reflexes was noted in the pups of dams receiving 720 mg/kg/day. rxlist.comfda.govfda.gov this compound did not show adverse effects on fertility and reproductive performance in rats at doses up to 510 mg/kg/day in males and 100 mg/kg/day in females. fda.govfda.gov Studies in non-lead-exposed rodents have also indicated that this compound treatment can produce lasting adverse neurobehavioral effects. nih.gov

Utilization of Rodent Models (Rats, Mice) for Efficacy and Toxicological Assessments

Rodent models, such as rats and mice, are widely used in this compound research for both efficacy and toxicological assessments. Studies in rodents have investigated this compound's ability to reduce lead levels in blood and tissues, as well as its potential effects on neurobehavioral outcomes following heavy metal exposure.

Research in lead-exposed rats has demonstrated that this compound treatment can be effective in normalizing certain behavioral deficits. For example, a study in rats exposed to lead during their early life showed that a course of this compound treatment was effective in normalizing heightened reactivity to errors and reward omission. researchgate.netnih.gov This suggests that this compound chelation can potentially mitigate lasting neurobehavioral dysfunction induced by early lead exposure. researchgate.netnih.govnih.gov However, these studies also highlight potential risks, as this compound treatment in rats not previously exposed to lead produced lasting cognitive and affective dysfunction. nih.gov

Studies in rodents have also explored the efficacy of this compound in reducing brain lead levels. While some studies in primates showed no significant reduction in brain lead concentrations after a 19-day course, a study in rodents exposed to lead demonstrated that a three-week course of this compound significantly reduced both blood and brain lead concentrations compared to a vehicle. researchgate.netnih.gov Two courses of this compound were found to be significantly more efficacious at reducing brain lead levels than one in this rodent model. nih.gov However, reductions in blood lead levels were not always a strong predictor of reductions in brain lead levels in these rodent studies. nih.gov

Toxicological assessments in rodents have provided information on the potential adverse effects of this compound. This compound has been reported to have low acute oral toxicity in rodents, with median lethal doses in excess of 3.6 g/kg. wikidoc.orgrecordatirarediseases.com However, higher doses (e.g., 2300 mg/kg in rats and 2400 mg/kg in mice) produced signs of toxicity including ataxia, convulsions, and labored respiration, and frequently resulted in death. drugbank.comfda.govrecordatirarediseases.com Developmental toxicity studies in rats have shown that this compound can cause maternal toxicity and deaths at certain doses during organogenesis, and impaired reflex development was noted in the pups of dams receiving higher doses. recordatirarediseases.comfda.gov Studies in pregnant mice have also indicated that this compound can be teratogenic, potentially mediated through disturbed maternal/fetal copper metabolism. nih.gov

Studies using rodent models of retained lead fragments have investigated whether this compound chelation can mobilize lead from these sources. In one rodent model, this compound chelation on day 1 led to significant blood lead reductions, and fragment lead was not mobilized into the blood initially. escholarship.org However, with continued chelation and over a period post-chelation, blood lead levels rebounded with mobilization of lead from the fragments, suggesting the need for long-term monitoring in cases of retained fragments. escholarship.org

Application of Non-Human Primate Models for Absorption and Retention Studies

Non-human primate models are valuable for studying the absorption and retention of this compound and chelated metals, providing data that is often more directly translatable to humans than rodent data. Studies in juvenile non-human primates have been conducted to investigate the effects of oral this compound chelation on the gastrointestinal absorption and whole-body retention of lead. researchgate.netresearchgate.netnih.gov

Contrary to concerns that this compound might increase gastrointestinal lead absorption, a study in a juvenile non-human primate model of moderate childhood lead intoxication found that oral this compound significantly reduced the gastrointestinal absorption of lead. researchgate.netnih.gov This study utilized a stable lead isotopic tracer methodology to track lead absorption and retention. researchgate.netresearchgate.netnih.gov this compound treatment in these primates also significantly increased the urinary excretion of endogenous lead. researchgate.netnih.gov While this compound reduced the whole-body retention of endogenous lead by approximately 10%, a significant portion (77%) of the administered internal dose of the lead tracer was still retained in the body after 5 days of treatment. researchgate.netnih.gov

Studies in adult primates exposed to lead have also assessed the efficacy of this compound in reducing brain lead levels. A single 19-day course of this compound in these models did not measurably reduce brain lead levels compared to control groups. researchgate.netnih.gov This contrasts with some findings in rodent models, highlighting potential species differences in the distribution and removal of chelated lead from the brain. researchgate.netnih.gov

Design and Outcomes of Randomized Controlled Trials and Placebo-Controlled Designs

Randomized controlled trials are crucial for minimizing bias and providing robust evidence of treatment effects. paho.org In placebo-controlled trials, participants are randomly assigned to receive either the active treatment (this compound) or a placebo that is identical in appearance but lacks the active compound. paho.org Blinding, where participants and researchers are unaware of the treatment assignment, further helps to reduce bias. paho.org

A notable example of a large-scale randomized, placebo-controlled, double-blind clinical trial of this compound is the Treatment of Lead-Exposed Children (TLC) trial. nih.govnih.govresearchgate.netaap.org This multicenter trial enrolled children with blood lead levels between 20 and 44 micrograms/dL to assess the effects of this compound treatment on cognitive, behavioral, and physical development. nih.govnih.govresearchgate.net Children were randomized to receive up to three courses of this compound or placebo and were followed for several years. nih.govnih.govresearchgate.net

Outcomes from the TLC trial provided important insights into the effectiveness of this compound in children with moderately elevated blood lead levels. While this compound treatment effectively lowered mean blood lead levels during the initial phase of the trial compared to placebo, this reduction did not translate into significant improvements in scores on standardized tests of cognition, behavior, or neuropsychological function at the 36-month follow-up. nih.govresearchgate.netaap.org The mean IQ score in the this compound group was slightly lower than in the placebo group at 36 months, and parental ratings indicated slightly worse behavior in the this compound group, although these differences were not statistically significant. nih.govresearchgate.net Some beneficial neuromotor effects, such as improved postural balance and functional locomotion, were observed in a subset of children from the TLC trial. nih.gov

Other controlled studies have also investigated this compound's efficacy in different populations and for different heavy metals. While this compound has been associated with increased urinary excretion of mercury and arsenic in limited patient numbers, controlled clinical studies specifically for mercury or arsenic poisoning are limited. wikidoc.orgrecordatirarediseases.com A randomized trial examining this compound chelation for low-level organic mercury exposure in children found limited efficacy in reducing blood mercury concentration. nih.gov

Biomarker Identification and Validation for Treatment Efficacy and Safety

Biomarkers play a vital role in drug development and clinical trials, serving as indicators of treatment efficacy and safety. bio-rad.comwisecube.ai Biomarkers can be used to select patients for trials, monitor treatment response, and predict outcomes. bio-rad.comwisecube.ai The identification and validation of reliable biomarkers are crucial for the efficient and accurate assessment of this compound's effects.

In the context of this compound treatment for heavy metal poisoning, blood lead levels are a primary and widely used biomarker for assessing exposure and monitoring the effectiveness of chelation in reducing the body burden of lead. nih.govnih.govresearchgate.netaap.orgmhmedical.com The ability of this compound to increase the urinary excretion of chelated metals is another key indicator of its activity, and urinary metal levels are often measured in research studies. patsnap.comdrugbank.comwikidoc.orgfda.govresearchgate.netnih.govoup.commhmedical.com

Discrepancies between Animal and Human Study Outcomes

Significant discrepancies have been observed between outcomes in animal studies and human clinical trials involving this compound. While animal models, particularly in rodents and non-human primates, are valuable for assessing the efficacy and safety of potential therapies, translating these findings directly to humans can be challenging due to fundamental differences in genetic background, developmental span, and organ structure and function researchgate.netosf.ionih.gov.

Studies in animal models have investigated the extent to which this compound reduces body lead, particularly in the brain, and whether reductions in blood lead accurately reflect changes in brain lead nih.govnih.gov. Results from juvenile primate studies indicated that this compound treatment accelerated lead elimination, but was only marginally more effective than stopping lead exposure alone nih.gov. Studies in lead-exposed adult primates showed that a single course of this compound did not measurably reduce brain lead levels compared to controls nih.govnih.gov. In contrast, rodent studies with one or two courses of this compound showed significant reductions in brain lead levels, with two courses being more effective than one nih.govnih.gov. These studies also highlighted that reductions in blood lead levels were relatively poor predictors of reductions in brain lead levels nih.govnih.gov.

Furthermore, some animal studies have suggested that this compound chelation therapy can alleviate certain lead-induced behavioral and cognitive dysfunctions nih.govnih.govresearchgate.netnih.govresearchgate.net. For instance, studies in lead-exposed rats demonstrated improvements in learning, attention, and arousal regulation following this compound treatment nih.govnih.govresearchgate.net. However, these findings contrast with outcomes from comprehensive human clinical trials, such as the Treatment of Lead-Exposed Children (TLC) trial, which did not find significant neurodevelopmental benefits in children with moderate blood lead levels (20-44 µg/dL) despite this compound effectively lowering blood lead levels for a period aap.orgresearchgate.net. The failure to demonstrate benefits in the human trial might be attributed to the relatively small and transient reduction in blood lead levels achieved with the this compound regimen used, and consequently, an even smaller reduction in brain lead aap.orgnih.gov.

An unexpected finding in some animal studies is that this compound treatment in the absence of lead exposure produced lasting adverse neurobehavioral effects, including cognitive dysfunction nih.govnih.govnih.govnih.govresearchgate.netnih.gov. This highlights potential risks associated with administering this compound to individuals without elevated tissue lead levels nih.govnih.govnih.govnih.govresearchgate.netnih.gov.

Radiopharmaceutical Applications (e.g., Technetium-99m this compound for Renal Imaging)

One significant area of expanded application is in nuclear medicine, specifically as a radiopharmaceutical agent. Technetium-99m (⁹⁹mTc) this compound (⁹⁹mTc-DMSA) is a widely used diagnostic tool for renal imaging. openmedscience.comdrugbank.com When labeled with the radioisotope technetium-99m, this compound exhibits specific uptake and retention in the renal cortex, allowing for scintigraphic evaluation of renal parenchymal disorders, assessment of differential renal function, and detection of conditions like acute pyelonephritis. openmedscience.comdrugbank.comappliedradiology.com This application is particularly valuable in pediatric patients for evaluating congenital anomalies and the impact of urinary tract infections on kidney function. openmedscience.comappliedradiology.com The binding of ⁹⁹mTc-succimer to renal tubular cells is believed to involve its affinity for sulfhydryl groups. openmedscience.com The use of ⁹⁹mTc-succimer provides detailed anatomical images and functional assessment of the kidneys with minimal invasiveness and low radiation exposure due to the short half-life of ⁹⁹mTc. openmedscience.comnih.gov

Potential in Other Toxicological Exposures

Research is also exploring the potential of this compound in mitigating the effects of other toxicological exposures beyond the classic heavy metals. While the primary focus remains on lead, mercury, and arsenic, its chelating properties and influence on oxidative stress pathways suggest potential in other scenarios where metal involvement or oxidative damage is a factor. drugbank.comcellmolbiol.org Studies have investigated its effects in animal models of toxicity from other metals and metalloids, sometimes in combination with other agents. nih.govresearchgate.net