meso-2,3-Dimercaptosuccinic acid

182.22

182.22

1725150

206-155-2

DX1U2629QE

DTXSID1023601

C61953

White crystals from aqueous methanol|White crystalline powder

2930909090

76.6

-1.01 (est)

White to off-white Powder

1.6±0.1 g/cm3

192-194 °C

267.6±40.0 °C at 760 mmHg

115.6±27.3 °C

1.617

soluble in water, and ethanol (25 mg/ml, results in colorless to light yellow, clear).

−20°C

1.56X10-6 mm Hg at 25 deg C (est)

LD50 i.p. in mice: >3000 mg/kg (Friedheim, Corvi)

Unpleasant, characteristic mercaptan odor

Unpleasant, characteristic mercaptan taste

Henry's Law constant = 6.81X10-15 atm-cu m/mol at 25 °C (est)

Hydroxyl radical reaction rate constant = 9.40X10-11 cu m/molec-sec at 25 °C (est)

NONH for all modes of transport

2

36/37/38

24/25-36-26

WM7650000

Xi

Stable. Combustible. Incompatible with strong oxidizing agents.

P201, P202, P261, P264, P271, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501

H315

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).|The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed drug products, including succimer, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

Oral LD50 in mice is over 5011 mg/kg. Doses of 2300 mg/kg in the rat and 2400 mg/kg in the mouse produced ataxia, convulsions, labored respiration and frequently death. No case of overdosage has been reported in humans. Limited data indicate that succimer is dialyzable.

In clinical trials conducted in children with lead poisoning, serum aminotransferase levels elevations occurred in 7% of succimer- vs 4% of placebo-treated subjects. However, ALT levels above 5 times the upper limit of normal were rare (

The effect of DMSA on sodium arsenate teratogenicity was studied in mice. Pregnant Swiss mice were injected ip with 45 mg/kg sodium arsenate on day eight of gestation. They were injected ip with 0, 37.5, 75, or 150 mg/kg sodium arsenate 0, 24, 48, and 72 hr later. The dams were killed on gestational day 18. The number of live,dead, and resorbed fetuses was recorded. The live fetuses were weighed and examined for malformations. Sodium arsenate significantly increased the number of resorptions and decreased the number of live fetuses and fetal body weight. The numbers of live, dead, and resorbed fetuses and fetal body weights in dams given 75 or 150 mg/kg DMSA plus sodium arsenate were similar to those of the untreated controls. DMSA at 37.5 mg/kg protected against the sodium arsenate induced increase in number of fetal resorptions only. Sodium arsenate caused a significant increase in the frequency of fetal exophthalmos, exencephaly, rib fusion, and decreases in ossification of the supraoccipital bone, tarsus, and carpus. All DMSA doses significantly reduced the number of these malformations. The authors conclude that DMSA can effectively protect against the embryolethality and teratogenicity of sodium arsenate. DMSA may act by increasing the rate of arsenic excretion to the extent that embryonic exposures to arsenic are too low to cause embryotoxicity.|Orally administered of DMSA is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 hr after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine ip along with DMSA orally resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Ip administered N-benzyl-N-dithiocarboxy-D-glucamine by itself is a very effective antagonist for cadmium chloride administered ip in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by N-benzyl-N-dithiocarboxy-D-glucamine; this showed that N-benzyl-N-dithiocarboxy-D-glucamine is one of the most effective cadmium mobilizing agents developed to date. /Results indicate/ the ability of N-benzyl-N-dithiocarboxy-D-glucamine to remove cadmium from animals which have been treated with cadmium over an extended period of time /as described in an earlier study/. Benzyl-N-dithiocarboxy-D-glucamine causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of (113)Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.|The influence of DMSA, as well as other chelating agents, on GI (203)Pb absorption and whole body (203)Pb retention was examined. Groups of Sprague-Dawley rats (230-260 g) were gavaged with a solution containing approximately 25 mg/kg Pb, as Pb(NO3)2 plus 15 uCi (203)Pb. Some groups were then immediately given 0.11 mmol/kg of either DMSA, calcium disodium edetate, D-penicillamine, or dimercaprol by oral gavage, while other groups received the same drugs by ip injection. Control groups received solutions of the drug vehicles orally or ip. Whole body Pb retention and GI Pb absorption (whole body retention + urinary Pb excretion) were significantly decreased in rats that received DMSA orally. This finding implies that the use of DMSA to treat childhood lead intoxication on an outpatient basis is not associated with a risk for increased Pb absorption.|Rats were treated with 1 mg/kg cadmium chloride ip, with or without treatment with DMSA sc shortly after access to a sodium-saccharin solution while on a limited water schedule. Doses were 25, 50, 100, or 200 mg/kg DMSA. Cadmium injection and DMSA treatment after consumption of the saccharin solution each produced an aversion on a free choice trial between the saccharin solution and tap water. Significant inverse relationships between saccharin intake and DMSA dosage were determined without effect on total fluid intake during the choice trial. DMSA produced an attenuation of the cadmium induced flavor aversion and an increase in total fluid intake during the choice trial when administered within 4 hr of cadmium pretreatment. It is concluded that flavor aversion conditioning is a sensitive behavioral test for cadmium neurotoxicity.|For more Interactions (Complete) data for Succimer (6 total), please visit the HSDB record page.

LD50 Mice ip > 3000 mg/kg

... A case of a 45-year-old black male with glucose-6-phosphate dehydrogenase deficiency and a 17 year history of occupational lead exposure who developed hemolysis during treatment with dimercaptosuccinic acid for symptomatic lead intoxication /is reported/..

For the treatment of lead poisoning in pediatric patients with blood lead levels above 45 µg/dL. May also be used to treat mercury or arsenic poisoning.

Succimer is an oral heavy metal chelating agent used to treat lead and heavy metal poisoning. Succimer has been linked to a low rate of transient serum aminotransferase elevations during therapy, but its use has not been linked to cases of clinically apparent liver injury with jaundice.

Chelating Agents

Antidotes; Chelating Agents|No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement. /Use NOT included in US product label/|Chemet is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 ug/dL. Chemet is not indicated for prophylaxis of lead poisoning in a lead-containing environment; the use of Chemet should always be accompanied by identification and removal of the source of the lead exposure. /Use included in US product label/|Orphan Drug. Drug (Trade Name): Succimer (Chemet). Proposed Use: Prevent cystine kidney stones in patients with homozygous cystinuria who are prone to stone development; mercury intoxication. /From table/|For more Therapeutic Uses (Complete) data for Succimer (10 total), please visit the HSDB record page.

It is not known whether this drug is excreted in human milk. Because many drugs and heavy metals are excreted in human milk, nursing mothers requiring Chemet therapy should be discouraged from nursing their infants.|Elevated blood lead levels and associated symptoms may return rapidly after discontinuation of CHEMET because of redistribution of lead from bone stores to soft tissues and blood. After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring.|All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using Chemet therapy in patients with compromised renal function. Limited data suggests that Chemet is dialyzable, but that the lead chelates are not.|The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on readministration (as well as during initial courses). Patients requiring repeated courses of Chemet should be monitored during each treatment course. One patient experienced recurrent mucocutaneous vesicular eruptions of increasing severity affecting the oral mucosa, the external urethral meatus and the perianal area on the third, fourth and fifth courses of the drug. The reaction resolved between courses and upon discontinuation of therapy.|For more Drug Warnings (Complete) data for Succimer (11 total), please visit the HSDB record page.

Succimer is an orally active, heavy metal chelating agent. It forms water soluble chelates and, consequently, increases the urinary excretion of lead. Succimer is not to be used for prophylaxis of lead poisoning in a lead-containing environment. In addition, the use of succimer should always be accompanied by identification and removal of the source of the lead exposure.

Agents counteracting or neutralizing the action of POISONS. (See all compounds classified as Antidotes.)|Chemicals that bind to and remove ions from solutions. Many chelating agents function through the formation of COORDINATION COMPLEXES with METALS. (See all compounds classified as Chelating Agents.)

Rapid but variable.|Unabsorbed drug is excreted primarily in feces and absorbed drug is excreted primarily in the urine as metabolites.|In a study performed in healthy adult volunteers, after a single dose of (14)Csuccimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.|In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.|The urinary excretion of succimer (meso-2,3-dimercaptosuccinic acid) was studied following oral administration of 10 mg succimer/kg to 6 normal men, aged 22-31 yr. The succimer that was absorbed was extensively biotransformed. After 14 hr only 2.53% of the drug was excreted in the urine as unaltered succimer and 18.1% as altered forms. The unaltered succimer was 12% of the total succimer found in the urine. The altered form(s) of succimer was 88% of the total urinary succimer. The altered succimer can be converted to unaltered succimer by electrolytic reduction, which indicates that the altered forms of succimer are disulfides. The excretion of altered succimer reached a peak between 2 and 4 hr after administration. There were small but significant increases in the excretion of zinc, copper, and lead after succimer. The chelating agent did not influence the urinary excretion of 27 other metals and elements.|(14)C DMSA was administered to mice iv; the mice were frozen by immersion in dry ice/hexane at 6 and 20 min and 1, 3, 9, and 24 hr after injection. The frozen mice were sectioned and processed for whole-body autoradiography for soluble substances. The radioactivity was highly localized in extracellular fluids such as the sc, intrapleural, ip, and periosteal spaces. There was a pronounced accumulation in the periosteal fluid above that in other fluids during the first hour after injection. Most of the radioactivity was eliminated by the kidney and liver. Pretreatment of a mouse with HgCl2 subcutaneously 1 hr before (14)C DMSA produced an increase in radioactivity in the liver and decrease in lung. A high concentration of radioactivity was seen at the sc site of injection of the HgCl2. The results are interpreted to indicate that most of the DMSA is in the extracellular space but that it can cross cellular membranes to some extent. The pronounced accumulation in periosteal fluid may be an interaction of DMSA with Ca2+ in this space. No tissue had a pronounced retention of the compound, but lung retained more than most other tissues.

Chemical analysis of succimer and its metabolites (primarily mixed disulfides of L-cysteine) in the urine showed that succimer was rapidly and extensively metabolized however the specific site of biotransformation is not known.|/Two/ subjects were given DMSA at 10 mg/kg orally, and urine samples were collected at 1, 2, 4, 6, 9 and 14 hr after administration. Samples were analyzed by HPLC, ion exchange, and TLC techniques. Most of the ingested DMSA was found in the urine in disulfide linkage with L-cysteine. Electrolytic reductive treatment, which breaks disulfide bonds, resulted in the conversion of the mixed disulfides to DMSA and L-cysteine. After the sulfhydryl group was derivatized and the bimane derivatives analyzed by HPLC and fluorescence, a high correlation between the excretion of L-cysteine and DMSA in the urine was evident. Four of the metabolites found in the urine contained L-cysteine and DMSA in different ratios. Results indicated that when DMSA is given orally to humans, it forms mixed disulfides with L-cysteine in preference to the formation of cyclic disulfides of DMSA. L-Cysteine preferentially forms these unique DMSA/mixed disulfides instead of the usual L-cystine. The amount of L-cysteine excreted in the urine as the mixed disulfides far exceeded the amount excreted as L-cystine. This increased excretion of L-cysteine caused by the DMSA exposure implied that a thiol-disulfide exchange between L-cystine and DMSA occurred and/or a direct reaction between L-cysteine and DMSA occurred to form more soluble mixed disulfides.

48 hours|The apparent elimination half-life of the radiolabeled material in the blood was about two days.

Succimer is a heavy metal chelator. It binds with high specificity to ions of lead in the blood to form a water-soluble complex that is subsequently excreted by the kidneys. Succimer can also chelate mercury, cadmium, and arsenic in this manner.|Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.|DMSA chelates by coordination of one sulfur and one oxygen atom with Pb. Solubility of the lead chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups. Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and racemic-DMSA have been summarized from the literature as have the formation constants of some of the DMSA chelates. DMSA is biotransformed to a mixed disulfide in humans. By 14 hr after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide. It consists of DMSA in disulfide linkages with two molecules of L-cysteine. One molecule of cysteine is attached to each of the sulfur atoms of DMSA. The remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far, the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine. Apparently there are species differences in how organisms metabolize meso-DMSA.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ In a study performed in healthy adult volunteers, after a single dose of (14)Csuccimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days.|/HUMAN EXPOSURE STUDIES/ In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority of mixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.|/CASE REPORTS/ ... A case of a 45-year-old black male with glucose-6-phosphate dehydrogenase deficiency and a 17 year history of occupational lead exposure who developed hemolysis during treatment with dimercaptosuccinic acid for symptomatic lead intoxication /is reported/..|/CASE REPORTS/ A 54-year-old male with chronic lead poisoning was treated with 2.3-dimercaptosuccinic acid (DMSA). A daily dosage of 30 mg/kg body weight for three days and 20 mg/kg for four days resulted in a decrease of the blood-lead concentration from 3.7 to 0.7 umol/l; the total amount of lead excreted in the urine during the first seven 24 hr periods was 75 umol. After the treatment, blood-lead concentration slowly increased to 3.3 umol/l. A second treatment was then initiated and resulted in similar changes in blood-lead concentration. However, during the third treatment, the patient developed a mucocutaneous vesicular flare; the eruptions faded after cessation of the chelation therapy, but could be provoked by DMSA doses of 10 mg/kg and above. Despite the small number of treatment courses, the patient showed obvious mental improvement and reported less headache and improved memory. Thus, DMSA is an efficient chelator that results in a rapid, though temporary decrease in blood-lead concentration. Although oral treatment with this chelator may be supervised from the out-patient clinic, careful monitoring for potential side effects is recommended.|/OTHER TOXICITY INFORMATION/ Growth deficits associated with lead exposure might be ameliorated by chelation. We examined the effect of succimer on growth in 780 children 12-33 months old who had blood lead levels of 20-44 ug/dL and were randomized to receive up to three 26-day courses of succimer or placebo in a multicenter, double-blind trial. The difference in changes in weight and height between succimer and placebo groups at 1-34 months was calculated by fitting cubic splines. The difference in height change in children on succimer compared with placebo was -0.27 cm (95% confidence interval (95% CI), -0.42 to -0.11) from baseline to 9 months, when 99% of children had completed treatment, and -0.43 cm (95% CI, -0.77 to -0.09) during 34 months of follow-up. Similar differences in weight gain were not statistically significant. Although succimer lowers blood lead in moderately lead-poisoned children, it does not have a beneficial effect on growth and may have an adverse effect.

2,3 Dimercaptosuccinic Acid

Each vial contains a sterile, pyrogen-free freeze-dried mixture of 1.0 mg DMSA, 0.42 mg stannous chloride dihydrate [0.38 mg (minimum) stannous chloride dihydrate (SnCl2*2H2O) and 0.46 mg (maximum) total tin expressed as stannous chloride dihydrate (SnCl2*2H2O)], 0.70 mg ascorbic acid, and 50.0 mg inositol (GE Healthcare).|Oral: Capsules: 100 mg Chemet (with povidone), (Sanofi-Aventis).

Butanedioic acid, 2,3-dimercapto-, (2R,3S)-rel-: ACTIVE|The monomethyl ester of meso-dimercaptosuccinic acid and its chelates with lead(II), cadmium(II), and mercury(II) have been synthesized. The mercury(II) chelate of monomethyl ester of meso-dimercaptosuccinic acid is formed by the coordination of the two sulfur atoms in monomethyl ester of meso-dimercaptosuccinic acid, whereas the lead(II) and cadmium(II) chelates are formed by the coordination of one sulfur and one oxygen atom. The solubilities of the chelates are pH dependent; the mercury(II) chelate dissolves when the uncoordinated carboxylic acid dissociates, but the lead(II) and cadmium(II) chelates are solubilized only after the uncoordinated mercapto group is dissociated. The cadmium(II) chelate is dimeric and the lead(II) and mercury(II) chelates are monomeric at the concentrations and conditions used in this study. The acid dissociation constants of the chelating agent and the uncoordinated groups in its metal chelates have been determined in 50% vol/vol methanol-water. These acid-base properties in addition to the polarity of the chelating agent contribute to the effectiveness in the in vivo mobilization of intracellular in vivo deposits of cadmium. The biliary excretion of cadmium in rats increased by a factor of 173 upon administration of the relatively toxic, nonpolar dimethyl ester of DMSA whereas the administration of the less toxic, more polar monomethyl ester increased the biliary excretion of cadmium by a factor of 63. On the other hand, meso-DMSA which is highly polar and less toxic is known to be without effect on biliary excretion of cadmium. The monomethyl DMSA, therefore, appears to have properties that are intermediate between those of DMSA and its dimethyl ester, as far as both chelating properties and biliary excretion of cadmium are concerned.

GC/MS determination in plasma.|Bimane derivatization, HPLC, and fluorescence, as well as GC can be used for analysis of DMSA in biological fluids.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients