Journal Article•
Dimercaptosuccinic Acid (DMSA), A Non-Toxic, Water-Soluble Treatment For Heavy Metal Toxicity
01 Jun 1998-Alternative medicine review : a journal of clinical therapeutic (Altern Med Rev)-Vol. 3, Iss: 3, pp 199-207
TL;DR: DMSA is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s and is established as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.
Abstract: Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint; to mercury in the atmosphere, in dental amalgams and in seafood; and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound’s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances. (Altern Med Rev 1998;3(3):199-207)
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01 Jan 2016
TL;DR: In treatment of metal poisonings, the top priorities should be prevention of further uptake, decreased absorption from the gastrointestinal tract, and general supportive therapy focusing on the maintenance of respiration, circulation, water and electrolyte balance, and control of cerebral function.
Abstract: In treatment of metal poisonings, the top priorities should be prevention of further uptake, decreased absorption from the gastrointestinal tract, and general supportive therapy focusing on the maintenance of respiration, circulation, water and electrolyte balance, and control of cerebral function. Elimination of the absorbed poison can be facilitated by diuresis, hemodialysis, or exchange transfusion. Chelating agents counteract the effects of an absorbed toxic metal by displacing the metal from its receptor site into urine or a tissue where it cannot exert toxic effects. Chelation therapy is indicated in the treatment of metal poisonings, metal storage diseases, and to aid the elimination of some radionuclides. Chelators may also have toxic effects, for example, by depletion of essential metals or by the reallocation of toxic metals to other vulnerable tissues. Use and misuse of chelators are discussed in this chapter. Dimercaprol (BAL), the classical but now a rather outdated chelator with high toxicity, competes with protein thiol groups for arsenic and some other metals. Today its less toxic analogs Dimaval (DMPS) and Succimer (DMSA) are used in the treatment of intoxications by arsenic, mercury, bismuth, and lead. The previous use of intravenous calcium EDTA, may redistribute lead to the brain after acute or chronic poisoning, and is therefore not recommended. Due to its serious side effects, the use of EDTA in atherosclerotic diseases is contraindicated. Penicillamine and trientine have proven to be effective in the treatment of copper accumulation and in the management of Wilson’s disease. Deferoxamine is the treatment of choice in acute iron poisoning. It can also be used in the treatment of transfusional siderosis, preferably in combination with deferiprone or deferasirox, the new oral agents that can mobilize intracellular iron from liver and heart. Derivatives of DTPA as aerosol have been used to decrease the lung deposits of inhaled plutonium.
12 citations
TL;DR: This study provides a convenient and economical biomaterial for preventing lead poisoning via the digestive tract and significantly inhibited the increase of blood lead levels, the impairment of hepatic function and the decrease of testosterone concentration in the serum, which were all impaired in rats treated by lead acetate alone.
Abstract: Low-level lead poisoning is an insidious disease that affects millions of children worldwide, leading to biochemical and neurological dysfunctions. Blocking lead uptake via the gastrointestinal tract is an important prevention strategy. With this in mind, we constructed the recombinant Lactococcus lactis strain pGSMT/MG1363, which constitutively expressed the fusion protein glutathione S-transferase (GST)–small molecule ubiquitin-like modifier protein (SUMO)–metallothionein-I (GST-SUMO-MT). The thermodynamic data indicated that the average number of lead bound to a GST-SUMO-MT molecule was 3.655 and this binding reaction was a spontaneous, exothermic and entropy-increasing process. The total lead-binding capacity of pGSMT/MG1363 was 4.11 ± 0.15 mg/g dry mass. Oral administration of pGSMT/MG1363 (1 × 1010 Colony-Forming Units) to pubertal male rats that were also treated with 5 mg/kg of lead acetate daily significantly inhibited the increase of blood lead levels, the impairment of hepatic function and the decrease of testosterone concentration in the serum, which were all impaired in rats treated by lead acetate alone. Moreover, the administration of pGSMT/MG1363 for 6 weeks did not affect the serum concentration of calcium, magnesium, potassium or sodium ions. This study provides a convenient and economical biomaterial for preventing lead poisoning via the digestive tract.
12 citations
TL;DR: In this paper, Coenzyme Q10 (CoQ10) was administered separately or in combination with 2,3-dimecaptosuccinic acid (DMSA) to nullify arsenite-induced toxicity in mice.
Abstract: Arsenic poisoning affects millions of people The inorganic forms of arsenic are more toxic Treatment for arsenic poisoning relies on chelation of extracellularly circulating arsenic molecules by 2,3-dimecaptosuccinic acid (DMSA) As a pharmacological intervention, DMSA is unable to chelate arsenic molecules from intracellular spaces The consequence is continued toxicity and cell damage in the presence of DMSA A two-pronged approach that removes extracellular arsenic, while protecting from the intracellular arsenic would provide a better pharmacotherapeutic outcome In this study, Coenzyme Q10 (CoQ10), which has been shown to protect from intracellular organic arsenic, was administered separately or with DMSA; following oral exposure to sodium meta-arsenite (NaAsO2) – a very toxic trivalent form of inorganic arsenic The aim was to determine if CoQ10 alone or when co-administered with DMSA would nullify arsenite-induced toxicity in mice Group one represented the control; the second group was treated with NaAsO2 (15 mg/kg) daily for 30 days, the third, fourth and fifth groups of mice were given NaAsO2 and treated with 200 mg/kg CoQ10 (30 days) and 50 mg/kg DMSA (5 days) either alone or in combination Administration of CoQ10 and DMSA resulted in protection from arsenic-induced suppression of RBCs, haematocrit and hemoglobin levels CoQ10 and DMSA protected from arsenic-induced alteration of WBCs, basophils, neutrophils, monocytes, eosinophils and platelets Arsenite-induced dyslipidemia was nullified by administration of CoQ10 alone or in combination with DMSA Arsenite induced a drastic depletion of the liver and brain GSH; that was significantly blocked by CoQ10 and DMSA alone or in combination Exposure to arsenite resulted in significant elevation of liver and kidney damage markers The histological analysis of respective organs confirmed arsenic-induced organ damage, which was ameliorated by CoQ10 alone or when co-administered with DMSA When administered alone, DMSA did not prevent arsenic-driven tissue damage Findings from this study demonstrate that CoQ10 and DMSA separately or in a combination, significantly protect against arsenic-driven toxicity in mice It is evident that with further pre-clinical and clinical studies, an adjunct therapy that incorporates CoQ10 alongside DMSA may find applications in nullifying arsenic-driven toxicity
10 citations
TL;DR: DMSA treatment during pregnancy enhances lead-induced fetal developmental toxicity and delayed the early physical and neural development of offspring, as well as decreasing blood lead levels of pregnant mice.
Abstract: To examine the effects of meso-2,3-dimercaptosuccinic acid (DMSA) on developmental toxicity resulting from exposure to lead in utero, female albino mice were exposed to lead by drinking water contaminated with lead acetate for 4 weeks. After the cessation of lead exposure, female mice were supplemented by gavage with saline solution, DMSA, or DMSA and calcium as well as ascorbic acid from the fourth day of gestation until parturition, respectively. Lead levels (blood, liver, and bone) were measured at birth. Pups were then tested about neural development including surface righting reflex, cliff avoidance and air righting reflex. The markers of physical maturation, such as body weight, pinna unfolding, incisor eruption, and eye opening were also recorded. DMSA treatment decreased blood lead levels of pregnant mice, however, increased lead levels in both liver and bone of fetus, and delayed the early physical and neural development of offspring. Calcium and ascorbic acid reduced the transfer of lead to fetus. In conclusion, DMSA treatment during pregnancy enhances lead-induced fetal developmental toxicity.
10 citations
Cites background from "Dimercaptosuccinic Acid (DMSA), A N..."
...Meso-2,3-dimercaptosuccinic acid (DMSA), is a water-soluble, sulfhydryl-containing compound which is an eVective oral chelator of heavy metals, and was identiWed as an eVective antidote to heavy metal poisoning (Miller 1998), and approved by the US....
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TL;DR: It is suggested that edetate disodium-based infusions may decrease the total body burden of lead, however, the data suggest no significant reduction in the bodyurden of cadmium.
Abstract: Environmentally acquired lead and cadmium are associated with increased cardiovascular disease risk. In the Trial to Assess Chelation Therapy, up to 40 infusions with edetate disodium over an approximately one-year period lowered the cardiovascular disease risk in patients with a prior myocardial infarction. We assessed whether a reduction in surrogate measures of total body lead and cadmium, post-edetate disodium urine lead and pre-edetate urine cadmium, could be detected after repeated edetate disodium-based infusions compared to the baseline. Fourteen patients with coronary artery disease received multiple open-label edetate disodium infusions. The urine metals pre- and post-edetate infusion, normalized for urine creatinine, were compared to urine levels pre and post final infusion by a paired t-test. Compared with the pre-edetate values, post-edetate urine lead and cadmium increased by 3581% and 802%, respectively, after the first infusion. Compared to baseline, post-edetate lead decreased by 36% (p = 0.0004). A reduction in post-edetate urine lead was observed in 84% of the patients after the final infusion. Pre-edetate lead decreased by 60% (p = 0.003). Pre-edetate lead excretion became undetectable in nearly 40% of patients. This study suggests that edetate disodium-based infusions may decrease the total body burden of lead. However, our data suggest no significant reduction in the body burden of cadmium.
10 citations
References
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TL;DR: This article reviews the pharmacological properties and the uses of two important antidotes for heavy metal poisoning, DMSA and DMPS, water soluble chemical analogs of dimercaprol, which have less toxicity, greater water solubility, and lim ited lipid solubilities, and are effective when given orally.
Abstract: This article reviews the pharmacological properties and the uses of two important antidotes for heavy metal poisoning. Meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-l-propanesulfonic acid, Na salt (DMPS) are relatively new antidotes-new, that is, to the western world. Although DMSA was introduced originally by Friedheim et al (1) to increase uptake of antimony during schistosomiasis therapy, Liang et al (77) at Shanghai in 1957 were the first to report its effectiveness as an antidote for heavy metal poisoning. The synthesis and some of the metal binding properties of DMPS were reported in 1956 by Petrunkin from Kiev (3). Shortly thereaf ter, DMPS became an official drug in the Soviet Union, where it is known as Unithiol (4). Between 1956 and 1975, DMSA and DMPS were studied extensively, at both the basic science and clinical levels, in the People's Republic of China, the Soviet Union, and Japan. Some of these investigations have been cited and can be found in an earlier review (5). In the USA and western Europe, however, these two compounds received very little attention until recently. A paper by Friedheim & Corvi (6) in 1975, dealing with DMSA for the treatment of mercury poisoning, and the recent production and availability of DMPS from Heyl & Co., Berlin, stimulated investigators to "rediscover" and study these two metal-binding agents. DMSA and DMPS are water soluble chemical analogs of dimercaprol (British Anti-Lewisite, BAL). In contrast to BAL, they have less toxicity, greater water solubility, and lim ited lipid solubility, and are effective when given orally.
309 citations
"Dimercaptosuccinic Acid (DMSA), A N..." refers background in this paper
...DMSA has been shown in recent studies to be a safe and effective chelator of lead, reducing blood levels significantly.(1,34,35) At a dose of 10 mg/kg for five days in adult males, DMSA lowered blood lead levels 35....
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...DMSA was subsequently studied for twenty years in the People’s Republic of China, Japan, and Russia before scientists in Europe and the United States “discovered” the substance and its potential usefulness in the mid-1970s.(1) DMSA is a dithiol (containing two sulfhydryl, or S-H, groups) and an analogue of dimercaprol (BAL, British Anti-Lewisite), a lipid-soluble compound also used for metal chelation (see Figure 1)....
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TL;DR: It has been discovered that microtubules are destroyed by this form of mercury and this effect may explain the inhibition of cell division and cell migration, processes that occur only in the developmental stages, and other hypotheses will stimulate considerable experimental challenges in the future.
Abstract: The nervous system is the principal target for a number of metals. Inorganic compounds of aluminum, arsenic, lead, lithium, manganese, mercury, and thallium are well known for their neurological and behavioral effects in humans. The alkyl derivatives of certain metals--lead, mercury and tin--are specially neurotoxic. Concern over human exposure and in some cases, outbreaks of poisoning, have stimulated research into the toxic action of these metals. A number of interesting hypotheses have been proposed for the mechanism of lead toxicity on the nervous system. Lead is known to be a potent inhibitor of heme synthesis. A reduction in heme-containing enzymes could compromise energy metabolism. Lead may affect brain function by interference with neurotransmitters such as gamma-amino-isobutyric acid. There is mounting evidence that lead interferes with membrane transport and binding of calcium ions. Methylmercury produces focal damage to specific areas in the adult brain. One hypothesis proposes that certain cells are susceptible because they cannot repair the initial damage to the protein sythesis machinery. The developing nervous system is especially susceptible to damage by methylmercury. It has been discovered that microtubules are destroyed by this form of mercury and this effect may explain the inhibition of cell division and cell migration, processes that occur only in the developmental stages. These and other hypotheses will stimulate considerable experimental challenges in the future.
196 citations
"Dimercaptosuccinic Acid (DMSA), A N..." refers background in this paper
...Methyl mercury also easily crosses the blood-brain barrier and the placenta.(7) Inorganic and methyl mercury have a high affinity for sulfhydryls, reacting intracellularly with the sulfhydryl group on glutathione and cysteine, and histidine residues in proteins, and allowing transport out of the cell....
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...After lead is absorbed in the human body, it reacts with thiol (sulfhydryl) groups on peptides and proteins, inhibiting enzymes involved in heme synthesis and interfering with normal neurotransmitter functions.(7) This natural reaction with thiols is also the body’s method of eliminating lead, especially from the liver....
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TL;DR: Analysis of the data from the questionnaires indicated that little or no exogenous exposure to mercury occurred among the two groups.
Abstract: Mercury levels in blood and in mouth air before and after chewing were measured in 47 persons with ana 14 persons without dental amalgam restorations. Questionnaires relating to exogenous sources of mercury exposure were administered to both groups. Differences in the mouth air mercury levels before and after chewing were statistically significant in the group with amalgams, but not in the group without amalgams. Analysis of the data from the questionnaires indicated that little or no exogenous exposure to mercury occurred among the two groups. Blood mercury concentrations were positively correlated with the number and surface area of amalgam restorations and were significantly lower in the group without dental amalgams.
194 citations
TL;DR: Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans.
Abstract: For more than 160 years dentistry has used silver amalgam, which contains approximately 50% Hg metal, as the preferred tooth filling material. During the past decade medical research has demonstrated that this Hg is continuously released as vapor into mouth air; then it is inhaled, absorbed into body tissues, oxidized to ionic Hg, and finally covalently bound to cell proteins. Animal and human experiments demonstrate that the uptake, tissue distribution, and excretion of amalgam Hg is significant, and that dental amalgam is the major contributing source to Hg body burden in humans. Current research on the pathophysiological effects of amalgam Hg has focused upon the immune system, renal system, oral and intestinal bacteria, reproductive system, and the central nervous system. Research evidence does not support the notion of amalgam safety.
178 citations
TL;DR: Results suggest that lead-induced oxidative stress in vivo can be mitigated by pharmacologic interventions, which encompass both chelating as well as thiol-mediated antioxidant functions.
172 citations