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)
Citations
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TL;DR: This present study provides the first evidence of the therapeutic efficacy of DMSA against oxidative stress and vascular dysfunction in Cd-intoxicated mice.
35 citations
TL;DR: Cadmium chronic poisoning causes mainly renal tubulopathy and could be the cause of osteomalacia and diffuse osteoporosis and some diseases caused by occupational exposure to cadmium may be compensated.
Abstract: Cadmium is a metallic impurity in various minerals The two main cadmium exposure sources in general population are food and tobacco smoking Its industrial exploitation has grown in the early twentieth century Cadmium is used in accumulators or alkaline batteries (80%) and in pigments for paints or plastics (10%), in electrolytic process by deposit or by cadmium plating on metals or to reduce melting points (welding rods) Cadmium is a cumulative toxic substance whose half-time for elimination is about 20 to 40 years and it is mainly stored in the liver and kidneys Inhalation of cadmium oxide fumes may cause inhalation fevers or chemical pneumonitis Cadmium chronic poisoning causes mainly renal tubulopathy and could be the cause of osteomalacia and diffuse osteoporosis Cadmium is classified as certain carcinogen agent for humans by International Agency for Research on Cancer (IARC) The most relevant biological index exposure is the urinary cadmium According to literature, no chelating agent can be still used in human cadmium poisonings In France, some diseases caused by occupational exposure to cadmium may be compensated
35 citations
TL;DR: The 4-month-old child ingested a dose of arsenic that was lethal despite extraordinary attempts at arsenic removal, including chelation therapy, extracorporeal membrane oxygenation, exchange transfusion, and hemodialysis.
Abstract: We report a case series of acute arsenic poisoning of 2 siblings, a 4-month-old male infant and his 2-year-old sister. Each child ingested solubilized inorganic arsenic from an outdated pesticide that was misidentified as spring water. The 4-month-old child ingested a dose of arsenic that was lethal despite extraordinary attempts at arsenic removal, including chelation therapy, extracorporeal membrane oxygenation, exchange transfusion, and hemodialysis. The 2-year-old fared well with conventional therapy.
33 citations
TL;DR: The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators, indicating that nature has developed proteins which are less restricted than simple non-protein molecules.
Abstract: Chelation therapy is used for diseases causing an imbalance of iron levels (for example haemochromatosis and thalassaemia) or copper levels (for example Menkes’ and Wilson’s diseases). Currently, most pharmaceutical chelators are relatively simple but often have side effects. Some have been taken off the market. This review attempts to find theory and knowledge required to design or find better chelators. Recent research attempting to understand the biological mechanisms of protection against iron and copper toxicity is reviewed. Understanding of molecular mechanisms behind normal iron/copper regulation may lead to the design of more sophisticated chelators. The theory of metal ion toxicity explains why some chelators, such as EDTA, which chelate metal ions in a way which exposes the ion to the surrounding environment are shown to be unsuitable except as a means of killing cancer cells. The Lewis theory of acids and bases suggests which amino acids favour the attachment of the hard/intermediate ions Fe2+, Fe3+, Cu2+ and soft ion Cu+. Non-polar amino acids will chelate the ion in a position not in contact with the surrounding cellular environment. The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators. Clearly, nature has developed proteins which are less restricted. Recent research on naturally produced chelators such as siderophores and phytochemicals show some promise as pharmaceuticals. Although an understanding of natural mechanisms of Fe/Cu regulation continues to increase, the pharmaceutical chelators for metal overload diseases remain simple non-protein molecules. Natural and synthetic alternatives have been studied but require further research before being accepted.
32 citations
TL;DR: In this paper, density functional theory calculations were performed to investigate the complex formation ability of Meso-2,3-dimercaptosuccinic acid (DMSA) with metal ions (Cd2+, Hg2+ and Pb2+) in water.
32 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