Principles and recent developments in chelation treatment of metal intoxication.
About: This article is published in Chemical Reviews.The article was published on 1999-09-08. It has received 330 citations till now.
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TL;DR: An overview of redox and non-redox metal-induced formation of free radicals and the role of oxidative stress in toxic action of metals is provided.
2,429 citations
Cites background from "Principles and recent developments ..."
...(Kell, 2009; Andersen, 1999)....
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...Can suitable iron chelator inhibit production of hydroxyl radicals to desirable extent? (Kell, 2009; Andersen, 1999)....
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897 citations
Journal Article•
TL;DR: A comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation is attempted, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects are attempted.
Abstract: Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa(2)EDTA), British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects. We have selected only arsenic, lead, mercury and cadmium for this article keeping in view current concerns and literature available.
840 citations
TL;DR: In a systematic review of scaffold architectures, the underlying effects and control options will be demonstrated, and suggestions will be given for designing effective multivalent binding systems, as well as for polyvalent therapeutics.
Abstract: Multivalent interactions can be applied universally for a targeted strengthening of an interaction between different interfaces or molecules. The binding partners form cooperative, multiple receptor-ligand interactions that are based on individually weak, noncovalent bonds and are thus generally reversible. Hence, multi- and polyvalent interactions play a decisive role in biological systems for recognition, adhesion, and signal processes. The scientific and practical realization of this principle will be demonstrated by the development of simple artificial and theoretical models, from natural systems to functional, application-oriented systems. In a systematic review of scaffold architectures, the underlying effects and control options will be demonstrated, and suggestions will be given for designing effective multivalent binding systems, as well as for polyvalent therapeutics.
820 citations
TL;DR: This review provides an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.
Abstract: Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.
765 citations
Cites background from "Principles and recent developments ..."
...The oral LD50 for rats for TETA is 2.5 g/kg body weight and is very close to the recommended dose for treatment of Wilson’s disease....
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...Two major metabolites of TETA have been identified, i.e., N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT)....
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...The 5–18% of TETA that is systemically absorbed is said to be extensively metabolized, with the majority being excreted in urine as metabolite(s) [67,68]....
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...Increased urinary copper excretion has been reported after administration of TETA [2]....
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...Wilson’s disease was originally treated with DPA but TETA was a better chelator and found to be potentially free of side effects like those of DPA....
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References
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TL;DR: In this paper, the rate data for the generalized nucleophilic displacement reaction were reviewed, and the authors presented a method to estimate the rate of the generalized displacement reaction in terms of the number of nucleophiles.
Abstract: Recently (1) the rate data for the generalized nucleophilic displacement reaction were reviewed.
8,433 citations
TL;DR: Exposure to lead in childhood is associated with deficits in central nervous system functioning that persist into young adulthood, and lead levels were inversely related to self-reports of minor delinquent activity.
Abstract: To determine whether the effects of low-level lead exposure persist, we reexamined 132 of 270 young adults who had initially been studied as primary school-children in 1975 through 1978. In the earlier study, neurobehavioral functioning was found to be inversely related to dentin lead levels. As compared with those we restudied, the other 138 subjects had had somewhat higher lead levels on earlier analysis, as well as significantly lower IQ scores and poorer teachers' ratings of classroom behavior. When the 132 subjects were reexamined in 1988, impairment in neurobehavioral function was still found to be related to the lead content of teeth shed at the ages of six and seven. The young people with dentin lead levels greater than 20 ppm had a markedly higher risk of dropping out of high school (adjusted odds ratio, 7.4; 95 percent confidence interval, 1.4 to 40.7) and of having a reading disability (odds ratio, 5.8; 95 percent confidence interval, 1.7 to 19.7) as compared with those with dentin lead levels less than 10 ppm. Higher lead levels in childhood were also significantly associated with lower class standing in high school, increased absenteeism, lower vocabulary and grammatical-reasoning scores, poorer hand-eye coordination, longer reaction times, and slower finger tapping. No significant associations were found with the results of 10 other tests of neurobehavioral functioning. Lead levels were inversely related to self-reports of minor delinquent activity. We conclude that exposure to lead in childhood is associated with deficits in central nervous system functioning that persist into young adulthood.
1,113 citations
TL;DR: Although early trials showed marked gastrointestinal and renal toxicities, treatment-related morbidity has been significantly alleviated with modern antiemetic therapy and adequate pretreatment hydration.
Abstract: Cisplatin is a metal coordination compound that was approved for clinical use in treating testicular cancer 5 years ago. Although early trials showed marked gastrointestinal and renal toxicities, treatment-related morbidity has been significantly alleviated with modern antiemetic therapy and adequate pretreatment hydration. More recent clinical studies of cisplatin have shown a broad range of activity and provide a better understanding of the drug's pharmacology, mechanism of action, and toxicity. Variations in the dosage and mode of administration as well as development of cisplatin analogues are being currently studied.
879 citations
TL;DR: A new form of oral treatment with dimethyl cysteine (penicillamine) is described, given in doses varying from 0.5 to 1.5 gm.
631 citations
TL;DR: Desferrioxamine (deferoxamine) is an inhibitor of iron-dependent free radical reactions that has been used to investigate the role of such reactions in several animal model systems for human disease as mentioned in this paper.
388 citations