Article

Mobilization of heavy metals by newer, therapeutically useful chelating agents

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Abstract

Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, DimavalR) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulflde in which each of the sulfur atoms of DMSA is in disulfide linkage with an l-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.

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... Whereas BPb is lowered during the therapeutic course, a rebound effect is usually observed in the drug-free intervals, explained from a redistribution of Pb from bone and presumably also from the brain (Andersen 1999). In the treatment of cases with moderate or severe Pb poisoning without encephalopathy, i.v., CaEDTA treatment should be replaced by p.o. DMSA monotherapy because of the adverse effects of CaEDTA (Aposhian et al. 1995). ...
... BAL treatment was later shown effective in human As and Hg poisonings. Therefore, BAL became the primary metal-binding antidote in the Western world for several decades (Eagle et al. 1946;Stocken 1947;Hruby and Donner 1987;Aposhian et al. 1995;Andersen 1999). It was later replaced by DMSA and DMPS (Hruby and Donner 1987;Aposhian et al. 1995;Andersen 1999), which are water-soluble dithiols and derivatives of BAL (Fig. 2). ...
... Therefore, BAL became the primary metal-binding antidote in the Western world for several decades (Eagle et al. 1946;Stocken 1947;Hruby and Donner 1987;Aposhian et al. 1995;Andersen 1999). It was later replaced by DMSA and DMPS (Hruby and Donner 1987;Aposhian et al. 1995;Andersen 1999), which are water-soluble dithiols and derivatives of BAL (Fig. 2). ...
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This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.
... Evaluations of arsine and As trioxide in rabbits (11,12), mice (13,14), and guinea pigs (15) all favor treatment with DMSA over BAL. The significantly lower toxicity and the ease of administration contributed to the clinical consensus that DMSA and DMPS, not BAL, are the first choice of therapy for human As poisoning (16). In our earlier controlled human study, DMSA was not found to be more effective than placebo in reversal of the clinical biochemical responses or histological responses to chronic arsenicosis (17). ...
... DMPS appears to be a clinically superior chelating agent than DMSA in the treatment of arsenicosis. The administration of DMPS to fasted normal male volunteers shows DMPS to be excreted in the urine over a longer period of time than DMSA (16). After administration of a single dose of DMPS 300 mg orally in 13 subjects consuming As in drinking water for a prolonged period, urine excretion of As was several-fold that of prechelation levels (21). ...
... DMPS appears to be biotransformed in humans to acyclic and cyclic disulfides whereas DMSA in humans is biotransformed almost completely to a DMSA-CySH (1: 2) mixed disulfide (22). A DMPS-cysteine mixed disulfide has been found only in minute amounts after DMPS administration (16). A major difference between DMSA and DMPS is that the latter is distributed both extracellularly and, to a small extent, intracellularly (23)(24)(25). ...
... DMPS is an analogue of BAL used for treating HM poisoning. It makes complex with Pb and eliminates Pb complex through the kidney (Aposhian et al. 1995). DMPS is listed as an antidote for various HM such as As, Pb, Cd, Hg (organic/inorganic), and number of unspecified compounds. ...
... DMPS is commercially available as capsule in Germany since 1997 under the trademark of unithiol. It enters the cell through special mechanism, and distribution is limited to majorly exterior of cells, but limited intracellular penetration has been also reported (Aposhian et al. 1995), (Modi and Flora 2007). DMPS use has been obsoleted because of its inefficiency when compared with another conventional chelating agents like CaNaEDTA and DMSA. ...
Article
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Toxicity due to heavy metals (HM), specifically mercury (Hg), arsenic (As), lead (Pb), and cadmium (Cd) remains a challenge to scientists till date. This review gives insights into natural antidotes for the management and prevention of HM toxicity. Various databases such as PubMed, Embase, and Science Direct were searched for available facts on natural antidotes and their commercial products against HM toxicity till date. Toxicity owing to such metals needs prevention rather than therapy. Natural antidotes, fruits and vegetables, rich in antioxidant are the answers to such toxicities. Synthetic chelators impart a major drawback of removing essential metals required for normal body function, along with the toxic one. Natural antioxidants are bestowed with scavenging and chelation properties and can be alternative for synthetic chelating agents. Natural compounds are abundantly available, economic, and have minimal side effects when compared with classical chelators. Prevention is better than cure and thus adding plentiful vegetables and fruits to our diet can combat HM toxicity-related illness. Graphical abstract
... Mercury elimination is accomplished through chelation therapy and urinary excretion. In acute intoxication, chelation therapy must be promptly administered to patients which exhibit symptoms [2]. ...
... In this particular instance, considering the high mercury levels found in blood and urine samples and also the multiple internal deposits (lungs, pleura, pericardium, kidney, spine, etc.), it became clear it was a chronic mercury intoxication. The high levels of mercury did not cause death directly, but indirectly through complications and accumulation in organs, ultimately to the point of multiple system organ failure [2,3]. ...
Article
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Both chronic and acute mercury exposure represents a threat to public health. Mercury is generally used in several industrial areas to manufacture a variety of chemical products such as paint, explosives, batteries, thermometers, electronics, etc. Although the medico-legal practice rarely deals with this specific pathology, it is not to be taken lightly, in most cases being result of suicide attempts through self-injection and oral administration with systemic and local consequences-mercurism. We present the case of a 56-year-old male admitted to the hospital with signs of acute renal failure of unknown origin and severe metabolic acidosis. At the time of admission, there wasn't sufficient data pointing to a chronic mercury intoxication. This diagnosis was later suspected and ultimately confirmed by autopsy and laboratory results (toxicology and histopathology).
... Depending on dose size and severity of the condition, different antidotes and chelating agents are prescribed. But, these agents intervene with essential metal ion like Ca 2+ , Cu 2+ , Zn 2+ , and results in aberrant physiologic function [6]. In addition, unbroken heavy metals are redistributed by these agents to potentiate toxicity at intracellular sites of liver and kidney [7]. ...
... Conversely, if Pb-level ranges in between 45 and 69 mg/dL for children, then oral chelation therapy with DMSA might be suggested [36]. But the repetitive dose of CaNa 2 EDTA could cause kidney damage particularly renal tubules, along with depleted essential metal ion like Zn, Cu, Ca concentration [6,37]. Profound role of vitamins and nutrients against Pb burden in the experimental animal were also documented. ...
Article
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Environmental pollution has become a concerning matter to human beings. Flint water crisis in the USA pointed out that pollution by heavy metal is getting worse day by day, predominantly by Lead, Cadmium, Mercury and Arsenic. Despite of not having any biological role in flora and fauna, they exhibit detrimental effect following exposure (acute or chronic). Even at low dose, they affect brain, kidney and heart. Oxidative stress has been termed as cause and effect in heavy metal-induced kidney toxicity. In treatment strategy, different chelating agent, vitamins and minerals are included, though chelating agents has been showed different fatal drawbacks. Interestingly, plants and plants derived compounds had shown possible effectiveness against heavy metals induced kidney toxicity. This review will provide detail information on toxicodynamics of Pb, Cd, Hg and As, treatment strategy along with the possible beneficiary role of plant derived compound to protect kidney.
... The threshold for toxicity is now considered to be when blood levels are Ͼ 10 g/dl (0.5 M) (Cory-Slechta, 1995;Davis et al., 1993). Lead toxicity can be successfully treated with chelators such as EDTA, DMSA and DMPS (Angle, 1993;Aposhian, 1983); DMSA appears to be the drug of choice due to its effectiveness and lower toxicity (Aposhian et al., 1995;Graziano et al., 1992). ...
... Experiments were performed to test the efficacy of heavy metal poisoning antidotes, such as EDTA or DMSA (Aposhian, 1983;Angle, 1993;Aposhian et al., 1995), to reverse the Pb ϩϩ block of L-type channels. To mimic the clinical situation, we first induced Pb ϩϩ block and then tried to reverse block using a solution containing both antidote and Pb ϩϩ . ...
... Actually, in animal models of mercury or arsenic intoxication, BAL treatment induces redistribution of these elements from peripheral organs to the brain (Aposhian et al., 1995;Emanuelli et al., 1996). Despite relevant evidence of the BAL therapeutic use, obtained from in vivo and in vitro animal data as well as clinical accounts, its use for metal poisoning treatment has been halted by data suggesting serious neurotoxicity (Pepin et al., 1995;Nogueira et al., 2000Nogueira et al., , 2001a. ...
... Other metal chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1sulfonic acid (DMPS), have also been shown to be effective for treating the toxicity induced by a number of heavy metals (Aposhian et al., 1992;Andersen, 1989;Smith et al., 2000). These compounds are more hydrophilic and less toxic than BAL (Aposhian et al., 1995;Domingo, 1995). ...
... Several chelating agents have been studied as potential MeHg antidotes and recently used for mercury elimination from the body. Of the agents that have been examined, meso-2,3-dimercaptosuccinic acid (DMSA, succimer) and 2,3-dimercapto-1-propanesulfonic acid (DMPS, dimaval) are the most efficient at enhancing methylmercury excretion and in preventing toxicity in both experimental animals [10][11][12][13] and humans. 14,15 However, these agents have limited stability in solution, limited availability for human use, and a propensity to mobilize other essential and nonessential metals. ...
... 14,15 However, these agents have limited stability in solution, limited availability for human use, and a propensity to mobilize other essential and nonessential metals. 10,[16][17][18] Thus, there is an urgent need to develop a more effective antidote that will be associated with less or ideally no toxic side effects. ...
Article
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This study was designed to evaluate protective effect of N-acetyl cysteine (NAC) in reducing methylmercury (MeHg) induced oxidative stress, lipid peroxidation, DNA damage in liver, kidney, brain and their ability to restore altered hepatic, renal and other biochemical variables. Male Sprague-Dawley rats (150 � 10 g) were randomly divided into 3 groups. Group 1 served as control. Group 2-3 were administered methylmercury (1 mg kg-1 orally, 5 days/week) for 12 weeks and Group 2 served as experimental control. Group 3 received N-acetyl cysteine (0.6 mg kg-1 intraperitoneally, 2 days/week) for 12 weeks after methylmercury exposure. Methylmercury exposure caused significant rise in bilirubin, gamma-glutamyl transpeptidase, protein, triglycerides, cholesterol, urea, creatinine, uric acid, blood urea nitrogen, with concomitant decrease in albumin content, reduced glutathione level and acetyl cholinesterase activity, antioxidant enzymes as glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, adenosine triphosphatase. However lipid peroxidation level, metallothionein expression and DNA damage with increment of tail length was observed after methylmercury intoxication. N-acetyl cysteine, a widely available, nontoxic amino acid derivative, promising antioxidant with wide spectrum of biological functions. Ability of NAC to enhance mercury excretion and its wide availability in clinical use indicate that it may be an ideal therapeutic agent against methylmercury poisoning.
... It is essential to highlight that the conjugation of toxic metals with glutathione, which is notably lower in autistic cases, is required for toxic metal detoxification (Fiłon et al., 2020). Meso-2,3-dimercaptosuccinic acid (DMSA), on the other hand, is utilized to manage Pb and Hg intoxication (Aposhian et al., 1995). DMSA has been shown to reduce Hg and Pb levels in the brains of animal models. ...
Article
Background and aim Autism spectrum disorder (ASD) is a neurodevelopmental illness characterized by difficulties in social communication and repetitive behaviors. There have been many previous studies of toxic metals in ASD. Therefore, the priority of this study is to review the relationships between exposure to toxic metals and ASD. Materials & methods This study was based on a comprehensive search of international databases, such as Web of Science, Science Direct, Scopus, PubMed, and Google Scholar, for all works related to the subject under discussion from 1982 to 2022. We further summarize published data linked to this topic and discuss with clarifying evidence that agrees and conflicts with the association between exposure to toxic metals, including mercury (Hg), lead (Pb), cadmium (Cd), arsenic (As), and aluminum (Al) and ASD. Results 40 out of 63 papers met the requirements for meta-analysis. Blood Pb levels (standardized mean difference (SMD) = 0.81; 95 % confidence interval (CI): 0.36–1.25), blood Hg (SMD = 0.90; CI: 0.30–1.49), hair Pb (SMD = 1.47; CI: 0.03–2.92), urine As (SMD = 0.65; CI: 0.22–1.09), and urine Al levels (SMD = 0.85; CI: 0.40–1.29) in autistic individuals were significantly higher than those of healthy control (HC). Whereas, blood As levels (SMD = 1.33; CI: −1.32–3.97), hair As (SMD = 0.55; CI: −0.14–1.24), hair Cd (SMD = 0.60; CI: −0.31–1.51), hair Hg (SMD = 0.41; CI: −0.30–1.12), hair Al (SMD = 0.87; CI: −0.02–1.77), urine Pb (SMD = −0.68; CI: −2.55–1.20), urine Cd (SMD = −0.26; CI: −0.94–0.41), and urine Hg levels (SMD = 0.47; CI: −0.09–1.04) in autistic individuals were significantly lower than those of HC. Conclusion Toxic metal content significantly differed between individuals with ASD and HC in the current meta-analysis. The results assist in clarifying the significance of toxic metals as environmental factors in the development of ASD.
... In order to protect body from Pb 2+ poisoning, it's the most common therapeutic strategy to use ethylenediaminetetraacetic acid (EDTA) and dimercaptosuccinic acid (DMSA) to promote Pb 2+ excretion. However, a series of side-effects of EDTA and DMSA were showed and these chelators are not suitable for the treatment of high-dose and long-term [9]. Thus, micronutrients, plant extracts, and probiotics, as safe dietary supplements, gain increasing attention to intervene and alleviate Pb 2+ intoxication. ...
Article
Lead (Pb²⁺) pollution poses severe healthy and ecological risks to humans. In this work, sulfate polysaccharide from Enteromorpha prolifera (SPE) was utilized for Pb²⁺ adsorption from simulated intestinal fluid. In order to evaluate its adsorption behaviors comprehensively, batch adsorption of Pb²⁺ was investigated under different conditions. Results showed that SPE presents high adsorption ability for Pb²⁺ through chemical adsorption process and the maximum adsorption capacity for Pb²⁺ was 278.5 mg/g. And SPE exhibited higher removal efficiency (≥60%) for trace Pb²⁺ (<10 mg/L) compared to that of other adsorbents based on polysaccharide. Besides, its adsorption can be described by Langmuir isotherm and pseudo-second-order kinetic models. Further, XRD, FTIR, and XPS were used to characterize the possible interaction of Pb²⁺ with SPE, and the results showed that carboxyl and hydroxyl groups in SPE play more important role than that of sulfate group. Our work represents the first assessment of Pb²⁺ adsorption properties of SPE. This investigation highlights the potential application of SPE to protect the body from hazard of food-derived heavy metals.
... Adverse effects include gastrointestinal symptoms and hypersensitivity reactions. [9][10][11] Although redistribution of mercury into the central nervous system has been demonstrated in rodents following repeated doses of DMSA many-fold higher than those used clinically, this is not a recognized risk in the treatment of mercury poisoning in human beings. 12 Although specific evidence-based guidelines are not established, it is generally believed, particularly for inorganic exposures, that chelation should be considered only in patients who have symptoms consistent with mercury toxicity and who demonstrate elevated urine mercury levels without provocation. ...
Article
Context.—Public awareness of methylmercury in fish has caused patients to seek testing for mercury poisoning. In some patients, the diagnosis of mercury poisoning has been made based on urine mercury excretions following oral dosing of meso-dimercaptosuccinic acid (DMSA), a metal chelator. However, studies comparing urine mercury excretion following DMSA in healthy non–fish eaters with healthy fish eaters could not be located. Objectives.—To describe urinary mercury excretion before and after DMSA in healthy fish eaters and non–fish eaters, and to determine whether urine mercury excretion after DMSA would rise above baseline levels to a greater extent in fish eaters. Design.—A total of 24 healthy physicians were assigned to 1 of 3 groups based on fish consumption: non–fish eaters; 1 to 2 fish servings per week; and 3 or more servings per week. Blood mercury concentrations and 12-hour urine mercury and creatinine excretions were measured before and after oral ingestion of 30 mg of DMSA per kilogram of body weight. Results.—A total of 24 subjects completed the study, and 2 subsequently were excluded. No difference in baseline urinary mercury excretion was detected between groups. All groups demonstrated an increase in urinary mercury excretion following DMSA, which was higher in fish eaters (P = .04). Multiple linear regression found that the best predictor of a rise in urine mercury excretion following DMSA challenge was the prechelation blood mercury concentration. Conclusions.—In this study of healthy physicians, oral DMSA produced a rise in urine mercury excretion both in non–fish eaters and fish eaters. The increase in chelated mercury excretion was higher in fish eaters. A simple rise in chelated mercury excretion over baseline excretion is not a reliable diagnostic indicator of mercury poisoning.
... Whereas, meso-DMSA form ( Figure 1) is available commercially and used clinically, which gets attention for treating heavy metals and nanoparticles intoxication in human beings (Cavanillas et al., 2012;Jahromi et al., 2014). meso-DMSA has been used in most published investigations of potential therapeutic drug for heavy metals removal due to its used as a chelating agent (Aposhian et al., 1995;Campbell et al., 1986). Therefore, the meso-DMSA form was carried out in this work. ...
Article
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Meso-2,3-dimercaptosuccinic acid (DMSA) is one of the efficient chelating reagents for treating the toxicity of several heavy metals. Currently, nanomaterial have been applied to various parts including zinc Oxide nanoparticles (ZnONPs). ZnONPs have several properties and are used as many applications. An increasing the amount of ZnONPs in commercial products causes risks related to free radicals or reactive oxygen species (ROS) in the body, leading to oxidative stress and eventually to the cancer process. In the present work, we mainly focused on the study of DMSA complexes in term of metal ions and nanoparticles. The synthesis of DMSA-ZnONPs by the co-precipitation method were determined, followed by Scanning Electron Microscope, Fourier Transform Infrared Spectroscopy and UV-Vis spectrophotometry confirming successful synthesis process. The stability study of the DMSA complexes with metal ions and ZnONPs were determined and evaluated the stability constant (K), with the Benesi- Hildebrand equation. All complexes with DMSA were formed at a 1:2 ratio by the dithiol group and the carboxyl group with different stability constants. Therefore, these results can help of an understanding of the interaction and its behavior between DMSA with heavy metal ion and ZnONPs. In addition, the stable structure of DMSA and metal ion complexes were predicted using the B3LYP and the 6-31G (d,p) basis set which the most stable structure of meso-DMSA was 2R,3S conformation and the metal ions and DMSA complexes was complex 2a with the binding energy of -1553.46 kcal mol⁻¹.
... The most commonly used therapeutic strategy for heavy metal poisoning is chelation therapy, which promotes metal excretion. However, chelators for Cd toxicity have numerous safety and efficacy concerns [2][3][4]. The development of safe and efficient strategies to reduce Cd toxicity remains an area of ongoing research. ...
Article
Cadmium (Cd) is an important environmental pollutant and long-term Cd exposure is closely related to autoimmune diseases, cancer, cardiovascular diseases (CVD), and hepatic dysfunction. Zinc (Zn) is an essential metal that plays key roles in protein structure, catalysis, and regulation of their function. Numerous studies have shown that Zn can reduce Cd toxicity; however, the underlying mechanisms have not been extensively explored. Preclinical studies have revealed direct competition for sarcolemmal uptake between these two metals. Multiple sarcolemmal transporters participate in Cd uptake, including Zn transporters, calcium channels, and DMT1 (divalent metal transporter 1). Zn also induces several protective mechanisms, including MT (metallothionein) induction and favorable redox homeostasis. This review summarizes current knowledge related to the role of Zn and metal transporters in reducing Cd toxicity and discusses potential future directions of related research.
... Studies on alternative treatment options against lead intoxication include the use of the chelating agent (Llobet et al. 1990;Tandon et al. 1997;Smith and Strupp 2013) which is often preferred to remove the systemic circulating component. However, chelating agents are also known to have individual toxic/adverse effect (Jaffe et al. 1968;Kean et al. 1980;Aposhian 1983, Aposhian et al. 1995Sachan et al. 1996;Mehta and Flora 2001;Mehta et al. 2002;Blanusa et al. 2005;Flora and Mehta 2003;Flora et al. 2004Flora et al. , 2007aBradberry and Vale 2009;Cao et al. 2015;Amadi et al. 2019) and cause oxidative stress (Mehta and Flora 2001;Mehta et al. 2002;Flora and Mehta 2003;Flora et al. 2004Flora et al. , 2007a. Since lead causes oxidative stress (Wang et al. 2012(Wang et al. , 2013Ozkaya et al. 2016;Aksu et al. 2017) and it is among the poisoning mechanisms of the metal (Jomova and Valko 2011;Rashid et al. 2013;Wani et al. 2015;Valko et al. 2016;Mitra et al. 2017), especially in terms of determining new treatment options against these negative effects of lead, it is very important to investigate the possible effects of diosmin, which has strong antioxidant properties (Silambarasan and Raja 2012;Barreca et al. 2013;Hajimahmoodi et al. 2014;Naso et al. 2016). ...
Article
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In this study, the effect of diosmin against the adverse effects of lead exposure in rats was investigated. Wistar Albino race 40 male rats weighing 150–200 g 2–3 months were used. A total of 4 groups were assigned, one of which was control and the other 3 were trial groups. The rats in the control group were treated with dimethyl sulfoxide, which was used only as a vehicle in diosmin administration. Groups 2, 3, and 4 from the experimental group were given diosmin at a dose of 50 mg/kg.bw, lead acetate at the dose of 1000 ppm, lead acetate at the dose of 1000 ppm, and diosmin at a dose of 50 mg/kg.bw for 6 weeks, respectively. Application of lead acetate with drinking water and also diosmin was performed by oral catheter. At the end of the experimental period, blood was taken to dry and with heparin by puncture to the heart under light ether anesthesia. Following the blood samples, some organs of the rats (the liver, kidney, brain, heart, and testis) were removed. Some biochemical parameters (glucose, triglyceride, cholesterol, BUN, creatinine, uric acid, LDH, AST, ALT, ALP, total protein, albumin) were measured in serum. Some oxidative stress parameters in tissue samples and blood (MDA, NO, SOD, CAT, GSH-Px, GSH) were evaluated. Body and organ (the liver, kidney, brain, heart, and testis) weights were also evaluated at the end of the study. No significant change was observed in the parameters examined in the diosmin alone-treated group by comparison to control group. On the other hand, significant changes were found in the values of lead acetate-treated group comparing control group. It was observed that the values approached the values of the control group in the combination of lead and diosmin. Exposure to lead acetate at a dose of 1000 ppm for 6 weeks causes organ damage; however the diosmin application at a dose of 50 mg/kg.bw had a positive effect on the regression of tissue damage.
... With the help of organic anion transport pathway, it enters the intracellular compartment. Without transporter, it cannot pass through membrane and leave extracellularly (Aposhian et al. 1995;Islinger et al. 2001;Flora and Pachauri 2010). DMPS is an effective chelating agent for acute or chronic arsenic poisoning. ...
Chapter
Arsenic (As) is a toxic and ubiquitously present element. It is present in some places of the world in excessively high concentrations in water and soil that threaten public health. North America constitutes one of the hotspots of As contamination. In Canada and the USA, a number of reports show the contamination of As in a number of food items including rice, rice-based products, fruits, beverages, animal food items, etc. Further, As contamination of water sources is also known to occur in different states of both Canada and the USA. Thus, the problem of As contamination is widespread and needs attention. This chapter provides an overview of As contamination of water and food sources of North America.
... In the previous research, garlic is effective in treating lead intoxication for workers who are exposed to environmental lead. In general, garlic and its derivatives have been gradually recommended as a promising agent for lead treatment because of the negative effect of the chelating agents that can deplete the body of essential metals resulting in secondary injury for health [1]. The positive effects of garlic on human health are ascribed to the presence of bioactive substances such as organosulfur compounds [2][3][4][5], flavonoids, and vitamins [6]. ...
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Based on the modulated electronic properties of Fe3O4-graphene (Fe3O4/GN composite) as well as the outstanding complexation between Pb²⁺ and natural substances garlic extract (GE), a novel electrochemical sensor for the determination of Pb²⁺ in wastewater was prepared by immobilization of Fe3O4/GN composite integrated with GE onto the surface of glassy carbon electrode (GCE). Fe3O4/GN composite was employed as an electrochemical active probe for enhancing electrical response by facilitating charge transfer while GE was used to improve the selectivity and sensitivity of the proposed sensor to Pb²⁺ assay. The electrochemical sensing performance toward Pb²⁺ was appraised by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and square wave voltammetry (SWV). Under the optimized condition, the sensor exhibited two dynamic linear ranges (LDR) including 0.001 to 0.5 nM and 0.5 to 1000 nM with excellent low detection limit (LOD) of 0.0123 pM (S/N = 3) and quantification limit (LOQ) of 0.41 pM (S/N = 10). Meanwhile, it displayed remarkable stability, reproducibility (RSD of 3.61%, n = 3), and selectivity toward the assay for the 100-fold higher concentration of other heavy metal ions. Furthermore, the novel sensor has been successfully employed to detect Pb²⁺ from real water samples with satisfactory results.
... For mammals or humans, the current therapeutic strategy for heavy metal poisoning involves heavy metal excretion by chelation therapy [18,19]. However, this therapy is limited in aquatic animals like fish. ...
Article
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Lead (Pb) is one of the most ubiquitous and toxic elements in the aquatic environment. Bacillus subtilis (B. subtilis) is a widely used probiotic in aquaculture. The aim of this study was to explore the toxic effects on bioaccumulation, hematological parameters, and antioxidant responses of Carassius auratus gibelio (C. gibelio) exposed to dietary lead at 0, 120, and 240 mg/kg and/or B. subtilis at 109 cfu/g. At 15 and 30 days, the fish were sampled and bioaccumulation, hematological parameters, and antioxidant responses were assessed. The result showed that B. subtilis administration can provide a significant protection against lead toxicity by reducing lead bioaccumulation in tissues, increasing the antioxidant enzymes activity, recovering δ-aminolevulinic acid dehydratase activity and optimizing the hematological parameters. Our results suggested that administration of B. subtilis (109 cfu/g) has the potential to combat dietary lead toxicity in C. gibelio.
... Chelation therapy is the recommended treatment of lead poisoning [10][11][12][13]. This is accomplished through the use of chelating agents that bind toxic lead and selectively remove it from circulation, and promote the removal of lead ions that are reversibly bound to enzymes and other tissue components [14]. ...
... Most of these complexes are water soluble. Dimaval has been extensively investigated as a scavenger molecule when heavy metals, especially mercury, poison enzymes [2,3,4,5]. ...
... Chelation therapy is the recommended treatment of lead poisoning [10][11][12][13]. This is accomplished through the use of chelating agents that bind toxic lead and selectively remove it from circulation, and promote the removal of lead ions that are reversibly bound to enzymes and other tissue components [14]. ...
Article
A number of new mono- and dihydroxypyridinethione ligands have been synthesized via reaction of dimethylamine and amino acid esters with the active amide obtained from the reaction of 1-hydroxy-2-pyridinethione-4-carboxylic acid (1) and 1,1′-carbonyldiimidazole in DMF. Moreover, the lead complexes of these new ligands were also prepared. Structures of the newly synthesized compounds have been confirmed by different spectroscopic methods such as IR, ¹H NMR, and ¹³C NMR, and by elemental analysis. The effect of these synthesized ligands on the excretion of lead, iron, and zinc, and their distribution in kidneys, liver, and bones in acutely intoxicated rats was investigated and results, for lead, were compared with those of the known drug meso-2,3-dimercaptosuccinic acid (DMSA). Results obtained revealed that compound 5 exhibits remarkable ability in total fecal and urinary excretion of lead and was superior to DMSA. In addition, results show that the concentration of lead in soft tissues and bones was lower in rats treated with HTPL than those treated with DMSA. Furthermore, the concentration of lead in liver tissues obtained from sub-chronic lead-intoxicated rats treated with HTPL was lower than those treated with DMSA and calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA).
... Following oral exposure to Cys-S-CH 3 Hg, it should be considered that thiol exchange likely occurs whereby the mercuric ion releases Cys and becomes bound to other available thiol-containing molecules [27,28]. In addition, previous studies have shown that following absorption/ingestion of CH 3 Hg + , a fraction of CH 3 Hg + is biotransformed to inorganic mercury (Hg 2+ ) [29,30]. ...
Article
Methylmercury (CH3Hg⁺) is an environmental toxicant that may lead to significant pathologies in exposed individuals. The current study assessed the disposition and toxicological effects of 2.5 or 7.5 mg kg⁻¹ CH3Hg⁺, conjugated to cysteine (Cys; Cys-S-CH3Hg) and administered orally to pregnant and non-pregnant Wistar and TR⁻ rats. Rats were euthanized on gestational day 20 and the content of mercury in each fetus, amniotic sac, and placenta was determined. The brain, liver, and kidneys were removed from each fetus for estimation of mercury content. From the dams, a sample of blood, kidneys, liver, and brain were removed at the time of euthanasia. The findings from this study indicate that pregnancy leads to significant changes in the handling of mercuric ions, particularly in the liver. Furthermore, there are significant differences in the handling of non-nephrotoxic and nephrotoxic doses of Cys-S-CH3Hg by maternal and fetal organs.
... These chelating agents trap the arsenic from body tissues by forming chemically inert metal-ligand complex and easily excreted from the body without any interaction within the body tissues [38]. However, there are various limitations associated with chelating agents like non-specificity, low therapeutic indexand failure to permeate the plasma membrane [39]. Moreover, antioxidants and chelating agents are not cost effective and mass effective and are limited to the particular body systems. ...
... At the same time new perspectives are arising from this for the prevention and treatment of oestrogen-dependent tumours: by deploying chelating agents, the stress on the body from metallo-oestrogens can be measured and treated [25][26][27][28]. Thus risk factors can be identified on an individual basis and treated accordingly. ...
Article
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Breast cancer is the most common cancer among women in the Western world. In 90 [%] of breast cancers environmental factors are among the causes. The frequency with which the tumor arises in the outer upper part of the chest is increased above average in recent decades. Aluminum salts as part of deodorants and antiperspirants are absorbed from the body to a greater extent than previously thought. Their toxicity to healthy and diseased breast tissue includes several well-documented pathological mechanisms. In terms of primary and secondary prevention the potentially carcinogenic potential of aluminum and its use in antiperspirant deodorants must be reassessed. For the same reason, access to a targeted diagnosis and therapy of aluminum loads must be facilitated.
... 1. Substances with nonspecific physiological effects: glutathione, NAC, alpha-lipoic acid, vitamin C, and selenium. 2. Chelating agents for detoxification of metals (296)(297)(298): the most important chelating agents are sodium thiosulfate 10%, DMPS (2,3-dimercapto-1-propanesulfonic acid), DMSA (mesodimercaptosuccinic acid), and EDTA (2,22,23,232ethane-1,2-diyldinitrotetraacetic acid). ...
Article
Full-text available
Chronic diseases and illnesses associated with non-specific symptoms are on the rise. In addition to chronic stress in social and work environments, physical and chemical exposures at home, at work, and during leisure activities are causal or contributing environmental stressors that deserve attention by the general practitioner as well as by all other members of the health care community. It seems necessary now to take "new exposures" like electromagnetic fields (EMF) into account. Physicians are increasingly confronted with health problems from unidentified causes. Studies, empirical observations, and patient reports clearly indicate interactions between EMF exposure and health problems. Individual susceptibility and environmental factors are frequently neglected. New wireless technologies and applications have been introduced without any certainty about their health effects, raising new challenges for medicine and society. For instance, the issue of so-called non-thermal effects and potential long-term effects of low-dose exposure were scarcely investigated prior to the introduction of these technologies. Common electromagnetic field or EMF sources: Radio-frequency radiation (RF) (3 MHz to 300 GHz) is emitted from radio and TV broadcast antennas, Wi-Fi access points, routers, and clients (e.g. smartphones, tablets), cordless and mobile phones including their base stations, and Bluetooth devices. Extremely low frequency electric (ELF EF) and magnetic fields (ELF MF) (3 Hz to 3 kHz) are emitted from electrical wiring, lamps, and appliances. Very low frequency electric (VLF EF) and magnetic fields (VLF MF) (3 kHz to 3 MHz) are emitted, due to harmonic voltage and current distortions, from electrical wiring, lamps (e.g. compact fluorescent lamps), and electronic devices. On the one hand, there is strong evidence that long-term exposure to certain EMFs is a risk factor for diseases such as certain cancers, Alzheimer's disease, and male infertility. On the other hand, the emerging electromagnetic hypersensitivity (EHS) is more and more recognized by health authorities, disability administrators and case workers, politicians, as well as courts of law. We recommend treating EHS clinically as part of the group of chronic multisystem illnesses (CMI), but still recognizing that the underlying cause remains the environment. In the beginning, EHS symptoms occur only occasionally, but over time they may increase in frequency and severity. Common EHS symptoms include headaches, concentration difficulties, sleep problems, depression, a lack of energy, fatigue, and flu-like symptoms. A comprehensive medical history, which should include all symptoms and their occurrences in spatial and temporal terms and in the context of EMF exposures, is the key to making the diagnosis. The EMF exposure is usually assessed by EMF measurements at home and at work. Certain types of EMF exposure can be assessed by asking about common EMF sources. It is very important to take the individual susceptibility into account. The primary method of treatment should mainly focus on the prevention or reduction of EMF exposure, that is, reducing or eliminating all sources of high EMF exposure at home and at the workplace. The reduction of EMF exposure should also be extended to public spaces such as schools, hospitals, public transport, and libraries to enable persons with EHS an unhindered use (accessibility measure). If a detrimental EMF exposure is reduced sufficiently, the body has a chance to recover and EHS symptoms will be reduced or even disappear. Many examples have shown that such measures can prove effective. To increase the effectiveness of the treatment, the broad range of other environmental factors that contribute to the total body burden should also be addressed. Anything that supports homeostasis will increase a person's resilience against disease and thus against the adverse effects of EMF exposure. There is increasing evidence that EMF exposure has a major impact on the oxidative and nitrosative regulation capacity in affected individuals. This concept also may explain why the level of susceptibility to EMF can change and why the range of symptoms reported in the context of EMF exposures is so large. Based on our current understanding, a treatment approach that minimizes the adverse effects of peroxynitrite - as has been increasingly used in the treatment of multisystem illnesses - works best. This EMF Guideline gives an overview of the current knowledge regarding EMF-related health risks and provides recommendations for the diagnosis, treatment and accessibility measures of EHS to improve and restore individual health outcomes as well as for the development of strategies for prevention.
... 15,18 Moreover, it shows no toxicity in the treatment of heavy metal intoxications 22 such as arsenic in mice and rabbits, 23,24 and can be orally administered without causing redistribution of metals from one organ to another. [23][24][25] In addition, DMSA-IONP have a high capacity and selectivity for heavy metals. 14 The thiol group on the surface of IONP mainly reacts with heavy metal ions directly to form stable metal-sulfur complexes through chelation. ...
Article
Magnetic iron oxide nanoparticles (IONP) have gained growing attention in recent years for their promising applications in medical treatment and environmental remediation. Among the IONP, dimercaptosuccinic acid coated-IONP (DMSA-IONP) have great potential because of their rapid uptake into cells and their potential to effectively adsorb heavy metals. The widespread use and potential release of IONP into the environment raises concern about their environmental impact. To date, little is known about the consequences of the exposure of aquatic organisms to such particles. In this context we investigated the colloidal stability of DMSA-IONP in different test media as well as their effects on green algae (Raphidocelis subcapitata), duckweed (Lemna minor) and water fleas (Daphnia magna). Moreover, a comparative analysis of stability and ecotoxicity data of DMSA-IONP with freshly prepared and aged uncoated IONP dispersions was performed, considering the importance of stability of particles in determining their toxicity. The green algae were the most sensitive organism with EC50 values (72 h) ranging between 0.86-2.27 μM Fe (i.e. 0.05 to 0.13 mg Fe L⁻¹) for the three types of IONP. The observed flocculation and (co-)sedimentation of algae with IONP are assumed to reduce the access of cells to nutrients and light. Lemna was not affected by any of the IONP due to the low availability of IONP induced by fast aggregation of IONP in the medium. Minor toxic effects on Daphnia were found for uncoated IONP (EC50 between 374-1181 μM Fe, i.e. 21-66 mg Fe L⁻¹) after 72 h. However, the ingestion and accumulation of coated and uncoated IONP in the gastrointestinal tract of daphnids was observed. Our evaluation of IONP has revealed a certain hazard potential to aquatic organisms. In this light it appears important to prevent the release of large amounts of IONP into the environment, which might limit their applicability.
... CaNa 2 EDTA has the tendency to accumulate Pb in the brain of experimental rats and exhibits neurotoxicity (Flora and Pachauri 2010 ). CaNa 2 EDTA also causes adverse effect on the renal system ( Aposhian et al. 1995 ). Thus CaNa 2 EDTA could not be regarded as a drug of choice against Pb poisoning. ...
Chapter
Toxic elements including lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) are ubiquitous in the environment and exposure of humans through food and water as well as occupational sources are known to have adverse effect on male reproductive health, and may be involved in the aetiology of several of human diseases including renal, neuronal, developmental retardation, cardiovascular and carcinogenesis. The results of the elemental analysis of these elements in biopsy materials (semen, urine, blood, nails, teeth and bone) indicate that their toxicity is associated to the metal overload in the body. However, inconsistencies exist in many cases and as such it is imperative to clarify the casuality of these associations before translating these data into public health impact. Moreover, the use of chelation therapy in medicine to reduce the concentrations of toxic metals in the body is a promising strategy in the treatment of metal toxicity.
... DMSA contains two sulfhydryl groups, which makes it a more effective chelator (Miller 1998). Moreover, DMSA is water soluble, orally administered, low in toxicity, and causes no redistribution of toxic metals from one organ to another (Aposhian et al. 1995). It has been demonstrated in animal experiments that DMSA is a powerful chelator (Jones et al. 1992). ...
Article
Cadmium (Cd) is a non-essential heavy metal with high toxicity potential. Humans are exposed to Cd present in diet, polluted air, and cigarette smoke. Cd exposure has been associated with increased risk of chronic diseases, including hypertension, atherosclerosis, diabetes, and nephropathy, all of which could be attributable to dysfunctional endothelial and smooth muscle cells. Cd toxicity is correlated with increased reactive oxygen formation and depletion of antioxidants, resulting in an oxidative stress. Chelation of Cd has proved useful in the removal of the Cd burden. However, several chelating agents cause side effects in clinical usage. Recent studies have shown that the antioxidant compounds curcumin and tetrahydrocurcumin can alleviate vascular dysfunction and high blood pressure caused by Cd toxicity. In chronic Cd exposure, these antioxidants protect vascular endothelium by increasing nitric oxide (NO•) bioavailability and improving vascular function. Antioxidant activity against Cd intoxication results directly and/or indirectly through free radical scavenging, metal chelation, enhanced expression of the antioxidant defense system, regulation of inflammatory enzymes, increase in NO• bioavailability, and reduction of gastrointestinal absorption and tissue Cd accumulation. This review summarizes current knowledge of Cd-induced oxidative stress and cardiovascular dysfunction and a possible protective effect conferred by the antioxidants curcumin and tetrahydrocurcumin.
... In a study of 84 patients treated with penicillamine, an adverse reaction occurred in 33% of patients and included transient leucopenia, transient thrombocytopenia, rash, enuresis, and abdominal pain [89]. Animal studies have shown that provocative chelation therapy can lead to mobilization of lead towards the nervous system [91,92]. Repeated chelation therapy could result in renal impairment as the kidney is the eliminatory route of the mobilized lead. ...
Article
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Lead, a ubiquitous metal, is one of the most abundant elements present on earth. Its easy availability and cost effectiveness made it an extremely popular component in the industrial revolution. However, its hazardous health effects were not considered at the time. Over the last few decades, with the adverse effects of lead coming to the forefront, nations across the world have started to recognize and treat lead toxicity. The most reliable and used method until now has been chelation therapy. Recent research has suggested the use of natural products and sources to treat lead poisoning with minimal or no side effects. This review has tried to summarize a few of the natural products/ sources being investigated by various groups.
... Although NAC and DMPS both produce a profound acceleration of urinary MeHg excretion, the mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine at high concentrations (Borgstrom et al., 1986;Aposhian et al., 1995;Ballatori et al., 1998b). The present study tested the hypothesis that the anionic MeHg-NAC and MeHg-DMPS complexes are cleared from peritubular blood by kidney organic anion transporters, in particular by Oat1 and Oat3 (Lopez-Nieto et al., 1997;Sekine et al., 1997;Sweet et al., 1997;Wolff et al., 1997;Cha et al., 2001). ...
Article
N -Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevis oocytes expressing rat Oat1 showed increased uptake of [14C]MeHg when complexed with either NAC or DMPS but not when complexed withl-cysteine, glutathione, dimercaptosuccinate, penicillamine, or γ-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparent K m values for Oat1-mediated transport were 31 ± 2 μM for MeHg-NAC and 9 ± 2 μM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [14C]MeHg-NAC and [14C]MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p -aminohippurate (PAH), and was trans -stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [3H]PAH from Oat1-expressing oocytes was trans -stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [3H]PAH uptake was competitively inhibited by NAC ( K i of 2.0 ± 0.3 mM) and DMPS ( K i of 0.10 ± 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals.
... In the present research guanine have been used to form complex with the free metal ion and to study how it can be made nontoxic in the body. Since chelation is the elimination of all the binding sites in the metal ion and as such chemical bonds to essential enzymes cannot be formed, lowering of toxicity by chelation of metal ions is ensured [8,9]. ...
Article
Full-text available
Voltammetric behaviors of Copper (II) nitrogen bearing nucleobases, such as Guanine (C 5 H 4 N 5 O 2 ) was studied in electro analyzer using cyclic voltammetry (CV) on a Glassy Carbon Electrode. Assessment of the chemical and physical conditions that may favor optimum current enhancement was done by studying the effect of variation of concentration of metal and ligand ions, variation of scan rate, variation of step height, variation of pH values, and variation of supporting electrolyte as (NH 4 ) 2 SO 4 , KCl, and NaCl. It was observed that Copper and Guanine forms a 1 : 2 ratio complex. The work reflects that increasing the concentration of either metal ion or ligand ion increases the corresponding current. Increasing the scan rate increases the corresponding current linearly with the square root of the scan rate. As the step height decreases the peaks become sharp. Anodic and cathodic current increases linearly with decreasing step height. For the complex mixture the complexation occurs maximum at a pH of 2.3–7.0 and is badly restricted in the slightly alkaline medium and the complexing order of the supporting electrolyte showed a trend as ( N H 4 ) 2 S O 4 > N a C l > K C l .
... Its chelation action is achieved by the incorporation of a metal or metaloid ion into heterocyclic ring structure. 25 EDTA forms stable complexes with many of the essential metals, as well as with some toxic metals, including mercury. 24 It can, therefore, be assumed that EDTA formed a stable chelate complex with mercury released from the amalgam exposed to NaOCl solutions and thus caused the bound mercury to not be detected by the cold-vapor mercury analyzer. ...
... However, CaNa2EDTA can cause renal toxicity (at the proximal tubule particularly), especially during repeated high doses treatment (above 75 mg/kg) and in subjects with previous history of kidney damage [29]. Because of its relative lack of specificity, other essential metals such as zinc, iron and manganese are also reported to be excreted and depleted following CaNa2EDTA therapy [30]. DMSA also has side effects such as appetite loss, nausea and diarrhea [31]. ...
Article
Full-text available
Cadmium (Cd) and lead (Pb) are toxic heavy metals that cause adverse health effects in humans and animals. Chelation therapy, the conventional treatment for heavy metal toxicity, is reported to have a number of safety and efficacy issues. Recent studies have shown that dietary supplements play important roles in protecting against Cd and Pb toxicity. This paper reviews the evidence for protective effects of essential metals, vitamins, edible plants, phytochemicals, probiotics and other dietary supplements against Cd and Pb toxicity and describes the proposed possible mechanisms. Based on these findings, dietary strategies are recommended for people at risk of Cd and Pb exposure. The application of these strategies is advantageous for both the prevention and alleviation of Cd and Pb toxicity, as such supplements can be added easily and affordably to the daily diet and are expected to have very few side effects compared to the chelation therapy.
... In the present research guanine have been used to form complex with the free metal ion and to study how it can be made nontoxic in the body. Since chelation is the elimination of all the binding sites in the metal ion and as such chemical bonds to essential enzymes cannot be formed, lowering of toxicity by chelation of metal ions is ensured [8,9]. ...
Article
Full-text available
Voltammetric behaviors of Copper (II) nitrogen bearing nucleobases, such as Guanine (C5H4N5O2) was studied in electro analyzer using cyclic voltammetry (CV) on a Glassy Carbon Electrode. Assessment of the chemical and physical conditions that may favor optimum current enhancement was done by studying the effect of variation of concentration of metal and ligand ions, variation of scan rate, variation of step height, variation of pHvalues, and variation of supporting electrolyte as (NH4)2SO4, KCl, andNaCl. Itwas observed that Copper and Guanine forms a 1 : 2 ratio complex.The work reflects that increasing the concentration of either metal ion or ligand ion increases the corresponding current. Increasing the scan rate increases the corresponding current linearly with the square root of the scan rate. As the step height decreases the peaks become sharp. Anodic and cathodic current increases linearly with decreasing step height. For the complex mixture the complexation occursmaximum at a pHof 2.3–7.0 and is badly restricted in the slightly alkaline medium and the complexing order of the supporting electrolyte showed a trend as (NH4)2SO4 > NaCl > KCl.
... At higher doses, IV and subcutaneous administration has resulted in necrotization and ulceration at the site. 67 DMPS does not significantly alter the concentrations of copper (at normal levels) or zinc. 62 Comparatively, DMSA is thought to be the least toxic of the two agents and has the highest LD 50 due to its inability to move into the intracellular space. ...
... Clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline, CQ) is a metal chelator. Studies on the effects of endogenous zinc under physiological and pathological conditions have exploited chelating agents to elucidate the specific role played by this ion [30][31][32]. Recent animal studies have demonstrated that CQ decreased basal neurogenesis as well as on seizure-induced transient hippocampal neurogenesis [33]. ...
Article
Numerous studies have demonstrated that traumatic brain injury (TBI) increases hippocampal neurogenesis in the rodent brain. However, the mechanisms underlying increased neurogenesis after TBI remain unknown. Continuous neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in the adult brain. The mechanism that maintains active neurogenesis in the hippocampal area is not known. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ (mossy fiber). The mossy fiber of dentate granular cells contains high levels of chelatable zinc in their terminal vesicles, which can be released into the extracellular space during neuronal activity. Previously, our lab presented findings indicating that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia or epilepsy. Using a weight drop animal model to mimic human TBI, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after TBI. Thus, we injected a zinc chelator, clioquinol (CQ, 30 mg/kg), into the intraperitoneal space to reduce brain zinc availability twice per day for 1 week. Neuronal death was evaluated with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after TBI. The number of degenerating neurons (FJB (+)) and live neurons (NeuN (+)) was similar in vehicle and in CQ treated rats at 1 week after TBI. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after TBI. The number of BrdU, Ki67 and DCX positive cell was increased after TBI. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. The present study shows that zinc chelation did not prevent neurodegeneration but did reduce TBI-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after TBI.
... It removes smear layer, softens the dentin and facilitates removal of calcific obstructions with in the root canal. Its chelating action is achieved by the incorporation of a metal or metaloid ion into the heterocyclic ring structure 30 . EDTA forms stable complexes with many of the essential metals, as well as with some toxic metals, including mercury 31 . ...
... Two more hydrophilic and less toxic BAL analogs have been developed and used for heavy metal intoxication, namely DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (D,L-2,3-dimercapto-1-propanesulfonic acid) ( Fig. 3) [163][164][165]. In particular, DMSA has been used to treat WD patients in China [166], where Trien is not commercially available. ...
Article
Full-text available
Copper is present in different concentrations and chemical forms throughout the earth crust, surface and deep water and even, in trace amounts, in the atmosphere itself. Copper is one of the first metals used by humans, the first artifacts dating back 10,000 years ago. Currently, the world production of refined copper exceeds 16,000 tons / year. Copper is a micro-element essential to life, principally for its red-ox properties that make it a necessary cofactor for many enzymes, like cytochrome-c oxidase and superoxide dismutase. In some animal species (e.g. octopus, snails, spiders, oysters) copper-hemocyanins also act as carriers of oxygen instead of hemoglobin. However, these red-ox properties also make the pair Cu+/Cu2+ a formidable catalyst for the formation of Reactive Oxygen Species, when copper is present in excess in the body or in tissues. The treatment of choice in cases of copper overloading or intoxication is the chelation therapy. Different molecules are already in clinical use as chelators or under study or clinical trial. It is worth noting that chelation therapy has also been suggested to treat some neurodegenerative diseases or cardiovascular disorders. In this review, after a brief description of the homeostasis and some cases of dyshomeostasis of copper, the main (used or potential) chelators are described; their properties in solution, even in relation to the presence of metal or ligand competitors, under physiological conditions, are discussed. The legislation of the most important Western countries, regarding both the use of chelating agents and the limits of copper in foods, drugs and cosmetics, is also outlined.
... During the last 15-30 years, several important developments have occurred in the possibility and clinical practice of chelation treatment of acute or chronic poisonings with mercury, lead, or copper compounds. Succimer (DMSA) is now recommended as antidote in clinical cases of lead and organic mercury poisonings, and might be more suitable than d-penicillamine or Trien in copper poisonings [55,56]. The introduction of DMSA in the treatment of Wilson's disease may represent an important development [57]. ...
... 67 Collectively, two of these three studies reported increased urinary excretion of heavy metals after administration of a chelator 65,67 which suggests a higher metal burden in the children with ASD. 68 However, these studies suffered from limitations as there was no placebo control and the status of the patient was not blinded to the treating physician. Therefore, further studies are warranted to investigate these findings in more detail. ...
Article
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Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.
... In addition, the use of chelating agents assists the body's ability to eliminate mercury from the tissues (Pingree et al., 2001;Carvalho et al., 2007). However, these drugs appear to be of limited use, because of their adverse side effects (Tchounwou et al., 2003) and limited ability to cross the blood-brain barrier (Aposhian et al., 1995). ...
... The mainstay treatment against metal toxicity is chelation therapy [5,6], where appropriate chelators are used to remove metals from the organism [7], and thereby reduce toxicity [8,9]. However, despite the available chelators, the search for new effective chelating compounds is still needed, since the ones currently used in clinic present a number of toxic side effects, low metal specificity and controversial efficacy [5,9,10]. ...
Article
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The purpose of this work was to synthesize and characterize the thiatetraaza macrocycle 1-thia-4,7,10,13-tetraazacyclopentadecane ([15]aneN4S). Its acid-base behaviour was studied by potentiometry at 25 °C and ionic strength 0.10 M in KNO3. The protonation sequence of this ligand was investigated by 1H-NMR titration that also allowed the determination of protonation constants in D2O. Binding studies of [15]aneN4S with Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ metal ions were further performed under the same experimental conditions. The results demonstrated that this compound has a higher selectivity and thermodynamic stability for Hg2+ and Cu2+, followed by Ni2+. The UV-visible-near IR spectroscopies and magnetic moment data for the Co(II) and Ni(II) complexes indicated a tetragonal distorted coordination geometry for both metal centres. The value of magnetic moment and the X-band EPR spectra of the Cu(II) complex are consistent with a distorted square pyramidal geometry.
Article
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Lead is a toxic heavy metal and there is no specific, safe and efficacious therapeutic management of lead toxicity. Scientific literature reported that some probiotic microorganisms alleviated experimentally induced lead toxicity. The present review attempts to collate the experimental studies on probiotics with ameliorative effects. Literature survey revealed that four (4) types of probiotic microorganisms exhibited significant protection from lead toxicity in experimental pre-clinical studies. No clinical study with significant outcome was found in the literature. From the outcomes of the preclinical studies it appears that probiotics are prospective for alleviation and treatment of lead toxicity.
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Background: Heavy metal poisoning can cause debilitating illness if left untreated, and its management in anuric patients poses challenges. Literature with which to guide clinical practice in this area is rather scattered. Case presentation: We present a case of symptomatic lead and arsenic poisoning from use of Ayurvedic medicine in a 28-year-old man with end-stage kidney disease on chronic hemodialysis. We describe his treatment course with chelating agents and extracorporeal blood purification, and review the relevant literature to provide general guidance. Conclusion: Cumulative clinical experience assists in identifying preferred chelators and modalities of extracorporeal blood purification when managing such patients. However, a larger body of real-world or clinical trial evidence is necessary to inform evidence-based guidelines for the management of heavy metal poisoning in anuric patients.
Article
Owing to advances in modern medicine, life expectancies are lengthening and leading to an increase in the population of older individuals. The aging process leads to significant alterations in many organ systems, with the kidney being particularly susceptible to age-related changes. Within the kidney, aging leads to ultrastructural changes such as glomerular and tubular hypertrophy, glomerulosclerosis, and tubulointerstitial fibrosis, which may compromise renal plasma flow (RPF) and glomerular filtration rate (GFR). These alterations may reduce the functional reserve of the kidneys, making them more susceptible to pathological events when challenged or stressed, such as following exposure to nephrotoxicants. An important and prevalent environmental toxicant that induces nephrotoxic effects is mercury (Hg). Since exposure of normal kidneys to mercuric ions might induce glomerular and tubular injury, aged kidneys, which may not be functioning at full capacity, may be more sensitive to the effects of Hg than normal kidneys. Age-related renal changes and the effects of Hg in the kidney have been characterized separately. However, little is known regarding the influence of nephrotoxicants, such as Hg, on aged kidneys. The purpose of this review was to summarize known findings related to exposure of aged and diseased kidneys to the environmentally relevant nephrotoxicant Hg.
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In this study we evaluated a method for the characterization of complexes, formed in different relative ratios of mercury(II) to dicysteinyl tetrapeptide, by electrospray ionization orbitrap mass spectrometry. This strategy is based on previous successful characterization of mercury-dicysteinyl complexes involving tripeptides by utilizing mass spectrometry among other techniques. Mercury(II) chloride and a dicysteinyl tetrapeptide were incubated in a degassed buffered medium at varying stoichiometric ratios. The complexes formed were subsequently analyzed on an electrospray mass spectrometer consisting of a hybrid linear ion- and orbi- trap mass analyzer. The electrospray ionization mass spectrometry (ESI-MS) spectra were acquired in the positive mode and the observed peaks were then analyzed for distinct mercury isotopic distribution patterns and associated monoisotopic peak. This work demonstrates that an accurate stoichiometry of mercury and peptide in the complexes formed under specified electrospray ionization conditions can be determined by using high resolution ESI MS based on distinct mercury isotopic distribution patterns.
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The present study investigates the possible effects of Hg2+, Pb2+, and Cd2+ on [3H]-glutamate binding. To better understand the role of the thiol-disulfide status on the toxicity of such metals toward glutamatergic neurotransmission, we used three thiol chelating agents, 2,3-dimercaptopropanol (BAL), 2,3-dimercaptopropane 1-sulfonate (DMPS), and meso-2,3-dimercaptosuccinic acid (DMSA). Dithiotreitol (DTT) was tested for its ability to prevent metals-induced inhibition on [3H]-glutamate binding. Hg2+, Pb2+, and Cd2+ showed a concentration-dependent inhibition on [3H]-glutamate binding, and mercury was the most effective inhibitor. BAL did not prevent [3H]-glutamate binding inhibition by Hg2+, Cd2+, and Pb2+. However, DMPS and DMSA prevented the inhibition caused by Cd2+ and Pb2+, but not by Hg2+. DTT did not prevent the inhibition on [3H]-glutamate binding caused by 10 M Hg2+. In contrast, it was able to partially prevent [3H]-glutamate binding inhibition caused by 40 M Pb2+ and Cd2+. These results demonstrated that the heavy metals present an inhibitory effect on [3H]-glutamate binding. In addition, BAL was less effective to protect [3H]-glutamate binding inhibition caused by these metals than other chelating agents studied.
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Both mercury(II) and monomethyl mercury(II) poisonings are of great concern for several reasons. As it happens for other metals, chelation therapy is the most indicated treatment for poisoned patients. The efficacy of the therapy and the reduction of side-effects can be sensibly enhanced by an accurate knowledge of all the physiological mechanisms involved in metal uptake, transport within and between various tissues, and (possibly) clearance. All these aspects, however, are strictly dependent on the chemical speciation (i.e., the distribution of the chemical species of a component in a given system) of both the metal and the chelating agent in the systems where they are present. In this light, this review analyzes the state of the art of research performed in this field for mercury(II) and methylmercury(II). After a brief summary of their main sources, the physiological patterns for the treatment of mercury poisoning have also been considered. The binding ability of various chelating agents toward mercury has been then analyzed by modeling the behavior of the main classes of ligands present in biological fluids and/or frequently used in chelation therapy. Their sequestering ability has been successively evaluated by means of a semiempirical parameter already proposed for its objective quantification, and the main characteristics of an efficient chelating agent have been evaluated on this basis.
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