Metal chelation in medicine

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You might breathe them in, eat them, or absorb them through your skin. If too much metal gets into your body, it can cause heavy metal poisoning. Heavy metal poisoning can lead to serious health problems. These include organ damage, behavioral changes, and difficulties with thinking and memory.

The specific symptoms and how it will affect you, depend on the type of metal and how much of it is in your system. Heavy metal testing is used to find out if you have been exposed to certain metals, and how much of the metal is in your system. Your health care provider may order a heavy metal blood test if you have symptoms of heavy metal poisoning. The symptoms depend on the type of metal and how much exposure there was. Some children under the age of 6 may need to be tested for lead because they have a higher risk for lead poisoning.

Lead poisoning is a very serious type of heavy metal poisoning. It is especially dangerous for children because their brains are still developing, so they are more vulnerable to brain damage from lead poisoning. In the past, lead was frequently used in paint and other household products.

It is still used in some products today. Young children get exposed to lead by touching surfaces with lead, then putting their hands in their mouths. Even low levels of lead can cause permanent brain damage and behavioral disorders. Your child's pediatrician may recommend lead testing for your child, based on your living environment and your child's symptoms. A health care professional will take a blood sample from a vein in your arm, using a small needle.

After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes. Some fish and shellfish contain high levels of mercury, so you should avoid eating seafood for 48 hours before being tested. There is very little risk to having a blood test. You may experience slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly. If your heavy metal blood test shows a high level of metal, you will need to completely avoid exposure to that metal.

If that doesn't reduce enough metal in your blood, your health care provider may recommend chelation therapy. Chelation therapy is a treatment where you take a pill or get an injection that works to remove excess metals from your body. If your levels of heavy metal are low, but you still have symptoms of exposure, your health care provider will likely order more tests. Some heavy metals don't stay in the bloodstream very long. These metals may stay longer in urine, hair, or other body tissues.

So you may need to take a urine test or provide a sample of your hair, fingernail, or other tissue for analysis. Tetraethylenetetraamine or trientine is a drug of choice for acute copper intoxication. Although nowadays there is less use of copper utensils, in ancient times the use of copper utensils could lead to extensive exposure to copper. Increased urinary copper excretion has been reported after administration of TETA [ 2 ].

Normally TETA is administered through the oral route but its absorption is relatively poor, as indicated by the as evident from the recovery observed in urine and caracass after administration of an oral dose of C 14 -labeled TETA. Two major metabolites of TETA have been identified, i. The former plays a significant role in the molecular mechanism by which TETA extracts copper from the system.

Mercury - How to Get this Lethal Poison Out of Your Body

Both of these forms have been used as chelating agents [ 69 ]. NTA has been used shown to possess the ability to mobilize nickel from brain, heart, kidney and liver of nickel poisoned rats. In a comparative study with six metal binding agents, NTA was highly effective in dialyzing out nickel from the subcellular fractions of liver, kidney and blood corpuscles in rats that were exposed to nickel sulphate [ 70 ].

Apart from nickel mobilization, a single dose of NTA has been tried in the removal of manganese from various organs and plasma in rats. Results from these studies have indicated that NTA binds rapidly to Mn and forms stable and diffusible complexes that result in faster excretion of Mn from the rats [ 71 ]. Since NTA is considered to be non-mutagenic in vitro [ 72 ] an epigenetic mechanism is assumed, based on the fact that there is sustained cytotoxicity of zinc ions transfer to the urinary tract [ 72 ]. With chronic application of a high dose level, these alterations lead as a continuum to hyperplastic foci, adenomas, and adenocarcinomas [ 77 ].

This ability of both NTA to form tumors cannot be ruled out. Studies however have indicated that tumor formation ability of both NTA is highly route and dose dependented. While FeNTA causes an iron overload and lipid peroxidation in cells and is genotoxic [ 78 , 79 ], Na 3 NTA predominantly binds to zinc and calcium, thereby exerting its toxic effects [ 72 ]. Most of the currently used chelating agents have serious side effects [ 80 ].

Since possible adverse effects and risk associated with conventionally used chelators has already been highlighted in the previous sections, mechanistic limitations are addressed here. CaNa 2 EDTA is a general chelating agent that complexes a wide variety of metal ions and is used clinically despite associated risks. CaNa 2 EDTA cannot pass through cellular membranes and therefore its use is restricted in removing metal ions from their complexes in the extracellular fluid. Similarly conventionally used succimer, DMSA although is considered safer, it shares the limitation of extracellular distribution.

The latter renders the drug effective in cases of slow, low dose, chronic metal poisoning especially lead and arsenic since metal reaches the cellular compartments behind the physiological barriers including the blood brain barrier. One such classical example was demonstrated during the clinical trial conducted in Bangladesh where DMSA was found ineffective in patients chronically exposed to arsenic [ 81 ]. Thus, it is of immediate environmental health concern to identify the limitations of currently available chelating agents and develop new drugs that are more effective in the cases of low, long term exposure to toxic metal.

Although treatment with DMSA and DMPS has shown lesser adverse effects, essential metal loss in particular of copper and zinc may be considered as one of the serious notable limitations. Specificity for the target metal may be another domain that needs to be addressed during new drug development. D-Penicillamine DPA exhibits disadvantage of possible risk to cause anaphylactic reaction in patient allergic to penicillin.

Also prolonged use of DPA may induce several cutaneous lesions, dermatomyosites, adverse effects on collagen, dryness, etc. We have summarized the beneficial and the drawbacks associated with chelation therapy are presented in Figure 8. A retrospective examination of various antidotes reveals that there is no global unanimity of opinion regarding the efficacy of a particular treatment regimen. This is mainly due to different experimental conditions, test protocols and species of animals employed in evaluating various antidotes.

Adoption of a particular treatment in a country is dictated by various factors including the regulatory bodies and the legislations. Also, the toxicity of a particular treatment regimen is overlooked in a particular country where as in other countries it is the reason for rejection. The success of any treatment relies on the fact that: i it is fast-acting, ii has long half and shelf lives, iii has minimal side effects and iv has ease of application.

The reason to look for newer antidotes are that: i there is no effective and safe pre-treatment available which could be instituted as preventive measure against possible arsenic exposure, ii the recommended treatments have serious limitations like side-effects or are contraindicated for various instances of heavy metal poisoning, iii most of the available treatments are to be given intravenously by a medical practitioner and under no circumstances victim can resort to self aid, iv there is no safe and effective oral treatment available and v there is no fast acting antidote available which could immediately remove toxic metal from blood and soft tissues.

It is thus clear from above that most of the conventional chelators are compromised with many side effects and drawbacks and there is no safe and effective treatment available for heavy metal poisoning. A new trend in chelation therapy is to use two structurally different chelators Table 2. The idea of using combined treatment is based on the assumption that various chelating agents are likely to mobilise toxic metals from different tissue compartments and therefore better results could be expected [ 18 , 82 ]. The combination therapy is an approach to ensure enhanced metal mobilization from the body, reduction in the dose of potential toxic chelators, and no redistribution of toxic metal from one organ to another following chronic metal exposure [ 18 , 83 — 85 ].

The principle mechanism behind administration of two structurally different chelating agents is illustrated in Figure 9. Flora et al. Treating experimental animals with MiADMSA along with DMSA, we could not only ensure enhanced arsenic elimination but also minimize many serious side-effects, leading to better therapeutic efficacy of the chelators [ 87 ]. Since MiADMSA is lipophilic it can chelate intracellular toxic metal and make it accessible to extracellularly available DMSA which may then facilitate rapid excretion of metal from the body.

The sulfhydryl groups present in these chelators may interact with free oxygen radical or by product of lipid peroxidation like lipid hydroperoxides and aldehydes produced by heavy metal thereby reducing oxidative stress. This observation greatly strengthens the possibility that co-administration of two chelating agents not only gives better efficacy in terms of recovery from arsenic-induced oxidative stress but also helps in reducing the dose of a potentially toxic chelator, thereby minimizing the possible side effects [ 87 ].

A reduced dose of chelating agent was found to be beneficial against lead toxicity, with optimum efficacy in the altered biochemical variables and body burden of lead [ 87 ]. Recently it has been reported that combined administration of thiol chelator MiADMSA and CaNa 2 EDTA is beneficial against chronic lead toxicity in terms of altering neurotransmitters level, neurobehavioral changes, and markers of apoptosis [ 83 ].

It was also beneficial in reducing body lead burden and neuronal cell death [ 83 ]. Combined administration of DMSA and MiADMSA has found to be highly effective in not only reducing lead burden but also provide better clinical recoveries especially in the brain than monotherapy [ 89 ]. Figure 10 describes effects of acute and chronic metal exposure and various preventive and therapeutic measures against it. Acute and chronic exposure symptoms of metal toxicity and possible preventive and therapeutic measures against them.

Arsenic is one of the most extensively studied metals that induce ROS generation and results in oxidative stress. Experimental results show that superoxide radical ion and H 2 O 2 are produced after exposure to arsenite in various cellular systems [ 48 , 86 , 90 ]. Shi et al. ROS play a significant role in altering the signal transduction pathway and transcription factor regulation. Oxidative DNA lesions induced by arsenic were observed both in vivo [ 96 ] and in vitro [ 97 , 98 ] studies. In a study by Schiller et al.

List of Chelating agents:

The mechanism of arsenite toxicity was reported owing to its effects on the generation of the hydroxyl radical [ ]. Cadmium, unlike other heavy metals is unable to generate free radicals by itself, however, reports have indicated superoxide radical, hydroxyl radical and nitric oxide radicals could be generated indirectly [ ]. Watanabe et al. Cadmium could replace iron and copper from a number of cytoplasmic and membrane proteins like ferritin, which in turn would release and increase the concentration of unbound iron or copper ions.

These free ions participate in causing oxidative stress via the Fenton reactions [ — ]. Acute intoxication of animals with cadmium has shown increased activity of antioxidant defense enzymes like copper-zinc containing superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione- S -transferase [ ].

Although various mechanisms have been suggested for the toxic effects of Hg, no single mechanism explains all of the pathological outcomes. The chemical reactivity of the metal suggests that oxidative stress might be involved in Hg-induced toxicity. GSH, the primary intracellular antioxidant, was shown to be depleted and to have impaired function in Hg toxicity [ ].

Oxidative stress may be considered as one of the prime contributing mechanism in metal toxicity and thus provide a strong rationale for including antioxidants during chelation therapy Table 2. Antioxidant supplementation with chelating agents has been found beneficial in increasing lead mobilization and providing recovery of altered biochemical variables [ , ]. Combinational therapies with antioxidants like N -acetylcysteine NAC [ 53 ], lipoic acid LA [ ], melatonin [ 53 ], and gossypin [ ] have shown considerable promise in improving clinical recoveries in animal models.

MiADMSA alone or in combination with captopril was significantly effective in reversing lead-induced apoptosis [ ]. This suggests that the antioxidant capacity of taurine becomes most effective when it is administered along with the thiol chelators or taurine might be facilitating the entry of chelator to the intracellular sites thereby reducing arsenic concentration. NAC is known to have metal-chelating properties and has been used in several clinical conditions [ ]. Thiol groups present in NAC act to reduce free radical and provide chelating site for metals.

Combined administration of NAC and succimer post arsenic exposure led to a significant turnover in the variables indicative of oxidative stress and removal of toxic metal arsenic from the soft organs [ ]. Pande et al. Co-administration of vitamin C and MiADMSA in reducing liver and kidney arsenic burden supports the view that vitamin C acts as detoxifying agent by forming a poorly ionized but soluble complex [ ].

Recently we have also reported that interaction of non-metal fluoride with metalloid arsenic also lead to some antagonistic effects [ ]. Lipoic acid might also have the capability to interfere with the absorption of arsenic. Beneficial role of LA against lead [ ] and GaAs [ ] toxicity in terms of lead and arsenic chelation form blood and soft tissues have also been reported.

Recently, the clinical importance of herbal drugs has received considerable attention Table 2. Combination treatment with the thiol chelator and the natural antioxidant C entella asiatica proved to be beneficial in the recovery from lead-induced oxidative stress, including the level of biogenic amines and body lead burden as compared with the monotherapy [ ].

Administration of C. Number of studies have been reported where a co-administration of a dietary nutrients like a vitamin e. Supplementation of trace metals has been found to be more effective when given during the course of chelation therapy compared to the chelating agents alone [ 23 , ]. Iron, in vitro , is a good chelator of arsenic [ ]. Simultaneous supplementation of zinc was found to effectively reverse inhibition of the lead sensitive zinc dependent enzyme ALAD in male Wistar rats [ , ].

When zinc was administered prior to arsenic, there was a reduction in arsenic concentration in several parts of the organism of adult mice, contributing to a decrease in toxicity from the metal [ ]. It was also well established that the biosynthesis of metallothionein can be influenced by zinc. The role of zinc supplementation during the course of chelation of lead [ 23 ] and cadmium [ , ] has been reported to have many beneficial effects.

A more effective removal of hepatic arsenic and recoveries in the arsenic sensitive biochemical indices following combined administration of zinc and MiADMSA [ ] may offer an answer to the problem raised with MiADMSA monotherapy [ 56 , 57 ]. Various trends in combination therapy and their beneficial aspects have been summarized in Figure Phenolic compounds acting as antioxidants may function as terminators of free radical chains and as chelators of redox-active metal ions that are capable of catalyzing lipid peroxidation [ ].

Mishra and Flora [ ] have also reported that the combined treatment with quercetin and MiADMSA was not only able to chelate arsenic from the cell but also ameliorate oxidant levels, i. These combined treatments were also effective in partially correcting the cadmium induced loss of liver and brain endogenous zinc. It has been reported that co-treatment with NAC reduces lipid peroxidation and prevents Cd-induced hepatotoxicity [ ]. NAC besides preventing hepatotoxicity and reducing the rate of CdMT release from the liver, protect directly by forming a complex with Cd [ ], or indirectly by scavenging free radicals [ ] or by serving as a cysteine donor for GSH synthesis.

Metal poisoning may be acute, sub acute or chronic. Usually acute poisoning is well defined and identifiable, with serious rapid manifestations that may be recovered with immediate medical attention. However, the sub chronic that may convert to chronic metal toxicities may be ill defined as general ill health and not identifiable as any classical syndrome. Moreover, the chronic toxicities may be reversible or irreversible leading to slow development of manifestations like cancer or teratogenic malformations after latent period.

The treatment of acute metal poisoning involves emergency medical care that may not be described in the present review. The present review will follow outline of general and specific metal toxicity management. Basic principles of metal toxicity management deals with step by step protocol, for easy understanding that follows as under:. Steps 1 and 2 are more applicable in cases of acute metal poisoning and step 3 is more directed to sub chronic or chronic metal toxicities [ ]. The most important and immediate measure is to remove the patient from the exposure.

Toxic metals may be absorbed by various routes of exposure including inhalation, dermally or orally. Depending on the intensity and extent of exposure further treatment is decided. In case of high metal exposure as vapours of Hg or concentrated fumes of Pb or As gas, immediate removal of patient not only from the site but removal of clothing, decontamination of skin, eyes, hair and the area around followed by emergency medical assistance may be needed, whereas in case of chronic occupational exposures, or exposure due to lifestyle household, contaminated drinking water, food, utensils, etc.

The normal excretory system may expel metals to provide a gradual recovery from mild toxicity. In cases of ingestion of toxic metals, acute cases will need stomach emptying within four hours of metal ingestion, or inactivation of metal in the stomach beyond four hours or when gastric emptying is not possible. Various inactivating antidotes, including activated charcoal, milk, egg white, sodium bicarbonate, sodium or magnesium sulphate, Prussian Blue, etc.

After metal absorption into the circulation in acute cases it may be eliminated from the body to avoid further distribution and penetration in tissues; thus reduce serious damage. Techniques like inducing diureses, modulating urinary pH for metal excretion, employing complexing agents to enhancing faecal excretion for metals undergoing extensive enterohepatic circulation or haemodialysis may be employed.

Although these techniques sounds promising there applicability and efficacy varies depending upon physicochemical properties of metal, route of exposure, intensity and extent of exposure and condition of the patient. Children are more vulnerable to lead exposure than adults because of the frequency of hand-to-mouth activity pica , and a higher rate of intestinal absorption and retention.

Blood lead has been reported to impair normal metabolic pathways in children at very low levels [ ]. Lead Pb binds to sulfhydryl and amide group components of enzymes, altering their configuration and diminishing their activities. It may also compete with essential metallic cations for binding sites, inhibiting enzyme activity, or altering the transport of essential cations such as calcium [ 83 ]. Lead produces a range of effects, primarily on the haematopoietic system, the nervous system, and the kidneys.

Lead inhibits many stages in the haem synthesis pathway. ALA in urine has been used for many years as an indicator of exposure, inhibition of haematopoiesis among industrial workers, and the diagnosis of lead poisoning [ , ]. Ferrochelatase catalyzes the incorporation of iron into the porpohyrin ring. As a result of lead toxicity, the enzyme is inhibited and zinc is substituted for iron, and zinc protoporphyrin concentration is increased [ ]. The most vulnerable target of lead poisoning is the nervous system.

One of the important mechanisms known for lead induced neurotoxicity is the disruption of calcium metabolism. Oxidative stress, a condition describing the production of oxygen radicals beyond a threshold for proper antioxidant neutralization, has been implicated as a pathologic condition in lead toxicity. Studies have shown that lead causes oxidative stress by inducing the generation of reactive oxygen species ROS and weakening the antioxidant defence system of cells [ , ]. The iv administration of CaNa 2 EDTA must always be as infusion over a period of 8—12 hrs, where by im route the drug is administered as two doses given at 8—12 hr intervals.

Initial therapy increases urinary lead excretion and reduced blood lead burden which is usually followed by a rebound high blood lead concentration at chelation cessation. This happens by virtue of redistribution mobilization of metal from reservoirs like skeletal system. Thus, after a two day interval a second course of therapy is prescribed to allow redistribution of lead and replenishment of zinc and other essential metals.

Further, anticonvulsive drugs e. Since the lead-EDTA complex is excreted by glomerulus filtration it aggravates chances of renal failure. This is no longer in use due to its adverse effects and availability of safer chelators like DMSA. DMSA has been approved by the U. A major advantage of DMSA is that, lead is not redistributed to the brain and other vital organs after its therapy in rats intoxicated with lead [ 18 , 84 ].

Animal studies suggest that DMSA is an effective chelator of lead concentrated in soft tissue but it is unable to chelate lead from bones [ ]. Ercal et al. DMSA for being an antioxidant and a strong lead chelator has been shown to deplete significantly lead from hippocampus leading to recovery in the oxidative stress and apoptosis induced by lead [ ]. It is important to note that in cases of occupational lead poisoning, chelation therapy with ongoing exposure is never recommended.

Instead patient heavily exposed to lead may be removed from the site and then only then chelation therapy should be administered. Major anthropogenic sources of arsenic in the environment include smelting operations and chromated copper arsenate, a variety of pesticide used in pressure treating wood for construction purposes.

Arsenic can be transmitted not just by drinking water, but also by direct exposure to skin and hair. It can also be transmitted through food grains and the possible transmit of arsenic through summer Boro rice grown in the Bengal basin is an issue of debate [ ]. High levels of arsenic have been found in 10 developing countries, including India [ , ].

In Bangladesh, Arsenic toxicity is associated with various hepatic, renal, neurological and skin disorders. At chronic exposure it is known to also produce carcinogenic effects. This occurs by complexation of trivalent arsenic with vicinal thiols necessary for the oxidation of this substrate [ ]. Dermatological changes following chronic arsenic intoxication are common features and the initial clinical diagnosis is often based on hyper pigmentation, palmar and solar keratosis.

Toxic effects of arsenic also include changes in behavior, confusion, and memory loss. Exposure to arsenic in drinking water has been associated with a decline in intellectual function in children. Arsenic is classified as a group 1 carcinogen to humans based on strong epidemiological evidence [ ].

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Areas in Bangladesh and India with arsenicosis showed high incidences of tumors in local residents [ ]. The mechanisms by which arsenic causes human cancers are not well understood. Recent in vivo studies indicate that methylated forms of arsenic may serve as co-carcinogens or tumour promoters [ , ]. One of the important mechanisms of arsenic induced disorders is its ability to bind with sulfhydryl group —SH containing molecules. Succimer or DMSA has been tried successfully in animal as well as in cases of human arsenic poisoning [ ].

We also reported significant depletion of arsenic and a significant recovery in the altered biochemical variables of chronically arsenic exposed rats [ ].

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  • However in a double blind, randomized controlled trial study conducted on few selected patients from arsenic affected West Bengal India regions with oral administration of DMSA suggested that DMSA was not effective in producing any clinical and biochemical benefits or any histopathological improvements of skin lesions [ ].

    Cadmium Cd is one of the most toxic metal ions of our environment and is found in air, food and water. Cd ions are absorbed by most tissues of the body and become concentrated mainly in liver and kidney and it has a long biological half-life of 11 to 20 years in humans [ ]. Cadmium is listed by the U.

    Environmental Protection Agency as one of priority pollutants. The most dangerous characteristic of cadmium is that it accumulates throughout a lifetime. Chronic human exposure to Cd results in renal dysfunction, anemia, hepatic dysfunction, osteotoxicities, and cancer in multiple organs, potentially including the kidney [ , ]. Because of its carcinogenic properties, cadmium has been classified as a 1 category human carcinogen by the International Agency for Research on Cancer, Lyon, France [ ].

    Cadmium is a potent human carcinogen and has been associated with cancers of the lung, prostate, pancreas, and kidney. Cadmium can cause osteoporosis, anemia, non-hypertrophic emphysema, irreversible renal tubular injury, eosinophilia, anosmia and chronic rhinitis. Cd-induced nephrotoxicity is clearly the most important and the most frequently occurring ailment in humans as a result of chronic exposure to the metal [ ]. The various toxic effects induced by cadmium and other heavy metals in biological systems might be due to alterations in the antioxidant defense system [ ].

    Cadmium-induced oxidative damage has been demonstrated by the increased lipid peroxidation and inhibition of enzymes required to prevent such oxidative damage [ ]. It has been suggested that the mechanisms of acute Cd toxicity involve the depletion of glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of ROS such as superoxide ion, hydrogen peroxide, and hydroxyl radicals [ , ]. ROS has been implicated in chronic Cd nephrotoxicity [ ], immunotoxicity [ ], and carcinogenesis [ ].

    Cd-induced inflammation in the liver is another important mechanism for Cd-induced oxidative stress [ ]. Mitochondrion is an important target of Cd toxicity [ ]. It has been proposed that Cd initially binds to protein thiols in mitochondrial membrane, affects mitochondrial permeability transition, inhibits respiratory chain reaction, and then generates ROS [ ]. Cadmium accumulation in the brain causes behavioral alteration, which is exacerbated in rats fed with low protein diet [ ].

    Metallothionein MT , a low-molecular-weight, cysteine-rich, metal-binding protein, has been shown to play a protective role in Cd-induced hepatotoxicity and nephrotoxicity [ ]. Effective chelation therapy against cadmium has yet to be identified, but CaNa 2 EDTA has also been recommended with no proven clinical benefits. Since decrease in efficacy of cadmium therapy happens in parallel to distribution of metal in the tissue. CaNa 3 DTPA, an effective antidote against cobalt is also found effective against acute cadmium toxicity. However, it is less effective as compared to carbodithioates [ 27 , 28 ].

    Various analogues of carbodithioates including diethyl De , dimethyl Dm , and diisopropyl Di —dithiocarbamates DTC have been investigated for their chelation efficacy against cadmium toxicity. The analogues although were effective but showed greater efficacy with delayed injection indicating interaction with Cd-thionein bound Cd rather than free ionic Cd. In recent years, elemental mercury has proven to be a potential source of toxicosis in children [ , ]. In the environment, humans and animals are exposed to numerous chemical forms of mercury, including elemental mercury vapor Hg , inorganic mercurous [Hg I ], mercuric [Hg II ] and organic mercuric compounds.

    Elemental mercury can be released from dental amalgam restorations [ ] and can then be converted into inorganic mercury in the body which can accumulate in the brain [ ]. Metallic mercury vapor is both neurotoxicant and nephrotoxicant. Exposure to significant levels of metallic mercury can result in neurologic, respiratory, renal, reproductive, immunologic, dermatologic, and a variety of other effects [ ]. Mercurous and mercuric ions impart their toxicological effects mainly through molecular interactions with sulfhydryl groups on various molecules like GSH, metallothionein MT and albumin [ — ].

    Mercurials have been reported to cause apoptosis in cultured neurons; however, the signaling pathways resulting in cell death have not been well characterized. It has been reported that skeletal muscle is an important deposit of MeHg [ ] and the activated antioxidant defense system of cells provides a compensatory mechanism for HgCl 2 induced oxidative stress. However, such a phenomenon has not been reported in neurons [ ] and hence Hg exhibits a more neurotoxic effect [ ].

    Dimercaprol and d -penicillamine has been the prescribed chelation agents against inorganic and elemental mercury poisoning. DMPS has shown effective mobilization of mercury from kidney and reduced its biological half life [ ]. DMPS is the drug of choice to reduce the burden of alkylmercury from the body including brain [ ]. Further, DMPS is an approved drug in Germany for the treatment of mercury it has also been used for its provocative test. It is important to note that BAL may be contraindicated in organic mercury phenyl- and alkylmercury poisoning as the lipid soluble complex formed by it may increase mercury distribution into tissue and brain making it more detrimental.

    Iron is an essential micronutrient utilized in almost every aspect of normal cell function and it is particularly crucial for the conservation of energy. Iron is a well known hepatotoxin. Iron overload is a less frequent condition, but a high content of tissue iron has been associated with several pathological conditions, including liver and heart diseases [ ], cancer [ ], neurodegenerative disorders [ ], diabetes and immunological disorders [ ].

    Hepatic fibrosis and cirrhosis are the major outcomes of chronic iron overload as well as to repeated blood transfusion [ ]. Iron toxicity is thus generally divided into five clinical stages, gastrointestinal toxicity, circulatory shock, relative stability, hepatotoxicity and gastrointestinal scarring. Iron toxicity is associated with primary hemochromatosis, high dietary iron intake and frequent blood transfusion. Oxidative stress is a general condition in hemodialysis patients [ ], the periodic intravenous iron injection being a factor contributing to oxidative stress.

    The gastrointestinal tract is the primary target site, which occur without systemic toxicity. The chief site of systemic toxicity is the heart while liver is susceptible because, unlike other organs it is capable of clearing nontransferrin-bound iron [ ]. Toxic shock is the most common cause of death in iron poisoning. At an early stage it is hypovolemic due to significant loss of blood and fluid from gastrointestinal tract. Hepatic necrosis is the next common cause of death.

    Common symptoms include vomiting within first 30 min to several hours, followed by abdominal pain, diarrhea, hyper-glycemia and fever. Treatment of iron poisoning involves decontamination of gastrointestinal, supportive care and the administration of a chelating agent. Its gastrointestinal absorption is very low. Irrespective of the route of administration the daily dose should not exceed 6 g. Patients should be monitored carefully for gastrointestinal complications and shock after the treatment is over. Oral Deferiprone 1,2-dimethylhydroxypyridone has been shown to be as effective as s.

    There are few recent encouraging developments following the introduction deferiprone in combination with deferoxamine [ ]. Various recent studies demonstrated the safety and efficacy of another new iron chelator, Deferasirox in reducing iron burden in iron-overloaded patients. Deferasirox, a tridentate oral chelator approved for the chronic iron overload offers a convenient, effective and promising alternative to deferoxamine [ 66 ]. This chelator is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide constant chelation coverage and the potential to improve compliance [ ].

    In the event that oxidative stress can be partially implicated in toxicity of metals, a therapeutic strategy to increase the antioxidant capacity of cells may fortify the long term effective treatment. This may be accomplished by either reducing the possibility of metal interacting with critical biomolecules and inducing oxidative damage, or by bolstering the cells antioxidant defenses through endogenous supplementation of antioxidant molecules. Although many investigators have confirmed metal induced oxidative stress, the usefulness of antioxidants along or in conjunction with chelation therapy has not been extensively investigated yet.

    Vitamins, essential metals or amino acid supplementation during chelation therapy has been found to be beneficial in increasing metal mobilization and providing recoveries in number of altered biochemical variables [ — ].

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    The important role of heavy metals in oxidative damage suggested a new mechanism for an old problem, whether metals are involved in the oxidative deterioration of biological macromolecules. Although several mechanisms have been proposed to explain the heavy metal induced toxicity, none of the mechanisms have been yet defined explicitly.

    Indirect in vivo evidence of oxidative involvement in metal induced pathotoxicity was demonstrated by alleviation of oxidative stress in the erythrocytes after treatment with thiol containing proven antioxidants, N -acetylcysteine and a succimer in arsenic exposed rats [ ]. In addition to the role of micronutrients in modifying metal toxicity, these nutritional components can also act as complimentary chelating agents adjuvants increasing the efficacy of a known chelator, or by acting independently.

    Metals on the one hand serve as essential components of the normal health physiology yet on the other hand, can cause serious toxic manifestations. Chelation therapy has been the mainstay treatment against metal toxicity. Chelation therapy complexes the metal and allows removal of excess or toxic metal from the system rendering it immediately nontoxic and reducing the late effects.

    Although a range of metal chelators are now available for toxic metal chelation, development of molecules that may be categorized anywhere close to an ideal chelator is far from reality. Most chelators have the disadvantages of numerous adverse effects, non-specific binding and administration inconvenience. In the world of increasing metal exposure although chelation therapy is an important tool in fighting metal storage disorders yet lack of larger clinical trials still offers controversy on its clinical therapeutic benefits.

    However, inspite of all the drawbacks it is important to understand the need for more specific and advanced chelation molecules to not only resolve the unanswered poisonings like cadmium toxicity but also to achieve complete clinical recovery in cases of other metal disorders. Further, newer therapeutic strategies should be investigated that may provide better therapeutic outcomes.

    Employing combination therapy with more than one chelating agent and or prescribing antioxidants or nutraceuticals may be more seriously considered as crucial recommendations of chelation therapy. The authors thank R. Vijayaraghavan, Director of the establishment for his support and encouragement.

    National Center for Biotechnology Information , U. Published online Jun Swaran J. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals.

    Keywords: chelating agents, combination therapy, oxidative stress, antioxidant, succimer, monoesters, heavy metals. Introduction Metals are an integral part of many structural and functional components in the body, and the critical role of metals in physiological and pathological processes has always been of interest to researchers.

    Chelation: Concept and Chemistry Although the concept of chelation is based on simple coordination chemistry, evolution of an ideal chelator and chelation therapy that completely removes specific toxic metal from desired site in the body involves an integrated drug design approach. Open in a separate window. Figure 1. Formation of metal ligand complexes using mono, bi and polydentate ligands. Table 1. EDTA-metal complex stability constants. Common Chelating Agents: Pharmacology and Toxicology An ideal chelator should have high solubility in water, resistance to biotransformation, ability to reach the sites of metal storage, retain chelating ability at the pH of body fluids and the property of forming metal complexes that are less toxic than the free metal ion Figure 2.

    Figure 2. Characteristics of an ideal chelating agent for better chelation of heavy metals.

    Chemistry of Chelation: Chelating Agent Antagonists for Toxic Metals | SpringerLink

    Figure 3. Figure 4. Structures of various chelating agents used to treat cases of heavy metal poisoning. Pharmacological Profile DPA is well absorbed via the gastrointestinal tract and can be administered orally or by iv route. Figure 5. Pharmacological Profile Due to its oily nature, the drug is not absorbed orally and administration of BAL requires deep intra-muscular injection that is extremely painful and allergenic. Thus, the major drawbacks of BAL include: Low therapeutic index small margin of safety Tendency to redistribute arsenic to brain and testes Need for painful intramuscular injection Unpleasant odor rotten eggs Other common adverse effects include fever, conjunctivitis eye inflammation , lacrimation tearing , constricted feeling chest, limbs, jaw, abdomen , headache, paresthesias tingling sensation , tremor, nausea, and pain at the injection site [ 37 ].

    Pharmacological Profile The hydrophilic nature of DMSA causes considerable absorption in gastro intestinal tract thus possible oral route of administration creates its distinct advantage over BAL. Figure 6. Pharmacological Profile DMPS, being hydrophilic in nature, is mainly distributed in the extracellular space but may enter cells by specific transport mechanisms. Figure 7. Pharmacological Profile MiADMSA is a potential drug candidate that is still in its developmental phase thus, its entire pharmacological profile has not been established yet.

    Deferoxamine DFO Deferoxamine is a trihydroxamic acid, siderphore secreted by Streptomyces pilosus , a fungus. Pharmacological Profile The absorption of DFO in the gastrointestinal tract is low and thus it is administered mainly through intravenous injection or infusion. Deferiprone L1 Deferiprone L1; CP20; 1,2-dimethylhydroxypyridone is an iron chelator and is considered a suitable alternative to deferoxamine in the trasfusional iron overload [ 64 ]. Pharmacological Profile The major advantages include oral administration and rapid absorption through gastrointestinal tract.

    TETA Tetraethylenetetraamine or trientine is a drug of choice for acute copper intoxication.

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    Pharmacological Profile Normally TETA is administered through the oral route but its absorption is relatively poor, as indicated by the as evident from the recovery observed in urine and caracass after administration of an oral dose of C 14 -labeled TETA. Limitations of Current Chelation Therapy Most of the currently used chelating agents have serious side effects [ 80 ]. Figure 8. Newer Strategies: Combination Therapy A new trend in chelation therapy is to use two structurally different chelators Table 2.

    Figure 9. Table 2. Therapeutic strategies to address limitations in conventional chelation therapy. Therapeutic Strategy Examples Refs. Centella asiatica Moringa Oleifera Garlic [ ] [ ] [ ] - Plant extracts have been shown to potentiate the efficacy of chelating agents. Figure Oxidative Stress in Metal Toxicity and the Role of Antioxidants Arsenic is one of the most extensively studied metals that induce ROS generation and results in oxidative stress. Therapeutic Recommendations for Heavy Metal Poisoning Metal poisoning may be acute, sub acute or chronic.

    Basic principles of metal toxicity management deals with step by step protocol, for easy understanding that follows as under: Prevention of further metal absorption into the system Elimination of metal from the circulation Inactivation of metal bioavailable in the system Steps 1 and 2 are more applicable in cases of acute metal poisoning and step 3 is more directed to sub chronic or chronic metal toxicities [ ].

    Prevention of Further Metal Absorption into the System The most important and immediate measure is to remove the patient from the exposure. Elimination of Metal from the Circulation After metal absorption into the circulation in acute cases it may be eliminated from the body to avoid further distribution and penetration in tissues; thus reduce serious damage. Inactivation of Metal Bioavailability in the System 7. Cadmium Cadmium Cd is one of the most toxic metal ions of our environment and is found in air, food and water. Iron Iron is an essential micronutrient utilized in almost every aspect of normal cell function and it is particularly crucial for the conservation of energy.

    Conclusions Metals on the one hand serve as essential components of the normal health physiology yet on the other hand, can cause serious toxic manifestations. Acknowledgments The authors thank R. References 1. Part II Acetyl acetones of selenium and tellurium. Andersen O. Principles and recent developments in chelation treatment of metal intoxication. Jones MM. Design of new chelating agents for removal of intracellular toxic metals.

    In: Kauffman GB, editor. Coordination Chemistry: A Century of Progress. Baum CR. Treatment of mercury intoxication.

    Chelation Therapy

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    A randomized controlled trail. Effect of chelation therapy on endothelial function in patients with coronary artery disease: PATCH substudy. Combined therapeutic potential of meso 2,3-dimercaptosuccinic acid and calcium disodium edetate in the mobilization and distribution of lead in experimental lead intoxication in rats. Long-term outcome of repeated lead chelation therapy in progressive non-diabetic chronic kidney diseases.

    Chelation therapy for patients with elevated body burden progressive renal insufficiency. A randomized, controlled trail. Depletion of essential elements by calcium disodium EDTA treatment in the dog. Beneficial effects of zinc supplementation during chelation treatment of lead intoxication in rats. Spoor NL. Harwell; Didcot, UK: Comparison of the effectiveness of several chelators after single administration on the toxicity, excretion and distribution of cobalt.

    Antidotes for zinc intoxication in mice. Comparative effects of diethyldithiocarbamate, dimercaptosuccinate and diethylenetriaminepentaacetate on organ distribution and excretion of cadmium. Comparative antidotal effects of diethyldithicarbamate, dimercaptosuccinate and diethylene triamine pentaacetate against cadmium induced testicular toxicity in mice. Oral administration of D-pencillamine causes neonatal mortality without morphological defects in CD-1 mice. A study on the penicillamine induced gastric ulceration in the rat.

    Grasedyck K. D-penicillamine—side effects, pathogenesis and decreasing the risks. BAL increases the arsenic content of rabbit brain. Berlin M, Ullberg S. Increasing uptake of mercury in mouse brain caused by 2,3-dimercaptopropanol BAL Nature. Chemical and biological considerations in the treatment of metal intoxications by chelating agents. Mini Rev.

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    Vitamin C, glutathione, or lipoic acid did not decrease brain or kidney mercury in rats exposed to mercury vapor. Ewan KB, Pamphlett R. Increased inorganic mercury in spinal motor neurons following chelating agents. Effects of repeated administration of dithiol chelating agent- sodium 2,3-dimercapto 1-propanesulphonate DMPS - on biochemical and hematological parameters in rabbits.

    Sodium 2,3-dimercaptopropanesulfonate DMPS treatment does not redistribute lead or mercury to the brain of rats. McNeill Consumer Products Co. Chemet Product Information. Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid. Lead induced oxidative stress and its recovery following co-administration of melatonin or n-acetylcysteine during chelation with succimer in male rats. Cadmium mobilization in vivo by intraperitoneal or oral administration of mono alkyl esters of meso-2,3-dimercaptosuccinic acid.

    Monoisoamyl dimercaptosuccinic acid abrogates arsenic-induced developmental toxicity in human embryonic stem cell-derived embryoid bodies: comparison with in vivo studies. Possible role of metal redistribution, hepatotoxicity and oxidative stress in chelating agents induced hepatic and renal metallothionein in rats. Food Chem. Biol Trace Elem Res. Hematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA I. Changes in male rats.

    Haematological, hepatic and renal alterations after repeated oral and intraperitoneal administration of monoisoamyl DMSA. Changes in female rats. Chelation therapy during pregnancy. Trace Elem. Monoisoamyl dimercaptosuccinic acid induced changes in pregnant female rats during late gestation and lactation.