Clinical aspects

Description

	• Several agents are used for chelation therapy, and each may be specific for 1 or more metals.
	• Several neurodegenerative disorders where metal neurotoxicity plays a role are indications for use of chelating agents.
	• Another indication for chelating agents is neurotoxicity due to metal poisoning.

Agents used for chelation therapy.

Various chelating agents used for heavy metal intoxication are listed in Table 1:

Table 1. Chelating Agents Used for Metal Intoxication

	• iron • aluminum
2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogues
	• iron
Dimercaprol
	• arsenic • lead • mercury
Ethylenediaminetetraacetic acid (EDTA): Edetate calcium disodium
	• lead • manganese
Penicillamine
	• copper
Succimer: dimercaptosuccinic acid
	• lead • arsenic • mercury
Triethylenetetramine (TETA, trientine)
	• copper
Clioquinol
	• copper • zinc • iron
Transgenic expression of ferritin
	• iron
Tetrathiomolybdate
	• copper

Iron chelators. There are several iron chelators. Some of these are described here along with their applications:

Deferoxamine mesylate. This chelating agent has a high affinity for iron. It is poorly absorbed from the gastrointestinal route and administered by injection, forming a water-soluble iron complex (that is readily excreted in the urine and the bile). The usual dose is 500 to 1000 mg daily by intramuscular injection. Deferoxamine removes both the free iron and bound iron from hemosiderin and ferritin but not from hemoglobin, transferrin, or cytochromes. It has an attraction to other trivalent ions such as aluminum.

Iron chelation has a neuroprotective effect even when iron dysregulation is not the primary cause of the disease (14). Zinc-desferrioxamine conjugate has been shown to attenuate oxidative injury in a mouse model of retinitis pigmentosa by chelation of labile iron in combination with release of zinc (33). Two oral preparations, deferasirox and deferiprone, are now available for iron chelation.

Indications for the use of deferoxamine include acute iron intoxication and chronic iron overload, which is usually due to blood transfusions for thalassemia. Unlabeled use has included Parkinson disease (based on the theory of iron-induced striatonigral degeneration). It is also used for the prevention of reperfusion injury following vascular procedures on the brain. Because of the high cost and requirement for administration by injection (usually subcutaneous infusion), deferiprone, an oral iron chelator, is now available as a safe alternative. It mobilizes iron from iron-loaded cells to donate to pre-erythroid cells for hemoglobin synthesis, which explains its efficacy for treating diseases involving regional iron accumulation.

Feralex. This is a novel compound, 2-deoxy-2-(N-carbamoylmethyl-[N'-2'-methyl-3'-hydroxypyrid-4'-one])-D-glucopyranose, which was designed to chelate iron and aluminum. It is synthesized from 3 naturally occurring products: maltol, glycine, and glucosamine.

2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogues. These agents are specifically designed to enter and target mitochondrial iron pools, which is a property lacking in deferoxamine.

Nanoparticles loaded with iron chelators. Currently available iron chelators are limited by their short circulation time and binding with ions in blood circulation. Poly(2-methacryloyloxyethyl phosphorylcholine) has been used in construction of iron chelation nanoparticles with delayed saturation in blood circulation, prolonged in vivo life, and ability to penetrate blood-brain barrier by use of HIV-1 transactivating transcriptor as a shuttle (41). Iron chelator-loaded therapeutic nanoparticles were shown to reverse functional deficits in a mouse model of Parkinson disease.

Dimercaprol. Dimercaprol is a chelating agent used in the treatment of several metallic poisons: arsenic, lead, gold, and mercury. It is administered by deep intramuscular injection; maximum blood concentrations are achieved within 30 to 60 minutes. It is rapidly metabolized, and the metabolites and dimercaprol metal chelates are excreted through the urine and the bile. Usually, elimination is complete within 4 hours. Recommended dose for severe arsenic or gold poisoning is 3 mg/kg of body weight given at 4-hour intervals throughout the first 2 days, 4 doses on the third day, and 2 doses on each of the next 10 days. For acute mercurial poisoning, an initial injection of 5 mg/kg is followed by 2.5 mg/kg once or twice daily for 10 days.

Dimercaprol is indicated for the treatment of arsenic, lead, and mercury poisoning. It is valuable for the treatment of acute lead encephalopathy. The use of dimercaprol in the treatment of severe arsenic neuropathy is associated with increased urinary elimination of arsenic and dramatic clinical recovery.

Edetate disodium calcium. Edetate forms a chelate with divalent and trivalent metals. It is poorly absorbed from the gastrointestinal tract and given by intravenous infusion or intramuscular injection for the treatment of lead poisoning. The half-life is 20 to 60 minutes; it is excreted mainly by the kidneys, with 50% excreted within one hour and 95% within 24 hours. It mobilizes lead from the bones and tissues and forces elimination from the body by forming a stable, water-soluble lead complex that is excreted by the kidneys. For administration by intravenous infusion, 1 g of edetate should be diluted with 250 to 500 mL of 5% glucose injection or 0.9% sodium chloride injection, and the concentration of ethylenediaminetetraacetic acid should not exceed 3%. The infusion may be administered over a period of one hour. The usual dose is 60 to 80 mg/kg, given daily in 2 doses up to 5 days and repeated if necessary, after an interval of at least 2 days. The proposed mechanisms of the efficacy of ethylenediaminetetraacetic acid (EDTA) chelation therapy against neurotoxicity are (15):

(1) Protection against endothelial activation (2) Removal of toxic metals (3) Anti-inflammatory effect (4) Antioxidant activity by reduction of levels of reactive oxygen species

Edetate is a calcium and is approved by the FDA for the treatment of lead encephalopathy and for the reduction of blood levels and depot stores of lead. Edetate may be used as a diagnostic test for lead poisoning when measuring the urinary excretion of lead after a standard dose. This is a sensitive method for determining the potentially toxic fraction of lead stored in the body and the response to chelation therapy in chronic lead poisoning.

Edetate was previously used to treat cardiovascular diseases and is known to be useful for the treatment of neurodegenerative diseases. Edetate has been used to treat parkinsonism due to occupational manganese exposure. Clinical improvement is correlated with reduction of heavy metal deposition in basal ganglia as demonstrated by MRI.

Penicillamine. Penicillamine is an amino acid used as a chelating agent for the removal of excess copper in patients with Wilson disease. It is well absorbed from the gastrointestinal tract and excreted unmetabolized through the urine. One atom of copper combines with 2 molecules of penicillamine, therefore, 1 g of penicillamine should be followed by excretion of 200 mg of copper. Only about 1% of this amount is excreted. Penicillamine is administered orally in capsule form prior to meals. The dosage is based on urinary copper excretion serum copper levels.

Penicillamine is used for the treatment of Wilson disease. Beneficial results on hepatic and neurologic manifestations have been reported in all but one of 24 patients with Wilson disease after very long-term treatment with D-penicillamine, supporting its role as first-line therapy for this disease (30). There is a significant decrease in copper excretion in Wilson disease after 1 to 2 years of treatment, which indicates a reduction in the body load of copper (40).

Penicillamine is also used for the treatment of rheumatoid arthritis, cystinuria, and scleroderma. A clinical trial has evaluated the use of penicillamine in glioblastoma multiforme to lower copper levels, which are implicated in the process of angiogenesis associated with tumor growth (05). Although serum copper was effectively reduced, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.

Triethylenetetramine, which has a similar mechanism of action to penicillamine, is approved for use only in patients intolerant of penicillamine, but it appears to be gaining favor as an alternative to penicillamine without any tolerance problem.

Succimer. Succimer is a chelating agent structurally related to dimercaprol. It forms water soluble chelates with heavy metals. It is given orally with a suggested dose of 10 mg/kg body weight every 8 hours for 5 days and then every 12 hours for an additional 14 days. The course of treatment may be repeated if necessary, usually after an interval of no less than 2 weeks.

The aim of chelation therapy is to increase excretion of the metal from the body. Although chelating agents administered for chronic intoxication accelerate the excretion of heavy metals, their therapeutic efficacy in terms of decreased morbidity and mortality is still somewhat controversial. Risk-benefit issues should be considered in clinical situations where the causative role of heavy metals in the patient's illness is not established (25).

Succimer is indicated for treatment of poisoning with lead, arsenic, or mercury. It is an effective and safe chelating agent for treatment of pediatric overexposure to metallic mercury.

Clioquinol. This is already known to chelate zinc, copper, and iron. Reduction in active iron through chelation by oral administration of clioquinol in experimental animals protects against the 1-methyl-4-phenyl-1,2,3,6-tetrapyridine toxicity, suggesting that iron chelation may be an effective therapy for prevention and treatment of Parkinson disease. Clioquinol has been shown to decrease amyloid-beta burden and reduce working memory impairment in a transgenic mouse model of Alzheimer disease (19).

Ferritin. It converts harmful ferrous iron to unreactive ferric iron, which it sequesters in large quantities.

Tetrathiomolybdate. This copper-chelating drug forms a complex with accumulated copper in liver as demonstrated by x-ray fluorescence imaging in an animal model of Wilson disease (44). It inhibits several cytokines that are dependent on available copper for their activity. It is being investigated for the treatment of Wilson disease, Alzheimer disease, multiple sclerosis, hepatic fibrosis, and as antiangiogenic chemopreventive therapy in cancer.

Contraindications

Edetate. Edetate is contraindicated in all forms of mercury poisoning because it cannot displace mercury from its tight binding to sulfhydryl enzymes. Furthermore, it has toxic effects on proximal renal tubules that are the sites of mercury-induced renal diseases. It should not be given orally as it may increase the absorption of lead from the gastrointestinal tract.

Deferoxamine. Deferoxamine is contraindicated in all forms of renal insufficiency because it is excreted through urine. Chelation is ineffective in Hallervorden-Spatz syndrome. Iron deposits in basal ganglia cannot be removed by chelation with deferoxamine.

Dimercaprol. Dimercaprol should be used carefully in patients with hypertension and should be discontinued if renal insufficiency develops. It is contraindicated in patients with chronic impairment of hepatic function unless the impairment is due to arsenic poisoning. It should not be used for treatment of iron poisoning because the dimercaprol-metal complexes formed are more toxic than iron. Similarly, it is contraindicated in patients engaging in concomitant iron therapy.

Penicillamine. Penicillamine is contraindicated in patients with renal insufficiency, lupus erythematosus, and in those with a history of penicillamine-related aplastic anemia, agranulocytosis, or thrombocytopenia. It cannot be given to patients actively ingesting lead because it enhances the absorption of lead through the gastrointestinal tract. Penicillamine should not be given with other drugs capable of causing similar serious hematological or renal adverse effects (eg, gold, salts, or immunosuppressive drugs).

Results

Metal chelators are used for treatment of metal poisoning as well as for treatment of neurologic disorders in which metal toxicity is implicated or there is some evidence of beneficial effect based on pathomechanism of the disease.

Use of chelating agents for treating neurotoxicity due to metals. Adverse effects of metals on the nervous system are well documented. A specific chelation agent is required for each metal, which has a different reactivity with a ligand. Combination of a chelating agent with an antioxidant to counteract metal-induced oxidative stress improves outcome (24). Some examples of use of chelation to treat neurotoxicity are:

Acute aluminum intoxication. Aluminum contributes to the encephalopathy of patients undergoing dialysis dementia. The use of deferoxamine combined with hemodialysis has been used for treatment of patients with severe acute aluminum intoxication.

Arsenic poisoning. Dimercaprol is the favored chelating agent in this case. Succimer is an effective alternative if the patient has a severe toxic reaction to dimercaprol. Recovery from some manifestations (eg, peripheral neuropathy) may take several months.

Lead poisoning. The most frequently used chelator is edetate for children and adults with mild to moderate lead intoxication. In acute cases, dimercaprol and succimer have also been used. Penicillamine can be used as an oral agent, over a long period, to enhance lead excretion from the bone. Chelation is recommended for children when their blood lead levels are greater than 2.7 µmol/L. Chelation is also recommended if the blood level is between 1.2 and 2.7 µmol/L and the total amount of lead excreted through urine during 8 hours after a single dose of edetate exceeds 9.7 µmol/L. Chelation is recommended for adults if blood lead levels exceed 3.9 µmol/L. The ability of chelation to improve subclinical symptoms such as performance on psychomotor testing is not established, but is currently being investigated.

Mercury poisoning. Dimercaprol, given by injection, is effective for acute mercury poisoning, but less effective in more chronic forms of mercury poisoning. It is contraindicated in organic mercury exposures. Headache is a common symptom of mercury poisoning, but a raised intracranial pressure with papilledema has also been reported in a case, which started to improve by use of dimercaprol plus acetazolamide (18).

Penicillamine has also been used. Extracorporeal infusion of succimer into an arterial blood line during hemodialysis can produce greater clearance of mercury in anuric patients than that achieved by dimercaprol followed by hemodialysis. The oral chelators, meso-2,3-dimercaptosuccinic acid and sodium 2,3-dimercapto-1-propanesulfonate, are less toxic than dimercaprol but do not form a true chelate complex with mercuric ions and are, thus, suboptimal for their clinical task of binding mercuric ions.

When chelating agents are administered, mercury concentrations of the blood increase for a few days initially due to rapid mobilization from the tissues. As the excretion of mercury progresses, the blood concentrations decline.

Cadmium poisoning. No proven effective treatment for cadmium poisoning is known. Use of dimercaprol is contraindicated because it may exacerbate nephrotoxicity. Succimer has been used for cadmium toxicity in animal experiments, but its use in humans has not been reported.

Gadolinium deposition from MRI contrast agents. Persistent accumulation of gadolinium in brain, bone, and other tissues following administration as MRI contrast agent has led the European Medicines Agency to recommend discontinuing the use of over half of the gadolinium-based contrast agents currently approved for clinical applications. An oral metal chelator, 3,4,3-LI(1,2-HOPO), is more efficient for removing gadolinium from the body compared to diethylenetriaminepentaacetic acid, a ligand commonly used in the United States in gadopentetate and does not interfere with its role as a contrast agent (34).

Metal chelators for the treatment of neurologic disorders. Metal overload, particularly involving copper and iron, is implicated in the pathogenesis of several neurologic disorders. The normal role of these metals in the CNS should be kept in mind when chelating. Copper is required for neuronal function and contributes to cell signaling (13).

Wilson disease. This is an example of copper toxicity. Mutations of the ATP7B gene induce an impaired functioning of a Cu-ATPase with resulting impairment of copper detoxification in the liver leading to copper overload in the body.

Penicillamine is the main effective treatment, but treatment must be continued for life. Sudden discontinuation of penicillamine treatment may lead to hepatic decompensation because penicillamine may act by formation of a nontoxic complex, rather than remove copper. Copper is released when treatment is stopped. In a case of Wilson disease with extensive subcortical white matter involvement, an appreciable improvement of these lesions resulted after 5 years of copper chelating therapy (27). DMSA (meso-2,3-dimercaptosuccinic acid), available as capsules for oral use, is a potent antidote against copper overload, although d-penicillamine is still widely used (01).

Tetrathiomolybdate, an FDA-approved copper-chelating drug, has shown excellent efficacy and acceptable toxicity in clinical trials for the initial treatment of Wilson disease (06). Triethylenetetramine (TETA) is approved by the FDA as a second-line treatment for Wilson disease. Two of the 3 clinical trials to compare control of free copper by tetrathiomolybdate with that by use of TETA showed the former was more effective (06). A strategy based on biological copper cell transporters has been described to design more specific chelators for treatment of localized copper accumulation in the liver to reduce the need for life-long use of copper chelators in Wilson disease (12).

Chelator 1,1'-xylyl bis-1,4,8,11-tetraaza cyclotetradecane, which specifically reduces copper concentration in the cerebral cortex, is undergoing experimental studies (31). A strategy based on biological copper cell transporters has been described to design more specific chelators to treat localized copper accumulation in the liver to reduce the need for life-long use of copper chelators in Wilson disease (12).

Iron overload. Considerable evidence in published studies implicates iron in the etiology of neurodegenerative disorders and this provides the rationale for treating them with iron chelators. Iron chelation therapy has potential for the treatment of neurodegenerative diseases with an iron accumulation component: Parkinson disease, Friedreich ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease, and Alzheimer disease. New multifunctional iron chelators are in development and may replace the conventional agents for the treatment of neurodegenerative diseases (32).

The main polyphenol constituent of green tea, (-)-epigallocatechin-3-gallate, exhibits iron-chelating activity comparable to that of desferrioxamine and may provide a potential therapeutic approach for Alzheimer disease and other iron-associated disorders.

Another example of iron overload and neurodegeneration is hereditary ferritinopathy, which is a severe movement disorder characterized by the presence of nuclear and cytoplasmic iron-containing ferritin inclusion bodies in glia and neurons of the central nervous system as well as in tissues of several other organs. Chelation therapy, which can remove iron from the central nervous system while maintaining normal systemic iron stores, has been shown to be effective in a mouse model of this disease (17).

Free iron plays a role in neuroinflammation in neurologic injury after ischemic and hemorrhagic stroke as it catalyzes the conversion of superoxide ion and hydrogen peroxide into hydroxyl radicals, which promote oxidative stress (21). Understanding of changes in brain iron metabolism and its relationship to neuronal injury in stroke may provide rationale for use of iron chelators to improve the outcome of stroke patients.

Alzheimer disease. Heavy metal ions may be implicated in the formation of plaques in Alzheimer disease. Copper is implicated in Alzheimer disease and can be chelated by clioquinol. Clioquinol is a chelator that crosses the blood-brain barrier, has a greater affinity for zinc and copper ions than for calcium and magnesium ions, and may diminish the accumulation of amyloid beta in plaques. Clioquinol inhibits zinc and copper ions from binding to amyloid beta, thereby promoting amyloid beta dissolution and diminishing its toxic properties. Further clinical trials with clioquinol were discontinued due to concern for adverse effects from impurities in this preparation during the manufacturing process. Compounds in this category are expected to restore brain metals to normal levels by redistributing metals from amyloid beta plaques back to normal cells, rather than merely depleting brain tissue of metals. This hypothesis is supported by a study involving assays of CSF copper, zinc, and other metals as well as amyloid beta in ventricular autopsy samples. The study concluded that although excessive interaction with copper and zinc may induce neocortical amyloid beta precipitation in Alzheimer disease, soluble amyloid beta degradation is normally promoted by physiological copper and zinc concentrations (37). PBT2, a commercial preparation of clioquinol, can decrease amyloid beta levels by sequestering the zinc that promotes extracellular formation of protease resistant amyloid beta:zinc aggregates; subsequent intracellular translocation of the zinc by PBT2 induces cellular responses with improvement of synaptic function (10). This may be an important mechanism by which PBT2 improves cognitive function in patients with Alzheimer disease. Phase 2 clinical trials of PBT2 have been completed, but the results are not yet published.

TETA, approved for the treatment of Wilson disease, acts as a highly selective divalent copper chelator that prevents or reverses copper overload, thereby suppressing oxidative stress, and has potential application for the treatment of Alzheimer disease (09).

Thioflavin-based multifunctional chelators of copper and zinc such as 2-(2-hydroxyphenyl)benzoxazole and 2-(2-hydroxyphenyl)benzothiazole are potential new therapeutics for Alzheimer disease as they have antioxidant properties, facilitate the formation of iodine-labeled biomarkers for detection of amyloid beta plaques, and can penetrate the blood-brain barrier (35). In vitro studies have shown that benzylideneindanone derivatives can inhibit copper-induced amyloid aggregation and are potential agents for treatment of Alzheimer disease (22). Desferrioxamine, an approved chelator for iron overload, has shown some benefit in Alzheimer disease, but there is difficulty in delivering it across the blood-brain barrier. Nanoparticle formulations of iron chelators may provide a safer and more effective method of delivery for reducing iron load in neural tissue (29). GMP-1, a 2-(methoxymethyl)pyrimido benzimidazol-4-ol, protects mitochondrial function in mouse models of Alzheimer disease, and improves memory indicating neuroprotective effect. A study has shown that GMP-1 specifically binds to copper and zinc, metals that are dysregulated in brains of patients with Alzheimer disease, indicating GMP-1 as a metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in brain in Alzheimer disease animal models (26).

A density functional theory method has been used to calculate the binding energies of each metal-molecule complex, which was compared with that of the metal-Aβ compound to determine the chelation potential of the selected chelator (28). Application of this method to chelating agents has shown that 8-hydroxyquinoline-2-carboxaldehyde 2-furoyl hydrazone can directly chelate copper, zinc, iron, and aluminum. In addition, graphene oxide with a 12.5% oxygen concentration demonstrates aluminum chelation ability. These 2 molecules can be used for targeting toxic metal-Aβ interactions and reduce Aβ aggregation.

Multiple sclerosis. Iron chelation therapy has been considered for multiple sclerosis based on the finding of iron deposits in the brains of these patients by MRI studies. However, it is uncertain whether iron deposition in multiple sclerosis is an epiphenomenon or a mediator of disease process (36). Patients with multiple sclerosis have been reported to tolerate the prolonged subcutaneous administration of deferoxamine (42). Side effects observed during therapy resolved on discontinuation of therapy. This approach needs to be tested further in controlled clinical trials.

Friedreich ataxia. Friedreich ataxia is a result of iron overload within the mitochondrion. Desferroxamine may not have any beneficial effect in Friedreich ataxia patients, probably because its hydrophilicity prevents access to mitochondrial location of iron. MRI has demonstrated local iron accumulation in dentate nuclei of patients with Friedreich ataxia. Deferiprone, an iron chelator, which can cross the blood-brain barrier and move chelated iron from dentate nucleus to transferrin, has been reported to reduce neuropathy and ataxic gait in young patients with Friedreich ataxia (02).

Hereditary aceruloplasminemia. Hereditary aceruloplasminemia is a disorder of iron metabolism that is characterized by iron accumulation in the brain, which is related to neurologic manifestations such as chorea and cognitive decline. Oral iron chelation with deferoxamine is used to prevent neurologic manifestations of aceruloplasminemia (03).

Brain tumors. Cancer has been associated with increased iron load, possibly because of factors such as increased free radical production and reduction capacity of the body to combat oxidative stress. Tumors of the nervous system respond to deferoxamine, and further study is needed to investigate its use as an adjunct to current chemotherapy regimens.

Copper chelators are under investigation as adjuncts to treatment of cancer based on the role of copper in enhancing tumor angiogenesis. Systemic administration of ATN-224, a copper chelator, has been shown to enhance oncolysis of malignant glioma by herpes simplex virus-1 in tumor-bearing mice (43).

Autism spectrum disorder. Although chelation therapy has been used for autism spectrum disorder, there is no proof of causal link with heavy metals. A Cochrane Database review of randomized trials reviews included data from only one study on this topic and it had methodological limitations. No clinical trial evidence suggests that chelation is an effective treatment for autism spectrum disorder, and in view of serious adverse events, the risks of using chelation for autism spectrum disorder currently outweigh proven benefits (23).

Adverse effects

A brief description of adverse reactions to chelating agents is given here:

Deferoxamine
	• Local skin reactions at site of injection
	• Hypersensitivity reactions
	• Tachycardia and hypotension
	• Ocular and auditory disturbances
	• Proximal muscular atrophy and weakness has been reported as an adverse effect of deferasirox iron chelation therapy for chronic transfusional iron overload, but full recovery occurred after cessation of therapy (38).
Dimercaprol
	• Pain at the injection site
	• Hypertension and tachycardia
	• Abdominal pain, nausea, and vomiting
	• Neurologic: convulsions, headache, muscle spasms, and tingling of extremities
Edetate
	• Pain at site of intramuscular injection, myalgia
	• Hypotension and cardiac arrhythmias
	• Necrosis of proximal renal tubules
	• Mild increases in liver enzymes
	• Transient bone marrow depression
	• Neurologic: tremors, headaches, numbness and tingling
Penicillamine
	• Hypersensitivity reactions. These are frequent and bothersome, but they can be managed by steroids or discontinuation of the drug.
	• Skin: penicillamine-induced dermopathy can result from long-term use of penicillamine and improves after reduction of the dose.
	• Gastrointestinal: nausea, vomiting, diarrhea
	• Liver: intra-hepatic cholestasis
	• Bone marrow depression: leucopenia, thrombocytopenia, agranulocytosis, hemolytic anemia
	• Cardiovascular system: myocarditis and heart block
	• Renal function impairment: proteinuria, hematuria, nephrotic syndrome
	• Neurologic: tinnitus, optic neuritis, peripheral neuropathy, myasthenia gravis, disturbances of taste. Hypoesthesia occurs in 25% to 30% of the patients within 6 weeks at dose level of 1 g daily. It is reversed by decrease of dose or discontinuation of the medication.
	• Penicillamine toxicity can be reduced by lowering the dose without sacrificing its efficacy.
Succimer
	• Gastrointestinal disorders
	• Skin rash
	• Increase in serum transaminases
	• Drowsiness and dizziness

Special considerations

Pregnancy. No adequate studies are available pertaining to the use of certain chelating agents; therefore, caution is exercised for the treatment of metal poisoning in pregnancy. The treatment may have adverse effects on the fetus. However, several case reports document pregnant women who have given birth to healthy babies after being treated with deferoxamine.

Pregnant patients who have Wilson disease often need continuation of treatment even though penicillamine has been shown to be teratogenic in experimental animals. Typically, untreated Wilson disease causes infertility or abortion due to increased intrauterine copper level. Therefore, chelation treatment is necessary during the entire pregnancy. A fetal penicillamine syndrome may develop; the syndrome is characterized by a connective tissue disorder of the fetus. These abnormalities are paradoxically rare in the offspring of treated Wilson disease mothers, perhaps owing to hypercupremia, which protects the fetus from excessive copper deficiency. No major congenital anomalies were observed in 20 pregnancies during chelation therapy of Wilson disease documented by the German Embryotox Project, but 3 pregnancies resulted in a spontaneous abortion and one pregnancy was electively terminated (11).

Some measures to reduce fetal abnormalities are: reduction of the dose of penicillamine, use of zinc acetate (which blocks the absorption of copper from gastrointestinal tract and is known to be nonteratogenic), and supplementation of diet with pyridoxine (because penicillamine produces deficiency of this vitamin).

Scientific basis

	• Oxidative stress and protein aggregation, which are associated with the involvement of metal ions, are part of the pathologic process in neurodegenerative disorders and provide the rationale for chelation therapy.
	• Management and treatment of hepatocerebral disorders such as Wilson disease with neurotoxicity due to metals such as copper include chelation therapy.
	• The aim of therapy in neurodegenerative disorders is regulation and redistribution of metals in the brain rather than simply trying to chelate them.

Homeostasis of metal ions, such as iron, copper, zinc, and calcium, in the brain is essential for maintaining normal physiological functions. A screening of a population with the chelation test using the chelating agent EDTA to identify the presence of 20 toxic metals in urine samples revealed that toxic metals were always significantly more elevated in neurodegenerative disorders than in healthy controls (16). Treatment with EDTA chelation therapy removes toxic-metal burdens and improves patient symptoms. Oxidative stress and protein aggregation, which are associated with the involvement of metal ions, are part of the pathologic process in neurodegenerative disorders and provide the rationale for chelation therapy.

Heavy metal toxicity binds to key sulfhydryl groups in the active centers of enzymes that produce disturbances in many organ systems. The basis of chelation therapy is the strong attraction of chelating agents to metallic ions–an attraction so strong that they compete with tissues carrying metals and reverse their attachment to essential body chemicals.

Metal toxicity is associated with oxidative stress. Several antioxidants including N-acetylcysteine, alpha-tocopherol, and ascorbic acid, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of metals. Antioxidants may support cellular antioxidant defenses in various ways that include metal chelation. Amyloid beta peptides and their aggregation with metals have been implicated in the pathogenesis of Alzheimer disease. Bifunctional small molecules have been designed that can specifically target metal-amyloid beta complexes and modulate their neurotoxicity (04).

Pathomechanisms of cerebral dysfunction and neuronal cell death in hepatocerebral disorders include neurotoxicity of metals such as copper, manganese, and iron, which produces oxidative/nitrosative stress, glutamate-receptor-mediated excitotoxicity, and neuroinflammation (08). Management and treatment of hepatocerebral disorders such as Wilson disease include chelation therapy.

A hallmark of several neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and motor neuron diseases, is deregulation of biologically active metal homeostasis. Metals, such as zinc, copper, and iron, are critical enzyme cofactors, which are important for synaptic transmission in the brain but can mediate oxidative neurotoxicity when homeostatic regulatory mechanisms fail (20). The aim of therapy in neurodegenerative disorders is regulation and redistribution of metals in the brain rather than simply trying to chelate them.