General Neurology
Brain death/death by neurologic criteria
Nov. 09, 2024
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Chelation therapy [Archived]
- Updated 03.26.2021
- Released 04.26.2000
- Expires For CME 03.26.2024
Chelation therapy [Archived]
Introduction
This article is no longer being updated. Please note the “Updated” date, shown above, which is the date of the last update.
Overview
Chelation therapy refers to the use of chelating drugs for the treatment of metallic poisoning and neurotoxicity due to other causes. Chelation therapy may be required for clearing gadolinium deposits resulting from use of contrast agents for MRI. Chelating agents are also used for the treatment of neurologic disorders where metals play a part in the pathogenesis. Penicillamine, a copper chelator, is well known for the treatment of Wilson disease. Several other chelating agents and their use for the treatment of neurologic disorders are described in this article. Evidence is accumulating that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer disease. Clioquinol as chelation therapy was in clinical trials for the treatment for Alzheimer disease, but further development was discontinued. Study of deferoxamine has been suggested for treatment of neoplasms of the nervous system.
Key points
• Chelation therapy refers to the use of chelating agents for the treatment of metallic poisoning. | |
• Neurologic disorders associated with accumulation of metals can benefit from agents that remove these metals. | |
• Chelating agents such as edetate calcium disodium may also be useful for the management of neurotoxicity associated with adverse effects of therapeutic drugs and neurodegenerative disorders. | |
• Some MRI contrast agents containing metals that can deposit in the brain require chelation therapy for removal of these metals. | |
• Brain requires an optimal concentration of metals for normal function, and the role of metal in the nervous system should be taken into consideration before chelating that metal. | |
• Some chelating agents are contraindicated diseases such as renal insufficiency, and their use should be avoided in the presence of these diseases. |
Historical note and terminology
Chelation therapy refers to the use of chelating drugs for the treatment of metallic poisoning. The term “chelator” stems from the Greek word chele, meaning claw. The chelating drugs bind the metal between 2 or more functional groups to form a metal-drug complex, which is then excreted through urine.
The history of modern chelation therapy begins during World War II, with the development of the British anti-Lewisite as an antidote against arsenic-containing lewisite gas. Anti-Lewisite use was later expanded to cover other metallic poisoning. D-penicillamine, a chelating agent for copper, was introduced for the treatment of Wilson disease in the 1950s (39).
This article describes the pharmacological basis of the use of chelating agents for heavy metal poisoning involving neurotoxicity. Chelating agents differ from other agents such as activated charcoal, which does not bind metals and is of limited use in metallic poisoning.
The action of drugs for some neurologic disorders, in which heavy metal toxicity is implicated, may involve chelating effect. An example is use of clioquinol for Alzheimer disease. Chelating agents may also be useful for the management of neurotoxicity associated with adverse effects of therapeutic drugs and neurodegenerative disorders.
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 | |
2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogues | |
• iron | |
Dimercaprol | |
• arsenic | |
Ethylenediaminetetraacetic acid (EDTA): Edetate calcium disodium | |
• lead | |
Penicillamine | |
• copper | |
Succimer: dimercaptosuccinic acid | |
• lead | |
Triethylenetetramine (TETA, trientine) | |
• copper | |
Clioquinol | |
• copper | |
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 |
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.
References
- 01
- Aaseth J, Skaug MA, Cao Y, Andersen O. Chelation in metal intoxication-principles and paradigms. Trace Elem Med Biol 2015;31:260-6. PMID 25457281
- 02
- Boddaert N, Le Quan Sang KH, Rotig A, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 2007;110:401-8. PMID 17379741
- 03
- Bove F, Fasano A. Iron chelation therapy to prevent the manifestations of aceruloplasminemia. Neurology 2015;85(12):1085-6. PMID 26311749
- 04
- Braymer JJ, Choi JS, DeToma AS, et al. Development of bifunctional stilbene derivatives for targeting and modulating metal-amyloid-β species. Inorg Chem 2011;50(21):10724-34. PMID 21954910
- 05
- Brem S, Grossman SA, Carson KA, et al. Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. Neuro-oncol 2005;7(3):246-53. PMID 16053699
- 06
- Brewer GJ. The use of copper-lowering therapy with tetrathiomolybdate in medicine. Expert Opin Investig Drugs 2009;18(1):89-97. PMID 19053885
- 07
- Brewer GJ, Askari F, Dick RB, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res 2009;154(2):70-7. PMID 19595438
- 08
- Butterworth RF. Metal toxicity, liver disease and neurodegeneration. Neurotox Res 2010;18(1):100-5. PMID 20369313
- 09
- Cooper GJ. Therapeutic potential of copper chelation with triethylenetetramine in managing diabetes mellitus and Alzheimer's disease. Drugs 2011;71(10):1281-320. PMID 21770477
- 10
- Crouch PJ, Savva MS, Hung LW, et al. The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem 2011;119:220-30. PMID 21797865
- 11
- Dathe K, Beck E, Schaefer C. Pregnancy outcome after chelation therapy in Wilson disease. Evaluation of the German Embryotox Database. Reprod Toxicol 2016;65:39-45.** PMID 27350316
- 12
- Delangle P, Mintz E. Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators. Dalton Trans 2012;41(21):6359-70. PMID 22327203
- 13
- Dodani SC, Firl A, Chan J, et al. Copper is an endogenous modulator of neural circuit spontaneous activity. Proc Natl Acad Sci U S A 2014;111(46):16280-5.** PMID 25378701
- 14
- Dunaief JL. Ironing out neurodegeneration: iron chelation for neuroprotection. Free Radic Biol Med 2011;51(8):1480-1. PMID 21616141
- 15
- Fulgenzi A, Ferrero ME. EDTA chelation therapy for the treatment of neurotoxicity. Int J Mol Sci 2019;20(5). PMID 30813622
- 16
- Fulgenzi A, Vietti D, Ferrero ME. EDTA chelation therapy in the reatment of neurodegenerative diseases: an update. Biomedicines 2020;8(8):269.** PMID 32756375
- 17
- Garringer HJ, Irimia JM, Li W, et al. Effect of systemic iron overload and a chelation therapy in a mouse model of the neurodegenerative disease hereditary ferritinopathy. PLoS One 2016;11(8):e0161341. PMID 27574973
- 18
- Gençpınar P, Büyüktahtakın B, İbişoğlu Z, Genç Ş, Yılmaz A, Mıhçı E. Mercury poisoning as a cause of intracranial hypertension. J Child Neurol 2015;30(6):760-3. PMID 25122110
- 19
- Grossi C, Francese S, Casini A, et al. Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 2009;17(2):423-40. PMID 19363260
- 20
- Grubman A, Pollari E, Duncan C, et al. Deregulation of biometal homeostasis: the missing link for neuronal ceroid lipofuscinoses. Metallomics 2014;6(4):932-43. PMID 24804307
- 21
- Hanafy KA, Gomes JA, Selim M. Rationale and current evidence for testing iron chelators for treating stroke. Curr Cardiol Rep 2019;21(4):20. PMID 30828740
- 22
- Huang L, Lu C, Sun Y, et al. Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease. J Med Chem 2012;55(19):8483-92. PMID 22978824
- 23
- James S, Stevenson SW, Silove N, Williams K. Chelation for autism spectrum disorder (ASD). Cochrane Database Syst Rev 2015;5:CD010766.** PMID 26106752
- 24
- Kim JJ, Kim Y-S, Kumar V. Heavy metal toxicity: an update of chelating therapeutic strategies. J Trace Elem Med Biol 2019;54:226-31. PMID 31109617
- 25
- Kosnett MJ. Chelation for heavy metals (arsenic, lead, and mercury): protective or perilous. Clin Pharmacol Ther 2010;88(3):412-5. PMID 20664538
- 26
- Kumar R, Pavlov PF, Winblad B. Binding by GMP-1 and its pyrimido [1, 2]benzimidazole analogs confirms protection against amyloid-β associated neurotoxicity. J Alzheimers Dis 2020;73(2):695-705. PMID 31839606
- 27
- Larnaout A, Ammar N, Mourad Z, Naji S, Hentati F. Wilson's disease: appreciable improvement of sub-cortical white matter abnormalities after copper chelating treatment: five years follow-up. Neuropediatrics 2008;39(3):176-8. PMID 18991198
- 28
- Liu C, Luo X. Potential molecular and graphene oxide chelators to dissolve amyloid-β plaques in Alzheimer's disease: a density functional theory study. J Mater Chem B 2021;9(11):2736-46. PMID 33688880
- 29
- Liu G, Men P, Zhu X, Perry G. Iron chelation and nanoparticle target delivery in the development of new multifunctional disease-modifying drugs for Alzheimer's disease. Ther Deliv 2012;3(5):571-4. PMID 22834400
- 30
- Lowette KF, Desmet K, Witters P, et al. Wilson's disease: long-term follow-up of a cohort of 24 patients treated with D-penicillamine. Eur J Gastroenterol Hepatol 2010;22(5):564-71. PMID 20042865
- 31
- Moret V, Laras Y, Pietrancosta N, et al. 1,1'-Xylyl bis-1,4,8,11-tetraaza cyclotetradecane: a new potential copper chelator agent for neuroprotection in Alzheimer's disease. Its comparative effects with clioquinol on rat brain copper distribution. Bioorg Med Chem Lett 2006;16(12):3298-301. PMID 16581247
- 32
- Nuñez MT, Chana-Cuevas P. New perspectives in iron chelation therapy for the treatment of neurodegenerative diseases. Pharmaceuticals (Basel) 2018;11(4).** PMID 30347635
- 33
- Obolensky A, Berenshtein E, Lederman M, et al. Zinc-desferrioxamine attenuates retinal degeneration in the rd10 mouse model of retinitis pigmentosa. Free Radic Biol Med 2011;51(8):1482-91. PMID 21824515
- 34
- Rees JA, Deblonde GJ, An DD, Ansoborlo C, Gauny SS, Abergel RJ. Evaluating the potential of chelation therapy to prevent and treat gadolinium deposition from MRI contrast agents. Sci Rep 2018;8(1):4419.** PMID 29535330
- 35
- Rodríguez-Rodríguez C, Sánchez de Groot N, Rimola A, et al. Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer's disease. J Am Chem Soc 2009;131(4):1436-51. PMID 19133767
- 36
- Stankiewicz JM, Neema M, Ceccarelli A. Iron and multiple sclerosis. Neurobiol Aging 2014;35 Suppl 2:S51-8. PMID 24929968
- 37
- Strozyk D, Launer LJ, Adlard PA, et al. Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid. Neurobiol Aging 2009;30(7):1069-77. PMID 18068270
- 38
- Vill K, Müller-Felber W, Teusch V, et al. Proximal muscular atrophy and weakness: an unusual adverse effect of deferasirox iron chelation therapy. Neuromuscul Disord 2016;26(4-5):322-5. PMID 27068298
- 39
- Walshe JM. Penicillamine: a new oral therapy for Wilson's disease. Am J Med 1956;21:487-95. PMID 13362281
- 40
- Walshe JM. The pattern of urinary copper excretion and its response to treatment in patients with Wilson's disease. QJM 2011;104(9):775-8. PMID 21622540
- 41
- Wang N, Jin X, Guo D, Tong G, Zhu X. Iron chelation nanoparticles with delayed saturation as an effective therapy for Parkinson disease. Biomacromolecules 2017;18(2):461-74. PMID 27989126
- 42
- Weigel KJ, Lynch SG, Levine SM. Iron chelation and multiple sclerosis. ASN Neuro 2014;6(1). PMID 24397846
- 43
- Yoo JY, Pradarelli J, Haseley A, et al. Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV. Clin Cancer Res 2012;18(18):4931-41. PMID 22753591
- 44
- Zhang L, Lichtmannegger J, Summer KH, et al. Tracing copper-thiomolybdate complexes in a prospective treatment for Wilson's disease. Biochemistry 2009;48(5):891-7. PMID 19146437
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
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K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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