Chelation therapy

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Chelation therapy is the administration of chelating agents to remove heavy metals from the body. For the most common forms of heavy metal intoxication—those involving lead, arsenic or mercury—the standard of care in the USA dictates the use of dimercaptosuccinic acid (DMSA).^{[citation needed]} Other chelating agents, such as 2,3-dimercapto-1-propanesulfonic acid (DMPS) and alpha lipoic acid (ALA), are used in conventional and alternative medicine.

History

Chelating agents were introduced into medicine as a result of the use of poison gas in World War I. The first widely used chelating agent, the organic dithiol compound dimercaprol (also named British Anti-Lewisite or BAL), was used as an antidote to the arsenic-based poison gas, Lewisite. The sulphur atoms in BAL's mercaptan groups strongly bond to the arsenic in Lewisite, forming a water-soluble compound that entered the bloodstream, allowing it to be removed from the body by the kidneys and liver. BAL had severe side-effects.

After World War II, a large number of navy personnel suffered from lead poisoning as a result of their jobs repainting the hulls of ships. The medical use of EDTA as a lead chelating agent was introduced. Unlike BAL, it is a synthetic amino acid and contains no mercaptans. EDTA side effects were not considered as severe as BAL.

In the 1960s, BAL was modified into DMSA, a related dithiol with far fewer side effects. DMSA quickly replaced both BAL and EDTA, becoming the US standard of care for the treatment of lead, arsenic, and mercury poisoning, which it remains today.

Research in the former Soviet Union led to the introduction of DMPS, another dithiol, as a mercury-chelating agent. The Soviets also introduced ALA, which is transformed by the body into the dithiol dihydrolipoic acid, a mercury- and arsenic-chelating agent. DMPS has experimental status in the US FDA, while ALA is a common nutritional supplement.

Since the 1970s, iron chelation therapy has been used as an alternative to regular phlebotomy to treat excess iron stores in people with haemochromatosis.^[1]

Other chelating agents have been discovered. They all function by making several chemical bonds with metal ions, thus rendering them much less chemically reactive. The resulting complex is water-soluble, allowing it to enter the bloodstream and be excreted harmlessly.

Calcium-disodium EDTA chelation is approved by the U.S. Food and Drug Administration (FDA) for treating lead poisoning and heavy metal toxicity.^[2]

In 1998, the U.S. Federal Trade Commission (FTC) pursued the American College for Advancement in Medicine (ACAM), an organisation that promotes "complementary, alternative and integrative medicine" over their advertising of EDTA chelation therapy, with claims including "Chelation therapy is a safe, effective and relatively inexpensive treatment to restore blood flow in victims of atherosclerosis without surgery." The FTC found that "scientific studies do not prove that EDTA chelation therapy is an effective treatment for atherosclerosis.", and that the statements by the ACAM were false.^[3] In 1999, the ACAM agreed to stop misrepresenting chelation therapy as effective in treating heart disease, avoiding legal proceedings.^[4][5]

Medical use

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Two molecules of deferasirox, an orally administered chelator, binding iron. Deferasirox is used in the treatment of transfusional iron overload in people with thalassemia.

Chelation therapy is used as a treatment for acute mercury, iron (including in cases of thalassemia), arsenic, lead, uranium, plutonium and other forms of toxic metal poisoning. The chelating agent may be administered intravenously, intramuscularly, or orally, depending on the agent and the type of poisoning. ^[6]

One example of successful chelation therapy is the case of Harold McCluskey, a nuclear worker who became badly contaminated with americium in 1976. He was treated with diethylene triamine pentaacetic acid (DTPA) over many years, removing 41 MBq (1.1 mCi) of americium from his body. His death, 11 years later, was from unrelated causes.

Several chelating agents are available, having different affinities for different metals. Common chelating agents include:

• Alpha lipoic acid (ALA)
• Aminophenoxyethane-tetraacetic acid (BAPTA)
• Deferasirox
• Deferiprone
• Deferoxamine
• Diethylene triamine pentaacetic acid (DTPA)
• Dimercaprol (BAL)
• Dimercapto-propane sulfonate (DMPS)
• Dimercaptosuccinic acid (DMSA)
• Ethylenediamine tetraacetic acid (calcium disodium versante) (CaNa₂-EDTA)
• Ethylene glycol tetraacetic acid (EGTA)
• D-penicillamine

Medically diagnosed heavy metal poisoning

Chelation therapy was used by the British after World War II to remove arsenic, lead, and other metals. Patients' conditions improved as these metals were removed from their bodies.^[7] Treatment may be applied to the skin via a transdermal patch.^[8] Another treatment is administered intravenously, a process that takes 2–3 hours, costs about $100 per treatment, and 20-30 treatments are often required.^[9]

Some common chelating agents are EDTA (ethylenediaminetetraacetic acid), DMPS (2,3-dimercaptopropanesulfonic acid), TTFD (thiamine tetrahydrofurfuryl disulfide), and DMSA (2,3-dimercaptosuccinic acid). Calcium-disodium EDTA and DMSA are only approved for the removal of lead by the Food and Drug Administration while DMPS and TTFD are not approved by the FDA. These drugs bind to heavy metals in the body and prevent them from binding to other agents. They are then excreted from the body. The chelating process also removes vital nutrients such as vitamins C and E, therefore these must be supplemented.^[10]

Use in alternative medicine

Alternative medicine uses chelation therapy as a non-standard treatment for some ailments, including heart disease and autism.^[11][12] Attempts have been made to use it in treating kidney dysfunction, calcific band keratopathy (an eye disorder), and ovarian cancer.^[13]Currently there is a US National Center for Complementary and Alternative Medicine (NCCAM) trial being conducted on the chelation therapy's safety and efficacy for patients with coronary artery disease.^[14] NCCAM Director Stephen E. Straus cited the "widespread use of chelation therapy in lieu of established therapies, the lack of adequate prior research to verify its safety and effectiveness, and the overall impact of coronary artery disease" as factors motivating the trial.^[15] The proposed study has been criticized as unnecessary and possibly dangerous.^[16]

Heart disease

Some alternative medicine practitioners administer chelating agents, usually EDTA, to patients with hardening of the arteries. The use of EDTA chelation therapy as a treatment for coronary artery disease has not been shown to be effective and is not approved by the U.S. Food and Drug Administration (FDA).^[17] Several possible mechanisms have been proposed, though none have been scientifically validated. The procedure might leach calcium directly from the fatty plaques that block the arteries; stimulate the release of a hormone that removes deposited calcium or lowers cholesterol levels; or reduce oxidative stress on the blood vessel walls.^[2] The US National Center for Complementary and Alternative Medicine began conducting the Trial to Assess Chelation Therapy (TACT) in 2003.^[14] Patient enrollment was to be completed around July 2009^[2] with final completion around July 2010,^[14] but enrollment in the trial was suspended on September 26, 2008 for an investigation by OHRP after complaints about ethical concerns such as inadequate informed consent.^[18] The trial has been criticized for lacking prior Phase I and II studies, and particularly because previous controlled trials have not indicated benefits.^[16] The American College for Advancement in Medicine, a controversial organization created to promote chelation therapy, has played a part in the adoption of the TACT clinical trial, which has led to further criticism of the trial.^[16] Atwood et al. have argued that methodological flaws and lack of prior probability make this trial "unethical, dangerous, pointless, and wasteful."^[16]

The American Heart Association states that there is "no scientific evidence to demonstrate any benefit from this form of therapy" and that the "United States Food and Drug Administration (FDA), the National Institutes of Health (NIH) and the American College of Cardiology all agree with the American Heart Association" that "there have been no adequate, controlled, published scientific studies using currently approved scientific methodology to support this therapy for cardiovascular disease."^[17] Like other scientific commentators, they note that any improvement among heart patients undergoing chelation therapy can be attributed to the placebo effect and lifestyle changes discovered in conventional medicine but recommended by chelationists; "quitting smoking, losing weight, eating more fruits and vegetables, avoiding foods high in saturated fats and exercising regularly".^[19] They note their concern that patients could put off proven treatments for heart disease like drugs or surgery.^[19] A 2005 systematic review found that controlled scientific studies did not support chelation therapy for heart disease.^[20] It found that very small trials and uncontrolled descriptive studies have reported benefits while larger controlled studies have found results no better than placebo

Autism

Based on speculation that mercury poisoning may trigger the symptoms of autism,^[21] chelation therapy is widely used to treat autism, with some surveys suggesting 2–8% of children with autism have had the therapy. Parents either have a doctor use a treatment for lead poisoning, or buy unregulated supplements.^[22] Aspies For Freedom, an autistic rights organization, considers this use of chelation therapy unethical and potentially dangerous.^[23] There is strong epidemiological evidence that refutes links between environmental triggers, in particular thimerosal-containing vaccines, and the onset of autistic symptoms.^{[24][25][26][27]} There is no scientific support for chelation therapy as a treatment for autism.^[12][28]

Controversy

The efficacy, safety, and much of the theory behind these alternative practices are disputed by the medical community. In 2001, researchers at the University of Calgary reported that cardiac patients receiving chelation therapy fared no better than those who received placebo treatment.^[29]

In 1998, the U.S. Federal Trade Commission (FTC) charged that the web site of the American College for Advancement in Medicine (ACAM) and a brochure they published had made false or unsubstantiated claims. In December 1998, the FTC announced that it had secured a consent agreement barring ACAM from making unsubstantiated advertising claims that chelation therapy is effective against atherosclerosis or any other disease of the circulatory system.^[30][31]

Prevalence

The American College for Advancement in Medicine, which promotes chelation therapy, estimates that 800,000 patient visits for chelation therapy were made in the United States in 1997.^[32]

Side effects and safety concerns

There is a low occurrence of side effects when chelation is used at the dose and infusion rates approved by the U.S. FDA as a treatment for heavy metal poisoning. A burning sensation at the site of delivery into the vein is common. Other side effects include fever, headache, nausea, stomach upset, vomiting, convulsions, bone marrow depression (dropping blood cell counts), a drop in blood pressure, cardiac arrhythmias, respiratory arrest, and hypocalcemia. Other concerns include kidney failure, which can require permanent life-limiting and expensive dialysis, or cause death.^[19]

2007 research with lab rats indicates giving chelating agent DMSA to rats without high levels of lead may cause lasting cognitive damage. ^[33]

When EDTA is not administered by a health professional for the treatment of heavy metal poisoning more serious side effects can occur.^[2]

Chelation therapy can be hazardous, even conducted with the FDA-approved chelation agents. In August 2005, botched chelation therapy conducted by an ACAM member killed a 5-year-old autistic boy,^[16] a 3-year-old nonautistic girl died in February 2005, and a nonautistic adult died in August 2003. These deaths were due to cardiac arrest caused by hypocalcemia during chelation therapy.^[34] Only the 3-year-old girl had been medically assessed and found to have an elevated blood lead level and resulting low iron levels and anemia, a proper medical cause for chelation therapy to be conducted.^[35]

More than 30 deaths have been recorded in association with IV-administered disodium EDTA since the 1970s.^[16]

References