Chelation therapy

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Chapter: Essentials of Inorganic Chemistry : Chelation Therapy

As previously mentioned, chelation therapy is one treatment option for most heavy-metal poisoning. A chelating agent (antidote), which is specific to the metal involved, is administered to the patient orally, intramuscularly or intravenously.

Chelation therapy

As previously mentioned, chelation therapy is one treatment option for most heavy-metal poisoning. A chelating agent (antidote), which is specific to the metal involved, is administered to the patient orally, intramuscularly or intravenously. Dimercaprol (BAL, British anti-Lewisite), calcium disodium edetate and penicillamine are the three most common chelating agents used in the treatment of heavy-metal poisoning. The unlicensed drug Succimer (DMSA, meso-2,3-dimercaptosuccinic acid) may be valuable in the treatment of most forms of heavy-metal poisoning including lead, arsenic and mercury. These and other chelating agents such as unithiol (DMPS, 2,3-dimercapto-1-propanesulfonic acid) and α-lipoic acid (ALA) are also used in alternative medicine, which has led to much criticism and discussion. So far, no medical study has proven the effectiveness of chelation therapy for any clinical application other than heavy-metal poisoning.

The mode of action is based on the ability of the chelating agent to bind to the metal in the body’s tissues and form a chelate. This complex is then released from the tissue and travels in the bloodstream. Finally, the complex is filtered by the kidneys and excreted in the urine. Unfortunately, this process requires admission to the hospital because it may be painful and it is important to stabilise the vital functions of the patient. The patient additionally may require treatment for complications associated with heavy-metal poisoning, including anaemia and kidney failure or shock reactions.

Chelation therapy is an especially effective treatment option for poisoning with lead, mercury and arsenic.

It is very difficult to treat cadmium poisoning, and so far no really effective therapy has been found.


1. Calcium disodium edetate

Calcium disodium edetate, also referred to as calcium sodium EDTA, stands for the chemical compound 2,2,2′′,2′′′-(ethane-1,2-diyldinitrilo)tetraacetic acid, which is a synthetic amino acid. Edetate refers to the calcium disodium salt of the chelating agent with the formula (HO2CCH2)2NCH2CH2N(CH2CO2H)2. In the United States, it is found under the name calcium disodium versenate. Edetate is mainly used to complex di and trivalent metal ions. Edetate can bind to metals via the four carboxylate and two amine groups, and it forms specially strong complexes with Co(III), Cu(II), Mn(II) and Fe(III) (Figure 11.7).

Edetate is indicated for the treatment of lead poisoning, which was especially a big problem for navy personnel after World War II. Staff repainting the navy ships with lead-based paint were exposed to the heavy metal and suffered from symptoms of lead poisoning. Around this time, edetate was introduced as a medicinal chelating agent. The side effects include nausea, diarrhoea and abdominal pain. It can lead to renal damage if given as over dosage . 

Nevertheless, these side effects are less serious/invasive than those of most other chelating agents being used. Edetate is typically administered by intravenous infusion for up to 5 days .

Other clinical applications include the application of chromium-EDTA, which can be used to evaluate kid-ney function. It is administered intravenously and its filtration into the urine is monitored. Chromium-EDTA exits the human body only via glomerular filtration as it is not secreted or metabolised in any other way. EDTA and its salts can act as an anticoagulant for blood samples and is therefore often found as additives in blood sampling bottles.


2. Dimercaprol (BAL)

Dimercaprol (BAL) is a chelating agent used as an antidote for arsenic, antimony, bismuth, gold and mercury poisoning . It has the chemical name 2,3-dimercapto-1-propanol and is a clear, colourless or slightly yellow liquid (Figure 11.8).

British scientists at the University of Oxford also developed BAL during World War II as an antidote to Lewisite. Lewisite is an arsenic-based chemical warfare agent used in form of a blister gas. Further research showed that it can be used as an antidote against a variety of toxic metals. Additionally, it was used in the treatment of Wilson disease, which is a chronic disease in which the body retains excess amounts of copper (see Chapter 7).

Heavy-metal poisoning often results from the coordination of the metal to sulfhydryl groups of enzymes, which means that these enzymes are blocked for their activity. BAL also contains sulfhydryl groups and basically competes with the enzymes for the coordination of the metal. The chelated complex is then excreted in the urine. Whilst BAL removes a range of heavy metals, it also seems to increase the concentration of some metals in the human body and therefore limits its use. It is not indicated as an antidote for cadmium (increased levels are found in the kidneys after treatment), selenium or iron poisoning .

Unfortunately, BAL itself is very toxic and has only a narrow therapeutic window. Its multiple side effects include, amongst others, hypertension, malaise, tachycardia, nausea, diarrhoea, burning sensation and muscle pain. The administration is by intramuscular injection and is fairly painful. Because of its instability in water, it is formulated with peanut oil as solvent.


3. Dimercaptosuccinic acid (DMSA)

DMSA is a modification of BAL containing two thiol groups, which are responsible for the unpleasant smell, and two carboxylic acid groups. DMSA is also known under the name Succimer. It chemical name is meso-2,3-dimercaptosuccinic acid and the chemical formula is HO2CCH(SH)CH(SH)CO2H. There are two diastereomeric forms, meso and the chiral DL forms, with the meso isomer being used as chelating agent (Figure 11.9).

DMSA was developed in the 1960s and replaced BAL and edetate in some countries for the treatment of lead, arsenic and mercury poisoning. Furthermore, the dimethylester modification of DMSA has been successfully used for the treatment of heavy-metal poisoning.


4. 2,3-Dimercapto-1-propanesulfonic acid (DMPS)

DMPS is also a thiol-containing chelating agent. It also contains sulfhydryl groups and an additional sulfate group. Researchers in the former Soviet Union found that DMPS is a useful chelating agent and has some effect as an antidote to mercury (Figure 11.10).


5. Lipoic acid (ALA)

Lipoic acid, also known as α-lipoic acid (alpha-lipoic acid) or thioctic acid, has the formula C8H14S2O2 and systematic name 5-(1,2-dithiolan-3-yl)pentanoic acid. It contains a disulfide group, which can be transformed in the body to a dithiol group (Figure 11.11).

ALA has been on the market since the 1950s as a dietary supplement. It is a natural antioxidant usually made by the body. The advantage of ALA over other antioxidants such as vitamin C and E is that it is soluble both in water and in fat . Researchers in the former Soviet Union found that ALA can chelate mercury once it is transformed into the dithiol-containing compound. ALA can penetrate both the blood– brain barrier and the cell membrane and therefore would be a very interesting chelating agent. Nevertheless, there is much debate about its mode of action, side effects and effectiveness. Other antidotes, such as BAL and DMSA, are more efficient in the removal of heavy metals. ALA has not received FDA approval as a chelating agent, but it is still sold as a food supplement.

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