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.
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
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.
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.
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.
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).
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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