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Chelators as Antidotes of Metal Toxicity: Therapeutic and Experimental Aspects

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The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.
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Current Medicinal Chemistry, 2005, 12, 2771-2794 2771
Chelators as Antidotes of Metal Toxicity: Therapeutic and Experimental
Aspects
Maja
Blanusa
*
˘
, Veda M. Varnai, Martina Piasek and Krista Kostial
Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2,
P.O. Box 291, HR-10001 Zagreb, Republic of Croatia
Abstract: The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human
exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium,
arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly
the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal
poisoning are also different for each chelating drug. The chelating drugs with worldwide application are
dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-
penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa
2
EDTA), calcium trisodium or zinc
trisodium diethylenetriaminepentaacetate (CaNa
3
DTPA, ZnNa
3
DTPA), deferoxamine (DFO), deferiprone (L1),
triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic
homologues and experimental chelating agents have been designed and tested in vivo for their metal binding
effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA
and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the
carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal
poisoning. Within this context it has been shown in experiments using young and adult animals that metal
toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of
new therapeutic chelation protocols for metal toxicity.
Keywords: Chelating agents, BAL derivatives, carbodithioates, deferiprone, deferoxamine, D-penicillamine,
polyaminopolycarboxylic acids, metals, metal toxicity.
1. INTRODUCTION of the most important information on common metal
poisonings and possibilities for their chelating treatment,
both by clinical and experimental agents, are listed in Table
1. The effects of chelating agents presently applied in human
clinical practice and the metal binding effects of newly
synthesized chelators are described in separate sections.
Three groups of chelators are described, namely the
polyaminopolycarboxylic acids, such as ethylenediaminete-
traacetic acid (EDTA) and diethylenetriaminepentaacetic acid
(DTPA); the derivatives of dimercaprol (British-Anti-
Lewisite, BAL), such as 2,3-dimercaptopropane-1-sulfonic
acid (DMPS), 2,3-dimercaptosuccinic acid (DMSA), and
mono- and dialkylesters of DMSA; and the carbodithioates.
Not only are newer agents being sought, but also
combinations of new or already known chelators are tested
for possible synergistic action. Age-related differences in
efficacy of chelation therapy are also included, since the
binding of toxic metals in the very young is an important
topic presently under investigation.
A chelating agent is a molecule that forms a complex
with a metal ion. The chelating agent molecule has electrons
available to form a bond with a positively charged transition
metal ion. Chelators can be attached to the metal ion by two
or more bonds forming a ring, which is called the chelate
ring [1]. The main goal of chelation treatment is to
transform the toxic metal complex with biological ligands
into a new, non-toxic complex between the metal ion and
chelator, which can be excreted from the organism. To fulfill
this purpose chelating agents must possess several
characteristics. The profile of a successful chelating drug
includes high affinity for the toxic metal(s) but low affinity
for essential metals, minimal toxicity, lipid solubility, and,
preferably, good absorbability from the gastrointestinal tract.
These conditions, however, are not easy to fulfill. For
example, the advantage of lipid soluble substances is that
they easily cross the cell membrane and bind metals within
the cell. Unfortunately, such chelators are usually more toxic
than those which are not lipid soluble. Thus, it is a
challenging task to find optimal conditions for binding
specific toxic metal with minimal risk of adverse effects.
The chemical structures of some clinically used and
experimental chelators are presented in Figs. 1 and 2.
2. METAL EXPOSURE AND HEALTH EFFECTS
Exposure and toxicity of several metals and metalloids
such as lead, cadmium, mercury, manganese, aluminum,
iron, copper, thallium, arsenic, chromium, nickel and
platinum, are of major concern to human health. A summary
Metals can disturb organ functions and cause disease
through excess, deficiency, or imbalance in the body. A
number of metal ions regulate a vast array of physiological
mechanisms that are essential for organ functioning and
development. However, under conditions of metal overload,
toxic side effects can occur. Metal overload can be caused by
*Address correspondence to this author at the Mineral Metabolism Unit,
Institute for Medical Research and Occupational Health, P.O. Box 291,
HR-10001 Zagreb, Republic of Croatia; E-mail: blanusa@imi.hr
0929-8673/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
2772 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
Table 1. Toxicity of Metals and Chelating Treatment
Toxic metal ion Toxicity Chelation treatment
Recommended Experimental* References
aluminum Acute: not likely to occur;
Chronic: in patients with chronic renal failure
(encephalopathy, renal osteomalacia and microcytic
anemia); exposure to aluminum dust (respiratory and CNS
symptoms)
DFO
L1
HEDTA
EDDHA
[31,32,
63-65]
arsenic Acute ingestion of large dose: serious GI symptoms,
muscle cramps, multi-organ failure, death;
Acute inhalation: irritation of respiratory tract;
Chronic inhalation (occupational): weakness, anorexia, GI
symptoms, hepatotoxicity, irritation of the eyes, throat and
respiratory tract, PNS damage, skin disorders;
Chronic exposure: CV disorders, cancerogenicity,
reproductive effects
DMPS
meso-DMSA
BAL
DPA
NAC
Mi-ADMS
[31,41,42,
66-69]
cadmium Acute inhalation: respiratory disorders, 'metal fume fever',
weakness, GI symptoms;
Acute ingestion: GI symptoms, muscle convulsions,
unconsciousness;
Chronic ingestion: kidney damage, itai itai byo, GI
irritation, osteomalacia, hypertension, lung and liver
damage
no effective
chelators
(CaNa
2
EDTA)
polyaminocarboxylic acids
(CaNa
3
DTPA or
ZnNa
3
DTPA and others)
carbodithioates, DFO, NAC,
DMSA and its esters
[16,41,
70-76]
chromium Acute ingestion: GI irritation, fever, muscle cramps,
hemorrhagic diathesis, toxic nephritis, circulatory collapse,
liver damage, coma, death;
Chronic inhalation or dermal exposure: changes in the
skin and mucous membranes, dermal and respiratory
allergy, kidney damage, lung cancer
uncertain
efficacy of
chelators
NAC
polyaminocarboxylic acids
ascorbic acid
[31,45,
77-82]
copper Acute ingestion: severe GI symptoms, headache,
tachycardia, hemolytic anemia, hematuria, liver and kidney
failure, possible fatal outcome;
Acute inhalation (fumes or dust): irritation of the upper
respiratory tract, ‘Metal fume fever’;
Chronic ingestion: GI symptoms, liver failure, hemolytic
anemia; Dermal: allergy;
Genetic disorders (e.g. Wilson’s disease)
DPA
Trientine
meso-DMSA
DMPS
TTM
BAL
[31,37,38,
41,83,84]
iron Acute ingestion (mostly in children): GI symptoms,
hypotension, metabolic acidosis, coagulopathy, liver
dysfunction, heart, kidneys and lungs impairments, possible
fatal outcome;
Chronic iron overload: hemochromatosis, hemosiderosis,
polycythemia, and iron-loading anemias (thalassemia and
sickle cell anemia); exacerbation of most chronic diseases
DFO
L1
CaNa
3
DTPA
Dexrazoxane
L1 analogues (L1NAll,
CP502), ICL670
GT56-252
phosphorothioate-
oligonucleotide
[31,35,36,
38,85]
lead Acute ingestion in young children with pica: anorexia,
vomiting, malaise, brain damage, renal injury; in adults:
abdominal colic, hemotoxic effects;
Chronic (oral, inhalation, transplacental passage):
in children serious damages to CNS and neurodevelopment;
in adults: effects of PNS (wrist drop); hemotoxic,
nephrotoxic, reproductive effects, gout, GI symptoms,
hypertension
meso-DMSA
DMPS
BAL
CaNa
2
EDTA
DPA
ascorbic acid
vitamin B
racemic DMSA
Mi-ADMS
[10,31,41,
86-91]
manganese Acute intoxication is rare;
Chronic exposure: CNS damage, ‘manganism’
(progressive irreversible brain impairment), renal damage,
lung irritation, increased chances of a lung infection,
impotence, decreased systolic blood pressure, skin irritation
and allergy
CaNa
2
EDTA
CaNa
3
DTPA
(uncertain
efficacy)
CDTA
EGTA
HEDTA
para-aminosalicylic acid
[29,31,92,
93]
mercury Acute inhalation: respiratory symptoms, interstitial
pneumonitis to death, CNS symptoms;
Acute ingestion: ulcerative gastroenteritis, tubular
necrosis;
Chronic ingestion and inhalation: neurologic effects (in
children irreversible CNS damage), tremor, erethism,
nephritis, immunotoxic response, contact dermatitis
DMPS
meso-DMSA
DPA
NAPA
BAL
$
thiol resins
NAC
rac-DMSA
monoalkyl esters of
meso-DMSA
NAPA
[22,31,41,
94-101]
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2773
(Table 1). contd.....
Toxic metal ion Toxicity Chelation treatment
Recommended Experimental* References
nickel Dermal exposure: hypersensitivity (contact allergic
dermatitis);
Acute ingestion: GI symptoms, vertigo, headache, cough,
shortness of breath;
Acute inhalation (nickel carbonyl - most acutely toxic):
headache, GI symptoms, insomnia, pulmonary disorders
(pneumonitis); affected liver, kidneys, adrenal glands,
spleen, brain;
Chronic inhalation: upper respiratory changes, COPB,
allergic dermatitis, nephrotoxicity, nasal dysplasia,
sinusoidal and bronchial carcinoma, pulmonary fibrosis
DDTC
disulfiram
(limited human
data)
BDCG
DMSA
[31,51,53,
56-60,
102-105]
platinum Chronic occupational exposure: hypersensitivity and
allergy: dermal (urticaria, contact dermatitis) and
respiratory (sneezing to severe asthma);
Cisplatin therapy: nausea, vomiting, diarrhea,
nephrotoxicity, neurotoxicity, ototoxicity, hematological
disorders
no routinely
recommended
chelation
therapy
DDTC
BGDC
NAC
[31,61,62,
106-109]
thallium Acute and chronic exposure is similar: GI symptoms, CNS
symptoms (confusion, psychosis, convulsions, coma),
sensory and motor polyneuropathy, blindness, "burning feet
syndrome", circulatory symptoms, respiratory failure, skin
changes and hair loss
Prussian Blue combined DPA and PB,
DPA (possible thallium
redistribution to the brain!)
[31,39,40,
110-114]
*Also include chelators tested in experimental animals or in limited number of human subjects.
$
BAL is contraindicated for methyl-mercury poisoning.
COPB = chronic obstructive pulmonary disease; GI = gastrointestinal; CNS=central nervous system; PNS=peripheral nervous system; CV = cardiovascular.
external means, environmental or occupational, or by genetic
factors such as disturbed metabolism of copper and iron.
Beside exposure levels, both essential and toxic effects of
metals are due to their specific chemical properties that
include reduction/oxidation potential, acid/base chemistry,
and structural or ligand properties. Several metals and
metalloids, such as chromium, copper, iron, manganese,
molybdenum and selenium, may have both essential and
toxic properties [2,3].
human activities (industrial emission, car exhaust from
leaded gasoline, burning coal or oil, and burning solid
waste). Occupational exposure to lead may occur in iron and
steel production, lead-acid-battery manufacturing, and non-
ferrous, brass and bronze foundries. The general population
is exposed to lead mostly by lead-contaminated food or
drinking water, which is the case for example where lead
pipes are used, or when food and beverages are stored in
improperly glazed pottery, ceramic dishes, leaded-crystal
glassware, and lead-soldered cans and containers. Cigarette
smoke also contains lead. Other sources of lead exposure are
leaded paints, illegal distillery of alcohol beverages, vicinity
of hazardous waste sites, cosmetics and hair dyes, folk
remedies, and certain non-Western cosmetics (surma and
kohl) [8-11].
Conditions with increased nutritional demands and
intake (gestation, lactation, perinatal period and adolescence)
and malabsorption (e.g. diarrhea) can result in essential
metal and trace element deficiencies that can, in turn,
enhance toxic metal absorption and retention. Toxic effects
of metals depend on nutritional status, age and sex, as well
as the amount and route of exposure, tissue distribution,
concentration achieved, and excretion rate [4-6]. Mechanisms
of toxicity include inhibition of enzyme activity and protein
synthesis, alterations in nucleic acid function, and changes
in cell membrane permeability. Virtually all organs and
organic systems can be affected. This is especially dangerous
for young developing organisms where toxic effects of
metals can leave immediate and/or late irreversible damage
in many organ structures and functions. Any detrimental
effect at a critical time in development is likely to have
long-lasting consequences, for example the damaging effects
of toxic metals on the developing brain [2,7].
Despite efforts to control lead exposure and despite
apparent success in decreasing the incidence, serious cases of
lead poisoning still appear in both developed and developing
countries all over the world. Compared to adult lead
poisoning, pediatric lead poisoning is a somewhat newer
problem and it is one of the most important chronic
environmental illnesses affecting modern children. Virtually
no organ system is immune to the effects of lead poisoning
in children. Lead perturbs multiple enzyme systems. As
with most heavy metals, any ligand with sulfhydryl groups
is vulnerable. Perhaps the best-known effect is that on the
production of heme, and because heme is essential for
cellular oxidation, deficiencies have far-reaching effects. Lead
easily crosses the placenta and may affect the fetus in utero,
having immediate and long-lasting consequences on
development and health. The main targets for lead toxicity
are the nervous system, especially in children, hematopoietic
system, sperm production, kidney, and possibly blood
2.1. Lead
Lead is an ubiquitous metal that has been used by
humans for more than three thousand years. It appears in the
environment both from natural sources and released by
2774 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
HS
SH
OH
HO
OH
SH
O
O
SH
SH
S
HS
OH
OO
DMPS
H
2
N
OH
O
SH
DPA
HO
HS
NH
O
O
NAPA
HN
O
O
HO
HS
NAC
N-acetylcysteine
OH
N
N
OH
O
O
OH
O
O
HO
N
OH
N
HO O
O
O
OH
N
HO
O
OHO
DTPA
(CH
2
)
5
N
N
(CH
2
)
5
N
OH
O
O
H
OH
O
NH
2
DFO
N O
OH
H
2
N
H
N
N
H
NH
2
Fe
-4
N
N
N
N
N N
Fe
Fe
-4
N
N
N
N
N
N
Fe
Fe
-4
N
N
N
N N
N
Fe
Fe
BAL
2,3-dimercapto-1-propanol
meso-DMSA
(R,S)-2,3-dimercaptosuccinic acid
2,3-dimercaptopropane-1-
-sulphonic acid
D-penicillamine N-acetyl-D-penicillamine
EDTA
Ethylenediaminetetraacetic acid
Diethylenetriaminepentaacetic acid
2
Deferoxamine
LI
1,2-dimethyl-3-hydroxy-
pyrid-4-one
TRIENTINE
Triethylenetetramine
+ + +
+ + +
+ + +
+ + +
Prussian Blue
Iron (III) hexacyanoferrate (II)
Fig. (1). Chemical structures of chelating drugs.
pressure regulation system [7,12]. It should be emphasized
that symptoms may be absent despite significant poisoning.
2.2. Cadmium
Exposure to cadmium occurs mostly in the workplace
from cadmium fumes and dust in industries where cadmium
products are made (smelting, battery manufacturing,
soldering, and pigment production). In the modern world
The regimen and choices for chelation therapy in lead
poisoning are generally well defined, especially in adults,
and are discussed in a separate section.
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2775
HS
HO
O
O
SHO
OH
HO
SH
O
O
SH
OH
HO
SH
O
O
SH
N
SS
OH OH
OH
OH
HO
Na
+
N
SS
OH OH
OH
OH
HO
O
N
S
S
Na
+
DDTC
O
OHHO
OH
HO
N N O
OHHO
OH
OH
-
S SS S
-
Mi-ADMS
Monoisoamyl meso-2,3-
-dimercaptosuccinic acid
(R,R)-2,3-DMSA (S,S)-2,3-DMSA
racemic-DMSA
BGDTC
Sodium N-benzyl-D-glucamine-
N-carbodithioate
MeOBGDTC
Sodium N-(4-methoxybenzyl)-
-D-glucamine-N-carbodithioate
Sodium diethylcarbodtithioate
C
9
G
2
DTC
Disodium N,N'-diglucosyl-1,9-nonane-
diamine-N,N'-biscarbodithioate
Na
+
Na
+
Fig. (2). Chemical structures of experimental chelators.
cadmium is ubiquitous and most of it has been introduced
into the environment by human activities. The general
population is exposed from breathing cigarette smoke or
eating cadmium-contaminated food (cereal products, grains,
sea food, potatoes, leafy vegetables) [8,13-16]. Cadmium
can cause kidney disease, it damages the lungs, and may
irritate the digestive tract. Long-term exposure to lower
levels of cadmium in air, food or water leads to an
accumulation of cadmium in the kidneys and possible
kidney disease. Other long-term effects are lung damage and
fragile bones, since cadmium exerts a direct effect on bone
[17].
efficient chelating treatment has been recommended for
human usage.
2.3. Mercury
Throughout the centuries, several incidents of mercury
toxicity have been reported (e.g. usage in hat making,
Minamata Bay mercury poisoning in Japan, episodes of
methylmercury-treated grain in Iraq and in the United States,
mercury contaminated fish in Canada, a beauty cream
product from Mexico, etc.). For centuries, mercury was an
essential part of many different medicines, such as
antisyphilitic agents, diuretics, antibacterial agents,
antiseptics, and laxatives. Mercury toxicity in environmental
pollution is a major concern because of increased usage of
fossil fuels and agricultural products, both of which contain
mercury [20-22].
The health effects in children are expected to be similar
to those in adults (kidney, lung and intestinal damage).
Cadmium does not readily pass from a pregnant woman's
body into the developing child, but it does accumulate in
placental tissue, disturbs transplacental nutrient passage, and
probably disrupts steroid hormone synthesis [18]. It can also
be found in breast milk. It is not a proven reproductive
toxicant in humans, but it is a human carcinogen and has
genotoxic potential [16,19].
Mercury is found in many industries (battery,
thermometer, and barometer manufacturing), contaminated
fish and seafood, dental amalgams, various antiseptic agents,
fungicides and earlier in paints (as an antimildew agent).
Investigations so far have not established a definite link
between the small amount of mercury in thimerosal, a
Improved regimen and choices of chelation therapy in
cadmium-exposed individuals are needed. To date no
2776 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
mercury-containing preservative used in some vaccines, and
any known disease [23]. This has attracted considerable
attention as a possible source of mercury exposure in young
children.
Workers with long-term exposure to high levels of
manganese may become impotent, and may develop
‘manganism’, a progressive irreversible brain impairment
characterized by psychological and neurological
manifestations in the form of Parkinson-like syndrome
(extrapyramidal disorder) [29-31]. Formula-fed infants
(especially with soy-based formulas) ingest considerably
more manganese than breast-fed infants and thus any
additional exposure to manganese in this group may cause
body burden of manganese that reaches a level for neurotoxic
effects. Placental and mammary transfer of manganese to
offspring is well documented [29].
Mercury exists in an organic and inorganic form.
Generally, any form of mercury is toxic. Mercury poisoning
can result from vapor inhalation, ingestion, injection, or
absorption through the skin. Elemental mercury as a vapor
has the ability to penetrate into the central nervous system
where it causes toxic effects, but it is not well absorbed by
the gastrointestinal tract. Inorganic mercury (mostly in the
mercuric salt form, e.g. batteries) is highly toxic and
corrosive. It enters the body orally or dermally and
accumulates mostly in the kidneys, causing their damage.
Chronic exposure and slow elimination allow also for
significant accumulation and toxicity of the central nervous
system. Organic mercury can be found in three forms, aryl
and short and long chain alkyl compounds. Organic
mercurials are absorbed more completely from the
gastrointestinal tract than inorganic salts, and then they are
converted to their inorganic forms, possessing similar toxic
properties as inorganic mercury. They cross the blood brain
barrier and placenta and penetrate erythrocytes, attributing to
neurological symptoms and teratogenic effects.
Methylmercury has a high affinity for sulfhydryl groups,
which attributes to its effect on enzyme dysfunction [22-26].
The use of chelating agents, such as calcium disodium
ethylenediaminetetraacetate (CaNa
2
EDTA), may be beneficial
in the early stages of poisoning, although sometimes only
temporarily. Chelation treatment cannot be expected to bring
about any improvement in cases where structural
neurological injury has already occurred [31].
2.5. Aluminum
Aluminum is the third most abundant element and the
most abundant metal in the Earth's crust. Dietary aluminum
exposure is unavoidable. Urban water supplies may contain a
greater concentration because water is usually treated with
this element before becoming part of the supply.
Nevertheless, its quantities are of insignificant concern in
persons with normal elimination capacity of the kidneys,
since most of the aluminum load becomes intravascularly
bound to transferrin and albumin, and is then eliminated
renally. The present epidemiological evidence does not
support a causal association between Alzheimer disease or
impaired cognitive function in the elderly and aluminum in
drinking water. There is no known physiologic need for
aluminum. Due to its atomic size and electric charge,
aluminum is sometimes a competitive inhibitor of several
essential elements of similar characteristics such as
magnesium, calcium, and iron [31,32].
Chelation therapy is presently the treatment of choice for
reducing the body burden of mercury. There are a number of
chelators either in practical use or under investigation in vivo
and in vitro. Presently, in intoxication with elemental
mercury vapor and either with inorganic or organic mercury,
DMPS, meso-DMSA, D-penicillamine (DPA), or N-acetyl-
D-penicillamine (NAPA) are recommended. DMPS and
meso-DMSA are considered to be more effective than the
other two chelators, and DMPS more effective than meso-
DMSA [27]. For elemental and inorganic mercury poisoning
BAL was also used, although there is a trend to be replaced
with less toxic and more efficient analogues, DMPS and
meso-DMSA [27,28]. BAL is contraindicated in organic
mercury poisoning [20].
Acute aluminum intoxication is extremely rare. Most
cases of aluminum toxicity in humans are observed in
patients with chronic renal failure, or in persons exposed to
aluminum in the workplace [31]. Patients with chronic renal
failure are exposed to aluminum from dialysate, parenteral
nutrition or other exogenous sources, such as aluminum-
containing phosphate binders and antacids (aluminum
hydroxide). Toxicity is manifested by defective
mineralization and vitamin-D-resistant osteomalacia that
result from excessive aluminum deposits at the site of
osteoid mineralization, brain damage due to oxidative stress
with the formation of Alzheimer-like neurofibrillary tangles,
and anemia caused by decreased heme and globulin
synthesis, increased hemolysis, and by direct effect on iron
metabolism [31-34]. Premature infants, even where kidney
impairment is not severe, may develop increased tissue
loading of aluminum, particularly in bone, when exposed to
iatrogenic sources of aluminum. If there is kidney failure,
seizures and encephalopathy may occur. In occupational
environments, chronic exposure to aluminum dust may
cause pulmonary changes, such as pulmonary fibrosis,
pneumothorax and pneumoconiosis. It may also cause
subclinical effects in the central nervous system, such as
EEG (electroencephalography) changes, subclinical tremor or
2.4. Manganese
Manganese is one of the most abundant trace elements in
the Earth's crust. It is also released in the environment by
human activities (iron- and steel-producing plants, power
plants, mining operations, burning of fossil fuels, gasoline
additive, and from pesticides Maneb and Mancozeb).
Manganese is both an essential and toxic trace element. Its
concentration in foodstuffs varies markedly, but on the
whole, food (grains, cereals, tea) constitutes the major source
of manganese intake in humans.
Acute poisonings due to ingestion of inorganic
manganese salts are rare, since they have low gastrointestinal
bioavailability. Symptoms of intoxication may occur only
after ingestion of large amounts of manganese or in workers
with inhalatory exposure. The respiratory and central nervous
system are mainly affected, and there are no significant toxic
effects on other organ systems. Manganese poisoning has
also been described in patients on chronic total parenteral
nutrition, when manganese was added as a trace element.
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2777
alterations in performance tests assessing reaction time, eye-
hand coordination, memory, and motor skills [32,33].
childhood, such as Indian childhood cirrhosis or idiopathic
copper toxicosis [31,38].
Chelation therapy when indicated (mostly in dialyzed
and/or uremic patients) resembles that for iron overload.
The mainstay of therapy for Wilson’s disease is the use
of chelating agents and medications that block copper
absorption from the gastrointestinal tract and enhance copper
excretion, such as DPA, triethylenetetraamine (trientine),
meso-DMSA, DMPS or tetrathiomolybdate (TTM) [38].
2.6. Iron
Iron is an essential trace element. It is generally
recommended that people who are not iron deficient should
not take iron supplements. Iron poisoning can occur when a
person, usually a child, swallows a large number of iron-
containing pills (as they appear similar to candies), most
often as a vitamin supplement and for treatment of anemia.
Iron overdose has been one of the leading causes of death
caused by toxic agents in children under the age of six [31].
2.8. Thallium
Thallium is ubiquitous in the environment as a result of
natural processes, generally in low concentrations, and from
man-made sources by emissions into the atmosphere (mainly
from mineral smelters – deposits of waste material and
emissions into the atmosphere, coal-burning power-
generating plants, brickwork, and cement plants). Thallium
salts have been easily available in the past and still are in
some developing countries. It is considered on a worldwide
scale to be as one of the most frequent causes of deliberate or
accidental human poisoning [39]. Knowledge of chronic
thallium intoxication is limited to occupational exposure, to
population groups in contaminated areas, and to cases of
homicide involving multiple low doses. The primary targets
of thallium toxicity are the central, peripheral and autonomic
nervous system, integumentary (dermis and epidermis with
derivatives) and reproductive system. Symptoms in acute
and chronic poisoning are similar, but are generally milder
in chronic intoxication. Alopecia is the most common
symptom of chronic thallium poisoning. In survivors of
acute poisoning, memory loss, ataxia, tremor, foot drop and
blindness can occur. Complete recovery takes months and
can be interrupted by relapses. Limited data are available on
the chronic effects on human reproduction (menstrual cycle,
male potency and sperm count disorders). Thallium crosses
the placental barrier [31,39].
Hemochromatosis, hemosiderosis, polycythemia, and
iron-loading anemias (such as thalassemia and sickle cell
anemia) are conditions involving excessive storage of iron.
Excess iron levels are linked to diabetes, cancer, increased
risk of infection, systemic lupus erythematosus, exacerbation
of rheumatoid arthritis, and Huntington’s disease. Great
concern has surrounded the possibility that excess storage of
iron in the body increases the risk of heart disease [35,36].
In the case of iron poisoning and overload (especially in
iron-loading anemias), chelation is the mainstay of therapy,
with deferoxamine (DFO) and deferiprone (L1) as the most
prominent chelators [36].
2.7. Copper
Copper occurs in the environment by natural sources
(windblown dust, volcanoes, decaying vegetation, forest
fires and sea spray) and by anthropogenic emissions (from
copper mines, sewage sludge, smelters, iron foundries,
power stations, municipal incinerators). Copper is widely
used in cooking utensils, water distribution systems,
fertilizers, bactericides, fungicides, algaecides and
antifouling paints, and in industry (an activator in froth
flotation of sulfide ores, production of wood preservatives,
electroplating, azo-dye manufacture, a mordant for textile
dyes, in petroleum refining and the manufacture of copper
compounds). For non-occupationally exposed humans, the
major route of exposure to copper is oral [37].
Therapies of thallium intoxication include prevention of
thallium absorption and reabsorption in the intestines by
administration of Prussian blue (potassium ferric hexacyano
ferrate(II)) [40,41].
2.9. Arsenic
Arsenic has a long history as a human poison. Its very
name has become synonymous with poison as it was the
factual or suspected favorite poison for political
assassinations. In nature, arsenic exists in the metallic state
in 3 allotropic forms (alpha or yellow, beta or black, gamma
or gray), and several ionic forms. Arsenic has been used as a
medicinal agent, a pigment, a pesticide, and an agent of
criminal intent. It is typically considered a heavy metal and
shares many toxic characteristics with other heavy metals
(e.g. lead, mercury). Adults may be exposed through work
in a metal foundry, mining, glass production, or
semiconductor industry. Arsenic is found in certain water
supplies, seafood, glues, pigments, and cigarette smoke.
Today, arsenic poisoning occurs through industrial exposure,
from contaminated wine or illegally distilled alcohol
beverages or because of malicious intent. The possibility of
heavy metal contamination of herbal preparations and so-
called nutritional supplements must also be considered.
Children may encounter accidentally arsenic trioxide as a
rodenticide [8,21,42].
Copper is an essential element and adverse health effects
are related to either deficiency or its excess. When copper
homeostatic control is defective and/or its intake excessive,
copper toxicity may occur. Effects of occasional single
(suicidal or accidental) oral exposure include gastrointestinal
symptoms, and potentially fatal hemolytic anemia and
kidney failure. Gastrointestinal effects and liver failure has
been reported following chronic ingestion of copper. Dermal
allergic responses are possible in sensitive individuals
[31,37].
An apparent disorder in copper homeostasis is Wilson’s
disease (hepatolenticular degeneration), a condition with a
well-defined genetic basis that leads to progressive
accumulation of copper with fatal outcome, if untreated.
There are several other serious conditions where copper
accumulates in the liver such as in patients on chronic
hemodialysis, subjects with chronic liver disease and
conditions related to excess copper in the liver in early
2778 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
Inorganic forms of arsenic are more toxic than organic
forms. The trivalent forms are more toxic and react with
thiol groups, while the pentavalent forms are less toxic but
uncouple oxidative phosphorylation. Very few organ
systems escape the toxic effects of arsenic. It is also listed as
a confirmed human carcinogen, based on the increased
prevalence of lung and skin cancer observed in human
populations with chronic exposures, primarily through
industrial inhalation [42-44].
to ensure high resistance to corrosion and temperature.
Nickel alloys and platings are used for example in vehicles,
coinage, household appliances, armaments, tools, and
electrical equipment [51]. In the general population, food,
drinking water, contaminated air, including tobacco smoke,
and skin contact with metals containing nickel (such as
coins or jewelry), are the main sources of exposure. Dietary
intake of nickel greatly varies, depending on dietary habits,
since certain types of food, such as cocoa, soybeans, some
legumes, oatmeal, and various nuts, contain high nickel
concentrations. Nickel can also be released in food from
kitchen utensils. Implants and prostheses, radiographic
contrast media and intravenous or dialysis fluids present
iatrogenic sources of exposure [52,53]. Allergic dermatitis is
the most common form of nickel toxicity in humans. Long-
term exposure to nickel in a professional environment, such
as nickel refineries or nickel-processing plants, can result in
chronic bronchitis and reduced lung function, as well as
increased incidence of cancers of the lung and paranasal
sinuses [53]. In professional settings, the most acutely toxic
nickel compound is nickel carbonyl. Inhalation of nickel
carbonyl may cause general symptoms and pulmonary
changes that resemble viral pneumonia, with pulmonary
hemorrhage, edema, and cellular derangement. Damage to
the liver, kidneys, adrenal glands, spleen, and brain is also
possible [51]. Cases of nickel poisoning have also been
described in chronic dialysis patients where nickel-
contaminated dialysate was used [54], and in workers in an
electroplating plant who accidentally drank nickel sulfate and
chloride contaminated water [55].
Chelation therapy is imperative in all symptomatic
patients. However, the use of chelators in patients exposed
to arsine gas is controversial. It was found that the most
efficacious chelators in arsenic poisonings are meso-DMSA
and DMPS, although less efficient chelators, BAL and
DPA, are still in use [28].
2.10. Chromium
Chromium enters the air, water, and soil mostly in the
chromium(III) (trivalent) and chromium(VI) (hexavalent)
forms, as a result of natural processes and human activities.
One can be exposed to chromium by breathing air, drinking
water or eating food containing chromium, or through skin
contact with chromium or chromium compounds [45].
Higher-than-normal exposure to chromium is possible in
areas near industries or busy roadways through air and water
emissions, and considerably high levels of chromium are
present in tobacco products [8,45]. Metallic chromium and
the trivalent and divalent chromium compounds are
considered less toxic than hexavalent chromium compounds
[31]. Chromium(III) is an essential nutrient for humans. It
occurs naturally in many fresh vegetables, fruits, meat,
yeast, and grain, and has been used as a dietary supplement.
Inorganic chromium compounds are poorly absorbed in the
gastrointestinal tract in animals and humans to the extent of
0.4-3% or less, regardless of dose and dietary chromium
status [46-48]. Trivalent chromium may cause dermatitis in
sensitive persons, mainly professionally exposed, but to a
lesser extent then hexavalent chromium [31,49].
Recommended chelation therapy for nickel poisoning is
sodium diethylcarbodithioate (DDTC). The use of DDTC
was considered beneficial in a large number of anecdotal
reports of human poisoning, although there are no
adequately controlled human trials to support its
effectiveness and lack of toxicity [31]. Disulfiram, another
nickel-chelating agent, was used in nickel dermatitis [56-58]
and in the case of nickel carbonyl poisoning [59]. However,
due to its hepatotoxicity and possible redistribution of
nickel to the brain, its use in both indications is still
controversial [58,60].
Hexavalent chromium compounds can exert serious toxic
effects. Inhalation exposure may cause nasal irritation,
asthma attacks in sensitive persons, and lung cancer in
workers with long-term exposure. Accidental or intentional
swallowing of larger amounts of hexavalent chromium
compounds causes stomach upsets and ulcers, convulsions,
kidney and liver damage, and even death. Dermal exposure
may cause allergic manifestations and sweat-gland lesions.
Certain hexavalent compounds (calcium chromate,
chromium trioxide, lead chromate, strontium chromate, and
zinc chromate) are known human carcinogens. There is no
evidence that chromium exposure can be related to birth
defects or other developmental effects in people, although
trivalent and hexavalent chromium compounds were found
to be embryotoxic and teratogenic in animals [31,45,49,50].
2.12. Platinum
In comparison to other elements, platinum is rare in the
environment. Exposure to platinum salts is mainly
occupational, primarily in platinum metal refineries and
catalyst manufacturing plants. It is also used as a cancer
therapeutic, in the form of cis-diaminedichloroplatinum(II)
(cisplatin). Beside usage as an automobile exhaust gas
catalyst, platinum is also used in jewelry, alloys in
dentistry, neurological prostheses, and pacemakers [61].
Clinical effects of occupational exposure to platinum salt are
mainly manifested as hypersensitivity and allergic disorders,
such as urticaria, contact dermatitis, and respiratory
disorders, from sneezing to severe asthmatic symptoms.
Hexachloroplatinic acid and some chlorinated salts are
mainly responsible for allergic reactions, while metallic
platinum seems to be non-allergenic [61]. The use of
cisplatin and other platinum-containing antineoplastic drugs
such as oxaliplatin or nedaplatin, is, unfortunately,
associated with serious toxic side effects, primarily
gastrointestinal symptoms, nephrotoxicity, neurotoxicity,
So far no recommendation for chelation therapy in
chromium intoxication is available; all data are either
experimental or unproved for human use.
2.11. Nickel
Nickel is a ubiquitous trace element, widely used for the
production of stainless steel and other nickel alloys, in order
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2779
ototoxicity, and hematological disorders. It seems that some
toxic effects are age-related, being less prominent in younger
age [31].
intraperitoneal injection. Acute LD
50
values of BAL and
some other clinically used chelators, as well as several
experimental chelating agents, applied intraperitoneally or
orally in rodents, are shown in Table 2. BAL has a number
of toxic side effects. Deep intramuscular injections of BAL
are painful, not only because of needle puncture, but also
because of painful spreading of BAL in the tissues [115].
Pain can be alleviated with a prior injection of procaine into
the site of BAL application [124]. The target organs for
BAL toxicity are the kidneys, cardiovascular and central
nervous systems. The incidence of adverse effects is
substantial. The most common adverse effects include
gastrointestinal symptoms, such as nausea and vomiting,
dose-related hypertension, and tachycardia. Nephrotoxicity,
seizures, hyperpyrexia, sweating, lacrimation and rhinorrhea,
urticaria, and paraesthesiae are also described [41]. BAL
should not be used in children who have an allergy to
peanuts or peanut products, since it is usually injected
dissolved in peanut oil due to its liposolubility and
instability in aqueous solutions [41]. It should not also be
administered to patients with glucose-6-phosphate
dehydrogenase deficiency due to risk of hemolysis [125].
BAL is contraindicated in patients with hepatic
insufficiency, unless related to postarsenical jaundice, and
should be discontinued or used at a reduced dosage and with
extreme caution in patients developing acute renal
insufficiency [41,125]. Contraindications for BAL
administration are also poisonings with alkyl mercury,
cadmium, iron or selenium. It has been observed that BAL
forms a toxic chelate with iron. Iron supplementation,
therefore, should not be applied during BAL treatment
[126,127]. Selenium is also more toxic in a complex form
with BAL [128], although at least in one case of human
poisoning with sodium selenate, BAL treatment was applied
with good results [129]. Treatment with BAL in methyl
mercury poisoning may exacerbate neurologic symptoms
[20]. It was found in animals that BAL facilitates the uptake
of cadmium by the kidneys, resulting in fatal kidney damage
[130].
There is no routinely recommended chelation therapy for
platinum exposure, although limited human data suggest
DDTC as possibly effective treatment in patients receiving
high-dose cisplatin therapy, in order to alleviate toxic side
effects, without significantly affecting cisplatin
antineoplastic properties [62].
3. CHELATORS IN CLINICAL USE
Chelating agents have been used as antidotes for metal
intoxication in humans since the Second World War. One of
the first applied chelators was British Anti-Lewisite (BAL),
a chelating drug developed during the Second World War in
England as an antidote for the arsenic containing warfare
agent lewisite. After the war, BAL was used to sequester
arsenicals, gold, and mercury [1]. Calcium disodium
ethylenediaminetetraacetate (CaNa
2
EDTA), deferoxamine,
and D-penicillamine were introduced in clinical use as well.
Today, these drugs, together with a wide array of newly
synthesized chelating agents, are in clinical use or under
preclinical or clinical investigations for treatment of
intoxication or overload caused by various transition metals.
3.1. Dimercaprol (BAL)
British-Anti-Lewisite (BAL) or dimercaprol is 2,3-
dimercapto-1-propanol. It is a lipophilic drug, which can
enter the cells and is distributed both intracellularly and
extracellularly [115]. It contains two sulfhydryl groups that
form a stable, relatively nontoxic five-membered heterocyclic
chelate ring with heavy metals. The most stable complexes
are formed with Class B metals, including arsenic, mercury,
and gold.
BAL is more effective when given soon after exposure
because it more efficiently prevents inhibition of sulfhydryl
enzymes than reactivates them [41,116]. It is applied by
deep intramuscular injections of 2 to 5 mg/kg per dose, one
to four times a day, up to 10 days [41]. Absorption from the
injected site is rapid and peak serum concentrations occur
within 30 to 60 minutes [28,41]. Repeated daily dosing is
required due to its rapid elimination in the urine and bile,
which is complete within 4 hours. It is metabolized to an
oxidized form of BAL, which is an active metabolite
detectable in the urine [115].
Data on use of dimercaprol during pregnancy are limited.
Embryotoxic effects of BAL in mice were found at a dose of
125 mg/kg [131], while lower doses did not affect in utero
development in mice [132,133]. In humans, anecdotal cases
of BAL treatment of Wilson's disease, and lead and
inorganic arsenic poisoning during pregnancy have been
described, with delivery of apparently normal infants
[41,134,135].
The available literature on clinical treatment of cases of
acute metal intoxication indicate that the older, more toxic,
and sometimes even less efficacious chelator BAL is still
used in many cases. In the meantime, more efficient, safe,
more stable, and cheaper preparations for oral or parenteral
use have been introduced (like meso-DMSA and DMPS).
Therefore, it is recommended that BAL should be replaced
with its less toxic derivatives or other efficient chelating
drugs whenever possible [28].
BAL is an efficient chelator in acute intoxication with
arsenic, inorganic or elemental mercury, gold and inorganic
lead. No efficacy was found for poisonings with organic
mercury or lead compounds [116]. It has been reported that
BAL treatment was successful in certain cases of arsine,
antimony, bismuth, copper, or nickel poisoning, while
experiences with BAL therapy in chromium poisoning are
controversial [41,102,117-121]. BAL could be used in the
treatment of Wilson's disease for decreasing copper body
burden in patients intolerant to DPA and trientine [84].
However, the use of the BAL derivatives meso-DMSA and
DMPS are more appropriate since they are as effective and
less toxic than BAL. BAL is the most toxic commercially
available chelating drug. Its LD
50
is 0.85 mmol/kg in rats
[122] and about 1.5 mmol/kg in mice [123] after
3.2. meso-2,3-Dimercaptosuccinic Acid (SUCCIMER,
meso-DMSA)
Succimer, meso-2,3-dimercaptosuccinic acid (meso-
DMSA), is an orally active and less toxic analogue of BAL.
2780 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
It is a weak acid with four ionizable hydrogens, and at
physiological pH (7.4) it is ionized and does not enter the
cells [136]. It is shown that toxic metals can coordinate with
one of the sulphur and one of the oxygen atoms in meso-
DMSA as in the case of lead and cadmium ions, or with
each of the two sulphur atoms as in the case of mercury
[137,138].
Meso-DMSA is an efficient chelator in the treatment of
lead poisoning both in children and adults [138,142-148]. It
has also been successfully used for elemental, inorganic and
organic mercury, arsenic, antimony, and copper chelation in
humans [136,138,149-152]. In animal experiments, meso-
DMSA was an efficient chelator for gold [153-156] and
nickel [104,105]. Controversial results were obtained for
cadmium [73,75,157,158], thallium [136,159], and
platinum, either for tissue platinum reduction, or for
platinum nephrotoxicity [160-163]. Graziano and coworkers
[163], for example, found that although meso-DMSA
treatment reduced renal platinum concentration in rats by
50%, it failed to prevent renal toxicity. One of the
advantages of meso-DMSA is that it apparently does not
form toxic complex with iron like BAL, which opens the
possibility for iron supplementation during the chelation
treatment [127]. This is especially important for anemic and
malnourished patients.
Table 2. Acute LD
50
Values of Several Clinically Used and
Experimental Chelating Agents Given Parenterally
(Intraperitoneally) in Rodents (Rats and Mice)
Chelating agent LD
50
(mmol/kg) Reference
Chelating drugs
BAL 0.85 [122]
DMPS 5.2 [68]
meso-DMSA 13.6
16.2
>18.7
[68,
122,
164]
Toxicity of meso-DMSA is low, with LD
50
of more than
18 mmol/kg when given in rats intraperitoneally (Table 2)
[164]. Contraindication for meso-DMSA therapy is
hypersensitivity to the drug. Precautions are necessary in
patients with renal or liver impairment, neutropenia, and
glucose-6-phosphate dehydrogenase deficiency [41,165].
Side effects of meso-DMSA treatment are mild and transient
in the majority of cases. The most common adverse effects
are gastrointestinal complaints, such as abdominal cramps,
nausea, vomiting, and diarrhea. Other side effects include
transient and reversible increase in liver function tests,
various dermatologic (rash, pruritus, urticaria,
mucocutaneous eruptions), neurologic (drowsiness,
dizziness, neuropathies, headache, paresthesias), and
musculoskeletal effects (back pain, rib pain, kneecap pain,
leg pains). Blood dyscrasias, such as thrombocytosis,
eosinophilia, decreased hemoglobin levels and neutropenia,
as well as cardiac arrhythmias, are rarely reported [41].
Concerning essential metal chelation, clinical studies
indicate that meso-DMSA in therapeutic doses has no
significant effect on renal excretion of iron, calcium or
magnesium. Zinc excretion is, however, doubled.
Nevertheless, these effects of meso-DMSA on essential
mineral excretion are minor compared to CaNa
2
EDTA,
especially in elimination of copper, iron, and zinc [139].
CaNa
3
DTPA 6.9 [122]
CaNa
2
EDTA 16.4 [122]
Trientine 3.2; 10.9-17.1* from [31]
DPA >8*
>16.8*
from [28,
357]
L1 4.3-5.0; 7.2-14.4* [36]
DFO 2.6 from [31]
Experimental chelating agents
racemic-DMSA >8 [164]
Diisopropyl DMSA 3.8 [310]
Mi-ADMS >2.0 from [311]
MGDTC >26.6 [312]
BGDTC 11.1 [313]
MeOBGDTC 10.0 [123]
C9G2DTC >4.0 [123]
* Given orally.
The usual dose of meso-DMSA for the treatment of lead
poisoning in children is 10 mg/kg every 8 hours for 5 days,
followed by 10 mg/kg every 12 hours for an additional 14
days; a course of therapy lasts a total of 19 days [41]. In
adults, 30 mg/kg/day for 5 days seems to be the optimal
dose [139].
Developmental toxicity of meso-DMSA was observed in
mice [166]. The no observable effect level (NOEL) for
maternal and developmental toxicity was less than 100 mg
meso-DMSA/kg/day in pregnant mice [167]. It is suggested
that embryofetotoxic effects are due to altered fetal zinc and
copper metabolism [131,168]. meso-DMSA therapy in
pregnant women with serious lead poisoning did not cause
some identifiable birth defect in newborns [135].
Meso-DMSA is rapidly but incompletely absorbed after
oral administration, with peak plasma levels occurring
approximately 1 to 2 hours after administration. It is
extensively metabolized and excreted in the urine
(approximately 25% of a dose) and in feces. Fecal excretion,
however, probably represents unabsorbed drug [41]. Peak
urinary excretion occurs between 2 and 4 hours after dosing.
In humans, more than 90% of urinary meso-DMSA is in the
form of mixed DMSA-cysteine disulfide conjugates, and the
rest is excreted unchanged [140]. Meso-DMSA elimination
half-life is about 2 hours, but longer half-life values (up to 2
days) are also documented [141].
With respect to oral administration of meso-DMSA, the
question emerged of whether chelation therapy with meso-
DMSA could be performed in cases where concomitant lead
exposure cannot be positively excluded. Some human and
animal studies aroused concern that treatment with meso-
DMSA might increase lead absorption if administered
during oral lead exposure, and therefore should be avoided
until cessation of exposure [169-171]. However,
experimental data on mature and suckling rats, as well as on
juvenile monkeys, indicate that meso-DMSA is a safe lead
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2781
chelator even when challenged with ongoing lead exposure
[172-177].
3.4. D-Penicillamine (DPA) and N-Acetyl-D-Penicillamine
(NAPA)
Further questions regarding lead chelation in general
include dilemma on benefits and adverse effects of oral
chelation treatment in children with moderate lead exposure.
Recent clinical trials showed that meso-DMSA treatment in
preschool children with moderately elevated blood lead
levels (20 to 44 µg/dL) did not have beneficial effect on
growth, and did not improve the cognitive, behavioral, or
neurophysiological functions [178-180]. Until new evidence
emerges, it is recommended that chelation treatment is
generally not justified in children with blood lead levels
below 45 µg/dL [179].
These drugs are degradation products of penicillin. They
are applied orally, and D-penicillamine (DPA) can also be
administered intravenously [28]. Thiol group seems to be
the most important functional group for chelation of metal
atoms [199].
Gastrointestinal absorption of DPA is approximately
50% in humans, ranging from 40% to 70% of an oral dose
[199]. It seems that it is predominantly distributed
extracellularly [28]. Peak plasma concentrations are reached
in 1 to 4 hours after oral dosing. DPA is not significantly
biotransformed. Minimal amounts are hepatically
metabolized to disulfides, while most of the drug is excreted
unchanged in the urine, which is the main route of
elimination [41,199]. Elimination half-life of DPA ranges
from 1 to more than 7 hours [41]. Metabolism of N-acetyl-
D-penicillamine (NAPA) is similar to that of DPA [28].
3.3. 2,3-Dimercaptopropane-1-Sulphonic Acid (DMPS)
Another BAL derivative is DMPS, sodium salt of 2,3-
dimercaptopropane-1-sulphonic acid, another orally active
chelating agent. It is distributed extracellularly and, to a
lesser extent, intracellularly [115,181]. There is some
evidence that DMPS enters the intracellular compartment via
the organic anion transport pathway [182].
DPA is used in treatment of Wilson's disease [38,83] and
heavy metal poisoning, since it is an effective chelator of
copper [200-202], lead [203], gold [204], mercury [94,205],
and zinc [201]. DPA was found to be beneficial in arsenic
poisoning [28,31,206]. It is also used in cystinuria [207],
and rheumatoid arthritis patients [208]. Oral doses of DPA
reach 2000 mg/day in the treatment of Wilson's disease and
lead poisoning.
Oral bioavailability of 39% was found for the parent drug
in humans [183]. DMPS is rapidly and extensively
metabolized to disulfide forms, acyclic and cyclic disulfides
[183,184]. Peak plasma concentration of total (parent and
metabolized) drug after oral dosing in humans is achieved
after approximately 3.5 hours, with elimination half-life of
about 10 hours [185]. When DMPS was administered
intravenously, elimination half-life of the parent drug was
1.8 hours, while elimination half-life of total DMPS (parent
and metabolized) was 20 hours [183]. Complexes of DMPS
with heavy metals are primarily excreted renally in humans
[41,184], while in experimental animals a great proportion is
also excreted by bile [186]. According to animal data,
DMPS does not redistribute lead to the brain [187].
NAPA is found to be successful in the treatment of
mercury poisoning [94,209]. In the Iraq outbreak of methyl
mercury poisoning in the winter of 1971-1972, due to
fungicide-treated wheat, NAPA was equally effective as
DPA, although DMPS was the most effective of the used
chelating agents, according to half-life of mercury in the
blood [94]. Its mercury chelating properties have been
confirmed in animal experiments of inorganic and methyl
mercury poisoning, although with lower efficacy than those
of meso-DMSA or DMPS [27,95]. Oral doses of NAPA
range from 1000 to 2000 mg/day [41].
In heavy metal poisoning in adults oral daily doses of
200 to 400 mg and intravenous doses of 250 mg every 4 to
6 hours have been used, while pediatric dosing is not yet
clearly established [41]. DMPS has been successfully used
for the treatment of poisonings with arsenic [184,188],
bismuth [189], copper [190,191], lead [192], and mercurial
compounds [94,140,193,194]. Based on the observation of
Guha Mazumder and coworkers [195], it seems that in
chronic arsenic poisoning DMPS is superior to meso-
DMSA. DMPS is also used as a provocative (challenge) test
for arsenic [196,197] or mercury [198] intoxication or
exposure. DMPS is approved for the treatment of arsenic
intoxication in the People's Republic of China, and for the
treatment of mercury and lead poisoning in Germany.
The toxicity of DPA is relatively low (Table 2).
However, it may cause serious adverse effects, including
hematologic disorders, such as thrombocytopenia, and rarely
aplastic anemia, lymphocytopenia, agranulocytosis, and
leukopenia [41]. Interestingly, thrombocytopenia and some
other adverse effects of DPA treatment are more common in
patients with rheumatoid arthritis than in those with
Wilson's disease. It appears that there is an association
between certain HLA (human lymphocyte antigens) markers
in rheumatoid arthritis patients and incidence of the
described adverse effects [210,211]. Other side effects
include gastrointestinal disorders, hepatotoxicity,
nephropathy, neurologic disorders, such as optic neuritis and
seizures, and hypersensitivity and autoimmune disorders,
like bronchospasm, pemphigus, rash, polymyositis,
myasthenia gravis, and lupus-like syndrome [41,212].
Transient worsening of neurologic symptoms at the
beginning of the treatment with DPA, as well as with
triethylenetetraamine (Trientin), is not uncommon
[83,213,214]. DPA is contraindicated in patients with
penicillin allergy. Avoidance of DPA is recommended in
patients with moderate to severe renal failure and it should
not be coadministered in patients who are receiving gold
DMPS is generally a well-tolerated chelating drug.
Dosage adjustments should be made in patients with renal
impairment, and it is contraindicated in the case of allergy to
DMPS. The most frequent adverse effects include headache,
fatigue, nausea, taste impairment, pruritus, and rash [41].
No developmental toxicity of DMPS was found in
experimental animals (rats and mice) up to peroral daily dose
of 630 mg/kg [131,162]. There are no data concerning
potential effects on human pregnancy.
2782 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
therapy, antimalarial or cytotoxic drugs, phenylbutazone, or
oxyphenbutazone. It is reported that concurrent therapy with
gold and DPA resulted in increased rate of rashes and bone
marrow depression [41,215].
zinc trisodium diethylenetriaminepentaacetate (CaNa
3
DTPA
and ZnNa
3
DTPA, respectively) are parenterally administered
chelating agents as they have a low gastrointestinal
absorption. Since EDTA has high affinity for calcium, it
may cause tetany due to rapid decrease in serum calcium.
Therefore, it is always applied as calcium salt CaNa
2
EDTA.
Both CaNa
2
EDTA and calcium or zinc salt of DTPA are
distributed mainly in extracellular fluid [28]. They are not
significantly metabolized, and are almost entirely excreted in
the urine, unchanged [28,41]. The elimination half-life of
CaNa
2
EDTA in adults is 1.4 to 3 hours, and it is excreted
within 24 hours [41,219]. The elimination half-life of
CaNa
3
DTPA is about 35 minutes, and it is almost
completely excreted within 12 hours [28,220].
According to some case reports, DPA seems capable of
inducing teratogenic effects in humans [166,216] and
teratogenicity of DPA has also been observed in experiments
with animals [166,217]. There are no available data on
developmental toxicity of NAPA.
Due to high affinity for lead, CaNa
2
EDTA and BAL
were for many years the mainstay of therapy for lead
intoxication. However, due to the necessity of parenteral
administration, hospitalization is mandatory for effective
treatment with these agents. Three orally efficient lead
chelators, meso-DMSA, DMPS and DPA, are today
available and can be used on an outpatient basis. Moreover,
meso-DMSA and DMPS are less toxic than BAL and
CaNa
2
-EDTA, and do not redistribute lead to the brain
[187,218]. Apart from its oral availability, the advantage of
DPA is that it, seemingly, produces less rebound effect than
treatment with either CaNa
2
EDTA or meso-DMSA, probably
because of the continuity of DPA treatment [203].
Nevertheless, due to lesser efficacy and increased adverse
reactions and precautions associated with DPA, meso-DMSA
and DMPS are still the drugs of choice when oral chelation
therapy is indicated in lead-poisoned persons.
CaNa
2
EDTA forms stable complexes with many metals,
and for a number of years it has been in clinical use for lead
intoxication, alone or in combination with BAL. It has also
been used in the lead mobilization test [126,221]. Several
clinical cases with successful CaNa
2
EDTA treatment for
manganese [222-225] and zinc [226,227] poisoning are
described in the literature. Animal studies suggest that
CaNa
2
EDTA is an efficacious chelator in cobalt intoxication
[228-230]. CaNa
2
EDTA is administered intravenously or by
deep intramuscular injections in usual doses of 50 to 75
mg/kg/day for adults, and 1000 to 1500 mg/square
meter/day for children during 5 days, followed by a two-day
interruption, with a repeated course(s) when necessary [41].
3.5. Ethylenediaminetetraacetic Acid (EDTA) and
Diethylenetriaminepentaacetic Acid (DTPA)
Contraindications for CaNa
2
EDTA therapy are anuria or
active renal disease, hepatitis, and hypersensitivity to edetate
products [41]. Adverse effects of CaNa
2
EDTA could be
potentially serious. The main toxic side effect is
nephrotoxicity, which is usually reversible following
cessation of therapy and can be reduced by assuring adequate
Calcium disodium ethylenediaminetetraacetate
(CaNa
2
EDTA, calcium edetate) and calcium trisodium or
Fig. (3). The influence of age on efficiency of CaNa
3
DTPA treatment in decreasing whole-body and organ retention of
115m
Cd in rats
of different age.
One, 2, 8, and 26 weeks old Wistar rats were intraperitoneally (i.p.) exposed to radioactive Cd (dose of 0.35 mCi) and received
aproximately 1.75 mg Cd/kg body wt. The treated group was administered 600 µmol/kg CaNa
3
DTPA i.p., and the untreated group
0.9% saline i.p. The results of radioactivity measurement on the 6
th
day after treatment are presented as percent of values in the
untreated group [314].
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2783
intake of fluids during the CaNa
2
EDTA treatment [126,231].
However, renal tubular injury is dose-related, and if
maximum recommended daily dose (75 mg/kg) is exceeded,
it could be fatal [232]. Other adverse effects, like headache,
fatigue, fever, myalgia, increased urinary frequency,
hepatotoxicity, changes in electrocardiogram (ECG) and
gastrointestinal symptoms are also described [41]. According
to experimental data, CaNa
2
EDTA causes internal
redistribution of lead during the therapy. Cory-Slechta and
coworkers [233] observed that in rats previously exposed to
lead, CaNa
2
EDTA treatment mobilizes lead from bone and
kidney and increases lead in the brain and liver. Although
brain and liver lead levels declined after treatment, there was
no net loss of lead in either organ. Based upon these
findings, it can be concluded that CaNa
2
EDTA is not
recommended as a monotherapy in patients with high blood
lead levels. In such cases, combined BAL and CaNa
2
EDTA
treatment is usually prescribed [221].
toxic effects occurred in the kidney, intestinal mucosa, and
liver [28,220]. Nevertheless, when CaNa
3
DTPA was
administered in recommended doses in humans, no serious
toxicity was observed in a large number of cases (over 4500)
[220,243]. Repeatedly administered CaNa
3
DTPA, with short
intervals for recovery, could cause nausea, vomiting,
diarrhea, chills, fever, pruritus, and muscle cramps during
the first 24 hours [243].
CaNa
3
DTPA had teratogenic effects in mice and dogs,
even at doses comparable to those used in humans
[243,244]. It is proposed that embryo/fetotoxic effects are
caused by zinc and manganese depletion due to CaNa
3
DTPA
treatment. On the other hand, ZnNa
3
DTPA also induced
teratogenicity, but at a dose 16 times higher than the lowest
observed teratogenic dose of CaNa
3
DTPA [131]. Therefore,
it is generally agreed that if DTPA has to be applied during
pregnancy, it should be in the form of ZnNa
3
DTPA.
3.6. Deferoxamine (DFO)
Zinc depletion caused by CaNa
2
EDTA therapy is usually
rapidly reversible, although zinc could be supplemented after
chelation therapy [31]. Enhanced excretion of zinc by
CaNa
2
EDTA, however, is considered responsible for
teratogenic effects of CaNa
2
EDTA observed in rats, which
occurred at doses comparable to those used in metal
poisonings in humans [234,235]. Although there are reports
of fetal tolerance of CaNa
2
EDTA treatment in humans
[135,236,237], literature data for human pregnancies are very
limited.
Deferoxamine is a trihydroxamic acid, siderophore
secreted by the fungus Streptomyces pilosus in order to
provide iron from the environment in the amount necessary
for its growth. Its high affinity for iron and low affinity for
other essential metals, such as calcium, magnesium, copper
and zinc, makes it a suitable iron-chelating drug [1].
DFO has low oral availability, and it is therefore
administered parenterally [28]. It is metabolized by plasma
enzymes, and major metabolite is ferrioxamine, formed
when DFO binds the ferric cation [245]. The volume of
distribution is extracellular [28]. DFO is excreted primarily
in the urine. The elimination half-life of DFO and its
metabolite, ferrioxamine, is 3 to 6 and 4 to 6 hours,
respectively. In healthy subjects, serum elimination pattern
is biphasic, 1 to 2 hours in the fast phase and about 6 hours
in the slow phase. In hemochromatosis patients, single-
phasic serum level decline for DFO and ferrioxamine was
observed, with half-life of 5.6 and 4.6 hours, respectively.
The elimination half-life of DFO in thalassemic patients is
about 3 hours [245,246].
Calcium or zinc salts of DTPA have been used as
chelating agents for plutonium and other transuranic
elements such as americium, californium, and curium [220].
DTPA is also used as a chelating vehicle in nuclear medicine
studies but at lower concentrations [238]. CaNa
3
DTPA is
shown to be an effective antidote for cobalt [228,229] and
zinc poisoning in an experimental model [239]. It has also
been tested as a cadmium chelator in experimental animals,
showing some effectiveness, especially after acute cadmium
exposure [70,240-242]. It was, however, less effective in
comparison to carbodithioates [71,72].
Calcium or zinc trisodium DTPA is administered
intravenously, but for no longer than 2 hours, or by
inhalation in a nebulizer [220,243]. It may also be
administered intramuscularly, although injections are
painful. The usual, widely accepted dose of CaNa
3
DTPA or
ZnNa
3
DTPA is 1 g per day in a single dose, 2 to 5 days a
week. Dosage is adjusted according to indication.
Fractionizing the daily dose is not recommended for
CaNa
3
DTPA due to increased toxicity [220]. CaNa
3
DTPA
can deplete zinc in the body, which can be prevented by zinc
supplementation or by administering zinc salt of DTPA.
However, since CaNa
3
DTPA is much more effective than
ZnNa
3
DTPA for initial chelation of transuranics, it is still
recommended at the beginning of treatment and in cases
with large body burden with transuranic elements. In
prolonged therapy, there are suggestions that ZnNa
3
DTPA
can be used instead of calcium salt of DTPA [220,243].
DFO is an effective chelating drug for acute iron
intoxication, chronic iron overload, and aluminum toxicity.
It has to be applied parenterally, by slow intravenous
infusions, intramuscular or subcutaneous injections,
intraperitoneally during peritoneal dialysis, or, rarely, in a
form of suppositories [28,247,248]. Dosing of DFO depends
on indication, severity of clinical symptoms, and degree of
iron overload. It was suggested that the maximum
recommended daily dose of DFO is 50 mg/kg, since it is
observed that most toxic effects of deferoxamine appear
when this dose is exceeded, or even with smaller doses in
patients with modestly elevated iron body burden [249]. It
has been proposed that toxic effects of DFO occur only when
the drug penetrates sensitive cells in amounts greater than
needed for chelation of iron cell deposits. Toxicity is
thought to be caused by free DFO, which remains after all
the available iron in affected cells has been chelated.
Therefore, iron overloaded cells are protected, while cells
with a lower amount of chelatable iron, such as in
moderately iron-overloaded patients, are at greater risk [250].
CaNa
3
DTPA is contraindicated in children, during
pregnancy, in patients with renal disease, and in cases with
bone marrow depression. In such situations, ZnNa
3
DTPA is
recommended [243]. According to animal data, CaNa
3
DTPA
is more toxic than CaNa
2
EDTA (Table 2). The most serious
DFO therapy is contraindicated in cases of anuria or
severe renal disease, or in cases of allergic reaction to DFO
2784 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
[41]. Adverse effects of DFO therapy include hypotension,
especially with high infusion rate, respiratory distress
syndrome after prolonged, high-dose administration,
thrombocytopenia, tachycardia, tinnitus and hearing loss,
retinal changes and vision loss, severe allergic reactions, and
even shock. During chronic therapy, Yersinia enterocolitica
infection, sepsis, and systemic fungal infections, such as
mucormycosis, were observed [34]. It is proposed that the
presence of DFO in patients with iron overload increases the
virulence of certain microorganisms, such as Yersinia
enterocolitica. This organism is iron-dependent, but cannot
synthesize siderophores. DFO, as an iron-chelating agent,
supplies the bacteria with iron, promoting their growth.
Other mechanisms that decrease immunological competence
in DFO-treated patients, are also included [34]. In children
with thalassemia major, in which chronic DFO therapy
started at a very young age (8 +/- 6 months), stunted growth
with a clinical and radiological rickets-like syndrome and
joint stiffness was reported. If DFO therapy was started after
3 years of age, even large doses did not result in growth
retardation [251]. It has been observed that DFO
administered in patients on chronic dialysis in order to
decrease aluminum concentrations, can precipitate or
exacerbate dialysis-related encephalopathy [252].
and other patients with chronic iron overload, especially in
poor countries. Its oral application should also ensure better
compliance. It is therefore hoped that oral L1 treatment will
improve therapy and prolong life span in these patients
[1,36]. The usual oral daily dose for the treatment of iron
overload is 75 mg/kg, with adjustments according to the
patient's iron overload and general health status [260-262].
Higher doses (larger than 100 mg/kg) were also applied in
order to increase iron excretion [263,264]. Recent
experimental data indicate that oral L1 administration could
also be used in acute oral iron poisoning, for
decontamination of the gastrointestinal tract [265-267]. Oral
L1 treatment in rats orally intoxicated with iron decreased
mortality and iron absorption from the gastrointestinal tract.
L1 also binds copper, aluminum, zinc and some other
metals at a lower affinity than iron [257]. Studies in renal
dialysis patients suggest L1 as an efficient chelator in
aluminum overload [258,268]. Experiments with L1
treatment in aluminum-loaded animals confirmed the
observations in humans [269-273].
Contraindications for L1 therapy are severe liver
dysfunction, existing neutropenia or agranulocytosis, and
allergy to the drug [41]. Adverse effects of L1 are mostly
mild and reversible. They usually depend on dose and
individual sensitivity, and include gastrointestinal
symptoms, transient musculoskeletal and joint pains, zinc
deficiency, weight gain, dry skin and itching,
agranulocytosis, and neutropenia [261,262,264,274].
Agranulocytosis, as the most serious complication of L1
therapy, is, nevertheless, transient and appears in less than
0.6% of treated patients [36]. Another problem is still the
controversial question of whether long-term L1 therapy can
maintain hepatic iron concentrations below hepatotoxic
levels, and is it able to prevent liver fibrosis [275,276]. On
the other hand, there are recent reports that long-term therapy
with L1 provides a greater cardio-protective effect against the
toxicity of iron overload than subcutaneous DFO [277,278].
Use of DFO during pregnancy has not been associated
with developmental toxicity in humans. Review of the
reports on DFO use in various periods of gestation in more
than 40 pregnancies, revealed no toxic or teratogenic effects
[253]. In an animal model, developmental toxicity in mice
was observed, but it appears that it occurred only in the
presence of overt maternal toxicity, suggesting that the cause
of fetotoxicity were toxic effects in pregnant mothers, and
not DFO-related depletion of essential elements in the fetus
[254]. This presumption is supported by the report that DFO
does not cross the placenta in an ovine (sheep) model [255].
3.7. Deferiprone (L1)
Oral administration of L1 produces dose-related
teratogenic effects in the absence of maternal toxicity in mice
and rabbits at doses below 25 mg/kg [131]. In a study on
mice, L1 did not prevent aluminum-induced maternal and
embryo/fetal toxicity [279]. On the contrary, L1 treatment at
a dose of 24 mg/kg in aluminum-exposed animals caused a
more pronounced decrease in maternal body weight gain, as
well as a higher incidence of fetal skeletal changes. Data on
L1 therapy during human pregnancy are not available.
For many years, the one and only chelation therapy for
iron overload and poisoning was parenteral administration of
DFO. Unfortunately, this drug is expensive, and necessitates
slow intravenous or subcutaneous administration over a
period of several hours. Deferiprone (L1), 1,2-dimethyl-3-
hydroxypyrid-4-one, is an oral chelator, discovered by G.J.
Kontoghiorghes as an alternative to deferoxamine for the
treatment of chronic iron overload [256]. L1 forms a neutral
3:1 chelator:ferric iron complex at pH 7.4, and may mobilize
iron from ferritin, hemosiderin, lactoferrin, and diferric
transferrin [257]. 3.8. Triethylenetetraamine (TRIENTINE)
Due to the moderate lipophilicity and low molecular
weight of the drug, absorption from the gastrointestinal tract
is high and rapid, and reaches maximum blood
concentrations within 1 hour [258]. The half-life in the
blood is about 45 minutes to 2 hours. It is metabolized in
the liver mainly by glucuronidation to inactive metabolite,
and the parent drug and metabolite are almost completely
excreted in the urine within 6 and 8 hours, respectively [36].
L1 can permeate the blood-brain barrier [259].
Trientine is an oral chelator, structurally dissimilar from
other known chelating agents [28]. It is a successful copper
chelator, and is used in patients with Wilson’s disease,
usually in penicillamine-intolerant or unresponsive patients
[83,202]. The recommended daily dose is 40 to 50 mg/kg,
up to a maximum of 2 g/day [38,41]. It seems that trientine
exerts a double action in copper metabolism as it increases
the urine copper excretion and decreases the intestinal copper
absorption [280]. Trientine also increases urinary excretion
of iron and zinc in humans [281].
L1 has been approved for treatment of iron overload in
India since 1994, and in the European Union since 1999
[36]. It is less toxic than DFO (Table 2). It is also much less
expensive, and therefore more easily available to thalassemic
Oral bioavailability of trientine is quite low, according to
human and animal data [281,282]. It seems that the
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2785
intestinal uptake mechanism of trientine is similar to that of
physiological polyamines, spermine and spermidine [283].
After absorption it is rapidly metabolized to 1-N-
acetyltriethylene tetraamine (acetyltrien), which has
significantly lower chelating activity than trientine. Most of
the parent drug is excreted within the first 6 hours, while the
metabolite, acetyltrien, is excreted over a period of 26 hours
[281]. There are indications that trientine is excreted actively
by proximal tubules of the kidney [282].
NAC is well absorbed from the gastrointestinal tract. Its
oral availability from tablets ranges from 6% to 10%
[295,296]. After an oral dose, peak plasma concentration of
NAC is achieved within 1 to 2 hours, and terminal
elimination half-life is about 6 hours [296]. Volume of
distribution is mainly extracellular [295,296]. It is assumed
that NAC is rapidly metabolized in the liver, and that the
major excretory product is inorganic sulphate [297]. Only
about 30% of the drug is excreted renally [295,297].
Contraindication for trientine therapy is hypersensitivity
to this drug. Drug has a low toxicity, with LD
50
of about 11
and 17 mmol/kg after oral administration in mice and rats,
respectively (Table 2) [31]. Adverse effects are rare and not
severe [28,284]. The most frequently reported adverse effect
is iron deficiency anemia, which can be prevented by iron
supplementation, but not simultaneously with trientine (it
should be administered several hours before or after trientine)
[285]. In patients with primary biliary cirrhosis, however,
treatment with trientine has been associated with serious
complications, such as rhabdomyolysis (destruction of
skeletal muscles), and gastrointestinal side effects including
epigastric pain, dyspepsia, gastritis, and melena. Therefore,
the use of trientine is not recommended in these patients
[286].
The main adverse effects of NAC are nausea and
vomiting, particularly after oral therapy, and allergic
reactions, cutaneous and systemic, including anaphylaxis
[297,298]. Allergic reactions are usually mild, dose-
dependent, and respond to discontinuation of the infusion
and treatment with antihistamines [298,299]. More severe,
systemic reactions are rare and they are mainly associated
with intravenous administration of excessive doses of NAC
[298]. However, special concern is necessary in asthmatic
patients, since a case of fatal anaphylactic reaction was
reported in an acetaminophen-poisoned patient with asthma
treated with the usual dose of NAC [300]. According to a
trial in ten healthy volunteers treatment with NAC does not
appear to promote the excretion of essential elements such as
calcium, magnesium, iron, zinc, and copper [301].
Teratogenicity of trientine has been observed in mice and
rats, probably due to drug-induced copper deficiency in
fetuses [287-289]. Dose-dependent increase in the incidence
of fetal brain abnormalities, such as hemorrhages, delayed
ossification in cranium, hydrocephaly, exencephaly, and
microcephaly, were observed in trientine-treated mice [289].
In humans, however, teratogenic effects were not found
[285,290].
Some animal experiments showed that NAC is not
useful in preventing developmental toxicity of certain toxic
metals (cadmium, chromium, mercury), and that it may
increase the incidence of congenital malformations in metal-
exposed animals, which were orally treated with NAC
supplied in the feed [302]. On the other hand, large
intravenous doses of NAC (400 and 800 mg/kg) drastically
reduced the embryotoxic effects of methyl mercury in mice
[303]. There are no data in the literature indicating that
acetylcysteine therapy is harmful to the fetus, and some
authors recommend its use in serious acetaminophen
poisonings [304,305].
In the treatment of Wilson’s disease, beside trientine and
DPA, zinc, which blocks intestinal copper absorption, and
tetrathiomolybdate (TTM), which forms complex with
copper and protein (tripartite or ternary complex) and blocks
copper absorption and/or decreases copper toxicity, are also
presently used [83,202,291]. TTM is especially
recommended in patients with neurological manifestations of
Wilson’s disease.
3.10. Iron Hexacyanoferrate - Prussian Blue (PB)
Prussian blue is iron(III) hexacyanoferrate(II). It appears
in two forms, insoluble and soluble or colloidal form [306].
It is used for the treatment of radioactive cesium and
radioactive or non-radioactive thallium intoxication [40,41].
PB is poorly absorbed from the gastrointestinal tract and is
practically completely excreted unchanged in the feces. It
binds metals within its crystal structure, acting as adsorbent,
and reduces gastrointestinal absorption and reabsorption via
enterohepatic circulation [307,308]. Administration of PB
with food is therefore encouraged, because food stimulates
peristalsis and bile secretion, increasing the amount of toxic
metals in the gastrointestinal tract where they can be
adsorbed to the drug [41].
3.9. N-Acetylcysteine (NAC)
This chelating agent is a N-acetyl derivative of the amino
acid cysteine. It is in clinical use for acetaminophen
overdose to prevent or decrease hepatic injury, and as an
adjuvant mucolytic therapy in patients with abnormal,
viscuous mucous secretions in bronchopulmonary diseases
and diagnostic bronchial studies [41]. Animal experiments
showed that NAC is capable of chelating certain metals,
such as inorganic and organic mercury [96-98], cadmium
[292], chromium and boron [77], arsenic [67], and to a lesser
extent gold [292]. Marked urinary excretion of methyl-
mercury is observed in mice orally treated with NAC [98].
Limited data in humans also indicate effectiveness of NAC
in organic mercury poisoning. Remarkable increase in
urinary methyl-mercury excretion occurred in patient with
acute methyl-mercury ingestion, in whom hemodialysis was
performed during NAC infusion [99]. Its antioxidant
properties are also tested in order to ameliorate toxic effects
of certain metals, such as cadmium and lead [76,293,294].
The usual dose of PB is 3 grams orally three times a day
in adults and adolescents 13 years of age or older, and the
usual pediatric dose is 1 g orally 3 times a day. Treatment
should be initiated as soon as possible following the metal
intoxication and should be continued for a minimum of 30
days [41].
Contraindication for treatment with PB is
hypersensitivity to this drug. Caution is needed in patients
2786 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
with impaired gastrointestinal motility, due to delayed fecal
excretion of cesium and thallium and consequent damage to
gastrointestinal mucosa. PB has low toxicity, and even
prolonged treatment does not cause toxic adverse effects
[28,309]. The main adverse effect of PB is constipation, in
which case laxative and high-fiber diet is recommended. It
can also bind electrolytes in the gastrointestinal tract and
therefore serum electrolytes, especially potassium, should be
monitored during the treatment [41].
treatment of this condition. The second one most commonly
used is diethylenetriaminepentaacetic acid (DTPA). Since
1959, CaNa
3
DTPA has been widely used to treat workers
contaminated with plutonium [220]. After numerous studies
in humans and animals with radionuclides (lanthanides and
actinides) it was shown that the chelating properties of
DTPA were superior to those of EDTA. However, in the
treatment of lead poisoning there is less difference in the
efficiency between EDTA and DTPA. When comparing the
toxicity of these two chelators it was found that
CaNa
2
EDTA was less toxic than CaNa
3
DTPA. Both
chelating agents promote renal lesions and urinary zinc
excretion. Administration of these chelators is parenteral
since their absorption from the intestines is very poor (<
5%), as mentioned earlier. A detailed review of EDTA and
DTPA studies up to 1977 was published by Spoor from the
British National Radiological Protection Board. Later
studies confirmed early findings and were reviewed by
Andersen in 1999 [28].
The majority of drugs presently recommended for
chelating treatment of metal intoxication or overload are
given in Table 3.
4. NEW ASPECTS OF CHELATION THERAPY
4.1. Polyaminopolycarboxylic Acids
Ethylenediaminetetraacetic acid (EDTA) was the first
member of a group of synthetic polyaminopolycarboxylic
acids used in humans. The first application of CaNa
2
EDTA
for the treatment of lead poisoning in 1951 was a dramatic
success and it soon became the preferred drug for the
These two chelators are compared with the efficacy of
others or newly synthesized chelating agents
Table 3. Chelating Drugs for Metal Intoxication or Overload
Generic name Trade names (examples) Administration route Main indications References
CaNa
2
EDTA Calcium disodium versenate intramuscular
intravenous
lead, manganese, zinc [126, 221-227]
CaNa
3
DTPA Pentetate calcium trisodium,
Ditripentat-Heyl
intravenous, inhalation plutonium and other transuranic
elements, iron, manganese
[220, 243]
ZnNa
3
DTPA Pentetate zinc trisodium, Zink-
Trinatrium-pentetat (Zn-DTPA)
intravenous, inhalation transuranic elements (long-term
therapy)
[220, 243]
desferrioxamine Desferal, Desferin, Deferoxamine
mesylate
intravenous
intramuscular
subcutaneous
iron, aluminum [28, 41, 247, 248]
DMPS Dimaval; DMPS-Heyl, Mercuval oral
intravenous
mercury, lead, arsenic, copper [184, 188, 190-
194]
deferiprone (L1) Ferriprox oral iron, aluminum [36, 258, 260-262]
dimercaprol BAL in Oil, Sulfactin intramuscular arsenic, gold, lead, elemental and
inorganic mercury (not organic!)
[41, 116]
D-penicillamine Cuprimine, DePen, Metalcaptase,
Trolovol
oral copper (Wilson’s disease), lead,
mercury, zinc, gold
[38, 83, 200-205]
meso-DMSA Chemet oral lead, mercury, arsenic, copper,
antimony
[136, 138, 142-
152]
N-acetylcysteine* Acetadote, Mucomyst,
Acetylcysteine
oral
intravenous
mercury [99]
N-acetyl-D-
penicillamine*
N-Acetyl-D-Penicillamine oral mercury [94, 209]
Prussian blue Radiogardase (Prussian Blue),
Antidotum Thallii-Heyl
oral radioactive cesium, radioactive or
non-radioactive thallium
[40, 41]
tetrathiomolybdate -
(orphan drug status)
oral copper (Wilson’s disease) [83, 202, 291]
thiopronine Tiopronin, Captimer, Thiola oral mercury, copper, iron, and zinc
poisoning, Wilson’s disease
[41, 358]
trientine Syprine oral copper (Wilson’s disasese) [83, 202]
*Drug approved for indications other than metal poisoning or overload, but efficient as metal chelator in limited number of human intoxications.
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2787
[240,241,314,315]. They are also used in experimental
studies in combined (concurrent) application with other
chelating substances in order to promote mobilization of
heavy metals from the body [75,90,240,316].
Almost all were superior to BAL in reducing hepatic
cadmium levels, though none was superior in reducing renal
cadmium levels. The predominant route of excretion of
cadmium subsequent to administration of these compounds
is the fecal route. A synergistic effect was found in the
reduction of whole body and kidney cadmium burdens when
diisopropyl ester was used in combination with
CaNa
3
DTPA [310]. When compared to carbodithioate
efficiency in cadmium chelation in vitro, however, the
diisopropyl ester was found to be less effective and more
toxic [329]. These diesters of DMSA were not further
studied.
4.2. Derivatives of BAL: DMPS, DMSA and its Mono-
and Dialkylesters
In 1956 the Ukrainian scientist, Petrunkin, described the
synthesis and properties of a chelating agent that was
obtained by replacing the OH group in 2,3-dimercapto-1-
propanol (BAL) by a sulfonic acid group. This derivative of
BAL, 2,3-dimercaptopropane-1-sulfonic acid (DMPS), was
soluble in water and it was found to be superior to various
other chelating agents in the case of arsenic and mercury
poisoning [317-319]. It was established as an official drug in
the former Soviet Union in 1958. About 20 years later, it
was introduced to the Western world, first in Germany,
where it is registered as Dimaval [115].
Later, a series of nine congeners, monoesters of DMSA,
were synthesized and it was found that maximum cadmium
and lead mobilization occurred after treatment with the iso-
C5 analog (monoisoamyl DMSA; Mi-ADMS), even when
given by the oral route [330]. The same series were tested for
mercury removal in rats [101,331-335] and were also found
to have a high mercury mobilizing activity, being superior
to DMSA (which was always used as a positive control).
The effect of all monoesters was higher in reducing kidney
than liver mercury retention. The results were similar after
oral and parenteral treatment, and the efficiency was even
higher in younger than in older rats. When testing Mi-
ADMS in suckling rats for lead mobilization, the major
effect was observed at low doses of this monoester. It causes
much higher reduction of lead in the brain than does DMSA.
This is important since the brain is considered to be the
target organ of lead toxicity in young age groups [91]. The
study of Mi-ADMS reactivity against metallothionein-bound
cadmium (Cd-MT) was compared to DMSA in vitro [336].
It was found that after incubation, Mi-ADMS removed about
70% of the cadmium from Cd-Mt, and only 15% of the
cadmium was removed from Cd-MT by DMSA. It was also
found by an experiment on mice that the access of Mi-
ADMS to intracellular cadmium is, at least in part, mediated
by the organic anion transport system. Developmental
toxicity of Mi-ADMS was studied by Domingo and
coworkers in mice [337,338]. It was found to be slightly
higher than toxicity of DMSA and DMPS, but it does not
cause any significant depletion of essential trace elements in
the body [339].
meso-2,3-dimercaptosuccinic acid (meso-DMSA) belongs
to the family of chelating agents containing two –SH groups
like BAL. A very extensive review on the antidotal effects of
meso-DMSA was published by Ding and Liang [136]. It was
synthesized in 1954 by the American scientists Friedheim
and DaSilva [320], as an integral part of a drug for
schistosomiasis treatment. Meso-DMSA was first applied in
patients with heavy metal poisoning in the People's
Republic of China [136], and has been included in the
Chinese Pharmacopoeia since 1977. It was “rediscovered” in
the Western world in 1975, and since then has frequently
been described in the western literature as an efficient new
agent for the treatment of lead and mercury poisoning
[95,115,140,321,322]. Finally, in 1991 the U.S. Food and
Drug administration approved meso-DMSA for oral
treatment of lead intoxication in children [323]. In 1970 a
Russian scientist, Okonishnikova, [324,325] published the
results of testing meso- and racemic- form of DMSA on
survival of rats after lethal dose of mercuric chloride. They
noticed that the racemate displayed greater antidotal activity
than meso-DMSA. In 1971 Okonishnikova and Rosenberg
[326] published for the first time an article on the treatment
of workers with meso-DMSA after mercury poisoning.
Both chelators, DMSA and DMPS, are antagonists for
the same types of heavy metals as BAL, and have the
additional advantage that they can be administered orally.
While BAL can enhance the biliary excretion of heavy
metals, their complexes formed with DMSA and DMPS are
usually ionic and are commonly excreted renally [74]. Both
chelators, DMSA and DMPS, are however less effective than
BAL in binding cadmium from intracellular
metallothionein-bound sites, so called aged cadmium
deposits. Between 1988 and 1993, various esters of DMSA
were prepared and described by Jones and coworkers
[310,311] and Rivera and coworkers [137,327]. It was found
that they were less toxic than BAL, soluble in NaHCO
3
solution, permitting administration by intraperitoneal (i.p.)
or peroral (p.o.) route, and more effective to bind cadmium
and mercury than the parent chelator DMSA [328]. Several
diesters of meso-DMSA were prepared by esterification,
purified and characterized by Jones and coworkers [310].
Their relative ability to mobilize cadmium from its aged
deposits was evaluated in mice in comparison to BAL.
Following the finding of Okonishnikova [324] that the
stability constant of the mercury complex with the rac-
DMSA is greater than that of the mercury complex with
meso-DMSA, Jones and coworkers [89] and Kostial and
coworkers [90] undertook in vivo study to determine if rac-
DMSA possessed any advantage over meso-DMSA in
mobilizing lead from lead loaded rats. They found that
racemic form is significantly more effective in reducing
femur, carcass and kidney lead levels than meso-DMSA.
Similar study was performed to compare these two isoforms
of DMSA in mobilizing inorganic mercury in rats [100]. It
was found that rac-DMSA decreases kidney retention of
mercury more efficiently than meso-DMSA even at lower
doses. However, rac-DMSA decreased organ zinc and copper
concentrations, which was not observed with meso-DMSA.
Acute toxicity testing of the two isoforms showed about
twice as high toxicity of racemic- as compared to meso-
DMSA [164]. Therefore, further work should include
additional dose related experiments. Such studies are
justified since rac-DMSA definitely seems to be superior to
2788 Current Medicinal Chemistry, 2005, Vol. 12, No. 23 Blanusa
et al.˘
meso-DMSA in decreasing metal retention, especially at the
beginning of the treatment.
in later life. It is also suggested that with increasing organ
cadmium concentration a smaller proportion of cadmium is
bound to inaccessible binding sites [344]. One aspect of the
toxicity of these carbodithioates (MeOBGDTC, BGDTC and
MGDTC) was tested by using ten repeated administrations
of each chelator and by measuring the essential elements
iron, zinc, copper and calcium in the organs and urine of
rats. Under these conditions, chelation therapy did not
increase essential element excretion from the body [345].
The high efficacy and low toxicity of these carbodithioate
analogues suggest the possibility of their further
development and application in cases of chronic cadmium
intoxication.
In up-to-date chelation therapy, there is a trend to use
combined treatment with different chelating agents in order
to improve the efficiency in mobilising the body burden of
toxic metals. The rationale is that different chelators are
likely to mobilize metals from different tissue compartments
and therefore combined treatments might be superior to
monotherapy. Interesting results were obtained when two iso
forms of DMSA (either meso- or racemic-) were given
simultaneously with CaNa
2
EDTA to reduce tissue lead
concentrations in rats. This study showed that the
combination of CaNa
2
EDTA plus rac-DMSA is more
efficient in removing lead from bone and kidney than the
combination of CaNa
2
EDTA plus meso-DMSA. However,
this combination also caused highest trace element (copper,
zinc, and iron) elimination in the urine [340]. The same
combination of chelators was applied to reduce tissue lead
concentrations in suckling rats. Rac-DMSA given alone
most efficiently reduced lead concentrations in the carcass,
kidneys and brain, but it also reduced zinc and copper in the
liver, and zinc in the kidneys. Combined treatment with
CaNa
2
EDTA never improved the efficacy of either DMSA
isoform in decreasing tissue lead or in reducing tissue zinc
concentrations. All these different treatments caused the
same decrease in the carcass calcium concentrations. The
results do not support the use of combined treatment in this
age group, which is especially sensitive to trace element
deficiencies, and suggest that meso-DMSA might still be the
treatment of choice in acute lead poisoning in infants [90].
Monocarbodithioates occupy only two of the
coordination positions on the Cd
2+
ion. Since cadmium has
four coordination positions, a study was conducted to
determine whether a chelating agent possessing two
carbodithioate groups (CS
2
Na), both of which can coordinate
to the same cadmium ion, would enhance the in vivo
cadmium mobilization. Therefore, a novel biscarbodithioate
was synthesized, disodium N,N’-diglucosyl-1,9-
nonanediamine-N,N’-biscarbodithioate (C
9
G
2
DTC). It was
compared in vivo with BGDTC as a positive control and
found to have higher efficacy to mobilize cadmium than
BGDTC, especially at the beginning of the treatment. A
mechanism for the removal of cadmium from cadmium-
metallothionein complex by C
9
G
2
DTC has been proposed
[123].
4.4. Age-Related Differences in Efficacy of Chelation
Therapy
4.3. Carbodithioates
The efficacy of chelating treatment can be strongly
influenced by age. A number of animal experiments showed
that chelation therapy could be less efficient in developing
animals compared to mature animals. Kostial and coworkers
showed that several chelating agents were significantly more
efficient in reducing whole body retention of certain metal
radioisotopes in 6 to 8 weeks old animals than in suckling
rats. For example, parenteral therapy with CaNa
3
DTPA for
cerium [346] and cadmium [314], CaNa
2
EDTA for lead
[315], and DMPS for inorganic mercury [347], was two to
three times more effective in older than in suckling animals.
In Fig. (3), the effects of CaNa
3
DTPA treatment in
cadmium-exposed rats of different age are presented. As
mentioned earlier, parenteral therapy with carbodithioate
analogues, BGDTC, MeOBGDTC and MGDTC, was also
significantly less effective in sucklings than in 6-week-old
rats, which were intraperitoneally exposed to cadmium
[342].
Several studies by Jones and coworkers (since 1983) have
shown that carbodithioates were able to mobilize cadmium
from its intracellular sites days and weeks after cadmium
administration. Newer studies showed that oral and
intraperitoneal treatment with sodium N-(4-methoxybenzyl)-
D-glucamine carbodithioate monohydrate (MeOBGDTC)
drastically reduced cadmium retention in whole body, gut,
kidneys and liver [341]. This finding was new, since it was
believed that oral carbodithioate treatment would increase the
toxicity and absorption of ingested cadmium. The influence
of age and the time of administration of the three most
promising carbodithioate analogues was evaluated in rats.
The chelating agents MeOBGDTC, sodium N-benzyl-D-
glucamine-N-carbodithioate (BGDTC), and N-methyl-N-
dithiocarboxy-D-glucamine (MGDTC) were administered i.p.
to young rats of different age and at different time intervals
after i.p.
115m
Cd administration. Mobilized cadmium was
excreted almost exclusively by the fecal route. The efficiency
of chelators was significantly higher in older than younger
animals, and in the case of early rather than late chelator
administration, MeOBGDTC was found to be the most
effective [341-343]. In another study the efficiency of
MeOBGDTC was determined in mother rats and their
offspring, which were exposed to cadmium during the
reproduction period, i.e. from 4 weeks before mating until
weaning. The efficiency of the chelator was shown to be
lower in the offspring. This suggests that cadmium
accumulated during the neonatal period is less accessible to
treatment with chelating agents than cadmium accumulated
Interestingly, the situation is different under condition of
oral administration of chelators in cadmium and mercury
ingestion. In experiments in suckling and 6-week-old rats,
where ZnNa
3
DTPA was given for cadmium and mercury,
and DMPS or meso-DMSA for mercury elimination, it was
observed that whole-body and gut retention of metal
radioisotopes is lower in suckling than in 6-week-old rats.
Nevertheless, carcass retention of cadmium and mercury
(except in DMPS treated rats) was equal or even higher in
suckling than in 6-week-old rats [315,348]. It is suggested
that better chelator efficacy in suckling animals after oral
chelator administration is due to efficient removal of the
Chelators and Metal Toxicity Current Medicinal Chemistry, 2005, Vol. 12, No. 23 2789
fraction of cadmium or mercury retained in the gut, which is
shown to be very high at this age [349,350].
DMPS = 2,3-dimercaptopropane-1-sulfonic acid
DPA = D-penicillamine
There are some indications that age could also affect the
efficiency of the iron-chelating treatment with subcutaneous
DFO and peroral L1, according to data in young and adult
aluminium-loaded uraemic rats [351].
DTPA = diethylenetriaminepentaacetic acid
EDDHA = ethylenediamine-N,N'-bis(2-hydroxy-
phenyl)acetic acid
EDTA = ethylenediaminetetraacetic acid
To summarize, animal data imply that the efficacy of
chelation therapy in the very young can differ significantly
from that in adults. Several factors can be involved,
including immaturity of the kidney and biliary transport,
differences in binding affinities and/or contents of metal
carrier proteins, or differences in disposition and/or
biotransformation of chelating agents [141,344,352-356].
The presented data, together with the results that were more
extensively reviewed earlier, suggest that age is a factor that
should be considered during chelation therapy, both in
experimental work and in clinical practice [315].
EGTA = ethyleneglycol-bis-(beta-aminoethylether)-
N,N-tetraacetic acid
Feralex-G = 2-deoxy-2-(N-carbamoylmethyl-[N'-2'-
methyl-3'-hydroxypyrid-4'-one])-D-
glucopyranose)
HEDTA = hydroxyethyl ethylenediamine triacetic
acid
GI = gastrointestinal
i.p. = intraperitoneal
CONCLUDING REMARKS
ICL670 = 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-
1-yl]-benzoic acid
Antidotal therapy by using chelating agents to promote
the elimination of toxic metals from the body is presently
the mainstay of the treatment for reducing metal body
burden in most cases of metal poisonings. The primary
goals of pharmacotherapy of metal poisoning, i.e. reducing
metal retention, decreasing morbidity and preventing
complications, could be achieved to a great extent by
chelation treatment. There are examples of quite successful
chelating therapy, such as for lead, mercury or arsenic
poisoning. Unfortunately, there are unsolved problems with
chelation of some other toxic metals such as cadmium,
where effective chelation procedure still does not exist.
Therefore, in spite of the number of chelating agents in
current use as antidotes in metal poisoning, search for new
substances and therapeutical regimens, including combined
chelator administration, is still necessary.
L1 = deferiprone, 1,2-dimethyl-3-hydroxypyrid-
4-one
LD
50
= lethal dose (50% percent mortality)
L1NAll = 1-allyl-2-methyl-3-hydroxypyrid-4-one
MGDTC = N-methyl-N-dithiocarboxy-D-glucamine
MeOBDCG = N-(4-methoxybenzyl)-D-glucamine
carbodithioate monohydrate
meso-DMSA = meso-2,3-dimercaptosuccinic acid
Mi-ADMS = monoisoamyl DMSA
NAC = N-acetylcysteine
NAPA = N-acetyl-D-penicillamine
PB = Prussian blue, iron(III) hexacyanoferrate(II)
ABBREVIATIONS
p.o. = peroral
rac-DMSA = racemic-2,3-dimercaptosuccinic acid
BAL = British-Anti-Lewisite, dimercaprol, 2,3-
dimercapto-1-propanol
Trientine = triethylenetetraamine
TTM = tetrathiomolybdate
BGDTC = N-benzyl-D-glucamine-N-carbodithioate
ZnNa
3
DTPA = zinc trisodium diethylenetriaminepent-
aacetic acid
C
9
G
2
DTC = N,N’-diglucosyl-1,9-nonanediamine-N,N’-
biscarbodithioate
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... Even though D-penicillamine binds to various toxic metals, it is only FDA-approved for chelating copper in Wilson's disease in the United States. D-penicillamine is the first-line treatment for copper poisoning and a second-or third-line treatment for lead, mercury, and arsenic toxicity [Eidelman and Lowry, 2016;Osman et al., 1983;Blanusa et al., 2005]. D-penicillamine is mainly used to remove copper and lead. ...
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... In medicine, chelation is commonly associated with chelation therapy, which designates metal sequestration and elimination from the organism by transforming toxic metal complexes into new, non-toxic chelates that can be easily excreted [4]. Chelation therapy began during World War II when chemists at the University of Oxford searched for an antidote for Lewisite, an arsenic-based chemical weapon. ...
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... Compared to the medium control, addition of the supernatant, the respectively paired identified products, or all products in combination led to up-regulation of the metal starvation genes PA14_11320 and pvdG at 20 minutes and intermediate metabolite uptake and metabolism genes opdH and acoR at 2 hours ( Fig 8A and Table M in S1 File). DTPA/DFX also induced PA14_11320, potentially due to chelation of zinc by DTPA (Fig 8A) [71]. We next determined what proportion of the P. aeruginosa response to S. aureus supernatant was explained by the identified products. ...
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Bacteria typically exist in dynamic, multispecies communities where polymicrobial interactions influence fitness. Elucidating the molecular mechanisms underlying these interactions is critical for understanding and modulating bacterial behavior in natural environments. While bacterial responses to foreign species are frequently characterized at the molecular and phenotypic level, the exogenous molecules that elicit these responses are understudied. Here, we outline a systematic strategy based on transcriptomics combined with genetic and biochemical screens of promoter–reporters to identify the molecules from one species that are sensed by another. We utilized this method to study interactions between the pathogens Pseudomonas aeruginosa and Staphylococcus aureus that are frequently found in coinfections. We discovered that P . aeruginosa senses diverse staphylococcal exoproducts including the metallophore staphylopine (StP), intermediate metabolites citrate and acetoin, and multiple molecules that modulate its iron starvation response. We observed that StP inhibits biofilm formation and that P . aeruginosa can utilize citrate and acetoin for growth, revealing that these interactions have both antagonistic and beneficial effects. Due to the unbiased nature of our approach, we also identified on a genome scale the genes in S . aureus that affect production of each sensed exoproduct, providing possible targets to modify multispecies community dynamics. Further, a combination of these identified S . aureus products recapitulated a majority of the transcriptional response of P . aeruginosa to S . aureus supernatant, validating our screening strategy. Cystic fibrosis (CF) clinical isolates of both S . aureus and P . aeruginosa also showed varying degrees of induction or responses, respectively, which suggests that these interactions are widespread among pathogenic strains. Our screening approach thus identified multiple S . aureus secreted molecules that are sensed by P . aeruginosa and affect its physiology, demonstrating the efficacy of this approach, and yielding new insight into the molecular basis of interactions between these 2 species.
... However, previous studies found no clear clinical benefit from DMSA treatment in mercury vapor poisoning (Risher and Amler, 2005). DMSA given orally may have fewer side effects and has been reported to be superior to BAL, DPCN and DMPS (Blanusa et al., 2005). Glutathione and alpha-lipoic acid may also be used in mercury poisoning treatment, but they may increase mercury concentrations in the kidney and the brain, although the underlying mechanism is still unknown (Rooney, 2007). ...