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Environmental
Health Perspectives Supplements Volume 110, Number 5, October 2002
Molecular Mechanisms of in Vivo Metal Chelation: Implications
for Clinical Treatment of Metal Intoxications
Ole Andersen1 and Jan Aaseth2
1Department of Life Sciences and Chemistry, Roskilde University,
Roskilde, Denmark; 2Department of Medicine, Kongsvinger Hospital,
Kongsvinger, Norway
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Full Article in PDF
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Abstract
Successful in vivo chelation treatment of metal intoxication requires
that a significant fraction of the administered chelator in fact chelate
the toxic metal. This depends on metal, chelator, and organism-related
factors (e.g., ionic diameter, ring size and deformability, hardness/softness
of electron donors and acceptors, route of administration, bioavailability,
metabolism, organ and intra/extracellular compartmentalization, and excretion).
In vivo chelation is not necessarily an equilibrium reaction, determined
by the standard stability constant, because rate effects and ligand exchange
reactions considerably influence complex formation. Hydrophilic chelators
most effectively promote renal metal excretion, but they complex intracellular
metal deposits inefficiently. Lipophilic chelators can decrease intracellular
stores but may redistribute toxic metals to, for example, the brain. In
chronic metal-induced disease, where life-long chelation may be necessary,
possible toxicity or side effects of the administered chelator may be
limiting. The metal selectivity of chelators is important because of the
risk of depletion of the patient's stores of essential metals. Dimercaptosuccinic
acid and dimercaptopropionic sulfonate have gained more general acceptance
among clinicians, undoubtedly improving the management of many human metal
intoxications, including lead, arsenic, and mercury compounds. Still,
development of new safer chelators suited for long-term oral administration
for chelation of metal deposits (mainly iron), is an important research
challenge for the future. Key words: BAL, British antilewisite,
clinical chelation, dimercaptopropionic sulfonate, dimercaptosuccinic
acid, DMPS, DMSA, metal intoxication. Environ Health Perspect 110(suppl
5):887-890 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/887-890anderson/abstract.html
This article is part of the monograph Molecular Mechanisms
of Metal Toxicity and Carcinogenicity.
Address correspondence to O. Andersen, Dept. of Life
Sciences and Chemistry, Roskilde University, Postbox 260, 4000 Roskilde,
Denmark. Telephone: 45-4674-2417. Fax: 45-4674-3011. E-mail: Andersen@ruc.dk
Received 18 February 2002; accepted 30 May 2002.
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Various human metal intoxications have been treated efficiently by administration
of a chelating agent. However, complexation reactions in the human body are
influenced by a multitude of factors, including competing metals and ligands,
dynamics of circulation, compartmentalization, and metabolism of the chelating
agent. Accordingly, in vivo chelation reactions may differ extensively
from what would be expected from our chemical knowledge about the metal and
the chelating agent. Chelating agents can affect metal toxicity by mobilizing
the toxic metal into (mainly) urine. However, an important effect of chelation
is reduction of metal toxicity. A chelating agent forming a stable complex with
a toxic metal may shield biological targets from the metal ion, thereby reducing
the local toxicity (1,2), even at times after administration when mobilization
has not yet occurred, or it may expose the metal to the biological environment
and thereby increase the toxicity of the metal. For example, desferrioxamine
(DFOA) completely covers the surface of Fe3+ during complex formation,
thereby preventing iron-catalyzed free radical reactions (3,4); however,
ethylenediamine-tetraacetic acid (EDTA) is not able to shield the surface of
the Fe3+ ion but forms an open complex ("basket complex"), thereby
increasing the catalytic capacity of Fe3+ for generating oxidative
stress by about one order of magnitude (5).
The oral use of chelating agents is generally considered to require that further
exposure to the metal cease in order to avoid chelator-mediated increased intestinal
metal absorption. However, orally administered chelating agents forming hydrophilic
metal complexes may efficiently reduce intestinal metal uptake and local toxicity
at early times after oral intoxication. This was shown for the diethylenetriamine
pentaacetic acid (DTPA) complex of Cd2+ (6). Also orally administered
dimercaptosuccinic acid (DMSA) reduced the intestinal uptake and toxicity of
oral Cd2+ (2). Chelation of Ni2+ with EDTA and
Hg2+ with DMSA or dimercaptopropionic sulfonate (DMPS) (7)
reduced intestinal uptake. Accordingly, oral administration of chelating agents
may in some cases offer both reduction of local toxicity and prevention of intestinal
metal uptake (1,2,8).
Thermodynamic Considerations
In simple cases of formation of metal complexes with polydentate ligands,
M + Li 
MLi, where M represents the solvated electron pair-accepting
metal ion and Li represents a chelator with i electron-pair-donating
ligands (Lewis bases and acids), the overall stability constants is
[1]
The
stability of this complex depends on 
G
= H
- T S
= RT lnßi. For a complex with i ligands
not associated in one molecule, the change in enthalpy related to bonding often
contributes considerably to the free energy because the unfavorable entropy
change associated with ordering i independent ligands around one ion
counteracts the entropy effect of desolvation of the groups. Accordingly, multidentate
ligands form more stable complexes than unidentate ligands because of the fully
available entropy contribution from desolvation, and the stability in general
increases with the number of rings formed. If one assumes that the enthalpy
change due to complex formation does not depend on whether the donor groups
are independent or joined in a multidentate ligand (which is not always true,
however), the chelate effect should be entirely due to the entropy change. The
entropy contribution is indeed often the primary determinant of increased stability
of metal complexes with multidentate ligands, but when mutual repulsive forces
between charged groups are overcome by introducing them into one molecule, a
considerable enthalpy effect may result. This may be illustrated by the thermodynamics
of iminodiacetic acid (IDA) and EDTA complex formation with Cd2+
(Table 1, Figure 1). Even though the two complexes have the same number of groups
(six) available for chelation, the number of rings is increased by one in the
EDTA complex, increasing the entropy contribution to stability. Further, assembling
the four negatively charged carboxyl groups in EDTA increases the enthalpy contribution.
It can easily be calculated that the two contributions are of similar size.
 |
| Figure 1. Chelating agents
considered in this review. DPA, d-penicillamine; TETA, triethylenetetramine.
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The size of the chelate effect can be visualized from the change in log ß
for complexes with multidentate ligands with increasing numbers of identical
donor groups. Thus, the stability of the Cd complexes with the polyaminopolycarboxylic
acids increases in the following series: IDA with three donor groups and log
ß = 5.71; nitrilotriacetic acid with four donor groups and log ß
= 9.78; EDTA with six donor groups and log ß = 16.36; and DTPA with eight
donor groups and log ß = 19.00 (9). Similar effects are seen with
the series of homologous polyamines, where log ß for the Cd complexes
increases from 5.45 to 16.10 when the number of donors increases from two to
five (9). Steric conditions (e.g. ion size and ring size) considerably
influence the stability, mainly through changes in H.
Hardness/Softness of Metal Ions and Ligands
Determining factors for complex stability are the hardness/softness (HS) characteristics
of electron donors and acceptors, discussed in the classical work by Schwarzenbach
(10) and Ahrland et al. (11) and further elaborated into the hard
and soft acids and bases (HSAB) concept by Pearson (12). The HS characteristics
of donor and acceptor atoms in complexation reactions determine not only stability
of the formed complex but also the chelator's degree of metal selectivity in
relation to competing essential metals present in biological fluids. Further,
the HS character determines the selectivity of the toxic metal for the chelator
in relation to the competing biological ligands, often available at high concentrations
compared with that of the chelating agent. Softness character is related to
the ability of the empty frontier orbital of metal ions to accept electrons
and to the deformability of the outermost occupied electron orbital of donor
groups--that is, the propensity of metals and donors for forming covalent bonds.
The ionic index, Z2/r, where Z and r
are the ion's charge and radius, respectively, is positively related to degree
of ionic bonding in an ion's complexes. Conversely, the softness of an ion increases
with the size of sum of the ionization energies divided by the ionic index (13),
rI/Z2. Nieboer and Richardson (14) described
softness by the covalent index, Xm2r, where
Xm is the electronegativity. The rationale is that Xm
is related to the ion's empty frontier orbital energy and thereby
to the ion's ability to accept electrons and form covalent bonds. In brief,
metal ions and donor groups prefer to form complexes with partners having similar
HS character; however, the stability of complexes increases with the softness
of both metal and donor. Thus, for a series of cadmium complexes with simple
tridentate ligands, made by substituting the imino H in IDA with different functional
groups, log ß increases from 5.71 (R = H) or 6.75 (R = CH3)
to 9.78 (R = COO-), 10.53 (R = NH2), or even 16.72
(R = SH) (9):
RN(COO-) + Cd2+
Cd2+RN(COO-). [2]
For another series of complexes, log ß varies between 12.43 (R = CH3)
and 22.33
(R = SH) (9):
2RN(COO-)2 + Cd2+
Cd2+[RN(COO-)2]2.
[3]
Competition, Rate Effects during Ligand Exchange, and Toxicokinetics
The concentrations of "free" toxic metals are often very low in biological
systems because of the availability of numerous small biological ligands forming
mixed aquo-bioligand complexes with metals. Therefore, complexation reactions
in vivo between toxic metals and "therapeutic" chelating agents most
often occur as a series of ligand and/or metal exchange reactions. Even if the
equilibrium constant is highly favorable, complex formation in vivo may
be limited because of rate effects, competition by other ligands/metals, and
systemic transport kinetics of the chelator. Under physiological conditions,
numerous small mono- and bidentate ligands as well as functional groups in proteins
participate in chelation reactions and compete for chelating agents. Ca2+,
present at a concentration of about 1 mM, is the most important metal species
competing for clinical chelating agents. Anticipating that equilibrium is achieved,
and that the ML complex is quantitatively excreted in urine, the efficiency,
E, of a chelating agent for mobilizing a toxic metal can be described
as
[4]
because the potential for mobilizing the metal depends on the degree of formation
of the ML complex. In the simple situation of one major biological competing
metal, Ca2+, and a total chelator concentration Lt,
the conditions for a large E can be visualized from the standard stability
constants:
[5]
By introducing the stability constants for the metal and calcium complexes
into this expression and defining the concentration of Lt
as the sum of all forms of the chelator in plasma, Schubert (15) derived
[6]
The mechanisms and kinetics of ligand exchange reactions have been extensively
reviewed by Margerum et al. (16). They supply data for a range of divalent
ions, that the rates of both solvent exchange and ligand exchange are related
to the HS character of electron donors and acceptors. The rate of complex formation
depends on whether the chelator can easily get a grip on the metal ion by displacing
a solvent molecule or a monodentate ligand to obtain the initial coordination
site. The nature of this ligand exchange reaction determines whether the formed
mixed complex is more or less stable than the disrupted complex. If a more stable
complex is formed, further ligand exchange reactions are thermodynamically facilitated,
sometimes even when subsequent ring opening is involved. The next step is formation
of the first ring by coordinating a second donor group of the multidentate ligand
to the metal ion, whereby the chelate effect decreases the rate of dissociation
of the complex. Such processes may occur at a reasonable speed. If the initial
complexation reaction involves breaking a preexisting chelate ring formed with
a biological multidentate ligand, the process is often much slower. Besides
the number of donor groups available for electron pair donation, that is, the
maximum number of rings formed contributing to the chelate effect (the HS character
of these donors), steric conditions for simultaneous access of ligands to coordination
positions on the metal ion determine formation rate and overall stability. Also,
lipophilicity, metabolic stability, and rate of (most often urinary) clearance
are important.
Because of the complexity of biological systems, effects of antidotal chelators
are often better described quantitatively from results of animal experiments
or clinical treatments than by theoretical calculations of, for example, E.
Increased mobilization of the toxic metal in experimental animals or humans,
most often evaluated from urinary output, and decreased mortality or toxicity
among exposed animals are major end points. The mobilizing effectiveness (ME)
is expressed either as the factorial increase MEF in urinary and fecal excretion
between treated and un- or pretreated animals or humans, or as the fractional
retention MEQ of the metal in organs of treated animals relative to controls
(17). The therapeutic effectiveness (TE) may be expressed for acute metal
intoxication by the factorial change TEF in LD50 (the dose killing
50% of exposed animals) due to the chelation treatment (17). Similarly,
two chelators may be compared from results of animal experiments by their relative
potency, which is the ratio between equally effective doses, or by their relative
efficiency (RE) the ratio of effects at equimolar doses (17). Because
the efficiency of different chelators toward acute metal toxicity may vary extensively
in some combinations allowing 100% survival even after doses considerably higher
than LD99 (1,2), the RE method has limited applicability.
New Paradigms in Clinical Chelation Treatment: The Exit of
BAL
EDTA, d-penicillamine, and British antilewisite [2,3-dimercaptopropanol (BAL)]
came into clinical use after World War II to treat lead and mercury intoxication,
and copper intoxication in Wilson disease (18), which is today treated
with triethylenetetramine (19,20). In 1962, DFOA was shown to increase
urinary iron excretion in patients with thalassemia (21). Today, DFOA
is also used to treat aluminum intoxication and iron storage toxicity in sickle
cell anemia patients. During the 1950s DMSA and DMPS came into use in China
(22-24) and the Soviet Union (25,26). Since the 1970s
these drugs have been available as experimental drugs in the Western countries.
DMSA and DMPS are efficient antidotes for intoxications with several divalent
metals besides lead and mercury as well as some organometal or metalloid compounds
(8,27). Both chelators are available as tablets for oral administration,
which are stable for long periods at room temperature, and DMPS also as a dry
preparation for parenteral administration after hydration. In China, DMSA has
been administered parenterally to hundreds of patients (22). BAL is unstable,
susceptible to oxidation, and difficult to store as a ready-for-use preparation.
It has a low therapeutic efficacy in most cases, and because of high toxicity,
BAL is suited only for brief treatment of acute intoxications. It can be administered
only by intramuscular injection, normally in peanut oil. Administration of local
anesthesia beforehand is necessary because the injection is very painful. Presently
available experience indicates that DMSA or DMPS can substitute for BAL in most
clinical situations, resulting in safer and more efficacious treatment.
Side Effects and Toxicity of BAL, DMSA, and DMPS
A considerable fraction of individuals treated with BAL experience unpleasant
side effects, including nausea, vomiting, sweating, high fever, hypertension,
and tachycardia. BAL administration increased the brain deposition of arsenite
(28) and organic mercury compounds (29) and increased the toxicity
of cadmium (30) and lead (31) in animal experiments. DMPS does
not redistribute arsenic, lead, or inorganic mercury to the brain (28,32),
and DMSA chelation decreases the brain deposition of lead (33) and methylmercury
(34). BAL is significantly more toxic than DMPS, which is slightly more
toxic than DMSA. Representative LD50 values selected from the large
number of published toxicity studies are are given in Table 2.
In the only reported case of a DMSA overdose, a 3-year-old girl ingested approximately
2.4 g DMSA or 185 mg/kg body weight without clinical signs of intoxication (40).
During the last two decades, many patients have been treated with DMSA in the
United States and with DMPS in Europe, with a very low frequency of toxic side
effects necessitating discontinued treatment. Adverse reactions during treatment
with DMSA or DMPS include gastrointestinal discomfort, skin reactions, mild
neutropenia, and elevated liver enzymes. For both compounds, symptoms may subside,
allowing continued therapy. DMPS seems to be better tolerated than is DMSA with
respect to gastrointestinal symptoms but may cause hypotension, especially after
rapid intravenous infusion. Some patients, especially those with allergic asthma
symptoms, may develop hypersensitivity to DMPS (41,42).
For DMSA two serious reactions to therapy have been reported: DMSA chelation
of a man with chronic lead intoxication was discontinued because of a strong
mucucutaneous reaction to the drug (43). A 45-year-old African-American
man developed hemolytic anemia during DMSA chelation for occupational lead intoxication.
After cessation of treatment, the hematological values normalized. The patient
was glucose 6-phosphate dehydrogenase deficient, a genetic trait known to contraindicate
BAL chelation because of risk of hemolysis (44). For DMPS, severe toxicity
has not been reported in peer-reviewed literature except for a case of Stevens-Johnson
syndrome in a lead-intoxicated patient after eight daily oral doses of 200 mg/m2
DMPS (45). DMSA is registered in the United States as a drug for treatment
of lead intoxication. DMPS is registered in Germany for treatment of mercury
intoxication; however, it is not approved in the United States, so unless special
permission is given by the U.S. Food and Drug Administration, it is not lawful
for physicians to use it in the United States, nor is it lawful for pharmacies
to compound it. Still, DMPS is being illegally used by members of the alternative
health industry to treat people allegedly suffering from mercury intoxication,
most often claimed to be due to amalgam fillings. Similar uses occur in European
countries. Anecdotal information suggests that a very low fraction of individuals
develops severe reactions after parenteral administration of DMPS.
Conclusions and Directions of Future Studies
During the last 15 years DMSA and DMPS have gained more general acceptance
among clinicians, undoubtedly improving the management of many human metal intoxications.
Still, knowledge is needed in several basic research areas of in vivo
chelation of metals, for example,
- molecular mechanisms of action of clinically important chelators
- intracellular and extracellular chelation in relation to mobilization of
aged metal deposits and the possible redistribution of toxic metal to sensitive
organs such as the brain
- effects of chelators on metal biokinetics during continued exposure to
the metal, especially possible enhancement or reduction of intestinal metal
uptake
- combined chelation treatment with lipophilic and hydrophilic chelators,
which presently has a minimal clinical role
- minimization of the mobilization of essential trace elements during long-term
chelation
- fetotoxic and teratogenic effects of chelators
- development of orally administrable chelators
- development of less toxic chelators for chronic treatment of genetic metal
storage diseases
Especially the two last points, continued development of orally administrable
chelating agents for efficient, nontoxic mobilization on a home-patient basis
over extended time periods (even life-long chelation) of aged deposits of toxic
metal (e.g., Al, Cd, Fe, Hg, and Cu) will probably be a main future research
issue. Also, extensive animal experiments comparing the efficacies of classical
chelators (especially BAL) with those of DMSA and DMPS in acute intoxications
using relevant exposure routes (i.e., oral administration of relevant species
of the metals, as well as inhalation of Hg vapor) is a prerequisite for phasing
out the old chelators in uses where more effective alternatives are now available.
References and Notes
1. Andersen O. Oral cadmium exposure in mice: toxicokinetics
and efficiency of chelating agents. CRC Crit Rev Toxicol 20:83-112 (1989).
2. Andersen O. Choice of chelating antidotes for acute
cadmium intoxication. Toxicol Environ Chem 23:105-120 (1989).
3. Halliwell B. Protection against tissue damage in
vivo by desferrioxamine: what is its mechanism of action? Free Rad Biol
Med 7:645-651 (1989).
4. Tilbrook GS, Hider RC. Iron chelators for clinical
use. Metal Ions Biol Syst 35:691-730 (1998).
5. Singh S, Khodr H, Tayler MI, Hider RC. Therapeutic
iron chelators and their potential side-effects. Biochem Soc Symp 61:127-137
(1995).
6. Andersen O, Nielsen JB, Svendsen P. Oral cadmium chloride
intoxication in mice: effects of chelation. Toxicology 52:65-79 (1988).
7. Nielsen JB, Andersen O. Effect of four thiol containing
chelators on disposition of orally administered mercuric chloride. Hum Exp Toxicol
10:423-430 (1991).
8. Andersen O. Principles and recent developments in chelation
treatment of metal intoxication. Chem Rev 99:2683-2710 (1999).
9. Martell AE, Smith RE, eds. Critical Stability Constants,
Vols 1-4. New York:Plenum Press, 1974-1977.
10. Schwarzenbach G. Organic complex forming compounds.
Experientia (suppl 5):162-192 (1956).
11. Ahrland S, Chatt J, Davies NR. The relative affinities
of ligand atoms for acceptor molecules and ions. Quant Rev Chem Soc 12:265-276
(1958).
12. Pearson RG, ed. Hard and Soft Acids and Bases. Stroudsburg,
PA:Dowden, Hutchinson and Ross, 1973.
13. Williams RJP, Hale JD. The classification of acceptors
and donors in inorganic reactions. Struct Bond 1:249-281 (1966).
14. Nieboer E, Richardson DHS. The replacement of the
nondescript term "heavy metals" by a biologically and chemically significant
classification of metal ions. Environ Pollut 1:3-26 (1980).
15. Schubert JS. Einige medizinische und biologische
anwendungen von chelatkomplexen. Chimia 11:113-114 (1957).
16. Margerum DW, Cayley GR, Weatherburn DC, Pagenkopf
GK. Kinetics and mechanisms of complex formation and ligand exchange. In: Coordination
Chemistry, Vol 2 (Martell AE, ed). ACS Monograph 174. Washington, D.C.:Americal
Chemical Society, 1978;1-220.
17. Catsch A, Harmuth-Hoehne AE. Pharmacology and therapeutic
applications of agents used in heavy metal poisoning. Pharmacol Ther A1:1-118
(1976).
18. Walshe JM. Penicillamine, a new oral therapy for
Wilson's disease. Am J Med 21:487 (1956).
19. Walshe JM. Copper chelation in patients with Wilson's
disease. A comparison of penicillamine and triethylene tetramine dihydrochloride.
Q J Med 42:441-452 (1973).
20. Walshe JM. Treatment of Wilson's disease with trientine
(triethylene tetramine). Lancet 1:643-647 (1982).
21. Smith RS. Iron excretion in thalassemia major after
administration of chelating agents. Br J Med 2:1577-1582 (1962).
22. Ding G-S, Liang Y-Y. Antidotal effects of dimercaptosuccinic
acid. J Appl Toxicol 11:7-14 (1991).
23. Liang YI, Shi J, Chen L, Ding G. Studies on antibilharzial
drugs VI. The antidotal effects of sodium dimercaptosuccinate and BAL-glucoside
against tartar emetic. Acta Physiol Sinica 21:230-234 (1957).
24. Wang CS, Ting KS, Wu CC. Chelating therapy with Na-DMS
in occupational lead and mercury intoxications. Chin Med J 84:437-439 (1965).
25. Petrunkin VE. Synthesis and properties of dimercapto
derivatives of alkylsulfonic acids. I: Synthesis of sodium 2,3-dimercaptopropylsulfonate
(unithiol) and sodium 2-mercaptoethyl sulfonate. Ukr Khim Zh 22:603-607
(1956).
26. Petrunkin VE. The synthesis of thiolic compounds
as antidotes of arsenic and heavy metals. Trudy Nauch Konf Kiev 7-18 (1959).
27. Aposhian HV, Maiorino RM, Gonzales-Ramirez D, Zuniga-Charles
M, Xu Z, Hurlbut KM, Junco-Munoz P, Dart RC, Aposhian MM. Mobilization of heavy
metals by newer, therapeutically useful chelating agents. Toxicology 97:23-38
(1995).
28. Hoover TD, Aposhian HV. BAL increases the arsenic-74
content of rabbit brain. Toxicol Appl Pharmacol 70:160-162 (1983).
29. Berlin M, Ullberg S. Increasing uptake of mercury
in mouse brain caused by 2,3-dimercaptopropanol (BAL). Nature 197:84-85
(1963).
30. Dalhamn T, Friberg L. Dimercaprol (2,3-dimercaptopropanol)
in chronic cadmium poisoning. Acta Pharmacol Toxicol 11:68-71 (1955).
31. Germuch FG, Eagle H. The efficacy of BAL (2,3-dimercaptopropanol)
in the treatment of experimental lead poisoning in rabbits. J Pharmacol Exp
Ther 92:397-410 (1948).
32. Aposhian MM, Maiorino RM, Xu Z, Aposhian HV. Sodium
2,3-dimercapto-1-propanesulfonate (DMPS) treatment does not redistribute lead
or mercury to the brain of rat. Toxicology 109:49-55 (1996).
33. Cory-Slechta DA. Mobilization of lead over the course
of DMSA chelation therapy and long term efficiacy. J Pharmacol Exp Ther 246:84-91
(1988).
34. Aaseth J, Friedheim EA. Treatment of methyl mercury
poisoning in mice with 2,3-dimercaptosuccinic acid and other complexing thiols.
Acta Pharmacol Toxicol 42:248-252 (1978).
35. Zvirblis P, Ellin RI. Acute systemic toxicity of
pure dimercaprol and trimercaptopropane. Toxicol Appl Pharmacol 36: 297-299
(1976).
36. Stine ER, Hsu C-A, Hoover TD, Aposhian HV, Carter
DE. N-(2,3-Dimercaptopropyl)phthalamidic acid: protection, in vivo
and in vitro, against arsenic intoxication. Toxicol Appl Pharmacol 75:329-336
(1984.
37. Stohler HR, Frey JR. Chemotherapy of experimental
Schistosomiasis mansoni--influence of dimercaptosuccinic acid on toxicity
and antischistosomal activity of sodium antimony dimercaptosuccinate and other
antimony compounds in mice. Ann Trop Med Parasitol 58:431-438 (1964).
38. Aposhian HV, Carter DE, Hoover TD, Hsu C-A, Mariano
RM, Stine E. DMSA, DMPS and DMPA as arsenic antidotes. Fundam Appl Toxicol 4:S58-S70
(1984).
39. Aposhian HV, Tadlock CH, Moon TE. Protection of mice
against lethal effects of sodium arsenite--a quantitative comparison of a number
of chelating agents. Toxicol Appl Pharmacol 61:385-92 (1981).
40. Sigg T, Burda A, Leikin JB, Gossman W, Umanos J.
A report of pediatric succimer overdose. Vet Hum Toxicol 40:90-91 (1998).
41. McNeill Consumer Products Co. Chemet product information.
Fort Washington, PA:McNeill Consumer Products Co., 1994.
42. Heyl GmbH. Fachinformation: Dimaval (DMPS). Berlin:
HEYL Chemish-pharmazeutische Fabrik GmbH & Co., 1990.
43. Grandjean P, Jacobsen IA, Jørgensen PJ. Chronic
lead poisoning treated with dimercaptosuccinic acid. Pharmacol Toxicol 68:266-269
(1991).
44. Gerr F, Frumkin H, Hodgins P. Hemolytic anemia following
succimer administration in a glucose-6-phosphate dehydrogenase deficient patient.
Clin Toxicol 32:569-575 (1994).
45. Chisolm JJ. BAL, EDTA, DMSA and DMPS in the treatment
of lead poisoning in children. Clin Toxicol 30:493-504 (1992).
Last Updated: October 21, 2002
