DRAFT for review - do not cite or quote
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IPCS EVALUATION OF ANTIDOTES
IN POISONING BY METALS AND METALLOIDS
Unithiol
(2,3-Dimercapto-1-propanesulphonic acid, DMPS)
April 2009
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1.
Introduction
Unithiol (2,3-dimercapto-1-propanesulphonic acid, DMPS) was developed and first
used in Russia in the 1950s (Petrunkin, 1956; Klimova, 1958), and later used in China
(He et al., 1984). It only became more widely used in America and Western Europe
since the mid-1970s (Hruby & Donner, 1987), and particularly since the late 1970s
when the Heyl Company in Germany began production (Aposhian, 1982; Aposhian et
al., 1984).
Both unithiol and succimer (2,3-dimercaptosuccinic acid, DMSA) are derivatives of
dimercaprol (2,3-dimercapto-1-propanol, British Anti-Lewisite, BAL), and they are
replacing dimercaprol as the main antidote used in the management of heavy metal
poisoning (Hruby & Donner, 1987; Aposhian et al., 1995; Andersen, 1999). These
derivatives have several advantages over dimercaprol including lower toxicity,
increased solubility in water and lower lipid solubility. It is due to these properties that
they are effective by oral administration (Hruby & Donner, 1987). Succimer is less
toxic than unithiol and where these two drugs appear to have similar efficacy as an
antidote for a particular metal, succimer is generally preferred.
Unithiol has been used in the management of acute and chronic poisoning with a
number of different metals and metalloids, and is particularly useful for arsenic,
bismuth and mercury. Unithiol can be given parenterally or orally depending on the
clinical situation and severity of poisoning. It is well tolerated and adverse effects are
relatively rare. Most common adverse effects are skin reactions such as rashes,
pruritis and blistering which are allergic in origin. Most resolve within a few days and
generally no treatment is required, but antihistamines and/or corticosteroids may be
given if necessary.
2.
Name and chemical formula
International non-proprietary name: Unithiol
Synonyms: DMPS, sodium (DL)-2,3-dimercaptopropane-1-sulphonate, sodium 2,3dimercaptopropanesulphonate
IUPAC name:
Sodium D,L-2,3-dimercapto-1-propanesulphonic acid
CAS No.:
4076-02-2
Chemical formula:
H2C(SH)-HC(SH)-H2CSO-3Na.H2O
HS
SO3H
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HS
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Relative molecular mass: 228.28 (monohydrate)
Commercial Names: Dimaval®
Conversion: 1 g
1 mmol
1 g/L
1 mmol/L
3.
=
=
=
=
4.4 mmol
228.3 mg
4.4 mmol/L
0.228 g/L
Physico-chemical properties
Physical condition:
White crystalline powder
Melting point:
2350C (decomposes)
Boiling point:
Not applicable
Solubility:
Readily soluble in water (350 mg/ml); not readily soluble in
ethanol; not soluble in apolar solvents
Optical properties:
Not applicable as the racemate is used
Acidity:
pH 4.5-5.5 of an 1% aqueous solution
pKa:
Not known
Stability in light:
No specific advice with respect to storage is necessary
Thermal stability:
Stable (e.g., aqueous solution may be sterilized and the
substance may also be heated for drying)
Refractive index and
specific gravity:
Not applicable
Loss of weight on drying:
6-8% when dried to constant weight at 1000C
4.
Pharmaceutical formulation and synthesis
4.1
Routes of Synthesis
Procedures for the synthesis of unithiol were first described in the 1950s (Johary &
Owen, 1955; Petrunkin, 1956). A short description of possible ways of synthesis for
unithiol is also given in Hopkins (1981): sodium 2-propanesulphonate is brominated in
acetic acid with bromine which gives sodium 2,3-dibromopropanesulphonate. The
latter may either be treated with sodium hydrosulphide to give unithiol or may be
treated with acetylthiopropane sulphonate which is then hydrolysed with hot aqueous
acetic acid thus leading to unithiol.
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4.2
Manufacturing Process
The Heyl company uses a patented manufacturing process which involves
precipitation of unithiol as the lead salt, after which unithiol is released by addition of
hydrogen sulphide. The unithiol is subsequently recrystallised from alcohol (Ruprecht,
1997).
4.2.1 Parenteral Solution
The crystalline unithiol is diluted in freshly distilled water suited for injection. The
sterile filtered solution is then filled into ampoules. All steps have to be performed in
an atmosphere of sterile nitrogen in order to protect the sensitive compound against
oxidation. For the same reason only non-metallic working materials should be used.
A complex-forming agent such as sodium edetate (1% of the amount of unithiol) may
be added to the solution (water for injection) in order to bind ions eventually released
from working materials. The ampoules are then sterilized.
4.2.2 Capsules
The active compound is thoroughly mixed with the filling aid until homogeneity is
achieved. Thereafter the mixture is filled into commercially available hard gelatine
capsules.
4.3
Presentation and formulation
At an analytical grade unithiol is available from several manufacturers. The
pharmaceutical product is available from Heyl Chemisch-pharmazeutische Fabrik
GmbH & Co. KG, Berlin, Germany, both for oral and parenteral administration. The
sodium salt of a racemic mixture is used for medical purposes.
Unithiol is available in a pharmaceutical preparation as capsules and a parenteral
injection. The capsules contain 100 mg unithiol and the ampoules 250 mg as a 5%
solution. The injection can be administered either intravenously or intramuscularly.
5.
Analytical methods
5.1
Quality control procedures for the antidote
The quality control procedures listed below are oriented towards national and
supranational pharmacopoeial standards. Quality control parameters for the antidote
include
• Identity
• Purity
• By-products (mainly disulphides) are assayed by high performance liquid
chromatography (HPLC) and should not amount to more than 5% of total
peak area.
• Bromide content: maximum 0.5% (as potassium bromide).
• Heavy metals: maximum 20 ppm (as lead).
• Loss of weight on drying: 6.0-8.0%.
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•
•
pH of an 1% aqueous solution: 4.5-5.5.
The content may be assayed by iodometric titration. The assay by HPLC is
preferred however, because of its specificity. At least 95% is set for
requirements. The method has been validated formerly possessing a
variation coefficient of 1.5% and a recovery rate of 99.7%.
The pharmaceutical preparations are additionally controlled for
• Ampoules
• Sterility.
• Filling volume.
• Optical appearance (colour, clarity of the solution, particulate matter).
• Testing for leaks.
•
5.2
Capsules
• Uniformity of filling weight.
• Disintegration time (maximum 30 minutes in water).
• Optical appearance.
Methods for identification of the antidote
Several methods are available to identify the antidote including HPLC, infrared
spectroscopy, colour reaction with sodium nitroprusside and flame spectroscopy
specifically for the sodium in the molecule.
5.3
Methods for identification of the antidote in biological samples
Methods for qualitative and quantitative determination of unithiol and its metabolites
are published by Maiorino et al. (1987; 1988; 1991) and Hurlbut et al. (1994). The
urine is treated with sodium borohydride and analysed by HPLC with fluorescence
detection.
5.4
Analysis of the toxic agent in biological samples
Heavy metals should be analysed in blood and urine before, during and after antidotal
therapy. Sensitive methods, such as atomic absorption spectroscopy (AAS) or
inductively coupled plasma-atomic emission spectroscopy (ICP-AES), can be used
(Berman, 1980; Bertram, 1983).
6.
Shelf-life
The shelf life for the commercial available pharmaceutical preparations Dimaval® is 5
years for the capsules and 4 years for the ampoules. The expiry date is stated on
each package. Although no special advice for storage is given, it is recommended
that capsules are stored in a dry place.
7.
General properties
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Unithiol, like succimer and dimercaprol, owes it metal-binding properties to the
presence of two adjacent thiol groups. Unithiol is a water-soluble dithiol, a derivative
of dimercaprol and is capable of forming complexes with a number of metals and
metalloids. The advantages of unithiol over dimercaprol are:
• Lower local and systemic toxicity.
• Better solubility in water.
• Active by oral administration.
It should be noted that unithiol is not a true chelating agent; a chelator is a molecule
which binds a metal or metalloid ion by at least two functional groups to form a stable
ring complex known as a chelate. For mercury, it has been shown that unithiol (and
succimer) do not form a true chelate and as such both could be considered
suboptimal as metal antidotes (George et al., 2004). However, there are currently
no other substances available with the advantages of these two drugs (high water
solubility with relatively low toxicity).
The mechanism of action of unithiol has not been fully elucidated. Most studies on
this subject have focused on its interaction with arsenic and mercury. In addition to
increasing urinary elimination of arsenic, unithiol has also been shown to alter the
relative urinary concentrations of organoarsenic metabolites by interfering with
arsenic methylation (Aposian et al., 1997; Gong et al., 2002; Heinrich-Ramm et al.,
2003).
Unithiol also promotes mercury excretion and is effective in inhibiting mercury
accumulation in renal proximal and distal tubular cells, and protecting against mercuryinduced renal damage. Studies in chickens (Stewart & Diamond, 1987) and rat
kidneys (Klotzbach & Diamond, 1988) have demonstrated that urinary excretion of
unithiol is blocked by both the substrate p-aminohippurate (PAH) and the inhibitor
probenecid of the organic transport process. In the in vitro study by Zalups et al.,
(1998) using isolated perfused segments of rabbit proximal tubules the removal of
mercury from proximal tubules by unithiol was blocked by the addition of PAH.
Islinger et al. (2001) postulated on the transport of unithiol in renal proximal cells.
Unithiol enters the cells across the basolateral membrane from the blood, via the
organic anion transporter (OAT). Both oxidised and reduced unithiol interact with the
transporter, but the majority of unithiol entering cells is probably oxidised since this is
present in the blood in a greater concentration. Once in the cell the unithiol is reduced
by a glutathione-dependent thiol-disulphide exchange reaction in the proximal tubule
cell (Stewart & Diamond, 1988). Unithiol then binds mercury within the cell and the
complex exits the cell, presumably via an export pump. The unithiol-mercury complex
is not reabsorbed and is excreted in the urine.
Owing to its high hydrophilicity unithiol is relatively ineffective at clearing metals from
the brain (unlike its lipophilic parent compound, dimercaprol) and excretion by the
organic anion transporter (expressed in the apical membrane of the choroid plexus)
may further reduce the efficacy of unithiol in the brain (Islinger et al., 2001). Of the
organic anion transporters expressed in the basolateral proximal tubule cells
determined in animal studies (Kojima et al., 2002), recent work has identified (OAT1)
as the transporter involved in movement of unithiol into cells; it is a comparatively poor
substrate of OAT3 (Koh et al., 2002).
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Recently, multidrug resistance protein 2 (MRP2 or ATP-binding cassette, sub-family
C [ABCC2]) has been showed to be involved in the renal proximal tubular elimination
of unithiol complexes of methylmecury (Zalups & Bridges, 2009).
It is often assumed, that clinical effectiveness of a metal-binding agent is linked to the
stability constant in vitro where the greater the stability constant of a metal-binding
agent, the greater the mobilisation of that ion following administration of the metalbinding agent. However, Jones et al. (1980) found no correlation in an in vivo study in
mercury-poisoned mice. Therefore data on stability constants are not given in this
monograph, but may be found elsewhere (Casa and Jones, 1979).
8.
Animal studies
8.1
Pharmacodynamics
There are numerous studies on the effect of unithiol in animals with experimental
metal poisoning. Many studies compare the effect of a number of different metalbinding agents and in some cases the antidotes are given immediately or sometimes
before dosing with the metal. Administration of the antidote with or before exposure
does not reflect the clinical situation in human metal poisoning. In addition, the effect
of antidotes are measured in a variety of ways including changes in survival rates,
urinary excretion, faecal excretion, metal concentrations in organs, body burden and
biochemical parameters in target organs. Many studies give conflicting results and
this is probably a reflection of a variety of factors including differences in doses of
metal and antidote, routes and times of administration and methods of determining
elimination and retention. Furthermore, direct extrapolation from animal studies to
humans is not possible because of the potential differences in the kinetics of both
heavy metals and metal-binding agents such as unithiol between animals and
humans.
8.1.1 Antimony
Unithiol has been shown to reduce antimony toxicity in animals.
In a study comparing survival rates of different antidotes in antimony poisoning, mice
were given intraperitoneal antimony potassium tartrate 120 mg/kg (LD50 54.6 mg/kg).
The antidotes were given by the same route 1 hour later at a dose of 10:1 mole ratio
of antidote to antimony (except for dimercaprol which was given at a 1:1 ratio).
Succimer and unithiol were found to be the most efficacious antidotes for antimony
potassium tartrate poisoning, with succimer the superior of the two (Basinger &
Jones, 1981a).
In an earlier study administration of unithiol was shown to reduce the LD50 of
subcutaneous antimony potassium tartrate by a factor of 8 compared to controls
(Chih-Chang, 1958).
8.1.2 Arsenic
Unithiol has been shown to be of benefit in poisoning with several arsenic
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compounds including lewisite (β-chlorovinyl-dichloroarsine). Mückter et al. (1997)
argue that unithiol and succimer have advantages over dimercaprol in the treatment of
arsenic poisoning since they are more effective in preventing arsenic from crossing
epithelial boundaries and entering cells and they enhance the excretion of arsenic
more rapidly and completely. In addition, unithiol and succimer are less toxic than
dimercaprol. However, dimercaprol appears to be more effective in restoring cellular
function to tissues which are poorly penetrated by unithiol or succimer. Dimercaprol
also has the disadvantage of increasing arsenic concentrations in the brain; this is not
the case with unithiol or succimer.
Aposhian et al. (1982) demonstrated the effectiveness of unithiol in rabbits exposed to
subcutaneous lewisite.
Unithiol increased survival when given orally or
subcutaneously. Similarly, in mice injected with sodium arsenite (0.14 mmol/kg
subcutaneously), intraperitoneal unithiol (0.25 mmol/kg) was a potent antidote, even
when given 2 hours later (Tadlock & Aposhian, 1980).
In rabbits poisoned with dermal lewisite dimercaprol, succimer and unithiol were all
shown to reduce the incidence and severity of liver changes. There was no difference
between the three agents at the dose of 40 µmol/kg. Compared to dimercaprol,
succimer and unithiol may have prolonged survival time and the relatively low toxicity
of unithiol and succimer allowed high doses (160 µmol/kg) to be given (Inns & Rice,
1993). In a study of intravenous lewisite poisoning in rabbits there was no difference
between the level of protection provided by the three antidotes (Inns et al., 1990).
In mice poisoned with sodium arsenite (0.129 mmol/kg subcutaneously) unithiol (0.8
mmol/kg intraperitoneally) given 90 minutes later was found to increase the LD50 by
4.2 fold (Aposhian et al., 1981).
In rabbits poisoned with sodium arsenite (1 mg subcutaneously) given either succimer,
unithiol or N-(2,3-dimercaptopropyl) phthalamidic acid (DMPA; 0.2 mmol/kg
intramuscularly) 1 hour later, the urinary excretion of total arsenic between 0 and 24
hours was elevated after antidote administration. However, urinary excretion of total
arsenic between 24 and 48 hours was significantly lower than controls. The three
antidotes differed in the proportion of arsenic metabolites in the urine. All increased
arsenite excretion by decreased dimethylarsinate excretion. Unithiol and DMPA
increased methylarsonate excretion but succimer did not. Both succimer and unithiol
increased arsenate excretion. Of the three antidotes used, unithiol was the most
effective at removing arsenic from the body (Maiorino & Aposhian, 1985). Unithiol and
succimer (both at 50 mg/kg) also significantly increased renal arsenic excretion in rats
with chronic arsenic poisoning (sodium arsenate 1 mg/kg orally 6 days a week of 3
weeks). Both also restored arsenic-induced inhibition of δ-aminolevulinic acid
dehydratase activity and hepatic glutathione concentrations. Although both antidotes
reduced arsenic-induced histopathological lesions, succimer was more effective (Flora
et al., 1995a).
Kreppel et al. (1989) compared the effectiveness of D-penicillamine, dimercaprol,
unithiol and succimer as antidotes in acute arsenic intoxication using different
controlled experimental settings. In one study mice and guinea pigs were injected
subcutaneously with 8.4 mg/kg arsenic trioxide (containing a tracer dose of arsenic74). An antidote (0.7 mmol/kg intraperitoneally) was given 30 minutes later. As
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determined 4 and 12 hours after the arsenic injection, D-penicillamine was unable to
reduce the arsenic-74 content in any organ investigated (blood, liver, kidneys, lungs,
heart, brain, testes, spleen, skeletal muscl, and skin). In contrast, dimercaprol,
unithiol and succimer markedly reduced the tissue content of arsenic-74 compared
to controls. Finally, the ability of the antidotes to reverse biochemical effects of
arsenic was investigated in vitro using suspensions of isolated renal tubule cells.
The marked inhibition of gluconeogenesis induced by 30 μmol/L arsenic trioxide was
almost completely reversed upon addition of 90 μmol of dimercaprol, unithiol or
succimer. In this experimental model, too, D-penicillamine was ineffective.
In mice given arsenic trioxide, intraperitoneal administration of unithiol (0.7 mmol/kg)
0.5 minutes later was less effective than the same dose of succimer. When the
antidote was given 30 minutes after the arsenic, succimer and unithiol showed
reduced but similar efficacy. The efficacy of the antidotes for reducing arsenic
organ concentrations was investigated in mice and guinea pigs.
Animals received
8.4 mg/kg (0.043 mmol/kg) of radiolabelled arsenic trioxide subcutaneously and an
antidote (0.7 mmol/kg intraperitoneally) 30 minutes later. Both unithiol and succimer
and the two in combination were more effective as reducing organ concentrations of
arsenic than dimercaprol. In addition, dimercaprol increased arsenic concentrations
in the brain, whereas succimer and unithiol did not. Succimer increased the arsenic
content of bile but unithiol and the two in combination did not (Kreppel et al., 1990).
In rabbits administered radiolabelled arsenic (1 mg/kg subcutaneously as sodium
arsenite), dimercaprol (0.2 mmol/kg intramuscularly) 1 hour later was shown to double
the arsenic-74 concentration in the brain. In contrast, unithiol (0.2 mmol/kg
intramuscularly) was found to decrease the arsenic-74 concentration to about one-fifth
of that observed with dimercaprol administration (Hoover & Aposhian, 1983). Schäfer
et al. (1991) demonstrated that arsenic depots after injection of arsenic trioxide into
mice could be mobilised by oral administration of unithiol or succimer without
increasing the brain deposition, however, oral administration of dimercaprol
extensively increased the brain deposition or arsenic.
In mice given arsenic (5 mg subcutaneously as arsenic trioxide) immediately followed
by unithiol (100 mg/kg intraperitoneally) arsenic excretion in the faeces exceeded that
in the urine (Maehashi & Murata, 1986). In guinea pigs poisoned subcutaneously with
arsenic trioxide (2.1 mg/kg) the combination of unithiol (0.1 mmol/kg both
intraperitoneally and orally) and cholestyramine (0.2 g/kg orally) significantly enhanced
the faecal elimination of arsenic suggesting that interruption of enterohepatic
circulation of arsenic may be a valuable adjunct in the treatment of arsenic poisoning.
Increased faecal excretion was not observed with intraperitoneal unithiol plus oral
cholestyramine or oral plus intraperitoneal unithiol (Reichl et al., 1995).
Flora et al. (2005) compared the efficiacy of succimer, unithiol and monoisoamylsuccimer in rats with chronic arsenic exposure (100 ppm sodium arsenite in drinking
water for 10 weeks). Antidotes were given after arsenic exposure at a dose of 50
mg/kg for 5 days. Succimer was not effective at resolving arsenic-induced oxidative
damage in cells or in reducing the arsenic burden. Unithiol was moderately effective
against generation of reactive oxygen species due to intracellular access. However,
monoisoamyl-succimer was the most effective antidote in reducing reactive oxygen
species in the blood and brain. It was also marginally better at restoring the activity
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of antioxidant enzymes.
An in vitro study of guinea-pig liver treated with arsenic trioxide demonstrated that
administration of unithiol (and other antidotes) resulted in a shift to faecal elimination
by increasing biliary excretion of arsenic. Unithiol was more effective than succimer
or dimercaprol but was not as effective as 2,3-bis-(acetylthio)-propanesulphonamide
(BAPSA) (Reichl et al., 1990).
8.1.3 Beryllium
Unithiol has been shown to enhance beryllium excretion and reduce berylliuminduced toxic effects in experimental animals.
Unithiol administration (0.7 mmol/kg intraperitoneally) appeared to increase the lethality
of beryllium chloride in mice, but the result was not significant (Pethran et al., 1990).
In rats treated with beryllium (2.5 mg/kg intraperitoneally, as beryllium nitrate),
immediate administration of unithiol (50 mg/kg intraperitoneally) or succimer (same
dose) was shown to prevent most beryllium-induced biochemical alterations and
reduce tissue beryllium concentrations. Unithiol was relatively more effective and
resulted in significantly less marked lesions in the liver and kidneys (Mathur et al.,
1994).
In another study beryllium nitrate was given to rats for 21 days (0.5 mg/kg, orally
daily for 5 days/week) and unithiol or succimer (25 or 50 mg/kg, twice daily for 5
days) was administered 24 hours after the last dose of beryllium. Unithiol was
effective at reducing beryllium in the liver, spleen and kidneys. The higher dose
marginally elevated the faecal excretion of beryllium but also resulted in
redistribution of beryllium into blood. Unithiol also reduced hepatic and renal lesions
compared to succimer (Flora et al., 1995b).
In studies comparing antidotal therapy combined with an antioxidant (sodium
selenite) supplementation, D-penicillamine with sodium selenite was found to be
more efficacious at reducing beryllium toxicity (as measured by glycogen and protein
concentrations in the liver, kidneys, lungs and uterus, with concentrations of liver
enzymes and beryllium) than unithiol and sodium selenite (Johri et al., 2002; Johri et
al., 2004).
8.1.4 Bismuth
Several studies comparing different antidotal agents have found unithiol to be an
effective antidote in bismuth poisoning.
In a study of several antidotes comparing efficacy in bismuth poisoning, mice were
given intraperitoneal bismuth citrate followed by an antidote 20 minutes later in a 10:1
molar ratio antidote:bismuth. All animals treated with unithiol survived and all in the
control group died (Basinger et al., 1983).
In a study of several antidotes comparing efficacy in bismuth poisoning, rats were
injected intraperitoneally with colloidal bismuth subcitrate (50 µmol/kg/day, for 14
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days). The antidotes were given twice daily (250 µmol/kg/day) for 3 days. The
animals were killed on the fourth day and tissue samples analysed. Unithiol, succimer
and dimercaprol were most effective in lowering bismuth concentrations in most
organs, particularly the kidney and liver, resulting from higher elimination in urine by
unithiol and dimercaprol. Dimercaprol was the only antidote effective in lowering
bismuth concentrations in brain tissue. It was concluded that unithiol and succimer
were the antidotes of choice with dimercaprol reserved for very severe bismuth
poisoning because of its own toxicity (Slikkerveer et al., 1992).
Unithiol was shown to reduce the whole-body burden of bismuth in mice given an
intraperitoneal injection of bismuth acetate. The unithiol was given in drinking water
(100, 300 or 600 µg/mL) two days prior to and three days after the bismuth. The
renal concentration of bismuth was reduced by up to 90% and unithiol also
significantly reduced deposition of bismuth in the femur (Jones et al., 1996).
8.1.5 Cadmium
Antidotal therapy for cadmium is particularly problematic because the absorbed
metal rapidly becomes strongly bound to metallothionein, a low-molecular weight
metal-binding protein, whose synthesis is induced by cadmium. Several studies
have compared antidote efficacy in cadmium poisoning and concluded that, although
unithiol is effective, other metal-binding agents appear to be more efficacious (Eybl
et al., 1984; Eybl et al., 1985; Andersen & Nielsen, 1988; Srivastava et al., 1996).
Unithiol administration (0.7 mmol/kg intraperitoneally) increased the LD50 of cadmium
chloride in mice from 9.1 mg/kg to 15.2 mg/kg (Pethran et al., 1990). Aposhian (1982)
also demonstrated that unithiol increases survival in mice injected with cadmium
chloride.
In a study comparing antidote efficacy, mice were given intraperitoneal cadmium
chloride at the previously determined LD50 (0.0267 mmol/kg). This was followed by
the antidote at a dose of 1:2 or 1:5 (cadmium:antidote) molar ratios by the same route.
The animals were killed after 14 days. Succimer and unithiol were found to be most
effective at reducing lethality and the cadmium burden of the liver, kidneys and brain
tissue. The therapeutic index and therapeutic efficacy was highest for succimer
followed by unithiol (Srivastava et al., 1996).
In a similar study mice were given radiolabelled cadmium chloride (0.53 mmol/kg by
stomach tube) followed by the antidote (2.12 mmol/kg) 15 minutes later. The
animals were killed after 10 days. Unithiol provided some protection against lethality
(whereas succimer provided complete protection). Penicillamine, succimer and
unithiol were all able to reduce peristaltic toxicity of cadmium chloride and all
reduced whole-body retention of cadmium; succimer was most effective at reducing
body retention. Succimer, and particularly unithiol, decreased hepatic deposition of
cadmium and increased relative deposition in the kidneys and lungs. It was
concluded that succimer was the most effective antidote for cadmium poisoning
(Andersen & Nielsen, 1988).
Another study in mice compared antidote efficacy when given intravenously 10
seconds, 1 or 3 hours after intravenous cadmium chloride (3 µmol/kg) administration.
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When given immediately after cadmium administration, all agents reduced the body
burden of cadmium but efficacy declined when dosing occurred at 1 or 3 hours after
administration. Unithiol was among the least effective of the antidotes investigated
(Planas-Bohne & Lehman, 1983).
Unithiol (50 mg/kg intraperitoneally) administered to rats 24 hours after injection of
radiolabelled cadmium (1 mg/kg intraperitoneally as cadmium chloride) did not have
any effect on the excretion or tissue distribution of cadmium. By the time the
antidote was given the cadmium was bound to metallothionein. Only dimercaprol
was effective in mobilising cadmium from metallothionein into bile (Cherian, 1980).
Unithiol (3.61 mmol/kg) was as effective as succimer (same dose) in promoting
survival in cadmium poisoned mice (1 mmol/kg cadmium chloride orally) when given
immediately after administration of cadmium. However, unithiol administration
resulted in a concentration of cadmium in the kidneys and liver that was approximately
four times greater than those in succimer-treated animals (Basinger et al., 1988).
Unithiol did not affect faecal excretion of cadmium and the increase in urinary
excretion was too small to affect body burden in rats given 0.4 mmol/kg of unithiol
following dosing with radiolabelled cadmium (3 µmol/kg as cadmium chloride). The
cadmium was given once; administration of the metal-binding agent started on the
third day and was given daily, 5 times a week for 2 weeks (Rau et al., 1987).
Administration of unithiol (0.1 mmol/kg) did not affect biliary excretion of cadmium in
rats 3 days after intravenous exposure to cadmium (Zheng et al., 1990).
Unithiol had no effect on survival rate in cadmium-poisoned mice when administered
intraperitoneally immediately after subcutaneous cadmium (20 mg/kg as cadmium
chloride) at antidote to metal molar ratios of 1:1 or 2:1. At a ratio of 5:1 the survival
rate was only 20%, whereas the survival rate with succimer was 100%. In another
study where cadmium (0.5 mg/kg intravenously) was immediately followed by
unithiol at a dose of 10:1, there was no increase in cadmium excretion or reduction in
body burden. Unithiol did, however, decrease the cadmium concentration in the liver
and gastrointestinal tract (Eybl et al., 1984).
In a study of antidotal efficacy in chronic cadmium poisoning in mice (2 mg of
cadmium chloride intraperitoneally at 48 hours intervals for 5 doses) unithiol
administration (225 mg/kg; 1.06 mmol/kg intraperitoneally) resulted in a significant
increase in liver cadmium concentrations (39%). However, interpretation of this
result is difficult since this group of mice were the only group to have a significant
loss in body weight. Therefore the apparent increase in cadmium concentration
could be due to changes in organ size rather than a reflection of the effect of unithiol
on cadmium distribution. Similarly there was also a slight increase in kidney
cadmium concentrations (Shinobu et al., 1983).
Unithiol had only a slight effect in reducing the cytotoxicity of cadmium in mammalian
cell culture (Fischer, 1995). In another in vitro study using human platelets, unithiol
was shown to protect against cadmium-induced stimulation of glutamate binding
(Borges & Nogueira, 2008) but unithiol increased cadmium-induced inhibition of δaminolevulinate dehydratase (ALAD) in rat lung in vitro (Luchese et al., 2007).
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8.1.6 Chromium
There is limited information on unithiol in chromium poisoning. Chromate-induced
cytotoxicity (as measured by the chromate content of cells and inhibition of cell
growth) was reduced in the presence of unithiol. This was only the case when cells
were incubated with unithiol and chromate. If the unithiol was added before or after
treatment with chromate it failed to restore chromate-induced cytotoxicity or reduce
cellular chromate concentrations (Susa et al, 1994).
Lethality was reduced in mice injected with chromate (40 mg/kg intraperitoneally as
potassium chromate) and then unithiol (500 mg/kg intraperitoneally) immediately
afterwards. At half the chromate dose and 300 mg/kg of unithiol the liver and kidney
content of chromium was reduced compared to controls. There was also increased
renal excretion of chromium and suppression of chromate-induced increase in serum
ornithine carbamyl transferase activity (Susa et al, 1994).
8.1.7 Cobalt
There is limited information on unithiol in cobalt poisoning. It has been shown to
reduce the lethality of cobalt in some studies (Cherkes & Braver-Chernobulskaya,
1958; Eybl et al., 1985). In the latter study, although unithiol increased survival it also
increased cobalt concentrations in the liver, gastrointestinal tract and carcass in mice
receiving 1 mmol/kg of cobalt chloride. The unithiol was given in a dose of 5:1,
antidote to metal ratio (Eybl et al., 1985).
8.1.8 Copper
Unithiol appears to be of benefit in copper-poisoned experimental animals.
Unithiol administration (0.7 mmol/kg intraperitoneally) increased the LD50 of copper
chloride in mice from 59 mg/kg to 143 mg/kg (Pethran et al., 1990).
Mice receiving copper sulphate (10 mg/kg intraperitoneally, the approximate LD50) and
then unithiol (132 mg/kg, 20 minutes later by the same route) were morphologically
free of hepatic or renal evidence of toxicity, whereas control animals have extensive
renal tubular necrosis (Mitchell et al., 1982).
In contrast unithiol has been shown to increase copper-induced haemolysis of
human red blood cells in vitro. At a concentration of 0.3 mM unithiol increased the
copper-induced haemolysis from 15% to approximately 25%. At 0.1 mM it was
ineffective (Aaseth et al., 1984).
8.1.9 Gold
Unithiol has been shown to be of benefit in experimentally induced gold toxicity. It is
able to reduce kidney gold concentrations and increase urinary excretion of gold.
In rats given 2 mg gold/kg intravenously (as Auro-Detoxin) and then oral unithiol (0.153 mmol/kg) 30 minutes later, it was demonstrated that unithiol reduced the gold
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concentration in all organs except the liver and spleen. Similar effects were observed
when unithiol was administered 24 hours after injection of gold. In contrast to the
immediate treatment with unithiol delayed treatment with the lowest dose (0.15
mmol/kg) resulted in significantly decreased gold concentrations in the red blood cells,
plasma, femur, muscle and skin. However, the concentration in the kidneys was
significantly higher compared to controls (Gabard, 1980).
In another study rats were given 2 mg gold/kg intraperitoneally daily for 10 days then
unithiol 0.75 mmol/kg daily from days 11 to 20. Unithiol administration decreased the
gold concentration in the kidneys and in the skin, and increased it in the plasma. The
concentrations in the other organs remained unchanged (Gabard, 1980).
In rats injected with gold sodium thiomalate (up to 0.198 mmol/kg intravenously),
treatment with D-penicillamine, unithiol or succimer reduced renal toxicity, measured
by urinary concentrations of protein, aspartate aminotransferase and glucose, and
the blood urea nitrogen concentration. In addition all three antidotes increased
urinary excretion of gold and significantly decreased liver and renal gold
concentrations. Unithiol was the most effective antidote tested (Kojima et al., 1991).
Characterisation of the gold in urine following treatment with gold sodium thiomalate
and then unithiol has shown that it is present as a gold-unithiol complex. In the bile it
was present as a gold-unithiol complex, high molecular weight compounds (probably
proteins) and gold-L-cysteine (Kojima et al., 1992).
Takahashi et al. (1994) also demonstrated that administration of unithiol reduced
renal toxicity (using the same parameters as above) in rats given an intraperitoneal
dose (1.2 mmol/kg) immediately after intravenous injection of gold sodium thiomalate
(0.026 mmol/kg). Compared to the other gold antidotes tested (bucillamine, captopril
and tiopronin), only unithiol was able to significantly reduce the renal gold
concentration at the lowest dose used (0.2 mmol/kg). None of the antidotes reduced
the hepatic gold concentrations at doses of 0.2 or 0.4 mmol/kg.
Succimer and unithiol were the most effective antidotes at increasing survival in mice
given gold sodium thiosulphate (200 mg/kg intraperitoneally, the approximate LD99).
The antidotes were given by the same route 20 minutes after dosing at a ratio of 3:1,
antidote to gold (Basinger et al., 1985).
8.1.10 Lead
Unithiol has been shown to increase lead excretion, reduce lead tissue
concentrations (except in the brain) and to reduce lead-induced biochemical toxic
effects, such as inhibition of δ-aminolevulinic acid dehydratase, in experimental
animals.
In a study comparing dimercaprol and unithiol, rats received lead (2 mg/kg as lead
acetate) intraperitoneally daily for 7 days, and then antidotal treatment (50 µmol/kg)
daily for 3 days beginning 48 hours after the last lead dose. Bone and blood lead
concentrations were not significantly different from controls. The concentration of lead
in the kidneys was significantly reduced by both antidotes. In addition, both antidotes
reduced δ-aminolevulinic acid excretion and appeared to reactivate δ-aminolevulinic
acid dehydratase (Twarog & Cherian, 1983).
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In another study rats received lead (2 mg/kg as lead acetate) intraperitoneally daily for
7 days and 6 days after the last dose unithiol was administered (25-200 µmol/kg). The
highest dose of unithiol removed lead from kidneys, liver and bone, while the lower
doses (25 and 50 µmol/kg) decreased only the kidney concentrations. Urinary
excretion of lead was higher in animals given 100 or 200 µmol/kg of unithiol. Urinary
excretion of δ-aminolevulinic acid was unchanged by unithiol administration in this
study (Twarog & Cherian, 1984).
Administration of unithiol (0.5 mmol/kg subcutaneously daily for 4 days) was of benefit
in rats poisoned with oral lead (10 mg/kg 6 days a week for 6 weeks). The effect of
the antidotes was measured by changes in the concentrations of indicators of lead
toxicity (blood δ-aminolevulinic acid dehydratase, zinc porphyrin, haemoglobin and
haemocrit and urinary δ-aminolevulinic acid). Unithiol was shown to reduce leadinduced inhibition of δ-aminolevulinic acid dehydratase and increase blood zinc
porphyrin and haemoglobin concentrations. Unithiol decreased lead-induced urinary
excretion of δ-aminolevulinic acid. Unithiol also decreased blood, hepatic and renal
lead concentrations, but did not mobilise lead from the brain (Sharma et al., 1987).
Another study in lead-poisoned rats (20 mg/kg intraperitoneally for 5 days)
demonstrated that unithiol (25, 50 or 100 µmol/kg intraperitoneally daily 5 days a
week for 7 weeks, starting 3 days after last lead dose) increased urinary excretion of
lead (due to mobilisation of lead in bone), and reduced δ-aminolevulinic acid
excretion but did not have a beneficial effect on lead-induced anaemia. In addition,
the lethality of lead was unaffected by antidote administration (Hofmann & Segewitz,
1975). In the study by Llobet et al. (1990) unithiol administration at a dose of 2.90
mmol/kg given 10 minutes after intraperitoneal lead (0.58 mmol/kg of lead acetate
trihydrate) reduced lethality in mice from 55% to 40%. Unithiol also caused a
significant increase in urinary lead and a decrease in kidney lead concentrations.
In rats with chronic lead poisoning (lead acetate in drinking water, 50 mg/L for 86
days) administration of unithiol (0.27 mmol/kg intraperitoneally for up to 4 days)
failed to alter lead concentrations in the brain (Aposhian et al., 1996). In a study on
acute parenteral lead intoxication in mice antidotes (2 mmol/kg) were injected during
3 consecutive days after 7 daily injections of lead (50 mg/kg). Unithiol, sodium
calcium edetate (EDTA, calcium disodium edetate, calcium disodium versenate,
calcium EDTA) and D-penicillamine did not protect against lethality. Unithiol was,
however, more efficient than succimer and several other antidotes including sodium
calcium edetate in removing lead from the brain and kidneys (Xu & Jones, 1988).
Tandon et al. (1994) investigated the efficacy of combined metal-binding agents in
lead-poisoned rats (lead acetate 0.1% in drinking water for 8 weeks). Animals were
treated with calcium disodium ethylenediaminetetraacetic acid (EDTA sodium calcium
edetate, succimer, unithiol, sodium calcium edetate and succimer or sodium calcium
edetate and unithiol. All metal-binding agents were given in the same dose (0.3
mmol/4 mL/kg intraperitoneally) for 5 days, followed, after a 5 day break by another 5
day course. Efficacy was measured by metal concentrations in tissues and
biochemical changes (blood δ-aminolevulinic acid dehydratase activity, zinc
protoporphyrin, urinary δ-aminolevulinic acid and total urinary proteins).
The
administration of sodium calcium edetate or succimer resulted in more urinary lead
excretion than unithiol. In addition, the combination of sodium calcium edetate and
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succimer was more effective than sodium calcium edetate and unithiol. Both sodium
calcium edetate and succimer were more effective than unithiol in reducing lead
concentrations in blood, liver, kidney and femur. Only succimer reduced brain lead
concentrations. All the metal-binding agents reversed lead-induced inhibition of δaminolevulinic acid dehydratase activity and increase in zinc protoporphyrin and
urinary excretion of δ-aminolevulinic acid, but the effect was greater with combined
therapy. Again the combination of sodium calcium edetate and succimer was more
effective than sodium calcium edetate and unithiol.
A study in rats demonstrated that antidotal therapy in combination with zinc and
copper supplementation was more effective at lowering blood lead concentrations
than the antidote alone. However, supplementation with unithiol administration (0.3
mmol/kg intraperitoneally, daily for 5 days) did not result in an increase in urinary
lead concentrations and unithiol was relatively less effective at promoting lead
excretion than sodium calcium edetate and succimer. The lead was administered at
a dose of 0.05 mmol/kg daily, 6 days/week for 6 weeks (Flora, 1991).
In mouse cortical cell cultures unithiol was shown to increase the toxicity of lead
chloride (Rush et al., 2009). In another in vitro study using human platelets, unithiol
was shown to protect against lead-induced stimulation of glutamate binding (Borges &
Nogueira, 2008). Unithiol increased lead-induced inhibition of ALAD in human blood
in vitro. In addition the inhibition of ALAD activity in the blood and liver of leadexposed mice was also increased by unithiol treatment (Santos et al., 2006).
8.1.11 Mercury
8.1.11.1
Inorganic mercury
Unithiol has been shown to increase mercury excretion and decrease tissue
concentrations in experimental animals. Most studies found that unithiol does not
increase faecal excretion of mercury (Aaseth et al., 1982; Kachru & Tandon, 1986).
However some studies have shown the opposite (Wannag A. & Aeaseth J., 1980),
but this may be an effect of decreased body burden of mercury with unithiol
treatment (Gabard, 1976a). In addition, although some studies have found that
unithiol mobilises mercury from the brain, others have found that unithiol is relatively
ineffective in reducing brain mercury concentrations. The former observation may be
due to contamination of brain tissue with blood which has a higher mercury
concentration (Buchet & Lauwerys, 1989).
In rats with mercury toxicity (5 µmol/kg as mercuric chloride) unithiol (400 μmol/kg
intramuscularly) was found to be the most effective antidote compared to sodium
diethyldithiocarbamate (DDC) and pentetic acid (diethylenetriaminepentaacetic acid,
DTPA) when given prior to exposure. Unithiol was shown to mobilise mercury in
the urine and reduce concentrations in the liver and spleen. It did not increase
faecal excretion (Kachru & Tandon, 1986). Treatment with unithiol (500 µmol/kg
intravenously) 24 hours after mercury administration (2 μmol/kg intravenously as
mercuric chloride) in mice reduced the mercury content of the kidneys to 60-70% of
controls by 48 hours after administration of the antidote (Wannag & Aaseth, 1980).
Immediate treatment with unithiol (500 µmol/kg intravenously) after mercury
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administration (5 µmol//kg intravenously as mercuric chloride) in rats prevented
pathological changes in the kidneys and increased mercury excretion in the urine.
When administration was delayed 24 hours, unithiol was relatively ineffective in
reversing mercury-induced anuria. The kidney mercury concentration was significantly
reduced, but pathological changes could not be prevented. Mercury concentrations in
the blood, kidney and brain were reduced irrespective of whether the administration of
unithiol was immediate or delayed. Immediate unithiol treatment did not change faecal
mercury elimination whereas delayed administration resulted in increased faecal
excretion (Wannag & Aaseth, 1980).
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Comparing succimer (100 µmol/kg orally) and unithiol (300 µmol/kg orally) in mercurypoisoned rats (0.5 mg as mercuric chloride) Planas-Bohne (1981) found that the rise in
urinary mercury excreted in the succimer treated animals corresponded to the mercury
content of the kidneys. In contrast, the urinary mercury concentration in the unithiol
treated group was higher indicating removal of mercury from other organs. The dose
of unithiol was three times that of succimer because only 30% of the unithiol was
absorbed from the gut compared with 100% of the succimer. However, Cherian et al.
(1988) reported that the increase in urinary excretion induced by unithiol (0.2-2.0
mmol/kg intraperitoneally) was almost equal to the amount of mercury lost from the
kidneys in mercury-poisoned rats (0.1-2 mg/kg intraperitoneally or mercury vapour 0.52 mg/m3).
Administration of oral unithiol (30 µmol/200 g) was shown to normalise renal excretion
of alkaline phosphatase in mercury-poisoned rats (0.75 mg/kg as intravenously
mercuric chloride). The dose of unithiol was given at 6 or 24 hours after mercury and
then once a day until the fifth day. Early administration of unithiol also abolished the
effect of mercury on renal excretion of leucine aminopeptidase, but there was no effect
on this enzyme if administration of unithiol was delayed until 24 hours after mercury
exposure. Furthermore, early treatment with unithiol reduced mercury-induced
lethality, whereas delayed treatment had no effect (Planas-Bohne, 1977).
In a study reported by Aaseth (1983), succimer or unithiol (1 mmol/kg daily for 4
days) given after a single intravenous dose of mercuric chloride (2 μmol/kg) to mice
reduced the renal mercury concentration almost by a factor of three. Brain mercury
concentrations were also reduced. Dimercaprol, in contrast, has long been known to
increase mercury deposition in the brain after exposure to methyl mercury in mice
(Berlin & Ullberg, 1963).
The efficacy of unithiol (220 mg/kg) and succimer (180 mg/kg) were compared in rats
exposed to mercury (0.5 mg/kg as mercuric chloride intraperitoneally 5 times a week
for 3 weeks). The antidotes were administered 7 days after the last mercury dose.
Both antidotes were ineffective in removing mercury from the brain and unithiol was
more effective in increasing urinary mercury excretion. This was also the case when
the same dose of mercury was administered as phenyl mercury (Buchet & Lauwerys,
1989). In a study of various antidotes given in mercury-poisoned mice (as mercuric
chloride 10 mg/kg), where the antidotes were given in doses of antidote:mercury molar
ratios of 10, 15, 20 and 30:1, unithiol reduced lethality and was significantly more
effective than succimer or dimercaprol. This was true for unithiol even at the smallest
dose ratio of 10:1 (Jones et al., 1980).
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In rats with chronic mercury poisoning (0.5 mg/mercury/kg, as mercuric chloride,
intraperitoneally 5 days a week for 32 or 41 days) unithiol (0.27 mmol/kg
intraperitoneally for up to 4 days) failed to alter mercury concentrations in the brain
(Aposhian et al., 1996).
Both renal and biliary excretion of mercury were increased after administration of
unithiol (12.5 mg intramuscularly) in mercury-poisoned rats (120 µg intravenously as
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mercuric chloride). The mercury content was decreased in all tissues, especially in
the kidneys and the brain. Treatment with the diuretic spironolactone before
administration of mercury further increased the biliary excretion of mercury observed
with unithiol. However, the overall excretion of mercury was unchanged (Cikrt, 1978).
In a similar study comparing unithiol (15 mg/kg intramuscularly) and unithiol combined
with spironolactone and oral polythiol resin in mercury-poisoned rats (same dose as
above) Cikrt & Lenger (1980) found that urinary excretion was higher with unithiol
alone but the combination therapy resulted in increased faecal excretion. Both
regimens significantly decreased the mercury content of all tissues.
Of 15 antidotes studied in mercury-poisoned mice (0.5 mg mercury intravenously
mercuric chloride) only unithiol (50 µmol/kg) was shown to have a favourable effect
with increased urinary mercury excretion and reduced tissue concentrations
(erythrocytes, plasma, liver, kidneys, brain, femur, muscle, spleen and intestine).
Unithiol reduced the mercury concentration of the kidneys to approximately 40% of
controls and the other organs to 50-80%. Faecal mercury excretion was decreased
but this was due to a decreased body burden, and overall elimination was increased
due to a large rise in the urinary mercury concentration (Gabard, 1976a). Similarly,
oral unithiol (1 mmol/kg/day for 4 days) reduced the mercury concentration in the
kidney to about 30% of controls in mercury-poisoned mice. Dosing with unithiol was
started immediately after intravenous injection of mercury (2 µmol/kg as mercuric
chloride). There was increased urinary excretion of mercury but faecal excretion
was unchanged (Aaseth et al., 1982).
In a study in mercury-poisoned mice (5, 200, 300 or 400 µmol/kg of mercuric chloride
orally) unithiol (100, 800, 1200 or 1600 µmol/kg orally) given 15 minutes later was
most effective at reducing lethality. In addition oral administration was more effective
than parenteral, probably because of reduction in gastrointestinal absorption of
mercury. Unithiol also reduced mercury concentrations in the brain; intraperitoneal
unithiol reduced mercury brain concentrations to about one third of controls whereas
oral administration reduced concentrations to less than 15% of controls (Nielson &
Andersen, 1991).
Simultaneous administration of sodium selenite and mercuric chloride decreased the
efficacy of unithiol (300 µmol/kg orally) on mercury elimination in rats. The metal salts
were given at a dose of 1.5 µmol/kg by intraperitoneal injection. When both metal
salts were given together there was redistribution of mercury with reduced
accumulation in the kidneys (decreased by more than 94%) and an increased
concentration in the liver (increased about 6 times). Urinary excretion of mercury was
also reduced compared to elimination in the absence of selenium (Jureša et al., 2005).
Kostial et al. (1984) investigated the influence of age on unithiol efficacy in rats (aged
2, 6 and 28 weeks old) with mercury toxicity (50 μg/kg intraperitoneally). Unithiol (50
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mg/kg 3 times, 1 day after mercury administration and then at 24 hour intervals)
decreased the body retention of mercury in all age groups, and was about twice as
effective in adults compared to suckling rats. The reduced effectiveness was due to
the reduced efficacy of unithiol in lowering kidney retention in young animals. This
age difference was also confirmed in a later study (Kostial et al., 1991). In addition
this study found that early treatment with oral unithiol in older rats given oral mercury
increased mercury retention. However, this was in contrast to succimer, where early
treatment while mercury was still in the gut decreased mercury retention.
An in vitro study on isolated perfused segments of rabbit proximal tubules exposed to
inorganic mercury found that mercury was rapidly taken up by the tubular epithelial
cells and resulted in cellular necrosis. The addition of unithiol provided complete
protection against this effect. This appeared to be due to a negligible rate of net
absorption of inorganic mercury ions from the lumen and low levels of ion
accumulation. Unithiol-mercury complexes are not readily transported into proximal
tubular cells and it is thought that unithiol reduces the renal mercury burden by
extraction of mercury during the trans-epithelial transport of unithiol. The therapeutic
efficacy of unithiol in mercury-induced renal damage may be linked to its transport at
the basolateral membrane by the organic anionic transporter (OAT) system and to
prevention of significant uptake of mercury by the proximal tubular cells due to the
formation of unithiol-mercury complexes (Zalups et al., 1998). Another in vitro study
confirmed that unithiol was effective at inhibiting mercury accumulation in renal
proximal and distal tubular cells, and protecting against mercury-induced renal
damage (Lash et al., 1998).
Unithiol, when incubated with mercuric chloride, partially restored cellular morphology,
viability, intracellular adenosine triphosphate (ATP) concentrations and mitochondrial
membrane potential in opossum kidney cells in vitro. Unithiol also had a protective
effect on mitochondrial morphology and showed potent antioxidant activity (CarranzaRosales et al., 2007). Similarly, unithiol was shown to reduce mercuric chloride
toxicity in mouse cortical cell cultures (Rush et al., 2009). In another in vitro study
using human platelets, unithiol was shown to protect against the inhibitory effect of
mercury on glutamate binding (Borges & Nogueira, 2008).
8.1.11.2
Organic mercury
Oral unithiol administration (1 mmol/kg) to rats with methyl mercury poisoning (0.23
mg/kg intravenous as methyl mercury) reduced the biological half-life of the mercury
body burden from 23.0 days to 4.3 days compared to controls. The mercury
concentration was decreased in all tissues, particularly in the kidneys and the brain
(Gabard, 1976b).
The effect of unithiol on motor impairment and cerebellar toxicity has been studied in
mercury-exposed mice. Methylmercury was given in drinking water (40 mg/L) for 17
days with unithiol given on days 15 to 17 (150 mg/kg by intraperitoneal injection). The
mice were tested for signs of toxicity 24 hours after the last dose of unithiol. The
mercury-induced motor deficit was reduced in unithiol treated mice and unithiol also
reduced mercury-induced lipid peroxidation in the cerebellum but did not prevent
mercury-induced reduction of cerebellar glutathione peroxidase. Unithiol significantly
reduced mercury deposition in the cerebellar cortex (Carvalho et al., 2007).
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Unithiol is able to increase elimination of both organic and inorganic mercury from
tissue, however with organic mercury the efficacy of unithiol is affected by the
relative capacity of tissue for dealkylation of organic to inorganic mercury. In rats
with chronic methyl mercury poisoning (10 ppm in drinking water for 9 weeks in a
single dose study and 6 weeks in a repeated dose study) a single dose of unithiol
(100 mg/kg intraperitoneally) was shown to reduce kidney inorganic and organic
mercury concentrations by 38% and 59%, respectively. In addition, urinary inorganic
and organic mercury concentrations increased by 7.2 and 28.3 fold, respectively,
compared with pre-treatment concentrations. A single dose of unithiol was relatively
ineffective at removing mercury from the brain and the mercury in this tissue was
predominantly in the organic form due to slow dealkylation to inorganic mercury. In
contrast, repeated doses of unithiol (100 mg/kg every 72 hours for 1, 2 or 3 doses)
significantly decreased mercury concentrations in the brain, kidney and blood, but
the decrease in the brain and blood was restricted to the organic mercury
component. This was thought to reflect the slow dealkylation of methyl mercury in
these tissues. This may be why unithiol is relatively ineffective at improving organic
mercury-induced neurotoxicity (Pingree et al., 2001).
Unithiol no effect on methylmercury and increased the toxicity of ethylmercury in
mouse cortical cell cultures (Rush et al., 2009).
8.1.12 Nickel
Unithiol has been shown to be efficacious in experimental nickel poisoning in
animals, in terms of increased survival and reduced nickel-induced toxic effects.
Unithiol administered intraperitoneally at a 10:1 mole ratio of antidote to nickel,
increased survival rate in mice poisoned with intraperitoneal nickel acetate (62
mg/kg). Antidotes were administrated 20 minutes after injection of nickel. Unithiol
was less effective than D-penicillamine or sodium calcium edetate, although the
small sample size prohibited any significant differentiation between them (Basinger
et al., 1980).
Administration of unithiol (0.5 mmol/kg subcutaneously daily for 4 days) significantly
enhanced the urinary excretion of nickel in rats poisoned with intraperitoneal nickel
sulphate (4 mg/kg 6 days/week for 4 weeks). In unithiol treated animals there were
significant reductions in nickel concentrations in renal and hepatic tissue and
decreases in evidence of nickel-induced kidney and liver damage (as measured by
plasma concentrations of ceruloplasmin and amino acids, blood glucose and
glutathione, urinary amino acids, and renal, hepatic and cardiac concentrations of
mitochondrial malic dehydrogenase, which is inhibited by nickel). Unithiol reduced the
increase in plasma and urinary amino acids and blood glucose, but did not change the
decreases in plasma ceruloplasmin and blood glutathione concentrations. There was
no significant effect on mitochondrial malic dehydrogenase concentrations. Faecal
nickel excretion was unchanged and unithiol was ineffective at mobilising nickel from
the brain (Sharma et al., 1987).
Rats given nickel (1.5 mg/kg intraperitoneally as nickel sulphate daily, 6 days a week
for 30 days) then unithiol (0.3 mmol/kg intraperitoneally daily for 5 days) had their
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organs harvested 24 hour after the last injection. Unithiol reduced the nickel
concentrations in the liver, blood, heart and kidney but not in the brain. Unithiol also
reversed nickel-induced biochemical changes (decreased ceruloplasmin
concentration and blood glucose; increased plasma and urine concentrations of
amino acids) and increased faecal nickel excretion (Tandon et al., 1996).
8.1.13 Palladium
There is limited information on the effect of unithiol on palladium toxicity. It did not
influence toxicity or reduce lethality in mice with acute palladium chloride poisoning
(586 µmol/kg intraperitoneally). Unithiol was given subcutaneously at the same time
as palladium at a dose of 2.93 mmol/kg (5 times the molar dose of metal) (Mráz et
al., 1985).
8.1.14 Platinum
There is limited information on the effect of unithiol on platinum toxicity. A single
injection of unithiol (1 mmol/kg) produced no significant change in renal platinum
concentration in rats treated with cisplatin (4 or 6.5 mg/kg) 24 hours previously.
After four daily treatments unithiol and succimer caused a significant increase in
urinary excretion of platinum, but this was low, and represented only about 3% of
the injected dose of platinum. It was concluded that none of the antidotes studied,
unithiol, succimer or pentetic acid, were likely to be of benefit in the management of
cisplatin-induced renal toxicity (Planas-Bohne et al., 1982).
8.1.15 Polonium
Several animal studies have shown that although unithiol can remove polonium-210
from most tissues it results in concentration of polonium in the kidneys, with the risk
of renal damage. In addition, unithiol has been shown to cause renal damage when
administered to polonium-poisoned animals (Poluboiarinova & Streltsova, 1964).
Rats were given approximately 0.3 µCi of polonium-210 intravenously followed 1.5
minutes later by intraperitoneal or oral administration an antidote (1 mmol/kg). The
α-activity of tissue was determined 48 hours later. Administration of an antidote
produced a marked decrease in polonium-210 retention in the blood, spleen and
bone and, to a lesser extent, in the plasma. Unithiol but did not decrease polonium210 retention in the kidneys and overall retention of polonium-210 in the blood, liver,
spleen, skeleton and kidneys was increased by 40%. The effect of oral unithiol was
approximately one third of the intraperitoneal dose, and following administration by
this route the overall retention of polonium-210 was increased by approximately
50%. Retention of polonium-210 was particularly seen in the kidneys where it was
transported but not excreted. In view of these findings it was concluded that
although unithiol increased survival of rats given lethal doses of polonium-210, it was
not a suitable antidote for polonium because it could potentiate the toxic effects of
polonium on the kidneys (Volf, 1973).
In a study of rats given a lethal dose (40 µCi) of polonium-210 by intraperitoneal
injection, administration of an antidote (0.2 mmol/kg) 1 minute, 90 minutes, 360
minutes and twice daily on days 2, 3, 4, 12, 22 and 32 increased the mean survival
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time from 39 days to 106 days. Unithiol significantly decreased the polonium-210
content of all tissues studied except the kidneys. However, DMPA was found to be a
more effective antidote and able to decrease polonium-210 in all tissues (Aposhian
et al., 1987).
The study by Rencová et al. (1993) comparing a number of antidotes for polonium210 also found that unithiol reduced retention in the bone, spleen and blood of rats
but increased it in the kidneys. Indeed, the total body retention of polonium-210
could not be reduced to less than 85% of controls with any of the 9 antidotes used.
The same investigators (Volf et al., 1995) looked at the use of antidotes in rats with
simulated wounds contaminated with polonium-210. After 2 weeks of unithiol
treatment (intramuscularly at injection site at 1 hour and 5 days, and systemic
treatment with intramuscular injection on days 1, 7, 9 and 12) polonium-210 at the
wound site was reduced to 12% of controls. The retention in the liver, spleen,
muscle and skeleton was reduced to 14-40%, but the blood content was unchanged
and retention in the kidneys was increased to 340% of controls.
Unithiol was
effective at removing polonium-210 from the wound site when given either locally or
systemically, but it was not effective at removing polonium-210 from the body as a
whole. In a series of other experiments it was concluded that treatment with unithiol
combined with another antidote (particularly sodium N,N’-di-(2-hydroxyethyl)ethylenediamine-N’N’-biscarbodithioate; HOEtTTC) was the most effective method of
removing polonium-210 from the body.
8.1.16 Selenium
There is limited information on the effect of unithiol on selenium toxicity. Unithiol
administration (60 mg/kg intraperitoneally) had no effect on selenium-poisoned rats
(2.24 mg of selenium/kg by subcutaneously). The concentration of selenium in urine
and faeces was unchanged (Paul et al., 1989).
8.1.17 Silver
There is limited information on the effect of unithiol on silver toxicity. Unithiol
administration (0.7 mmol/kg intraperitoneally) increased the LD50 of silver chloride in
mice from 13.6 to 74 mg/kg (Pethran et al., 1990). In dogs given intravenous silver
nitrate unithiol prevented the development of toxic pulmonary oedema and death
(Romanov, 1967).
In an in vitro study of silver inhibition of Na,K-ATPase, which was probably due to
deposition of the metal on sulphydryl groups in the enzyme, it was found that the
process was completely reversed by administration of unithiol (Hussain et al., 1994).
8.1.18 Strontium
There is limited information on the effect of unithiol on strontium toxicity. Unithiol did
not affect survival rate in mice poisoned with strontium chloride (Domingo et al., 1990;
Pethran et al., 1990).
8.1.19 Thallium
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Unithiol is not of benefit in thallium poisoning in experimental animals.
In a study comparing the efficacy of Prussian blue (potassium ferric hexacyanoferrate
II) and unithiol, rats were given an oral dose of 20 mg thallium (as thallium sulphate)
and antidotal therapy was started 24 hours later. The rats were divided into 3
treatment groups: Prussian blue 50 mg/kg for 4 days, unithiol 5 mg/kg 6 times a day on
day 1, 4 times on day 2 and 3 times on days 3 and 4. In the third group the animals
were given both antidotes. Animals were killed on day 5 and the thallium content of
organs determined. Prussian blue administration limited thallium distribution into
tissues, whereas unithiol did not decrease thallium concentration in any organ,
although it did decrease thallium concentrations in blood. The two drugs in
combination decreased the thallium content in all organs but no more than Prussian
blue alone. It was concluded that unithiol is not a useful antidote in thallium poisoning
(Mulkey & Oehme, 2000).
Similarly, unithiol did not affect survival rate in mice given thallium sulphate (Pethran et
al., 1990).
8.1.20 Tin
There is limited information on the effect of unithiol on tin toxicity. Unithiol and
succimer have been investigated as antidotes in rats following a single intravenous
dose dibutyltin dichloride (27 µmol/kg). The antidotes were given at two doses, 100
and 500 µmol/kg, orally and by intraperitoneal injection. Several parameters of
organ toxicity were monitored from 6 hours to 8 weeks. Both drugs reduced
dibutyltin dichloride-induced lesions of the bile duct, pancreas and liver. Unithiol was
more effective than succimer in most measured parameters and the drugs were
though to exert their protective effects on these organs by reducing biliary organotin
excretion (Merkord et al., 2000).
In vitro studies with human erythrocytes incubated with tributyl tin have
demonstrated that unithiol is unable to prevent the tributyl tin-mediated haemolysis of
the cells (Gray et al., 1986; 1987).
8.1.21 Vanadium
There is limited information on the effect of unithiol on vanadium toxicity. However, it is
unlikely to be useful since antidotes containing oxygen, rather than thiol groups such as
unithiol, are more effective at binding vanadium.
Unithiol had no effect on lethality in mice poisoned with sodium vanadate (50 mg/kg
intraperitoneally) or vanadyl sulphate (110 mg/kg intraperitoneally). Unithiol was
given intraperitoneally 20 minutes after administration of vanadium, at a dose of 5:1
antidote to metal compound (Jones & Basinger, 1983).
Unithiol had no significant effect on the death rate, body weight reductions, or
reduction in weights of legs and toes in chick eggs incubated with vanadium
(Hamada, 1994).
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A recent study, however, has shown that oxovanadium (VO2+) is capable of forming a
[VO(DMPS)2]4- complex with unithiol in aqueous solution (Williams & Baran, 2008).
The significance of this in vivo remains to be elucidated.
8.1.22 Zinc
Unithiol can increase excretion of zinc and reduced lethality in zinc-poisoned animals,
but more effective antidotes are available.
In a comparison of several antidotes against the effects of acute parenteral zinc
intoxication in mice, unithiol efficiently reduced acute lethality. Succimer (10:1
antidote:zinc ratio) was given 20 minutes after a fatal dose of zinc (50 mg/kg) was
administered. Survival was 73% with unithiol but other antidotes were equally or
more effective (Basinger & Jones, 1981b).
In mice given zinc acetate (0.49 mmol/kg intraperitoneally) unithiol (2:1 or 5:1 molar
ratios of antidote to metal) was the least effective of the six antidotes tested. Disodium
calcium cyclohexanediaminetetraacetate (CDTA), sodium calcium edetate and
pentetic acid and were the most effective (Llobet et al., 1988).
In a study comparing the efficacy of several antidotes mice were given intraperitoneal
zinc acetate (66-330 mg/kg; LD50 108 mg/kg). Antidotal therapy was given 10 minutes
later, also by intraperitoneal injection. Unithiol reduced the lethality in animals given
66-241 mg/kg of zinc acetate. In those given 330 mg/kg of zinc acetate lethality was
30% compared to 100% in control animals. Unithiol also increased renal excretion of
zinc and reduced blood and heart tissue concentrations compared to controls.
However, pentetic acid and CDTA were found to be more effective zinc antidotes in
this study (Domingo et al., 1988).
8.2
Pharmacokinetics
There is information on unithiol pharmacokinetics in various species of experimental
animals.
Following oral administration between 60% (dogs; Wiedemann et al., 1982) and 30%
(rats; Gabard, 1978) of the dose is absorbed and plasma peak concentrations are
reached after 30 to 45 minutes. Plasma protein binding was measured at 70% in dogs
by equilibrium dialysis (Wiedemann et al., 1982). This is in agreement with the figure
of 65-75%, determined in rats (Planas-Bohne & Lehmann, 1983).
After intravenous administration unithiol is mainly distributed in plasma and kidneys,
only minor concentrations were measured in the brain and other organs. The
apparent volume of distribution in dogs was calculated to be 0.160 mL/kg (Wiedemann
et al., 1982). Most unithiol excreted in the bile of rats is in its altered form and
recovery in bile was 40% of the administered dose (Zheng et al., 1990).
Although unithiol is mainly distributed to the extracellular compartment, studies have
demonstrated uptake by cells.
Planas-Bohne & Olinger (1981) studying the
interaction of antidotes with methyl mercury bound to erythrocytes demonstrated that
unithiol is lost from the extracellular fluid. Wiedemann et al. (1982) found that the
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distribution volume of radiolabelled unithiol exceeded the extracellular volume in dogs.
In vitro studies have demonstrated that unithiol is taken up by cells of the basolateral
membrane of the kidney and can bind mercury within cells (see section 7).
Unithiol is rapidly eliminated from the body. The serum half life is approximately 20 to
60 minutes and plasma clearance is approximately 2.6 mL/min/kg. In dogs given
radiolabelled unithiol 93% was eliminated within 3 days, with the bulk (98%) eliminated
in the urine and the rest in the faeces (Wiedemann et al., 1982).
Gabard & Walser (1979) stated that unithiol is not involved in important metabolic
pathways and a quantity is excreted unchanged; Maiorino et al. (1988) demonstrated
the presence of several acyclic and cyclic oxidized metabolites in the urine of rabbits.
8.3
Toxicology
Unithiol is of low acute and chronic toxicity. Studies have determined the LD50 for
various species and examined the effect of acute or chronic unithiol administration on
trace element concentrations.
In order of decreasing sensitivity to unithiol, animal species can be ranked as follows:
cat, dog, guinea pig, rabbit, rat and mouse (Klimova, 1958; Aposhian, 1983). The
optical isomers of unithiol do not differ in their toxicity (Hsu et al., 1983).
8.3.1 Acute toxicity
Unithiol is of relatively low toxicity. By the parenteral route the acute LD50 of unithiol
for various species is about 1 to 2 g/kg (Planas-Bohne et al., 1980; Aposhian et al.,
1981; Aposhian, 1982; Hruby and Donner, 1987; Pethran et al., 1990). After
intraperitoneal injection of lethal doses rats are highly irritable for some minutes before
they become apathetic followed by cessation of breathing and death within 12 hours.
The LD50 for a single dose in rats was 5 mmol/kg (1.14 g/kg) and after dosing on 10
consecutive days was 30.8 mmol/kg (Planas-Bohne et al., 1980). No acute toxicity
was observed in mice receiving oral unithiol (100, 300 or 600 µg/mL) for 5 days in
drink water. These doses are equivalent to 18, 55 and 109 mg/kg/day or 0.1, 0.3
and 0.5 mmol/kg/day (Jones et al., 1996).
In rats treated with a single intraperitoneal dose of 1 mmol/kg of unithiol, urinary zinc
and copper excretion was increased whereas the excretion of iron and manganese
was unchanged (Gabard et al., 1979).
A single subcutaneous injection of unithiol (1.6 mmol/kg) in mice caused a significant
increase in δ-aminolevulinic dehydratase activity in the blood and a decrease in the
kidney, with no change in the liver or brain. Unithiol also significantly increased the
zinc concentration of the kidneys but did not change liver or brain concentrations.
There was also a significant increase in liver and kidney lipid peroxidation (Santos et
al., 2005).
8.3.2 Chronic toxicity
Unithiol is of relatively low toxicity even in chronic administration. Hrdina et al. (1998)
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studied the effects of repeated injection of unithiol on the heart of rabbits. The animals
were given intravenous unithiol, 50 mg/kg once a week for 10 weeks. There was no
change in iron or selenium concentrations. There was a slight decrease in myocardial
concentrations of calcium, potassium and magnesium, but only the later was
significantly different. These changes were not associated with any haematological,
histological or physiological changes.
Mice receiving unithiol 300 µg/mL in drinking water for 3 months showed no signs of
toxicity. Haematological and biochemical parameters were also unchanged (Jones
et al., 1996).
Rats receiving 600 µmol/kg/day orally (126 mg/kg/day) on 5 days per week for 66
weeks did not show any adverse effects. Treatment for 36 weeks led to a reduction in
copper-concentrations in the kidneys, liver and skin (Planas-Bohne et al., 1980).
Beagle dogs treated for 6 months with doses up to 15 mg/kg/day intravenously or 45
mg/kg/day orally showed no significant changes in blood-concentrations of glucose,
uric acid, creatinine, total protein, sodium, potassium, calcium, magnesium and iron,
and activity of liver enzymes and cholinesterase in the serum. In addition, the red and
white blood picture as well as gain in body weight remained unchanged. A dosedependent decrease in the copper content was found in the serum, liver, kidney and
spleen. The macroscopic and microscopic examination of several organs revealed no
pathological changes. After treatment for 10 weeks at a dose of 2 x 75 mg/kg/day
intravenously the following changes were noted: a depletion of copper in the serum
and in various organs, an increase of the iron content of the liver and spleen, and a
decrease in haemoglobin, haematocrit, red blood cells, alkaline phosphatase activity
and zinc content in the blood (Szincicz et al., 1983).
8.3.3 Reproductive toxicity and teratogenicity
Unithiol does not appear to produce reproductive toxicity or teratogenicity.
No teratogenic effects were reported in the offspring of rats given 600 µmol/kg/day
orally (126 mg/kg/day) on 5 days per week. Female rats were mated with untreated
males after 14, 26 or 60 weeks of treatment with unithiol. Treatment was continued
during pregnancy and nursing. The number of pregnant animals and the litter size
was smaller in the treated group but the difference was not significant (Planas-Bohne
et al., 1980).
No adverse effects were observed in mothers or offspring in mice given up to 630
mg/kg/day in two dosing regimens: from gestation day 14 until birth or from gestation
day 14 until post-natal day 21. The no observed effect level (NOEL) of 630
mg/kg/day is much higher than that used in the treatment of human heavy metal
poisoning (Domingo et al., 1990).
Mice given unithiol, up to 300 mg/kg, on days 6 to 15 of gestation showed no
maternal or reproductive effects. Unithiol had a minor effect on maternal and fetal
mineral metabolism which was variable and not dose related. These effects did not
produce maternal or embryofetal toxicity (Bosque et al., 1990).
No teratogenic effects were reported in rabbits given unithiol (up to 100 mg/kg
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intravenously daily) from days 6 to 18 of gestation (Anon, 1992/1993).
Unithiol has been shown to protect against the developmental toxicity of arsenic
(Domingo et al., 1992) and mercury (Gomez et al., 1994) in experimental animals.
Mice were given a single intraperitoneal injection of sodium arsenite on day 9 of
gestation followed by immediate injection of dimercaprol or unithiol with further doses
at 24, 48 and 72 hours. Dimercaprol did not protect against arsenic-induced
developmental toxicity, whereas unithiol was protective at 150 and 300 mg/kg/day
and was able to prevent embryotoxicity and fetotoxicity. The higher dose also
prevented maternal arsenic toxicity (Domingo et al., 1992). Pregnant mice were
given a single oral dose of 30 mg/kg of methyl mercury chloride on day 10 of
gestation followed by dimercaprol (by subcutaneous injection) or unithiol (by gavage)
at 24, 48 and 72 hours. Dimercaprol administration did not prevent maternal or
developmental toxicity, whereas unithiol in doses up to 360 mg/kg/day significantly
reduced maternal lethality. Treatment with the higher doses, 180 and 360
mg/kg/day, also protected against mercury-induced embryotoxicity and teratogenicity
(Gomez et al., 1994).
8.3.4 Genotoxicity
Unithiol has been evaluated for mutagenicity in the Ames test with negative results
(Aposhian et al., 1983; Ruprecht, 1997). Normal DNA synthesis was maintained with
unithiol concentrations up to 8 µg/mL in an in vitro study using 3 murine tumour cell
lines. Above 8 µg/mL unithiol inhibited DNA synthesis, and above 30 µg/mL inhibition
exceeded 80% (Jones et al., 1996).
An in vitro study found that unithiol increased the incidence of nickel-induced DNA
breaks in a human leukaemia cell line. There was also an increase in DNA breaks in
bacterial plasmids (a simpler system). Succimer and dimercaprol also increased
DNA breaks in plasmids in the presence of nickel, but the effect was strongest with
succimer. These metal binding agents all generate hydrogen peroxide in solution
but succimer is the most potent. Free radicals are throught to be involved in the
DNA damage observed. For the most potent compound, succimer, the breakage of
DNA was completely prevented by the presence of mannitol and partially reduced by
antioxidants. This protective effect was not investigated for unithiol (Lynn et al.,
1999).
9.
Volunteer studies
There are three main studies of unithiol pharmacokinetics, all conducted by the same
group, consequently some volunteers took part in more than one study. The
characteristics of each study are as follows:
• The study by Maiorino et al. (1991) involved 10 male volunteers, aged 24-34 years,
weighing 68-98 kg.
• The study by Hurlbut et al. (1994) involved 5 volunteers (4 male, 1 female), aged 24
to 32 years, weighing 49-93 kg.
• The study by Maiorino et al. (1996) involved 4 male volunteers, aged 23 to 27
years, weighing 86-91 kg.
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9.1
Absorption
Unithiol is rapidly absorbed. In volunteers given 3 x 100 mg capsules, unithiol was
detected in blood within 0.5 to 4 hours after ingestion. Maximal concentrations were
reached within 3 to 4 hours (Maiorino et al., 1991).
In 4 male volunteers the oral bioavailability of unithiol was calculated to be 39%, with a
range of 19-62% (Hurlbut et al., 1994).
9.2
Distribution
In volunteers given 3 x 100 mg capsules, metabolites (altered unithiol) were confined
to the plasma portion of the blood suggesting that they were bound to plasma
proteins (Maiorino et al., 1991). Plasma protein binding of unithiol was approximately
90% when measured by equilibrium dialysis in human plasma samples from 3
volunteers (Wiedemann et al., 1982). However in a further study by Maiorino et al.
(1996), less than 1% of unithiol was present in an unaltered form in the plasma 5
hours after a single oral dose of 300 mg. The protein-bound unithiol and non-proteinbound unithiol disulphides were present as 62.5% and 36.6% of the total unithiol,
respectively. The protein-bound unithiol was present as a unithiol-albumin complex
(84%) and a higher molecular weight complex (16%).
In volunteers given unithiol 3 mg/kg intravenously over 5 minutes the volume of
distribution varied from 2.67 to 15.4 L/kg (Hurlbut et al., 1994).
Although unithiol is mainly distributed to the extracellular compartment, studies have
demonstrated uptake by cells. An in vitro study investigating the interaction of
antidotes with methylmercury bound to erythrocytes demonstrated that unithiol is lost
from the extracellular fluid (Planas-Bohne & Olinger, 1981) and uptake by human
erythrocytes has been demonstrated in vitro (Wildenauer et al., 1982). Uptake of
unithiol by the renal proximal cells is thought to be mediated by the organic anion
transporter (Islinger et al., 2001; see section 7).
9.3
Elimination
Unithiol is rapidly metabolised and subject to renal elimination.
In volunteers given 3 x 100 mg unithiol capsules the elimination half-life in blood of
unithiol and metabolites (altered unithiol) was 4.4 and 9.6 hours, respectively
(Maiorino et al., 1991). Maiorino et al. (1996) determined the half-lives of unithiol and
metabolites to be 1.8 and 20 hours, respectively. The long half-life of altered unithiol
was thought to reflect the stability of the unithiol-albumin complex and since unithiol is
released slowly, albumin may act as a reservoir for unithiol.
In volunteers given unithiol 3 mg/kg intravenously over 5 minutes blood concentrations
declined rapidly with an apparent elimination half-life of 1.8 hours. By 96 hours 12% of
the total unithiol found in the urine was excreted as the parent compound,
representing 10% of the administered dose; 88% was present as disulphide
metabolites (74% of the administered dose). The metabolites are eliminated more
slowly than the parent compound, with an elimination half-life of 23 hours (range 19.8-
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37.5 hours). The elimination half-life in urine is 20 hours (Hurlbut et al., 1994).
The apparent difference in blood and urine half-lives in the Maiorino et al. (1991) oral
and Hurlbut et al. (1994) intravenous study may be due to different metabolites
produced following administration by different routes. In addition the total unithiol
concentration was determined at different time points (Hurlbut et al., 1994).
9.4
Metabolism
Unithiol is extensively metabolised and unchanged drug is present as only a small
concentration in blood and urine. In volunteers given unithiol 3 mg/kg intravenously
over 5 minutes only 12% of unchanged unithiol was detected in the blood after 15
minutes (Hurlbut et al., 1994). In volunteers given 3 x 100 mg unithiol capsules 3.7%
was excreted as unchanged unithiol and 38.7% as metabolites by 15 hours. Of the
total unithiol found in the urine by 15 hours, unchanged unithiol and metabolites
represented 9% and 91%, respectively. The metabolites are thought to be
disulphide compounds (Maiorino et al., 1991). In a later study (Maiorino et al., 1996)
the unithiol disulphide metabolites were determined to be cyclic polymeric unithiol
disulphides (97%), unithiol-cysteine mixed disulphide (2.5%) and acyclic unithiol
disulphide (0.5%).
9.5
Effect of DMPS on the excretion of metals
Few volunteer studies on the effect of unithiol on metal excretion are available.
9.5.1 Arsenic elimination
In addition to increasing urinary elimination of arsenic, unithiol has also been shown
to alter the relative urinary concentrations of organoarsenic metabolites.
The arsenic-antidote complex was determined in the urine of Romanian subjects
exposed to high concentrations of arsenic in drinking water (up to 16 µg/L). Samples
were collected before and after oral administration of 300 mg of unithiol. Subjects
had been asked to avoid seafood for three days prior to and during the collection
period. The presence of a unithiol-monomethylarsenous acid (As3) complex was
demonstrated in the urine samples of subjects given unithiol. Administration of
unithiol resulted in a decrease in dimethylarsenic acid (As5) and an increase in
monomethylarsonic acid (As5) concentrations. Monomethylarsenous acid (As3) is a
substrate for the biomethylation of arsenic from monomethylarsonic acid (As5) to
dimethylarsenic acid (As5); the formation of the unithiol-monomethylarsenous acid
complex reduces the availability of monomethylarsenous acid (As3) for
biomethylation and inhibits further methylation (Gong et al., 2002).
A similar change in urine concentrations of dimethylarsinic acid and
monomethylarsonic acid was also found in the study by Aposhian et al. (1997)
investigating arsenic excretion in two populations in Chile. In one town the drinking
water contained 593 µg/L of arsenic, and in the other 21 µg/L (controls). Subjects
were asked to exclude seafood from their diet for 3 days prior to the study and
bottled water (arsenic <0.5 mg/L) was drunk throughout. Subjects were excluded if
they had a history of previous antidotal therapy, hypersensitivity to similar metal-
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binding agents or administration of other investigational drugs, serious renal or
psychiatric disease, abnormalities in blood biochemistry or urine analysis that could
interfere with evaluation, pregnancy, lactation or abuse of alcohol or recreational
drugs. There were 13 subjects in the high arsenic exposure group and 11 controls.
Urine samples were collected before and after oral administration of 300 mg unithiol.
In the 2 hour period after unithiol administration the urinary concentration of the
metabolites monomethylarsonic acid and dimethylarsinic acid represented 42% and
37-38%, respectively, with an inorganic arsenic concentration representing 20-22%
of the total urinary arsenic. The normal range of monomethylarsonic acid is 10-20%
and the percentage increase was almost the same for the two groups. The rise in
monomethylarsonic acid was accompanied by a decrease in dimethylarsinic acid.
The percentage of inorganic arsenic also increased with unithiol treatment.
9.5.2 Bismuth elimination
Two groups of 12 volunteers (age 26-65 years), who had been treated with colloidal
bismuth subcitrate for 28 days because of Helicobacter pylori-associated gastritis, took
part in a study of bismuth elimination with unithiol and succimer. Each subject
received a single oral dose of succimer or unithiol 30 mg/kg in a randomised single
blind study. The succimer or unithiol was given 7 to 14 days after the last dose of
bismuth. Both antidotes produced a 50-fold increase in urinary bismuth excretion
compared to control urine samples. The highest concentration was excreted within
the first 4 hours after dosing. No significant difference was observed in bismuth
elimination between succimer and unithiol and both were well tolerated (Slikkerveer et
al., 1998).
9.5.3 Cadmium elimination
Of the 6 metal-binding agents investigated in an in vitro study using human cell
cultures, unithiol, succimer and mercaptosuccinic acid were found to the most
effective at increasing cadmium movement from cells. Unithiol produced the most
rapid elimination from cells in the first two hours, but the other two agents mobilised
more cadmium than unithiol (Bakka et al., 1981).
9.5.4 Mercury elimination
Significant increases in urinary mercury elimination have been demonstrated with
unithiol administration.
The mercury elimination rate was determined in 5 healthy volunteers (4 male, 1
female, aged 24 to 32 years, 49-93 kg) given unithiol 3 mg/kg intravenously over 5
minutes. Unithiol increased mercury excretion by a factor of 24.2 in the 11 hours
after administration. No relationship was observed between the dose of unithiol and
the quantity of mercury excreted in the urine (Hurlbut et al., 1994). In the 4 male
subjects who had taken part in a previous oral study (Maiorino et al., 1991) the
quantity of mercury excreted in the 12 hours after intravenous administration was
less than that excreted in the same period after oral unithiol (Hurlbut et al., 1994).
Mercury elimination was examined after a unithiol challenge test in 12 male (66-96
kg), former chloralkali workers exposed to metallic mercury vapour for 2-18 years.
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The investigation was undertaken 18-56 months after exposure has ceased. A
single 300 mg dose of unithiol was given and this increased 24 urinary excretion of
mercury by a factor of 7.6. A high proportion (62%) was excreted within the first 6
hours and this probably reflects mercury stored in the kidney (Sallsten et al., 1994).
The clinical efficacy of unithiol was investigated in 10 male volunteers (aged 19-45
years) with occupational mercury exposure (with a urine mercury concentration
equal to or greater than 50 μg/g of creatinine). Each subject received unithiol 100
mg orally three times a day for 5 days. They had been asked to omit seafood from
the diet for one month and to take no iron-containing vitamin preparations or
medications for 2 weeks prior to the study. One subject developed a macular rash
which resolved in two days. Otherwise, all the subjects remained well with no
changes in renal or liver function, blood biochemistry or vital signs. In 9 of the 10
subjects mercury elimination was significantly enhanced during the first 24 hours
after unithiol administration, and in all subjects the mean increase in mercury
excretion was higher over the 5 day period compared to the baseline (Torres- Alanís
et al., 1995).
Gonzalez-Ramirez et al. (1998) also studied the effect of unithiol on mercury
elimination in volunteers with occupational exposure (5 males, 3 females, aged 2157 years). The unithiol was given in 3 cycles: 3 days after an initial challenge test,
unithiol was given for 8 days with 5 subsequent days with no treatment. This was
followed by second cycle of 7 days of unithiol, a 5 day period of no treatment and
then 6 days of unithiol. The unithiol was given orally 1 hour before breakfast, lunch
and dinner in doses of 100 mg, 100 mg and 200 mg, respectively, on each treatment
day. One subject developed a maculopapular rash and raised liver enzymes after
the first course and did not receive further doses. Prior to treatment the mean total
urinary mercury excreted in 24 hours was 504 µg (range 140-1692 µg) and during
the first course of unithiol this rose to 1754 µg (range 657-2880 µg). The figure for
the two subsequent courses became progressively lower (314 µg [range 152-658 µg]
and 173 µg [range 74-443 µg]) but in both cases was higher than the period of no
treatment which preceded it (106 µg [range 66-212 µg] and 48 µg [range 30-97 µg]).
Unithiol was effective in lowering the body burden of mercury and increasing the
urinary mercury concentration.
The elimination of mercury following unithiol administration was examined in 75
mercury-exposed volunteers from a gold mining area in the Philippines. Urine
samples were collected before and 2 to 3 hours after unithiol administration (200 mg
orally). In the first urine the mean concentration of inorganic mercury was 15.7 µg/g
of creatinine and for organic mercury it was 2.2 µg/g of creatinine. In the samples
after unithiol dosing the concentrations were 262 µg/g of creatinine and 14.5 µg/g of
creatinine, respectively. Unithiol increased the inorganic urinary concentration by a
factor of 16 and the organic mercury concentration by a factor of 5.1 (Drasch et al.,
2007).
Mercury clearance during dialysis was investigated in an in vitro experiment using
pooled plasma samples to which mercury and metal-binding agents had been added.
Of the agents investigated acetylcysteine was the most effective in clearing mercury
after 90 minutes of in vitro dialysis, reducing the mercury concentration in the
perfusate by 73%, whereas unithiol removed almost 70% of mercury in the perfusate.
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Unithiol was more effective than succimer but the results were not statistically
different. In contrast the quantity of mercury removed from plasma without the
presence of a metal-binding agent was very low at 5% (Ferguson & Cantilena, 1992).
9.5.5 Palladium elimination
There is limited information on palladium elimination with unithiol. In a study of 50
volunteers the elimination of palladium increased from 0.3 to 38 µg/g of creatinine
and there was no difference between oral and intravenous administration of unithiol
(Runow, 1996).
9.5.6 Trace element elimination
Unithiol has been shown to increase elimination of some trace elements in volunteer
studies.
Trace element elimination was examined after a unithiol challenge test in 12 male
(66-96 kg), former chloralkali workers exposed to metallic mercury vapour for 2-18
years. The investigation was undertaken 18-56 months after exposure has ceased.
A single 300 mg dose of unithiol was given and this increased 24 hour urinary
excretion of copper by a factor of 12 and zinc by 1.5 (Sallsten et al., 1994).
Eleven patients presenting with concerns over exposure to mercury in dental amalgam
were given a unithiol challenge test, and the urinary elimination of trace elements
examined. The patients (8 female, 3 male) had no known occupational exposure to
mercury. The dose of unithiol was 3 mg/kg intravenously and urine samples were
taken 1 hour before and 1 hour after. There was a significant increase in mercury
excretion (3-107 fold) in all subjects. The elimination of chromium and manganese
was unchanged and the urinary concentrations of cobalt, aluminium and molybdenum
were too low for reliable measurement. The urine copper (2-119 fold), selenium (343.8 fold), zinc (1.6-44 fold) and magnesium (1.75-42.7 fold) concentrations were
increased in most patients (Torres- Alanís et al., 2000).
Trace element blood concentrations were examined in 80 volunteers (51 females, 29
males) given 2 mg/kg unithiol intravenously. An increase in urinary copper and zinc
concentrations were observed 30 and 120 minutes after injection. The selenium
concentration was unaffected. There was also a decrease in blood concentrations of
copper, zinc and selenium. However, this may have been due to a dilution effect since
the concentrations returned to normal within 120 minutes of the injection and a similar
effect was observed within iron concentrations (Høl et al., 2003).
10.
Clinical studies – clinical trials
Few controlled clinical trials on unithiol are available, and most concern mercury.
10.1
Arsenic and unithiol clinical trials
Unithiol was investigated in a randomised placebo-controlled trial in the management
of chronic arsenicosis due to contaminated drinking water (arsenic >50 μg/L) in
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India. All the patients weighed 40-56 kg and had been drinking the water for more
than 3 years.
Subjects were excluded if they had ceased drinking arseniccontaminated water for more than 3 months, had been treated with other antidotes,
had a history of smoking, alcoholism, were taking hepatotoxic drugs or were serum
positive for hepatitis B virus surface antigen. Pregnant or lactating women were also
excluded.
A total of 21 patients were randomly assigned to 2 treatment groups: 11 patients (9
males, 2 females, mean age 30.63 years) received unithiol and 10 patients (5 males,
5 females, mean age 34.4 years) received the placebo. The unithiol dosage regimen
was 100 mg 4 times a day for 1 week, repeated in the third, fifth and seventh week.
Further ingestion of arsenic-contaminated drinking water was also stopped. Therapy
with unithiol resulted in significant clinical improvement as evaluated by an objective
clinical scoring system. Cessation of exposure and placebo also reduced clinical
scores but the post-treatment scores were significantly lower for unithiol-treated
subjects. Improvement in clinical scores for the placebo group was attributed to
cessation of exposure, rest and provision of an adequate hospital diet. The most
significant improvement was seen in the clinical score of weakness, pigmentation
and lung disease. There were also significant increases in total urinary arsenic
excretion with unithiol treatment, compared to no increase in the placebo group.
Unithiol was well tolerated with no adverse effects reported (Guha Mazumder et al.,
2001).
10.2
Copper (Wilson’s disease) and unithiol clinical trials
Wang et al. (2003) studied 28 patients with Wilson’s disease (18 males, 10 females
aged 14-20 years).
Patients were included on the basis of presence of
extrapyramidal symptoms and signs, presence of characteristic corneal KayserFleischer ring observed with a slit lamp, a serum ceruloplasmin <200 mg/L and
copper oxidase concentration <0.21 units and urinary copper >100 μg (1.56 µmol)/24
hours. Group A received captopril, 1 mg/kg orally daily in 3 divided doses, Group B
unithiol 20 mg/day intravenously and Group C both. Group D was the control group
and did not receive either drug. Serum sulphydryl concentrations and 24 hour
urinary copper concentrations were the markers of anticopper efficacy. Unithiol had
a more potent anticopper effect than captopril and increased urinary copper
concentrations and serum sulphydryl concentrations. Only 1 patient developed an
adverse effect with transient elevation of alanine aminotransferase.
10.3
Lead and unithiol clinical trials
There are few clinical trials on the use of unithiol in lead poisoning.
One of the earliest reports of unithiol use in the treatment of lead poisoning was by
Anatovskaya (1962). Sixty men with chronic lead toxicity were given 250 mg
intramuscularly for 20 days. Blood concentrations of lead fell and urinary excretion
increased. The clinical signs and symptoms improved subjectively and objectively.
Haematological parameters and liver function improved in more patients in the
unithiol-treatment group compared to controls given only supportive care. In addition
patients treated with unithiol could be discharged from hospital 6 weeks earlier than
controls.
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A more recent study involved children attending a lead poisoning treatment clinic in
Baltimore, USA, where lead paint was the main source of poisoning. The criteria for
inclusion were a blood lead concentration of 400-600 µg/L, normal hepatic, renal and
haematological function, no history of antidotal therapy within the previous 3 months,
no concurrent disease and an age of 30 to 72 months. Six children (5 males, 1
female, aged 31 to 53 months) received a 5 day course of unithiol, 200 mg/m2 daily.
Another 6 children (1 male, 5 females, aged 38-69 months), received 400 mg/m2 daily
for 5 days. The drug was well tolerated in all cases. Administration of either dose
reduced the blood lead concentration to approximately 78% of its pre-treatment
concentration by 48 hours. After 96 hours the blood lead concentration was 76% and
68% of its pre-treatment concentration in the low and high dose group, respectively.
Blood lead concentrations did not increase until 48 hours after cessation of therapy.
Urinary excretion of both copper and zinc were increased, 2-30 fold and 1.2-9.1 fold,
respectively with higher concentrations of both in the higher treatment group. There
were no significant changes in plasma copper or zinc concentrations. The urinary
concentration of lead increased 1.3-15 fold between the last pre-treatment day and the
first treatment day (Chisolm & Thomas, 1985). This trial was later terminated following
the occurrence of at least one case of Stevens-Johnson syndrome and succimer was
used instead (Chisolm, 1990).
10.4
Mercury and unithiol clinical trials
There are a small number of clinical trials investigating the effect of unithiol on
mercury toxicity. An early study undertaken in Iraq, with preliminary results reported
by Bakir et al. (1976) was limited in scope due to various circumstances (Clarkson et
al., 1981). A more recent study examined patients with chronic mercury exposure in
the Philippines (Böse-O’Reilly et al., 2003). Another study in China examined the
effects of antidotal treatment in acutely poisoned patients treated 5 months after
exposure (Zhang, 1984).
A Mexican study examined the effect of unithiol on
mercury excretion in patients with high mercury concentrations due to use of
mercury-containing facial cream (Garza-Ocañas et al., 1997).
The early study investigated antidotal therapy in patients with methyl mercury
poisoning. The source was homemade bread made from wheat contaminated with a
methyl mercury fungicide over the winter of 1971-1972. Antidotal agents where in
limited supply and were not available until February 1972 after exposure had ceased.
The conditions of the time did not allow for the implementation of a clinically controlled
study but it was possible to obtain data on the effects of antidotes on blood mercury
concentrations. D-penicillamine (12 patients), N-acetyl-DL-penicillamine (17), unithiol
(10) and a thiolated resin (8) were used. There were 27 females and 20 males, aged
from 18 months to 55 years. Ten other patients received a placebo and 6 received no
specific treatment. The duration of treatment was variable but for unithiol was 4 to 15
days. All agents reduced blood mercury concentrations but unithiol was the most
effective. However, the patients did not show any immediate clinical improvement,
presumably because the duration of therapy was too short (Clarkson et al., 1981).
Unithiol was evaluated in the management of chronic mercury exposure, including
exposure from mercury vapour, inorganic mercury and organic methyl mercury, in the
gold mining area of Mount Diwata, in the Philippines. A total of 95 patients (no details
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given) were included in the study. There was no control group. Unithiol was given
orally at a dose of 200 mg twice daily for 14 days for adults and 5 mg/kg/day for
children. Patients were assessed by questionnaire, medical, including neurological,
examination and neuropsychological testing before and after therapy. Blood, urine
and hair samples were analysed for mercury concentrations before therapy and blood
and urine after therapy. Two study populations were identified: those living near
Mount Diwata and exposed to metallic and/or inorganic mercury (60 patients), and
those living downstream in Monkayo who were exposed to methyl mercury (35
patients). Exposure to mercury continued during therapy with unithiol. The mercury
concentrations in hair and blood did not differ between the two populations before
unithiol therapy. The urine concentration was significantly higher in the Mount
Diwata population (due to the differing pharmacokinetics of organic and inorganic
mercury). There was therefore a higher renal excretion of mercury in the Mount
Diwata population when treated with unithiol. However, the Monkayo population
demonstrated a relative increase in renal excretion of mercury almost as high as the
Mount Diwata population when given unithiol. Some patients (number not specified)
did not respond to unithiol administration and showed no increase in mercury
excretion. In the Monkayo group there was only a modest decrease in blood
mercury concentrations, indicating the duration of treatment was too short to have a
long-term effect on mercury stored in tissues. More than two-thirds of patients
reported an improvement in subjective complaints after therapy and objective
neurological parameters also showed significant improvement.
Significant
improvement was also demonstrated in two neuropsychological tests. The authors
concluded that unithiol could increase mercury excretion but that a 14 day regimen
was too short to have a permanent effect on mercury concentrations (Böse-O’Reilly
et al., 2003). This study has a number of limitations including the absence of a control
group, lack of details of patients (age, weight) and continued exposure to mercury
during therapy.
Forty-one patients (aged 2 to 65 years) from 8 families were poisoned with mercury
following ingestion of rice contaminated with an ethyl mercury seed dressing. One
patient died soon after onset of symptoms and 8 were admitted in the initial acute
phase of intoxication. The remaining 40 patients demonstrated a variety of clinical
features 5 months after ingestion and 27 were treated with unithiol (250 mg daily by
intramuscular injection) and/or succimer (500 mg twice daily by intravenous injection).
The drugs were given for 3 days followed by a 4 day break and then another 3 day
course, if required. Patients were given 1 to 8 courses until the urinary mercury
concentration was normal. The 13 untreated patients showed little improvement in
clinical features of toxicity but all those on therapy had some relief and 19 became
asymptomatic. In 2 cases there was only slight improvement. In patients where the
urinary concentration was measured before therapy, all but one had increased
mercury excretion during antidotal administration. Side effects were mild and
generally resolved within 30 minutes to 4 hours. Unithiol was found to be more
effective, although no data distinguishing between the two drugs is given. In addition,
the two antidotes were used interchangeably in some patients (Zhang, 1984).
Unithiol was also used in 12 females (aged 19-45 years) with mercury toxicity
following use of a facial cream containing 5.9% mercurous chloride (calomel) for 2 to
10 years. Two patients were symptomatic (exanthema and tremor) and all had
elevated urinary mercury concentrations. Subjects were given a 5 day course of
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unithiol (200 mg/day) as outpatients. Only 8 subjects took the unithiol as prescribed
and supplied 24 hours urine samples for analysis. In all cases there was a significant
increase in urinary mercury concentrations after 24 hours of unithiol.
One
symptomatic patient has complete resolution of effects and the other had persistent
tremor. Unithiol was well tolerated in all patients (Garza-Ocañas et al., 1997).
11.
Case reports - clinical studies
In many clinical case reports of unithiol use in poisoning the authors do not determine
a balance between the quantity of metal absorbed and excreted; this can be difficult
where the dose ingested, injected or inhaled cannot be quantified. Clinical efficacy of
unithiol is often only stated in terms of enhancing excretion and/or decreasing blood
concentrations in the absence of severe adverse effects. In many cases, the authors
are unable to distinguish between the effect of unithiol administration and the effect of
supportive therapy (including removal from the source).
The efficacy of a metal-binding agent may be difficult to determine.
After
discontinuation of metal exposure (and absorption) a decrease in the blood
concentration will occur without any therapy. Clinical efficacy should not be judged
only by the amount of metal excretion or the decrease of blood concentrations. The
reduction of the tissue content in the target organ and the restoration of pathological
alterations also need to be considered. It is important to note that enhancement of the
metal excretion by mobilisation may increase the metal burden of the target organ by
redistribution, and conversely the body burden may be reduced without a striking
decrease of the blood concentrations. However, in some case reports severe toxicity
usually associated with a demonstrated high blood or urine concentration does not
occur, and this may reasonably be assumed to be due to antidotal therapy. With
these reservations in mind, it is clear that administration of unithiol can prevent
development of toxicity and in symptomatic patients it can reduce recovery time and
improve clinical signs and symptoms of toxicity.
Reference values for the metal and metalloids (Walker, 1998) are given as a guide at
the start of each section to aid interpretation of the concentrations given in the case
reports.
11.1
Use in antimony poisoning
Reference values for antimony (Walker, 1998):
Children
Serum/plasma
0.18 µg/L
Blood
0.26 µg/L
Urine
0.05 µg/L
Adults (unexposed) Urine
0.8 µg/L
There is limited information on the use of unithiol in antimony poisoning, but it appears
to be of benefit in the management of poisoning with trivalent antimony compounds.
There is no information on its use in the management of poisoning with the less toxic
pentavalent antimony compounds.
A 2 year 11 month old child was treated with unithiol after ingestion of an unknown
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quantity of tartar emetic (antimony potassium tartrate). The clinical features,
particularly massive fluid loss and dehydration, were consistent with antimony
poisoning. She was given unithiol 65 mg intravenously then 3 x 100 mg daily for 10
days followed by 3 x 50 mg daily for another 10 days. She was also treated with
exchange transfusion at 39 hours post-ingestion. The serum antimony concentration
at 4.5 hours post-ingestion was 0.6 mg/L and the urine concentration at 7 hours 31
mg/L. Unithiol was considered effective in reducing the antimony concentration in the
early stages of poisoning (Iffland & Bösche, 1987).
Unithiol has also been used with apparent success in other paediatric cases of
antimony potassium tartrate poisoning (Kemper et al., 1989; Jekat & Kemper, 1990)
and is recommended by others for the management of antimony poisoning (ChzhiTysan, 1959; Lauwers et al., 1990).
11.2
Use in arsenic poisoning
Reference values for arsenic (Walker, 1998):
Blood
<0.13 µmol/L (<10 µg/L)
Urine
<0.13 µmol/24 hours (<10 µg/24 hours) of inorganic arsenic
Urine
<40 nmol/mmol creatinine (unexposed)
<173 nmol/mmol creatinine (occupational exposure)
Unithiol has been used successfully in a number of cases of acute and chronic
arsenic poisoning and is considered the antidote of choice for arsenic toxicity (Adam
et al., 2003).
A 33-year-old female (62 kg) was treated with unithiol after accidental ingestion of
arsenic paste (approximately 1.85 g of arsenic trioxide). She presented 100 hours
after ingestion and was started on unithiol (250 mg intravenously every 6 hours for
48 hours, then 250 mg orally 3 times a day for 48 hours, followed by 250 mg every
12 hours for 23 days). Her condition improved after 2 days and she made a full
recovery. The highest urinary arsenic concentrations occurred on hospital days 1-3
(Kruszewska et al., 1996).
Two brothers, aged 21 and 19 years, were treated with unithiol after ingestion of 4 g
and 1 g, respectively, of a powder which was later identified as arsenic trioxide.
Treatment with unithiol was started 32 and 48 hours after ingestion. In the older
brother the blood arsenic concentration at 26 hours was 400 µg/L. He suffered a
cardiac arrest just before unithiol was started but was successfully resuscitated. At
36 hours the blood arsenic concentration of the younger brother was 98 µg/L. Both
men made a full recovery with no clinical or electrophysiological signs of arsenic
neuropathy (Moore et al., 1994).
A 21-year-old male was treated with unithiol after intentional ingestion of 0.6 g of
arsenic trioxide. He presented to hospital seven hours after ingestion and was
dehydrated following diarrhoea, intestinal colic and vomiting. He was given a gastric
lavage, rehydrated (on average 5.5 L of fluid/daily over 5 days) and given high dose
unithiol. The parenteral regimen was 250 mg/hour on day 1, 125 mg/hour on day 2
and then 62.5 mg/hour on days 3-5. From days 6-12 he was given oral doses of 600700 mg/day. The total dose given was 15.225 g. The serum arsenic concentration
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on day 1 was 143 mg/L (urine 210,000 µg/L), on day 2, 29 mg/L (3800 µg/L), on day
3, 10 mg/L (1675 µg/L) and by day 8 was <1 mg/L (115 µg/L). He developed mild
increases in transaminase concentrations but remained otherwise well (Horn et al.,
2002). Heinrich-Ramm et al. (2003) examined the arsenic compounds excreted in this
patient. In urine sampled on days 2-8 he excreted about 50 mg of arsenic of an
estimated total ingested dose of 230 mg of arsenic. In the first urine sampled after
unithiol therapy (11 hours post-ingestion) the arsenic concentration was 215 mg/L.
This fell by a 1000-fold to 169 µg/L after 8 days of unithiol administration. As reported
in other studies (see section 9.5.1), administration of unithiol resulted in a decrease
in the urinary concentration of dimethylarsinic acid.
In this patient the urinary
concentration of dimethylarsinic acid did not exceed that observed in a reference
population where it had accounted for 95% of the total arsenic excreted. In contrast,
the urinary dimethylarsinic acid concentration in this patient accounted for <5% of
the total arsenic excreted. This supports the theory that unithiol interferes with
methylation of arsenic.
A 27-year-old female developed gastrointestinal effects, ECG changes and liver
damage after ingestion of 9 g of arsenic trioxide. She was treated with intravenous
fluids, activated charcoal and continous alkaline irrigation of the stomach over 36
hours. She was given succimer (15 mg/kg every 8 hours for 26 days) and
intramuscular dimercaprol (4 mg/kg every 4 hours) for 24 hours. A second course of
dimercaprol was administered on day 5 due to continued deterioration. She was
also started on a regimen designed to enhance methylation of arsenic derivatives
which are less toxic and more readily excreted. She was given hydroxocobalamin,
methionine, folinic acid, sodium bicarbonate, glutathione and intravenous unithiol
(250 mg every 4 hours for 5 days). She began to improve within 48 hours with
improved pulmonary function and ECG. Liver function tests began to resolve but
were elevated for more than a month. She also received unithiol from days 15 to 18.
Urinary arsenic concentrations fell rapidly in the first 10 days. At follow up one year
later she had mild polyneuropathy. The role of succimer in this patient’s recovery
was not evaluated. Unithiol, with and without the methylating regimen, increased the
proportion of methylated arsenic metabolites (monomethylarsonic acid and
dimethylarsenic acid) in the urine (Vantroyen et al., 2004).
A 33-year-old female with chronic arsenic poisoning from an unknown source was
treated with unithiol. She presented with a 1.5 year history of episodes of peripheral
neuropathy, pancytopenia, ventricular tachycardia, gastrointestinal symptoms, skin
rash and nail changes. Her blood arsenic concentration was 56 µg/L and the 24
hour urine concentration 130 µg/L. Analysis of well water demonstrated an arsenic
concentration of 78 µg/L. Electromyography revealed moderate demyelinating
neuropathy with axonal involvement. She was started on succimer 10 mg 3 times a
day but serial urinary arsenic determination did not show any elimination. Her
neuropathy continued to progress and she required ventilation. She was then
started on unithiol at 250 mg/kg intravenously every 4 hours. During the first 24
hours of treatment the urinary arsenic concentration rose from 101 to 300 µg/L.
There was also improvement in her neuropathy and she was continued on unithiol
for 12 days. She was much improved, extubated and discharged in a wheelchair 10
days later. By 3 months she was walking on her own with some residual
paraesthesiae and weakness in distal lower extremities. At follow up one year later
she had only mild weakness and residual paraesthesiae controlled with amitriptyline
38
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(Wax & Thornton, 2000).
Adam et al. (2003) reports 6 cases of arsenic poisoning, with retrospective
comparison of the use of dimercaprol and unithiol. Three patients were treated with
dimercaprol. Two of these patients with blood arsenic concentrations of 540 µg/L
and 620 µg/L died within 34 hours and 6 days of exposure, respectively. One patient
had a maximal blood arsenic concentration of 558 µg/L and developed paraplegia as
a result of arsenic poisoning. The three patients treated with unithiol recovered fully.
Two of these patients (including one with anuric renal failure) had very high blood
arsenic concentrations of 2240 µg/L and 4469 µg/L. The third patient had a
relatively mild course, after the early use of unithiol, despite a blood arsenic
concentration of 245 µg/L. The authors concluded that unithiol is the treatment of
choice for arsenic poisoning and that dimercaprol is obsolete.
11.3
Use in beryllium poisoning
No well documented case reports of unithiol use in beryllium poisoning could be
found.
11.4
Use in bismuth poisoning
Reference values for bismuth (Walker, 1998):
Blood
<0.5 nmol/L (<0.1 µg/L) basal
Up to 240 nmol/L (up to 50 µg/L) acceptable therapeutic
>480 nmol/L (>100 µg/L) risk of toxicity
Urine
<0.5 nmol/L (<0.1 µg/L)
Unithiol has been used in both acute (Stevens et al., 1995; Bogle et al., 2000;
Dargan et al., 2001; Dargan et al., 2003b; Ovaska et al., 2008) and chronic (Playford
et al., 1990) bismuth poisoning, although clinical deterioration has been reported in
one chronic case due to redistribution of tissue stores of bismuth (Teepker et al.,
2002). Unithiol is considered an effective antidote for acute bismuth poisoning
(Andersen, 1999).
Unithiol was started 24 hours after intentional ingestion of 2.88 g of bismuth
subcitrate in a 13-year-old girl. She was given 30 mg/kg orally for 10 days and 10
mg/kg for 9 days. The serum bismuth concentration at 4 hours was 300 µg/L, 14
μg/L at 48 hours and 8 µg/L at 72 hours. At 10 days post-ingestion the serum
bismuth concentration was 1.8 µg/L. She remained well throughout (Bogle et al.,
2000).
In a similar case a 30-year-old male was started on unithiol after ingestion of 4.8 g of
tripotassium dicitratobismuthate. He was admitted 2 hours post-ingestion with
vomiting, but was otherwise well. The initial bismuth blood concentration was 424
µg/L and urine 10,000 µg/L. Oral unithiol was started on day 2 (200 mg four times
daily for 10 days, then 200 mg twice daily for 10 days). He remained well and after
antidotal therapy the blood concentration was 17 µg/L and urine 37 µg/L (Dargan et
al., 2001).
A 21-year-old male developed bismuth toxicity after ingestion of 50 to 60 tablets of
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tripotassium dicitratobismuthate. The blood bismuth concentration was 590 µg/L
and he was initially given dimercaprol 150 mg intramuscularly. Four hours later he
was started on haemodialysis. He was subsequently given unithiol 250 mg
intravenously 4 hourly for 48 hours and then 250 mg 6 hourly for 48 hours, then 500
mg orally in two divided doses for 14 days (days 6 to 19 after ingestion). He
received haemodialysis for the first 6 days and on days 8, 9 and 12. Each session
lasted 4 hours and started 1 hour after unithiol administration. No significant
clearance of bismuth occurred with dimercaprol. In contrast significant bismuth
clearance was obtained with unithiol and despite improving renal function cessation
of unithiol on day 20 resulted in a decrease in urinary bismuth clearance (Stevens et
al., 1995).
Unithiol has been used in poisoning resulting from the use of bismuth iodoform
paraffin paste used to pack a large wound of the sacrum following tumour excision.
The patient began to develop neurological effects 5 days later and blood and urine
bismuth concentrations were raised (340 µg/L and 2800 µg/L, respectively). The
packing was removed and he was started on unithiol (intravenously 5 mg/kg four
times daily for 5 days, 5 mg/kg 3 times daily for 5 days, and 5 mg/kg twice daily for
17 days, then orally 200 mg 3 times daily for 10 days, 200 mg twice daily for 14
days; 61 days in total). His neurological effects improved over the next month and
the bismuth concentrations were normal after 55 days (Dargan et al., 2003b; Ovaska
et al., 2008).
A 68-year-old male with renal impairment developed encephalopathy from ingestion
of double the dose of tripotassium dicitratobismuthate (864 mg of bismuth daily) for 2
years. He was given unithiol 100 mg 3 times daily for 10 days. Renal clearance of
bismuth increased 10-fold from 0.24 mL/minute to 2.4 mL/minute during this time.
The whole blood bismuth concentration decreased from 880 µg/L to 46 µg/L over a
50 day period and he had marked improvement in cerebral function. There were no
adverse effects (Playford et al., 1990).
In a 49-year-old female with encephalopathy from 5 years of chronic oral abuse of
bismuth, unithiol had to be discontinued due to deterioration in her clinical condition.
She was given 100 mg daily and there was a marked decrease in plasma bismuth
concentrations with an increase in urinary bismuth concentrations. However, she
deteriorated with cluster-like myoclonic jerks and stupor and the unithiol was stopped
after 3 days. Her clinical condition improved over the next few weeks and lagged
behind the plasma bismuth concentrations. They deceased from 550 µg/L to 30.4
µg/L by day 21 when she demonstrated marked improvement. The unithiol may
have caused redistribution of bismuth from tissue stores and caused the clinical
deterioration in this patient (Teepker et al., 2002).
11.5
Use in cadmium poisoning
Reference values for cadmium (Walker, 1998):
Blood
<27 nmol/L (<3 µg/L) non smokers
<54 nmol/L (<6 µg/L) smokers
Urine
44.5 nmol/L (5 g/L)
0.4-1.3 nmol/mmol creatinine (unexposed)
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1991
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1995
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1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
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2022
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2026
There is limited information on the use of unithiol in cadmium poisoning. In a woman
with chronic occupational exposure to cadmium and signs and symptoms of toxicity,
administration of unithiol increased the urinary concentration of cadmium from 1.8 to
4.2 μg/L (Daunderer, 1995).
11.6
Use in chromium poisoning
Reference values for chromium (Walker, 1998):
Blood
<10 nmol/L (<0.5 µg/L)
Urine
<5 nmol/L (<0.25 µg/L) non-occupational exposure
Up to 98 nmol/mmol creatinine, depending on type of occupation
There is limited information on the use of unithiol in chromium poisoning. An adult
who fell in a pool of chromic acid was started on unithiol within an hour of exposure.
He became anuric and chromium was detected in the dialysate. Urine excretion
returned 2 days after exposure and the chromium concentration was 5859 μg/L. The
maximum urinary chromium concentration, 13,614 μg/L, was obtained 12 hours after
the start of unithiol therapy. The serum chromium concentration was 1,983 mg/L 24
hours after exposure. The patient recovered but no further details are given (Donner
et al., 1986).
A 20-year-old male died after ingestion of 10-30 g of potassium dichromate. He was
treated with haemodialysis (commenced at 2.5 hours) and continuous arterio-venous
haemofiltration (at 16 hours). Unithiol (250 mg intravenously every 4 hours for 24
hours then 6 hourly) was started 13 hours after admission. The initial plasma
concentration of chromium was 5.8 mg/L and urine 159 mg/L. He had a cardiac
arrest and died 48 hours after admission (Pudill et al., 1989).
11.7
Use in cobalt poisoning
There is limited information on the use of unithiol in cobalt poisoning. Unithiol was
used in 2 paediatric patients with ingestion of an unspecified cobalt compound from
a chemistry set. The children were initially treated with penicillamine and then on the
fifth day started on the less toxic unithiol (3 x 50 mg orally). There were slight
increases in serum cobalt concentrations during unithiol therapy and it was stopped
once the urine cobalt concentrations were normal. No further details are given
(Müller et al., 1989).
11.8
Use in copper poisoning
There is limited information on the use of unithiol in acute copper poisoning. A 3year-old child who ingested more than 3 g of copper sulphate received a gastric
lavage within 30 minutes of ingestion and was commenced on unithiol therapy within
an hour. The serum copper concentration did not reach a toxic concentration and
urinary copper excretion was more than 10 times normal; no further details are given
(Donner et al., 1986).
A 33-year-old female ingested an unknown quantity of copper sulphate and developed
severe haemorrhagic gastroenteritis, dehydration, metabolic acidosis, renal failure, liver
damage, intravascular haemolysis and methaemoglobinaemia. She was given unithiol
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(250 mg intravenously every 4 hours) within 24 hours of ingestion until she developed
anuria (more than 48 hours later). This patient survived with 10 days of intensive
therapy and 5 weeks of hospitalisation. The serum copper concentration was normal
on admission (5 hours post-ingestion) and as there were no measurements of copper
excretion, the effectiveness of unithiol administration cannot be determined (Sinković et
al., 2008).
11.8.1 Use in Wilson’s disease
Unithiol has been used with some success in patients with Wilson’s disease, usually
those who fail to respond to penicillamine.
Walshe (1985) reported the use of unithiol (200 mg twice daily) in an adult patient with
Wilson’s disease. He had initially been managed with penicillamine and trientine but
had become intolerant to them. He developed proteinuria but remained well with
unithiol. His copper excretion was maintained at 31.5-47.2 µmol (2000-3000 µg) daily.
Two other patients were also tried on unithiol. One developed fever and a
decreased leucocyte count which also occurred with a second test dose and further
treatment was not given. The other patient took it for 10 days but then refused
because of intense nausea. Other patients (number not specified) were given test
doses and the resulting cupruresis was comparable with that obtained with
penicillamine and trientine in most cases.
11.9
Use in gold poisoning
Unithiol has been used in iatrogenic gold poisoning and although the patient died
from heart failure the unithiol was thought to be effective in removing gold from the
body. No further details are given (Ashton et al., 1992a).
11.10 Use in lead poisoning
Reference values for lead (Walker, 1998):
Blood
<0.5 µmol/L (<10 µg/L) environmental exposure
Urine
<100 nmol/24 hours (<10 µg/24 hours) normal adults
Unithiol was first used in the management of chronic lead poisoning in Russia
(Anatovskaya, 1962), and although unithiol has been used in subsequent cases of
lead poisoning and has been shown to be of benefit in animal studies, succimer is
usually the preferred antidote for lead poisoning, particularly in children (Angle,
1993) as it is the less toxic of the two antidotes (Andersen, 1999).
An adult with lead poisoning due to the use of a lead-containing ointment was treated
with oral unithiol (400 mg then 200 mg 2 hourly). She had a blood lead concentration
of 1150 µg/L with gastrointestinal effects and a paraesthesia. Within 36 hours the
concentration has decreased to 570 µg/L and the maximum urinary lead concentration
in 24 hours was 73000 µg/L. The blood concentration rose to 890 µg/L during an
interruption of therapy due to lack of drug supply, but decreased rapidly once unithiol
was recommenced. Therapy was continued over 2 months without adverse effects
(Donner et al., 1987; Hruby & Donner, 1987).
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A 24-year-old female developed lead poisoning after ingestion of instant lemon tea
from a lead-glazed cup, over a period of 2.5 months. The reason for her illness was
difficult to establish at first due to the unusual source, but once lead toxicity was
confirmed she was treated with oral unithiol (5-10 mg/kg 3 times a day for 2 days, then
2.5 mg/kg twice daily) until the blood and urine lead concentrations were normal. Her
initial whole blood and urine lead concentrations were 600 µg/L and 1700 µg/L,
respectively. She recovered over a 4 month period (Autenrieth et al., 1998).
Unithiol treatment (parenteral and then two 5 day cycles) improved optic neuropathy
caused by lead deposition in the eye. There was improvement in visual acuity, visual
field and dark adaptation (Dambite, 1966).
11.11 Use in mercury poisoning
Unithiol is the antidote of choice in patients with mercury poisoning. It has been used
successfully in the treatment of acute and chronic poisoning, involving metallic
mercury, inorganic mercury salts and organic compounds. Andersen (1999) suggests
that unithiol is the optimal antidote for inorganic mercury poisoning and that succimer
is more effective in organic mercury intoxication.
In acute poisoning with mercuric salts the initial doses usually have to be given by the
parenteral route because of damage to the gastrointestinal tract. Unithiol should be
used in combination with haemofiltration in patients with mercury-induced renal failure.
Reference values for mercury (Walker, 1998):
Blood
<20 nmol/L (<4 µg/L)
Urine
<50 nmol/24 hours (<10 µg/24 hours)
11.11.1 Inorganic mercury compounds
Campbell et al. (1986) reported two patients with high mercury concentrations, due to
occupational exposure, treated with unithiol. One patient aged 22 years was
asymptomatic despite a urinary mercury concentration of 832 µg/24 hours. The other,
aged 23 years, had clinical features of mercury toxicity (weight loss, muscle twitching,
excessive salivation, night sweats). His urinary mercury concentration was 429 µg/24
hours. Both were given unithiol, 100 mg 3 times a day then 400 mg daily, for 2
months. The drug was well tolerated and during therapy the elimination half-life of
mercury deceased from 33 days to 11 days. After 2 months the symptomatic patient
had improved and the urinary mercury concentration was within acceptable limits.
Ashton & House (1989) describe two patients treated with unithiol after ingestion of
inorganic mercury. The first patient, aged 19 years, ingested approximately 29 g of
mercuric nitrate and presented to hospital within 1.5 hours. He was treated with
dimercaprol initially and he developed acute renal tubular necrosis and hypotension.
He was then given high dose intravenous unithiol, haemodialysis, haemofiltration and
plasma exchange. The initial blood mercury concentration was very high but renal
function returned at 10 days post-ingestion and he made a full recovery.
Haemodialysis, haemofiltration and plasma exchange were ineffective as promoting
mercury removal. The second patient, aged 42, ingested approximately 1 g of
mercuric chloride. He was treated with high dose intravenous unithiol and then oral
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2147
2148
2149
2150
2151
2152
2153
2154
2155
2156
2157
2158
2159
2160
2161
2162
2163
2164
2165
2166
2167
2168
2169
2170
2171
2172
2173
2174
2175
2176
administration. He recovered without developing renal impairment, despite an initial
mercury blood concentration of 600 µg/L.
Prompt administration of unithiol (at 8 hours post-ingestion) with intravenous fluid
therapy was thought to be responsible for the lack of renal impairment in a 53-year-old
man who had ingested approximately 50 g of mercuric iodide. He had vomited
repeatedly and this may also have decreased absorption, however, the blood and
urine mercury concentrations were high, at 1197 nmol/L and 159 nmol/L, respectively.
He was given unithiol intravenously 250 mg every 4 hours for 60 hours and then orally
twice daily for 18 days (Anderson et al., 1996).
A 19-year-old female vomited 30 minutes after ingestion of 3g of mercuric chloride and
was given a gastric lavage. She developed anuria one hour later and was started on
peritoneal dialysis and haemodialysis. She was given unithiol and dimercaprol and
urine excretion returned after 10 days with a polyuric phase at 20 days. Creatinine
clearance was normal by 100 days after ingestion (Nadig et al., 1985).
A 38-year-old male intentionally ingested 100 ml of mercuric chloride solution (of
unknown concentration) and developed vomiting, haematemesis and bloody diarrhoea
shortly afterwards. He was given a gastric lavage and once the history of ingestion
had been determined was stated on dimercaprol. However, he rapidly developed
oliguria and acute tubular necrosis. By 8 hours post-ingestion the urine output was
less than 10 mL/hour. The blood mercury concentration was 14,300 µg/L. The urine
mercury concentration before onset of anuria was 36,000 µg/L. He was started on
intravenous unithiol 10 hours after ingestion: 250 mg every 4 hours for 48 hours, then
250 mg every 6 hours for 48 hours and 250 mg 8 hourly. He required intravenous
fluids for hypovolaemic shock and haemodialysis for renal failure. The blood mercury
concentration remained high (at least 2 mg/L for the first 10 days) but kidney function
returned within 10 days and haemodialysis was no longer required. Administration of
unithiol was continued by the parenteral route because of ulceration of the
oesophagus and stomach. After about 4 weeks oral unithiol was given (300 mg 3
times a day), and unithiol was given for a total of 7 weeks until blood and urine
concentrations were considered to be non-toxic. The average mercury half-life is 4060 days and in this patient it was 2.5 days in the initial distribution phase and 8.1 days
in the terminal phase of metabolism and elimination. The patient made a full recovery
(Toet et al., 1994).
Haemodialysis is ineffective in enhancing mercury elimination (Toet et al., 1994; Pai
et al., 2000) even in patients treated with unithiol (Toet et al., 1994). However,
continuous venovenous haemofiltration was successful in enhancing elimination of
the mercury-unithiol complex in a patient with elevated blood mercury concentrations
(initially 5200 µg/L) following ingestion of an inorganic mercury salt (Pai et al., 2000).
Continuous venovenous haemofiltration in combination with unithiol was also
effective in the patient reported by Dargan et al. (2003a). A 40-year-old male
ingested approximately 1 g of mercuric sulphate and soon after presentation required
intubation and ventilation due to respiratory distress (his pharynx and epiglottis were
oedematous and haemorrhagic). He was started on intravenous unithiol (250 mg
every 4 hours for 4 days) 4.5 hours after ingestion. However he developed an
erythematous maculopapular rash with blistering on the lower legs and the dose of
44
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2178
2179
2180
2181
2182
2183
2184
2185
2186
2187
2188
2189
2190
2191
2192
2193
2194
2195
2196
2197
2198
2199
2200
2201
2202
2203
2204
2205
2206
2207
2208
2209
2210
2211
2212
2213
2214
2215
2216
2217
2218
2219
2220
2221
2222
2223
2224
2225
2226
unithiol was reduced to 250 mg every 8 hours. After another 6 days he was started
on oral unithiol (200 mg/day for 9 days). Anuria developed by 12 hours post-ingestion
and he was commenced in continuous venovenous haemofiltration 7 hours after
ingestion. He was anuric for 11 days with oliguria for days 12 to 43. Continuous
venovenous haemofiltration was continued for 14 days with 8 sessions of
haemodialysis for renal support between days 16 and 37. He was discharged on
day 50 asymptomatic with no neurological signs or symptoms. Continuous
venovenous haemofiltration removed 12.7% of the ingested dose, mostly over the
first 72 hours.
11.10.2 Organic mercury compounds
A 20-year-old male was given a gastric lavage and activated charcoal within 2 hours of
ingesting haloperidol, benztropine and 2-3 mouthfuls of a fungicide containing 0.69%
methyl mercury and ethanol. The estimated dose of methyl mercury was 800 mg. He
was started on oral D-penicillamine within 4 to 5 hours of ingestion. The whole blood
mercury concentration 2 hours after ingestion was 1930 μg/L and at 24 hours was
1007 μg/L. Approximately 36 hours after ingestion he was started on acetylcysteine
and haemodialysis. D-penicillamine was discontinued 3 days after ingestion and oral
unithiol (200 mg every 6 hours) was started. He received unithiol for 14 days but due
to mild anorexia and nausea elected not to continue taking it as an outpatient. The
whole blood mercury concentration at this time was 355 μg/L and he remained well.
Serum zinc and copper concentrations remained normal during unithiol therapy.
Neurological examination was normal at 6 weeks and 1 year post-ingestion.
Haemodialysis and D-penicillamine were relatively ineffective in clearing the mercury.
The unithiol was also relatively ineffective but this may have been due to
administration of a multivitamin and mineral preparation containing copper and zinc at
the same time, which may have reduced efficacy (Lund et al., 1984).
In a 49-year-old female who ingested 125 g of fungicide containing 3.5% mercury in
the form of methoxyethyl mercury treated with penicillamine and unithiol alternating
every 2 weeks, unithiol reduced the protein binding of methoxyethyl mercury from 93%
to 83%. Antidote therapy was continued for 12 weeks and she developed no renal or
neurological effects (Köppel et al., 1982).
A 44-year-old man was treated with unithiol and succimer after ingestion of a solution
of thiomersal. The ingested dose was 83 mg/kg although he vomited about 15
minutes later. He was given a gastric lavage just over 1 hour after ingestion and 300
mg of unithiol was instilled into the stomach via a nasogastric tube. This dose was
repeated on days 2, 3, 9 and 10, and he was given 250 mg of intravenous unithiol on
days 3, 8 and 17, with 750 mg on days 4, 5 and 11, and 1000 mg on days 12-16 and
23-29. He was also given oral succimer on days 17-23, 33-46 and 51-70. He
received no antidotal therapy on days 6, 30-32 and 47-50. He developed renal failure
on day 1 which persisted until day 40. He also developed gastritis, dermatitis,
gingivitis, polyneuropathy and coma. He made a full recovery but the decline in
mercury concentrations in the blood, urinary mercury excretion and renal mercury
clearance were not influenced by antidotal therapy to a great extent. There was
minimal or no increase in renal and blood clearance and no effect was detected after
day 30 (Pfab et al., 1996).
45
2227
2228
2229
2230
2231
2232
2233
2234
2235
2236
2237
2238
2239
2240
2241
2242
2243
2244
2245
2246
2247
2248
2249
2250
2251
2252
2253
2254
2255
2256
2257
2258
2259
2260
2261
2262
2263
2264
2265
2266
2267
2268
2269
2270
2271
2272
2273
2274
2275
2276
11.11.3 Metallic mercury
In a patient with intrabronchial aspiration of metallic mercury the urine and plasma
mercury concentrations remained high despite intermittent therapy with unithiol and
penicillamine over a 14 month follow up period. However, the patient remained well
apart from vomiting and faintness on admission and intermittent mild arthralgia
thereafter (Batora et al., 2001). In a similar case, a 35-year-old male remained
asymptomatic after rupture of a Miller-Abbot tube and subsequent aspiration. The 24
hour blood mercury concentration was 940 µg/L. He was treated with unithiol and the
blood concentration decreased rapidly (Kummer & Michot, 1984).
There are a number of case reports of unithiol use in children with mercury toxicity
(Bertram et al., 1989; Jekat & Kemper, 1990; Ruprecht, 1997). Unithiol was used in
three children, aged 33 and 20 months and 6 years 10 months, with mercury toxicity
from a broken thermometer. The thermometer had been broken on the carpet of the
children’s room, which had under floor heating, about 8 months previously. Unithiol
(50 mg 3 times daily) was given for up to 4 months and all the children recovered (von
Mühlendahl, 1990).
Unithiol was used in the management of mercury poisoning in a 14-year-old girl with
acrodynia. For 3 months her clinical features were diagnosed as a neurotic anxiety
disorder but once the diagnosis of mercury toxicity was made she was treated with
unithiol, 100 mg every other day and made a slow recovery. The source was metallic
mercury spilt on a carpet that had been vacuumed up (Böckers et al., 1983).
11.11.4 Dermal mercury exposure
Unithiol was used in a 21-year-old diabetic male who developed mercury intoxication
following use of a mercury-containing ointment for eczema for about 3 weeks. He
developed classic signs of mercury poisoning with tiredness, sweating, mild
fasciculation of extremities, ataxia, hand tremors, weight loss, proteinuria, anxiety
and behavioural changes. The urinary mercury concentration was 0.252 mg/L and
he was given oral unithiol for 12 days. The highest urine mercury concentration
during therapy was 2.1 mg/L. He improved rapidly over a 2 week period, however,
signs of neurological and renal damage, not typical of diabetes persisted (Pelclová et
al., 2001).
Use of a mercury-containing cosmetic bleaching cream for 4 years caused nail
dyschromia in a 56 year female. The nails were discoloured greenish-black and she
had features of mercury toxicity with night sweats, insomnia and nervousness.
Treatment with unithiol reduced the serum mercury concentration from 64 to15 µg/L;
the urinary mercury concentration rose and peaked at 1660 µg/L on the 10th day.
After the initial course of unithiol the serum mercury concentration increased and she
was given a second course, lasting 3 weeks. The unithiol was well tolerated (Böckers
et al., 1985).
11.11.5 Parenteral mercury exposure
Long-term unithiol administration has been used in the management of parenteral
mercury poisoning. A 23-year-old male injected about 20 ml of metallic mercury
46
2277
2278
2279
2280
2281
2282
2283
2284
2285
2286
2287
2288
2289
2290
2291
2292
2293
2294
2295
2296
2297
2298
2299
2300
2301
2302
2303
2304
2305
2306
2307
2308
2309
2310
2311
2312
2313
2314
2315
2316
2317
2318
2319
2320
2321
2322
2323
2324
2325
2326
intravenously and mercury was visible on x-ray in the right ventricle with multiple
emboli in the lung. Mercury was also seen in the abdomen and right forearm. Only
0.2 ml was removed from the heart by cardiac catheterisation and the blood mercury
concentration rose to 294 µg/L. He was started on oral unithiol 300-800 mg a day and
this continued for at least 4.5 years. The blood mercury and urine concentrations
peaked at 1608 µg/L and 73,500 µg/L, respectively. He remained well except for
intermittent chest pain. He developed no adverse effects to unithiol, and no reduction
in plasma zinc, copper or selenium concentrations, although the urine copper
concentrations were elevated (Ashton et al., 1992b). Batora et al. (2000) also used
unithiol in a patient with intravenous mercury injection with elevated blood and urine
concentrations (21.4 µg/L and 183.3 μg/L, respectively). They used only two courses
of treatment over 17 days, and 6 weeks after therapy the blood concentration had
fallen to 8.1 µg/L and the urine concentration increased to 397.6 µg/L. Mercury
deposits were visible on both lung fields but by 1 year had almost completely
disappeared. He remained well with only a temporary enzymuria (N-acetyl beta
glucosaminidase) indicating subtle renal tubular damage.
A 35-year-old male presented with a history of gingivitis, weakness, pyrexia, anorexia
and weight loss 6 weeks after intravenous injection of metallic mercury. Mercury was
visible in the lungs, abdomen and injection site on X-ray and the urinary concentration
was 500 µg/L. He was started on unithiol 2 days after admission on a 6 day course of
600 mg/day in 3 divided doses. After the first 24 hours of treatment the urinary
mercury concentration rose to 7750 µg/L and he developed a moderate
hypersensivity-type skin reaction with resolved within 2 days. He was discharged
one week after completion of unithiol therapy and had urine concentration 1100 µg/L
with irritability and weakness. He did not return for a year when he presented with
irritability, weakness, insomnia and tremor. The urinary mercury concentration was
2206 µg/L. Mercury was still visible on X-ray and he was given another course of
unithiol. Over the next 4 years he was reviewed every 6 months and the urinary
mercury concentration was 800-1000 µg/L. Two years after the original presentation
he was given a third course of unithiol. At 5 years the concentration was 807 µg/L
and a fourth course of untihiol produced a less dramatic increase in urinary
elimination.
Tremor and weakness persisted.
Although unithiol increased
elimination there appeared to be no change in the radiographic deposits mercury in
the lungs and abdomen. It was not clear that the infrequent administration of unithiol
was of any benefit to this patient (Torres-Alanís et al., 1997).
In another case of elemental mercury injection, a 27-year-old male, 65 kg, injected
1.5 mL (20 g) into his left cubital vein. Within 12 hours he developed pyrexia,
tachycardia and dyspnoea and mercury was visible on chest X-ray. The serum
mercury concentration was 172 µg/L on admission and peaked on day 6 at 274 µg/L.
At 37 hours he was started on unithiol (200 mg orally every 8 hours) for 5 days,
during which time he eliminated 8 mg of mercury. Three days later he was started
on succimer (500 mg daily) for another 5 days. This resulted in the excretion of
another 3 mg of mercury. Neither unithiol nor succimer were effective in enhancing
elimination of mercury after intravenous injection (Eyer et al., 2006).
Unithiol was shown to be effective in enhancing mercury elimination and reducing
renal irradiation in patients given radioactive chlormerodrin, an obsolete mercurial
diuretic, for renal scintigraphy (Ogiński & Kloczkowski, 1973; Kloczkowski & Ogiński,
47
2327
2328
2329
2330
2331
2332
2333
2334
2335
2336
2337
2338
2339
2340
2341
2342
2343
2344
2345
2346
2347
2348
2349
2350
2351
2352
2353
2354
2355
2356
2357
2358
2359
2360
2361
2362
2363
2364
2365
2366
2367
2368
2369
2370
2371
2372
2373
2374
2375
2376
1973).
11.12 Use in nickel poisoning
There are no case reports of unithiol administration in nickel poisoning but it has been
recommended (Daunderer, 1982).
11.13 Use in palladium poisoning
No well documented case reports of unithiol use in platinum poisoning could be
found.
11.14 Use in platinum poisoning
No well documented case reports of unithiol use in platinum poisoning could be
found.
11.15 Use in polonium poisoning
Experience with use of unithiol in polonium exposure is limited. Shantyr et al. (1969)
reported 10 children who were contaminated with polonium-210 from a damaged
polonium-beryllium neutron source. They had body burdens of 0.2-7.0 µCi, far
above the maximal permissible burden. Some were treated with unithiol (number
unknown) and all remained well with no changes in general health, blood or renal
function over the 46 month period of monitoring. However, most of the children
developed impairment of protein formation in the liver, manifested as an increase in
albumin and a decrease in globulin. This was observed from 21 months and
persisted through the remaining period of observation.
11.16 Use in selenium poisoning
No well documented case reports of unithiol use in selenium poisoning could be
found.
11.17 Use in silver poisoning
There is limited information on the use of unithiol in silver poisoning. Unithiol was
used in a patient with argyria after penicillamine had failed to increase the urinary
excretion of silver. The patient was 60 years old and had developed argyria after 15
years use of silver nitrate to treat gingivitis due to ill-fitting dentures. Unithiol was
given at a dose of 1-5 x 500 mg for 5 days then 2.5 g/day for another 5 days with a 5
day period in between. Even though the renal excretion of silver was increased by
unithiol administration the total amount of excreted silver was low, only 1 µmol of silver
in total. This was estimated to be approximately 1% or less of the total body burden of
silver and it was concluded that unithiol was of no benefit in argyria (Aaseth et al.,
1986).
In a 55-year-old patient with argyria, use of unithiol (3 x 100 mg/day) increased the
urinary excretion of silver by approximately 100 fold. However, the total quantity of
silver excreted was low. Administration of penicillamine did not affect silver excretion
48
2377
2378
2379
2380
2381
2382
2383
2384
2385
2386
2387
2388
2389
2390
2391
2392
2393
2394
2395
2396
2397
2398
2399
2400
2401
2402
2403
2404
2405
2406
2407
2408
2409
2410
2411
2412
2413
2414
2415
2416
2417
2418
2419
2420
2421
2422
2423
2424
2425
(Kemper et al., 1989; Jekat and Kemper, 1990).
11.18 Use in strontium poisoning
No well documented case reports of unithiol use in strontium poisoning could be
found.
11.19 Use in tin poisoning
There is limited information on the use of unithiol in tin poisoning. Unithiol was used
in dental assistant with tin exposure due to kneading of amalgam in the unprotected
palm of the hand. The urinary concentration of tin was increased to 1094.4 µg/L with
unithiol administration and clinical features (tiredness, dizziness and tremor) improved
(Hruschka, 1990).
12.
Summary of evaluation
12.1
Indications
Unithiol appears to be effective (in terms of accelerating metal excretion without
causing severe adverse effects) in most cases of:
• acute and chronic intoxication by organic and inorganic mercury
• acute and chronic intoxication by bismuth
• chronic lead poisoning
• acute and chronic arsenic poisoning.
It has also been used with some success in cases of human poisoning with the
following, but data are limited:
• trivalent antimony (there is no information on the less toxic pentavalent
antimony compounds)
• chromium
• cobalt
• copper, including patients with Wilson’s disease
• gold
Animal studies have demonstrated apparent benefit but experience of unithiol use in
human poisoning is lacking for the following:
• beryllium
• cadmium
• nickel
• tin
• zinc
On the basis of animal or human case reports unithiol does not appear to be useful for
the following:
• palladium
• platinum
• polonium
49
2426
2427
2428
2429
2430
2431
2432
2433
2434
2435
2436
2437
2438
2439
2440
2441
2442
2443
2444
2445
2446
2447
2448
2449
2450
2451
2452
2453
2454
2455
2456
2457
2458
2459
2460
2461
2462
2463
2464
2465
2466
2467
2468
2469
2470
•
•
•
•
silver (argyria)
strontium
thallium
vanadium
See Table 5 (section 16.2) for a summary of the available information on unithiol use
in metal and metalloid poisoning.
12.2
Advised routes and dose
Unithiol may be administered both orally and parenterally. In cases of acute heavy
metal ingestion the parenteral route is strongly recommended, because given orally
the drug may bind residues of the metal in the gut, promote absorption and decrease
body burden.
High dose therapy should be avoided in patients with chronic poisoning without severe
clinical symptoms because of the risk of sudden mobilisation of the metal from tissue
stores with resultant clinical deterioration. This occurred, for example, in a patient with
chronic bismuth toxicity, necessitating cessation of unithiol therapy (Teepker et al.,
2002).
12.2.1 Oral administration
There is no standard regimen for unithiol administration; dosing and duration depends
on clinical condition and blood and urine concentrations of the metal. High doses
have been used and are well tolerated, but are not advised in chronically poisoned
patients without severe clinical effects (see section 12.2). Unithiol should be taken on
an empty stomach.
• Adults: The usual initial dose is 100-200 mg every 6-8 hours (3-4 times/day); this is
then tapered over the following days or weeks.
• Children: The usual initial dose 50-100 mg every 6-8 hours (3-4 times/day); this is
then tapered over the following days or weeks. Alternatively 5 mg/kg daily in 2 to 4
divided doses has been used (Willig et al., 1984; Chisholm and Thomas, 1985;
Karpinski & Markoff, 1997; Böse-O’Reilly et al., 2003).
12.2.2 Parenteral administration
Unithiol may be administered parenterally by the intramuscular or slow intravenous
injection over 5 minutes (1 mL/minute). The parental doses of unithiol for adults and
children are given in Table 1. From day 4 frequency of dosing should be based on the
patient’s clinical condition; parental unithiol may be continued or oral treatment may be
started. Unithiol solution must be administered immediately after opening the vials,
and any remaining after dosing must be discarded. Parenteral unithiol must not be
mixed with other infusion solutions (as this may reduce antidotal efficacy).
50
2471
2472
Table 1: Parenteral unithiol dosage
Day of
treatment
2473
2474
2475
2476
2477
2478
2479
2480
2481
2482
2483
2484
2485
2486
2487
2488
2489
2490
2491
2492
2493
2494
2495
2496
2497
2498
2499
2500
2501
2502
2503
2504
2505
2506
2507
Adults
Children
Dose IM or
slow IV
Total daily
dose
Dose IM or slow IV
Total daily
dose
1
250 mg every 34 hours
1.5-2.0 g
5 mg/kg every 3-4
hours
30-40 mg/kg
2
250 mg every 46 hours
1.0-1.5 g
5 mg/kg every 4-6
hours
20-30 mg/kg
3
250 mg every 68 hours
0.75-1.0 g
5 mg/kg every 6-8
hours
15-20 mg/kg
4,5…
250 mg every 812 hours
0.50- 0.75 g
5 mg/kg every 8-12
hours
10-15 mg/kg
12.3
Supportive therapy
Other supportive therapy, and gut decontamination, rehydration or cardiovascular
support may be required. Haemofiltration in conjunction with unithiol administration is
the renal replacement method of choice in patients with renal failure because it may
enhance elimination of heavy metals (particularly mercury).
In cases of chronic poisoning identification and removal from source should also be
undertaken.
12.4
Controversial issues
There are indications from animal studies that unithiol may be useful in the treatment of
acute poisoning by beryllium, cadmium, nickel and tin and from a small number of
human case reports for trivalent antimony, chromium, cobalt, copper and gold.
However, there is a lack of good quality clinical data.
Diagnostic use of unithiol in cases of asymptomatic or suspected poisoning cannot be
recommended. The metal-binding agent mobilises the metal resulting in redistribution
which could increase the concentration at the target organ, despite an increased
excretion.
It is still controversial, whether concurrent administration of more than one metalbinding agent is harmful or beneficial. If adequate doses of unithiol are given, are well
tolerated and the duration of therapy long enough, then use of more than one metalbinding agent is not necessary.
12.5
Proposals for further studies
The mode of action of unithiol has not been fully elucidated and recent work has
tended to focus on arsenic and mercury. Further study is required to determine the
interaction of unithiol with individual metals and metalloids but also with the target
organs. Modern tools, such as computer molecule modelling for complex formation,
should be used to provide a better understanding of the biological processes involved.
51
2508
2509
2510
2511
2512
2513
2514
2515
2516
2517
2518
2519
2520
2521
2522
2523
2524
2525
2526
2527
2528
2529
2530
2531
2532
2533
2534
2535
2536
2537
2538
2539
2540
2541
2542
2543
2544
2545
2546
2547
2548
2549
2550
2551
2552
2553
2554
2555
2556
2557
There is also a clear need for more clinical trials on the role of unithiol in the treatment
of poisoned patients, in particular to define the optimum dose, duration of therapy and
route of administration of unithiol and compare it to other metal-binding agents such as
succimer and sodium calcium edetate. There are large populations of individuals
poisoned with metals and metalloids, particularly arsenic and mercury, from
environmental sources. For the metals which are less commonly involved in poisoning
and where clinical trials are unlikely to be practical unless a mass incident occurs, there
is a need for well documented case reports with biochemical and chemical analyses
used to determine the efficacy of the antidote used.
Evaluation of the risks and benefits of combined antidotal therapy is also an area that
warrants father investigation.
The suggestion that unithiol is the optimal antidote for inorganic mercury poisoning
and that succimer is more effective in organic mercury intoxication requires verification
(Andersen, 1999).
12.6
Adverse effects
Unithiol is generally well tolerated and the incidence of adverse effects is low.
Administration of unithiol also increases elimination of some trace elements, particularly
zinc and copper (Bertram, 1977; Mant, 1985; Aaseth et al., 1986; Sallsten et al., 1994;
Torres- Alanís et al., 2000; Høl et al., 2003), but also selenium and magnesium
(Torres- Alanís et al., 2000). This effect is only likely to be of clinical significance in
patients on chronic unithiol therapy.
Skin reactions including rashes, pruritis and blistering have been reported (Dubinsky &
Guida, 1979; Mant, 1985; Ashton et al., 1992a; Hla et al., 1992; Toet et al., 1994;
Torres- Alanís et al., 1995; Torres-Alanís et al., 1997; Gonzalez-Ramirez et al., 1998;
Böse-O’Reilly et al., 2003; Dargan et al., 2003a). Erytheme multiforme with buccal
ulceration (Ashton et al., 1992a) and depigmentation (Pagliuca et al., 1990) has been
reported. Stevens-Johnson syndrome has been reported in a small number of cases
(Chisholm, 1990; Chisholm, 1992; Van der Linde et al., 2008). Anaphylactic shock has
not been reported (Ruprecht, 1997). In most cases allergic reactions have resolved
within 3-5 days and generally no treatment is required. However, antihistamines and/or
corticosteroids may be given if necessary.
Nausea may occur from oral administration (Lund et al., 1984; Walshe, 1985;
Stevens et al., 1995; Gonzalez-Ramirez et al., 1998), and body fluids usually have a
sulphur odour for 6-8 hours after unithiol administration. Mild elevation of liver
enzymes (Chisolm & Thomas, 1985; Gonzalez-Ramirez et al., 1998; Wang et al.,
2003), diuresis (Glukharev, 1965), fever and leucocytosis (Walshe, 1985) have
been reported.
With the parenteral preparation cardiovascular reactions may occur, particularly if
injected too rapidly. These effects are hypotension (Hurlbut et al., 1994), nausea
(Stevens et al., 1995), dizziness and weakness (Dubinsky & Guida, 1979; Zhang,
1984). Necrosis and ulceration may occur at the injection site, but this is associated
with high doses e.g. 100 mg/kg (Sanotsky et al., 1967).
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12.7
Restrictions of use
Unithiol should not be administered in acute arsine poisoning (AsH3), because it is
ineffective and can increase arsine toxicity (Mizyukova & Petrunkin, 1974).
The administration of unithiol in cases of asymptomatic or suspected poisoning (a
challenge or mobilisation test) cannot be recommended, because the metal-binding
agent mobilises the metal from tissue stores resulting in redistribution and potentially
increasing the concentration in the target organ, despite increasing excretion.
Renal impairment is not a restriction of use; haemofiltration is the renal replacement
method of choice in patients with renal failure and in conjunction with unithiol
administration may enhance elimination of heavy metals (particularly mercury).
13.
Model information sheet
13.1 Uses
Unithiol is a derivative of dimercaprol (2,3-dimercapto-1-propanol, British Anti-Lewisite,
BAL), and is replacing dimercaprol as one of the main antidotes used in the
management of heavy metal poisoning. Unithiol has several advantages over
dimercaprol including lower toxicity, increased solubility in water and lower lipid
solubility. It is due to these properties that it is effective by oral administration.
Unithiol has been used in the management of acute and chronic poisoning with a
number of different metals and metalloids, and is particularly useful for arsenic,
bismuth and mercury. It has been used for other metals and metalloids. Unithiol can
be given parenterally or orally depending on the clinical situation and severity of
poisoning.
13.2 Dosage and route
Unithiol may be administered both orally and parenterally. In severe cases and/or
acute poisoning parenteral administration is recommended. In cases of acute heavy
metal ingestion the parenteral route is strongly recommended, because given orally
the drugs may bind residues of the metal in the gut, promote the absorption and
increase the body burden by this way.
High dose therapy should be avoided in patients with chronic poisoning without severe
clinical symptoms because of the risk of sudden mobilisation of the metal from tissue
stores with resultant clinical deterioration.
13.2.1 Oral administration
There is no standard regimen for unithiol administration; dosing and duration depends
on clinical condition and blood and urine concentrations of the metal. High doses
have been used and are well tolerated, but are not advised in chronically poisoned
patients without severity clinical effects (see section 12.2). Unithiol should be taken on
an empty stomach.
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• Adults: The usual initial dose is 100-200 mg every 6-8 hours (3-4 times/day); this is
then tapered over the following days or weeks.
• Children: The usual initial dose 50-100 mg every 6-8 hours (3-4 times/day); this is
then tapered over the following days or weeks. Alternatively 5 mg/kg daily in 2 to 4
divided doses has been used.
13.2.2 Parenteral administration
Unithiol is given by IM or slow IV injection over 5 minutes (1 mL/minute). See table for
dosing regimen. From day 4 frequency of dosing should be based on the patient’s
clinical condition; parental unithiol may be continued or oral treatment may be started.
Unithiol must not be mixed with other infusion solutions, as this may reduce its
efficacy.
Table: Parenteral unithiol dosage
Day of
treatment
Adults
Children
Dose IM or slow
IV
Total daily
dose
Dose IM or slow IV
Total daily
dose
1
250 mg every 3-4
hours
1.5-2.0 g
5 mg/kg every 3-4
hours
30-40 mg/kg
2
250 mg every 4-6
hours
1.0-1.5 g
5 mg/kg every 4-6
hours
20-30 mg/kg
3
250 mg every 6-8
hours
0.75-1.0 g
5 mg/kg every 6-8
hours
15-20 mg/kg
4,5…
250 mg every 812 hours
0.50-0.75 g
5 mg/kg every 8-12
hours
10-15 mg/kg
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13.3 Precautions and contraindications
Unithiol should not be administered in acute arsine poisoning (AsH3), because it is
ineffective and can increase arsine toxicity.
The administration of unithiol in cases of asymptomatic or suspected poisoning (a
challenge or mobilisation test) cannot be recommended, because the metal-binding
agent mobilises the metal from tissue stores resulting in redistribution and potentially
increasing the concentration in the target organ, despite increasing excretion.
The administration of more than one metal-binding agent at the same time cannot be
recommended, as the risks and/or benefits of such therapy have not been evaluated.
The efficacy of a metal-binding agent may be difficult to determine.
After
discontinuation of metal exposure (and absorption) a decrease in the blood
concentration will occur without any therapy. Clinical efficacy should not be judged
only by the quantity of metal excretion or the decrease of blood concentrations. The
reduction of the tissue content in the target organ and the restoration of pathological
alterations also need to be considered. It is important to note that enhancement of the
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metal excretion by mobilisation may increase the metal burden of the target organ by
redistribution, and conversely the body burden may be reduced without a striking
decrease of the blood concentrations.
During long-term therapy the blood concentrations and excretion of trace elements
should be monitored carefully, because depletion of trace metals may play a role in the
toxicity of metal-binding agent agents.
13.4
Pharmaceutical incompatibilities and drug interactions
Unithiol must not be mixed with other infusion solutions, as this may reduce antidotal
efficacy.
Unithiol solution should be administered immediately after opening of the vials and all
remainder must be discarded, because the compound is oxidised rapidly in contact
with air.
Unithiol should not be given orally with mineral preparations or activated charcoal
because unithiol may be inactivated. For the same reason the unithiol capsules
should be taken at least one hour before a meal.
13.5
Side effects
Unithiol is generally well tolerated and the incidence of adverse effects is low.
Administration of unithiol also increases elimination of some trace elements, particularly
zinc and copper, but also selenium and magnesium. This effect is only likely to be of
clinical significance in patients on chronic unithiol therapy.
Skin reactions including rashes, pruritis and blistering have been reported. Erytheme
multiforme with buccal ulceration and depigmentation has been reported. StevensJohnson syndrome has been reported in a small number of cases. Anaphylactic shock
has not been reported. In most cases allergic reactions have resolved within 3-5 days
and generally no treatment is required. However, antihistamines and/or corticosteroids
may be given if necessary.
Nausea may occur from oral administration, and body fluids usually have a sulphur
odour for 6-8 hours after unithiol administration. Mild elevations of liver enzymes,
diuresis, fever and leucocytosis have also been reported.
With the parenteral preparation cardiovascular reactions may occur, particularly if
injected too rapidly. These effects are hypotension, nausea, dizziness and weakness.
Necrosis and ulceration may occur at the injection site, but this is associated with high
doses.
13.6
Pregnancy and lactation
Teratogenic effects have not been demonstrated in animal studies, indeed studies
have demonstrated that unithiol can protect against the developmental toxicity of
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arsenic and mercury. Even though safety in human has not been established,
pregnancy is not regarded as a contraindication. If unithiol is administered to
pregnant women, the essential minerals should be monitored carefully, because
metal-binding may cause a depletion of trace elements and it has been shown that
zinc deficiency can cause teratogenic effects.
In general lactation should be avoided in metal poisoning.
13.7
Storage
The capsules should be stored in a dry place.
The shelf-life for the commercial available pharmaceutical preparations Dimaval® is
claimed to be 5 years for the capsules 4 years for the ampoules. The expiry date is
stated on each package.
14.
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3642
3643
15.
Author names, address
74
3644
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3647
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3649
3650
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3652
Initial draft by FW Jekat & FH Kemper
Updated by Nicola Bates MSc, MA: Guy's & St Thomas' Poisons Unit, London, UK
16.
Additional information
16.1
Description of search strategy
3653
3654
Table 2: Results of EMBASE search, 5 April 2009.
3655
Number
1
2
3
4
5
6
7
8
Keywords
Unithiol [any field]
DMPS [any field]
(dimercaptopropanol OR dimercaptopropane AND sulfonate)
[any field]
poisoning OR toxicity OR overdose [any field]
1 and 4
2 and 4
3 and 4
5 and 6 and 7 remove duplicates
Results
569
446
100
186824
277
145
51
295
3656
3657
3658
Table 3: Results of Pubmed search, using the EMBASE interface, 5 April 2009.
Number
1
2
3
4
5
6
7
8
Keywords
Unithiol [any field]
DMPS [any field]
dimercaptopropanol OR dimercaptopropane AND sulfonate
[any field]
poisoning OR toxicity OR overdose [any field]
1 and 4
2 and 4
3 and 4
5 and 6 and 7 remove duplicates
Results
541
437
103
265512
208
158
62
276
3659
3660
Table 4: Results of Cochrane Library, 5 April 2009
3661
Number
1
2
3
4
Keywords
Unithiol [MeSH term] in Central Register of Controlled Trials
Unithiol [MeSH term] in Cochrane reviews
Unithiol [MeSH term] in other reviews
Unithiol [MeSH term] in economic evaluations
Results
11
0
0
1
3662
3663
16.2
Description of published evidence
3664
3665
Table 5: Summary of evidence of use of unithiol in metal and metalloid poisoning.
75
3666
Metal
Antimony
Clinical trial data
No data.
Arsenic
One randomized,
single blinded,
placebo-controlled
study of 21 patients
with chronic
arsenicosis. Unithiol
resulted in significant
clinical improvement.
Cessation of
exposure and
placebo also reduced
clinical scores but
these were
significantly lower for
unithiol-treated
subjects. In the
placebo group
improvement was
attributed to
cessation of
exposure and
hospitalisation.
There were
significant increases
in urinary arsenic
excretion with unithiol
treatment, compared
to no increase in the
placebo group. No
adverse effects were
reported (Guha
Mazumder et al.,
2001).
Case reports
Used with apparent benefit
in a small number of
paediatric trivalent antimony
compounds (Iffland &
Bösche, 1987; Kemper et
al., 1989; Jekat & Kemper,
1990). There is no
information on its use in
pentavalent antimony
compounds.
5 reports of acute arsenic
poisoning involving 7 adult
patients treated with unithiol
as the only antidote (Moore
et al., 1994; Kruszewska et
al., 1996; Horn et al., 2002;
Adam et al., 2003; HeinrichRamm et al. 2003). All
patients showed increased
urinary excretion and
decreased plasma
concentrations of arsenic.
All patients recovered.
1 report where dimercaprol
was used followed by
succimer and unithiol
together. Patient showed
clinical improvement but
contribution of unithiol
difficult to determine
(Vantroyen et al., 2004)
Animal studies
Unithiol has been shown to
increase survival (Basinger
& Jones, 1981a) and
reduce the LD50 (ChihChang, 1958) in antimonypoisoned experimental
animals.
Unithiol increases survival
(Tadlock & Aposhian, 1980;
Aposhian et al., 1982; Inns
et al., 1990), increases the
LD50 (Aposhian et al., 1981),
increases urinary (Maiorino
& Aposhian, 1985; Flora et
al., 1995a) and faecal
(Maehashi & Murata, 1986;
Reichl et al., 1995)
elimination, reduces tissue
concentrations (Kreppel et
al., 1989; Kreppel et al.,
1990; Schäfer et al., 1991)
and reduces the severity of
toxicity (Kreppel et al., 1989,
Inns & Rice, 1993; Flora et
al., 1995a; Flora et al.,
2005) in arsenic poisoned
experimental animals.
1 report of chronic arsenic
poisoning. Administration of
unithiol resulted in increased
urinary excretion of arsenic
and clinical improvement
(Wax & Thornton, 2000).
Beryllium
No data.
No data.
Bismuth
No data.
3 cases of acute bismuth
poisoning, involving a 13year-old (Bogle et al., 2000)
and 2 adults (Stevens et al.,
1995; Dargan et al., 2001;
76
Unithiol increases beryllium
excretion and reduces
beryllium-induced toxic
effects in experimental
animals (Mathur et al.,
1994; Flora et al., 1995b;
Johri et al., 2002; Johri et
al., 2004).
Unithiol increases survival
(Basinger et al., 1983) and
reduces tissue
concentrations (Slikkerveer
et al., 1992; Jones et al.,
Metal
Clinical trial data
Cadmium
No data.
Chromium
No data.
Case reports
Ovaska et al., 2008). All
showed improved clearance
of bismuth, though one
patient was also
haemodialysed (Stevens et
al., 1995).
2 cases of chronic bismuth
poisoning. In 1 case unithiol
resulted in improvement of
neurological toxicity
(Playford et al., 1990) and
in the other the patient
deteriorated and unithiol
was stopped (Teepker et
al., 2002).
1 case report. Unithiol in a
patient with chronic
occupational exposure
increased urinary cadmium
concentrations. No further
information available
(Daunderer, 1995).
2 case reports in adults; the
effect of unithiol is unclear
in both. 1 patient recovered
(Donner et al., 1986); the
other also received
haemodialysis and
haemofiltration but died 48
hours after admission
(Pudill et al., 1989).
77
Animal studies
1996) in bismuth-poisoned
experimental animals.
Unithiol increases the LD50
(Pethran et al., 1990),
increases survival (Aposhian
(1982; Andersen & Nielsen,
1988; Basinger et al., 1988;
Srivastava et al., 1996),
reduces tissue
concentrations (PlanasBohne & Lehman, 1983;
Eybl et al., 1984; Srivastava
et al., 1996) in cadmium
poisoned experimental
animals. However, in some
studies there was no effect
on survival (Eybl et al.,
1984), excretion (Eybl et al.,
1984, Rau et al., 1987;
Zheng et al., 1990) or tissue
distribution of cadmium
(Cherian, 1980) and an
increase in tissue
concentrations was
reported in some studies
(Shinobu et al., 1983;
Basinger et al., 1988).
Although unithiol may be
effective, other metalbinding agents appear to be
more efficacious (Eybl et
al., 1984; Eybl et al., 1985;
Andersen & Nielsen, 1988;
Srivastava et al., 1996).
Apparent benefit
demonstrated, but data are
limited. Unithiol reduces
chromate-induced
cytotoxicity (in some
circumstances) (Susa et al,
1994), reduces lethality and
increases renal excretion of
(Susa et al, 1994) in
chromium-poisoned
experimental animals.
Metal
Cobalt
Clinical trial data
No data.
Case reports
2 paediatric cases of acute
exposure. Unithiol was
used after penicillamine and
was associated within
increased urinary cobalt
concentrations (Müller et al.,
1989).
Copper
No data.
One paediatric case of
acute ingestion; unithiol was
associated with increased
urinary copper excretion
(Donner et al., 1986).
Gold
Lead
Wilson’s disease
In a randomised trial
of 28 patients
comparing unithiol
and captopril, unithiol
had a more potent
anticopper effect. 1
patient on unithiol
developed a
transient, adverse
effect (Wang et al.,
2003).
One controlled study
of 60 males with
chronic lead toxicity.
Unithiol-treated
patients had
increased elimination
and biochemical and
clinical improvement,
and were discharged
6 weeks earlier than
controls
(Anatovskaya, 1962).
In an adult case there was
no measurement of copper
excretion; the patient
survived (Sinković et al.,
2008).
Wilson’s disease
In an unspecified number of
patients copper excretion
with unithiol was
comparable to that of
penillicamine. Unithiol was
discontinued in 2 patients
due to adverse effects
(Walshe, 1985)
Copper poisoning
1 case of iatrogenic
poisoning where unithiol
was thought to be effective
in removing gold although
no details are given (Ashton
et al., 1992a).
In 2 adult patients with
chronic lead exposure
unithiol decreased blood
lead concentrations and
increased urinary lead
excretion (Donner et al.,
1987; Hruby & Donner,
1987; Autenrieth et al.,
1998).
Succimer is more commonly
used in the management of
lead poisoning.
12 children (aged 31
to 69 months) with
chronic lead toxicity
received one of two
dose regimens of
unithiol. All had
reduced blood lead
concentrations and
78
Animal studies
Apparent benefit
demonstrated, but data are
limited. Unithiol has been
shown to reduce the
lethality of cobalt (Cherkes
& Braver-Chernobulskaya,
1958; Eybl et al., 1985) but
to increase cobalt
concentrations in some
tissues (Eybl et al., 1985).
Apparent benefit
demonstrated, but data are
limited. Unithiol increased
the LD50 (Pethran et al.,
1990) and reduced toxicity
(Mitchell et al., 1982) in
copper-poisoned
experimental animals.
Unithiol increases survival
(Basinger et al., 1985),
reduces renal
concentrations (Gabard,
1980; Kojima et al., 1991;
Takahashi et al., 1994),
increases urinary excretion
(Kojima et al., 1991) and
reduces renal toxicity
(Kojima et al., 1991;
Takahashi et al., 1994) in
gold-poisoned in
experimental animals
Unithiol increases survival
(Llobet et al., 1990),
increases excretion
(Hofmann & Segewitz,
1975; Llobet et al., 1990),
reduces tissue
concentrations (Twarog &
Cherian, 1983; Twarog &
Cherian, 1984; Xu & Jones,
1988; Llobet et al., 1990),
except in the brain (Sharma
et al., 1987; Aposhian et al.,
1996) and reduces toxicity
(Twarog & Cherian, 1983;
Sharma et al., 1987;
Tandon et al., 1994) in leadpoisoned experimental
animals.
Metal
Clinical trial data
increased urinary
excretion (Chisolm &
Thomas, 1985).
Case reports
Animal studies
Mercury
In patients with
chronic exposure
penicillamine (12
patients), N-acetyl-DLpenicillamine (17),
unithiol (10) and a
thiolated resin (8)
were compared. The
study was not
clinically controlled.
Although all agents
reduced blood
mercury
concentrations and
unithiol was the most
effective there was no
immediate clinical
improvement,
presumably because
the duration of therapy
was too short and
therapy was started
months after exposure
(Clarkson et al.,
1981).
Inorganic mercury
6 acute cases reported; 3
patients initially received
dimercaprol (Nadig et al.,
1985; Ashton & House,
1989; Toet et al., 1994) and
4 developed renal failure
(Nadig et al., 1985; Ashton
& House, 1989; Toet et al.,
1994; Dargan et al., 2003a).
Unithiol was shown to
reduce the mercury
elimination half-life in two
cases (Toet et al., 1994;
Dargan et al., 2003a). All
patients recovered.
Unithiol increases excretion
(Gabard, 1976a; Gabard,
1976b; Wannag & Aaseth,
1980; Planas-Bohne, 1981;
Aaseth et al., 1982; Buchet
& Lauwerys, 1989),
decreases tissue
concentrations (Gabard,
1976a; Gabard, 1976b Cikrt
& Lenger, 1980; Wannag &
Aaseth, 1980; Aaseth et al.,
1982; Aaseth, 1983; Kachru
& Tandon, 1986) and
reduces toxicity (PlanasBohne, 1977; Jones et al.,
1980; Nielson & Andersen,
1991) in mercury-poisoned
experimental animals.
27 patients were
treated with unithiol
and/or succimer. All
had some relief (19
became
asymptomatic). Most
had increased
mercury excretion.
Unithiol was found to
be more effective
(data not provided
and the two antidotes
were used
interchangeably in
some patients)
(Zhang, 1984).
In a study of 95
patients with chronic
exposure (vapour,
inorganic mercury and
methyl mercury)
unithiol increased
urinary mercury
excretion in some but
others (number not
specified) showed no
increase in mercury
excretion. In more
In 2 chronic exposure cases
unithiol decreased the
elimination half-life of
mercury (Campbell et al.,
1986).
Organic mercury
3 acute cases in adults.
In 1 case unithiol was
determined to be relatively
ineffective possibly due to
coadministration of a
copper and zinc
supplement (Lund et al.,
1984). In another case
where unithiol was
alternated with
penicillamine, the unithiol
reduced mercury protein
binding (Köppel et al.,
1982). The 3rd patient was
also treated with succimer;
neither significantly
increased mercury
clearance (Pfab et al.,
1996).
Metallic mercury
2 cases of aspiration; both
patients remained well but in
1 the mercury blood and
urine concentrations
remained high (Batora et al.,
2001) and in the other the
blood concentration
decreased rapidly (Kummer
& Michot, 1984).
79
Metal
Clinical trial data
than two-thirds there
was improvement in
subjective complaints
and objective
neurological
parameters. The 14
day regimen was too
short to have a
permanent effect on
mercury
concentrations (BöseO’Reilly et al., 2003).
Study limitations:
absence of a control
group, lack of details
of patients (age,
weight) and continued
exposure to mercury
during therapy.
Case reports
In 3 children (<7 years)
unithiol was associated with
improved clinical signs and
enhanced mercury excretion
(von Mühlendahl, 1990). In
a 14-year-old with acrodynia
there was slow recovery
with unithiol (Böckers et al.,
1983).
Animal studies
Dermal mercury
In 2 cases of chronic
exposure, unithiol
increased urinary mercury
concentrations (Böckers et
al., 1985l Pelclová et al.,
2001).
Parenteral mercury
4 cases of mercury injection
(Ashton et al., 1992b;
Torres-Alanís et al., 1997;
Batora et al., 2000; Eyer et
al., 2006). Although unithiol
increases urinary mercury
concentrations, the effect
may be small (Eyer et al.,
2006) and there may be no
change in radiographic
deposits of mercury
(Torres-Alanís et al., 1997)
or clinical signs.
Nickel
In 8 patients with
chronic exposure from
facial mercurous
chloride cream there
was a significant
increase in urinary
mercury
concentrations after
24 hours of unithiol.
One symptomatic
patient recovered and
the other had
persistent tremor
(Garza-Ocañas et al.,
1997).
No data.
No data.
Palladium
No data.
No data.
Platinum
No data.
No data.
Polonium
No data.
Children (number not
80
Unithiol increases survival
(Basinger et al., 1980),
increases excretion
(Sharma et al., 1987) and
reduces nickel-induced
toxic effects (Sharma et al.,
1987; Tandon et al., 1996).
No benefit demonstrated,
but data are limited. Unithiol
did not influence toxicity or
reduce lethality in
palladium-poisoned animals
(Mráz et al., 1985).
No benefit demonstrated,
but data are limited. A
single dose of unithiol had
no significant effect on renal
platinum concentrations.
After 4 treatments there
was significant increase in
urinary excretion of
platinum, but this was low
(Planas-Bohne et al., 1982).
Not recommended.
Metal
Clinical trial data
Case reports
known, but <10) treated
with unithiol after
contamination with
poloniumn-210 remained
well over the 46 month
period of monitoring with
only impairment of protein
formation in the liver
(Shantyr et al., 1969).
No data.
Selenium
No data.
Silver
No data.
In 2 cases of chronic silver
toxicity unithiol increased
urinary silver excretion but
the quantity excreted was
low (Aaseth et al., 1986;
Kemper et al., 1989; Jekat
and Kemper, 1990).
Strontium
No data.
No data
Thallium
No data.
No data.
Tin
No data.
In 1 case unithiol increased
urinary tin concentrations
and clinical signs improved
(Hruschka, 1990).
Vanadium
No data.
No data.
81
Animal studies
Although unithiol can
remove polonium-210 from
most tissues (Aposhian et
al., 1987) it results in
concentration of polonium in
the kidneys (Volf, 1973;
Rencová et al., 1993; Volf
et al., 1995).
No benefit demonstrated,
but data are limited. Unithiol
had no effect in seleniumpoisoned animals; the
concentration of selenium in
urine and faeces was
unchanged (Paul et al.,
1989).
Unithiol increased the LD50
of silver chloride in mice
(Pethran et al., 1990),
prevented the development
of toxic pulmonary oedema
and death in dogs
(Romanov, 1967) and in
vitro completely reversed
silver inhibition of Na,KATPase (Hussain et al.,
1994).
No benefit demonstrated,
but data are limited. Unithiol
did not affect survival rate in
strontium-poisoned
experimental animals
(Domingo et al., 1990;
Pethran et al., 1990).
Unithiol is ineffective in
thallium-poisoned
experimental animals
(Pethran et al., 1990; Mulkey
& Oehme, 2000).
Apparent benefit
demonstrated with reduced
tin-induced lesions in rats
(Merkord et al., 2000), but
data are limited.
Unithiol had no effect on
lethality in vanadiumpoisoned mice (Jones &
Basinger, 1983) and no
significant effect on the
death rate, body weight
reductions, or reduction in
weights of legs and toes in
chick eggs incubated with
vanadium (Hamada, 1994).
An in vitro study has shown
that oxovanadium forms a
complex with unithiol
(Williams & Baran, 2008).
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
3685
3686
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
Metal
Clinical trial data
Case reports
Zinc
No data.
No data.
Animal studies
The significance of this in
vivo remains to be
elucidated.
Unithiol increases excretion
(Domingo et al., 1988) and
reduced lethality in zincpoisoned experimental
animals (Basinger & Jones,
1981b), but more effective
antidotes are available
(Basinger & Jones, 1981b;
Domingo et al., 1988; Llobet
et al., 1988).
Abbreviations
AAS
ABCC2
AES
ALAD
BAL
BAPSA
CAS
CDTA
DDC
DMPA
DMSA
DTPA
EDTA
g
HOEtTTC
HPLC
ICP
i.m.
i.p.
IPCS
IR
i.v.
k
L
LD
m
µ
µCi
min
MRP2
NOEL
OAT1
OAT3
PAH
ppm
Atomic Absorption Spectroscopy
ATP-binding cassette, sub-family C
Atomic Emission Spectroscopy
δ-aminolevulinate dehydratase
2,3-dimercaptopropanol; British Anti-Lewisite; dimercaprol (rINN)
2,3-bis-(acetylthio)-propanesulphonamide
Chemical Abstracts Service
cyclohexanediamintetraacetic acid
sodium diethyldithiocarbamate
N-(2,3-dimercaptopropyl) phthalamidic acid
Dimercaptosuccinic acid; succimer (rINN)
Diethylenetriaminepentaacetic acid; pentetic acid (rINN)
Ethylenediaminetetraacetic acid; sodium calcium edetate (rINN)
gram
N,N’-di-(2-hydroxyethyl)-ethylenediamine-N’N’-biscarbodithioate
High Performance Liquid Chromatography
Inductively Coupled Plasma
intramuscular
intraperitoneal
International Programme on Chemical Safety
infra-red
intravenous
kilo (103)
litre
Lethal Dose (subscript indicates percent mortality)
milli (10-3)
micro (10-6)
microCurie
minute
multidrug resistance protein 2
no observed effect level
organic anion transporter 1
organic anion transporter 3
p-aminohippurate
parts per million (10-6)
82
3705
3706
3707
rINN
recognised international non-proprietary name
83