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IPCS EVALUATION OF ANTIDOTES FOR POISONING BY
METALS AND METALLOIDS
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PRUSSIAN BLUE
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Potassium ferric (III) hexacyanoferrate (II) (colloidal soluble Prussian Blue,
KFe[Fe(CN)6) and ferric (III) hexacyanoferrate (II) (insoluble Prussian Blue, Fe4
[Fe(CN)6]3)
Initial draft (1994):
A.N.P. van Heijst (National Poisons Control Centre, Utrecht, The Netherlands), A. von Dijk
(Apotheek, Academisch Ziekenhuis, Utrecht, The Netherlands) & J. Ruprecht (Heyl
Pharmaceuticals, Berlin, Germany)
Update (2009):
M McParland and P Dargan (Medical Toxicology Information Services, Guy's & St Thomas'
NHS Foundation Trust, London, UK)
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1.
Introduction .................................................................................................................. 3
2.
Name and Chemical Formula of Antidote.................................................................... 3
3.
Physico-chemical Properties ........................................................................................ 4
4.
Synthesis and Pharmaceutical Formulation ................................................................. 5
5.
Analytical Methods ...................................................................................................... 7
6.
Shelf-life ....................................................................................................................... 9
7.
General Properties ........................................................................................................ 9
8.
In Vitro Studies .......................................................................................................... 11
9.
Animal Studies ........................................................................................................... 12
10.
Volunteer Studies ....................................................................................................... 21
11.
Clinical Studies – Clinical Trials ............................................................................... 23
12.
Clinical Studies - Case Reports .................................................................................. 23
13.
Summary of Evaluation.............................................................................................. 36
14.
Model Information Sheet............................................................................................ 40
15.
References .................................................................................................................. 42
16.
Author(s) Name, Address........................................................................................... 51
17.
Additional Information............................................................................................... 51
Results of Cochrane Library Search 4th November 2009 ................................................... 52
Table 3: Summary of evidence of use of Prussian blue in metal poisoning ......................... 1
Table 4: Summarized case reports of thallium poisoning..................................................... 6
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1.
Introduction
Prussian blue was first prepared in 1704 and used principally as an inorganic pigment
(Faustino, 2008). Work in the 1960s investigated the use of Prussian blue as an antidote for
thallium poisoning and a decorporation agent for radiocaesium (caesium-134 and caesium137). From the 1970s Prussian blue was recommended as an antidote in thallium
intoxication and it is now routinely used for this purpose. Further studies into its use for
increasing the elimination rate of radiocaesium were undertaken following the Chernobyl
nuclear reactor accident in 1986 but it was only after Goiânia incident in 1987 that it was
used in the management of a large scale radiation accident (Faustino, 2008).
There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian
blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue). It
is essential to be specific about which form of Prussian blue has been used in future
publications. The different forms should be identified by citing the correct chemical name
and/or chemical formula and/or the physical nature (insoluble or colloidal soluble).
Prussian blue is given orally and acts via ion exchange, adsorption and mechanical trapping
to bind thallium and caesium within its crystal lattice, interrupting their enterohepatic
circulation, enhancing faecal elimination and reducing body burden.
Insoluble Prussian blue is used to treat patients with known or suspected internal
contamination with radioactive caesium, radioactive thallium and non-radioactive thallium,
to increase their rates of elimination. Prussian blue can reduce the biological half-life of
radiocaesium by about a third. There is one report where Prussian blue has been used for the
treatment of non radioactive caesium toxicity (Thurgur et al., 2006) and rubidium has also
been shown to bind to Prussian blue (Hoffman, 2006).
Prussian blue is well tolerated but can result in constipation. It is essential to treat
constipation as it will decrease elimination of thallium and caesium and some authors advise
administration of Prussian Blue with laxatives to prevent constipation.
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2.
Name and Chemical Formula of Antidote
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There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian
blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue).
Synonyms which apply to both compounds include Berlin blue, Milori Blue, Chinese blue,
Hamburg blue, mineral blue, Pigment blue 27 and Paris blue.
Synonyms
Potassium ferric (III)
hexacyanoferrate (II)
colloidal soluble Prussian blue,
SPB, potassium ferric
ferrocyanide,
Molecular formula
Molecular weight
KFe[Fe(CN)6]
306.9
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Ferric (III) hexacyanoferrate (II)
insoluble Prussian blue, IPB, ferric
ferrocyanide, Iron (III) ferrocyanide,
Ferrotsin, Ferrocin,
Ferrihexacyanoferrate, ferric
cyanoferrate (II)
Fe4[Fe(CN)6]3
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CAS Registry No
Colour Index No.
RTECS number
Structural diagram
(ChemIDplus Lite)
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Potassium ferric (III)
hexacyanoferrate (II)
12240-15-2
77520
Ferric (III) hexacyanoferrate (II)
14038-43-8
77510
LJ8200000
Prussian blue is a non-stoichiometric compound and the chemical formulae for both forms
shown above are therefore idealized. Additionally all precipitates of insoluble Prussian blue
contain nonstoichiometric amounts of potassium, protons and water (Dvořák, 1971; Nielsen
et al., 1987; Nielsen et al, 1988b). The water is partially adsorbed at the large surface of this
pigment, partially distributed in the cavities of the crystal lattice (zeolithical water) and
partially coordinatively bound (Ludi, 1988). Colloidal soluble Prussian blue may
additionally contain nonstoichiometric amounts of cations (H+, alkali metal ions) and anions
(Cl-, OH) and water (Bozorgzadeh, 1971; Dvořák, 1970; Dvořák, 1971).
Insoluble Prussian blue is the only commercially available pharmaceutical preparation
however in the literature there is confusion over the two available forms of Prussian blue and
inconsistencies in the nomenclature of Prussian blue (Hoffman, 2006). For example, some
authors who used the commercially available Prussian blue Antidotum Thallii-Heyl®
containing insoluble ferric hexacyanoferrate have incorrectly described the chemical formula
as KFe[Fe(CN)6] (Franke et al., 1979) or named the compound as potassium ferric
ferrocyanide (Spoerke et al., 1986). In another report both formulae are used KFe[Fe(CN)6]
and Fe4[Fe(CN)6]3 for Antidotum Thallii-Heyl® (Trenkwalder et al., 1984). In other cases
the drug Antidotum Thallii-Heyl® is described as "colloidal soluble Prussian blue" (Jax et
al., 1973; Kemper, 1979; Gansser, 1982; Forth, 1986) or potassium ferric (III)
hexacyanoferrate (II) is described as insoluble (Lehmann & Favari, 1984). As a result it is
often very difficult or impossible to determine which form of Prussian blue was used.
Where possible, the two forms of Prussian blue are identified here as soluble Prussian blue
and insoluble Prussian blue.
3.
Physico-chemical Properties
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Melting point: Not available.
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4.
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4.1
Routes of Synthesis
Both substances can be synthesized according to the method of Dvořák (1969). The basic
chemicals needed are the same for both substances. However, the salt ultimately formed will
depend on the ratio of the raw materials and the way in which they are added to each other.
Solubility: Potassium ferric (III) hexacyanoferrate (II) is colloidally soluble in water, ferric
(III) hexacyanoferrate (II) is insoluble in water and diluted acids (solubility product
=10-40, i.e. practically insoluble) (Ludi, 1988). 59Fe-labelled measurements resulted
in a solubility of 1.1 µmol/L for potassium ferric (III) hexacyanoferrate (II) and 0.7
µmol/L for ferric (III) hexacyanoferrate (II) (Dvořák, 1970).
Optical properties: Not available.
pH: Not available.
pKa: Not available.
Stability in light: Prussian blue should be stored in tightly closed containers protected from
light.
Thermal stability: Not available.
Refractive index: Not available.
Specific gravity: 1.8
Loss of weight on drying: Potassium ferric (III) hexacyanoferrate (II) 6-15% loss of weight
on drying at 150°C. Ferric (III) hexacyanoferrate (II) 28-34% loss of weight on
drying at 105°C.
Excipients and pharmaceutical aids: In both pharmaceutical preparations, Antidotum ThalliiHeyl® and Radiogardase®-Cs, ferric (III) hexacyanoferrate (II) is provided as 500mg
of Prussian blue powder in gelatine capsules with 0-38mg of microcrystalline
cellulose. The powder may vary in coarseness and colour shade (Heyl, 2004).
Pharmaceutical incompatibilities: None known.
Binding to some therapeutic drugs and essential nutrients is possible. Insoluble Prussian blue
may bind electrolytes in the gastrointestinal tract. Hypokalaemia (potassium 2.5-2.9)
was reported in 3 of 42 patients (7%) treated with insoluble Prussian blue (Heyl,
2004; Thompson & Callen, 2004; Thompson & Church, 2001). There are some
anecdotal reports of Prussian blue decreasing the bioavailability of oral tetracycline
and the serum levels and, or clinical response to critical orally administered products
should be monitored (Heyl, 2004).
Synthesis and Pharmaceutical Formulation
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FeCl3 + K4[Fe(CN)6] ------ > KFe[Fe(CN)6] + 3 KCl
4 FeCl3 + 3 K4[Fe(CN)6]----- > Fe4[Fe(CN)6]3 + 12 KC1
Raw materials:
Ferric chloride (FeCl3) and potassium ferrocyanide (K4[Fe(CN)6])
Water suitable for injection or of comparable quality (i.e. water with cation and anion
concentrations equal or less than water for injection).
Synthesis:
(a)
Basic solutions
Dissolve appropriate amounts of FeCl3 and K4[Fe(CN)6] in water so that the molar ratio of
the two solutions is 2.0. This means that when a 0.2 M ferric chloride solution has been
prepared, the molarity of the K4[Fe(CN)6] solution should be 0.1 M.
(b1)
Potassium ferric (III) hexacyanoferrate (II)
It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6 ]4- in the reaction
mixture equals 0.33. When 1 litre of 0.2 M ferric chloride solution is used, then
(1000 x 0.2)/(0.33 x 0.1) 6060 ml of a 0.1 M (Fe(CN)6]4- solution is necessary. The
quantity of [Fe (CN)6]4- is added drop wise to the ferric chloride solution whilst
stirring vigorously. Centrifuge at 120000g after one hour standing. Wash the
precipitate three times with water and centrifuge after each washing step. Dry the
precipitate obtained after the last washing step at 105 oC until the weight remains
constant.
To remove possible low molecular impurities some authors have dialysed the
colloidal soluble Prussian blue exhaustively against water (Müller et al., 1974;
Nielsen et al., 1987; Nielsen et al., 1988a; Nielsen et al., 1988b).
(b2)
Ferric (III) hexacyanoferrate (II)
It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6]4- in the reaction
mixture equals 1.33. When 1 litre of 0.2 M ferric chloride solution is used, then
(1000 x 0.2)/(1.33 x 0.1) 1504 ml of a 0.1 M [Fe(CN)6]4- solution is necessary. The
quantity of [Fe(CN)6]4- is added drop wise to the ferric chloride solution whilst
stirring vigorously. Filter standing for one hour. Wash the precipitate and filter
three times after each washing step. Dry the precipitate obtained after the last
washing step at 105 oC until weight remains constant. The drying process influences
the efficacy of the substance (Nigrović et al., 1966). The effectiveness of Radiogardase®-Cs in binding caesium was higher than that of the ferric (III) hexacyanoferrate
(II) synthesized by the authors (Nielsen et al., 1987). Among other things this can be
attributed to a special drying procedure.
After synthesis as described, and after one year's storage in tightly closed containers
at room temperature, neither substance showed any significant decomposition into
cyanide ion (Dvořák, 1970). The effectiveness of ferric (III) hexacyanoferrate (II)
was not decreased after storage during one year (Nigrović et al., 1966).
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4.2
Manufacturing processes
Not known.
4.3
Presentation and formulation
Prussian blue is available as Radiogardase®-Cs (Radiogardase® in the United States of
America) and Antidotum Thallii-Heyl® distributed by Heyl Chemisch-pharmazeutische
Fabrik GmbH, Berlin, Germany.
Both products are available in bottles of 30 hard gelatine capsules, each containing 0.5 g of
insoluble Prussian blue.
5.
Analytical Methods
5.1
Quality control procedures for the antidote and/or its formulation
5.1.1 Test for the presence of colloidal Prussian blue:
A mixture of 10 g insoluble Prussian blue and 50 ml of distilled water is shaken and filtered
using a membrane filter. The filtrate should show no blue colouration (absence of colloidal
soluble Prussian blue).
5.1.2 Test for the presence of insoluble Prussian blue:
Shake 100 mg of colloidal soluble Prussian blue with 20 ml of water. An intensely dark blue
solution is obtained. Precipitation should not occur before a standing time of two days has
passed (test to exclude the insoluble form).
5.1.3 Test for the presence of hexacyanoferrate (II) and hexacyanoferrate (III):
10 g Prussian blue and 50 ml distilled water are shaken and filtered using a membrane filter.
The filtrate is then mixed with the hydrochloric acid salt of ferrous ammonium sulphate
((NH4)2Fe (II)(SO4)2) or ferric ammonium sulphate ((NH4)Fe (III)(SO4)2). The absence of
blue colour indicates that K3[Fe (III)(CN)6] is less than 5 ppm and K4[Fe (II)(CN)6] is less
than 20 ppm respectively.
5.1.4 Test for iron content:
500 mg Prussian blue in 50 ml water are shaken and filtered. Compared with an iron
standard solution the iron content should be not more than 100 ppm.
5.1.5 Test for heavy metal content:
After digestion of Prussian blue with concentrated sulphuric acid the heavy metal content
(measured as lead) should be less than 50 ppm. Arsenic content must be less than 5 µg/g.
5.1.6 Removal of oxalic acid:
Prussian blue may contain oxalic acid, originating from the manufacturing process. Shake 1
g of Prussian blue with 10 ml sodium acetate solution (Dutch Pharmacopoeia, 1966).
Centrifuge and filter the upper layer through a paper filter folded three times. Add to 5 ml
filtrate 1 ml of calcium acetate solution (Dutch Pharmacopoeia, 1966). No precipitate of
calcium oxalate should occur after 24 hours. Since no oxalic acid is used in the above specified synthesis, quality control for this acid may be omitted provided that the raw materials do
not contain it. The commercially available pharmaceuticals Prussian blue in Antidotum
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Thallii-Heyl® and Radiogardase®-Cs do not contain oxalic acid.
5.2
Methods for identification of the antidote
Detection of ferric (III) and hexacyanoferrate (II) ions: 500 mg of Prussian blue is heated in
5 ml of 3M potassium hydroxide resulting in decomposition to brown, flocculent ferric
hydroxide. After deposition the supernatant fluid appears yellow (K4[Fe(CN)6]). After filtration, 2 ml of the fluid is acidified with concentrated hydrochloric acid and mixed with a
FeCl3 solution and this will result in blue colouration or formation of a blue precipitate.
5.3
Methods for analysis of the antidote in biological samples
Not applicable.
N.B. It is often stated that Prussian blue is not absorbed to any significant extent however
anecdotal reports suggest prolonged therapy results in a blue discolouration of sweat and
tears suggesting some absorption.
5.4
Analysis of the toxic agents in biological samples
5.4.1 Analysis of thallium in urine, plasma and erythrocytes
Thallium can be measured by spectrophotometry, flame atomic absorption
spectrophotometry (AAS) and electrothermal atomic absorption spectrophotometry
(ETAAS) (Moffat et al, 2004).
5.4.1.1 Spectrophotometry
A spectrophotometric method was described by de Wolff and Lenstra (1964). It involves the
determination of thallium at 550nb using rhodamine 'B' or brilliant green and can be used on
urine and on blood diluted with water. The limit of quantification is approximately 50µg/L
(Moffat et al, 2004). This method is described in the Thallium Poisons Information
Monograph (IPCS, 1990).
Another spectrophotometric method is described by Flanagan et al (1995). In this method a
pink-red colour indicates the presence of thallium at concentrations of 1mg/l or more. A
calibration graph of absorbance against thallium concentration in standard samples can be
used to measure the thallium concentration more precisely. The limit of sensitivity is 0.1
mg/L.
5.4.1.2 Atomic Absorption Spectrophotometry
Flame AAS can be used to measure thallium in plasma, blood or urine by extracting it as a
pyrrolidine dithiocarbamate complex in an organic solvent (de Groot et al, 1985). The lowest
quantifiable concentration is at least 0.2 mg/l and depends on the atomic absorption
spectrophotometer used. Linearity is up to 5 mg/l. Higher concentrations can be measured
by diluting the sample under investigation with blank sample. This method is described in
the Thallium Poisons Information Monograph (IPCS, 1990).
ETAAS has been used for monitoring occupational exposure and has a limit of detection of
less than 1 µg/L (Moffat et al, 2004).
5.4.2 Analysis of caesium in biological samples
Caesium-134 and caesium-137 decay by emitting beta particles and these nuclides are
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detected using gamma spectrometry.
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The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C;
occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004).
For the pharmaceutical preparations Antidotum Thallii-Heyl® and Radiogardase®-Cs the
shelf-life is given as five years.
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Specialist advice is essential for dose assessment following a radiation accident as this assists in
determining appropriate management and the expected clinical course. Radioactivity
measurements of the wound (if applicable), skin or chest (following inhalation), nasal swabs,
urine and faeces are also used to assess dose. In many cases the victim is not wearing a
dosimeter (and this only measures external exposure not the internal dose). In addition the
standard models for calculating intake from routine occupational exposures may not be
applicable and individual-specific models may have to be developed and applied for internal
dose calculations (Toohey, 2003).
A quantitative baseline of the internal contamination of radiocaesium should be obtained by
appropriate whole body counting and/or by bioassay, or faeces/urine sample whenever
possible to obtain the following type of information to establish an elimination curve:
• Estimated internalised radiation contamination of caesium, and
• Rate of measured elimination of radiation in the faeces (Heyl, 2004).
Shelf-life
General Properties
Orally administered Prussian blue binds thallium or caesium in the gut and increases the
concentration gradient, enhancing elimination by gut dialysis. Thallium (Forth & Henning,
1979) and caesium (Nigrović, 1965) also undergo enterohepatic circulation and Prussian
blue interrupts their reabsorption from the gastrointestinal tract thereby increasing faecal
excretion. Prussian blue therefore reduces the biological half-life of caesium and thallium.
The mechanism of caesium and thallium adsorption by hexacyanoferrates is believed to
involve chemical ion exchange whereby nonstoichiometric and stoichiometric cations of the
drug are exchanged by thallium or caesium ions. The affinity of Prussian blue increases as
the ionic radius of the cation increases, so Prussian blue preferentially binds caesium (ionic
radius 0.169 nm) and thallium (0.147 nm) over potassium (0.133 nm) and sodium (0.116
nm) (Forth, 1983; Nielsen et al., 1987). An influence of Prussian blue on potassium and
sodium levels is therefore not expected (Nigrović et al., 1966). Rubidium (ionic radius
0.148) has also been shown to bind to Prussian blue (Hoffman, 2006).
Evidence is provided by a number of experimental studies. After binding of thallium to
colloidal soluble and insoluble Prussian blue, the content of potassium and hydrogen ions
was reduced (Dvořák, 1970). 40K labelled colloidal Prussian blue showed no radioactivity
after mixing with thallium. The pH value was decreased, indicating release of H+ ions
(Dvořák, 1971). In in vitro experiments insoluble Prussian blue bound more caesium than
potassium, and hydrogen and iron ions were released.
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There may be other mechanisms in addition to ion exchange. Nielsen et al. (1987) found that
colloidal soluble Prussian blue released more potassium than it adsorbed caesium,
suggesting that an additional, physical adsorption on its large surface, possibly interacting
with water, may be involved (Ludi, 1983; Richmond, 1968). Yang et al (2008) found that
the binding capacity of insoluble Prussian blue for thallium decreased as the water content of
Prussian blue was decreased. Forms of Prussian blue with a smaller crystal size, and
therefore a larger surface area, have a higher adsorptive capacity and antidotal efficacy for
thallium (Kravzov et al., 1993; Yang et al, 2008).
Non-dialyzed colloidal soluble Prussian blue initially proved to combine with thallium much
more effectively than ferric (III) hexacyanoferrate (II) in vitro as well as in vivo (Dvořák,
1969; Dvořák, 1970; Kamerbeek et al., 1971). This greater binding was not only the result
of the larger surface area of the colloidal soluble preparations (Dvořák, 1970), but also
because of the larger amount of extra-stoichiometric potassium in these preparations
(Dvořák, 1971). The sodium salt-derived preparation did not meet these requirements
(Rauws et al., 1979), and subtle differences in the dimensions of the crystal lattice might also
play a role (Keggin & Miles, 1936; Kravzov et al, 1993).
Colloidal soluble Prussian blue may, however, present problems. The production of a
standard colloidal soluble Prussian blue was found to be difficult resulting in a different
toxicity of the different preparations (Dvořák et al., 1971). Long-term treatment of rats with
non-dialysed colloidal soluble Prussian blue resulted in actual caesium retention in the body
in treated rats compared to control animals (Bozorgzadéh & Catsch, 1972; Müller et al.,
1974). Dresow et al., (1993) investigated the effect of soluble and insoluble Prussian blue in
rats, pigs and humans and concluded that for medical use in man, a separation of the low
molecular weight compounds from crude commercial preparations is recommended.
Following the introduction of colloidal potassium ferric (III) hexacyanoferrate (II) as an
antidote for thallium poisoning in 1970 (Kamerbeek, 1971; Kamerbeek et al., 1971), the
results of treatment with potassium ferric (III) hexacyanoferrate (II) as well as with ferric
(III) hexacyanoferrate (II) in patients with severe thallium poisoning published in the
literature have been associated with a favourable outcome, particularly when it is used early.
Treatment with Prussian blue in patients with thallotoxicosis can be life-saving but it does
not improve all the clinical signs, such as neurological signs or alopecia, particularly in latepresenting patients.
Thompson & Callen (2004) reviewed the English language literature concerning the efficacy
of soluble and insoluble Prussian blue and its use as a therapeutic agent in radiocaesium and
thallium poisoning. They noted that most of the evidence describing the efficacy of Prussian
blue for radiocaesium poisoning is based on the use of the insoluble form, whilst similar
evidence for thallium poisoning involves the use of the soluble form. They concluded that
while there is sufficient evidence that the insoluble form of Prussian blue is effective in
radiocaesium poisoning, there is a lack of analogous data supporting its use in thallium
poisoning. The authors acknowledged that further research is needed to determine the
significance of any differences between the two forms of Prussian blue and whether their
physicochemical differences have any effect on outcomes in human poisoning is currently
unknown. However, the commercial products in current use are formulated with the
insoluble form of Prussian blue and most data collated from future use is likely to refer to
this form only.
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8.
In Vitro Studies
8.1
In vitro binding of caesium
Various in vitro studies have shown that Prussian blue binds caesium (Bozorgzadéh, 1971;
Nielsen et al., 1987; Verzijl et al., 1992; Faustino et al., 2008).
In vitro binding of caesium to insoluble Prussian blue is affected by pH, exposure time,
storage temperature (affecting moisture content) and particle size. The lowest caesium
binding was at pH 1.0 and 2.0 and the highest at pH 7.5. Dry storage conditions results in
loss of moisture from Prussian blue which causes a negative effect on caesium binding
capacity. There is batch to batch variation in particle size and variation in binding capacity.
At 1, 4 and 24 hours it was determined that caesium binding increases as particle size
decreases. The maximum caesium binding capacity of insoluble Prussian blue was
approximately 715 mg/g (Faustino et al., 2008).
In a study comparing the binding capacity of soluble and insoluble Prussian blue, the
binding of caesium-137 was greater with insoluble Prussian blue (Radiogardase®-Cs) and
was pH-dependent for both formulations. The maximum binding capacities for insoluble
Prussian blue were 87 mg/kg at pH 1.0, 194 mg/g at pH 6.5, and 238 mg/g at pH 7.5. For
soluble Prussian blue the maximum binding capacities were 48 at pH 1.0, 73 mg/g at pH 6.5,
and 78 mg/g at pH 7.5 (Verzijl et al., 1992).
Nielsen et al. (1987) investigated caesium binding by various hexacyanoferrate compounds
(iron, copper, cobalt, nickel, zinc, manganese) at pH 1.2 and 6.8. All the compounds bound
caesium; potassium copper hexacyanoferrate (II) and potassium zinc hexacyanoferrate (II)
were the most efficient at pH 1.2 and 6.8. These compounds had twice the binding capacity
of soluble and insoluble Prussian blue. These authors also demonstrated that whey
contaminated with caesium-134 and caesium-137 was almost completely decontaminated by
dialysing a whey suspension against a buffer solution containing insoluble Prussian blue.
The whey had been produced from the milk of South German cows contaminated in the
summer of 1986 following the Chernobyl accident.
8.2
In vitro binding of thallium
In vitro studies have demonstrated that thallium binds to both soluble (Dvořák, 1970;
Kamerbeek et al., 1971; Krazov et al., 1993) and insoluble Prussian blue (Dvořák, 1970;
Yang et al., 2008). The adsorption is rapid: after 10 minutes all thallium was bound (Dvořák
et al., 1971). The effectiveness of soluble Prussian blue (as measured by mg of thallium/mg
Prussian blue or % adsorbed) was higher than that of insoluble Prussian blue (Dvořák, 1970;
Kamerbeek et al., 1971). In vitro, thallium binds more strongly to Prussian blue than to
activated charcoal (Kamerbeek et al., 1971).
As with caesium, the thallium binding capacity of Prussian blue is affected by pH, exposure
time, storage temperature (affecting moisture content) and particle size. The adsorption of
thallium on Prussian blue depended on the pH-value of the solution and a maximal
adsorption could be detected at a neutral or slightly alkaline pH (Dvořák, 1970). In the in
vitro study by Yang et al. (2008) the maximum thallium binding capacity of insoluble
Prussian blue was approximately 1400 mg/g at pH 7.5 after 24 hours. The lowest binding
occurred at pH 1.0 at 1 hour and thereafter, binding increased as pH increased (determined
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up to pH 7.5). The binding constant was higher for fully hydrated Prussian blue compared to
Prussian blue which had been dried for 24 hours and the smaller the particle size the higher
the binding constant.
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Animal Studies
9.1
Pharmacodynamics
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An in vitro study examined the adsorption of thallium-201 by insoluble Prussian blue to
investigate the use of Prussian blue in reducing the radiation burden in thallium-201
myocardial scintigraphy. The maximum adsorption peaked at approximately 30 minutes
irrespective of the concentration (1, 10 or 100 mg or Prussian blue in 5 mL of water). It
reached a plateau at 30 to 60 minutes with no further increase in adsorption of thallium until
4 hours. The rate of absorption was constant for up to 1 hour but slowed down thereafter.
Thallium-201 removal increased from 46 to 95% when the pH was increased from 2.0 to 8.0.
In the most favourable conditions the maximal adsorption capacity was 5000 MBq of
thallium-201/g of Prussian blue and maximal adsorption occurred at 30 minutes (Bhardwaj
et al., 2006).
9.1.1 Caesium
A number of animal studies have examined the impact of Prussian blue on the absorption of
caesium, its effect on the enhancement of excretion (or reduced retention) of caesium and
the impact of these actions on final outcomes.
9.1.1.1 Prevention of absorption/uptake from gut
Administration of a single dose of radiocaesium and concomitant oral dosing of Prussian
blue resulted in reduction of caesium uptake from the gastrointestinal tract (Brenot &
Rinaldi, 1967; Dresow et al., 1990, 1993; Giese & Hantzch, 1970; Nielsen et al., 1988b;
Nigrović, 1963; Nigrović, 1965). In piglets potassium ferric (III) hexacyanoferrate (II) and
ferric (III) hexacyanoferrate (II) reduced the caesium-134 uptake by more than 97%. The
diminution of the caesium-134 body burden depended on the dose of administered
hexacyanoferrate (II). The difference between the colloidal and insoluble Prussian blue
compounds in decreasing enteral absorption of caesium-134 was small (Nielsen et al.,
1988b).
If Prussian blue was given as late as 60 minutes after caesium-137 administration the enteral
caesium-137 absorption was also suppressed (Nigrović, 1963). Autoradiography of rats
showed, that the radioactivity was limited to the gastrointestinal-tract (Brenot & Rinaldi,
1967).
In rats administered a composite treatment mixture containing calcium alginate, potassium
iodide and insoluble Prussian blue in their diet and exposed to various radionucleotides, the
Prussian blue, even as a component of the mixture, decreased the absorption of caesium into
the organism and reduced the whole-body retention (Kargacin & Kostial, 1985; Kostial et
al., 1980; Kostial et al., 1981; Kostial et al., 1983).
In a study in pigs the animals (82 kg) were fed twice daily with pellet food and 500 mL of
milk together with 200 g of radiocaesium-contaminated whey powder. Prior to each feeding
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the pigs were given 0.5g, 1.5g or 2.5 g of soluble Prussian blue, insoluble Prussian blue or
ammonium iron hexacyanoferrate (II) (NH4Fe[Fe(CN)6]) in gelatine capsules. The animals
were slaughtered after 27 days of feeding. All compounds were found to be effective at
reducing caesium-134 and caesium-137 absorption. Administration of increasing quantities
of the compounds resulted in a dose-dependent reduction in the radioactivity of the tissues
tested. Soluble Prussian blue and ammonium iron hexacyanoferrate were most effective,
possibly due to more favourable distribution of colloidal soluble compounds in the
gastrointestinal tract (Dresow et al., 1993). Similarly, soluble Prussian blue and ammonium
iron hexacyanoferrate were most effective in rats (260 to 280 g) given 0.5 mg of Prussian
blue in water 2 minutes before 0.5 mL of water containing a tracer dose of caesium-134, by
gastric tube. There was almost complete blockade of radiocaesium absorption as judged by
urinary excretion and whole body retention measured 7 days after ingestion. Insoluble
Prussian blue was less effective (Dresow et al., 1993).
9.1.1.2 Enhancement of decorporation (reduced retention)
Chronic feeding of rats (Dresow et al., 1993; Stather, 1972) or piglets (Dresow et al., 1993;
Giese et al., 1970) with caesium-137 contaminated food and concomitantly administration of
Prussian blue resulted in reduced whole body retention. Most of the daily caesium-137 dose
was excreted in the faeces.
After ingestion of radiocaesium, administration of insoluble Prussian blue (Bozorgzadéh &
Catsch, 1972; Dresow et al., 1990; Nigrović, 1963; Nigrović, 1965; Nigrović et al., 1966;
Stather, 1972;) and colloidal soluble Prussian blue (Bozorgzadeh, 1971; Bozorgzadéh &
Catsch, 1972; Dresow et al., 1990; Giese et al., 1970; Müller et al., 1974) decreased the
whole-body-retention of the caesium isotopes. Also in a mixture with other substances
Prussian blue increased the excretion of the caesium-137 (Kostial et al., 1983). In rats the
effect on the whole-body retention was age-dependent. In younger animals the whole body
retention was lower than in older animals. Probably because of the higher basal metabolic
rate more caesium was excreted into the gut in young animals (Bozorgzadeh, 1971; Stather,
1972).
Prussian blue increased the cumulative excretion of incorporated radiocaesium in faeces and
urine (Brenot & Rinaldi, 1967; Nigrović, 1965; Nigrović et al., 1966). Whereas in untreated
animals most caesium is excreted in the urine, in animals treated with Prussian blue faecal
excretion predominates (Nigrović et al., 1966; Brenot & Rinaldi, 1967; Müller, 1969; Giese
et al., 1970; Giese & Hantzsch, 1970; Richmond, 1968). The biological half-life was
reduced (Madshus et al., 1966; Nigrović et al., 1966; Havliček et al., 1967; Havliček, 1968;
Müller et al., 1974; Richmond, 1968; Strömme, 1968). In rats the half-life was reduced by
50% (11 days compared to 6 days) (Nigrović et al., 1966; Müller et al., 1974), and in dogs
from 11 to 6.5 days (Madshus et al., 1966).
Colloidal soluble Prussian blue was more efficient in increasing the excretion of
radiocaesium than the insoluble form (Müller, 1969). In long-term use however, colloidal
soluble Prussian blue decreased the excretion compared with control animals. Insoluble
Prussian blue did not show this effect (Bozorgzadéh & Catsch, 1972). After thorough
dialysis with water to remove any possible low molecular impurities this effect of the
colloidal Prussian blue disappeared (Müller et al., 1974). The efficacy of the dialyzed
colloidal soluble Prussian blue, however, was only marginally better than that of insoluble
Prussian blue (biological half-lives: control 10.51 days, insoluble Prussian blue 5.6 days,
colloidal Prussian blue 4.88 days) (Müller et al., 1974).
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The efficacy of therapy with Prussian blue is time-dependent. The best effect resulted in
administration of Prussian blue 2 minutes before application of caesium (Dresow et al.,
1990). Start of treatment immediately after intoxication was also successful (Bozorgzadéh,
1971; Bozorgzadéh & Catsch, 1972), but it was still effective after a delayed start of 3.5
days (Stather, 1972).
The reduced whole-body retention of caesium after treatment with Prussian blue can also be
seen in individual organs. This reduced caesium content of the different organs has been
reported in muscle (Bozorgzadéh, 1971; Bozorgzadéh & Catsch, 1972; Brenot & Rinaldi,
1967; Kostial et al., 1983; Müller et al., 1974; Stather, 1972; Wolsieffer et al., 1969), bone
(Bozorgzadéh & Catsch, 1972; Müller et al., 1974; Wolsieffer et al. 1969), carcass (Kostial
et al., 1983; Wolsieffer et al. 1969), liver (Bozorgzadéh, 1971; Müller et al., 1974; Stather,
1972) and kidney (Bozorgzadéh, 1971; Bozorgzadéh & Catsch, 1972; Brenot & Rinaldi,
1967; Kostial et al., 1983; Müller et al., 1974; Stather, 1972). Due to a different turnover
rate of the organs the rate of diminution of caesium in the different organs varied. In the
gastrointestinal-tract the caesium content was increased due to binding on the non-resorbable
Prussian blue (Brenot & Rinaldi, 1967).
After 15 days of dietary acclimatization to insoluble Prussian blue as 1% of their food, rats
were given intraperitoneal casesium-137. The animals were killed 30 days later. There was
significant reduction in the retention of caesium-137 in the carcass, femur and muscle
(Wolsieffer et al., 1969).
Oral insoluble Prussian blue was given to rats in drinking water (400 mg/kg/day) for 11 days
which was started immediately after an intravenous injection with caesium-137. On
evaluation at 11 days Prussian blue had increased the faecal excretion of caesium-137 5-fold
and this consequently also reduced urine excretion. There was also reduced retention of Cs137 in all the tissues tested (blood, liver, kidneys, spleen and skeleton) (Le Gall et al., 2006).
Oral administration of insoluble Prussian blue shortened the retention of caesium-137 in
mated, pregnant and lactating rats and the deposition of caesium-137 in the embryos and
nursed young animals was reduced (Havliček, 1967; Havliček, 1968).
The effect of Prussian blue provided in drinking water to rats of various ages, on the
excretion of intraperitoneally administered caesium-137 was investigated. In 19-week old
rats the body burden of caesium-137 was reduced to 34% of the controls 1 week after
injection whilst in 9-week and 4-week old rats, the corresponding values were 28% and 9%
respectively. Tissue analysis suggested that the rate limiting factor of excretion of caesium137 during Prussian blue therapy was the turnover rate of caesium-137 in muscle tissue. The
turnover rate of caesium-137 in muscle tissues of young animals is faster than that of older
animals and this is reflected in an increased efficacy of Prussian blue in removing caesium137 from the younger animals (Stather, 1972).
9.1.1.3 Impact on outcomes
Richmond & Bunde, (1966) investigated the effect of three different concentrations of
Prussian blue on caesium-137 contaminated rats. Each rat (approximately 92 days old with
and average bodyweight of 372g) received approximately 0.84 microcurie of caesium-137,
the rats were then measured 30 minutes later for total body activity and then returned to their
respective cages. Insoluble Prussian blue was incorporated into their drinking water which
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they had free access to over the following 60 days. The concentrations of Prussian blue in
the water were 0, 0.025, 0.25 and 2.5 g/L, and the estimated daily dose of Prussian blue was
0, 0.9, 8.5 and 84 mg/rat, respectively. There was significant reduction in the whole body
retention of caesium-137 with continuous ingestion of Prussian blue at 0.25 and 2.5 g/L, but
no effect was observed at 0.025 g/L. Retention of caesium was described in 3 exponential
terms and the third component had a half-life of 8.77 days in high-dose Prussian blue rats
compared to 14 days in control rats. The authors concluded that the rate of caesium-137
secretion would depend partially on the turnover rate in body tissues, particularly muscle,
which accounts for a large proportion of the total body caesium-137 activity.
The effect of Prussian blue was studied in sheep fed wheat and grass contaminated with
caesium after the Chernobyl accident. The lactating sheep (average 35 kg) were given 0.5
kg of wheat (average radiocaesium content 1684 ± 17 Bq/kg) and 200 g (9840 ± 442 Bq/kg)
daily. The average milk yield was 110 g per day. When the radiocaesium content of the
milk had reached a state of equilibrium half the animals were given colloidal Prussian blue,
5 g in 5 L of drinking water for 23 days. The colloidal Prussian blue settled in the container
and the drinking water had to be stirred repeatedly during the day and it took about 2 days
before the sheep became used to the water. Treatment with Prussian blue reduced the
radiocaesium content of the milk by approximately 85% and the effect was seen within a few
days of the start of treatment (Ioannides et al., 1991).
The role of Prussian blue in removing caesium-137 internal contamination from rats was
studied to evaluate the possible side effects caused by chronic consumption on various
biomarkers for exposure. Rats of two age groups (growing rats (2-months old) and adult rats
(4month old)), were observed over a 60 day period having had either caesium-137 alone,
Prussian blue alone, or a combination of both, administered at different time intervals (e.g.
both given simultaneously or with a time lapse between). The authors reported that in both
growing and adult rats Prussian blue administration, particularly when given before or
immediately after Caesium-137 intake, could eliminate the effects of caesium-137
irradiation on red blood cell count and haemoglobin content, and on serum levels of: total
proteins (in adult rats only), globulins (in adult rats only), creatinine, urea, urea nitrogen,
ALT activity, T3, and T4. When given one or seven days post caesium-137 irradiation,
Prussian blue eliminated the effects of caesium-137 treatment on serum cholesterol, serum
calcium and serum bilirubin, in both growing and adult rats (Fekry et al., 2003).
The efficacy of insoluble and colloidal soluble Prussian blue in removing a single dose of
internally deposited caesium-134 was compared in rats (6 rats in each experimental group).
Prussian blue was administered twice daily and treatment started immediately after injection
of caesium-134. For the first few days the colloidal form initially showed greater efficacy in
removing the caesium but with continuous administration it brought about a complete
blockage of caesium-134 excretion from the liver, spleen and skeleton. This was attributed
to in vivo disintegration of the colloidal compound yielding free [Fe(CN)6]4- which when
absorbed from the gut reacts with endogenous metal ions. The authors highlight the practical
clinical consequences of this finding in that the insoluble compound should be the antidote
of choice for caesium-134 toxicity; the slight transient superiority of the colloidal form is
over-shadowed by its untoward long-term effect (Bozorgzadéh & Catsch, 1972).
9.1.2 Rubidium
There is limited information on the decorporation effect of Prussian blue in rubidium
exposure. Rats were fed insoluble Prussian blue in their food (as 5%) from 2 days before an
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intraperitoneal injection of rubidium-86. Prussian blue reduced the half-life of rubidium-86
from 10.3 days to 1.7 days, reducing the whole body retention to 9% that of controls after 7
days (Stather, 1972).
9.1.3 Thallium
9.1.3.1 Prevention of absorption/uptake from gut
Concomitant oral administration of thallium and of Prussian blue in rats resulted in a lower
uptake of the metal and lower concentrations found in organs (Dvořák, 1969; Heydlauf,
1969; Rauws, 1974). Soluble Prussian blue was more effective than the insoluble Prussian
blue (Dvořák, 1969).
In a study by Heydlauf (1969) aqueous solutions of thallium-204 sulphate were administered
to rats by gastric tube. Aqueous suspensions of ferric cyanoferrate (II) (insoluble Prussian
blue) in doses of 0.5-50 g were then administered by gastric tube 1 to 60 minutes later. The
maximal protective effect, i.e. approximately ten times lower absorption of thallium-204,
was observed when Prussian blue was given immediately, although an effect was still seen
when Prussian blue was administered at 60 minutes. As expected, there was a marked
dependence of antidotal efficacy on the dose of Prussian blue administered.
9.1.3.2 Enhancement of decorporation (reduced retention)
It was also shown that insoluble Prussian blue was able to remove thallium across the
gastrointestinal wall. Carrier-free thallium-204 was injected intravenously and the animals
fed with Prussian blue pellets at will (Heydlauf, 1969). The thallium-204 content of
Prussian blue treated animals was drastically reduced even when treatment was initiated on
the fourth day. This was due to markedly enhanced faecal excretion whereas urinary
elimination did not reach the control level.
Insoluble Prussian blue (Heydlauf, 1969) as well as colloidal soluble Prussian blue (Dvořák,
1969; Günther, 1971) reduced the retention of thallium in the body. The excretion in the
faeces was increased and decreased in the urine when compared to the control animals
(Heydlauf, 1969; Lehmann & Favari, 1985; Leloux et al. 1990; Manninen et al., 1976;
Rauws, 1974; van der Stock & de Schepper, 1978). The cumulative excretion in faeces and
urine was increased (Heydlauf, 1969; Lehmann & Favari, 1985; Rauws, 1974). The biological half-life of thallium in the body was reduced. In dogs the biological half-life was
decreased from 6.5 days (measured in control animals) to 2.5 days (animals treated with
Prussian blue) (van der Stock & de Schepper, 1978), in rats it was decreased from 4 days to
2 days (Rauws, 1974).
A study in rats demonstrated that soluble Prussian blue increased excretion of thallium and
reduced the LD50 but only if started within 24 hours of exposure. Thereafter thalliuminduced pathological changes were irreversible (Günther, 1971).
The reduced retention and the increased excretion of thallium by Prussian blue results in a
decrease of the thallium content in liver (Dvořák, 1969; Günther, 1971; Heydlauf, 1969;
Kravzov et al., 1993; Manninen et al., 1976; Rìos & Monroy-Noyola, 1992; Sabbioni et al.,
1982), kidney (Dvořák, 1969; Günther, 1971; Heydlauf, 1969; Kravzov et al., 1993;
Manninen et al., 1976; Rauws, 1974; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 1982),
skeleton (Heydlauf, 1969) blood (Rìos et al., 1991), heart (Kravzov et al., 1993; Rìos &
Monroy-Noyola, 1992) and muscles (Dvořák, 1969; Günther, 1971; Heydlauf, 1969;
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Manninen et al, 1976; Rauws, 1974).
9.1.3.3 Impact on outcomes
Kamerbeek et al. (Kamerbeek, 1971; Kamerbeek et al., 1971) showed the influence of
Prussian blue on the concentration of thallium in the brain. Thirty-five rats, divided into
seven groups of five animals, were given 0.075 mM/kg thallous nitrate in 5% glucose
solution by intraperitoneal injection. After 24 hours, one group was sacrificed. Three of the
remaining groups were subsequently treated with 50 mg Prussian blue suspended in saline,
twice daily by gavage. The other groups served as controls. At 48, 72 and 120 hours after
administration of thallium, one control and one treated group were killed. The thallium
concentration was determined in the brain and in a muscle specimen (quadriceps). After
four days of Prussian blue therapy the concentration of thallium in the brain of the treated
groups was less than half that of the control group. The muscle thallium concentration in the
treated group was almost one-fourth of that of the control group. A dose-dependent
relationship was observed. Also in other experiments reduced thallium levels in the brain
were measured (Kravzov et al., 1993; Leloux et al., 1990; Manninen et al., 1976; Rauws.
1974; Rìos et al., 1991; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 1982).
Trying to establish an optimal dosage scheme for use of Prussian blue in human
thallotoxicosis, Kamerbeek (1971) gave five groups of five rats 0.1 mm/kg thallous nitrate
intraperitoneally. After 24 hours four groups were treated by gavage once daily with 10, 50,
250 and 1000 mg/kg Prussian blue, suspended in 15% mannitol. After four days of
treatment, the animals were sacrificed and the thallium concentrations were determined in
the brain and in a muscle specimen. A daily dose of 250 mg/kg Prussian blue appeared to be
as effective as 1000 mg/kg/day with respect to thallium-concentration in muscle specimen
but with respect to thallium in the brain the highest dosage was more efficacious.
Kamerbeek (1971) further investigated the protection afforded by Prussian blue against
thallium toxicity. Two groups of rats were given 0.25 mg/kg thallous nitrate intraperitoneally. Four hours later one group received Prussian blue 100 mg/kg in a 15% mannitol
solution by gavage. The other group received mannitol only. This regimen was repeated for
10 days. In the control group, 10 of 20 animals died, while in the treated group only two
deaths occurred.
It was further shown that enhanced thallium-204 excretion as a result of Prussian blue
therapy was accompanied by reduced thallium toxicity (Kravzov et al., 1993; Rìos et al.,
1991; Rìos & Monroy-Noyola 1992). Treatment with potassium ferric hexacyanoferrate (II)
(colloidal soluble Prussian blue) increased the LD50 by a factor 2.3 (Günther, 1971). After
application of 30 mg thallium/kg the survival in the control group was 0% and in the
Prussian blue group 50% (Heydlauf, 1969).
After intraperitoneal injection of thallium (32 mg/kg) on day 1, a group of 16 rats was given
soluble Prussian blue (50 mg/kg orally twice daily), D-penicillamine (intraperitoneal
injection 25 mg/kg) or a combination of the two from days 2 to 5. The mortality in the
different treatment groups by day 6 was: control group 87.5%, Prussian blue group 56.25%,
D-penicillamine group 100% and Prussian blue + D-penicillamine group 25%. Only the
combination of antidotes produced a significant difference in mortality compared to controls.
Prussian blue alone protected against thallium-induced neurotoxicity (as measured by the
number of altered Purkinje cells) but the effect was greater with combined Prussian blue +
D-penicillamine. D-penicillamine alone did not protect against thallium-induced changes in
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Purkinje cells (Barroso-Moguel et al, 1994).
9.2
Pharmacokinetics
9.2.1 Oral
There is limited information on the pharmacokinetics of Prussian blue as these compounds
are very poorly absorbed from the gastrointestinal tract. Most studies have been performed
with iron-59 or carbon-14 labelled Prussian blue examining intestinal absorption and
bioavailability of iron and cyanide (see section 9.4 for studies on assessment of cyanide
toxicity).
The release of iron from potassium ferric (III) hexacyanoferrate (II) and ferric (III)
hexacyanoferrate (II) was examined in piglets. The compounds were labelled with iron-59
in the ferric or ferrous position. When labelled in the ferric position only 1.47% of the iron
was absorbed from potassium ferric (III) hexacyanoferrate (II) and 1.34% from ferric (III)
hexacyanoferrate (II), as determined by the whole-body retention 14 days after oral dosing.
Only 0.2% and 0.15%, respectively, of the iron was absorbed from the ferrous position.
Most of the dose was excreted in the faeces; 0.1 to1% of the iron-59 was in the urine but it
could not be determine how much of may have been due to faecal contamination (Nielsen et
al., 1988a). This study suggests that iron is not significantly absorbed from Prussian blue.
Administration of labelled (59Fe, 14C) Prussian blue to rats resulted whole-body retention of
0.03% of the dose (only in the gastrointestinal tract) and in traces of radioactivity in the
urine (0.15%). The amount in blood and skeleton was below the detection limit. After
administration of iron-59 labelled potassium ferric (III) hexacyanoferrate (II)
(K59Fe[Fe(CN)6]) to rats traces of radioactivity were found in the skeleton (0.11% of the
administered dose) and in blood (0.046%). Again, with radio-labelled iron in the ferric and
ferrous positions, the differences in distribution showed that Prussian blue is not absorbed,
but the different ions K+, Fe3+ and [Fe(CN)6]4- are metabolized instead. No evidence was
obtained for decomposition of [Fe(CN)6]4- (Dvořák et al., 1971). Histopathological
examination of organs showed no deposits of Prussian blue after oral administration of
insoluble and colloidal soluble Prussian blue (Giese & Hantzsch, 1970).
9.2.2 Parenteral
After intraperitoneal administration of radio-labelled colloidal soluble Prussian blue the
substance is eliminated by the reticuloendothelial system. On the first day 40.5% of the
radioactivity was excreted in the urine, the content in the faeces was very small. On the
second day 42% was found in the faeces with only traces in the urine. After 4 days the body
retention was 4.5%, mostly in the liver (Müller, 1969).
Intravenous administration of KFe[59Fe(CN)6] and K59Fe[Fe(CN)6] resulted in entirely
different metabolic behaviour in rats between the two forms. With potassium ferric (III)
hexacyanoferrate (II) labelled in the ferrous position (KFe[59Fe(CN)6]) more than 50% of the
radioactivity was excreted in the urine, by contrast when labelled in the ferric position
(K59Fe[Fe(CN)6]) only 0.06%. The faecal excretion was low for both. The distribution of
the radioactivity into the organs after administration of KFe[59Fe(CN)6] differed from that of
K59Fe[Fe(CN)6]. Whereas the radioactivity of KFe[59Fe(CN)6] persisted in the liver for 8
days, the activity of K59Fe[Fe(CN)6] varied from the liver to the blood (Dvořák et al., 1971).
9.3
Toxicology
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9.3.1 Acute toxicity
Ferric (III) hexacyanoferrate (II)
Oral:
According to a Soviet study, 8g/kg body weight was not lethal to laboratory animals
(presumed to be rats or mice) and produced no clinical signs of toxicity (BIBRA, 1997)
Intraperitoneal administration:
LD50 rat: 1.13 mg/g body weight (Brenot & Rinaldi, 1967).
LD50 rat: 2.1g/kg body weight (BIBRA, 1997).
LD50 mouse: 2 g/kg body weight (BIBRA, 1997).
Rats or mice given lethal doses suffered inertia, breathlessness and sluggishness with excess
blood in the liver, spleen and kidney (BIBRA, 1997).
Potassium ferric (III) hexacyanoferrate (II)
In studies by Dvořák et al. (1971) the lethality of intravenous injection of 1 mg of colloidal
soluble Prussian blue in rats varied from 0% to 100%, despite the same manufacturing
processes. Some animals became unwell within 15 minutes and developed respiratory
distress. A blue colouration was noted in the lungs at post-mortem examination. This
variation in toxicity was thought to be due to differences in the degree of dispersion of the
Prussian blue in the solution of each batch.
Pigment blue 27
Oral LD50 rat: >5g/kg body weight (BIBRA, 1997).
9.3.2 Chronic toxicity
In rats colloidal soluble Prussian blue given as 2% of drinking water for 12 weeks resulted in
no significant body weight changes or histopathological changes in the organs, including the
gut (Dvořák et al., 1971). Similarly, sheep (average weight 35 kg) given colloidal soluble
Prussian blue, 5 g in 5 L of drinking water daily for 23 days had no change in body weight
(Ioannides et al., 1991).
There were no significant differences in average fluid intake in rats given insoluble Prussian
blue in drinking water (0.025, 0.25 or 2.5 g/L) for 60 days. The estimated daily dose of
Prussian blue was 0.9, 8.5 and 84 mg/rat, respectively (equating to 2.4, 23, 226 mg/kg)
(Richmond & Bunde, 1966).
Oral insoluble Prussian blue caused no adverse effects and no impairment of growth in
young rats when given as 1% of the diet for 120 days (Nigrović et al., 1966) or as 1% of
their food for 60 days in rats (Wolsieffer et al., 1969). Also in rats, food consumption and
body weight were unchanged during 9 days of treatment with a mixture of sodium alginate
(daily consumption 2 g), insoluble Prussian blue (250 mg) and sodium perchlorate (100 mg)
(Kostial et al., 1980) or during 4 weeks treatment with a mixture of calcium alginate
(average 4.8 g/day), insoluble Prussian blue (average 0.8 g/day) and potassium iodide
(0.0048 g/day) (Kostial et al., 1981).
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There were no adverse effects in dogs (7 to 8 kg) given oral insoluble Prussian blue (3 or 6
doses of 0.5 g daily) for 11 days. The doses equate to approximately 200 and 400 mg/kg,
respectively (Madshus et al., 1966). At autopsy no pathological changes were observed
(Nigrović et al., 1966).
9.3.3 Reproductive toxicology and teratogenicity
There is no information available on the reproductive toxicity of Prussian blue.
In pregnant rats intoxicated with oral thallium soluble Prussian blue started 8 hours later
increased the survival rate, reduced the thallium content of the placenta by 5-fold and in the
foetuses reduced the thallium content of the brain and liver (Sabbioni et al., 1982).
9.3.4 Genotoxicity
No information available.
9.4
Assessment of possible cyanide toxicity
Prussian blue contains cyanide ions bound to iron. At extremely low pH values in the
presence of oxidizing agents Prussian blue decomposes and, under these circumstances,
cyanide can be released. Since oral administration of Prussian blue is indicated in the
treatment of thallium poisoning and caesium incorporation, various studies have examined
the possibility of cyanide release from these hexacyanoferrate compounds.
When gastric juice (pH 2) and soluble Prussian blue were incubated for 4 hours no cyanide
was detected. Similarly no cyanide was detected when the study was conducted with 0.1 N
hydrochloric acid at room temperature. Cyanide was only detected when this last
experiment was repeated at 100 °C (Kamerbeek, 1971). Other in vitro studies have also
shown that the release of cyanide is negligible (Dvořák, 1970).
Verzijl et al. (1993) studied in vitro cyanide release of four Prussian blue salts, potassium
ferric (III) hexacyanoferrate (II), ferric (III) hexacyanoferrate (II) and ammonium ferric (III)
hexacyanoferrate (II), both unpurified and purified compounds (that is, with and without
33% ammonium chloride as a manufacturing impurity). These salts were added to water,
artificial gastric (pH 1.2) or intestinal (pH 6.8) juices and the content flasks were allowed to
stand for 5 hours, protected from light, at 370C. Cyanide was detected in all tests and the
quantity released ranged from 22 to 535 µg/g of Prussian blue in water, 64 to 418 µg/g in
artificial gastric juice and 15 to 58 µg/g in artificial intestinal juice. For all salts tested the
release of cyanide was greatest in artificial gastric juice than the other test media. The
unpurified ammonium ferric (III) hexacyanoferrate (II) released the most cyanide and ferric
(III) hexacyanoferrate (II) (insoluble Prussian blue) the least in all test media.
In an in vitro study the release of cyanide from insoluble Prussian blue was measured over a
pH range of 1.0 to 12 following incubation for 1 to 48 hours in a shaking water bath at 370C
(Yang et al., 2007). Five batches of active pharmaceutical ingredients were tested and three
batches of drug product. The release of cyanide was both pH-dependent and incubation-time
dependent. The greatest release occurred at pH 1.0 with a gradual decline as the pH
increased to 7.0. At this pH the lowest quantity of cyanide was released and as the pH
increased again the cyanide concentration also increased. Increasing the incubation time at
different pH also increased the amount of cyanide released. The highest cyanide
concentration occurred when Prussian blue was incubated at pH 1.0 for 48 hours. The
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authors concluded that, based on a dose of 17.5 g of Prussian blue per day, a total of 1.5-1.6
mg of cyanide would be released, which was well below the minimum toxic dose of cyanide
of 14.4 mg.
929
10.
930
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The release of cyanide from potassium ferric (III) hexacyanoferrate (II) and ferric (III)
hexacyanoferrate (II) was examined in piglets. The compounds were labelled with carbon14 in the cyanide group. No carbon-14 dioxide was detected in expired air after ferric (III)
hexacyanoferrate (II), indicating that the quantity of cyanide released is very small or nil
(Nielsen et al., 1988a).
Volunteer Studies
10.1 Pharmacokinetics
There is very little published pharmacokinetic data on Prussian blue in humans.
10.1.1 Release of iron and cyanide from Prussian blue
Three volunteers (all male, 36 years, 81 kg; 38 years, 81 kg; 45 years, 70 kg) were given
radio-labelled soluble Prussian blue (500 mg) to determine the release of iron and cyanide in
humans in vivo. The compound was labelled with iron-59 in the ferric or ferrous position
and carbon-14 in the cyanide group. Only 0.22% of iron (II) and <0.04% of iron (III) was
absorbed. Only 2 mg of non-complex bound carbon-14 labelled cyanide was absorbed. This
is a factor of 20 to 100 below the lethal dose of 0.5 to 3.5 mg cyanide/kg in humans (Nielsen
et al., 1990a).
10.2
Caesium
10.2.1 Studies on absorption
In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of
caesium the studies involved self-dosing by the study authors. These authors (to include 8
observations, 5 volunteers undertook the study once and one author repeated the experiment
twice) showed that 3 g daily of Prussian blue given before caesium-137 did not reduce
caesium absorption. The increase in caesium-137 excretion was small following 0.5 g of
Prussian blue three times daily (Madshus & Strömme, 1968).
In 6 volunteers a preliminary study showed that insoluble Prussian blue (4 x 0.5 g or 10 x
0.2 g daily for 2 to 3 weeks) did not fully block caesium uptake from contaminated food
(Volf et al., 1987).
Two male volunteers (age 36 and 38 years, both 81 kg) ingested three single test meals
consisting of 170 g of milk labelled with a tracer dose of caesium-134 along with bread,
margarine and cheese 10 minutes after ingestion of 1 g of Prussian blue in gelatine capsules.
Both forms of Prussian blue were equally effective in reducing radiocaesium absorption.
The absorption of radiocaesium from the meal judged by urinary excretion of caesium-134
and whole body retention 14 days after administration was reduced from 100.9% (control
without Prussian blue) to 5.6% by soluble Prussian blue and to 6.4% by insoluble Prussian
blue (Dresow et al., 1993). In a similar study in two male adult volunteers, the ingestion of
Prussian blue ten minutes before eating a test meal containing caesium-134 labelled milk
(along with bread, margarine and cheese) reduced the caesium absorption more than the
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simultaneous administration of Prussian blue along with the labelled test meal.
Administration of Prussian blue prior to the meal reduced absorption of the radiocaesium to
3-10% of the ingested dose whereas simultaneous ingestion of Prussian blue and the test
meal only reduced absorption to 38-63%. The 100% control was the absorption rate of the
radiocaesium test meal alone without Prussian blue (Nielsen et al., 1991).
10.2.2 Studies on decorporation/excretion
In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of
caesium the studies involved self-dosing by the study authors. Studying the decorporation
of caesium involved ingestion of Prussian blue (3 g daily as 2 or 3 doses for several weeks)
in 2 adult males given 180 days after ingestion of caesium-137 and it was found to reduce
the biological half-life of caesium from the pre-treatment values of 110 and 115 days to 40
days. The only adverse effect was mild constipation (Madshus et al., 1966).
In five cases when Prussian blue (1g three times daily) was given several months after
caesium ingestion the biological half-life of caesium was reduced on average from 94 to 31
days, that is, to one third of its original half-life (Madshus & Strömme, 1968; Strömme,
1968).
A 37-year-old male was given oral caesium-137 for 24 days followed by 2 g of insoluble
Prussian blue (as 10 x 200 mg daily over a 9 hours period) from day 12 to day 17 then after a
rest period of 2 days was given Prussian blue for another 5 days. The biological half-life of
the caesium was reduced from 140 days to approximately 50 days. There was no
constipation and no change in whole-body potassium values (Richmond, 1968).
Fifteen Chinese exchange students in Bulgaria were exposed to caesium-134 and 137
released following the accident at the Chernobyl Nuclear Power Station in April 1986, and
following their return to China in June they were assessed for contamination. In three
volunteers the biological half-life of caesium ranged from 42 to 71 days. Insoluble Prussian
blue (1 g three times daily for 6 days repeated for 3 courses with a 6 day rest period in
between) was given from day 114 to 145 after exposure. This reduced the half-life of
caesium and enhanced elimination (Tang et al., 1988).
10.3 Rubidium exposure
There are no volunteer studies on the effect of Prussian blue in rubidium exposure.
10.4 Thallium poisoning
There are no volunteer studies on the effect of Prussian blue in thallium exposure.
Bhardwaj et al. (2006) studied the effect of insoluble Prussian blue on whole body
radioactivity in two patients following thallium-201 myocardial scintigraphy. Each patient
had two sessions of scintigraphy, one with and one without Prussian blue (100 mg 3 times
daily after meals for 3 days), so each patient acted as their own control. In the first patient
whole body radioactivity was reduced by 18 and 30% after 24 and 48 hours, respectively, of
oral Prussian blue therapy. The second patient developed constipation and did not pass any
stools after oral Prussian blue for 48 hours. The whole body radiation counts were similar to
those when Prussian blue was not given but there was a concentration of radioactivity in the
colon suggesting that the radioactivity was unavailable for resorption.
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11.
Clinical Studies – Clinical Trials
There are no controlled clinical trials on the use of Prussian blue in human thallium poisoning or
radiocaesium decorporation.
12.
Clinical Studies - Case Reports
12.1
Decorporation of radiocaesium
12.1.1 Goiânia incident, Brazil, 1987
At the end of 1985 a private radiotherapy institute moved premises and left a caesium-137
teletherapy unit behind. The building was partly demolished and in 1987 two men removed
the source assembly head from the machine thinking it may have scrap value but without
being aware of what it was. They took this home and tried to dismantle it during which they
ruptured the source capsule. This contained caesium chloride which is highly soluble and
easily dispersed. After the rupture the source capsule was sold for scrap to a junkyard
dealer. He observed that the material glowed blue in the dark and over the next 5 days this
was a source of interest to family and friends. During this time several individuals started to
become unwell with gastrointestinal signs and eventually the source capsule was suspected
and it was taken to the public health department. This triggered a major response to the
incident. In total 112,000 people were assessed and 249 were found to contaminated either
internally or externally with caesium-137. Some had very high exposure due to eating with
contaminated hands or rubbing the glowing material over their body. Twenty patients
developed bone marrow suppression. Eight developed acute radiation syndrome (BrandãoMello et al., 1991) and four of these victims died within 4 weeks of their admission to
hospital (IAEA, 1988). Prussian blue (Radiogardase®-Cs) treatment was given to 46
patients (aged 4 to 46 years) for up to 150 days. The adults were initially given 3 g daily and
the 13 children were given 1 to 1.5 g daily. These doses were later increased to 10 g and 3 g
daily, respectively, when it was established that larger doses resulted in higher radioactivity
of faecal samples. In four cases 20 g of Prussian blue was given over 24 hours. Of 46
patients, 10 developed mild to moderate constipation and this was managed with a high fibre
diet or laxatives (Farina & Brandão-Mello, 1991). Prussian blue treatment significantly
increased the rate of faecal caesium excretion and reduced whole body retention of caesium
(IAEA, 1988). The physiological faeces to urine excretion ratio of caesium was 1:4 and this
was changed to 4:1 with Prussian blue treatment (Farina & Brandão-Mello, 1991). In 15
adult patients who received Prussian blue the body burden of caesium-137 was reduced by
51% to 84% with an average of 71% within the first 2 months after exposure. This dose
reduction was independent of the Prussian blue dose in the range of 3 to 10 g/day (Melo et
al., 1994).
In vivo data from patients internally contaminated with caesium-137 in the Goiânia accident
was analysed to compare the half-life of caesium-137 with and without Prussian blue
treatment. Additionally the possible influences of various body parameters (age, height,
weight and radioactivity) on the half-lives were evaluated. Subjects were monitored using a
whole-body counter and the findings are from data collected for the period of one year post
the accident. Patients under treatment had previously followed different Prussian blue dosing
patterns but during the monitoring period received 3 g/day, 6 g/day or 10 g/day. Caesium137 elimination from the body followed first order kinetics with or without Prussian blue
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therapy. Without Prussian blue treatment the half lives of caesium-137 in the 10 adult
females studied varied widely (range 39 to 104 days; mean: 65.5 days) with less variation
seen in the 8 adult males (66 to 106 days; mean: 83 days). Overall Prussian blue reduced the
half-life of caesium-137 by about 32%. The actual calculations showed that for those
subjects receiving 3 g/day of Prussian blue the mean reduction was 28%, it was 31% in those
receiving 6 g/day and was 32% in subjects receiving 10 g/day. The strongest parameter
influencing the half-life in both males and females was body weight. Height and age were
correlated to the half-lives through their correlation to the weight parameter but were not
additional variables. Investigating the estimated caesium-137 body burden at the initial time
of elimination found an inverse relationship between initial activity and half-life: the larger
the initial body burden, the faster the nucleotide removal from the body. The influence of
this parameter was much weaker than that of body weight (Lipsztein et al., 1991).
12.1.2 Chernobyl incident, 1986
Measurements were made on 15 Chinese subjects internally contaminated with
radionucleotides released from the Chernobyl accident on 26th April 1986. The students had
been visiting Sofia, Bulgaria from 19th April until 23 May 1986 and monitoring was done on
their return to Beijing. Internal contamination with radioactive caesium (caesium-134 and
caesium-137) was measured in all 15 students. The measured activity in the body for the 15
volunteers ranged from 68-840 Bq for cesium-137 and 110-630 Bq for caesium-134. The
estimated intakes were calculated and ranges were 95-1200 Bq (Caesium-137) and 170-930
Bq (Caesium-134). The biological half-life was calculated for three volunteers along with
the effect of Prussian blue on their rate of elimination of radiocaesium. Prussian blue was
given at doses of 1g three times a day for a 6 day course, 3 courses in total were give with a
6 day time interval between each course. The biological half-life of the radiocaesium ranged
from 43-71 days. Prussian blue was given to the three volunteers in the period of 114-141
days after contamination and the body retention of radiocaesium declined more rapidly
following Prussian blue administration than in those of controls (Tang et al., 1988).
12.1.3 Other case reports
Five persons, two adults (aged 34 and 38 years, weight 56 and 55 kg) and three children
(aged 4 to 11 years; weight 13.5 to 34 kg) accidentally received caesium-137 chloride for
approximately 20 days (no details given). The patients were evaluated as soon as the
accident was discovered and started on Prussian blue. The adults received 3 g daily from
days 35 to day 128 or 143. The children received 1, 1.5 or 2 g daily from days 35 to 86, 76
or 99. The half-life of the caesium was very variable and was 124, 54, 61, 36 and 36 days
without treatment. With Prussian blue treatment the half-life of caesium was 38, 39, 25, 17
and 16 days, respectively (Ma et al., 1985).
12.1.4 Non-radioactive caesium
A 65 year old woman presented to a hospital accident and emergency department with a one
day history of recurrent fainting. The patient claimed to have essential hypertension and was
having treatment for this from her family doctor. Six months prior to her presentation she
had been diagnosed with rectal cancer and liver metastasis and she had experienced frequent
episodes of watery diarrhoea in the past 4 weeks. On admission her blood pressure was
138/55 mmHg, pulse 52/min regular, temperature 36.80C, respiratory rate 18/min and blood
glucose 10.7 mmol/L. She developed and episode of Torsades de points (TDP) polymorphic
ventricular tachycardia with transient loss of consciousness during initial assessment. The
arrhythmia spontaneously converted back to normal sinus rhythm in about 10 seconds. Her
electrocardiogram (ECG) showed QT prolongation with a corrected QT interval of 620 ms
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1124
1125
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1128
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calculated by Bazett’s formula. Serum electrolytes showed mild hypokalaemia (2.8mmol/L)
whilst serum magnesium and serum calcium were normal. She was treated with intravenous
magnesium sulphate and vigorous potassium replacement however there was no
improvement in the QT prolongation after these therapies. At this stage it was discovered
that in the previous 6 weeks the patient had been taking anticancer naturopathic drugs
obtained from an alternative medical centre in Hong Kong. A detailed drug history was
obtained. Her medications included methyldopa, Dologesic™ (dextropropoxyphene 32.5mg
and paracetamol 325mg) and Lomotil™ (diphenoxylate 2.5mg, atropine 0.025mg) all
prescribed by her family physician. In addition, a bottle of herbal powder (1 teaspoon taken
daily), 3 oral medications including “Gigamax” (labelled as multivitamins), Slow K™ (slow
release potassium supplement) and “multi-C” were prescribed by the naturopathic
practitioner. On the basis of the clinical findings and along with previous case reports of
caesium chloride use in anticancer therapy, the diagnosis of caesium poisoning was highly
suspected. Whole blood and serum were assayed and the serum caesium concentration was
elevated markedly at 288µmol/L (normal range 0.0045-0.0105µmol/L). Whole blood
arsenic concentration was normal. One of the naturopathic medicines (“multi-C”) was found
to contain 89% caesium chloride by weight. No undeclared contents or toxins were found
on analysis of the herbal powder “Gigamax” and Slow K™ tablets. The patient was
hospitalized for 2 weeks with intensive cardiac assessment and monitoring. The use of
naturopathic medicines was stopped after hospitalization. Oral Prussian blue 3g 3 times
daily was started on day 7 after hospital admission and continued for 4 weeks (day 7 to day
34). Hypokalaemia was noticed during Prussian blue therapy and an oral potassium
supplement was given to keep the serum potassium concentration at around 4mmol/L. Serial
serum and urine caesium concentrations were measured. The calculated serum half-life of
caesium was shortened from 61.7 days to 29.4 days with Prussian blue therapy. The
corrected QT interval of her ECG returned to normal baseline on day 27 (Chan et al. 2009).
Thurgur et al. (2006) report a case where Prussian blue was used in the treatment of nonradioactive caesium. The patient was a 58 year old female with chronic caesium toxicity
from the use of caesium chloride as an alternative cancer therapy. High levels of caesium are
arrhythmogenic and this patient showed recurrent syncope, polymorphic ventricular
tachycardia, hypokalaemia, and a QT prolongation of 690 ms. Along with conventional
measures Prussian blue was used to treat her caesium toxicity. The Prussian blue treatment
decreased the half-life of caesium from 86.6 days to 7.9 days, with associated normalization
of QT interval and cardiac rhythm.
12.2 Rubidium
There are no reports on the use of Prussian blue in rubidium exposure in humans.
12.3 Thallium poisoning
Reference values for thallium (Walker, 1998):
Blood
<5 nmol/L (<1 µg/L)
Urine
<5 nmol/L (<1 µg/L)
A 45 year old man with no significant medical history was hospitalized with peripheral
neuropathy and paraesthesia of the extremities of all 4 limbs for 2 days. Clinical
examination revealed an erythematous popular rash on the face and folliculitis on the lower
limbs associated with hyperaesthesia of the feet and hands. An electromyogram showed
severe polyneuropathy. The patient had a cardiac arrest 9 days after admission followed by
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1177
1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189
1190
1191
1192
1193
1194
1195
1196
1197
1198
1199
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214
1215
post-anoxic coma. The patient worked in a technical crystals factory and handled thallium,
bromide, caesium and iodide. The urinary thallium concentration measured twenty days
after his cardiac arrest was 5118µg/g of creatinine. Despite the late diagnosis treatment with
insoluble Prussian blue (Radiogardase™) was started 2 weeks later (42 days from his
original admission to hospital) and continued for 24 days at a dose of 6g three times daily.
Urinary thallium concentrations decreased from 1333µg/g of creatinine to 166µg/g of
creatinine. After evaluation of the efficacy of the treatment a second course of Prussian blue
therapy was started at 77 days post admission and continued for 1 month when the patient
died. The urinary thallium concentration decreased from 86µg/g of creatinine to 3µg/g of
creatinine (Villa et al., 2009).
Ten members of two families (family A and family B) sought treatment at a health care
facility in Baghdad, Iraq. All patients were experiencing vomiting, abdominal pain and
dysphagia. Over the next 4 days, 5 of the patients developed neurological signs and
symptoms of varying severity (pain, abnormal sensations and weakness-particularly of the
lower limbs). Four days after admission biological samples and a sample of a cake that all
10 patients had consumed were submitted for toxicology testing. Thallium was detected in
both the biological samples and the cake. On the eighth day after admission one of the
patients, a child aged 11 years, died and two days later the 9 surviving patients were
evacuated to Jordan for Prussian blue therapy which was not available in Iraq. A second
patient, a 2 year old child died soon after arrival in Jordan, prior to receiving therapy.
Prussian blue therapy was begun in the 8 surviving patients, now 11 days after they had
eaten the cake. Two of these 8 patients were already comatose with severe cerebral oedema
and subsequently died. Over the next thirty days, all 6 long-term survivors developed hair
loss and 5 of the 6 survivors developed muscle weakness and spasticity of the lower limbs,
with differing severity. An epidemiological investigation was started and it was discovered
that the fathers of the two families were both board members of an Iraqi sporting club and
had attended a routine board meeting on the day before hospital attendance in the club’s
conference room. The cake, prepared by a local bakery and pre-divided into 10 pieces, had
been delivered to the board meeting as a gift from a former board member. However the
cake arrived late, after most board members had already left the meeting so no cake was
eaten then. The two members that remained (the fathers of the two families) divided the
cake and took the halves home to their families and it was eaten by both families at home
that evening. Family A comprised seven members (parents and five children) and family B
comprised five members (parents, two children and an uncle). Ten cases of abdominal pain,
vomiting and dysphagia were identified among family members who consumed any amount
of the cake. No other board members or their families were ill and no similar illnesses were
reported at the health facility in Baghdad or at any nearby health facilities. Food exposure
histories were collected in Jordan through interviews with family members. Ten people who
ate portions of the cake became unwell; neither of the two persons who did not eat cake
became unwell, however one of the two had tasted some of the cake icing and although
asymptomatic, his blood and urine samples tested positive for thallium. A more rapid onset
of illness occurred in adults and in persons who ate the most cake. Fatality was not
significantly associated with sex, age, the amount of cake eaten, or the time to illness onset.
Quantitative thallium levels were determined from blood and urine samples of nine patients
taken on day 16 after eating the cake. Thallium was detected in all nine patients; the median
blood thallium level was 289µg/L (range 53-1,408 µg/L; reference range expected <2µg/L),
and the median calculated 24 hour urine excretion of thallium was 3063 µg/L (range 54212,556 µg/L; reference range expected <5µg/L). Blood thallium levels correlated weakly
with the amount of cake reported to have been eaten (CDC., 2008)
26
DRAFT for comment - not for distribution
1216
1217
1218
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229
1230
1231
1232
1233
1234
1235
1236
1237
1238
1239
1240
1241
1242
1243
1244
1245
1246
1247
1248
1249
1250
1251
1252
1253
1254
1255
1256
1257
1258
1259
1260
1261
1262
1263
1264
1265
A previously healthy forty-year old male was admitted to hospital complaining of
progressive weakness of his limbs, repeated vomiting and recurrent episodes of confusion.
He had initially presented to the hospital six weeks previous to this admission complaining
of thirst, nausea, vomiting, dizziness, parathaesias and arthralgias (predominantly of the
lower limbs). The paraesthesias were not described as ascending or notably painful. A
supine blood pressure of 180/90mmHg and a mild fever were the only physical findings
noted. Neurological examination showed the cranial nerves to be intact and the results of
muscle strength tendon reflex and cerebellar function tests were normal. There was no
evidence of impaired superficial or position senses. The results of a complete blood cell
count and blood chemistry tests were normal. He was discharged and symptomatic
treatment (non-steroidal anti-inflammatory drugs) was prescribed. Two weeks before the
present admission he returned complaining of general weakness, anxiety, myalgias
(particularly of the legs), delayed growth of facial hair after shaving and thirst. Physical
examination and routine laboratory tests were again normal. His symptoms were diagnosed
as “non-specific”, partly attributed to stress. On his present final presentation he was alert
and complained of double vision. Physical examination revealed hyperhidrosis, tachycardia
(100beats/min) and supine blood pressure of 140/100 mmHg. Alopecia of the scalp was
noted but eyebrows, eye lashes and body hair were intact. Neurological assessment
disclosed horizontal and upbeat nystagmus, severe weakness of the lower extremities (more
prominent proximally), bilateral absence of Achilles tendon reflexes, and lower limb ataxia.
He did not complain of extreme pain and no objective signs of sensory changes were
detected. He was found to have raised blood alanine aminotransferase and raised aspartate
aminotransferase. There was no evidence of proteinuria. Lumbar tap revealed an elevated
protein. Electroencephalogram showed persistent generalized slowing; the electromyogram
displayed bilateral, severe, lower limb motor axonal neuropathy. Rapid deterioration of his
neurological state was observed over the next few days, including flaccid paraparesis, lower
limb areflexia, severe sensory impairment, mild distal arm and neck weakness, as well as
occasional urinary and faecal incontinence. Visual disturbance progressed from impaired
colour vision and decreased acuity to optic disc atrophy. Cognitive disturbances and
hoarseness were also noted. Sural nerve biopsy showed early acute axonal degeneration
with no evidence of vasculitis. At this stage he was started on intravenous immunoglobulin
as a variant of Guillain-Barré syndrome (Milllar-Fisher type) could not be excluded, and
alternative causes were explored. Several days later thallium poisoning was diagnosed as
heavy metal urinalysis showed renal thallium excretion of 7mg/24 hours. Prussian blue was
administered (250mg/kg/day, dissolved in 15% mannitol) daily through a nasogastric tube,
along with forced diuresis. At this stage Mees’ lines appeared on his nail beds. No
improvement in his general state was noted within the next two weeks. He became drowsy,
required respiratory assistance and subsequently developed aspiration pneumonia. The
suspicion of cardiotoxicity was raised by elevations of alanine aminotransferase, aspartate
aminotransferase and creatine phosphokinase (MB fraction) levels however this was not
substantiated by electrocardiographic follow-up and echocardiography. There was swelling
and pain in his right knee, however, some clear fluid drained was inconsistent with any
particular diagnosis. Rheumatoid factor was mildly elevated, without any other supporting
evidence of concurrent arthritic disease. His condition stabilized over the next weeks and
there was a gradual decrease in thallium urinary output (table below). He was transferred to
a rehabilitation hospital after forty two days. A follow-up examination 3 months later the
alopecia and Mees’ lines had completely resolved. There were no cognitive disturbances, his
proximal strength was restored and his colour vision was normal. Decreased visual acuity
and bilateral drop-foot were still evident however and the patient had only a vague
27
DRAFT for comment - not for distribution
1266
1267
1268
1269
1270
1271
1272
1273
1274
1275
1276
1277
1278
1279
1280
1281
1282
1283
1284
1285
1286
1287
1288
1289
1290
1291
1292
1293
1294
1295
1296
1297
1298
1299
1300
1301
1302
1303
1304
recollection of his period in hospital.
Daily excretion of thallium in urine
Hospitalization day
Daily excretion (mg/day)
9
7
17
9
18
7.6
19
3.2
21
5.6
24
2.9
25
2.9
28
2.5
38
0
(Atsmon et al., 2000)
A 67 year old woman was admitted to a county hospital because of acute pain in the chest,
abdomen and lower limbs. The pain in the lower limbs was described as burning and severe.
There was no vomiting or diarrhoea. The patient was discharged after 3 days with the cause
of her illness undetermined. The patient then presented one week later to a private clinic
because of persistent symptoms. Physical examination showed mild tenderness over the
abdomen and electrocardiography showed non-specific T-wave inversion in the anterior
waves. Routine urinalysis results were normal and laboratory tests showed normal blood
cell counts, blood glucose level and kidney and liver function. The patient was treated
symptomatically with analgesics. She was soon readmitted to hospital because of fainting
spells and persistent symptoms. The patient suspected she was being poisoned. Paranoid
psychosis and trichotillomania were diagnosed and she was admitted under restraint to the
psychiatric department for observation. After being discharged home at week 5, the woman
then re-presented at the private clinic. According to the patient the pain had become less
severe. Physical examination showed diffuse alopecia which had started 2 weeks after the
onset of the initial symptoms. Thallium poisoning was suspected. Urinalysis showed a
thallium level of 8.56µmol/L (normal level, 0.003µmol/L; a level of 0.98µmol/L is toxic).
The case was reported to the police and the prime suspect was the patient’s 73 year old
cohabitant. A dose of activated charcoal was given in the emergency department of a nearby
district hospital and the patient was discharged home with a 2-week supply of succimer (2,
3-dimercaptosuccinic acid) (no reason for this was given). At follow-up at week 6 however,
it was found that the pain in her chest, abdomen and lower limbs had subsided, but
symptoms of peripheral neuropathy had emerged - namely bilateral numbness and loss of
exteroceptive and proprioceptive sensations in the toes. She had mild weakness in the
proximal muscles of the lower limbs, as indicated by the patient’s difficulty in rising from
the squatting position. She also complained of right-sided headache and tachycardia. She
was immediately admitted to a University Medical Centre for treatment with oral Prussian
blue (potassium ferric hexacyanoferrate) 4g every 8 hours. The blood thallium level at the
time of hospitalization was 0.15µmol/L. No other heavy metals were present. The patient
tolerated Prussian blue very well, but hypoaesthesia developed over the medial aspect of her
left calf on the second day of treatment. She was discharged 1 week later, when the urine
level of thallium was 0.14µmol/L. In week 9 the patient experienced neurological
deterioration, impairment of short-term memory, double incontinence, tremor ataxia and
falls. Physical examination showed hypoaesthesia of the right trigeminal nerve, general
weakness of the extremities, cerebellar ataxia, tremor and dyskinesia. Plantar reflexes were
normal and the urine thallium level was 0.33µmol/L. By week fourteen the right facial
28
DRAFT for comment - not for distribution
1305
1306
1307
1308
1309
1310
1311
1312
1313
1314
1315
1316
1317
1318
1319
1320
1321
1322
1323
1324
numbness fully recovered, by week twenty there was recovery of sphincter control and
regrowth of hair. Urine thallium was undetectable 2 weeks later. The weakness in the lower
limbs, unsteady gait, falls and bruises persisted until 11 months after the initial presentation,
when her condition improved noticeably although residual weakness continued (Pau., 2000)
A 24-year old female was admitted to hospital with a 4-month history of illness. Eight days
after admission a diagnosis of thallium poisoning was made based on rapid diffuse alopecia,
gastro-intestinal disturbance and a worsening neurological state combined with laboratory
results. Whole blood thallium was measured and the first level was 300 µg/L (normal
<10µg/L, toxic >100 µg/L); the corresponding 24-hour urinary thallium value was 4300
µg/L (normal < 10 µg/L, toxic > 200 µg/L), consistent with severe intoxication. Colloidal
soluble Prussian blue (KFe[Fe(CN)6]) was given orally at a dose of 250mg/kg/day in 2-4
divided doses for 14 days. The patient also received mannitol as a cathartic, cisapride for
her persistent constipation (started on the 5th day of treatment) and forced diuresis, which
was achieved with furosemide, glucose, potassium and sodium chloride. The patient’s
clinical course after treatment was uncomplicated with recovery of her vital signs within a
week. Four months after treatment thallium was undetectable in a 24-hour assay. However
after 6 months she still suffered from a lack of concentration and insomnia and never fully
returned to her previous functional level. The source of thallium was never established
Days before/after treatment
1325
1326
1327
1328
1329
1330
1331
1332
1333
1334
1335
1336
1337
1338
1339
1340
1341
1342
1343
1344
1345
-8
0
4
10
14
18
31
(Vrij et al., 1995).
24 hour-urinary thallium
level µg/L
4300
4200
1450
330
468
440
260
Whole blood thallium level
µg/L
300
< 10
A thirty nine year old male with a history of heavy alcohol consumption became ill one
week after returning from holiday in Spain. His symptoms started acutely with generalized
pain and tingling all over his head and body and he was admitted to hospital where he was
greatly distressed and complaining of shooting pains in his legs and back and leg weakness.
It was thought initially that his illness was an alcoholic syndrome. Because of his continued
deterioration despite multivitamin treatment he was transferred initially to the regional
neurology unit and then further to an intensive care unit, 20 days after first becoming ill. On
initial neurological examination he had respiratory distress, evidence of scalp hair loss, gaze
evoked nystagmus in all directions, bilateral lower motor neuron, facial and bulbar
weakness; his arms were minimally weak with normal reflexes but his legs showed a flaccid
paralysis with absent reflexes. Initial biochemical investigations were within normal ranges
(electrolytes, urea, creatinine and liver function tests). The electrophoresis pattern of serum
proteins was normal and a non-specific auto-immune profile did not detect any autoantibodies. Screening tests for abnormal urinary porphyrins gave negative results. A
complete blood count was within the reference range, except for a slightly increased mean
corpuscular volume. Cerebrospinal fluid was acellular with a protein count of 1.5g/L.
Nerve conduction studies showed absent sensory and motor responses for the legs but
normal values for the arms. On the basis of the clinical picture at this stage, in particular
29
DRAFT for comment - not for distribution
1346
1347
1348
1349
1350
1351
1352
1353
1354
1355
1356
1357
1358
1359
1360
with respect to the hair loss, serum and urine were assayed for thallium and it was found to
be present at toxic levels (value not stated). The patient deteriorated further and developed
visual failure, complete external ophthalmoplegia, and total arreflexic paralysis of all limb
and neck muscles. He was given two treatments of plasma exchange and treatment with
potassium ferrihexacyanate (colloidal soluble Prussian blue), 5g every 6 hours by
nasogastric tube was started (now thirty five days into the illness) and continued for 2
months. At the same time intravenous potassium supplements (100-400mmol/day) were
given. Excretion concentrations of thallium in serum and urine are tabulated below. The
patient made a slow recovery which was complicated by septicaemia, recurrent
supraventricular tachycardias and psychosis. He required 96 days of assisted ventilation and
a total of 224 days in hospital. Some 500 days after the initial insult he still had a significant
visual handicap, no fine finger function and could only walk a few steps with assistance.
The source of the thallium poisoning was never discovered.
Excretion of thallium in serum
Hospitalization day
Excretion (nmol/L)
28
914.4
46
54.8
48
25.4
49
19.0
55
8.8
56
6.9
57
6.9
58
7.5
59
6.3
60
7.4
1361
1362
1363
1364
1365
1366
1367
1368
1369
1370
Excretion of thallium in whole blood
Hospitalization day
Excretion (nmol/L)
42
156.5
43
190.7
44
141.8
45
92.2
50
39.1
51
36.7
52
14.7
56
7.8
58
7.8
59
5.4
Day zero = date of admission to hospital
(Chandler et al., 1990)
Villanueva et al (1990) describe 5 cases of thallium poisoning in Spain. Four were members
of a single family and the source of thallium was never ascertained. The fifth case was a
female adult with a history of depression who intentionally ingested a thallium sulphate
rodenticide. The family members (2 adults and two children aged 10 years and 3 years)
presented initially with varying symptoms and the two children required admission to
30
DRAFT for comment - not for distribution
1371
1372
1373
1374
1375
1376
1377
1378
1379
1380
1381
1382
1383
1384
1385
1386
1387
1388
1389
1390
1391
1392
1393
1394
1395
1396
1397
1398
1399
1400
1401
1402
1403
1404
1405
1406
1407
1408
intensive care. Total hair loss of the 10-year old 2 weeks after admission led to the
diagnosis of thallium poisoning. In all of the 5 cases urinary thallium was measured. The
10 year old child’s first measured thallium level was 18.4 mg/L, seven days later it was 5.8
mg/L, at 27 days later it was 0.14 and by approximately 4 months it was 0.004 mg/L. The
child had been treated with Prussian blue at a dose of 250mg/kg by duodenal tube
administration every 6 hours until the urinary excretion of thallium was 0.5 mg/day. Her
symptoms resolved in 20 days. The female adult who intentionally ingested the thallium had
an initial urinary level of 2.4mg/L which decreased to 0.9mg/L in 4 days and to 0.1 mg/L in
5 weeks. She had also been given Prussian blue at a dose of 250mg/kg/day (duration of
treatment not stated) and 6 weeks later recovery was complete. The case reports also outline
the thallium concentrations of the other family members but it is unclear whether or not they
received Prussian blue therapy.
A 20-year-old chemistry student presented with a 3 day history of malaise and polyuria with
paraesthesia of the fingers and lips. He had been using thallium and blood and urine
analyses showed very high concentrations (5750 µg/L and 60000 µg/L, respectively),
although he denied ingestion. Tests for thallium in hair samples were negative which
excluded chronic ingestion however, despite exhaustive enquiries by the police and college
authorities, the mode of thallium administration remained undetermined. Shortly after
admission he became drowsy and had a convulsion. He developed progressive weakness
over the next 12 hours, with severe pain in the calf muscles. He had peripheral and sensory
impairment, dysarthria, dysphagia, paralytic ileus, tachycardia and ECG changes. He was
started on soluble Prussian blue (5 g in 50 ml of 15% mannitol 4 times daily) and forced
diuresis. On day 6 dialysis and haemofiltration were started and diethyldithiocarbamate was
given. The diethyldithiocarbamate produced a short-lived increase in thallium excretion
(from 17 to 142mg/24 h in urine, and 63 to 81mg/6 h dialysis) but also led to a rise in serum
thallium concentration (from 800 to 1350 µg/L and worsening neurological signs (including
respiratory failure) and it was stopped. He required ventilation for 4 weeks. He developed
almost complete alopecia before hair regrowth started. By 13 weeks he could swallow fluids
and by 20 weeks he had normal upper limb function. But after 12 months he was still in a
wheelchair owing to nerve damage to the lower limbs. Prussian blue and laxatives were the
most effective means of enhancing thallium elimination, even though paralytic ileus caused
long periods of constipation. High concentrations of thallium were present in the faeces up
to day 18, and it was estimated that at least 2000 mg of thallium was excreted via this route
in the first 20 days (see table). This is twice the quantity excreted by all the other methods
in the same period. Forced diuresis was estimated to have eliminated 820 mg of thallium in
46 days with 225 mg eliminated via haemodialysis in 25 days.
No. of
days from
admission
1
2-5
6-10
11-15
16-20
21-25
Concentrations
Excretion
Serum
(µg/L)
Urine
(µg/L)
Urine
(mg)
Faeces
(mg)
Dialysate
(mg)
Urine
Filtrate
(mg)
5750
2390
680
225
35
15
60000
35900
7750
1520
640
280
129
398
230
42
12
2.6
550
155
1280
0.5
146
64
5.0
5.4
3.5
1.0
<0.1
<0.1
31
DRAFT for comment - not for distribution
26-30
12
315
31-40
11
110
41-50
<7
64
51-70
<7
24
Total quantities excreted (mg):
1409
1410
1411
1412
1413
1414
1415
1416
1417
1418
1419
1420
1421
1422
1423
1424
1425
1426
1427
1428
1429
1430
1431
1432
1433
1434
1435
1436
1437
1438
1439
1440
1441
1442
1443
1444
1445
1446
2.7
2.9
1.0
0.9
820
2.5
4.5
<0.1
1990
225
4.5
The serum and urine concentrations presented in the table above are daily averages for the
periods stated. The quantities excreted are totals for each period. All values are given as
elemental thallium, measured by atomic absorption spectrometry (Wainwright et al., 1988).
A group of 14 people ate dinner together and the following morning all complained of
abdominal pain, vomiting and diarrhoea and were taken to hospital. Five of the 14 patients
died in hospital within the next four days. The remaining nine patients (age range 16-70
years) were seen over the following 4-7 days. One patient was pregnant, one had preexisting Parkinson’s disease and a third had elephantiasis of the legs. All of them
complained of varying degrees of pain in the feet and legs and 6 were unable to walk. Some
had headaches, constipation, abdominal pains, chest discomfort, loss of appetite, and loss of
sleep. On examination they all had varying degrees of peripheral neuritis with
hyperaesthesia, hyperalgesia, mental confusion, tachycardia, muscle and abdominal
tenderness. A diagnosis of heavy metal poisoning was made based on the sudden onset of
peripheral neuritis in a group of people who had eaten the same food and also because of
similar case presentations in the previous year that had proven to be thallium poisoning.
Blood and urine samples were sent for heavy metal analysis. Thallium was detected
quantitatively in all the samples. The food they ate was suspected of being contaminated
with a thallium-containing rodenticide but this could not be confirmed. Prussian blue was
started between the 4th and 7th day at a dose of 2g three times a day orally, together with
magnesium sulphate solution (30ml three times a day) to avoid constipation. For the first
few days some of the patients required parenteral pethidine (100mg every six hours) for
severe lower limb pain later changed to oral pentazocine (50mg three times a day). They
were also given oral vitamin B complex and amiloride/hydrochlorothiazide daily. Over the
next 5 days the leg pains rapidly subsided and analgesics were stopped. Seven of the
patients started walking freely without much pain. In the 3rd week all of them gradually
started losing scalp hair and there was almost complete alopecia after 4 weeks. Six patients
developed Mee's lines on the finger nails along with hyperpigmentation over the knuckles.
Four patients were discharged from hospital after the 4th week and the remaining patients
after 6 weeks. Prussian blue was continued in all patients at the same dose for a total of 6
weeks and no side effects were noted. On discharge 5 patients had fine tremor of the upper
limbs with slight incoordination of movement. After sixteen weeks regrowth of scalp hair
was complete. The pregnant woman had a premature delivery in the sixth month of
pregnancy at another hospital but no details were available. By sixteen weeks all patients
had returned to active life.
Serum and urine thallium concentrations after two weeks of Prussian blue therapy
Patient number
Patient age (years)
Serum Thallium
Urine Thallium
(µgm/ml)
(µgm/ml)
1
62
16
2200
2
37
4
48
3
29
4
250
4
70
4
250
32
DRAFT for comment - not for distribution
1447
1448
1449
1450
1451
1452
1453
1454
1455
1456
1457
1458
1459
1460
1461
1462
1463
1464
1465
1466
1467
1468
1469
1470
1471
1472
1473
1474
1475
1476
1477
1478
1479
1480
1481
1482
1483
1484
1485
1486
1487
1488
1489
1490
1491
5
6
7
8
9
(Pai., 1987)
60
16
29
30
26
6
11
5
6
4
660
1100
37
87
23
A 21-month old girl arrived at a hospital in the UK from Qatar for investigation of ataxia of
five days duration. On admission she was semi-conscious and irritable but extensive
investigations including routine toxicology screen on blood and urine, could only achieve a
diagnosis of encephalopathy. On the 5th day of hospitalization hair loss was noted and a
suggestion of thallium poisoning was made by a nurse in charge of the child (the subject of
the crime thriller she was reading at the time, Agatha Christie’s A Pale horse). The child
was treated with oral Prussian blue and potassium chloride (doses not stated) and after 3
weeks of treatment there was marked clinical improvement and no thallium was detected in
her urine. The clinical improvement continued and after four months the child was alert,
ataxic but able to walk with help. The source of thallium was never determined but was
thought to be the cockroach bait that was used in the home (Robb-Smith, 1987).
A 32 year-old woman was admitted to hospital 6 hours after allegedly ingesting 100mg of
thallium sulphate. On admission the patient had malaise, nausea, vomiting and a burning
retrosternal pain. After gastric lavage Prussian blue was administered 250mg/kg in divided
doses) and combined haemoperfusion-haemodialysis (HP-HD) was started 7 hours after the
alleged ingestion. HP-HD was instigated because the dose of thallium and whether there
were possible co-ingestants were unknown. The patient was treated for 4 hours by HP-HD.
Blood samples were taken before and after the charcoal column and after the artificial
kidney at 1 hour intervals. Blood flow was 200ml/min. After HP-HD treatment 7 more
blood samples were taken, initially at 1-hour intervals later at 2-hour intervals. During HPHD treatment the patient’s blood pressure remained constant however there were frequent
supraventricular extrasystoles. The patient improved and after 4 hours of HP-HD she felt
well. Subsequent to her treatment no neurological or dermatological symptoms were noted.
The combination of HP-HD in this patient obtained an overall clearance of 150ml/min in
blood compared to 47ml/min (mean value) using HD only (De Backer et al., 1982).
A 28-year-old female presented 4 days after ingestion of nearly 1 g of thallium sulphate with
lower abdominal pain, nausea, and hyperaesthesia of the limbs. Thallium was detected in
the urine (3 mg/L) and gastric aspirate (10.8 mg/L). She was started on intravenous fluids
and soluble Prussian blue (5 g four times daily via duodenal tube with 50 mL of 15%
mannitol). Over the next two days the abdominal and lower limb pain persisted, with
drowsiness and vomiting. On the third day she became hypotensive with bilateral ptosis.
Alopecia was also noted. Neurological signs and gastrointestinal symptoms began to
improve 4 days later, but hair loss continued. She had severe constipation for the first 6 days
despite laxative administration. By 11 days her symptoms improved; Prussian blue was
discontinued after 20 days, by which time hair regrowth had started. Thallium
concentrations fell dramatically over the first 2 days of admission, with a slower decline
thereafter (see table). No faecal samples could be obtained until the 10th day after poisoning
(hospital day 6) owing to the severe constipation. At this time 1.6 mg of thallium was
detected in the 24 hour faeces and 1.93 mg in the urine. In 28 days of hospitalization
approximately 5 mg of thallium was eliminated via the intestinal tract and 35 mg in the
urine. Approximately 55 mg was eliminated in the saliva between days 9 and 26 after
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1498
1499
1500
1501
1502
1503
1504
1505
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1508
1509
poisoning. In total the quantity eliminated was thought to be <5% of the dose ingested. She
was discharged asymptomatic at 28 days.
Excretion of thallium (mg/day) in urine, faeces and saliva at various times during
hospital course
No. days after
Urine (mg/day)
Faeces (mg/day)
Saliva (mg/day)
poisoning
4
5.68*
Not determined
Not determined
5-6
4.54
Not determined
Not determined
7-9
2.26
Not determined
10.15
10-12
1.93
0.84
4.69
13-16
1.08
Not determined
2.03
17-22
0.27
0.41
0.38
23-26
0.25
0.02
0.18
*Value calculated on 14 hour urine (Richelmi et al., 1980).
Comment: In the above case study the patient’s response to Prussian blue was slow to
manifest and this may possibly have been due to her constipation. A very small amount of
thallium was excreted in the faeces, and in fact, a very small amount was excreted overall so
possibly the patient may have improved anyway regardless of therapy.
The efficacies of different therapies were evaluated in 18 cases of thallium poisoning treated
between 1971 and 1979 at the University Hospital of Utrecht, the Netherlands. Patients
were treated with gastric lavage if ingestion had occurred within the preceding 48 hours and
then given 10 g soluble Prussian blue with 100 ml 15% mannitol via a duodenal tube twice
daily. Eight patients were also treated with forced diuresis. Furosemide was given only if
necessary to prevent fluid overload. Sixteen patients survived and two patients with cardiovascular insufficiency died. The cases are summarized in the table below.
Patient
A
B1)
C
D
E
F
G
H2)
I
J
K
L
Sex
Age
F
F
F
F
M
M
F
F
F
M
M
M
21
22
21
55
23
28
19
24
32
45
50
26
Amount
of
thallium
ingested
(mg) from
patient
history
500
2400
350
1000
1000
480
unknown
1000
1000
unknown
750
875
34
Time
between
thallium
ingestion
&
admissio
n (days)
Thallium
concentra
tion in
urine on
admissio
n (mg/L)
28
2
1
4
2
½
2
1
2 hours
?
4
1
2.1
47.4
8.8
20.2
71.1
1.0
2.0
84.0
40.0
3.0
24.6
54.0
Treated
with
forced
diuresis
+
+
Treated
with
haemope
rfusion
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M
N
O3)
P3)
Q
R
1510
1511
1512
1513
1514
1515
1516
1517
1518
1519
1520
1521
1522
1523
1524
1525
1526
1527
1528
1529
1530
1531
1532
1533
1534
1535
1536
1537
1538
1539
1540
1541
1542
1543
1544
1545
1546
1547
1548
1549
1550
1551
1552
1553
M
21
1500
14
F
25
1500
1
M
44
unknown ?
M
19
unknown ?
F
58
unknown 2
F
19
3000
1
1) Patient died after 4 days.
2) The patient survived this suicide attempt. Four months
after ingestion of an unknown amount of thallium
3) These patients were admitted with hair loss of the head
79.8
80.0
8.0
10.0
2.2
50.0
+
+
+
+
+
+
+
+
later she died within 6 hours
With soluble Prussian blue therapy, the mean half-life of thallium was 3.0 ± 0.7 days. When
administration of Prussian blue was combined with forced diuresis, the mean half-life of
thallium was 2.0 ± 0.3 days (van Kesteren et al., 1980).
An early report on the use of Prussian blue therapy in thallium poisoning reviewed 11
patients hospitalized between 1971 and 1973. There were three men (aged 30 to 44 years),
six women (aged 24 to 64 years) and two children (both female, aged 2 and 6 years). Three
patients received Prussian blue by duodenal tube (2 x 10 g every two days, 2 x 10 g or 20 g
daily). The other nine patients received oral Prussian blue (4 x 5 g daily in the adults, 4 x 1
g daily in the 6-year-old and 4 x 1.7 g daily in the 2-year-old). Four patients treated within
24 hours of ingestion of thallium did not develop any signs of toxicosis. Improvement also
occurred in most of the other patients even though treatment was started late (between 9 and
151 days after exposure). Thallium elimination was primarily via the faeces. Although no
adverse effects were attributed to the Prussian blue therapy, one patient developed
constipation and had constantly high blood thallium concentrations during the first few
weeks of treatment (Stevens et al., 1974).
A 26 year old female student, epileptic and treated with phenobarbital and phenytoin,
ingested approximately 700mg of thallium sulphate when she was in a depressed mood. She
ingested half of the amount during the evening and the remainder the following morning.
She was admitted to hospital twelve hours later and was at this stage asymptomatic. On the
third day hyperaesthesia of the legs and feet developed and she had abdominal discomfort.
The next day (day 4) she developed a prickly, burning sensation in the feet and pain in the
legs and shoulders. No other neurological symptoms could be demonstrated. The pain
subsided during the subsequent days and then a slight polyneuropathy was found. Hair loss
began on the tenth day and progressed but was not extreme. After two weeks only traces of
neurological damage could be demonstrated and this disappeared during the following
weeks. No Mees’ lines were seen on the nails. On initial admission to hospital, no thallium
was evident after gastric lavage but it was shown to be present pharmacologically. She was
treated with Prussian blue 250mg/kg body weight/day (given in 4 daily doses of 3.75g)
along with 15% mannitol through a duodenal tube. Potassium chloride and activated
charcoal were also given on the first two days. A multivitamin preparation was given
intramuscularly 3 times a week and a fluid intake of 3-4 litres/day was prescribed. The
decrease in urinary thallium concentration during the patient’s hospitalization is shown in
the table below. Prussian blue was stopped on the 13th day when the amount of thallium in
the urine was below 0.5 mg/24hours.
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1557
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1559
1560
1561
1562
1563
1564
1565
1566
1567
1568
1569
1570
1571
1572
1573
1574
1575
1576
1577
1578
1579
1580
1581
1582
1583
1584
1585
1586
1587
1588
1589
Daily excretion of thallium in urine
Hospitalization day
Daily excretion (mg/24 hr)
2
13
6
5.1
8
1.4
13
0.5
(Van der Merwe., 1972-Case study 1)
A twenty two year-old alcoholic ingested approximately 700 mg of thallous sulphate in a
suicide attempt. He was admitted to hospital 6 hours later with no complaints. Gastric
lavage showed only a trace of thallium. He was treated with Prussian blue 250mg/kg body
weight in 15% mannitol via duodenal tube in 4 doses a day. Fluid intake of 3-4 litres a day
was prescribed. After 4 days slight paraesthesia and sensory impairment of the toes could be
demonstrated, however this improved and disappeared during the next few days. Hair loss
started after 2 weeks but was mild. Thallium excretion in the urine is shown in the table
below. Prussian blue treatment was stopped after the 10th day results were known.
Daily excretion of thallium in urine
Hospitalization day
Daily excretion (mg/24 hr)
2
3.3
3
3.4
5
1.8
10
0.2
(Van der Meerwe., 1972-Case study 2)
13.
Summary of Evaluation
13.1 Indications
Prussian blue is indicated in the treatment of patients with known or suspected internal
contamination with radioactive caesium, radioactive thallium and non-radioactive thallium,
to increase their rates of elimination. Treatment should be started as soon as possible after
exposure.
13.1.1 Thallium
The recommendation for the use of Prussian blue in thallium poisoning is based on evidence
derived from animal studies and limited clinical data from human poisoning in the form of
case reports and case series.
In animals experimentally poisoned with thallium, Prussian blue has been shown
significantly to reduce absorption of thallium, increase its elimination and reduce its
concentration in the brain. Moreover, Prussian blue significantly lowered mortality in
animals poisoned by this metal.
Uncontrolled case reports / series have generally been associated with a favourable outcome,
although there are some cases where patients were slow to respond to treatment and some
patients have been left with long-term sequelae. In many of these cases other treatments
were given concurrently (e.g. activated charcoal) and it is therefore difficult to clearly
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1598
1599
1600
1601
1602
1603
1604
1605
1606
1607
1608
1609
1610
1611
1612
1613
1614
1615
1616
1617
1618
1619
1620
1621
1622
1623
1624
1625
1626
1627
1628
1629
1630
1631
1632
1633
1634
1635
1636
1637
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1639
identify the benefits of Prussian blue alone.
Soluble Prussian blue has been shown to more than halve the elimination half-life, when
compared to historical controls, in a large series of thallium poisoned patients. Although
such extensive clinical documentation is not available for insoluble Prussian blue, the overall
evaluation is that insoluble Prussian blue is also effective.
13.1.2 Caesium
The recommendation to use Prussian blue in patients having ingested radioisotopes of
caesium is based on its ability significantly to decrease absorption of, and increase the faecal
excretion of, caesium in animals exposed to caesium-137. The body half-life was halved in
the species tested and reduced content of caesium-134 in various organs was also
documented. In healthy volunteers, insoluble Prussian blue more than halved the body half
life of this radioisotope of caesium. The limited case studies available are consistent with
the effect in healthy volunteers. There appears to be no data on the use of soluble Prussian
blue in this situation.
13.2 Advised routes and dose
Prussian blue should only be given orally. The manufacturers of the pharmaceutical
preparation recommend the following doses (Heyl data sheets Radiogardase and Antidotum
Thallii-Heyl, 2004):
• Adults: In early-presenting cases when thallium or caesium may still remain in the gut an
initial dose of 3g is suggested. In late-presenting cases when thallium or caesium have
already been mostly absorbed, 3 to 20 g per day in divided doses should be given.
The individual dose should be based on the severity of exposure and clinical features.
• Children 2 to 12 years: 1 g orally 3 times a day.
The efficacy and dosing for the paediatric population of insoluble Prussian blue has been
extrapolated from adult data and supported by paediatric patients who were internally
contaminated with cesium-137 and treated with Prussian blue in the Goiânia incident.
Paediatric patients aged 2-4 years are expected to have biliary and gastrointestinal function
that is comparable with a 4-year old (Heyl, 2004).
• Children less than 2 years
The dosing regimen for children less than 2 years old has not been established although it
has been used in this age group (Robb-Smith, 1987). Variations exist in the developmental
maturity of the gastrointestinal and biliary systems of neonates and infants and the doserelated effects of Prussian blue on an immature gastrointestinal tract are unknown (Heyl,
2004).
Administration
The capsules of Prussian blue can be swallowed whole with liquid or if the patient is unable
to swallow large numbers of capsules they can be opened and dispersed in bland food or
fluid. A suspension of Prussian blue can also be administered via a stomach tube following
gastric lavage.
In many patients with thallium poisoning mannitol (100 ml of 15% solution) has also been
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1650
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1653
1654
1655
1656
1657
1658
1659
1660
1661
1662
1663
1664
1665
1666
1667
1668
1669
1670
1671
1672
1673
1674
1675
1676
1677
1678
1679
1680
1681
1682
1683
1684
1685
1686
1687
1688
1689
given with each dose in an effort to prevent constipation. This may not work and other
measure to prevent or treat constipation may need to be undertaken.
End point of therapy
The clinical end-point of Prussian blue therapy is generally considered to be when urinary
thallium levels fall below 0.5mg/day (however this is clearly only a guide as most of the
elimination will be faecal particularly in patients receiving Prussian blue therapy).
13.3
Other consequential or supportive therapy
13.3.1 Caesium
Specialist advice should be sought for the management of radiation accidents. This may require
a multidisciplinary approach with radiation protection and dosimetry professionals, and medical
and nursing staff trained and experienced in managing victims of radiation exposure
(Breitenstein, 2003).
It is essential to prevent further incorporation of any radioactive material. Additional measures
include the administration of laxatives to enhance gastrointestinal transit, antacids for
radionuclides that become colloid or insoluble in the gastrointestinal tract (and therefore less
absorbable), nasal and/or lung lavage and decontamination of skin and wounds (Gerber &
Thomas, 1992).
In preliminary studies based on animal data, co-administration of Prussian blue with other radioeliminators does not affect the efficacy of Prussian blue (Heyl, 2004; Kostail et al., 1983).
13.3.2 Thallium poisoning
The treatment of thallium poisoning is primarily concerned with the prevention of absorption
from the intestinal tract and enhanced elimination from the body.
Gastric lavage should be considered in patients who present early. As patients generally
present to healthcare facilities many hours after exposure it is unlikely that lavage would be
beneficial however gastric decontamination has been has been undertaken as late as 48 hours
after thallium ingestion in some previous cases (van Kesteren et al, 1980). Many patients
will also have vomited spontaneously by the time they attend hospital so as with gastric
lavage, emesis should be considered but may not be of any benefit. Enhanced elimination is
often required in severe cases and haemodialysis (Barckow & Jenss, 1976; Pederson et al.,
1978), forced diuresis (Nogué et al., 1982; Heath et al., 1983; de Groot & van Heijst, 1988;
Malbrain et al., 1997) and charcoal haemoperfusion (de Groot et al., 1985; van Kesteren et
al., 1980) have all been used in thallium-poisoned patients.
13.4
Controversial issues and areas of use where there is insufficient information to
make recommendations
13.4.1 Optimal form of Prussian blue
Uncertainty exists in the historical literature regarding which of the two forms of Prussian
blue (soluble or insoluble) is most effective as an antidote for radiocaesium and thallium.
Human case study data is limited and this combined with the lack of analogous animal data
on Prussian blue use (for both thallium and radiocaesium), means that whether the
physicochemical differences between soluble and insoluble Prussian blue have any effect on
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1698
1699
1700
1701
1702
1703
1704
1705
1706
1707
1708
1709
1710
1711
1712
1713
1714
1715
1716
1717
1718
1719
1720
1721
1722
1723
1724
1725
1726
1727
1728
1729
1730
1731
1732
1733
1734
1735
1736
1737
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1739
outcomes in human poisoning is currently unknown. A relatively recent literature review by
Thompson & Callen, (2004) highlights these controversies although they do conclude that
that there is sufficient evidence to state that insoluble Prussian blue is effective in
radiocaesium toxicity but that data are inconclusive for thallium.
From a pragmatic point of view, however, preference should be given to insoluble Prussian
blue as this is the only commercially available pharmaceutical preparation.
13.4.2 Optimal dosage regimen
The optimal dose of Prussian blue has not been established in clinical studies. The doses
recommended by the manufacturer are empirical, reflecting the doses that have been used to
treat cases of poisoning with thallium and radioactive caesium. In the case reports of
poisoning with radioactive caesium the doses of Prussian blue used were smaller than those
used for cases of thallium poisoning, typically 3g compared with 20g. Moreover, in one case
series adults given doses of 3g, 6g and 10g per day showed very similar reductions in the
half-life of caesium-137 (Lipsztein et al 1991). Since, however, the half-life of caesium-137
was also found to be influenced by patient body weight and body burden of caesium-137
interpretation of the impact of dosing is difficult.
In the case reports of poisoning with radioactive caesium, treatment was with insoluble
Prussian blue, whereas for thallium poisoning treatment was often with the soluble form.
Whether the form of Prussian blue has an impact on the effective dose for thallium poisoning
is unknown.
Food may increase the effectiveness of insoluble Prussian blue by stimulating bile secretion
and increasing enterohepatic circulation. The increase in enterohepatic circulation may
increase the amount of caesium and thallium in the gastrointestinal lumen and hence
increase the amounts available for binding with Prussian blue (Heyl, 2004).
13.5 Proposals for further studies
In their review Thompson & Callen (2004) concluded that further research is needed to
determine the significance of any differences between the two forms of Prussian blue and
whether their physicochemical differences have any effect on outcomes in human poisoning.
Studies of the effect of Prussian blue in exposures to other radioisotopes may be warranted,
e.g. in the case of rubidium-86. Although animal experiments suggest that Prussian blue may
reduce the whole body retention of rubidium-86, the use of Prussian blue in this situation
should be considered controversial.
13.6 Adverse effects
Severe adverse effects have not been reported with Prussian blue (Hoffman, 2003). Mild to
moderate constipation may occur which can be managed with a high fibre diet or bulk
laxatives. In 46 patients involved in the Goiânia incident treated with Prussian blue, 10
developed constipation (Farina & Brandão-Mello, 1991). It is essential to monitor for and
treat constipation because elimination of thallium and caesium are dependent on the transit
and elimination of Prussian blue from the gut. Faeces will be coloured blue and blue sweat
and tears have been reported with prolonged administration, however this effect appears to
be benign and transient (Hoffman, 2003). If capsules are opened and mixed with food or
fluid, the teeth and mouth may be discoloured blue (Heyl, 2004).
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1747
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1749
1750
1751
1752
1753
1754
Hypokalaemia is a potential risk as Prussian blue can bind potassium, however no significant
variations in serum potassium concentrations have been reported, even when large doses
have been given (IAEA, 1988). In 46 patients involved in the Goiânia incident treated with
Prussian blue there were only 3 cases of hypokalaemia (2.5 to 2.9 mmol/L) without clinical
complications. Oral and intravenous potassium supplements resulted in prompt correction of
hypokalaemia (Farina & Brandão-Mello, 1991).
1755
14.
1756
1757
1758
1759
1760
1761
1762
1763
1764
1765
1766
1767
1768
1769
1770
1771
1772
1773
1774
1775
1776
1777
1778
1779
1780
1781
1782
1783
1784
1785
1786
1787
1788
Cyanide toxicity has not been reported from oral dosing with Prussian blue.
13.7 Restrictions for use
None known. Prussian blue has been used in the treatment of thallium poisoning in
pregnancy (Hoffman, 2000).
Model Information Sheet
14.1 Uses
Prussian blue (soluble or insoluble) is indicated
• for antidotal therapy in acute or chronic thallium poisoning,
• in the case of incorporation of radioisotopes of caesium (caesium-134, caesium137),
14.2 Dosage and route
Prussian blue is available as Radiogardase®-Cs (Radiogardase® in the United States of
America) and Antidotum Thallii-Heyl® distributed by Heyl Chemisch-pharmazeutische
Fabrik GmbH, Berlin, Germany. Both products are available in bottles of 30 hard gelatine
capsules, each containing 0.5 g of insoluble Prussian blue.
Prussian blue should only be given orally.
Adults and adolescents see comments above
The recommended dose of Prussian blue is 3g orally three times/day
When the dose of radioactivity is substantially decreased the dose may be reduced to 1 or 2g
three times/day to improve gastrointestinal tolerance
Paediatric dose (2-12 years)
The recommended dose of Prussian blue is 1g orally 3 times/day
Neonates and infants
Dose has not been established
In patients who cannot tolerate swallowing large numbers of capsules, the capsules may be
mixed with bland food or liquids (this may result in blue discolouration of mouth and teeth).
Radiocaesium contamination: Treatment should be initiated as soon as possible after
contamination is expected. Treatment should continue for a minimum of 30 days and then
the patient should be reassessed for the amount of whole body radioactivity. The duration of
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1797
1798
1799
1800
1801
1802
1803
1804
1805
1806
1807
1808
1809
1810
1811
1812
1813
1814
1815
1816
1817
1818
1819
1820
1821
1822
1823
1824
1825
1826
1827
1828
1829
1830
1831
1832
1833
1834
1835
1836
1837
1838
treatment after exposure will be dictated by the level of contamination.
Thallium contamination: Ideally treatment should be initiated as soon as possible after
exposure however Prussian blue is still thought to be effective after a delay in starting
treatment and should not be withheld.
14.3 Precautions/contraindications
As the antidotal effect of Prussian blue is due to the binding of thallium or caesium in the
gut, it is only effective if the motility of the intestines is intact. In patients in coma or
needing sedation, with reduced intestinal motility, medications to increase intestinal motility
should be considered, although they are not proven effective in this setting.
Prussian blue decreases the duration of radiation exposure but does not treat the
complications of radiation exposure. Supportive treatment for radiation toxicity symptoms
should be given concomitantly with Prussian blue treatment.
In radiological emergencies the type of elemental exposure may not be known, Prussian blue
may not bind to all the radioactive components and these elements may not undergo
enterohepatic circulation which is necessary for Prussian blue binding and elimination. Thus
patients contaminated with unknown or multiple radioactive elements may require additional
treatments.
In severe thallium poisoning additional means for enhancing elimination should be
considered; both charcoal haemoperfusion and haemodialysis have been used, although there
are limited data to suggest that they have an impact on outcome. .
14.4 Pharmaceutical incompatibilities and drug interactions
Prussian blue may bind oral drugs. When given together with oral tetracycline it is
anecdotally reported to decrease the bioavailability of tetracycline.
Prussian blue may bind electrolytes in the gastrointestinal tract and asymptomatic
hypokalaemia has occasionally been reported with its use.
14.5 Adverse effects
Prussian blue is well tolerated; death or serious adverse effects have not been reported with
Prussian blue. Mild to moderate constipation may occur which can be managed with a high
fibre diet or bulk laxatives. It is essential to treat constipation as it will decrease elimination
of thallium and caesium. Faeces will be coloured blue and blue sweat and tears have been
reported with prolonged administration.
14.6 Use in pregnancy and lactation
No contraindications. Prussian blue has been used in pregnant women and since it is not
absorbed from the gastro-intestinal tract, effects on the fetus are not expected. The risk of
toxicity from untreated radioactive caesium or thallium exposure is expected to be greater
than the risk of reproductive toxicity from Prussian blue.
Prussian blue is unlikely to be excreted in breast milk as it is not significantly absorbed from
the gastrointestinal tract, however, women with thallium toxicosis or exposure to
radiocaesium should not breast feed due the risks to the baby from these elements.
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1840
1841
1842
1843
14.7 Storage
The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C;
occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004).
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1861
1862
1863
1864
1865
1866
1867
1868
1869
1870
1871
1872
1873
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1875
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1877
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References
Atsmon J, Taliansky E, Landau M, Neufeld M (2000) Thallium poisoning in Israel. Am J
Med Sci, 320(5):327-330
Barckow J & Jenss H (1976) [Thallium intoxication treated by haemodialysis, forced
diuresis and antidote] (in German). Med Klin, 71(35): 1377-1382.
Barroso-Moguel R, Villeda-Hernández J, Méndez-Armenta M, Rìos C & Monroy-Noyola A
(1994) Combined D-penicillamine and Prussian blue as antidotal treatment against
thallotoxicosis in rats: evaluation of cerebellar lesions. Toxicology, 89:15-24.
Bhardwaj N, Bhatnagar A, Pathak DP & Singh AK (2006) Dynamic, equilibrium and human
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Villanueva E, Hernandez.Cueto C, Lachia E, Rodrigo MD & Ramos V (1990) Poisoning by
thallium. A study of five cases. Drug Safety, 5(5): 384-389.
Vogel AI (1954) A textbook of macro and semimicro qualitative inorganic analysis. 4th
Edition London, Longmans.
Volf V, Doerfel H, Krug H, Prech V, Schuppler U, Sontag W & Stahr B (1987) The effect of
Prussian blue on caesium in man after the Tchernobyl reactor accident. In: Radiation
research. Proceedings of the 8th International Congress of Radiation Research, Edinburgh,
July 1987. EM Fielden (ed). International Congress of Radiation Research (8th 1987
Edinburgh, Scotland). London: Taylor and Francis, abstract B10-7V, p57.
Vrij AA, Cremers HM & Lustermans FA (1995) Successful recovery of a patient with
thallium poisoning. Neth J Med, 47:121-126.
Wainwright AP, Kox WJ, House IM, Henry JA, Heaton R & Seed WA (1988) Clinical
features and therapy of acute thallium poisoning. Q J Med, 69(258): 939-944.
Wolsieffer JR, Stookey GK & Muhler JS (1969) Studies concerning the effect of ferric
ferrocyanide, beet pulp, and fluoride upon 137cesium retention in the rat. Proc Soc Exp Biol
Med, 130(3): 953-956.
Yang Y, Brownell CR, Sadrieh N, May JC, Del Grosso AV, Place D et al (2007)
Quantitative measurement of cyanide released from Prussian blue. Clinical Toxicology, 45:
776-781.
Yang Y, Faustino PJ, Progar JJ, Brownell CR, Sadrieh N, May JC, Leutzinger E, Place DA,
Duffy EP, Yu LX, Khan MA & Lyon RC (2008) Quantitative determination of thallium
binding to ferric hexacyanoferrate: Prussian blue. Int J Pharm, 353(1-2): 187-194.
Walker AW (1998) SAS Trace Element Laboratories. Clinical and analytical handbook, 3rd
edition. Guildford, Royal Surrey Hospital.
50
DRAFT for comment - not for distribution
2286
2287
2288
2289
2290
2291
2292
2293
2294
2295
2296
2297
2298
16.
Author(s) Name, Address
Initial draft by ANP van Heijst, A von Dijk & J Ruprecht.
Update and revision by Maeve McParland, Paul Dargan, London
November 2009
17.
Additional Information
Table 1: Results of EMBASE search 4th November 2009
Number
Keywords
Results
1
Prussian AND Blue 631
2
Thallium
7299
3
Caesium
959
4
Caesium
2718
5
Radiocesium
392
6
Poisoning OR
193447
Toxicity OR
Overdose
7
1 AND 2
47
8
Duplicate filtered: 1 47 unique results
AND 2
0 duplicate results
9
6 AND 7
33
10
1 AND 4
15
11
1 AND 5
14
12
1 AND 4 AND 6
1
13
1 AND 5 AND 6
4
14
Rubidium
1098
15
1 AND 15
0
Table 2: Results of Medline search 4th November 2009
Number
Keywords
Results
1
Prussian AND Blue 860
2
Thallium
8122
3
Caesium
1138
4
Caesium
3733
5
Radiocesium
297
6
Poisoning OR
240196
Toxicity OR
Overdose
7
1 AND 2
49
Duplicate filtered: 1 49 unique results
AND 2
0 duplicate results
8
6 AND 7
32
9
1 AND 4
25
10
1 AND 5
14
11
1 AND 4 AND 6
3
51
DRAFT for comment - not for distribution
12
14
15
1 AND 5 AND 6
Rubidium
1 AND 14
4
1935
0
2299
Results of Cochrane Library Search 4th November 2009
2300
No results found for Prussian blue using all possible MeSH terms.
52
Table 3: Summary of evidence of use of Prussian blue in metal poisoning
Metal
Clinical trial data
Case reports
Radiocaesium
No controlled trials
Prussian blue treatment reduced
the half-life of caesium in 5
Volunteer studies:
patients accidentally exposed to
137
3 g daily of Prussian blue given
Cs (Ma et al, 1985)
before 137Cs did not reduce
caesium absorption. The
Goiânia incident Of 249 people
increase in 137Cs excretion was contaminated with 137Cs, 46 were
small following 0.5 g of
treated with Prussian blue and this
Prussian blue three times daily
significantly increased the rate of
(Madshus & Strömme, 1968).
faecal excretion and reduced the
whole body burden retention of
In 6 volunteers it was shown
caesium (IAEA, 1988). In 15 of
that Prussian blue (4 x 0.5 g or
these patients the body burden of
10 x 0.2 g daily for 2-3 weeks) 137Cs was reduced by an average
did not fully block caesium
of 71% within 2 months of the
uptake from contaminated food exposure (Melo et al, 1994).
(Volf et al., 1987).
Comparing the elimination of
137
Both forms of Prussian blue
Cs from the bodies of 18 adults
were equally effective in
after varying regimens of Prussian
reducing radiocaesium
blue therapy, Lipsztein et al
absorption in 2 male volunteers (1991) found that overall the halfwho ingested meals labelled
life of 137Cs was reduced by 32%
134
with a tracer dose of Cs, 10
and higher dose rates of Prussian
minutes after ingestion of 1 g of blue gave a greater reduction.
Prussian blue (Dresow et al.,
1993).
Chernobyl incident
Fifteen students were exposed to
Animal studies
Administration of a single dose
of radiocaesium and
concomitant oral dosing of
Prussian blue resulted in
reduction of caesium-uptake
from the gastrointestinal tract
(Brenot & Rinaldi, 1967;
Dresow et al., 1990, 1993; Giese
& Hantzch, 1970; Nielsen et al.,
1988b; Nigrović, 1963;
Nigrović, 1965).
The biological half-life was
reduced (Madshus et al., 1966;
Nigrović et al., 1966; Havliček
et al., 1967; Havliček, 1968;
Müller et al., 1974; Richmond,
1968; Strömme, 1968).
The reduced whole-body
retention of caesium after
treatment with Prussian blue was
seen in individual organs:
muscle, bone, carcass, liver and
kidney (Bozorgzadéh, 1971;
Bozorgzadéh & Catsch, 1972;
Brenot & Rinaldi, 1967; Kostial
et al., 1983; Müller et al., 1974;
DRAFT for comment - not for distribution
Metal
Clinical trial data
In volunteer studies with 2 male
adults, the ingestion of Prussian
blue ten minutes before eating a
meal containing 134Cs reduced
the caesium absorption more
than the simultaneous administration of Prussian blue along
with the labelled test meal.
Administration of Prussian blue
prior to the meal reduced
absorption of the radiocaesium
to 3-10% of the ingested dose
whereas simultaneous ingestion
of Prussian blue and the test
meal only reduced absorption to
38-63% (Nielsen et al., 1991).
Case reports
Cs and Cs following the
Chernobyl accident. In 3
volunteers the biological half-life
of caesium ranged from 42 to 71
days. Insoluble Prussian blue was
given from day 114 to 145 postexposure and this was reported to
reduce the half-life of caesium
and enhance elimination (Tang et
al., 1988).
134
137
In volunteer studies involving
self-dosing by the study
authors, ingestion of Prussian
blue 180 days after ingestion of
137
Cs reduced the biological
half-life of caesium from the
pre-treatment values of 110 and
115 days to 40 days (Madshus
et al., 1966).
In five cases where Prussian
blue was given several months
after caesium ingestion the
2
Animal studies
Stather, 1972; Wolsieffer et al.,
1969).
In piglets soluble and insoluble
Prussian blue reduced the uptake
of 134Cs by more than 97%
(Nielsen et al., 1988b).
Prussian blue reduces the body
content of 137Cs fed chronically
to rats (Stather, 1972)
DRAFT for comment - not for distribution
Metal
Clinical trial data
biological half-life of caesium
was reduced on average to one
third of its original half-life
(Madshus & Strömme, 1968;
Strömme, 1968).
Non-radiocaesium
A 37-year-old male was given
oral 137Cs followed by Prussian
the biological half-life of
caesium was reduced from 140
days to approximately 50 days
(Richmond, 1968).
No controlled clinical trials
Rubidium
No human data
Thallium
No volunteer studies.
Bhardwaj et al, 2006 (thallium201) studied the effect of
Prussian blue in 2 patients
following 201Tl myocardial
scintigraphy. In patient-1 whole
body radioactivity was reduced
by 18 and 30% after 24 and 48
Case reports
Prussian blue therapy has been
reported to reduce the half-life of
non-radioactive caesium in two
separate case reports (Chan et al,
2009; Thurgar et al, 2009).
No Human data
A total of 30 published reports of
thallium poisoning treated with
Prussian blue were found,
involving 144 cases. These
reports varied in terms of amount
of detail provided on treatment. In
addition there were a number of
other variables that makes
comparison difficult. These
3
Animal studies
Prussian blue reduced the
biological half-time of retention
of Rubidium-86 in rats (Stather,
1972)
Concomitant oral administration
of thallium and of Prussian blue
in rats resulted in a lower uptake
of the metal and lower
concentrations found in organs
(Dvořák, 1969; Heydlauf, 1969;
Rauws, 1974).
Reduced retention and increased
DRAFT for comment - not for distribution
Metal
Clinical trial data
hours, respectively, of oral
Prussian blue therapy. Patient2 developed constipation and
did not pass any stools after
oral Prussian blue for 48 hours.
The whole body radiation
counts were similar to those
when Prussian blue was not
given but there was a
concentration of radioactivity in
the colon suggesting that the
radioactivity was unavailable
for resorption.
Van Kesteren, (1980)
retrospectively assessed the
efficacy of different therapies
used in conjunction with
Prussian blue for thallium
poisoning in 18 patients. Two
patients died, and for the other
16 mean half-life of thallium
was 3.0 ± 0.7 days whilst when
Prussian blue was combined
with forced diuresis this was
reduced to 2.0± 0.3 days
Kamerbeek et al, (1971) are
credited with the first use of
Prussian blue in thallium
Case reports
reports are tabulated below.
Animal studies
excretion of thallium by
Prussian blue results in a
decrease of the thallium content
There are single case reports:
in liver, kidney, skeleton, blood,
(Atsmon, 2000; Chandler 1990;
heart and muscles (Dvořák,
DeBacker, 1982; Fred & Accad,
1969; Günther, 1971; Heydlauf,
1997; Hologittas et al, 1980;
1969; Kravzov et al., 1993;
Malbrain et al; Niehues et al
Manninen et al., 1976; Rauws,
1995; Pau, 2000; Pedersen et al
1978; Richelmi, 1980; Rob-Smith, 1974; Rìos et al., 1991; Rìos &
Monroy-Noyola, 1992; Sabbioni
1987; Schwartz et al 1988;
et al., 1982).
Stevens 1978; Villa et al, 2009;
Vrij, 1995; Wainwright, 1988;
Rìos & Monroy-Noyola (1992)
demonstrated that Prussian blue
and multiple case reports:
increased LD50 of thallium by
(CDC, 2008; Diaz et al 1990;
Ghezzi et al, 1979; Kamerbeek et 31%.
al 1971; Meggs et al 1994; Moore
et al 1993; Pai, 1987; Pelclova et
Meggs et al (1997) found that
al 2009; Rangel-Guerra et al
Prussian blue decreased the
1990; Stevens, 1974; Van
mortality from thallium
Kesteren, 1980; Villanueva, 1990) poisoning in mice
The extent and source of thallium
exposure is often unknown,
diagnosis delayed and hence a
delay in starting Prussian blue
therapy. Therapy was started
within 24 hours in only 14 of the
above reports (see case summary
table below). In other cases there
4
In an evaluation of the effect of
Prussian blue in thallium-fed
rats Lehman & Favari (1985)
observed that whilst the control
group eliminated only 53% of
the administered thallium dose
over the study period, the rats
that received Prussian blue
DRAFT for comment - not for distribution
Metal
Clinical trial data
poisoning, demonstrating an
approximately 7-fold increase
in faecal elimination with its
use.
Case reports
were varying delays: Villa et al,
(2009) - 42 days; CDC, (2008) - 8
days; Atsmon, (2000) -10-11
weeks; Pau, (2000) - 6 weeks;
Vrij, (1995)> 4 months; Chandler
A reduction in thallium half-life (1990) - 35 days; Villanueva,
(1990) > 2 weeks; Wainwright,
was observed in thallium
(1988) approx. 5 days; Pai, (1987)
poisoned patients when
compared with no therapy at all - 4 to 7 days; Rob-Smith, (1987) 5 days.
(De Groot & van Heijst, 1988)
Dosing patterns for Prussian blue
varied from case to case (amount
given and duration of treatment)
as did use of concomitant therapy.
From the limited case studies
Prussian blue appears to be well
tolerated and reported to be
effective in enhancing the
excretion of thallium.
Constipation is reported in earlier
case studies (Wainwright, 1988;
Richelmi, 1980), less so in later
cases however many have given
mannitol along with the Prussian
blue.
5
Animal studies
eliminated 82% of the dose.
Kamerbeek, (Kamerbeek, 1971;
Kamerbeek et al., 1971) showed
that after four days of Prussian
blue therapy the concentration of
thallium in the brain of the
treated groups was less than half
that of the control group. The
muscle thallium concentration in
the treated group was almost
one-fourth of that of the control
and a dose dependent
relationship was determined.
(Günther, 1971) demonstrated
that soluble Prussian blue
increased excretion of thallium
in rats and reduced the LD50
however only if started within
24 hours of exposure.
DRAFT for comment - not for distribution
Table 4: Summarized case reports of thallium poisoning (NB - please complete the table where there are "?" if you have access to the full papers)
Author
No cases
Amount thallium
Thallium level on
presentation
Villa et al
2009
1
NK
Urine: 5118 µg/g
creatinine
Atsmon et al
2000
Pau, 2000
1
NK
Renal excretion
7mg/24 hours
Urine at 35d: 8.56
µmol/L (NR =
0.003 µmol/L)
Vrij et al 1995
Malbrain et al
1997
1
1
1
NK
8.75g thallium
sulphate
Blood at 42d: 0.15
µmol/L (NR <0.07
µmol/L)
Urine (24 hr): 4300
µg/L
(NR <10 µg/L)
Blood: 300 µg/L
(NR <10 µg/L)
Urine: 69,600 µg/L
Interval
between
onset of
illness and
treatment
42 days
Form of PB
Dosing
regimen
Insoluble
>9 days
?
6g tds
(18g/day) for
24 d, second
course for 31d
250 mg/kg/d
~42 days
Colloidal
soluble
4g every 8
hours
(12g/day)
Activated charcoal,
Succimer,
Neurological
sequelae
Persistent
weakness
~128 days
Colloidal
soluble
250 mg/kg per
day for 14
days
Mannitol, cisapride,
forced diuresis
Neurological
sequelae
2 hours
Colloidal
soluble
3g then 0.5g
6xday
(3g/day) for
20 days
Emesis & gastric lavage
Mannitol, lactulose
Potassium,
haemodialysis
Neurological
sequelae
35 days
Colloidal
soluble
Plasma exchange, i.v.
potassium,
Neurological
sequelae
3 days
Colloidal
5g every 6 hrs
(20g/day) for
2 mths
5g every 6 hrs
Mannitol, forced
Neurological
Blood: 5,240 µg/L
Chandler
1990
1
NK
Wainwright et
1
NK
Urine: 6000 µg/L
6
Other treatments
Outcome
Died (final Tl
level 3 µg/g
creatinine
mannitol
DRAFT for comment - not for distribution
Author
No cases
Amount thallium
Thallium level on
presentation
Interval
between
onset of
illness and
treatment
al 1988
Form of PB
Dosing
regimen
Other treatments
Outcome
soluble
(20g/day)
diuresis, haemodialysis,
haemofiltration,
diethyldithiocarbamate
NK, for 3
weeks
250mg/kg
(per day?)
Potassium
sequelae
(estimated faecal
excretion of Tl
2g over 20d; by
forced diuresis
820mg; by
dialysis 225mg)
Neurological
sequelae
Recovered
Blood 5750 µg/L
Robb-Smith
1987
De Backer et
al 1982
1 (21 mth
child)
1
Richelmi et al
1980
1
Fred & Accad
1997
Hologgitas et
al 180
Niehues et al
1995
NK
?
>10 days
?
100 mg thallium
sulphate
Blood: 415 µg/L
6 hours
Colloidal
soluble
1 g thallium sulphate
Urine: 3000 µg/L
4 days
Colloidal
soluble
1
?
Gastric aspirate:
10800 µg/L
?
?
?
5g every 6
hours
(20g/day) for
20 days
?
1
?
?
?
?
?
1 (2
admissions)
NK
Urine: 9000 µg/L
2nd adm.: 3700 µg/L
0.5 hours
NK
?
0.5 mg (sic
/day for 6
days
Same dose
Nogue et al
1
750 mg thallium
Blood: 950 µg/L
>1.5 days
7
Not stated
1g 8 hourly
Gastric lavage,
combined
haemoperfusionhaemodialysis for 4 hrs
Mannitol
Recovered
?
?
Kayexelate (sodium
polystyrene)
Gastric
decontamination
Haemodialysis
died
2nd adm: aemodialysis,
forced diuresis (1 l
urine/h), orthograde
intestinal infusions,
potassium
Mannitol
DRAFT for comment - not for distribution
Author
No cases
CDC 2008
De Groot et al
1985
Díaz et al
1990
Other treatments
(30g/day)
days 1-4 and
16-19
Forced diuresis with
potassium
Haemodialysis
IV and oral Diethyl
dithiocarbamate
Oral
Diphenylthiocarbazone
(dithizone)
?
?
?
?
?
Forced diuresis
haemodialysis
?
?
?
?
?
?
?
recovered
Blood: 289 µg/L
(median); range 53 1408 µg/L
11 days
Insoluble
(AntidotumThallii-Heyl &
Radiogardase)
250 mg/kg/d
<48 hrs
Not stated
10g twice per
day
Thallium level on
presentation
sulphate
(approx)
1
2g
?
?
1
?
?
1
?
10 (5
children)
NK
1982
Pedersen et al
1978
Schwartz et al
1988
Stevens 1978
Dosing
regimen
Amount thallium
Interval
between
onset of
illness and
treatment
Case 1
NK
Urine (24hr): 3063
µg/L (median);
range 542 - 12556
µg/L
Blood 2800 µg/L
Case 2
Case 3
Case 1
NK
NK
NK
Blood 5800 µg/L
Blood 1900 µg/L
Urine: 11400 µg/L
5 days
Case 2
NK
Urine: 6300 µg/L
12 days
8
Form of PB
Not stated
12 days
Not stated
Outcome
2 children died
before treatment;
2 adults died
(already
comatose before
treatment started)
Gastric lavage
Mannitol
Forced diuresis
Haemoperfusion
Magnesium sulphate,
potassium, furosemide,
Potassium
Diuretics
Recovered
Recovered
Recovered
Recovered
Recovered
DRAFT for comment - not for distribution
Author
Villanueva et
al 1990
Van der
Merwe 1972
Pai 1987
Form of PB
Urine: 3500 µg/L
Interval
between
onset of
illness and
treatment
7 days
15 mg
Urine: 3090 µg/L
15 days
Not stated
Not stated
4 (2
children)
NK
10yr old: 18400
µg/L
>14 days
?
250mg/kg 6
hourly
Recovery
1 adult
NK
2400 µg/L
250 mg/kg/d
Recovery
Case 1
700 mg thallium
sulphate
12 hrs
?
250 mg/kg/d
(4 x
3.75g/day) for
13 days
Case 2
700 mg thallium
sulphate
>6 hours
?
4-7 days
Colloidal
soluble
250
mg/kg/day in
4 doses for 10
days
2g every 8 hrs
(6g/day) for 6
weeks
No cases
Amount thallium
Thallium level on
presentation
Case 3
NK
Case 4
14
Case 1
Case 2
NK
Urine 2200 µg/mL
(sic)
Blood 16 µg/mL
(sic)
Urine 48 µg/mL
9
Dosing
regimen
Other treatments
Outcome
Not stated
Magnesium sulphate,
potassium, furosemide,
Potassium
Diuretics
Recovered
Activated charcoal
Mannitol
Potassium
Multivitamins
High fluid intake
Gastric lavage
Mannitol
High fluid intake
Magnesium sulphate,
analgesia, diuretics,
vitamin B complex
Recovered
Note: 6000µg/L
thallium level at
45 days after
intoxication. No
new ingestion of
thallium
reported.
Recovered?
Recovered?
5 died before
treatment
9 recovered
DRAFT for comment - not for distribution
Author
No cases
Amount thallium
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Van Kesteren
et al 1980
18 (details
below):
A
B
C
D
E
500 mg
2.4 g
350 mg
1g
1g
Thallium level on
presentation
(sic)
Blood 4 µg/mL (sic)
Urine 250 µg/mL
(sic)
Blood 4 µg/mL (sic)
Urine 250 µg/mL
(sic)
Blood 4 µg/mL (sic)
Urine 660 µg/mL
(sic)
Blood 6 µg/mL (sic)
Urine 1100 µg/mL
(sic)
Blood 11 µg/mL
(sic)
Urine 37 µg/mL
(sic)
Blood 5 µg/mL (sic)
Urine 87 µg/mL
(sic)
Blood 6 µg/mL (sic)
Urine 23 µg/mL
(sic)
Blood 4 µg/mL (sic)
Urine concentration
(mg/L)
2.1
47.4
8.8
20.2
71.1
Interval
between
onset of
illness and
treatment
28 days
2 days
1 day
4 days
2 days
10
Form of PB
Dosing
regimen
Colloidal
soluble
10g twice per
day (20g/day)
Other treatments
Outcome
Gastric lavage
Gastric lavage
Died
Gastric lavage
DRAFT for comment - not for distribution
Author
Stevens et al
1974
No cases
Amount thallium
Thallium level on
presentation
F
G
H
480 mg
unknown
1g
1.0
2.0
84.0
Interval
between
onset of
illness and
treatment
½ day
2 days
1 days
I
J
K
L
1g
unknown
750 mg
875 mg
40.0
3.0
24.6
54.0
2 hours
?
4 days
1 day
M
N
1.5 g
1.5 g
79.8
80.0
14 days
1 day
O
P
Q
unknown
unknown
unknown
8.0
10.0
2.2
?
?
2 days
R
3g
50.0
1
Case 1
NK
Urine 1430 µg/L
30 days
Case 2
1000mg
Not stated
Few hours
Case 3
NK
Urine: 7100 µg/L
42 days
11
Form of PB
Dosing
regimen
Other treatments
Gastric lavage
Gastric lavage
Gastric lavage
Outcome
Survived but
died 6hrs after
second overdose
with thallium
Gastric lavage
Not stated
10g twice per
day every 2
days. Duration
not stated
10g twice per
day every 2
days for 11
days
20g per day
Forced diuresis
Gastric lavage, Forced
diuresis
Forced diuresis
Gastric lavage
Forced diuresis,
haemoperfusion
Forced diuresis
Forced diuresis
Gastric lavage
Forced diuresis
Gastric lavage
Forced diuresis,
haemoperfusion
Activated charcoal
Potassium
Gastric lavage
Recovered with
some muscular
weakness at 3
mth
Recovered
Neurological
DRAFT for comment - not for distribution
Author
Ghezzi &
Bozza
Marrubini,
1979
Kamerbeek et
Form of PB
Dosing
regimen
No cases
Amount thallium
Thallium level on
presentation
Interval
between
onset of
illness and
treatment
Case 4
300 mg
Urine elimination
3220 µg/24 hrs
10 hours
Case 5
NK
Urine elimination
120 µg/24 hrs
94 days
Case 6
NK
Urine 570 µg/L
28 days
Case 7
NK
Urine 232 µg/L
2nd admission: urine
230 µg/L
62 days
Case 8
NK
Not stated
151 days
Case 9
300 mg
Urine elimination
2310 µg/24 hrs
2 hours
Case
10
(child 6yrs)
225 mg
Urine elimination
840 µg/24 hrs
9 days
Case
11
(child 2yrs)
5
(1
neonate)
NK
1 day
?
Urine elimination
180 µg/24 hrs
?
?
?
5g four times
per day for 45
days
5g four times
per day for 25
days
1g four times
per day for 35
days
1.7g four
times
?
Case 1
400 mg
Not stated
Not stated
Colloidal
?
12
for 15 days
5g four times
per day for 19
days
5g four times
per day.
Duration not
stated
5g four times
per day for
>50 days
5g four times
per day for 18
days
Other treatments
Gastric lavage
mannitol
Outcome
sequelae
Recovered
mannitol
Neurological
sequelae
mannitol
Recovered
mannitol
Recovered
Mannitol,
Potassium, antibiotics
Recovered
Gastric lavage
Potassium
Recovered
mannitol
Recovered
Lactulose, furosemide
Recovered
Dithizone (1 patient)
Died
4 recovered
?
?
DRAFT for comment - not for distribution
Author
No cases
Amount thallium
Thallium level on
presentation
Interval
between
onset of
illness and
treatment
Case 2
400 mg
Not stated
Not stated
Case 3
2000 mg
Not stated
14 days
Meggs et al
1994
4
NK
Urine: 10837 µg/L
and 9569 µg/L
2 days
Moore et al
1993
Pelclova et al
2009
2
NK
>28 days
Case 1
NK
Blood: 600 µg/L
(approx)
Urine: 8.5 µg/L
Blood 0.3 µg/L
Case 2
NK
50
NK
Case 1
NK
Urine: 420 µg/L
4 weeks
Case 2
(neonate
from Case
1)
NK placental exposure
Urine: 60 µg/L
14 days
al 1971
RangelGuerra et al
1990
Urine: 2800 µg/L
Blood: 770 µg/L
Ranges:
Urine 100 - 28000
µg/L
Blood: 100 - 1360
µg/L
NK - had
probably be
poisoned
several times
over 2 years
4
weeks
approx
Not stated
13
Form of PB
soluble?
Colloidal
soluble?
Colloidal
soluble?
?
Dosing
regimen
Other treatments
Outcome
2g tds
(6g/day)
Multiple dose activated
charcoal,
haemodialysis,
analgesia
Recovered
Colloidal
soluble
Insoluble
250 mg/kg/d
sequelae
6g per day for
5 days
Neurological
sequelae
Insoluble
6g per day for
21 days
3g/day for 1014 days
Neurological
sequelae
1 death
Colloidal
soluble?
Colloidal
soluble?
Colloidal
soluble?
3 g/day?
Not stated
Gastric lavage
Forced diuresis
3 patients also received
sodium iodide,
5 patients also received
potassium iodide
Forced diuresis,
painkillers
Not stated
Recovered
Neurological
sequelae
DRAFT for comment - not for distribution
Author
No cases
Amount thallium
Thallium level on
presentation
Case 45
NK
Urine: 950 µg/L
Interval
between
onset of
illness and
treatment
2 months
14
Form of PB
Dosing
regimen
Other treatments
Outcome
Insoluble
3 g/day?
Not stated
Neurological
sequelae