ipcs evaluation of antidotes for poisoning by …56 (faustino, 2008). work in the 1960s investigated...

DRAFT for comment - not for distribution

1

1 2

3

IPCS EVALUATION OF ANTIDOTES FOR POISONING BY 4

METALS AND METALLOIDS 5

6

7

8

PRUSSIAN BLUE 9

10

Potassium ferric (III) hexacyanoferrate (II) (colloidal soluble Prussian Blue, 11 KFe[Fe(CN)6) and ferric (III) hexacyanoferrate (II) (insoluble Prussian Blue, Fe4 12 [Fe(CN)6]3) 13 14 15 16 17 Initial draft (1994): 18 A.N.P. van Heijst (National Poisons Control Centre, Utrecht, The Netherlands), A. von Dijk 19 (Apotheek, Academisch Ziekenhuis, Utrecht, The Netherlands) & J. Ruprecht (Heyl 20 Pharmaceuticals, Berlin, Germany) 21 22 Update (2009): 23 M McParland and P Dargan (Medical Toxicology Information Services, Guy's & St Thomas' 24 NHS Foundation Trust, London, UK) 25 26 27 28 29 30 31


2

32

1. Introduction .................................................................................................................. 3 33 2. Name and Chemical Formula of Antidote.................................................................... 3 34 3. Physico-chemical Properties ........................................................................................ 4 35 4. Synthesis and Pharmaceutical Formulation ................................................................. 5 36 5. Analytical Methods ...................................................................................................... 7 37 6. Shelf-life ....................................................................................................................... 9 38 7. General Properties ........................................................................................................ 9 39 8. In Vitro Studies .......................................................................................................... 11 40 9. Animal Studies ........................................................................................................... 12 41 10. Volunteer Studies ....................................................................................................... 21 42 11. Clinical Studies – Clinical Trials ............................................................................... 23 43 12. Clinical Studies - Case Reports .................................................................................. 23 44 13. Summary of Evaluation.............................................................................................. 36 45 14. Model Information Sheet............................................................................................ 40 46 15. References .................................................................................................................. 42 47 16. Author(s) Name, Address........................................................................................... 51 48 17. Additional Information............................................................................................... 51 49

Results of Cochrane Library Search 4th November 2009 ................................................... 52 50 Table 3: Summary of evidence of use of Prussian blue in metal poisoning ......................... 1 51 Table 4: Summarized case reports of thallium poisoning..................................................... 6 52


3

1. Introduction 53

54 Prussian blue was first prepared in 1704 and used principally as an inorganic pigment 55 (Faustino, 2008). Work in the 1960s investigated the use of Prussian blue as an antidote for 56 thallium poisoning and a decorporation agent for radiocaesium (caesium-134 and caesium-57 137). From the 1970s Prussian blue was recommended as an antidote in thallium 58 intoxication and it is now routinely used for this purpose. Further studies into its use for 59 increasing the elimination rate of radiocaesium were undertaken following the Chernobyl 60 nuclear reactor accident in 1986 but it was only after Goiânia incident in 1987 that it was 61 used in the management of a large scale radiation accident (Faustino, 2008). 62 63 There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian 64 blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue). It 65 is essential to be specific about which form of Prussian blue has been used in future 66 publications. The different forms should be identified by citing the correct chemical name 67 and/or chemical formula and/or the physical nature (insoluble or colloidal soluble). 68 69 Prussian blue is given orally and acts via ion exchange, adsorption and mechanical trapping 70 to bind thallium and caesium within its crystal lattice, interrupting their enterohepatic 71 circulation, enhancing faecal elimination and reducing body burden. 72 73 Insoluble Prussian blue is used to treat patients with known or suspected internal 74 contamination with radioactive caesium, radioactive thallium and non-radioactive thallium, 75 to increase their rates of elimination. Prussian blue can reduce the biological half-life of 76 radiocaesium by about a third. There is one report where Prussian blue has been used for the 77 treatment of non radioactive caesium toxicity (Thurgur et al., 2006) and rubidium has also 78 been shown to bind to Prussian blue (Hoffman, 2006). 79 80 Prussian blue is well tolerated but can result in constipation. It is essential to treat 81 constipation as it will decrease elimination of thallium and caesium and some authors advise 82 administration of Prussian Blue with laxatives to prevent constipation. 83 84 85

2. Name and Chemical Formula of Antidote 86

87 There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian 88 blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue). 89 Synonyms which apply to both compounds include Berlin blue, Milori Blue, Chinese blue, 90 Hamburg blue, mineral blue, Pigment blue 27 and Paris blue. 91 92

Potassium ferric (III) hexacyanoferrate (II)

Ferric (III) hexacyanoferrate (II)

Synonyms colloidal soluble Prussian blue, SPB, potassium ferric ferrocyanide,

insoluble Prussian blue, IPB, ferric ferrocyanide, Iron (III) ferrocyanide, Ferrotsin, Ferrocin, Ferrihexacyanoferrate, ferric cyanoferrate (II)

Molecular formula KFe[Fe(CN)6] Fe4[Fe(CN)6]3 Molecular weight 306.9 859.3


4

Potassium ferric (III) hexacyanoferrate (II)

Ferric (III) hexacyanoferrate (II)

CAS Registry No 12240-15-2 14038-43-8 Colour Index No. 77520 77510 RTECS number LJ8200000 Structural diagram (ChemIDplus Lite)

93 94 95 96 Prussian blue is a non-stoichiometric compound and the chemical formulae for both forms 97 shown above are therefore idealized. Additionally all precipitates of insoluble Prussian blue 98 contain nonstoichiometric amounts of potassium, protons and water (Dvořák, 1971; Nielsen 99 et al., 1987; Nielsen et al, 1988b). The water is partially adsorbed at the large surface of this 100 pigment, partially distributed in the cavities of the crystal lattice (zeolithical water) and 101 partially coordinatively bound (Ludi, 1988). Colloidal soluble Prussian blue may 102 additionally contain nonstoichiometric amounts of cations (H+, alkali metal ions) and anions 103 (Cl-, OH) and water (Bozorgzadeh, 1971; Dvořák, 1970; Dvořák, 1971). 104 105 Insoluble Prussian blue is the only commercially available pharmaceutical preparation 106 however in the literature there is confusion over the two available forms of Prussian blue and 107 inconsistencies in the nomenclature of Prussian blue (Hoffman, 2006). For example, some 108 authors who used the commercially available Prussian blue Antidotum Thallii-Heyl® 109 containing insoluble ferric hexacyanoferrate have incorrectly described the chemical formula 110 as KFe[Fe(CN)6] (Franke et al., 1979) or named the compound as potassium ferric 111 ferrocyanide (Spoerke et al., 1986). In another report both formulae are used KFe[Fe(CN)6] 112 and Fe4[Fe(CN)6]3 for Antidotum Thallii-Heyl® (Trenkwalder et al., 1984). In other cases 113 the drug Antidotum Thallii-Heyl® is described as "colloidal soluble Prussian blue" (Jax et 114 al., 1973; Kemper, 1979; Gansser, 1982; Forth, 1986) or potassium ferric (III) 115 hexacyanoferrate (II) is described as insoluble (Lehmann & Favari, 1984). As a result it is 116 often very difficult or impossible to determine which form of Prussian blue was used. 117 118 Where possible, the two forms of Prussian blue are identified here as soluble Prussian blue 119 and insoluble Prussian blue. 120 121

3. Physico-chemical Properties 122

123


5

Melting point: Not available. 124 125 Solubility: Potassium ferric (III) hexacyanoferrate (II) is colloidally soluble in water, ferric 126

(III) hexacyanoferrate (II) is insoluble in water and diluted acids (solubility product 127 =10-40, i.e. practically insoluble) (Ludi, 1988). 59Fe-labelled measurements resulted 128 in a solubility of 1.1 µmol/L for potassium ferric (III) hexacyanoferrate (II) and 0.7 129 µmol/L for ferric (III) hexacyanoferrate (II) (Dvořák, 1970). 130

131 Optical properties: Not available. 132 133 pH: Not available. 134 135 pKa: Not available. 136 137 Stability in light: Prussian blue should be stored in tightly closed containers protected from 138

light. 139 140 Thermal stability: Not available. 141 142 Refractive index: Not available. 143 144 Specific gravity: 1.8 145 146 Loss of weight on drying: Potassium ferric (III) hexacyanoferrate (II) 6-15% loss of weight 147

on drying at 150°C. Ferric (III) hexacyanoferrate (II) 28-34% loss of weight on 148 drying at 105°C. 149

150 Excipients and pharmaceutical aids: In both pharmaceutical preparations, Antidotum Thallii-151

Heyl® and Radiogardase®-Cs, ferric (III) hexacyanoferrate (II) is provided as 500mg 152 of Prussian blue powder in gelatine capsules with 0-38mg of microcrystalline 153 cellulose. The powder may vary in coarseness and colour shade (Heyl, 2004). 154

155 Pharmaceutical incompatibilities: None known. 156 157 Binding to some therapeutic drugs and essential nutrients is possible. Insoluble Prussian blue 158

may bind electrolytes in the gastrointestinal tract. Hypokalaemia (potassium 2.5-2.9) 159 was reported in 3 of 42 patients (7%) treated with insoluble Prussian blue (Heyl, 160 2004; Thompson & Callen, 2004; Thompson & Church, 2001). There are some 161 anecdotal reports of Prussian blue decreasing the bioavailability of oral tetracycline 162 and the serum levels and, or clinical response to critical orally administered products 163 should be monitored (Heyl, 2004). 164

165

4. Synthesis and Pharmaceutical Formulation 166

167 4.1 Routes of Synthesis 168 Both substances can be synthesized according to the method of Dvořák (1969). The basic 169 chemicals needed are the same for both substances. However, the salt ultimately formed will 170 depend on the ratio of the raw materials and the way in which they are added to each other. 171 172


6

FeCl3 + K4[Fe(CN)6] ------ > KFe[Fe(CN)6] + 3 KCl 173 174 4 FeCl3 + 3 K4[Fe(CN)6]----- > Fe4[Fe(CN)6]3 + 12 KC1 175 176 Raw materials: 177 Ferric chloride (FeCl3) and potassium ferrocyanide (K4[Fe(CN)6]) 178 179 Water suitable for injection or of comparable quality (i.e. water with cation and anion 180 concentrations equal or less than water for injection). 181 182 Synthesis: 183 (a) Basic solutions 184 185 Dissolve appropriate amounts of FeCl3 and K4[Fe(CN)6] in water so that the molar ratio of 186 the two solutions is 2.0. This means that when a 0.2 M ferric chloride solution has been 187 prepared, the molarity of the K4[Fe(CN)6] solution should be 0.1 M. 188 189 (b1) Potassium ferric (III) hexacyanoferrate (II) 190 191 It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6 ]4- in the reaction 192

mixture equals 0.33. When 1 litre of 0.2 M ferric chloride solution is used, then 193 (1000 x 0.2)/(0.33 x 0.1) 6060 ml of a 0.1 M (Fe(CN)6]4- solution is necessary. The 194 quantity of [Fe (CN)6]4- is added drop wise to the ferric chloride solution whilst 195 stirring vigorously. Centrifuge at 120000g after one hour standing. Wash the 196 precipitate three times with water and centrifuge after each washing step. Dry the 197 precipitate obtained after the last washing step at 105 oC until the weight remains 198 constant. 199

200 To remove possible low molecular impurities some authors have dialysed the 201

colloidal soluble Prussian blue exhaustively against water (Müller et al., 1974; 202 Nielsen et al., 1987; Nielsen et al., 1988a; Nielsen et al., 1988b). 203

204 (b2) Ferric (III) hexacyanoferrate (II) 205 206 It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6]4- in the reaction 207

mixture equals 1.33. When 1 litre of 0.2 M ferric chloride solution is used, then 208 (1000 x 0.2)/(1.33 x 0.1) 1504 ml of a 0.1 M [Fe(CN)6]4- solution is necessary. The 209 quantity of [Fe(CN)6]4- is added drop wise to the ferric chloride solution whilst 210 stirring vigorously. Filter standing for one hour. Wash the precipitate and filter 211 three times after each washing step. Dry the precipitate obtained after the last 212 washing step at 105 oC until weight remains constant. The drying process influences 213 the efficacy of the substance (Nigrović et al., 1966). The effectiveness of Radiogar-214 dase®-Cs in binding caesium was higher than that of the ferric (III) hexacyanoferrate 215 (II) synthesized by the authors (Nielsen et al., 1987). Among other things this can be 216 attributed to a special drying procedure. 217

218 After synthesis as described, and after one year's storage in tightly closed containers 219

at room temperature, neither substance showed any significant decomposition into 220 cyanide ion (Dvořák, 1970). The effectiveness of ferric (III) hexacyanoferrate (II) 221 was not decreased after storage during one year (Nigrović et al., 1966). 222


7

223 4.2 Manufacturing processes 224 Not known. 225 226 4.3 Presentation and formulation 227 Prussian blue is available as Radiogardase®-Cs (Radiogardase® in the United States of 228 America) and Antidotum Thallii-Heyl® distributed by Heyl Chemisch-pharmazeutische 229 Fabrik GmbH, Berlin, Germany. 230 231 Both products are available in bottles of 30 hard gelatine capsules, each containing 0.5 g of 232 insoluble Prussian blue. 233 234

5. Analytical Methods 235

236 5.1 Quality control procedures for the antidote and/or its formulation 237 238 5.1.1 Test for the presence of colloidal Prussian blue: 239 A mixture of 10 g insoluble Prussian blue and 50 ml of distilled water is shaken and filtered 240 using a membrane filter. The filtrate should show no blue colouration (absence of colloidal 241 soluble Prussian blue). 242 243 5.1.2 Test for the presence of insoluble Prussian blue: 244 Shake 100 mg of colloidal soluble Prussian blue with 20 ml of water. An intensely dark blue 245 solution is obtained. Precipitation should not occur before a standing time of two days has 246 passed (test to exclude the insoluble form). 247 248 5.1.3 Test for the presence of hexacyanoferrate (II) and hexacyanoferrate (III): 249 10 g Prussian blue and 50 ml distilled water are shaken and filtered using a membrane filter. 250 The filtrate is then mixed with the hydrochloric acid salt of ferrous ammonium sulphate 251 ((NH4)2Fe (II)(SO4)2) or ferric ammonium sulphate ((NH4)Fe (III)(SO4)2). The absence of 252 blue colour indicates that K3[Fe (III)(CN)6] is less than 5 ppm and K4[Fe (II)(CN)6] is less 253 than 20 ppm respectively. 254 255 5.1.4 Test for iron content: 256 500 mg Prussian blue in 50 ml water are shaken and filtered. Compared with an iron 257 standard solution the iron content should be not more than 100 ppm. 258 259 5.1.5 Test for heavy metal content: 260 After digestion of Prussian blue with concentrated sulphuric acid the heavy metal content 261 (measured as lead) should be less than 50 ppm. Arsenic content must be less than 5 µg/g. 262 263 5.1.6 Removal of oxalic acid: 264 Prussian blue may contain oxalic acid, originating from the manufacturing process. Shake 1 265 g of Prussian blue with 10 ml sodium acetate solution (Dutch Pharmacopoeia, 1966). 266 Centrifuge and filter the upper layer through a paper filter folded three times. Add to 5 ml 267 filtrate 1 ml of calcium acetate solution (Dutch Pharmacopoeia, 1966). No precipitate of 268 calcium oxalate should occur after 24 hours. Since no oxalic acid is used in the above speci-269 fied synthesis, quality control for this acid may be omitted provided that the raw materials do 270 not contain it. The commercially available pharmaceuticals Prussian blue in Antidotum 271


8

Thallii-Heyl® and Radiogardase®-Cs do not contain oxalic acid. 272 273 5.2 Methods for identification of the antidote 274 Detection of ferric (III) and hexacyanoferrate (II) ions: 500 mg of Prussian blue is heated in 275 5 ml of 3M potassium hydroxide resulting in decomposition to brown, flocculent ferric 276 hydroxide. After deposition the supernatant fluid appears yellow (K4[Fe(CN)6]). After fil-277 tration, 2 ml of the fluid is acidified with concentrated hydrochloric acid and mixed with a 278 FeCl3 solution and this will result in blue colouration or formation of a blue precipitate. 279 280 5.3 Methods for analysis of the antidote in biological samples 281 Not applicable. 282 283 N.B. It is often stated that Prussian blue is not absorbed to any significant extent however 284 anecdotal reports suggest prolonged therapy results in a blue discolouration of sweat and 285 tears suggesting some absorption. 286 287 5.4 Analysis of the toxic agents in biological samples 288 289 5.4.1 Analysis of thallium in urine, plasma and erythrocytes 290 Thallium can be measured by spectrophotometry, flame atomic absorption 291 spectrophotometry (AAS) and electrothermal atomic absorption spectrophotometry 292 (ETAAS) (Moffat et al, 2004). 293 294 5.4.1.1 Spectrophotometry 295 A spectrophotometric method was described by de Wolff and Lenstra (1964). It involves the 296 determination of thallium at 550nb using rhodamine 'B' or brilliant green and can be used on 297 urine and on blood diluted with water. The limit of quantification is approximately 50µg/L 298 (Moffat et al, 2004). This method is described in the Thallium Poisons Information 299 Monograph (IPCS, 1990). 300 301 Another spectrophotometric method is described by Flanagan et al (1995). In this method a 302 pink-red colour indicates the presence of thallium at concentrations of 1mg/l or more. A 303 calibration graph of absorbance against thallium concentration in standard samples can be 304 used to measure the thallium concentration more precisely. The limit of sensitivity is 0.1 305 mg/L. 306 307 5.4.1.2 Atomic Absorption Spectrophotometry 308 Flame AAS can be used to measure thallium in plasma, blood or urine by extracting it as a 309 pyrrolidine dithiocarbamate complex in an organic solvent (de Groot et al, 1985). The lowest 310 quantifiable concentration is at least 0.2 mg/l and depends on the atomic absorption 311 spectrophotometer used. Linearity is up to 5 mg/l. Higher concentrations can be measured 312 by diluting the sample under investigation with blank sample. This method is described in 313 the Thallium Poisons Information Monograph (IPCS, 1990). 314 315 ETAAS has been used for monitoring occupational exposure and has a limit of detection of 316 less than 1 µg/L (Moffat et al, 2004). 317 318 319 5.4.2 Analysis of caesium in biological samples 320 Caesium-134 and caesium-137 decay by emitting beta particles and these nuclides are 321


9

detected using gamma spectrometry. 322 323 Specialist advice is essential for dose assessment following a radiation accident as this assists in 324 determining appropriate management and the expected clinical course. Radioactivity 325 measurements of the wound (if applicable), skin or chest (following inhalation), nasal swabs, 326 urine and faeces are also used to assess dose. In many cases the victim is not wearing a 327 dosimeter (and this only measures external exposure not the internal dose). In addition the 328 standard models for calculating intake from routine occupational exposures may not be 329 applicable and individual-specific models may have to be developed and applied for internal 330 dose calculations (Toohey, 2003). 331 332 A quantitative baseline of the internal contamination of radiocaesium should be obtained by 333 appropriate whole body counting and/or by bioassay, or faeces/urine sample whenever 334 possible to obtain the following type of information to establish an elimination curve: 335

• Estimated internalised radiation contamination of caesium, and 336 • Rate of measured elimination of radiation in the faeces (Heyl, 2004). 337

338 339

6. Shelf-life 340

341 The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C; 342 occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004). 343 For the pharmaceutical preparations Antidotum Thallii-Heyl® and Radiogardase®-Cs the 344 shelf-life is given as five years. 345 346

7. General Properties 347

348 Orally administered Prussian blue binds thallium or caesium in the gut and increases the 349 concentration gradient, enhancing elimination by gut dialysis. Thallium (Forth & Henning, 350 1979) and caesium (Nigrović, 1965) also undergo enterohepatic circulation and Prussian 351 blue interrupts their reabsorption from the gastrointestinal tract thereby increasing faecal 352 excretion. Prussian blue therefore reduces the biological half-life of caesium and thallium. 353 354 The mechanism of caesium and thallium adsorption by hexacyanoferrates is believed to 355 involve chemical ion exchange whereby nonstoichiometric and stoichiometric cations of the 356 drug are exchanged by thallium or caesium ions. The affinity of Prussian blue increases as 357 the ionic radius of the cation increases, so Prussian blue preferentially binds caesium (ionic 358 radius 0.169 nm) and thallium (0.147 nm) over potassium (0.133 nm) and sodium (0.116 359 nm) (Forth, 1983; Nielsen et al., 1987). An influence of Prussian blue on potassium and 360 sodium levels is therefore not expected (Nigrović et al., 1966). Rubidium (ionic radius 361 0.148) has also been shown to bind to Prussian blue (Hoffman, 2006). 362 363 Evidence is provided by a number of experimental studies. After binding of thallium to 364 colloidal soluble and insoluble Prussian blue, the content of potassium and hydrogen ions 365 was reduced (Dvořák, 1970). 40K labelled colloidal Prussian blue showed no radioactivity 366 after mixing with thallium. The pH value was decreased, indicating release of H+ ions 367 (Dvořák, 1971). In in vitro experiments insoluble Prussian blue bound more caesium than 368 potassium, and hydrogen and iron ions were released. 369


10

370 There may be other mechanisms in addition to ion exchange. Nielsen et al. (1987) found that 371 colloidal soluble Prussian blue released more potassium than it adsorbed caesium, 372 suggesting that an additional, physical adsorption on its large surface, possibly interacting 373 with water, may be involved (Ludi, 1983; Richmond, 1968). Yang et al (2008) found that 374 the binding capacity of insoluble Prussian blue for thallium decreased as the water content of 375 Prussian blue was decreased. Forms of Prussian blue with a smaller crystal size, and 376 therefore a larger surface area, have a higher adsorptive capacity and antidotal efficacy for 377 thallium (Kravzov et al., 1993; Yang et al, 2008). 378 379 Non-dialyzed colloidal soluble Prussian blue initially proved to combine with thallium much 380 more effectively than ferric (III) hexacyanoferrate (II) in vitro as well as in vivo (Dvořák, 381 1969; Dvořák, 1970; Kamerbeek et al., 1971). This greater binding was not only the result 382 of the larger surface area of the colloidal soluble preparations (Dvořák, 1970), but also 383 because of the larger amount of extra-stoichiometric potassium in these preparations 384 (Dvořák, 1971). The sodium salt-derived preparation did not meet these requirements 385 (Rauws et al., 1979), and subtle differences in the dimensions of the crystal lattice might also 386 play a role (Keggin & Miles, 1936; Kravzov et al, 1993). 387 388 Colloidal soluble Prussian blue may, however, present problems. The production of a 389 standard colloidal soluble Prussian blue was found to be difficult resulting in a different 390 toxicity of the different preparations (Dvořák et al., 1971). Long-term treatment of rats with 391 non-dialysed colloidal soluble Prussian blue resulted in actual caesium retention in the body 392 in treated rats compared to control animals (Bozorgzadéh & Catsch, 1972; Müller et al., 393 1974). Dresow et al., (1993) investigated the effect of soluble and insoluble Prussian blue in 394 rats, pigs and humans and concluded that for medical use in man, a separation of the low 395 molecular weight compounds from crude commercial preparations is recommended. 396 397 Following the introduction of colloidal potassium ferric (III) hexacyanoferrate (II) as an 398 antidote for thallium poisoning in 1970 (Kamerbeek, 1971; Kamerbeek et al., 1971), the 399 results of treatment with potassium ferric (III) hexacyanoferrate (II) as well as with ferric 400 (III) hexacyanoferrate (II) in patients with severe thallium poisoning published in the 401 literature have been associated with a favourable outcome, particularly when it is used early. 402 Treatment with Prussian blue in patients with thallotoxicosis can be life-saving but it does 403 not improve all the clinical signs, such as neurological signs or alopecia, particularly in late-404 presenting patients. 405 406 Thompson & Callen (2004) reviewed the English language literature concerning the efficacy 407 of soluble and insoluble Prussian blue and its use as a therapeutic agent in radiocaesium and 408 thallium poisoning. They noted that most of the evidence describing the efficacy of Prussian 409 blue for radiocaesium poisoning is based on the use of the insoluble form, whilst similar 410 evidence for thallium poisoning involves the use of the soluble form. They concluded that 411 while there is sufficient evidence that the insoluble form of Prussian blue is effective in 412 radiocaesium poisoning, there is a lack of analogous data supporting its use in thallium 413 poisoning. The authors acknowledged that further research is needed to determine the 414 significance of any differences between the two forms of Prussian blue and whether their 415 physicochemical differences have any effect on outcomes in human poisoning is currently 416 unknown. However, the commercial products in current use are formulated with the 417 insoluble form of Prussian blue and most data collated from future use is likely to refer to 418 this form only. 419


11

420

8. In Vitro Studies 421

422 8.1 In vitro binding of caesium 423 Various in vitro studies have shown that Prussian blue binds caesium (Bozorgzadéh, 1971; 424 Nielsen et al., 1987; Verzijl et al., 1992; Faustino et al., 2008). 425 426 In vitro binding of caesium to insoluble Prussian blue is affected by pH, exposure time, 427 storage temperature (affecting moisture content) and particle size. The lowest caesium 428 binding was at pH 1.0 and 2.0 and the highest at pH 7.5. Dry storage conditions results in 429 loss of moisture from Prussian blue which causes a negative effect on caesium binding 430 capacity. There is batch to batch variation in particle size and variation in binding capacity. 431 At 1, 4 and 24 hours it was determined that caesium binding increases as particle size 432 decreases. The maximum caesium binding capacity of insoluble Prussian blue was 433 approximately 715 mg/g (Faustino et al., 2008). 434 435 In a study comparing the binding capacity of soluble and insoluble Prussian blue, the 436 binding of caesium-137 was greater with insoluble Prussian blue (Radiogardase®-Cs) and 437 was pH-dependent for both formulations. The maximum binding capacities for insoluble 438 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 439 soluble Prussian blue the maximum binding capacities were 48 at pH 1.0, 73 mg/g at pH 6.5, 440 and 78 mg/g at pH 7.5 (Verzijl et al., 1992). 441 442 Nielsen et al. (1987) investigated caesium binding by various hexacyanoferrate compounds 443 (iron, copper, cobalt, nickel, zinc, manganese) at pH 1.2 and 6.8. All the compounds bound 444 caesium; potassium copper hexacyanoferrate (II) and potassium zinc hexacyanoferrate (II) 445 were the most efficient at pH 1.2 and 6.8. These compounds had twice the binding capacity 446 of soluble and insoluble Prussian blue. These authors also demonstrated that whey 447 contaminated with caesium-134 and caesium-137 was almost completely decontaminated by 448 dialysing a whey suspension against a buffer solution containing insoluble Prussian blue. 449 The whey had been produced from the milk of South German cows contaminated in the 450 summer of 1986 following the Chernobyl accident. 451 452 8.2 In vitro binding of thallium 453 In vitro studies have demonstrated that thallium binds to both soluble (Dvořák, 1970; 454 Kamerbeek et al., 1971; Krazov et al., 1993) and insoluble Prussian blue (Dvořák, 1970; 455 Yang et al., 2008). The adsorption is rapid: after 10 minutes all thallium was bound (Dvořák 456 et al., 1971). The effectiveness of soluble Prussian blue (as measured by mg of thallium/mg 457 Prussian blue or % adsorbed) was higher than that of insoluble Prussian blue (Dvořák, 1970; 458 Kamerbeek et al., 1971). In vitro, thallium binds more strongly to Prussian blue than to 459 activated charcoal (Kamerbeek et al., 1971). 460 461 As with caesium, the thallium binding capacity of Prussian blue is affected by pH, exposure 462 time, storage temperature (affecting moisture content) and particle size. The adsorption of 463 thallium on Prussian blue depended on the pH-value of the solution and a maximal 464 adsorption could be detected at a neutral or slightly alkaline pH (Dvořák, 1970). In the in 465 vitro study by Yang et al. (2008) the maximum thallium binding capacity of insoluble 466 Prussian blue was approximately 1400 mg/g at pH 7.5 after 24 hours. The lowest binding 467 occurred at pH 1.0 at 1 hour and thereafter, binding increased as pH increased (determined 468


12

up to pH 7.5). The binding constant was higher for fully hydrated Prussian blue compared to 469 Prussian blue which had been dried for 24 hours and the smaller the particle size the higher 470 the binding constant. 471 472 An in vitro study examined the adsorption of thallium-201 by insoluble Prussian blue to 473 investigate the use of Prussian blue in reducing the radiation burden in thallium-201 474 myocardial scintigraphy. The maximum adsorption peaked at approximately 30 minutes 475 irrespective of the concentration (1, 10 or 100 mg or Prussian blue in 5 mL of water). It 476 reached a plateau at 30 to 60 minutes with no further increase in adsorption of thallium until 477 4 hours. The rate of absorption was constant for up to 1 hour but slowed down thereafter. 478 Thallium-201 removal increased from 46 to 95% when the pH was increased from 2.0 to 8.0. 479 In the most favourable conditions the maximal adsorption capacity was 5000 MBq of 480 thallium-201/g of Prussian blue and maximal adsorption occurred at 30 minutes (Bhardwaj 481 et al., 2006). 482 483 484

9. Animal Studies 485

486 9.1 Pharmacodynamics 487 488 9.1.1 Caesium 489 A number of animal studies have examined the impact of Prussian blue on the absorption of 490 caesium, its effect on the enhancement of excretion (or reduced retention) of caesium and 491 the impact of these actions on final outcomes. 492 493 9.1.1.1 Prevention of absorption/uptake from gut 494 Administration of a single dose of radiocaesium and concomitant oral dosing of Prussian 495 blue resulted in reduction of caesium uptake from the gastrointestinal tract (Brenot & 496 Rinaldi, 1967; Dresow et al., 1990, 1993; Giese & Hantzch, 1970; Nielsen et al., 1988b; 497 Nigrović, 1963; Nigrović, 1965). In piglets potassium ferric (III) hexacyanoferrate (II) and 498 ferric (III) hexacyanoferrate (II) reduced the caesium-134 uptake by more than 97%. The 499 diminution of the caesium-134 body burden depended on the dose of administered 500 hexacyanoferrate (II). The difference between the colloidal and insoluble Prussian blue 501 compounds in decreasing enteral absorption of caesium-134 was small (Nielsen et al., 502 1988b). 503 504 If Prussian blue was given as late as 60 minutes after caesium-137 administration the enteral 505 caesium-137 absorption was also suppressed (Nigrović, 1963). Autoradiography of rats 506 showed, that the radioactivity was limited to the gastrointestinal-tract (Brenot & Rinaldi, 507 1967). 508 509 In rats administered a composite treatment mixture containing calcium alginate, potassium 510 iodide and insoluble Prussian blue in their diet and exposed to various radionucleotides, the 511 Prussian blue, even as a component of the mixture, decreased the absorption of caesium into 512 the organism and reduced the whole-body retention (Kargacin & Kostial, 1985; Kostial et 513 al., 1980; Kostial et al., 1981; Kostial et al., 1983). 514 515 In a study in pigs the animals (82 kg) were fed twice daily with pellet food and 500 mL of 516 milk together with 200 g of radiocaesium-contaminated whey powder. Prior to each feeding 517


13

the pigs were given 0.5g, 1.5g or 2.5 g of soluble Prussian blue, insoluble Prussian blue or 518 ammonium iron hexacyanoferrate (II) (NH4Fe[Fe(CN)6]) in gelatine capsules. The animals 519 were slaughtered after 27 days of feeding. All compounds were found to be effective at 520 reducing caesium-134 and caesium-137 absorption. Administration of increasing quantities 521 of the compounds resulted in a dose-dependent reduction in the radioactivity of the tissues 522 tested. Soluble Prussian blue and ammonium iron hexacyanoferrate were most effective, 523 possibly due to more favourable distribution of colloidal soluble compounds in the 524 gastrointestinal tract (Dresow et al., 1993). Similarly, soluble Prussian blue and ammonium 525 iron hexacyanoferrate were most effective in rats (260 to 280 g) given 0.5 mg of Prussian 526 blue in water 2 minutes before 0.5 mL of water containing a tracer dose of caesium-134, by 527 gastric tube. There was almost complete blockade of radiocaesium absorption as judged by 528 urinary excretion and whole body retention measured 7 days after ingestion. Insoluble 529 Prussian blue was less effective (Dresow et al., 1993). 530 531 9.1.1.2 Enhancement of decorporation (reduced retention) 532 Chronic feeding of rats (Dresow et al., 1993; Stather, 1972) or piglets (Dresow et al., 1993; 533 Giese et al., 1970) with caesium-137 contaminated food and concomitantly administration of 534 Prussian blue resulted in reduced whole body retention. Most of the daily caesium-137 dose 535 was excreted in the faeces. 536 537 After ingestion of radiocaesium, administration of insoluble Prussian blue (Bozorgzadéh & 538 Catsch, 1972; Dresow et al., 1990; Nigrović, 1963; Nigrović, 1965; Nigrović et al., 1966; 539 Stather, 1972;) and colloidal soluble Prussian blue (Bozorgzadeh, 1971; Bozorgzadéh & 540 Catsch, 1972; Dresow et al., 1990; Giese et al., 1970; Müller et al., 1974) decreased the 541 whole-body-retention of the caesium isotopes. Also in a mixture with other substances 542 Prussian blue increased the excretion of the caesium-137 (Kostial et al., 1983). In rats the 543 effect on the whole-body retention was age-dependent. In younger animals the whole body 544 retention was lower than in older animals. Probably because of the higher basal metabolic 545 rate more caesium was excreted into the gut in young animals (Bozorgzadeh, 1971; Stather, 546 1972). 547 548 Prussian blue increased the cumulative excretion of incorporated radiocaesium in faeces and 549 urine (Brenot & Rinaldi, 1967; Nigrović, 1965; Nigrović et al., 1966). Whereas in untreated 550 animals most caesium is excreted in the urine, in animals treated with Prussian blue faecal 551 excretion predominates (Nigrović et al., 1966; Brenot & Rinaldi, 1967; Müller, 1969; Giese 552 et al., 1970; Giese & Hantzsch, 1970; Richmond, 1968). The biological half-life was 553 reduced (Madshus et al., 1966; Nigrović et al., 1966; Havliček et al., 1967; Havliček, 1968; 554 Müller et al., 1974; Richmond, 1968; Strömme, 1968). In rats the half-life was reduced by 555 50% (11 days compared to 6 days) (Nigrović et al., 1966; Müller et al., 1974), and in dogs 556 from 11 to 6.5 days (Madshus et al., 1966). 557 558 Colloidal soluble Prussian blue was more efficient in increasing the excretion of 559 radiocaesium than the insoluble form (Müller, 1969). In long-term use however, colloidal 560 soluble Prussian blue decreased the excretion compared with control animals. Insoluble 561 Prussian blue did not show this effect (Bozorgzadéh & Catsch, 1972). After thorough 562 dialysis with water to remove any possible low molecular impurities this effect of the 563 colloidal Prussian blue disappeared (Müller et al., 1974). The efficacy of the dialyzed 564 colloidal soluble Prussian blue, however, was only marginally better than that of insoluble 565 Prussian blue (biological half-lives: control 10.51 days, insoluble Prussian blue 5.6 days, 566 colloidal Prussian blue 4.88 days) (Müller et al., 1974). 567


14

568 The efficacy of therapy with Prussian blue is time-dependent. The best effect resulted in 569 administration of Prussian blue 2 minutes before application of caesium (Dresow et al., 570 1990). Start of treatment immediately after intoxication was also successful (Bozorgzadéh, 571 1971; Bozorgzadéh & Catsch, 1972), but it was still effective after a delayed start of 3.5 572 days (Stather, 1972). 573 574 The reduced whole-body retention of caesium after treatment with Prussian blue can also be 575 seen in individual organs. This reduced caesium content of the different organs has been 576 reported in muscle (Bozorgzadéh, 1971; Bozorgzadéh & Catsch, 1972; Brenot & Rinaldi, 577 1967; Kostial et al., 1983; Müller et al., 1974; Stather, 1972; Wolsieffer et al., 1969), bone 578 (Bozorgzadéh & Catsch, 1972; Müller et al., 1974; Wolsieffer et al. 1969), carcass (Kostial 579 et al., 1983; Wolsieffer et al. 1969), liver (Bozorgzadéh, 1971; Müller et al., 1974; Stather, 580 1972) and kidney (Bozorgzadéh, 1971; Bozorgzadéh & Catsch, 1972; Brenot & Rinaldi, 581 1967; Kostial et al., 1983; Müller et al., 1974; Stather, 1972). Due to a different turnover 582 rate of the organs the rate of diminution of caesium in the different organs varied. In the 583 gastrointestinal-tract the caesium content was increased due to binding on the non-resorbable 584 Prussian blue (Brenot & Rinaldi, 1967). 585 586 After 15 days of dietary acclimatization to insoluble Prussian blue as 1% of their food, rats 587 were given intraperitoneal casesium-137. The animals were killed 30 days later. There was 588 significant reduction in the retention of caesium-137 in the carcass, femur and muscle 589 (Wolsieffer et al., 1969). 590 591 Oral insoluble Prussian blue was given to rats in drinking water (400 mg/kg/day) for 11 days 592 which was started immediately after an intravenous injection with caesium-137. On 593 evaluation at 11 days Prussian blue had increased the faecal excretion of caesium-137 5-fold 594 and this consequently also reduced urine excretion. There was also reduced retention of Cs-595 137 in all the tissues tested (blood, liver, kidneys, spleen and skeleton) (Le Gall et al., 2006). 596 597 Oral administration of insoluble Prussian blue shortened the retention of caesium-137 in 598 mated, pregnant and lactating rats and the deposition of caesium-137 in the embryos and 599 nursed young animals was reduced (Havliček, 1967; Havliček, 1968). 600 601 The effect of Prussian blue provided in drinking water to rats of various ages, on the 602 excretion of intraperitoneally administered caesium-137 was investigated. In 19-week old 603 rats the body burden of caesium-137 was reduced to 34% of the controls 1 week after 604 injection whilst in 9-week and 4-week old rats, the corresponding values were 28% and 9% 605 respectively. Tissue analysis suggested that the rate limiting factor of excretion of caesium-606 137 during Prussian blue therapy was the turnover rate of caesium-137 in muscle tissue. The 607 turnover rate of caesium-137 in muscle tissues of young animals is faster than that of older 608 animals and this is reflected in an increased efficacy of Prussian blue in removing caesium-609 137 from the younger animals (Stather, 1972). 610 611 9.1.1.3 Impact on outcomes 612 Richmond & Bunde, (1966) investigated the effect of three different concentrations of 613 Prussian blue on caesium-137 contaminated rats. Each rat (approximately 92 days old with 614 and average bodyweight of 372g) received approximately 0.84 microcurie of caesium-137, 615 the rats were then measured 30 minutes later for total body activity and then returned to their 616 respective cages. Insoluble Prussian blue was incorporated into their drinking water which 617


15

they had free access to over the following 60 days. The concentrations of Prussian blue in 618 the water were 0, 0.025, 0.25 and 2.5 g/L, and the estimated daily dose of Prussian blue was 619 0, 0.9, 8.5 and 84 mg/rat, respectively. There was significant reduction in the whole body 620 retention of caesium-137 with continuous ingestion of Prussian blue at 0.25 and 2.5 g/L, but 621 no effect was observed at 0.025 g/L. Retention of caesium was described in 3 exponential 622 terms and the third component had a half-life of 8.77 days in high-dose Prussian blue rats 623 compared to 14 days in control rats. The authors concluded that the rate of caesium-137 624 secretion would depend partially on the turnover rate in body tissues, particularly muscle, 625 which accounts for a large proportion of the total body caesium-137 activity. 626 627 The effect of Prussian blue was studied in sheep fed wheat and grass contaminated with 628 caesium after the Chernobyl accident. The lactating sheep (average 35 kg) were given 0.5 629 kg of wheat (average radiocaesium content 1684 ± 17 Bq/kg) and 200 g (9840 ± 442 Bq/kg) 630 daily. The average milk yield was 110 g per day. When the radiocaesium content of the 631 milk had reached a state of equilibrium half the animals were given colloidal Prussian blue, 632 5 g in 5 L of drinking water for 23 days. The colloidal Prussian blue settled in the container 633 and the drinking water had to be stirred repeatedly during the day and it took about 2 days 634 before the sheep became used to the water. Treatment with Prussian blue reduced the 635 radiocaesium content of the milk by approximately 85% and the effect was seen within a few 636 days of the start of treatment (Ioannides et al., 1991). 637 638 The role of Prussian blue in removing caesium-137 internal contamination from rats was 639 studied to evaluate the possible side effects caused by chronic consumption on various 640 biomarkers for exposure. Rats of two age groups (growing rats (2-months old) and adult rats 641 (4month old)), were observed over a 60 day period having had either caesium-137 alone, 642 Prussian blue alone, or a combination of both, administered at different time intervals (e.g. 643 both given simultaneously or with a time lapse between). The authors reported that in both 644 growing and adult rats Prussian blue administration, particularly when given before or 645 immediately after Caesium-137 intake, could eliminate the effects of caesium-137 646 irradiation on red blood cell count and haemoglobin content, and on serum levels of: total 647 proteins (in adult rats only), globulins (in adult rats only), creatinine, urea, urea nitrogen, 648 ALT activity, T3, and T4. When given one or seven days post caesium-137 irradiation, 649 Prussian blue eliminated the effects of caesium-137 treatment on serum cholesterol, serum 650 calcium and serum bilirubin, in both growing and adult rats (Fekry et al., 2003). 651 652 The efficacy of insoluble and colloidal soluble Prussian blue in removing a single dose of 653 internally deposited caesium-134 was compared in rats (6 rats in each experimental group). 654 Prussian blue was administered twice daily and treatment started immediately after injection 655 of caesium-134. For the first few days the colloidal form initially showed greater efficacy in 656 removing the caesium but with continuous administration it brought about a complete 657 blockage of caesium-134 excretion from the liver, spleen and skeleton. This was attributed 658 to in vivo disintegration of the colloidal compound yielding free [Fe(CN)6]4- which when 659 absorbed from the gut reacts with endogenous metal ions. The authors highlight the practical 660 clinical consequences of this finding in that the insoluble compound should be the antidote 661 of choice for caesium-134 toxicity; the slight transient superiority of the colloidal form is 662 over-shadowed by its untoward long-term effect (Bozorgzadéh & Catsch, 1972). 663 664 9.1.2 Rubidium 665 There is limited information on the decorporation effect of Prussian blue in rubidium 666 exposure. Rats were fed insoluble Prussian blue in their food (as 5%) from 2 days before an 667


16

intraperitoneal injection of rubidium-86. Prussian blue reduced the half-life of rubidium-86 668 from 10.3 days to 1.7 days, reducing the whole body retention to 9% that of controls after 7 669 days (Stather, 1972). 670 671 9.1.3 Thallium 672 673 9.1.3.1 Prevention of absorption/uptake from gut 674 Concomitant oral administration of thallium and of Prussian blue in rats resulted in a lower 675 uptake of the metal and lower concentrations found in organs (Dvořák, 1969; Heydlauf, 676 1969; Rauws, 1974). Soluble Prussian blue was more effective than the insoluble Prussian 677 blue (Dvořák, 1969). 678 679 In a study by Heydlauf (1969) aqueous solutions of thallium-204 sulphate were administered 680 to rats by gastric tube. Aqueous suspensions of ferric cyanoferrate (II) (insoluble Prussian 681 blue) in doses of 0.5-50 g were then administered by gastric tube 1 to 60 minutes later. The 682 maximal protective effect, i.e. approximately ten times lower absorption of thallium-204, 683 was observed when Prussian blue was given immediately, although an effect was still seen 684 when Prussian blue was administered at 60 minutes. As expected, there was a marked 685 dependence of antidotal efficacy on the dose of Prussian blue administered. 686 687 9.1.3.2 Enhancement of decorporation (reduced retention) 688 It was also shown that insoluble Prussian blue was able to remove thallium across the 689 gastrointestinal wall. Carrier-free thallium-204 was injected intravenously and the animals 690 fed with Prussian blue pellets at will (Heydlauf, 1969). The thallium-204 content of 691 Prussian blue treated animals was drastically reduced even when treatment was initiated on 692 the fourth day. This was due to markedly enhanced faecal excretion whereas urinary 693 elimination did not reach the control level. 694 695 Insoluble Prussian blue (Heydlauf, 1969) as well as colloidal soluble Prussian blue (Dvořák, 696 1969; Günther, 1971) reduced the retention of thallium in the body. The excretion in the 697 faeces was increased and decreased in the urine when compared to the control animals 698 (Heydlauf, 1969; Lehmann & Favari, 1985; Leloux et al. 1990; Manninen et al., 1976; 699 Rauws, 1974; van der Stock & de Schepper, 1978). The cumulative excretion in faeces and 700 urine was increased (Heydlauf, 1969; Lehmann & Favari, 1985; Rauws, 1974). The bio-701 logical half-life of thallium in the body was reduced. In dogs the biological half-life was 702 decreased from 6.5 days (measured in control animals) to 2.5 days (animals treated with 703 Prussian blue) (van der Stock & de Schepper, 1978), in rats it was decreased from 4 days to 704 2 days (Rauws, 1974). 705 706 A study in rats demonstrated that soluble Prussian blue increased excretion of thallium and 707 reduced the LD50 but only if started within 24 hours of exposure. Thereafter thallium-708 induced pathological changes were irreversible (Günther, 1971). 709 710 The reduced retention and the increased excretion of thallium by Prussian blue results in a 711 decrease of the thallium content in liver (Dvořák, 1969; Günther, 1971; Heydlauf, 1969; 712 Kravzov et al., 1993; Manninen et al., 1976; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 713 1982), kidney (Dvořák, 1969; Günther, 1971; Heydlauf, 1969; Kravzov et al., 1993; 714 Manninen et al., 1976; Rauws, 1974; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 1982), 715 skeleton (Heydlauf, 1969) blood (Rìos et al., 1991), heart (Kravzov et al., 1993; Rìos & 716 Monroy-Noyola, 1992) and muscles (Dvořák, 1969; Günther, 1971; Heydlauf, 1969; 717


17

Manninen et al, 1976; Rauws, 1974). 718 719 9.1.3.3 Impact on outcomes 720 Kamerbeek et al. (Kamerbeek, 1971; Kamerbeek et al., 1971) showed the influence of 721 Prussian blue on the concentration of thallium in the brain. Thirty-five rats, divided into 722 seven groups of five animals, were given 0.075 mM/kg thallous nitrate in 5% glucose 723 solution by intraperitoneal injection. After 24 hours, one group was sacrificed. Three of the 724 remaining groups were subsequently treated with 50 mg Prussian blue suspended in saline, 725 twice daily by gavage. The other groups served as controls. At 48, 72 and 120 hours after 726 administration of thallium, one control and one treated group were killed. The thallium 727 concentration was determined in the brain and in a muscle specimen (quadriceps). After 728 four days of Prussian blue therapy the concentration of thallium in the brain of the treated 729 groups was less than half that of the control group. The muscle thallium concentration in the 730 treated group was almost one-fourth of that of the control group. A dose-dependent 731 relationship was observed. Also in other experiments reduced thallium levels in the brain 732 were measured (Kravzov et al., 1993; Leloux et al., 1990; Manninen et al., 1976; Rauws. 733 1974; Rìos et al., 1991; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 1982). 734 735 Trying to establish an optimal dosage scheme for use of Prussian blue in human 736 thallotoxicosis, Kamerbeek (1971) gave five groups of five rats 0.1 mm/kg thallous nitrate 737 intraperitoneally. After 24 hours four groups were treated by gavage once daily with 10, 50, 738 250 and 1000 mg/kg Prussian blue, suspended in 15% mannitol. After four days of 739 treatment, the animals were sacrificed and the thallium concentrations were determined in 740 the brain and in a muscle specimen. A daily dose of 250 mg/kg Prussian blue appeared to be 741 as effective as 1000 mg/kg/day with respect to thallium-concentration in muscle specimen 742 but with respect to thallium in the brain the highest dosage was more efficacious. 743 744 Kamerbeek (1971) further investigated the protection afforded by Prussian blue against 745 thallium toxicity. Two groups of rats were given 0.25 mg/kg thallous nitrate intraperi-746 toneally. Four hours later one group received Prussian blue 100 mg/kg in a 15% mannitol 747 solution by gavage. The other group received mannitol only. This regimen was repeated for 748 10 days. In the control group, 10 of 20 animals died, while in the treated group only two 749 deaths occurred. 750 751 It was further shown that enhanced thallium-204 excretion as a result of Prussian blue 752 therapy was accompanied by reduced thallium toxicity (Kravzov et al., 1993; Rìos et al., 753 1991; Rìos & Monroy-Noyola 1992). Treatment with potassium ferric hexacyanoferrate (II) 754 (colloidal soluble Prussian blue) increased the LD50 by a factor 2.3 (Günther, 1971). After 755 application of 30 mg thallium/kg the survival in the control group was 0% and in the 756 Prussian blue group 50% (Heydlauf, 1969). 757 758 After intraperitoneal injection of thallium (32 mg/kg) on day 1, a group of 16 rats was given 759 soluble Prussian blue (50 mg/kg orally twice daily), D-penicillamine (intraperitoneal 760 injection 25 mg/kg) or a combination of the two from days 2 to 5. The mortality in the 761 different treatment groups by day 6 was: control group 87.5%, Prussian blue group 56.25%, 762 D-penicillamine group 100% and Prussian blue + D-penicillamine group 25%. Only the 763 combination of antidotes produced a significant difference in mortality compared to controls. 764 Prussian blue alone protected against thallium-induced neurotoxicity (as measured by the 765 number of altered Purkinje cells) but the effect was greater with combined Prussian blue + 766 D-penicillamine. D-penicillamine alone did not protect against thallium-induced changes in 767


18

Purkinje cells (Barroso-Moguel et al, 1994). 768 769 9.2 Pharmacokinetics 770 771 9.2.1 Oral 772 There is limited information on the pharmacokinetics of Prussian blue as these compounds 773 are very poorly absorbed from the gastrointestinal tract. Most studies have been performed 774 with iron-59 or carbon-14 labelled Prussian blue examining intestinal absorption and 775 bioavailability of iron and cyanide (see section 9.4 for studies on assessment of cyanide 776 toxicity). 777 778 The release of iron from potassium ferric (III) hexacyanoferrate (II) and ferric (III) 779 hexacyanoferrate (II) was examined in piglets. The compounds were labelled with iron-59 780 in the ferric or ferrous position. When labelled in the ferric position only 1.47% of the iron 781 was absorbed from potassium ferric (III) hexacyanoferrate (II) and 1.34% from ferric (III) 782 hexacyanoferrate (II), as determined by the whole-body retention 14 days after oral dosing. 783 Only 0.2% and 0.15%, respectively, of the iron was absorbed from the ferrous position. 784 Most of the dose was excreted in the faeces; 0.1 to1% of the iron-59 was in the urine but it 785 could not be determine how much of may have been due to faecal contamination (Nielsen et 786 al., 1988a). This study suggests that iron is not significantly absorbed from Prussian blue. 787 788 Administration of labelled (59Fe, 14C) Prussian blue to rats resulted whole-body retention of 789 0.03% of the dose (only in the gastrointestinal tract) and in traces of radioactivity in the 790 urine (0.15%). The amount in blood and skeleton was below the detection limit. After 791 administration of iron-59 labelled potassium ferric (III) hexacyanoferrate (II) 792 (K59Fe[Fe(CN)6]) to rats traces of radioactivity were found in the skeleton (0.11% of the 793 administered dose) and in blood (0.046%). Again, with radio-labelled iron in the ferric and 794 ferrous positions, the differences in distribution showed that Prussian blue is not absorbed, 795 but the different ions K+, Fe3+ and [Fe(CN)6]4- are metabolized instead. No evidence was 796 obtained for decomposition of [Fe(CN)6]4- (Dvořák et al., 1971). Histopathological 797 examination of organs showed no deposits of Prussian blue after oral administration of 798 insoluble and colloidal soluble Prussian blue (Giese & Hantzsch, 1970). 799 800 9.2.2 Parenteral 801 After intraperitoneal administration of radio-labelled colloidal soluble Prussian blue the 802 substance is eliminated by the reticuloendothelial system. On the first day 40.5% of the 803 radioactivity was excreted in the urine, the content in the faeces was very small. On the 804 second day 42% was found in the faeces with only traces in the urine. After 4 days the body 805 retention was 4.5%, mostly in the liver (Müller, 1969). 806 807 Intravenous administration of KFe[59Fe(CN)6] and K59Fe[Fe(CN)6] resulted in entirely 808 different metabolic behaviour in rats between the two forms. With potassium ferric (III) 809 hexacyanoferrate (II) labelled in the ferrous position (KFe[59Fe(CN)6]) more than 50% of the 810 radioactivity was excreted in the urine, by contrast when labelled in the ferric position 811 (K59Fe[Fe(CN)6]) only 0.06%. The faecal excretion was low for both. The distribution of 812 the radioactivity into the organs after administration of KFe[59Fe(CN)6] differed from that of 813 K59Fe[Fe(CN)6]. Whereas the radioactivity of KFe[59Fe(CN)6] persisted in the liver for 8 814 days, the activity of K59Fe[Fe(CN)6] varied from the liver to the blood (Dvořák et al., 1971). 815 816 9.3 Toxicology 817


19

818 9.3.1 Acute toxicity 819 Ferric (III) hexacyanoferrate (II) 820 Oral: 821 According to a Soviet study, 8g/kg body weight was not lethal to laboratory animals 822 (presumed to be rats or mice) and produced no clinical signs of toxicity (BIBRA, 1997) 823 824 Intraperitoneal administration: 825 LD50 rat: 1.13 mg/g body weight (Brenot & Rinaldi, 1967). 826 LD50 rat: 2.1g/kg body weight (BIBRA, 1997). 827 LD50 mouse: 2 g/kg body weight (BIBRA, 1997). 828 829 Rats or mice given lethal doses suffered inertia, breathlessness and sluggishness with excess 830 blood in the liver, spleen and kidney (BIBRA, 1997). 831 832 833 Potassium ferric (III) hexacyanoferrate (II) 834 In studies by Dvořák et al. (1971) the lethality of intravenous injection of 1 mg of colloidal 835 soluble Prussian blue in rats varied from 0% to 100%, despite the same manufacturing 836 processes. Some animals became unwell within 15 minutes and developed respiratory 837 distress. A blue colouration was noted in the lungs at post-mortem examination. This 838 variation in toxicity was thought to be due to differences in the degree of dispersion of the 839 Prussian blue in the solution of each batch. 840 841 842 Pigment blue 27 843 Oral LD50 rat: >5g/kg body weight (BIBRA, 1997). 844 845 846 847 9.3.2 Chronic toxicity 848 In rats colloidal soluble Prussian blue given as 2% of drinking water for 12 weeks resulted in 849 no significant body weight changes or histopathological changes in the organs, including the 850 gut (Dvořák et al., 1971). Similarly, sheep (average weight 35 kg) given colloidal soluble 851 Prussian blue, 5 g in 5 L of drinking water daily for 23 days had no change in body weight 852 (Ioannides et al., 1991). 853 854 There were no significant differences in average fluid intake in rats given insoluble Prussian 855 blue in drinking water (0.025, 0.25 or 2.5 g/L) for 60 days. The estimated daily dose of 856 Prussian blue was 0.9, 8.5 and 84 mg/rat, respectively (equating to 2.4, 23, 226 mg/kg) 857 (Richmond & Bunde, 1966). 858 859 Oral insoluble Prussian blue caused no adverse effects and no impairment of growth in 860 young rats when given as 1% of the diet for 120 days (Nigrović et al., 1966) or as 1% of 861 their food for 60 days in rats (Wolsieffer et al., 1969). Also in rats, food consumption and 862 body weight were unchanged during 9 days of treatment with a mixture of sodium alginate 863 (daily consumption 2 g), insoluble Prussian blue (250 mg) and sodium perchlorate (100 mg) 864 (Kostial et al., 1980) or during 4 weeks treatment with a mixture of calcium alginate 865 (average 4.8 g/day), insoluble Prussian blue (average 0.8 g/day) and potassium iodide 866 (0.0048 g/day) (Kostial et al., 1981). 867


20

868 There were no adverse effects in dogs (7 to 8 kg) given oral insoluble Prussian blue (3 or 6 869 doses of 0.5 g daily) for 11 days. The doses equate to approximately 200 and 400 mg/kg, 870 respectively (Madshus et al., 1966). At autopsy no pathological changes were observed 871 (Nigrović et al., 1966). 872 873 9.3.3 Reproductive toxicology and teratogenicity 874 There is no information available on the reproductive toxicity of Prussian blue. 875 876 In pregnant rats intoxicated with oral thallium soluble Prussian blue started 8 hours later 877 increased the survival rate, reduced the thallium content of the placenta by 5-fold and in the 878 foetuses reduced the thallium content of the brain and liver (Sabbioni et al., 1982). 879 880 9.3.4 Genotoxicity 881 No information available. 882 883 9.4 Assessment of possible cyanide toxicity 884 Prussian blue contains cyanide ions bound to iron. At extremely low pH values in the 885 presence of oxidizing agents Prussian blue decomposes and, under these circumstances, 886 cyanide can be released. Since oral administration of Prussian blue is indicated in the 887 treatment of thallium poisoning and caesium incorporation, various studies have examined 888 the possibility of cyanide release from these hexacyanoferrate compounds. 889 890 When gastric juice (pH 2) and soluble Prussian blue were incubated for 4 hours no cyanide 891 was detected. Similarly no cyanide was detected when the study was conducted with 0.1 N 892 hydrochloric acid at room temperature. Cyanide was only detected when this last 893 experiment was repeated at 100 °C (Kamerbeek, 1971). Other in vitro studies have also 894 shown that the release of cyanide is negligible (Dvořák, 1970). 895 896 Verzijl et al. (1993) studied in vitro cyanide release of four Prussian blue salts, potassium 897 ferric (III) hexacyanoferrate (II), ferric (III) hexacyanoferrate (II) and ammonium ferric (III) 898 hexacyanoferrate (II), both unpurified and purified compounds (that is, with and without 899 33% ammonium chloride as a manufacturing impurity). These salts were added to water, 900 artificial gastric (pH 1.2) or intestinal (pH 6.8) juices and the content flasks were allowed to 901 stand for 5 hours, protected from light, at 370C. Cyanide was detected in all tests and the 902 quantity released ranged from 22 to 535 µg/g of Prussian blue in water, 64 to 418 µg/g in 903 artificial gastric juice and 15 to 58 µg/g in artificial intestinal juice. For all salts tested the 904 release of cyanide was greatest in artificial gastric juice than the other test media. The 905 unpurified ammonium ferric (III) hexacyanoferrate (II) released the most cyanide and ferric 906 (III) hexacyanoferrate (II) (insoluble Prussian blue) the least in all test media. 907 908 In an in vitro study the release of cyanide from insoluble Prussian blue was measured over a 909 pH range of 1.0 to 12 following incubation for 1 to 48 hours in a shaking water bath at 370C 910 (Yang et al., 2007). Five batches of active pharmaceutical ingredients were tested and three 911 batches of drug product. The release of cyanide was both pH-dependent and incubation-time 912 dependent. The greatest release occurred at pH 1.0 with a gradual decline as the pH 913 increased to 7.0. At this pH the lowest quantity of cyanide was released and as the pH 914 increased again the cyanide concentration also increased. Increasing the incubation time at 915 different pH also increased the amount of cyanide released. The highest cyanide 916 concentration occurred when Prussian blue was incubated at pH 1.0 for 48 hours. The 917


21

authors concluded that, based on a dose of 17.5 g of Prussian blue per day, a total of 1.5-1.6 918 mg of cyanide would be released, which was well below the minimum toxic dose of cyanide 919 of 14.4 mg. 920 921 The release of cyanide from potassium ferric (III) hexacyanoferrate (II) and ferric (III) 922 hexacyanoferrate (II) was examined in piglets. The compounds were labelled with carbon-923 14 in the cyanide group. No carbon-14 dioxide was detected in expired air after ferric (III) 924 hexacyanoferrate (II), indicating that the quantity of cyanide released is very small or nil 925 (Nielsen et al., 1988a). 926 927 928

10. Volunteer Studies 929

930 10.1 Pharmacokinetics 931 There is very little published pharmacokinetic data on Prussian blue in humans. 932 933 10.1.1 Release of iron and cyanide from Prussian blue 934 Three volunteers (all male, 36 years, 81 kg; 38 years, 81 kg; 45 years, 70 kg) were given 935 radio-labelled soluble Prussian blue (500 mg) to determine the release of iron and cyanide in 936 humans in vivo. The compound was labelled with iron-59 in the ferric or ferrous position 937 and carbon-14 in the cyanide group. Only 0.22% of iron (II) and <0.04% of iron (III) was 938 absorbed. Only 2 mg of non-complex bound carbon-14 labelled cyanide was absorbed. This 939 is a factor of 20 to 100 below the lethal dose of 0.5 to 3.5 mg cyanide/kg in humans (Nielsen 940 et al., 1990a). 941 942 10.2 Caesium 943 944 10.2.1 Studies on absorption 945 In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of 946 caesium the studies involved self-dosing by the study authors. These authors (to include 8 947 observations, 5 volunteers undertook the study once and one author repeated the experiment 948 twice) showed that 3 g daily of Prussian blue given before caesium-137 did not reduce 949 caesium absorption. The increase in caesium-137 excretion was small following 0.5 g of 950 Prussian blue three times daily (Madshus & Strömme, 1968). 951 952 In 6 volunteers a preliminary study showed that insoluble Prussian blue (4 x 0.5 g or 10 x 953 0.2 g daily for 2 to 3 weeks) did not fully block caesium uptake from contaminated food 954 (Volf et al., 1987). 955 956 Two male volunteers (age 36 and 38 years, both 81 kg) ingested three single test meals 957 consisting of 170 g of milk labelled with a tracer dose of caesium-134 along with bread, 958 margarine and cheese 10 minutes after ingestion of 1 g of Prussian blue in gelatine capsules. 959 Both forms of Prussian blue were equally effective in reducing radiocaesium absorption. 960 The absorption of radiocaesium from the meal judged by urinary excretion of caesium-134 961 and whole body retention 14 days after administration was reduced from 100.9% (control 962 without Prussian blue) to 5.6% by soluble Prussian blue and to 6.4% by insoluble Prussian 963 blue (Dresow et al., 1993). In a similar study in two male adult volunteers, the ingestion of 964 Prussian blue ten minutes before eating a test meal containing caesium-134 labelled milk 965 (along with bread, margarine and cheese) reduced the caesium absorption more than the 966


22

simultaneous administration of Prussian blue along with the labelled test meal. 967 Administration of Prussian blue prior to the meal reduced absorption of the radiocaesium to 968 3-10% of the ingested dose whereas simultaneous ingestion of Prussian blue and the test 969 meal only reduced absorption to 38-63%. The 100% control was the absorption rate of the 970 radiocaesium test meal alone without Prussian blue (Nielsen et al., 1991). 971 972 10.2.2 Studies on decorporation/excretion 973 In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of 974 caesium the studies involved self-dosing by the study authors. Studying the decorporation 975 of caesium involved ingestion of Prussian blue (3 g daily as 2 or 3 doses for several weeks) 976 in 2 adult males given 180 days after ingestion of caesium-137 and it was found to reduce 977 the biological half-life of caesium from the pre-treatment values of 110 and 115 days to 40 978 days. The only adverse effect was mild constipation (Madshus et al., 1966). 979 980 In five cases when Prussian blue (1g three times daily) was given several months after 981 caesium ingestion the biological half-life of caesium was reduced on average from 94 to 31 982 days, that is, to one third of its original half-life (Madshus & Strömme, 1968; Strömme, 983 1968). 984 985 A 37-year-old male was given oral caesium-137 for 24 days followed by 2 g of insoluble 986 Prussian blue (as 10 x 200 mg daily over a 9 hours period) from day 12 to day 17 then after a 987 rest period of 2 days was given Prussian blue for another 5 days. The biological half-life of 988 the caesium was reduced from 140 days to approximately 50 days. There was no 989 constipation and no change in whole-body potassium values (Richmond, 1968). 990 991 Fifteen Chinese exchange students in Bulgaria were exposed to caesium-134 and 137 992 released following the accident at the Chernobyl Nuclear Power Station in April 1986, and 993 following their return to China in June they were assessed for contamination. In three 994 volunteers the biological half-life of caesium ranged from 42 to 71 days. Insoluble Prussian 995 blue (1 g three times daily for 6 days repeated for 3 courses with a 6 day rest period in 996 between) was given from day 114 to 145 after exposure. This reduced the half-life of 997 caesium and enhanced elimination (Tang et al., 1988). 998 999 10.3 Rubidium exposure 1000 There are no volunteer studies on the effect of Prussian blue in rubidium exposure. 1001 1002 10.4 Thallium poisoning 1003 There are no volunteer studies on the effect of Prussian blue in thallium exposure. 1004 1005 Bhardwaj et al. (2006) studied the effect of insoluble Prussian blue on whole body 1006 radioactivity in two patients following thallium-201 myocardial scintigraphy. Each patient 1007 had two sessions of scintigraphy, one with and one without Prussian blue (100 mg 3 times 1008 daily after meals for 3 days), so each patient acted as their own control. In the first patient 1009 whole body radioactivity was reduced by 18 and 30% after 24 and 48 hours, respectively, of 1010 oral Prussian blue therapy. The second patient developed constipation and did not pass any 1011 stools after oral Prussian blue for 48 hours. The whole body radiation counts were similar to 1012 those when Prussian blue was not given but there was a concentration of radioactivity in the 1013 colon suggesting that the radioactivity was unavailable for resorption. 1014 1015 1016


23

11. Clinical Studies – Clinical Trials 1017

1018 There are no controlled clinical trials on the use of Prussian blue in human thallium poisoning or 1019 radiocaesium decorporation. 1020 1021 1022

12. Clinical Studies - Case Reports 1023

1024 12.1 Decorporation of radiocaesium 1025 1026 12.1.1 Goiânia incident, Brazil, 1987 1027 At the end of 1985 a private radiotherapy institute moved premises and left a caesium-137 1028 teletherapy unit behind. The building was partly demolished and in 1987 two men removed 1029 the source assembly head from the machine thinking it may have scrap value but without 1030 being aware of what it was. They took this home and tried to dismantle it during which they 1031 ruptured the source capsule. This contained caesium chloride which is highly soluble and 1032 easily dispersed. After the rupture the source capsule was sold for scrap to a junkyard 1033 dealer. He observed that the material glowed blue in the dark and over the next 5 days this 1034 was a source of interest to family and friends. During this time several individuals started to 1035 become unwell with gastrointestinal signs and eventually the source capsule was suspected 1036 and it was taken to the public health department. This triggered a major response to the 1037 incident. In total 112,000 people were assessed and 249 were found to contaminated either 1038 internally or externally with caesium-137. Some had very high exposure due to eating with 1039 contaminated hands or rubbing the glowing material over their body. Twenty patients 1040 developed bone marrow suppression. Eight developed acute radiation syndrome (Brandão-1041 Mello et al., 1991) and four of these victims died within 4 weeks of their admission to 1042 hospital (IAEA, 1988). Prussian blue (Radiogardase®-Cs) treatment was given to 46 1043 patients (aged 4 to 46 years) for up to 150 days. The adults were initially given 3 g daily and 1044 the 13 children were given 1 to 1.5 g daily. These doses were later increased to 10 g and 3 g 1045 daily, respectively, when it was established that larger doses resulted in higher radioactivity 1046 of faecal samples. In four cases 20 g of Prussian blue was given over 24 hours. Of 46 1047 patients, 10 developed mild to moderate constipation and this was managed with a high fibre 1048 diet or laxatives (Farina & Brandão-Mello, 1991). Prussian blue treatment significantly 1049 increased the rate of faecal caesium excretion and reduced whole body retention of caesium 1050 (IAEA, 1988). The physiological faeces to urine excretion ratio of caesium was 1:4 and this 1051 was changed to 4:1 with Prussian blue treatment (Farina & Brandão-Mello, 1991). In 15 1052 adult patients who received Prussian blue the body burden of caesium-137 was reduced by 1053 51% to 84% with an average of 71% within the first 2 months after exposure. This dose 1054 reduction was independent of the Prussian blue dose in the range of 3 to 10 g/day (Melo et 1055 al., 1994). 1056 1057 In vivo data from patients internally contaminated with caesium-137 in the Goiânia accident 1058 was analysed to compare the half-life of caesium-137 with and without Prussian blue 1059 treatment. Additionally the possible influences of various body parameters (age, height, 1060 weight and radioactivity) on the half-lives were evaluated. Subjects were monitored using a 1061 whole-body counter and the findings are from data collected for the period of one year post 1062 the accident. Patients under treatment had previously followed different Prussian blue dosing 1063 patterns but during the monitoring period received 3 g/day, 6 g/day or 10 g/day. Caesium-1064 137 elimination from the body followed first order kinetics with or without Prussian blue 1065


24

therapy. Without Prussian blue treatment the half lives of caesium-137 in the 10 adult 1066 females studied varied widely (range 39 to 104 days; mean: 65.5 days) with less variation 1067 seen in the 8 adult males (66 to 106 days; mean: 83 days). Overall Prussian blue reduced the 1068 half-life of caesium-137 by about 32%. The actual calculations showed that for those 1069 subjects receiving 3 g/day of Prussian blue the mean reduction was 28%, it was 31% in those 1070 receiving 6 g/day and was 32% in subjects receiving 10 g/day. The strongest parameter 1071 influencing the half-life in both males and females was body weight. Height and age were 1072 correlated to the half-lives through their correlation to the weight parameter but were not 1073 additional variables. Investigating the estimated caesium-137 body burden at the initial time 1074 of elimination found an inverse relationship between initial activity and half-life: the larger 1075 the initial body burden, the faster the nucleotide removal from the body. The influence of 1076 this parameter was much weaker than that of body weight (Lipsztein et al., 1991). 1077 1078 12.1.2 Chernobyl incident, 1986 1079 Measurements were made on 15 Chinese subjects internally contaminated with 1080 radionucleotides released from the Chernobyl accident on 26th April 1986. The students had 1081 been visiting Sofia, Bulgaria from 19th April until 23 May 1986 and monitoring was done on 1082 their return to Beijing. Internal contamination with radioactive caesium (caesium-134 and 1083 caesium-137) was measured in all 15 students. The measured activity in the body for the 15 1084 volunteers ranged from 68-840 Bq for cesium-137 and 110-630 Bq for caesium-134. The 1085 estimated intakes were calculated and ranges were 95-1200 Bq (Caesium-137) and 170-930 1086 Bq (Caesium-134). The biological half-life was calculated for three volunteers along with 1087 the effect of Prussian blue on their rate of elimination of radiocaesium. Prussian blue was 1088 given at doses of 1g three times a day for a 6 day course, 3 courses in total were give with a 1089 6 day time interval between each course. The biological half-life of the radiocaesium ranged 1090 from 43-71 days. Prussian blue was given to the three volunteers in the period of 114-141 1091 days after contamination and the body retention of radiocaesium declined more rapidly 1092 following Prussian blue administration than in those of controls (Tang et al., 1988). 1093 1094 12.1.3 Other case reports 1095 Five persons, two adults (aged 34 and 38 years, weight 56 and 55 kg) and three children 1096 (aged 4 to 11 years; weight 13.5 to 34 kg) accidentally received caesium-137 chloride for 1097 approximately 20 days (no details given). The patients were evaluated as soon as the 1098 accident was discovered and started on Prussian blue. The adults received 3 g daily from 1099 days 35 to day 128 or 143. The children received 1, 1.5 or 2 g daily from days 35 to 86, 76 1100 or 99. The half-life of the caesium was very variable and was 124, 54, 61, 36 and 36 days 1101 without treatment. With Prussian blue treatment the half-life of caesium was 38, 39, 25, 17 1102 and 16 days, respectively (Ma et al., 1985). 1103 1104 12.1.4 Non-radioactive caesium 1105 A 65 year old woman presented to a hospital accident and emergency department with a one 1106 day history of recurrent fainting. The patient claimed to have essential hypertension and was 1107 having treatment for this from her family doctor. Six months prior to her presentation she 1108 had been diagnosed with rectal cancer and liver metastasis and she had experienced frequent 1109 episodes of watery diarrhoea in the past 4 weeks. On admission her blood pressure was 1110 138/55 mmHg, pulse 52/min regular, temperature 36.80C, respiratory rate 18/min and blood 1111 glucose 10.7 mmol/L. She developed and episode of Torsades de points (TDP) polymorphic 1112 ventricular tachycardia with transient loss of consciousness during initial assessment. The 1113 arrhythmia spontaneously converted back to normal sinus rhythm in about 10 seconds. Her 1114 electrocardiogram (ECG) showed QT prolongation with a corrected QT interval of 620 ms 1115


25

calculated by Bazett’s formula. Serum electrolytes showed mild hypokalaemia (2.8mmol/L) 1116 whilst serum magnesium and serum calcium were normal. She was treated with intravenous 1117 magnesium sulphate and vigorous potassium replacement however there was no 1118 improvement in the QT prolongation after these therapies. At this stage it was discovered 1119 that in the previous 6 weeks the patient had been taking anticancer naturopathic drugs 1120 obtained from an alternative medical centre in Hong Kong. A detailed drug history was 1121 obtained. Her medications included methyldopa, Dologesic™ (dextropropoxyphene 32.5mg 1122 and paracetamol 325mg) and Lomotil™ (diphenoxylate 2.5mg, atropine 0.025mg) all 1123 prescribed by her family physician. In addition, a bottle of herbal powder (1 teaspoon taken 1124 daily), 3 oral medications including “Gigamax” (labelled as multivitamins), Slow K™ (slow 1125 release potassium supplement) and “multi-C” were prescribed by the naturopathic 1126 practitioner. On the basis of the clinical findings and along with previous case reports of 1127 caesium chloride use in anticancer therapy, the diagnosis of caesium poisoning was highly 1128 suspected. Whole blood and serum were assayed and the serum caesium concentration was 1129 elevated markedly at 288µmol/L (normal range 0.0045-0.0105µmol/L). Whole blood 1130 arsenic concentration was normal. One of the naturopathic medicines (“multi-C”) was found 1131 to contain 89% caesium chloride by weight. No undeclared contents or toxins were found 1132 on analysis of the herbal powder “Gigamax” and Slow K™ tablets. The patient was 1133 hospitalized for 2 weeks with intensive cardiac assessment and monitoring. The use of 1134 naturopathic medicines was stopped after hospitalization. Oral Prussian blue 3g 3 times 1135 daily was started on day 7 after hospital admission and continued for 4 weeks (day 7 to day 1136 34). Hypokalaemia was noticed during Prussian blue therapy and an oral potassium 1137 supplement was given to keep the serum potassium concentration at around 4mmol/L. Serial 1138 serum and urine caesium concentrations were measured. The calculated serum half-life of 1139 caesium was shortened from 61.7 days to 29.4 days with Prussian blue therapy. The 1140 corrected QT interval of her ECG returned to normal baseline on day 27 (Chan et al. 2009). 1141 1142 Thurgur et al. (2006) report a case where Prussian blue was used in the treatment of non-1143 radioactive caesium. The patient was a 58 year old female with chronic caesium toxicity 1144 from the use of caesium chloride as an alternative cancer therapy. High levels of caesium are 1145 arrhythmogenic and this patient showed recurrent syncope, polymorphic ventricular 1146 tachycardia, hypokalaemia, and a QT prolongation of 690 ms. Along with conventional 1147 measures Prussian blue was used to treat her caesium toxicity. The Prussian blue treatment 1148 decreased the half-life of caesium from 86.6 days to 7.9 days, with associated normalization 1149 of QT interval and cardiac rhythm. 1150 1151 1152 12.2 Rubidium 1153 There are no reports on the use of Prussian blue in rubidium exposure in humans. 1154 1155 12.3 Thallium poisoning 1156 Reference values for thallium (Walker, 1998): 1157

Blood <5 nmol/L (<1 µg/L) 1158 Urine <5 nmol/L (<1 µg/L) 1159

1160 A 45 year old man with no significant medical history was hospitalized with peripheral 1161 neuropathy and paraesthesia of the extremities of all 4 limbs for 2 days. Clinical 1162 examination revealed an erythematous popular rash on the face and folliculitis on the lower 1163 limbs associated with hyperaesthesia of the feet and hands. An electromyogram showed 1164 severe polyneuropathy. The patient had a cardiac arrest 9 days after admission followed by 1165


26

post-anoxic coma. The patient worked in a technical crystals factory and handled thallium, 1166 bromide, caesium and iodide. The urinary thallium concentration measured twenty days 1167 after his cardiac arrest was 5118µg/g of creatinine. Despite the late diagnosis treatment with 1168 insoluble Prussian blue (Radiogardase™) was started 2 weeks later (42 days from his 1169 original admission to hospital) and continued for 24 days at a dose of 6g three times daily. 1170 Urinary thallium concentrations decreased from 1333µg/g of creatinine to 166µg/g of 1171 creatinine. After evaluation of the efficacy of the treatment a second course of Prussian blue 1172 therapy was started at 77 days post admission and continued for 1 month when the patient 1173 died. The urinary thallium concentration decreased from 86µg/g of creatinine to 3µg/g of 1174 creatinine (Villa et al., 2009). 1175 1176 Ten members of two families (family A and family B) sought treatment at a health care 1177 facility in Baghdad, Iraq. All patients were experiencing vomiting, abdominal pain and 1178 dysphagia. Over the next 4 days, 5 of the patients developed neurological signs and 1179 symptoms of varying severity (pain, abnormal sensations and weakness-particularly of the 1180 lower limbs). Four days after admission biological samples and a sample of a cake that all 1181 10 patients had consumed were submitted for toxicology testing. Thallium was detected in 1182 both the biological samples and the cake. On the eighth day after admission one of the 1183 patients, a child aged 11 years, died and two days later the 9 surviving patients were 1184 evacuated to Jordan for Prussian blue therapy which was not available in Iraq. A second 1185 patient, a 2 year old child died soon after arrival in Jordan, prior to receiving therapy. 1186 Prussian blue therapy was begun in the 8 surviving patients, now 11 days after they had 1187 eaten the cake. Two of these 8 patients were already comatose with severe cerebral oedema 1188 and subsequently died. Over the next thirty days, all 6 long-term survivors developed hair 1189 loss and 5 of the 6 survivors developed muscle weakness and spasticity of the lower limbs, 1190 with differing severity. An epidemiological investigation was started and it was discovered 1191 that the fathers of the two families were both board members of an Iraqi sporting club and 1192 had attended a routine board meeting on the day before hospital attendance in the club’s 1193 conference room. The cake, prepared by a local bakery and pre-divided into 10 pieces, had 1194 been delivered to the board meeting as a gift from a former board member. However the 1195 cake arrived late, after most board members had already left the meeting so no cake was 1196 eaten then. The two members that remained (the fathers of the two families) divided the 1197 cake and took the halves home to their families and it was eaten by both families at home 1198 that evening. Family A comprised seven members (parents and five children) and family B 1199 comprised five members (parents, two children and an uncle). Ten cases of abdominal pain, 1200 vomiting and dysphagia were identified among family members who consumed any amount 1201 of the cake. No other board members or their families were ill and no similar illnesses were 1202 reported at the health facility in Baghdad or at any nearby health facilities. Food exposure 1203 histories were collected in Jordan through interviews with family members. Ten people who 1204 ate portions of the cake became unwell; neither of the two persons who did not eat cake 1205 became unwell, however one of the two had tasted some of the cake icing and although 1206 asymptomatic, his blood and urine samples tested positive for thallium. A more rapid onset 1207 of illness occurred in adults and in persons who ate the most cake. Fatality was not 1208 significantly associated with sex, age, the amount of cake eaten, or the time to illness onset. 1209 Quantitative thallium levels were determined from blood and urine samples of nine patients 1210 taken on day 16 after eating the cake. Thallium was detected in all nine patients; the median 1211 blood thallium level was 289µg/L (range 53-1,408 µg/L; reference range expected <2µg/L), 1212 and the median calculated 24 hour urine excretion of thallium was 3063 µg/L (range 542-1213 12,556 µg/L; reference range expected <5µg/L). Blood thallium levels correlated weakly 1214 with the amount of cake reported to have been eaten (CDC., 2008) 1215


27

1216 A previously healthy forty-year old male was admitted to hospital complaining of 1217 progressive weakness of his limbs, repeated vomiting and recurrent episodes of confusion. 1218 He had initially presented to the hospital six weeks previous to this admission complaining 1219 of thirst, nausea, vomiting, dizziness, parathaesias and arthralgias (predominantly of the 1220 lower limbs). The paraesthesias were not described as ascending or notably painful. A 1221 supine blood pressure of 180/90mmHg and a mild fever were the only physical findings 1222 noted. Neurological examination showed the cranial nerves to be intact and the results of 1223 muscle strength tendon reflex and cerebellar function tests were normal. There was no 1224 evidence of impaired superficial or position senses. The results of a complete blood cell 1225 count and blood chemistry tests were normal. He was discharged and symptomatic 1226 treatment (non-steroidal anti-inflammatory drugs) was prescribed. Two weeks before the 1227 present admission he returned complaining of general weakness, anxiety, myalgias 1228 (particularly of the legs), delayed growth of facial hair after shaving and thirst. Physical 1229 examination and routine laboratory tests were again normal. His symptoms were diagnosed 1230 as “non-specific”, partly attributed to stress. On his present final presentation he was alert 1231 and complained of double vision. Physical examination revealed hyperhidrosis, tachycardia 1232 (100beats/min) and supine blood pressure of 140/100 mmHg. Alopecia of the scalp was 1233 noted but eyebrows, eye lashes and body hair were intact. Neurological assessment 1234 disclosed horizontal and upbeat nystagmus, severe weakness of the lower extremities (more 1235 prominent proximally), bilateral absence of Achilles tendon reflexes, and lower limb ataxia. 1236 He did not complain of extreme pain and no objective signs of sensory changes were 1237 detected. He was found to have raised blood alanine aminotransferase and raised aspartate 1238 aminotransferase. There was no evidence of proteinuria. Lumbar tap revealed an elevated 1239 protein. Electroencephalogram showed persistent generalized slowing; the electromyogram 1240 displayed bilateral, severe, lower limb motor axonal neuropathy. Rapid deterioration of his 1241 neurological state was observed over the next few days, including flaccid paraparesis, lower 1242 limb areflexia, severe sensory impairment, mild distal arm and neck weakness, as well as 1243 occasional urinary and faecal incontinence. Visual disturbance progressed from impaired 1244 colour vision and decreased acuity to optic disc atrophy. Cognitive disturbances and 1245 hoarseness were also noted. Sural nerve biopsy showed early acute axonal degeneration 1246 with no evidence of vasculitis. At this stage he was started on intravenous immunoglobulin 1247 as a variant of Guillain-Barré syndrome (Milllar-Fisher type) could not be excluded, and 1248 alternative causes were explored. Several days later thallium poisoning was diagnosed as 1249 heavy metal urinalysis showed renal thallium excretion of 7mg/24 hours. Prussian blue was 1250 administered (250mg/kg/day, dissolved in 15% mannitol) daily through a nasogastric tube, 1251 along with forced diuresis. At this stage Mees’ lines appeared on his nail beds. No 1252 improvement in his general state was noted within the next two weeks. He became drowsy, 1253 required respiratory assistance and subsequently developed aspiration pneumonia. The 1254 suspicion of cardiotoxicity was raised by elevations of alanine aminotransferase, aspartate 1255 aminotransferase and creatine phosphokinase (MB fraction) levels however this was not 1256 substantiated by electrocardiographic follow-up and echocardiography. There was swelling 1257 and pain in his right knee, however, some clear fluid drained was inconsistent with any 1258 particular diagnosis. Rheumatoid factor was mildly elevated, without any other supporting 1259 evidence of concurrent arthritic disease. His condition stabilized over the next weeks and 1260 there was a gradual decrease in thallium urinary output (table below). He was transferred to 1261 a rehabilitation hospital after forty two days. A follow-up examination 3 months later the 1262 alopecia and Mees’ lines had completely resolved. There were no cognitive disturbances, his 1263 proximal strength was restored and his colour vision was normal. Decreased visual acuity 1264 and bilateral drop-foot were still evident however and the patient had only a vague 1265


28

recollection of his period in hospital. 1266 1267

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) 1268 1269 A 67 year old woman was admitted to a county hospital because of acute pain in the chest, 1270 abdomen and lower limbs. The pain in the lower limbs was described as burning and severe. 1271 There was no vomiting or diarrhoea. The patient was discharged after 3 days with the cause 1272 of her illness undetermined. The patient then presented one week later to a private clinic 1273 because of persistent symptoms. Physical examination showed mild tenderness over the 1274 abdomen and electrocardiography showed non-specific T-wave inversion in the anterior 1275 waves. Routine urinalysis results were normal and laboratory tests showed normal blood 1276 cell counts, blood glucose level and kidney and liver function. The patient was treated 1277 symptomatically with analgesics. She was soon readmitted to hospital because of fainting 1278 spells and persistent symptoms. The patient suspected she was being poisoned. Paranoid 1279 psychosis and trichotillomania were diagnosed and she was admitted under restraint to the 1280 psychiatric department for observation. After being discharged home at week 5, the woman 1281 then re-presented at the private clinic. According to the patient the pain had become less 1282 severe. Physical examination showed diffuse alopecia which had started 2 weeks after the 1283 onset of the initial symptoms. Thallium poisoning was suspected. Urinalysis showed a 1284 thallium level of 8.56µmol/L (normal level, 0.003µmol/L; a level of 0.98µmol/L is toxic). 1285 The case was reported to the police and the prime suspect was the patient’s 73 year old 1286 cohabitant. A dose of activated charcoal was given in the emergency department of a nearby 1287 district hospital and the patient was discharged home with a 2-week supply of succimer (2, 1288 3-dimercaptosuccinic acid) (no reason for this was given). At follow-up at week 6 however, 1289 it was found that the pain in her chest, abdomen and lower limbs had subsided, but 1290 symptoms of peripheral neuropathy had emerged - namely bilateral numbness and loss of 1291 exteroceptive and proprioceptive sensations in the toes. She had mild weakness in the 1292 proximal muscles of the lower limbs, as indicated by the patient’s difficulty in rising from 1293 the squatting position. She also complained of right-sided headache and tachycardia. She 1294 was immediately admitted to a University Medical Centre for treatment with oral Prussian 1295 blue (potassium ferric hexacyanoferrate) 4g every 8 hours. The blood thallium level at the 1296 time of hospitalization was 0.15µmol/L. No other heavy metals were present. The patient 1297 tolerated Prussian blue very well, but hypoaesthesia developed over the medial aspect of her 1298 left calf on the second day of treatment. She was discharged 1 week later, when the urine 1299 level of thallium was 0.14µmol/L. In week 9 the patient experienced neurological 1300 deterioration, impairment of short-term memory, double incontinence, tremor ataxia and 1301 falls. Physical examination showed hypoaesthesia of the right trigeminal nerve, general 1302 weakness of the extremities, cerebellar ataxia, tremor and dyskinesia. Plantar reflexes were 1303 normal and the urine thallium level was 0.33µmol/L. By week fourteen the right facial 1304


29

numbness fully recovered, by week twenty there was recovery of sphincter control and 1305 regrowth of hair. Urine thallium was undetectable 2 weeks later. The weakness in the lower 1306 limbs, unsteady gait, falls and bruises persisted until 11 months after the initial presentation, 1307 when her condition improved noticeably although residual weakness continued (Pau., 2000) 1308 1309 A 24-year old female was admitted to hospital with a 4-month history of illness. Eight days 1310 after admission a diagnosis of thallium poisoning was made based on rapid diffuse alopecia, 1311 gastro-intestinal disturbance and a worsening neurological state combined with laboratory 1312 results. Whole blood thallium was measured and the first level was 300 µg/L (normal 1313 <10µg/L, toxic >100 µg/L); the corresponding 24-hour urinary thallium value was 4300 1314 µg/L (normal < 10 µg/L, toxic > 200 µg/L), consistent with severe intoxication. Colloidal 1315 soluble Prussian blue (KFe[Fe(CN)6]) was given orally at a dose of 250mg/kg/day in 2-4 1316 divided doses for 14 days. The patient also received mannitol as a cathartic, cisapride for 1317 her persistent constipation (started on the 5th day of treatment) and forced diuresis, which 1318 was achieved with furosemide, glucose, potassium and sodium chloride. The patient’s 1319 clinical course after treatment was uncomplicated with recovery of her vital signs within a 1320 week. Four months after treatment thallium was undetectable in a 24-hour assay. However 1321 after 6 months she still suffered from a lack of concentration and insomnia and never fully 1322 returned to her previous functional level. The source of thallium was never established 1323 1324

Days before/after treatment 24 hour-urinary thallium level µg/L

Whole blood thallium level µg/L

-8 4300 0 4200 300 4 1450 < 10 10 330 14 468 18 440 31 260

(Vrij et al., 1995). 1325 1326 1327 A thirty nine year old male with a history of heavy alcohol consumption became ill one 1328 week after returning from holiday in Spain. His symptoms started acutely with generalized 1329 pain and tingling all over his head and body and he was admitted to hospital where he was 1330 greatly distressed and complaining of shooting pains in his legs and back and leg weakness. 1331 It was thought initially that his illness was an alcoholic syndrome. Because of his continued 1332 deterioration despite multivitamin treatment he was transferred initially to the regional 1333 neurology unit and then further to an intensive care unit, 20 days after first becoming ill. On 1334 initial neurological examination he had respiratory distress, evidence of scalp hair loss, gaze 1335 evoked nystagmus in all directions, bilateral lower motor neuron, facial and bulbar 1336 weakness; his arms were minimally weak with normal reflexes but his legs showed a flaccid 1337 paralysis with absent reflexes. Initial biochemical investigations were within normal ranges 1338 (electrolytes, urea, creatinine and liver function tests). The electrophoresis pattern of serum 1339 proteins was normal and a non-specific auto-immune profile did not detect any auto-1340 antibodies. Screening tests for abnormal urinary porphyrins gave negative results. A 1341 complete blood count was within the reference range, except for a slightly increased mean 1342 corpuscular volume. Cerebrospinal fluid was acellular with a protein count of 1.5g/L. 1343 Nerve conduction studies showed absent sensory and motor responses for the legs but 1344 normal values for the arms. On the basis of the clinical picture at this stage, in particular 1345


30

with respect to the hair loss, serum and urine were assayed for thallium and it was found to 1346 be present at toxic levels (value not stated). The patient deteriorated further and developed 1347 visual failure, complete external ophthalmoplegia, and total arreflexic paralysis of all limb 1348 and neck muscles. He was given two treatments of plasma exchange and treatment with 1349 potassium ferrihexacyanate (colloidal soluble Prussian blue), 5g every 6 hours by 1350 nasogastric tube was started (now thirty five days into the illness) and continued for 2 1351 months. At the same time intravenous potassium supplements (100-400mmol/day) were 1352 given. Excretion concentrations of thallium in serum and urine are tabulated below. The 1353 patient made a slow recovery which was complicated by septicaemia, recurrent 1354 supraventricular tachycardias and psychosis. He required 96 days of assisted ventilation and 1355 a total of 224 days in hospital. Some 500 days after the initial insult he still had a significant 1356 visual handicap, no fine finger function and could only walk a few steps with assistance. 1357 The source of the thallium poisoning was never discovered. 1358 1359 1360

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

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 1363 (Chandler et al., 1990) 1364 1365 Villanueva et al (1990) describe 5 cases of thallium poisoning in Spain. Four were members 1366 of a single family and the source of thallium was never ascertained. The fifth case was a 1367 female adult with a history of depression who intentionally ingested a thallium sulphate 1368 rodenticide. The family members (2 adults and two children aged 10 years and 3 years) 1369 presented initially with varying symptoms and the two children required admission to 1370


31

intensive care. Total hair loss of the 10-year old 2 weeks after admission led to the 1371 diagnosis of thallium poisoning. In all of the 5 cases urinary thallium was measured. The 1372 10 year old child’s first measured thallium level was 18.4 mg/L, seven days later it was 5.8 1373 mg/L, at 27 days later it was 0.14 and by approximately 4 months it was 0.004 mg/L. The 1374 child had been treated with Prussian blue at a dose of 250mg/kg by duodenal tube 1375 administration every 6 hours until the urinary excretion of thallium was 0.5 mg/day. Her 1376 symptoms resolved in 20 days. The female adult who intentionally ingested the thallium had 1377 an initial urinary level of 2.4mg/L which decreased to 0.9mg/L in 4 days and to 0.1 mg/L in 1378 5 weeks. She had also been given Prussian blue at a dose of 250mg/kg/day (duration of 1379 treatment not stated) and 6 weeks later recovery was complete. The case reports also outline 1380 the thallium concentrations of the other family members but it is unclear whether or not they 1381 received Prussian blue therapy. 1382 1383 A 20-year-old chemistry student presented with a 3 day history of malaise and polyuria with 1384 paraesthesia of the fingers and lips. He had been using thallium and blood and urine 1385 analyses showed very high concentrations (5750 µg/L and 60000 µg/L, respectively), 1386 although he denied ingestion. Tests for thallium in hair samples were negative which 1387 excluded chronic ingestion however, despite exhaustive enquiries by the police and college 1388 authorities, the mode of thallium administration remained undetermined. Shortly after 1389 admission he became drowsy and had a convulsion. He developed progressive weakness 1390 over the next 12 hours, with severe pain in the calf muscles. He had peripheral and sensory 1391 impairment, dysarthria, dysphagia, paralytic ileus, tachycardia and ECG changes. He was 1392 started on soluble Prussian blue (5 g in 50 ml of 15% mannitol 4 times daily) and forced 1393 diuresis. On day 6 dialysis and haemofiltration were started and diethyldithiocarbamate was 1394 given. The diethyldithiocarbamate produced a short-lived increase in thallium excretion 1395 (from 17 to 142mg/24 h in urine, and 63 to 81mg/6 h dialysis) but also led to a rise in serum 1396 thallium concentration (from 800 to 1350 µg/L and worsening neurological signs (including 1397 respiratory failure) and it was stopped. He required ventilation for 4 weeks. He developed 1398 almost complete alopecia before hair regrowth started. By 13 weeks he could swallow fluids 1399 and by 20 weeks he had normal upper limb function. But after 12 months he was still in a 1400 wheelchair owing to nerve damage to the lower limbs. Prussian blue and laxatives were the 1401 most effective means of enhancing thallium elimination, even though paralytic ileus caused 1402 long periods of constipation. High concentrations of thallium were present in the faeces up 1403 to day 18, and it was estimated that at least 2000 mg of thallium was excreted via this route 1404 in the first 20 days (see table). This is twice the quantity excreted by all the other methods 1405 in the same period. Forced diuresis was estimated to have eliminated 820 mg of thallium in 1406 46 days with 225 mg eliminated via haemodialysis in 25 days. 1407 1408

No. of days from admission

Concentrations

Excretion

Serum (µg/L)

Urine (µg/L)

Urine (mg)

Faeces (mg)

Dialysate (mg)

Urine Filtrate (mg)

1 5750 60000 129 2-5 2390 35900 398 6-10 680 7750 230 550 146 3.5 11-15 225 1520 42 155 64 1.0 16-20 35 640 12 1280 5.0 <0.1 21-25 15 280 2.6 0.5 5.4 <0.1


32

26-30 12 315 2.7 2.5 4.5 <0.1 31-40 11 110 2.9 41-50 <7 64 1.0 51-70 <7 24 0.9

Total quantities excreted (mg): 820 1990 225 4.5 1409 The serum and urine concentrations presented in the table above are daily averages for the 1410 periods stated. The quantities excreted are totals for each period. All values are given as 1411 elemental thallium, measured by atomic absorption spectrometry (Wainwright et al., 1988). 1412 1413 1414 A group of 14 people ate dinner together and the following morning all complained of 1415 abdominal pain, vomiting and diarrhoea and were taken to hospital. Five of the 14 patients 1416 died in hospital within the next four days. The remaining nine patients (age range 16-70 1417 years) were seen over the following 4-7 days. One patient was pregnant, one had pre-1418 existing Parkinson’s disease and a third had elephantiasis of the legs. All of them 1419 complained of varying degrees of pain in the feet and legs and 6 were unable to walk. Some 1420 had headaches, constipation, abdominal pains, chest discomfort, loss of appetite, and loss of 1421 sleep. On examination they all had varying degrees of peripheral neuritis with 1422 hyperaesthesia, hyperalgesia, mental confusion, tachycardia, muscle and abdominal 1423 tenderness. A diagnosis of heavy metal poisoning was made based on the sudden onset of 1424 peripheral neuritis in a group of people who had eaten the same food and also because of 1425 similar case presentations in the previous year that had proven to be thallium poisoning. 1426 Blood and urine samples were sent for heavy metal analysis. Thallium was detected 1427 quantitatively in all the samples. The food they ate was suspected of being contaminated 1428 with a thallium-containing rodenticide but this could not be confirmed. Prussian blue was 1429 started between the 4th and 7th day at a dose of 2g three times a day orally, together with 1430 magnesium sulphate solution (30ml three times a day) to avoid constipation. For the first 1431 few days some of the patients required parenteral pethidine (100mg every six hours) for 1432 severe lower limb pain later changed to oral pentazocine (50mg three times a day). They 1433 were also given oral vitamin B complex and amiloride/hydrochlorothiazide daily. Over the 1434 next 5 days the leg pains rapidly subsided and analgesics were stopped. Seven of the 1435 patients started walking freely without much pain. In the 3rd week all of them gradually 1436 started losing scalp hair and there was almost complete alopecia after 4 weeks. Six patients 1437 developed Mee's lines on the finger nails along with hyperpigmentation over the knuckles. 1438 Four patients were discharged from hospital after the 4th week and the remaining patients 1439 after 6 weeks. Prussian blue was continued in all patients at the same dose for a total of 6 1440 weeks and no side effects were noted. On discharge 5 patients had fine tremor of the upper 1441 limbs with slight incoordination of movement. After sixteen weeks regrowth of scalp hair 1442 was complete. The pregnant woman had a premature delivery in the sixth month of 1443 pregnancy at another hospital but no details were available. By sixteen weeks all patients 1444 had returned to active life. 1445 1446

Serum and urine thallium concentrations after two weeks of Prussian blue therapy Patient number Patient age (years) Serum Thallium

(µgm/ml) Urine Thallium

(µgm/ml) 1 62 16 2200 2 37 4 48 3 29 4 250 4 70 4 250


33

5 60 6 660 6 16 11 1100 7 29 5 37 8 30 6 87 9 26 4 23 (Pai., 1987) 1447 1448 A 21-month old girl arrived at a hospital in the UK from Qatar for investigation of ataxia of 1449 five days duration. On admission she was semi-conscious and irritable but extensive 1450 investigations including routine toxicology screen on blood and urine, could only achieve a 1451 diagnosis of encephalopathy. On the 5th day of hospitalization hair loss was noted and a 1452 suggestion of thallium poisoning was made by a nurse in charge of the child (the subject of 1453 the crime thriller she was reading at the time, Agatha Christie’s A Pale horse). The child 1454 was treated with oral Prussian blue and potassium chloride (doses not stated) and after 3 1455 weeks of treatment there was marked clinical improvement and no thallium was detected in 1456 her urine. The clinical improvement continued and after four months the child was alert, 1457 ataxic but able to walk with help. The source of thallium was never determined but was 1458 thought to be the cockroach bait that was used in the home (Robb-Smith, 1987). 1459 1460 A 32 year-old woman was admitted to hospital 6 hours after allegedly ingesting 100mg of 1461 thallium sulphate. On admission the patient had malaise, nausea, vomiting and a burning 1462 retrosternal pain. After gastric lavage Prussian blue was administered 250mg/kg in divided 1463 doses) and combined haemoperfusion-haemodialysis (HP-HD) was started 7 hours after the 1464 alleged ingestion. HP-HD was instigated because the dose of thallium and whether there 1465 were possible co-ingestants were unknown. The patient was treated for 4 hours by HP-HD. 1466 Blood samples were taken before and after the charcoal column and after the artificial 1467 kidney at 1 hour intervals. Blood flow was 200ml/min. After HP-HD treatment 7 more 1468 blood samples were taken, initially at 1-hour intervals later at 2-hour intervals. During HP-1469 HD treatment the patient’s blood pressure remained constant however there were frequent 1470 supraventricular extrasystoles. The patient improved and after 4 hours of HP-HD she felt 1471 well. Subsequent to her treatment no neurological or dermatological symptoms were noted. 1472 The combination of HP-HD in this patient obtained an overall clearance of 150ml/min in 1473 blood compared to 47ml/min (mean value) using HD only (De Backer et al., 1982). 1474 1475 A 28-year-old female presented 4 days after ingestion of nearly 1 g of thallium sulphate with 1476 lower abdominal pain, nausea, and hyperaesthesia of the limbs. Thallium was detected in 1477 the urine (3 mg/L) and gastric aspirate (10.8 mg/L). She was started on intravenous fluids 1478 and soluble Prussian blue (5 g four times daily via duodenal tube with 50 mL of 15% 1479 mannitol). Over the next two days the abdominal and lower limb pain persisted, with 1480 drowsiness and vomiting. On the third day she became hypotensive with bilateral ptosis. 1481 Alopecia was also noted. Neurological signs and gastrointestinal symptoms began to 1482 improve 4 days later, but hair loss continued. She had severe constipation for the first 6 days 1483 despite laxative administration. By 11 days her symptoms improved; Prussian blue was 1484 discontinued after 20 days, by which time hair regrowth had started. Thallium 1485 concentrations fell dramatically over the first 2 days of admission, with a slower decline 1486 thereafter (see table). No faecal samples could be obtained until the 10th day after poisoning 1487 (hospital day 6) owing to the severe constipation. At this time 1.6 mg of thallium was 1488 detected in the 24 hour faeces and 1.93 mg in the urine. In 28 days of hospitalization 1489 approximately 5 mg of thallium was eliminated via the intestinal tract and 35 mg in the 1490 urine. Approximately 55 mg was eliminated in the saliva between days 9 and 26 after 1491


34

poisoning. In total the quantity eliminated was thought to be <5% of the dose ingested. She 1492 was discharged asymptomatic at 28 days. 1493 1494

Excretion of thallium (mg/day) in urine, faeces and saliva at various times during hospital course

No. days after poisoning

Urine (mg/day) Faeces (mg/day) Saliva (mg/day)

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). 1495 1496 Comment: In the above case study the patient’s response to Prussian blue was slow to 1497 manifest and this may possibly have been due to her constipation. A very small amount of 1498 thallium was excreted in the faeces, and in fact, a very small amount was excreted overall so 1499 possibly the patient may have improved anyway regardless of therapy. 1500 1501 The efficacies of different therapies were evaluated in 18 cases of thallium poisoning treated 1502 between 1971 and 1979 at the University Hospital of Utrecht, the Netherlands. Patients 1503 were treated with gastric lavage if ingestion had occurred within the preceding 48 hours and 1504 then given 10 g soluble Prussian blue with 100 ml 15% mannitol via a duodenal tube twice 1505 daily. Eight patients were also treated with forced diuresis. Furosemide was given only if 1506 necessary to prevent fluid overload. Sixteen patients survived and two patients with cardio-1507 vascular insufficiency died. The cases are summarized in the table below. 1508 1509

Patient Sex Age Amount of

thallium ingested (mg) -from

patient history

Time between thallium ingestion

& admission (days)

Thallium concentra

tion in urine on admission (mg/L)

Treated with

forced diuresis

Treated with

haemoperfusion

A F 21 500 28 2.1 - - B1) F 22 2400 2 47.4 - - C F 21 350 1 8.8 - - D F 55 1000 4 20.2 - - E M 23 1000 2 71.1 - - F M 28 480 ½ 1.0 - - G F 19 unknown 2 2.0 - - H2) F 24 1000 1 84.0 - - I F 32 1000 2 hours 40.0 - - J M 45 unknown ? 3.0 - - K M 50 750 4 24.6 + - L M 26 875 1 54.0 + -


35

M M 21 1500 14 79.8 + - N F 25 1500 1 80.0 + + O3) M 44 unknown ? 8.0 + - P3) M 19 unknown ? 10.0 + - Q F 58 unknown 2 2.2 + - R F 19 3000 1 50.0 + +

1) Patient died after 4 days. 1510 2) The patient survived this suicide attempt. Four months later she died within 6 hours 1511

after ingestion of an unknown amount of thallium 1512 3) These patients were admitted with hair loss of the head 1513

1514 With soluble Prussian blue therapy, the mean half-life of thallium was 3.0 ± 0.7 days. When 1515 administration of Prussian blue was combined with forced diuresis, the mean half-life of 1516 thallium was 2.0 ± 0.3 days (van Kesteren et al., 1980). 1517 1518 An early report on the use of Prussian blue therapy in thallium poisoning reviewed 11 1519 patients hospitalized between 1971 and 1973. There were three men (aged 30 to 44 years), 1520 six women (aged 24 to 64 years) and two children (both female, aged 2 and 6 years). Three 1521 patients received Prussian blue by duodenal tube (2 x 10 g every two days, 2 x 10 g or 20 g 1522 daily). The other nine patients received oral Prussian blue (4 x 5 g daily in the adults, 4 x 1 1523 g daily in the 6-year-old and 4 x 1.7 g daily in the 2-year-old). Four patients treated within 1524 24 hours of ingestion of thallium did not develop any signs of toxicosis. Improvement also 1525 occurred in most of the other patients even though treatment was started late (between 9 and 1526 151 days after exposure). Thallium elimination was primarily via the faeces. Although no 1527 adverse effects were attributed to the Prussian blue therapy, one patient developed 1528 constipation and had constantly high blood thallium concentrations during the first few 1529 weeks of treatment (Stevens et al., 1974). 1530 1531 1532 A 26 year old female student, epileptic and treated with phenobarbital and phenytoin, 1533 ingested approximately 700mg of thallium sulphate when she was in a depressed mood. She 1534 ingested half of the amount during the evening and the remainder the following morning. 1535 She was admitted to hospital twelve hours later and was at this stage asymptomatic. On the 1536 third day hyperaesthesia of the legs and feet developed and she had abdominal discomfort. 1537 The next day (day 4) she developed a prickly, burning sensation in the feet and pain in the 1538 legs and shoulders. No other neurological symptoms could be demonstrated. The pain 1539 subsided during the subsequent days and then a slight polyneuropathy was found. Hair loss 1540 began on the tenth day and progressed but was not extreme. After two weeks only traces of 1541 neurological damage could be demonstrated and this disappeared during the following 1542 weeks. No Mees’ lines were seen on the nails. On initial admission to hospital, no thallium 1543 was evident after gastric lavage but it was shown to be present pharmacologically. She was 1544 treated with Prussian blue 250mg/kg body weight/day (given in 4 daily doses of 3.75g) 1545 along with 15% mannitol through a duodenal tube. Potassium chloride and activated 1546 charcoal were also given on the first two days. A multivitamin preparation was given 1547 intramuscularly 3 times a week and a fluid intake of 3-4 litres/day was prescribed. The 1548 decrease in urinary thallium concentration during the patient’s hospitalization is shown in 1549 the table below. Prussian blue was stopped on the 13th day when the amount of thallium in 1550 the urine was below 0.5 mg/24hours. 1551 1552 1553


36

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) 1554 1555 A twenty two year-old alcoholic ingested approximately 700 mg of thallous sulphate in a 1556 suicide attempt. He was admitted to hospital 6 hours later with no complaints. Gastric 1557 lavage showed only a trace of thallium. He was treated with Prussian blue 250mg/kg body 1558 weight in 15% mannitol via duodenal tube in 4 doses a day. Fluid intake of 3-4 litres a day 1559 was prescribed. After 4 days slight paraesthesia and sensory impairment of the toes could be 1560 demonstrated, however this improved and disappeared during the next few days. Hair loss 1561 started after 2 weeks but was mild. Thallium excretion in the urine is shown in the table 1562 below. Prussian blue treatment was stopped after the 10th day results were known. 1563 1564

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) 1565 1566 1567

13. Summary of Evaluation 1568

1569 13.1 Indications 1570 Prussian blue is indicated in the treatment of patients with known or suspected internal 1571 contamination with radioactive caesium, radioactive thallium and non-radioactive thallium, 1572 to increase their rates of elimination. Treatment should be started as soon as possible after 1573 exposure. 1574 1575 13.1.1 Thallium 1576 The recommendation for the use of Prussian blue in thallium poisoning is based on evidence 1577 derived from animal studies and limited clinical data from human poisoning in the form of 1578 case reports and case series. 1579 1580 In animals experimentally poisoned with thallium, Prussian blue has been shown 1581 significantly to reduce absorption of thallium, increase its elimination and reduce its 1582 concentration in the brain. Moreover, Prussian blue significantly lowered mortality in 1583 animals poisoned by this metal. 1584 1585 Uncontrolled case reports / series have generally been associated with a favourable outcome, 1586 although there are some cases where patients were slow to respond to treatment and some 1587 patients have been left with long-term sequelae. In many of these cases other treatments 1588 were given concurrently (e.g. activated charcoal) and it is therefore difficult to clearly 1589


37

identify the benefits of Prussian blue alone. 1590 1591 Soluble Prussian blue has been shown to more than halve the elimination half-life, when 1592 compared to historical controls, in a large series of thallium poisoned patients. Although 1593 such extensive clinical documentation is not available for insoluble Prussian blue, the overall 1594 evaluation is that insoluble Prussian blue is also effective. 1595 1596 13.1.2 Caesium 1597 The recommendation to use Prussian blue in patients having ingested radioisotopes of 1598 caesium is based on its ability significantly to decrease absorption of, and increase the faecal 1599 excretion of, caesium in animals exposed to caesium-137. The body half-life was halved in 1600 the species tested and reduced content of caesium-134 in various organs was also 1601 documented. In healthy volunteers, insoluble Prussian blue more than halved the body half 1602 life of this radioisotope of caesium. The limited case studies available are consistent with 1603 the effect in healthy volunteers. There appears to be no data on the use of soluble Prussian 1604 blue in this situation. 1605 1606 13.2 Advised routes and dose 1607 Prussian blue should only be given orally. The manufacturers of the pharmaceutical 1608 preparation recommend the following doses (Heyl data sheets Radiogardase and Antidotum 1609 Thallii-Heyl, 2004): 1610 1611 • Adults: In early-presenting cases when thallium or caesium may still remain in the gut an 1612

initial dose of 3g is suggested. In late-presenting cases when thallium or caesium have 1613 already been mostly absorbed, 3 to 20 g per day in divided doses should be given. 1614

1615 The individual dose should be based on the severity of exposure and clinical features. 1616 1617 • Children 2 to 12 years: 1 g orally 3 times a day. 1618 1619 The efficacy and dosing for the paediatric population of insoluble Prussian blue has been 1620 extrapolated from adult data and supported by paediatric patients who were internally 1621 contaminated with cesium-137 and treated with Prussian blue in the Goiânia incident. 1622 Paediatric patients aged 2-4 years are expected to have biliary and gastrointestinal function 1623 that is comparable with a 4-year old (Heyl, 2004). 1624 1625 • Children less than 2 years 1626 The dosing regimen for children less than 2 years old has not been established although it 1627 has been used in this age group (Robb-Smith, 1987). Variations exist in the developmental 1628 maturity of the gastrointestinal and biliary systems of neonates and infants and the dose-1629 related effects of Prussian blue on an immature gastrointestinal tract are unknown (Heyl, 1630 2004). 1631 1632 Administration 1633 The capsules of Prussian blue can be swallowed whole with liquid or if the patient is unable 1634 to swallow large numbers of capsules they can be opened and dispersed in bland food or 1635 fluid. A suspension of Prussian blue can also be administered via a stomach tube following 1636 gastric lavage. 1637 1638 In many patients with thallium poisoning mannitol (100 ml of 15% solution) has also been 1639


38

given with each dose in an effort to prevent constipation. This may not work and other 1640 measure to prevent or treat constipation may need to be undertaken. 1641 1642 End point of therapy 1643 The clinical end-point of Prussian blue therapy is generally considered to be when urinary 1644 thallium levels fall below 0.5mg/day (however this is clearly only a guide as most of the 1645 elimination will be faecal particularly in patients receiving Prussian blue therapy). 1646 1647 1648 13.3 Other consequential or supportive therapy 1649 1650 13.3.1 Caesium 1651 Specialist advice should be sought for the management of radiation accidents. This may require 1652 a multidisciplinary approach with radiation protection and dosimetry professionals, and medical 1653 and nursing staff trained and experienced in managing victims of radiation exposure 1654 (Breitenstein, 2003). 1655 1656 It is essential to prevent further incorporation of any radioactive material. Additional measures 1657 include the administration of laxatives to enhance gastrointestinal transit, antacids for 1658 radionuclides that become colloid or insoluble in the gastrointestinal tract (and therefore less 1659 absorbable), nasal and/or lung lavage and decontamination of skin and wounds (Gerber & 1660 Thomas, 1992). 1661 1662 In preliminary studies based on animal data, co-administration of Prussian blue with other radio-1663 eliminators does not affect the efficacy of Prussian blue (Heyl, 2004; Kostail et al., 1983). 1664 1665 13.3.2 Thallium poisoning 1666 The treatment of thallium poisoning is primarily concerned with the prevention of absorption 1667 from the intestinal tract and enhanced elimination from the body. 1668 1669 Gastric lavage should be considered in patients who present early. As patients generally 1670 present to healthcare facilities many hours after exposure it is unlikely that lavage would be 1671 beneficial however gastric decontamination has been has been undertaken as late as 48 hours 1672 after thallium ingestion in some previous cases (van Kesteren et al, 1980). Many patients 1673 will also have vomited spontaneously by the time they attend hospital so as with gastric 1674 lavage, emesis should be considered but may not be of any benefit. Enhanced elimination is 1675 often required in severe cases and haemodialysis (Barckow & Jenss, 1976; Pederson et al., 1676 1978), forced diuresis (Nogué et al., 1982; Heath et al., 1983; de Groot & van Heijst, 1988; 1677 Malbrain et al., 1997) and charcoal haemoperfusion (de Groot et al., 1985; van Kesteren et 1678 al., 1980) have all been used in thallium-poisoned patients. 1679 1680 13.4 Controversial issues and areas of use where there is insufficient information to 1681

make recommendations 1682 1683 13.4.1 Optimal form of Prussian blue 1684 Uncertainty exists in the historical literature regarding which of the two forms of Prussian 1685 blue (soluble or insoluble) is most effective as an antidote for radiocaesium and thallium. 1686 Human case study data is limited and this combined with the lack of analogous animal data 1687 on Prussian blue use (for both thallium and radiocaesium), means that whether the 1688 physicochemical differences between soluble and insoluble Prussian blue have any effect on 1689


39

outcomes in human poisoning is currently unknown. A relatively recent literature review by 1690 Thompson & Callen, (2004) highlights these controversies although they do conclude that 1691 that there is sufficient evidence to state that insoluble Prussian blue is effective in 1692 radiocaesium toxicity but that data are inconclusive for thallium. 1693 1694 From a pragmatic point of view, however, preference should be given to insoluble Prussian 1695 blue as this is the only commercially available pharmaceutical preparation. 1696 1697 13.4.2 Optimal dosage regimen 1698 The optimal dose of Prussian blue has not been established in clinical studies. The doses 1699 recommended by the manufacturer are empirical, reflecting the doses that have been used to 1700 treat cases of poisoning with thallium and radioactive caesium. In the case reports of 1701 poisoning with radioactive caesium the doses of Prussian blue used were smaller than those 1702 used for cases of thallium poisoning, typically 3g compared with 20g. Moreover, in one case 1703 series adults given doses of 3g, 6g and 10g per day showed very similar reductions in the 1704 half-life of caesium-137 (Lipsztein et al 1991). Since, however, the half-life of caesium-137 1705 was also found to be influenced by patient body weight and body burden of caesium-137 1706 interpretation of the impact of dosing is difficult. 1707 1708 In the case reports of poisoning with radioactive caesium, treatment was with insoluble 1709 Prussian blue, whereas for thallium poisoning treatment was often with the soluble form. 1710 Whether the form of Prussian blue has an impact on the effective dose for thallium poisoning 1711 is unknown. 1712 1713 Food may increase the effectiveness of insoluble Prussian blue by stimulating bile secretion 1714 and increasing enterohepatic circulation. The increase in enterohepatic circulation may 1715 increase the amount of caesium and thallium in the gastrointestinal lumen and hence 1716 increase the amounts available for binding with Prussian blue (Heyl, 2004). 1717 1718 13.5 Proposals for further studies 1719 In their review Thompson & Callen (2004) concluded that further research is needed to 1720 determine the significance of any differences between the two forms of Prussian blue and 1721 whether their physicochemical differences have any effect on outcomes in human poisoning. 1722 1723 Studies of the effect of Prussian blue in exposures to other radioisotopes may be warranted, 1724 e.g. in the case of rubidium-86. Although animal experiments suggest that Prussian blue may 1725 reduce the whole body retention of rubidium-86, the use of Prussian blue in this situation 1726 should be considered controversial. 1727 1728 13.6 Adverse effects 1729 Severe adverse effects have not been reported with Prussian blue (Hoffman, 2003). Mild to 1730 moderate constipation may occur which can be managed with a high fibre diet or bulk 1731 laxatives. In 46 patients involved in the Goiânia incident treated with Prussian blue, 10 1732 developed constipation (Farina & Brandão-Mello, 1991). It is essential to monitor for and 1733 treat constipation because elimination of thallium and caesium are dependent on the transit 1734 and elimination of Prussian blue from the gut. Faeces will be coloured blue and blue sweat 1735 and tears have been reported with prolonged administration, however this effect appears to 1736 be benign and transient (Hoffman, 2003). If capsules are opened and mixed with food or 1737 fluid, the teeth and mouth may be discoloured blue (Heyl, 2004). 1738 1739


40

Hypokalaemia is a potential risk as Prussian blue can bind potassium, however no significant 1740 variations in serum potassium concentrations have been reported, even when large doses 1741 have been given (IAEA, 1988). In 46 patients involved in the Goiânia incident treated with 1742 Prussian blue there were only 3 cases of hypokalaemia (2.5 to 2.9 mmol/L) without clinical 1743 complications. Oral and intravenous potassium supplements resulted in prompt correction of 1744 hypokalaemia (Farina & Brandão-Mello, 1991). 1745 1746 Cyanide toxicity has not been reported from oral dosing with Prussian blue. 1747 1748 1749 13.7 Restrictions for use 1750 None known. Prussian blue has been used in the treatment of thallium poisoning in 1751 pregnancy (Hoffman, 2000). 1752 1753 1754

14. Model Information Sheet 1755

1756 14.1 Uses 1757 Prussian blue (soluble or insoluble) is indicated 1758

• for antidotal therapy in acute or chronic thallium poisoning, 1759 • in the case of incorporation of radioisotopes of caesium (caesium-134, caesium-1760

137), 1761 1762 14.2 Dosage and route 1763 Prussian blue is available as Radiogardase®-Cs (Radiogardase® in the United States of 1764 America) and Antidotum Thallii-Heyl® distributed by Heyl Chemisch-pharmazeutische 1765 Fabrik GmbH, Berlin, Germany. Both products are available in bottles of 30 hard gelatine 1766 capsules, each containing 0.5 g of insoluble Prussian blue. 1767 1768 Prussian blue should only be given orally. 1769 1770 Adults and adolescents see comments above 1771 The recommended dose of Prussian blue is 3g orally three times/day 1772 1773 When the dose of radioactivity is substantially decreased the dose may be reduced to 1 or 2g 1774 three times/day to improve gastrointestinal tolerance 1775 1776 Paediatric dose (2-12 years) 1777 The recommended dose of Prussian blue is 1g orally 3 times/day 1778 1779 Neonates and infants 1780 Dose has not been established 1781 1782 In patients who cannot tolerate swallowing large numbers of capsules, the capsules may be 1783 mixed with bland food or liquids (this may result in blue discolouration of mouth and teeth). 1784 1785 Radiocaesium contamination: Treatment should be initiated as soon as possible after 1786 contamination is expected. Treatment should continue for a minimum of 30 days and then 1787 the patient should be reassessed for the amount of whole body radioactivity. The duration of 1788


41

treatment after exposure will be dictated by the level of contamination. 1789 1790 Thallium contamination: Ideally treatment should be initiated as soon as possible after 1791 exposure however Prussian blue is still thought to be effective after a delay in starting 1792 treatment and should not be withheld. 1793 1794 14.3 Precautions/contraindications 1795 As the antidotal effect of Prussian blue is due to the binding of thallium or caesium in the 1796 gut, it is only effective if the motility of the intestines is intact. In patients in coma or 1797 needing sedation, with reduced intestinal motility, medications to increase intestinal motility 1798 should be considered, although they are not proven effective in this setting. 1799 1800 Prussian blue decreases the duration of radiation exposure but does not treat the 1801 complications of radiation exposure. Supportive treatment for radiation toxicity symptoms 1802 should be given concomitantly with Prussian blue treatment. 1803 1804 In radiological emergencies the type of elemental exposure may not be known, Prussian blue 1805 may not bind to all the radioactive components and these elements may not undergo 1806 enterohepatic circulation which is necessary for Prussian blue binding and elimination. Thus 1807 patients contaminated with unknown or multiple radioactive elements may require additional 1808 treatments. 1809 1810 In severe thallium poisoning additional means for enhancing elimination should be 1811 considered; both charcoal haemoperfusion and haemodialysis have been used, although there 1812 are limited data to suggest that they have an impact on outcome. . 1813 1814 14.4 Pharmaceutical incompatibilities and drug interactions 1815 Prussian blue may bind oral drugs. When given together with oral tetracycline it is 1816 anecdotally reported to decrease the bioavailability of tetracycline. 1817 1818 Prussian blue may bind electrolytes in the gastrointestinal tract and asymptomatic 1819 hypokalaemia has occasionally been reported with its use. 1820 1821 14.5 Adverse effects 1822 Prussian blue is well tolerated; death or serious adverse effects have not been reported with 1823 Prussian blue. Mild to moderate constipation may occur which can be managed with a high 1824 fibre diet or bulk laxatives. It is essential to treat constipation as it will decrease elimination 1825 of thallium and caesium. Faeces will be coloured blue and blue sweat and tears have been 1826 reported with prolonged administration. 1827 1828 14.6 Use in pregnancy and lactation 1829 No contraindications. Prussian blue has been used in pregnant women and since it is not 1830 absorbed from the gastro-intestinal tract, effects on the fetus are not expected. The risk of 1831 toxicity from untreated radioactive caesium or thallium exposure is expected to be greater 1832 than the risk of reproductive toxicity from Prussian blue. 1833 1834 Prussian blue is unlikely to be excreted in breast milk as it is not significantly absorbed from 1835 the gastrointestinal tract, however, women with thallium toxicosis or exposure to 1836 radiocaesium should not breast feed due the risks to the baby from these elements. 1837 1838


42

14.7 Storage 1839 The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C; 1840 occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004). 1841 1842 1843

15. References 1844

1845 Atsmon J, Taliansky E, Landau M, Neufeld M (2000) Thallium poisoning in Israel. Am J 1846 Med Sci, 320(5):327-330 1847 1848 Barckow J & Jenss H (1976) [Thallium intoxication treated by haemodialysis, forced 1849 diuresis and antidote] (in German). Med Klin, 71(35): 1377-1382. 1850 1851 Barroso-Moguel R, Villeda-Hernández J, Méndez-Armenta M, Rìos C & Monroy-Noyola A 1852 (1994) Combined D-penicillamine and Prussian blue as antidotal treatment against 1853 thallotoxicosis in rats: evaluation of cerebellar lesions. Toxicology, 89:15-24. 1854 1855 Bhardwaj N, Bhatnagar A, Pathak DP & Singh AK (2006) Dynamic, equilibrium and human 1856 studies of absorption of 201TI by Prussian blue. Health Phys, 90(3): 250-257 1857 1858 BIBRA (1997) Toxicity Profile: Prussian Blue. 1859 1860 Bozorgzadéh A (1971) [Decorporation of radiocaesium by various hexacyanoferrates (II)] 1861 (German). Strahlentherapie, 142(6): 734-738. 1862 1863 Bozorgzadéh A & Catsch A (1972) Evaluation of the effectiveness of colloidal and insoluble 1864 ferrihexacyanoferrates (II) in removing internally deposited radiocaesium. Arch Intern 1865 Pharmacodyn Ther, 197(1): 175-188. 1866 1867 Brandão-Mello CE, Oliveira AR, Valverde NJ, Farina R & Cordeiro JM (1991) Clinical and 1868 hematological aspects of 137Cs: The Goiana radiation accident. Health Phys, 60(1): 31-39. 1869 1870 Breitenstein BD (2003). The medical management of unintentional radionuclide intakes. Radiat 1871 Prot Dosimetry, 105: 495-497. 1872 1873 Brenot A & Rinaldi R (1967) Toxicite et efficacite comparees de quatre ferrocyanures dans 1874 la decontamination du caesium radioactif 134. Pathol Biol (Paris), 15(1): 55-59. 1875 1876 CDC (2008) Thallium poisoning from eating contaminated cake-Iraq 2008. Morb Mortal 1877 Wkly Rep 57(37):1015-1018 1878 1879 Chan CK, Chan ML, Tse ML, Chan IHS, Cheung RCK, Lam CWK, Lau FL (2009) Life-1880 threatening Torsades de Pointes resulting from “natural“ cancer treatment. Clin Toxicology 1881 47 (6): 592-594 1882 1883 Chandler HA, Archbold GPR, Gibson JM, O’Callaghan P, Marks JN, Pethybridge RJ 1884 (1990). Excretion of a Toxic Dose of Thallium. Clinical Chemistry, 36(8): 1506-1509 1885 1886 De Backer W, Zachee P, Verpooten GA, Majelyne W, Vanheule A & De-Broe ME (1982) 1887


43

Thallium intoxication treated with combined hemoperfusion-hemodialysis. J Toxicol Clin 1888 Toxicol, 19(3): 259-264. 1889 1890 de Groot G (1982) Haemoperfusion in clinical toxicology. PhD Thesis, State University of 1891 Utrecht, The Netherlands. 1892 1893 de Groot G (1985) Thallium concentrations in body fluids and tissues in a fatal case of 1894 thallium poisoning . Veterinary and Human Toxicology, 27:1115-1119. 1895 1896 de Groot G & van Heijst ANP (1988) Toxicokinetic aspects of thallium poisoning. Methods 1897 of treatment by toxin elimination. Sci Total Environ, 71(3): 411-418. 1898 1899 de Groot G, van Heijst ANP, van Kesteren RG & Maes RAA (1985) An evaluation of the 1900 efficacy of charcoal hemoperfusion in the treatment of three cases of acute thallium poiso-1901 ning. Arch Toxicol, 57: 61-66. 1902 1903 De Wolff JNM, Lenstra JB (1964) The determination of thallium in urine. Pharmaceutisch 1904 Weekblad 99: 377-382. 1905 1906 Díaz V, Tapia R, Brinck G, Gutiérrez M, Hurtado C, del Peso G. [Thallium 1907 poisoning: Prussian blue treatment in 4 cases]. (Spanish) Rev Med Chil. 1990 1908 118(2):183-5. 1909 1910 Dresow B, Nielsen P, Fischer R, Pfau AA & Heinrich HH (1993) In vivo binding of 1911 radiocesium by two forms of prussian blue and by ammonium iron hexacyanoferrate (II). J 1912 Toxicol Clin Toxicol, 31(4): 563-569. 1913 1914 Dresow B, Nielsen P & Heinrich HC (1990) Efficacy of different hexacyanoferrates (II) in 1915 inhibiting the intestinal absorption of radiocaesium. Z Naturforsch, 45(6C): 676-680. 1916 1917 Dutch Pharmacopoeia (1966) 6th Edition. The Hague, Staatsuitgeverij. 1918 1919 Dvořák P (1971) [Binding by hexacyanoferrates (II) of thallium (I)] (German). Z 1920 Naturforsch, 26(4B): 277-281. 1921 1922 Dvořák P (1970) [Hexacyanoferrates (II) as thallium antidotes. Preparation and properties] 1923 (German). Arzneimittelforschung, 20(12): 1886-1888. 1924 1925 Dvořák P (1969) [Colloidal hexacyanoferrates (II) as antidotes in thallium poisoning] 1926 (German). Z Gesamte Exp Med, 151(1): 89-92. 1927 1928 Dvořák P, Günther M, Zorn U & Catsch A (1971) [Metabolic behaviour of colloidal 1929 ferrihexacyanoferrate (II)] (German). Naunyn Schmiedebergs Arch Pharmakol, 269(1): 48-1930 56 1931 1932 Farina R & Brandão-Mello CE (1991) Medical aspects of 137 Cs decorporation: The Goiana 1933 radiological accident. Health Phys, 60(1): 63-66. 1934 1935 Faustino PJ, Yongsheng Y, Progar JJ, Brownell CR, Sadrieh N, May JC, Leutzinger E, Place 1936 DA, Duffy EP, Houn F, Loewke SA, Mecozzi VJ, Ellison CD, Khan MA, Hussain AS & 1937


44

Lyon RC (2008) Quantitative determination of caesium binding to ferric hexacyanoferrate: 1938 Prussian blue. J Pharm Biomed Anal, 47(1): 114-125. 1939 1940 Fekry AE, El-Bieh NM, Elwan KM, Mangood SA (2003) The role of Prussian Blue in 1941 reducing the physiological effects of Cs-137 internal contamination. J Radioanalyt Nuclear 1942 Chem, 257 (1):75-82 1943 1944 Flanagan RJ, Braithwaite RA, Brown SS, Widdop B, de Wolff FA. Basic Analytical 1945 Toxicology, pp222-3. Geneva, World Health Organization, 1995. 1946 1947 Forth W (1986) [How useful is administration of colloidal Berlin blue for the 1948 decontamination of radio-caesium?] (German). Klin Wochenschr, 64(17): 810-812. 1949 1950 Forth W (1983) [Thallium poisoning] (German). Münch Med Wochenschr, 125(3): 45-50. 1951 1952 Forth W & Henning CH (1979) [Thallium intoxication and its therapy] (German). Dtsch 1953 Ärzteblatt, 76(43): 2803-2808. 1954 1955 Franke A, Rodiek S & Neu I (1979) [Thallium poisoning] (German). Notfallmedizin, 5(3): 1956 141-151. 1957 1958 Fred HL, Accad MF.(1997) Abdominal pain, leg weakness, and alopecia in a teenage boy. 1959 Hosp Pract (Minneap). Apr 15;32(4):69-70. 1960 1961 Gansser R (1982) [Acute thallium poisoning after a stay in the Near East] (German). Med 1962 Klin, 77(26): 60-67. 1963 1964 Gerber GB & Thomas RS (1992) Guidebook for the treatment of accidental internal 1965 radionuclide contamination of workers. Radiat Perot Dosimetry, 41: 3-49. 1966 1967 Ghezzi R, Bozza Marrubini M. (1979) Prussian blue in the treatment of thallium 1968 intoxication. Vet Hum Toxicol. 21 (Suppl):64-6. 1969 1970 Giese W & Hantzsch D (1970) [Comparative studies on caesium-137 elimination by various 1971 hexacyanoferrate complexes in the rat] (German). Zbl Vet Med, 185-190. 1972 1973 Giese W, Schanzel H & Hill H (1970) [Biological decontamination of highly radioactive 1974 milk given to pigs. 1. The behaviour of Cs-137 after daily dosage and under specific feeding 1975 conditions] (German). Zbl Vet Med, 11: 191-197. 1976 1977 Günther M (1971) [Influence of colloidal ferrihexacyanoferrate (II) on distribution and 1978 toxicity of thallium] (German). Arch Toxikol, 28(1): 39-45. 1979 1980 Havliček F (1968) Metabolism of radiocesium during gestation and lactation as influenced 1981 by ferric cyanoferrate (II). Int J Appl Radiat Isot, 19: 487-488. 1982 1983 Havliček F (1967) [The effect of ferric cyanoferrate (II) on the action of radiocaesium in 1984 pregnant and lactating rats] (German). Studia Biophysica Berlin, 2(3): 239-246. 1985 1986 Havliček F, Kleisner I, Dvořák P & Pospisil J (1967) [Effects of cyanoferrates on the 1987


45

excretion of radiocesium in rats and goats] (German). Strahlentherapie 134(1): 123-129. 1988 1989 Heath A, Ahlmén J, Branegård B, Lindstedt S & Wickström I (1983) Thallium poisoning - 1990 Toxin elimination and therapy in three cases. J Toxicol Clin Toxicol, 20(5): 451-463. 1991 1992 Heydlauf H (1969) Ferric-cyanoferrate (II): an effective antidote in thallium poisoning. Eur J 1993 Pharmacol, 6(3): 340-344. 1994 1995 Heyl (2004) Product Information for Radiogardase™ Radiogardase™ flyer 09/04 1996 www.heyltex.com site accessed October 08 1997 1998 Hoffman RS (2006) Prussian blue. In: Flomenbaum NE, Howland MA, Goldfrank LR, 1999 Lewin NA, Hoffman RS, Nelson LS (eds). Goldfrank’s Toxicologic Emergencies, 8th 2000 edition. New York, McGraw Hill, pp 1373-1377. 2001 2002 Hoffman RS (2003) Thallium toxicity and the role of Prussian Blue in therapy. Toxicol Rev, 2003 22(1): 29-40. 2004 2005 Hoffman RS (2000) Thallium poisoning during pregnancy: a case report and comprehensive 2006 literature review. J Toxicol Clin Toxicol, 38: 767-775. 2007 2008 Hologgitas J, Ullucci P, Driscoll J, Grauerholz J, Martin H. (1980) Thallium 2009 elimination kinetics in acute thallotoxicosis. J Analytical Toxicology. 4(2):68-75. 2010 2011 IAEA (1988) The radiological accident in Goiânia. International Atomic Energy Agency, 2012 Vienna. 2013 2014 Ioannides KG, Mantzios AS & Pappas CP (1991) Influence of Prussian blue in reducing 2015 transfer of radiocesium into ovine milk. Health Phys, 60(2): 261-264. 2016 2017 IPCS (1990) Poisons Information Monograph 525: Thallium. Available at 2018 http://www.inchem.org/documents/pims/chemical/pim525.htm 2019 2020 Jax W, Grabensee B & Schröder E (1973) [Treatment of thallium poisoning] (German). Med 2021 Welt, 24(17): 691-693. 2022 2023 Kamerbeek HH (1971) Therapeutic problems in thallium poisoning. Dissertation, Utrecht. 2024 2025 Kamerbeek HH, Rauws AG, ten Ham M & Van Heijst ANP (1971) Prussian blue in therapy 2026 of thallotoxicosis An experimental and clinical investigation. Acta Med Scand, 189: 321-2027 324. 2028 2029 Kargaćin B & Kostial K (1985) Reduction of 85Sr, 137Cs, 131I and 141Ce retention in rats by 2030 simultaneous oral administration of calcium alginate, ferrihexacyanoferrate (II), KI and Zn-2031 DTPA. Health Phys, 49: 859-864. 2032 2033 Keggin JF & Miles FD (1936) Structures and formulae of the prussian blues and related 2034 compounds. Nature, 137: 577-578. 2035 2036 Kemper FH (1979) [Thallium poisoning] (German). Münch Med Wochenschr, 121(42): 2037


46

1357-1358. 2038 2039 Kostial K, Kargaćin B, Rabar I, Blanusa M, Maljkovic T, Matkovic V, Ciganovic M, 2040 Simonovic I & Bunarevic A (1981) Simultaneous reduction of radioactive strontium, 2041 caesium and iodine retention by single treatment in rats. Sci Total Environ, 22(1): 1-10. 2042 2043 Kostial K, Kargaćin B & Šimonović I (1983) Efficiency of a composite treatment for mixed 2044 fission products in rats. J Appl Toxicol, 3(6): 291-296. 2045 2046 Kostial K, Vnučec M, Tominac Č & Šimonović I (1980) A method for a simultaneous 2047 decrease of strontium, caesium and iodine retention after oral exposure in rats. Int J Radiat 2048 Biol, 37(3): 347-350. 2049 2050 Kravzov J, Rìos C, Altagracia M, Monroy-Noyola A & Lopez F (1993) Relationship 2051 between physiochemical properties of prussian blue and its efficacy as antidote against 2052 thallium poisoning. J Appl Toxicol, 13: 213-216. 2053 2054 Le Gall B, Taran F, Renault D, Wilk JC & Ansoborlo E (2006) Comparison of Prussian blue 2055 and apple-pectin efficacy on 137Cs decorporation in rats. Biochimie, 88(11): 183718-41. 2056 2057 Lehmann PA & Favari L (1985) Acute thallium intoxication: kinetic study of the 2058 relative efficacy of several antidotal treatments in rats. Arch Toxicol, 57(1): 56-60 2059 2060 Lehmann PA & Favari L (1984) Parameters for the adsorption of thallium ions by activated 2061 charcoal and Prussian blue. J Toxicol Clin Toxicol, 22(4): 331-339. 2062 2063 Leloux MS, Nguyen PL & Claude JR (1990) Experimental studies on thallium toxicity in 2064 rats. II. The influence of several antidotal treatments on the tissue distribution and 2065 elimination of thallium after subacute intoxication. J Toxicol Clin Exp, 10(3): 147-156. 2066 2067 Lipsztein JL, Bertelli L, Melo DR, Azeredo AMGF, Juliao L & Santos MS (1991) 2068 Studies of Cs retention in the human body related to body parameters and Prussian blue 2069 administration. Health Phys, 60(1): 57-61. 2070 2071 Ludi A. (1988) Berliner Blau. Chemie in unserer Zeit; 4:123-127 2072 2073 Ludi A (1983) A comment on "Isotopic exchange in Prussian blue". J Chem Educat, 60: 528. 2074 2075 Ma R, Jin Y, Wang S & Zhou Y (1985) Study of 137-Cs metabolism in humans. In: 2076 Assessment of radioactive contamination in man 1984: proceedings of an International 2077 Symposium on the Assessment of Radioactive Contamination in Man. International Atomic 2078 Energy Agency in cooperation with the World Health Organization. Paris, 19-23 November 2079 1984. Vienna, International Atomic Energy Agency, pp 499-506. 2080 2081 Madshus K & Strömme A (1968) Increased excretion of 137Cs in humans by Prussian Blue. 2082 Z Naturforsch, 23(3B): 391-392. 2083 2084 Madshus K, Strömme A, Bohne F & Nigrović V (1966) Diminution of radiocaesium body-2085 burden in dogs and human beings by Prussian blue. Int J Rad Biol, 10(5): 519-520. 2086 2087


47

Malbrain MLNG, Lambrecht GLY, Zandijk E, Demedts PA, Neels HM, Lambert W, de 2088 Leenheer AP, Lins RL & Daelmans R (1997) Treatment of severe thallium intoxication. J 2089 Toxicol Clin Toxicol, 35 (1):97-100. 2090 2091 Manninen V, Mälkönen M & Skulskii IA (1976) Elimination of thallium in rats as 2092 influenced by Prussian blue and sodium chloride. Acta Pharmacol Toxicol, 39: 256-261. 2093 2094 Melo DR, Lipsztein JL, de Olivera CAN & Bertelli L (1994) 137Cs internal contamination 2095 involving a Brazilian accident, and the efficacy of Prussian blue treatment. Health Phys, 2096 66(3): 245-252. 2097 2098 Meggs WJ, Cahill-Morasco R, Shih RD, Goldfrank LR, Hoffman RS (1997) Effects of 2099 Prussian blue and N-acetylcysteine on thallium toxicity in mice. Clin Toxicol, 35(2):163-166 2100 2101 Moffat AC, Osselton MD, Widdop B, Galichet LY (eds) Clarke's Analysis of Drugs and 2102 Poisons 3rd ed, London, Pharmaceutical Press, 2004 2103 2104 Moore D, House I, Dixon A.(1993) Thallium poisoning. Diagnosis may be elusive but 2105 alopecia is the clue. British Medical Journal. 306(6891):1527-9. Erratum in: BMJ 1993 Jun 2106 12;306(6892);1603. 2107 2108 Müller WH (1969) [Cs137 decorporation using colloidal soluble Berlin blue in rats] 2109 (German). Strahlentherapie, 137(6): 705-707. 2110 2111 Müller WH, Ducousso R, Causse A & Walter C (1974) Long-term treatment of cesium-137 2112 contamination with colloidal and a comparison with insoluble Prussian blue in rats. 2113 Strahlentherapie, 147(3): 319-322. 2114 2115 Niehues R, Horstkotte D, Klein RM, Kühl U, Kutkuhn B, Hort W, Iffland R, 2116 Strauer BE.(1995) [Repeated ingestion with suicidal intent of potentially lethal amounts of 2117 thallium](German) Deutsch Med Wochenschr 24;120(12):403-8 2118 2119 Nielsen P, Dresow B & Heinrich HC (1987) In vitro study of 137Cs sorption by 2120 hexacyanoferrates (II). Z Naturforsch, 42B 1451-1460. 2121 2122 Nielsen P, Dresow B, Fischer R, Gabbe EE, Heinrich HC & Pfau AA (1988a) Intestinal 2123 absorption of iron from 59Fe-labelled hexacyanoferrates (II) in piglets. 2124 Arzneimittelforschung, 38(10): 1469-1471. 2125 2126 Nielsen P, Dresow B, Fischer R Heinrich HC (1991) Inhibition of intestinal absorption of 2127 radiocaesium in humans by hexacyanoferrates (II). Nucl Med Biol, 18(7): 821-826. 2128 2129 Nielsen P, Dresow B, Fischer R & Heinrich HC (1990a) Bioavailability of iron and cyanide 2130 from oral potassium ferric hexacyanoferrate (II) in humans. Arch Toxicol, 64(5): 420-422. 2131 2132 Nielsen P, Fischer R, Heinrich HC & Pfau AA (1988b) Prevention of enteral radiocesium 2133 absorption by hexacyanoferrates (II) in piglets. Experientia, 44(6): 502-504. 2134 2135 Nigrović V (1965) Retention of radiocaesium by the rat as influenced by prussian blue and 2136 other compounds. Phys Med Biol, 10(1): 81-91. 2137


48

2138 Nigrović V (1963) Enhancement of the excretion of radiocaesium in rats by ferric 2139 cyanoferrate (II). Int J Rad Biol, 7(3): 307-309. 2140 2141 Nigrović V, Bohne F & Madshus K (1966) [Decorporation of radionuclide: research on 2142 radiocaesium] (German). Strahlentherapie, 130(3): 413-419. 2143 2144 Nogué S, Mas A, Parés A, Nadal P, Bertrán A, Millá J, Carrera M, To J, Pazos MR & 2145 Corbella J (1982) Acute thallium poisoning: An evaluation of different forms of treatment. J 2146 Toxicol Clin Toxicol, 19(10): 1015-1021. 2147 2148 Pai V (1987) Acute thallium poisoning: Prussian blue therapy in 9 cases. West Ind Med J, 2149 36: 256-258 2150 2151 Pau PWI (2000) Management of thallium poisoning. HKMJ, 6(3): 316-319 2152 2153 Pederson RS, Olesen AS, Freund LG, Solgaard P & Larsen E (1978) Thallium intoxication 2154 treated with long-term hemodialysis, forced diuresis and prussian blue. Acta Med Scand, 2155 204(5): 4 2156 2157 Pelclová D, Urban P, Ridzon P, Senholdová Z, Lukás E, Diblík P, Lacina L. (2009)Two-2158 year follow-up of two patients after severe thallium intoxication. Human & Experimental 2159 Toxicology ;28(5):263-72. 2160 2161 Rangel-Guerra R, Martínez HR, Villarreal HJ.(1990) [Thallium poisoning. Experience with 2162 50 patients] (Spanish). Gac Med Mex.126(6):487-94; 2163 2164 Rauws AG (1974) Thallium pharmacokinetics and its modification by Prussian Blue. 2165 Naunyn Schmiedebergs Arch Pharmacol, 284(3): 294-306. 2166 2167 Rauws AG & van-Heijst AN (1979) Check of Prussian blue for antidotal efficacy in thallium 2168 intoxication. Arch Toxicol, 43(2): 153-154. 2169 2170 Richelmi P, Bono F, Guardia L, Ferrini B & Manzo L (1980) Salivary levels of thallium in 2171 acute human poisoning. Arch Toxicol, 43(4): 321-325. 2172 2173 Richmond CR (1968) Accelerating the turnover of internally deposited radiocesium. In: 2174 Kornberg HA & Norwood WD (eds). Diagnosis and treatment of deposited radionuclides. 2175 Amsterdam, Excerpta Medica Foundation, pp 315-327. 2176 2177 Richmond CR & Bunde DE (1966) Enhancement of cesium-137 excretion by rats 2178 maintained chronically on ferric ferrocyanide. Proc Soc Exp Biol Med, 121(3): 664-670. 2179 2180 Rìos C, Kravsov J, Altagracia M, Lopez-Naranjo F & Monroy A (1991) Efficacy of prussian 2181 blue against thallium poisoning: effect of particle size. Proc West Pharmacol 34: 61-63. 2182 2183 Rìos C & Monroy-Noyola A (1992) D-penicillamine and prussian blue as antidotes against 2184 thallium intoxication in rats. Toxicology, 74: 69-76. 2185 2186 Robb-Smith AHT (1987) Thallium and a pale horse. Lancet, I: 872. 2187


49

2188 Sabbioni E, Gregotti C, Edel J, Marafante E, Di Nucci A & Manzo L (1982) Organ/tissue 2189 disposition of thallium in pregnant rats. Arch Toxicol, Suppl 5: 225-230. 2190 2191 Schwartz JG, Stuckey JH, Kunkel SP, Dowd DC, Kagan-Hallet KS.(1988) Poisoning from 2192 thallium. Tex Med. 84(8):46-8. 2193 2194 Spoerke DG, Smolinske SC, Wruk KM & Rumack BH (1986) Infrequently used antidotes: 2195 indications and availability. Vet Hum Toxicol, 28(1): 69-75. 2196 2197 Stather JW (1972) Influence of Prussian blue on metabolism of 137Cs and 86Rb in rats. Health 2198 Phys, 22(1): 1-8. 2199 2200 Stevens W, van Peteghem C, Heyndrickx A & Barbier F (1974) Eleven cases of thallium 2201 intoxication treated with Prussian blue. Int J Clin Pharmacol, 10(1): 1-22. 2202 2203 Stevens WJ.(1978) Thallium intoxication caused by a homoeopathic preparation. Toxicol 2204 Eur Res. 1(5):317-20. 2205 2206 Strömme A (1968) Increased excretion of 137Cs in humans by Prussian blue. In: Kornberg 2207 HA & Norwood WD (eds). Diagnosis and treatment of deposited radionuclides. Amsterdam, 2208 Excerpta Medica Foundation, pp 329-332. 2209 2210 Tang MH, Gong YF, Shen CY, Ye CQ & Wu DC (1988) Measurement of internal 2211 contamination with radioactive caesium released from Chernobyl accident and enhanced 2212 elimination by Prussian blue. J Radiol Prot, 8(1): 25-28. 2213 2214 Thompson DF & Callen ED (2004) Soluble or Insoluble Prussian Blue for Radiocesium and 2215 Thallium Poisoning? Ann Pharmacother, 38: 1509 - 1514. 2216 2217 Thompson DF & Church CO (2001) Prussian Blue for treatment of Radiocesium poisoning. 2218 Pharmacother, 21: (11) – 1364-1367. 2219 2220 Thurgar LD, Singh JM & Thompson MA (2006) Non radioactive caesium toxicity: A case 2221 of treatment using Prussian blue [abstract]. Clin Toxicol, 44: 730-731. 2222 2223 Toohey RE (2003) Internal dose assessment in radiation accidents. Radiat Prot Dosimetry, 105: 2224 329-331. 2225 2226 Trenkwalder P, Bencze K & Lydtin H (1984) [Chronic thallium poisoning. Report of a case 2227 of criminal poisoning] (German). Dtsch Med Wochenschr, 109(41): 1561-1566. 2228 2229 Van Der Merwe CF (1972) The treatment of thallium poisoning: A report of 2 cases. S.A. 2230 Med J, 46: 960-961 2231 2232 Van der Stock J & De Schepper J (1978) The effect of Prussian blue and sodium- 2233 ethylenediaminetetraacetic acid on the faecal and urinary elimination of thallium by the dog. 2234 Res Vet Sci, 25(3): 337-342. 2235 2236 Van Kesteren RG, Rauws AG, de Groot G & van Heijst ANP (1980) Thallium intoxication. 2237


50

An evaluation of therapy. Intensivmed, 17: 293-297. 2238 2239 Verzijl JM, Joore JCA, van Dijk A, Glerum JH, Savelkoul TJF, Sangster B & van het Schip 2240 AD (1992) In vitro binding characteristics for caesium of Prussian blue, activated charcoal 2241 and resonium A. J Toxicol Clin Toxicol, 30(2): 215-222. 2242 2243 Verzijl JM, Joore HCA, van Dijk A, Wierckx FCJ, Savelkoul TJF & Glerum JH (1993) In 2244 vitro cyanide release of four Prussian blue salts used for the treatment of caesium 2245 contaminated persons. J Toxicology Clinical Toxicology, 31(4): 553-562. 2246 2247 Villa AF, Poupon J, Cantanese V, El Balkhi S, Nikolova N, Dupont A, Garnier R (2009) 2248 Interest of late and prolonged treatment by Prussian blue in acute thallium poisoning 2249 (abstract). Clinical Toxicology, 47(5): 502 2250 2251 Villanueva E, Hernandez.Cueto C, Lachia E, Rodrigo MD & Ramos V (1990) Poisoning by 2252 thallium. A study of five cases. Drug Safety, 5(5): 384-389. 2253 2254 Vogel AI (1954) A textbook of macro and semimicro qualitative inorganic analysis. 4th 2255 Edition London, Longmans. 2256 2257 Volf V, Doerfel H, Krug H, Prech V, Schuppler U, Sontag W & Stahr B (1987) The effect of 2258 Prussian blue on caesium in man after the Tchernobyl reactor accident. In: Radiation 2259 research. Proceedings of the 8th International Congress of Radiation Research, Edinburgh, 2260 July 1987. EM Fielden (ed). International Congress of Radiation Research (8th 1987 2261 Edinburgh, Scotland). London: Taylor and Francis, abstract B10-7V, p57. 2262 2263 Vrij AA, Cremers HM & Lustermans FA (1995) Successful recovery of a patient with 2264 thallium poisoning. Neth J Med, 47:121-126. 2265 2266 Wainwright AP, Kox WJ, House IM, Henry JA, Heaton R & Seed WA (1988) Clinical 2267 features and therapy of acute thallium poisoning. Q J Med, 69(258): 939-944. 2268 2269 Wolsieffer JR, Stookey GK & Muhler JS (1969) Studies concerning the effect of ferric 2270 ferrocyanide, beet pulp, and fluoride upon 137cesium retention in the rat. Proc Soc Exp Biol 2271 Med, 130(3): 953-956. 2272 2273 Yang Y, Brownell CR, Sadrieh N, May JC, Del Grosso AV, Place D et al (2007) 2274 Quantitative measurement of cyanide released from Prussian blue. Clinical Toxicology, 45: 2275 776-781. 2276 2277 Yang Y, Faustino PJ, Progar JJ, Brownell CR, Sadrieh N, May JC, Leutzinger E, Place DA, 2278 Duffy EP, Yu LX, Khan MA & Lyon RC (2008) Quantitative determination of thallium 2279 binding to ferric hexacyanoferrate: Prussian blue. Int J Pharm, 353(1-2): 187-194. 2280 2281 Walker AW (1998) SAS Trace Element Laboratories. Clinical and analytical handbook, 3rd 2282 edition. Guildford, Royal Surrey Hospital. 2283 2284 2285


51

16. Author(s) Name, Address 2286

Initial draft by ANP van Heijst, A von Dijk & J Ruprecht. 2287 2288 Update and revision by Maeve McParland, Paul Dargan, London 2289 2290 November 2009 2291 2292

17. Additional Information 2293

2294 Table 1: Results of EMBASE search 4th November 2009 2295 Number Keywords Results 1 Prussian AND Blue 631 2 Thallium 7299 3 Caesium 959 4 Caesium 2718 5 Radiocesium 392 6 Poisoning OR

Toxicity OR Overdose

193447

7 1 AND 2 47 8 Duplicate filtered: 1

AND 2 47 unique results 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 2296 2297 Table 2: Results of Medline search 4th November 2009 2298 Number Keywords Results 1 Prussian AND Blue 860 2 Thallium 8122 3 Caesium 1138 4 Caesium 3733 5 Radiocesium 297 6 Poisoning OR

Toxicity OR Overdose

240196

7 1 AND 2 49 Duplicate filtered: 1

AND 2 49 unique results 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


52

12 1 AND 5 AND 6 4 14 Rubidium 1935 15 1 AND 14 0

Results of Cochrane Library Search 4th November 2009 2299

No results found for Prussian blue using all possible MeSH terms. 2300

Table 3: Summary of evidence of use of Prussian blue in metal poisoning Metal Clinical trial data Case reports Animal studies Radiocaesium No controlled trials

Volunteer studies: 3 g daily of Prussian blue given before 137Cs did not reduce caesium absorption. The increase in 137Cs excretion was small following 0.5 g of Prussian blue three times daily (Madshus & Strömme, 1968). In 6 volunteers it was shown that Prussian blue (4 x 0.5 g or 10 x 0.2 g daily for 2-3 weeks) did not fully block caesium uptake from contaminated food (Volf et al., 1987). Both forms of Prussian blue were equally effective in reducing radiocaesium absorption in 2 male volunteers who ingested meals labelled with a tracer dose of 134Cs, 10 minutes after ingestion of 1 g of Prussian blue (Dresow et al., 1993).

Prussian blue treatment reduced the half-life of caesium in 5 patients accidentally exposed to 137Cs (Ma et al, 1985) Goiânia incident Of 249 people contaminated with 137Cs, 46 were treated with Prussian blue and this significantly increased the rate of faecal excretion and reduced the whole body burden retention of caesium (IAEA, 1988). In 15 of these patients the body burden of 137Cs was reduced by an average of 71% within 2 months of the exposure (Melo et al, 1994). Comparing the elimination of 137Cs from the bodies of 18 adults after varying regimens of Prussian blue therapy, Lipsztein et al (1991) found that overall the half-life of 137Cs was reduced by 32% and higher dose rates of Prussian blue gave a greater reduction. Chernobyl incident Fifteen students were exposed to

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;


2

Metal Clinical trial data Case reports Animal studies 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 admini-stration 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). In volunteer studies involving self-dosing by the study authors, ingestion of Prussian blue 180 days after ingestion of 137Cs 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

134Cs and 137Cs 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 post-exposure and this was reported to reduce the half-life of caesium and enhance elimination (Tang et al., 1988).

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)


3

Metal Clinical trial data Case reports Animal studies biological half-life of caesium was reduced on average to one third of its original half-life (Madshus & Strömme, 1968; Strömme, 1968). 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).

Non-radiocaesium No controlled clinical trials

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).

Rubidium No human data

No Human data Prussian blue reduced the biological half-time of retention of Rubidium-86 in rats (Stather, 1972)

Thallium No volunteer studies. Bhardwaj et al, 2006 (thallium-201) 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

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

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


4

Metal Clinical trial data Case reports Animal studies hours, respectively, of oral Prussian blue therapy. Patient-2 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

reports are tabulated below. There are single case reports: (Atsmon, 2000; Chandler 1990; DeBacker, 1982; Fred & Accad, 1997; Hologittas et al, 1980; Malbrain et al; Niehues et al 1995; Pau, 2000; Pedersen et al 1978; Richelmi, 1980; Rob-Smith, 1987; Schwartz et al 1988; Stevens 1978; Villa et al, 2009; Vrij, 1995; Wainwright, 1988; and multiple case reports: (CDC, 2008; Diaz et al 1990; Ghezzi et al, 1979; Kamerbeek et al 1971; Meggs et al 1994; Moore et al 1993; Pai, 1987; Pelclova et al 2009; Rangel-Guerra et al 1990; Stevens, 1974; Van Kesteren, 1980; Villanueva, 1990) 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

excretion of thallium by Prussian blue results in a decrease of the thallium content in liver, kidney, skeleton, blood, heart and muscles (Dvořák, 1969; Günther, 1971; Heydlauf, 1969; Kravzov et al., 1993; Manninen et al., 1976; Rauws, 1974; Rìos et al., 1991; Rìos & Monroy-Noyola, 1992; Sabbioni et al., 1982). Rìos & Monroy-Noyola (1992) demonstrated that Prussian blue increased LD50 of thallium by 31%. Meggs et al (1997) found that Prussian blue decreased the mortality from thallium poisoning in mice 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


5

Metal Clinical trial data Case reports Animal studies poisoning, demonstrating an approximately 7-fold increase in faecal elimination with its use. A reduction in thallium half-life was observed in thallium poisoned patients when compared with no therapy at all (De Groot & van Heijst, 1988)

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 (1990) - 35 days; Villanueva, (1990) > 2 weeks; Wainwright, (1988) approx. 5 days; Pai, (1987) - 4 to 7 days; Rob-Smith, (1987) - 5 days. 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.

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.


6

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

Interval between onset of illness and treatment

Form of PB Dosing regimen

Other treatments Outcome

Villa et al 2009

1 NK Urine: 5118 µg/g creatinine

42 days Insoluble 6g tds (18g/day) for 24 d, second course for 31d

Died (final Tl level 3 µg/g creatinine

Atsmon et al 2000

1 NK Renal excretion 7mg/24 hours

>9 days ? 250 mg/kg/d mannitol Neurological sequelae

Pau, 2000 1 Urine at 35d: 8.56 µmol/L (NR = 0.003 µmol/L) Blood at 42d: 0.15 µmol/L (NR <0.07 µmol/L)

~42 days Colloidal soluble

4g every 8 hours (12g/day)

Activated charcoal, Succimer,

Persistent weakness

Vrij et al 1995 1 NK Urine (24 hr): 4300 µg/L (NR <10 µg/L) Blood: 300 µg/L (NR <10 µg/L)

~128 days Colloidal soluble

250 mg/kg per day for 14 days

Mannitol, cisapride, forced diuresis

Neurological sequelae

Malbrain et al 1997

1 8.75g thallium sulphate

Urine: 69,600 µg/L Blood: 5,240 µg/L

2 hours Colloidal soluble

3g then 0.5g 6xday (3g/day) for 20 days

Emesis & gastric lavage Mannitol, lactulose Potassium, haemodialysis


Chandler 1990

1 NK 35 days Colloidal soluble

5g every 6 hrs (20g/day) for 2 mths

Plasma exchange, i.v. potassium,


Wainwright et 1 NK Urine: 6000 µg/L 3 days Colloidal 5g every 6 hrs Mannitol, forced Neurological


7





al 1988 Blood 5750 µg/L

soluble (20g/day) diuresis, haemodialysis, haemofiltration, diethyldithiocarbamate

sequelae (estimated faecal excretion of Tl 2g over 20d; by forced diuresis 820mg; by dialysis 225mg)

Robb-Smith 1987

1 (21 mth child)

NK ? >10 days ? NK, for 3 weeks

Potassium Neurological sequelae

De Backer et al 1982

1 100 mg thallium sulphate

Blood: 415 µg/L 6 hours Colloidal soluble

250mg/kg (per day?)

Gastric lavage, combined haemoperfusion-haemodialysis for 4 hrs

Recovered

Richelmi et al 1980

1 1 g thallium sulphate Urine: 3000 µg/L Gastric aspirate: 10800 µg/L

4 days Colloidal soluble

5g every 6 hours (20g/day) for 20 days

Mannitol Recovered

Fred & Accad 1997

1 ? ? ? ? ? ? ?

Hologgitas et al 180

1 ? ? ? ? ? Kayexelate (sodium polystyrene)

died

Niehues et al 1995

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

Gastric decontamination Haemodialysis 2nd adm: aemodialysis, forced diuresis (1 l urine/h), orthograde intestinal infusions, potassium

Nogue et al 1 750 mg thallium Blood: 950 µg/L >1.5 days Not stated 1g 8 hourly Mannitol


8





1982 sulphate (approx) (30g/day) days 1-4 and 16-19

Forced diuresis with potassium Haemodialysis IV and oral Diethyl dithiocarbamate Oral Diphenylthiocarbazone (dithizone)

Pedersen et al 1978

1 2g ? ? ? ? Forced diuresis haemodialysis

Schwartz et al 1988

1 ? ? ? ? ? ? ?

Stevens 1978 1 ? ? ? ? ? ? recovered CDC 2008 10 (5

children) NK Blood: 289 µg/L

(median); range 53 - 1408 µg/L Urine (24hr): 3063 µg/L (median); range 542 - 12556 µg/L

11 days

Insoluble (Antidotum-Thallii-Heyl & Radiogardase)

250 mg/kg/d 2 children died before treatment; 2 adults died (already comatose before treatment started)

De Groot et al 1985

Case 1 NK Blood 2800 µg/L Recovered

Case 2 NK Blood 5800 µg/L Recovered Case 3 NK Blood 1900 µg/L

<48 hrs

Not stated

10g twice per day

Gastric lavage Mannitol Forced diuresis Haemoperfusion Recovered

Díaz et al 1990

Case 1 NK Urine: 11400 µg/L 5 days 12 days Magnesium sulphate, potassium, furosemide,

Recovered

Case 2 NK Urine: 6300 µg/L 12 days

Not stated

Not stated Potassium Diuretics

Recovered


9





Case 3 NK Urine: 3500 µg/L 7 days Not stated Magnesium sulphate, potassium, furosemide,

Recovered

Case 4 15 mg Urine: 3090 µg/L 15 days Not stated Not stated Potassium Diuretics

Recovered Note: 6000µg/L thallium level at 45 days after intoxication. No new ingestion of thallium reported.

4 (2 children)

NK 10yr old: 18400 µg/L

>14 days ? 250mg/kg 6 hourly

Recovery Villanueva et al 1990

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

Activated charcoal Mannitol Potassium Multivitamins High fluid intake

Recovered? Van der Merwe 1972

Case 2 700 mg thallium sulphate

>6 hours ? 250 mg/kg/day in 4 doses for 10 days

Gastric lavage Mannitol High fluid intake

Recovered?

14 Case 1

Urine 2200 µg/mL (sic) Blood 16 µg/mL (sic)

Pai 1987

Case 2

NK

Urine 48 µg/mL

4-7 days Colloidal soluble

2g every 8 hrs (6g/day) for 6 weeks

Magnesium sulphate, analgesia, diuretics, vitamin B complex

5 died before treatment 9 recovered


10





(sic) Blood 4 µg/mL (sic)

Case 3 Urine 250 µg/mL (sic) Blood 4 µg/mL (sic)






Case 9

Urine 23 µg/mL (sic) Blood 4 µg/mL (sic)

18 (details below):

Urine concentration (mg/L)

A 500 mg 2.1 28 days B 2.4 g 47.4 2 days Gastric lavage Died C 350 mg 8.8 1 day Gastric lavage D 1 g 20.2 4 days

Van Kesteren et al 1980

E 1 g 71.1 2 days

Colloidal soluble

10g twice per day (20g/day)

Gastric lavage


11





F 480 mg 1.0 ½ day Gastric lavage G unknown 2.0 2 days Gastric lavage H 1 g 84.0 1 days Gastric lavage Survived but

died 6hrs after second overdose with thallium

I 1 g 40.0 2 hours Gastric lavage J unknown 3.0 ? K 750 mg 24.6 4 days Forced diuresis L 875 mg 54.0 1 day Gastric lavage, Forced

diuresis

M 1.5 g 79.8 14 days Forced diuresis N 1.5 g 80.0 1 day Gastric lavage

Forced diuresis, haemoperfusion

O unknown 8.0 ? Forced diuresis P unknown 10.0 ? Forced diuresis Q unknown 2.2 2 days Gastric lavage

Forced diuresis

R 3 g 50.0 1 Gastric lavage Forced diuresis, haemoperfusion

Stevens et al 1974

Case 1 NK Urine 1430 µg/L 30 days 10g twice per day every 2 days. Duration not stated

Activated charcoal Potassium

Recovered with some muscular weakness at 3 mth

Case 2 1000mg Not stated Few hours 10g twice per day every 2 days for 11 days

Gastric lavage Recovered

Case 3 NK Urine: 7100 µg/L 42 days

Not stated

20g per day Neurological


12





for 15 days sequelae Case 4 300 mg Urine elimination

3220 µg/24 hrs 10 hours 5g four times

per day for 19 days

Gastric lavage mannitol

Recovered

Case 5 NK Urine elimination 120 µg/24 hrs

94 days 5g four times per day. Duration not stated

mannitol Neurological sequelae

Case 6 NK Urine 570 µg/L 28 days 5g four times per day for >50 days

mannitol Recovered

Case 7 NK Urine 232 µg/L 2nd admission: urine 230 µg/L

62 days 5g four times per day for 18 days

mannitol Recovered

Case 8 NK Not stated 151 days 5g four times per day for 45 days

Mannitol, Potassium, antibiotics

Recovered

Case 9 300 mg Urine elimination 2310 µg/24 hrs

2 hours 5g four times per day for 25 days

Gastric lavage Potassium

Recovered

Case 10 (child 6yrs)

225 mg Urine elimination 840 µg/24 hrs

9 days 1g four times per day for 35 days

mannitol Recovered

Case 11 (child 2yrs)

NK Urine elimination 180 µg/24 hrs

1 day 1.7g four times

Lactulose, furosemide Recovered

Ghezzi & Bozza Marrubini, 1979

5 (1 neonate)

? ? ? ? ? Dithizone (1 patient) Died 4 recovered

Kamerbeek et Case 1 400 mg Not stated Not stated Colloidal ? ? ?


13





soluble? Case 2 400 mg Not stated Not stated Colloidal

soluble?

al 1971

Case 3 2000 mg Not stated 14 days Colloidal soluble?

Meggs et al 1994

4 NK Urine: 10837 µg/L and 9569 µg/L

2 days ? 2g tds (6g/day)

Multiple dose activated charcoal, haemodialysis, analgesia

Recovered

Moore et al 1993

2 NK Blood: 600 µg/L (approx)

>28 days Colloidal soluble

250 mg/kg/d

sequelae

Case 1 NK Urine: 8.5 µg/L Blood 0.3 µg/L

NK - had probably be poisoned several times over 2 years

Insoluble 6g per day for 5 days


Pelclova et al 2009

Case 2 NK Urine: 2800 µg/L Blood: 770 µg/L

4 weeks approx

Insoluble 6g per day for 21 days


Rangel-Guerra et al 1990

50 NK Ranges: Urine 100 - 28000 µg/L Blood: 100 - 1360 µg/L

Not stated Colloidal soluble?

3g/day for 10-14 days

Gastric lavage Forced diuresis 3 patients also received sodium iodide, 5 patients also received potassium iodide

1 death

Case 1 NK Urine: 420 µg/L 4 weeks Colloidal soluble?

3 g/day? Forced diuresis, painkillers

Recovered

Case 2 (neonate from Case 1)

NK placental exposure Urine: 60 µg/L 14 days Colloidal soluble?

Not stated Not stated Neurological sequelae


14





Case 45 NK Urine: 950 µg/L 2 months Insoluble 3 g/day? Not stated Neurological sequelae

ipcs evaluation of antidotes for poisoning by …56 (faustino, 2008). work in the 1960s investigated...

Documents