1 DRAFT for review - do not cite or quote 2 3 4 5 6 7 IPCS EVALUATION OF ANTIDOTES 8 9 IN POISONING BY METALS AND METALLOIDS 10 11 12 13 14 15 16 17 Succimer 18 (2,3-Dimercaptosuccinic acid, DMSA) 19 20 21 22 23 24 25 26 27 First Draft: Professor Ole Anderson, dr.med., 28 Department of Life Sciences and Chemistry, Roskilde University, 29 Denmark 30 31 32 33 Revision, November 2005: Nicola Bates MSc, MA, Medical Toxicology Unit, Guy's & 34 St Thomas' NHS Foundation Trust, London, UK 35 . 36 Units corrected Feb 07, updated March 2009 37 1 38 39 40 1. INTRODUCTION 5 41 2. NAME AND CHEMICAL FORMULA 5 42 3. PHYSICO-CHEMICAL PROPERTIES 6 43 4. PHARMACEUTICAL FORMULATION AND SYNTHESIS 7 44 4.1 Routes of synthesis 7 45 4.2 Presentation and formulation 7 46 5. ANALYTICAL METHODS 7 47 5.1 Quality control procedures for the antidote 7 48 5.2 Methods for identification of the antidote 8 49 5.3. Methods for analysis of the antidote in biological samples 8 50 5.4 Analysis of the toxic agent in biological samples 8 51 6. SHELF-LIFE 8 52 7. GENERAL PROPERTIES 8 53 8. ANIMAL STUDIES 9 54 8.1 Pharmacodynamics 10 55 8.1.1 Aluminium 10 56 8.1.2 Antimony 10 57 8.1.3 Arsenic 10 58 8.1.4 Beryllium 13 59 8.1.5 Bismuth 14 60 8.1.6 Cadmium 14 61 8.1.7 Chromium 17 62 8.1.8 Cobalt 18 63 8.1.9 Copper 18 64 8.1.10 Gold 19 65 8.1.11 Lead 19 66 8.1.11.1 Effect of succimer on gastrointestinal lead absorption 23 67 8.1.11.2 Effect of succimer on brain lead concentrations 24 68 8.1.11.3 Effect of succimer on lead-induced neurotoxicity 24 69 8.1.12 Manganese 25 70 8.1.13 Mercury 25 71 8.1.14 Nickel 29 72 8.1.15 Palladium 29 73 8.1.16 Platinum 30 74 8.1.17 Polonium 30 75 8.1.18 Promethium 31 76 8.1.19 Selenium 31 2 77 8.1.20 Silver 31 78 8.1.21 Strontium 32 79 8.1.22 Thallium 32 80 8.1.23 Tin 32 81 8.1.24 Vanadium 33 82 8.1.25 Zinc 33 83 8.2 Pharmacokinetics 34 84 8.3 Toxicology 35 85 8.3.1 Acute toxicity 35 86 8.3.1.2 Subacute toxicity (28 days) 35 87 8.3.2 Chronic toxicity (180 days) 35 88 8.3.3 Reproductive toxicity and teratogenicity 35 89 8.3.4 Genotoxicity 36 90 9. VOLUNTEER STUDIES 37 91 9.1 Absorption 37 92 9.2 Distribution 37 93 9.3 Elimination 38 94 9.4 Metabolism 38 95 9.5 Effect of succimer on the excretion of metals 38 96 9.5.1 Bismuth elimination 38 97 9.5.2 Cadmium elimination 38 98 9.5.3 Lead elimination 39 99 9.5.4 Mercury elimination 39 100 9.5.5 Trace element elimination 40 101 10. CLINICAL STUDIES – CLINICAL TRIALS 41 102 10.1 Arsenic and succimer clinical trials 41 103 10.2 Copper and succimer clinical trials 41 104 10.3 Lead and succimer clinical trials 42 105 10.3.1 Study by the Treatment of Lead-Exposed Children (TLC) Study Group 45 106 10.4 Mercury and succimer clinical trials 46 107 11 CASE REPORTS – CLINICAL STUDIES 47 108 11.1 Aluminium 47 109 11.2 Antimony 47 110 11.3 Arsenic 48 111 11.4 Beryllium 51 112 11.5 Bismuth 52 113 11.6 Cadmium 52 114 11.7 Cobalt 52 115 11.8 Copper 52 3 116 11.8.1 Use in Wilson’s disease 52 117 11.9 Gold 52 118 11.10 Lead 53 119 11.10.1 Acute lead poisoning in children 53 120 11.10.2 Chronic lead poisoning in children 54 121 11.10.3 Chronic lead poisoning in adults 54 122 11.10.4 Chronic lead poisoning in pregnancy 56 123 11.11 Manganese 57 124 11.12 Mercury 57 125 11.13 Thallium 61 126 11.14 Tin 61 127 12. SUMMARY OF EVALUATION 61 128 12.1 Indications 61 129 12.2 Advised routes and dose 62 130 12.3 Other consequential or supportive therapy 62 131 12.4 Controversial issues and areas of insufficient information 63 132 12.5 Proposals for further studies 63 133 12.6 Adverse effects 64 134 12.7 Restrictions for use 65 135 13. MODEL INFORMATION SHEET 66 136 13.1 Use 66 137 13.2 Dosage and route 67 138 13.3 Precautions/contraindications 68 139 13.4 Pharmaceutical incompatibilities and drug interactions 68 140 13.5 Adverse effects 68 141 13.6 Use in pregnancy and lactation 68 142 13.7 Storage 69 143 14. REFERENCES 69 144 ABBREVIATIONS 90 4 145 1. INTRODUCTION 146 147 Succimer (meso-2,3-dimercaptosuccinic acid, DMSA) was orginally used to increase 148 antimony uptake during treatment for schistosomiasis, in the form of antimony a,a'- 149 dimercapto potassium succinate (Friedman et al., 1954); it was Liang et al. (1957a) 150 who first demonstrated its effectiveness as a metal-binding agent. From the mid- 151 1950s succimer was studied and used in China (Liang et al., 1957a; Wang et al., 152 1965; Li & Ding, 1989; Ding & Liang, 1991) and Russia (Petrunkin, 1956; 1959) for the 153 treament of metal poisoning. 154 155 Friedheim (1963) published an improved synthetic method in the early 1960s but the 156 wider use of succimer as a therapeutic metal-binding agent did not occur until 157 Friedheim & Corvi (1975) demonstrated the efficiency of succimer in mercury 158 poisoning in mice and guinea pigs. 159 160 Both succimer and unithiol (2,3-dimercapto-1-propanesulphonic acid, DMPS) are 161 derivatives of dimercaprol (2,3-dimercapto-1-propanol, British Anti-Lewisite, BAL), and 162 they are replacing dimercaprol as the main antidote used in the management of heavy 163 metal poisoning (Aposhian et al., 1995; Andersen, 1999). These derivatives have 164 several advantages over dimercaprol including lower toxicity, increased solubility in 165 water and lower lipid solubility. It is due to these properties that they are effective by 166 oral administration. Also, succimer decreases the brain deposition of lead (Cory- 167 Slechta, 1988) and methyl mercury (Aaseth & Friedheim, 1978). Succimer is less 168 toxic than unithiol and where these two drugs appear to have similar efficacy as an 169 antidote for a particular metal, succimer is generally preferred. 170 171 Succimer has been demonstrated to be an efficient antidote for many heavy metals 172 and metalloids, including antimony, inorganic and organic arsenic, lead, and inorganic 173 and organic mercury, and to posses some antidotal efficiency for others, such as 174 cobalt, organic tin and platinum. Its antidotal spectrum is still under investigation. 175 Also, clinical investigations of its efficiency in human metal intoxications are 176 accumulating, and the efficacy of succimer has been reported in the treatment of 177 human intoxications with lead, mercury and arsenic. Due to the high stability of the 178 succimer complexes with technetium, they are also used as scintigraphic agents, e. g. 179 in various renal disorders. 180 181 Succimer is well tolerated and adverse effects are relatively rare. The most common 182 adverse effects are mild gastrointestinal discomfort, skin reactions, and transient, 183 clinically insignificant elevated liver enzymes. Symptoms are usually mild, self-limiting 184 and do not require cessation of therapy. 185 186 Experimental and clinical uses of metal-binding agents with special emphasis on 187 succimer have previously been reviewed by Aposhian (1983), Aposhian & Aposhian 188 (1990), Ding & Liang (1991), Aposhian et al. (1992); Aposhian et al. (1995) and 189 Andersen (2004). 190 191 192 2. NAME AND CHEMICAL FORMULA 193 194 Succimer is structurally analogous to dimercaprol. It has an asymmetric carbon atom 195 and can occur in the D-, L- or meso-form. The meso-form is easier to prepare, more 5 196 readily available and used in most animal and clinical studies; it is the form available in 197 pharmaceutical preparations. 198 199 International non-proprietary name: Succimer 200 201 Synonyms: DMSA, DMS, dimercaptosuccinic acid, 2,3-dimercaptobutanedioic acid, 202 DIM-SA, meso-2,3-dithiosuccinic acid, Rol-7977 203 204 IUPAC name: 2,3-bis-sulfanylbutanedioic acid 205 206 CAS number: 304-55-2 207 208 Molecular formula: C4H6O4S2 209 210 O SH OH OH SH O 211 212 213 Relative molecular mass: 182.22 214 215 Conversion table: 1 g = 5.5 mmol 216 1 mmol = 182.2 mg 217 g/L = 5.5 mmol/L 218 mmol/L = 0.182 g/L 219 220 Manufacturer: Succimer is available in the the west as Chemet® from Sanofi-Aventis, 221 174, av. de France 75013, Paris, France and distributed by Ovation Pharmaceuticals, 222 Inc., Deerfield, Illinois, USA. It is also available from pharmaceutial manufacturers in 223 Asia (e.g. YoungCom Company Ltd, Shenzhen, China). 224 225 226 3. PHYSICO-CHEMICAL PROPERTIES 227 228 229 Physical condition: White crystalline powder with characteristic mecaptan 230 odour and taste 231 232 Melting point: 196-198oC (meso-form) 233 124-125oC (DL-form) 234 235 Boiling point: Not applicable 6 236 237 Solubility: Meso-succimer is sparingly soluble; it can be titrated with 238 alkali to pH around 5.5 or mixed in sodium bicarbonate 239 5.5% to dissolve it (Aposhian, 1983). 240 DL-succimer is readily soluble in water.