succimer and Poisoning

The standard medical treatment for metal toxicity is chelation therapy. Chelating agents work by forming less toxic complexes with the toxic metal ions which are readily excreted from the body. These compounds, based on their hydrophilic/lipophilic property, can either remove toxic metal ions from extracellular sites or can penetrate the intracellular compartments to facilitate the removal of toxic metal ions. However, there are various disadvantages associated with this kind of therapy, notably, selectivity. Other problems and challenges are that the therapy regime is expensive, time consuming and has poor patient compliance. Two chelating agents, dimercaptosuccinic acid (DMSA) and dimercaptopropionicsulfonate (DMPS) have gained increased acceptance among clinicians, undoubtedly improving the management of metal intoxications.. The present review provides an insight into the conventional chelating agents, new chelators under development, and the new opportunities presented by the use of nanotherapy for the treatment of metal poisoning cases.. Today's research should not only focus towards development of alternate chelators but also targeted therapy such as the nanotherapy.

Topics: Animals; Chelating Agents; Drug Delivery Systems; Heavy Metal Poisoning; Humans; Poisoning; Succimer

The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review.

Topics: Administration, Oral; Antidotes; Benzoates; Chelating Agents; Deferasirox; Deferiprone; Deferoxamine; Heavy Metal Poisoning; Humans; Penicillamine; Poisoning; Pyridones; Succimer; Triazoles; Trientine; Unithiol

Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.

Topics: Arsenic Poisoning; Cadmium Poisoning; Chelating Agents; Heavy Metal Poisoning; Humans; Lead Poisoning; Mercury Poisoning; Poisoning; Succimer

Poisonings are a common problem. In 1995, over 2 million exposures were reported to American poison information centres alone. The majority of poisoning exposures can be treated without major therapeutic intervention. If therapy is indicated, it is usually in the form of gastrointestinal decontamination with activated charcoal, to prevent absorption of the toxin and the subsequent toxicity that may occur. In a limited number of cases, more aggressive life-support measures may be necessary to treat the adverse effects of poisons. Occasionally, that intervention may include the use of pharmacological antagonists, more commonly referred to as antidotes. According to the American Association of Poison Control Centers, the most commonly used antidotes are acetylcysteine, naloxone, atropine, deferoxamine (desferrioxamine) and antivenins. Overall, 17 antidotes account for 99% of all antidote use and those agents are reviewed in this article. With the exception of naloxone, most antidotes have pharmacological effects that are independent of their inherent antidotal properties. Therefore, antidotes should be used judiciously because their pharmacological properties may exacerbate pre-existing toxicity and only in rare circumstances are they used prophylactically. Some antidotes, such as digoxin-specific antigen binding fragments (digoxin immune Fab), are very expensive, and both the risk: benefit ratio and the associated cost should be considered before the antidote is administered. The principle aims are to "treat the patient, not the poison' and to do no harm to the patient. Antidotes should be used only when they are indicated and may help a patient.

Topics: Acetylcysteine; Antidotes; Antivenins; Atropine; Deferoxamine; Flumazenil; Humans; Hydroxocobalamin; Naloxone; Physostigmine; Poisoning; Succimer

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

Topics: Animals; Antidotes; Arsenic Poisoning; Dimercaprol; Dogs; Guinea Pigs; Humans; Mice; Poisoning; Rats; Succimer; Unithiol

Acute arsenic toxicity is rare, and there have been no pediatric cases of acute arsenic poisoning in the recent literature. We report a pediatric case of acute arsenic ingestion treated initially with British antilewisite (BAL) and D-penicillamine (DP), and later with dimercaptosuccinic acid (DMSA). A 22-month-old girl ingested 1 oz 2.27% sodium arsenate and developed immediate vomiting and diarrhea. The patient presented to a community emergency department with the following vital signs: blood pressure 96/72 mm Hg, pulse 160 beats/min, respirations 22 breaths/min. She was pale and lethargic. Gastric lavage was performed, and abdominal X-ray was normal. She continued to have gastrointestinal symptoms and received 3 mg/kg BAL. Sinus tachycardia persisted, with heart rate increasing to 200 beats/min. In 12 hours, she was asymptomatic and was started on oral DP. On day 1, 24-hour urine arsenic was 4,880 micrograms/L. She remained asymptomatic and was discharged on day 6 on oral DP. She did well except for a rash that could have been a side effect of DP. On day 8, when the day 5 24-hour urine arsenic level was returned at 650 micrograms/L, the patient was readmitted and started on DMSA. After 4 days on DMSA, the 24-hour urine arsenic level was 96 micrograms/L. White blood cell count and renal and hepatic function remained normal. The excretion half-life was approximately 2.5 days, which is at least 2 to 3 times faster than the spontaneous excretion half-life expected in adults. Long-term follow-up was unavailable.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arsenates; Chelating Agents; Dimercaprol; Drug Therapy, Combination; Female; Humans; Infant; Penicillamine; Poisoning; Succimer

Topics: Animals; Arsenic Poisoning; Chelating Agents; Chelation Therapy; Dimercaprol; Edetic Acid; Humans; Lead Poisoning; Mercury Poisoning; Poisoning; Succimer

Dimercaptosuccinic acid (DMS), HOOC-CH(SH)-CH(SH)-COOH, was first developed in China as an effective antidote for poisoning from many heavy metals, such as Pb, Hg, As, Cd, Sb, Tl, Au, Zn, Ni, Pt, Ag, Co and Sn. DMS increases the excretion of Ce, Pm, Sr and Po from the body. Hundreds of patients suffering from hepatolenticular degeneration (Wilson's disease) have been treated successfully with DMS. Recently, DMS was found to be effective also in treating certain non-metallic intoxications, like some of the new non-phosphate pesticides and mushroom poisonings.

Topics: Animals; Antidotes; Humans; Metals; Poisoning; Succimer

Chronic arsenic toxicity producing various clinical manifestations is currently epidemic in West Bengal, India, Bangladesh, and other regions of the world. Animal studies have indicated that 2,3-dimercaptosuccinic acid can be used as an oral chelating agent. A prospective, double-blind, randomized controlled trial was carried out to evaluate the efficacy and safety of 2,3-dimercaptosuccinic acid for chronic arsenicosis due to drinking arsenic-contaminated (> or = 50 micrograms/L) subsoil water in West Bengal.. Twenty-one consecutive patients with chronic arsenicosis were individually randomized (random number; assignment made by individual not evaluating patients) into 2 groups: 11 patients (10 male, age 25.5 +/- 8 years) received 2,3-dimercaptosuccinic acid 1400 mg/d (1000 mg/m2) in the first week and 1050 mg/d (750 mg/m2) during the next 2 weeks with a repeat course 3 weeks later. The other 10 patients (all male, age 32.2 +/- 9.7 years) were given placebo capsules for the same schedule. The clinical features were evaluated by an objective scoring system before and after treatment. Routine investigations including liver function tests, arsenic concentrations in urine, hair, and nails, and skin biopsy evaluations were also completed.. Though there was improvement in the clinical score of 2,3-dimercaptosuccinic acid-treated patients, similar improvement was observed in the placebo-treated group. There were no statistical differences in the clinical scores between the 2 groups at the beginning and at the end of treatment. Similarly, no differences were found for the other investigated parameters.. Under the conditions of this study, 2,3-dimercaptosuccinic acid was not effective in producing any clinical or biochemical benefit or any histopathological improvement of skin lesions in patients with chronic arsenicosis.

Topics: Adolescent; Adult; Antidotes; Arsenic; Chronic Disease; Double-Blind Method; Humans; India; Liver Function Tests; Male; Poisoning; Prospective Studies; Skin; Succimer; Water Pollutants, Chemical

A recently developed methodology, which combines voltammetry, ITC, ESI-MS and several chemometric tools, has been applied for the first time to the study of As(III) complexes. The ligands considered, DMSA and DMPS, are commonly used to treat heavy metal poisoning. The study yields a reliable and consistent picture of the binding of As(III) by the chelating therapy agents DMSA and DMPS providing an unambiguous description of the stoichiometries of the complexes (ML(2), with the occasional appearance of ML in the case of DMSA), both ligands have stability constants of the same order, with a logβ(2) of 9.2 and 9.8, respectively. These values confirm the potential efficiency of both ligands in the treatment of As(III) poisoning.

Topics: Arsenates; Arsenic Poisoning; Calorimetry; Chelating Agents; Electrochemical Techniques; Heavy Metal Poisoning; Humans; Least-Squares Analysis; Metals, Heavy; Normal Distribution; Poisoning; Spectrometry, Mass, Electrospray Ionization; Succimer; Unithiol

Arsenic trioxide is available for home use in ant baits. Potential arsenic toxicity from unintentional pediatric ingestion is not well studied. The goal of this study is to describe the clinical course and urinary arsenic concentrations of children who ingested ant bait containing arsenic trioxide (0.46%).. This is a case series of pre-school children who unintentionally ingested arsenic trioxide ant bait gel bars in the home reported to two U.S. poison control centers from January 2003 to July 2007.. Six children (age range, 8 months to 4 years) ingested varying portions of ant bait gel bars containing arsenic trioxide (0.46%). All vomited shortly after exposure. The initial, pre-chelation urine total arsenic concentrations ranged from 1,858 to 13,981 mcg/L. All children had resolution of symptoms and received chelation with succimer. Follow-up urine arsenic concentrations were in the normal range 14-35 days after chelation and no further clinical toxicity was noted.. Children who ingest all or part of a household ant bait gel bar that contains relatively low concentration of arsenic trioxide can develop markedly elevated urine arsenic concentrations with minor initial symptoms. Prompt chelation with succimer is recommended for children with these exposures and continued until urine arsenic concentrations are normal.

Topics: Administration, Oral; Arsenic Trioxide; Arsenicals; Chelating Agents; Child, Preschool; Female; Household Products; Humans; Infant; Insecticides; Male; Oxides; Poison Control Centers; Poisoning; Succimer; Vomiting

Topics: Arsenic Poisoning; Cadmium Poisoning; Chelating Agents; Humans; Lead Poisoning; Mercury Poisoning; Poisoning; Succimer

The therapeutic efficacy of two thiol chelators, meso 2,3-dimercaptosuccinic acid (DMSA) or 2,3-dimercaptopropane sulfonate (DMPS) in treating chronic arsenic intoxication was investigated in male rats. Both the chelators were effective in promoting urinary arsenic excretion and restoring arsenic induced inhibition of blood delta-aminolevulinic acid dehydratase activity and hepatic glutathione level. Elevation of urinary delta-aminolevulinic acid excretion and arsenic concentration in blood, liver and kidneys were reduced significantly by both the chelators. Histopathological lesions induced by arsenic were also effectively reduced by the above chelators. DMSA being more effective than DMPS. The results suggest DMSA and DMPS to be effective antidotes for treating chronic arsenic toxicity in experimental animals.

Topics: Animals; Arsenic Poisoning; Chronic Disease; Kidney Tubules; Liver; Male; Poisoning; Rats; Succimer; Unithiol

The effects of two chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane 1-sulfonate (DMPS) on the mobilization, distribution, hepatic and hematopoietic toxicity of beryllium were compared in male rats exposed to beryllium. Animals were exposed to beryllium nitrate (0.5 mg/kg, orally, daily 5 days/week) for 21 days. Twenty-four hours after the last dose they were injected with a chelating agent (DMSA or DMPS) (25 or 50 mg/kg, twice daily for 5 days). The administration of DMSA and DMPS at a dose of 50 mg/kg marginally elevated the fecal excretion of beryllium. DMPS was effective in depleting beryllium from the liver, spleen and kidneys. However, DMPS (50 mg/kg) results in the redistribution of beryllium to blood. Beryllium-induced inhibition of hepatic alkaline phosphatase and hepatic adenosine triphosphatase (ATPase) were restored considerably with the chelating agents. Also, hepatic and renal histopathological lesions were less marked in rats treated with DMPS (50 mg/kg) compared with those treated with beryllium per se and DMSA. These effects were more prominent at the 50-mg/kg dose of chelating agents than at 25 mg/kg. These results suggest that treatment with DMPS has some beneficial effects in experimental beryllium intoxication.

Topics: Animals; Beryllium; Feces; Kidney; Liver; Male; Poisoning; Rats; Succimer; Tissue Distribution; Unithiol

The effect of various antidotes on the excretion of arsenic into the feces in vivo and on the biliary and enteric excretion in situ was investigated on segments of jejunum and colon in anesthetized guinea-pigs using the pendular perfusion technique, according to Henning and Forth (1982). In the in situ experiments guinea-pigs received As2O3 (0.02 mmol As(III)/kg) and 30 min later, British-Anti-Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) or 2,3-bis-(acetylthio)propanesulfonamide (BAPSA) (0.1 or 0.7 mmol/kg each) into the jugular vein. In the in vivo experiments guinea-pigs received As2O3 s.c. (same dose as above) and 30 min later the same antidotes (0.1 mmol/kg i.p.). The feces were collected for 24 h and the arsenic content measured. During the 60-min perfusion period the amount of arsenic excreted into the jejunum or colon was only 3% or 0.4% of the dose administered, respectively. Of the arsenic dose, 8% was found in the bile. None of the antidotes had an effect on the arsenic excretion into the jejunum or colon. No change in biliary excretion was found in animals treated with BAL, 0.1 or 0.7 mmol/kg, respectively. DMSA, BAPSA or DMPS, 0.1 mmol/kg, increased the biliary excretion of arsenic to 14, 33, or 43% of the dose administered and after 0.7 mmol/kg to 29, 37, or 42%, respectively. Furthermore, a significant increase (P > 0.05) was found for the bile/blood concentration ratio in the following order: control < BAL < DMSA < BAPSA approximately DMPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antidotes; Arsenic; Arsenic Poisoning; Arsenic Trioxide; Arsenicals; Bile; Colon; Dimercaprol; Feces; Guinea Pigs; Injections, Intravenous; Jejunum; Male; Oxides; Perfusion; Poisoning; Succimer; Sulfonamides; Unithiol

The therapeutic efficacy of six newly synthesized analogues of dimercaptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poisoning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso-2,3- di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with protected thiol groups ("prodrugs"), and DMDMS, DEDMS, DnPDMS, and DiPDMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and isopropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 mumol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i.p. or one of the analogues i.p. or via gastric tube (i.g.). Control animals received arsenic trioxide and saline 30 min later. The survival rate was recorded for 30 days. All of the animals treated with DMSA i.p. survived and all controls died within 2 days. Administered i.g., DATSA and DBTSA increased the survival rate to 29% and 43%, and injected i.p. to 86%. Treatment with DMDMS i.p. and i.g., and with DEDMS, DnPDMS, and DiPDMS i.g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To investigate the efficacy of the DMSA analogues in reducing the tissue content of arsenic, male NMRI mice received an s.c. injection of an LD5 of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 mumol/kg body wt). Thirty minutes later, saline (controls) or a single equimolar dose (0.7 mmol/kg) of DMSA i.p., or one of the analogues i.p. or i.g. was administered. The arsenic content of various organs (blood, liver, kidneys, heart, lungs, spleen, small intestine, large intestine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma counter.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antidotes; Arsenic; Arsenic Poisoning; Arsenic Trioxide; Arsenicals; Injections, Intraperitoneal; Injections, Subcutaneous; Intubation, Gastrointestinal; Male; Mice; Oxides; Poisoning; Succimer

117 cases of acute arsenic poisoning, caused by ingestion of food contaminated by As2O2, presented with abdominal pain, vomiting, nausea and diarrhea. The average level of urinary arsenic was 3.926 mg/L. The incidence of neuritis, poisoning hepatopathy and abdominal ECG was respectively 7.7%, 32.54%, 35.9%. All the cases recovered after oral or parenteral administration of dimecapto succinate (DMS) in six weeks. DMS is the drug of choice in the treatment of arsenic poisoning.

Topics: Adolescent; Adult; Arsenic Poisoning; Female; Food Contamination; Humans; Male; Poisoning; Succimer

The heavy metal antidotes sodium-2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) were investigated in anaesthetized dogs for their effects on a variety of physiological variables and parameters. In addition, the influence of both dithiols on oxygen consumption and ferrihaemoglobin production was studied in blood and red blood cells in vitro. DMPS (15 and 75 mg/kg i.v.) did not affect respiration, central venous pressure, left ventricular pressure or cardiac output and showed only marginal, statistically non-significant effects on aortic and effective perfusion pressure. In contrast to the slight, non-significant changes due to DMPS (15 mg/kg i.v.), an equimolar dose of DMSA (12 mg/kg i.v.) led to a slight transient decrease in femoral blood pressure with strong reflex tachycardia and increase in blood flow. The higher DMPS dose (75 mg/kg i.v.), however, caused marked decreases in femoral blood pressure and blood flow, strong changes in blood gases and pH, and lactacidosis. Most of the physiological variables and parameters did not return to the initial level by 60 min. The R-spike of the electrocardiogram decreased, and the T-wave increased. Experiments on the denervated hind leg indicate that DMPS may be a direct vasodilator. The fall of blood pressure due to DMPS was markedly reduced when 30% ferrihaemoglobin had been formed by 4-dimethylaminophenol.HCl (DMAP). The highest DMPS dose (150 mg/kg i.v.) provoked circulatory failure and respiratory arrest. Artificial ventilation with room air restored spontaneous respiration, but one of three animals did not survive this dose for more than 90 min. DMPS and DMSA reacted with oxygen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Circulation; Dogs; Dose-Response Relationship, Drug; Erythrocytes; Female; Homeostasis; Injections, Intravenous; Male; Metals; Methemoglobin; Oxygen Consumption; Poisoning; Respiration; Succimer; Unithiol

Topics: Adult; Arsenic Poisoning; Humans; India; London; Male; Medicine, Traditional; Mercury Poisoning; Poisoning; Succimer; Unithiol

Topics: Amyl Nitrite; Antidotes; Dimercaprol; Humans; Mustard Gas; Poisoning; Succimer

Topics: Humans; Mercury; Mercury Poisoning; Poisoning; Succimer; Succinates