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PubMed2006

The effect of chelation on blood pressure in lead-exposed children: a randomized study.

Studies in children suggest a weak association between blood lead concentration and blood pressure. To understand this better, we tested the strength of the association in children with elevated blood lead concentrations and whether succimer chelation changed blood pressure as it did blood lead. In a randomized clinical trial of 780 children with blood lead concentrations of 20-44 microg/dL at 12-33 months of age, we compared the systolic and diastolic blood pressure in the succimer-treated group and placebo group for up to 5 years of follow-up. We also analyzed the relation of blood lead to blood pressure. Children in the succimer group had lower blood lead concentrations for 9-10 months during and after treatment, but their blood pressure did not differ from those in the placebo group during this period. During 1-5 years of follow-up, children in the succimer group had systolic blood pressure 1.09 (95% confidence interval, 0.27-1.90) mmHg higher than did untreated children in a model with repeated measurements, but the difference in diastolic blood pressure was not statistically significant. No association between blood lead and blood pressure was found. Overall, there is no association between blood lead and blood pressure in these children with moderately high lead exposure, nor does chelation with succimer change blood pressure.

Blood Pressure↗
PubMed1997

Uptake of 99mTc(5+)-complexes in ischemic myocardial slices and their dissociable ability.

AIM: To find how some technetium-complexes to deliver the active species, TcO4(3-), to the target tissue from a dissociable polynuclear Tc5+ species in preserved states in vivo. METHODS: Effect of dissociation ability of the polynuclear Tc5+ complexes on their accumulation in ischemic myocardium was tested. Ability of dissociation as having an appropriate conformation to become biologically functional after entering the blood circulation was tested using a simple dilution method by thin layer chromatography (TLC) analysis. Various degree of ischemic myocardium slices of rat were incubated with 1/100 diluted 99mTc(5+)-succimer, 99mTc(5+)-GH and 99mTc(5+)-PPi. RESULTS: The TLC patterns of 99mTc(5+)-GH and 99mTc(5+)-PPi showed the presence of a fast increasing of free Tc-species as dilution degree increased. The relative radioactivity of peak of free pertechnetate (Rf = 0.85-1.0) with 1:500 dilution was: 99mTc(5+)-succimer 0%, 99mTc(5+)-GH 28.1% +/- 1.3%, and 99mTc(5+)-PPi 46.0% +/- 2.9% respectively. The uptake of the myocardium after ischemia for 3 h was 99mTc(5+)-succimer 420% +/- 110% dose/g tissue, 99mTc(5+)-GH 710% +/- 180% dose/g tissue, and 99mTc(5+)-PPi 1295% +/- 390% dose/g tissue respectively. CONCLUSION: The dissociation and myocardial uptake showed: 99mTc(5+)-succimer < 99mTc(5+)-GH < 99mTc(5+)-PPi, the uptake by the ischemic myocardium is positively correlated to their dissociation.

Animals↗
PubMed1998

Effects of N-acetylcysteine and 2,3-dimercaptosuccinic acid on lead induced oxidative stress in rat lenses.

Lead (Pb) is known to disrupt the pro-oxidant/anti-oxidant balance of tissues which leads to biochemical and physiological dysfunction. The present study investigated the effects of exposure on the redox status of the lenses of Fisher 344 rats and examined whether antioxidant or chelator administration reversed these changes. Animals were given 5 weeks of 2000 ppm Pb exposure followed by 1 week of either antioxidant, chelator or distilled water administration. Glutathione (GSH) and cysteine (CYS) levels decreased in the Pb-exposed group. N-acetylcysteine or 2,3-dimercaptopsuccinic acid (Succimer) supplementation following Pb intoxication resulted in increases in the GSH and CYS levels. Protein bound glutathione (PSSG) and cysteine (PSSC) increased following Pb exposure. In the Succimer-treated animals, the PSSG decreased significantly. The glutathione disulfide (GSSG) levels remained unchanged. Malondialdehyde (MDA) levels, a major lipid peroxidation byproduct, increased following Pb exposure and decreased following Succimer treatment. Our results suggest that antioxidant supplementation, as well as chelation, following Pb exposure may enhance the reductive status of lenses.

Acetylcysteine↗
PubMed1996

Attention deficit hyperactivity disorder, infantile autism, and elevated blood-lead: a possible relationship.

This case involves a 4 1/2-year-old boy diagnosed with autism, attention deficit hyperactivity disorder (ADHD), and an elevated blood-lead level of 42 mcg/dl. The child was treated for the elevated blood-lead with the chelating agent succimer. The parents reported a decrease in repetitive behaviors while on succimer with a regression to previous symptoms when medication was discontinued. Also seen was a decrease of hyperactive behavior while being treated with succimer. This article explores the interaction and possible casual relationship of an elevated blood-lead, autism, and ADHD as well as treatment of the behavioral symptoms.

Attention Deficit Disorder with Hyperactivity↗
PubMed1998

Aggressive approach in the treatment of acute lead encephalopathy with an extraordinarily high concentration of lead.

OBJECTIVE: To report a case of a 3-year-old child with an extraordinarily massive lead concentration, 26.4 micromol/L (550 microg/dL), following environmental exposure to lead paint in the home. LITERATURE REVIEW: The relevant literature concerning the treatment of lead encephalopathy was reviewed during the treatment of this child and preparation of the manuscript. To our knowledge, the landmark article written by Julian Chisolm in 1968 is the only recent article that reported similarly high levels of lead concentration. This case, however, is the first in which 3 chelating agents were used for the treatment of lead encephalopathy. We also reviewed the literature on the use of whole bowel irrigation in heavy metal intoxications. CONCLUSIONS: In this case, aggressive gut decontamination with whole bowel irrigation and triple chelation therapy with British anti-Lewisite, EDTA, and oral succimer was well tolerated and seemed effective for rapidly deleading the child. The extent to which her lead concentration increased while being treated with oral succimer alone necessitated further chelation with EDTA. Further evaluation is necessary to determine if triple chelation therapy is an appropriate method for severe lead intoxication, and if the use of whole bowel irrigation should be considered in heavy metal intoxication.

Brain Diseases↗
PubMed1999

A comparison of the effects of three chelating agents on the root canals of extracted human teeth.

The effects of EDTA were compared in vitro with the effects of two other chelating agents: succimer and trientine HCl. Thirty extracted human teeth with single canals were used. Groups of 10 were treated by the three agents and then examined under the scanning electron microscope. The results showed that EDTA widened the dentinal tubules. Trientine HCl also produced widening of the dentinal tubules very similar to EDTA, whereas succimer produced more extensive widening.

Chelating Agents↗
PubMed2003

Lead toxicosis in cats-a review.

Although the incidence of lead toxicosis in small animals continues to decrease, it remains a significant malady. We have reviewed the literature of the past 45 years, which revealed 70 cases involving cats. Sources, signs, diagnosis, pathology and treatment of feline lead toxicosis are reviewed. In 84% of these cases the source of lead was old paint usually from home renovation. The most common signs in cats are anorexia, vomiting, and seizures. The younger individuals seem more likely to show CNS signs. Since signs are often vague, lead toxicosis may be significantly under diagnosed in cats. The gold standard of diagnostic tests is blood lead concentration, although it does not necessarily correlate with total body burden of lead or with metabolic effects including clinical signs. Diagnostic tests including erythropoietic protoporphyrin (EPP), urine aminolevulinic acid, and others are discussed. Gross findings on necropsy are few and include a yellow-brown discoloration of the liver often with a nutmeg-like appearance. Histological examination may reveal pathognomonic inclusion bodies in liver and renal tissues. Characteristic histological changes in the CNS include neuronal necrosis and demyelination. Treatment of lead toxicosis in cats, as in any species, involves removing the exposure, decontaminating the individual and the environment, supportive care and chelation therapy. The most recently available chelator is succimer (meso 2,3-dimercaptosuccinic acid). Succimer given orally is well tolerated and has a wide margin of safety. A high index of suspicion of lead toxicosis is warranted in cats since they often present with vague and non-specific signs. With any consistent history owners need to be asked about home renovation. Early diagnosis and treatment affords a good prognosis.

Animals↗
PubMed2002

Lead poisoning: case studies.

Early clinical features of lead toxicity are non-specific and an occupational history is particularly valuable. Lead in the body comprises 2% in the blood (t1/2 35 days) and 95% in bone and dentine (t1/2 20-30 years). Blood lead may remain elevated for years after cessation from long exposure, due to redistribution from bone. Blood lead concentration is the most widely used marker for inorganic lead exposure. Zinc protoporphyrin (ZPP) concentration in blood usefully reflects lead exposure over the prior 3 months. Symptomatic patients with blood lead concentration >2.4 micromol l-1 (50 microg dl-1) or in any event >3.8 micromol l-1 (80 microg dl-1) should receive sodium calciumedetate i.v., followed by succimer by mouth for 19 days. Asymptomatic patients with blood lead concentration >2.4 micromol l-1 (50 microg dl-1) may be treated with succimer alone. Sodium calciumedetate should be given with dimercaprol to treat lead encephalopathy.

Acute Disease↗
PubMed1998

The Treatment of Lead-exposed Children (TLC) trial: design and recruitment for a study of the effect of oral chelation on growth and development in toddlers.

Exposure to lead impairs cognitive development in young children, but the benefits of lowering blood lead pharmacologically are not clear. This report describes the design, recruitment, enrolment and baseline results of the Treatment of Lead-Exposed Children (TLC) trial, a randomised, multicentre, placebo-controlled, double-blind clinical trial of the effects of treating lead-exposed children with succimer, a drug that enhances urinary excretion of lead, on cognitive, behavioural and physical development. TLC clinical sites were in Baltimore, Cincinnati and Columbus, Newark and Philadelphia. Children were eligible for TLC if they were between 12 and 33 months of age, had a confirmed blood lead concentration between 20 and 44 micrograms/dL and lived in a residence suitable for lead dust reduction. Randomised children received up to three 26-day courses of succimer or placebo, and were then followed for 3 years. The study can detect a three-point difference in full-scale IQ at 3-year follow-up. Statistical power for the other end points is more difficult to estimate. A total of 1854 children were evaluated and 780 children were randomised between August 1994 and January 1997. The mean age of randomised children was 24 months and mean blood lead level 26 micrograms/dL. Three-quarters were African-American. Most children had poor, single mothers who had completed 12 or fewer years of school and who lived in older, poorly maintained residences.

Chelating Agents↗
PubMed1997

Placebo response in environmental disease. Chelation therapy of patients with symptoms attributed to amalgam fillings.

Treatment of patients who attribute their environmental illness to mercury from amalgam fillings is largely experimental. On the Symptom Check List, overall distress, and somatization, obsessive-compulsive, depression, and anxiety symptom dimensions, were increased in 50 consecutive patients examined, and Eysenck Personality Questionnaire scores suggested less extroversion and increased degree of emotional liability. Succimer (meso-2, 3-dimercaptosuccinic acid) was given at a daily dose of 30 mg/kg for five days in a double-blind, randomized placebo-controlled trial. Urinary excretion of mercury and lead was considerably increased in the patients who received the chelator. Immediately after the treatment and 5 to 6 weeks later, most distress dimensions had improved considerably, but there was no difference between the succimer and placebo groups. These findings suggest that some patients with environmental illness may substantially benefit from placebo.

Adult↗
PubMed2001

Bite the bullet: lead poisoning after ingestion of 206 lead bullets.

A 45-y-o male with a history of schizophrenia was admitted to a local VA psychiatric unit. Five days later, endoscopy due to abdominal pain, gastrointestinal bleeding and blood hemoglobin of 5.6 g/dL revealed bullets in the stomach. On subsequent radiograph, > 50 bullets were visualized in the stomach and intestines. Poison Center recommendations included whole bowel irrigation and a blood lead level. After poor results with gastrointestinal decontamination and a repeat radiograph showing > 100 cartridges, surgical intervention was considered but not performed due to perceived risk of bullet detonation from electrocautery. The blood lead was reported as 391 mcg/dL. Calcium EDTA therapy was initiated, followed by aggressive gastrointestinal decontamination. Four days of whole bowel irrigation facilitated passage of 206 cartridges over the next 10 days. The patient was discharged on a 14-day course of 600 mg Succimer tid to treat the bone lead deposits and blood lead level of 49 mcg/dl. An outpatient visit 6 w later showed the blood lead level had dropped to 24 mcg/dl. Aggressive gastrointestinal decontamination and calcium EDTA and Succimer administration successfully treated an ingestion lead bullets and the resulting lead poisoning.

Antidotes↗
PubMed2003

Gunshot-induced plumbism in an adult male.

Our objective is to present a case of symptomatic lead toxicity (plumbism) with abdominal colic and hemolytic anemia following a gunshot wound. It is a retrospective case report and the setting is in a teaching hospital in south central Los Angeles. The case report is that of a patient who presented with abdominal pain, generalized weakness, and hypertension following multiple gunshot wounds, 15 years previously. Other causes of abdominal pain and weakness--such as diabetes mellitus, alcohol abuse, pancreatitis, and substance abuse--were ruled out. Interventions included treatment with the newer oral chelating agent, Succimer (2, 3-dimercaptosuccinic acid), and subsequent surgery. The main outcome was the initial reduction in blood lead levels with improvement of symptoms. Because of a recurrent rise in the blood lead levels, the patient was again treated with Succimer and underwent surgery to remove two bullet fragments from the face. We conclude that lead toxicity should be ruled out in patients presenting with abdominal cramps and a history of a gunshot wound. Prompt therapy--including environmental intervention and chelation therapy--is mandatory, and surgical intervention may be necessary.

Abdominal Pain↗
PubMed1995

Mobilization of heavy metals by newer, therapeutically useful chelating agents.

Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.

Animals↗
PubMed2002

Mercuric oxide poisoning treated with whole-bowel irrigation and chelation therapy.

Most reported cases of inorganic mercury poisoning are from mercuric chloride. We report a case of mercuric oxide (HgO) powder ingestion. A 31-year-old man presented to an emergency department after ingestion of approximately 40 g of HgO. Soon after ingestion, he developed nausea, vomiting, and abdominal cramping. Abdominal radiograph revealed densely radiopaque material in the stomach. Gastrointestinal decontamination was accomplished with activated charcoal and whole-bowel irrigation with polyethylene glycol solution (Golytely) for 24 hours until repeat abdominal radiographs no longer demonstrated the substance in the gastrointestinal tract. He was also chelated with British anti-Lewisite for 5 days, followed by succimer for 10 days. He had markedly elevated urine and blood mercury levels after ingestion, but except for a mildly depressed serum bicarbonate (19 mEq/L), his chemistry results remained normal including blood urea nitrogen and creatinine. He had an uncomplicated hospital course and remained asymptomatic at 6 months postingestion. Despite elevated urine and blood mercury levels after ingestion of HgO, our patient did not develop the end-organ toxicity typical of inorganic mercury poisoning.

Adult↗
PubMed2000

Symptomatic lead poisoning in infancy: a prospective case analysis.

This report of a case of symptomatic lead poisoning in infancy reinforces the need for continued vigilance in screening and the application of effective therapies to prevent serious physiologic, neurocognitive, and behavioral sequelae. Furthermore, this case illustrates the efficacy of repeated courses of outpatient succimer therapy in limiting a rebound in blood lead concentrations.

Antidotes↗
PubMed2001

Lead poisoning and chelation in a mother-neonate pair.

We report the case of a pregnant woman with chronic lead toxicity and a blood lead of 57 microg/dL (2.7 micromol/L) who gave birth to a healthy-appearing neonate with a cord blood lead of 126 microg/dL (6.08 micromol/L). The mother was prescribed a single course of oral succimer late in the third trimester of pregnancy, without any appreciable change in her blood lead. The neonate was initially treated with intramuscular dimercaprol and intravenous edetate calcium disodium. After 3 days, the neonate was then switched to oral 2,3-dimercaptosuccinic acid because the blood lead had declined. The child received two 19-day courses of 2,3-dimercaptosuccinic acid and had a blood lead level of 21.5 microg/dL (1.04 micromol/L) at 5 months of age. Despite extensive investigation, the precise source of the mother's lead toxicity remained undetermined.

Adult↗
PubMed2003

Acute arsenic poisoning treated by intravenous dimercaptosuccinic acid (DMSA) and combined extrarenal epuration techniques.

Arsenic poisoning was diagnosed in a 26-year-old man who had been criminally intoxicated over the last two weeks preceding admission by the surreptitious oral administration of probably 10 g of arsenic trioxide (As2O3). The patient developed severe manifestations of toxic hepatitis and pancreatitis, and thereafter neurological disorders, respiratory distress, acute renal failure, and cardiovascular disturbances. In addition to supportive therapy, extrarenal elimination techniques and chelating agents were used. Dimercaprol (BAL) and dimercaptosuccinic acid (DMSA or succimer) were used simultaneously as arsenic chelating agents for two days, and thereafter DMSA was used alone. DMSA was administered by intravenous (20 mg/kg/d for five days, then 10 mg/kg/d for six days) and intraperitoneal route. Intravenous DMSA infusion was well tolerated and resulted in an increase in arsenic blood concentration immediately after the infusion. Continuous venovenous hemofiltration combined with hemodialysis, and peritoneal dialysis were proposed to enhance arsenic elimination. It was calculated that over an 11-day period 14.5 mg arsenic were eliminated by the urine, 26.7 mg by hemodialysis, 17.8 mg by peritoneal dialysis, and 7.8 mg by continuous venovenous hemofiltration. These amounts appeared negligible with regard to the probable ingested dose. The patient died on day 26 from the consequences of multiple organ failure, with subarachnoid hemorrhage and generalized infection caused by Aspergillus fumigatus.

Acute Kidney Injury↗
PubMed2002

The renal Na(+)-dependent dicarboxylate transporter, NaDC-3, translocates dimethyl- and disulfhydryl-compounds and contributes to renal heavy metal detoxification.

The active transport of Krebs cycle intermediates, such as succinate, alpha-ketoglutarate, and citrate, is mediated by sodium-coupled transporters found in the luminal (NaDC-1) and basolateral plasma membranes (NaDC-3) of proximal tubule cells. This study used the two-electrode voltage clamp technique to examine steady-state currents associated with the influx of three sodium ions and one divalent dicarboxylate into oocytes expressing the sodium-dicarboxylate transporter from winter flounder kidney, fNaDC-3. The substrate concentration, where half-maximal current was observed (K(0.5)), was 30 micro M for succinate. Besides 2,2-dimethylsuccinate, fNaDC-3 also accepted 2,3-dimethylsuccinate and the oral lead-chelating agent, meso-2,3-dimercaptosuccinate (DMSA or Succimer). Whereas the K(0.5) for succinate and 2,2-dimethylsuccinate was independent of membrane voltage within -90 and -10 mV, K(0.5) for 2,3-dimethylsuccinate and 2,3-dimercaptosuccinate increased with decreasing voltage, indicating a critical role of the position of the methyl- or sulfhydryl-group in voltage-sensitive affinity. In addition to meso-2,3-dimercaptosuccinate, fNaDC-3 translocated dimercaptopropane-1-sulfonate (DMPS or Dimaval), an oral chelator for the treatment of mercury intoxication. The chelates formed by HgCl(2) and DMSA or DMPS and by Pb(NO(3))(2) and DMSA, however, were not translocated by fNaDC-3. The data suggest that NaDC-3 is an essential component in the delivery of uncomplexed antidotes for renal heavy metal detoxification.

Animals↗