Succimer and the Reduction of Tissue Lead in Juvenile Monkeys

Smith, Donald R.; Woolard, D.; Luck, Melissa L.; Laughlin, Nellie K.

doi:10.1006/taap.2000.8973

Cited by 31 publications

(34 citation statements)

References 28 publications

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“…To address the first series of questions we will present results from a non-human primate study conducted several years ago [11]. This study utilized a 2×3 factorial design with two levels of succimer treatment (presence or absence) and three levels of lead exposure (no lead, daily lead exposure over the first year of life, lead exposure over the first 2 years of life).…”

Section: Introductionmentioning

confidence: 99%

“…This indicates that the majority of lead diuresis occurred within the first 5 days of treatment, with little additional Fig. 1 Study design and timing of testing in the primate lead chelation study (Smith et al [11] urinary lead elimination after that. Overall, however, measures of the cumulative 5-day total urinary lead elimination show that there was a significant increase in lead diuresis with succimer treatment (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…***Statistically different (p < 0.001) from placebo group (comparisons performed only on data in b). Data from Smith et al [11]. [Reprinted from Toxicology and Applied Pharmacology with permission from Elsevier] Pb tracer data revealed that the increase in urinary lead elimination with succimer treatment came somewhat at the expense of a decrease in fecal lead elimination, evidenced by a significant reduction in fecal lead elimination with succimer treatment compared to placebovehicle (Fig.…”

Section: Introductionmentioning

confidence: 99%

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The Scientific Basis for Chelation: Animal Studies and Lead Chelation

Smith

Strupp

2013

J. Med. Toxicol.

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This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Scientific Basis for Chelation: Animal Studies and Lead Chelation

Smith

Strupp

2013

J. Med. Toxicol.

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“…This investigation was a substudy of a larger study that investigated the efficacy of succimer chelation therapy for reducing tissue Pb concentrations and alleviating cognitive impairment. Results from that larger study have been reported elsewhere (15)(16)(17) or are forthcoming.…”

mentioning

confidence: 75%

“…We assigned animals to vehicle (n = 8) and succimer (n = 9) treatment groups at birth. Complete details of the animal recruitment and care procedures are reported elsewhere (15,17). Briefly, the infants were housed in a single cage with their mothers until weaning at age 26 weeks; they were subsequently housed in groups of five females and one nonstudy male in group cages.…”

Section: Methodsmentioning

confidence: 99%

Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys.

Cremin

Luck

Laughlin

et al. 2001

Environ Health Perspect

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Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. This concern is justified because the availability of Pb-safe housing during outpatient treatment with oral succimer is limited. We used a juvenile nonhuman primate model of moderate childhood Pb intoxication and a sensitive double stable Pb isotope tracer methodology to determine whether oral succimer chelation affects the GI absorption and whole-body retention of Pb. Infant rhesus monkeys (n = 17) were exposed to Pb daily for 1 year postpartum to reach and maintain a target blood lead (BPb) level of 35-40 microg/dL. Animals were administered succimer (n = 9) or vehicle (n = 8) over two successive 19 day succimer treatment regimens beginning at 53 and 65 weeks of age. The present study was conducted over the second chelation regimen only. Animals received a single intravenous (iv) dose of stable (204)Pb tracer (5 microg, 24.5 nmol) followed by a single oral dose of stable (206)Pb tracer (72.6 microg, 352 nmol) immediately before chelation, in order to specifically evaluate GI Pb absorption and whole-body Pb retention with treatment. We collected complete urine and fecal samples over the first 5 days and whole blood over the first 8 days of treatment for analyses of stable Pb isotopes using magnetic sector inductively-coupled plasma mass spectrometry. Results indicate that succimer significantly reduced the GI absorption of Pb (vehicle, 64.9% +/- 5.5; succimer, 37.0% +/- 5.8; mean +/- SEM). Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.

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The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs—Walter Reed National Medical Center

Gaitens

Potter

D’Alleyrand

et al. 2020

American J Industrial Med

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Exposure to retained metal fragments from war‐related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short‐term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.

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Succimer and the Reduction of Tissue Lead in Juvenile Monkeys

Cited by 31 publications

References 28 publications

The Scientific Basis for Chelation: Animal Studies and Lead Chelation

The Scientific Basis for Chelation: Animal Studies and Lead Chelation

Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys.

The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs—Walter Reed National Medical Center

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