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PubMed2006

Maternal IQ, child IQ, behavior, and achievement in urban 5-7 year olds.

In one study of children in 27 families with maternal retardation, those children with higher intelligence quotient (IQ) were more likely to have multiple behavior problems than those with lower IQ. If true, this result would affect clinical practice, but it has not been replicated. Because the setting of the initial observation is similar to the setting of childhood lead poisoning, we attempted a replication using data from the Treatment of Lead-Exposed Children (TLC) study, in which 780 children aged 12-33 mo with blood lead levels 20-44 microg/dL were randomized to either succimer treatment or placebo and then followed up to 5 y. Of 656 mothers of TLC children with IQ measured, 113 demonstrated mental retardation (IQ <70). Whether maternal IQ was <70 or >or=70, children with IQ >or=85 were rated more favorably on cognitive tests and behavioral questionnaires than children with IQ <85; these measures included Conners' Parent Rating Scale-Revised at age 5, the Developmental Neuropsychological Assessment at ages 5 and 7, and the Behavioral Assessment System for Children at age 7. Among children of mothers with IQ <70, those with IQ >or=85 did not show more severe clinical behavioral problems, nor were they more likely to show multiple behavior problems. Children with higher IQ have fewer behavior problems, irrespective of the mother's IQ. In the special setting of mothers with IQ <70, children with higher IQ are not at greater risk of behavior problems.

Achievement↗
PubMedDate not supplied

Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults.

Meso-2,3-dimercaptosuccinic acid (DMSA, or succimer) is an oral chelating agent for heavy-metal poisoning. While studying the urinary elimination of unaltered DMSA, altered DMSA (i.e., its mixed disulfides), and lead in children with lead poisoning, we observed a pattern of urinary drug elimination after meals suggestive of enterohepatic circulation. The excretion of lead in urine patterned the elimination of altered DMSA rather than the parent molecule. In addition, the half-life of elimination of DMSA via the kidney was positively associated with blood lead concentration. Two additional crossover studies of DMSA kinetics were conducted in normal adults to confirm the presence of enterohepatic circulation of DMSA after meals. In one, increases in plasma total DMSA concentration were observed after meals in all six subjects; these increases were prevented by cholestyramine administration 4, 8, and 12 hr after DMSA. In the second, the administration of neomycin also prevented increases in DMSA after meals. These studies indicate that 1) a metabolite(s) of DMSA undergoes enterohepatic circulation and that microflora are required for DMSA reentry; 2) in children, moderate lead exposure impairs renal tubular drug elimination; and 3) a metabolite of DMSA appears to be an active chelator.

Adult↗
PubMed2002

Do children with falling blood lead levels have improved cognition?

OBJECTIVE: Exposure to lead at levels encountered by urban children impairs cognitive development. An observational study suggested improvement in IQ when blood lead level fell, but the only randomized trial of chelation showed no benefit in IQ. METHODS: We did a new analysis of the data from the clinical trial using change in blood lead level as the independent variable. The 741 children began with blood lead levels between 20 and 44 microg/dL, and were 13 to 33 months old at randomization to chelation or placebo. Blood lead levels were measured repeatedly, and cognitive tests were given at baseline, 6 months, and 36 months follow-up. RESULTS: By 6 months after randomization, blood lead levels had fallen by similar amounts in both chelated and placebo children, despite the immediate drops in the chelated group; there was no association between change in blood lead level and change in cognitive test score. Blood lead levels continued to fall. At 36 months follow-up, in the placebo group only, cognitive test scores had increased 4.0 points per 10 microg/dL fall in blood lead level from baseline to 36 months follow-up and 5.1 points from 6 to 36 months. CONCLUSIONS: The improvement in scores in the placebo group only implies that factors other than declining blood lead levels per se are responsible for cognitive improvement; it is possible but less likely that succimer, the active drug, impairs cognition.

Chelating Agents↗
PubMed2003

Oral treatment of avian lead intoxication with meso-2,3-dimercaptosuccinic acid.

The efficacy of meso-dimercaptosuccinic acid (DMSA) (succimer) in treating avian lead intoxication was studied in a retrospective, nonrandomized, longitudinal study. Nineteen birds with moderate to high blood lead concentration and neurologic signs compatible with lead toxicity were treated with DMSA (30 mg/kg p.o., b.i.d.; n = 15) for a minimum of 7 days. In cases with severe neurologic signs, DMSA was supplemented with a single dose of edetate calcium disodium (<50.0 mg/kg of body weight i.m.; n = 4). Blood lead concentrations were measured two or more times (before and after treatment). Median blood lead concentration decreased (87%), neurologic signs were resolved, and there were no apparent adverse secondary effects.

Administration, Oral↗
PubMed1998

Hemolytic activity of copper sulfate as influenced by epinephrine and chelating thiols.

AIM: To study the effects of epinephrine, homocysteine, and other complexing agents on the cytotoxicity of copper sulfate. METHODS: In vitro suspensions of human red cells incubated with cupric sulfate were used, and hemolysis was determined by extracellular hemoglobin. RESULTS: The hemolytic activity of CuSO4 (0.3 mmol.L-1) was enhanced by the presence of epinephrine and to a lesser extent by homocysteine, whereas D-penicillamine, succimer, and mercaptodextran reduced the copper-induced hemolysis. The latter 3 chelating thiols also reduced the copper-epinephrine-induced hemolysis. The plasma protein ceruloplasmin reduced markedly the copper-epinephrine-induced hemolysis, even upon concentrations < 20% of that of copper. Chromic chloride, as well, acted anti-hemolytically. CONCLUSION: The latter protectors may interact with the production or activity of toxic oxygen, while classical copper chelators sequester cupric ions from interaction with epinephrine or homocysteine.

Adult↗
PubMed1992

Chelation therapy to treat lead toxicity in children.

The most recent Centers for Disease Control guidelines recommend routine screening of children for lead exposure. The CDC recommends close lead-level monitoring of children with lead levels greater than 10 micrograms/dL. The indications for chelation therapy have not changed. Identification and removal of sources of lead exposure are equally as important as chelation therapy. Experimental data have raised concerns about potential central nervous system effects of the most widely used chelating agent, edetate calcium disodium. A newly licensed chelating agent, succimer, appears to have fewer side effects, appears to be more effective, and has the advantage of oral administration. Indications for its use are somewhat limited but may be expanded as experience with its use increases.

Chelation Therapy↗
PubMedDate not supplied

Conceptual and practical advances in the measurement and clinical management of lead toxicity.

The purpose of this paper is to discuss issues which relate to the risks and benefits of pharmacologic intervention in children with elevated blood lead (BPb) concentrations. In January, 1991, 2,3-dimercaptosuccinic acid (DMSA; succimer or CHEMET) was approved by the FDA for administration to children with blood lead concentrations of 45 micrograms/dl or higher. Thus, it is now considerably simpler to treat children with elevated BPb's. DMSA is orally actively, relatively safe and specific, and can, in some situations, be used on an out-patient basis. The author is concerned that the recent CDC statement on lead poisoning, whose aim is to reduce (by various means) children's BPb's below 10 micrograms/dl, may unintentionally encourage pediatricians to treat children with relatively low BPb's with DMSA, both for medical and legal reasons. Should children with BPb's of less than 45 ug/dl be treated, and why? The risks and benefits of treatment in such children are uncertain. A randomized, placebo controlled, double-blind drug intervention trial is needed (and justified) in order to more carefully assess the benefits and the risks associated with the treatment of lower BPb's.

Humans↗
PubMed1999

Recall of a lead-contaminated vitamin and mineral supplement in a clinical trial.

PURPOSE: The Treatment of Lead-exposed Children (TLC) trial tested whether developmental outcome differed between children treated for lead poisoning with succimer or placebo. On 7 July 1997, TLC was informed that the vitamin and mineral supplements it gave to all children were contaminated with about 35 microg of lead per tablet. METHODS: TLC recalled the contaminated supplements and measured the children's exposure. RESULTS: The families of 96% of the children were contacted with 30 days. Among the 571 children to whom the contaminated supplements were dispensed, the mean increase in blood lead was 0.06+/-0.01 micromol/L (1.2+/-0.2 microg/dL); among 78 children to whom they were not, it was 0.09+/-0.03 micromol/L (1.8+/-0.7 microg/dL). There was no evidence of a dose-response relation between estimated supplement consumption and increase in blood lead concentration. CONCLUSIONS: The children's blood lead concentrations were not detectably affected by the contamination. Since the association of cognitive delay with lead exposure is best described for blood lead, we believe that the trial's inference about the effect of drug therapy on lead induced cognitive delay should be unaffected.

Journal Article↗
PubMed2003

Transport of organic anions across the basolateral membrane of proximal tubule cells.

Renal proximal tubules secrete diverse organic anions (OA) including widely prescribed anionic drugs. Here, we review the molecular properties of cloned transporters involved in uptake of OA from blood into proximal tubule cells and provide extensive lists of substrates handled by these transport systems. Where tested, transporters have been immunolocalized to the basolateral cell membrane. The sulfate anion transporter 1 (sat-1) cloned from human, rat and mouse, transported oxalate and sulfate. Drugs found earlier to interact with sulfate transport in vivo have not yet been tested with sat-1. The Na(+)-dicarboxylate cotransporter 3 (NaDC-3) was cloned from human, rat, mouse and flounder, and transported three Na(+) with one divalent di- or tricarboxylate, such as citric acid cycle intermediates and the heavy metal chelator 2,3-dimercaptosuccinate (succimer). The organic anion transporter 1 (OAT1) cloned from several species was shown to exchange extracellular OA against intracellular alpha-ketoglutarate. OAT1 translocated, e.g., anti-inflammatory drugs, antiviral drugs, beta-lactam antibiotics, loop diuretics, ochratoxin A, and p-aminohippurate. Several OA, including probenecid, inhibited OAT1. Human, rat and mouse OAT2 transported selected anti-inflammatory and antiviral drugs, methotrexate, ochratoxin A, and, with high affinities, prostaglandins E(2) and F(2alpha). OAT3 cloned from human, rat and mouse showed a substrate specificity overlapping with that of OAT1. In addition, OAT3 interacted with sulfated steroid hormones such as estrone-3-sulfate. The driving forces for OAT2 and OAT3, the relative contributions of all OA transporters to, and the impact of transporter regulation by protein kinases on renal drug excretion in vivo must be determined in future experiments.

Animals↗
PubMed2000

Antioxidants attenuate gentamicin-induced free radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant.

We have recently suggested antioxidant therapy against aminoglycoside-induced hearing loss based on the hypothesis of a redox-active aminoglycoside-iron complex causing ototoxicity. The present study compares seven antioxidants and iron chelators for their ability to attenuate gentamicin-induced free radical generation in vitro and ototoxicity in guinea pig in vivo. Free radical formation by gentamicin was measured by chemiluminescence detection both in a non-enzymatic system in vitro and in cell culture. Deferoxamine, 2,3-dihydroxybenzoate, or salicylic acid suppressed gentamicin-induced luminescence in both tests. This indicated the usefulness of the assay as a screen for potential protectants since these agents had previously been shown to attenuate gentamicin-induced ototoxicity in vivo. Histidine and D-methionine, amino acids with chelating and antioxidant properties, also suppressed gentamicin-mediated luminosity both in vitro and in cell culture. In contrast, the metal chelators succimer (2, 3-dimercaptosuccinic acid (DMSA)) and trientine (N, N'-bis[2-aminoethyl]-1,2 ethanediamine) promoted free radical formation and were excluded from further studies. Histidine and D-methionine were then administered to guinea pigs receiving concurrent treatment with gentamicin (120 mg/kgx19 days). Threshold shifts induced by gentamicin were significantly attenuated by twice-daily injections of D-methionine. Once-daily injections of histidine or D-methionine were less effective, pointing to the importance of pharmacokinetics in antioxidant protection in vivo. The study presents a simple screening system for agents with the potential to attenuate gentamicin-induced hearing loss. It also supports the hypothesis of free radical formation as an underlying cause of gentamicin ototoxicity.

Animals↗
PubMed1999

Antioxidant role of alpha-lipoic acid in lead toxicity.

The assumption of oxidative stress as a mechanism in lead toxicity suggests that antioxidants might play a role in the treatment of lead poisoning. The present study was designed to investigate the efficacy of lipoic acid (LA) in rebalancing the increased prooxidant/antioxidant ratio in lead-exposed Chinese hamster ovary (CHO) cells and Fischer 344 rats. Furthermore, LA's ability to decrease lead levels in the blood and tissues of lead-treated rats was examined. LA administration resulted in a significant improvement in the thiol capacity of cells via increasing glutathione levels and reducing malondialdehyde levels in the lead-exposed cells and animals, indicating a strong antioxidant shift on lead-induced oxidative stress. Furthermore, administration of LA after lead treatment significantly decreased catalase and red blood cell glucose-6-phosphate dehydrogenase activity. In vitro administration of LA to cultures of CHO cells significantly increased cell survival, that was inhibited by lead treatment in a concentration-dependent manner. Administration of LA was not effective in decreasing blood or tissue lead levels compared to a well-known chelator, succimer, that was able to reduce them to control levels. Hence, LA seems to be a good candidate for therapeutic intervention of lead poisoning, in combination with a chelator, rather than as a sole agent.

Animals↗
PubMed2000

Iron catalyzed oxidative damage, in spite of normal ferritin and transferrin saturation levels and its possible role in Werner's syndrome, Parkinson's disease, cancer, gout, rheumatoid arthritis, etc.

Iron loading in hemochromatosis attains extremely high levels and is accompanied by many signs (ferritin >300 microg/l, hematocrit >50%, transferrin saturation >70%, etc.). Nevertheless, the disease is often overlooked by physicians, until several organs have been damaged permanently (heart, liver, brain, pancreas, kidneys, spleen, etc.). Therefore, severe oxidative damage catalyzed by Fe could occur, without the extremely high ferritin, hematocrit and transferrin saturation levels of hemochromatosis, and it is unlikely that it would ever be detected or even suspected. I postulate a mechanism, by which a cell can continue to express transferrin receptors, without producing ferritin, even when it is saturated with iron. Furthermore, I suggest that this silent iron loading, induced by cadmium and other metals, plays an important role in many degenerative diseases involving free radicals, DNA damage and peroxynitrite, all of which are intimately linked to iron.Moreover, since ferritin, transferrin saturation and hematocrit levels are not directly related to cellular iron levels, and since excess iron can wreak havoc in the cell, we can conclude that there is a need for a better way to evaluate intracellular iron levels and especially the intracellular free iron levels by a non-invasive technique.Finally, phlebotomy is suggested as the best way to reduce Fe and Mo stores, and chelation with succimer is recommended in order to eliminate Cd.

Chelating Agents↗
PubMed2000

Recovery from severe arsenic-induced peripheral neuropathy with 2,3-dimercapto-1-propanesulphonic acid.

CASE REPORT: A 33-year-old female with a 1.5-year history of multisystem illness was diagnosed with arsenic poisoning. Twenty-four-hour urine arsenic was 1030 microg/dL (normal 0-99) and root hair arsenic was 130 microg/g (normal 0-3). Despite treatment with succimer meso-2,3-dimercaptosuccinic acid, her neuropathy progressed to ventilator dependence and quadriplegia. Subsequent intravenous treatment with 2,3-dimercapto-1-propanesulfonic acid sodium salt was associated with arsenic diuresis, marked neuropathic improvement, and extubation. At 1-year follow-up, neuropathy was limited to mild distal lower extremity weakness and sensory loss. The use of 2,3-dimercapto-1-propanesulphonic acid in the treatment of severe arsenic neuropathy was associated with increased urinary elimination of arsenic and dramatic clinical recovery.

Adult↗
PubMed2002

Treatment and toxicokinetics of acute pediatric arsenic ingestion: danger of arsenic insecticides in children.

OBJECTIVES: To describe the toxicokinetics and management of acute pediatric arsenic ingestion. DESIGN: Case report and literature review. SETTING: Tertiary pediatric intensive care unit, St. John's Children's Hospital, Springfield, IL. PATIENT: A 22-month-old boy ingested approximately twice the estimated lethal dose of arsenic trioxide (As(2)O(3)) ant bait. Only one household arsenical insecticide is available in the United States and is presumed to be shielded from human exposure. He survived without detectable sequelae. Initially, the patient developed signs of acute hemodynamic compromise with tachycardia, hypertension, gastrointestinal symptoms, and poor urine output. He became lethargic with muscle weakness and was somnolent but never developed encephalopathy, seizures, or late onset peripheral neuropathy. INTERVENTIONS: He was stabilized with fluid resuscitation, placed on a sodium bicarbonate intravenous drip, and treated with intramuscular dimercaprol (British anti-Lewisite), 5 mg/kg every 6 hrs for 3 days. When the British anti-Lewisite and the sodium bicarbonate drip were discontinued, oral meso 2,3-dimercaptosuccinic acid (Succimer) was administered three times a day for 5 days and thereafter twice daily until the urine arsenic concentration decreased below 50 microg/L. MEASUREMENTS AND MAIN RESULTS: Continuous monitoring in the pediatric intensive care unit included continuous electrocardiogram, arterial blood pressure, urine output, vital signs, arterial blood gases, serum and urine arsenic concentrations, electrolytes, electromyography, and determination of arsenic toxicokinetics. The child's serum arsenic concentration was the highest ever reported with survival. CONCLUSIONS: Recovery from arsenic poisoning was attributable to the restoration and maintenance of adequate cardiac output and renal perfusion in early shock, which allowed depot intramuscular British anti-Lewisite to circulate and eliminate the poison. Although an intravenous antiarsenical chelating agent would be advantageous in treating shock from arsenic poisoning, none is currently available. We urge the immediate use of British anti-Lewisite therapy on patient presentation with suspected toxic arsenic ingestion.

Journal Article↗
PubMed2006

Weakening effect of cell permeabilizers on gram-negative bacteria causing biodeterioration.

Gram-negative bacteria play an important role in the formation and stabilization of biofilm structures on stone surfaces. Therefore, the control of growth of gram-negative bacteria offers a way to diminish biodeterioration of stone materials. The effect of potential permeabilizers on the outer membrane (OM) properties of gram-negative bacteria was investigated and further characterized. In addition, efficacy of the agents in enhancing the activity of a biocide (benzalkonium chloride) was assessed. EDTA, polyethylenimine (PEI), and succimer (meso-2,3-dimercaptosuccinic) were shown to be efficient permeabilizers of the members of Pseudomonas and Stenotrophomonas genera, as indicated by an increase in the uptake of a hydrophobic probe (1-N-phenylnaphthylamine) and sensitization to hydrophobic antibiotics. Visualization of Pseudomonas cells treated with EDTA or PEI by atomic force microscopy revealed damage in the outer membrane structure. PEI especially increased the surface area and bulges of the cells. Topographic images of EDTA-treated cells were compatible with events assigned for the effect of EDTA on outer membranes, i.e., release of lipopolysaccharide and disintegration of OM structure. In addition, the effect of EDTA treatment was visualized in phase-contrast images as large areas with varying hydrophilicity on cell surfaces. In liquid culture tests, EDTA and PEI supplementation enhanced the activity of benzalkonium chloride toward the target strains. Use of permeabilizers in biocide formulations would enable the use of decreased concentrations of the active biocide ingredient, thereby providing environmentally friendlier products.

Anti-Bacterial Agents↗
PubMed2004

Suicidal mercury injection into the upper limb: a case study.

We report a rare case of self-injection of mercury into the subcutaneous tissue of the upper limb. A multi-disciplinary management approach was adopted including cooperation between toxicologists, orthopaedic surgeons, radiologists and environment safety personnel. Surgical removal of mercury under radiological screening and systemic intoxication treated by chelating agents, namely dimercaprol and succimer. Serial serum and urine mercury levels showed an initial rise despite surgical removal and returned to normal after a prolonged period of time. Safety precautions were taken during surgery to avoid inadvertent intoxication of staff. Contamination of the operation theatre was monitored by the amount of mercury vapour released into the air. All personnels involved in the management of the patient did not show any evidence of mercury intoxication.

Adult↗
PubMed1998

Role of glutathione in the antiulcer effect of hot water extract of black tea (Camellia sinensis).

The role of a hot water extract of black tea (Camellia sinensis (L). O. Kuntze Theaceae) in the gastric cytoprotective mechanisms was studied using gastric mucosal lesions produced by various ulcerogens in rats as an experimental model. Prior oral administration of black tea extract (BTE) at 20 ml/kg, i.g. once a day for 7 days significantly reduced the incidence of gastric erosions and severity induced by ethanol, diethyldithiocarbamate (DDC) and diethylmaleate (DEM). This treatment also favorably altered the changes in acid and peptic activity of gastric juice in these ulcerogen-treated animals. Singular administration of succimer (60 mg/kg, i.g.), the standard sulfhydryl containing antiulcer drug used as a reference drug, was also effective. The levels of glutathione and glutathione peroxidase were significantly decreased after treatment with ethanol, DDC and DEM, and this decrease was prevented by BTE pretreatment in the aforesaid manner. Other major features of BTE-induced reversal of ulcerogenic agents include a significant decrease in the protein content and a marked increase in hexosamine and sialic acid content. These results suggest a major role for glutathione, an endogenous antioxidant, in the cytoprotection against ulceration afforded by BTE.

Animals↗
PubMed2001

Role of reduced glutathione and nitric oxide in the black tea extract-mediated protection against ulcerogen-induced changes in motility and gastric emptying in rats.

The aim of the present study was to investigate the underlying mechanism of the role of hot water extract of black tea [Camellia sinensis (L). O. Kuntze Theaceae] in normalizing the changes in intestinal transit and gastric emptying induced by various ulcerogenic agents in experimental rats. Intestinal transit as well as gastric emptying were significantly reduced in rats treated with glutathione (GSH) depleting agents, diethyl maleate (DEM), indoacetamide (IDA) and N-ethyl maleimide (NEM). Prior oral administration of black tea extract (BTE) at 20 ml/kg of a 10% solution, i.g. once a day for 7 days significantly increased the intestinal transit and gastric emptying with restoration of serum GSH level. Singular administration of succimer (60 mg/kg, i.g.), the standard sulfhydryl containing antiulcer agent used as a reference drug, was also effective. Increase in intestinal transit caused by BTE was reversed both by N-omega-nitro-L-arginine methyl ester (L-NAME) (25 mg/kg, i.p.) and N-omega-monomethyl-L-arginine (L-NMMA) (25 mg/kg, i.p.), but not with N-omega-nitro-D-arginine methyl ester (D-NAME) (25 mg/kg, i.p.). Furthermore, restoration of intestinal nitric oxide synthase (NOS) activity was found to be associated with BTE treatment. These results provide evidence that nitric oxide may play a role in BTE-mediated improvement of intestinal motility changes and gastric emptying induced by DEM, IDA and NEM.

Animals↗