The cadmium mobilizing efficiency of a combined treatment with a novel cadmium chelating agent disodium N,N'-bis(D-glucosyl)-1,9-nonanediamine-N,N'-biscarbodithioate++ + (C9G2DTC) and with sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) was evaluated in albino rats. They received 109Cd intraperitoneally once and 1 week later chelation therapy six times over 12 days at 2-day intervals. The treatment groups were: 1, control; 2, BGDTC six times; 3, C9G2DTC six times; 4, C9G2DTC three times followed by BGDTC three times; 5, C9G2DTC twice followed by BGDTC four times; 6, C9G2DTC once followed by BGDTC five times. The radioactivity in liver, kidney and brain was determined 19 days after 109Cd administration. Results were expressed as a percentage of the 109Cd dose and differences were analyzed by Duncan's multiple range test (P < 0.05). Treatment with C9G2DTC resulted in higher Cd reduction in the liver and lower in the kidney than with BGDTC, which is in agreement with our previous findings. Combined treatment resulted in a greater reduction of Cd in the liver and kidney than by using either chelating agent alone, irrespective of the number of C9G2DTC or BGDTC treatments, and without causing redistribution to the brain. The important aspect of this work is that C9G2DTC--the novel cadmium chelating agent which is extremely efficient in reducing Cd liver deposits and about three times more toxic than BGDTC--has to be used only once at the beginning of the treatment to obtain optimal reduction of aged organ cadmium deposits.

Animals↗

PubMedDate not supplied

Racemic-2,3-dimercaptosuccinic acid for inorganic mercury mobilization in rats.

The efficiency of racemic-2,3-dimercaptosuccinic acid (rac-DMSA) compared with meso-2,3-dimercaptosuccinic acid (meso-DMSA) in mobilizing inorganic mercury was evaluated in female rats. Chelators were administered orally at a dose of 0.5, 1.0 or 2.0 mmol kg-1 on four consecutive days, 5 days after a single intraperitoneal 203Hg injection (with 0.5 mg HgCl2 kg-1). Both chelators reduced 203Hg retention in whole body and kidney and at higher doses also in the liver. Racemic-DMSA was more efficient at lower dose levels and equal to meso-DMSA at the highest dose level. Kidney retention decreased after rac-DMSA to 27, 10 and 10% of controls and after meso-DMSA to 68, 39 and 10% of control values at the 0.5, 1.0 and 2.0 mmol kg-1 dose level, respectively. Since meso-DMSA is already approved for human use, its stereoisomeric form, rac-DMSA, deserves further attention for treatment of mercury poisoning.

Administration, Oral↗

PubMedDate not supplied

Combined chelation therapy in reducing tissue lead concentrations in suckling rats.

The very young are more prone to lead poisoning than adults, and the treatment with chelating agents, either as monotherapy or combined treatment, is still a matter of dispute. The purpose of this work was to evaluate the efficiency of three chelating agents administered either as monotherapies or as combined treatments in sucklings. Lead acetate (5 mg Pb kg(-1) i.p.) was administered to the 7-day-old rat pups in eight litters on experimental day 1 and chelating agents on experimental days 2 and 3. Pups were divided into six groups: (1) untreated control; (2) EDTA (calcium disodium ethylendiaminetetraacetate, 0.3 mmol kg(-1) i.p. at 4 p.m.); (3) meso-DMSA (meso-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (4) rac-DMSA (racemic-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (5) EDTA+meso-DMSA; and (6) EDTA+rac-DMSA. Rats were killed on experimental day 5. Tissue element concentrations were analyzed by atomic absorption spectrometry. Treatment with EDTA did not affect tissue Pb, but it reduced Zn in the carcass and liver. Meso-DMSA reduced Pb in the kidneys and brain, and it did not affect organ essential elements. Rac-DMSA most efficiently reduced Pb concentrations in the carcass, kidneys and brain, but it also reduced Zn and Cu in the liver and Zn in the kidneys. Combined treatments with EDTA never improved the efficiency of either DMSA isoform in decreasing tissue Pb but they did reduce tissue Zn concentrations. All treatments caused the same decrease in the carcass Ca concentrations. The results do not support combined treatment in this age group, which is especially sensitive to trace element deficiencies, and suggest that meso-DMSA might be the treatment of choice in acute lead poisoning in infants.

Animals↗

PubMedDate not supplied

Organ cadmium deposits in orally exposed female rats and their pups and the depleting efficiency of sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate monohydrate (MeOBDCG).

Cadmium was given to female rats in the drinking water (50 ppm Cd) from 4 weeks before mating until weaning (a total of 10 weeks). Four weeks after the discontinuation of exposure, mothers and offspring were then given two i.p. doses of 1 mmol kg-1 sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate monohydrate (MeOBDCG) on subsequent days. Cadmium in kidneys and liver was determined in groups of mothers before mating and in mothers and pups after parturition, at the end of lactation and 4 and 5 weeks after the discontinuation of exposure. An additional measurement was made in pups in the middle of the lactation period. Cadmium deposition rapidly increased in the two organs between the 11th and 21st day of lactation. At all times, Cd concentrations in the liver and kidneys of mothers were several orders higher than in the offspring. After the discontinuation of exposure, maternal hepatic and renal Cd contents showed a significant decrease. Treatment with the chelator depleted the hepatic Cd stores in mothers by 90% and in pups by 80%, while the corresponding renal depletions were only 23% and 12%, respectively. The liver and kidney contents of Cd (but not the concentration) increased by a higher factor during lactation than during pregnancy and exposure during lactation was also more important for pups than prenatal exposure. The lower efficiency of the chelator in the offspring indicates that Cd accumulated during the neonatal period was less accessible to treatment with chelating agents than Cd accumulated in later life.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Decreasing 203Hg retention by intraperitoneal treatment with monoalkyl esters of meso-2,3-dimercaptosuccinic acid in rats.

The effect of nine monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) on 203Hg retention after a single i.p. dose was evaluated in 6-7 week-old female albino rats. The monoesters were the monomethyl (MMDMS), monoethyl (MEDMS), mono-n-propyl (Mn-PDMS), monoisopropyl (Mi-PDMS), mono-n-butyl (Mn-BDMS), monoisobutyl (Mi-BDMS), mono-n-amyl (Mn-ADMS), monoisoamyl (Mi-ADMS) and mono-n-hexyl (Mn-HDMS). Dimercaptosuccinic acid or one of the monoesters were administered at a dose of 0.25 mmol kg-1 body wt. twice, i.e. 30 min and 24 h after 203Hg administration. The whole body (WB) radioactivity was determined on the 2nd, 4th and 6th days. The radioactivity in the carcass (C) (whole body without the gastrointestinal tract), liver (L), both kidneys (K) and brain (B) was determined 6 days after 203Hg administration. All treated animals had a significantly lower body burden of mercury than the controls. The reduction of 203Hg retention in WB and other body compartments was higher in animals treated with monoesters than in rats treated with DMSA. The relative effectiveness of the monoesters was dependent on the nature of the alkyl groups, the efficiency being higher in higher analogues. Maximum activity was attained with the C5 (Mn-ADMS, Mi-ADMS) and C6 (Mn-HDMS) esters. These chelators reduced WB, C, L, K and B mercury retention by 90, 89, 76, 93 and 80%, respectively. Iso derivatives were more efficient than the normal isomers (Mi-PDMS > Mn-PDMS; Mi-BDMS > Mn-BDMS; Mi-ADMS > Mn-ADMS).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Monoisoamyl and mono-n-hexyl meso-2,3-dimercaptosuccinate in mobilizing 203Hg retention in relation to age of rats and route of administration.

Monoisoamyl (Mi-ADMS) and mono-n-hexyl (Mn-HDMS) monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) were given orally or parenterally for the mobilization of inorganic mercury in suckling and older rats. Chelators were administered at a dose of 2 x 0.5 mmol kg-1 on two consecutive days 2 weeks after a single 203Hg injection. Six days later, whole-body, kidney, liver and brain radioactivities were determined in gamma scintillation counters. Both Mi-ADMS and Mn-HDMS were found to be superior to DMSA in mobilizing mercury from body and organs. The results were similar after oral or parenteral treatment. The efficiency of both monoesters was even higher in younger than in older rats. This is the first report on the mobilization of mercury from the body of sucklings under conditions of late oral treatment.

Administration, Oral↗

PubMedDate not supplied

Cigarette smoking in a multiethnic population of youth: methods and baseline findings.

BACKGROUND: To expand upon recent research studies that have identified dramatic ethnic differences in adolescent cigarette smoking, this study was designed to characterize smoking among a multiethnic population of adolescents and to identify significant factors that may protect against smoking initiation. METHODS: During the first 2 years, this mixed cross-sectional, longitudinal study recruited and collected baseline data from a volunteer sample of 1,441 Houston-area public school students in the 5th, 8th, or 12th grade. A wide range of new and established predictors of smoking behavior was assessed, and their associations with ever smoking and susceptibility to smoking were assessed within ethnicity (white, N = 537; African-American, N = 454; and Hispanic, N = 297). RESULTS: Consistent with previous studies, white students smoked in substantially higher proportions than African-American students, with Hispanic adolescents in-between. Simultaneously adjusting for other variables, the odds of ever smoking (OR = 0.47, P < 0.01) and susceptibility to smoking (OR = 0.64, P < 0.01) were significantly lower among African-American adolescents when compared with whites; odds ratios for Hispanics and whites did not differ. Across all three ethnicities, the most important predictor of both ever smoking and susceptibility to smoking was the smoking status of the three best friends. Several ethnicity-specific variables also were identified. CONCLUSIONS: In concordance with previous investigations, cigarette smoking prevalence differs by ethnicity, and the factors associated with ever smoking and susceptibility to smoking differ among white, African-American, and Hispanic adolescents. The results of this study may be used to develop theory-based, culturally appropriate smoking intervention programs for adolescents.

Adolescent↗

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Carbodithioate MeOBDCG for decreasing intracellular cadmium deposits in rats of different ages.

The efficiency of chelating agents to remove aged intracellular deposits of cadmium in young and older rats was studied. The administration of the chelating agent sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate monohydrate (MeOBDCG) 2 wk after a single intraperitoneal 115m Cd administration reduced the whole body, liver, and kidney retention in suckling rats to about 63, 42, and 71 percent and in older rats to 39, 17, and 76 percent of values obtained in respective controls. Chelation therapy was generally more effective in older than younger rats and the age-related effect was most pronounced in the liver. These results indicate that specific features of young organisms may significantly alter the effect of chelation treatment.

Aging↗

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Use of the Topliss scheme for the design of more effective chelating agents for cadmium decorporation.

The Topliss scheme, which designates a special series of substituents for use in sequence in the search for suitably substituted aromatic compounds with biological properties superior to the parent unsubstituted aromatic compound, has been applied to the design of new chelating agents for the decorporation of cadmium from its deposits in vivo. Substituted benzylamines have been used in the syntheses of the corresponding substituted sodium N-benzyl-D-glucamine-N-carbodithioates, i.e., RC6H4CH2N(CS2Na)CH2(CHOH)4CH2OH (or RBGDTC): CF3BGDTC, R = 3-CF3; MeBGDTC, R = 4-CH3; MeOBGDTC, R = 4-OCH3; ClBGDTC, R = 4-Cl. Examination of the behavior of these compounds as agents for the mobilization of cadmium from its deposits in vivo shows that such substitution can have an appreciable effect on the organ selectivity for cadmium removal, as well as the efficacy. Of the four compounds suggested by the Topliss scheme for pilot studies, two were much more effective than the parent compound (BGDTC), and of these the best one, sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate (MeOBGDTC) reduced kidney cadmium levels to 30% and liver cadmium levels to 50% of those obtained with the parent compound. Sodium N-[3-(trifluoromethyl)benzyl]-D-glucamine-N-carbodithioate (CF3BGDTC) was also found to be superior to the parent compound in reducing the liver cadmium levels, though it was equivalent in reducing renal cadmium levels.

Animals↗

PubMedDate not supplied

Chemical models for the lethality curves of toxic metal ions.

Several equilibrium models are presented for the calculation of the lethality curves due to toxic metal ions. In the first, a generalized Langmuir model is used to examine the occupancy of linear arrays of 1, 2, ..., 6 interacting adsorption sites on a macromolecular species. This model permits one to take into account cooperative or anticooperative interaction of occupied adjacent sites. In the second model, a variety of nonlinear distributions of interacting sites (in triangular, square, tetrahedral, and octahedral array) are analyzed, and the corresponding adsorption isotherms are calculated. The third model treated, the Ising model, represents a linear infinite array of sites with nearest-neighbor interactions. The fourth and fifth models examined are the Bragg-Williams model and the quasi-chemical model, both of which permit approximate treatment of infinite arrays of adsorption sites having arbitrary numbers of interacting nearest neighbors. These models are then combined with the assumption that the differential distribution of mortality is a known function of the fraction of sites occupied by the toxic metal ion to generate lethality curves. Results are computed for the special case in which the differential mortality distribution is Gaussian, and it is shown that all of the models are capable of generating lethality curves of the sort found experimentally when plots are made of percentage lethality versus log dosage. The models can also be used for situations in which toxic effects other than lethality arise from the interaction of a toxic molecule or ion with more than one site on a linear macromolecule or for reactions involving certain other arrays of specified configuration.

Binding Sites↗

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Optimization of chelating agent structure for the mobilization of aged renal and hepatic cadmium deposits: sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate.

An examination of the structure-activity relationships for the mobilization of intracellular cadmium by previously synthesized dithiocarbamates indicates that superior compounds can be prepared by increasing the molecular weight by using bulky polar but nonionic substituents. This suggested the synthesis and characterization of sodium N-benzyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioate++ +. The preparation of this compound and its characterization as an agent for the mobilization of aged renal and hepatic cadmium deposits in mice show it to be superior to the compounds reported earlier which have been used for this purpose. Five ip injections at 0.40 mmol/kg reduced hepatic cadmium levels to 35% of their initial level and renal cadmium levels to 37%. The nature of the structural factors responsible for the efficacy of such agents is outlined as well as the relationship of these to the toxicity of the compounds and their cadmium complexes. These factors indicate clearly the differences in the molecular requirements for the mobilization of extracellular and intracellular toxic metal ions. The requirement that intracellular toxic metals be mobilized places several constraints on the structures of potentially efficacious compounds in addition to the thermodynamic and kinetic restrictions imposed by the requirements for extracellular efficacy.

Animals↗

PubMedDate not supplied

Chirality, charge, and chain branching effects on dithiocarbamate-induced mobilization of cadmium from intracellular deposits in mice.

The effects of three major structural features on the intracellular cadmium mobilizing potency of dithiocarbamates have been examined. These features, the chirality of the groups, the total ionic charge of the chelating agent, and the extent of chain branching, would be expected to affect the pharmacological properties of these chelating agents but to have little effect on the stability constants of the cadmium complexes involved. A total of 25 compounds (including 21 new ones) was prepared and used in animal studies designed to evaluate these effects. These included a series of amphipathic dithiocarbamates of the general type R1N(R2)CS2-Na+, where R1 is a relatively nonpolar organic group and R2 is derived from a reducing hexose. All of the factors examined influenced the potency of dithiocarbamates in the mobilization of cadmium from intracellular deposits. The compounds with R2 = galactose or mannose and R1 = benzyl were both more effective than the corresponding glucose derivatives in inducing the removal of cadmium from the liver and the whole body. Increases in the net negative charge of the chelating agent uniformly decreased the observed potency in the mobilization of hepatic and renal cadmium deposits. The replacement of a normal alkyl group by a branched-chain group of the same molecular weight also led to an increase in potency for the two pairs of compounds examined. Dithiocarbamates which are not amphipathic because of the presence of similar polar substituents for both R1 and R2, such as sodium diarabitylamine carbodithioate, were relatively ineffective as agents for the mobilization of intracellular cadmium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Structure-activity relationships for intracellular cadmium mobilization by N-alkyl-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodithioates+ ++.

An examination of a group of dithiocarbamate chelating agents derived from various alkylamines and lactose reveals that the relative potencies in the mobilization of intracellular cadmium from renal and hepatic deposits in mice are highly dependent upon the size and nature of the alkyl groups. For those compounds containing straight-chain alkyl groups, the potency drops off as the number of carbon atoms is increased beyond seven. Branched-chain alkyl groups are more effective in promoting the removal of cadmium than straight-chain alkyl groups with the same number of carbon atoms. The fact that these compounds are effective in the mobilization of intracellular cadmium deposits suggests that the size and shape of the alkyl group are important in the determination of the facility with which the compound can pass through cellular membranes. Straight-chain derivatives with 10 or more carbon atoms were more toxic than those with nine or fewer carbon atoms. Of the new compounds, four (the n-hexyl, n-heptyl, n-octyl, and 2-ethylhexyl derivatives) are more effective than the corresponding benzyl derivative in inducing a reduction of hepatic cadmium levels from animals given cadmium at least 1 week previously. The results obtained indicate that modest modifications in the groups on the basic dithiocarbamate structure can produce agents of significantly enhanced effectiveness for the removal of cadmium from its hepatic deposits.

Animals↗

PubMedDate not supplied

Structure-activity relationships for in vivo cadmium mobilization by dithiocarbamates derived from lactose and maltotriose.

The relationships between chemical structure and the relative ability to mobilize cadmium in vivo from its aged renal and hepatic deposits have been examined in a series of newly synthesized dithiocarbamates derived from lactose and maltotriose. The results suggest that, in the selection of hydrophobic groups to counter the hydrophilicity contributed by the disaccharides, aromatic groups provide compounds which have a superior efficacy to compounds containing aliphatic groups. The compounds derived from trisaccharides are much less effective than those derived from disaccharides, suggesting that there is a practical size limit to the hydrophilic groups which can be used in the structures of such compounds. With both di- and trisaccharides, aliphatic derivatives with straight chains containing more than eight carbon atoms tend to be less effective than the ones with seven or fewer carbon atoms in the alkyl chain. The three compounds prepared from lactose which contain a benzyl or a methyl-substituted benzyl group are the most effective compounds reported to date for the reduction of whole-body cadmium levels.

Animals↗