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At least 343 records · Page 19Linked to original sources
PubMed1991

meso-2,3-Dimercaptosuccinic acid and prevention of arsenite embryotoxicity and teratogenicity in the mouse.

meso-2,3-Dimercaptosuccinic acid (DMSA), an antidote for the treatment of experimental and human poisoning by a number of heavy metals, has been reported to reduce the lethality of animals poisoned with arsenic more effectively than 2,3-dimercaptopropanol. In the present study, the effect of DMSA on arsenite-induced embryotoxic and teratogenic effects was evaluated in mice. In a first experiment, a series of four DMSA injections was administered sc to pregnant Swiss mice immediately after a single ip injection of 12 mg/kg of sodium arsenite (NaAsO2) given on Day 10 of gestation, and at 24, 48, and 72 hr thereafter. DMSA effectiveness was assessed at dosage levels of 0, 80, 160, and 320 mg/kg/day. Treatment with DMSA significantly reduced the embryolethality and the incidence of gross external and skeletal malformations and variations provoked by NaAsO2. Based on these findings, the effect of increasing the time interval between acute arsenite exposure and initiation of DMSA therapy was investigated in a second experiment. On Day 10 of gestation, DMSA (320 mg/kg) was administered sc to pregnant mice at 0, 0.25, 0.50, 1, 4, or 12 hr after a 12-mg/kg ip dose of NaAsO2. Embryotoxicity and teratogenicity derived from NaAsO2 exposure were significantly reduced when DMSA was given during the first hour after NaAsO2 injection. According to these results, a delay between acute arsenite intoxication and DMSA treatment should be avoided to have a practical beneficial effect on the arsenite exposed conceptus.

Animals↗
PubMed1984

The protective effects of thiol-containing compounds on mercuric chloride-induced acute inhibition of enzymes from mouse kidney.

The inhibitory effect of mercuric chloride on mouse kidney enzymes and the treatment of this inhibition with some thiol-containing compounds, e.g., dithiothreitol (DTT), dimercaptosuccinic acid (DMS) and D-penicillamine (Pen) was examined. To produce a significant inhibition of renal enzymes in vivo, it was necessary to administer 5 mg Hg/kg/day, s.c., once daily for 3 doses, and to sacrifice the animals 1 day after the last injection. With this Hg dose, microsomal Mg2+-Na+-K+-ATPase, mitochondrial Mg2+-HCO-3-ATPase and supernatant carbonic anhydrase activities decreased to about 30%, 70% and 60% of normal values, respectively. Combined administration of DTT (5-20 mg/kg, i.p.) and DMS (5-20 mg/kg, i.p.) with HgCl2 restored the enzyme activities to near normal or normal levels in parallel to the administered doses. The effect of Pen was slightly less than that of the above 2 compounds. This may be due to the number of thiol radicals, as Pen is a monothiol and the other 2 compounds are dithiol compounds. Since the toxicity of DMS is very low compared with DTT, DMS may be more suitable for the treatment of mercury poisoning.

Adenosine Triphosphatases↗
PubMed1987

tri-n-Butyltin: a membrane toxicant.

Increased use of the biocidal compound tri-n-butyltin (TBT) in antifouling paints has prompted research aimed at determining the mechanism for TBT toxicity. Past investigations indicate that the primary cellular target for TBT is the cell membrane. Erythrocyte suspensions treated with TBT concentrations 2 greater than or equal to 5 microM undergo hemolysis described by a sigmoidal kinetic pattern. Transformation of cell shape from discocyte to echinocyte occurs at TBT concentrations greater than or equal to 0.1 microM, indicating that the compound enters the outer membrane bilayer. TBT at concentrations greater than or equal to 10 microM forms electron-dense aggregates that are intercalated within plasma membranes as viewed in ultrathin sections by transmission electron microscopy. Qualitative X-ray microanalysis of these aggregates confirms the presence of tin. The size of these structures can be modified by either 10 mM cyanide or 2,3-dimercaptopropanol (British Anti-Lewisite, BAL). Adding 10 mM cyanide to hemolytic TBT concentrations resulted in a synergistic stimulation of hemolysis attributable to high cyanide anion concentrations in or near the cell membrane. The elevated cyanide anion levels are thought to contribute to membrane lysis. The lipophilic dimercapto compounds BAL, dithiothreitol, and 2,3-dimercaptosuccinate are effective inhibitors of TBT-induced lysis. Water-soluble 2,3-dimercapto-1-propane sulfonate, a BAL analog, was largely ineffective as an inhibitor. The detailed molecular mechanism for TBT-induced membrane lysis is not yet clear. Cellular ATP depletion could be induced by TBT as well as by delipidation of anionic phospholipids or even formation of tributylstannylperoxy radicals, resulting in lipid peroxidation.

Chemical Phenomena↗
PubMed1989

Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.

The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.

Administration, Inhalation↗
PubMed1990

Beneficial effects of zinc supplementation during chelation treatment of lead intoxication in rats.

The ability of zinc to enhance the efficacy of commonly used chelating drugs in lead intoxication and to reduce the resulting zinc imbalance, was investigated in rats. The simultaneous zinc supplementation increased urinary lead elimination by calcium disodium ethylenediaminetetraacetate (Ca disodium EDTA) and 2,3 dimercaptosuccinic acid (DMSA). Combination therapy was also effective in potentiating the depletion of blood, hepatic and renal lead by calcium disodium EDTA and D-penicillamine (DPA), renal lead by DMSA and reversal of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity by calcium disodium EDTA and DPA. The body zinc status was also maintained as reflected by urinary, blood and tissue levels of zinc.

Acetates↗
PubMed1992

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

Animals↗
PubMed1992

Characterization of gold in urine and bile following administration of gold sodium thiomalate with chelating agents to rats.

Gold was characterized in the urine and bile of rats treated with D-penicillamine (D-PEN), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropane sulphonate (DMPS), or N-(2-mercapto-2-methylpropanoyl)-L-cysteine (bucillamine) immediately after gold sodium thiomalate (AuTM) injection by both gel chromatographic and electrophoretic methods. It is suggested that the gold in the urine and bile after AuTM administration was predominantly bound to high molecular weight compounds. The characterization of gold in the urine after administration of AuTM with D-PEN, DMSA, or DMPS showed that most of the gold was bound to the chelating agents. In the treatment with the chelating agents such as D-PEN and DMPS, the gold was mainly excreted as a gold-chelating agent compound in the bile and a minor portion of the gold was present in the form of a gold-L-cysteine compound and high molecular weight compounds. DMSA treatment showed that a major portion of the gold was bound to high molecular weight compounds in the bile and a minor portion of the gold was present in the forms of gold-DMSA and gold-L-cysteine compounds. The administration of AuTM and bucillamine indicated that the gold was mainly present as a gold-Me-bucillamine compound in the urine and a gold-bucillamine compound in the bile.

Animals↗
PubMed1992

Meso-2,3-dimercaptosuccinic acid (DMSA) affects maternal and fetal copper metabolism in Swiss mice.

Meso-2,3-dimercaptosuccinic acid (DMSA) is a chelating agent used to treat heavy metal intoxication. DMSA has been reported to be teratogenic in the mouse, and it has been suggested that this teratogenicity may be secondary to DMSA-induced alterations in Zn metabolism. In the present study, 0, 400 or 800 mg DMSA/kg body weight were administered on gestation days 6-15 to pregnant Swiss mice by gavage (PO) or subcutaneous injection (SC). Mice were fed a diet containing 14 micrograms Zn, 10 micrograms Cu, 120 micrograms Fe, 1175 micrograms Mg and 6.8 mg Ca/g diet. A sub-group of mice in the 800 mg DMSA/kg SC group was fed a diet containing 250 micrograms Zn/g. DMSA administration did not result in overt maternal toxicity. There was no effect of the drug on fetal or placental weight, or on crown-rump length. However, some fetuses from DMSA-treated dams were characterized by skeletal abnormalities including supernumerary ribs, unossified anterior phalanges and malformed sternebrae. Drug exposure was not associated with consistent changes in tissue Zn, Fe, Ca or Mg levels. Supplemental Zn had no marked effects on the fetus. Fetal liver Cu concentrations exhibited dose-dependent decreases with increasing DMSA dose. This finding suggests that the developmental toxicity of DMSA may be mediated through disturbed maternal/fetal copper metabolism.

Animals↗
PubMed1993

meso-2,3-dimercaptosuccinic acid monoalkyl esters: effects on mercury levels in mice.

Seven monoesters of meso-2,3-dimercaptosuccinic acid (DMSA) were evaluated for relative activities in mobilizing and promoting excretion of mercury in mercury-laden mice. Compounds assessed were the ethyl (M-EDMS), n-propyl (Mn-PDMS), isopropyl (Mi-PDMS), n-butyl (Mn-BDMS), isobutyl (Mi-BDMS), n-amyl (Mn-ADMS), and isoamyl (Mi-ADMS) esters. 2,3-Dimercaptopropane-1-sulfonate (DMPS) and DMSA were used as positive controls. After the first oral dose of each compound at 0.5 mmol/kg, DMSA and DMPS reduced the corporal mercury burden 16% and 24%, respectively, compared to controls, while the monoesters effected reductions of 35% (M-EDMS) to 49% (Mi-ADMS). After the second treatment at the same dose, the respective reductions produced by DMSA and DMPS were 24% and 38%, and those conferred by the monoesters ranged from 52% (M-EDMS) to 61% (Mn-BDMS). Determination of the comparative dose-response relationships of DMSA and Mi-ADMS on corporal and renal mercury concentrations revealed the monoester to be more active than DMSA on both parameters at each dose used. The cumulative amount of mercury excreted in urine by control mice over a 3-day period was 7.08 micrograms; this was increased 22%, 85%, and 94% by daily i.p. injections of DMSA, DMPS, and Mi-ADMS, respectively, at a daily dose of 0.1 mmol/kg. The respective cumulative 3-day totals recovered in feces from control mice and from mice treated with DMSA, DMPS, and Mi-ADMS were 9.76, 8.21, 10.44, and 11.73 micrograms. Parallel daily measurements of retained whole body radioactivity from 203Hg in mice were in good agreement with the values calculated from the excretion data.

Animals↗
PubMed1995

Effects of meso-2,3-dimercaptosuccinic acid or 2,3-dimercaptopropane 1-sulfonate on beryllium-induced biochemical alterations and metal concentration in male rats.

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.

Animals↗
PubMed1994

Effect of chelate treatments on kidney, bone and brain lead levels of lead-intoxicated mice.

The effects of chelating agent treatment with meso-2,3-dimercaptosuccinic acid (DMSA), Na2CaEDTA, Na2ZnEDTA, and Na3ZnDTPA on the organ lead levels of lead-loaded mice have been determined. At 1 mmol/kg/day i.p., all caused reductions in the lead levels of the kidney after four injections, but only Na2CaEDTA produced a significant reduction in brain lead. All chelating agents caused significant reductions in kidney and brain lead levels when administered at a daily dose of 1 mmol/kg/day for eight days, but only DMSA reduced the bone lead level. In animals given 50 mg Pb/kg or 100 mg Pb/kg, the administration of Na2CaEDTA or DMSA at 1 mmol/kg/day x 8 produced significant reductions in kidney, bone and brain lead levels, but DMSA produced greater reductions of bone lead in both groups and of kidney lead in the group given 100 mg Pb/kg. An examination of published data describing the effect of chelating agent treatment on brain lead levels indicates that DMSA produces a reduction in brain lead levels under all conditions examined to date.

Animals↗
PubMed1995

Effects of chelating agents on testicular toxicity in mice caused by acute exposure to nickel.

N-Benzyl-D-glucaminedithiocarbamate (BGD), diethyldithiocarbamate (DDTC), dihydroxyethyldithiocarbamate (DHED), trans-1,2-cyclohexanediamine N,N,N',N'-tetraacetic acid (CDTA), and meso-2,3-dimercaptosuccinic acid (DMSA) were studied for their protective effects against the testicular toxicity in mice induced by acute exposure to nickel (Ni). Mice were injected intraperitoneally with NiCl2 (5 mgNi/kg) and 30 min or 24 h later, they were injected intraperitoneally with chelating agents (400 mumol/kg). Ni injection increased lipid peroxidation and concentrations of Ca and Fe in the testes, liver, and kidney, and decreased the testicular weight and the fertility rate. At 30 min after Ni treatment, the chelating agents other than CDTA effectively depressed Ni concentration in the testes. At 24 h after Ni treatment, DMSA, BGD, and DDTC were effective in mobilizing Ni from the testes. DMSA, BGD, and CDTA significantly prevented the increase in the lipid peroxidation, the increase in the concentrations of Ca and Fe in the testes, liver, and kidney, and the decrease in the fertility rate caused by Ni injection. Treatment with DMSA or BGD was more effective than that with the others in decreasing the testicular Ni concentration, resulting in effective protection against Ni-induced testicular damage.

Animals↗
PubMed1996

Assessment of the protective activity of monisoamyl meso-2,3-dimercaptosuccinate against methylmercury-induced maternal and embryo/fetal toxicity in mice.

The protective activity of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new monoester of 2,3-dimercaptosuccinic acid (DMSA), on methylmercury-induced maternal and developmental toxicity was assessed in mice. A series of four Mi-ADMS injections was given s.c. at 0.25, 6, 24, and 48 h after oral administration of 25 mg/kg of methylmercury chloride (MMC) given on day 10 of gestation. Mi-ADMS effectiveness was tested at 0, 23.8, 47.6 and 95 mg/kg. Cesarean sections were performed on gestation day 18. All live fetuses were examined for external, internal, and skeletal abnormalities. Oral MMC administration resulted in an increase in the number of resorptions, and a decrease in fetal body weight, whereas the incidence of cleft palate, micrognathia, and skeletal variations was also increased in the fetuses of the MMC-treated groups. Although significant amelioration of MMC-induced embryolethality by Mi-ADMS was not noted at any dose, MMC-induced fetotoxicity was reduced by administration of this agent at 23.8, 47.6, and 95 mg/kg. However, the intrinsic toxicity of Mi-ADMS would be a restrictive factor for the possible therapeutic use of this chelator in pregnant women exposed to organic mercury.

Abnormalities, Drug-Induced↗
PubMed1996

In vivo studies of cadmium-induced apoptosis in testicular tissue of the rat and its modulation by a chelating agent.

In vivo CdCl2-induced apoptotic DNA fragmentation in the testes of the male Wistar rat has been demonstrated on agarose gel. Characteristic DNA migration patterns (laddering) provide evidence of apoptosis (programmed cell death) in testicular tissue of rats administered CdCl2 at a level of 0.03 mmol/kg 48 h previously. Evidence that administration of an appropriate cadmium chelating agent within the first 24 h can suppress some or all of the apoptotic changes in testicular DNA has also been obtained for the first time. A greater reduction in apoptosis is observed as the interval between the administration of the cadmium and that of the chelating agent is shortened. Administration of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) to male Wistar rats given CdCl2 is effective in the modulation of the typically apoptotic DNA fragmentation and associated histopathologic injury when the antagonist is given within approximately 1 h after the CdCl2 exposure. When the antagonist is given at later times there is a progressively more pronounced degradation of the DNA into oligonucleotides as seen in the typical electrophoretic DNA ladder pattern found with apoptosis. There is also a progressive increase in histopathological tissue changes as the antagonist is administered at progressively greater intervals after the cadmium.

Animals↗
PubMed1996

Pharmacological prevention of acute lead poisoning in Paramecium.

To understand how lead (Pb2+) and other metals and chelating agents effect living cells, behavioral experiments in the marine ciliate Paramecium calkinsi were carried out. The duration of Backward Swimming Behavior (BSB) of Paramecium was partially reduced when cells were exposed to 100 microM of Ni2+, CD2+ and Co2+. In contrast, Pb2+ increased Paramecium BSB in a dose-dependent manner. Thus, 1, 10, 20, 50 and 100 microM of Pb2+ increased the duration of BSB by 20.4, 83.9, 143.2, 163.2 and 185.2%, respectively. The naphthalenesulphonamide W-7, a calcium channel blocker in lower organisms, abolished the increase of Paramecium BSB initially produced by Pb2+. Paramecium, poisoned with 10 MicroM of Pb2+, were also treated with putative Pb2+ chelating agents, such as meso-2-3-dimercaptosuccinic acid (DMSA), Ca-Na2-EDTA and ascorbic acid. These compounds inhibited the increase of the duration of BSB initially produced by Pb2+ in a dose-dependent manner. The potency of these antidotes in blocking the effects of Pb2+ was as follows: DMSA >> Ca-Na2-EDTA > ascorbic acid. These results provide evidence for a membrane-based mechanism of lead poisoning and support the use of DMSA as a lead antidote.

Animals↗
PubMed1988

Unilateral kidney irradiation and late retreatment with cis-dichlorodiammineplatinum (II): functional measurements with 99mtechnetium-dimercaptosuccinic acid.

A rat model was used to study renal function after unilateral kidney irradiations. The left kidney was irradiated with a single dose (6-14 Gy), 2 equal sized fractions (10-16 Gy total dose) or 4 equal sized fractions (12 to 21 Gy total dose). At regular time intervals after treatment, the left kidney function was assessed with the use of 99mTc-Dimercaptosuccinic acid for a period of about 1 year. It was found that renal function declined in a dose- and time-dependent manner. The threshold dose for detecting functional impairment was 8 Gy for 1 fraction, 12 Gy for 2 fraction and 15 Gy for 4 fraction irradiations, demonstrating the sensitivity of the isotope tracer test used in these experiments. Retreatment of the rats with a single i.p. dose of 5 mg/kg cis-Dichlorodiammineplatinum (II) (cis-DDP) given at about 1 year after X ray exposure revealed an important relative decrease in the function of the irradiated compared to the unirradiated kidney. Reductions in function of 11 to 70% (depending on radiation dose and schedule) compared with control values were observed at 11 weeks after drug injection. These results demonstrate that a previously irradiated kidney is more sensitive to a subsequent treatment with cis-DDP than the contralateral hypertrophied kidney in the same animal.

Animals↗
PubMed1990

Radiation injury in the human kidney: a prospective analysis using specific scintigraphic and biochemical endpoints.

Renal function was prospectively analyzed in 26 evaluable patients, irradiated to various doses on their kidneys for neoplastic disease. Glomerular function was assessed by 99mTc-DTPA renography, creatinine clearance, and serum beta 2-microglobulin, whereas tubular function was monitored by 99mTc-DMSA scintigraphy, urine beta 2-microglobulin, urine N-acetyl glucosaminidase, and alanine aminopeptidase and a urine concentration test. In the patients given the highest irradiation dose to the entire left kidney, that is, 40 Gy in 5 1/2 weeks, glomerular and tubular functional impairment, as assessed scintigraphically, progressed at a rate of 2.0 +/- 1.0% (+/- 1 SD) and 2.0 +/- 0.5% per month, respectively, down to 30-40% after 3 to 5 years. The overall glomerular function, as assessed by creatinine clearance, decreased by only 20%. In the patients irradiated unilaterally on the upper pole to 40 Gy in 4 weeks, glomerular and tubular function in the left kidney deteriorated at 0.75 +/- 0.33% and 0.75 +/- 0.20% per month in the first 2 years, down to 75-80% at 5 years. This smaller reduction was due to shielding of a part of the left kidney. No changes were observed, thus far, after bilateral whole kidney irradiation to 17-18 Gy in 3 1/2 weeks. The concentration capacity of the kidney after total volume irradiation was not impaired. There was a trend for an increase in diastolic blood pressure in 3 out of 5 patients given the high dose irradiation to the entire left kidney and in 2 out of 7 patients irradiated on the upper pole of the left kidney. The progressive nature of the radiation nephropathy stresses the need for long term follow-up to determine more accurately the "tolerance dose" of the human kidney for irradiation.

Acetylglucosaminidase↗