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PubMed2001

Effect of dithiol chelating agents on [3H]MK-801 and [3H]glutamate binding to synaptic plasma membranes.

2,3-Dimercaptopropanol (BAL- British Anti-Lewesite) is a dithiol chelating agent used for the treatment of heavy metal poisoning, however, BAL can produce neurotoxic effects in a variety of situations. Based on the low therapeutic efficiency of BAL other dithiols were developed and DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid) are becoming used for treatments of humans exposed to heavy metals. In the present investigation the effect of dithiols in the glutamatergic system was examined. The results showed that BAL inhibited [3H]MK-801 and [3H]glutamate binding in a concentration-dependent manner. At 100 microM BAL and DMSA caused a significantly inhibition of [3H]MK-801 binding to brain membranes (p < 0.05 by Duncan's multiple range test). BAL at 100 microM caused an inhibition of 40% on [3H]glutamate binding. DMPS and DMSA had no significant effect on [3H]glutamate binding. Dithiotreitol (DTT), abolished the inhibitory effect of BAL on [3H]MK-801 binding. The protection exerted by DTT suggests that BAL inhibit [3H]MK-801 binding by interacting with cysteinyl residues that are important for redox modulation of receptor responses. ZnCl2 inhibited [3H]glutamate and [3H]MK-801 binding to brain synaptic membrane; nevertheless, the inhibitory effect was slight more accentuated for [3H]MK-801 than [3H]glutamate binding (p < 0.05). The inhibition caused by 10 microM ZnCl2 on [3H]MK-801 binding was attenuated by BAL. The findings present in this study may provide the evidence that BAL affect the glutamatergic system and these effects can contributed to explain, at least in part, why BAL, in contrast to DMPS and DMSA is neurotoxic.

Animals↗
PubMed2000

Mobilisation of cadmium by meso- and racemic-2,3-dimercaptosuccinic acid (DMSA) in rats.

A higher efficiency of cadmium binding with racemic than with meso-2,3-dimercaptosuccinic acid (rac-DMSA; meso-DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso- and rac-DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso- and rac-DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole-body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole-body retention with rac-DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso- and rac-DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac-DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac-DMSA being slightly more efficient than meso-DMSA.

Analysis of Variance↗
PubMed2003

Ascorbic acid supplementation does not improve efficacy of meso-dimercaptosuccinic acid treatment in lead-exposed suckling rats.

It was suggested that ascorbic acid as a natural chelating agent can influence lead toxicokinetics and improve chelating properties of dimercaptosuccinic acid (DMSA) in adult rats. In this paper potential benefits of ascorbic acid supplementation, alone or combined with DMSA, in decreasing lead retention in suckling rats were evaluated. Such data in young mammals are not available. L-Ascorbic acid (daily dose 650 mg/kg b.wt.) and/or DMSA (daily dose 91 mg/kg b.wt.) were administered orally to suckling Wistar rats either during ongoing 8-day oral lead exposure (as acetate; daily dose 2 mg lead/kg b.wt.) or after 3-day lead exposure (total dose 12 mg lead/kg b.wt.). Lead concentrations were analysed in the carcass (skeleton), liver, kidneys and brain by atomic absorption spectrometry. By ascorbic acid supplementation lead retention was not reduced under either lead exposure condition. Lead concentration was even increased in the carcass. Treatment with DMSA under both exposure conditions significantly reduced lead in all analysed tissues. Combined treatment with ascorbic acid and DMSA during ongoing lead exposure was substantially less effective than DMSA treatment alone, and did not affect DMSA efficacy when administered after lead exposure. It was concluded that ascorbic acid administered either during or after lead exposure in suckling rats has no beneficial effect on either lead retention or DMSA chelation effectiveness.

Administration, Oral↗
PubMed1979

Effect of endogenous and exogenous prostaglandin E on Friend erythroleukaemia cell growth and differentiation.

The effect of exogenous and endogenous prostaglandins on the patterns of growth and differentiation of Friend erythroleukaemia cells (FLC) were studied. During the differentiation process, DMSO stimulated PGE synthesis by an average of 95%. The addition of a long-acting synthetic analogue of PGE2,16,16-dimethyl-PGE2-methyl ester (di-M-PGE2) to the culture medium only slightly and temporarily slowed cell growth, with no appreciable induction of differentiation. However, in the presence of DMSO, the same concentration of di-M-PGE2 produced 73% inhibition of cell growth and accelerated and potently stimulated haemoglobin production. The action of both di-M-PGE2 and DMSO on cell proliferation was dependent upon the state of cell growth at the time of the administration of these compounds. FLC cultures treated with DMSO + di-M-PGE2 produced considerable amounts of haemoglobin before even one duplication cycle was completed. Both DMSO and di-M-PGE2 stimulated endogenous PGE biosynthesis, and the biosynthetic effect of these compounds was synergistic. Inhibition of endogenous prostaglandin synthesis by indomethacin completely abolished the effects produced by DMSO + di-M-PGE2 on the growth, and substantially reduced the stimulated differentiation of FLC. These data suggest that an endogenously synthesized prostaglandin plays a significant role in both the inhibition of replication and in the stimulation of differentiation induced by DMSO and di-M-PGE2 in Friend erythroleukaemia cells.

Cell Differentiation↗
PubMed1985

2,3-Dimercaptosuccinic acid as an antidote for lead intoxication.

2,3-Dimercaptosuccinic acid (DMSA) is an orally effective drug more specific and with a wider therapeutic index than currently available drugs for lead intoxication. Eighteen men with elevated blood lead (BPb) concentrations received either 30, 20, or 10 mg/kg DMSA for 5 days in three divided daily doses. The mean BPb level decreased 72.5%, 58.3%, and 35.5% of the pretreatment values, with a simultaneous elevation in urinary Pb excretion. Clinical symptoms and biochemical indices of lead toxicity also improved. Red blood cell d-aminolevulinic acid dehydratase activity increased, while urinary excretion of d-aminolevulinic acid and coproporphyrin fell. DMSA was well tolerated; the only observed adverse drug reaction was a mild, transient elevation of serum SGPT levels in two subjects. DMSA appears promising and may greatly simplify the treatment of lead intoxication.

Administration, Oral↗
PubMed1989

Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects.

The urinary excretion of meso-2,3-dimercaptosuccinic acid (DMSA), which is an effective chelating agent for lead, was determined after the oral administration of 10 mg DMSA/kg to six normal young men. The DMSA that was absorbed was extensively biotransformed. After 14 hours only 2.53% of the administered DMSA was excreted in the urine as unaltered DMSA and 18.1% as altered forms. The unaltered DMSA was 12% of the total DMSA found in the urine. The altered form(s) of DMSA was 88% of the total urinary DMSA. The altered DMSA can be converted to unaltered DMSA by electrolytic reduction, which indicates that the altered forms of DMSA are disulfides. The excretion of altered DMSA reached a peak between 2 and 4 hours after DMSA administration. There were small but statistically significant increases in the excretion of zinc, copper, and lead after DMSA administration. DMSA did not influence the urinary excretion of 27 other metals and elements.

Adult↗
PubMed1996

Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat. I. Role of reactive oxygen species.

2,3-Dimercaptosuccinic acid (DMSA), a sulfhydryl-containing chelator, has previously been shown to reduce mean blood pressure in lead-treated rats. In the present study we have demonstrated that DMSA (0.5% for 5 days every 2 weeks) also reduces mean blood pressure in the Dahl salt-sensitive (SS) rat. Six-week-old Dahl SS and salt resistant (SR) rats were placed on a 0.3% NaCl diet for two weeks, followed by an 8% NaCl diet for four weeks. Eight SS and 8 SR rats remained untreated while 8 SS and 8 SR rats were treated with DMSA. DMSA treatment ameliorated the mean blood pressure rise in the Dahl SS rats (141 +/- 5 vs. 120 +/- 4 mm Hg at 6 weeks, P < 0.001). Nephrosclerosis was severe in untreated SS rats but absent in treated SS rats as well as in both treated and untreated SR rats. Reactive oxygen species formation, as assessed by kidney cortex content of malondialdehyde (MDA) and immunohistochemical demonstration of nitrotyrosine (a byproduct of peroxynitrite) in interlobular arteries, was increased in Dahl SS rats, but abolished by DMSA (MDA 9.65 +/- 0.33 nmol/g wet wt, untreated SS, vs. 6.46 +/- 0.51, treated SS, P < 0.001). The anti-nephrosclerotic action of DMSA was clearly disproportionate to the reduction in blood pressure. We conclude that the effect of DMSA was related instead to the reactive oxygen species scavenging properties of the thiol groups.

Animals↗
PubMed1997

Congenitally small kidneys with reflux as a common cause of nephropathy in boys.

Congenital maldevelopment is sometimes found in small kidneys with ureteral reflux. However, the incidence of congenitally small kidneys and the frequency of its association with ureteral reflux remains unknown. Ultrasound scanning, performed in 4,000 apparently healthy neonates or young infants (males 2,129, females 1,871), detected 51 children suspected of having small kidneys. A careful ultrasound re-examination performed one month later in 45 of the 51 children confirmed small kidneys in eight children, one bilateral and seven unilateral. Dimercaptosuccinate (DMSA) renoscintigraphy revealed small kidneys with generally diminished uptake in six infants and no uptake unilaterally in the other two infants. One of the 12 children, who had normal findings on the initial scanning and subsequently developed urinary infection, was later diagnosed having unilateral small kidney with generally reduced DMSA uptake. All seven infants having small kidneys with reduced tracer uptake were male (incidence, 1:300 boys). All eight small kidneys in the seven boys and four of the six contralateral non-small kidneys were associated with ureteral reflux, while neither of the two infants with a non-functioning kidney had ureteral reflux. Serial ultrasounds documented the poor growth of all small kidneys. Thus, congenitally small kidneys with generally diminished DMSA uptake were highly associated with ureteral reflux and especially observed in boys.

Female↗
PubMed2005

Impaired differential renal function in a child with pheochromocytoma.

We report a girl with extra-adrenal pheochromocytoma complicated with impaired renal function of the ipsilateral kidney, discussing aetiologies. A 14-year-old girl presented with uncontrolled hypertension, high urinary vanillylmandelic acid level and a 5 x 6 cm mass at the right renal hilum. Her blood pressure was under control with propranolol, prazosin, and nifedipine before surgery, and with sodium nitroprusside during surgical intervention. The total tumour removal required reconstruction of the right renal vein. Histopathology confirmed pheochromocytoma. Dimercaptosuccinic acid (DMSA) after surgery showed low uptake of isotope by the right kidney; it was unclear if this was due to the surgery or the tumour causing renal artery stenosis, but fortunately her blood pressure returned to normal thereafter. We recommend obtaining a DMSA in the preoperative evaluation of pheochromocytoma.

Adolescent↗
PubMed1998

Comparison of enhanced elimination of bismuth in humans after treatment with meso-2,3-dimercaptosuccinic acid and D,L-2,3-dimercaptopropane-1-sulfonic acid.

Two groups of 12 human volunteers, who had been treated with colloidal bismuth subcitrate, because of Helicobacter pylori-associated gastritis, participated in the study. The patients received a single dose of meso-2,3-dimercaptosuccinic acid (DMSA) or D,L-2,3-dimercaptopropane-1-sulfonic acid (DMPS) at a dose of 30 mg kg-1 in a randomized single blind study. In contrast to DMPS, increasing concentrations of bismuth in blood were observed during the first 4 h after intake of DMSA. In urine, both chelators induced a 50-fold increase in urinary bismuth excretion compared with the control urines. The treatment was well tolerated. The results indicate that both DMSA and DMPS effectively increase the elimination of bismuth in human urine. Consequently, both chelators may be of benefit in the treatment of patients with bismuth intoxication.

Adult↗
PubMed1995

Effect of chelators, monoisoamyl meso-2,3-dimercaptosuccinate and N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbodit hioate, on cadmium and essential element levels in mice.

In experiments performed on male mice (ICR) the mobilizing effect of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and a dithiocarbamate analogue, N-(4-methylbenzyl)-4-O-(beta-D-galactopyranosyl)-D-glucamine-N-carbod ithioate (MeBLDTC) on the cadmium deposits was studied. The influence of these compounds on the changes in the level of essential elements caused by cadmium was explored. CdCl2.H2O was injected intravenously. The chelators were administered every 48 h over 12 d. Both compounds are effective in mobilizing cadmium from the body in animal experiments. On an equimolar basis MeBLDTC was superior to Mi-ADMS. Mi-ADMS can, however, be administered orally. Both compounds were able to correct, at least partly, the changes in the level of essential elements caused by cadmium.

Animals↗
PubMed1995

Reduction of lead retention by mono-3-methylbutan-1-yl meso-2,3-dimercaptosuccinate in suckling rats.

The mono-3-methylbutan-1-yl (monoisoamyl) ester of meso-2,3-dimercaptosuccinic acid (Mi-ADMS) was previously found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in mobilizing cadmium and mercury deposits in young and adult mice and rats. It was also tested to mobilize lead in and adult mice. It was also tested to mobilized lead in adult mice. The purpose of this study was to evaluate the ability of Mi-ADMS to chelate lead at a very young age, in sucking rats. Lead was applied intraperitoneally at the dose of 5 mg kg-1 in the form of lead acetate to six-day-old rats. Treatment with DMSA and Mi-ADMS was administered orally at the dose of 0.25 mmol kg-1, either as early (0.5 and 24 h) or a delayed (4th and 5th day after lead application) therapy. At the end of the experiment (6th day) lead was determined by atomic absorption spectrometry in the skeleton, liver, kidney and brain of the animals. Results showed that Mi-ADMS was more efficient than DMSA after early application in reducing the skeletal, kidney and brain content of lead. After delayed application it was either (skeleton and kidneys) or better (brain) than DMSA. There was no statistically significant influence of either chelator on liver lead content. The major finding is that Mi-ADMS at low doses causes a much higher reduction in brain retention of lead in sucklings than DMSA. This is important because the brain is considered to be the target organ of lead toxicity in the youngest age group.

Animals↗
PubMed1997

Kidney size estimation in piglets using dimercaptosuccinic acid (DMSA) scintigraphy.

The objective of this study was to validate kidney size measurements obtained by DMSA scintigraphy in kidneys of sizes relevant in paediatric practice. Kidney length, width and volume were measured by DMSA scintigraphy in 10 piglets in vivo and compared with measurements on excised kidneys using callipers, planar scintigraphy and submersion in water. In addition, a kidney phantom was constructed and placed in a torso phantom. The length, width and volume of the kidney phantom were compared with planar and tomographic scintigraphic measurements. The mean overestimation of kidney length by scintigraphy was 1.7% (+/- 1.2%) on excised kidneys and 3.9% (+/- 2.4%) in vivo. The corresponding figures for width measurements were 7.0% (+/- 3.9%) and 7.8% (+/- 4.4%). Tomography volume estimation overestimated the submersion volume by 23% (+/- 12%). Scintigraphic measurements on the phantom over-estimated length by 5%, width by 8% and volume by 11%. Scintigraphic renal length measurements are reliable and differ from the anatomical length by < 4% compared with excised kidneys and < 8% in vivo. Scintigraphic width measurements and volume estimations, especially on small kidneys, are less reliable.

Animals↗
PubMed1999

Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid in rats.

1. The present study examined whether arsenic induces oxidative stress in liver, brain and erythrocytes (RBC) based on the investigation of certain selected parameters. It also explored the possibility that combined administration of N-acetylcysteine (NAC) and meso 2,3-dimercaptosuccinic acid (DMSA) was capable of achieving better reversibility in the parameters indicative of arsenic-induced oxidative stress than individual treatment with either of these drugs. 2. Male rats were exposed to 100 p.p.m. sodium arsenite in their drinking water for 12 weeks (equivalent to 12 mg/kg As). The arsenic was then removed and rats were given NAC (1 mmol/kg per day), DMSA (1 mmol/kg per day) or a combination of the two, orally, once daily for 5 days. Animals not given arsenic and those given arsenic but not NAC or DMSA served as negative and positive controls, respectively. 3. Twelve weeks of arsenic exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG) and promote malondialdehyde (MDA) production in both liver and brain samples. In addition to a significant reduction in RBC delta-aminolevulinic acid dehydratase (ALAD) activity and GSH levels, a marked elevation in MDA production may also contribute to arsenic-induced oxidative stress. 4. Treatment with either NAC or DMSA alone partially reversed arsenic-induced alterations in hepatic GSH and MDA, while only brain MDA levels responded favourably to these drugs. Only DMSA appeared to restore blood ALAD, while RBC MDA levels responded favourably to both drugs. Treatment with DMSA also produced an effective depletion of blood and hepatic arsenic concentrations. In the liver, most of these parameters were more effectively reversed by combined treatment with NAC and DMSA compared with the effects of either drug alone. 5. These results provide in vivo evidence of arsenic-induced oxidative stress in liver, brain and RBC and indicate that these effects can be mitigated by pharmacological intervention that encompasses combined treatment with NAC and DMSA.

3,4-Methylenedioxyamphetamine↗
PubMed1997

Ischaemia-reperfusion injury in the rat kidney: the effect of preconditioning.

OBJECTIVES: To design and establish a model to examine whether brief periods of renal artery occlusion (ischaemic preconditioning, IP) confers protection from the effects of a subsequent period of ischaemia and reperfusion of the rat kidney. MATERIALS AND METHODS: Ninety rats were randomized into six groups, i.e. sham-operated controls; IP alone; a 20 or 40 min period of left renal ischaemia (RI) alone; and IP followed by a 20 or 40 min period of RI. Preconditioning involved the sequential clamping of the left renal artery for 4 min and its release for 11 min, a total of four times, a 'critical interval' of 30 min before the ischaemic insult. Left renal tissue integrity was determined by dimercapto-succinic acid (DMSA) radionuclide imaging on a gamma-camera both immediately (day 0) and 2 and 9 days later. Acute tubular necrosis was also assessed histologically. RESULTS: RI for 20 min resulted in a significant decrease in left renal tissue integrity on day 2 only (P < 0.001), whereas RI for 40 min caused significant left renal dysfunction on day 0, day 2 and day 9 (P < or = 0.01). For a given duration of ischaemia, there was no significant difference between results from (IP + RI) rats compared with RI-only rats at any of the three times. There was no significant alteration in renal tissue integrity in the IP-only rats compared with sham-operated controls. Histological findings paralleled the data obtained from DMSA uptake. CONCLUSIONS: The IP regimen and 30 min 'critical interval' confers no protection to the kidney from a 20 or 40 min ischaemic episode. The IP regimen itself appears to have no effect, confirming the validity of our experimental model.

Animals↗