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PubMed2002

Combined administration of oxalic acid, succimer and its analogue for the reversal of gallium arsenide-induced oxidative stress in rats.

Gallium arsenide (GaAs), a group III-VA intermetallic semiconductor, possesses superior electronic and optical properties and has a wide application in the electronics industry. Exposure to GaAs in the semiconductor industry is a potential occupational hazard because cleaning and slicing GaAs ingots to yield the desired wafer could generate GaAs particles. The ability of GaAs to induce oxidative stress has not yet been reported. The present study reports the role of oxidative stress in GaAs-induced haematological and liver disorders and its possible reversal overturn by administration of meso-2,3-dimercaptosuccinic acid (DMSA) and one of its analogue, monoisoamyl DMSA (MiADMSA), either individually or in combination with oxalic acid. While DMSA and MiADMSA are potential arsenic chelators, oxalic acid is reported to be an effective gallium chelator. Male rats were exposed to 10 mg/kg GaAs orally, 5 days a week for 8 weeks. GaAs exposure was then stopped and rats were given a 0.5 mmol/kg dose of succimers (DMSA or MiADMSA), oxalic acid or a combination of the two, intraperitoneally once daily for 5 consecutive days. We found a significant fall in blood delta-aminolevulinic acid dehydratase (ALAD) activity and blood glutathione (GSH) level, and an increased urinary excretion of delta-aminolevulinic acid (ALA) and an increased malondialdehyde (MDA) level in erythrocytes of rats exposed to GaAs. Hepatic GSH levels decreased, whereas there was an increase in GSSG and MDA levels. The results suggest a role of oxidative stress in GaAs-induced haematological and hepatic damage. Administration of DMSA and MiADMSA produced effective recovery in most of the above variables. However, a greater effectiveness of the chelation treatment (i.e. removal of both gallium and arsenic from body organs) could be achieved by combined administration of succimer (DMSA) with oxalic acid since, after MiADMSA administration, a marked loss of essential metals (copper and zinc) is of concern.

Aminolevulinic Acid↗
PubMed2002

Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats.

Alpha-lipoic acid (LA) has been reported to be highly effective in improving the thiol capacity of the cells and in reducing lead induced oxidative stress. These results suggested its possible role as a therapeutic intervention of lead poisoning in combination with a chelator. We investigated the effects of LA, either alone or when administered in combination with succimer (meso 2,3-dimercaptosuccinic acid; DMSA or one of its analogue monoisoamyl DMSA), in influencing the lead induced alterations in haem synthesis pathway, hepatic, renal and brain oxidative stress and lead concentration from blood and soft tissues. The results suggest a significant lead induced inhibition of delta-aminolevulinic acid dehydratase (ALAD), reduction in glutathione (GSH) and an increased zinc protoporphyrin (ZPP) level in blood, indicating altered heme synthesis pathway. Both the thiol chelators were able to increase blood ALAD activity and GSH level towards normal. The most prominent effect on blood ALAD activity was however observed when monoisoamyl DMSA (MiADMSA) was co-administered with LA. Lead exposure produced significant depletion of hepatic GSH, while, oxidized glutahione (GSSG), thiobarbituric acid reactive substances (TBARS) and catalase activity increased significantly, suggesting hepatic oxidative stress. All the treatments were able to increase hepatic GSH and reduce GSSG levels, while, TBARS level reduced significantly in animals administered LA and MiADMSA, individually or in combination. Lead induced increase in renal GSSG, TBARS levels and catalase activity, were effectively reduced by LA, while, the two chelators when administered alone were effective only in reducing GSSG and catalase activity. The most prominent beneficial effects, however, were observed in animals treated concomitantly with LA and one of the chelators (DMSA or MiADMSA). Brain GSH and GSSG levels decreased moderately while superoxide dismutase (SOD) activity remained statistically unaltered on lead exposure. Brain catalase activity, on the other hand, increased significantly. Administration of LA was effective in reducing these alterations in the brain, however, the best effects were achieved in animals co-administered LA and one of the thiol chelators. The results point to a significant beneficial role of LA in the recovery of altered biochemical variables both during monotherapy and when given in combination with succimer. It however, showed no chelating properties in decreasing lead burden from blood, liver and kidneys except for a significantly more pronounced decrease in brain lead concentration in animals administered LA plus thiol chelators, compared to the effects of chelating agents alone. This is an interesting and notable observation, which requires further exploration. The results thus provide evidence of an encouraging role of LA when given in combination with a thiol chelator in the therapeutic intervention of lead poisoning, particularly in reducing the oxidative stress and brain lead concentration.

Animals↗
PubMed1999

A comparison of two dosing regimens of succimer in children with chronic lead poisoning.

There is limited information defining the optimal dosing regimen of succimer in the treatment of children with chronic lead poisoning. It is typically administered as a five day course of high dose therapy (1,050 mg/m2/day) followed by 14 days of low dose therapy (700 mg/m2/day). This study compared the effect on blood lead concentrations (BPb) of treatment with this standard regimen and an alternate regimen consisting of two courses of high dose therapy separated by one week. There were significant reductions in the mean BPb in both the standard (n = 7) and alternate (n = 4) treatment groups but there was not a significant difference between the groups. In the standard group, the BPb decreased from 33 +/- 4 to 27 +/- 6 mcg/dL. The BPb decreased from 33 +/- 6 to 23 +/- 4 mcg/dL in those treated with alternate therapy. This study suggests that two short courses of high dose therapy may be an acceptable alternative to standard succimer therapy. Because of the small size of this study, other studies are warranted.

Chelating Agents↗
PubMedDate not supplied

Succimer (meso-2,3-dimercaptosuccinic acid (DMSA)) treatment of Andean children with environmental lead exposure.

The authors studied children in Andean villages contaminated by a lead-glazing cottage industry. Mean blood lead (PbB) level in 35 exposed children, aged 3-14 years, a year before treatment, at the time of initiation of a comprehensive lead education and prevention program, was 53.4 microg/dL. PbB levels immediately before and three weeks after a ten-day regimen of succimer treatment of the 35 children were 43.4 microg/dL and 34.3 microg/dL, respectively, showing a 21% reduction and a significant difference between means (t = 5.09, p = 0.0001). PbB levels of the same children a year before treatment and immediately pre-treatment were also significantly different (t = 10.59, p = 0.0001). Thus, a ten-day course of succimer chelation effectively reduced PbB in children with moderate to severe Pb intoxication, and the education and prevention program, initiated with parents, health care providers, and educators, also contributed significantly to reducing PbB.

Adolescent↗
PubMed1994

The treatment of lead poisoning from gunshot wounds with succimer (DMSA)

Lead poisoning is an unusual complication of gunshot wounds that occurs when retained lead bullet fragments are in contact with body fluids capable of solubilizing lead. The epidemic of violence by gunfire may result in increasing numbers of lead poisoning cases from this exposure. The use of oral chelation for toxicity resulting from this mode of exposure has not been previously discussed. Cases of lead poisoning arising from bullet lead in the synovial cavity of the hip, synovial cavity of the chest, and pleural space are reported. A combination of surgical debridement and chelation therapy with oral succimer produced a satisfactory outcome in all three cases. Oral succimer may be a safe and effective chelation agent for treating lead toxicity in adults with high lead levels secondary to gun shot wounds.

Adult↗
PubMed1993

Succimer: the first approved oral lead chelator.

The Centers for Disease Control and Prevention has redefined the threshold of concern for low-level lead toxicity, reducing it from a blood lead level of 25 micrograms per dL (1.21 mumol per L) to a blood lead level of 10 micrograms per dL (0.48 mumol per L), and has recommended universal screening of young children. Succimer (2,3-dimercaptosuccinic acid) is an effective oral lead chelating agent that has been approved for outpatient treatment of children with blood lead levels higher than 45 micrograms per dL (2.17 mumol per L). In the United States, clinical experience with succimer is limited; however, observed side effects, including gastrointestinal symptoms, rash and transient elevations of serum aminotransferase levels, are uncommon and mild. Isolated cases of neutropenia have been reported. Weekly monitoring of complete blood counts and serum aminotransferase levels is recommended during the 19-day treatment. Blood lead levels should be checked weekly to identify rebound from bone and soft tissue mobilization.

Administration, Oral↗
PubMed1993

Hemolytic anemia associated with lead poisoning from shotgun pellets and the response to Succimer treatment.

Symptomatic lead poisoning with severe hemolytic anemia was observed in a patient with retained shot gun pellets. Surgical resection of the retained pellets and the use of a newer chelating agent, Succimer (2,3-dimercaptosuccinic acid) successfully lowered blood lead level. Hemolytic anemia was associated with deficient erythrocyte pyrimidine 5'-nucleotidase, and lowering of the lead level corrected the deficiency, suggesting that the enzyme deficiency is responsible for the hemolysis associated with lead poisoning. This case illustrates that retained lead pellets from shotgun wounds can cause severe lead poisoning.

Adult↗
PubMedDate not supplied

Succimer treatment during ongoing lead exposure reduces tissue lead in suckling rats.

There is a concern that oral treatment with succimer (meso-2, 3-dimercaptosuccinic acid, DMSA) can promote gastrointestinal lead absorption if not performed in a lead-safe environment. The scope of our investigation was to evaluate the efficacy of oral DMSA treatment during oral lead exposure on tissue lead in suckling rats. Six-day-old Wistar rats of both genders were divided into two groups-untreated (Pb) and treated (Pb + DMSA)-with 10 animals per group. Lead (as acetate) was given orally at a dose of 2 mg kg(-1) body weight day(-1) for eight consecutive days (total dose 16 mg kg(-1), i.e. 0.08 mmol kg(-1)). During this period the treated group received a daily dose of 0.5 mmol DMSA kg(-1) body weight p.o. six times on days 1-3 and 6-8 of the experiment (total dose 3 mmol kg(-1)). Tissue lead was determined by means of atomic absorption spectrometry. The DMSA efficiently reduced the lead concentration in the analysed tissues (carcass, liver, kidneys and brain) by approximately 50% compared with untreated controls. The pups' growth and organ weights were not affected. In conclusion, our results indicate that DMSA is an efficient oral lead chelator in sucklings even if challenged with ongoing lead exposure.

Animals↗
PubMed1988

Renal scintigraphy with technetium Tc 99m succimer: clinical utility in newborns with cystic renal dysplasia.

We have presented the case of a neonate with bilateral cystic renal dysplasia and normal pulmonary development, in whom technetium Tc 99m succimer scintigraphy demonstrated absence of normal renal cortical tubular tissue and correctly predicted that life-sustaining renal function would not occur. Since renal uptake of this radioactive agent depends on the functional mass of cortical tubular tissue, and the cystic dysplasias are characterized by abnormal dysplastic renal ductal and tubular tissue, this imaging agent can provide important prognostic information concerning renal function in these patients.

Humans↗
PubMed2001

Succimer for treatment of lead toxicosis in two cats.

Two cats from a single household were examined because of neurologic abnormalities suggestive of central vestibular disease. The owner had been renovating her 150-year-old house for the preceding 3 months, and renovations included chipping and sanding of old paint from windowsills and stair railings. Lead toxicosis was diagnosed on the basis of history and concentrations of lead in blood and urine. Both cats were treated with succimer. Treatment was not associated with any adverse effects, and both cats recovered completely. Ingestion of old paint from house renovations is the most common source of lead exposure in cats. Owners of cats with gastrointestinal tract or neurologic abnormalities should be questioned specifically about house renovations.

Animals↗
PubMed1998

The effect of succimer therapy in lead intoxication using postural balance as a measure: a case study in a nine year old child.

Postural balance testing was used as a measure of the effect of therapy on a 9 year old boy with high lead levels. Following therapy with CaEDTA and succimer, the patient's postural sway responses were comparable to a low-lead (< 10 micrograms/dL) comparison group for 3 out of 4 tests which rely relatively less on the higher centers for balance. This improvement in postural balance may be attributable to the combined influence of pharmacologic and age associated maturational effects. This case study provides suggestive evidence that while chelation therapy can reduce PbB levels quickly, it can also modify gross neuromotor function manifested by postural balance characteristics.

Administration, Oral↗
PubMed1998

Comparison of long lasting therapeutic effects between succimer and penicillamine on hepatolenticular degeneration.

AIM:To compare the long-term effect of succimer (Suc) with that of penicillamine (Pen) in treating hepatolenticular degeneration (HLD).METHODS:One hundred and twenty patients with HLD were divided into 2 groups. Group A (n =60) received Suc 750mg,po.bid.Group B (n =60) received Pen 250mg, po. qid. The period of maintenance treatment varied from 6 months to 3 years, averaging 1.5 years. Symptoms and therapeutic effects were evaluated by modified Goldstein scale.RESULTS:The total effectiveness of group A in two different periods of treatment were 80% and 85% respectively, higher than those of group B (58% and 59% respectively)(P < 0.05). Suc also had obvious curative effects for the patients who failed in the use of Pen. There were fewer side effect in group A than in group B (P < 0.05). Suc and Pen could increase urinary copper excretion effectively and continually.CONCLUSION:Suc is more effective and safer than Pen. Clinically, it can replace Pen as first-choice drug for long-term maintenance therapy of HLD.

Journal Article↗
PubMedDate not supplied

Succimer treatment and calcium supplementation reduce tissue lead in suckling rats.

The effect of combined treatment with meso-2,3-dimercaptosuccinic acid (DMSA) and calcium supplementation in reducing lead absorption and enhancing lead elimination was evaluated in suckling rats under two experimental conditions: during ongoing oral lead exposure (lead acetate, 2 mg Pb kg(-1) day(-1), total dose 16 mg Pb kg(-1)) or after lead exposure (72 h after a 2-day lead exposure, total dose 12 mg Pb kg(-1) s.c.). The artificial feeding method was used for calcium supplementation, with 6% Ca (as CaHPO(4)) suspension in cow's milk to increase the daily calcium intake about three times above control values. Artificial feeding lasted for 7 h a day over eight consecutive days. During this period DMSA was administered on 6 days twice a day (0.5 mmol kg(-1) day(-1) p.o.). At the end of the experiments, Pb, Ca and Zn in the carcass and Pb, Fe and Cu in the liver, kidneys and brain were analysed by atomic absorption spectrometry. Calcium supplementation during lead exposure reduced tissue lead but had no effect when applied after lead exposure, and DMSA administered either during or after lead exposure lowered the tissue lead. Combined treatment during ongoing lead exposure caused a greater reduction in tissue lead than either DMSA or calcium treatment alone. When administered after lead exposure, it had no advantage over DMSA treatment alone but did not impair its efficacy. Combined treatment had no influence on growth and did not seriously disturb essential element status. It is concluded that calcium supplementation could be applied during DMSA therapy, when indicated.

Animals↗
PubMed2004

Cadmium induced testicular damage and its response to administration of succimer and diphenyl diselenide in mice.

Acute effects of cadmium in mice testes were evaluated. Animals received a single dose of CdCl2 (2.5 mg/kg or 5 mg/kg, intraperitoneally) and a number of toxicological parameters in mice testes were examined such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, hemoglobin content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible protective effect of meso-2,3-dimercaptosuccinic acid (DMSA) and diphenyl diselenide (PhSe)2 are studied. The results demonstrated inhibition of delta-ALA-D and SOD activities, reduction in ascorbic acid, increase of lipid peroxidation induced by cadmium, indicating testes damage. DMSA (400 micromol/Kg) and (PhSe)2 (100 micromol/Kg) protected inhibitory effect of 2.5 mg/kg CdCl2 on delta-ALA-D and restored the increase of TBARS levels. Otherwise, (PhSe)2 treatment was effective in reducing the increase of TBARS levels induced by 5 mg/kg CdCl2, whereas DMSA and (PhSe)2, in combination, were ineffective in reducing TBARS level. However, these compounds alone or in combination, were unable to protect SOD activity and to improve ascorbic acid levels near to the normal value. The use of combined therapy (DMSA plus (PhSe)2) not proved be better than the monotherapy, in improving toxicological parameters evaluated in this model of testicular damage induced by cadmium.

Animals↗
PubMed2004

Chronic arsenic poisoning in the rat: treatment with combined administration of succimers and an antioxidant.

The influence of the coadministration of vitamin C or vitamin E on the efficacy of two thiol chelators, meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA, in counteracting chronic arsenic toxicity was investigated in rats. Vitamin C and vitamin E were only mildly effective when given alone or in combination with the above chelators in mobilizing arsenic from the target tissues. However, combined administration of vitamin C plus DMSA and vitamin E plus MiADMSA led to a more pronounced depletion of brain arsenic. The supplementation of vitamins was significantly effective in restoring inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) oxidative stress in liver, kidneys, and brain as reflected by reduced levels of thiobarbituric acid reactive substance and oxidized and reduced glutathione levels. The results thus lead us to suggest that coadministration of vitamin E or vitamin C may be useful in the restoration of altered biochemical variables (particularly the effects on heme biosynthesis and oxidative injury) although it has only a limited role in depleting arsenic burden.

Animals↗