MiADMSA abrogates chronic copper-induced hepatic and immunological changes in Sprague Dawley rats.

Wilson disease (WD) is an autosomal-recessive disorder associated with the impaired copper metabolism, resulting in hepatic and neurologic manifestations. D-Pencillamine (DPA) is a first-line of treatment however, monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA), is gaining recognition recently as a future chelating agent of choice. We evaluated the effects of MiADMSA against copper-induced (20 mg/kg, orally, once, daily for 16 weeks) hepatic and immunological changes in the male Sprague Dawley (SD) rats. Copper overload increased the levels of pro-oxidant and concurrently decreased the levels of antioxidant enzymes in the liver. Increased oxidative stress triggered the up-regulation of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) in the liver and down-regulated the anti-inflammatory cytokine IL-4. Altered liver function parameters as well as serum immunoglobulins' (IgG, IgA, IgE, and IgM) levels, were also noted. MiADMSA treatment restored most of copper altered biochemical and immunological changes. Further, the histopathological changes proved that MiADMSA treatment ameliorated copper induced hepatic injury. Infra red spectra of liver tissue indicated shift in the characteristic -OH peak during copper exposure while the shifting came to normal in MiADMSA administered rat liver. We conclude that MiADMSA could be a promising antidote for the chronic copper toxicity and possibly in the clinical management of WD.

Ask-Upmark kidney in a girl with neurofibromatosis type 1.

Ask-Upmark kidney (AUK) is a scarred segment of the kidney, characterized by formation of primitive tubular and glomerular structures, and sporadically diagnosed as a cause of hypertension (HTN). A 6-year-old girl with neurofibromatosis type 1 (NF1) and moyamoya syndrome had severe HTN. Based on past history, she had HTN at the age of 1.5 years. Laboratory examination revealed slightly elevated plasma and renal venous renin activity without lateralization. No evidence of pheochromocytoma, or coarctation of the aorta was found. Contrast-enhanced computed tomography (CT) showed an area of hypoperfusion in the upper and middle poles with reduced size of the right kidney. The results of dimercaptosuccinic acid scintigraphy were in accordance with those of contrast-enhanced CT. Selected renal arteriography revealed a paucity of peripheral vascularity in the same parts of the right kidney. In the absence of a history of urinary tract infection and vesicoureteral reflux by cystography, we presumed that the severe HTN may be due to segmental hypoplasia of the kidney, AUK, with a possible contribution from NF1. Although renal artery stenosis and pheochromocytoma are well-known causes of HTN in NF1, this case demonstrates that HTN can be caused by AUK in patients with NF1.

Effects of combined administration of calcium, iron, zinc, chrysanthemum flavonoids, and DMSA on the treatment of lead intoxication in mice.

The effect of combined administration of calcium (Ca), iron (Fe), zinc (Zn), chrysanthemum flavonoids, and meso-2,3-dimercaptosuccinic acid (DMSA) on the treatment of lead (Pb) intoxication in mice was studied. One hundred ninety female mice (SPF level, aged 18-22 days) were randomly divided into two groups as experimental animals. Mice in group I (10 mice) served as normal control animals, and were administered deionized water containing 12.5 µL/L acetate acid for 6 weeks, whereas mice in group II (180 mice) were exposed to 0.1% (wt/vol) of lead acetate in deionized water for 6 weeks and served as experimental animals. After 6 weeks of successful modeling, 180 mice from group II (lead-exposed) were divided into 18 groups of 10 mice each, 16 of which were treated by the combined administration of Ca, Fe, Zn, chrysanthemum flavonoids, and DMSA by L16 (215 ) orthogonal design. The remaining two groups were given treatment with low and high doses of DMSA, respectively. After three weeks of intervention (ig), the optimal treatment group was identified according to its blood lead level, as well as some antioxidant indices in the blood, liver, and hippocampus. The results indicated that the combined administration of Fe, Zn, chrysanthemum flavonoids, and DMSA with low dosage had the most significant effect on increasing the activities of blood delta-aminolevulinic acid dehydratase and superoxide dismutase (SOD), hepatic SOD and hippocampus nitric oxide synthase while decreasing the blood lead level, the content of hepatic malondialdehyde and hippocampus nitric oxide; this was considered the optimal treatment group. There was no difference in the level of blood hemoglobin between the optimal treatment group and the model control group (the first group of the orthogonal experiment). The activities of blood glutathione (GSH), hepatic GSH and glutathione peroxidase of the optimal treatment group were the same as other groups', and the recovery of the related indexes in the optimal effect group closely resembled the high dosage DMSA group. It can be concluded that the coadministration of Fe, Zn, and chrysanthemum flavonoids along with a low-dose DMSA effectively reduces Pb poisoning and lead-induced oxidative damage in lead-exposed mice; the result may provide a theoretical reference for the treatment of Pb poisoning.

Changes in tissue gadolinium biodistribution measured in an animal model exposed to four chelating agents.

PURPOSE: This study investigated the potential to reduce gadolinium levels in rodents after repetitive IV Gadodiamide administration using several chelating agents. MATERIALS AND METHODS: The following six groups of rats were studied. Group 1: Control; Group 2: Gadodiamide only; Group 3: Meso-2,3-Dimercaptosuccinic acid (DMSA) + Gadodiamide; Group 4: N-Acetyl-L-cysteine (NAC) + Gadodiamide; Group 5: Coriandrum sativum extract + Gadodiamide; and Group 6: Deferoxamine + Gadodiamide. Brain, kidney, and blood samples were evaluated via inductively coupled plasma mass spectrometry. The brain was also evaluated histologically. RESULTS: Kidney gadolinium levels in Groups 4 and 5 were approximately double that of Group 2 (p = 0.033 for each). There was almost no calcification in rat hippocampus for Group 4 rodents when compared with Groups 2, 3, 5 and 6. CONCLUSION: Our preliminary study shows that excretion to the kidney has a higher propensity in NAC and Coriandrum sativum groups. It may be possible to change the distribution of gadolinium by administrating several agents. NAC may lower Gadodiamide-induced mineralization in rat hippocampus.

Combinatorial drug delivery strategy employing nano-curcumin and nano-MiADMSA for the treatment of arsenic intoxication in mouse.

Chelation therapy is the mainstream treatment for heavy metal poisoning. Apart from this, therapy using antioxidant/herbal extracts are the other strategies now commonly being tried for the treatment. We have previously reported individual beneficial efficacy of nanoparticle mediated administration of an antioxidant like 'curcumin' and an arsenic chelator 'monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)' for the treatment of arsenic toxicity compared to bulk drugs. The present paper investigates our hypothesis that a combination drug delivery therapy employing two nanosystems, a chelator and a strong antioxidant, may produce more pronounced therapeutic effects compared to individual effects in the treatment of arsenic toxicity. An in-vivo study was conducted wherein arsenic as sodium arsenite (100 ppm) was administered in drinking water for 5 months to Swiss albino mice. This was followed by a treatment protocol comprising of curcumin encapsulated chitosan nanoparticles (nano-curcumin, 15 mg/kg, orally for 1 month) either alone or in combination with MiADMSA encapsulated polymeric nanoparticles (nano-MiADMSA, 50 mg/kg for last 5 days) to evaluate the therapeutic potential of the combination treatment. Our results demonstrated that co-treatment with nano-curcumin and nano-MiADMSA provided beneficial effects in a synergistic way on the adverse changes in oxidative stress parameters and metal status induced by arsenic.

In vitro exposure of bull sperm cells to DMSA-coated maghemite nanoparticles does not affect cell functionality or structure.

Magnetic nanoparticles can be used in different areas of biology. It is therefore important to know the effects of such nanomaterials on germline cells as they may traverse the blood-testis barrier. This work aimed to evaluate the response of bull sperm after exposure to a magnetic fluid containing DMSA-coated maghemite nanoparticles (MNP-DMSA) in order to determine nanotoxicity. Bull sperm was incubated with MNP-DMSA at final concentrations of 0.06, 0.03 or 0.015 mg Fe/mL. Sperm kinetics, plasma membrane integrity and acrosome reaction were evaluated over a 4 h incubation period. The sperm cells were also evaluated by transmission electron microscopy. Exposure of bull sperm to MNP-DMSA did not affect sperm kinetics or integrity. Neither ultrastructural damage of sperm cells nor uptake of nanoparticles by the spermatozoa was observed. In conclusion, MNP-DMSA does not affect sperm function or structure under the conditions tested.

N-acetylcysteine and meso-2,3-dimercaptosuccinic acid alleviate oxidative stress and hepatic dysfunction induced by sodium arsenite in male rats.

Environmental exposure to arsenic represents a serious challenge to humans and other animals. The aim of the present study was to test the protective effect of antioxidant N-acetylcysteine (NAC) either individually or in combination with a chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), against sodium arsenite oral toxicity in male rats. Five groups were used: control; arsenic group (orally administrated in a concentration of 2 mg/kg body weight [b.w.]); the other three groups were orally administrated sodium arsenite in a concentration of 2 mg/kg b.w. followed by either NAC (10 mg/kg b.w., intraperitoneally [i.p.]), DMSA (50 mg/kg b.w., i.p.) or NAC plus DMSA. Arsenic toxicity caused significant rise in serum aspartate aminotransferase, alanine aminotransferase and total bilirubin, and a significant decrease in total protein (TP) and albumin levels after 3 weeks of experimental period. In addition, arsenic-treated rats showed significantly higher arsenic content in liver and significant rise in hepatic malondialdehyde level. By contrast, sharp decreases in glutathione content and catalase and glutathione reductase activities were discernible. NAC and/or DMSA counteracted most of these physiologic and biochemical defects. NAC monotherapy was more effective than DMSA in increasing TP, while DMSA was more effective in decreasing alanine aminotransferase. The combined treatment was superior over monotherapies in recovery of TP and glutathione. Biochemical data were well supported by histopathological and ultrastructural findings. In conclusion, the combination therapy of NAC and DMSA may be an ideal choice against oxidative insult induced by arsenic poisoning.

Effectiveness of magnetic fluid hyperthermia against Candida albicans cells.

Candida albicans is one of the most frequently isolated fungal pathogens causing opportunistic infections in humans. Targeted magnetic fluid hyperthermia (MFH) is a promising method in thermal therapy facilitating selective heating of pathogen cells like C. albicans. In the paper, we used meso-2,3-dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles (MNPs) and functionalised anti-C. albicans immunomagnetic nanoparticles (IMNPs) to investigate the potential of MFH in combating C. albicans cells in vitro. Using Mössbauer spectroscopy it was found that synthesised MNPs exhibited superparamagnetic phenomena. On the basis of calorimetric experiments, the maximum SAR (specific absorption rate) was found and a proper concentration of MNPs was established to control the temperature. MFH based on both DMSA-coated MNPs and functionalised anti-C. albicans IMNPs was more effective in combating C. albicans cells in vitro than thermostat hyperthermia. Especially promising results were obtained using functionalised IMNPs, which eradicated most of the pathogen colonies at the temperature of 43 °C.

Chelation for autism spectrum disorder (ASD).

BACKGROUND: It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms. OBJECTIVES: To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. SEARCH METHODS: We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase,PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. In addition we checked references lists and contacted experts. SELECTION CRITERIA: All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. We did not conduct a meta-analysis, as only one study was included. MAIN RESULTS: We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment.We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. AUTHORS' CONCLUSIONS: This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.

Intoxicación familiar por mercurio elemental: caso clínico / Family poisoned by elemental mercury: a case report

Introduction: mercury is a heavy metal widely dispersed in nature, occurring in three chemical forms. Exposure to mercury at work sites and even at home may be clinically significant. Objective: to update the knowledge about the risks of this toxic element. Case report: the case of a teenager and his family poisoned by elemental mercury is reported. The diagnostic process was difficult, mainly due to an initial presumption of probable infectious etiology, unavailability of key anamnestic data and unusual clinical behavior, with signs and symptoms of multisystem compromise (neurological, hepatic, renal and dermatological compromise). Discussion: the study was based on literature review of various clinical presentations regarding this poisoning and its management, emphasizing the need for dimercaptosuccinic acid chelator. As a major public health problem, the importance of education and implementation of public policies to have a mercury-free environment is discussed.

Introducción: el mercurio es un metal pesado ampliamente distribuido en el medio ambiente, en sus tres formas químicas. La exposición a dicho metal en recintos laborales e incluso en el hogar, puede llegar a ser clínicamente significativa. Objetivo: actualizar el conocimiento acerca de los riesgos de este tóxico. Caso clínico: se presenta el caso clínico de un adolescente y su familia intoxicados por mercurio elemental, cuyo proceso diagnóstico fue difícil, principalmente por la presunción inicial de una probable etiología infecciosa, falta de disponibilidad de datos anamnésticos claves y el inusual comportamiento clínico, con signos y síntomas de compromiso multisistémico (neurológico, hepático, renal y dermatológico). Discusión: se revisa la literatura en relación a las diversas formas de presentación clínica de esta intoxicación y su manejo, destacando la utilidad del quelante ácido dimercaptosuccínico. Por ser un importante problema de salud pública, se destaca la trascendencia de la educación e implementación de políticas públicas por un ambiente libre de mercurio.

Monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA) demonstrates higher efficacy by oral route in reversing arsenic toxicity: a pharmacokinetic approach.

Monoisoamyl DMSA (MiADMSA), a lipophilic chelating agent has emerged as a promising drug for the treatment of arsenic. The present study aimed at exploring the optimum dose and route of administration for achieving maximum arsenic elimination with minimal side effects. We also carried out a pharmacokinetic analysis of this drug to support arsenic chelation. Rats were exposed to arsenic (25 ppm) for 6 months and later received MiADMSA (50 or 100 mg/kg) orally and via i.p. route for 5 days. Oxidative stress parameters and arsenic levels in soft tissues, liver function test and histopathology of liver and kidney were performed. Plasma kinetic of MiADMSA (plasma-free drug and total drug) at 50 and 100 mg/kg p.o. was carried out. Arsenic exposure resulted in significant oxidative stress and hepatotoxicity. MiADMSA at 50 mg/kg dose administered orally provided about 45% and 75% protection against oxidative stress and in lowering body arsenic burden, respectively, against 25% and 40% via i.p. route. Pharmacokinetic analysis supported prolonged availability of the drug through oral administration. Collectively, these findings led us to conclude that oral administration of MiADMSA was more effective than intraperitoneal administration and that the minimum effective dose with least side effects was 50 mg/kg.

EDTA redistribution of lead and cadmium into the soft tissues in a human with a high lead burden - should DMSA always be used to follow EDTA in such cases?

Intravenous sodium calcium ethylene diamine tetra acetic acid (EDTA) and oral 2,3-dimercaptosuccinic acid (DMSA) have both been used to reduce the burden of lead in humans. Each of these agents enhances the mobilization of lead from different areas of the body - EDTA from the trabecular bone and DMSA from the soft tissue. A study of Korean battery workers revealed that EDTA appeared to increase the soft tissue burden of lead, resulting in increased levels of aminolevulinic acid and greater subsequent lead mobilization with DMSA. This case report discusses a patient with a higher-than-normal lead burden who exhibited increased tissue lead burden after intravenous EDTA. The elevated tissue burden of lead was still present, albeit lower, after five consecutive days of oral DMSA therapy. If this single case is representative of a typical human response to the use of intravenous (IV) EDTA for lead, then it suggests that all persons undergoing such treatment should be administered oral DMSA for a minimum of one week after EDTA treatment.

Leukocyte transepithelial migration in lung induced by DMSA functionalized magnetic nanoparticles.

Magnetic nanoparticles surface-covered with meso-2,3-dimercaptosuccinic acid (MNPs-DMSA) constitute a promising approach for tissue- and cell-targeted delivery of therapeutic drugs in the lung. However, they can also induce a transient transendothelial migration of leukocytes in the organ as a side effect after endovenous administration of MNPs-DMSA. We demonstrated that monocytes/macrophages constitute the main subpopulation of leukocytes involved in this process. Our recent research found that MNPs-DMSA up-regulated the mRNA expression of E-, L- and P-selectin and macrophage-1 antigen, and increased concentration of tumor necrosis factor-α in lung, in a time dependent manner. The critical relevance of the ß2 integrin-dependent pathway in leukocyte transmigration elicited by MNPs-DMSA was demonstrated by use of knockout mice. Our work characterizes mechanisms of the pro-inflammatory effects of MNPs-DMSA in the lung, and identifies ß2 integrin-targeted interventions as promising strategies to reduce pulmonary side effects of MNPs-DMSA during biomedical applications. In addition, MNPs-DMSA could be used as modulators of lung immune response.

Paradoxical effect of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on enhancing antitumor activity of cisplatin in ascites sarcoma 180 cells.

We investigated the enhancing effect of two metal-chelating compounds, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), on the antitumor activity of cisplatin (CDDP). In the in vivo experiments, DMPS showed a clear synergistic effect and significantly enhanced the antitumor activity of CDDP in terms of survival and life span in mice transplanted with ascites sarcoma 180 cells (S180 cells) at a dose of <100 micromol/kg, s.c., but not at a dose of >500 micromol/kg. On the other hand, DMSA did not enhance the antitumor activity of CDDP. DMPS (50 micromol/kg, s.c.) combined with CDDP also potently suppressed [(3)H]thymidine uptake in S180 cells implanted in mice, whereas DMSA did not. In the in vitro experiments, DMPS (10(-6) to 10(-5) M) produced a time- and dose-dependent decrease in intracellular Ca(2+) concentrations ([Ca(2+)](i)) in S180 cells and, in combination with CDDP, yielded a significant increase in intracellular platinum accumulation compared to that in cells treated with CDDP alone. These results indicate that DMPS used in combination with CDDP may be of considerable benefit in enhancing the cytotoxicity of CDDP in tumor cells, especially at a low dose. The results also suggest that the enhancing effect of DMPS is closely related to a decrease in [Ca(2+)](i) and that the suitable dose and adequate administrational time of DMPS are important for its effective action.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results.

BACKGROUND: This study investigated the effect of oral dimercapto succinic acid (DMSA) therapy for children with autism spectrum disorders ages 3-8 years. METHODS: Phase 1 involved 65 children who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo. RESULTS: DMSA greatly increased the excretion of lead, substantially increased excretion of tin and bismuth, and somewhat increased the excretion of thallium, mercury, antimony, and tungsten. There was some increase in urinary excretion of essential minerals, especially potassium and chromium. The Phase 1 single round of DMSA led to a dramatic normalization of RBC glutathione in almost all cases, and greatly improved abnormal platelet counts, suggesting a significant decrease in inflammation. CONCLUSION: Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.

Amphotericin B in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles against paracoccidioidomycosis.

OBJECTIVES: The present study reports on the preparation and testing of a desoxycholate amphotericin B (D-AMB) sustained delivery system based on poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) polymeric blends (Nano-D-AMB) aimed at reducing the number of AMB administrations required to treat mycosis. METHODS: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis intravenously to mimic the chronic form of paracoccidioidomycosis. At 30 days post-infection, the animals were treated with Nano-D-AMB [6 mg/kg of encapsulated D-AMB, intraperitoneally (ip), interval of 72 h] or D-AMB (2 mg/kg, ip, interval of 24 h). Drug efficacy was investigated by the fungal burden recovery from tissues. Toxicity was assessed by renal and hepatic biochemical parameters, physical appearance of the animals and haematological investigation. The control groups used were non-infected and the infected mice mock treated with PBS. RESULTS: Nano-D-AMB presented results comparable to free D-AMB, with a marked antifungal efficacy. The Nano-D-AMB-treated group presented lower loss of body weight and absence of stress sign (piloerection and hypotrichosis) observed after D-AMB treatment. No renal [blood urea nitrogen (BUN), creatinine] or hepatic (pyruvic and oxalacetic glutamic transaminases) biochemical abnormalities were found. The micronucleus assay showed no significant differences in both the micronucleus frequency and percentage of polychromatic erythrocytes for Nano-D-AMB, indicating the absence of genotoxicity and cytotoxic effects. CONCLUSIONS: The D-AMB-coated PLGA-DMSA nanoparticle showed antifungal efficacy, fewer undesirable effects and a favourable extended dosing interval. Nano-D-AMB comprises an AMB formulation able to lessen the number of drug administrations. Further studies would elucidate whether Nano-D-AMB would be useful to treat systemic fungal infections such as paracoccidioidomycosis, candidiasis, aspergillosis and cryptococcosis.

Quercetin administration during chelation therapy protects arsenic-induced oxidative stress in mice.

We studied the efficacy of quercetin and a thiol chelating agent, monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA) either individually or in combination against arsenic-induced oxidative stress and mobilization of metal in mouse. Animals were chronically exposed to 25 ppm arsenite as sodium arsenite in drinking water for 12 months followed by treatment with MiADMSA (0.2 mmol/kg, orally), quercetin (0.2 mmol, orally) either alone or in combination, once daily for 5 consecutive days. Arsenic exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione, white (WBC) and red blood cell (RBC) counts, and an increase in platelet levels while significantly increasing the level of reactive oxygen species (in RBCs). Hepatic reduced catalase (CAT) and glutathione peroxidase activities showed a depletion, whereas thiobarbituric acid reactive substances (TBARS) levels increased on arsenic exposure indicating arsenite-induced oxidative stress in blood and liver. Kidney CAT activity showed a depletion, whereas TBARS levels increased on arsenic exposure. These biochemical changes were accompanied by an increase in blood, liver, and kidney arsenic concentration. Treatment with MiADMSA was effective in increasing ALAD activity, whereas quercetin was ineffective when given alone. Quercetin when co-administered with MiADMSA also provided no additional beneficial effect on blood ALAD activity but significantly brought altered platelet counts nearer to the normal value. In contrast, administration of quercetin alone provided significant beneficial effects on hepatic oxidative stress and kidney TBARS levels. Renal biochemical variables remained insensitive to arsenic and any of the treatments. Interestingly, combined administration of quercetin with MiADMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that quercetin administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity and depletion of arsenic level from target organs. The study supports our earlier conclusion that a co-administration of an antioxidant particularly flavonoids more beneficial than monotherapy with the chelating agents to achieve optimal effects of chelation in arsenite toxicity.

Combined administration of iron and monoisoamyl-DMSA in the treatment of chronic arsenic intoxication in mice.

Co-administration of iron in combination with monoisoamyl dimercaptosuccinic acid (MiADMSA) against chronic arsenic poisoning in mice was studied. Mice preexposed to arsenic (25 ppm in drinking water for 6 months) mice were treated with MiADMSA (50 mg/kg, intraperitoneally) either alone or in combination with iron (75 or 150 mg/kg, orally) once daily for 5 days. Arsenic exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, hematocrit, and white blood cell (WBC) counts accompanied by small decline in blood hemoglobin level. Hepatic reduced glutathione (GSH) level, catalase and superoxide dismutase (SOD) activities showed a significant decrease while, oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS) levels increased on arsenic exposure, indicating arsenic-induced hepatic oxidative stress. Liver aspartate and alanine transaminases (AST and ALT) activities also decreased significantly on arsenic exposure. Kidney GSH, GSSG, catalase level and SOD activities remained unchanged, while, TBARS level increased significantly following arsenic exposure. Brain GSH, glutathione peroxidase (GPx), and SOD activities decreased, accompanied by a significant elevation of TBARS level after chronic arsenic exposure. Treatment with MiADMSA was marginally effective in reducing ALAD activity, while administration of iron was ineffective when given alone. Iron when co-administered with MiADMSA restored blood ALAD activity. Administration of iron alone had no beneficial effects on hepatic oxidative stress, while in combination with MiADMSA it produced significant decline in hepatic TBARS level compared to the individual effect of MiADMSA. Renal biochemical variables were insensitive to any of the treatments. Combined administration of iron with MiADMSA also had no additional beneficial effect over the individual protective effect of MiADMSA on brain oxidative stress. Interestingly, combined administration of iron with MiADMSA provided more pronounced depletion of blood arsenic, while no additional beneficial effects on tissue arsenic level over the individual effect of MiADMSA were noted. The results lead us to conclude that iron supplementation during chelation has some beneficial effects particularly on heme synthesis pathway and blood arsenic concentration.

Pre-clinical evaluation of 2,3-dimercaptosuccinic acid as a radiation nephrotoxicity protective agent during radiopeptide therapy of neuroendocrine malignancy.

AIM: To determine if dimercaptosuccinic acid (DMSA), an agent originally developed as a safe non-toxic antidote for heavy metal poisoning, would be useful as a kidney radiation dose reduction agent in patients undergoing radiopeptide therapy for cancer. METHODS: Thirty-six adult male Wistar rats were injected via the penile vein with 10 MBq of 177Lu-DOTA-tyr(3)-octreotate. At 30 min after the radiopeptide injection, 18 of the animals (intervention group) were injected with 0.15 mg x g(-1) of DMSA (i.p.). Samples were collected for gamma counting at 24 (n=12), 48 (n=12) and 72 h (n=12) after administration of the radiopeptide. At each time point, the percentage injected dose per gram of tissue in each sample of the six control animals was compared with that of the six animals from the DMSA injection regimen. RESULTS: The i.p. injection of 0.15 mg x g(-1) of DMSA 30 min following the administration of the 177Lu-DOTATATE reduced the mean (95% CI) kidney retention of radiopeptide by 15.6% (2.6-24.6) at 72 h while not significantly affecting uptake in other organs. Statistical testing of the difference between the two groups of animals (DMSA versus controls) at 72 h post-administration of the radiopeptide indicated only a 3% chance that the magnitude of the reduction in kidney radiopeptide retention observed would be expected due to natural variation (i.e., if there was no difference between the groups). CONCLUSION: This study has indicated that DMSA has the potential to selectively reduce radiopeptide kidney retention. Further work is necessary to determine the most effective dose of DMSA and the most effective timing regimen, and to examine the clinical efficacy of several other chelating agents.