succimer and Disease-Models--Animal

This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.

Topics: Animals; Behavior, Animal; Body Burden; Brain; Chelating Agents; Chelation Therapy; Disease Models, Animal; Humans; Lead; Lead Poisoning; Risk Assessment; Risk Factors; Succimer; Time Factors; Treatment Outcome

The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with

Topics: Animals; Apigenin; Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Drug Carriers; Drug Liberation; Female; Humans; Lung Neoplasms; Melanoma; Mice; Nanoparticles; Neoplasm Invasiveness; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Skin Neoplasms; Spheroids, Cellular; Succimer; Tissue Distribution

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 L

Topics: Animals; Calcium; Chrysanthemum; Disease Models, Animal; Drug Therapy, Combination; Female; Flavonoids; Glutathione; Glutathione Peroxidase; Hippocampus; Iron; Lead; Lead Poisoning; Liver; Malondialdehyde; Mice; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Plant Extracts; Porphobilinogen Synthase; Succimer; Superoxide Dismutase; Treatment Outcome; Zinc

Lead (Pb) is observed in all areas of the environment, mainly derived from human operations such as mining, processing, and burning fossil fuels. Pb toxicity is one of the most prevalent causes of human hepatotoxicity. The available chelator drugs used now have many adverse effects and therefore the world is looking for natural and secure alternatives.. Here, we evaluated the hepatoprotective role of the oral administration (1 g/kg b.w.) of the lyophilized Beta vulgaris juice (BVJ) against Pb-induced rat hepatotoxicity. We also examined the possible synergistic hepatoprotective impact of the combination between BVJ and 2,3- dimercaptosuccinic acid (DMSA, the currently approved drug for Pb-toxicity). The evaluation depends on the ability of BVJ, DMSA, or their combination (BVJ-DMSA) to reduce serum and hepatic Pb level and to avoid oxidative stress and inflammation caused by Pb. The level of lipid peroxidation, reduced glutathione (GSH), total antioxidant capacity, and the activity of the antioxidant enzymes were quantified. In addition, the level of interleukin (IL)-6, nitric oxide (NO), DNA fragmentation, and liver histology were studied.. The results showed that BVJ contained considerable amounts of betalains, vitamin C, and various types of phenolic compounds. Therefore, BVJ displayed a significant (p < 0.05) preventive influence on the elevation of Pb levels in blood and liver as well as the hepatic DNA fragmentation. In addition, it significantly (p < 0.05) improved most of the studied antioxidant and inflammatory markers in the Pb-intoxicated rats. However, the combined extract (BVJ-DMSA) revealed synergistic (combination index < 1) activities in most of the tested parameters. The histopathological results verified the biochemical findings of this research.. BVJ has a potent efficiency in the protection from Pb-induced hepatotoxicity through the reduction of its accumulation in blood and liver and the prevention of the oxidative stress and inflammation induced by Pb. Additionally, the treatment of hepatotoxicity with BVJ and DMSA in combination showed a synergistic effect and reduced the adverse effects induced by DMSA. Thus, BVJ can be a promising hepatoprotective extract against lead toxicity and its combination with DMSA potentiates this effect.

Topics: Administration, Oral; Animals; Antioxidants; Beta vulgaris; Chelating Agents; Disease Models, Animal; Drug Synergism; Egypt; Fruit and Vegetable Juices; Inflammation; Lead; Lead Poisoning; Liver; Male; Oxidative Stress; Rats; Succimer

Chelation therapy is considered as a safe and effective strategy to combat metal poisoning. Arsenic is known to cause neurological dysfunctions such as impaired memory, encephalopathy, and peripheral neuropathy as it easily crosses the blood-brain barrier. Oxidative stress is one of the mechanisms suggested for arsenic-induced neurotoxicity. We prepared Solid Lipid nanoparticles loaded with Monoisoamyl 2, 3-dimercaptosuccinic acid (Nano-MiADMSA), and compared their efficacy with bulk MiADMSA for treating arsenic-induced neurological and other biochemical effects. Solid lipid nanoparticles entrapping MiADMSA were synthesized and particle characterization was carried out by transmission electron microscopy (TEM) and dynamic light scattering (DLS). An in vivo study was planned to investigate the therapeutic efficacy of MiADMSA-encapsulated solid lipid nanoparticles (Nano-MiADMSA; 50 mg/kg orally for 5 days) and compared it with bulk MiADMSA against sodium meta-arsenite exposed rats (25 ppm in drinking water, for 12 weeks) in male rats. The results suggested the size of Nano-MiADMSA was between 100-120 nm ranges. We noted enhanced chelating properties of Nano-MiADMSA compared with bulk MiADMSA as evident by the reversal of oxidative stress variables like blood δ-aminolevulinic acid dehydratase (δ-ALAD), Reactive Oxygen Species (ROS), Catalase activity, Superoxide Dismutase (SOD), Thiobarbituric Acid Reactive Substances (TBARS), Reduced Glutathione (GSH) and Oxidized Glutathione (GSSG), Glutathione Peroxidase (GPx), Glutathione-S-transferase (GST) and efficient removal of arsenic from the blood and tissues. Recoveries in neurobehavioral parameters further confirmed nano-MiADMSA to be more effective than bulk MiADMSA. We conclude that treatment with Nano-MiADMSA is a better therapeutic strategy than bulk MiADMSA in reducing the effects of arsenic-induced oxidative stress and associated neurobehavioral changes.

Topics: Animals; Antioxidants; Arsenic Poisoning; Arsenites; Behavior, Animal; Biomarkers; Brain; Chelating Agents; Disease Models, Animal; Drug Compounding; Lipids; Male; Motor Activity; Nanoparticles; Oxidative Stress; Rats, Transgenic; Sodium Compounds; Succimer

Rupture of an atherosclerotic plaque is the primary cause of acute cardiovascular and cerebrovascular syndromes. Early and non-invasive detection of vulnerable atherosclerotic plaques (VP) would be significant in preventing some aspects of these syndromes. As a new contrast agent, dimercaptosuccinic acid (DMSA) modified ultra-small super paramagnetic iron oxide (USPIO) was synthesized and used to identify VP and rupture plaque by magnetic resonance imaging (MRI).. Atherosclerosis was induced in male New Zealand White rabbits by feeding a high cholesterol diet (n = 30). Group A with atherosclerosis plaque (n = 10) were controls. VP was established in groups B (n = 10) and C (n = 10) using balloon-induced endothelial injury of the abdominal aorta. Adenovirus-carrying p53 genes were injected into the aortic segments rich in plaques after 8 weeks. Group C was treated with atorvastatin for 8 weeks. Sixteen weeks later, all rabbits underwent pharmacological triggering, and imaging were taken daily for 5 d after DMSA-USPIO infusion. At the first day and before being killed, serum MMP-9, sCD40L, and other lipid indicators were measured.. DMSA-USPIO particles accumulated in VP and rupture plaques. Rupture plaques appeared as areas of hyper-intensity on DMSA-USPIO enhanced MRI, especially T2*-weighted sequences, with a signal strength peaking at 96 h. The group given atorvastatin showed few DMSA-USPIO particles and had lower levels of serum indicators. MMP-9 and sCD40L levels in group B were significantly higher than in the other 2 groups (P <0.05).. After successfully establishing a VP model in rabbits, DMSA-USPIO was used to enhance MRI for clear identification of plaque inflammation and rupture. Rupture plaques were detectable in this way probably due to an activating inflammatory process. Atorvastatin reduced the inflammatory response and stabilizing VP possibly by decreasing MMP-9 and sCD40L levels.

Topics: Animals; Anticholesteremic Agents; Aorta, Abdominal; Atherosclerosis; Atorvastatin; CD40 Ligand; Cholesterol; Contrast Media; Dextrans; Diet, High-Fat; Disease Models, Animal; Gene Expression; Hypercholesterolemia; Magnetic Resonance Imaging; Magnetite Nanoparticles; Male; Matrix Metalloproteinase 9; Plaque, Atherosclerotic; Rabbits; Succimer; Transgenes; Tumor Suppressor Protein p53

Cancer stem cells (CSCs) are thought to be responsible for the relapse of multiple myeloma (MM). The objective of this study was to target therapy of MM cancer stem cells using gamma-Fe2O3@DMSA magnetic nanoparticle combination with paclitaxel and anti-ABCG2 monoclonal antibody, and to evaluate the combined therapeutic efficacy. CSCs were isolated from human MM cell line RPMI 8226 based on negative expression of CD138 and CD34. In vivo and in vitro studies demonstrated that the isolated CD138-CD34- cells displayed certain stem cell characteristics, including significant increase in expression of ABCG2 transporter, proliferation, mobility, drug resistance, clonogenic potential in soft agar media and tumorigenecity in mice. Treatment with nanoparticles, paclitaxel and anti-ABCG2 antibody remarkably inhibited the growth of CD138-CD34- cells in vitro and their derived tumors in xenografts. The inhibition was also correlated with elevated expression of caspase-9, caspase-8 and caspase-3, and down-regulation of NF-KB. Our data indicate that the nanoparticle combination with paclitaxel and anti-ABCG2 monoclonal antibody offers an effective approach to treatment of MM CSCs through an apoptotic pathway.

Topics: Animals; Antibodies, Monoclonal; Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Caspases; Cell Line, Tumor; Cell Movement; Cell Survival; Disease Models, Animal; Humans; Magnetite Nanoparticles; Mice; Multiple Myeloma; Neoplasm Proteins; Neoplastic Stem Cells; NF-kappa B; Paclitaxel; Particle Size; Signal Transduction; Succimer; Tumor Burden

Adipose-derived stem cells (ADSCs) exhibit tremendous potential for repair of ischemic diseases. However, studies on the fate, migration, differentiation, and body distribution of the labeled ADSCs are rarely reported. In this study, magnetic iron oxide nanoparticles were designed, synthesized, and coated with meso-2,3-dimercaptosuccinic acid (DMSA) to produce DMSA nanoparticles (DMSA-NPs). The properties, size distribution, and characterization of DMSA-NPs were evaluated. Green fluorescent protein expressing ADSCs (GFP-ADSCs) were obtained and labeled with DMSA-NPs. The viability, cytotoxicity and multi-differentiation capacity of labeled GFP-ADSCs were evaluated in vitro. Labeled and non-labeled GFP-ADSCs were injected into a mouse model of hindlimb ischemia, and 3T magnetic resonance imaging (MRI) was acquired. The synthesized DMSA-NPs efficiently labeled the GFP-ADSCs in vitro and in vivo without affecting cell viability, proliferation, cell cycle, and multi-differentiation capacity. The MRI showed hypointense spots in the labeled GFP-ADSCs that lasted up to 8 weeks. Prussian blue staining and immunofluorescence assay at 4 and 8 weeks indicated that the labeled GFP-ADSCs were in and around the ischemic sites and some differentiated into capillaries. This observation is identical to that seen for transplants of unlabeled cells. Labeled cells were also identified mainly in the liver and spleen, with significantly smaller amounts in the lungs, intestines, heart, and kidney. Developed DMSA-NPs were shown to exhibit a considerable potential for use as nanoprobes for MRI of stem cells, which will enhance our understanding of cell-based therapeutic strategies for ischemic diseases.

Topics: Adipose Tissue; Animals; Cell Death; Cell Differentiation; Cell Survival; Disease Models, Animal; Ferric Compounds; Ferrocyanides; Flow Cytometry; Fluorescent Antibody Technique; Green Fluorescent Proteins; Hindlimb; Hydrodynamics; Immunohistochemistry; Ischemia; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Multipotent Stem Cells; Nanoparticles; Particle Size; Staining and Labeling; Stem Cell Transplantation; Stem Cells; Succimer

Arsenic contaminated drinking water has affected more than 200 million people globally. Chronic arsenicism has also been associated with numerous neurological diseases. One of the prime mechanisms postulated for arsenic toxicity is reactive oxygen species (ROS) mediated oxidative stress. In this study, we explored the kinetic relationship of ROS with calcium and attempted to dissect the calcium ion channels responsible for calcium imbalance after arsenic exposure. We also explored if mono- or combinational chelation therapy prevents arsenic-induced (25ppm in drinking water for 4 months) neuronal apoptosis in a guinea pig animal model. Results indicate that chronic arsenic exposure caused a significant increase in ROS followed by NO and calcium influx. This calcium influx is mainly dependent on L-type voltage gated channels that disrupt mitochondrial membrane potential, increase bax/bcl2 levels and caspase 3 activity leading to apoptosis. Interestingly, blocking of ROS could completely reduce calcium influx whereas calcium blockage partially reduced ROS increase. While in general mono- and combinational chelation therapies were effective in reversing arsenic induced alteration, combinational therapy of DMSA and MiADMSA was most effective. Our results provide evidence for the role of L-type calcium channels in regulating arsenic-induced calcium influx and DMSA+MiADMSA combinational therapy may be a better protocol than monotherapy in mitigating chronic arsenicosis.

Topics: Animals; Apoptosis; Arsenic Poisoning; Arsenites; bcl-2-Associated X Protein; Calcium; Calcium Channels, L-Type; Caspase 3; Chelating Agents; Cytoprotection; Disease Models, Animal; Drug Therapy, Combination; Guinea Pigs; Kinetics; Male; Membrane Potential, Mitochondrial; Neurons; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sodium Compounds; Succimer

Lead (Pb) toxicity is one of the commonest environmental problems in our life; it causes many reversible and irreversible changes in our tissues. This study was carried out to investigate the effect of meso-2,3-dimercaptosuccinic acid (DMSA) on treatment of oxidative stress caused by lead poisoning in rabbits. Lead acetate (Pb(Ac)(2)) was orally administrated to rabbits for 21 days and then treated by DMSA for another 21 days. The effect of this treatment was investigated by measuring 2 of the apoptosis proteins p53 and Bcl2. Also, the auto-oxidation rate and their histopathological changes in brain, bone and liver were investigated. Hemoglobin auto-oxidation rate is measured as well as histopathological study of liver. Our data indicate that exposure to rabbits to Pb(Ac)(2) caused a significant increase of apoptosis protein p53 and decrease in the antiapoptotic BCl2 proteins.

Topics: Animals; Bone and Bones; Brain; Chelating Agents; Disease Models, Animal; Lead Poisoning; Liver; Male; Organometallic Compounds; Oxidation-Reduction; Oxidative Stress; Oxyhemoglobins; Proto-Oncogene Proteins c-bcl-2; Rabbits; Succimer; Tumor Suppressor Protein p53

Chronic arsenic exposure causes oxidative stress and mitochondrial dysfunction in the liver and brain. The ideal treatment would be to chelate arsenic and prevent oxidative stress. meso-2,3-Dimercaptosuccinic acid (DMSA) is used to chelate arsenic but its hydrophilicity makes it membrane-impermeative. Conversely, quercetin (QC) is a good antioxidant with limited clinical application because of its hydrophobic nature and limited bioavailability, and it is not possible to solubilize these two compounds in a single nontoxic solvent. Nanocapsules have emerged as a potent drug delivery system and make it feasible to incorporate both hydrophilic and lipophilic compounds. Nanoencapsulated formulations with QC and DMSA either alone or coencapsulated in polylactide-co-glycolide [N(QC+DMSA)] were synthesized to explore their therapeutic application in a rat model of chronic arsenic toxicity. These treatments were compared to administration of quercetin or DMSA alone using conventional delivery methods. Both nanoencapsulated quercetin and nanoencapsulated DMSA were more effective at decreasing oxidative injury in liver or brain compared to conventional delivery methods, but coencapsulation of quercetin and DMSA into nanoparticles had a marked synergistic effect, decreasing liver and brain arsenic levels from 9.5 and 4.8μg/g to 2.2 and 1.5μg/g, respectively. Likewise, administration of coencapsulated quercetin and DMSA virtually normalized changes in mitochondrial function, formation of reactive oxygen species, and liver injury. We conclude that coencapsulation of quercetin and DMSA may provide a more effective therapeutic strategy in the management of arsenic toxicity and also presents a novel way of combining hydrophilic and hydrophobic drugs into a single delivery system.

Topics: Animals; Antioxidants; Arsenic; Arsenic Poisoning; Brain; Chelating Agents; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Drug Synergism; Female; Humans; Hydrophobic and Hydrophilic Interactions; Lactic Acid; Liver; Nanoparticles; Oxidative Stress; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Quercetin; Rats; Rats, Wistar; Succimer

Smilax glabra Roxb. is a traditional Chinese herb, the rhizome of Smilax glabra has been used in folk medicine for the treatment of lead poisoning.. The present study was conducted to investigate the protective role of Smilax glabra extract (SGE) individually or combined with meso-2,3-dimercaptosuccinic acid (DMSA) against the effects of lead acetate on oxidative stress and lead burden in rats.. The biochemical parameters and enzymes in different treated rats were determined by commercial kits. The metal concentrations were measured using atomic absorption spectrophotometer.. SGE (300 mg/kg) showed very low toxicity to organs in non-lead exposed rats. Administration of SGE individually had no effect on blood zinc protoporphyrin (ZPP) level but significantly enhanced the glutathione (GSH) content and delta-aminolevulinic acid dehydratase (ALAD), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities in lead exposed rats. The co-treatment of SGE and DMSA had a synergism in increasing brain, liver and kidney superoxide dismutase (SOD), catalase (CAT) activities and GSH level, and decreasing oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS) levels. Moreover, the co-treatment could improve the hepatic and renal histopathology changes. SGE as chelating agent showed significant efficiency in reducing blood and tissue lead burden.. The in vivo results suggested that SGE individually or combined with DMSA exhibited remarkable protective effects on lead-induced oxidative stress and lead burden in rats.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antidotes; Antioxidants; Body Burden; Brain; Catalase; Chelating Agents; Disease Models, Animal; Flavonoids; Glutathione; Kidney; Lead Poisoning; Liver; Male; Organometallic Compounds; Oxidative Stress; Phenols; Plant Extracts; Porphobilinogen Synthase; Protoporphyrins; Rats; Rats, Wistar; Rhizome; Smilax; Succimer; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril+DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

Topics: Animals; Antioxidants; Apoptosis; Behavior, Animal; Biogenic Amines; Calcium; Captopril; Chelating Agents; Cytochromes c; Disease Models, Animal; DNA Damage; Drug Therapy, Combination; Exploratory Behavior; Lead Poisoning, Nervous System; Learning; Male; Membrane Potential, Mitochondrial; Memory; Mitochondria; Motor Activity; Nerve Degeneration; Neurons; Nitric Oxide; Organometallic Compounds; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Succimer

To observe early renal parenchymal cellular changes in an experimental model of vesico-ureteral reflux (VUR) and to show whether the apoptotic pathway plays a role in these cellular changes.. Fourteen New Zealand breed rabbits were used and were divided into two equal groups (control and experimental groups). Urine samples were obtained in a sterile manner and cultured. In the study group, reflux was created in the right kidneys surgically. Renal scintigraphy and voiding cystourethrography (VCUG) were performed in both groups on Day 17. The kidneys were examined in terms of histology, apoptotic activity and caspase activity.. No growth was observed in urine cultures in either group. VUR was manifested in only two rabbits in the experimental group on VCUG. On renal scintigraphy, no renal scarring was observed in either of the groups and renal uptake values were in the normal range. There was a greater increase in collagen in the right kidneys in the experimental group than in the control group and apoptotic activity was significantly increased in the study group: 0% in the control group, 10.8%+/-0.7% in the experimental group (p<0.001). Caspase-6 activity was strongly positive and caspase-8 and -9 activities were moderately positive in the right kidneys of the experimental group. Caspase-6 activity was moderately positive, and caspase-8 and -9 activities were weakly positive in the contralateral kidneys of the experimental group. Caspase activities in the control group were negative (p<0.001).. In this experimental model of VUR, apoptotic activity was initiated via the caspase-8 and -9 pathway and collagen tissue increased in the renal parenchyma where reflux occurred. The balance of apoptotic activity may play a key role in the occurrence of reflux nephropathy.

Topics: Animals; Apoptosis; Caspase 10; Caspase 6; Caspase 8; Disease Models, Animal; Female; Immunohistochemistry; In Situ Nick-End Labeling; Kidney; Rabbits; Radionuclide Imaging; Succimer; Vesico-Ureteral Reflux

Arsenicosis, due to contaminated drinking water in the Indo-Bangladesh region, is a serious health hazard in terms of morbidity and mortality. Reactive oxygen species (ROS) generated due to arsenic toxicity have been attributed as one of the initial signals that impart cellular toxicity, which is controlled by the internal antioxidant glutathione (GSH). In the present study, we investigated (i) the role of GSH and its linked enzymes, glutathione peroxidase and glutathione reductase, in reversing chronic arsenic toxicity using a thiol chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), or one of its analogues individually or in combination; (ii) if alterations in the carbon side chain of DMSA increased efficacy; and (iii) whether the combination therapy enhance arsenic removal from hepatic tissue and prevent hepatic apoptosis. Results indicated that chronic arsenic exposure led to a ROS-mediated, mitochondrial-driven, caspase-dependent apoptosis in hepatic cells with a significant increase in glutathione disulfide (GSSG) levels and decreased glutathione reductase levels. Monotherapy with DMSA and its analogues did show minimal recovery postchelation. However, the combination of DMSA with long carbon chain analogues like monoisoamyl DMSA (MiADMSA) or monocyclohexyl DMSA (MchDMSA) showed a better efficacy in terms of reducing the arsenic burden as well as reversing altered biochemical variables indicative of oxidative stress and apoptosis. We also observed that GSH and its linked enzymes, especially glutathione reductase, play a vital role in scavenging ROS, maintaining GSH pools, and providing clinical recoveries. On the basis of the above observations, we recommend that combinational therapy of DMSA and its long carbon chain analogues MiADMSA or MchDMSA would be more effective in arsenic toxicity.

Topics: Animals; Antidotes; Apoptosis; Arsenic Poisoning; Arsenites; Chelating Agents; Disease Models, Animal; Enzyme Inhibitors; Enzymes; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Guinea Pigs; Liver; Male; Oxidative Stress; Reactive Oxygen Species; Sodium Compounds; Succimer

The dose dependent effects of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid (DMSA) (0.1, 0.3 and 0.5 mmol kg(-1), intraperitoneally (i.p.) once daily for 5 days) to offset the characteristic biochemical, immunological, oxidative stress consequences and DNA damage (based on DNA fragmentation and comet assay) following sub-chronic administration of gallium arsenide and the mobilization of gallium and arsenic were examined. The effects of these chelators alone in normal animals too were examined on above-mentioned variables. Male Wistar rats were exposed to 10 mg kg(-1), GaAs, orally once daily for 12 weeks and were administered DMSA or two of its monoesters (monoisoamyl or monomethyl) for 5 consecutive days. DMSA was used as a positive control. DMSA and its derivatives, when given alone, generally have no adverse effects on various parameters. After 5 days of chelation therapy in GaAs pre-exposed rats, MiADMSA was most effective in the reduction of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin level while, all three chelators effectively reduced urinary ALA excretion, compared to GaAs alone exposed rats. MiADMSA was also effective, particularly at a dose of 0.3 mmol kg(-1), in enhancing the inhibited hepatic transaminase activities. Parameters indicative of oxidative stress responded less favorably to the chelation therapy, however, three chelators significantly restored the altered immunological variables. MiADMSA was relatively more effective than the other two chelators. GaAs produced significant DNA damage in the liver and kidneys and the chelation treatment had moderate but significant influence in reducing DNA damage. All three chelators significantly reduced arsenic concentration and, however, MiADMSA was more effective than the other two chelators in depleting arsenic concentration from blood and other soft tissues. A dose of 0.3 mmol kg(-1) was found to be relatively better than the other two doses examined. Gallium contents of blood and soft tissues remained uninfluenced by the chelation therapy. Significant loss of copper after MiADMSA administration, however, is of concern and requires further exploration. Additionally, further studies are required for the choice of appropriate dose, duration of treatment and possible toxic/side effects. Keeping in view the promising role of MiADMSA in the treatment of GaAs poisoning, these data will be needed for the registration of this ch

Topics: Aminolevulinic Acid; Animals; Antidotes; Arsenic Poisoning; Arsenicals; Biomarkers; Chelating Agents; Chelation Therapy; Comet Assay; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Gallium; Injections, Intraperitoneal; Liver; Male; Protoporphyrins; Rats; Rats, Wistar; Succimer; Treatment Outcome

Although many studies have demonstrated the efficacy of succimer chelation in reducing blood and brain lead levels, the relative efficacy of the drug in the two tissues is less well understood. This issue is important because blood lead levels after chelation are used clinically to estimate reductions in the brain, the most critical organ in considering lead-induced neurotoxicity. The present study was designed to further investigate this issue, using multiple chelation regimens. Long-Evans rats were exposed to one of three lead exposure regimens from birth until postnatal day 40, followed by treatment with succimer (one or two 3-week regimens) or vehicle. The results indicated that one succimer regimen was significantly superior to vehicle treatment in lowering lead levels in both blood and brain across the entire 8-week follow-up period. Similarly, a second succimer regimen offered significant additional benefit relative to one regimen for both blood and brain across the 4-week follow-up period. However, several findings revealed that succimer-induced reductions in brain lead lagged behind reductions in blood lead and were generally smaller in magnitude. Furthermore, a rebound was detected in blood, but not brain, lead levels after both succimer regimens. Given the results of this study, we urge caution in using blood lead as a surrogate for brain lead levels, particularly during and immediately after chelation treatment when reductions in blood lead levels overestimate reductions in brain lead levels. The present results suggest that, in clinical use, succimer treatment may need to extend beyond the point at which blood lead levels have dropped to an "acceptable" target value in order to effectively reduce brain lead levels and minimize neurotoxicity.

Topics: Animals; Biomarkers; Brain; Chelating Agents; Disease Models, Animal; Endpoint Determination; Female; Forecasting; Lead; Lead Poisoning; Male; Models, Theoretical; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Succimer; Tissue Distribution; Treatment Outcome

The combined therapeutic potentials of lipoic acid and dimercaptosuccinic acid were compared against their sole administrations in restoring the altered lead sensitive indices in urine and isolated renal brush-border preparations. Toxicity was induced in male albino rats (Wistar strain) by administering lead acetate (0.2%) in drinking water for 5 weeks, followed by therapy comprising lipoic acid (25 mg/kg body weight) and dimercaptosuccinic acid (20 mg/kg body weight) solely as well as combined during the 6th week. Changes in kidney weights encountered upon lead administration improved after therapy with lipoic acid and dimercaptosuccinic acid. Renal integrity was assessed by measuring the activities of alkaline phosphatase, acid phosphatase, lactate dehydrogenase, leucine aminopeptidase, N-acetyl-beta-D-glucosaminidase, gamma-glutamyl transferase and beta-glucuronidase in urine along with some urinary constituents (urea, uric acid, creatinine, protein and phosphorous). The effects of lead were also studied on isolated brush-border enzymes (alkaline phosphatase, acid phosphatase, gamma-glutamyl transferase and beta-glucuronidase) that showed a decline upon its administration. Increased activities of urinary enzymes were accompanied by increase in the urinary constituents. Increase in renal lead content was paralleled by a drastic fall in the renal delta-aminolevulinic acid dehydratase and a rise in urinary lead levels. Relative to the administration of lead, the combined therapy showed betterment on the renal integrity with respect to the functional parameters assessed, thereby indicating its efficacy over the monotherapies.

Topics: 5-Aminolevulinate Synthetase; Animals; Antioxidants; Biomarkers; Body Weight; Chelating Agents; Disease Models, Animal; Drug Therapy, Combination; Kidney Cortex; Kidney Diseases; Kidney Tubules; Lead Poisoning; Male; Microvilli; Organ Size; Organometallic Compounds; Rats; Rats, Wistar; Succimer; Thioctic Acid

The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), a new monoester of 2,3-dimercaptosuccinic acid on arsenic induced oxidative stress in liver and kidneys, alterations in hematopoietic system and depletion of arsenic burden was assessed, in mice. Three different doses of MiADMSA (25, 50 or 100 mg/kg) for five consecutive days were administered in chronically arsenic exposed mice (10 ppm in drinking water for six months). Oral administration of MiADMSA particularly at a dose of 50 mg/kg, produced relatively more pronounced beneficial effects on the inhibited blood delta-aminolevulinic acid dehydratase (ALAD), biochemical variables indicative of hepatic and renal oxidative stress and depletion of arsenic concentration in blood, liver and kidneys, compared with intraperitoneal administration of the drug. The treatment with MiADMSA although, produced essential metals imbalance which could be a restrictive factor for the possible therapeutic use of this compound in chronic arsenic poisoning and thus require further exploration.

Topics: Administration, Oral; Animals; Arsenic Poisoning; Disease Models, Animal; Infusions, Parenteral; Kidney; Liver; Male; Mice; Oxidative Stress; Succimer

Ameliorative effects of few naturally occurring antioxidants like ascorbic acid (vitamin C), alpha-tocopherol (vitamin E) either alone or in combination with meso-2,3-dimercaptosuccinic acid (DMSA) or monoisoamyl DMSA (MiADMSA), on parameters indicative of oxidative stress in the liver, kidney, brain and blood of lead-exposed rats were studied. Male Wistar rats were exposed to 0.1% lead acetate in drinking water for 3 months and treated thereafter with DMSA or its analogue MiADMSA (50 mg/kg, intraperitoneally), either individually or in combination with vitamin E (5 mg/kg, intramuscularly) or vitamin C (25 mg/kg, orally) once daily for 5 days. The effects of these treatments in influencing the lead-induced alterations in haem synthesis pathway, hepatic, renal and brain oxidative stress and lead concentration from the soft tissues were investigated. Exposure to lead produced a significant inhibition of delta-aminolevulinic acid dehydratase (ALAD) activity from 8.44+/-0.26 in control animals to 1.76+/-0.32 in lead control, reduction in glutathione (GSH) from 3.56+/-0.14 to 2.57+/-0.25 and an increase in zinc protoporphyrin level from 62.0+/-3.9 to 170+/-10.7 in blood, suggesting altered haem synthesis pathway. Both the thiol chelators and the two vitamins were able to increase blood ALAD activity towards normal, however, GSH level responded favorably only to the two thiol chelators. The most prominent effect on blood ALAD activity was, however, observed when MiADMSA was co-administered with vitamin C (7.51+/-0.17). Lead exposure produced a significant depletion of hepatic GSH from 4.59+/-0.78 in control animals to 2.27+/-0.47 in lead controls and catalase activity from 100+/-3.4 to 22.1+/-0.25, while oxidized glutathione (GSSG; 0.34+/-0.05 to 2.05+/-0.25), thiobarbituric acid reactive substance (TBARS; 1.70+/-0.45 to 5.22+/-0.50) and glutathione peroxidase (GPx) levels (3.41+/-0.09 to 6.17+/-0.65) increased significantly, pointing to hepatic oxidative stress. Altered, reduced and oxidized GSH levels showed significant recovery after MiADMSA and DMSA administration while, vitamins E and C were effective in reducing GSSG and TBARS levels and increasing catalase activity. Administration of MiADMSA alone and the combined administration of vitamin C along with DMSA and MiADMSA were most effective in increasing hepatic GSH levels to 4.88+/-0.14, 4.09+/-0.12 and 4.30+/-0.06, respectively. Hepatic catalase also reached near normal level in animals co-administered v

Topics: Animals; Antidotes; Antioxidants; Ascorbic Acid; Chelating Agents; Cysteinyldopa; Disease Models, Animal; Drug Therapy, Combination; Lead Poisoning; Male; Oxidative Stress; Porphobilinogen Synthase; Protoporphyrins; Rats; Rats, Wistar; Succimer; Treatment Outcome; Vitamin E

The deleterious effect of lead has been attributed to lead-induced oxidative stress with the consequence of lipid peroxidation. The present study was designed to investigate the combined effect of DL-alpha-lipoic acid (LA) and meso-2,3-dimercaptosuccinic acid (DMSA) on lead-induced peroxidative damages in rat kidney. The increase in peroxidated lipids in lead-poisoned rats was accompanied by alterations in antioxidant defence systems. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce lead toxicity. LA (25 mg/kg body weight per day i.p.) and DMSA (20 mg/kg body weight per day i.p.) were administered individually and also in combination during the sixth week. Nephrotoxic damage was evident from decreases in the activities of gamma-glutamyl transferase and N-acetyl beta- D-glucosaminidase, which were reversed upon combined treatment with LA and DMSA. Rats subjected to lead intoxication showed a decline in the thiol capacity of the cell, accompanied by high malondialdehyde levels along with lowered activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione metabolizing enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione- S-transferase). Supplementation with LA as a sole agent showed considerable changes over oxidative stress parameters. The study has highlighted the combined effect of both drugs as being more effective in reversing oxidative damage by bringing about an improvement in the reductive status of the cell.

Topics: Acetylglucosaminidase; Animals; Catalase; Chelating Agents; Disease Models, Animal; Drug Therapy, Combination; gamma-Glutamyltransferase; Glutathione; Glutathione Peroxidase; Kidney; Lead Poisoning; Lipid Peroxidation; Lipid Peroxides; Male; Rats; Rats, Wistar; Succimer; Superoxide Dismutase; Thioctic Acid

Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. This concern is justified because the availability of Pb-safe housing during outpatient treatment with oral succimer is limited. We used a juvenile nonhuman primate model of moderate childhood Pb intoxication and a sensitive double stable Pb isotope tracer methodology to determine whether oral succimer chelation affects the GI absorption and whole-body retention of Pb. Infant rhesus monkeys (n = 17) were exposed to Pb daily for 1 year postpartum to reach and maintain a target blood lead (BPb) level of 35-40 microg/dL. Animals were administered succimer (n = 9) or vehicle (n = 8) over two successive 19 day succimer treatment regimens beginning at 53 and 65 weeks of age. The present study was conducted over the second chelation regimen only. Animals received a single intravenous (iv) dose of stable (204)Pb tracer (5 microg, 24.5 nmol) followed by a single oral dose of stable (206)Pb tracer (72.6 microg, 352 nmol) immediately before chelation, in order to specifically evaluate GI Pb absorption and whole-body Pb retention with treatment. We collected complete urine and fecal samples over the first 5 days and whole blood over the first 8 days of treatment for analyses of stable Pb isotopes using magnetic sector inductively-coupled plasma mass spectrometry. Results indicate that succimer significantly reduced the GI absorption of Pb (vehicle, 64.9% +/- 5.5; succimer, 37.0% +/- 5.8; mean +/- SEM). Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.

Topics: Administration, Oral; Animals; Chelating Agents; Child; Disease Models, Animal; Female; Humans; Intestinal Absorption; Isotopes; Lead; Lead Poisoning; Macaca mulatta; Succimer

Succimer is considered to be a safe and effective treatment for lead (Pb) poisoning, since it reduces body Pb levels without an apparent diuresis of other essential elements. However, while existing clinical data indicate that succimer does not significantly increase the excretion of non-target elements, those studies have also reported a wide range of outcomes. Therefore, we investigated whether succimer treatment measurably increased the urinary excretion of essential elements in a primate model of childhood Pb exposure. Infant rhesus monkeys (Macaca mulatta) were exposed to Pb from birth through one year of age, and presented blood Pb levels of approximately 40-50 microg/dL at the start of treatment. Subsequently, they were treated with succimer (30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days, n = 15) or vehicle (n = 14) for 19 days. Complete urine samples were collected over the first 5 days of treatment, and were analyzed for levels of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), magnesium (Mg), manganese (Mn), nickel (Ni), and zinc (Zn), using trace metal-clean techniques and magnetic sector-ICP-MS. Succimer treatment significantly (p < 0.05) reduced blood Pb levels when compared to the vehicle group over the treatment period, and concomitantly produced a significant >4-fold increase in urinary Pb excretion. Succimer treatment also significantly (p < 0.05, multivariate ANOVA) increased the urinary excretion of essential elements, but only when the cumulative total excretion over treatment days 1-5 for all elements were considered. None of these relative increases reached statistical significance for any particular element x day, although increases in Zn (day 3) excretion were only marginally non-significant (0.1 > p > 0.05). Multivariate analyses of a subset of elements (Cu, Fe, Mn, Zn) similarly indicated no significant effect of succimer treatment overall, although the urinary excretion of Mn was significantly increased on day 3 of treatment. Collectively, these data indicate that succimer does contribute to an increase in the urinary excretion of essential elements, although not significantly for any single element considered here. This may be important in Pb-exposed children, who can possess reduced trace element reserves due to nutritional deficiencies.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Lead; Lead Poisoning; Macaca mulatta; Male; Succimer; Trace Elements

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of

Topics: Animals; Brain; Chelating Agents; Chelation Therapy; Disease Models, Animal; Environmental Exposure; Humans; Lead; Lead Poisoning, Nervous System; Macaca mulatta; Male; Succimer

Increasing evidence indicates that early low-level lead (Pb) exposure produces enduring cognitive impairment in children, underscoring the need to develop improved therapeutic intervention. Although chelating agents have been shown to effectively reduce body Pb levels, it is not yet known whether this treatment ameliorates Pb-induced cognitive dysfunction. Clinical research in this area is hampered by the need to rely on reductions in blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greatest relevance to neurocognitive outcomes. The present studies were designed to provide information that will aid future research in this area in both human and animal models. The objectives of these studies were (1) to evaluate the efficacy of different doses and durations of succimer (meso-2,3-dimercaptosuccinic acid; DMSA) chelation for reducing brain and blood Pb levels and (2) to determine the extent to which blood Pb can serve as a surrogate of brain Pb following chelation. Long-Evans hooded rats were exposed to Pb from birth until day 31 (Study 1) or day 40 (Study 2) of life, followed by oral treatment with a vehicle or one of two succimer regimens for a duration of either 7 or 21 days. Results indicated that 7 days of succimer treatment produced a 1.5- to 2.5-fold greater reduction of Pb in blood than in brain, relative to time-matched vehicle groups. Prolonged treatment (21) days did not further reduce blood Pb levels (relative to 7-day succimer treatment), but did produce further reductions in brain Pb level compared to time-matched vehicle groups. Thus, chelation-mediated reductions in brain Pb did not parallel reductions in blood Pb over the course of treatment. While the relevance of these data to humans may be confounded by anatomical and physiological differences between rodents and primates, as well as differences in the metabolism of succimer (DMSA), they suggest that clinical studies should exercise caution when using blood Pb as an index of the efficacy of chelation treatment for reducing brain Pb levels.

Topics: Administration, Oral; Animals; Animals, Newborn; Brain; Brain Chemistry; Chelating Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lead; Lead Poisoning; Male; Random Allocation; Rats; Succimer

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.. 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.. 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.. 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.

Topics: Animals; Constriction; Disease Models, Animal; Female; Ischemic Preconditioning; Kidney; Kidney Tubular Necrosis, Acute; Organotechnetium Compounds; Radiography; Radionuclide Imaging; Rats; Rats, Wistar; Renal Artery; Reperfusion Injury; Succimer; Technetium Tc 99m Dimercaptosuccinic Acid

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.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Chelating Agents; Chelation Therapy; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetal Death; Male; Methylmercury Compounds; Mice; Pregnancy; Succimer

Methyl mercury has been reported to be embryotoxic and teratogenic in numerous systems such as fish, birds, and mammals. meso-2,3-Dimercaptosuccinic acid (DMSA) has been useful for prevention and treatment of mercury poisoning. In this study, the protective activity of DMSA on methyl mercury-induced embryo/fetotoxicity was evaluated in mice. A series of four DMSA injections was administered subcutaneously to pregnant Swiss mice immediately after oral administration of 25 mg/kg methyl mercury chloride (MMC) given on Day 10 of gestation, and at 24, 48, and 72 hr thereafter. DMSA effectiveness was tested at 0, 80, 160, and 320 mg/kg/day. Oral administration of MMC resulted in a high rate of resorptions and dead fetuses as well as a reduced fetal body weight. Moreover, cleft palate (46.9%) and various developmental variations were found in the positive control group. Treatment with DMSA at 160 and 320 mg/kg/day significantly decreased the embryolethality of MMC, whereas at 320 mg DMSA/kg/day the incidence of skeletal anomalies and cleft palate (2.8%) was also significantly reduced. According to these results, DMSA offers encouragement with regard to its therapeutic potential for pregnant women exposed to methyl mercury.

Topics: Animals; Bone and Bones; Disease Models, Animal; Drug Evaluation, Preclinical; Embryonic and Fetal Development; Female; Fetal Death; Mercury Poisoning; Mice; Pregnancy; Succimer

Single kidney glomerular filtration rate (SK GFR), single kidney blood flow (SK BF) and differential renal function (DRF), using both technetium labelled diethylene-pentaacetic acid (99mTc-DTPA) and dimercaptosuccinic acid (99mTc-DMSA), were examined as predictors of outcome in a pig model of complete unilateral ureteric obstruction. SK GFR and SK BF were unable to predict outcome following relief of obstruction but there was a high curvilinear correlation between DRF assessed at the end of defined periods of obstruction and after relief of obstruction using 99mTc-DMSA. Functional recovery was near complete using DMSA when the loss in DRF did not exceed 30%, after which there was an exponential decline in expected recovery. There was no difference between DRF using 99mTc-DTPA or 99mTc-DMSA in controls or before or after obstruction but significant differences between assessment by these radionuclides existed in the obstructed kidney at 24 h, 5 days, 10 days and 20 days. 99mTc-DMSA is a sensitive agent in the prediction of outcome following acute complete obstruction in the pig but its assessment of DRF in the obstructed kidney differs markedly from that of 99mTc-DTPA.

Topics: Animals; Disease Models, Animal; Glomerular Filtration Rate; Kidney; Organotechnetium Compounds; Renal Circulation; Succimer; Swine; Swine, Miniature; Technetium Tc 99m Dimercaptosuccinic Acid; Technetium Tc 99m Pentetate; Treatment Outcome; Ureter; Ureteral Obstruction

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.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Esters; Male; Mercury; Mercury Poisoning; Mice; Succimer; Unithiol

The influence of unilateral vesicoureteric reflux (VUR) on renal growth and the uptake of 99mTc DMSA by the kidney has been investigated in a 2-kidney model in the growing minipig over a period of approximately 5 months. Animals with reflux in association with low voiding pressures and normal bladder function (n = 5), as well as those with raised voiding pressures and abnormal bladder function (n = 7), were investigated with appropriate non-refluxing controls (n = 12). Urinary infection and renal scarring were avoided since these factors may affect kidney function and growth independently. Statistical tests of difference failed to demonstrate any effect of VUR on renal growth or renal uptake of 99mTc DMSA even in the presence of elevated voiding pressures and abnormal detrusor function.

Topics: Animals; Disease Models, Animal; Female; Kidney; Male; Organometallic Compounds; Radionuclide Imaging; Succimer; Sulfhydryl Compounds; Swine; Swine, Miniature; Technetium; Technetium Tc 99m Dimercaptosuccinic Acid; Vesico-Ureteral Reflux

Partial obstruction of the left ureter was created in 19 rats and a relative 99Tcm-DMSA uptake was obtained 5 and 24 h after intravenous injection of the tracer. A systematic and variable overestimation of the left to right uptake ratio was found at 5 h, with a mean error of 15.8% (S.D. = 12.2).

Topics: Animals; Disease Models, Animal; Hydronephrosis; Kidney; Male; Organometallic Compounds; Radionuclide Imaging; Rats; Succimer; Sulfhydryl Compounds; Technetium; Technetium Tc 99m Dimercaptosuccinic Acid; Time Factors

A daily dosing model for methylmercury (MM) intoxication was developed for the purpose of testing for possible adverse effects resulting from the administration of complexing agents used in the treatment of MM poisoning. The dithiol complexing agents 2,3-dimercaptopropanol (BAL) and meso-2,3-dimercaptosuccinic acid (DMSA) were chosen to test the discriminative ability of this model, since the former is contraindicated for MM poisoning and causes an increase in target organ MM burden, while the latter compound is known to be efficacious in reducing both toxicity and brain MM content. The basic design of the model called for daily observation of treated animals with identification of the following signs of MM intoxication: loss of body weight, onset of signs of toxicity, and mortality. The degree of toxicity was evaluated, and a toxicity score (0-5) was provided for each animal. A dose-dependent decrease in body weight was found in MM-treated mice. The latent period for development of signs of intoxication varied inversely with the dose rate. The rate of progression of severity of signs of intoxication was also dependent upon the dose. A dose rate of 14 mg Hg per kg per day was utilized to test the effects of BAL and DMSA on the onset and progression of signs of MM intoxication. Onset and progression of signs of methylmercury intoxication were similar for animals receiving methylmercury either alone or with administration of BAL at 2 mg per kg per day. Animals which received BAL at a dose rate of 20 mg per kg per day developed signs of intoxication significantly earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Chelating Agents; Dimercaprol; Disease Models, Animal; Male; Mercury; Methylmercury Compounds; Mice; Succimer; Time Factors

A new technique for experimental reversible hydronephrosis in the rat was developed. A noninvasive radioisotopic investigation, using Tc-99m dimercaptosuccinic acid, permitted sequential assessment of the separate renal function at different stages of the study. After 1 week of unilateral ureteral obstruction, reversibility was obtained by the removal of the obstructive device. Ten days after the obstruction release, the ipsilateral kidney had returned to 71 per cent of its preligation uptake value. Histological findings demonstrated the reversibility of the surgical obstruction.

Topics: Animals; Constriction; Disease Models, Animal; Hydronephrosis; Kidney; Male; Methods; Radionuclide Imaging; Rats; Rats, Inbred Lew; Succimer; Technetium; Technetium Tc 99m Dimercaptosuccinic Acid; Ureter; Ureteral Obstruction

Topics: Animals; Arsenic; Arsenic Poisoning; Chelating Agents; Dimercaprol; Disease Models, Animal; Mice; Succimer; Sulfhydryl Compounds; Unithiol