Aging erythrocyte membranes as biomimetic nanometer carriers of liver-targeting chromium poisoning treatment.

Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.

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.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

CONTEXT: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. OBJECTIVE: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. MATERIAL AND METHODS: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. RESULTS: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. CONCLUSIONS: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Increased Background Activity in DMSA Scintigraphy of a Nonazotemic Patient With ß-Thalassemia Major.

Renal DMSA uptake provides an index for evaluation of the functional tubular mass, which depends on the renal blood flow, proximal tubular cell membrane function, and urinary acid-base balance. We present a case of a nonazotemic 48-year-old adult with ß-thalassemia major under regular blood transfusions and iron chelation therapy that underwent DMSA scan showing minor cortical abnormalities and high background activity, featuring prominent cardiac blood pool and liver uptake. This case highlights the pitfall of high background activity during DMSA study in patients with ß-thalassemia major due to tubular disorders.

Attenuation of lead-induced oxidative stress in rat brain, liver, kidney and blood of male Wistar rats by Moringa oleifera seed powder.

Moringa oleifera is a tree belonging to Moringaceae family and its leaves and seeds are reported to have ameliorative effects against metal toxicity. In the present investigation, M. oleifera seed powder was tested against lead-induced oxidative stress and compared against meso-2, 3-dimercaptosuccinic acid (DMSA) treatment. Male Wistar rats (100-120 g) were divided into four groups: control (2000 ppm of sodium acetate for 2 weeks), exposed (2000 ppm of lead acetate for 2 weeks), Moringa treated (500 mg/kg for 7 days after lead exposure), and DMSA treated (90 mg/kg for 7 days after lead exposure). After exposure and treatment periods, rats were sacrificed and the brain was separated into cerebellum, hippocampus, frontal cortex, and brain stem; liver, kidney, and blood were also collected. The data indicated a significant (p<0.05) increase in reactive oxygen species (ROS), lipid perioxidation products (LPP), total protein carbonyl content (TPCC), and metal content of brain regions, liver, and kidney in the exposed group compared with their respective controls. In the blood, delta-amino levulinic acid dehydratase (ALAD) activity, RBC, WBC, hemoglobin, and hematocrit showed significant (p<0.05) decrease on lead exposure. However, administration of M. oleifera restored all the parameters back to control, tissue-specifically, and also showed improvement in restoration better than DMSA treatment, indicating reduction of the negative effects of lead-induced oxidative stress.

[Comparison of the targeting properties of 2-deoxy-D-glucose-conjugated nanoparticles to breast cancer MDA-MB-231 cells and breast fibroblasts cells].

OBJECTIVE: To compare the differences in uptake of 2-deoxy-D-glucose (2-DG)-conjugated nanoparticles between breast carcinoma MDA-MB-231 cells with high metabolism and breast fibroblasts with normal metabolism, and investigate the feasibility of using the coated nanoparticles as a MRI-targeted contrast agent for highly metabolic carcinoma cells. METHODS: The γ-Fe2O3@DMSA-DG was prepared. The glucose metabolism level of both cell lines was determined. The targeting efficacy of γ-Fe2O3@DMSA-DG and γ-Fe2O3@DMSA NPs to breast carcinoma MDA-MB-231 cells and breast fibroblasts at 10 min, 30 min, 1 h and 2 h was measured with Prussian blue staining and UV colorimetric assay. MRI was performed to visualize the changes of T2WI signal intensity. RESULTS: Prussian blue staining showed more intracellular blue granules in the MDA-MB-231 cells of γ-Fe2O3@DMSA-DG NPs group than that in the γ-Fe2O3@DMSA NPs group, and the γ-Fe2O3@DMSA-DG uptake was greatly competed by free D-glucose. As revealed by UV colorimetric assay, MDA-MB-231 cells also showed that the cellular iron amount of γ-Fe2O3@DMSA-DG group was significantly higher than that of the γ-Fe2O3@DMSA group and γ-Fe2O3@DMSA-DG + D-glucose group, statistically with a significant difference between them. MRI showed that the signal intensity of γ-Fe2O3@DMSA-DG group was decrease significantly, the T2 signal intensity was decreased by 10.5%, 37.5%, 72.9%, 92.0% for 10 min, 30 min, 1 h and 2 h, respectively. In contrast, the signal intensity did not show obvious decrease in the γ-Fe2O3@DMSA-DG group, the T2 signal intensity was decreased by 8.5%, 11.4%, 32.0%, 76.7% for 10 min, 30 min, 1 h and 2 h, respectively. However, HUM-CELL-0056 cells did not produce apparent difference for positive staining in the γ-Fe2O3@DMSA-DG group, γ-Fe2O3@DMSA group and γ-Fe2O3@DMSA-DG+D-glucose group, and the signal intensity also did not produce apparent difference. CONCLUSIONS: γ-Fe2O3@DMSA-DG has good targeting ability to highly metabolic breast carcinoma (MDA-MB-231) cells. It is feasible to serve as a specific MRI-targeted contrast agent for highly metabolic carcinoma cells, and deserves further studies in vivo.

Long term biotransformation and toxicity of dimercaptosuccinic acid-coated magnetic nanoparticles support their use in biomedical applications.

Although iron oxide magnetic nanoparticles (MNP) have been proposed for numerous biomedical applications, little is known about their biotransformation and long-term toxicity in the body. Dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles have been proven efficient for in vivo drug delivery, but these results must nonetheless be sustained by comprehensive studies of long-term distribution, degradation and toxicity. We studied DMSA-coated magnetic nanoparticle effects in vitro on NCTC 1469 non-parenchymal hepatocytes, and analyzed their biodistribution and biotransformation in vivo in C57BL/6 mice. Our results indicate that DMSA-coated magnetic nanoparticles have little effect on cell viability, oxidative stress, cell cycle or apoptosis on NCTC 1469 cells in vitro. In vivo distribution and transformation were studied by alternating current magnetic susceptibility measurements, a technique that permits distinction of MNP from other iron species. Our results show that DMSA-coated MNP accumulate in spleen, liver and lung tissues for extended periods of time, in which nanoparticles undergo a process of conversion from superparamagnetic iron oxide nanoparticles to other non-superparamagnetic iron forms, with no significant signs of toxicity. This work provides the first evidence of DMSA-coated magnetite nanoparticle biotransformation in vivo.

Comparison of chromatographic methods for quality control of DMSA complexes with 99mTc and 188Re at (III) and (V) oxidation states.

BACKGROUND: The reliable method for determination of identity and radiochemical purity (RCP) is of great importance in radiopharmaceutical development. This is especially relevant when more than one form of radiometal/ligand complex can be formed during radiolabelling, such as complexes of 99mTc or 188Re with meso-2,3-dimercaptosuccinic acid (DMSA), where depending on the pH, metal can occur either at +3 or +5 oxidation state. The aim of our study was to evaluate possibilities for optimization of chromatographic systems leading to specific and reliable analytical method for determination of the identity and RCP of DMSA complexes with 99mTc or 188Re. MATERIAL AND METHODS: The commercial DMSA kits (POLATOM) were used for preparation of technetium-99m (III) and (V) complexes with DMSA. 99mTc(V)-DMSA complexes were prepared by addition of NaHCO3 to the kit vial prior to 99mTc-eluate to obtain pH ~8. 188Re(V)-DMSA was prepared either directly or using intermediate 188Re(III)-EDTA complex added to DMSA. RCP was evaluated by TLC using: ITLC-SG developed in methylethylketon, SG60 coated plates developed in: n-BuOH/H2O/CH3COOH and n-PrOH/H2O/CH3COOH systems, and in H2O. Comparative biodistribution studies were performed in normal Wistar rats. RESULTS: Using silica gel plates and n-PrOH, H2O and acetic acid in the developing solution, we observed that 99mTc/188Re(III)-DMSA and 99mTc/188Re(V)-DMSA complexes could be well separated from each other and from the impurities in the form of free pertechnetate/perrhenate. In vivo studies showed quite different biodistribution of 99mTc(III)- and 99mTc(V)-DMSA. The trivalent complex accumulated mainly in kidneys (>40%ID), while 99mTc(V)-DMSA revealed high excretion with urine and relatively high concentration in osseous tissue (ca. 2 %ID/g). Accumulation of this complex in kidneys was very low (ca. 2.5 %ID). Biodistribution pattern of 188Re(V)-DMSA prepared directly was almost identical to that of 99mTc(V)-DMSA. Biodistribution results of the 188Re preparation obtained using 188Re(III)-EDTA intermediate indicated that the preparation contained the mixture of penta- and trivalent 188Re complexes. The quite high accumulation of radioactivity in kidneys (23 %ID) gave evidence of the presence of 188Re(III)-DMSA in this preparation, what was also confirmed by the results of TLC analysis performed using silica gel plate and n-propanol/water/acetic acid as developing system. CONCLUSIONS: Based on our study, we have made recommendation on the suitable methods for investigations of RCP of DMSA complexes, i.e.: SG60 plates developed in the mixture of n-propanol/water/acetic acid, which enable determination of the tri- and pentavalent DMSA complexes, as well as, the pertechnetate/perrhenate impurity, and developed in water for determination of the colloidal residue.

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.

Biodistribution and biocompatibility of DMSA-stabilized maghemite magnetic nanoparticles in nonhuman primates (Cebus spp.).

AIM: This work represents the first reported investigation on the effects of magnetic nanoparticles (MNPs) in nonhuman primates. Biodistribution, biocompatibility and nanotoxicity of maghemite nanoparticles stabilized with dimercaptosuccinic acid (DMSA) were accessed. MATERIALS & METHODS: A control animal was used and three other animals were intravenously injected with DMSA-MNPs and euthanized 12 h, 30 and 90 days following administration. Extracted organs were processed by histological techniques. An additional animal was used to collect blood samples to complementarily assess biocompatibility 12 h, 7, 15, 30, 60 and 90 days after DMSA-MNP injection. RESULTS: DMSA-MNPs were preferentially addressed to the lungs, liver and kidneys. Hematological and serum biochemical results corroborated histological findings, supporting DMSA-MNP biocompatibility while preserving both hepatic and renal normal activity. CONCLUSION: DMSA-MNPs were preferentially distributed to the lung, liver and kidneys. Furthermore, DMSA-MNPs were considered biocompatible, supporting their application as a promising nanomaterial platform for future biomedical use.

Intracellular and extracellular T1 and T2 relaxivities of magneto-optical nanoparticles at experimental high fields.

This study reports the T(1) and T(2) relaxation rates of rhodamine-labeled anionic magnetic nanoparticles determined at 7, 11.7, and 17.6 T both in solution and after cellular internalization. Therefore cells were incubated with rhodamine-labeled anionic magnetic nanoparticles and were prepared at decreasing concentrations. Additionally, rhodamine-labeled anionic magnetic nanoparticles in solution were used for extracellular measurements. T(1) and T(2) were determined at 7, 11.7, and 17.6 T. T(1) times were determined with an inversion-recovery snapshot-flash sequence. T(2) times were obtained from a multispin-echo sequence. Inductively coupled plasma-mass spectrometry was used to determine the iron content in all samples, and r(1) and r(2) were subsequently calculated. The results were then compared with cells labeled with AMI-25 and VSOP C-200. In solution, the r(1) and r(2) of rhodamine-labeled anionic magnetic nanoparticles were 4.78/379 (7 T), 3.28/389 (11.7 T), and 2.00/354 (17.6 T). In cells, the r(1) and r(2) were 0.21/56 (7 T), 0.19/37 (11.7 T), and 0.1/23 (17.6 T). This corresponded to an 11- to 23-fold decrease in r(1) and an 8- to 15-fold decrease in r(2) . A decrease in r(1) was observed for AMI-25 and VSOP C-200. AMI-25 and VSOP exhibited a 2- to 8-fold decrease in r(2) . In conclusion, cellular internalization of iron oxide nanoparticles strongly decreased their T(1) and T(2) potency.

Sorting out the spinning of autism: heavy metals and the question of incidence.

The reasons for the rise in autism prevalence are a subject of heated professional debate. Featuring a critical appraisal of some research used to question whether rising levels of autism are related to environmental exposure to toxins (Soden et al. 2007, Barbaresi et al. 2009, Thompson et al. 2007) we aim to evaluate the actual state of scientific knowledge. In addition, we surveyed the empirical research on the topic of autism and heavy metal toxins. In our opinion empirical investigations are finding support for a link with heavy metal toxins. The various causes that have led to the increase in autism diagnosis are likely multi-faceted, and understanding the causes is one of the most important health topics today. We argue that scientific research does not support rejecting the link between the neurodevelopmental disorder of autism and toxic exposures.

A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning.

INTRODUCTION: This article reviews the experimental and clinical studies that have compared the efficacy (impact on urine lead excretion, blood and tissue lead concentrations, resolution of features and survival) of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. It also summarizes the pharmacokinetic and pharmacodynamic aspects and the adverse effects of treatment. METHODS: Medline, Toxline, and Embase were searched for all available years to June 2009. PHARMACOKINETICS AND PHARMACODYNAMICS: The absorption of oral DMSA is more complete than sodium calcium edetate; the latter has to be administered parenterally. Both antidotes are distributed predominantly extracellularly. Sodium calcium edetate is not metabolized, whereas DMSA is extensively metabolized to mixed disulfides of cysteine. The two antidotes have elimination half-lives of less than 60 min. There is no evidence that either antidote crosses the blood-brain barrier to any major extent. Sodium calcium edetate chelates lead by displacement of the central Ca2+ ion with Pb2+. The nature of the DMSA-lead chelate is less clearly defined. There is evidence that the mixed disulfides of cysteine are the active chelating moiety in humans. If this is the case, this suggests that chelation occurs principally, if not exclusively, in the kidney. The primary source of lead mobilized by sodium calcium edetate is bone with an additional contribution from kidney and liver. EFFICACY: Comparison of the experimental studies is complicated by substantial variations in study design, particularly the antidote dose, the route and duration of treatment, the amount and duration of lead dosing, and lack of direct comparison between antidotes (comparison was usually made with control). In experimental studies that used equimolar and clinically relevant antidote doses and assessed the impact of DMSA and sodium calcium edetate on urine lead excretion and/or blood lead concentrations, similar results were found, though no direct comparison between antidotes was undertaken. DMSA was more effective than sodium calcium edetate in reducing the kidney lead concentration, sodium calcium edetate was more effective than DMSA in reducing bone lead concentrations, and there was no consistently observed effect of chelation therapy on brain lead concentrations in these experimental studies. Only two clinical studies have compared equimolar or similar antidote doses in enhancing urine lead excretion; there was no statistical difference between the antidotes, though both studies had limitations. DMSA and sodium calcium edetate had a comparable impact on lowering blood lead concentrations in a clinical study using similar molar antidote doses. ADVERSE EFFECTS: Sodium calcium edetate causes dose-related nephrotoxicity. Both agents deplete zinc and copper, the effect on zinc being significantly greater with sodium calcium edetate. A transient increase in hepatic transaminase activity has been reported with both antidotes but appears to be more common with DMSA and neither has been associated with clinically significant hepatic toxicity. Skin lesions during treatment with sodium calcium edetate are unusual and have been attributed to zinc deficiency. DMSA has occasionally been associated with a severe mucocutaneous reaction necessitating discontinuation of therapy. CONCLUSIONS: Oral DMSA and parenteral sodium calcium edetate are both effective chelators of lead. There are currently insufficient data, however, to conclude that either antidote is superior in enhancing lead excretion. Both antidotes resolve the symptoms of moderate and severe lead toxicity rapidly. Although there is greater clinical experience with sodium calcium edetate, particularly in the treatment of lead encephalopathy, oral DMSA may now be considered as an alternative in circumstances where oral therapy is preferable.

Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning.

INTRODUCTION: This article reviews data on the efficacy of succimer (dimercaptosuccinic acid, DMSA) in the treatment of human inorganic lead poisoning, the adverse effects associated with its use, and summarizes current understanding of the pharmacokinetic and pharmacodynamic aspects. METHODS: Medline, Toxline, and Embase were searched and 912 papers were identified and considered. PHARMACOKINETICS AND PHARMACODYNAMICS: DMSA is absorbed rapidly but incompletely after oral administration, probably through an active transporter. There is evidence that enterohepatic circulation occurs. Most DMSA in plasma is protein (mainly albumin)-bound through a disulfide bond with cysteine; only a very small amount is present as free drug, which is filtered at the glomerulus then extensively reabsorbed into proximal tubule cells. Nonfiltered protein-bound DMSA in peritubular capillaries is also available for uptake into proximal tubule cells by active anion transport at the basolateral membrane. DMSA therefore accumulates in the kidney where it is extensively metabolized in humans to mixed disulfides of cysteine. Some 10-25% of an orally administered dose of DMSA is excreted in urine, the majority within 24 h and most (>90%) as DMSA-cysteine disulfide conjugates. It is not known whether protein-bound DMSA can chelate lead; there is evidence that the mixed disulfides of cysteine are the active chelating moiety in humans. If this is the case, this suggests that chelation occurs principally, if not exclusively, in the kidney. DOSE: DMSA 30 mg/kg/day is more effective than either 10 or 20 mg/kg/day in enhancing urine lead excretion. DURATION OF THERAPY: Initial clinical studies with DMSA involved the administration of a 5-day course of treatment. Subsequently, a 19- to 26-day regimen was introduced with the intent of preventing or at least blunting a rebound in the blood lead concentration. Studies suggest, however, that repeated courses of DMSA 30 mg/kg/day for at least 5 days are equally efficacious if a treatment-free period of at least 1 week between courses is included to allow redistribution of lead from bone to soft tissues and blood. There is also evidence that in more severely poisoned patients DMSA 30 mg/kg/day can be given for more than 5 days with benefit. EFFICACY: DMSA 30 mg/kg/day significantly increases urine lead elimination and significantly reduces blood lead concentrations in lead-poisoned patients, though there is substantial individual variation in response. Over a 5-day course, mean daily urine lead excretion exceeds baseline by between 5- and 20-fold and blood lead concentrations fall to 50% or less of the pretreatment concentration, with wide variation. Maximum enhancement of urine lead elimination typically occurs with the first dose. Most symptomatic patients report improvement after 2 days of treatment. However, DMSA did not improve cognition in children < 3 years old with mild lead poisoning, presumably because lead-induced neurological damage occurred during development in utero and/or early infancy. DMSA IN PREGNANCY AND IN THE NEONATE: DMSA is not teratogenic but did produce maternal toxicity (decreased weight gain) and fetotoxicity when given in high dose (100-1,000 mg/kg/day) in experimental studies. For this reason sodium calcium edetate is generally preferred in pregnancy. ADVERSE EFFECTS: A transient modest rise in transaminase activity during chelation occurs in up to 60% of patients but has not resulted in clinically significant sequelae. Skin reactions occur in approximately 6% of treated patients and are occasionally severe. DMSA also increases urine copper and zinc excretion but not to a clinically important extent. CONCLUSIONS: DMSA is an effective lead chelator that primarily chelates renal lead. It is generally well tolerated but may occasionally cause clinically important adverse effects. DMSA may now be considered as an alternative to sodium calcium edetate, particularly when an oral antidote is preferable.

The effect of arsenic exposure and the efficacy of DMSA on the proteins and lipids of the gill tissues of Labeo rohita.

Arsenic is a naturally occurring, highly toxic environmental pollutant. Fourier transform infrared (FT-IR) spectroscopy is a non-disturbing technique which provides quantitative information about the molecular composition of biological samples. The aim of this work is to study the compositional and structural changes at the molecular level occurring in gill tissues of Labeo rohita fingerlings due to arsenic exposure for various exposure periods by using FT-IR spectroscopic technique. The results of the present study suggest that arsenic exposure causes significant changes on the major biochemical constituents such as proteins, lipids and nucleic acids in the gill tissues of L. rohita. The changes are more pronounced as the period of exposure is increased. The significant decrease in the intensity and area of the amide I peak and CH(3) asymmetric stretching band suggests an alteration in the protein profile and lipid levels respectively, due to arsenic exposure. The amide A peak shifts suggests a change in the level of protein amide hydrogen bonding due to arsenic exposure. Further, the treatment with meso-2,3-dimercaptosuccinic acid (DMSA) improves the levels of biochemical constituents significantly, which suggest that DMSA treatment reduces the toxic effects and helps the recovery of gill tissues and its return to the level of the control.

A comparative study of 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA: preparation and in vivo evaluation in nude mice xenografted with a neuroendocrine tumor.

UNLABELLED: Dimercaptosuccinic acid (DMSA) exists in meso and racemic (rac) forms. Unlike a meso isomer, rac-2,3-DMSA is very soluble in water, strongly acidic solutions and organic solvents. Despite these differences, rac-2,3-DMSA has not been studied as a radiopharmaceutical. In this study, (188)Re complexes with diastereomeric DMSA were prepared to compare the properties of 188Re(V)-rac-DMSA with those of 188Re(V)-meso-DMSA in in vitro and in vivo models. METHODS: rac-2,3-DMSA was synthesized and radiolabeled with 188Re. The biodistribution and gamma camera imaging of 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA were performed in nude mice subcutaneously implanted with PC-12 cell lines. RESULTS AND CONCLUSIONS: Both 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA showed excellent radiochemical purity and stability at room temperature. Compared with 188Re(V)-meso-DMSA, 188Re(V)-rac-DMSA needed a higher concentration of rac-DMSA and metabisulfite for maximum yields. 188Re(V)-meso-DMSA showed high labeling efficiency at pH 2, whereas 188Re(V)-rac-DMSA showed maximum yields at pH 5. The tumor uptake of 188Re(V)-rac-DMSA was 3.5 times higher than that of 188Re(V)-meso-DMSA at 1 h (P<.01). Gamma camera images showed that 188Re(V)-rac-DMSA was more selectively localized than 188Re(V)-meso-DMSA at the tumor region in a xenograft model. These results demonstrate that 188Re(V)-rac-DMSA may have better potential than 188Re(V)-meso-DMSA as a therapeutic agent against neuroendocrine tumors.

The changes in renal function after a single dose of intravenous furosemide in patients with compensated liver cirrhosis.

BACKGROUND: Patients with compensated Child-A cirrhosis have sub clinical hypovolemia and diuretic treatment could result in renal impairment. AIM: To evaluate the changes in renal functional mass as reflected by DMSA uptake after single injection of intravenous furosemide in patients with compensated liver cirrhosis. METHODS: Eighteen cirrhotic patients were divided in two groups; eight patients (group 1, age 56 +/- 9.6 yrs, Gender 5M/3F, 3 alcoholic and 5 non alcoholic) were given low intravenous 40 mg furosemide and ten other patients (group 2, age 54 +/- 9.9, Gender 6M/4F, 4 alcoholic and 6 non alcoholic) were given high 120 mg furosemide respectively. Renoscintigraphy with 100MBq Of Tc 99 DMSA was given intravenously before and 90 minutes after furosemide administration and SPECT imaging was determined 3 hours later. All patients were kept under low sodium diet (80mEq/d) and all diuretics were withdrawn for 3 days. 8-hours UNa exertion, Calculated and measured Creatinine clearance (CCT) were performed for all patients. RESULTS: Intravenous furosemide increased the mean renal DMSA uptake in 55% of patients with compensated cirrhosis and these changes persist up to three hours after injection. This increase was at the same extent in either low or high doses of furosemide. (From 12.8% +/- 3.8 to 15.2% +/- 2.2, p < 0.001 in Gr I as compared to 10.6% +/- 4.6 to 13.5% +/- 3.6 in Gr 2, p < 0.001). In 8 patients (45%, 3 pts from Gr 1 and 5 pts from Gr 2) DMSA uptake remain unchanged. The mean 8 hrs UNa excretion after intravenous furosemide was above 80 meq/l and was higher in Gr 2 as compared to Gr 1 respectively (136 +/- 37 meq/l) VS 100 +/- 36.6 meq/l, P = 0.05). Finally, basal global renal DMSA uptake was decreased in 80% of patients; 22.5 +/- 7.5% (NL > 40%), as compared to normal calculated creatinine clearance (CCT 101 +/- 26), and measured CCT of 87 +/- 30 cc/min (P < 0.001). CONCLUSION: A single furosemide injection increases renal functional mass as reflected by DMSA in 55% of patients with compensated cirrhosis and identify 45% of patients with reduced uptake and who could develop renal impairment under diuretics. Whether or not albumin infusion exerts beneficial effect in those patients with reduced DMSA uptake remains to be determined.

Preparation and biological characterization of isomeric 188Re(V) oxocomplexes with tetradentate S4 ligands derived from meso-dimercaptosuccinic acid for labeling of biomolecules.

A new type of tetradentate S4 ligand has been synthesized by bridging two molecules of meso-2,3-dimercaptosuccinic acid for stable binding and easy conjugation of rhenium-188 to tumor targeting structures. The stereoisomeric tetrathiolato S4 ligands form very robust anionic five-coordinated oxorhenium(V) and oxotechnetium(V) complexes. Two routes for the preparation of the (188)Re(V) oxocomplexes with (iBu)2N(O)C-C(SH)C(SH)C(O)NH(CH2)3NH(CH2)3NHC(O)C(SH)C(SH)C(O)N(iBu)2 (ligand 1) and its hydrophilic crown ether derivative (ligand 2) were tested and optimized. Several isomers were separated by HPLC from the preparation solutions and characterized in vitro and in vivo. The identity of the species obtained was determined by comparison with the HPLC profiles of reference (185/187)Re analogues and (99/99m)Tc complexes which were characterized by ESI-MS. All of them were absolutely stable in rat and human plasma solutions. Challenge experiments with cysteine corroborated the high inertness of the isomers toward ligand exchange reactions. Various in vivo samples, taken off at different times from blood, intestine, and urine of rats, confirmed the high in vivo stability of the (188)Re-S4 complexes. Biodistribution studies using male Wistar rats were performed and exhibited a high uptake and fast clearance from the liver of the more lipophilic cis and trans isomers of complex I (log P(o/w) between 1.5 and 1.7), whereas the isomers of the hydrophilic complex II (log P(o/w) about -1.75) were rapidly excreted via the renal and the hepatobiliary pathway. The low level of activity in the stomach confirms good in vivo stability. Thus, these new (188)Re-S4 complexes fulfill the requirements for a stable and high specific activity labeling of biomolecules with rhenium-188.

[Relative renal function based on DMSA uptake corrected for volume: normalized relative renal function]. / Función renal relativa basada en captación de ácido dimercaptosuccínico corregida por volumen: función renal relativa normalizada.

OBJECTIVE: Relative renal function (RRF) quantification based on dimercaptosuccinic acid (DMSA) uptake is an established method for determining differential renal function. An abnormal kidney size may lead to an alteration in its RRF value, although it has no dysfunction. Therefore, it is useful to correct RRF values taking into account relative renal volumes, thus obtaining the normalized relative renal function (NRRF). The feasibility of the method used for volume correction, differences with respect to usual quantification and different normality intervals were studied. MATERIAL AND METHODS: A total of 187 DMSA renal scintigraphies (130 children and 57 adults) were studied. RRF was quantified and volume corrected to obtain NRRF. Patients were classified as normal or pathological using various normality intervals for NRRF. A second classification was performed depending on how the diagnostic changed after volume correction. RESULTS: An increase of pathological diagnosis was observed after volume correction, mainly in children. Using an intermediate estimation for the normality interval, 53% of the initially pathological diagnosis for children may be caused simply by different renal volumes. CONCLUSIONS: NRRF provides complementary information to RRF and helps to distinguish between a smaller kidney and a really hypofunctioning one in cases with abnormal RRF.

Función renal relativa basada en captación de ácido dimercaptosuccínico corregida por volumen: función renal relativa normalizada / Relative renal function based on DMSA uptake corrected for volume: normalized relative renalfunction

Objetivo. La cuantificación de la función renal relativa (FRR) basada en la incorporación de ácido dimercaptosuccínico (DMSA) es un método establecido para la determinación del nivel de funcionamiento renal. Un tamaño anormal del riñón puede producir una alteración en el valor de su FRR, aunque no tenga disfunción alguna. Por tanto, resulta de utilidad corregir por volumen renal relativo los valores de la FRR, obteniendo así la función renal relativa normalizada (FRRN). En este trabajo se estudiará la viabilidad del método utilizado para la corrección por volumen, las diferencias respecto a la cuantificación habitual, y la influencia del margen de normalidad a aplicar. Material y métodos. Se estudiaron las gammagrafías renales con 99mTc-DMSA de 187 pacientes, 130 infantiles y 57 adultos. Se cuantificó la FRR y se corrigió por volumen para evaluar la FRRN. Se clasificaron los pacientes en normales o patológicos estableciendo varios márgenes de normalidad para la FRRN. Se realizó una segunda clasificación de los casos según cómo cambió su valoración al corregir por volumen. Resultados. Se observó un aumento de los diagnósticos patológicos al corregir por volumen, sobre todo en niños. Para el margen de normalidad aceptado se observó que del total de casos infantiles diagnosticados como patológicos inicialmente, el 53 % puede ser debido simplemente a una diferencia de volumen renal. Conclusiones. La FRRN proporciona una información complementaria a la FRR y ayuda a distinguir entre un riñón de menor tamaño y uno realmente hipocaptante en el caso de que la FRR resulte fuera de la normalidad

Objective. Relative renal function (RRF) quantification based on dimercaptosuccinic acid (DMSA) uptake is an established method for determining differential renal function. An abnormal kidney size may lead to an alteration in its RRF value, although it has no dysfunction. Therefore, it is useful to correct RRF values taking into account relative renal volumes, thus obtaining the normalized relative renal function (NRRF). The feasibility of the method used for volume correction, differences with respect to usual quantification and different normality intervals were studied. Material and methods. A total of 187 DMSA renal scintigraphies (130 children and 57 adults) were studied. RRF was quantified and volume corrected to obtain NRRF. Patients were classified as normal or pathological using various normality intervals for NRRF. A second classification was performed depending on how the diagnostic changed after volume correction. Results. An increase of pathological diagnosis was observed after volume correction, mainly in children. Using an intermediate estimation for the normality interval, 53 % of the initially pathological diagnosis for children may be caused simply by different renal volumes. Conclusions. NRRF provides complementary information to RRF and helps to distinguish between a smaller kidney and a really hypofunctioning one in cases with abnormal RRF