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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.

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.

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.

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 β-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 β-thalassemia major due to tubular disorders.

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.

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., (© 2013.)

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.

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 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., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

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.

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., (Copyright © 2010 Wiley-Liss, Inc.)

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.

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.

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.

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.

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.

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.

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.

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.

Background: The lead mobilization test reflects the mobilizable and likely toxicologically active fraction of the lead body burden. We propose a safe and convenient protocol for this test, to assess concomitant copper and zinc excretion and to determine the size of the chelatable lead pool in nonoccupationally exposed adults., Methods: The study population included 80 white adults: 40 controls [median blood lead concentration (PbB), 25 microg/L] and 40 lead-exposed individuals (315 microg/L). After collection of 4- and 24-h baseline urine specimens and a blood sample, dimercaptosuccinic acid (DMSA) was administered orally (1 g), and additional 4- and 24-h urine specimens were obtained. Determinants of the chelatable urinary lead (DMSA-PbU) were traced by linear regression analysis., Results: Urinary DMSA and lead excretion peaked within 2-3 h after DMSA administration. The amounts of DMSA, lead, copper, and zinc recovered in the 4-h urinary collections were highly correlated with those in 24-h collections (r = 0.857, 0.859, 0.958, and 0.757, respectively). At PbB concentrations >300 microg/L, the relationship between DMSA-PbU and PbB showed a steep increase and a widespread dispersion of DMSA-PbU around the regression line. After DMSA, copper and zinc excretion rates were increased up to 91- and 33-fold, respectively. No side effects were reported after DMSA., Conclusions: Determination of DMSA-PbU in a 4-h collection after DMSA is convenient, apparently safe, and inexpensive. An upper reference limit value of 22 microg/4 h is proposed for Belgian reference individuals. The diagnostic value of DMSA-PbU is likely to be contributive for PbB >300 microg/L.

Purpose: The objective of this study was to compare the uptake changes of Tc-99m 2-methoxy isobutyl isonitrile (MIBI) and Tc-99m pentavalent dimercaptosuccinic acid (V-DMSA) in multiple myeloma (MM) lesions in response to high-dose chemotherapy (HDC)., Materials and Methods: The authors compared Tc-99m MIBI and Tc-99m V-DMSA scans before and after HDC in a patient with focal MM lesions without amyloidosis who had received previous standard chemotherapy as well., Results: HDC had the effect of eliminating all Tc-99m MIBI uptake in the lesions. Tc-99m V-DMSA uptake was increased in lesions presenting significant initial Tc-99m MIBI uptake. In 1 particular lesion that demonstrated this phenomenon, magnetic resonance showed necrosis of the area of MM., Conclusion: The authors consider that the effect of increasing Tc-99m V-DMSA uptake in the absence of an increase in viable plasma cells possibly reflects the treatment-generated inflammatory and fibrotic changes and not necessarily viable tumor tissue. Exclusive focal Tc-99m V-DMSA uptake in this clinical setting could be considered as a sign of effectively treated lesions and not a sign of deterioration.

The active transport of Krebs cycle intermediates, such as succinate, alpha-ketoglutarate, and citrate, is mediated by sodium-coupled transporters found in the luminal (NaDC-1) and basolateral plasma membranes (NaDC-3) of proximal tubule cells. This study used the two-electrode voltage clamp technique to examine steady-state currents associated with the influx of three sodium ions and one divalent dicarboxylate into oocytes expressing the sodium-dicarboxylate transporter from winter flounder kidney, fNaDC-3. The substrate concentration, where half-maximal current was observed (K(0.5)), was 30 micro M for succinate. Besides 2,2-dimethylsuccinate, fNaDC-3 also accepted 2,3-dimethylsuccinate and the oral lead-chelating agent, meso-2,3-dimercaptosuccinate (DMSA or Succimer). Whereas the K(0.5) for succinate and 2,2-dimethylsuccinate was independent of membrane voltage within -90 and -10 mV, K(0.5) for 2,3-dimethylsuccinate and 2,3-dimercaptosuccinate increased with decreasing voltage, indicating a critical role of the position of the methyl- or sulfhydryl-group in voltage-sensitive affinity. In addition to meso-2,3-dimercaptosuccinate, fNaDC-3 translocated dimercaptopropane-1-sulfonate (DMPS or Dimaval), an oral chelator for the treatment of mercury intoxication. The chelates formed by HgCl(2) and DMSA or DMPS and by Pb(NO(3))(2) and DMSA, however, were not translocated by fNaDC-3. The data suggest that NaDC-3 is an essential component in the delivery of uncomplexed antidotes for renal heavy metal detoxification.

The uptake of the rhenium-188 (188Re(V)-DMSA) complex of dimercaptosuccinic acid by cervical carcinoma cells in nude mice was evaluated. The pharmacokinetics and dosimetry calculations in normal rats were also evaluated. The images obtained in mice did not show significant accumulation in metabolic organs and the biodistribution studies showed that 3.52 +/- 0.76% of the injected activity per gram (n = 4) was taken up by the tumor. This percentage produces a cumulated activity of 35.63 +/- 8.40 MBq h and an equivalent dose per injected activity of 260 +/- 8.91 mSv/MBq. Pharmacokinetics and dosimetry of the 1887e(V)-DMSA complex indicate that this radiopharmaceutical could be evaluated in patients with soft tissue tumors, since the risk of radiation damage to the kidney or red bone marrow could not be an obstacle for its application in therapeutic nuclear medicine.

Rhenium-188 dimercaptosuccinic acid complex [188Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent 99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if 99mTc(V)DMSA could be used to predict tumour and kidney retention of 188Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of 99mTc(V)DMSA and 188Re(V)DMSA. This would determine whether a scan with 99mTc(V) DMSA could be used to identify patients for whom 188Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in 188Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent 99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq 99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq 188Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the 188Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on 188Re scans than on 99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for 188Re than for 99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between 99mTc and 188Re scans, and kidney-to-background ratios on 188Re scans were not higher than on 99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus 99mTc(V)DMSA scans are predictive of 188Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for 188Re(V)DMSA treatment.

Radiolabeling with rhenium (Re-186, Re-188), a tumor agent to resemble the pentavalent polynuclear technetium complex of dimercaptosuccinic acid (99mTc[V]-DMS) has been reported for radiotherapeutical use. Nevertheless, despite the periodic analogies between both radiometals, differences in the redox potential and the carrier concentration have made the radiolabeling of the rhenium counterpart difficult. In the present study, the effect of the carrier contained in the reactor-produced Re-186 was estimated as an important factor relevant to the Re-186 radiolabeling of DMS at an alkaline pH. Great effect of the carrier Re with an inverse correlation with the stannous ion was an interesting phenomenon relevant for an assumption on the Sn participation in the complex. Under strict control of various labeling parameters, the 186Re(V)-DMS was made available with high yield (93-97%) at an alkaline pH and at room temperature. The great effect of carrier offers support to the polymeric or polynuclear nature of the rhenium complex of DMS as depicted in the drug design basis of its parent Tc(V)-DMS. The biodistribution studies of Re(V)-DMS showed mimetic characteristics with its parent Tc(V)-DMS drug.

99mTc(V)-DMSA is widely used for imaging medullary carcinoma and hence 186/188Re(V)-DMSA is suggested as a potential agent for treating medullary carcinoma. In the present paper, we report the work carried out for the preparation of [186Re]Re(V)-DMSA and it's bio-distribution studies in Wistar rats. The complex was prepared by reducing 186Re (100 micrograms, 0.54 microM, approximately 150 MBq) in the presence of DMSA (2 mg, 11 microM) with stannous chloride (0.4 mg, 2.2 microM) in acidic medium at pH 2. The reaction was taken to completion by heating the complex in a boiling water bath for 30 min. Bio-distribution studies carried out revealed that pharmacological behaviour of 186Re(V)-DMSA is similar to that of 99mTc(V)-DMSA except that the kidney uptake is marginally higher. The kidney uptake reduced significantly when the pH of the complex was adjusted to 8 prior to injection. The in vitro stability studies of this complex suggest that the product formed is stable and could be used for clinical trials.

Seven analogues of the bacterial osmoprotectant glycine betaine (GB, trimethylammonioacetate), in which the methyl groups of the Me3N+ moiety are replaced by various substituents, were obtained by SPOS using Wang resin. Their biological activities (osmoprotection vs toxicity), appeared closely related to their uptake efficiency and their catabolism in the betaine-demethylating model bacterium Sinorhizobium meliloti.

A variety of software is used to determine quantitative parameters from radionuclide imaging procedures. Knowledge of the variability of parameter values found in different hospitals is an important aspect of clinical audit of these techniques. This study investigated the variation in relative renal function measurement from static DMSA scintigraphy in the UK. Ten studies representing a range of ages and relative function values were distributed in digital form to 100 hospitals with the assistance of the gamma camera computer suppliers and regional audit coordinators. The studies were analysed at each participating hospital and details of the different techniques and computer systems used were documented. The median value of relative percentage function was assessed for each of the studies. Methods varied in terms of the view used for analysis (54% geometric mean, 46% posterior), the type of background subtraction (single region 32%, separate regions 60%, none 8%) and the definition of the renal regions of interest (73% manual, 27% semi-automatic). Eighty-eight percent of results were within two percentage points of the study median and 98% within five percentage points. There were statistically significant differences observed in the results arising from the view used for the analysis and the background subtraction protocol. The results indicate that relative renal function assessment from static DMSA scintigraphy in the UK is essentially a reliable procedure, although improvements could be made by standardizing the technique used.

Pentavalent rhenium-188 dimercaptosuccinic acid [188Re(V)DMSA] is a beta-emitting analogue of 99mTc(V)DMSA, a tracer that is taken up in a variety of tumours and bone metastases. The aim of this study was to develop the kit-based synthesis of the agent on a therapeutic scale, to assess its stability in vivo, and to obtain preliminary biodistribution and dosimetry estimates, prior to evaluation of its potential as a targeted radiotherapy agent. The organ distribution of 188Re in mice was determined 2 h after injection of 3 MBq 188Re(V)DMSA prepared from eluate from a 188W/188Re generator. Three patients with cancer of the prostate and three with cancer of the bronchus, all with bone metastases confirmed with a standard 99mTc-hydroxymethylene diphosphonate (99mTc-HDP) scan, were given 370 MBq 188Re(V)DMSA and imaged at 3 h and 24 h using the 155-keV gamma-photon (15%). Blood and urine samples were collected to determine clearance and to analyse the speciation of 188Re. Organ residence times were estimated from the scans, and used to estimate radiation doses using MIRDOSE 3. In mice, 188Re(V)DMSA was selective for bone and kidney. In patients, it showed selectivity for bone metastases (particularly those from prostate carcinoma) and kidney, but uptake in normal bone was not significantly greater than in surrounding soft tissues. Of the normal tissues the kidneys received the highest radiation dose (0.5-1.3 mGy/MBq). The images were strongly reminiscent of 99mTc(V)DMSA scans in similar patients. High-performance liquid chromatography analysis of blood and urine showed no evidence of 188Re in any chemical form other than 188Re(V)DMSA up to 24 h. In conclusion, 188Re(V)DMSA and its 186Re analogue warrant further clinical assessment as generator/kit-derived agents for treatment of painful bone metastases. These agents should also be assessed in medullary thyroid carcinoma and other soft tissue tumours which have been shown to accumulate 99mTc(V)DMSA.

Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.

Purpose: Serum soluble interleukin-2 receptor level is a sensitive and quantitative marker of lymphocyte activation. We determined levels of serum soluble interleukin-2 receptor in children with reflux nephropathy to evaluate its clinical significance in the prediction for the progression of renal injuries., Materials and Methods: Serum soluble interleukin-2 receptor values were determined in 63 children with reflux nephropathy. The group consisted of 37 boys and 26 girls 10 to 18 years old. T cells (naive and memory), B cells and macrophages were evaluated immunohistochemically in the scarred kidneys of 4 other patients (3 boys and 1 girl 5 to 16 years old) who underwent nephrectomy due to severe reflux nephropathy with little function seen on (99m)technetium-dimercapto-succinic acid (DMSA) renal scan. Levels of serum soluble interleukin-2 receptor were measured by an enzyme-linked immunosorbent assay. We simultaneously determined serum levels of creatinine and beta2-microglobulin, and urinary levels of alpha1-microglobulin and microalbumin. Individual functions of the right and left kidneys were estimated by renal dimercaptosuccinic acid uptake., Results: Levels of serum soluble interleukin-2 receptor in the patients who had low total uptake of DMSA (right uptake plus left uptake) were significantly higher than those from patients with normal total uptake. Levels of serum soluble interleukin-2 receptor correlated significantly with levels of creatinine (r=0.616, p <0.0001) and beta2-microglobulin (r=0.803, p <0.0001), and levels of urinary alpha1-microglobulin (r=0.753, p <0.0001) and microalbumin (r=0.673, p <0.0001). A significant negative correlation was observed between levels of serum soluble interleukin-2 receptor and total DMSA uptake values (right uptake plus left uptake r=-0.678, p <0.0001). In the scarred kidneys leukocyte infiltrates were markedly increased in fibrosed spaces. The predominant cell type in these lesions was memory T cells., Conclusions: These results suggest that elevated levels of serum soluble interleukin-2 receptor are likely to reflect activated T cells in the kidneys of patients with reflux nephropathy and may be a useful predictor of progression of renal injury in these children.

Methods of preparation and biodistribution in mice of tin-free 99Tcm(V)-DMSA and 188Re(V)-DMSA, a potential matching pair of radiopharmaceuticals for diagnosis and therapy of certain cancers, are described. Preparation of tin-free 188Re(V)-DMSA (I) is based on reduction with either SO2-releasing compounds like Na2S2O4 (30 mg Na2S2O4, 10 mg DMSA, 1 mg L-ascorbic acid, 37 degrees C, 60 min incubation), Na2S2O5 (as before, 70 degrees C, 15 min incubation), or HBr (0.2 ml 48% HBr, 0.2 ml 7 M HCl, 10 mg DMSA, 1 mg L-ascorbic acid, 70 degrees C, 60 min incubation). I exhibits significantly lower kidney uptake than tin-containing 188Re(V)-DMSA (II) (2-3% and 49% injected dose per gram organ, 1 h post-injection, respectively). HPLC profiles of I and II are similar. DMSA excess in tin-free 188Re(V)-DMSA is not responsible for the low kidney uptake of I. High kidney uptake of II is explained by formation of a mixed 188Re(V)-Sn-DMSA complex in vivo. Age-linked bone uptake in mice dependent on the maturation of the bone is demonstrated for both I and II.

Purpose: The accumulation of radioactivity in the dilated collecting system potentially influences the calculation of differential renal function on the radionuclide test. We focused on this reservoir effect in unilateral hydronephrosis and assessed the reliability of calculating differential renal function by dimercapto-succinic acid (DMSA) uptake 2 hours after injection., Materials and Methods: Unilateral partial ureteral obstruction was created in 8-week-old rats. Four weeks after surgery the animals were sacrificed 2 and 24 hours after the injection of tracer. The DMSA uptake rates of the renal parenchyma and collecting system were measured separately by autowell gamma counter. Differential function was calculated according to renal parenchymal and whole kidney (parenchyma and collecting system) uptake., Results: There was a higher accumulation of DMSA in the dilated renal pelvis at 2 than at 24 hours. However, DMSA uptake in the collecting system was extremely small in comparison to that in the parenchyma. As a result; differential renal function calculated using parenchymal uptake was similar to that calculated using whole kidney uptake measured 2 and 24 hours after injection., Conclusions: Our data suggest that the pure reservoir effect of DMSA uptake at early measurement is much smaller than reported in previous experimental animal studies. Further clinical studies are needed to reexamine this reservoir effect in children with unilateral hydronephrosis.

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

Previous studies have suggested that more defects are detected on SPET than on planar DMSA images. The aim of this study was to evaluate differences between planar and SPET imaging. Sixty-four kidneys from pyelonephritic patients were studied using both techniques. An automated algorithm for reorientation and centring of the SPET images was used to minimize inter-observer variability. Reduced uptake and contour defects showed different localization on planar and SPET imaging. Coincidence of defects on both types of image was low. We also noted a dependence on defect frequency content for detectability. Image contrast played a noticeable role in the detection of defects. Differences in contrast between SPET and planar images may be responsible for the variable success in the detection of defects. Contour defects are seen more frequently on tomographic slices, whereas reduced uptake defects are seen more frequently on planar images. A difference is also noted between the cortical and calyceal zones for differently contrasted lesions. SPET and planar DMSA images can potentially provide a different diagnosis of renal lesions.

Significant uptake and retention of 99Tc(m)-dextran (molecular weight: 81,000) in renal parenchyma was discovered during evaluation of its intravascular use. Renal SPET images confirmed this. This study was designed to evaluate 99Tc(m)-dextran as a renal cortex imaging agent. Stability of parenchymal retention was shown by insignificant outflow at 24 h and by frusemide intervention. Evaluation of the renal parameters of intravenous 99Tc(m)-dextran (n = 71 normal kidneys) and its comparison with 99Tc(m)-DTPA n = 10) and 99Tc(m)-DMSA(III) (n = 23) was undertaken. The early glomerular extraction phase of the renograms of 99Tc(m)-DTPA and 99Tc(m)-dextran appeared identical; parenchymal uptake of 99Tc(m)-dextran continued to increase and reached a near-plateau by 40-60 min. The mean cortex-to-background and cortex-to-liver ratios at 2 h with 99Tc(m)-dextran and 99Tc(m)-DMSA(III) were 14.9 and 9.2, and 16.0 and 8.9, respectively. The target-to-nontarget ratios were similar despite different absolute renal uptake values (12 vs 20% at 2 h) because of faster background clearance of 99Tc(m)-dextran. The mechanism of parenchymal retention of 99Tc(m)-dextran appears to be trapping at the endothelial-epithelial interphase of the glomerulus. Our initial experience suggests 99Tc(m)-dextran is a viable renal parenchyma imaging agent.

Purpose: We determined urinary levels of epidermal growth factor in children with reflux nephropathy to evaluate the clinical significance of urinary epidermal growth factor., Materials and Methods: We studied 59 boys and 41 girls 3 to 15 years old with reflux nephropathy, and 64 boys and 36 girls 3 to 15 years old who were healthy. Levels of urinary epidermal growth factor were determined by sandwich enzyme immunoassay using spot urine samples. We also determined the levels of serum creatinine, urinary alpha 1-microglobulin and urinary microalbumin. Absolute values of function of the left and right kidneys were assessed by 99mtechnetium dimercapto-succinic acid (DMSA) uptake., Results: Levels of urinary epidermal growth factor gradually decreased with age in healthy children. There were low levels of urinary epidermal growth factor in 20 of the 44 patients (45%) with unilateral low DMSA uptake and 18 of the 19 (95%) with low total DMSA uptake (right and left uptakes). Urinary epidermal growth factor significantly correlated with serum creatinine (R = -0.702, p < 0.0001), urinary alpha 1-microglobulin (R = -0.606, p < 0.0001), urinary microalbumin (R = -0.708, p < 0.0001) and total DMSA uptake (R = 0.744, p < 0.0001)., Conclusions: These results suggest that urinary epidermal growth factor may be a useful clinical tool to monitor functional nephron mass in children with reflux nephropathy.

Objective: To develop criteria identifying swollen kidneys on dimercaptosuccinic acid (DMSA) renal scintigraphy in acute pyelonephritis with regard to the DMSA distribution pattern, kidney functional size, and radioactive uptake., Subjects and Methods: Thirty-eight children aged 15 days to 7 years with known pyelonephritis were examined with DMSA renal scintigraphy. All children were observed 2 or 3 times. In total, 94 scintigrams were evaluated. Qualitative and quantitative criteria for swelling were defined., Results: Thirty-one observed kidneys satisfied the criteria of swelling. Quantitatively, kidney length and width/length were greater in swollen kidneys. Kidney uptake in percent of injected dose and kidney uptake/background were lower in swollen kidneys. Qualitatively, focal radioactive uptake defects known from a previous examination were sometimes obscured by swelling, and reappeared at follow-up. In 5 children with signs of swelling on repeat imaging, scintigraphy reinfection at the time of swelling was verified., Conclusions: Swollen kidneys may be the only sign of acute pyelonephritis on DMSA scintigraphy and swelling may obscure focal radioactive uptake defects. Measurement of kidney size and radioactive uptake can help identify swollen kidneys at DMSA scintigraphy and disclose acute pyelonephritis in the absence of overt clinical symptoms.

Purpose: We detected renal parenchymal damage after nephrolithotomy., Materials and Methods: We studied 12 patients with renal stones treated with nephrolithotomy. Renal function was determined with serum blood urea nitrogen (BUN) and creatinine values, and 99mtechnetium dimercapto-succinic acid scintigraphy of renal parenchymal tissue was performed before, and 7 days and 3 months after nephrolithotomy. Qualitative and quantitative analyses were done with the Wilcoxon signed rank test., Results: There was no visual difference in size and appearance of the nephrotomy site between preoperative and postoperative visual scintigraphic evaluations. Quantitative data did not reveal any significant difference between kidneys with and without a nephrotomy incision (p > 0.05), as well as between nephrotomy regions and intact parenchyma within the same kidney (p > 0.05) 3 months after nephrolithotomy. There was no significant difference in serum BUN and creatinine levels between values preoperatively and 3 months postoperatively (p > 0.05)., Conclusions: There was no significant change in renal cortical function and functioning renal parenchymal mass after nephrolithotomy as shown by serum BUN and creatinine levels, and 99mtechnetium dimercapto-succinic acid scintigraphy.

Background: Rhabdomyosarcoma is a common soft tissue sarcoma of childhood. While Ga is currently the most accurate modality for imaging residual or recurrent tumour its dosimetry is unfavourable. Pentavalent 99mTc DMSA [99mTc (V) DMSA] has been shown to accumulate in this tumour in a limited number of clinical cases., Methods: Biodistribution of 99mTc (V) DMSA was determined in non-tumour bearing BALB-C mice. Operative specimens from four clinically 67Ga avid tumours were xenografted into nude mice and allowed to reach a significant size. Biodistribution studies were performed after the injection of 99mTc (V) DMSA in all animals and 125I HSA and 67Ga in a limited number of animals., Results: None of the tumours investigated demonstrated significant 99mTc (V) DMSA accumulation. Biodistribution was identical in tumour and non-tumour bearing animals., Conclusions: Rhabdomyo-sarcoma xenografts do not demonstrate significant uptake of 99mTc (V) DMSA.

Unlabelled: This study assessed pentavalent 99mTc-DMSA uptake in primary brain tumors and evaluated the relationship between retention and histologic malignancy., Methods: SPECT images of the brain were obtained at 30 min and 3 hr after intravenous administration of approximately 555 MBq 99mTc(V)-DMSA in patients with brain tumors. Sixty studies were performed in 57 patients and 63 lesions were demonstrated: 11 glioblastomas, 13 anaplastic astrocytomas (Grade 3), 11 astrocytomas (Grade 2), 18 meningiomas and 10 schwannomas. Uptake ratios, retention ratio and retention index were calculated and compared with tumor histology and malignancy grade., Results: Approximately 95% of both benign and malignant primary brain tumors were demonstrated by 99mTc(V)-DMSA SPECT images. False negative was noted in three cases. The early uptake ratios were closely related to the tumor vascularity but had no statistically significant difference in the tumor histology or histologic malignancy. The delayed uptake ratio, retention ratio and retention index were higher in the malignant tumors than the benign tumors., Conclusion: Technetium-99m(V)-DMSA washout from the tumor was highly dependent upon its histology and histologic malignancy. The delayed uptake ratio considerably reflected tumor histology and differentiated benign tumors from malignant tumors. The retention ratio and retention index significantly reflected tumor histology and histologic grade of primary brain tumors and clearly distinguished between benign and malignant tumors with statistically significant difference (p < 0.05). These results could suggest the clinical utility of 99mTc(V)-DMSA in imaging primary brain tumors and differentiating their histological malignancy grade noninvasively.

The purpose of this investigation was to characterise the in vivo chemistry and binding mechanisms of technetium-99m dimercaptosuccinic acid [99mTc(V)DMSA]. Biodistribution was studied in mice by frozen section whole-body autoradiography and microautoradiography in selected tissues. Binding to bone mineral analogues was studied in vitro using various forms of calcium phosphate and hydroxyapatite under varied conditions. Similar studies with 99mTc-hydroxymethylene diphosphonate (HDP) were also carried out for comparison. The in vivo stability of 99mTc(V)DMSA was monitored by high-performance liquid chromatographic analysis of blood and urine samples taken over 24 h from patients injected with the tracer. Whole-body autoradiography shows that 99mTc(V)DMSA has highest affinity for bone (cortical rather than medullary) in mice. Substantial uptake of the tracer was also observed in the kidney (cytoplasm of cortical renal tubular cells). No specific localisation was observed in the liver at either the microscopic or the macroscopic level. While 99mTc-HDP bound strongly to calcium phosphates under all conditions, 99mTc(V)DMSA binding was inhibited in the presence of phosphate and was stronger at pH 6.0 than at pH 7. 4. In non-phosphate buffers, however, the binding of 99mTc(V)DMSA remained high across the pH range 4-7.4. 99mTc(V)DMSA binds to calcium phosphates chemically unaltered, and no radioactive species other than the three isomers of 99mTc(V)DMSA were detected in blood or urine samples taken from patients up to 24 h after injection. 99mTc(V)DMSA is stable in vivo, and no conversion of the complex to other chemical species needs to be invoked to explain its uptake in bone metastases or soft tissue tumour. Bone affinity may be due to reversible binding of the unaltered complex to the mineral phase of bone.

We propose a renal imaging agent, the 99mTc complex of the bidentate-N,S chelate N-(mercaptoacetyl)glycine (99mTc-2GAM), with the imaging characteristics of 99mTc-DMSA but a faster kidney uptake; chemical evidence supports the formulation of 99mTc-2GAM as [Tc(v)(O)(GAM)2]-. After biodistribution and toxicity studies in animals, 99mTc-2GAM was evaluated in five normal volunteers. 99mTc-2GAM is rapidly cleared from the blood (t1/2 = 9 min) and 50% of the ID is excreted in the urine in the first 2 h. Dynamic data show a rapid renal uptake that increases up to 1 h with no significant wash-out between 1 and 8 h. The uptake in each kidney ranges from 11.3% to 20.7% ID. Low, stable liver uptake is observed. No significant activity is detected in other organs. We showed no differences between 99mTc-2GAM and 99mTc-DMSA compared in three patients with unilateral kidney disease. We conclude that 99mTc-2GAM has good practical and dosimetric features for renal imaging.

The present study evaluated 99mTc(V) DMSA as an agent for the visualization of inflammatory lesions in comparison to 99mTc(III) DMSA and 99mTC-HIG. All three radiopharmaceuticals were prepared with commercial kits. 99mTc(V) DMSA was prepared at neutral pH by the addition of first bicarbonate and then pertechnetate to the kit contents. The labeling efficiency was 99% as determined by ITLC. Abscesses were induced by i.m. injection of 50 microliters turpentine into the right thighs of 36 Swiss albino mice. Six days later 3.7 MBq of each radiopharmaceutical was i.v. administered to 12 mice. The mice were sacrificed at 1, 3, 6 and 24 h later. Scintigrams were obtained with a gamma camera. The abscesses were better visualized on scintigrams with 99mTc(V) DMSA compared to 99mTc(III) DMSA, starting at 1 h. The animals were dissected and the organs were removed, weighed and the radioactivity determined with a gamma counter. The abscess to other tissue ratios were higher with 99mTc(V) DMSA than the other radiopharmaceuticals. The max. abscess/muscle ratios were 9.46 +/- 3.20 (24 h), 4.19 +/- 1.39 (6 h) and 5.98 +/- 1.17 (24 h) and max. abscess/blood ratios were 6.22 +/- 1.41, 4.09 +/- 0.84 and 0.914 +/- 0.351 all at 24 h for 99mTc(V) DMSA, 99mTc(III) DMSA and 99mTc-HIG, respectively. Experimental arthritis was produced in New Zealand white rabbits by intra-articular injection of ovalbumin. Four days later 37 MBq of 99mTc(V) DMSA and 99mTc-HIG were each i.v. administered to 3 rabbits. Scintigrams obtained at 1, 3, 6, and 24 h clearly demonstrated arthritic joints. ROI's over arthritic joints were compared to contralateral normal joints (A/C). The max. A/C ratios were 2.10 +/- 0.31 (3 h) and 2.92 +/- 0.99 (24 h) for 99mTc(V) DMSA and 99mTc-HIG, respectively. Our results indicated the feasibility of imaging inflammatory lesions with 99mTc(V) DMSA.

Unlabelled: After intravenous administration of 99mTc-DMSA, biokinetic data were collected from studies on 24 children aged from 5 wk to 14.8 yr (15 normal and 9 with renal pathology)., Methods: Patients were imaged with a gamma camera up to 30 hr postinjection and the absolute activities in the kidneys, liver, spleen, bladder, knees and whole body were estimated using an attenuation-corrected conjugate counting technique. Renal uptake and elimination rates and urinary excretion of radioactivity were also measured., Results: In children with normal renal function, maximal kidney uptake was 42.4% +/- 5.4% and was taken up with a half-time of 1.0 +/- 0.2 hr. Renal excretion amounted to 18.0% +/- 4.4% at 24 hr and was lowest in children aged less than 1 yr. In children with abnormal renal function, apart from the expected reduction in renal uptake there was evidence of wider variations in uptake rate and increased urinary excretion. Mean uptakes in liver and spleen were approximately 5% and 2%, respectively, in all patients and uptake in knees, assumed to reside in the metaphyseal growth complexes, was 1.4%., Conclusion: In children with normal renal function, there was little evidence of age-dependent biokinetic factors other than reduced urinary excretion and lower uptake in knees in children aged less than 1 yr. The results therefore suggest that a single biokinetic model may suffice for radiation dosimetry purposes in normal children irrespective of age.

Unlabelled: Radiation dosimetry was performed on 24 children (aged 5 wk to 14.8 yr) who were undergoing routine diagnostic investigation of renal impairment with 99mTc-DMSA., Methods: Organ doses were calculated using MIRDOSE 3 with biokinetic data obtained in previously described studies, and effective doses and effective dose equivalents were estimated. Interpolation by inverse weight between pediatric anthropomorphic phantoms was compared with age-matching to discrete phantoms. Administered activities were scaled by body surface area from the adult activity of 100 MBq and the resulting radiation doses in normal children were compared with those that would have resulted from a schedule based on body weight., Results: The effective doses estimated by interpolation differed by up to 46% from those based on discrete phantoms and showed less variation. In children with normal bilateral renal function, the mean effective dose per administered activity was 0.91 +/- 0.08 mSv or 0.98 +/- 0.29 mSv by the two methods, respectively. Renal pathology reduced the effective dose, on average, by 15% of the value for normal patients., Conclusion: Over the pediatric age range, the uniformity of effective dose values was improved by scaling the administered activity according to body surface area rather than to body weight.

Four patients with the clinical diagnosis of nephronophthisis are presented, all having a very poor renal uptake of 99mtechnetium-dimercaptosuccinic acid (99mTc-DMSA) but clearly visualized kidneys on early images with 99mtechnetium-mercaptoacetyltriglycine and a normal or almost normal renogram. There was no difference between a young patient in an early stage of the disease and the other three patients with more advanced renal disease. In contrast, a patient with tubulointerstitial nephritis with uveitis had considerably better renal uptake of 99mTc-DMSA despite impaired renal function. We suggest that the specific tubular function defect in nephronophthisis might be the cause of the poor uptake of 99mTc-DMSA. We also recommend the method to support the clinical suspicion of nephronophthisis, even in the early stages of the disease.

Unlabelled: Intrarenal handling of 99mTc-DMSA is still controversial, particularly in the existence of tubular reabsorption from the tubular fluid. Experiments were performed with micropuncture technique on the rat kidney in an attempt to elucidate this question., Methods: The concentration profile of 99mTc-DMSA along the nephron was measured in fluid from Bowman's space of surface glomeruli and from the proximal and distal tubules collected by micropuncture. Superficial loops of proximal tubules were micropunctured and microperfused with 99mTc-DMSA or [99mTc] pertechnetate for 10 or 20 min at physiological flow rates; the recovery of activity was measured in the final urine., Results: Bowman's space urine contained only 14% of the 99mTc activity of arterial plasma, indicating low filtration of 99mTc-DMSA, likely due to high plasma protein binding. Tubular fluid-to-plasma activity ratios of 0.31 in the proximal tubules and 1.31 in the distal tubules suggest that 99mTc-DMSA is neither secreted nor reabsorbed along the nephron. Ninety-eight percent of the 99mTc-DMSA activity was recovered in the final ipsilateral urine, while only 0.5% was found in the urine of the contralateral kidney., Conclusion: A low fraction of 99mTc-DMSA enters the tubule by glomerular filtration and is not reabsorbed from the tubular fluid. Thus, only peritubular extraction by the tubular cell is responsible for renal uptake of 99mTc-DMSA.