Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen.

2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with platinum compounds. The influence of ebselen on cis-diamminedichloroplatinum(II) (cisplatin)-induced nephrotoxicity in mice was assessed, using single doses of both compounds. Ebselen prevented cisplatin-induced elevations of blood urea nitrogen and serum creatinine levels and morphological kidney damage in BALB/c mice. This protective effect of ebselen was dose dependent: at a cisplatin dose of 14.5 mg/kg, maximal protection was achieved when a single dose of 10 mg of ebselen/kg was administered 1 h before cisplatin. Administration of ebselen, 10 mg/kg, 1 h after cisplatin also protected against severe nephrotoxicity. Treatment with ebselen did not reduce the antitumor activity of cisplatin against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. However, this reduction of cisplatin-induced nephrotoxicity would be of little clinical value if it was achieved at toxic doses of ebselen. Ebselen, 10 mg/kg, did not induce blood urea nitrogen, serum creatinine, serum glutamic pyruvate transaminase, or serum glutamic oxalate elevations in the mice. These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug. The present results indicate that ebselen may provide protection against cisplatin-induced nephrotoxicity, when it is given before or after cisplatin. This might open new perspectives in cancer chemotherapy.

Selenium-induced protection against cis-diamminedichloroplatinum(II) nephrotoxicity in mice and rats.

The influence of selenium on cis-diamminedichloroplatinum(II) (c-DDP) nephrotoxicity in mice and rats was assessed, using single doses of both compounds. Sodium selenite, 2 mg of selenium per kg, given 1 h before c-DDP, greatly reduced blood urea nitrogen and creatinine levels and morphological kidney damage in both BALB/c mice and Wistar rats, while administration 1 h after c-DDP did not. Liver toxicity of selenium was evaluated by measuring serum glutamic pyruvate transaminase and serum glutamic oxalate transaminase and by routine histology. No liver damage was observed in animals treated with sodium selenite, 2 mg of selenium per kg, and physiological saline or c-DDP. Pretreatment with sodium selenite did not reduce the antitumor activity of c-DDP against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. The present results indicate that sodium selenite may provide protection against c-DDP nephrotoxicity, when it is given before c-DDP. Moreover, selenium has an antineoplastic activity against several tumors. The combination of these qualities may open new perspectives in cancer chemotherapy.

Evaluation method for krypton-81m reservoir administration systems.

Large variations have been reported in counting rates during lung ventilation studies using different 81mKr administration systems and among different patients. A method was set up to determine the activity utilization efficiency (AUE) using various administration systems. For that purpose a simple lung simulator was developed for combination with reservoir administration systems to be tested. It was found that under normal breathing conditions the AUE is 50% using a reservoir system and only 18% in the absence of a reservoir in the administration system. The measured results were confirmed by a mathematic model. The suggested simulator is suitable for use in hospitals and also enables an indirect check on the 81Rb/81mKr generator performance.

Dosimetric optimization of postproduction neutron-activated erbium-170-oxide-enriched pancreatin.

UNLABELLED: The feasibility of postproduction neutron activation of an enteric-coated pancreatic enzyme preparation for in vivo gastric emptying studies has been investigated. METHODS: During production of this multicomponent preparation, small amounts of 170Er-enriched erbium oxide, suitable for neutron activation, were added. RESULTS: Postproduction neutron irradiation of the labeled preparation resulted in short-lived (7.5 hr) gamma-emitting 171Er. Various radiocontaminants, however, are produced also. Because of variations in activation yields, half-lives, decay schemes and radiotoxicities, both major and trace constituents were considered for optimization of both dosimetry and the diagnostic measurement. Conditions were optimized for the best ratio of the committed dose equivalent due to 171Er to the total committed dose equivalent. CONCLUSION: The results show that postproduction neutron activation of a 170Er-enriched multicomponent preparation can be performed safely within the guidelines set by the WHO for experiments in humans involving radioactive materials.

Selenium levels in blood and plasma, and glutathione peroxidase activity in blood of breast cancer patients during adjuvant treatment with cyclophosphamide, methotrexate and 5-fluorouracil.

Glutathione peroxidase activity in whole blood and selenium levels in whole blood and plasma from breast cancer patients, were measured during combination chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil. No significant change in either glutathione peroxidase activity or selenium levels was observed. Comparison with matched controls showed no significant differences for either parameter.

Cisplatin-induced changes of selenium levels and glutathione peroxidase activities in blood of testis tumor patients.

Haematocrit and glutathione peroxidase activity in blood, as well as selenium levels in blood, erythrocytes and plasma, were determined in 15 patients during four courses of cisplatin combination treatment for testicular teratoma. The haematocrit steadily declined, necessitating frequent blood transfusions during or after treatment. For patients without blood transfusions during treatment the reduction of the haematocrit averaged 40%. Glutathione peroxidase activity in blood declined also; for patients without blood transfusion the reduction was 30%, which is fully explained by the decrease of the haematocrit. The enzyme activity per volume of erythrocytes remained constant during the treatment. Erythrocyte selenium level did not change significantly, but plasma selenium levels of all patients dropped within each course of chemotherapy, and progressively with each subsequent course. Between cycles the levels were largely restored to almost normal values. These results may be explained by a decreasing availability of selenium in the body to maintain the normal plasma level, due to increased retention of cisplatin in tissues and subsequent alteration of selenium metabolism.

The mechanism of interaction between cisplatin and selenite.

Cisplatin is a widely used antitumor drug, highly effective in the treatment of several tumors. Cisplatin exerts its antitumor activity through an interaction with DNA, which results in the formation of bidentate adducts. An important side-effects of cisplatin is nephrotoxicity. Selenite can reduce the nephrotoxicity of cisplatin without reducing the antitumor activity of the drug. We have studied the mechanism of selenite protection against cisplatin-induced nephrotoxicity. The protection correlates with higher levels of selenium in the kidney (about eight times) and with higher levels of glutathione in the kidney, both compared to tumors. Selenite is metabolized into selenols, specifically into methylselenol and glutathionylselenol; this bioactivation of selenite into selenols is a glutathione-dependent process. HPLC with on-line radioactivity detection of 195mPt showed that methylselenol is capable of forming a complex with cisplatin in vitro. 1H-NMR gave evidence that the complex contains one or more Pt-Se-CH3 bonds. Attempts to obtain further structural information by Desorption Chemical Ionization and Fast Atom Bombardment mass-spectrometry failed. It is proposed that the formation of a cisplatin-selenol complex also takes place in vivo, especially in the kidney, thereby preventing cisplatin exerting its nephrotoxic activity.

Selenium in in vitamin-E-deficient diets and the occurrence of myopathy as a symptom of vitamin E deficiency.

The occurrence of myopathy in vitamin-E-deficient ducklings, which is used for the determination of the degree of vitamin E deficiency, is depending on the selenium content of the diet. The selenium content of a semi-synthetic diet and its constituents was determined by neutron activation analysis, which showed to be an adequately sensitive and precise method of analysis for selenium. The casein compound was the main source of the selenium in the diet. Myopathy occurred with diets containing about 50 ppb Se; diets containing about 100 ppb Se failed to induce any signs of myopathy.

Mercury and selenium in marine mammals and birds.

Information is provided concerning the concentrations of mercury and selenium in tissues of marine animals. In marine mammals a 1:1 Hg/Se molecular increment ratio was found and an almost perfect linear correlation between mercury and selenium. It is suggested that marine mammals are able to detoxify methylmercury by a specific chemical mechanism in which selenium is involved. The results also indicate that the fate of methylmercury in fish-eating marine birds differs fundamentally from that in marine mammals.

Influence of salinity and eutrophication on bioaccumulation of 99technetium in duckweed.

This study concerns the bioaccumulation of the long-lived nuclear waste product 99Tc in duckweed (Lemna minor L.). 99Tc was present as the oxyanion TcO4-, being the main chemical form of technetium in aerobic water systems. In contrast with terrestrial plants, bioaccumulation in duckweed proved to be independent of the nitrate concentration in the medium. However, uptake is controlled by electrostatic effects in the cell wall, which affects the bioaccumulation of 99Tc in duckweed in natural environments. These waters are characterized by a range of salinity and hardness, and this study suggests that this may result in up to a threefold difference in 99Tc accumulation. Because of screening of negative charges in the cell wall, the highest accumulation may be expected in hard, brackish water. This behavior can be described by a general model, which includes electrostatic effects and binding of cations at the cell wall. The model also explains why cationic radionuclides are preferably taken up in soft, fresh water while anionic species are concomitantly taken up in hard, chlorine-rich waters.

Nuclear analytical methods in the life sciences.

A survey is given of various nuclear analytical methods. The type of analytical information obtainable and advantageous features for application in the life sciences are briefly indicated. These features are: physically different basis of the analytical method, isotopic rather than elemental determination, no interfering effect of electrons and molecular structure, and penetrating character of nuclear radiation. Suggestions are given for exploitation of the sometimes unique potentials of nuclear analytical methods, particularly when requiring considerable investment for equipment, supporting facilities, and specialized staff.

Radiochemical neutron activation analysis in the life sciences. A look back and ahead.

The contribution of radiochemical neutron activation analysis (RCNAA) to a better understanding of trace element analytics and physiology in the life sciences is outlined. Now, various non-nuclear powerful techniques for trace element analysis have become available, competing with RCNAA. This necessitates re-evaluation of the position of RCNAA, in particular versus inductively coupled plasma--mass spectrometry (ICP-MS). On basis of the characteristic features of RCNAA and the capabilities of various competing non-nuclear analytical techniques, future niches for RCNAA in the analytical market are indicated.

Normal hair zinc levels of children : Are they affected by drinking-water hardness?

From literature data, a negative correlation was derived between the normal average hair zinc levels of 5-yr-old children and the calcium levels in their drinking water (hair zinc level in mg/kg=-(0.158±0.003) calcium level in mg/L+134;r=0.993,n=6,p=0.0006). Exposure of hair samples of a 5-yr-old child to water with different levels of calcium and zinc did not provide evidence for an exogenous effect of calcium in drinking water on hair zinc levels. Thus, these results support Gibson's hypothesis that calcium in hard drinking water interferes with Zn absorption.

In vitro exchangeable erythrocytic zinc.

Exchangeable erythrocytic zinc is measured by 65Zn uptake in and release from erythrocytes under standardized and near, physiological conditions: 7.6 microM zinc and 580 microM albumin in the medium. The intracellular exchangeable erythrocytic zinc pool in healthy volunteers amounts to 5 mumol zinc/L packed cells. The half-time of the exchange is 7 h, its activation energy 84 kJ/mol. The effects of the variation in temperature and the concentrations of albumin, as well as the effects of some zinc carriers, cell transport inhibitors, and stress hormones on the 65Zn uptake are measured.

Microbeam PIXE analysis of Na, K, Mg, and Ca in severely damaged cardiac tissue.

The aim of the study was to measure with microbeam PIXE elements such as Na, K, Mg, and Ca in cardiac tissue after various treatments in vivo, which affect the cardiomyocyte integrity. It was assumed that local deviations from normal electrolyte levels indicate the degree of cardiac damage. The first step in this feasibility study was comparison of severely damaged cardiac tissues with controls. Severe cardiac damage was introduced by the so-called Ca paradox. Experiments were performed with isolated rat hearts, perfused retrogradely with an oxygenated crystalloid buffer. Results indicated that severe cardiac damage was accompanied with almost complete disappearance of the normal intracellular electrolyte composition as a result of the loss of membrane integrity. Identifications of smaller and more locally present ischemic damages on basis of altered electrolyte levels appeared to be feasible. However, the prerequisite was that the mobility of electrolytes be kept under control during tissue sampling and sample preparation, when physiological mechanisms stop to maintain gradients.

Absorption and retention studies of trace elements and minerals in rats using radiotracers and whole-body counting.

A description is given of a whole-body counting technique using radiotracers, permitting the determination of true absorption and endogenous excretion of trace elements and minerals in the rat in vivo. This non-invasive counting method involves oral and intraperitoneal administration of tracer doses of a radioisotope in a cross-over fashion and subsequent measurement of the whole-body retention in a whole-body counter. Thus, true absorption can be determined in one animal which contributes to the reduction of animal use. To study the variations in counting response due to radioisotope distribution, to size or shape of the animal body, the influence of the position of a point source and distribution over different phantoms to simulate various body sizes are experimentally evaluated for 64Cu, 65Zn, 59Fe and 28Mg. Results from 2 studies, with 64Cu and 28Mg, as an example for a trace element and a mineral respectively, are presented and illustrate that absorption as measured by apparent absorption does not necessarily reflect true absorption. True absorption as determined by the whole-body retention method using radioisotopes corrects for faecal losses of endogenous origin.

In-target production of high specific radioactivity [15O]nitrous oxide by deuteron irradiation of nitrogen gas.

A simple and rapid production method for high specific radioactivity [15O]N2O has been developed based on the 14N(d,n)15O reaction on high-purity nitrogen gas in a flow-through target irradiated with a 0.5 microA beam of 7 MeV deuterons. The [15O]N2O formed during irradiation is selectively concentrated from the target effluent by adsorption on a zeolite during 150 s and subsequently released by rapid heating into a pulse with a full width at half maximum of 3.5 s. The radioactivity and specific radioactivity in the pulse amount to 4 MBq [15O]N2O and 4.5 x 10(13) Bq/mol respectively with a radiochemical purity >99.95%. A tenfold higher specific radioactivity may be feasible at larger beam currents. It was shown that stable N2O was also formed during irradiation. Based on responses to variations in various parameters during irradiation and on analyses performed on the products, an explanation is given on the mechanisms of in-target [15O]N2O and N2O formation, involving reaction of a particular excited state of O3 with N2.

An extension set for 81Rb-81mKr solution generators for lung ventilation studies.

For 81Rb-81mKr solution generators, an extension set has been developed, which strips the 81mKr from the liquid eluate with a stream of air for use in lung ventilation studies. Via a three-way valve the 81Rb-81mKr solution generator can be operated alternately in the perfusion mode or in the ventilation mode. Measurements and calculations have been performed to get more insight into the parameters of interest for an optimum design of the extension set and its operation conditions.

Iodine-129 as a protein label for studies of plasma protein turnover and its measurement with neutron activation analysis.

Iodine-129 (t 1/2 = 1.57 x 10(7) y) was used as a protein label for the measurement of the turnover rate of albumin in two human subjects. Plasma samples were assayed for 129I using destructive neutron activation analysis. The experiment entailed an estimated radiation dose of 0.2 muSv to the total body of the subjects. The turnover parameters showed reasonable agreement with literature values. When in a rabbit the catabolism of (129I + 131I)-labeled autologous albumin was followed, the results obtained with both labels agreed well.

Determination of 75Se-labelled selenite and metabolites in plasma and urine by high-performance liquid chromatography with on-line radioactivity detection.

A reversed-phase ion-pair high-performance liquid chromatographic method with on-line radioactivity detection for the simultaneous determination of 75Se-labelled selenite and metabolites has been developed. With this system a good resolution of various radiolabelled selenium complexes can be achieved. The detection limit of the radioactivity detector (signal-to-noise ratio = 3) is 49 pg of selenium (specific activity of 3 GBq/mg selenium) per millilitre of urine or plasma ultrafiltrate. The detector response is independent of both the chemical structure of the selenium complexes and the matrix composition of the samples. This method may serve as a reference system for other high-performance liquid chromatographic systems with less specific and sensitive detectors.