Disubstituted diaryl diselenides inhibit [3H]-serotonin uptake in rats.

Diphenyl diselenide (PhSe)2, the parent compound of disubstituted diaryl diselenides, produces significant antidepressant-like effect when evaluated in the forced swimming test (FST) in rats. The goal of this study was to investigate the effects of diphenyl diselenide (PhSe)2, m-trifluoromethyl-diphenyl diselenide (F3CPhSe)2 and p-methoxy-diphenyl diselenide (CH3OPhSe)2 on [3H]-serotonin uptake in rat platelets and synaptosomes. At concentrations higher than 10 microM (PhSe)2, and (F3CPhSe)2 inhibited about 20% [3H]-serotonin uptake in platelets. (CH3OPhSe)2 inhibited [3H]-serotonin uptake in platelets at concentrations higher than 1 microM. Similarly, (PhSe)2, (F3CPhSe)2, and (CH3OPhSe)2 significantly inhibited [3H]-serotonin uptake (about 50%) in synaptosomes from rat brain at concentrations higher than 1 microM. The maximal inhibitory effects of (PhSe)2, (F3CPhSe)2, and (CH3OPhSe)2 on [3H]-serotonin uptake from rat synaptosomes were 65%, 96%, and 80%, respectively. In conclusion, our results demonstrate that disubstituted diaryl diselenides altered monoaminergic system by interacting with monoamine uptake.

Effect of oral administration of diphenyl diselenide on antioxidant status, and activity of delta aminolevulinic acid dehydratase and isoforms of lactate dehydrogenase, in streptozotocin-induced diabetic rats.

Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (eth-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.

Vinylic telluride derivatives as promising pharmacological compounds with low toxicity.

The aim of the present study was to evaluate pharmacological and toxicological properties of (Z)-2-(methylthio)-1-(butyltelluro)-1-phenylethene 1a, (Z)-1-(4-methylphenylsulfonyl)-2-(phenyltelluro)-2-phenylethene 1b, (Z)-2-(butyltelluro)-1-(benzylthio)-1-heptene 1c and (Z)-2-(phenylthio)-1-(butyltelluro)-1-phenylethene 1d. In vitro, vinylic telluride derivatives 1a, 1d and 1c were more effective in reducing lipid peroxidation than compound 1b. The maximal inhibitory effect of vinylic telluride derivatives on lipid peroxidation was in the following order: 1a = 1d > 1c > 1b. Compound 1b was more potent in inhibiting delta-ALA-D activity (delta-aminolevulinate dehydratase) than compounds 1c and 1d. Based on the in vitro properties presented by compounds 1a (an antioxidant) and 1b (a pro-oxidant), toxicological parameters were assessed in vivo and ex vivo in rats. Calculated LD50 of compounds 1a and 1b, administered by oral route, were 20.5 and 1.44 micromol kg(-1), respectively. Compound 1b induced behavioral alterations in the open field test. Renal and spleenic delta-ALA-D activities were inhibited in rats treated orally with compound 1a. Compound 1b stimulated delta-ALA-D activity in liver and spleen of rats. Rats treated with compound 1b had increased hepatic, renal and spleenic lipid peroxidation. Renal and hepatic markers were not altered when compounds 1a and 1b were administered to rats at doses of around LD50, while compound 1a at high doses changed aspartate aminotransferase activity and urea levels. Based on in vitro results, this study demonstrated that compounds 1a and 1d are promising antioxidant compounds. Ex vivo data reinforce compound 1a as a promising drug for more detailed pharmacological studies.

The role of thiol-reducing agents on modulation of glutamate binding induced by heavy metals in platelets.

In the present study, we investigated if thiol-reducing agents are capable of altering mercury (Hg2+), lead (Pb2+) and cadmium (Cd2+) effects on platelet glutamatergic system. Dimercaprol (BAL), a dithiol chelating agent therapeutically used for the treatment of heavy metals poisoning, was capable of protecting the [3H]-glutamate binding against the effects caused by Pb2+ and Hg2+. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), another dithiol-reducing chelating agent, was capable of protecting the effect caused by Cd2+, Pb2+ and Hg2+. The similar effect was observed with addition of dithiothreitol (DTT) on [3H]-glutamate binding in human platelets. Dithiol-reducing agents (BAL, DMPS and DTT) alone did not alter [3H]-glutamate binding. In contrast, reduced glutathione (GSH), a monothiol-reducing agent, caused a significant inhibition on [3H]-glutamate binding at all concentrations tested. GSH did not modify heavy metal effects on [3H]-glutamate binding in platelets. The findings of the present investigation indicate that dithiol-reducing agents are capable of altering Hg2+, Pb2+ and Cd2+ effects on platelet glutamatergic system. In vitro data on chelating-metal interactions provide only an estimated guide to the treatment of heavy metal poisoning. Consequently, more studies in intoxicated patients are necessary to determine the precise use of the peripheral models and chelating agents.

Repeated administration of diphenyl ditelluride induces hematological disorders in rats.

In the present study, we investigated potential toxic effects of diphenyl ditelluride, as measured by biochemical and hematological parameters. Rats were given a daily dose of 0.3 micromol/kg diphenyl ditelluride by subcutaneous route and sacrificed at different times (24 and 48 h). Hepatic and renal TBARS levels were changed by diphenyl ditelluride exposure at the dose 0.9 micromol/Kg in rats. Diphenyl ditelluride exposure demonstrated an increase in AST (aspartate aminotransferase), ALT (alanine aminotransferase) and LDH (lactate dehydrogenase) activities. Plasma creatinine and urea levels increase after diphenyl ditelluride exposure. Diphenyl ditelluride also produced a significant decrease in plasma triglyceride and cholesterol levels. In contrast, this compound, at all doses tested, induced a marked increase in total leukocyte counts. The present study suggests that diphenyl ditelluride induces hematological disorders and provides evidence for renal and hepatic toxicity in rats.

Heavy metals modulate glutamatergic system in human platelets.

Research strategies have been developed to characterize parameters in peripheral tissues that might easily be measured in humans as surrogate markers of damage, dysfunction or interactions involving neural targets of toxicants. The similarities between platelet and neuron may even be clinically important, as a number of biochemical markers show parallel changes in the central nervous system (CNS) and platelets. The purpose of our research was to investigate the effect of Hg(2+), Pb(2+) and Cd(2+) on the [(3)H]-glutamate binding and [(3)H]-glutamate uptake in human platelets. The involvement of oxidative stress in the modulation of glutamatergic system induced by heavy metals was also investigated. The present study clearly demonstrates that Hg(2+), Cd(2+), and Pb(2+) inhibited [(3)H]-glutamate uptake in human platelets. Hg(2+) inhibited [(3)H]-glutamate binding, while Cd(2+) and Pb(2+) stimulated [(3)H]-glutamate binding in human platelets. Hg(2+), Cd(2+) and Pb(2+) increased lipid peroxidation levels and reactive oxygen species (ROS) measurement in platelets. The present limited results could suggest that glutamatergic system may be used as a potential biomarker for neurotoxic action of heavy metals in humans.

Effect of diphenyl diselenide, diphenyl ditelluride and ebselen on cerebral Na(+), K(+)-ATPase activity in rats.

In the present study, we investigated the in vitro effect of diphenyl ditelluride, diphenyl diselenide and ebselen on Na(+), K(+)-ATPase activity of rat brain. The results demonstrated that all compounds significantly inhibited (in the muM range) Na(+), K(+)-ATPase activity. Diphenyl ditelluride, at low concentrations, provoked an increase in Na(+), K(+)-ATPase activity. Dithiothreitol (DTT), at 3mM, protected the inhibition caused by diphenyl ditelluride, diphenyl diselenide and ebselen in Na(+), K(+)-ATPase activity. Post-incubation of diphenyl diselenide-treated homogenate with DTT completely recovered enzyme activity. DTT was able to recover the enzyme inhibition induced by 20muM of diphenyl ditelluride, but was partially able to recover inhibition induced by high concentrations of organotellurium compound. Conversely, DTT did not recover ebselen-induced Na(+), K(+)-ATPase inhibition. The mechanism of inhibition by diphenyl diselenide, diphenyl ditelluride and ebselen in Na(+), K(+)-ATPase activity revealed: decreased maximal velocity and K(m). Cerebral Na(+), K(+)-ATPase is a potential molecular target for the toxic effect of organochalcogens and the inhibition may occur through a change in the crucial thiol groups of this enzyme.

Organochalcogens affect the glutamatergic neurotransmission in human platelets.

Blood platelets have repeatedly been suggested as an excellent model for various aspects of the synaptic apparatus. Considering that organochalcogens affect some parameters of glutamatergic neurotransmission in rats, in the current study we evaluated the effect of diphenyl diselenide (PhSe)2, diphenyl ditelluride (PhTe)2, and Ebselen on glutamatergic neurotransmission in human platelets. (PhTe)2 and (PhSe)2 caused a significant inhibition, but Ebselen did not interfere in Na-independent glutamate binding. Dithiothreitol (DTT) did not completely prevent the [3H]glutamate binding inhibition caused by 100 microM (PhTe)2. (PhSe)2, (PhTe)2, and Ebselen (100 microM) significantly inhibited [3H]glutamate uptake, whereas organochalcogens at 1 and 10 microM had no significant effect on the [3H]glutamate uptake in human platelets. In this study, platelets were demonstrated to be a suitable model for neurotoxicological research, and, to the best of our knowledge, this is the first report documenting the toxic effects of organochalcogens in human platelets.

Organochalcogens effects on delta-aminolevulinate dehydratase activity from human erythrocytic cells in vitro.

Organochalcogens are important intermediates and useful reagents in organic synthesis, which can increase human exposure risk to these chemicals in the workplace. As well, there are a number of reported cases of acute toxicity following organochalcogen ingestion of vitamins and dietary supplements. Since, the erythrocytic delta-ALA-D activity could be an important indicator of toxicity this report investigated the organochalcogens effects on blood delta-ALA-D in vitro. To investigate a possible involvement of cysteinyl groups in the inhibitory actions of diphenyl diselenide, diphenyl ditelluride and Ebselen (4-100 micro M), the effects of thiol reducing agents (0-3 mM) or zinc chloride (0-2 mM) were examined. Diphenyl ditelluride, diphenyl diselenide and Ebselen inhibited in a concentration-dependent manner delta-ALA-D activity from human erythrocytes. Ebselen was lesser delta-ALA-D inhibitor than (PhSe)(2) and (PhTe)(2), whereas the diorganoyldichalcogenides displayed similar inhibitory potency towards delta-ALA-D. Dithiothreitol, a hydrophobic SH-reducing agent, was able to reactivate and to protect inhibited delta-ALA-D. The pre-incubation of blood with the inhibitors changed considerably the reversing potency of thiols. From these findings we suggest that organochalcogens inactivate in vitro human erythrocyte delta-ALA-D by an interaction with the sulfhydryl group essential of the enzyme activity.

Potential renal and hepatic toxicity of diphenyl diselenide, diphenyl ditelluride and Ebselen for rats and mice.

The occupational importance of tellurium and selenium is growing rapidly, but the biochemistry of exposure is poorly understood. Here we report the potential toxic effects of diphenyl diselenide (PhSe)(2), diphenyl ditelluride (PhTe)(2) and Ebselen in rats and mice. The results suggest that (PhTe)(2) is more toxic in rats than mice. (PhSe)(2), (PhTe)(2) and Ebselen are more toxic by intraperitoneal (i.p.) than subcutaneous (s.c.) route. Calculated LD(50) for (PhTe)(2), i.p., was 0.65 micromol/kg in rats and 150 micromol/kg in mice, and LD(50), s.c., was 0.9 micromol/kg in rats and >500 micromol/kg in mice. Calculated LD(50) for Ebselen, i.p., was 400 micromol/kg in rats and 340 micromol/kg in mice and LD(50), s.c., was >500 micromol/kg in both mice and rats. (PhTe)(2) at small doses increased 2-fold serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in rats. LD(50) for all organochalcogens administrated in mice inhibited blood delta-ALA-D activity. The present study provides evidence for liver and renal toxicity of (PhTe)(2).

Clinical use of growth hormone and glutamine in short bowel syndrome.

Growth hormone (GH) and glutamine (GLN) are considered bowel trophic factors and are used experimentally after bowel resection. Their clinical uses in short bowel syndrome (SBS) are still not standardized. It is of interest to verify metabolic, nutritional and side effects of the association of GH and GLN in SBS. Three patients, 39 (A), 33 (B), and 01 years old (C) underwent bowel resection with jejunum anastomosis 15 cm (A) and 60 cm (B) distant from the Treitz angle, and 40 cm (C) preserving the ileo cecal valve. GH Saizen (Serono-A), Genotropin (Pharmacia-B), and Norditropin (Novonordisk C) were administered in doses of 0.14 mg/kg/day. GLN (0.4 g/kg/day) was given orally for 10 days (A), 30 days (B) and 60 days to patient C (0.28 g/kg/day). Central TPN and adequate oral diet was administered according to the bowel adaptation phase. On the first day after beginning treatment patient A exhibited symptoms of hypoglycemia. There were no other side effects. After treatment, body weight was higher and analysis by bioelectrical impedance showed more lean mass and less fat mass compared to pre-treatment measurements. Nitrogen retention was progressively higher with treatment. Simultaneous treatment with GH and GLN does not cause significant side effects, and is associated with a favorable distribution of the body compartments and nitrogen retention in patients with the short bowel syndrome.

[Infections of central venous catheters]. / Infecções do catéter venoso central.

The central venous catheter is considered the lifeline of patients requiring long-term parenteral nutrition, and its infectious complications accordingly represent a frequent cause for hospitalization and morbidity. Modern catheters made of Silastic increase the duration and efficiency of venous access, but their substitution is also more complex and expensive. In a small series of patients undergoing home parenteral nutrition due to short bowel syndrome, and carrying. Silastic catheters, infection of the cannula was treated by administration of systemic as well as local antimicrobial agents. The septic process was resolved without the need of removing the catheters, and with excellent tolerance to the medications. It is concluded that in-situ sterilization of long-term catheters should be attempted in selected cases.

Aminoacidos escenciales y no escenciales en la insuficiencia renal aguda

Existen controversias acerca de la eficiencia del uso exclusivo de aminoácidos esenciales en nutrición parenteral (NPT) para pacientes con insuficiencia renal aguda. Para estudiar el impacto sobre la insuficiencia renal, en pacientes post cirugía cardíaca, fueron randomizados los pacientes en la unidad de terapia intensiva divididos en dos grupos. Grupo AE con 17 pacientes en NPT con solo aminoácidos esensiales y el grupo AT con 17 pacientes en NPT con aminoácidos esenciales y no esenciales. La NPT fue dada en promedio por 10 días. Los pacientes dializados tuvieron menor recuperación de la función renal y mortalidad mas alta (p<0.05). En conclusión la NPT con AE en insuficiencia renal aguda no modificó los niveles de urea y creatina y tasa de mortalidad, cuando se comparó con la NPT con mezcla completa de aminoácidos.

Aminoacidos escenciales y no escenciales en la insuficiencia renal aguda

Existen controversias acerca de la eficiencia del uso exclusivo de aminoácidos esenciales en nutrición parenteral (NPT) para pacientes con insuficiencia renal aguda. Para estudiar el impacto sobre la insuficiencia renal, en pacientes post cirugía cardíaca, fueron randomizados los pacientes en la unidad de terapia intensiva divididos en dos grupos. Grupo AE con 17 pacientes en NPT con solo aminoácidos esensiales y el grupo AT con 17 pacientes en NPT con aminoácidos esenciales y no esenciales. La NPT fue dada en promedio por 10 días. Los pacientes dializados tuvieron menor recuperación de la función renal y mortalidad mas alta (p<0.05). En conclusión la NPT con AE en insuficiencia renal aguda no modificó los niveles de urea y creatina y tasa de mortalidad, cuando se comparó con la NPT con mezcla completa de aminoácidos.(AU)