RESUMEN
In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aß) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 µM and after 48 h the maintenance temperature was increased to 25 ° C for Aß expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aß toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aß aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.
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Péptidos beta-Amiloides/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Compuestos de Organoselenio/farmacología , Pirimidinonas/farmacología , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Caenorhabditis elegans , Modelos Animales de Enfermedad , Levamisol/farmacología , Fármacos Neuroprotectores/efectos adversos , Organismos Modificados Genéticamente , Compuestos de Organoselenio/efectos adversos , Oviposición/efectos de los fármacos , Pirimidinonas/efectos adversosRESUMEN
Photoactivatable molecules enable ablation of malignant cells under the control of light, yet current agents can be ineffective at early stages of disease when target cells are similar to healthy surrounding tissues. In this work, we describe a chemical platform based on amino-substituted benzoselenadiazoles to build photoactivatable probes that mimic native metabolites as indicators of disease onset and progression. Through a series of synthetic derivatives, we have identified the key chemical groups in the benzoselenadiazole scaffold responsible for its photodynamic activity, and subsequently designed photosensitive metabolic warheads to target cells associated with various diseases, including bacterial infections and cancer. We demonstrate that versatile benzoselenadiazole metabolites can selectively kill pathogenic cells - but not healthy cells - with high precision after exposure to non-toxic visible light, reducing any potential side effects in vivo. This chemical platform provides powerful tools to exploit cellular metabolic signatures for safer therapeutic and surgical approaches.
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Infecciones Bacterianas/tratamiento farmacológico , Colorantes Fluorescentes/administración & dosificación , Glioblastoma/tratamiento farmacológico , Compuestos de Organoselenio/administración & dosificación , Fotoquimioterapia/métodos , Animales , Técnicas de Cocultivo , Colorantes Fluorescentes/efectos adversos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/efectos de la radiación , Glioblastoma/patología , Humanos , Microscopía Intravital , Luz , Pruebas de Sensibilidad Microbiana , Microscopía Confocal , Microscopía Fluorescente , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/efectos de la radiación , Esferoides Celulares , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
Behavioral studies have suggested that (p-ClPhSe)2 elicits an anorectic-like action in rats by inducing multiple effects such as satiety-enhancing effect, malaise and specific flavor; however, the molecular mechanisms underlying its anorexigenic action remain unclarified. Here, male Sprague-Dawley rats received acute and sub-chronic intraperitoneal treatments with (p-ClPhSe)2; thereafter, in vivo and ex vivo analyses were carried out. The present study reveals that the reduction of food intake resulting from a single treatment with (p-ClPhSe)2 (1mg/kg, i.p.) was associated with decreased hypothalamic levels of pro-melanin-concentrating hormone (pro-MCH) and orexin precursor. In addition, repeated administrations of (p-ClPhSe)2 (10mg/kg; i.p.) for 7 days induced sustained food intake suppression, body weight loss and white fat reduction. Measurements of brown adipose tissue content and temperature as well as data obtained from a pair-fed group indicated that the effects of (p-ClPhSe)2 on the body weight are closely related to its anorexigenic actions, ruling out the possibility of increased thermogenesis. Furthermore, (p-ClPhSe)2 reduced the hypothalamic orexin precursor levels when repeatedly administered to rats. Sub-chronic treatment with (p-ClPhSe)2 caused a decrease of serum triglyceride levels and down-regulation of hepatic cholesterol content. Therefore, the current study characterized the anorectic and reducing body weight actions of (p-ClPhSe)2 in Sprague-Dawley rats. Besides, the set of results suggests that food intake suppressant effects triggered after (p-ClPhSe)2 administration to rats are mainly related with the lower orexin levels in hypothalamus after acute and sub-chronic treatments.
Asunto(s)
Anorexia/inducido químicamente , Anorexia/patología , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Compuestos de Organoselenio/efectos adversos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Anorexia/sangre , Anorexia/psicología , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Respuesta de Saciedad/efectos de los fármacos , Factores de Tiempo , Triglicéridos/sangreRESUMEN
New data have been accumulated in the scientific literature in recent years which allow a more adequate risk assessment of selenium with reference to human health. This new evidence comes from environmental studies, carried out in populations characterized by abnormally high or low selenium intakes, and from high-quality and large randomized controlled trials with selenium recently carried out in the US and in other countries. These trials have consistently shown no beneficial effect on cancer and cardiovascular risk, and have yielded indications of unexpected toxic effects of selenium exposure. Overall, these studies indicate that the minimal amount of environmental selenium which is source of risk to human health is much lower than anticipated on the basis of older studies, since toxic effects were shown at levels of intake as low as around 260 µg/day for organic selenium and around 16 µg/day for inorganic selenium. Conversely, populations with average selenium intake of less than 13-19 µg/day appear to be at risk of a severe cardiomyopathy, Keshan disease. Overall, there is the need to reconsider the selenium standards for dietary intake, drinking water, outdoor and indoor air levels, taking into account the recently discovered adverse health effects of low-dose selenium overexposure, and carefully assessing the significance of selenium-induced proteomic changes.
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Cardiomiopatías/etiología , Infecciones por Enterovirus/etiología , Contaminantes Ambientales/efectos adversos , Compuestos de Organoselenio/efectos adversos , Selenio/efectos adversos , Ensayos Clínicos como Asunto , Suplementos Dietéticos , Humanos , Neoplasias/prevención & control , Compuestos de Organoselenio/administración & dosificación , Medición de Riesgo , Selenio/administración & dosificaciónRESUMEN
Herpes simplex viruses can cause uncommon systemic complications as acute liver failure (ALT) or urinary tract dysfunctions. Diphenyl diselenide, (PhSe)2 , a classical studied organic selenium compound, has a novel antiviral action against HSV-2 infection and well-known antioxidant and anti-inflammatory properties. This study aimed to investigate if (PhSe)2 reduces oxidative stress and systemic toxicity caused by HSV-2 infection in mice. Adult BALB/c mice were pre-treated with (PhSe)2 (5 mg kg-1 /day, intragastric, i.g.) during 5 days; at day 6 mice were infected with HSV-2 (10 µl-105 PFU/mL-1 ) and post-treated with (PhSe)2 for more 5 days. At day 11, they were killed and samples of liver and kidney were obtained to determine: reactive species (RS); malondialdehyde (MDA), and non-protein thiols (NPSH) levels; the activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT). The activities of adenosine deaminase (ADA), Na+ /K+ -ATPase (liver and kidney); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the levels of urea (plasma) were determined as markers of hepatic and renal toxicity. The results revealed that (PhSe)2 treatment was effective against the increase of renal and hepatic oxidative stress in infected mice and also normalized hepatic and renal ADA activity. It recovered the activity of Na+ /K+ - and was not effective against the increase in urea levels in infected mice. Different from (PhSe)2 , acyclovir (positive control), caused an increase in ADA activity and a decrease in hepatic CAT activity. Considering the interest of alternative therapies to treat HSV-2 infections and secondary complications, (PhSe)2 become a notable candidate. J. Cell. Biochem. 118: 1028-1037, 2017. © 2016 Wiley Periodicals, Inc.
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Antioxidantes/administración & dosificación , Antivirales/administración & dosificación , Derivados del Benceno/administración & dosificación , Herpes Genital/tratamiento farmacológico , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Compuestos de Organoselenio/administración & dosificación , Adenosina Desaminasa/metabolismo , Animales , Antioxidantes/efectos adversos , Antioxidantes/farmacología , Antivirales/efectos adversos , Antivirales/farmacología , Derivados del Benceno/efectos adversos , Derivados del Benceno/farmacología , Catalasa/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Herpes Genital/virología , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 2/patogenicidad , Riñón/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/farmacología , Estrés Oxidativo/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Preclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BPD. Drug Dev Res 77 : 368-373, 2016. © 2016 Wiley Periodicals, Inc.
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Antimaníacos/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Animales , Antimaníacos/efectos adversos , Azoles/efectos adversos , Azoles/farmacología , Azoles/uso terapéutico , Biomarcadores/metabolismo , Trastorno Bipolar/genética , Humanos , Isoindoles , Compuestos de Litio/efectos adversos , Terapia Molecular Dirigida , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Farmacogenética , ARN Largo no Codificante/genéticaAsunto(s)
Evaluación Preclínica de Medicamentos/métodos , Reposicionamiento de Medicamentos/métodos , Animales , Azoles/efectos adversos , Azoles/farmacología , Trastorno Bipolar/tratamiento farmacológico , Carbazoles/farmacología , Carbazoles/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Dipiridamol/uso terapéutico , Aprobación de Drogas/estadística & datos numéricos , Industria Farmacéutica/economía , Industria Farmacéutica/métodos , Medicamentos Genéricos/farmacología , Medicamentos Genéricos/uso terapéutico , Síndromes de Ojo Seco/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Humanos , Isoindoles , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Uso Fuera de lo Indicado , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/farmacología , Patentes como Asunto , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/uso terapéutico , Zidovudina/farmacología , Zidovudina/uso terapéuticoRESUMEN
There is growing evidence to suggest that chronic, low-grade inflammation occurs in abdominal obesity, insulin resistance, type 2 diabetes mellitus and related complications, and that proinflammatory cytokines play an important role in the onset and progression of type 2 diabetes. These findings consequently provide new opportunities for the use of anti-inflammatory strategies to correct the metabolic disorders. Discovery of new synthetic bioactive small molecules to interfere with chronic, low-grade inflammation and type 2 diabetes has attracted considerable attention in medicinal chemistry. To date, a number of organoselenium small molecules and chromium(III) complexes have been shown to have the potential to alleviate chronic low-grade inflammation and type 2 diabetes, including ebselen, selenomethionine, chromium picolinate, chromium dinicocysteinate, chromium phenylalaninate, trinuclear chromium propionate, chromium histidinate, chromium nicotinate, etc. Here, we review recent advances in development of organoselenium small molecules and chromium(III) complexes to intervene in chronic low-grade inflammation and type 2 diabetes, and discuss their mode of action, potential molecular mechanisms and toxicity.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Compuestos de Cromo/farmacología , Hipoglucemiantes/farmacología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/farmacología , Antiinflamatorios no Esteroideos/química , Azoles/farmacología , Compuestos de Cromo/química , Cisteína/análogos & derivados , Cisteína/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/química , Inflamación/tratamiento farmacológico , Inflamación/etiología , Isoindoles , Obesidad/complicaciones , Obesidad/etiología , Compuestos Organometálicos/farmacología , Compuestos de Organoselenio/efectos adversos , Ácidos Picolínicos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
BACKGROUND: Selenium is a trace mineral essential to health and has an important role in immunity, defence against tissue damage and thyroid function. Improving selenium status could help protect against overwhelming tissue damage and infection in critically ill adults. This Cochrane review was originally published in 2004 updated in 2007 and again 2015. OBJECTIVES: The primary objective was to examine the effect of nutrition supplemented with selenium or ebselen on mortality in critically ill patients.The secondary objective was to examine the relationship between selenium or ebselen supplementation and number of infections, duration of mechanical ventilation, length of intensive care unit stay and length of hospital stay. SEARCH METHODS: In this update, we searched the current issue of the Cochrane Central Register of Controlled Trials, the Cochrane Library (2014, Issue 5); MEDLINE (Ovid SP, to May 20, 2014), EMBASE (Ovid SP, to May 20, 2014), CAB, BIOSIS and CINAHL. We handsearched the reference lists of the newest reviews and cross-checked with our search in MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The latest search was performed up to 21 May 2014. The search is now from inception until 21 May 2014. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted the trial investigators and authors in order to retrieve relevant and missing data. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effects of selenium in critically ill patients. We presented pooled estimates of the effects of intervention as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS: We included six new RCTs in this review update. In total we included 16 RCTs (2084 participants) in this review. Most trials were at high risk of bias. The availability of outcome data was limited and trials involving selenium supplementation were, with the exception of one trial, small regarding sample size. Thus the results must be interpreted with caution.Thirteen trials of intravenous sodium selenite showed a statistically significant reduction in overall mortality (RR 0.82, 95% CI 0.72 to 0.93, 1391 participants, very low quality of evidence). However, the overall point estimate on mortality is primarily influenced by trials of high risk of bias. Meta-analysis of three trials of ebselen had a RR of 0.83 (95% CI 0.52 to 1.34, 693 participants, very low quality of evidence).Nine trials of intravenous sodium selenite were analysed for 28 days mortality with no statistically significant difference (RR 0.84, 95% CI 0.69 to 1.02, 1180 participants, very low quality of evidence) while three trials were analysed for 90 days mortality with similar findings (RR 0.96, 95% Cl 0.78 to 1.18, 614 participants, very low quality of evidence).Two trials of ebselen were analysed for 90 days mortality and were not found to yield any benefit (RR 0.72, 95% Cl 0.42 to 1.22, 588 participants, very low quality of evidence).For mortality among intensive care patients selenium supplementation failed to indicate any statistically significant advantage (RR 0.88, 95% CI 0.77 to 1.01, nine trials, 1168 participants, very low quality of evidence).Six trials of intravenous sodium selenite found no statistically significant difference for participants developing infection (RR 0.96, 95% CI 0.75 to 1.23, 934 patients, very low quality of evidence). Similarly, three trials of ebselen provided data for participants developing infections (pyrexia, respiratory infections or meningitis) with no obvious benefit (RR 0.60, 95% CI 0.36 to 1.02, 685 participants, very low quality of evidence).Our analyses showed no effect of selenium or ebselen on adverse events (Selenium: RR 1.03, 95% Cl 0.85 to 1.24; six trials, 925 participants ; Ebselen: RR 1.16, 95% CI 0.40 to 3.36; two trials, 588 participants, very low quality of evidence).No clear evidence emerged in favour of selenium supplementation for outcomes such as number of days on a ventilator (mean difference (MD) -0.86, 95% CI -4.39 to 2.67, four trials, 191 participants, very low quality of evidence), length of intensive care unit stay (MD 0.54, 95% CI -2.27 to 3.34, seven trials, 934 participants, very low quality of evidence) or length of hospital stay (MD -3.33, 95% Cl -5.22 to -1.44, five trials, 693 participants, very low quality of evidence).The quality of trial methodology was low. Due to high risk of bias in the included trials, results must be interpreted with caution. AUTHORS' CONCLUSIONS: Despite publication of a number of trials, the current evidence to recommend supplementation of critically ill patients with selenium or ebselen remains disputed. Trials are required which overcome the methodological inadequacies of the reviewed studies, particularly in relation to sample size, design and outcomes.
Asunto(s)
Antioxidantes/uso terapéutico , Azoles/uso terapéutico , Enfermedad Crítica/terapia , Suplementos Dietéticos , Compuestos de Organoselenio/uso terapéutico , Selenito de Sodio/uso terapéutico , Adulto , Antioxidantes/efectos adversos , Azoles/efectos adversos , Enfermedad Crítica/mortalidad , Humanos , Isoindoles , Compuestos de Organoselenio/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Selenium is generally known as an antioxidant due to its presence in selenoproteins as selenocysteine, but it is also toxic. The toxic effects of selenium are, however, strictly concentration and chemical species dependent. One class of selenium compounds is a potent inhibitor of cell growth with remarkable tumor specificity. These redox active compounds are pro-oxidative and highly cytotoxic to tumor cells and are promising candidates to be used in chemotherapy against cancer. Herein we elaborate upon the major forms of dietary selenium compounds, their metabolic pathways, and their antioxidant and pro-oxidant potentials with emphasis on cytotoxic mechanisms. Relative cytotoxicity of inorganic selenite and organic selenocystine compounds to different cancer cells are presented as evidence to our perspective. Furthermore, new novel classes of selenium compounds specifically designed to target tumor cells are presented and the potential of selenium in modern oncology is extensively discussed.
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Antineoplásicos/uso terapéutico , Antioxidantes/uso terapéutico , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Compuestos de Organoselenio/uso terapéutico , Compuestos de Selenio/uso terapéutico , Selenoproteínas/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antioxidantes/efectos adversos , Antioxidantes/química , Antioxidantes/toxicidad , Humanos , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/química , Compuestos de Organoselenio/toxicidad , Oxidación-Reducción , Compuestos de Selenio/efectos adversos , Compuestos de Selenio/química , Compuestos de Selenio/toxicidad , Selenoproteínas/efectos adversos , Selenoproteínas/química , Selenoproteínas/toxicidadRESUMEN
Anxiety-related disorders are frequently observed in the population. Because the available pharmacotherapies for anxiety can cause side effects, new anxiolytic compounds have been screened using behavioral tasks. For example, diphenyl diselenide (PhSe)2, a simple organoselenium compound with neuroprotective effects, has demonstrated anxiolytic effects in rodents. However, this compound has not yet been tested in a novelty-based paradigm in non-mammalian animal models. In this study, we assessed the potential anxiolytic effects of (PhSe)2 on the behavior of adult zebrafish under novelty-induced stress. The animals were pretreated with 0.1, 0.25, 0.5, and 1µM (PhSe)2 in the aquarium water for 30min. The fish were then exposed to a novel tank, and their behavior was quantified during a 6-min trial. (PhSe)2 treatment altered fish behavior in a concentration-dependent manner. At 0.01 and 0.25µM, (PhSe)2 did not elicit effects on fish behavior. At 0.5µM, moderate behavioral side effects (e.g., lethargy and short episodic immobility) were noted. At the highest concentration tested (1µM), dramatic side effects were observed, such as burst behavior and longer periods of immobility. The results were confirmed by spatiotemporal analysis of each group. Occupancy plot data showed dispersed homebase formation in the 0.25µM (PhSe)2-treated group compared with the control group (treated with 0.04% DMSO). Furthermore, animals treated with 0.25µM (PhSe)2 showed a reduction in latency to enter the top and spent more time in the upper area of the tank. These data suggest that (PhSe)2 may induce an anxiolytic-like effect in situations of anxiety evoked by novelty.
Asunto(s)
Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Derivados del Benceno/farmacología , Conducta Exploratoria/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Estrés Psicológico/tratamiento farmacológico , Animales , Ansiolíticos/efectos adversos , Derivados del Benceno/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Pruebas Neuropsicológicas , Compuestos de Organoselenio/efectos adversos , Distribución Aleatoria , Pez CebraRESUMEN
Several diets employed in aquaculture are enriched with selenium (Se), as it is a fundamental element to aquatic vertebrates. Diphenyl diselenide [(PhSe)2], which is a synthetic organoselenium compound, has been considered a potential antioxidant agent in different experimental models. Thus, the aim of this study was to evaluate the effects of dietary diphenyl diselenide at concentrations of 1.5, 3.0, and 5.0 mg/kg for 60 days and to determine its optimal supplemental level for carp, Cyprinus carpio. Neither growth retardation nor hepatoxicity was induced by the inclusion of diphenyl diselenide at concentrations ranging from 1.5 to 5.0 mg/kg. In addition, the inclusion of 3.0 mg/kg of diphenyl diselenide stimulated the weight and length of the carp. The supplementation with 1.5 and 3.0 mg/kg of diphenyl diselenide did not produce oxidative damage in the tissues, verified by peroxidation lipid and protein carbonyl assays. However, at 5.0 mg/kg, it caused an increase of the lipid peroxidation in the liver, brain, and muscle, and inhibited the cerebral acetylcholinesterase activity. An increase of the hepatic superoxide dismutase activity and non-protein thiols content in all tissues and ascorbic acid in the liver, gills, and brain was verified in carp fed with the diet containing 3.0 mg/kg of diphenyl diselenide. This diet had advantageous effects for the fish used in experiments. Therefore, this compound could be considered a beneficial dietary supplement for carp nutrition.
Asunto(s)
Derivados del Benceno/administración & dosificación , Carpas , Compuestos de Organoselenio/administración & dosificación , Acetilcolinesterasa/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Acuicultura , Derivados del Benceno/efectos adversos , Peso Corporal/efectos de los fármacos , Catalasa/metabolismo , Dieta , Glutatión Transferasa/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Compuestos de Organoselenio/efectos adversos , Porfobilinógeno Sintasa/sangre , Carbonilación Proteica/efectos de los fármacos , Compuestos de Sulfhidrilo/metabolismo , Superóxido Dismutasa/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25-100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25-100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10-50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10-50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.
Asunto(s)
Dolor Agudo/prevención & control , Analgésicos no Narcóticos/uso terapéutico , Neuronas/efectos de los fármacos , Dolor Nociceptivo/prevención & control , Compuestos de Organoselenio/uso terapéutico , Dolor Agudo/sangre , Dolor Agudo/fisiopatología , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Animales , Conducta Animal , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Locomoción/efectos de los fármacos , Masculino , Ratones , Dolor Nociceptivo/sangre , Dolor Nociceptivo/fisiopatología , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/efectos adversos , Dimensión del Dolor , Distribución Aleatoria , Pruebas de Toxicidad Aguda , Aumento de Peso/efectos de los fármacosRESUMEN
The purpose of this study was to provide data about in vivo tissue distribution and excretion of diphenyl diselenide ((PhSe)2) in rats and mice through determination of selenium levels in different biological samples. (PhSe)2 (500 mg/kg, dissolved in canola oil) was administered to animals once a day per oral. After this, mice and rats were housed in metabolic cages (one animal per cage) and urine and feces were collected at specific times after treatment. Three to five animals per group (for each time-point) were anesthetized and blood samples were collected at 0 and 30 min, 24 h, at day 5, 15, and 30 after (PhSe)2 administration. The plasma and red blood cells were separated. Brain, liver, lungs, kidneys, and adipose tissue were also collected. The determination of selenium levels was performed by inductively coupled plasma atomic emission spectrometry. The main results indicate that: (1) urine is an important route of excretion of selenium originated from (PhSe)2 in mice and rats; (2) a large amount of (PhSe)2 or some of its metabolites are stored in fat; (3) the content of selenium found in plasma was low; and (4) liver and kidneys are the tissues with high amounts of selenium.
Asunto(s)
Tejido Adiposo/metabolismo , Derivados del Benceno/farmacocinética , Riñón/metabolismo , Hígado/metabolismo , Compuestos de Organoselenio/farmacocinética , Selenio/metabolismo , Tejido Adiposo/química , Tejido Adiposo/efectos de los fármacos , Animales , Derivados del Benceno/efectos adversos , Derivados del Benceno/análisis , Derivados del Benceno/metabolismo , Biotransformación , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Eritrocitos/química , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Heces/química , Riñón/química , Riñón/efectos de los fármacos , Hígado/química , Hígado/efectos de los fármacos , Pulmón/química , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Tasa de Depuración Metabólica , Ratones , Neuronas/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/análisis , Compuestos de Organoselenio/metabolismo , Ratas , Ratas Wistar , Selenio/análisis , Selenio/sangre , Selenio/orina , Especificidad de la Especie , Espectrofotometría Atómica , Distribución TisularRESUMEN
INTRODUCTION: Despite progress, chemotherapeutic response in solid malignancies has remained limited. Although initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicate that the surviving cancer is not only able to surmount therapy, but also actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents in a combinatorial setting. AREAS COVERED: Against the broad spectrum of antiangiogenic agents used at present in the clinic, the putative benefits of the use of organoselenium compounds, such as methylselenocysteine (MSC), are discussed in this review. EXPERT OPINION: MSC, being part of the mammalian physiology, is a well-tolerated, versatile and economical antiangiogenic agent. It downregulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisteína/análogos & derivados , Neoplasias/tratamiento farmacológico , Compuestos de Organoselenio/farmacología , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisteína/administración & dosificación , Cisteína/efectos adversos , Cisteína/farmacología , Cisteína/uso terapéutico , Sinergismo Farmacológico , Humanos , Compuestos de Organoselenio/administración & dosificación , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/uso terapéutico , Selenocisteína/análogos & derivadosRESUMEN
Diphenyl diselenide [(PhSe)2], an organoselenium compound, presents pharmacological and toxicological properties in rodents. The aim of this study was to carry out the determination and quantification of (PhSe)2 in plasma after oral administration (p.o.) of this compound (500 mg/kg), dissolved in canola oil, in rats and mice. The second objective was to verify the involvement of different routes of administration ((p.o.), intraperitoneal (i.p.) and subcutaneous (s.c.)) and vehicle solutions (canola oil and dimethyl sulfoxide (DMSO)) in the appearance of seizure episodes and in the plasmatic levels of (PhSe)2 in rats and mice. Analysis of (PhSe)2 in blood samples was performed by gas chromatography/flame ionized detector system (GC/FID). Rat and mouse peak plasma (PhSe)2 levels were 13.13 and 10.11 microg/ml (C(max)), respectively, and occurred at 0.5h (T(max)) post-dosing. The use of different administration routes (p.o., i.p. and s.c.) and vehicle solutions (canola oil or DMSO) in rats and mice indicated that the appearance of seizures and (PhSe)2 plasmatic levels are dependent of administration routes (i.p.>p.o.>s.c.), vehicle solutions (DMSO>canola oil) and animal species (mice>rat).
Asunto(s)
Derivados del Benceno/efectos adversos , Derivados del Benceno/sangre , Compuestos de Organoselenio/efectos adversos , Compuestos de Organoselenio/sangre , Convulsiones/inducido químicamente , Administración Oral , Animales , Derivados del Benceno/administración & dosificación , Dimetilsulfóxido , Relación Dosis-Respuesta a Droga , Ácidos Grasos Monoinsaturados , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Compuestos de Organoselenio/administración & dosificación , Aceite de Brassica napus , Ratas , Ratas Wistar , Convulsiones/sangre , Soluciones , Especificidad de la Especie , Factores de TiempoRESUMEN
Selenium compounds, like diphenyl diselenide (Ph(2)Se(2)), possess glutathione peroxidase (GSHPx)-like activities and other antioxidant properties. The aim of this study was to evaluate the effects of a long-term oral supplementation with Ph(2)Se(2) on various toxicological parameters in rabbits. Adult New Zealand male rabbits were divided into four groups: Group I served as control; Groups II, III and IV received 0.3, 3.0 and 30 p.p.m. of Ph(2)Se(2) pulverized in the chow for 8 months. A number of toxicological parameters were examined in liver, kidney, cerebral cortex and hippocampus, such as delta-aminolaevulinic acid dehydratase (delta-ALA-D), catalase (CAT), GSHPx activities, non-protein thiol (-SH), lipid peroxidation and ascorbic acid levels. The results indicated that supplementation 30 p.p.m. Ph(2)Se(2 )significantly increased delta-ALA-D activity in liver and in cerebral cortex. Non-protein -SH levels were significantly increased in liver but not in kidney, cerebral cortex and hippocampus of rabbits. Ascorbic acid content was significantly lower in the liver and cerebral cortex after supplementation with 30 p.p.m. Ph(2)Se(2). Conversely, no alterations in GSHPx and CAT activities, nor in thiobarbituric acid reactive substances levels were observed in rabbit tissues. These results indicate that oral supplementation with Ph(2)Se(2) is relatively secure in rabbits after 8 months of exposure. The findings encourage further experiments on the potential therapeutic effects of such compound.
Asunto(s)
Antioxidantes/efectos adversos , Derivados del Benceno/efectos adversos , Encéfalo/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Compuestos de Organoselenio/efectos adversos , Animales , Antioxidantes/farmacocinética , Ácido Ascórbico/metabolismo , Derivados del Benceno/farmacocinética , Catalasa/metabolismo , Relación Dosis-Respuesta a Droga , Glutatión Peroxidasa/metabolismo , Peroxidación de Lípido/fisiología , Masculino , Compuestos de Organoselenio/farmacocinética , Porfobilinógeno Sintasa/metabolismo , Conejos , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factores de TiempoRESUMEN
PURPOSE: It was previously shown that nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for cyclophosphamide (CP) induced cystitis. In this study we evaluated whether peroxynitrite is also responsible for CP induced bladder damage in rats. MATERIALS AND METHODS: A total of 38 male albino Wistar rats were divided into 4 groups. Group 1 served as controls and was given 2 ml saline, while 3 groups received a single dose of CP (200 mg/kg) at the same intervals. Group 2 received CP only, group 3 received the selective iNOS inhibitor aminoguanidine (AG) (100 mg/kg) and group 4 received the peroxynitrite scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]-one) (20 mg/kg). RESULTS: CP injection resulted in severe cystitis with continuous macroscopic hemorrhage, strong edema, inflammation and ulceration. Moreover, bladder tissue malondialdehyde levels, iNOS activation and urine nitrite-nitrate levels were dramatically increased. AG histologically protected bladder against CP damage and decreased urine nitrite-nitrate levels, bladder malondialdehyde and iNOS induction. Ebselen showed results similar to those of AG without changing the urinary nitrite-nitrate level and iNOS activity. CONCLUSIONS: These results suggest that not only nitric oxide, but also peroxynitrite may be important in the pathogenesis of CP induced cystitis.
Asunto(s)
Azoles/efectos adversos , Ciclofosfamida/efectos adversos , Cistitis/inducido químicamente , Depuradores de Radicales Libres/efectos adversos , Guanidinas/efectos adversos , Compuestos de Organoselenio/efectos adversos , Ácido Peroxinitroso/fisiología , Animales , Antioxidantes/administración & dosificación , Azoles/administración & dosificación , Ciclofosfamida/administración & dosificación , Depuradores de Radicales Libres/administración & dosificación , Guanidinas/administración & dosificación , Isoindoles , Masculino , Compuestos de Organoselenio/administración & dosificación , Ratas , Ratas WistarRESUMEN
BACKGROUND: Selenium is a trace mineral essential to human health, which has an important role in the immune response, defence against tissue damage and thyroid function. Improving selenium status could help protect against overwhelming tissue damage and infection in critically ill adults. OBJECTIVES: This review assessed the effects of selenium supplementation including the selenium-containing compound, ebselen, on adults recovering from critical illness. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library, Issue 2, 2003), MEDLINE, (1966 to July 2003), EMBASE (1980 to Week 30 2003),CAB NAR (1973 to March 2003), BIOSIS (1985 to July 2003), CINAHL (1982 to July 2003), HEALTHSTAR (1975 to September 2002), Current Controlled Trials, and reference lists. We contacted investigators, and handsearched four journals. Date of the most recent search: December 2003. SELECTION CRITERIA: Randomized trials of selenium or ebselen supplementation by any route, in adults with critical illness (including burns, head injury, brain haemorrhage, cerebrovascular accident and surgery). DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. We sought additional information as required from trialists. We also undertook pooling of data for outcomes and selected exploratory analyses were undertaken. MAIN RESULTS: Seven randomized trials involving813participants were included. The quality of trials, as reported, was poor, particularly for allocation concealment. The availability of outcome data was limited and trials involving selenium supplementation, were small. Thus the results must be interpreted with caution. Because of heterogeneity, results are presented for the random effects models. Four selenium trials showed no statistically significant difference in mortality (relative risk (RR) 0.52, 95% confidence interval (CI) 0.20 to 1.34). Three trials of ebselen also showed no statistically significant difference in mortality (RR 0.83, 95% CI 0.51 to 1.35). One trial of selenium found no statistically significant difference between groups for participants developing infection (RR 1.33, 95% CI 0.55 to 3.24). Three trials of ebselen provided data for participants developing infections (pyrexia, respiratory infections or meningitis), which was not statistically significant (RR 0.60, 95% CI 0.36 to 1.02). No clear evidence emerged for the benefits of selenium or ebselen supplementation for the outcomes of days on a ventilator, length of intensive care unit stay, length of hospital stay or quality of life. REVIEWERS' CONCLUSIONS: There is insufficient evidence to recommend supplementation of critically ill patients with selenium or ebselen. Trials are required which overcome the defects of the reviewed studies, particularly inadequate size and methodology. This review will be updated when four ongoing trials are completed.
Asunto(s)
Antioxidantes/uso terapéutico , Azoles/uso terapéutico , Enfermedad Crítica/terapia , Suplementos Dietéticos , Compuestos de Organoselenio/uso terapéutico , Selenio/uso terapéutico , Adulto , Antioxidantes/efectos adversos , Azoles/efectos adversos , Enfermedad Crítica/mortalidad , Humanos , Isoindoles , Compuestos de Organoselenio/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Selenio/efectos adversosRESUMEN
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a seleno-organic compound, mimics glutathione peroxidase and reacts with peroxynitrite. It is reported to protect against gentamicin- and cisplatin-induced ototoxicity. We investigated whether it protects the cochlea from acoustic trauma. Male pigmented guinea pigs (250-300 g) with normal auditory brainstem response (ABR) thresholds were exposed for 5 h to 125 dB sound pressure level octave band noise centered at 4 kHz. One hour before and 18 h after exposure, they received orally 0.25 ml chloroform solution containing 0, 10, or 30 mg/kg ebselen (n=6, 5 and 5, respectively). The protective effect of ebselen was evaluated by ABR measurement and quantitative hair cell assessment. Treatment significantly (P<0.01) reduced the extent of permanent threshold shifts and outer hair cell loss. Interestingly, the protective effect of a 30 mg/kg dose was less than that of a 10 mg/kg dose. There were no adverse systemic or auditory function effects in three unexposed control subjects given 30 mg/kg ebselen. These findings indicate that ebselen attenuates noise-induced cochlear damage. The concentration that provides optimal protection against such damage has now to be determined.