Genetic toxicology and preliminary in vivo studies of nitric oxide donor tocopherol analogs as potential new class of antiatherogenic agents.

Nitric oxide donor tocopherol analogs were found to be incorporated in low-density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs.

Identification of chalcones as in vivo liver monofunctional phase II enzymes inducers.

Cancer preventive agents (CPA) are drugs able to suppress the carcinogen metabolic activation or block the formation of ultimate carcinogens. CPA could act through various molecular mechanisms, for example by interfering with the action of procarcinogen. This could be attained by increasing the phase II enzymes levels of quinone reductase (QR) and glutathione S-transferase (GST). New flavonoids, especially chalcones, have been identified as in vivo monofunctional phase II enzymes inducers. Oral administration of chalcone, 4, and both p-methoxy-substituted chalcones, 6 and 14, increased hepatic QR activity with concomitant decrease in CYP1A1 activity, a member of the most important group of phase I enzymes cytochrome P450. Among them, 4 also increased GST activity. While p-bromo-substituted chalcone 8 was the best inducer of QR it decreased hepatic GST expression and cytochrome P450, being the most effective decreasing cytochrome P450-expression. Thienyl-chalcone 20 being the bioisostere of chalcone 4 did not display the same in vivo profile in the phase I level modification. As chalcone 4 its bioisostere, chalcone 20, displayed low DNA strand breakage and absence of mutagenicity. Also, in our preliminary in vivo tumourigenesis/chemopreventive and acute-toxicity studies, chalcones 4, 6 and 8 showed the best behaviours as CPA justifying additional studies that are ongoing.

Valores de referencia de analitos en orina en la edad pediatrica / Reference values of analytes in urine in the pediatric age / Valores de referência de analitos na urina na idade pediátrica

La deteccion de trastornos metabolicos minerales puede explicar diversas anomalias fisiologicas que exigen para su interpretacion la comparacion con valores de referencia validados. El objetivo de este trabajo fue la determinacion de valores de referencia en la poblacion infantil uruguaya, de los analitos sodio, potasio, calcio, magnesio, fosforo y urato relacionados con la creatinina en muestras de la segunda miccion de la manana en 470 escolares (240 ninas y 230 ninos) con edades comprendidas entre 7 y 12 anos. Las medianas obtenidas fueron: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. A excepcion de los cocientes Na/Crea y K/Crea se encontro una disminucion de la excrecion de estos analitos con la edad, independientemente del sexo. Los valores obtenidos resultaron ser analogos a los de otras poblaciones con tipo de alimentacion similar.

The detection of mineral metabolic disorders can explain several pathologies which require the comparison with reference values for their interpretation. The aim of this study was to determine the reference values of 470 Uruguayan school children with ages between 7 and 12 for sodium, potassium, calcium, magnesium, phosporous and urate and their relationship with creatinine in urine samples of the second urination of the morning. The median obtained were: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. A diminishment of excretion with the age was found, regardless the sex, except for Na/Crea and K/Crea. The values obtained were similar to those of others populations with a similar diet.

A detecção de distúrbios metabólicos minerais pode explicar várias anomalias fisiológicas, que exigem a comparação com valores de referência validados para serem interpretados. O objetivo deste estudo foi determinar valores de referência na população infantil uruguaia, dos analitos sódio, potássio, cálcio, magnésio, fósforo e urato relacionados com a creatinina em amostras da segunda micção da manhã em 470 alunos (240 meninas e 230 meninos) com idades entre 7 e 12 anos. As medianas obtidas foram: Na/Crea: 139 mmol/g, K/Crea: 78 mmol/g, Ca/Crea: 77 mg/g, Mg/Crea: 71 mg/g, P/Crea: 500 mg/g, Ur/Crea: 554 mg/g, Crea: 117 mg/dL. Com exceção dos quocientes Na/Crea e K/Crea, foi encontrada uma diminuição na excreção destes analitos com a idade independentemente do sexo. Os valores obtidos foram análogos aos de outras populações com um tipo similar de dieta.

Encuesta de ioduria como control de la ingesta de iodo / Survey on urinary iodine as iodine intake control / Pesquisa de iodúria como um controle da ingestão de iodo

Desde 1964, año en que se incorporó iodo a la sal de mesa, ha disminuido notoriamente el bocio endémico en Uruguay. Por haberse modificado con posteridad, en dos oportunidades la proporción del iodo en la misma, se tornó imprescindible reevaluar los niveles de la ingesta poblacional siguiendo las recomendaciones de la OMS. Los objetivos de este estudio fueron evaluar los niveles de iodo en la población a través de las iodurias, seleccionar la mejor forma de expresar su excreción y estudiar la relación de las mismas con el sodio urinario. Se analizaron 491 muestras de orina de niños en edad escolar, de nueve departamentos del Uruguay y se determinó iodo, sodio y creatinina. Se observó una mediana de 0,248 mg/L de iodo, valor adecuado según las recomendaciones de la OMS (0,100-0,300 mg/L), una distribución no paramétrica de la ioduria expresada como cociente de Iodo/ creatinina en mg/g que discrimina mejor los valores atípicos respecto de la expresión de iodurias en mg/L, una pobre relación entre la excreción de iodo y el sodio, (r2=0,199) lo que indica que su aporte no es exclusivo de la sal de mesa y un predominio de excreción más elevado en los niños de menor edad respecto de los mayores.

The presence of endemic goiter in Uruguay has decreased markedly since the addition of iodine to table salt in 1964. It was essential to evaluate the population levels of iodine intake accordingly to WHO specifications, since iodine support to the table salt has been modified twice. The aims of this study were to evaluate the levels of iodine in the population through the urinary iodine levels, select the best way to express their excretion and study the relationship thereof with urinary sodium. Four hundred ninety- one urine samples were analyzed from school children from nine states of Uruguay and sodium, creatinine and iodine were measured. The iodine median was 0.248 mg/L, an adequate value according to WHO specifications (0.100-0.300 mg/L). The expression of urinary iodine as the ratio between urinary iodine and urinary creatinine (mg/g) had a non-parametric distribution that discriminate the atypical values better than the urinary iodine (mg/L). The relationship between iodine excretion and sodium was poor (r2=0.199), indicating that the input of iodine does not come exclusively from table salt. Younger children had a greater excretion than older ones.

Desde 1964, quando o iodo foi adicionado ao sal de mesa, diminuiu acentuadamente o bócio endêmico no Uruguai. Por ter sido modificada posteriormente, em duas oportunidades, a proporção do iodo no mesmo, tornou-se essencial reavaliar os níveis de ingestão da população seguindo as recomendações da OMS. Os objetivos deste estudo foram avaliar os níveis de iodo na população através das iodúrias, selecionar a melhor maneira de expressar sua excreção e estudar a relação das mesmas com o sódio urinário. 491 amostras de urina de crianças em idade escolar, de nove departamentos do Uruguay foram analisadas, determinando-se iodo, sódio e creatinina. Foi observada uma mediana de 0.248 mg/L de iodo, valor apropriado de acordo com as recomendações da OMS (0.100-0.300 mg/L), também uma distribuição não paramétrica expressa como quociente de iodo/creatinina em mg/g que discrimina de uma maneira melhor os valores atípicos para a expressão de iodúrias em mg/L, uma pobre relação entre a excreção de iodo e de sódio, (r2=0,199 ), indicando que a sua contribuição não é exclusiva do sal de mesa e uma predominância de excreção maior nas crianças mais novas em relação às maiores.

Novel Phenazine 5,10-Dioxides Release OH in Simulated Hypoxia and Induce Reduction of Tumour Volume In Vivo.

Phenazine 5,10-dioxides (PDOs) are a new class of bioreductive cytotoxins, which could act towards tumours containing hypoxic regions. The PDOs selective-hypoxic bioreduction was probed in vitro; however, the mechanism of action has not been completely explained. Besides, PDOs in vivo antitumour activities have not been demonstrated hitherto. We study the mechanism of hypoxic/normoxic cytotoxicity of PDO representative members. Electron spin resonance is used to confirm (•)OH production, alkaline comet assay to determine genotoxicity, and gel electrophoresis and flow cytometry to analyze DNA fragmentation and cell cycle distribution. Chemically induced rat breast tumours are employed to evaluate in vivo activities. For the most selective cytotoxin, 7(8)-bromo-2-hydroxyphenazine 5,10-dioxide (PDO1), exclusive hypoxic (•)OH production is evidenced, while for the unselective ones, (•)OH is produced in both conditions (normoxia and simulated hypoxia). In normoxia (Caco-2 cells), PDO1 induces cell-cycle arrest and DNA fragmentation but does not significantly induce apoptosis neither at IC(50) nor IC(80). No difference in the comet-assay scores are observed in normoxia and simulated hypoxia being the unselective 2-amino-7(8)-bromophenazine 5,10-dioxide (PDO2) the most genotoxic. The in vivo efficacy with the absence of systemic toxicity of PDO1 and PDO2 is checked out. Results from this study highlight the potential of PDOs as new therapeutics for cancer.

5-Nitro-2-furyl derivative actives against Trypanosoma cruzi: preliminary in vivo studies.

Ten 5-nitro-2-furyl derivatives, with good to excellent in vitro anti-Trypanosoma cruzi activity, and nifurtimox were tested oral and intraperitoneally on healthy animals for its acute toxicity on murine models. According to animals' survival percentage, organ histological results, biochemical and haematological findings, three new derivatives, with toxicity like nifurtimox, were selected to test in vivo as antichagasic agents. Clearly, dependences between chemical structure and both acute toxicity and in vivo anti-T. cruzi activity were observed. 4-Hexyl-1-[3-(5-nitro-2-furyl)-2-propenylidene]semicarbazide displayed good profile as anti-T. cruzi agent and better acute toxicity profile than nifurtimox.

Colesterol total y fracciones en mujeres embarazadas normales / Serum total cholesterol and fractions in normal pregnant women

Se reportan las variaciones del colesterol total y del HDL y no HDL colesterol, así como el Indice de Castelli, en un estudio transversal realizado en intervalos de tiempo similares en embarazadas normales. Los datos provenientes de 210 mujeres embarazadas normales en diferentes estadios, se compararon con los de una población de referencia de 30 mujeres normales no grávidas con edades similares. El colesterol HDL fue aislado con ácido fosfotúngstico/cloruro de magnesio, el colesterol se determinó enzimáticamente y el Indice de Castelli así como el no HDL colesterol fueron calculados en cada caso. Nuestro objetivo es estudiar los cambios lipídicos en esta en esta población de embarazadas con el propósito de establecer los valores de referencia e investigar si la gestación podría estar relacionada a situaciones de riesgo cardiovascular. El HDL colesterol decreció significativamente entre las semanas 24a y 28a, al tiempo que el Indice de Castelli alcanzó el máximo valor de riesgo. Desde este punto de vista se puede deducir que este proceso puede estar relacionado con el comienzo de la resistencia a la insulina y el mayor riesgo de aparición de diabetes gestacional(AU)

Colesterol total y fracciones en mujeres embarazadas normales / Serum total cholesterol and fractions in normal pregnant women

Se reportan las variaciones del colesterol total y del HDL y no HDL colesterol, así como el Indice de Castelli, en un estudio transversal realizado en intervalos de tiempo similares en embarazadas normales. Los datos provenientes de 210 mujeres embarazadas normales en diferentes estadios, se compararon con los de una población de referencia de 30 mujeres normales no grávidas con edades similares. El colesterol HDL fue aislado con ácido fosfotúngstico/cloruro de magnesio, el colesterol se determinó enzimáticamente y el Indice de Castelli así como el no HDL colesterol fueron calculados en cada caso. Nuestro objetivo es estudiar los cambios lipídicos en esta en esta población de embarazadas con el propósito de establecer los valores de referencia e investigar si la gestación podría estar relacionada a situaciones de riesgo cardiovascular. El HDL colesterol decreció significativamente entre las semanas 24a y 28a, al tiempo que el Indice de Castelli alcanzó el máximo valor de riesgo. Desde este punto de vista se puede deducir que este proceso puede estar relacionado con el comienzo de la resistencia a la insulina y el mayor riesgo de aparición de diabetes gestacional