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.

A Summary of Worldwide National Activities in Chronic Kidney Disease (CKD) Testing.

Chronic kidney disease (CKD) is a major public health issue worldwide and is associated with adverse health outcomes, especially in low- and middle-income countries. In a cash limited healthcare system, guidelines that improve the efficiency of health care free up resources needed for other healthcare services. This short review presents some examples from national acitivities in CKD testing, including countries throughout the globe: Mexico in North America, Uruguay in South America, Italy in Europe, Nigeria in Africa and India in Asia. Considering the fact that treatment of CKD is cost-effective and improves outcomes, this observation argue in favor of including CKD in national guidelines and noncommunicable chronic disease (NCD) programs. This diverse example of national activities fullfil the very first step in achieving this goal.

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.

Primer Consenso Nacional sobre Proteinuria en el diagnóstico y la evaluación de la enfermedad renal crónica en Adultos / First National Consensus on Proteinuria in the diagnosis and evaluation of chronic kidney disease in Adults

Mediante revisión de PubMed y opinión de expertos los autores concluyeron que proteinuria y albuminuria son marcadores de diagnóstico de enfermedad renal crónica (ERC), son indicadores de progresión y por lo tanto un objetivo terapéutico y además son marcadores de riesgo de muerte y enfermedad CV tanto en población general como en pacientes con ERC. Estos resultados se confirmaron utilizando la tira reactiva, el cociente albuminuria/creatininuria (A/C) o el cociente proteinuria/creatininuria (P/C) en muestra de orina con referencia a la proteinuria en orina de 24 hs (gold standard). El índice A/C parece ser el método ideal porque será el más fácil de estandarizar, pero su costo es mayor y el índice P/C es buen predictor a un costo menor. Las tiras reactivas tienen 29% de falsos positivos pero si somos estrictos en la recolección de la muestra de orina y la lectura es automatizada se reduce la posibilidad de error y la variabilidad de resultados. Se establecen por consenso las etapas preanalíticas, analíticas y post-analíticas de la medición de proteinuria y albuminuria en laboratorio para precisar mejor el diagnóstico y evolución de ERC.

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 (ò)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 (ò)OH production is evidenced, while for the unselective ones, (ò)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(AU)

Evaluación de inhibidores fisiológicos de la coagulación en pacientes diabéticos tipo 2 / Evaluation about coagulation physiological inhibitors in type 2 diabetic patients

La diabetes mellitus está asociada a disturbios en la hemostasis que pueden contribuir al desarrollo de enfermedad vascular diabética. El objetivo de este trabajo fue estudiar la coagulación en una población diabética de Uruguay y compararla con una población de referencia normal. Se trabajó con 100 pacientes diabéticos tipo 2, de ambos sexos (49 mujeres y 51 hombres), con edades comprendidas entre 42 y 79 años, y una población control representada por 130 individuos aparentemente sanos (73 mujeres y 57 hombres) cuyas edades oscilaron entre 37 y 78 años, los que fueron tomados como referencia. Se realizaron las determinaciones de tiempo de protrombina (TP), fibrinógeno (Fib), proteína C (PC), proteína S (PS), antitrombina III (ATIII) e inhibidor del activador de plasminógeno (PAI) en plasma citratado. El TP y el Fib se realizaron por nefelometría, la PC, ATIII y PAI se midieron cromogénicamente y la PS se determinó por coagulometría. Se encontró que los inhibidores fisiológicos de la coagulación PS y ATIII son significativamente menores en la población diabética, en tanto que los factores procoagulantes Fib y PAI son significativamente mayores, comparados con la población de referencia. De los hallazgos precedentes se confirma una tendencia a un disbalance hemostático que contribuiría al estado protrombótico que acompaña a un alto porcentaje de la población diabética.

Diabetes mellitus is associated with disturbances in hemostasis, which may contribute to the development of diabetic vascular disease. Coagulation tests were performed both in diabetic patients and healthy individuals in Uruguay. The results obtained were compared. Diabetic patients were 100, with ages between 42 and 79 years, 49 females and 51 males. Reference population were 130 healthy individuals between 37 and 78 years, 73 females and 57 males. Prothrombin time (PT), fibrinogen( Fib), protein C (PC), protein S (PS), antithrombin III (ATIII) and plasminogen activator inhibitor (PAI) were measured on citrated plasma. PT and Fib were determined nephelometrically, PC, ATIII y PAI were measured cromogenically and PS was determined by coagulometry. Coagulation physiological inhibitors outcomes such as PS and ATIII showed significantly lower levels in the diabetic patient than in the healthy person, and at the same time, Fib and PAI, which are procoagulant factors, have significantly higher concentrations in the diabetic patient than in the healthy person. These findings permit to assess that an impaired haemostatic balance is present in the diabetic population, which may contribute to the hypercoagulability that accompanies a high percentage of these patients.

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

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)