Estudio de la descomposición térmica de cis-6-fenil-5,6-(2-fenilpropiliden)-3,3-tetrametilen-1,2,4-trioxaciclohexano en solución

En los últimos años diferentes autores han orientado sus investigaciones a la síntesis de compuestos útiles en el tratamiento farmacológico de la enfermedad malaria. Entre estas sustancias se encuentra el cis-6-fenil-5,6-(2- fenilpropiliden)-3,3-tetrametilen-1,2,4-trioxaciclohexano (AJ-30) sintetizado en la Universidad de Ginebra, Suiza, en 1955. Diversos investigadores sostienen que la función principal responsable de la potente acción antimalárica de este compuesto es el anillo 1,2,4-trioxano, siendo el mecanismo de acción actualmente aceptado la generación de radicales libres que ejercen su acción en puntos específicos del agente causante de la enfermedad. Esta alternativa mecanicista propuesta implica la ruptura del enlace O-O, por lo que sigue siendo la vía más probable de explicación de la actividad antimalárica. En este trabajo se presenta el estudio cinético de la descomposición térmica del AJ-30 en solución de solventes de diferentes propiedades fisicoquímicas y los resultados se comparan con los obtenidos para compuestos con estructuras similares. En todos los solventes estudiados se ha demostrado que la reacción de descomposición térmica del AJ-30 responde a una ley cinética de pseudo-primer orden hasta conversiones del trioxano superiores al 50%, para bajas concentraciones iniciales del trioxano (10-3 a 10-5 M) y en un amplio ámbito de temperaturas (89 a 140 °C). La reacción de termólisis se efectuó en condiciones experimentales que inhiben procesos de descomposición inducida por el ataque de radicales libres presentes en el medio de reacción. Los diferentes productos de reacción identificados permiten postular que la descomposición térmica de 1,2,4-trioxanos ocurriría a través de un mecanismo en etapas que se inicia por la ruptura homolítica del enlace O-O de las moléculas, con formación de un birradical como intermediario, siendo esta la etapa determinante de la velocidad de reacción. En todos los sistemas trioxano-solvente estudiados se determinaron las constantes de velocidad y los parámetros de activación correspondientes. Se aplicaron diferentes criterios para evaluar el efecto de solvente sobre la reacción de termólisis, efectuando correlaciones que permitieron concluir que no hay una clara compensación de los parámetros de activación, ya que el intervalo de variación de los respectivos ΔH‡ y ΔS‡ no es lo suficientemente amplio y levemente supera los errores cometidos en las determinaciones experimentales. Del análisis de los valores de constantes de velocidad surge que un aumento en la polaridad del solvente produce un aumento de la reactividad del AJ-30 en solución, con lo que se evidencia un claro efecto de solvente sobre la reactividad del anillo 1,2,4-trioxano. La reacción de termólisis del AJ-30 se comparó con la misma reacción estudiada para otros 1,2,4-trioxanos sustituidos en los mismos solventes y a la misma temperatura, concluyendo que existen variaciones en las constantes de velocidad, que indicarían efectos de sustituyentes significativos sobre la reactividad de los mismos. El estudio del efecto de la naturaleza del medio de reacción sobre la estabilidad térmica del AJ-30 permite obtener conclusiones sobre la forma en que este tipo de sustancias deberían administrarse para producir una acción terapéutica óptima en el tratamiento de la malaria.Facultad de Ciencias Exacta

A kinetic and mechanistic study on the thermal decomposition reactions of cis- and trans- fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reactions of artemisinine (1), a cis-fused 1,2,4-trioxane, and trans-3,3dimethyl-1,2,4-trioxane (6) in solutions of benzene, toluene, and methanol in sealed tubes were compared at temperatures between 100.1° and 171.4 °C. Pseudo first-order rate constant values were determined for conversions of both cyclic peroxides up to ca. 60%. The activation parameters and the composition of the reaction products were indicative of homolytic cleavage of their O-O bonds as the rate-determining steps followed by stepwise fragmentation. The free energies of activation (ΔG#) for 1 and 6 reactions in the aromatic solvents were calculated at the middle of each temperature range, giving values of 30.7 and 35.1 kcal/mol, respectively, which are evaluated considering their different molecular configurations. Furthermore, the rates of the thermal decomposition reactions of those trioxanes were sensitive to solvent effects.Laboratorio de Estudio de Compuestos OrgánicosCentro de Investigación y Desarrollo en Ciencias Aplicada

A kinetic and mechanistic study on the thermal decomposition reactions of cis- and trans- fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reactions of artemisinine (1), a cis-fused 1,2,4-trioxane, and trans-3,3dimethyl-1,2,4-trioxane (6) in solutions of benzene, toluene, and methanol in sealed tubes were compared at temperatures between 100.1° and 171.4 °C. Pseudo first-order rate constant values were determined for conversions of both cyclic peroxides up to ca. 60%. The activation parameters and the composition of the reaction products were indicative of homolytic cleavage of their O-O bonds as the rate-determining steps followed by stepwise fragmentation. The free energies of activation (ΔG#) for 1 and 6 reactions in the aromatic solvents were calculated at the middle of each temperature range, giving values of 30.7 and 35.1 kcal/mol, respectively, which are evaluated considering their different molecular configurations. Furthermore, the rates of the thermal decomposition reactions of those trioxanes were sensitive to solvent effects.Laboratorio de Estudio de Compuestos OrgánicosCentro de Investigación y Desarrollo en Ciencias Aplicada

Thermal decomposition reaction of cis-6-phenyl-5,6-(2-phenyl-propilydene)- 3,3-tetramethylene-1,2,4-trioxacyclohexane in different solvents

The kinetics of the thermal decomposition reaction of cis-6-phenyl-5,6-(2- phenyl-propilydene)-3,3-tetramethylene-1,2,4-trioxacyclohexane (I) was investigated in the temperature range of 100-130°C in selected solvents of different physicochemical properties to evaluate a solvent effect on the reaction.Facultad de Ciencias Exacta

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Kinetics of tocopherol degradation during the storage of wheat germ oil

Tocopherol degradation in wheat germ oil was studied during storage at different temperatures. Two types of wheat germ were used: heat-treated germ (HT) and raw germ (RG). The oil was extracted (Soxhlet, n-hexane) and stored at 25 and 47°C (82 days) and at -20 and 5°C (600 days). Tocopherols were determined by HPLC. Total tocopherol, α-tocopherol, and β-tocopherol decreased following first-order kinetics. At 25 and 47°C, the values of the degradation rate constants for total tocopherol were 5.00×10-3 days-1 (RG), 3.00×10-3 days-1 (HT), and 5.37 ×10-2 days-1 (RG), 2.57×10-2 days-1 (HT), respectively, indicating an increase in tocopherol degradation rate with increasing temperature. The reaction rates of total tocopherol were similarly affected at 5 and -20°C, with lower rate constants (4×10-4 and 2×10-4 days-1, respectively). α-tocopherol degraded faster than β-tocopherol, presenting higher rate constants. Low temperatures favour the preservation of tocopherols.Fil: Magariño, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; ArgentinaFil: Mateo, Carmen Margarita. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; ArgentinaFil: Nolasco, Susana Maria. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; Argentin

Dynamics of oil and tocopherol accumulation in sunflower grains and its impact on final oil quality

Tocopherols are one of the most important bioactive compounds in vegetable oils. It is known that these antioxidants present a dilution like relationship with oil weight per grain but the mechanism underlying this relationship are unknown. The aim of this work was to analyze the dynamics of tocopherol accumulation in sunflower grains, its relationship with oil accumulation and its effects on final oil quality in genotypes with different fatty acid composition. Three field experiments were conducted with genotypes with different potential fatty acid composition (a traditional, a high oleic and a high stearic−high oleic) and treatments with different source (intercepted solar radiation) or sink (grains) during grain filling to obtain varied grain filling conditions and grains with different oil concentration and oil unsaturation. Intercepted solar radiation modified oil per grain but did not affect tocopherol per grain. The rate of accumulation explained 79% and 74% of the oil and tocopherol per grain variation, respectively. When intercepted solar radiation increased, the duration of the period of oil and tocopherols accumulation increased, being the first the most responsive. These differences in the duration of accumulation periods are reflected in a larger relative increase in oil than tocopherols per grain and thus a dilution of the latter in the oil. These differences in the dynamics of oil and tocopherol accumulation are common to genotypes with different level of unsaturation. These results help to understand the mechanism associated with the dilution curve of oil tocopherol concentration reported in the literature.Fil: González Belo, Raúl. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Nolasco, S.. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Mateo, Carmen Margarita. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Izquierdo, Natalia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias; Argentina. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; Argentin

Bidimensional modeling applied to oil extraction kinetics of microwave-pretreated canola seeds

The effect of microwaves on canola oil extraction kinetics and on tocopherol and canolol content in oil was studied. Oil was extracted with hexane at constant temperature (298–333 K) at different times (300–64800 s). In general, for each temperature and time, a significant yield increase was achieved by effect of the pretreatment. A modified Fick's diffusion model was proposed to explain the extraction process; the parameters were adjusted to obtain washing fractions and the effective diffusion coefficient, which presented an Arrhenius-type temperature-dependence. The analysis of the parameters allowed to develop a modified bidimensional diffusion model (temperature and time-dependent), appropriately correlating the data for pretreated and untreated samples. An increase in the pre-exponential parameter due to pretreatment was observed, evidencing the influence of microwave radiation on the sample structure. The pretreatment did not significantly affect the oil quality indices, but increased the content of canolol and β and δ-tocopherol isomers.Fil: Sánchez, Ramiro Julián. Ministerio de Ciencia. Tecnología e Innovación Productiva. Agencia Nacional de Promoción Cientifíca y Tecnológica; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; ArgentinaFil: Mateo, Carmen Margarita. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; ArgentinaFil: Fernández, María Belén. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires. - Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigaciones en Física e Ingeniería del Centro de la Provincia de Buenos Aires; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; ArgentinaFil: Nolasco, Susana Maria. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingeniería Olavarría. Grupo Tecnologías de Semillas; Argentin

A kinetic and mechanistic study on the thermal decomposition reactions of cis- and trans- fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reactions of artemisinine (1), a cis-fused 1,2,4-trioxane, and trans-3,3dimethyl-1,2,4-trioxane (6) in solutions of benzene, toluene, and methanol in sealed tubes were compared at temperatures between 100.1° and 171.4 °C. Pseudo first-order rate constant values were determined for conversions of both cyclic peroxides up to ca. 60%. The activation parameters and the composition of the reaction products were indicative of homolytic cleavage of their O-O bonds as the rate-determining steps followed by stepwise fragmentation. The free energies of activation (ΔG#) for 1 and 6 reactions in the aromatic solvents were calculated at the middle of each temperature range, giving values of 30.7 and 35.1 kcal/mol, respectively, which are evaluated considering their different molecular configurations. Furthermore, the rates of the thermal decomposition reactions of those trioxanes were sensitive to solvent effects.Fil: Cafferata, Lazaro. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Jeandupeax, Rene. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; ArgentinaFil: Romanelli, Gustavo Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Mateo, Carmen Margarita. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ingenieria de Olavarria; ArgentinaFil: Jefford, Charles W.. Università degli Studi di Genova; Itali