Rifampicina y biodisponibilidad en productos combinados

The drug rifampicin (R) is used as a first line antibiotic treatment for tuberculosis (TB), together withIsoniazide (H), Pyrazinamide (Z) and Ethambutol (E). According to recent statistics, there has been anincrease in TB on a worldwide scale, with the main causes being: monotherapies, the appearance ofresistant microorganisms, the lack of effective preventative programs, non-compliance to treatment andmistaken dosage schedules. The world health organisation (WHO) and the International Union AgainstTuberculosis and Lung Diseases(IUTALD) declared a state of emergency with respect to the disease andestablished programs to increase compliance to therapy and to reduce the incidence of problems arisingfrom such. Along these lines, a list of first line drug therapy treatments were established, whichincluded R, Z, H & E combinations at fixed dosage combinations (FDC), permitting safe combinedadministrations of the drugs at correct dosage levels. These fixed dose combinations have been officiallyrecommended by the WHO in the treatment of TB. However, as has been widely recognised in numerousscientific publications, in such formulations, there are factors that alter the bioavailability of R. Theobjective of this work has been to study the most relevant aspects concerning R bioavailability alterationsand to consider possible solutions to the problem.La rifampicina (R) es un antibiótico de primera elección en el tratamiento de la tuberculosis (TB) juntoa la Isoniazida (H), Pirazinamida (Z) y Etambutol (E). De acuerdo a las últimas estadísticas, la TBaumentó a nivel mundial y entre las causas más citadas figuran: las monoterapias, la aparición demicroorganismos resistentes, la carencia de programas efectivos, el incumplimiento en el tratamiento ylas dosis erróneas. La Organización Mundial de la Salud (OMS) y la Unión Internacional Contra laTuberculosis y Enfermedades de Pulmón (IUATLD) declararon a la enfermedad en emergencia mundialy establecieron programas terapéuticos para asegurar el cumplimiento y disminuir los problemas relacionadosa la terapia. Sobre esta base, figura en la lista oficial la asociación de los cuatro fármacos deprimera línea R, Z, H y E combinados en dosis fijas (FDC) que permiten la administración conjunta delos mismos y, en las dosis correctas. Los productos FDC son recomendados oficialmente por la OMSpara el tratamiento de la TB. No obstante existen factores que alteran la biodisponibilidad de la R enestas formulaciones, hecho ampliamente reconocido en publicaciones científicas. El objetivo de estetrabajo es estudiar los aspectos más relevantes que alteran la biodisponibilidad de la R en los productosFDC y plantear posibles soluciones al problema

Rifampicina y biodisponibilidad en productos combinados

The drug rifampicin (R) is used as a first line antibiotic treatment for tuberculosis (TB), together withIsoniazide (H), Pyrazinamide (Z) and Ethambutol (E). According to recent statistics, there has been anincrease in TB on a worldwide scale, with the main causes being: monotherapies, the appearance ofresistant microorganisms, the lack of effective preventative programs, non-compliance to treatment andmistaken dosage schedules. The world health organisation (WHO) and the International Union AgainstTuberculosis and Lung Diseases(IUTALD) declared a state of emergency with respect to the disease andestablished programs to increase compliance to therapy and to reduce the incidence of problems arisingfrom such. Along these lines, a list of first line drug therapy treatments were established, whichincluded R, Z, H & E combinations at fixed dosage combinations (FDC), permitting safe combinedadministrations of the drugs at correct dosage levels. These fixed dose combinations have been officiallyrecommended by the WHO in the treatment of TB. However, as has been widely recognised in numerousscientific publications, in such formulations, there are factors that alter the bioavailability of R. Theobjective of this work has been to study the most relevant aspects concerning R bioavailability alterationsand to consider possible solutions to the problem.La rifampicina (R) es un antibiótico de primera elección en el tratamiento de la tuberculosis (TB) juntoa la Isoniazida (H), Pirazinamida (Z) y Etambutol (E). De acuerdo a las últimas estadísticas, la TBaumentó a nivel mundial y entre las causas más citadas figuran: las monoterapias, la aparición demicroorganismos resistentes, la carencia de programas efectivos, el incumplimiento en el tratamiento ylas dosis erróneas. La Organización Mundial de la Salud (OMS) y la Unión Internacional Contra laTuberculosis y Enfermedades de Pulmón (IUATLD) declararon a la enfermedad en emergencia mundialy establecieron programas terapéuticos para asegurar el cumplimiento y disminuir los problemas relacionadosa la terapia. Sobre esta base, figura en la lista oficial la asociación de los cuatro fármacos deprimera línea R, Z, H y E combinados en dosis fijas (FDC) que permiten la administración conjunta delos mismos y, en las dosis correctas. Los productos FDC son recomendados oficialmente por la OMSpara el tratamiento de la TB. No obstante existen factores que alteran la biodisponibilidad de la R enestas formulaciones, hecho ampliamente reconocido en publicaciones científicas. El objetivo de estetrabajo es estudiar los aspectos más relevantes que alteran la biodisponibilidad de la R en los productosFDC y plantear posibles soluciones al problema

Síntesis y evaluación citotoxica de derivados halogenados y peracetylados de nucleósidos en celulas de cancer de mama

Objectives. To make the synthesis of halogenated derivatives on the nitrogenous base and their respective acyl ester and amide type derivatives for all hydroxyl and amine groups of the uridine and cytarabine nucleosides, and evaluate cytotoxicity against breast cancer cell line. Methods. First, it was accomplished the halogenation reaction on the 5-position of the nitrogenous base, subsequently, the ester and amide derivatives were performed for all hydroxyl and amine group present in the nucleosides. Besides, the uridine acetonide derivatives as prepared by acid catalysis. The products were characterized by nuclear magnetic resonance spectroscopy (1H RMN y 13C RMN) and mass spectrometry in positive mode by direct injection. Derivatives were evaluated in Chinese hamster ovary (CHO-K1) and human breast cancer (MCF-7) cell lines. Results. The four derivatives were obtained with chlorine and bromine for the uridine and cytarabine, respectively, their respective per-acetylated derivatives, the per-acetylated nucleoside and the uridine acetonide; the compounds were obtained with efficiency over 90%. The per-acetylated nucleosides and the halogenated and per-acetylated derivatives did not show inhibitory effects on cell viability in MCF-7 cell line. However, the per-acetylated and halogenated derivatives presented a higher cytotoxic activity than their respective per-acetylated nucleoside. The uridine 3’,4’-acetonide showed a significant cytotoxicity on both cell lines. Conclusions. The per-acetylated nucleoside, and the respective halogenated derivatives with chlorine and bromine were obtained with high yields, nevertheless, these compounds did not exhibit a significant anti-proliferative activity (p˂0.05), possibly due to a low intra-cellular activation.Objetivos: Sintetizar derivados halogenados sobre la base nitrogenada, sus respectivos derivados tipo éster o amida de todos los grupos hidroxilo y amina presentes en los nucleósidos uridina y citarabina, y evaluar su actividad citotóxica sobre una línea celular de cáncer de mama. Metodología: primero se realizó la reacción de halogenación en la posición 5 de la base nitrogenada, posteriormente se formaron los ésteres y amidas de todos los grupos hidroxilos y amino presentes en los nucleósidos. Además, se preparó el derivado acetónido con catálisis ácida. Los compuestos se caracterizaron por espectroscopía de resonancia magnética nuclear (RMN 1H y RMN 13C) y espectrometría de masas por inyección directa en modo positivo. Los derivados se evaluaron sobre líneas celulares de tumor de Ovario de Hámster Chino (CHO) y de cáncer de mamá (MCF-7). Resultados: Se obtuvieron 4 derivados mono-halogenados con cloro y bromo de la uridina y citarabina, respectivamente, sus respectivos derivados per-acetilados, los nucleósidos per-acetilados y el acetónido de la uridina; los compuestos se obtuvieron con rendimientos superiores a 90%. Los nucleósidos per-acetilados, y los derivados per-acetilados y halogenados no exhibieron una inhibición significativa de la viabilidad celular en ambas líneas celulares, sin embargo, de estos, los derivados per-acetilados y halogenados presentaron mayor actividad citotóxica que los respectivos nucleósidos per-acetilados. El derivado acetónido de la uridina mostró citotoxicidad significativa sobre ambas líneas celulares. Conclusiones: se obtuvieron los nucleósidos per-acetilados y los respectivos derivados clorados y bromados de estos, con rendimientos altos, sin embargo, estos compuestos no exhibieron una actividad anti-proliferativa significativa (p˂0,05), posiblemente debido a una baja activación intra-celular de los nucleósidos

Anomalous material-dependent transport of focused, laser-driven proton beams.

Intense lasers can accelerate protons in sufficient numbers and energy that the resulting beam can heat materials to exotic warm (10 s of eV temperature) states. Here we show with experimental data that a laser-driven proton beam focused onto a target heated it in a localized spot with size strongly dependent upon material and as small as 35 μm radius. Simulations indicate that cold stopping power values cannot model the intense proton beam transport in solid targets well enough to match the large differences observed. In the experiment a 74 J, 670 fs laser drove a focusing proton beam that transported through different thicknesses of solid Mylar, Al, Cu or Au, eventually heating a rear, thin, Au witness layer. The XUV emission seen from the rear of the Au indicated a clear dependence of proton beam transport upon atomic number, Z, of the transport layer: a larger and brighter emission spot was measured after proton transport through the lower Z foils even with equal mass density for supposed equivalent proton stopping range. Beam transport dynamics pertaining to the observed heated spot were investigated numerically with a particle-in-cell (PIC) code. In simulations protons moving through an Al transport layer result in higher Au temperature responsible for higher Au radiant emittance compared to a Cu transport case. The inferred finding that proton stopping varies with temperature in different materials, considerably changing the beam heating profile, can guide applications seeking to controllably heat targets with intense proton beams

Cluster and virial expansions for the multi-species tonks gas

We consider a mixture of non-overlapping rods of different lengths ℓk moving in R or Z. Our main result are necessary and sufficient convergence criteria for the expansion of the pressure in terms of the activities zk and the densities ρk. This provides an explicit example against which to test known cluster expansion criteria, and illustrates that for non-negative interactions, the virial expansion can converge in a domain much larger than the activity expansion. In addition, we give explicit formulas that generalize the well-known relation between non-overlapping rods and labelled rooted trees. We also prove that for certain choices of the activities, the system can undergo a condensation transition akin to that of the zero-range process. The key tool is a fixed point equation for the pressure

Heat shock protein amplification improves cerebellar myelination in the Npc1nih mouse model.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1nih (Npc1-/-) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1-/- mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination. METHODS: We administered bimoclomol daily or rhHSP70 6 times per week to Npc1-/- (BALB/cNctr-Npc1m1N/J, also named Npc1nih) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects. FINDINGS: Treatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1-/- mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex. INTERPRETATION: These data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC. FUNDING: Funding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust

Micropartículas de alginato conteniendo paracetamol

Micropartículas conteniendo paracetamol (PCT) han sido obtenidas por emulsificación/gelificación interna de unasolución de alginato dispersada en un aceite vegetal. La morfología y la distribución de tamaño de partícula fuerondeterminadas. Se estudió la concentración de ión calcio resultando ser un parámetro crítico en la producción de lasmicropartículas. Se observó que el incremento en la concentración de calcio produce un aumento en el rendimientototal de micropartículas y en el encapsulación de PCT. La técnica desarrollada permite obtener un sistema concaracterísticas micrométricas óptimas y una mayor eficacia de encapsulación de PCT

Applying blockchain to improve the integrity of the software development process

Software development is a complex endeavor that encompasses application and implementation layers with functional (refers to what is done) and non-functional (how is done) aspects. The efforts to scale agile software development practices are not wholly able to address issues such as integrity, which is a crucial non-functional aspect of the software development process. However, if we consider most software failures are Byzantine failures (i.e., where components may fail and there is imperfect information on which a component has failed.) that might impair the operation but do not completely disable the production line. In this paper, we assume software practitioners who cause defects as Byzantine participants and claim that most software failures can be mitigated by viewing software development as the Byzantine Generals Problem. Consequently, we propose a test-driven incentive mechanism based on a blockchain concept to orchestrate the software development process where production is controlled by a similar infrastructure based on the working principles of blockchain. We discuss the model that integrates blockchain with the software development process, and provide some recommendations for future work to address the issues while orchestrating software productio