Ruthenium ion catalysed C-C bond activation in lignin model compounds - towards lignin depolymerisation.

Lignin is the most abundant renewable feedstock to produce aromatic chemicals, however its depolymerisation involves the breaking of several C-O and C-C inter-unit linkages that connect smaller aromatic units that are present in lignin. Several strategies have been reported for the cleavage of the C-O inter-unit linkages in lignin. However, till today, only a few methodologies have been reported for the effective breaking or the conversion of the recalcitrant C-C inter unit linkages in lignin. Here we report the ruthenium ion catalysed oxidative methodology as an effective system to activate or convert the most recalcitrant inter unit linkages such as ß-5 and 5-5' present in lignin. Initially, we used biphenyl as a model compound to study the effectiveness of the RICO methodology to activate the 5-5' C-C linkage. After 4 h reaction at 22 °C, we achieved a 30% conversion with 75% selectivity towards benzoic acid and phenyl glyoxal as the minor product. To the best of our knowledge this is the first ever oxidative activation of the C-C bond that connects the two phenyl rings in biphenyl. DFT calculation revealed that the RuO4 forms a [3 + 2] adduct with one of the aromatic C-C bonds resulting in the opening of the phenyl ring. Biphenyl conversion could be increased by increasing the amount of oxidant; however, this is accompanied by a reduction in the carbon balance because of the formation of CO2 and other unknown products. We extended this RICO methodology for the oxidative depolymerisation of lignin model hexamer containing ß-5, 5-5' and ß-O-4 linkages. Qualitative and quantitative analyses of the reaction mixture were done using 1H, 13C NMR spectroscopy methods along with GC-MS and Gel Permeation Chromatographic (GPC) methods. Advanced 2D NMR spectroscopic methods such as HSQC, HMBC and 31P NMR spectroscopy after phosphitylation of the mixture were employed to quantitatively analyse the conversion of the ß-5, 5-5' and ß-O-4 linkages and to identify the products. After 30 min, >90% of the 5-5' and linkages and >80% of the ß-5' are converted with this methodology. This is the first report on the conversion of the 5-5' linkage in lignin model hexamer.

Long-Term Nonclinical Pulmonary Safety Assessment of Afrezza, a Novel Insulin Inhalation Powder.

Afrezza delivers inhaled insulin using the Gen2 inhaler for the treatment of patients with type 1 and type 2 Diabetes. Afrezza was evaluated in long-term nonclinical pulmonary safety studies in 2 toxicology species. Chronic inhalation toxicology studies in rat (26 weeks) and dog (39 weeks) and an inhalation carcinogenicity study in rats were conducted with Technosphere insulin (Afrezza) and with Technosphere alone as a vehicle control. Respiratory tract tissues were evaluated by histopathology and cells expressing proliferating cell nuclear antigen (PCNA) were quantified in lungs of rats. Microscopic findings in rats exposed to Afrezza were attributed to the Technosphere particle component, were confined to nasal epithelia, and consisted of eosinophilic globules and nasal epithelial degeneration. There were no Afrezza-related changes in pulmonary PCNA labeling indices in alveoli, large bronchioles, or terminal bronchioles. Microscopic findings in rats exposed to Technosphere particles included eosinophilic globules, mucus cell hyperplasia, and epithelial degeneration in the nasal cavities. PCNA labeling indices were increased in large bronchioles and terminal bronchioles but not in alveoli. There were no Technosphere particle-related findings in the dog study. Afrezza did not exhibit carcinogenic potential in the 2-year study in rats. These nonclinical inhalation studies support the use of Afrezza in humans over extended periods.

Human ex-vivo action potential model for pro-arrhythmia risk assessment.

While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

Identification and elucidation of the biology of adverse events: the challenges of safety assessment and translational medicine.

There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U.S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process.

Análisis de costos: Guía del usuario / Cost Analysis: User's Guide

La serie está diseñado para el usuario, es decir, el propio trabajador, la cual consta de directivas y herramientas, que los gerentes de los APS puedan usar para desarrollar y analizar estrategias y fijar sistemas simples de monitoreo de costos, para poder realizar proyecciones sobre ingresos y egresos futuros

Evaluación de las necesidades de información: Guía del facilitador / Information Needs Assessment: Facilitator's Guide

La guía del facilitador o instructor contiene el diseño de un taller de trabajo para uso de las personas que ayudarán a los administradores APS y al personal que utilizará la serie del Programa Avanzado de Administración de Atención Primaria de Salud (PDG-APS). Existe una guía del instructor para cada módulo de las serie de PDG-APS. Las instrucciones han sido elaboradas para sesiones de una o dos horas. El número de sesiones depende de la cantidad de información y/o el número de pasos que contiene la guía del usuario. La primera página de cada sesión enumera los objetivos de la sesión, los encabezados de los temas importante, el tiempo que se requiere y los materiales y equipos. Las siguientes páginas describen las actividades de las instrucciones en forma esquemática. El esquema está dividido en dos columnas. La columna de la derecha indica lo que debe decir o hacer el instructor al conducir la sesión. La columna de la izquierda enumera el material a distribuir, las transparencias a proyectar u otros materiales necesarios para apoyar la actividad. Las copias de estos materiales preparados para duplicarse, aparecen al final de la sesión la primera vez que se utilice. Algunas transparencias son utilizadas en más de una sesión

Análisis de costos: Guía del usuario / Cost Analysis: User's Guide

La presente serie está diseñado para el usuario, es decir, el propio trabajador, la cual consta de directivas y herramientas, que los gerentes de los APS puedan usar para desarrollar y analizar estrategias y fijar sistemas simples de monitoreo de costos, para poder realizar proyecciones sobre ingresos y egresos futuros(AU)