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Use of subcutaneous tocilizumab to prepare intravenous solutions for COVID-19 emergency shortage:Comparative analytical study of physicochemical quality attributes

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Journal of Pharmaceutical Analysis 2020年第6期10卷 532-545页

作者： Natalia Navas Jesús Hermosilla Anabel Torrente-Lopez Jose Hernandez-Jimenez Jose Cabeza raquel Perez-Roblesa Antonio Salmeron-garcía Department of Analytical Chemistry Science Faculty/Biomedical Research Institute ibs.GranadaUniversity of GranadaGranadaE-18071Spain UGC Farmacia Hospitalaria Biomedical Research Institute ibs.Granada.Hospital Universitario San Cecilio de GranadaGranadaE-18012Spain

COVID-19,a disease caused by the novel coronavirus SARS-Co V-2,has produced a serious emergency for global public health,placing enormous stress on national health systems in many countries.Several studies suggest that cytokine storms(interleukins)may play an important role in severe cases of COVID-19.Neutralizing key inflammatory factors in cytokine release syndrome(CRS)could therefore be of great value in reducing the mortality rate.Tocilizumab(TCZ)in its intravenous(IV)form of administration-Ro Actemra?20 mg/m L(Roche)-is indicated for treatment of severe CRS patients.Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe,with several ongoing clinical trials.This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals,which has resulted in drug shortages.Here,we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion,at 6 mg/m L and 4 mg/m L,prepared from Ro Actemra?20 mg/m L(IV form)and from Ro Actemra?162 mg(0.9 m L solution pre-filled syringe,subcutaneous(SC)form),to evaluate the use of the latter for preparing clinical solutions required for IV administration,so that in a situation of shortage of the IV medicine,the SC form could be used to prepare the solutions for IV delivery of TCZ.It is important to remember that during the current pandemic all the medicines are used off-label,since none of them has yet been approved for the treatment of COVID-19.

关键词： COVID-19 Tocilizumab Critical quality attributes IV and SC medicines

Project for Residues Valorisation and Reutilization from an Oxy-Combustion Circulating Fluidized Bed Boiler with CO<sub>2</sub>Capture

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Journal of Power and Energy Engineering 2019年第1期7卷 19-26页

作者： Jose A. Gutierrez Bravo Raquel García Department of Mining Engineering Universidad de León Campus de Vegazana León Spain

Power generation industry has tackled waste reuse and valorisation for decades. Nevertheless, new technologies, like Circulating fluidized bed (CFB) boilers operating in oxy-combustion, have an important gap of knowledge in residues characterization and valorisation. This project will tackle this. Furthermore, as a result of the high quantity of waste that these installations generate new business models can be opened. The project aims at characterizing the residues from a large scale oxy-CFB facility with carbon, capture, use and storage (CCUS) focusing on the larger and main residues produced: fly ash, bottom ash, and algae production from captured CO2. An analysis of possible uses and treatment needs, such as additives or preparation for use in agriculture or industry, will be carried out. Best re-utilization and valorisation options will be stated for fly ash, bottom ash and algae, aiming for a novel combination of CO2 capture technologies with recovery of valuable materials from different wastes, addressing different and sustainable solutions for their reuse, enhancing the feasibility of CCUS, and combining research with the creation of new business models towards a green economy more attractive to the public perception.

关键词： Coal Residues Valorization Coal Ash CCUS Oxycombustion

Economics of Coalbed Methane in North West Spain

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International Journal of Clean Coal and Energy 2018年第2期7卷 21-38页

作者： Jose A. Gutiérrez Raquel García Campus de Vegazana Universidad de León León Spain

Coal during its carbonization process produces a gas. This gas, mainly formed by methane, can be used. The use of CBM (Coal bed methane) as an energetic resource is not much known in Spain. This work is the first step to enhance the development of this resource in Castilla y León. A theoretical review and a state of the art description have been carried out, taking into account all the factors that can influence in the development of a CBM project. Then CBM resources have been quantified by Castilla y León accurately for every coal bed. After that, technical feasibility has been used to evaluate total amount of gas that can be recovered. The last step was to evaluate economic feasibility to know how much gas could be economically profitable. This paper covers the economic factor and exploitation options of CBM in Castilla y León, considering technical parameters together with costs and economic requirements for the tow most promising areas in north-west Spain. The main findings include that a CBM system would be feasible in Guardo-Barruelo, however, the economic feasibility will be limited to long operation time of the wells and an increase of the prices of natural gas. In North Leon, the results show a high profitability even under low natural gas prices.

关键词： Coalbed Methane Coal Feasibility Coal Economics Unconventional Natural Gas

Distribution, habitat and adaptability of the genus Tapirus

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Integrative Zoology 2012年第4期7卷 346-355页

作者： Manolo J.garcÍA Emília Patrícia MEDICI, Eduardo J.NARANJO Wilson NOVARINO raquel S.LEONARDO Conservationist Research Center San Carlos UniversityGuatemala CityGuatemala Institute for Ecological Research Campo GrandeBrazil El Colegio de la Frontera Sur ChiapasMexico Biology Department Andalas UniversityWest SumatraIndonesia Defensores de la Naturaleza Foundation Guatemala CityGuatemala

In this manuscript,as a starting point,the ancient and current distribution of the genus Tapirus are summarized,from its origins,apparently in Europe,to current ranges.Subsequently,original and current tapir habitats are de-scribed,as well as changes in ancient habitats.As the manuscript goes on,we examine the ways in which tapir species interact with their habitats and the main aspects of habitat use,spatial ecology and adaptability.Having reviewed the historic and current distribution of tapirs,as well as their use and selection of habitats,we intro-duce the concept of adaptability,considering that some of the tapir physiological characteristics and behavior-al strategies can reduce the negative impact of habitat alteration and climate change.Finally,we provide rec-ommendations for future research priorities.The conservation community is still missing important pieces of information for the effective conservation of tapirs and their remaining habitats in Central and South America and Southeast Asia.Reconstructing how tapir species reached their current distribution ranges,interpreting how they interact with their habitats and gathering information regarding the strategies they use to cope with habitat changes will increase our understanding about these animals and contribute to the development of conservation strategies.

关键词： adaptability climate change distribution habitat Tapirus

Cardiovascular prevention in elderly patients

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Journal of Geriatric Cardiology 2022年第5期19卷 377-392页

作者： Clara Bonanad Rosa Fernández-Olmo Sergio garcía-Blas Jose Antonio Alarcon Pablo Díez-Villanueva Carmen Rus Mansilla Héctor garcía-Pardo Pablo Toledo Ana Ayesta Eva Pereira Antoni Carol Almudena Castro-Conde Carmen de Pablo-Zarzoso Manuel Martínez-Sellés Vicente Arrarte raquel Campuzano Albert Ariza-Solé Servicio de Cardiología Hospital Clínico Universitario de ValenciaValenciaSpain Instituto de Investigación Sanitaria INCLIVA ValenciaSpain Servicio Cardiología Hospital Universitario de Jaén Spain Servicio Cardiología Hospital de Donosti Spain Servicio de Cardiología Hospital Universitario La Princesa de MadridSpain Servicio de Cardiología Hospital Alto Gudalquivir de AndújarJaénSpain Servicio de Cardiología Hospital Rio Hortega de ValladolidSpain Servicio Cardiología Hospital Clínico San Cecilio de Granada Spain Servicio de Cardiología Hospital Universitario Central de AsturiasSpain Servicio de Cardiologia Hospital de LugoSpain Servicio de Cardiología Hospital Moisés Broggi de BarcelonaSpain Servicio de Cardiología Hospital Universitario de la Paz de Madrid Spain Servicio de Cardiología Hospital Ramón y Cajal de MadridSpain Department of Cardiology.Hospital Universitario Gregorio Marañón CIBERCV.Universidad EuropeaUniversidad Compluten Servicio de Cardiología del Hospital General de Alicante Spain Servicio de Cardiología Hospital Universitario Fundación de Alcorcón de MadridSpain Servicio de Cardiología Hospital Bellvitge de BarcelonaBioheartGrup de Malalties CardiovascularsInstitut d’InvestigacióBiomèdica de BellvitgeIDIBELLL’Hospitalet de LlobregatBarcelonaSpain

In recent decades,life expectancy has been increasing significantly.In this scenario,health interventions are ne-cessary to improve prognosis and quality of life of elderly with cardiovascular risk factors and cardiovascular disease.However,the number of elderly patients included in clinical trials is low,thus current clinical practice guidelines do not include specific re-commendations.This document aims to review prevention recommendations focused in patients≥75 years with high or very high cardiovascular risk,regarding objectives,medical treatment options and also including physical exercise and their inclusion in cardiac rehabilitation programs.Also,we will show why geriatric syndromes such as frailty,dependence,cognitive impair-ment,and nutritional status,as well as comorbidities,ought to be considered in this population regarding their important pro-gnostic impact.

关键词： prevention patients cardiovascular

Novel Simplified Method for Coalbed Methane Feasibility Evaluation

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International Journal of Clean Coal and Energy 2018年第4期7卷 59-92页

作者： Jose A. Gutiérrez Raquel García Erasmo Cadena Department of Mining Engineering University of León Leon Spain

Coal during its carbonization process produces a gas. This gas, mainly formed by methane, can be used. This gas, coalbed methane (CBM), is usually mainly formed by methane and can be considered similar to natural gas as energy source. The evaluation of the techno-economic feasibility of the extraction of this gas depends on a large number of complex different factors. The work carried out covers the different aspects to simplify the first approach for CBM feasibility quantification considering a short number of indicators. A theoretical review and a state of the art description have been carried out, taking into account all the factors that can influence in the development of a CBM project. After that, technical feasibility has been used to evaluate total amount of gas that can be recovered. The last step was to evaluate economic feasibility to know how much gas could be economically profitable. Conclusions got have been used to develop a simple method for evaluating CBM economic feasibility considering just four easy known parameters of coal beds. These are: the rank, the thickness, the gas concentration, and the permeability.

关键词： CBM Feasibility Assessments Coal Natural Gas

Cdk5 and aberrant cell cycle activation at the core of neurodegeneration

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Neural Regeneration Research 2023年第6期18卷 1186-1190页

作者： raquel Requejo-Aguilar Department of Biochemistry and Molecular Biology University of CórdobaCórdobaSpain Maimónides Biomedical Research Institute of Córdoba(IMIBIC) 14071 CórdobaSpain

Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.

关键词： Alzheimer´s disease amyotrophic lateral sclerosis apoptosis Cdk5 cell cycle Huntington´s disease neurodegeneration neuron oxidative stress Parkinson´s disease signaling Tau phosphorylation

Conditioned Taste and Place Preferences Induced by Electrical Stimulation of the External Lateral Parabrachial Nucleus: A General Reinforcing Mechanism?

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Journal of Behavioral and Brain Science 2013年第5期3卷 422-431页

作者： Maria J. Simon Raquel García Amadeo Puerto Department of Psychobiology University of Granada Granada Spain

This study examined the stimulus specificity of external lateral parabrachial (LPBe) rewarding stimulation by using two identical learning procedures that may dissociate conditioned reinforcement to either the place or the flavor stimulus. Animals were presented with two distinct flavors in two different positions (left and right) that were varied throughout the experimental sessions. In the first experiment, LPBe stimulation was associated with one or other flavor, while in the second it was conditioned to one or other place in which these flavors were offered. The results show that, despite stimulus interferences, the animals develop specific conditioned preferences for the flavor stimuli (experiment 2A), and also for the place of their presentation (experiment 2B). These data are discussed in the context of brain reward systems and the biological constraints that characterize some learning modalities.

关键词： Electrical Stimulation External Lateral Parabrachial Nucleus (LPBe) Reward Conditioning Flavor Placement

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2322-2331页

作者： Xavier Palomer MSilvia Román-Azcona Javier Pizarro-Delgado Ana Planavila Francesc Villarroya Brenda Valenzuela-Alcaraz Fátima Crispi Álvaro Sepúlveda-Martínez Irene Miguel-Escalada Jorge Ferrer JFrancisco Nistal Raquel García Mercy MDavidson Emma Barroso Manuel Vázquez-Carrera Department of Pharmacology Toxicology and Therapeutic ChemistryIBUB(Institut de Biomedicina de la Universitat de Barcelona)Research Institute-Pediatric Research InstituteHospital Sant Joan de Déuand CIBER de Diabetes y Enfermedades Metabólicas Asociadas(CIBERDEM)Faculty of Pharmacy and Food SciencesUniversity of BarcelonaBarcelonaSpain Department of Biochemistry and Molecular Biomedicine IBUB and CIBER Fisiopatología de la Obesidad y Nutrición(CIBEROBN)Faculty of BiologyUniversity of BarcelonaBarcelonaSpain aBCNatal-Barcelona Center for Maternal–Fetal and Neonatal Medicine(Hospital Clínic and Hospital Sant Joan de Deu) Institut d’Investigacions Biomèdiques August Pi i SunyerUniversitat de Barcelonaand Center for Biomedical Research on Rare Diseases(CIBER-ER)BarcelonaSpain Genomic Programming of Betacells Laboratory Institut d’Investigacions August Pi i Sunyer(IDIBAPS)and CIBERDEMBarcelonaSpain Section of Epigenomics and Disease Department of Medicineand National Institute for Health Research(NIHR)Imperial Biomedical Research CentreImperial College LondonLondonUK Servicio de Cirugía Cardiovascular Hospital Universitario Marqués de ValdecillaDepartamento de Ciencias Médicas y QuirúrgicasFacultad de MedicinaUniversidad de CantabriaInstituto de Investigación Marqués de Valdecilla(IDIVAL)Centro de Investigación Biomédica en Red Cardiovascular(CIBERCV)Instituto de Salud Carlos IIISantanderSpain Departamento de Fisiología y Farmacología Facultad de MedicinaUniversidad de CantabriaInstituto de Investigación Marqués de Valdecilla(IDIVAL)SantanderSpain Department of Radiation Oncology Columbia UniversityNew YorkNYUSA

Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.

关键词： SIRT3 inflammation cardiac