Search

Este artículo analiza el historial completo del foro de Facebook de Gran Hermano España durante el período 2011-2019. En el estudio se obtuvieron más de 1,2 millones de comentarios del grupo de Facebook. Se investiga cuáles son los temas más recurrentes de los que hablan los fans del programa y cuál es su posición ante ellos. Los participantes aceptan la lógica del reality (mecánica y objetivo final), pero a veces cuestionan la imparcialidad de la cadena si aprecian que interviene en la realidad para obtener una ventaja comercial. Sin embargo, pasa inadvertida la censura que ejerce el programa sobre los comentarios de sucesos que puedan dañar su imagen. Los espectadores, mayoritariamente de género femenino, critican tres veces más (2,79) a las mujeres concursantes que a los hombres. Sin embargo, también hay cierta alianza de género entre foristas y concursantes femeninas: se las apoya más a ellas para que ganen.

Esta investigación tiene como objetivo estudiar la construcción de sentido en La pelota vasca. La piel contra la piedra (Julio Medem, 2003), el documental sobre terrorismo que más éxito comercial y más polémica ha generado en el cine español. A través de un análisis del montaje, este artículo busca descubrir las pautas, esquemas o estructuras narrativas utilizadas por el director para construir el texto fílmico y para influir en la opinión de los espectadores. Para ello se ha creado una base de datos que permite un minuicioso análisis cuantitativo y cualitativo de todAs las intervenciones que hay en la película. Esta propuesta metodológica pretende servir al análisis de otros documentales con similares características narrativas. Las conclusiones obtenidas muestran que el director usa la estructura de parte del documental y las entrevistas a diferentes personalidades del País Vasco para configurar un sentido propio de lo que denomina conflicto vasco, que está muy cercano a las tesis nacionalistas. Queda demostrada la crítica a la acción del PP en sus años de gobierno y el deterioro de la imagen del Estado, principalmente a través de un 80% de referencias negativas sobre las fuerzas de seguridad del Estado. También se prueba que las personas entrevistadas son más o menos creíbles dependiendo de cómo quedan situadas dentro del montaje y de si otros personajes refutan o respaldan lo que dicen.

Se analizan las prácticas de programación de las sitcoms familiares estadounidenses en la programación infantil y juvenil de cadenas de televisión españolas durante la edad de oro de la televisión comercial (1990-2005). Se valora también la popularidad que alcanzaron en su momento de emisión, así como el recuerdo que mantienen, en la actualidad, espectadores de aquella época. Se observa que existe, por parte de la audiencia de aquel momento, una identificación de los contenidos de estas sitcoms y una idealización tanto de los contenidos como del momento en el que se percibieron, lo cual puede afectar al efecto cultivo. Las sitcoms familiares americanas se ven como una serie única por su capacidad para producir una realidad claramente distinta a la real, pero que se acepta como buena: no se rechaza, se asimila. El efecto de la nostalgia permite, con el tiempo, crear una visión acrítica y positiva de estas series.

Therapeutic monoclonal antibodies (mAbs) represent a very important class of the current biopharmaceutics. The great complexity of their structure made necessary the use of different analytical approaches for assessing different physico-chemical properties. In this work, weak cation exchange (WCX) high performance liquid chromatography with diode array detection ((WCX)HPLC/DAD) is used to assess the charge variant profile. The method here developed combined the effect of ionic strength and controlled pH gradient and allows for the charge variants analysis of the five mAbs studied, namely bevacizumab (BVZ), cetuximab (CTX) infliximab (INF), rituximab (RTX) and trastuzumab (TTZ), which are among the most used mAbs worldwide. The differences in the charge variants in the natural isoforms of the mAbs promoted characteristic WCX chromatograms for each of mAbs that can be also useful for identification purposes. These chromatograms have provided to be suitable for tracking changes in the charge variants of each mAb analyzed both in controlled degraded and in stabilities study along time of in-use samples solutions at 2 mg/mL in 0.9% NaCl stored refrigerated (at 4 ?C) and frozen (-20 ?C) for two months. The results obtained indicated different stabilities of these mAbs, all IgG1, against degradation by different stressed environmental conditions and in-use stability along two months., Instituto Carlos III, Ministerio de Economia y Competitividad, Spain FIS-PI10/00201 FIS-PI17/00547, European Commission Junta de Andalucia European Commission

El talk show como género televisivo en España se extendió por todos los horarios y formatos durante las dos décadas estudiadas (1990-2010). En ese tiempo desarrolló sus propias reglas sobre cómo presentar la intimidad en televisión: la telerrealidad no significaba el fin de la privacidad, sino el inicio de su expansión. Este artículo analiza la evolución del talk show, desde los formatos más tímidos que limitaban la exposición emocional, hasta aquellos influenciados por el éxito de Big Brother, que obligó al género a gestionar la intimidad de las personas de la forma más espectacular posible en la lucha por el share. Esta búsqueda permanente de audiencias llegó a provocar que el talk show excediera los límites de la autenticidad y utilizase la ficción y el espectáculo, alterando la realidad por motivos utilitarios para hacerla más entretenida e introduciendo actores y presentadores que incitaran al conflicto e incluso al engaño.

This study was supported by research grants from CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Spain (PI16/01858, PI18/01573, PI20/01568), co-funded by European Union (ERDF), "A way to make Europe"., Supplementary data to this article can be found online at https://doi. org/10.1016/j.envint.2021.106734, Background Despite restrictions on their production and use, most of the population is still exposed to Persistent Organic Pollutants (POPs), including organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). These chemicals are thought to contribute to the aetiology of highly prevalent chronic conditions, such as cardiovascular diseases (CVDs), although current evidences are still controversial. Objectives To explore the potential contribution of historical POP exposure to 15-year pharmaceutical consumption in relation to CVD. Methods This study is framed within GraMo adult cohort. Participants (n = 387) were recruited in two hospitals in Granada province, Southern Spain (2003–2004). Historical exposure to 5 OCPs and 3 non-dioxine-like PCBs was estimated by analysing adipose tissue concentrations at recruitment. Pharmaceutical consumption from recruitment until year 2017 was quantified by reviewing dispensation databases. Average consumption increase (ACI) in CVD medication was calculated by subtracting average consumption in 2002 to the average yearly consumption during follow-up. ACI was expressed as Defined Daily Dose (DDD)/year units. Data analyses were carried out using a multivariable multinomial logistic regression and weighted quantile sum regression (WQS), with ACI categorized in quartiles (Q) as the dependent variable. Results Concentrations of most pollutants showed a positive trend with the quartiles of ACI. Particularly, PCB-153 showed increasing and statistically significant odds ratios (ORs) for Q2 (OR: 1.27, 95% confidence interval (CI): 1.07–1.52), Q3 (OR: 1.49, 95 %CI: 1.17–1.88) and Q4 (OR: 1.42, 95 %CI: 1.13–1.78) vs Q1. Similarly, beta-hexachlorocyclohexane (β-HCH) also showed increasing ORs, that reached statistical significance in Q4 (OR: 1.36, 95 %CI: 1.06–1.74) vs Q1. These findings were corroborated by WQS analyses, that revealed a significant mixture effect, predominantly accounted for by PCB-153 and β-HCH. Discussion Our results suggest that long-term POP exposure might represent a modifiable risk factor for CVD. These findings are relevant for public health campaigns and management, since pharmaceutical consumption is considered an indicator of both morbidity and health expenditure., CIBER de Epidemiología y Salud Pública, Santa Ana and San Cecilio Hospitals RYC-2016-20155, European Commission, Instituto de Salud Carlos III PI16/01858, PI18/01573, PI20/01568 ISCIII Ministerio de Economía, Industria y Competitividad, Gobierno de España, European Regional Development Fund, Ministerio de Economía, Industria y Competitividad, Gobierno de España

This study was partially funded by Project FIS: PI-17/00547 (Institute of Health 'Carlos III', Ministry of Economy and Competitiveness, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic monoclonal antibodies (mAbs) have been the subject of widespread investigation focusing on two target-based groups, i.e., non-SARS-CoV-2 specific mAbs, that target immune system responses, and SARS-CoV-2 specific mAbs, designed to neutralize the virus protein structure. Here we review the latest literature about the use of mAbs in order to describe the state of the art of the clinical trials and the benefits of using these biotherapeutics in the treatment of COVID-19. The clinical trials considered in the present review include both observational and randomized studies. We begin by presenting the studies conducted using non-SARS-CoV-2 specific mAbs for treating different immune disorders that were already on the market. Within this group of mAbs, we focus particularly on anti-IL-6/IL-6R. This is followed by a discussion of the studies on SARS-CoV-2 specific mAbs. Our findings indicate that SARS-CoV-2 specific mAbs are significantly more effective than non-specific ones., Institute of Health 'Carlos III', Ministry of Economy and Competitiveness, Spain - European Regional Development Funds (ERDF) FIS: PI-17/00547

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics , metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.

The study was entirely funded by Project FIS: PI-17/00547(Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., A range of biopharmaceutical products are used to target Vascular Endothelial Growth Factor (VEGF), including Eylea (R) (aflibercept, AFL) and Zaltrap (R) (ziv-aflibercept, ziv-AFL). The first is indicated for ophthalmological diseases such as neovascular (wet) age-related macular degeneration, while the second is used in the treatment of metastatic colorectal cancer. The stability of AFL in prefilled syringes has been widely studied; however, no research has yet been done on the stability of ziv-AFL in polyolefin infusion bags. Therefore, the purpose of the present research is to evaluate the stability of ziv-AFL (Zaltrap (R)) clinical solutions prepared under aseptic conditions in polyolefin infusion bags at two different concentrations, i.e. 4.0 and 0.6 mg/mL, and stored refrigerated in darkness at 2-8 degrees C for 14 days. With that aim, the ziv-AFL clinical solutions were assessed by analysing changes in its physicochemical and functional properties. The distribution of the particulates was studied over a range of 0.001-10 mu m by Dynamic Light Scattering (DLS); oligomers were analysed by Size-Exclusion High-Performance Chromatography with Diode Array Detection (SE/HLPC-DAD); the secondary structure of the protein was studied by far UV Circular Dichroism (CD) and the tertiary structure by Intrinsic Tryptophan Fluorescence (IT-F) and Intrinsic Protein Fluorescence (IP-F); charge variants were assessed by Strong Cation Exchange Ultra High-Performance Chromatography with UV detection (SCX/UHPLC-UV); functionality was evaluated by ELISA by measuring the biological activity as manifested in the extension of the immunological reaction of the ziv-AFL with its antigen (VEGF). Neither aggregation nor oligomerization were detected by the techniques mentioned above. Secondary and tertiary structures remained unchanged over the 14-day period, as did charge variants. The functionality observed initially was maintained along time. Therefore, it could be proposed that the ziv-AFL clinical solutions studied showed great physicochemical and functional stability over a period of two weeks, regardless of the concentration, i.e. 4 or 0.6 mg/mL., Project FIS (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain) PI-17/00547, European Commission

espanolEste articulo muestra la evolucion en el dating show en Espana entre 1992 y 2010. Se estudian los cambios en la estructura de los programas mas vistos de este subgenero del reality, que paso de preguntar curiosidades sobre las relaciones amorosas a comprobar y desafiar su grado de complicidad En estos anos, los participantes de los dating shows estuvieron condicionados por las decisiones que tomaban las productoras para hacer mejores productos de entretenimiento, pero tambien tuvieron libertad para mostrar su intimidad y su espontaneidad dentro de los limites definidos por el reality. Paradojicamente, hasta que las personas no aprendieron a actuar dentro de un formato y asumieron su condicion de personajes, estos programas no lograron mas profundidad y realismo. EnglishThis paper shows the evolution of the dating shows in Spain between 1992 and 2010. We study their structural changes based on the most-viewed programs of this sub-genre, which developed from initially exploring innocent relationship anecdotes towards eventually testing and challenging the relationship itself. In these years, the dating show participants were influenced by the broadcasters’ choices aiming for entertainment, but they were also free to show intimacy and spontaneity within the reality-show boundaries. Paradoxically, it was only when participants learned to act in line with the format and assumed their role as characters that these programs achieved more depth and realism.

Background and importance Nivolumab (Opdivo) is a human IgG4 monoclonal antibody from the group of immunomodulators which bind to the programmed death receptor 1 (PD-1). As a complex protein, physical aggregation and chemical degradation can occur throughout its life, and even modest environmental stresses can cause extensive damage.1 As indicated in its technical report,2 the unopened vials can be stored at a controlled room temperature up to 25°C with room light for up to 48 hours. Aim and objectives To assess the impact on the isoform profile of nivolumab 10 mg/mL (Opdivo) promoted by exposure to light in its own opened vial at a controlled temperature of 25°C to evaluate likely risks from unintentional mishandling in real hospital conditions. Material and methods Nivolumab (Opdivo, 10 mg/mL) was placed in an accelerated stress test chamber to simulate sunlight (Solarbox 3000e RH, Cofomegra, Milan, Italy) for 24 hours at 25°C. Irradiation was set at 250 W/m2, between 320 and 800 nm.3 A validated reverse phase ultra high resolution liquid chromatography coupled to high resolution mass spectrometry and exact mass ((RP)UHPLC-UV-(HESI/Orbitrap)-MS) method was used to analyse intact nivolumab. UV-chromatograms and total ion chromatograms (TICs) were recorded and the deconvoluted mass spectra gave the nivolumab mass isoform profile. Results UV chromatograms and TICs suggested no degradation products after light exposure. However, isoform profiles clearly showed changes in the light submitted nivolumab samples. An important increase in the number of isoforms even with changes in their masses, including the main isoform, was detected. Conclusion and relevance Exposure to light may cause modifications in the nivolumab isoform profile which suggests protein degradation. This work shows the importance of protecting opened vials of the medicine Opdivo from light (and by extension, bags for infusion) when they are at room temperature (up to 25°C). References and/or acknowledgements Nejadnik MR, et al. J Pharm Sci 2018;107:2013–19. Nivolumab Technical Report. https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf Scientific discussion ICH Q1B photostability testing of new active substances and medicinal products. European Medicines Agency (EMEA) 1998 https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1-b-photostability-testing-new-active-substances-medicinal-products-step-5_en.pdf Funded by project FIS: PI-17/00547 (Instituto Carlos III, Spain), which means that it was also partially supported by European Regional Development Funds. AT-L is currently receiving an FPU predoctoral grant (reference FPU18/03131) from the Ministry of Universities, Spain. Conflict of interest No conflict of interest

Background and importance Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that binds to programmed death receptor 1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. As a complex protein, routine handling or unintentional mishandling of its solutions may cause degradation that could remain unnoticed but could potentially compromise the clinical safety and efficacy of the drug product.1 Aim and objectives To assess the impact on the nivolumab (Opdivo) aggregation process promoted by slight modification in the concentration of the compound (NaCl 0.9% or glucose 5%) used to prepare the clinical diluted solution of nivolumab at 1.0 mg/mL. Also, to assess the impact on the aggregation on nivolumab clinical diluted solutions (1.0 mg/mL, in NaCl 0.9% and glucose 5%) promoted by agitation stress. Material and methods Nivolumab (Opdivo, 10 mg/mL) was diluted at 1 mg/mL using different NaCl (from 0.5% to 1.5%) and glucose (from 1% to 10%) solution concentrations. Also, clinical diluted solutions were subjected to manual gentle agitation (for 30 s and 1 min) and vortex agitation (Vortex VibraMix, 3000 rpm for 10 s, 30 s and 1 min). Particulate was tracked by dynamic light scattering (DLS) using a Malvern Zetasizer Nano ZS90. Results Reference samples of diluted nivolumab at 1.0 mg/mL in NaCl 0.9% and 5% glucose showed a single particulate population with a hydrodynamic diameter (HD) of 9.66±2.96 nm and 10.67±2.68 nm, respectively, attributed to nivolumab monomers. No significant changes were obtained for HD when the concentration of the diluents was changed. Also, no significant changes were observed after performing the agitation stresses, showing that the HR values were always in the interval of the size of the monomers. Conclusion and relevance Variation in NaCl and glucose concentrations around the clinical concentrations of 0.9% and 5% did not promote aggregation in a 1 mg/mL nivolumab solution detected by DLS. Also, agitation did not have any impact on aggregation on this clinical nivolumab solution. References and/or acknowledgements Nejadnik MR, et al. J Pharm Sci 2018;107:2013–19. Funded by project FIS: PI-17/00547 (Instituto Carlos III, Spain), which means it was also partially supported by European Regional Development Funds. AT-L is currently receiving an FPU predoctoral grant (reference FPU18/03131) from the Ministry of Universities, Spain. Conflict of interest No conflict of interest

Marketed monoclonal antibodies (mAbs) represent a very important class of the current biopharmaceutics. The great complexity of their structure made necessary the use of different analytical approaches for assessing different physico-chemical properties. In this work, weak cation exchange (CEX) high performance liquid chromatography with diode array detection ((CEX)HPLC/DAD) is used to assess the charge variant profile. The method developed combined the effect of ionic strength and controlled pH gradient and allows for the charge variants analysis of the five mAbs studied, namely bevacizumab (BVZ), cetuximab (CTX) infliximab (INF), rituximab (RTX) and trastuzumab (TTZ), which are among the most used mAbs worlwide. The differences in the charge variant in the natural isoforms of the mAbs generated characteristic CEX chromatograms for each of mAbs that can be useful for identification purposes. These chromatograms have provided to be very useful to track changes in the charge variants of each particular mAb both in controlled degraded studies and in long-term stability study of in-use samples solutions at 2 mg/mL in 0.9% NaCl stored refrigerated (at 4 oC) and frozen (-20 oC) for two months.

La crisis de los refugiados ha sido el caldo de cultivo para unos discursos del odio, extendidos a través de las redes sociales, que presentan a los inmigrantes como un peligro y una amenaza. Los medios de comunicación han contribuido inconscientemente a su difusión, aunque algunos han reaccionado ampliando su actividad periodística tradicional a la creación de newsgames para buscar nuevas formas de contrarrestar el efecto de estos discursos. Esta investigación analiza cinco newsgames desarrollados por medios de comunicación de referencia a partir de una metodología basada en un análisis multimodal de carácter cualitativo (informativo y ludo-narrativo). Los resultados muestran que el jugador de newsgames tiene acceso a información veraz, como en otros formatos periodísticos, pero también dispone de otro tipo de información más próxima y emocional (circunstancias, sentimientos, vínculos familiares). Estos datos no aparecen de forma aislada, sino que se integran en la experiencia del juego. La investigación concluye identificando la interacción entre información e inmersión de los newsgames que componen la muestra, así como su diferente gradación: un mayor control del jugador dentro de la historia permite introducir matices que favorecen la empatía con los refugiados. Sin embargo, la mayor libertad en la experiencia de juego en los newsgames los aleja del modelo informativo clásico y puede implicar un mayor riesgo de distorsión de las ideas que intentan defender The refugee crisis has been a fertile ground for hate speech that has portrayed migrants as a dangerous threat and has been spread through social networks. While the media have unconsciously contributed to the proliferation of these racist messages, some have reacted by extending their traditional journalistic activity to the creation of newsgames to find new ways of addressing the situation. This study examines the use of five newsgames developed by leading media outlets using a methodology based on a multimodal qualitative analysis (informative and ludonarrative). The results showed that newsgames players have access to truthful information, as is the case for other journalistic genres, and draw on other types of personal and emotional information (circumstances, feelings, family ties). These data did not appear in isolation but integrated into the gaming experience. The study concludes by identifying the interaction between the levels of information and immersion of the newsgames that make up the sample, as well as their different gradation: giving the player the opportunity to make more significant decisions within the story allows for the introduction of nuances that promote empathy towards refugees; however, greater freedom in the gaming experience in newsgames distances them from the classic informational model and may involve a greater risk of distortion of the ideas that they seek to promote

La crisis de los refugiados ha sido el caldo de cultivo para unos discursos del odio, extendidos a través de las redes sociales, que presentan a los inmigrantes como un peligro y una amenaza. Los medios de comunicación han contribuido inconscientemente a su difusión, aunque algunos han reaccionado ampliando su actividad periodística tradicional a la creación de newsgames para buscar nuevas formas de contrarrestar el efecto de estos discursos. Esta investigación analiza cinco newsgames desarrollados por medios de comunicación de referencia a partir de una metodología basada en un análisis multimodal de carácter cualitativo (informativo y ludo-narrativo). Los resultados muestran que el jugador de newsgames tiene acceso a información veraz, como en otros formatos periodísticos, pero también dispone de otro tipo de información más próxima y emocional (circunstancias, sentimientos, vínculos familiares). Estos datos no aparecen de forma aislada, sino que se integran en la experiencia del juego. La investigación concluye identificando la interacción entre información e inmersión de los newsgames que componen la muestra, así como su diferente gradación: un mayor control del jugador dentro de la historia permite introducir matices que favorecen la empatía con los refugiados. Sin embargo, la mayor libertad en la experiencia de juego en los newsgames los aleja del modelo informativo clásico y puede implicar un mayor riesgo de distorsión de las ideas que intentan defender, The refugee crisis has been a fertile ground for hate speech that has portrayed migrants as a dangerous threat and has been spread through social networks. While the media have unconsciously contributed to the proliferation of these racist messages, some have reacted by extending their traditional journalistic activity to the creation of newsgames to find new ways of addressing the situation. This study examines the use of five newsgames developed by leading media outlets using a methodology based on a multimodal qualitative analysis (informative and ludonarrative). The results showed that newsgames players have access to truthful information, as is the case for other journalistic genres, and draw on other types of personal and emotional information (circumstances, feelings, family ties). These data did not appear in isolation but integrated into the gaming experience. The study concludes by identifying the interaction between the levels of information and immersion of the newsgames that make up the sample, as well as their different gradation: giving the player the opportunity to make more significant decisions within the story allows for the introduction of nuances that promote empathy towards refugees; however, greater freedom in the gaming experience in newsgames distances them from the classic informational model and may involve a greater risk of distortion of the ideas that they seek to promote

COVID-19, a disease caused by the novel coronavirus SARS-CoV-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 COVID19. 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 -RoActemra® 20 mg/mL (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/ mL and 4 mg/mL, prepared from RoActemra® 20 mg/mL (IV form) and from RoActemra® 162 mg (0.9 mL 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., Instituto Carlos III, Ministerio de Economia y Competitividad, Spain FIS: PI-17/00547, European Union (EU), Ministry of Universities, Spain FPU18/03131, University of Granada (Spain)

Background and importance Ziv-aflibercept (Zaltrap) is an Fc-fusion protein used in the treatment of colorectal cancer. Changes in the structure or aggregation, which may arise from handling and storage, may affect the efficacy of the treatment and it could cause severe immune reactions in patients. The shelf life indicated by the manufacturer for the unopened vial is 3 years; there is no information on the surplus of opened vials. Aim and objectives To compare the biophysical stability of ziv-aflibercept (Zaltrap) stored refrigerated at 4°C and at room temperature protected from light for 2 weeks. Material and methods Three independent samples of fresh ziv-aflibercept were collected from hospital and stored in amber glass vials protected from light at 4°C and at room temperature. Particulate: dynamic light scattering (DLS) readings were carried out in a protein solution DynaPro-99 system dynamic light scattering module equipped with a temperature control micro sampler (Wyatt, Santa Barbara, California, USA) for obtaining the hydrodynamic radius and polydispersity. Tertiary structure: intrinsic tryptophan fluorescence measurements were carried out on a Cary eclipse spectrofluorometer (Agilent, Santa Clara, California, USA). Each spectrum was reduced to a single a dimensional number (centroid): LMW aggregates: size exclusion chromatography (SEC) was used. The analysis was performed by liquid chromatography using an Agilent 1100 chromatograph equipped with a quaternary pump, degasser, autosampler, column oven and photodiode array detector (Agilent). Results No significant changes were detected in the samples stored refrigerated by any of the techniques used: aggregation did not occur, supported by the results from DLS and SEC. No changes in conformation were detected: fluorescence centroid was maintained. Significant changes were detected in the samples stored at room temperature: the start of aggregation was detected by SEC but larger aggregates were not detected by DLS. Centroid value increased significantly, indicating conformational modifications. Conclusion and relevance Ziv-Aflibercept (Zaltrap) remained stable for 14 days regarding visual appearance, LMW aggregates, particulate and conformation when stored at 4°C. However, storage at room temperature promoted ziv-aflibercept modifications. This result encourages more studies with samples stored at 4°C to establish the stability of opened vials of Zaltrap. References and/or acknowledgements Project FIS- PI-17/00547 (Institute Carlos III, Spain), which means that it was also partially supported by European Regional Development Funds. No conflict of interest.

Background and importance Rituximab (RTX) is a therapeutic monoclonal antibody used for the treatment of certain types of cancer. As a complex protein, routine handling or unintentional mishandling of its solutions may cause degradation that could remain unnoticed but could potentially compromise the clinical safety and efficacy of the drug product.1 Aim and objectives To assess the impact on the RTX (Mabthera) aggregation process promoted by slight modification in the concentration of the compound (NaCl 0.9% and glucose 5%) used to prepare the clinical diluted solution of RTX 1.0 mg/mL. Also, to assess the impact on the aggregation of RTX clinical diluted solutions (1.0 mg/mL in NaCl 0.9% and glucose 5%) promoted by manual shaking. Material and methods RTX (Mabthera 10 mg/mL) was diluted to 1 mg/mL using different NaCl (from 0.5% to 1.5%) and glucose (from 1% to 10%) concentrations. Manual gentle shaking was performed for 10 minutes. Particulate was tracked by dynamic light scattering (DLS) and readings were carried out in a protein solution DynaPro-99 system dynamic light scattering module equipped with a temperature control micro sampler (Wyatt, Santa Barbara, California, USA) for obtaining the hydrodynamic radius (HR) and polydispersity. Results Reference 1.0 mg/mL RTX samples diluted in NaCl 0.9% and glucose 5% showed a single particulate population with a HR of 10.51±2.210 nm and 10.72±2.694 nm, respectively, attributed to monomers of RTX. No significant changes were obtained for HR when the concentration of the diluents was changed. Also, no significant changes were observed when the samples were shaken, with the HR values always within the interval of the size of the monomers. Polydispersity remained unchanged in all of the samples analysed. Conclusion and relevance Variation in NaCl and glucose concentrations around clinical concentrations of 0.9% and 5% did not promote aggregation in a 1 mg/mL RTX solution detected by DLS. Also, shaking did not have any impact on aggregation in this clinical RTX solution. References and/or acknowledgements 1. Nejadnik MR, et al. J Pharm Sci 2018;107:2013–2019. Funded by Project FIS: PI-17/00547 (Instituto Carlos III, Spain), which means that it was also partially supported by the European Regional Development Funds. No conflict of interest.

This study was entirely funded by Project FIS: PI-17/00547 (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., Aflibercept (AFL) is an Fc fusion protein used in the treatment of colorectal cancers and different ophthalmological diseases. There are two medicines in which AFL is the active substance: Zaltrap and Eylea, referred as ziv-AFL and AFL respectively. No proper accelerated degradation studies were published on either AFL or ziv-AFL. These studies are essential during research, development and manufacturing stages. Here, we characterized ziv-AFL and submitted it to different stress conditions: light, 60 °C, freeze-thaw cycles, changes in pH, high hypertonic solution and strong denaturing conditions. We used an array of techniques to detect aggregation (SE-HPLC/DAD and DLS), changes in secondary structure (Far-UV circular dichroism), changes in conformation or tertiary structure (Intrinsic tryptophan fluorescence) and alterations in functionality (ELISA). Results indicate that aggregation is common degradation pathway. Two different types of aggregates were detected: dimers and high molecular weight aggregates attributed to β-amyloid-like structures. Secondary structure was maintained in most of the stress tests, while conformation was altered by almost all the tests except for the freeze-thaw cycles. Functionality, evaluated by its immunochemical reaction with VEGF, was found to be stable but with decrease when exposed to light and with likely partial inactivation of the drug when pH was altered., European Union (EU) FIS: PI-17/00547