PET study of intravitreal adalimumab pharmacokinetics in a uveitis rat model

X. García-Otero is grateful to the IDIS (Health Research Institute of Santiago de Compostela) for financing his predoctoral research fellowship. C. Mondelo-García, E. Bandín-Vilar and A. Fernández-Ferreiro are grateful to the Carlos III Health Institute for financing their personnel contracts: JR20/00026, CM20/00135 and JR18/00014.S

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of lifeThis project was partially supported by Fundación Española de Farmacia Hospitalaria “Convocatoria de ayudas de proyectos para grupos de trabajo de la SEFH 2021-2022”, Plan Galego de Saude Mental (SERGAS) and Axencia Galega Innovación (Grupos de Potencial Crecimiento IN607B2020/11). Bandín-Vilar E.: Mondelo-García C. and Fernández-Ferreiro A. are grateful to the Carlos III Health Institute for financing their personnel contracts: CM20/00135, JR20/00026 and JR18/00014S

Análisis de la salud circadiana como factor predictivo de éxito en la pérdida de peso

OBJETIVOS: Objetivo 1: Investigar la relación entre la pérdida de peso y la ritmicidad circadiana, utilizando la temperatura de la muñeca y mediciones de actimetría, en mujeres sometidas a un programa de pérdida de peso, con el fin de evaluar si la ritmicidad circadiana pudiera ser un marcador de la eficacia de los tratamientos de pérdida de peso. Objetivo 2: Investigar los efectos de los cambios en el horario de las comidas sobre el gasto de energía, la tolerancia a la glucosa y variables circadianas. Objetivo 3: Determinar, si la presencia de CLOCK 3111T/C en mujeres con sobrepeso está relacionado con (a) trastornos circadianos, y (b) cambios en la calidad del sueño, para mejorar la comprensión de las asociaciones previamente demostradas con la obesidad y la reducción de la pérdida de peso de las portadoras C. METODOS: I. Para la consecución del objetivo 1: Participaron 85 mujeres ( IMC: 30.24 ± 4.95 kgm-2) sometidas a un programa de reducción de peso. La eficacia del tratamiento se definió mediante: la pérdida de peso total, el porcentaje de pérdida de peso respecto al peso inicial y la pérdida de peso semanal. La ritmicidad circadiana se determinó mediante: temperatura de la muñeca, actividad motora y posición del cuerpo. II. Para la consecución del objetivo 2: 32 mujeres [edad 24 ± 4 e IMC 22,9 ± 2,6 kg/m2] participaron en este estudió. Se diseñaron dos protocolos de forma aleatoria y cruzada. Para el protocolo (P1) (n = 10) se realizaron medidas de gasto energético en reposo mediante calorimetría indirecta y tolerancia a la glucosa durante el periodo postprandial, para el protocolo (P2) se incluyeron mediciones relacionadas con el sistema circadiano basados en perfiles de cortisol salivar y temperatura medida en la muñeca (n = 22). A los participantes se les proporcionó comidas estandarizadas durante las dos semanas de intervención y se estudiaron bajo dos condiciones: comiendo temprano (13:00h) y comiendo tarde (16:30h). III. Para la consecución del objetivo 3: Se reclutaron 85 mujeres con sobrepeso, [edad 43 ± 12 e IMC 28,6 ±4,3 kg/m2]. Las variables de temperatura de muñeca (T), actimetría (A), posición del cuerpo (P) y TAP se midieron como marcadores de la funcionalidad sistema circadiano. Se completó un cuestionario de actividad, un registro de comida y sueño diario, mientras que la calidad del sueño se determinó mediante polisomnografía domiciliaria. De esta muestra, 43 mujeres portaban el SNP del alelo menor (C) para CLOCK 3111 y 42 mujeres eran no portadoras de dicho alelo (TT). Ambos grupos de pacientes estaban igualados en número, edad, parámetros de obesidad e ingesta de energía. CONCLUSIONES: [I] Los ritmos circadianos en el inicio del tratamiento son buenos indicadores de la futura pérdida de peso. El tratamiento adicional debe considerar aspectos cronobiológicos para diagnosticar la obesidad y la eficacia de los tratamientos. [II] Comer tarde se asoció con una disminución del gasto energético en reposo, una disminución de la oxidación de carbohidratos en ayunas, disminución de tolerancia a la glucosa, con un perfil diario más aplanado en las concentraciones de cortisol libre y una disminución del efecto térmico de los alimentos según la temperatura periférica medida en la muñeca. Estos resultados pueden estar implicados en los efectos diferenciales de horario de las comidas en la salud metabólica. [III] Individuos portadores del alelo menor C del CLOCK 3111 presentan un ritmo circadiano menos robusto que el TT y una acrofase retrasada que caracteriza a los sujetos con cronotipo vespertino. Apoyamos la idea de que la identificación de genotipos de reloj en los pacientes puede ayudar al terapeuta en la caracterización de las raíces del problema metabólico. OBJECTIVES: Objective 1: To investigate the potential relationship between weight loss and circadian rhythmicity, using wrist temperature and actimetry measurements, in women undergoing a weight-loss program, in order to assess whether circadian rhythmicity could be a marker of weight-loss effectiveness. Objective 2: To investigate the effects of changes in meal timing on energy-expenditure, glucose-tolerance and circadian-related variables. Objective 3: Determine, in free-living conditions, if the presence of CLOCK 3111C in overweight women could be related to (a) circadian disorders, and (b) changes in sleep quality, to improve understanding of the previously demonstrated associations with obesity and reduced weight loss of the C carriers. METHODS: I. To get the objective 1: Participants were 85 overweight and obese women (body mass index, BMI: 30.24±4.95 kg m-2) subjected to a weight reduction program. Efficacy of the treatment was defined as total weight loss, percentage of initial weight and weekly weight loss rates. Circadian rhythmicity in wrist temperature motor activity and position were analyzed using different sensors. II. To get the objective 2: Thirty-two women (aged 24 ± 4 years and body mass index 22.9 ± 2.6 kgm− 2) completed two randomized, crossover protocols: one protocol (P1) including assessment of resting-energy expenditure (indirect-calorimetry) and glucose tolerance (mixed-meal test) (n = 10), the other (P2) including circadian-related measurements based on profiles in salivary cortisol and wrist temperature (Twrist) (n = 22). In each protocol, participants were provided with standardized meals (breakfast, lunch and dinner) during the two meal intervention weeks and were studied under two lunch-eating conditions: Early Eating (EE; lunch at 13:00) and Late Eating (LE; lunch 16:30). III. To get the objective 3: Wrist temperature, actimetry and position (TAP) and TAP variables were measured as markers of circadian functionality during 8 consecutive days. A rest–activity and food diary was also completed, whereas sleep quality was determined by domiciliary polysomnography. We recruited 85 women who were overweight with body mass index (BMI) of 28.59±4.30 kg m-2 and age 43±12 years. From this sample, we found that 43 women were carrying the minor allele (C) for CLOCK 3111T/C SNP and 42 women were TT carriers (major allele carriers). Both groups of patients were matched for number, age, obesity parameters and energy intake. CONCLUSIONS: [I] Circadian rhythms at the beginning of the treatment are good predictors of future weight loss. Further treatment should consider chronobiological aspects to diagnose obesity and effectiveness of treatments. [II] Eating late is associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance, blunted daily profile in free cortisol concentrations and decreased thermal effect of food on Twrist. These results may be implicated in the differential effects of meal timing on metabolic health. [III] C genetic variants in CLOCK 3111T/C display a less robust circadian rhythm than TT and a delayed acrophase that characterizes ‘evening-type’ subjects. We support the notion that identifying CLOCK genotypes in patients may assist the therapist in characterization of the roots of the metabolic problem

Nervous Necrosis Virus (NNV) Booster Vaccination Increases Senegalese Sole Survival and Enhances Immunoprotection

A re-immunization programme has been tested to improve the protective response elicited in sole by a previously developed BEI-inactivated betanodavirus vaccine. The vaccine was prepared using a reassortant RGNNV/SJNNV strain which is highly pathogenic for sole, and vaccination assays were performed by intraperitoneal injection. Experimental design included a prime- and a booster-vaccination group, which consisted of individuals that received a second vaccine injection at 30 days post vaccination), and their respective controls. A month after prime/booster vaccination, fish were challenged by intramuscular injection with the homologous NNV strain. Samples were collected at different times post vaccination and post challenge to assess the immune response and viral replication. Booster dose enhanced the protection against NNV infection because a significant increase in survival was recorded when compared with prime-vaccinated individuals (relative percent survival 77 vs. 55). In addition, a clear decrease in viral replication in the brain of challenged sole was observed. During the immune induction period, no differences in IgM production were observed between prime- and booster-vaccinated fish, and the expression of the antigen presenting cells (APC)-related molecule MHC class II antigen was the only differential stimulation recorded in the re-immunized individuals. However, a significant upregulation of mhcII and the lymphocytes T helper (Th) marker cd4 was observed after the challenge in the booster-vaccinated group, suggesting these cells play a role in the protection conferred by the booster injection. In addition, after viral infection, re-immunized fish showed specific and neutralizing antibody production and overexpression of other immune-related genes putatively involved in the control of NNV replication

Current Situation and Challenges in Vitreous Substitutes

Vitreo-retinal disorders constitute a significant portion of treatable ocular diseases. These pathologies often require vitreo-retinal surgery and, as a consequence, the use of vitreous substitutes. Nowadays, the vitreous substitutes that are used in clinical practice are mainly divided into gases (air, SF6, C2F6, C3F8) and liquids (perfluorocarbon liquids, silicone oils, and heavy silicone oils). There are specific advantages and drawbacks to each of these, which determine their clinical indications. However, developing the ideal biomaterial for vitreous substitution continues to be one of the most important challenges in ophthalmology, and a multidisciplinary approach is required. In this sense, recent research has focused on the development of biocompatible, biodegradable, and injectable hydrogels (natural, synthetic, and smart), which also act as medium and long-term internal tamponade agents. This comprehensive review aims to cover the main characteristics and indications for use of the extensive range of vitreous substitutes that are currently used in clinical practice, before going on to describe the hydrogels that have been developed recently and which have emerged as promising biomaterials for vitreous substitutionC.M.-G., E.B.-V., L.G.-Q., and A.F.-F. are grateful to the Carlos III Health Institute for financing the CM18/00090, CM20/00135, CM20/00024, and JR18/00014 personnel contracts. This work was partially supported by the following projects of Carlos III Health Institute (PI17/00940 and PI20/00719)S

Recent Advances in Proteomics-Based Approaches to Studying Age-Related Macular Degeneration: A Systematic Review

Age-related macular degeneration (AMD) is a common ocular disease characterized by degeneration of the central area of the retina in the elderly population. Progression and response to treatment are influenced by genetic and non-genetic factors. Proteomics is a powerful tool to study, at the molecular level, the mechanisms underlying the progression of the disease, to identify new therapeutic targets and to establish biomarkers to monitor progression and treatment effectiveness. In this work, we systematically review the use of proteomics-based approaches for the study of the molecular mechanisms underlying the development of AMD, as well as the progression of the disease and on-treatment patient monitoring. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines were followed. Proteomic approaches have identified key players in the onset of the disease, such as complement components and proteins involved in lipid metabolism and oxidative stress, but also in the progression to advanced stages, including factors related to extracellular matrix integrity and angiogenesis. Although anti-vascular endothelial growth factor (anti-VEGF)-based therapy has been crucial in the treatment of neovascular AMD, it is necessary to deepen our understanding of the underlying disease mechanisms to move forward to next-generation therapies for later-stage forms of this multifactorial disease

Proyecto HISTRA: marco metodológico y expectativas de desarrollo

HISTRA se concibe como un recurso electrónico para la investigación en la Historia de la Traducción, posibilitando el desarrollo de estudios sobre la recepción literaria de obras traducidas del inglés al español, de autores y traductores. Permite igualmente emprender estudios de carácter diacrónico en las áreas de edición, ascenso de nuevos géneros literarios y usarse como un instrumento más de análisis de las demandas cambiantes del público lector, entre otros

Ampicillin Stability in a Portable Elastomeric Infusion Pump: A Step Forward in Outpatient Parenteral Antimicrobial Therapy

Outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion pumps is postulated as a very promising solution to treat complicated infections, such as endocarditis or osteomyelitis, that require patients to stay in hospital during extended periods of time, thus reducing their quality of life and increasing the risk of complications. However, stability studies of drugs in elastomeric devices are scarce, which limits their use in OPAT. Therefore, we evaluated the stability of ampicillin in sodium chloride 0.9% at two different concentrations, 50 and 15 mg/mL, in an elastomeric infusion pump when stored in the refrigerator and subsequently in real-life conditions at two different temperatures, 25 and 32 °C, with and without the use of a cooling device. The 15 mg/mL ampicillin is stable for up to 72 h under refrigeration, allowing subsequent dosing at 25 °C for 24 h with and without a cooling device, but at 32 °C its concentration drops below 90% after 8 h. In contrast, 50 mg/mL ampicillin only remains stable for the first 24 h under refrigeration, and subsequent administration at room temperature is not possible, even with the use of a cooling system. Our data support that 15 mg/mL AMP is suitable for use in OPAT if the volume and rate of infusion are tailored to the dosage needs of antimicrobial treatments

Cysteamine Eye Drops in Hyaluronic Acid Packaged in Innovative Single-Dose Systems: Stability and Ocular Biopermanence

Cystinosis is a rare genetic disorder characterized by the accumulation of cystine crystals in different tissues and organs causing, among other symptoms, severe ocular manifestations. Cysteamine eye drops are prepared in hospital pharmacy departments to facilitate access to treatment, for which vehicles that provide adequate biopermanence, as well as adaptable containers that maintain its stability, are required. Difficulties related to cysteamine preparation, as well as its tendency to oxidize to cystamine, show the importance of conducting rigorous galenic characterization studies. This work aims to develop and characterize an ophthalmic compounded formulation of cysteamine prepared with hyaluronic acid and packaged in innovative single-dose systems. For this task, the effect of different storage temperatures and the presence/absence of nitrogen on the physicochemical stability of the formulation and its packaging was studied in a scaled manner, until reaching the optimal storage conditions. The results showed that 0.55% cysteamine, prepared with hyaluronic acid and packaged in single-dose containers, is stable for 30 days when stored at −20 °C. In addition, opening vials every 4 h at room temperature after 30 days of freezing maintains the stability of the cysteamine formulation for up to 16 h. Moreover, ocular biopermanence studies were conducted using molecular imaging, concluding that the biopermanence offered by the vehicle is not affected by the freezing process, where a half-life of 31.11 min for a hyaluronic acid formulation stored for 30 days at −20 °C was obtained, compared with 14.63 min for 0.9% sodium chloride eye drops