Radiomarcaje y estudios de biodistribución de nanopartículas poliméricas como adyuvantes para la vacunación oftálmica frente a la brucelosis

Objetivos: Optimizar el radiomarcaje con 99mTc de nanopartículas de Gantrez® manosiladas y cargadas con el antígeno de Brucella Ovis (Man-NP-HS) y llevar a cabo estudios de biodistribución en ratón tras la administración de las nanopartículas por vía ocular. Metodología: Las Man-NP-HS se obtuvieron por el método de desplazamiento de disolvente. Se purificaron, liofilizaron y caracterizaron. A continuación, se marcaron con 74 MBq de 99mTcO4 - previamente reducido con una disolución ácida de cloruro de estaño, trabajando en ausencia de oxígeno y con un pH final de 4. El rendimiento del marcaje se evaluó mediante TLC. Los estudios de biodistribución se llevaron a cabo en ratones tras la administración oftálmica de la formulación y de un control de 99mTcO4 - libre. Para ello, se sacrificaron los animales a las 2 y a las 24 horas tras la administración ocular y se contaron los órganos en un contador gamma. Resultados: Se obtuvo un rendimiento de marcaje superior al 90%. Los estudios de biodistribución de 99mTc-Man-NP-HS permitieron detectar la actividad concentrada en mucosa nasal y ocular y tracto gastrointestinal tanto a las 2 como a las 24 horas, frente a la biodistribución de 99mTcO4 - libre que permaneció concentrado en la piel alrededor del ojo y en tracto gastrointestinal. Conclusión: Los estudios de biodistribución de 99mTc-Man-NP-HS tras administración oftálmica han permitido demostrar su biodistribución en mucosas y tracto gastrointestinal, característica indispensable como sistema de liberación de antígenos a través de mucosa ocular. Esto, junto con su elevada respuesta inmune, efectiva protección y no virulencia, convierte a estas nanopartículas en una vacuna ideal anti Brucelosis

A NOVEL INDEX OF ABUNDANCE OF JUVENILE YELLOWFIN TUNA IN THE ATLANTIC OCEAN DERIVED FROM ECHOSOUNDER BUOYS

The collaboration with the Spanish vessel-owners associations and the buoy-providers companies, has made it possible the recovery of the information recorded by the satellite linked GPS tracking echosounder buoys used by the Spanish tropical tuna purse seiners and associated fleet in the Atlantic since 2010. These instrumental buoys inform fishers remotely in real-time about the accurate geolocation of the FAD and the presence and abundance of fish aggregations underneath them. Apart from its unquestionable impact in the conception of a reliable CPUE index from the tropical purse seine tuna fisheries fishing on FADs, echosounder buoys have also the potential of being a privileged observation platform to evaluate abundances of tunas and accompanying species using catch-independent data. Current echosounder buoys provide a single acoustic value without discriminating species or size composition of the fish underneath the FAD. Therefore, it has been necessary to combine the echosounder buoys data with fishery data, species composition and average size, to obtain a specific indicator. This paper presents a novel index of abundance of juvenile yellowfin tuna in the Atlantic Ocean derived from echosounder buoys for the period 2010-2018

Evaluation of spacial resolution of a PET scanner through the simulation and experimental measurement of the Recovery coefficient

Purpose: In order to measure spatial resolution of a PET tomograph in clinical conditions, this study describes and validates a method based on the recovery coefficient, a factor required to compensate underestimation in measured radioactivity concentration for small structures. Methods: In a PET image, the recovery factors of radioactive spheres were measured and their comparison with simulated recovery coefficients yielded the tomographic spatial resolution. Following this methodology, resolution was determined in different surrounding media and several conditions for reconstruction, including clinical conditions for brain PET studies. All spatial resolution values were compared with those obtained using classical methods with point and line sources. Results: In each considered condition, spatial resolution of the PET image estimated using the recovery coefficient showed good agreement with classical methods measurements, validating the procedure. Conclusion: Measurement of the recovery coefficient provides an assessment of tomographic spatial resolution, particularly in clinical studies conditions

Zein nanoparticles for oral folic acid delivery

The aim of this work was to prepare and evaluate the capability of zein nanoparticles for oral drug delivery. More particularly, in this work, the ability of these nanoparticles to improve the oral bioavailability of folic acid is reported. The nanoparticles were prepared by a desolvation process, followed by purification via ultrafiltration and drying in a spray-drier apparatus. The resulting nanoparticles displayed a mean size close to 200 nm with negative zeta potential and a payload of 54 μg folic acid per mg nanoparticle. From the in vitro release studies, it was observed that folic acid was only released from nanoparticles in simulated intestinal conditions. In vivo biodistribution studies,with radiolabelled or fluorescently marked nanoparticles, revealed that nanoparticles remained within the gut and were capable of interacting with the protective mucus layer of the jejunum. For the pharmacokinetic study, folic acid was orally administered to rats as a single dose of 1 mg/kg.The relatively oral bioavailability of folic acid, when encapsulated in zein nanoparticles, was around 70%: two-times higher than the value obtained with an aqueous solution of the vitamin. This fact might be explained by the mucoadhesive properties of these nanoparticles

Tomografía por emisión de positrones en el cáncer de mama

PET18FDG is an imaging diagnostic technique that shows changes in glycolitic metabolism that appear at a very early phases in the tumoral process. The main limitation of PET in breast cancer is the detection of small tumor lesions and axillary micrometastases. However it offers important information in the staging of high risk patients, in clinical relapse or in therapeutic evaluation. The new PET-CT devices offer advantages over conventional techniques. It provides a greater precision in the localization of tumoral foci. In spite of current difficulties for clinical applications, fluoro-estradiol (18F-ES) offers the possibilty of studying the presence of estrogenic receptors both in the primary and in the metastases. It may prove to be a useful tool to obtain information about therapeutic management and prognosis of breast cancer

Dissolving microneedles for intradermal vaccination against shigellosis

Intradermal (ID) immunization is of increasing interest due to the easy accessibility and excellent immunogenic properties of the skin. Among ID immunization methods, dissolving microneedles (MNs) have appeared as an alternative to traditional hypodermic immunization, offering many advantages, such as being an easily administered method, with no need for health personnel, painless, and avoiding the use of needles and sharp wastage. In this study, an affordable and easy-to-produce MNs method was developed based on aqueous blends of 30% w/w poly (methyl vinyl ether-co-maleic anhydride). As an antigen model, a subunit vaccine candidate based on outer membrane vesicles from Shigella flexneri was used. Both unloaded and antigen-loaded MNs were synthetized and characterized. The MNs were successfully validated in an in vitro Parafilm M skin model and in a pig skin ex vivo model. Biodistribution studies were performed in BALB/c mice using 99mTcO4- radiolabeled samples. Results indicated that the vesicle vaccine was successfully released from the MNs and targeted gastrointestinal tract after 6 h post-administration. In vivo immunization and protection studies were performed in BALB/c mice. Mice were intradermally immunized through ear skin with one single dose of 200 g antigenic complex, eliciting the production of specific systemic IgG and mucosal IgA

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of 18F-DOPA and 11C-(+)-α-dihydrotetrabenazine (11C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, 18F-DOPA and 11C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of 11C-DTBZ PET. A symmetric reduction in striatal 11C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Desarrollo de procedimientos automatizados de síntesis de radiofármacos PET marcados con carbono-11 a temperatura ambiente y purificación mediante extracción en fase sólida

The continued increase in the number of PET studies with carbon-11 labelled radiopharmaceuticals, along with the limitations in space and laboratory equipment is a real problem and a radiation protection challenge. Adaptation of synthesis procedures to solid-phase supported approaches implies a global simplification of the synthesis system, an increase in safety and a substantial decrease in the overall necessary time to carry out the synthesis. Objectives The aims of this study were: (1) to design, assemble and test a fully-automated solid-phase supported synthesis system based on commercial modules for the simultaneous production of L-[Methyl-(11C)]Methionine (MET) and [11C]-Choline (CHOL); (2) set-up such system also for the routine production of [11C]-(+)-á- dihydrotetrabenazine (DTBZ); and (3) design and test a solid phase extraction based simplified system using whole-sterile single use "plug & play" kits for synthesis of MET and CHOL using Eckert&Ziegler Modular Lab modules. Methodology A commercial Tracerlab FXc module (GE) was modified to carry out the simultaneous production of MET and CHOL starting from [11C]methyl iodide. A completely automated synthesis sequence was programmed and 48 synthesis runs made to demonstrate performance of the system. Reaction times, synthesis yields and full QC of both radiopharmaceuticals were carried out. Such system was further adapted (including control interface and running sequences) for the synthesis of DTBZ using two Alumina N cartridges for final purification of the product and 54 synthesis runs carried out. Solvents were then evaporated under vacuum with helium flow. Finally, for the "plug and play" approach kits were set-up in a LFC using single-use sterile medical material, sterilised and further used for the synthesis of MET and CHOL using the designed Modular Lab based synthesis system. A control interface and a synthesis sequence programs were also designed for such purpose. Results and conclusions Simultaneous production of MET and CHOL was finalised in just six minutes with mean productions of 2.4 and 2.7 GBq respectively, and radiopharmaceutical purity according to pharmacopoeia standards. [11C]DTBZ (1.94 ±0.13 GBq) was obtained with radiochemical purity >99% while residual solvents were below PhEur stablished levels. The ¿plug &play¿ system produced MET and CHOL with radiopharmaceutical purity with 5.0 and 5.3 GBq mean production yields. The new procedures minimises the time required for the preparation of the system, avoids cleaning runs, facilitates fulfilment of GMP quality standards and improves radiation protection to personnel

Desarrollo de procedimientos automatizados de síntesis de radiofármacos PET marcados con carbono-11 a temperatura ambiente y purificación mediante extracción en fase sólida

The continued increase in the number of PET studies with carbon-11 labelled radiopharmaceuticals, along with the limitations in space and laboratory equipment is a real problem and a radiation protection challenge. Adaptation of synthesis procedures to solid-phase supported approaches implies a global simplification of the synthesis system, an increase in safety and a substantial decrease in the overall necessary time to carry out the synthesis. Objectives The aims of this study were: (1) to design, assemble and test a fully-automated solid-phase supported synthesis system based on commercial modules for the simultaneous production of L-[Methyl-(11C)]Methionine (MET) and [11C]-Choline (CHOL); (2) set-up such system also for the routine production of [11C]-(+)-á- dihydrotetrabenazine (DTBZ); and (3) design and test a solid phase extraction based simplified system using whole-sterile single use "plug & play" kits for synthesis of MET and CHOL using Eckert&Ziegler Modular Lab modules. Methodology A commercial Tracerlab FXc module (GE) was modified to carry out the simultaneous production of MET and CHOL starting from [11C]methyl iodide. A completely automated synthesis sequence was programmed and 48 synthesis runs made to demonstrate performance of the system. Reaction times, synthesis yields and full QC of both radiopharmaceuticals were carried out. Such system was further adapted (including control interface and running sequences) for the synthesis of DTBZ using two Alumina N cartridges for final purification of the product and 54 synthesis runs carried out. Solvents were then evaporated under vacuum with helium flow. Finally, for the "plug and play" approach kits were set-up in a LFC using single-use sterile medical material, sterilised and further used for the synthesis of MET and CHOL using the designed Modular Lab based synthesis system. A control interface and a synthesis sequence programs were also designed for such purpose. Results and conclusions Simultaneous production of MET and CHOL was finalised in just six minutes with mean productions of 2.4 and 2.7 GBq respectively, and radiopharmaceutical purity according to pharmacopoeia standards. [11C]DTBZ (1.94 ±0.13 GBq) was obtained with radiochemical purity >99% while residual solvents were below PhEur stablished levels. The ¿plug &play¿ system produced MET and CHOL with radiopharmaceutical purity with 5.0 and 5.3 GBq mean production yields. The new procedures minimises the time required for the preparation of the system, avoids cleaning runs, facilitates fulfilment of GMP quality standards and improves radiation protection to personnel