Exploring Environmental Settings to Improve the Printability of Paroxetine-Loaded Filaments by Fused Deposition Modelling.

The successful integration of hot-melt extrusion (HME) and fused deposition modelling (FDM) depends on a better understanding of the impact of environmental conditions on the printability of formulations, since they significantly affect the properties of the raw materials, whose control is crucial to enable three-dimensional printing (3DP). Hence, the objective of this work was to investigate the correlation between the environmental settings and the properties of paroxetine (PRX)-loaded filaments, previously produced by HME, which affect printability by FDM. The influence of different drying methods of the physical mixtures (PMs) and HME-filaments (FILs) on the quality and printability of these products was also assessed. The printability of FILs was evaluated in terms of the water content, and the mechanical and thermal properties of the products. Stability studies and physicochemical, thermal, and in vitro dissolution tests were carried out on the 3D-printed tablets. Stability studies demonstrated the high ductility of the PRX loaded FILs, especially under high humidity conditions. Under low humidity storage conditions (11% RH), the FILs became stiffer and were successfully used to feed the FDM printer. Water removal was slow when carried out passively in a controlled atmosphere (desiccator) or accelerated by using active drying methods (heat or microwave). Pre-drying of the PRX/excipients and/or PMs did not show any positive effect on the printability of the FIL. On the contrary, dry heat and, preferably, microwave mediated drying processes were shown to reduce the holding time required for successful FDM printing, enabling on-demand production at the point of care.

Performance and paroxetine stability in tablets manufactured by fused deposition modelling-based 3D printing.

OBJECTIVES: The objective of this study was to develop a method for the preparation and characterization of paroxetine (PRX) tablets, obtained by coupling hot-melt extrusion and fused deposition modelling (FDM)-based three-dimensional printing (3DP) technology. The impact of the printing process parameters on the drug stability and on the tablets performance was assessed. METHODS: Tablets were obtained by FDM of hot-melt extruded PRX-loaded filaments. Physicochemical, thermal, spectroscopic, diffractometric analysis and in-vitro dissolution tests of the intermediate products and the finished dosage forms were performed. KEY FINDINGS: The characterization of printed tablets evidenced mass and dimensions uniformity, and consistency of drug content and dissolution profile. The formation of amorphous solid dispersions and interaction of formulation components throughout the manufacturing process were demonstrated. Layer thickness, printing temperature, printing and travelling speeds, and infill were the most impacting process parameters on both the physicochemical properties and the in-vitro performance of the 3D-printed tablets. CONCLUSIONS: PRX tablets, meeting compendial limits, were manufactured by 3DP, envisaging their clinical use as individually designed dosage forms. The assessment of the impact of processing parameters on the printed tablets provided insights, which will ultimately allow streamlining of the 3D process set-up for quicker and easier production of patient-centric medicines.

Limitations and perceived delays for diagnosis and staging of lung cancer in Portugal: A nationwide survey analysis.

BACKGROUND: We aimed to identify the perception of physicians on the limitations and delays for diagnosing, staging and treatment of lung cancer in Portugal. METHODS: Portuguese physicians were invited to participate an electronic survey (Feb-Apr-2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR). The association between categorical variables was assessed through Pearson's chi-square test. Mann-Whitney test was used to compare categorical and continuous variables (Stata v.15.0). RESULTS: Sixty-one physicians participated in the study (45 pulmonologists, 16 oncologists), with n = 26 exclusively assisting lung cancer patients. Most experts work in public hospitals (90.16%) in Lisbon (36.07%). During the last semester of 2019, responders performed a median of 85 (IQR 55-140) diagnoses of lung cancer. Factors preventing faster referral to the specialty included poor articulation between services (60.0%) and patients low economic/cultural level (44.26%). Obtaining National Drugs Authority authorization was one of the main reasons (75.41%) for delaying the begin of treatment. The cumulative lag-time from patients' admission until treatment ranged from 42-61 days. Experts believe that the time to diagnosis could be optimized in around 11.05 days [IQR 9.61-12.50]. Most physicians (88.52%) started treatment before biomarkers results motivated by performance status deterioration (65.57%) or high tumor burden (52.46%). Clinicians exclusively assisting lung cancer cases reported fewer delays for obtaining authorization for biomarkers analysis (p = 0.023). Higher waiting times for surgery (p = 0.001), radiotherapy (p = 0.004), immunotherapy (p = 0.003) were reported by professionals from public hospitals. CONCLUSIONS: Physicians believe that is possible to reduce delays in all stages of lung cancer diagnosis with further efforts from multidisciplinary teams and hospital administration.

Polymer Selection for Hot-Melt Extrusion Coupled to Fused Deposition Modelling in Pharmaceutics.

Three-dimensional (3D) printing offers the greatest potential to revolutionize the future of pharmaceutical manufacturing by overcoming challenges of conventional pharmaceutical operations and focusing design and production of dosage forms on the patient's needs. Of the many technologies available, fusion deposition modelling (FDM) is considered of the lowest cost and higher reproducibility and accessibility, offering clear advantages in drug delivery. FDM requires in-house production of filaments of drug-containing thermoplastic polymers by hot-melt extrusion (HME), and the prospect of connecting the two technologies has been under investigation. The ability to integrate HME and FDM and predict and tailor the filaments' properties will extend the range of printable polymers/formulations. Hence, this work revises the properties of the most common pharmaceutical-grade polymers used and their effect on extrudability, printability, and printing outcome, providing suitable processing windows for different raw materials. As a result, formulation selection will be more straightforward (considering the characteristics of drug and desired dosage form or release profile) and the processes setup will be more expedite (avoiding or mitigating typical processing issues), thus guaranteeing the success of both HME and FDM. Relevant techniques used to characterize filaments and 3D-printed dosage forms as an essential component for the evaluation of the quality output are also presented.

Atuação do profissional de educação física em CAPS representada pelos demais profissionais do serviço / The work of the physical education professional in "CAPS" represented by other health professionals / El trabajo del profesional de la educación física en "CAPS" representado por otros profesionales de la salud

O objetivo deste estudo é analisar a atuação do profissional de Educação Física nos Centros de Atenção Psicossociais, representada pe- los demais profissionais de saúde. Com base na teoria das representa - ções sociais foram realizadas entrevistas com 11 profissionais. A técnica do discurso do sujeito coletivo como procedimento resultou em três dis- cursos, que apontam: o reconhecimento pela promoção de atividades físicas; o desenvolvimento de trabalhos próprios do serviço e desenvol- vimento de atividades extramuros; bem como a importância de espaço e material apropriado. Conclui-se que a representação social da atuação da Educação Física ficou ancorada no trabalho em equipe nos diversos grupos terapêuticos e objetivada na mudança de comportamento para a melhoria da saúde.

The aim of this study is to analyse the performance of the Physical Education professional in the Psychosocial Care Centers (CAPS), represented by the other health professionals. Based on the theory of social representations, interviews were conducted with 11 professionals. The Collective Subject Discourse as a procedure resulted in three discourses, points: to recognition by the promotion of physical activities; the development of intrinsic activities of CAPS and of extramural activities; and the importance of local and appropriate material. It is concluded that the social representation of the Physical Education performance was anchored in the teamwork in the different therapeutic groups and objectified in the change of behaviour for the improvement of health.

El objetivo de este estudio es analizar el desempeño del profesional de Educación Física en los Centros de Atención Psicosocial (CAPS), representado por los otros profesionales. Sobre la base de la teoría de las representaciones sociales, se realizaron entrevistas con 11 profesionales. El discurso del sujeto colectivo como un procedimiento dio lugar a tres discursos, puntos: al reconocimiento por la promoción de actividades físicas; el desarrollo de actividades intrínsecas de CAPS y de actividades extramuros; y la importancia del material local y apropiado. Se concluye que la representación social del desempeño de la Educación Física se basó en el trabajo en equipo en los diferentes grupos terapéuticos y se objetivó en el cambio de comportamiento para mejorar la salud.

Genomic imbalances defining novel intellectual disability associated loci.

BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.

Respiratory Care for the Ventilated Neonate.

Invasive ventilation is often necessary for the treatment of newborn infants with respiratory insufficiency. The neonatal patient has unique physiological characteristics such as small airway caliber, few collateral airways, compliant chest wall, poor airway stability, and low functional residual capacity. Pathologies affecting the newborn's lung are also different from many others observed later in life. Several different ventilation modes and strategies are available to optimize mechanical ventilation and to prevent ventilator-induced lung injury. Important aspects to be considered in ventilating neonates include the use of correct sized endotracheal tube to minimize airway resistance and work of breathing, positioning of the patient, the nursing care, respiratory kinesiotherapy, sedation and analgesia, and infection prevention, namely, the ventilator-associated pneumonia and nosocomial infection, as well as prevention and treatment of complications such as air leaks and pulmonary hemorrhage. Aspects of ventilation in patients under ECMO (extracorporeal membrane oxygenation) and in palliative care are of increasing interest nowadays. Online pulmonary mechanics and function testing as well as capnography are becoming more commonly used. Echocardiography is now a routine in most neonatal units. Near infrared spectroscopy (NIRS) is an attractive tool potentially helping in preventing intraventricular hemorrhage and periventricular leukomalacia. Lung ultrasound is an emerging tool of diagnosis and can be of added value in helping monitoring the ventilated neonate. The aim of this scientific literature review is to address relevant aspects concerning the respiratory care and monitoring of the invasively ventilated newborn in order to help physicians to optimize the efficacy of care.

Multifunctional gold-nanoparticles: A nanovectorization tool for the targeted delivery of novel chemotherapeutic agents.

Due to their small size and unique properties, multifunctional nanoparticles arise as versatile delivery systems easily grafted with a vast array of functional moieties, such as anticancer cytotoxic chemotherapeutics and targeting agents. Here, we formulated a multifunctional gold-nanoparticle (AuNP) system composed of a monoclonal antibody against epidermal growth factor receptor (EGFR) (anti-EGFR D-11) for active targeting and a Co(II) coordination compound [CoCl(H2O)(phendione)2][BF4] (phendione=1,10-phenanthroline-5,6-dione) (TS265) with proven antiproliferative activity towards cancer cells (designated as TargetNanoTS265). The efficacy of this nanoformulation, and the non-targeted counterpart (NanoTS265), were evaluated in vitro using cancer cell models and in vivo using mice xenografts. Compared to the free compound, both nanoformulations (TargetNanoTS265 and NanoTS265) efficiently delivered the cytotoxic cargo in a controlled selective manner due to the active targeting, boosting tumor cytotoxicity. Treatment of HCT116-derived xenografts tumors with TargetNanoTS265 led to 93% tumor reduction. This simple conceptual nanoformulation demonstrates the potential of nanovectorization of chemotherapeutics via simple assembly onto AuNPs of BSA/HAS-drug conjugates that may easily be expanded to suit other cargo of novel compounds that require optimized controlled delivery to cancer target.

Liposomes as Delivery System of a Sn(IV) Complex for Cancer Therapy.

PROPOSE: Tin complexes demonstrate antiproliferative activities in some case higher than cisplatin, with IC50 at the low micromolar range. We have previously showed that the cyclic trinuclear complex of Sn(IV) bearing an aromatic oximehydroxamic acid group [nBu2Sn(L)]3 (L=N,2-dihydroxy-5-[N-hydroxyethanimidoyl]benzamide) (MG85) shows high anti-proliferative activity, induces apoptosis and oxidative stress, and causes destabilization of tubulin microtubules, particularly in colorectal carcinoma cells. Despite the great efficacy towards cancer cells, this complex still shows some cytotoxicity to healthy cells. Targeted delivery of this complex specifically towards cancer cells might foster cancer treatment. METHODS: MG85 complex was encapsulated into liposomal formulation with and without an active targeting moiety and cancer and healthy cells cytotoxicity was evaluated. RESULTS: Encapsulation of MG85 complex in targeting PEGylated liposomes enhanced colorectal carcinoma (HCT116) cancer cell death when compared to free complex, whilst decreasing cytotoxicity in non-tumor cells. Labeling of liposomes with Rhodamine allowed assessing internalization in cells, which showed significant cell uptake after 6 h of incubation. Cetuximab was used as targeting moiety in the PEGylated liposomes that displayed higher internalization rate in HCT116 cells when compared with non-targeted liposomes, which seems to internalize via active binding of Cetuximab to cells. CONCLUSIONS: The proposed formulation open new avenues in the design of innovative transition metal-based vectorization systems that may be further extended to other novel metal complexes towards the improvement of their anti-cancer efficacy, which is usually hampered by solubility issues and/or toxicity to healthy tissues.

Characterization of antiproliferative potential and biological targets of a copper compound containing 4'-phenyl terpyridine.

Several copper complexes have been assessed as anti-tumor agents against cancer cells. In this work, a copper compound [Cu(H2O){OS(CH3)2}L](NO3)2 incorporating the ligand 4'-phenyl-terpyridine antiproliferative activity against human colorectal, hepatocellular carcinomas and breast adenocarcinoma cell lines was determined, demonstrating high cytotoxicity. The compound is able to induce apoptosis and a slight delay in cancer cell cycle progression, probably by its interaction with DNA and induction of double-strand pDNA cleavage, which is enhanced by oxidative mechanisms. Moreover, proteomic studies indicate that the compound induces alterations in proteins involved in cytoskeleton maintenance, cell cycle progression and apoptosis, corroborating its antiproliferative potential.

MRI tracking of macrophages labeled with glucan particles entrapping a water insoluble paramagnetic Gd-based agent.

PURPOSE: This study is aimed at demonstrating the in vivo potential of Gd(III)-loaded glucan particles (Gd-GPs) as magnetic resonance imaging (MRI)-positive agents for labeling and tracking phagocytic cells. PROCEDURE: GPs were obtained from Saccharomyces cerevisae and loaded with the water-insoluble complex Gd-DOTAMA(C18)2. The uptake kinetics of Gd-GPs by murine macrophages was studied in vitro and the internalization mechanism was assessed by competition assays. The in vivo performance of Gd-GPs was tested at 7.05 T on a mouse model of acute liver inflammation. RESULTS: The minimum number of Gd-GPs-labeled J774.A1 macrophages detected in vitro by MRI was ca. 300 cells/µl of agar, which is the lowest number ever reported for cells labeled with a positive T1 agent. Intravenous injection of macrophages labeled with Gd-GPs in a mouse model of liver inflammation enabled the MRI visualization of the cellular infiltration in the diseased area. CONCLUSIONS: Gd-GPs represent a promising platform for tracking macrophages by MRI as a T1 alternative to the golden standard T2-based iron oxide particles.

Yeast cell wall particles: a promising class of nature-inspired microcarriers for multimodal imaging.

This communication demonstrates that yeast cell wall particles (YCWPs) are a promising class of nature-inspired biocompatible microcarriers for the delivery of amphipathic/lipophilic imaging reporters. When a paramagnetic MRI agent is loaded, the longitudinal relaxivity per particle at 0.5 T is the highest ever reported for Gd-based systems.

Supramolecular protamine/Gd-loaded liposomes adducts as relaxometric protease responsive probes.

A new approach to enzyme-responsive MRI agents based on the use of liposomes loaded with a high number of paramagnetic metal complexes (Gd-HPDO3A) is presented. It relies on the disruption of low relaxivity aggregates formed by liposomes and a macromolecular substrate that is selectively cleaved by the enzyme of interest. The interaction of anionic liposomes composed of POPC:CHOL:DPGS and the cationic protein protamine yields a poorly soluble supramolecular assembly endowed with a low relaxivity. The action of the serine protease trypsin causes the digestion of protamine and the consequent de-assembly of the supramolecular adduct. The process is accompanied by an overall relaxation enhancement of solvent water protons as consequence of the dissolution of the aggregated liposomes. The observed increase of relaxivity is linearly dependent on the enzyme concentration. An illustrative example of the possible use of the herein presented responsive agent has been reported. It consists of the entrapment of the supramolecular assembly in alginate microcapsules that have often been used as envelopes for in vivo applications of stem cells and pancreatic islets. The change in the observed longitudinal relaxation rate R(1) (leading to an hyperintense signal in the corresponding MR images) may act as a sensor of the protease activity in the biological environment in which the capsules is located.