Evaluation of Two Osmosis-Based Methods for the Preparation of Drug Delivery Systems Based on Red Blood Cells.

Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods, outstanding the osmosis-based methods as the most used ones. Most of them involve too much handling of blood components and the immediate obtention of fresh blood. Based on our group's considerable experience in dialysis-based carrier erythrocyte preparation, this study details a simple method based on hypotonic dilution and subsequent resealing that has been developed for stavudine using packed erythrocytes from a local blood bank. Properties of the obtained carrier erythrocytes were studied in comparison to those prepared by dialysis. Erythrocytes' morphology, osmotic fragility, hematological parameters, and in vitro release profiles were evaluated. Loaded erythrocytes obtained with the proposed method did not show impaired properties in comparison with those obtained with our reference method, provided that the buffer composition remained the same. In the present work, we have optimized a simplified method for erythrocytes' drug loading, which can use blood transfusion products and could be easily automatized and scalable.

Physiologically Based Pharmacokinetic (PBPK) Model of Gold Nanoparticle-Based Drug Delivery System for Stavudine Biodistribution.

Computational modelling has gained attention for evaluating nanoparticle-based drug delivery systems. Physiologically based pharmacokinetic (PBPK) modelling provides a mechanistic approach for evaluating drug biodistribution. The aim of this work is to develop a specific PBPK model to simulate stavudine biodistribution after the administration of a 40 nm gold nanoparticle-based drug delivery system in rats. The model parameters used have been obtained from literature, in vitro and in vivo studies, and computer optimization. Based on these, the PBPK model was built, and the compartments included were considered as permeability rate-limited tissues. In comparison with stavudine solution, a higher biodistribution of stavudine into HIV reservoirs and the modification of pharmacokinetic parameters such as the mean residence time (MRT) have been observed. These changes are particularly noteworthy in the liver, which presents a higher partition coefficient (from 0.27 to 0.55) and higher MRT (from 1.28 to 5.67 h). Simulated stavudine concentrations successfully describe these changes in the in vivo study results. The average fold error of predicted concentrations after the administration of stavudine-gold nanoparticles was within the 0.5-2-fold error in all of the tissues. Thus, this PBPK model approach may help with the pre-clinical extrapolation to other administration routes or the species of stavudine gold nanoparticles.

Recent advances in functionalized nanomaterials for the diagnosis and treatment of bacterial infections.

The growing problem of resistant infections due to antibiotic misuse is a worldwide concern that poses a grave threat to healthcare systems. Thus, it is necessary to discover new strategies to combat infectious diseases. In this review, we provide a selective overview of recent advances in the use of nanocomposites as alternatives to antibiotics in antimicrobial treatments. Metals and metal oxide nanoparticles (NPs) have been associated with inorganic and organic supports to improve their antibacterial activity and stability as well as other properties. For successful antibiotic treatment, it is critical to achieve a high drug concentration at the infection site. In recent years, the development of stimuli-responsive systems has allowed the vectorization of antibiotics to the site of infection. These nanomaterials can be triggered by various mechanisms (such as changes in pH, light, magnetic fields, and the presence of bacterial enzymes); additionally, they can improve antibacterial efficacy and reduce side effects and microbial resistance. To this end, various types of modified polymers, lipids, and inorganic components (such as metals, silica, and graphene) have been developed. Applications of these nanocomposites in diverse fields ranging from food packaging, environment, and biomedical antimicrobial treatments to diagnosis and theranosis are discussed.

A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity.

The antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.

Advances in Exosomes-Based Drug Delivery Systems.

Exosomes, a subgroup of extracellular vesicles, are important mediators of long-distance intercellular communication and are involved in a diverse range of biological processes such as the transport of lipids, proteins, and nucleic acids. Researchers, seeing the problems caused by the toxic effects and clearance of synthetic nanoparticles, consider exosomes as an interesting alternative to such nanoparticles in the specific and controlled transport of drugs. In recent years, there have been remarkable advances in the use of exosomes in cancer therapeutics or for treating neurological diseases, among other applications. The objective of this work is to analyze studies focused on exosomes used in drug delivery system, present and future applications in this field of research are discussed based on the results obtained.

Cell-Based Drug Delivery Platforms.

Within the framework of nanomedicine, drug delivery has experienced rapid progress in recent years [...].

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles.

Hepatic macrophage populations include different types of cells with plastic properties that can differentiate into diverse phenotypes to modulate their properties in response to different stimuli. They often regulate the activity of other cells and play an important role in many hepatic diseases. In response to those pathological situations, they are activated, releasing cytokines and chemokines; they may attract circulating monocytes and exert functions that can aggravate the symptoms or drive reparation processes. As a result, liver macrophages are potential therapeutic targets that can be oriented toward a variety of aims, with emergent nanotechnology platforms potentially offering new perspectives for macrophage vectorization. Macrophages play an essential role in the final destination of nanoparticles (NPs) in the organism, as they are involved in their uptake and trafficking in vivo. Different types of delivery nanosystems for macrophage recognition and targeting, such as liposomes, solid-lipid, polymeric, or metallic nanoparticles, have been developed. Passive targeting promotes the accumulation of the NPs in the liver due to their anatomical and physiological features. This process is modulated by NP characteristics such as size, charge, and surface modifications. Active targeting approaches with specific ligands may also be used to reach liver macrophages. In order to design new systems, the NP recognition mechanism of macrophages must be understood, taking into account that variations in local microenvironment may change the phenotype of macrophages in a way that will affect the uptake and toxicity of NPs. This kind of information may be applied to diseases where macrophages play a pathogenic role, such as metabolic disorders, infections, or cancer. The kinetics of nanoparticles strongly affects their therapeutic efficacy when administered in vivo. Release kinetics could predict the behavior of nanosystems targeting macrophages and be applied to improve their characteristics. PBPK models have been developed to characterize nanoparticle biodistribution in organs of the reticuloendothelial system (RES) such as liver or spleen. Another controversial issue is the possible toxicity of non-degradable nanoparticles, which in many cases accumulate in high percentages in macrophage clearance organs such as the liver, spleen, and kidney.

Influence of Color in a Lactation Room on Users' Affective Impressions and Preferences.

OBJECTIVE: The present study aims to examine the influence of environmental color hue in a lactation room at a health center on users' affective response and preference. BACKGROUND: Hospital design plays an important role in the emotional experience of patients. In this regard, many studies have attempted to find relationships between design variables and healthcare facilities users' response. Color has been frequently examined because it is always present in the environment and can be easily changed. However, most of the studies dealing with color-emotion relationships acquire users' affective response by questionnaires developed by experts which could lead to inaccurate results since nonexperts may misunderstand concepts set by experts and use nonimmersive images to simulate the environments to assess. METHODS: To overcome these limitations, a Kansei Engineering-based approach was proposed. In the first phase, users' specific affective factors for lactation rooms were determined using Semantic Differential. In the second phase, the influence of nine different color hues on users' affective factors was obtained. An immersive display system was used to visualize the room altering hues in an isolated and controlled way. RESULTS: (1) Six user's affective factors connected to the lactation rooms were discovered: safety, elegance, coziness, spaciousness, simplicity, and luminosity, of which coziness has the most impact on the assessment of the room. (2) Warm colors like orange and yellow tend to score highly for coziness which puts them in leading positions when users' assess lactation rooms. CONCLUSIONS: Results provide recommendations for designers and show the advantages of using semantic differential and immersive displays to analyze user's affective response to environments.

Nanoparticles for Signaling in Biodiagnosis and Treatment of Infectious Diseases.

Advances in nanoparticle-based systems constitute a promising research area with important implications for the treatment of bacterial infections, especially against multidrug resistant strains and bacterial biofilms. Nanosystems may be useful for the diagnosis and treatment of viral and fungal infections. Commercial diagnostic tests based on nanosystems are currently available. Different methodologies based on nanoparticles (NPs) have been developed to detect specific agents or to distinguish between Gram-positive and Gram-negative microorganisms. Also, biosensors based on nanoparticles have been applied in viral detection to improve available analytical techniques. Several point-of-care (POC) assays have been proposed that can offer results faster, easier and at lower cost than conventional techniques and can even be used in remote regions for viral diagnosis. Nanoparticles functionalized with specific molecules may modulate pharmacokinetic targeting recognition and increase anti-infective efficacy. Quorum sensing is a stimuli-response chemical communication process correlated with population density that bacteria use to regulate biofilm formation. Disabling it is an emerging approach for combating its pathogenicity. Natural or synthetic inhibitors may act as antibiofilm agents and be useful for treating multi-drug resistant bacteria. Nanostructured materials that interfere with signal molecules involved in biofilm growth have been developed for the control of infections associated with biofilm-associated infections.

Efectividad de un programa formativo en reanimación cardiopulmonar en docentes de educación secundaria en el medio rural. Estudio piloto / A pilot study on the effectiveness of a training program in cardiopulmonary resuscitation for high school teachers in rural areas

Objetivo. Evaluar la eficacia de un programa formativo en reanimación cardiopulmonar con manejo de desfibrilador externo semiautomático en docentes de un Instituto de Educación Secundaria en el medio rural. Metodología. Estudio cuasiexperimental mediante muestreo por conveniencia. La duración total del programa formativo fue de 10 horas repartidas en 4 sesiones. Al inicio y final del programa formativo se administró a todos los participantes un cuestionario con 5 preguntas. Participantes. 15 docentes de un Instituto de Educación Secundaria perteneciente a la provincia de Teruel. Emplazamiento. Las sesiones formativas se llevaron a cabo en el propio instituto. Mediciones principales. Se utilizó el programa SPSS versión 21, con un IC del 95 %. Se realizó un análisis descriptivo: para variables cuantitativas (media y DE±) y para variables cualitativas frecuencias y porcentajes. Resultados. Un 73.3 % de los participantes fueron mujeres y un 26.7 % hombres. La media de edad de los participantes fue de 44.8 años. En el cuestionario pretest se observó que un 93.4 % de los participantes obtuvieron calificaciones de «no apto» y tan solo un 6.7 % obtuvo una calificación de «apto». En el cuestionario de evaluación postest se observó que el 100 % de los participantes obtuvieron calificaciones de «apto». La prueba de Wilcoxon constata que el programa formativo consiguió una eficacia elevada. Conclusiones. Los programas formativos pueden servir para estimular el desarrollo de nuevos programas de formación. Este tipo de formaciones resultan efectivas y deberían formar parte en la educación obligatoria en España (AU)

Objective. To evaluate the effectiveness of a training program in cardiopulmonary resuscitation, targeting high school teachers in rural areas for semi-automated external defibrillator management. Methodology. Quasi-experimental study using convenience sampling. The program lasted 10 hours, distributed among 4 sessions. At the beginning and end of the training program all participants answered a 5-issue questionnaire, which rated them as «suitable» or «unfit» to perform cardiorespiratory resuscitation. Participants. 15 high school teachers from Teruel province. LOCATION. The training sessions were conducted at the school premises. Main measurements. Program SPSS version 21 was used. The confidence interval was of 95 %. A descriptive analysis for quantitative (mean and SD ±) variables, qualitative variables, frequencies and percentages was performed. Results. 73.3 % of participants were women and 26.7 % men. The average age of participants was 44.8 years. For the pre-test questionnaire, 93.4 % of participants received «unfit» grades and only 6.7 % were rated as «suitable». In the posttraining evaluation questionnaire, 100 % of participants were graded as «suitable». Wilcoxon test established that the training program was highly efficient. Conclusions. Training programs make a difference in the capacity to correctly perform life-saving interventions. They also stimulate the development of new and better training programs. Such trainings are very effective and should be included as part of Spain’s compulsory education (AU)

Psychological and physiological human responses to simulated and real environments: A comparison between Photographs, 360° Panoramas, and Virtual Reality.

Psychological research into human factors frequently uses simulations to study the relationship between human behaviour and the environment. Their validity depends on their similarity with the physical environments. This paper aims to validate three environmental-simulation display formats: photographs, 360° panoramas, and virtual reality. To do this we compared the psychological and physiological responses evoked by simulated environments set-ups to those from a physical environment setup; we also assessed the users' sense of presence. Analysis show that 360° panoramas offer the closest to reality results according to the participants' psychological responses, and virtual reality according to the physiological responses. Correlations between the feeling of presence and physiological and other psychological responses were also observed. These results may be of interest to researchers using environmental-simulation technologies currently available in order to replicate the experience of physical environments.

User Evaluation of Neonatology Ward Design.

OBJECTIVE: The object of this article is to identify the set of affective and emotional factors behind users' assessments of a space in a neonatology unit and to propose design guidelines based on these. BACKGROUND: The importance of the neonatology service and the variety of users place great demands on the space at all levels. Despite the repercussions, the emotional aspects of the environment have received less attention. METHODS: To avoid incurring limitations in the user mental scheme, this study uses two complementary methodologies: focus group and semantic differential. The (qualitative) focus group methodology provides exploratory information and concepts. The (quantitative) semantic differential methodology then uses these concepts to extract the conceptual structures that users employ in their assessment of the space. Of the total 175 subjects, 31 took part in focus groups and 144 in semantic differential. RESULTS: Five independent concepts were identified: privacy, functionality and professional nature, spaciousness, lighting, and cleanliness. In relation to the importance of the overall positive assessment of the space, the perception of privacy and sensations of dominance and pleasure are fundamental. Six relevant design aspects were also identified: provide spacious surroundings, facilitate sufficient separation between the different posts or cots, use different colors from those usually found in health-care centers, as some aversion was found to white and especially green, design areas with childhood themes, use warm artificial light, and choose user-friendly equipment. CONCLUSIONS: Results provide design recommendations of interest and show the possibilities offered by combining both systems to analyze user response.

Adverse reactions and tolerability of high-dose sublingual allergen immunotherapy.

BACKGROUND: Sublingual allergen immunotherapy is an effective treatment against allergic respiratory disease. Many studies have shown the safety of this type of therapy, although the factors that might affect the tolerability of high-dose sublingual immunotherapy have not been well established. The aim of this study was to determine the factors that affect the tolerability of sublingual allergen immunotherapy. PATIENTS AND METHODS: A total of 183 subjects aged ≥5 years, diagnosed with allergic rhinitis with/without mild to moderate asthma due to sensitization to grass, olive pollen, or mites, were included in this open, retrospective, multicentric, noninterventional study. Sublingual immunotherapy was administered for at least 3 months. RESULTS: The most frequent adverse reaction was oral pruritus (13.7% of the patients). Most of the reactions were local (84.7%) and immediate (93.5%) and occurred during the initiation phase (60.6%). All reactions were mild to moderate in severity. No serious adverse reactions were registered. When comparing factors with potential influence on the occurrence of adverse reactions, the results between the groups of subjects with and without adverse reactions showed no statistically significant differences in sex (P=0.6417), age (P=0.1801), years since the disease was first diagnosed (P=0.3800), treatment composition (P=0.6946), polysensitization (P=0.1730), or clinical diagnosis (P=0.3354). However, it was found that treatment duration had a statistically significant influence (3 months, >3 months: P=0.0442) and the presence of asthma was close to statistical significance (P=0.0847). CONCLUSION: In our study, treatment duration is significantly associated with the occurrence of adverse reactions after the administration of high doses of sublingual allergen immunotherapy.

Exploratory study of tolerability and immunological effect of a short up-dosing immunotherapy phase with a standardised allergen extract derived from pollen of Olea europaea.

BACKGROUND: A new subcutaneous specific immunotherapy (SCIT) product adsorbed on aluminium hydroxide has been developed with a short and simplified up-dosing phase, containing a biologically standardized allergen pollen extract from Olea europaea. OBJECTIVE: To assess the tolerability profile of the updosing phase and its immunological effect, in terms of specific IgG4 and IgE levels and immediate skin reactivity. MATERIAL AND METHODS: The study was an exploratory, multi-centre, open-label, single-arm, phase II/III clinical trial. Adults with a clinical history of allergic rhinoconjunctivitis with/without asthma due to sensitization to olive pollen were selected. Five up-dosing doses (300, 600, 3000, 6000 and 15000SQ+) were administered at weekly intervals, followed by a maintenance dose (15000SQ+) after 2 weeks. Adverse events were collected during the 30 min observation period after injections, after a telephone contact 2 days after each visit, and after reviewing the subjects' diary. IgG4 and IgE levels and immediate skin reactivity were evaluated at the beginning and at the end of the trial. RESULTS: Ninety-three subjects were included in the trial (mean age, 35.7 ± 10.3 years; women, 66.7 %). A total of 95 adverse drug reactions, all mild in intensity and non-serious, were reported during the trial: 85 local in 34.4 % subjects, 9 systemic in 4.3 % subjects and one non-specific (grade 0). Within 6 weeks, significant changes in IgG4 and IgE levels and in immediate skin reactivity to Olea europaea were accomplished. CONCLUSION: This new SCIT derived from pollen of Olea europaea presented a good tolerability profile and induced significant immunological responses already after a 6 week treatment. However, the non-controlled design may limit the interpretation of these results. TRIAL REGISTRATION: EudraCT no: 2011-004852-20; ClinicalTrials.gov Identifier: NCT01674595.

Cell-based drug-delivery platforms.

Cell systems have recently emerged as biological drug carriers, as an interesting alternative to other systems such as micro- and nano-particles. Different cells, such as carrier erythrocytes, bacterial ghosts and genetically engineered stem and dendritic cells have been used. They provide sustained release and specific delivery of drugs, enzymatic systems and genetic material to certain organs and tissues. Cell systems have potential applications for the treatment of cancer, HIV, intracellular infections, cardiovascular diseases, Parkinson's disease or in gene therapy. Carrier erythrocytes containing enzymes such us L-asparaginase, or drugs such as corticosteroids have been successfully used in humans. Bacterial ghosts have been widely used in the field of vaccines and also with drugs such as doxorubicin. Genetically engineered stem cells have been tested for cancer treatment and dendritic cells for immunotherapeutic vaccines. Although further research and more clinical trials are necessary, cell-based platforms are a promising strategy for drug delivery.

Application of the solid state NMR to the study of the alcohol/alkane mixtures adsorption onto graphite.

The mixing of molecules adsorbed from solution to different interfaces has both industrial and academic relevance and the mixing behaviour at the interface is a key to understanding for example, that the surface tension of a mixture of two surfactants is lower than either of the two pure materials and many other effects. In this paper, we report, for the first time, the application of Solid State NMR to the study of alkane/alcohol mixtures, in a range of relative size ratio between 0 and 0.35, adsorbed onto graphite at high, multilayer coverage. Moreover, this paper evaluated, for the first time, the utility of the combined used of 1H and 2H NMR for: (i) determining the surface composition and (ii) making a theoretical approach to the sorption isotherm. A variety of preferential adsorption behaviour is reported. Preferential adsorption of the longer molecule (decane vs. heptanol) from a mixture has been observed. However, if both components are of similar length, the alcohol is preferentially adsorbed (heptanol vs. octane and octanol vs. octane). Finally, a linear relation between the relative size ratio and the amount of alcohol at monolayer coverage is observed.

Changes of ochratoxin A in grapes inoculated with Aspergillus carbonarius and subjected to chamber-drying under controlled conditions.

The production pattern for ochratoxin A in grapes inoculated with Aspergillus carbonarius and changes in its concentration during raisining of Merlot, Syrah, Tempranillo, and Cabernet Sauvignon red grapes and Pedro Ximenez white grape were studied. Grapes were chamber-dried under controlled temperature and humidity conditions, with and without dipping pretreatments in alkaline emulsions of olive oil or ethyl oleate. Based on the results for the grapes that developed the fungus (Merlot and Pedro Ximenez), a temperature of 50 °C in the absence of dipping stopped ochratoxin A production and even degraded part of the toxin already formed. Both dipping pretreatments facilitated removal of the toxin and led to its virtually complete disappearance. However, dipping in the ethyl oleate emulsion caused substantial changes in the sensory characters of the musts obtained from the raisins, so it should be avoided to ensure the expected quality in the sweet wines elaborated from them.

Plasma membrane sterols are involved in yeast's ability to adsorb polyphenolic compounds resulting from wine model solution browning.

The aim of this work was to demonstrate the direct interaction between membrane sterols of yeast lees and some polymerized phenolic compounds resulting from wine model solution browning. For this purpose, we first demonstrated by measurement of steady-state fluorescence anisotropy of the cationic fluorescent TMA-DPH probe the effect of polymerized compounds from the model reactions of (+)-catechin/acetaldehyde and (+)-catechin/glyoxylic acid on the plasma membrane order of Saccharomyces cerevisiae yeast lees enriched with different sterols. In a second set of experiments, we used S. cerevisiae plasma membrane vesicles spiked with different sources of sterol (ergosterol, cholesterol or a mix of grape phytosterols) to assess the effect of the same polymerized compounds on both vesicle integrity and membrane leakiness to protons by ACMA fluorescence. All the obtained results prove that yeast membrane sterols are able to strongly interact with some polymerized compounds resulting from the browning of model solutions, likely explaining the yeast ability to adsorb polyphenolic compounds and mainly the colorless intermediate compounds of the browning reactions.

Increasing the selectivity of amikacin in rat peritoneal macrophages using carrier erythrocytes.

The selectivity of amikacin in macrophages in vitro and its biodistribution in peritoneal macrophages and other tissues were studied in rats using carrier erythrocytes. Amikacin-loaded erythrocytes were prepared using a hypotonic dialysis method. The in vitro uptake of amikacin by peritoneal macrophages was studied using cell monolayers. The in vivo uptake by macrophages and the tissue distribution of amikacin were studied in two groups of rats that received either amikacin in saline solution, or amikacin-loaded erythrocytes. Pharmacokinetic analyses were performed using model-independent methods. The administration of the antibiotic using carrier erythrocytes elicited a higher accumulation in macrophages, both in vitro and in vivo. The tissue pharmacokinetics of amikacin in vivo using carrier erythrocytes revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen. Minor changes in the pharmacokinetics were observed in organs and tissues such as renal cortex and medulla. According to the partition coefficients obtained, the relative uptake of amikacin when carrier erythrocytes were used was: spleen>peritoneal macrophages>liver>lung>renal cortex>renal medulla. Loaded erythrocytes can be seen to be potentially useful for the delivery of aminoglycoside antibiotics in macrophages.

Effect of different yeast strains and their culture conditions on the prevention of wine model solution browning by yeast lees.

The purpose of this work was to examine the possible involvement of yeast membrane components in the adsorption of browning compounds from oxidized white wine. For this purpose, different yeast strains and growth conditions (aerobiosis and anaerobiosis) were tested for their ability to prevent browning of two model solutions consisting of (+)-catechin/acetaldehyde and (+)-catechin/glyoxylic acid. The obtained results showed that the effects of yeast lees are different according to the type of the studied model solution and the growth conditions that affect both the quantity and the quality of membrane sterols of the yeasts. Moreover, in vitro experiments proved that yeast membrane sterols could be likely involved in the yeast's ability to adsorb polyphenolic compounds and mainly the colorless intermediate compounds of the browning reactions.