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.

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.

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.

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.

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.

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.

Pharmacokinetics and biodistribution of amikacin encapsulated in carrier erythrocytes.

OBJECTIVES: To study the changes in the pharmacokinetics and tissue distribution of the aminoglycoside amikacin in rats using amikacin carrier erythrocytes as a delivery system. METHODS: Amikacin-loaded erythrocytes were obtained using a hypotonic dialysis method. The pharmacokinetic and tissue distribution of amikacin were studied in three groups of rats receiving intravenous amikacin in saline solution, amikacin-loaded erythrocytes and amikacin-loaded erythrocytes treated with glutaraldehyde. Pharmacokinetic analysis was accomplished using model-independent methods. RESULTS: Administration of the antibiotic using carrier erythrocytes elicited a sustained release effect, with an increase in the plasma half-life and in the area under the curve of the antibiotic. The tissue pharmacokinetics of amikacin using carrier erythrocytes in comparison with a control group revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen, a similar pharmacokinetics in the lung and moderate changes in the pharmacokinetics in the kidney. Studies of tissue concentrations after the injection of glutaraldehyde-treated loaded erythrocytes demonstrated important changes in organs of the reticulo-endothelial system (RES) in comparison with the results observed for standard carrier erythrocytes, higher levels being observed in the liver whereas spleen levels decreased. CONCLUSIONS: The administration of amikacin in loaded erythrocytes in rats leads to significant changes in the pharmacokinetic behaviour of the antibiotic, a greater accumulation being observed in RES organs such as liver and spleen. This shows that loaded erythrocytes are potentially useful for the delivery of antibiotics in phagocytic cells located in the RES.

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.

Hemoglobin levels and acute radiotherapy-induced toxicity.

AIMS AND BACKGROUND: To analyze the possible correlation between hemoglobin concentration and the appearance of acute radiotherapy-induced toxicity. METHODS: We prospectively studied hemoglobin levels and acute radiotherapy-induced toxicity in 86 patients treated for 3 months. Both sexes were considered to have anemia if their hemoglobin level was < or = 12 g/dL. No patient received corrective treatment for hemoglobin levels. Acute toxicity was analyzed weekly during radiotherapy and 45 days after therapy ended. The possible relationship between anemia and toxicity was analyzed, as was the correlation between hemoglobin values and the degree of toxicity. RESULTS: The findings were similar for all prognostic factors in patients with and without anemia. Hemoglobin concentration was < or = 12 g/dL in 24 patients (27.9%; mean, 10.93 +/- 0.78 g/dL). At the end of radiotherapy, hemoglobin levels were < or = 12 g/dL in 18 patients (20.9%; mean, 11.26 +/- 1.06 g/dL). The correlation between pretherapy and posttherapy hemoglobin concentration was significant at r = 0.729 (P = 0.01). The correlation between absolute hemoglobin values and the degree of toxicity, and the possible relationship between hemoglobin concentration and the appearance or the degree of toxicity after radiotherapy, was not significant. CONCLUSIONS: The relationship between hemoglobin concentration and oxygenation of the tumor and healthy tissues was not linear. This may account for the influence of hemoglobin levels on control of the disease as reported in earlier studies, but it does not account for their influence on acute toxicity after radiotherapy.

Encapsulation and in vitro evaluation of amikacin-loaded erythrocytes.

The aim of our present work was to establish the effect of the osmolality of the hypotonic buffer on the encapsulated amount and the in vitro properties of Amikacin-loaded erythrocytes. Amikacin was encapsulated in rat erythrocytes using a hypotonic dialysis method with hypotonic buffers of different osmolalities with mean values around 90 and 150 mOsm/kg. Morphological examination of the ghost erythrocytes was accomplished using scanning electron microscopy (SEM). The osmotic fragility of normal and loaded erythrocytes was tested using hypotonic solutions. Evaluation of the hematological parameters of the control and loaded erythrocytes was carried out using a hematology system analyzer. Amikacin release from loaded erythrocytes was tested in autologous plasma at 37 degrees C over a 24-h period. The quantification of Amikacin in loaded erythrocytes and in autologous plasma was performed using an HPLC technique. A higher osmotic fragility of loaded erythrocytes was observed using a low osmolality buffer. Some hematological parameters showed statistically significant differences between the loaded erythrocytes obtained using two buffers of different osmolalities with respect to untreated erythrocytes. According to our results, Amikacin carrier erythrocytes obtained by hypotonic dialysis using a low osmolality buffer (90 mOsm/kg) should afford a good encapsulation yield, appropriate morphological properties, and sustained release in vitro.

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.

Drug, enzyme and peptide delivery using erythrocytes as carriers.

Erythrocytes are potential biocompatible vectors for different bioactive substances, including drugs. These can be used successfully as biological carriers of drugs, enzymes and peptides. There are currently diverse methods that permit drug encapsulation in erythrocytes with an appropriate yield. The methods most commonly employed are based on a high-haematocrit dialysis procedure, mainly hypo-osmotic dialysis. Erythrocytes loaded with drugs and other substances allow for different release rates to be obtained. Encapsulation in erythrocytes significantly changes the pharmacokinetic properties of drugs in both animals and humans, enhancing liver and spleen uptake and targeting the reticulo-endothelial system (RES). Amongst other applications, erythrocytes have been used for drug-targeting the RES with aminoglycoside antibiotics; the selective transport to certain organs and tissues of certain antineoplastic drugs, such as methotrexate, doxorubicine, etoposide, carboplatin, etc.; the encapsulation of angiotensin-converting enzyme (ACE) inhibitors, systemic corticosteroids, the encapsulation of new prodrugs with increased duration of action, etc. Erythrocytes are also attractive systems in the sense of their potential ability to deliver proteins and therapeutic peptides. Thus, erythrocytes have been used for the transport of enzymes destined for the correction of metabolic alterations as l-asparaginase, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AlDH) among others. Erythrocytes have been used successfully as carriers of anti-HIV peptides, such as AZT, nucleoside analogues, antisense oligonucleotides, antineoplastic peptides, erythropoietin, interleukin 3, etc. Amongst other applications, mention may be made of paramagnetic erythrocytes, encapsulation of MRI contrast agents or the study of the metabolism of the red cell. Although erythrocytes have been applied with different uses in human medicine, their deployment is still very limited due to difficulties involving storage, its exposure to contamination and the absence of a validated industrial procedure for its preparation.

Influence of blending on the content of different compounds in the biological aging of sherry dry wines.

Principal components analysis to examine the effect of blending (viz. the mixing and transfer of wine between cask rows in a "criaderas and solera" system) on metabolic activity in flor yeasts during biological aging of sherry dry wines was carried out. The variables used in the analysis were the wine compounds most deeply involved in the flor yeast metabolism, namely ethanol, acetaldehyde, glycerol, acetic acid, and l-proline. The greatest blending effect was found to be on the third and second "criadera", which are the stages where the yeasts show a high metabolic activity. The stages holding the oldest wine (viz. the first criadera and the solera) exhibited no differences before and after blending; therefore, the yeasts have a decreased biological activity in them and physical-chemical aging processes seemingly prevail over it.

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.