A nationwide survey of Antimicrobial Stewardship in Pediatric Intensive Care Unit: implementation notes from the Brazilian underground.

A multicenter diagnostic study was conducted to investigate the implementation of an Antimicrobial Stewardship Program in Brazilian Pediatric Intensive Care Units. The analysis unveiled the main implementation impediments of the Antimicrobial Stewardship Program such as the lack of professionals and resources available to the program.

Enhanced alpha-amylase inhibition activity of amine-terminated PAMAM dendrimer stabilized pure copper-doped magnesium oxide nanoparticles.

The present work aims to prepare copper-doped MgO nanoparticles via a sol-gel approach and study their antidiabetic alpha-amylase inhibition activity with undoped MgO nanoparticles. The ability of G5 amine-terminated polyamidoamine (PAMAM) dendrimer for the controlled release of copper-doped MgO nanoparticles to exhibit alpha-amylase inhibition activity was also evaluated. The synthesis of MgO nanoparticles via sol-gel approach and optimization of calcination temperature and time has led to the formation of nanoparticles with different shapes (spherical, hexagonal, and rod-shaped) and a polydispersity in size ranging from 10 to 100 nm with periclase crystalline phase. The presence of copper ions in the MgO nanoparticles has altered their crystallite size, eventually modifying their size, morphology, and surface charge. The efficiency of dendrimer to stabilize spherical copper-doped MgO nanoparticles (ca. 30 %) is higher than in other samples, which was confirmed by UV-Visible, DLS, FTIR, and TEM analysis. The amylase inhibition assay emphasized that the dendrimer nanoparticles stabilization has led to the prolonged enzyme inhibition ability of MgO and copper-doped MgO nanoparticles for up to 24 h.

Biochemical changes in cancer cells induced by photoactive nanosystem based on carbon dots loaded with Ru-complex.

Carbon dots (CDs) and N-carbon dots (N-CDs) loaded with Ru-complex (CDs@RuCN, N-CDs@RuCN, respectively) were investigated as media imposing biochemical changes induced by UV illumination of ovarian cancer, A2780, and osteosarcoma, CAL72, cells. Synchrotron radiation-based Fourier Transform Infrared Spectroscopy was performed, and the spectra were subjected to a Principal Component Analysis. The CDs@RuCN and N-CDs@RuCN effects on cancer cells were analyzed by the theoretical modelling of the stability of the composite systems and a protein database search. Moreover, a detailed evaluation of surface and optical properties of CDs@RuCN and N-CDs@RuCN was carried out. Results demonstrated selective action of the CDs@RuCN and N-CDs@RuCN-based photodynamic therapy, with N-CDs@RuCN being the most active in inducing changes in A2780 and CDs@RuCN in CAL72 cells. We assume that different surface charges of nanoparticles led to direct interactions of N-CDs@RuCN with a Wnt signalling pathway in A2780 and those of CDs@RuCN with PI3-K/Akt in CAL72 cells and that further biochemical changes occurred upon light illumination.

Lipid Status of A2780 Ovarian Cancer Cells after Treatment with Ruthenium Complex Modified with Carbon Dot Nanocarriers: A Multimodal SR-FTIR Spectroscopy and MALDI TOF Mass Spectrometry Study.

In the last decade, targeting membrane lipids in cancer cells has been a promising approach that deserves attention in the field of anticancer drug development. To get a comprehensive understanding of the effect of the drug [Ru(η5-Cp)(PPh3)2CN] (RuCN) on cell lipidic components, we combine complementary analytical approaches, matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI TOF MS) and synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectroscopy. Techniques are used for screening the effect of potential metallodrug, RuCN, without and with drug carriers (carbon dots (CDs) and nitrogen-doped carbon dots (N-CDs)) on the lipids of the human ovarian cancer cell line A2780. MALDI TOF MS results revealed that the lysis of ovarian cancer membrane lipids is promoted by RuCN and not by drug carriers (CDs and N-CDs). Furthermore, SR-FTIR results strongly suggested that the phospholipids of cancer cells undergo oxidative stress after the treatment with RuCN that was accompanied by the disordering of the fatty acid chains. On the other hand, using (N-)CDs as RuCN nanocarriers prevented the oxidative stress caused by RuCN but did not prevent the disordering of the fatty acid chain packing. Finally, we demonstrated that RuCN and RuCN/(N-)CDs alter the hydration of the membrane surface in the membrane-water interface region.

Polyester Dendrimers Based on Bis-MPA for Doxorubicin Delivery.

Although doxorubicin (DOX) is one of the most used chemotherapeutic drugs due to its efficacy against a wide group of cancer types, it presents severe side effects. As such, intensive research is being carried out to find new nanoscale systems that can help to overcome this problem. Polyester dendrimers based on the monomer 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) are very promising systems for biomedical applications due to their biodegradability properties. In this study, bis-MPA-based dendrimers were, for the first time, evaluated as DOX delivery vehicles. Generations 4 and 5 of bis-MPA-based dendrimers with hydroxyl groups at the surface were used (B-G4-OH and B-G5-OH), together with dendrimers partially functionalized with amine groups (B-G4-NH2/OH and B-G5-NH2/OH). Partial functionalization was chosen because the main purpose was to compare the effect of different functional groups on dendrimers' drug delivery behavior without compromising cell viability, which is often affected by dendrimers' cationic charge. Results revealed that bis-MPA-based dendrimers were cytocompatible, independently of the chemical groups that were present at their surface. The B-G4-NH2/OH and B-G5-NH2/OH dendrimers were able to retain a higher number of DOX molecules, but the in vitro release of the drug was faster. On the contrary, the hydroxyl-terminated dendrimers exhibited a lower loading capacity but were able to deliver the drug in a more sustained manner. These results were in accordance with the cytotoxicity studies performed in several models of cancer cell lines and human mesenchymal stem cells. Overall, the results confirmed that it is possible to tune the drug delivery properties of bis-MPA-based dendrimers by modifying surface functionalization. Moreover, molecular modeling studies provided insights into the nature of the interactions established between the drug and the bis-MPA-based dendrimers─DOX molecules attach to their surface rather than being physically encapsulated.

The Protagonism of the Brazilian Health Regulatory System in the Evolution of Patient Safety in the Country: History, Dilemmas, and Current Challenges.

OBJECTIVE: This article aims to identify and analyze the legal and regulatory frameworks with an interface with patient safety, considering the historical path of the patient safety policy in Brazil. METHODS: This is a historical review based on the relevant literature to the topic such as papers, legislation, and official documents with an interface with public health policies from 1988 to 2019. We also performed a documentary search to include data from the Brazilian Health Regulatory Agency (ANVISA) such as normative and nonnormative regulatory instruments. After organizing the data, the process of content analysis was performed. RESULTS: We debated initially the historical aspects of sanitary surveillance of health services in addition to main actions taken by the Brazilian Health Regulatory System, which includes sanitary regulation and patient safety challenges. We identified a diversity of regulations published by ANVISA in the past decade related to patient safety, in addiction to sanitary actions. These initiatives culminated in the establishment of the National Patient Safety Program in 2013, followed by other health improvements, such as surveillance, incidents monitoring, and safe practices self-assessment. CONCLUSIONS: The regulation and sanitary actions directed to patient safety in Brazil have increased after the creation of ANVISA. In the face of this activities, the social role played by the Brazilian Health Regulatory System toward the advancement in the field of risk minimization in health services can be highlighted as a protagonist in the process of promoting patient safety.

A glance over doxorubicin based-nanotherapeutics: From proof-of-concept studies to solutions in the market.

Cancer is one of the leading causes of death worldwide and, as such, efforts are being done to find new chemotherapeutic drugs or, alternatively, novel approaches for the delivery of old ones. In this scope, when used as vehicles for drugs, nanomaterials may potentially maximize the efficacy of the treatment and reduce its side effects, for example by a change in drug's pharmacokinetics, cell targeting and/or specific stimuli-responsiveness. This is the case of doxorubicin (DOX) that presents a broad spectrum of activity and is one of the most widely used chemotherapeutic drugs as first-line treatment. Indeed, DOX is a very interesting example of a drug for which several nanosized delivery systems have been developed over the years. While it is true that some of these systems are already in the market, it is also true that research on this subject remains very active and that there is a continuing search for new solutions. In this sense, this review takes the example of doxorubicin, not so much with the focus on the drug itself, but rather as a case study around which very diverse and imaginative nanotechnology approaches have emerged.

Fine tuning of the pH-sensitivity of laponite-doxorubicin nanohybrids by polyelectrolyte multilayer coating.

Despite the wide research done in the field, the development of advanced drug delivery systems with improved drug delivery properties and effective anticancer capability still remains a great challenge. Based on previous work that showed the potentialities of the nanoclay Laponite as a pH-sensitive doxorubicin (Dox) delivery vehicle, herein we report a simple method to modulate its extent of drug release at different pH values. This was achieved by alternate deposition of cationic poly(allylamine) hydrochloride and anionic poly(sodium styrene sulfonate) (PAH/PSS) polyelectrolytes over the surface of Dox-loaded Laponite nanoparticles using the electrostatic layer-by-layer (LbL) self-assembly approach. The successful formation of polyelectrolyte multilayer-coated Dox/Laponite systems was confirmed by Dynamic Light Scattering and zeta potential measurements. Systematic studies were performed to evaluate their drug release profiles and anticancer efficiency. Our results showed that the presence of the polyelectrolyte multilayers improved the sustained release properties of Laponite and allowed a fine tuning of the extension of drug release at neutral and acidic pH values. The cytotoxicity presented by polyelectrolyte multilayer-coated Dox/Laponite systems towards MCF-7 cells was in accordance with the drug delivery profiles. Furthermore, cellular uptake studies revealed that polyelectrolyte multilayer-coated Dox/Laponite nanoparticles can be effectively internalized by cells conducting to Dox accumulation in cell nucleus.

Thermo/redox/pH-triple sensitive poly(N-isopropylacrylamide-co-acrylic acid) nanogels for anticancer drug delivery.

The clinical application of doxorubicin (DOX), like other anticancer drugs, is limited by insufficient cellular uptake and the numerous drug resistance mechanisms existing in cells. The development of smart nanomaterials capable of carrying the drugs into the cells and of releasing them under the control of the microenvironment is an interesting approach that may increase the success of the anticancer drugs currently in use. Herein, we report an easy process to prepare biocompatible nanogels (NGs) with thermo/redox/pH-triple sensitivity, which are highly effective in the intracellular delivery of DOX. Redox-sensitive/degradable NGs (PNA-BAC) and nondegradable NGs (PNA-MBA) were prepared through in situ polymerization of N-isopropylacrylamide (NIPAM) and acrylic acid (AA) in the presence of sodium dodecyl sulfate (SDS) as a surfactant, using N,N'-bis(acryloyl)cystamine (BAC) as a biodegradable crosslinker or N,N'-methylene bisacrylamide (MBA) as a nondegradable crosslinker, respectively. After that, the cationic DOX drug was loaded into the NGs through electrostatic interactions, by simply mixing them in aqueous solution. Compared to nondegradable PNA-MBA NGs, PNA-BAC NGs not only presented a higher DOX drug loading capacity, but also allowed a more sustainable drug release behavior under physiological conditions. More importantly, PNA-BAC NGs displayed thermo-induced drug release properties and an in vitro accelerated release of DOX under conditions that mimic intracellular reductive conditions and acidic tumor microenvironments. The thermo/redox/pH multi-sensitive NGs can quickly be taken up by CAL-72 cells (an osteosarcoma cell line), resulting in a high DOX intracellular accumulation and an improved cytotoxicity when compared with free DOX and DOX-loaded nondegradable PNA-MBA NGs. The developed NGs can be possibly used as an effective platform for the delivery of cationic therapeutic agents for biomedical applications.

Dendrimer-assisted formation of fluorescent nanogels for drug delivery and intracellular imaging.

Although, in general, nanogels present a good biocompatibility and are able to mimic biological tissues, their unstability and uncontrollable release properties still limit their biomedical applications. In this study, a simple approach was used to develop dual-cross-linked dendrimer/alginate nanogels (AG/G5), using CaCl2 as cross-linker and amine-terminated generation 5 dendrimer (G5) as a cocrosslinker, through an emulsion method. Via their strong electrostatic interactions with anionic AG, together with cross-linker Ca(2+), G5 dendrimers can be used to mediate the formation of more compact structural nanogels with smaller size (433 ± 17 nm) than that (873 ± 116 nm) of the Ca(2+)-cross-linked AG nanogels in the absence of G5. Under physiological (pH 7.4) and acidic (pH 5.5) conditions, the sizes of Ca(2+)-cross-linked AG nanogels gradually decrease probably because of their degradation, while dual-cross-linked AG/G5 nanogels maintain a relatively more stable structure. Furthermore, the AG/G5 nanogels effectively encapsulate the anticancer drug doxorubicin (Dox) with a loading capacity 3 times higher than that of AG nanogels. The AG/G5 nanogels were able to release Dox in a sustained way, avoiding the burst release observed for AG nanogels. In vitro studies show that the AG/G5-Dox NGs were effectively taken up by CAL-72 cells (a human osteosarcoma cell line) and maintain the anticancer cytotoxicity levels of free Dox. Interestingly, G5 labeled with a fluorescent marker can be integrated into the nanogels and be used to track the nanogels inside cells by fluorescence microscopy. These findings demonstrate that AG/G5 nanogels may serve as a general platform for therapeutic delivery and/or cell imaging.

Antitumor efficacy of doxorubicin-loaded laponite/alginate hybrid hydrogels.

Degradable hybrid hydrogels with improved stability are prepared by incorporating nanodisks of biocompatible laponite (LP) in alginate (AG) hydrogels using Ca(2+) as a crosslinker. The Dox-loaded hybrid hydrogels give a controlled Dox release at physiological environment in a sustained manner. Under conditions that mimic the tumor environment, both the sustainability in the Dox release (up to 17 d) and the release efficiency from LP/AG-Dox hydrogels are improved. The in situ degradation of these hybrid hydrogels gives rise to nanohybrids that might serve as vehicles for carrying Dox through the cell membrane and diminish the effect of Dox ion-trapping in the acidic extracellular environment of the tumor and/or in the endo-lysosomal cell compartments.

pH-sensitive Laponite(®)/doxorubicin/alginate nanohybrids with improved anticancer efficacy.

The efficacy of the anticancer drug doxorubicin (Dox) is limited by an insufficient cellular uptake and drug resistance, which is partially due to ion trapping in acidic environments such as the extracellular environment of solid tumors and the interior of endolysosome vesicles. Herein, we describe the preparation and in vitro evaluation of a new type of nanohybrid for anticancer drug delivery which is capable of carrying a high load of the cationic Dox through the cell membrane. In addition, the nanohybrids use the acidic environment of the endolysosomes to release the drug, simultaneously helping to disrupt the endolysosomes and diminishing endolysosome Dox trapping. Furthermore, as the nanohybrid carriers are capable of sustained drug delivery, those that remain in the cytoplasm and still contain Dox are expected to exert a prolonged anticancer activity. Briefly, Dox is loaded onto biocompatible anionic Laponite(®) (LP) nanodisks with a high aspect ratio (25 nm in diameter and 0.92 nm in thickness) through strong electrostatic interactions to get Dox-loaded LP disks. Alginate (AG), a biocompatible natural polymer, is then coated onto the Dox-loaded LP disks (LP/Dox/AG nanohybrids) to prevent the burst release of the drug. The results demonstrate that the nanohybrids have a high encapsulation efficiency (80.8 ± 10.6%), are sensitive to pH and display a sustained drug release behavior. Cell culture experiments indicate that the LP/Dox/AG nanohybrids can be effectively internalized by CAL-72 cells (an osteosarcoma cell line), and exhibit a remarkable higher cytotoxicity to cancer cells than the free Dox. The merits of Laponite(®)/alginate nanohybrids, such as biocompatibility, high loading capacity and stimulus responsive release of cationic chemotherapeutic drugs, render them as excellent platforms for drug delivery.

Spectrofotometric determination of copper in sugar cane spirit using biquinoline in the presence of ethanol and Triton X-100.

The present paper proposes a method for molecular spectrophotometric determination of copper in sugar cane spirits. The copper(I) reacts with biquinoline forming a pink complex with maximum absorption at 545 nm. The reaction occurs in the presence of hydroxylamine, ethanol and Triton X-100 tensioative. Determination of copper is possible in a linear range 0.2-20.0 mgL(-1) with a detection limit 0.05 mgL(-1). The great advantages of the proposed methodology are the elimination of liquid-liquid extraction step and the use of toxic organics solvents, like dioxane, to dissolve the reagent.