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Vulvovaginal candidiasis (VVC) represents a considerable health burden for women. Despite the availability of a significant array of antifungal drugs and topical products, the management of the infection is not always effective, and new approaches are needed. Here, we explored cationic N -(2-hydroxy)-propyl-3-trimethylammonium, O- palmitoyl chitosan nanoparticles (NPs) as carriers of clotrimazole (CLT) for the topical treatment of VVC. CLT-NPs with approximately 280 nm in diameter were obtained by self-assembly in water and subsequent stabilization by ionic crosslinking with tripolyphosphate. The nanosystem featured pH-independent sustained drug release up to 24 h, which affected both in vitro anti- Candida activity and cytotoxicity. The CLT-loaded nanostructured platform yielded favorable selectivity index values for a panel of standard strains and clinical isolates of Candida spp. and female genital tract cell lines (HEC-1-A, Ca Ski and HeLa), as compared to the free drug. CLT-NPs also improved in vitro drug permeability across HEC-1-A and Ca Ski cell monolayers, thus suggesting that the nanocarrier may provide higher mucosal tissue levels of the active compound. Overall, data support that CLT-NPs may be a valuable asset for the topical treatment of VVC. Topical azoles such as clotrimazole (CLT) are first line antifungal drugs for the management of vulvovaginal candidiasis (VVC), but their action may be limited by issues such as toxicity and poor capacity to penetrate the genital mucosa. Herein, we report on the ability of a new cationic N -(2‑hydroxy)-propyl-3-trimethylammonium, O -dipalmitoyl chitosan derivative (DPCat35) to yield tripolyphosphate-reinforced micelle-like nanostructures that are suitable carriers for CLT. In particular, these nanosystems were able to improve the in vitro selectivity index of the drug and to provide enhanced epithelial drug permeability when tested in cell monolayer models. These data support that CLT-loaded DPCat35 nanoparticles feature favorable properties for the development of new nanomedicines for the topical management of VVC. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] The aqueous solubility of active pharmaceutical ingredients is one of the most important features to be considered during the development of parenteral formulations in the pharmaceutical industry. Computational modelling has become in the last years an integral part of pharmaceutical development. In this context, ab initio computational models, such as COnductor-like Screening MOdel (COSMO), have been proposed as promising tools for the prediction of results without the effective use of resources. Nevertheless, despite the clear evaluation of computational resources, some authors had not achieved satisfying results and new calculations and algorithms have been proposed over the years to improve the outcomes. In the development and production of aqueous parenteral formulations, the solubility of Active Pharmaceutical Ingredients (APIs) in an aqueous and biocompatible vehicle is a decisive step. This work aims to study the hypothesis that COSMO models could be useful in the development of new parenteral formulations, mainly aqueous ones. [ABSTRACT FROM AUTHOR]

Quality by Design (QbD) was originated in the broad domain of Quality Management and was recently adapted and formalized in specific terms for assisting pharmaceutical companies efforts towards market and operational excellence. However, despite some impressive success stories, the pharmaceutical industry have not yet fully embraced QbD, particularly in routine commercial manufacturing (Rantanen and Khinast, 2015; Puñal Peces et al., 2016). In this review, we aim to analyse the current state of implementation of QbD methodologies and tools in the pharmaceutical industry, extracting patterns and trends and identifying gaps and opportunities that may be considered to improve QbD adoption. For this purpose, a critical analysis of 60 research papers was performed, whose contents were classified, compared and summarized at different abstraction levels. Our analysis reveals the following tools as the frequently adopted for conducting each activity: Risk Assessment (RA) - Ishikawa Diagram, Failure Mode and Effects Analysis (FMEA) and Risk Estimation Matrix (REM); Screening Design of Experiments (DoE) – 2-level Full and Fractional Factorial Designs; Optimisation DoE – Central Composite Design (CCD). Emerging trends include the growing interest in quantifying and managing the impact of raw materials' attributes variability on process and product, as well as the development of Retrospective QbD approaches (rQbD) in complement to standard QbD. [ABSTRACT FROM AUTHOR]

A quaternized derivative of chitosan, namely N -(2-hydroxy)-propyl-3-trimethylammonium chitosan chloride (QCh), was synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) and chitosan (Ch) in acid medium under microwave irradiation. Full-factorial 2 3 central composite design and response surface methodology (RSM) were applied to evaluate the effects of molar ratio GTMAC/Ch, reaction time and temperature on the reaction yield, average degree of quaternization ( D Q ¯ ) and intrinsic viscosity ([ η ]) of QCh. The molar ratio GTMAC/Ch was the most important factor affecting the response variables and RSM results showed that highly substituted QCh ( D Q ¯ = 71.1%) was produced at high yield (164%) when the reaction was carried out for 30 min. at 85 °C by using molar ratio GTMAC/Ch 6/1. Results showed that microwave-assisted synthesis is much faster (≤30 min.) as compared to conventional reaction procedures (>4 h) carried out in similar conditions except for the use of microwave irradiation. [ABSTRACT FROM AUTHOR]

This paper discusses the production of chitosan by applying high intensity ultrasound irradiation to alpha-chitin suspended in 40% aqueous sodium hydroxide. The average degree of acetylation (DA) of chitosan was determined by 1 H NMR spectroscopy and titrimetry while its viscosity average molecular weight (Mv) was calculated from the intrinsic viscosity as determined by capillary viscometry. The results show that fully acid-soluble chitosans (DA < 32%; 100,000 g/mol ⩽ Mv ⩽ 200,000 g/mol) are produced at very high yield (>95%) by applying non-isothermal ultrasound-assisted N -deacetylation process to alpha-chitin suspension (44 mg/mL). It is also shown that such a process is more efficient than thermochemical N -deacetylation, even being carried out at a lower temperature due to the effects of high intensity ultrasound irradiation. [ABSTRACT FROM AUTHOR]

• Patients with suspected brain diagnosis often use sedatives, which may lead to a late confirmed diagnosis. • In patients with suspected BD, TCD may cause circulatory collapse, hyperemia, and oligemia. • TCD accuracy in predicting BD was 92%. • Even in sedated patients, TCD was able to identify circulatory collapse and, in such patients, all confirmed BD later. Diagnosing brain death (BD) with accuracy and urgency is of great importance because an early diagnosis may guide the clinical management, optimize hospital beds, and facilitate organ transplantation. The clinical diagnosis of nonreactive and irreversible coma can be confirmed with additional tests. Among the complimentary exams that may testify brain circulatory arrest, transcranial Doppler (TCD) can be an option. It is a real-time, bedside, inexpensive, noninvasive method that assesses cerebral blood flow. In patients with suspected BD, especially those who are under sedative drugs, early diagnosis is imperative. The aim of the present study was to evaluate the role of TCD in predicting BD. One hundred consecutive comatose patients with a Glasgow Coma Scale score of less than 5, owing to different etiologies, were included. TCD was performed in all patients. The TCD operator was blinded for clinical and neurologic data. This study is in compliance with the Declaration of Helsinki. Sixty-nine patients with TCD-brain circulatory collapse were diagnosed later with BD. Of the 31 patients with brain circulatory activity, 8 (25.8%) were clinically brain dead and 23 (74.2%) were alive. TCD showing brain circulatory collapse had a sensitivity of 89.6%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 74.2%. TCD is highly specific (100%) and sensitive (89.6%) as a method to confirm the clinical diagnosis of BD, even in patients under sedation. The possibility of patients presenting with cerebral circulatory activity and clinical diagnosis of BD was demonstrated to occur. [ABSTRACT FROM AUTHOR]

Two samples of N -(2-hydroxy)-propyl-3-trimethylammonium, O- palmitoyl chitosan (DPCat) with different average degrees of quaternization named as DPCat35 (DQ ¯ = 35%) and DPCat80 (DQ ¯ = 80%), were successfully synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) with O -palmitoyl chitosan (DPCh) derivative (DS ¯ = 12%). Such amphiphilic derivatives of chitosan were fully water-soluble at 1.0 < pH < 12.0 and showed significant electrostatic stability enhancement of a self-assembly micellar nanostructure (100–320 nm) due to its positively-charged out-layer. In vitro mucoadhesive and cytotoxicity essays toward healthy fibroblast cells (Balb/C 3T3 clone A31 cell), human prostate cancer (DU145) and liver cancer (HepG2/C3A) cell lines revealed that the biological properties of DPCat derivatives were strongly dependent on DQ ¯. Additionally, DPCat35 had better interactions with the biological tissue and with mucin glycoproteins at pH 7.4 as well as exhibited potential to be used on the development of drug delivery systems for prostate and liver cancer treatment. • Permanent-charged amphiphilic chitosans with different degrees of quaternization • Fully water-soluble self-assembled micelle-like nanostructures were produced. • Quaternization increases the mucoadhesion of former hydrophobically-modified chitosan. • Cytotoxicity is highly dependent on the content of positively-charged groups. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Chitosan/poly(NVCL- co -IA- co -EGDMA) microparticles with multi-response properties. • Chitosan as protective agent against undesirable colloidal destabilization. • Extended release of ketoprofen at pH 7.4 and 37 °C. Abstract In this paper, chitosan was used as protective agent for dual temperature-/pH-sensitive poly(N -vinylcaprolactam- co -itaconic acid- co -ethylene- glycol dimethacrylate)- based hydrogel nanoparticles (poly(NVCL- co -IA- co -EGDMA)) aiming avoid their undesirable colloidal destabilization at different conditions of body human tissues. Thus, poly(NVCL- co -IA- co -EGDMA) was embedded into chitosan and a new solid dispersion was prepared via spray-drying and ketoprofen was used as carrier. Two different sizes of hydrogel nanoparticles (120.6 nm and 185.9 nm) were evaluated and they exhibited a drug encapsulation efficiency of the 39.6% and 57.8%, respectively. The smaller nanoparticles showed to be faster for releasing of ketoprofen at pH 7.4 and 37 °C due to their larger surface area and higher swelling ability. Chitosan played a role of a secondary barrier for the ketoprofen diffusion, extending its release compared to hydrogel nanoparticles alone. Among two concentrations (40 wt% and 70 wt%) of hydrogel nanoparticles related to chitosan, the first one induced higher percentages of ketoprofen release: 74.2% against 64.6%. In addition, the interactions between chitosan matrix and poly(NVCL- co -IA- co -EGDMA) did not change the multi-responsive behavior of hydrogels, suggesting the chitosan was efficient for keeping integrity of nanoparticles hydrogels. Chitosan/poly(NVCL- co -IA- co -EGDMA) hybrid microparticles seems to be a promising new carrier for release of hydrophobic drugs, such as ketoprofen. [ABSTRACT FROM AUTHOR]

Blend solutions of poly(ε-caprolactone) (PCL) and N -(2-hydroxy)-propyl-3-trimethylammonium chitosan chloride (QCh) were successfully electrospun. The weight ratio PCL/QCh ranged in the interval 95/5–70/30 while two QCh samples were used, namely QCh1 ( D Q ¯  = 47.3%; D P v ¯  = 2218) and QCh2 ( D Q ¯  = 71.1%; D P v ¯  = 1427). According to the characteristics of QCh derivative and to the QCh content on the resulting PCL/QCh nonwoven, the nanofibers displayed different average diameter (175 nm–415 nm), and the nonwovens exhibited variable porosity (57.0%–81.6%), swelling capacity (175%–425%) and water vapor transmission rate (1600 g m −2 24 h–2500 g m −2 24 h). The surface hydrophilicity of nonwovens increases with increasing QCh content, favoring fibroblast (HDFn) adhesion and spreading. Tensile tests revealed that the nonwovens present a good balance between elasticity and strength under both dry and hydrated state. Results indicate that the PCL/QCh electrospun nonwovens are new nanofibers-based biomaterials potentially useful as wound dressings. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the influence of cellulose and/or lignin on the properties of mats prepared from dissolution (for 48 h or 72 h, solvent: trifluoroacetic acid) of recycled poly (ethylene terephthalate) (PET). Briefly, the presence of cellulose led to a tendency of higher average fiber diameter and average pore area as well as lower average porosity compared to the neat mat (PET ref , 242 ± 59 nm, 9.6 ± 1.1 10 4 nm 2 and 19.0 ± 1.1%, respectively). The T g values for electrospun PET combined with cellulose and/or lignin were higher than that of PET ref (92.5 ± 0.1 °C), and the tensile strength increased with the cellulose and/or lignin loading. In addition, the presence of lignin (72 h of dissolution) led to a mat with an elongation at break of 149 ± 9% compared to 14 ± 2% for PET ref . The results indicated that the properties of mats based on PET can be tuned by adding cellulose and/or lignin to solutions posteriorly electrospun as well as by varying the dissolution time. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are multipotent cells characterized by self-renewal and cellular differentiation capabilities. Oxysterols comprise a very heterogeneous group derived from cholesterol through enzymatic and non-enzymatic oxidation. Potent effects in cell death processes, including cytoxicity and apoptosis induction, were described in several cell lines. Very little is known about the effects of oxysterols in MSCs. 7-ketocholesterol (7-KC), one of the most important oxysterols, was shown to be cytotoxic to human adipose tissue-derived MSCs. Here, we describe the short-term (24 h) cytotoxic effects of cholestan-3α-5β-6α-triol, 3,5 cholestan-7-one, (3α-5β-6α)- cholestane-3,6-diol, 7-oxocholest-5-en-3β-yl acetate, and 5β-6β epoxy-cholesterol, on MSCs derived from human adipose tissue. MSCs were isolated from adipose tissue obtained from three young, healthy women. Oxysterols, with the exception of 3,5 cholestan-7-one and 7-oxocholest-5-en-3β-yl acetate, led to a complex mode of cell death that include apoptosis, necrosis and autophagy, depending on the type of oxysterol and concentration, being cholestan-3α-5β-6α-triol the most effective. Inhibition of proliferation was also promoted by these oxysterols, but no changes in cell cycle were observed. [ABSTRACT FROM AUTHOR]

Abstract: The chemokine stromal-derived factor-1α (SDF-1α) and its receptor CXCR4 are critically involved in directional migration and homing of plasma cells in multiple myeloma. Here, we show that the expression of SDF-1α and CXCR4 was significantly down-regulated in patients treated with thalidomide (n =10) as compared to newly diagnosed MM patients (n =31) and MM patients treated with other drugs (n =38). SDF-1 α and CXCR4 expression was also significantly decreased in a RPMI 8226 cell line treated with 10 and 20μmol/L of thalidomide. Our findings indicate that thalidomide therapy induces down-regulation of CXCR4 and its ligand SDF-1α in multiple myeloma. [Copyright &y& Elsevier]

We systematically investigated the effect of β-chitin (BCH) particle size on the preparation of nanocrystals/nanowhiskers (CWH) by acid hydrolysis. Regardless this variable, CWH aqueous suspension exhibited outstanding stability and the average degree of acetylation remained nearly constant after the acid treatment. In contrast, the morphology, dimensions, crystallinity, and molecular weight of CHW were significantly affect by the particle size. Although needle-like crystals have predominated, BCH particles sizes significantly affected the dimensions and asymmetry of CWH, as confirmed by the rheological and NMR relaxation (T 2) behaviors. According to different SSNMR approaches, the acid hydrolysis meaningless affected the local chain conformation, while the spatial freedom of BCH intersheets, rated upon the mobility of methyl segments, was taken as evidence of higher permeability of acid into small particle sizes. Thus, this study demonstrated the importance of standardizing the surface/bulk proportions of β-chitin aiming to predict and control the CWH morphology and related properties. [ABSTRACT FROM AUTHOR]

• Degree of acetylation and crystallinity of chitosan can be evaluated by TD-NMR. • RK-ROSE signal decay is mainly associated with the methyl hydrogens of GlcNAc units of chitosan chain. • The rigid and mobile-part signals are modulated by the local chain packing. Chitosans with different average degrees of acetylation and weight molecular weight were analyzed by time-domain NMR relaxometry using the recently proposed pulse sequence named Rhim and Kessemeier - Radiofrequency Optimized Solid-Echo (RK-ROSE) to acquire 1H NMR signal of solid-state materials. The NMR signal decay was composed of faster (tenths of μs) and longer components, where the mobile-part fraction exhibited an effective relaxation transverse time assigned to methyl hydrogens from N -acetyl- d -glucosamine (GlcNAc) units. The higher intrinsic mobility of methyl groups was confirmed via DIPSHIFT experiments by probing the 1H-13C dipolar interaction. RK-ROSE data were modeled by using Partial Least Square (PLS) multivariate regression, which showed a high coefficient of determination (R 2 > 0.93) between RK-ROSE signal profile and average degrees of acetylation and crystallinity index, thus indicating that time-domain NMR consists in a promising tool for structural and morphological characterization of chitosan. [ABSTRACT FROM AUTHOR]

• 13C CPMAS method was successfully used to quantify the crystallinity of chitosans; • The accuracy of 13C SSNMR is higher than conventional X-ray diffraction method; • 13C SSNMR did not require amorphous standards to quantify the crystallinity of chitosans. We propose a novel approach relied on high-resolution solid-state 13C NMR spectroscopy to quantify the crystallinity index of chitosans (Ch) prepared with variable average degrees of acetylation (D A ¯) from 5% to 60 % and average weight molecular weight ( M ¯ w) ranged in 0.15 × 106 g mol−1–1.2 × 106 g mol−1. The Dipolar Chemical Shift Correlation (DIPSHIFT) curve of the C(6)OH segment revealed increased mobility dynamic, which induced different distribution from trans- to -gauche conformations in relation to C(4). Indeed, 1H-13C Heteronuclear Correlation (2D HETCOR) showed that distinguished C4 chemical shifts correlates with the same aliphatic protons. The short-range ordering can be assigned to C4/C6 signals on 13C CPMAS and, for our case, the deconvolution procedure between disordered and ordered phases revealed increasing crystallinity with D A ¯ , as confirmed by SVD multivariate analysis. This work extended the knowledge regarding the use of 13C CPMAS technique to predict the crystallinity of chitosans without the use of amorphous standards. [ABSTRACT FROM AUTHOR]

• Dot-ELISA with saliva samples may be a suitable tool for diagnosing strongyloidiasis. • Enable of a commercial test for detecting IgA anti- S. stercoralis in saliva. • Sample saliva is an important alternative tool on immunodiagnostic of strongyloidiasis. This study aimed to evaluate the use of saliva samples in the Dot-ELISA test for immunodiagnosis of human strongyloidiasis. The Dot-ELISA presented similar results to the ELISA test, with 70% and 60% sensitivity and 85% and 90% specificity, respectively, for IgA in the saliva. The Dot-ELISA with alternative saliva samples may be a suitable tool for diagnosing human strongyloidiasis, especially in populations with high levels of exposure to helminth. [ABSTRACT FROM AUTHOR]