Zobrazení zdroje stránky Gallegosgates6162

Treatment of brain tumors is challenging since the blood-brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and development. Here, we provide an update on nano-carrier strategies for improving brain drug delivery for treatment of brain tumors, focusing on liposomes, extracellular vesicles and biomimetic strategies as the most clinically feasible strategies. Finally, we describe the obstacles in translation of these technologies including pre-clinical models, analytical methods and regulatory issues.One of the key requirements for successful vaccination via the mucosa is particulate antigen uptake. Poly-lactic-co-glycolic acid (PLGA) particles were chosen as well-known model carriers and ovalbumin (OVA) as the model antigen. Aiming at application to the respiratory tract, which allows direct interaction of the formulation with the mucosal immune system, this work focuses on the feasibility of delivering the antigen in a nanoparticulate carrier within a powder capable of pulmonary delivery. Further requirements were adequate antigen encapsulation in order to use the characteristics of the particulate carrier for (tunable) antigen release, and capability of the production process for industrialisation (realisation in industry). For an effective particulate antigen uptake, nanoparticles with a size of around 300 nm were prepared. For this, two production methods for nanoparticles, solvent change precipitation and the double emulsion method, were evaluated with respect to antigen incorporation, transfer to aThe phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. [https://www.selleckchem.com/products/hydroxy-cinnamic-acid.html check details] Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.The selection of an appropriate dressing for each type of wound is a very important procedure for a faster and more accurate healing process. So, the aim of this study was to develop innovative Spanish Broom and flax wound dressings, as alternatives to cotton used as control, with polymeric films containing glycyrrhetinic acid (GA) to promote wound-exudate absorption and the healing process. The different wound dressings were prepared by a solvent casting method, and characterized in terms of drug loading, water uptake, and in vitro release. Moreover, biological studies were performed to evaluate their biocompatibility and wound-healing efficacy. Comparing the developed wound dressings, Spanish Broom dressings with GA-loaded sodium hyaluronate film had the best functional properties, in terms of hydration ability and GA release. Moreover, they showed a good biocompatibility, determining a moderate induction of cell proliferation and no cytotoxicity. In addition, the wound-healing test revealed that the Spanish Broom dressings promoted cell migration, further facilitating the closure of the wound.Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from -7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of -0.74 to -0.29 mg/L and mean percent error of -16.6 to -0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.Pharmaceutical grade bentonite, containing a high amount of montmorillonite, enriched with zinc (Zn) or copper (Cu) (ZnBent and CuBent, respectively) was used as the main component for the creation of formulations for cutaneous use and tested for their antimicrobial capacity. Bentonite (Bent) with added phenoxyethanol (PH) as a preservative and unmodified bentonite were used as control groups. The mineralogical composition, structural state, and physical or chemical properties, before and after the modification of the samples, were characterized utilizing X-ray Diffraction Analysis (XRD), Fourier-Transform Infrared Spectroscopy (FTIR) and X-ray Fluorescence (XRF) techniques, and Scanning Electron Microscope-Energy Dispersive Spectroscopy (SEM, SEM-EDS) analyses. In addition, the profile of zinc and copper concentration from two types of surfaces ZnBent and CuBent, and into Phosphate-Buffered Saline (PBS) are discussed. Finally, the formulations in the form of basic pastes were challenged against bacteria, molds, and yeasts, and their performance was evaluated based on the European Pharmacopeia criteria. The Cu-modified bentonite performed excellently against bacteria and yeasts, while the Zn-modified bentonite only showed great results against yeasts. Therefore, Cu-modified bentonite formulations could offer antimicrobial protection without the use of preservatives.The structure and biocompatibility analysis of a hydrogel based on cellulose nanofibers (CNFs) combined with alginate/pectin (A.CNF or P.CNF) and enriched with 1% or 5% 5-FU revealed more favorable properties for the cellular component when pectin was dispersed within CNFs. 5-Fluorouracil (5-FU) is an antimetabolite fluoropyrimidine used as antineoplastic drug for the treatment of multiple solid tumors. 5-FU activity leads to caspase-1 activation, secretion and maturation of interleukins (IL)-1, IL-18 and reactive oxygen species (ROS) generation. Furthermore, the effects of embedding 5-FU in P.CNF were explored in order to suppress breast tumor cell growth and induce inflammasome complex activation together with extra- and intracellular ROS generation. Exposure of tumor cells to P.CNF/5-FU resulted in a strong cytotoxic effect, an increased level of caspase-1 released in the culture media and ROS production-the latter directly proportional to the concentration of anti-tumor agent embedded in the scaffolds. Simultaneously, 5-FU determined the increase of p53 and caspase-1 expressions, both at gene and protein levels. In conclusion, P.CNF/5-FU scaffolds proved to be efficient against breast tumor cells growth due to pyroptosis induction. Furthermore, biocompatibility and the potential to support human adipose-derived stem cell growth were demonstrated, suggesting that these 3D systems could be used in soft tissue reconstruction post-mastectomy.Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.Tramadol hydrochloride is a synthetic analogue of codeine and shows activity on the central nervous system as an opioid agonist and inhibitor of serotonin and norepinephrine reuptake. It has been used for controlling moderate to severe pain. Mucoadhesive fast-dissolving films can present greater drug availability and patient acceptance when compared to the systems of peroral administration. The films were prepared using the solvent casting method with ethylcellulose, polyvinylpyrrolidone and poly(vinyl alcohol). The effect of each polymer concentration was investigated using a 2³ factorial design with repetition at the central point. The formulations were subjected to physicochemical, mechanical, ex vivo mucoadhesive and in vitro drug release profile analysis. These properties were dependent on the polymeric composition (independent factors) of each system. The optimized formulations showed good macroscopic characteristics, improved resistance to bending, rigidity, rapid swelling up to 60 s, improved mechanical and mucoadhesive characteristics, and also fast dissolving and tramadol release.