Pharmaceutics

Selenium nanoparticles (SeNPs) have been receiving special attention in recent years due to their antioxidant capacity and antitumor properties. However, the mechanisms associated with these properties remain to be elucidated. For this reason, a global transcriptome analysis has been designed in this work and it was carried out using human hepatocarcinoma cells and chitosan-stabilized SeNPs (Ch-SeNPs) to identify new targets and pathways related to the antitumor mechanisms associated with Ch-SeNPs. The results obtained confirm the alteration of the cell cycle and the effect of Ch-SeNPs on different tumor suppressors and other molecules involved in key mechanisms related to cancer progression. Furthermore, we demonstrated the antioxidant properties of these nanoparticles and their capacity to induce senescence, which was further confirmed through the measurement of β-galactosidase activity. Full article

The epoch of nanotechnology has authorized novel investigation strategies in the area of drug delivery. Liposomes are attractive biomimetic nanocarriers characterized by their biocompatibility, high loading capacity, and their ability to reduce encapsulated drug toxicity. Nevertheless, various limitations including physical instability, lack of site specificity, and low targeting abilities have impeded the use of solo liposomes. Metal nanocarriers are emerging moieties that can enhance the therapeutic activity of many drugs with improved release and targeted potential, yet numerous barriers, such as colloidal instability, cellular toxicity, and poor cellular uptake, restrain their applicability in vivo. The empire of nanohybrid systems has shelled to overcome these curbs and to combine the criteria of liposomes and metal nanocarriers for successful theranostic delivery. Metallic moieties can be embedded or functionalized on the liposomal systems. The current review sheds light on different liposomal-metal nanohybrid systems that were designed as cellular bearers for therapeutic agents, delivering them to their targeted terminus to combat one of the most widely recognized diseases, cancer. Full article

Drugs that inhibit bone resorption are prescribed most often by orthopedists, hematologists, or oncologists. Dental practice rarely draws attention to their importance and the effects they carry. The problem concerns mainly older people owing to oncological problems or postmenopausal consequences, but everyone can be at risk. Carefully conducted interviews and analysis of history and disease should always be performed before any action is taken by patients taking this type of medicine. Further action should consider possible complications and, above all, the risk of their occurrence. In this article, the most important issues related to the treatment of drug-induced osteonecrosis of the jaws (ONJ) are raised, including medication-related osteonecrosis of the jaw (MRONJ); conservative treatment, including the use of laser; and the impact of vitamin D supplementation on the overall treatment, prognosis, and prevention before complication, which is osteonecrosis of the jaw in the course of treatment with bisphosphonates and other drugs predisposing to MRONJ, such as denosumab and angiogenesis inhibitors. The degree of osteonecrosis is also critical, as it is possible to avoid surgical procedures for only conservative methods that sometimes bring good results. Surgical treatment of advanced stages is complicated and carries a high risk of error and complications. MRONJ is a disease that is easy to avoid, but it is difficult to treat and treatment sometimes leads only to a partial remission of the disease, not a complete cure. Full article

The transformation of a crystalline drug into an amorphous form is a promising way to enhance the oral bioavailability of poorly water-soluble drugs. Blending of a carrier, such as a hydrophilic polymer, with an amorphous drug is a widely used method to produce a solid dispersion and inhibit crystallization. This study investigates an experimental grade of hydroxypropyl methylcellulose acetate succinate, HPMCAS-MX (MX), as a solid dispersion carrier. Enhancement of thermal stability and reduction of the glass transition temperature (Tg) of MX compared with those of the conventional grade were evaluated through thermogravimetric analysis and differential scanning calorimetry (DSC). The formation of a homogeneous amorphous solid dispersion between MX and indomethacin was confirmed by X-ray powder diffraction analysis, DSC, and Raman mapping. It was observed that 10–30% MX did not act as an anti-plasticizer, but the utilization of >40% MX caused an increase in Tg and reduction of molecular mobility. This could be explained by a change in intermolecular interactions, inferred from infrared spectroscopy combined with principal component analysis. HPMCAS-MX exhibited similar performance to that of conventional-grade, HPMCAS-MG. Although HPMCAS-MX has thermal properties different from those of conventional-grade HPMCAS-MG, it retains its ability as a solid dispersion carrier. Full article

Antibiotic resistance is a significant crisis that threatens human health and safety worldwide. There is an urgent need for new strategies to control multidrug-resistant (MDR) bacterial infections. The latest breakthrough in gene-editing tools based on CRISPR/Cas9 has potential application in combating MDR bacterial infections because of their high targeting ability to specifically disrupt the drug resistance genes that microbes use for infection or to kill the pathogen directly. Despite the potential that CRISPR/Cas9 showed, its further utilization has been hampered by undesirable delivery efficiency in vivo. Nanotechnology offers an alternative way to overcome the shortcomings of traditional delivery methods of therapeutic agents. Advances in nanotechnology can improve the efficacy and safety of CRISPR/Cas9 components by using customized nanoparticle delivery systems. The combination of CRISPR/Cas9 and nanotechnology has the potential to open new avenues in the therapy of MDR bacterial infections. This review describes the recent advances related to CRISPR/Cas9 and nanoparticles for antimicrobial therapy and gene delivery, including the improvement in the packaging and localizing efficiency of the CRISPR/Cas9 components in the NP (nanoparticle)/CRISPR system. We pay particular attention to the strengths and limitations of the nanotechnology-based CRISPR/Cas9 delivery system to fight nosocomial pathogens.We highlight the need for more scientific research to explore the combinatorial efficacy of various nanoparticles and CRISPR technology to control and prevent antimicrobial resistance. Full article

Background: In neonatal intensive care units (NICUs), the simultaneous administration of drugs requires complex infusion methods. Such practices can increase the risk of drug incompatibilities resulting in the formation of a particulate load with possible clinical consequences. Methods: This paper evaluates strategies to reduce the particulate load of a protocol commonly used in NICUs with a potential medical incompatibility (vancomycin/cefepime combination). The protocol was reproduced in the laboratory and the infusion line directly connected to a dynamic particle counter to evaluate the particulate matter administered during infusion. A spectrophotometry UV assay of cefepime evaluated the impact of filters on the concentration of cefepime administered. Results: A significant difference was observed between the two infusion line configurations used in the NICU, with higher particulate load for cefepime infused via the emergency route. There was no change in particulate load in the absence of vancomycin. A filter on the emergency route significantly reduced this load without decreasing the cefepime concentration infused. Preparation of cefepime seemed to be a critical issue in the protocol as the solution initially contained a high level of particles. Conclusion: This study demonstrated the impact of a reconstitution method, drug dilution and choice of infusion line configuration on particulate load. Full article

Taro (Colocasia esculenta) corm is traditionally consumed as a medicinal plant to stimulate immune responses and restore a health status. Tarin, a taro lectin, is considered responsible for the immunomodulatory effects of taro. In the present study, in order to investigate the effects of tarin on bone marrow hematopoietic population, murine cells were stimulated with tarin combined with a highly enriched conditioned medium containing either IL-3 or GM-CSF. Cells challenged with tarin proliferated in a dose-dependent manner, evidenced by the increase in cell density and number of clusters and colonies. Tarin exhibited a cytokine-mimetic effect similar to IL-3 and GM-CSF, increasing granulocytic cell lineage percentages, demonstrated by an increase in the relative percentage of Gr-1+ cells. Tarin does not increase lymphocytic lineages, but phenotyping revealed that the relative percentage of CD3+ cells was increased with a concomitant decrease in CD19+ and IL-7Rα+ cells. Most bone marrow cells were stained with tarin-FITC, indicating non-selective tarin binding, a phenomenon that must still be elucidated. In conclusion, taro corms contain an immunomodulatory lectin able to boost the immune system by promoting myeloid and lymphoid hematopoietic progenitor cell proliferation and differentiation. Full article

Diabetic wound infections caused by conventional antibiotic-resistant Staphylococcus aureus strains are fast emerging, leading to life-threatening situations (e.g., high costs, morbidity, and mortality) associated with delayed healing and chronic inflammation. Electrospinning is one of the most widely used techniques for the fabrication of nanofibers (NFs), induced by a high voltage applied to a drug-loaded polymer solution. Particular attention is given to electrospun NFs for pharmaceutical applications (e.g., original drug delivery systems) and tissue regeneration (e.g., as tissue scaffolds). However, there is a paucity of reports related to their application in diabetic wound infections. Therefore, we prepared eco-friendly, biodegradable, low-immunogenic, and biocompatible gelatin (GEL)/polyvinyl alcohol (PVA) electrospun NFs (BNFs), in which we loaded the broad-spectrum antibiotic cephradine (Ceph). The resulting drug-loaded NFs (LNFs) were characterized physically using ultraviolet-visible (UV-Vis) spectrophotometry (for drug loading capacity (LC), drug encapsulation efficiency (EE), and drug release kinetics determination), thermogravimetric analysis (TGA) (for thermostability evaluation), scanning electron microscopy (SEM) (for surface morphology analysis), and Fourier-transform infrared spectroscopy (FTIR) (for functional group identification). LNFs were further characterized biologically by in-vitro assessment of their potency against S. aureus clinical strains (N = 16) using the Kirby–Bauer test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, by ex-vivo assessment to evaluate their cytotoxicity against primary human epidermal keratinocytes using MTT assay, and by in-vivo assessment to estimate their diabetic chronic wound-healing efficiency using NcZ10 diabetic/obese mice (N = 18). Thin and uniform NFs with a smooth surface and standard size (<400 nm) were observed by SEM at the optimized 5:5 (GEL:PVA) volumetric ratio. FTIR analyses confirmed the drug loading into BNFs. Compared to free Ceph, LNFs were significantly more thermostable and exhibited sustained/controlled Ceph release. LNFs also exerted a significantly stronger antibacterial activity both in-vitro and in-vivo. LNFs were significantly safer and more efficient for bacterial clearance-induced faster chronic wound healing. LNF-based therapy could be employed as a valuable dressing material to heal S. aureus-induced chronic wounds in diabetic subjects. Full article

Cardiovascular diseases (CVDs) are a group of conditions associated with heart and blood vessels and are considered the leading cause of death globally. Coronary heart disease, atherosclerosis, myocardial infarction represents the CVDs. Since CVDs are associated with a series of pathophysiological conditions with an alarming mortality and morbidity rate, early diagnosis and appropriate therapeutic approaches are critical for saving patients’ lives. Conventionally, diagnostic tools are employed to detect disease conditions, whereas therapeutic drug candidates are administered to mitigate diseases. However, the advent of nanotechnological platforms has revolutionized the current understanding of pathophysiology and therapeutic measures. The concept of combinatorial therapy using both diagnosis and therapeutics through a single platform is known as theranostics. Nano-based theranostics are widely used in cancer detection and treatment, as evident from pre-clinical and clinical studies. Nanotheranostics have gained considerable attention for the efficient management of CVDs. The differential physicochemical properties of engineered nanoparticles have been exploited for early diagnosis and therapy of atherosclerosis, myocardial infarction and aneurysms. Herein, we provided the information on the evolution of nano-based theranostics to detect and treat CVDs such as atherosclerosis, myocardial infarction, and angiogenesis. The review also aims to provide novel avenues on how nanotherapeutics’ trending concept could transform our conventional diagnostic and therapeutic tools in the near future. Full article

Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples. Full article

Feline mammary carcinoma (FMC) is a common neoplasia in cat, being HER2-positive the most prevalent subtype. In woman’s breast cancer, tyrosine kinase inhibitors (TKi) are used as a therapeutic option, by blocking the phosphorylation of the HER2 tyrosine kinase domain. Moreover, clinical trials demonstrated that TKi produce synergistic antiproliferative effects in combination with mTOR inhibitors, overcoming resistance to therapy. Thus, to uncover new chemotherapeutic strategies for cats, the antiproliferative effects of two TKi (lapatinib and neratinib), and their combination with a mTOR inhibitor (rapamycin), were evaluated in FMC cell lines (CAT-M, FMCp and FMCm) and compared with a human breast cancer cell line (SkBR-3). Results revealed that both TKi induced antiproliferative effects in all feline cell lines, by blocking the phosphorylation of EGFR members and its downstream effectors. Furthermore, combined treatments with rapamycin presented synergetic antiproliferative effects. Additionally, the DNA sequence of the her2 TK domain (exons 18 to 20) was determined in 40 FMC tissue samples, and despite several mutations were found none of them were described as inducing resistance to therapy. Altogether, our results demonstrated that TKi and combined protocols may be useful in the treatment of cats with mammary carcinomas, and that TKi-resistant FMC are rare. Full article

Urinary tract infection (UTI) is a common health care-associated adverse event and the leading nosocomial complication following pediatric urological surgery. While continuous antimicrobial prophylaxis effectively reduces the risk of UTI following such a surgery, non-adherence is common and represents a distinct clinical entity that is associated with renal scarring. Acceptability is likely to have a significant impact on patient adherence. Herein we used a validated data-driven approach—the ClinSearch acceptability score test (CAST)—to investigate the acceptability of cefaclor, an oral antibiotic widely used for the prevention of pediatric UTI in Japan. Standardized observer reports were collected for 58 intakes of cefaclor 10% fine granules in patients aged from 0 to 17 years. The medicine was classified as positively accepted on the acceptability reference framework. According to the percentage of the prescribed dose taken reported at the end of the treatment, patients exhibited good adherence to this well-accepted medicine. Nonetheless, requirements for greater dosing frequency or poor acceptability in certain patients could affect adherence. Acceptability should be established to ensure patient adherence to medicines used for long-term prophylaxis and consequently guarantee the safety and efficacy of the treatment. Full article

Rivaroxaban (RXB), a novel oral anticoagulant that directly inhibits factor Xa, is a poorly soluble drug belonging to Biopharmaceutics Classification System (BCS) class II. In this study, a hot-melt extruded amorphous solid dispersion (HME-ASD) containing RXB is prepared by changing the drug:polymer ratio (Polyvinylpyrrolidione-vinyl acetate 64, 1:1–1:4) and barrel temperature (200‒240 °C), fixed at 20% of Cremophor^® RH 40 and 15 rpm of the screw speed, using the hot-melt extruding technique. This study evaluates the solubility, dissolution behavior, and bioavailability for application to oral drug delivery and optimizes the formulation of rivaroxaban amorphous solid dispersion (RXB-ASD). Based on a central composite design, optimized RXB-ASD (PVP VA 64 ratio 1:4.1, barrel temperature 216.1 °C, Cremophor^® RH 40 20%, screw speed 15 rpm) showed satisfactory results for dependent variables. An in vitro drug dissolution study exhibited relatively high dissolution in four media and achieved around an 80% cumulative drug release in 120 min. Optimized RXB-ASD was stable under the accelerated condition for three months without a change in crystallinity and the dissolution rate. A pharmacokinetic study of RXB-ASD in rats showed that the absorption was markedly increased in terms of rate and amount, i.e., the systemic exposure values, compared to raw RXB powder. These results showed the application of quality by design (QbD) in the formulation development of hot-melt extruded RXB-ASD, which can be used as an oral drug delivery system by increasing the dissolution rate and bioavailability. Full article

Despite advances in medical knowledge, parasitic diseases remain a significant global health burden and their pharmacological treatment is often hampered by drug toxicity. Therefore, drug delivery systems may provide useful advantages when used in combination with conventional therapeutic compounds. Dendrimers are three-dimensional polymeric structures, characterized by a central core, branches and terminal functional groups. These nanostructures are known for their defined structure, great water solubility, biocompatibility and high encapsulation ability against a wide range of molecules. Furthermore, the high ratio between terminal groups and molecular volume render them a hopeful vector for drug delivery. These nanostructures offer several advantages compared to conventional drugs for the treatment of parasitic infection. Dendrimers deliver drugs to target sites with reduced dosage, solving side effects that occur with accepted marketed drugs. In recent years, extensive progress has been made towards the use of dendrimers for therapeutic, prophylactic and diagnostic purposes for the management of parasitic infections. The present review highlights the potential of several dendrimers in the management of parasitic diseases. Full article

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19; EudraCT number: 2020-001760-29). Full article

Dermatillomania or skin picking disorder (SPD) is a chronic, recurrent, and treatment resistant neuropsychiatric disorder with an underestimated prevalence that has a concerning negative impact on an individual’s health and quality of life. The current treatment strategies focus on behavioral and pharmacological therapies that are not very effective. Thus, the primary objective of this review is to provide an introduction to SPD and discuss its current treatment strategies as well as to propose biomaterial-based physical barrier strategies as a supporting or alternative treatment. To this end, searches were conducted within the PubMed database and Google Scholar, and the results obtained were organized and presented as per the following categories: prevalence, etiology, consequences, diagnostic criteria, and treatment strategies. Furthermore, special attention was provided to alternative treatment strategies and biomaterial-based physical treatment strategies. A total of six products with the potential to be applied as physical barrier strategies in supporting SPD treatment were shortlisted and discussed. The results indicated that SPD is a complex, underestimated, and underemphasized neuropsychiatric disorder that needs heightened attention, especially with regard to its treatment and care. Moreover, the high synergistic potential of biomaterials and nanosystems in this area remains to be explored. Certain strategies that are already being utilized for wound healing can also be further exploited, particularly as far as the prevention of infections is concerned. Full article

Cardiovascular disease is a major cause of death globally. This has led to significant efforts to develop new anti-thrombotic therapies or re-purpose existing drugs to treat cardiovascular diseases. Due to difficulties of obtaining healthy human blood vessel tissues to recreate in vivo conditions, pre-clinical testing of these drugs currently requires significant use of animal experimentation, however, the successful translation of drugs from animal tests to use in humans is poor. Developing humanised drug test models that better replicate the human vasculature will help to develop anti-thrombotic therapies more rapidly. Tissue-engineered human blood vessel (TEBV) models were fabricated with biomimetic matrix and cellular components. The pro- and anti-aggregatory properties of both intact and FeCl₃-injured TEBVs were assessed under physiological flow conditions using a modified parallel-plate flow chamber. These were perfused with fluorescently labelled human platelets and endothelial progenitor cells (EPCs), and their responses were monitored in real-time using fluorescent imaging. An endothelium-free TEBV exhibited the capacity to trigger platelet activation and aggregation in a shear stress-dependent manner, similar to the responses observed in vivo. Ketamine is commonly used as an anaesthetic in current in vivo models, but this drug significantly inhibited platelet aggregation on the injured TEBV. Atorvastatin was also shown to enhance EPC attachment on the injured TEBV. The TEBV, when perfused with human blood or blood components under physiological conditions, provides a powerful alternative to current in vivo drug testing models to assess their effects on thrombus formation and EPC recruitment. Full article

Certain lysosomal cathepsin proteins have come into focus as being good candidates for therapeutic targeting, based on them being over-expressed in a variety of cancers and based on their regulation of the apoptotic pathway. Here, we report novel findings that highlight the ability of cathepsin S expression to be up-regulated under Paclitaxel-stimulatory conditions in kidney cell lines and it being able to cleave the apoptotic p21 BAX protein in intact cells and in vitro. Consistent with this, we demonstrate that this effect can be abrogated in vitro and in mammalian cells under conditions that utilize dominant-inhibitory cathepsin S expression, cathepsin S expression-knockdown and through the activity of a novel peptide inhibitor, CS-PEP1. Moreover, we report a unique role for cathepsin S in that it can cleave a polyubiquitinated-BAX protein intermediate and is a step that may contribute to down-regulating post-translationally-modified levels of BAX protein. Finally, CS-PEP1 may possess promising activity as a potential anti-cancer therapeutic against chemotherapeutic-resistant Renal Clear Cell Carcinoma kidney cancer cells and for combined uses with therapeutics such as Paclitaxel. Full article

To develop an effective pH-sensitive drug carrier, alginate (Alg), carboxymethyl chitosan (CMCs), and aminated chitosan (AmCs) derivatives were employed in this study. A simple ionic gelation technique was employed to formulate [email protected] dual polyelectrolyte complexes (PECs) microcapsules as a pH-sensitive carrier for efficient encapsulation and release of diclofenac sodium (DS) drug. The developed microcapsules were characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analyzer (TGA), and scanning electron microscope (SEM). The results clarified that formation of dual PECs significantly protected Alg microcapsules from rapid disintegration at colon conditions (pH 7.4), and greatly reduced their porosity. In addition, the dual PECs microcapsules can effectively encapsulate 95.4% of DS-drug compared to 86.3 and 68.6% for Alg and Alg-CMCs microcapsules, respectively. Higher DS-release values were achieved in simulated colonic fluid [SCF; pH 7.4] compared to those obtained in simulated gastric fluid [SGF; pH 1.2]. Moreover, the drug burst release was prevented and a sustained DS-release was achieved as the AmCs concentration increased. The results confirmed also that the developed microcapsules were biodegradable in the presence of the lysozyme enzyme. These findings emphasize that the formulated pH-sensitive microcapsules could be applied for the delivery of diclofenac sodium. Full article