Polymer nanotherapeutics: A promising approach toward microglial inhibition in neurodegenerative diseases.

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases.

Reducing Temperature of Fused Deposition Modelling 3D Printing for Linalool Fast Dissolving Oral Films by Increasing Printer Nozzle Diameter.

Oral thrush and throat infections can occur in a wide range of patients. Treatments are available; however, resistance to drugs is a major problem for treating oral and throat infections. Three-dimensional printing (3DP) of fast dissolving oral films (FDFs) of linalool oil may provide an alternative solution. Linalool oil FDFs were printed by fused deposition modelling across 1-18 % w/w linalool content range with nozzle diameters of 0.4 or 1 mm at the temperature range of 150 °C-185 °C. The FDFs were evaluated for physicochemical and mechanical properties. Increasing the printer nozzle diameter to 1 mm allowed reducing the printing temperature from 185 °C to 150 °C; consequently, more linalool was quantified in the films with improved content uniformity. The higher linalool content in the films increased the film disintegration time and mechanical strength. FDFs containing 10% w/w linalool showed clear antifungal activity against Candida albicans. Raman spectroscopy suggested linalool separation from excipients at higher temperature printing. Viscoelastic measurements indicated that to achieve printing; the elastic modulus of molten filament needed to be higher than the loss modulus at low angular frequencies. In conclusion, increasing the printing nozzle diameter may avoid loss of the active ingredient by reducing the temperature of the 3DP process.

The protective effects of statins in traumatic brain injury.

Traumatic brain injury (TBI), often referred to as the "silent epidemic", is the most common cause of mortality and morbidity worldwide among all trauma-related injuries. It is associated with considerable personal, medical, and economic consequences. Although remarkable advances in therapeutic approaches have been made, current treatments and clinical management for TBI recovery still remain to be improved. One of the factors that may contribute to this gap is that existing therapies target only a single event or pathology. However, brain injury after TBI involves various pathological mechanisms, including inflammation, oxidative stress, blood-brain barrier (BBB) disruption, ionic disturbance, excitotoxicity, mitochondrial dysfunction, neuronal necrosis, and apoptosis. Statins have several beneficial pleiotropic effects (anti-excitotoxicity, anti-inflammatory, anti-oxidant, anti-thrombotic, immunomodulatory activity, endothelial and vasoactive properties) in addition to promoting angiogenesis, neurogenesis, and synaptogenesis in TBI. Supposedly, using agents such as statins that target numerous and diverse pathological mechanisms, may be more effective than a single-target approach in TBI management. The current review was undertaken to investigate and summarize the protective mechanisms of statins against TBI. The limitations of conducted studies and directions for future research on this potential therapeutic application of statins are also discussed.

The Effect of Statins on the Differentiation and Function of Central Nervous System Cells.

Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) reduce plasma cholesterol and improve endothelium-dependent vasodilation, inflammation, and oxidative stress. The effect of statins on the central nervous system (CNS), particularly on cognition and neurological disorders such as cerebral ischemic stroke, multiple sclerosis (MS), and Alzheimer's disease (AD), has received increasing attention in recent years, both within the scientific community and in the media. This review aims to provide an updated discussion on the effects of statins on the differentiation and function of various nervous system cells, including neurons and glial cells. Additionally, the mechanisms of action and how different types of statins enter the CNS will be discussed.

The effects of statins on the function and differentiation of blood cells.

Statins are inhibitors of ß-hydroxy ß-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR). They are used in patients with cardiovascular risk and/or suffering with cardiovascular disease. In addition to their efficient lipid-lowering effects, statins exhibit independent so called pleiotropic effects potentially affecting several immune response properties including immune cell activation, migration, cytokine generation, immune metabolism, and survival. Statins also regulate innate and acquired immunity. The focus of this review is to highlight the role of statins in modulating the function and differentiation of various blood cells. Given the proposed wider application of these medicines and their potentially important advantages in treatment of inflammatory and autoimmune disorders, more studies are needed with special focus on the molecular targets of statins included in regulating the immune response.

Antibiotic prescribing trends in primary care 2014-2022.

Antimicrobial resistance (AMR) is a global healthcare challenge that governments and health systems are tackling primarily through antimicrobial stewardship (AMS). This should, improve antibiotic use, avoid inappropriate prescribing, reduce prescription numbers, aligning with national/international AMS targets. In primary care in the United Kingdom (UK) antibiotics are mainly prescribed for patients with urinary and respiratory symptoms (22.7% and 46% of all antibiotic prescriptions respectively). This study aimed to capture the time-series trends (2014-2022) for commonly prescribed antibiotics for respiratory and urinary tract infections in primary care in England. Trends for Amoxicillin, Amoxicillin sodium, Trimethoprim, Clarithromycin, Erythromycin, Erythromycin ethylsuccinate, Erythromycin stearate, Doxycycline hyclate, Doxycycline monohydrate and Phenoxymethylpenicillin (Penicillin V) were determined. In doing so providing evidence regarding meeting UK antibiotic prescribing rate objectives (a 15% reduction in human antibiotic use 2019-2024). Time series trend analysis of 62,949,272 antibiotic prescriptions from 6,370 General Practices in England extracted from the National Health Service (NHS) Business Services Authority web portal were explored. With additional investigation of prescribing rate trends by quintiles of the Index of Multiple Deprivation (IMD). Overall, there is a downwards trend in antibiotic prescribing for those explored. There is an association between IMD, geographical location, and higher antibiotic prescribing levels (prescribing hot spots). England has a well-documented North-South divide of health inequalities, this is reflected in antibiotic prescribing. The corona virus pandemic (COVID-19) impacted on AMS, with a rise in doxycycline and trimethoprim prescriptions notable in higher IMD areas. Since then, prescribing appears to have returned to pre-pandemic levels in all IMDs and continued to decline. AMS efforts are being adhered to in primary care in England. This study provides further evidence of the link between locality and poorer health outcomes (reflected in higher antibiotic prescribing). Further work is required to address antibiotic use in hot spot areas.

A review on the efficacy and safety of lipid-lowering drugs in neurodegenerative disease.

There is a train of thought that lipid therapies may delay or limit the impact of neuronal loss and poor patient outcomes of neurodegenerative diseases (NDDs). A variety of medicines including lipid lowering modifiers (LLMs) are prescribed in NDDs. This paper summarizes the findings of clinical and observational trials including systematic reviews and meta-analyses relating to LLM use in NDDs published in the last 15 years thus providing an up-to-date evidence pool. Three databases were searched PubMed, CINAHL, and Web of Science using key terms relating to the review question. The findings confirm the benefit of LLMs in hyperlipidemic patients with or without cardiovascular risk factors due to their pleotropic effects. In NDDs LLMs are proposed to delay disease onset and slow the rate of progression. Clinical observations show that LLMs protect neurons from α-synuclein, tau, and Aß toxicity, activation of inflammatory processes, and ultimately oxidative injury. Moreover, current meta-analyses and clinical trials indicated low rates of adverse events with LLMs when used as monotherapy. LLMs appear to have favorable safety and tolerability profiles with few patients stopping treatment due to severe adverse effects. Our collated evidence thus concludes that LLMs have a role in NDDs but further work is needed to understand the exact mechanism of action and reach more robust conclusions on where and when it is appropriate to use LLMs in NDDs in the clinic.

KidzMed e-learning to upskill student pharmacists to teach pill swallowing to children.

BACKGROUND: Appropriate medication use is essential in ensuring optimal pharmacotherapeutic outcomes. It is mistakenly assumed that adults can swallow solid oral dosage forms (SODFs, e.g. tablets/capsules colloquially referred to as 'pills'), without difficulty and that children cannot. KidzMed is a 'pill swallowing' training programme designed to teach effective SODF use in patients of all ages. It may be utilised by healthcare professionals to assist patients taking SODFs. E-learning was essential for training during COVID pandemic to reduce viral transmission. The aim of this study was to explore UK student pharmacists views of e-learning to support swallowing solid oral dosage forms. METHODS: This study used pre- and post-intervention online surveys on Microsoft Forms to evaluate self-directed eLearning about pill swallowing on MPharm programmes at three UK Universities using a 13-item survey. A combination of five-point Likert Scales and free-text items were used. The eLearning was available via the virtual learning environment at the University and embedded within existing curriculum. Descriptive statistical analysis was used to explore responses. RESULTS: In total, 113 of 340 (33%) students completed the survey. Seventy-eight percent (n = 65) reported the eLearning would enable them to teach adults and children to swallow SODFs successfully. Learners either agreed or strongly agreed that they felt comfortable to teach patients (95%, n = 62/113) and parents or carers (94%, n = 60) to swallow medications having completed the e-learning. Student pharmacists generally found eLearning as an acceptable way to reflect on their own experiences of 'pill' swallowing and how to support patients to swallow SODFs. CONCLUSION: The KidzMed eLearning was well received by student pharmacists. Further work is needed to explore whether skills translates into real life application in the clinical settings.

Solid lipid nanoparticles: a promising tool for insulin delivery.

INTRODUCTION: Insulin plays a critical role in metabolism modulation including carbohydrate, lipid, and protein metabolism. There is room to improve insulin delivery but optimizing the best carrier remains challenging. Traditional and conventional approaches for insulin delivery do not emulate the normal fate of insulin release in the body. Despite extensive research attempts to overcome this and other challenges, the goal of achieving optimal insulin delivery that emulates the natural system remains unresolved. AREAS COVERED: Solid Lipid Nanoparticles (SLNs) may provide a solution, because they are nontoxic, biocompatible, and straightforward to formulate thus providing a promising platform for achieving targeted and controlled delivery of various therapeutic agents. This review aims to provide an overview on the suitability and application of SLNs for insulin delivery. A special emphasis is placed on the biopharmaceutical aspects of insulin loaded SLNs which have not been explored in detail to date. EXPERT OPINION: SLNs have proven to be safe and versatile drug delivery systems suitable for insulin delivery and capable of improving the efficacy and pharmacokinetic profile of encapsulated insulin. There is still some work to be done to fully explore SLNs' true potential as drug delivery and specifically insulin delivery vehicles suitable for clinical use.

Identifying and addressing pill aversion in adults without physiological-related dysphagia: A narrative review.

Solid oral dosage forms (SODFs) (often called pills by patients) are the default formulation to treat medical ailments. Beneficial therapeutic outcomes rely on patients taking them as directed. Up to 40% of the population experience difficulties swallowing SODFs, resulting in reduced adherence and impaired therapeutic efficacy. Often associated with children, this also presents in adults with dysphagia, and without any organic dysphagia (non-physiological-related or functional dysphagia). This review aims to identify and appraise current interventions used to screen for and overcome pill aversion in adults with functional dysphagia. A comprehensive search of the literature was conducted. Articles reporting pill aversion in adults aged ≥18 years with no underlying cause, history of, or existing dysphagia were included. Study quality was determined using the STROBE tool for observational studies. A narrative synthesis of the findings was prepared. We identified 18 relevant cohort studies, which demonstrate that pill aversion is a global problem. Perceived ease of and/or SODF swallowability appears to be influenced by female gender, younger age, co-morbidities (e.g., depression), and physical SODF properties. Patients often modify their medicines rather than raise this issue with their healthcare team. Screening for pill aversion is haphazard but controlled postural adjustments, coating SODFs and behavioural interventions appear to be successful solutions. SODF swallowing difficulties are a barrier to effective medication use. Healthcare professionals must recognise that pill aversion is a problem requiring identification through effective screening and resolution by training interventions, appropriate formulation selection or specialist referral.

Spoken propositional idea density, a measure to help second language English speaking students: A multicentre cohort study.

PURPOSE: Idea density has been shown to influence comprehension time for text in various populations. This study aims to explore the influence of spoken idea density on attainment in young, healthy subjects using demographic characteristics. METHODS: Students watched two online lectures and answered 10 multiple choice questions on them. Students received one more idea dense (MID) and one less idea dense (LID) lecture on two different subjects. RESULTS: Seventy-five students completed the study achieving a higher median score after a less idea-dense lecture (LID = 7(3), MID = 6(3), p = 0.04). Artificial neural network models revealed the first language as the main predictor of exam performance. The odds ratio (OR) of obtaining ≥70% after a more idea-dense lecture was six-time higher for the first language versus second language English speakers (OR = 5.963, 95% CI 1.080-32.911, p = 0.041). The odds ratio was not significant when receiving a less dense lecture (OR = 2.298, 95% CI 0.635-8.315, p = 0.205). Second-language speakers benefited from receiving a lower idea density, achieving a 10.8% score increase from high to low density, versus a 3.2% increase obtained by first language speakers. CONCLUSIONS: The propositional idea density of lectures directly influences students' comprehension, and disproportionately for second language speakers; revealing the possibility of reduced spoken idea density in levelling the attainment differential between first and second language speakers.

Effective nebulization of interferon-γ using a novel vibrating mesh.

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 µm and 4.39 ± 0.25 µm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 µm for the PDAP and 4.30 ± 0.02 µm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ.

Pharmacy student and pharmacist perceptions of professional socialism and communication in a real-life clinical setting.

OBJECTIVES: To determine the impact of authentic clinical tasks on student confidence in interprofessional communication and assess the perceptions of pharmacists and pharmacy undergraduate students on how their degree prepares them to communicate and integrate with other healthcare professionals. METHODS: Pharmacists completed a questionnaire regarding how their degree prepared them to communicate with other healthcare professionals. Third- and fourth-year pharmacy undergraduate students completed a modified questionnaire with questions relating to interprofessional learning and their experiences of reflective interprofessional communication tasks whilst on hospital placement. The questionnaires produced a combination of qualitative and quantitative data. KEY FINDINGS: Pharmacists (n = 36) and pharmacy students (n = 186) were in agreement that interprofessional training is important for undergraduate pharmacy students. Over 80% of student respondents viewed the interprofessional communication skills task as a useful method to develop communication skills with an increase in confidence following completion of the task. A variety of methods ranging from classroom- to practical-based sessions may be used to develop communication skills and professional socialism. CONCLUSIONS: Interprofessional learning has an important role for all working within the multidisciplinary healthcare team and contributes to the development of collaborative working relationships. It should be introduced and reinforced throughout undergraduate studies and continued in the workplace.

Ultrashort self-assembling Fmoc-peptide gelators for anti-infective biomaterial applications.

Biomaterial-related infections have a significant impact on society and are a major contributor to the growing threat of antimicrobial resistance. Current licensed antibiotic classes struggle to breakdown or penetrate the exopolysaccharide biofilm barrier, resulting in sub-therapeutic concentrations of antibiotic at the surface of the biomaterial, treatment failure and increased spread of resistant isolates. This paper focuses for the first time on the ability of ultrashort Fmoc-peptide gelators to eradicate established bacterial biofilms implicated in a variety of medical device infections (Gram-positive: Staphylococcus aureus, Staphylococcus epidermidis and Gram-negative Escherichia coli, Pseudomonas aeruginosa). The effect of increasing the cationicity of FmocFF via addition of di-lysine and di-orntithine was also studied with regard to antibacterial activity. Our studies demonstrated that Fmoc-peptides (FmocFF, FmocFFKK, FmocFFFKK, FmocFFOO) formed surfactant-like soft gels at concentrations of 1% w/v and above using a method of glucono-δ-Lactone pH induction. The majority of Fmoc-peptides (0.5-2% w/v) demonstrated selective action against established (grown for 24 h) biofilms of Gram-positive and Gram-negative pathogens. These results are likely to increase the clinical translation of short-peptide gelator platforms within the area of anti-infective biomaterials including as wound dressings and coatings for prostheses, catheters, heart valves and surgical tubes. In the long term, this will lead to wider treatment choices for clinicians and patients involved in the management of medical device infections and reduce the burden of antimicrobial resistance. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients.

Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somatostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or monotherapy for prostate and breast cancer, and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutical industry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers.

Potential strategies for the eradication of multidrug-resistant Gram-negative bacterial infections.

Antimicrobial resistance is one of the leading threats to society. The increasing burden of multidrug-resistant Gram-negative infection is particularly concerning as such bacteria are demonstrating resistance to nearly all currently licensed therapies. Various strategies have been hypothesized to treat multidrug-resistant Gram-negative infections including: targeting the Gram-negative outer membrane; neutralization of lipopolysaccharide; inhibition of bacterial efflux pumps and prevention of protein folding. Silver and silver nanoparticles, fusogenic liposomes and nanotubes are potential strategies for extending the activity of licensed, Gram-positive selective, antibiotics to Gram-negatives. This may serve as a strategy to fill the current void in pharmaceutical development in the short term. This review outlines the most promising strategies that could be implemented to solve the threat of multidrug-resistant Gram-negative infections.