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BACKGROUND: Limited health literacy often results in people inadequately understanding medicines-related information and subsequently not taking medicines as prescribed. Using health literacy interventions is important for community pharmacists, as they are increasingly managing long-term conditions. However, there appear to be no previous studies of community pharmacists' everyday use of health literacy interventions in the UK. OBJECTIVES: To explore UK community pharmacists' perspectives on the usability of health literacy interventions in their everyday practice. METHODS: Semi-structured interviews were conducted with participants, following attendance at health literacy training that included practicing the use of four health literacy interventions (Teach-Back, Chunk and Check, Simple Language and visual aids) and two months experience of attempting to use them in their everyday practice. Participants were pharmacists from community pharmacies in Staffordshire, England who were invited to participate by an email sent to the pharmacy. Interviews were audio-recorded, transcribed verbatim and analysed using the Framework Analysis technique. RESULTS: Four themes emerged from 11 interviews undertaken: intervention appeal, limitations, adaptations and continued use. Participants reported using all four health literacy interventions in their everyday practice but Teach-Back appeared to be favoured most. Most participants talked about practicing Teach-Back before using it with patients but described it as useable with patients of all ages, without being prohibitively time consuming. Chunk and Check seemed to be viewed as a type of Teach-Back, whilst visual aids were reported as being used in conjunction with Teach Back rather than as a standalone intervention. Participants reported that Simple Language was an easy concept but easily 'slipped back' into medical jargon and were challenged to use simple enough words. All participants said they would continue to use all four health literacy interventions. CONCLUSIONS: The findings suggest that with training, community pharmacists can successfully incorporate these four health literacy interventions into their everyday practice.

A bioassay-guided phytochemical investigation of propolis samples from Tanzania and Zambia that screened for activity against Trypanosoma brucei has led to the isolation of two novel flavanones with promising antitrypanosomal activity. The compounds were characterized based on their spectral and physical data and identified as 6-(1,1-dimethylallyl) pinocembrin and 5-hydroxy-4″,4″-dimethyl-5″-methyl-5″-H-dihydrofuranol [2″,3″,6,7] flavanone. The two compounds, together with the propolis extracts and fractions, were assayed against a standard drug-sensitive strain of T. b. brucei (s427 wild-type), multi-drug resistant-resistant T. b. brucei (B48), drug-sensitive T. congolense (1L300) and a derived diminazene-resistant T. congolense strain (6C3), and for toxicity against U947 human cells and RAW 246.7 murine cells. Activity against T. b. brucei was higher than against T. congolense. Interestingly, the Tanzanian propolis extract was found to be more active than its fractions and purified compounds in these assays, with an IC50 of 1.20 μg/mL against T. b. brucei. The results of a cytotoxicity assay showed that the propolis extracts were less toxic than the purified compounds with mean IC50 values > 165.0 μg/mL., Graphical abstract Image 1, Highlights • Two samples of propolis from East Africa display good activity against Trypanosoma brucei and T. congolense. • Activity against both wild type and pentamidine and diminazene resistant forms. • Two novel flavonoids and one known flavonoid were isolated from Tanzanian and Zambian propolis samples and characterized. • Pure isolated compounds not much more active than crude extracts. • Repeated observation of anti-protozoal activity shows the importance of propolis indefending the hive against infections.

The upsurge of multiple drug resistance (MDR) bacteria substantially diminishes the effectiveness of antibiotic arsenal and therefore intensifies the rate of therapeutic failure. The major factor in MDR is efflux pump-mediated resistance. A unique pump can make bacteria withstand a wide range of structurally diverse compounds. Therefore, their inhibition is a promising route to eliminate resistance phenomenon in bacteria. Phytochemicals are excellent alternatives as resistance-modifying agents. They can directly kill bacteria or interact with the crucial events of pathogenicity, thereby decreasing the ability of bacteria to develop resistance. Numerous botanicals display noteworthy efflux pumps inhibitory activities. Edible plants are of growing interest. Likewise, some plant families would be excellent sources of efflux pump inhibitors (EPIs) including Apocynaceae, Berberidaceae, Convolvulaceae, Cucurbitaceae, Fabaceae, Lamiaceae, and Zingiberaceae. Easily applicable methods for screening plant-derived EPIs include checkerboard synergy test, berberine uptake assay and ethidium bromide test. In silico high-throughput virtual detection can be evaluated as a criterion of excluding compounds with efflux substrate-like characteristics, thereby improving the selection process and extending the identification of EPIs. To ascertain the efflux activity inhibition, real-time PCR and quantitative mass spectrometry can be applied. This review emphasizes on efflux pumps and their roles in transmitting bacterial resistance and an update plant-derived EPIs and strategies for identification., Graphical abstract Image 1, Highlights • Active efflux as the main resistance strategy in bacteria. • Phytochemicals as promising alternatives against efflux pumps-mediated MDR. • Herbals-based efflux pump inhibitors screening, the methods.

This cross-sectional study estimates the costs incurred by the National Health Service (NHS) in England as a consequence of the unnecessary prescribing (i.e. non-indicated or dispensable) of dependency-forming medicines (antidepressants, opioids, gabapentinoids, benzodiazepines, Z-drugs). It assesses prescribing in primary care from April 2015-March 2018. Analyses were based upon the following data sets: the number of adults continuously prescribed dependency forming medications and the duration of prescriptions (obtained from Public Health England); the Net Ingredient Cost (NIC) and the dispensing costs for each medicine (obtained from the NHS Business Service Authority [NHSBSA]). Consultation costs were calculated based on guideline recommendations and the number of consultations evidenced in prior research for long-term medication monitoring. Across opioids, gabapentinoids, benzodiazepines, Z-drugs the total estimated unnecessary cost over three years (April 2015-March 2018) was £1,367,661,104 to £1,555,234,627. For antidepressants the total estimated unnecessary cost for one year was £37,321,783 to £45,765,504. The data indicate that the NHS in England may incur a significant estimated mean annual loss of £455,887,035 to £518,411,542 for opioids, gabapentinoids, benzodiazepines, Z-drugs and an estimated annual loss of £37,321,783 to £45,765,504 for antidepressants. Combined, this gives an estimated annual loss of £493,208,818 to £564,177,046 as a result of non-indicated or dispensable prescribing of dependency-forming medicines. Estimates are conservative and figures could be higher.

Density Functional Theory (DFT) and Quantitative Structure-Activity Relationship (QSAR) studies were performed on four benzimidazoles (compounds 1–4) and two benzothiazoles (compounds 5 and 6), previously synthesized by our group. The compounds were also investigated for their binding affinity and interactions with the SARS-CoV-2 Mpro (PDB ID: 6LU7) and the human angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6 M18) using a molecular docking approach. Compounds 1, 2, and 3 were found to bind with equal affinity to both targets. Compound 1 showed the highest predictive docking scores, and was further subjected to molecular dynamics (MD) simulation to explain protein stability, ligand properties, and protein–ligand interactions. All compounds were assessed for their structural, physico-chemical, pharmacokinetic, and toxicological properties. Our results suggest that the investigated compounds are potential new drug leads to target SARS-CoV-2.

Introduction Values-based practice is an important concept within healthcare decision-making that sits alongside evidence-based practice. Values Exchange (Vx) ( http://www.vxcommunity.com ) is an online tool that supports the development of ethical and professional decision-making skills through values transparency. The aim of this research was to explore the perceived impact of long-term use of the tool during undergraduate study on pharmacy graduates' early practice. Methods Alumni in their pre-registration year or up to two years qualified were invited to participate via a question at the end of a survey, with additional students invited prospectively during an undergraduate lecture. All had completed three cases per year on Vx during the four-year master of pharmacy course. Semi-structured interviews were audio-recorded and transcribed verbatim, and framework analysis was applied. Ethical approval was obtained. Results A total of 18 interviews (nine pharmacists and nine pre-registration tutees) were conducted between May 2015 and March 2016. Thirteen participants were female, 13 were based in community pharmacy, and 10 were Caucasian. Interviews ranged from 50 min to 2 hours. Three themes emerged from the data: (1) the Vx learning environment, (2) learning and reflection, and (3) potential enhancements for learning. Participants perceived Vx to be an effective teaching tool supporting the development of skills necessary to exercise professional judgement in pharmacy practice. Conclusions Vx appears to be a worthy addition to the armoury of teaching methods necessary to support future pharmacists in their preparedness to deal with ethical and professional dilemmas in practice.

Data sharing: The data used to inform this policy paper can be made able, upon reasonable request from Esmita Charani, e.charani@imperial.ac.uk. Copyright © 2021 The Author(s). Addressing the silent pandemic of antimicrobial resistance (AMR) is a focus of the 2021 G7 meeting. A major driver of AMR and poor clinical outcomes is suboptimal antimicrobial use. Current research in AMR is inequitably focused on new drug development. To achieve antimicrobial security we need to balance AMR research efforts between development of new agents and strategies to preserve the efficacy and maximise effectiveness of existing agents. Combining a review of current evidence and multistage engagement with diverse international stakeholders (including those in healthcare, public health, research, patient advocacy and policy) we identified research priorities for optimising antimicrobial use in humans across four broad themes: policy and strategic planning; medicines management and prescribing systems; technology to optimise prescribing; and context, culture and behaviours. Sustainable progress depends on: developing economic and contextually appropriate interventions; facilitating better use of data and prescribing systems across healthcare settings; supporting appropriate and scalable technological innovation. Implementing this strategy for AMR research on the optimisation of antimicrobial use in humans could contribute to equitable global health security. Wellcome Trust; Economic and Social Research Council (ESRC); National Institute for Health Research ASPIRES project (Antibiotic use across Surgical Pathways: Investigating, Redesigning and Evaluating Systems) (https://www.imperial.ac.uk/arc/aspires/); National Institute for Health Research, UK Department of Health [HPRU-2012-10047] in partnership with Public Health England.

Prostate cancer is one of the prominent causes of cancer mortality in men all over the world and a challenge to treat. In this study, transferrin (Tf) bioconjugated solid lipid nanoparticles (SLNs) were developed and loaded with curcumin (CRC) for active targeting of prostate cancer cells. Curcumin is an anticancer agent, but its clinical applications are impeded due to the poor water solubility and bioavailability. Prepared blank Tf-SLNs showed minimal cytotoxicity while Tf-CRC-SLNs demonstrated significant in-vitro anti-proliferative activity compared to CRC-SLNs alone. Cellular uptake of Tf-CRC-SLNs were found to be significantly higher (p < 0.05/=0.01) compared to unconjugated SLNs or pure drug alone. Bioconjugated Tf-CRC-SLNs also showed improved early apoptotic and late apoptotic or early necrotic populations (6.4% and 88.9% respectively) to CRC-SLNs and CRC solution. Most importantly, in-vivo studies with Tf-CRC-SLNs in mice bearing prostate cancer revealed significant tumour regression (392.64 mm3 after 4 weeks, p < 0.001) compared to the control group. The findings of this work encourage future investigations and further in-vivo clinical studies on the potential of bioconjugated SLNs for cancer cure.

The Knowledge about the use of counterfeit medicines in Lebanon is still very limited. Thus, the objective of this study was to evaluate the degree of awareness of counterfeit medicines among the Lebanese population and the harm associated with their consumption. A cross-sectional study based on a questionnaire survey has been applied where a semi-structured survey questionnaire was distributed, between June 2017 and May 2018, among 750 participants from 98 Lebanese areas to assess their awareness regarding counterfeit medicines. Seven hundred and four participants completed the questionnaire. 55.4% purchased medicines regularly. The main sources of medicines were pharmacies (52.6%), government clinics (16.3%) and private clinics (8.7%). The most common purchased medicines were lifesaving ones (80%). In the majority of cases (71.9%), participants could not identify the manufacturer country. Overall, 46.2% of the participants were aware of counterfeit medicines. 5.4% of the participants experienced self-reporting adverse effects, among which 89.5% of cases were reported to pharmacists or other authorities. Despite the risk, 4.7% of participants were willing to buy a potential counterfeit medicine. In fact, 56. 4% of the participants associated low harm level with the use of counterfeit medicines. Despite their awareness of counterfeit drugs-associated risks, the majority of participants tend to buy them again. Informative public health campaign and health professionals training, to prevent counterfeit medicines-associated harms, should be implemented.

The advancement of drug delivery devices is critical for the individualization of patient treatment and the improvement of healthcare. Here, we introduce the 3DMNMEMS, a novel device that combines 3D printing, microneedles (MNs) and Microelectromechanical Systems (MEMS), allowing versatile and controllable by the user transdermal drug delivery. Hollow MNs were designed and 3D printed using Stereolithography, followed by integrating into a MEMS. By employing advanced imaging techniques, we monitored the distribution of liquid delivered by the device within skin tissue in real-time. In vivo testing revealed that the delivery of insulin using the 3DMNMEMS achieved improved glycemic control to diabetic animals compared to subcutaneous injections. These results demonstrated the potential of the 3DMNMEMS as a universal transdermal drug delivery system for personalized care.

The application of X-ray microtomography for quantitative structural analysis of pharmaceutical multi-particulate systems was demonstrated for commercial capsules, each containing approximately 300 formulated ibuprofen pellets. The implementation of a marker-supported watershed transformation enabled the reliable segmentation of the pellet population for the 3D analysis of individual pellets. Isolated translation- and rotation-invariant object cross-sections expanded the applicability to additional 2D image analysis techniques. The full structural characterisation gave access to over 200 features quantifying aspects of the pellets' size, shape, porosity, surface and orientation. The extracted features were assessed using a ReliefF feature selection method and a supervised Support Vector Machine learning algorithm to build a model for the detection of broken pellets within each capsule. Data of three features from distinct structure-related categories were used to build classification models with an accuracy of more than 99.55% and a minimum precision of 86.20% validated with a test dataset of 886 pellets. This approach to extract quantitative information on particle quality attributes combined with advanced data analysis strategies has clear potential to directly inform manufacturing processes, accelerating development and optimisation., Graphical abstract Unlabelled Image, Highlights • Coupling micro-XRT analysis with feature selection and machine learning for advanced pharmaceutical product characterisation. • Information on particle 3D-orientation were utilised to extract translation- and rotation-invariant object cross-sections. • Successful extraction of over 200 quantitative pellet descriptors linked to size, shape, porosity, surface and orientation. • Sensitivity analysis and ReliefF feature selection approach to identify predictive features for pellet classification. • Feature-based binary SVM classification model for the detection of broken pellets within the formulated system.

Funding: Astellas Pharma, Inc. Background Clostridioides difficile infection (CDI) is associated with high healthcare demands and related costs. Aim To evaluate the healthcare and economic burden of CDI in hospitalised patients with community- (HOCA-CDI) or hospital-associated CDI (HOHA-CDI) in the National Health Service in Scotland. Methods A retrospective cohort study was conducted, examining data between August 2010 and July 2013 from four patient-level Scottish datasets, linked to death data. Data examined included prior antimicrobial prescriptions in the community, hospitalisations, length of stay and mortality. Each CDI case was matched to three hospital-based controls on the basis of age, gender, hospital and date of admission. Descriptive economic evaluations were based on bed-day costs for different types of wards. Findings Overall, 3304 CDI cases were included in the study. CDI was associated with additional median lengths of stay of 7.2 days for HOCA-CDI and 12.0 days for HOHA-CDI compared with their respective, matched controls. The 30-day mortality rate was 6.8% for HOCA-CDI and 12.4% for HOHA-CDI. Overall, recurrence within 90 days of the first CDI episode occurred in 373/2740 (13.6%) survivors. The median additional expenditure for each initial CDI case compared with matched controls was £1713. In the 6 months after the index hospitalisation, the cost associated with a CDI case was £5126 higher than for controls. Conclusion Using routinely collected national data, we demonstrate the substantial burden of CDI on healthcare services, including lengthy hospital stays and readmissions, which increase the costs of managing patients with CDI compared with matched controls. Postprint

We consider a pharmaceutical Research & Development (R & D) pipeline management problem under two significant uncertainties: the outcomes of clinical trials and their durations. We present an Approximate Dynamic Programming (ADP) approach to solve the problem efficiently. Given an initial list of potential drug candidates, ADP derives a policy that suggests the trials to be performed at each decision point and state. For the classical R&D pipeline planning problem with deterministic trial durations, we compare our ADP approach with other methods from the literature, and find that it can find better solutions more quickly in particular for larger problem instances. For the case with stochastic trial durations, we compare the ADP algorithm with a myopic approach and show that the expected net profit obtained by the derived ADP policy is higher (almost 20% for a 10-drug portfolio).

Activated platelets generate an eicosanoid proposed to be 8-hydroxy-9,10-dioxolane A3 (DXA3). Herein, we demonstrate that significant amounts of DXA3 are rapidly attached to phosphatidylethanolamine (PE) forming four esterified eicosanoids, 16:0p, 18:0p, 18:1p and 18:0a/DXA3-PEs that can activate neutrophil integrin expression. These lipids comprise the majority of DXA3 generated by platelets, are formed in ng amounts (24.3±6.1 ng/2×108) and remain membrane bound. Pharmacological studies revealed DXA3-PE formation involves cyclooxygenase-1 (COX), protease-activated receptors (PAR) 1 and 4, cytosolic phospholipase A2 (cPLA2), phospholipase C and intracellular calcium. They are generated primarily via esterification of newly formed DXA3, but can also be formed in vitro via co-oxidation of PE during COX-1 co-oxidation of arachidonate. All four DXA3-PEs were detected in human clots. Purified platelet DXA3-PE activated neutrophil Mac-1 expression, independently of its hydrolysis to the free eicosanoid. This study demonstrates the structures and cellular synthetic pathway for a family of leukocyte-activating platelet phospholipids generated on acute activation, adding to the growing evidence that enzymatic PE oxidation is a physiological event in innate immune cells. Keywords: Eicosanoids, Platelets, Cyclooxygenase, Phospholipids, Mass spectrometry

Summary: Objective: This study investigated the effect of hUC-MSCs on osteoarthritis (OA) progression in a xenogeneic model. Design: Male, 10 week-old C57BL/6 mice underwent sham surgery (n = 15) or partial medial meniscectomy (PMM; n = 76). 5x105 hUC-MSCs (from 3 donors: D1, D2 and D3) were phenotyped via RT-qPCR and immunoprofiling their response to inflammatory stimuli.They were injected into the mouse joints 3 and 6 weeks post-surgery, harvesting joints at 8 and 12 weeks post-surgery, respectively. A no cell ‘control’ group was also used (n = 29). All knee joints were assessed via micro-computed tomography (μCT) and histology and 10 plasma markers were analysed at 12 weeks. Results: PMM resulted in cartilage loss and osteophyte formation resembling human OA at both time-points. Injection of one donor's hUC-MSCs into the joint significantly reduced the loss of joint space at 12 weeks post-operatively compared with the PMM control.This ‘effective’ population of MSCs up-regulated the genes, IDO and TSG6, when stimulated with inflammatory cytokines, more than those from the other two donors.No evidence of an inflammatory response to the injected cells in any animals, either histologically or with plasma biomarkers, arose. Conclusion: Beneficial change in a PMM joint was seen with only one hUC-MSC population, perhaps indicating that cell therapy is not appropriate for severely osteoarthritic joints. However, none of the implanted cells appeared to elicit an inflammatory response at the time-points studied. The variability of UC donors suggests some populations may be more therapeutic than others and donor characterisation is essential in developing allogeneic cell therapies.

Understanding metabotype (multicomponent metabolic characteristics) variation can help to generate new diagnostic and prognostic biomarkers, as well as models, with potential to impact on patient management. We present a suite of conceptual approaches for the generation, analysis, and understanding of metabotypes from body fluids and tissues. We describe and exemplify four fundamental approaches to the generation and utilization of metabotype data via multiparametric measurement of (i) metabolite levels, (ii) metabolic trajectories, (iii) metabolic entropies, and (iv) metabolic networks and correlations in space and time. This conceptual framework can underpin metabotyping in the scenario of personalized medicine, with the aim of improving clinical outcomes for patients, but the framework will have value and utility in areas of metabolic profiling well beyond this exemplar.

Background The World Health Organization Essential Medicines List (WHO-EML) includes ‘access’ antibiotics, judged essential to treat common infections. The European Society of Clinical Microbiology and Infectious Diseases Study Group for Antimicrobial Stewardship defined a list of ‘forgotten’ antibiotics, some old and often off-patent antibiotics, which have particular value for specific indications. Objective To investigate which WHO-EML ‘access’ and ‘forgotten’ antibiotics are approved at national level in a sample of low- to middle-income countries (LMICs). Methods The Scientific Committee used a consensus procedure to select 26 WHO-EML ‘access’ and 15 ‘forgotten’ antibiotics. Paediatric formulations were explored for 14 antibiotics. An internet-based questionnaire was circulated to 40 LMIC representatives. Antibiotics were defined as approved if an official drug regulatory agency and/or the national ministry of health licensed their use, making them, at least theoretically, available on the market. Results Twenty-eight LMICs (11 in Africa, 11 in Asia and six in America) were surveyed. Nine WHO-EML ‘access’ antibiotics (amoxicillin, ampicillin, benzylpenicillin, ceftriaxone, clarithromycin, ciprofloxacin, doxycycline, gentamicin and metronidazole) were approved in all countries, and all 26 ‘access’ antibiotics were approved in more than two-thirds of countries. Among the 15 ‘forgotten’ antibiotics, only one was approved in more than two-thirds of countries. The median number of approved antibiotics per country was 30 (interquartile range 23–35). Six of 14 paediatric formulations (amoxicillin, amoxicillin-clavulanic acid, oral antistaphylococcal penicillin, cotrimoxazole, erythromycin and metronidazole) were approved in more than two-thirds of countries. Conclusions WHO-EML ‘access’ antibiotics and the most frequently used formulations for paediatrics were approved in the vast majority of the 28 surveyed LMICs. This was not the case for many of the ‘forgotten’ antibiotics, despite their important role, particularly in areas with high prevalence of multi-drug-resistant bacteria.

Direct compaction tabletting, a widely used secondary downstream processing operation, has recently received significant research attention. Experimental data can be used to fit model parameters for the prediction of single-component tablet thickness and hardness with good agreement, and this has been done for two components (Avicel® PH-101 and Pharmatose® 50M). These pure component parameters have then been used to predict multicomponent tablet properties, with the use of novel modified parameter averaging calculations improving predictions. Furthermore, a relation has been developed to estimate the required gap between tablet press punch faces for multicomponent tablets based on the gaps required for pure components; a quick and efficient way to estimate the necessary equipment settings to generate the desired compaction forces is a useful tool.

Analysis of catechol estrogens (2 & 4 hydroxy-estrone and estradiol) has proven troublesome by liquid chromatography tandem mass spectrometry due to their low concentrations, short half-lives and temperature-labile nature. Derivatization to methyl piperazine analogues has been reported for a panel of 9 estrogens in, "Derivatization enhances analysis of estrogens and their bioactive metabolites in human plasma by liquid chromatography tandem mass spectrometry" (Denver et al., 2019). Data show alteration of the base catalyst in this method was required to allow detection of catechol estrogens to low levels. Data also highlight the challenges faced in chromatographic separation of isomers and isotopologues, which were partially overcome by employing an extended column length and reduced oven temperature. In addition, data analysis displayed significant matrix effects during quantitation in plasma, following solid-phase extraction, despite efficient recoveries.

CITATION: Du Preez, K., et al. 2019. Global shortages of BCG vaccine and tuberculous meningitis in children. Lancet Global Health, 7(1):e28-e29, doi:10.1016/S2214-109X(18)30474-1.

WOS: 000433257200026, PubMed: 29778325, Background Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage. Methods We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1: 1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214. Findings We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0.88, 95% CI 0.76-1.03, p= 0.11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0.73, 0.53-0.99, p= 0.0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0.92, 95% CI 0.77-1.10, p= 0.37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]). Interpretation Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect. Funding National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license., National Institute of Health Research Health Technology Assessment ProgrammeNational Institute for Health Research (NIHR); Swiss Heart Foundation, Funding National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

Our aim was to compare the efficacy of the Therabite® jaw motion rehabilitation system (Atos Medical) with that of wooden spatulas to relieve and prevent trismus in patients who have had radiotherapy for stage three and four oral and oropharyngeal cancer. Secondary aims were to assess the feasibility and the impact of exercise on health-related quality of life (QoL), and the use of health services after treatment. We designed a randomised, open-label, controlled, three-centre feasibility study to compare the effectiveness and cost of the Therabite® and wooden spatulas. We studied compliance with exercises and health-related QoL, assessed cost using three health economics measures, and conducted semistructured interviews with patients. Patients were randomised into two groups: the Therabite® group (n=37) and the wooden spatula group (n=34). All patients had some sense of jaw tightening before the study started. Mean mouth opening after six months increased in both groups, but the difference between the groups was not significant (p=0.39). Completion rates for the three economic measures were good. There was no significant difference between the two groups in frequency of contact with care services or in QoL. Exercises during and after radiotherapy can ameliorate trismus in patients with stage three and four oral and oropharygeal cancers, but differences between groups in efficacy, compliance, QoL, or use of hospital or community health services, were not significant.

Recent evidence has continued to support the applicability of progesterone in preventing preterm birth, hence the development of an appropriate vaginal delivery system for this drug would be of considerable interest. Here, we describe the development of progesterone-loaded bioadhesive nanofibers using pressurized gyration for potential incorporation into a vaginal insert, with a particular view to addressing the challenges of incorporating a poorly water-soluble drug into a hydrophilic nanofiber carrier. Polyethylene oxide and carboxymethyl cellulose were chosen as polymers to develop the carrier systems, based on previous evidence of their yielding mucoadhesive nanofibers using the pressurized gyration technique. The fabrication parameters such as solvent system, initial drug loading and polymer composition were varied to facilitate optimisation of fiber structure and efficiency of drug incorporation. Such studies resulted in the formation of nanofibers with satisfactory surface appearance, diameters in the region of 400 nm and loading of up to 25% progesterone. Thermal and spectroscopic analyses indicated that the drug was incorporated in a nanocrystalline state. Release from the drug-loaded fibers indicated comparable rates of progesterone dissolution to that of Cyclogest, a commercially available progesterone pessary, allowing release over a period of hours. Overall, the study has shown that pressurized gyration may produce bioadhesive progesterone-loaded nanofibers which have satisfactory loading of a poorly water-soluble drug as well as having suitable structural and release properties. The technique is also capable of producing fibers at a yield commensurate with practical applicability, hence we believe that the approach shows considerable promise for the development of progesterone dosage forms for vaginal application.

For the creation of scaffolds in tissue engineering applications, it is essential to control the\ud physical morphology of fibres and to choose compositions which do not disturb normal\ud physiological function. Collagen, the most abundant protein in the human body, is a wellestablished\ud biopolymer used in electrospinning compositions. It shows high in-vivo stability\ud and is able to maintain a high biomechanical strength over time. In this study, the effects of\ud collagen type I in polylactic acid-drug electrospun scaffolds for tissue engineering\ud applications are examined. The samples produced were subsequently characterised using a\ud range of techniques. Scanning electron microscopy analysis shows that the fibre\ud morphologies varied across PLA-drug and PLA-collagen-drug samples – the addition of\ud collagen caused a decrease in average fibre diameter by nearly half, and produced\ud nanofibres. Atomic force microscopy imaging revealed collagen-banding patterns which\ud show the successful integration of collagen with PLA. Solid-state characterisation suggested\ud a chemical interaction between PLA and drug compounds, irgasan and levofloxacin, and the\ud collagen increased the amorphous regions within the samples. Surface energy analysis of\ud drug powders showed a higher dispersive surface energy of levofloxacin compared with\ud irgasan, and contact angle goniometry showed an increase in hydrophobicity in PLAcollagen-drug\ud samples. The antibacterial studies showed a high efficacy of resistance against\ud the growth of both E. coli and S. Aureus, except with PLA-collagen-LEVO which showed a\ud regrowth of bacteria after 48 h. This can be attributed to the low drug release percentage\ud incorporated into the nanofibre during the in vitro release study. However, the studies did\ud show that collagen helped shift both drugs into sustained release behaviour. These ideal modifications to electrospun scaffolds may prove useful in further research regarding the\ud acceptance of human tissue by inhibiting the potential for bacterial infection.\ud

Hybrid nanoparticles (HNPs) have shown huge potential as drug delivery vehicles for pancreatic cancer. Currently, the first line treatment, gemcitabine, is only effective in 23.8% of patients. To improve this, a thermally activated system was developed by introducing a linker between HNPs and gemcitabine. Whereby, heat generation resulting from laser irradiation of the HNPs promoted linker breakdown resulting in prodrug liberation. In vitro evaluation in pancreatic adenocarcinoma cells, showed the prodrug was 4.3 times less cytotoxic than gemcitabine, but exhibited 11-fold improvement in cellular uptake. Heat activation of the formulation led to a 56% rise in cytotoxicity causing it to outperform gemcitabine by 26%. In vivo the formulation outperformed free gemcitabine with a 62% reduction in tumor weight in pancreatic xenografts. This HNP formulation is the first of its kind and has displayed superior anti-cancer activity as compared to the current first line drug gemcitabine after heat mediated controlled release.

Oral dosage forms are an integral part of modern health care and account for the majority of drug delivery systems. Traditionally the analysis of the dissolution behaviour of a dosage form is used as the key parameter to assess the performance of a drug product. However, understanding the mechanisms of disintegration is of critical importance to improve the quality of drug delivery systems. The disintegration performance is primarily impacted by the hydration and subsequent swelling of the powder compact. Here we compare liquid ingress and swelling data obtained using terahertz pulsed imaging (TPI) to a set of mathematical models. The interlink between hydration kinetics and swelling is described by a model based on Darcy's law and a modified swelling model based on that of Schott. Our new model includes the evolution of porosity, pore size and permeability as a function of hydration time. Results obtained from two sets of samples prepared from pure micro-crystalline cellulose (MCC) indicate a clear difference in hydration and swelling for samples of different porosities and particle sizes, which are captured by the model. Coupling a novel imaging technique, such as TPI, and mathematical models allows better understanding of hydration and swelling and eventually tablet disintegration.

Objective\ud To review the effects of pharmaceutical care on hospitalizations, mortality and clinical outcomes in patients.\ud \ud \ud Methods\ud Systematic searches were conducted in MEDLINE, EMBASE and International Pharmaceutical Abstracts (IPA) databases to identify studies that were published between 2004 and January 2017. Studies included in this review were randomized controlled trials (RCTs) that spanned across both community and hospital settings. Using strict inclusion/exclusion criteria studies were included if they reported level 1 or 2 outcomes in the hierarchy of outcome measure i.e. clinical and surrogate outcomes (e.g. blood pressure (BP) control, blood glucose level, cholesterol BMI). Each study was assessed for quality using the Jadad scoring system.\ud \ud \ud Results\ud Fifty-four RCTs were included in the present review. Forty-six of these studies ranked high quality according to the Jadad scoring system. Studies were categorized into their general condition groups. Interventions in patients with diabetes, depression, respiratory disorders, cardiovascular disorders, epilepsy, osteoporosis, and interventions in older adults were identified. In the majority of studies pharmaceutical care was found to lead to significant improvements in clinical outcomes and/or hospitalizations when compared to the non-intervention group. Some conditions had a large number of RCTs, for example for cardiovascular conditions and in diabetes. Statistically significant improvements were seen in the majority of the studies included for both of these conditions, with studies indicating positive clinical outcomes and/or hospitalizations rates. Within the cardiovascular condition, a subset of studies, focusing on cardiac heart failure and coronary heart disease, had more mixed results. In other conditions the number of RCTs conducted was small and the evidence did not show improvements after pharmaceutical care, i.e. in depression, osteoporosis, and epilepsy. The majority of interventions were face to face interactions with patients, whilst a smaller number were conducted via the telephone and one via a web-based system. Patient education was a key component of most interventions, either verbal and/or written. Longitudinal data, post intervention cessation, was not collected in the majority of cases.\ud \ud \ud Conclusions\ud RCTs conducted to evaluate pharmaceutical care appear to be effective in improving patient short-term outcomes for a number of conditions including diabetes and cardiovascular conditions, however, other conditions such as depression are less well researched. Future research should attempt to evaluate the conditions where there is a lack of data, whether the positive effects of pharmaceutical care persist in patient populations after the interventions cease and what the long-term clinical outcomes would be of continued pharmaceutical care.

Novel excipients are entering the market to enhance the bioavailability of drug particles by having a high porosity and, thus, providing a rapid liquid uptake and disintegration to accelerate subsequent drug dissolution. One example of such a novel excipient is functionalized calcium carbonate, which enables the manufacture of compacts with a bimodal pore size distribution consisting of larger interparticle and fine intraparticle pores. Five sets of functionalized calcium carbonate tablets with a target porosity of 45%-65% were prepared in 5% steps and characterized using terahertz time-domain spectroscopy and X-ray computed microtomography. Terahertz time-domain spectroscopy was used to derive the porosity using effective medium approximations, that is, the traditional and an anisotropic Bruggeman model. The anisotropic Bruggeman model yields the better correlation with the nominal porosity (R2 = 0.995) and it provided additional information about the shape and orientation of the pores within the powder compact. The spheroidal (ellipsoids of revolution) shaped pores have a preferred orientation perpendicular to the compaction direction causing an anisotropic behavior of the dielectric porous medium. The results from X-ray computed microtomography confirmed the nonspherical shape and the orientation of the pores, and it further revealed that the anisotropic behavior is mainly caused by the interparticle pores. The information from both techniques provides a detailed insight into the pore structure of pharmaceutical tablets. This is of great interest to study the impact of tablet microstructure on the disintegration and dissolution performance., published version, peerReviewed

Drug reprofiling is emerging as an effective paradigm for discovery of cancer treatments. Herein, an antipsychotic drug is immobilised using the Magic Tag® chemical genomics tool and screened against a T7 bacteriophage displayed library of polypeptides from Drosophila melanogaster, as a whole genome model, to uncover an interaction with a section of 17-β-HSD10, a proposed prostate cancer target. A computational study and enzyme inhibition assay with full length human 17-β-HSD10 identifies risperidone as a drug reprofiling candidate. When formulated with rumenic acid, risperidone slows proliferation of PC3 prostate cancer cells in vitro and retards PC3 prostate cancer tumour growth in vivo in xenografts in mice, presenting an opportunity to reprofile risperidone as a cancer treatment.

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24 h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE.

Aristolochic acids (AAs) are the active components of herbal drugs derived from Aristolochia species that have been used for medicinal purposes since antiquity. However, AAs have recently been discovered to be highly nephrotoxic and induced urothelial cancer in humans and malignant tumors in the kidney and urinary tract of rodents. In this study, we exposed rat renal proximal tubule cells in vitro to a sub-cytotoxic level of AAs at three different time points (6h, 24h and 72h). We then analyzed the gene expression profile after the compound exposure. Functional analysis with Ingenuity Pathways Analysis and DAVID tools revealed that at the late time point (72h) there are many significantly altered genes involved in cancer-related pathways such as p53 signaling.MIAMI-compliant microarray data are deposited in the NCBI GEO database under accession number GSE68687 and can be found at: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68687.

Winter wheat freeze injury is one of the main agro-meteorological disasters affecting wheat production. In order to evaluate the severity of freeze injury on winter wheat systematically, we proposed a grey-system model (GSM) to monitor the degree and the distribution of the winter wheat freeze injury. The model combines remote sensing (RS) and geographic information system (GIS) technology. It gave examples of wheat freeze injury monitoring applications in Gaocheng and Jinzhou of Hebei Province, China. We carried out a quantitative evaluation method study on the severity of winter wheat freeze injury. First, a grey relational analysis (GRA) was conducted. At the same time, the weights of the stressful factors were determined. Then a wheat freezing injury stress multiple factor spatial matrix was constructed using spatial interpolation technology. Finally, a winter wheat freeze damage evaluation model was established through grey clustering algorithm (GCA), and classifying the study area into three sub-areas, affected by severe, medium or light disasters. The evaluation model were verified by the Kappa model, the overall accuracy reached 78.82% and the Kappa coefficient was 0.6754. Therefore, through integration of GSM with RS images as well as GIS analysis, quantitative evaluation and study of winter wheat freeze disasters can be conducted objectively and accurately, making the evaluation model more scientific.

A ligand-based approach was applied to screen in silico a library of commercially available compounds, with the aim to find novel inhibitors of the HCV replication starting from the study of the viral NS3 helicase. Six structures were selected for evaluation in the HCV subgenomic replicon assay and one hit was found to inhibit the HCV replicon replication in the low micromolar range. A small series of new pyrrolone compounds was designed and synthesised, and novel structures were identified with improved antiviral activity.

A structure-based virtual screening of commercial compounds was carried out on the HCV NS3 helicase structure, with the aim to identify novel inhibitors of HCV replication. Among a selection of 13 commercial structures, one compound was found to inhibit the subgenomic HCV replicon in the low micromolar range. Different series of new piperazine-based analogues were designed and synthesised, and among them, several novel structures exhibited antiviral activity in the HCV replicon assay. Some of the new compounds were also found to inhibit HCV NS3 helicase function in vitro, and one directly bound NS3 with a dissociation constant of 570 ± 270 nM.

Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported as a potential new topical treatment for Herpes simplex virus (HSV) infections. In the current work we examined the in vitro topical delivery of punicalagin (major phytochemical of PRE) and zinc from hydrogels across epithelial membranes that can become infected with HSV.\ud \ud Porcine epidermal, buccal and vaginal mucous membranes were excised and mounted in Franz diffusion cells and dosed with a simple hydrogel containing PRE and zinc sulphate (ZnSO4). The permeation of punicalagin and zinc were determined by HPLC and ICPMS respectively; punicalagin was also determined in the basal layers by reverse tape stripping. Receptor phases from the epidermal membrane experiment were also used to challenge HSV-1 in Vero host cells, and ex vivo porcine skin was used to probe COX-2 modulation.\ud \ud Punicalagin and zinc permeated each of the three test membranes, with significantly greater amounts of both delivered across the epidermal membrane. The amounts of punicalagin permeating the buccal and vaginal membranes were similar, although the amount of zinc permeating the vaginal membrane was comparatively very large – it is known that zinc interacts with vaginal mucosa. The punicalagin recovered by reverse tape stripping of the epidermal, buccal and vaginal membranes gave 0.47 ± 0.016, 0.45 ± 0.052 and 0.51 ± 0.048 nM cm− 2 respectively, and were statistically the same (p < 0.05). A 2.5 log reduction was achieved against HSV-1 using diffusion cell receptor phase, and COX-2 expression was reduced by 64% in ex vivo skin after 6 h.\ud \ud Overall, a hydrogel containing 1.25 mg mL− 1 PRE and 0.25 M ZnSO4 was able to topically deliver both the major bioactive compound within PRE and Zn (II) across all membranes and into the site specific region of Herpes simplex vesicular clusters, while maintaining potentiated virucidal and anti-inflammatory properties. This novel therapeutic system therefore has potential for the topical treatment of HSV infections.

Diclofenac topical formulations are often preferred for drug administration to patients who experience serious GIT problems. Absorption of the drug through the skin, however, can be challenging due to the natural protective feature of the stratum corneum (SC). In this article, fluid gels prepared from gellan gum were explored as a topical drug delivery vehicle. Rheological analysis of the formulations showed that it was possible to produce a topical gel with a viscosity and the mechanical strength similar to that of the commercially available Voltaren® gel using 1 % w/w of a 50:50 low acyl/high acyl (LA/HA) gellan blend. Soft-tribology was used to assess the lubrication properties of gellan fluid gels. The lubrication of the gellan gum fluid gel formulations at high rubbing speeds was similar to the lubrication of the Voltaren® gel. The use of gellan gum dramatically increased skin permeation of diclofenac when compared with the commercially available formulation and could be controlled by changing the gellan gum concentration and/or sodium ion concentration in the formulation. This study highlights the potential use of fluid gels that can be easily tuned to have physical properties suitable for topical formulations with the added advantage of increasing drug permeation.

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually and in combination using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ~90 to 300 nm. In terms of drug loading, microfluidics production promoted high loading within ~100 nm vesicles for both the water soluble drug (20 - 25% of initial amount added) and the bilayer embedded drug (40 – 42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug.

Recent studies of the sunscreen constituent oxybenzone have suggested that the dominant mechanism underlying the efficient photoprotection it offers relies on an initial ultrafast enol -> keto tautomerisation, followed by nonadiabatic transfer to the ground electronic state. Subsequent collisions with the solvent bath then reform the original enol tautomer. Utilising femtosecond transient electronic absorption spectroscopy we explore the dissipation of electronic excitation energy in oxybenzone in the presence of titanium dioxide, a widely used, and complementary sunscreen component. We find the relaxation dynamics of this popular organic filter are unaltered by the presence of this favoured inorganic scatterer and the overall dynamics can be described by the additive contribution of the individual constituents. The combination of the two components provides broadband photoprotective properties justifying the widely used organic filter and inorganic scatterer mixtures in commercial sunscreen products.

Spironolactone (SP) known as an anti-androgen drug, has been proven to be effective in treatment of acne. The quest to minimize the unnecessary systemic side effects associated with the oral drug administration of spironolactone, has led to a growing interest of loading SP on lipid nanoparticles to deliver the drug in a topical formulation. The aim of the current investigation was to prepare and compare the performance of SP loaded nanostructured lipid carrier (SP-NLC) and SP alcoholic gels (SP-ALC) on two groups of respective patient populations, group A and group B in the treatment of mild to moderate acne vulgaris. The results showed that SP-NLCs were spherical in shape with an average diameter of ∼240 nm. The polydispersity index (PI) and zeta potential of these nanoparticles were 0.286 and −21.4 respectively. The gels showed non-Newtonian independent pseudoplastic and shear thinning behavior. The SP-NLCs was not toxic to fibroblast cell strains at the 24 and 48 h periods. Results showed that the mean number of total lesions (37.66 ± 9.27) and non-inflammatory lesions (29.26 ± 7.99) in group A significantly decreased to 20.31 ± 6.58 (p < 0.05) and to 13.95 ± 5.22 (p < 0.05) respectively. A similar pattern was observed for group B where the mean number of total lesions and non-inflammatory lesions reduced from 33.73 ± 9.40 to 19.13 ± 5.53 (p < 0.05) and from 25.65 ± 8.12 to 13.45 ± 4.48 (p < 0.05) respectively. The total lesion count (TLC) was significantly decreased from 37.16 ± 9.28 to 19.63 ± 6.36 (for group A; p < 0.071) and 32.60 ± 9.32 to 18.33 ± 5.55 (for group B; p < 0.05) respectively. After treatment with SP-NLC for 8 weeks, the water content of the skin significantly (p < 0.05) increased from 37.44 ± 8.85 to 45.69 ± 19.34 instrumental units. Therefore, the SP-NLC gel may help in controlling acne vulgaris with skin care benefits.

Highlights • One new phenoxazin analogue, strepoxazine A was identified from the solid culture of Streptomyces sp. SBT345. • Additionally, two known phenazine compounds phencomycin and tubermycin B were also reported. • Strepoxazine A (1) showed antiproliferative activity against leukaemia cells HL-60. Abstract One new phenoxazin analogue, strepoxazine A (1), along with two known antibiotic phenazines phencomycin (2) and tubermycin B (3) were isolated from the solid culture of Streptomyces sp. SBT345 which had previously been recovered from the Mediterranean sponge Agelas oroides. The structures of compounds 1, 2 and 3 were determined by spectroscopic analyses including 1D and 2D NMR, and HR-ESI-MS experiments as well as comparison to the literature. We further investigated the apoptotic effect of the three compounds on the human promyelocytic leukaemia cells HL-60 and human breast adenocarcinoma cells MCF-7. Only strepoxazine A (1) showed cytotoxicity against leukaemia cells HL-60 cells. These results demonstrate that sponge-associated actinomycetes are rich sources for natural products with new pharmacological activities and relevance to drug discovery.

Pharmaceutical tests for hard shell capsules are designed for orally administered capsules. The use of capsules in dry powder inhalers is widespread and increasing and therefore more appropriate tests are required to ensure quality and determine if these capsules are fit for purpose. This study aims to determine the flexibility, reproducibility and sensitivity of a quantitative method that is designed to evaluate the puncture characteristics of different capsule shell formulations under different climatic conditions. A puncture testing method was used to generate force displacement curves for five capsule formulations that were stored and tested at two different temperatures (5 °C and 19 °C). Force-displacement puncture profiles were reproducible for individual capsule shell formulations. The methodology was able to discriminate between capsules produced using different primary materials i.e. gelatin versus hypromellose, as well as more minor changes to capsule formulation i.e. different material grades and excipients. Reduced temperature increased the forces required for capsule puncture however further work is required to confirm its significance. Results indicate the method provides a reproducible and sensitive means of evaluating capsule puncture. Future studies should validate the methodology at different test sites, using different operators and with different capsule shell formulations.