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The clinical and pharmaceutical interventions of pharmacy professionals are considered impactful inputs towards optimised patient care and safety, by rationalising prescriptions, enhancing therapeutic choices and reducing and preventing medication errors and adverse effects. Pharmacy interventions (PIs), related to the identification, prevention and resolution of drug-related problems, should be recorded for optimal clinical governance and potential health outcomes.Between October 2020 and October 2021, the community hospitals at Powys Teaching Health Board recorded 158 PIs, corresponding to 0.4 interventions per staff per week. Only two members of the team were recording these PIs. Poor indicative PIs can result in lost opportunities for medication optimisation and prescribing rationalisation, increased costs and unidentified training potential.The aims of this project were (1) to record 180 interventions between 22 November 2021 and 8 April 2022 (20 weeks), corresponding to an average threefold increase, compared to the interventions recorded between October 2020 and October 2021 (52 weeks); (2) to have all hospital pharmacy staff recording at least one intervention during the same period.The number of interventions recorded and the number of pharmacy staff recording each intervention were two process measures. The project was completed through two Plan-Do-Study-Act cycles and applied theory on managing change in healthcare.The most successful intervention influencing positively the process measures was the implementation of a new Pharmacy Intervention Record Tool (xPIRT) toolkit that included an online recording tool (xPIRT) and an interactive panel with up-to-date results from all interventions recorded (xPIRT Dashboard). Motivating change was proven to be one of the best determinants of user satisfaction and engagement that contributed to meet the project's targets. xPIRT Dashboard provided staff the capacity to act on possible personal motivators and the possibility to improving care with medicines on their wards. The implementation of xPIRT toolkit was able to increase the representativity and significance of PIs recorded by the hospital pharmacy team, and it is expected to be used for personal professional development, demonstrating team activity and impact, service planning, prescribing practice optimisation and to identify education/training needs. This toolkit can be easily applied and adapted to other health organisations, settings and services., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this study was to examine the concurrent contributions of body size, estimates of whole-body composition, and appendicular volume in addition to participation in competitive basketball to explain inter-individual variance in anaerobic peak power output during late adolescence. The study also tested non-participation versus participation in basketball as an independent predictor of peak power output., Methods: The sample of this cross-sectional study was composed of 63 male participants (basketball: n=32, 17.0±0.9 years; school: n=31, 17.4±1.0 years). Anthropometry included stature, body mass, circumferences, lengths, and skinfolds. Fat-free mass was estimated from skinfolds and lower limbs volume predicted from circumferences and lengths. Participants completed the force-velocity test using a cycle ergometer to determine peak power output., Results: For the total sample, optimal peak power was correlated to body size (body mass: r=0.634; fat-free mass: r=0.719, lower limbs volume: r=0.577). The best model was given by fat-free mass and explained 51% of the inter-individual variance in force-velocity test. The preceding was independent of participating in sports (i.e., the dummy variable basketball vs. school did not add significant explained variance)., Conclusion: Adolescent basketball players were taller and heavier than school boys. The groups also differed in fat-free mass (school: 53.8±4.8 kg; basketball: 60.4±6.7 kg), which was the most prominent predictor of inter-individual variance in peak power output. Briefly, compared to school boys, participation in basketball was not associated with optimal differential braking force. Higher values in peak power output for basketball players were explained by a larger amount of fat-free mass.

Medication errors and omissions can potentially cause harm, prolong a hospital stay, lead to co-morbidities and even death. Pharmacy interventions (PI) ensure that these errors are identified and addressed, leading to improved patient safety and prescriber practice. Particularly in community hospitals, many only having general practitioners and not specialist doctors in their medical teams, PIs assume a strategic role. The PIs recorded throughout 8 months (between November 2021 and June 2022) in the community hospital wards in Powys, Wales, UK, using xPIRT (Pharmacy Intervention Recording Tool), a new pharmacy intervention record toolkit, were subjected to a retrospective analysis. The data were organised by location, drug, severity, acceptance, cost avoidance and intervention type. Significant prescribing errors were identified, which can potentially be different from those recorded in acute settings. Our results also informed on the need for integrated electronic prescribing systems paired with a PI recording tool to address effectively prescribing inaccuracies. Overall, this study was able to identify pharmacy teams as key to improve patient safety and care while contributing to significant cost-savings, through the recording of PI using xPIRT.

Alchornea cordifolia Müll. Arg. (commonly known as Christmas Bush) has been used traditionally in Africa to treat sickle cell anaemia (a recessive disease, arising from the S haemoglobin (Hb) allele), but the active compounds are yet to be identified. Herein, we describe the use of sequential fractionation coupled with in vitro anti-sickling assays to purify the active component. Sickling was induced in HbSS genotype blood samples using sodium metabisulphite (Na2S2O5) or through incubation in 100% N2. Methanol extracts of A. cordifolia leaves and its sub-fractions showed >70% suppression of HbSS erythrocyte sickling. The purified compound demonstrated a 87.2 ± 2.39% significant anti-sickling activity and 93.1 ± 2.69% erythrocyte sickling-inhibition at 0.4 mg/mL. Nuclear magnetic resonance (NMR) spectra and high-resolution mass spectroscopy identified it as quercitrin (quercetin 3-rhamnoside). Purified quercitrin also inhibited the polymerisation of isolated HbS and stabilized sickle erythrocytes membranes. Metabolomic comparisons of blood samples using flow-infusion electrospray-high resolution mass spectrometry indicated that quercitrin could convert HbSS erythrocyte metabolomes to be like HbAA. Sickling was associated with changes in antioxidants, anaerobic bioenergy, and arachidonic acid metabolism, all of which were reversed by quercitrin. The findings described could inform efforts directed to the development of an anti-sickling drug or quality control assessments of A. cordifolia preparations.

Basketball is characterized by high-intensity episodes predominantly reliant on anaerobic metabolism. The force-velocity test enables individual determination of an optimal braking force and emerged as appropriate to estimate optimal peak power. It has rarely been used in youth basketball. This study aimed to examine the contribution of body size, composition, and biological maturation to interindividual variation in force-velocity test output among pre-pubertal basketball players. The sample consisted of 64 male participants (8.4-12.3 years). Stature, sitting height, body mass and two skinfolds were measured, and leg length estimated. Fat-free mass and lower limb volume were estimated from anthropometry. Age at peak height velocity was predicted from maturity offset. Optimal peak power was correlated with all body size descriptors (correlation: 0.541-0.700). Simple allometric models explained 30-47% of inter-individual variance, with fat-free mass being the best predictor of performance. Whole-body fat-free mass (as a surrogate for active muscle mass) plus the indicator of maturation emerged as the best proportional allometric model (53% explained variance). Even at pre-pubertal ages, the interpretation of the force-velocity test requires assessing the metabolically active component of body mass., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Tuberculosis (TB) is a major global threat, mostly due to the development of antibiotic-resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents several natural products (NPs) have been shown to have in vitro activities against M. tuberculosis . The utility of any NP as a drug lead is augmented when the anti-mycobacterial target(s) is unknown. To suggest these, we used a molecular reverse docking approach to predict the interactions of 53 selected anti-mycobacterial NPs against known "druggable" mycobacterial targets ClpP1P2, DprE1, InhA, KasA, PanK, PknB and Pks13. The docking scores/binding free energies were predicted and calculated using AutoDock Vina along with physicochemical and structural properties of the NPs, using PaDEL descriptors. These were compared to the established inhibitor (control) drugs for each mycobacterial target. The specific interactions of the bisbenzylisoquinoline alkaloids 2-nortiliacorinine, tiliacorine and 13'-bromotiliacorinine against the targets PknB and DprE1 (-11.4, -10.9 and -9.8 kcal·mol -1 ; -12.7, -10.9 and -10.3 kcal·mol -1 , respectively) and the lignan α -cubebin and Pks13 (-11.0 kcal·mol -1 ) had significantly superior docking scores compared to controls. Our approach can be used to suggest predicted targets for the NP to be validated experimentally, but these in silico steps are likely to facilitate drug optimization.

Sclareol, a plant-derived diterpenoid widely used as a fragrance and flavoring substance, is well-known for its promising antimicrobial and anticancer properties. However, its activity on helminth parasites has not been previously reported. Here, we show that sclareol is active against larval (IC 50 ≈ 13 μM), juvenile (IC 50 = 5.0 μM), and adult (IC 50 = 19.3 μM) stages of Schistosoma mansoni , a parasitic trematode responsible for the neglected tropical disease schistosomiasis. Microwave-assisted synthesis of Heck-coupled derivatives improved activity, with the substituents choice guided by the Matsy decision tree. The most active derivative 12 showed improved potency and selectivity on larval (IC 50 ≈ 2.2 μM, selectivity index (SI) ≈ 22 in comparison to HepG2 cells), juvenile (IC 50 = 1.7 μM, SI = 28.8), and adult schistosomes (IC 50 = 9.4 μM, SI = 5.2). Scanning electron microscopy studies revealed that compound 12 induced blebbing of the adult worm surface at sublethal concentration (12.5 μM); moreover, the compound inhibited egg production at the lowest concentration tested (3.13 μM). The observed phenotype and data obtained by untargeted metabolomics suggested that compound 12 affects membrane lipid homeostasis by interfering with arachidonic acid metabolism. The same methodology applied to praziquantel (PZQ)-treated worms revealed sugar metabolism alterations that could be ascribed to the previously reported action of PZQ on serotonin signaling and/or effects on glycolysis. Importantly, our data suggest that compound 12 and PZQ exert different antischistosomal activities. More studies will be necessary to confirm the generated hypothesis and to progress the development of more potent antischistosomal sclareol derivatives.

A library of 14 minimally cytotoxic diterpenoid-like compounds (CC 50 > 70 μM on HepG2 human liver cells) was screened against Mycobacterium smegmatis , Staphylococcus aureus , and Escherichia coli to determine antimicrobial activity. Some compounds with a phenethyl alcohol (PE) core substituted with a β-cyclocitral derivative demonstrated anti-mycobacterial activity, with the most active being compound 1 (MIC = 23.4 mg/L, IC 50 = 0.6 mg/L). Lower activity was exhibited against S. aureus , while no activity was displayed against E. coli. Low cytotoxicity was re-confirmed on HepG2 cells and additionally on RAW 264.7 murine macrophages (SI for both cell lines > 38). The sub-lethal (IC 50 at 6 h) effect of compound 1 on M. smegmatis was examined through untargeted metabolomics and compared to untreated bacteria and bacteria treated with sub-lethal (IC 50 at 6 h) concentrations of the antituberculosis drugs ethambutol, isoniazid, kanamycin, and streptomycin. The study revealed that compound 1 acts differently from the reference antibiotics and that it significantly affects amino acid, nitrogen, nucleotides and folate-dependent one-carbon metabolism of M. smegmatis , giving some insights about the mode of action of this molecule. A future medicinal chemistry optimization of this new anti-mycobacterial core could lead to more potent molecules.

Aim: Naringenin (1), isolated in large amount from the aerial parts of Euphorbia pedroi, was chemically derivatized to yield 18 imine derivatives (2-19) and three alkylated derivatives through a Mannich-type reaction (20-22) that were tested as multidrug resistance (MDR) reversers in cancer cells. Results/methodology: While hydrazone (2-4) and azine (5-13) derivatives showed an improvement in their MDR reversal activities against the breast cancer resistance protein, carbohydrazides 14-19 revealed an enhancement in MDR reversal activity toward the multidrug resistance protein 1., Conclusion: The observed activities, together with pharmacophoric analysis and molecular docking studies, identified the spatial orientation of the substituents as a key structural feature toward a possible mechanism by which naringenin derivatives may reverse MDR in cancer.

Tuberculosis is a major global health hazard. The search for new antimycobacterials has focused on such as screening combinational chemistry libraries or designing chemicals to target predefined pockets of essential bacterial proteins. The relative ineffectiveness of these has led to a reappraisal of natural products for new antimycobacterial drug leads. However, progress has been limited, we suggest through a failure in many cases to define the drug target and optimize the hits using this information. We highlight methods of target discovery needed to develop a drug into a candidate for clinical trials. We incorporate these into suggested analysis pipelines which could inform the research strategies to accelerate the development of new drug leads from natural products.

Pretomanid is a promising anti-tubercular drug currently at clinical phase III, but its mechanisms of action are currently unclear. This study aimed to: (i) reveal the metabolome of Mycobacterium smegmatis under pretomanid treatment; (ii) compare major sources of metabolite variation in bacteria treated with pretomanid treatment and other antibiotics; and (iii) to target metabolites responsible for the killing activity of pretomanid in mycobacteria. Untargeted high-resolution metabolite profiling was carried out using flow infusion electrospray ion high resolution mass spectrometry (FIE-HRMS) to identify and quantify metabolites. The identification of key metabolites was independently confirmed by gas-chromatography time-of flight mass spectrometry (GC-tofMS) in comparison to standards. Pretomanid treatments generated a unique distinctive metabolite profile when compared to ampicillin, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, rifampicin and streptomycin. Metabolites which differed significantly only with pretomanid treatment were identified and mapped on to bacterial metabolic pathways. This targeted the pentose phosphate pathway with significant accumulation seen with fructose-6-phosphate, ribose-5-phosphate and glyceraldehyde-3-phosphate. These effects were linked to the accumulation of a toxic metabolite methylglyoxal. This compound showed significant antimicrobial activity (MIC 0.65 mM) against M. smegmatis.

Background: From a dataset obtained by chemical derivatization of a macrocyclic diterpenic scaffold, in silico approaches identified which structural features correlate with experimental modulation of P-gp activity. Results/methodology: Ninety-two percent of the strongest MDR modulators were positively identified within the dataset by virtual screening. Quantitative structure-activity relationships models with high robustness and predictability were obtained for both MDR1-transfected L5178Y mouse lymphoma T-cells (q(2) 0.875, R(2) pred 0.921) and human colon adenocarcinoma (q(2) 0.820, R(2) pred 0.951) cell lines. A new pharmacophoric model suggests that charge distribution within the molecule is important for biological activity., Conclusion: For the studied diterpenes, the conformation of the macrocyclic scaffold and its substitution pattern are the main determinants for the biological activity, being related with steric and electrostatic factors.

The antioxidant and antimycotic activities of the essential oils and extracts of two native Portuguese Lavandula species, L. stoechas subsp. luisieri and L. pedunculata, were evaluated by in vitro assays. The total phenolics and flavonoids content were also determined. The antioxidant potential was assessed through DPPH radical scavenging, inhibition of lipid peroxidation (ILP), and DNA protection assays. All samples displayed a high DPPH scavenging activity, some of them showing concentration dependence. The majority of the samples were also able to inhibit lipid peroxidation. A strong correlation was observed between the results of DPPH and ILP assays and the flavonoids content of the samples. In the DNA protection assay, all the extracts were able to preserve DNA integrity. The antimycotic activity was performed against twelve fungi belonging to Basidiomycota and Ascomycota Divisions. L. stoechas subsp. luisieri exhibited the broadest activity spectra. L. pedunculata extracts were active against five fungi. Cryptococcus neoformans was the most sensitive, being inhibited by all the extracts. Our results led to the conclusion that L. stoechas subsp. luisieri and L. pedunculata can be useful as new sources of natural antioxidants and antimycotic agents, providing a possible valorization of the existing biodiversity and resources of Portuguese flora.