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The article focuses on opioid-induced respiratory depression, highlighting its potentially fatal consequences and the role of naloxone, a short-acting opioid receptor antagonist, in reversing this effect. Topics discussed include the mechanism of action of naloxone in reversing opioid-induced respiratory depression, the short elimination half-life of naloxone, and the importance of receptor kinetics of opioid agonists in determining the effectiveness of naloxone reversal.

Abstract Background Drug-drug interactions (DDIs) are common but less concerning in clinical practice of time-sensitive situations. We aimed to identify factors associated with a basic common DDI knowledge among an emergency physician (EP), an emergency medicine resident (EMR), and an emergency care nurse (ECN). Methods This was a prospective cross-sectional study. EP, EMR, and ECN did the examination (multiple-choice questions, 40 points) about common DDI. Prespecified factors associated with examination scores were profession, longer emergency medicine experience, pharmacological training, last advanced cardiovascular life support (ACLS) training, DDI checker book, and application user experience. The outcome was an examination score to evaluate the ability of DDI knowledge. Univariable and multivariable means regressions were used. Results A total of 244 participants were enrolled. Factors associated with high examination score were EP (unadjusted mean difference 3.3 points, 95% confidence interval [CI] 2.1 to 4.5, p

Background: Drug-drug interactions (DDIs) are common but less concerning in clinical practice of time-sensitive situations. We aimed to identify factors associated with a basic common DDI knowledge among an emergency physician (EP), an emergency medicine resident (EMR), and an emergency care nurse (ECN). Methods: This was a prospective cross-sectional study. EP, EMR, and ECN did the examination (multiple-choice questions, 40 points) about common DDI. Prespecified factors associated with examination scores were profession, longer emergency medicine experience, pharmacological training, last advanced cardiovascular life support (ACLS) training, DDI checker book, and application user experience. The outcome was an examination score to evaluate the ability of DDI knowledge. Univariable and multivariable means regressions were used. Results: A total of 244 participants were enrolled. Factors associated with high examination score were EP (unadjusted mean difference 3.3 points, 95% confidence interval [CI] 2.1 to 4.5, p < 0.001), EMR (2.1, 95% CI 0.7 to 3.5, p 0.005) compared to ECN. Last ACLS training within 2 years (3.7, 95% CI 0.7 to 6.6, p 0.015), 2–4 years (3.4, 95% CI 0.4 to 6.5, p 0.027), and ≥4 years (4.4, 95% CI 1.2 to 7.6, p 0.007) were higher score than no ACLS training. Moreover, the DDI checker application experience user (1.7, 95% CI 0.6 to 2.8, p 0.003) also had a high score compared to the non-experienced user. After adjustment for all factors, EP (adjusted mean difference 3.3 points, 95% CI 1.8 to 4.7, p < 0.001), EMR (2.5, 95% CI 0.6 to 4.3, p 0.010) were higher scores compared to ECN. Meanwhile, the last ACLS training ≥4 years (3.3, 95% CI 0.1 to 6.6, p 0.042) was a higher score than no ACLS training. Conclusion: EP, EMR, and the last ACLS training ≥4 years were associated with higher DDI knowledge than ECN and no ACLS training, respectively. [ABSTRACT FROM AUTHOR]

Background: Percutaneous coronary intervention (PCI) is frequently used for patients with chronic coronary syndrome (CCS). However, the role of PCI beyond symptom relief in CCS remains controversial. The objective of this study was to determine whether PCI is associated with better outcomes, compared with medical therapy (MT) alone., Methods: We conducted a retrospective cohort study. Using the Swedish Coronary Angiography and Angioplasty Registry, we included all patients with CCS undergoing coronary angiography in Sweden between 2010 and 2020. Two groups were formed based on treatment strategy: PCI+MT versus MT alone. One-to-one propensity score (PS) matching was used to address confounding. Outcome was assessed using matched win ratio analysis, a statistical method that ranks the components of the composite by clinical importance. The primary outcome was net adverse clinical event (NACE) within 5 years. In the win ratio analysis, the components of NACE were ranked as follows: (1) all-cause mortality, (2) myocardial infarction (MI), (3) bleeding and (4) urgent revascularisation. Secondary outcomes were the individual components of NACE, major adverse cardiovascular events (MACE) and cardiovascular mortality., Results: After PS matching, two groups of 7220 patients each were formed. The hierarchical outcome analysis of NACE and MACE showed that PCI was associated with improved outcome (matched win ratio: 1.28 (95% CI 1.20 to 1.36, p<0.001) and matched win ratio: 1.38 (95% CI 1.29 to 1.48, p<0.001), respectively). The use of PCI was associated with higher win ratio of MI (matched win ratio: 1.15, 95% CI 1.04 to 1.28, p=0.008), urgent revascularisation (matched win ratio: 1.85, 95% CI 1.69 to 2.03, p<0.001) and cardiovascular mortality (matched win ratio: 1.15, 95% CI 1.00 to 1.34, p=0.044). No difference in win ratio was observed for all-cause mortality or bleeding., Conclusions: In this study, which sought to evaluate the outcomes of patients with CCS using a hierarchical approach, patients selected for revascularisation with PCI experienced better outcome compared with MT alone., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD 1-10 ) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. SIGNIFICANCE STATEMENT: The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification, and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds., (Copyright © 2024 by The Author(s).)

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Clinical pharmacology is often the nexus in any cross-disciplinary team that is seeking solutions for human healthcare issues. The use and application of real-world data and artificial intelligence to better understand our ecosystem has influenced our view at the world and how we do things. This has resulted in remarkable advancements in the healthcare space and development of personalized medicines with great attributes from the application of models and simulations, contributing to a more efficient healthcare development process. A cross-disciplinary symposium was held in December 2023, whereby experts from different scientific disciplines engaged in a high-level discussion on the opportunities and challenges of mathematical models in different fields, possible future developments and decision making. A strong interlink amongst the disciplines represented was apparent, with clinical pharmacology identified as the one which integrates various scientific disciplines. Deliberate and strategic cross-disciplinary dialogues are required to break out of the silos and implement integration for efficiency and cost-effectiveness of novel interventions., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

For patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, iron deficiency is common and associated with more severe symptoms, worse quality of life and an increased risk of hospitalisations and death. Iron deficiency can be swiftly, effectively and safely treated by administering intravenous iron, either as ferric carboxymaltose or ferric derisomaltose, which improves patient well-being and reduces the risk of hospitalisations including those for heart failure. However, the current definition of iron deficiency in heart failure has serious flaws. A serum ferritin <100 µg/L does not identify patients more likely to respond to intravenous iron. In contrast, patients with transferrin saturations <20%, most of whom are also anaemic, are more likely to have a beneficial response to intravenous iron. In this review, we summarise the available evidence for use of intravenous iron in heart failure and provide recommendations for targeted future research and practical considerations for the general cardiologist., Competing Interests: Competing interests: FJG reports receipt of sponsorship from Pharmacosmos to attend an international meeting and consultancy fees from Vifor. KG has received honoraria from Novartis, AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim and Servier Laboratories. JGC reports receipt of personal honoraria for lectures and advisory boards from Pharmacosmos and Vifor, and from AstraZeneca, Amgen, Bayer, Novartis and Servier. The University of Glasgow has received research grants from Pharmacosmos and Vifor. PRK reports consulting fees from Amgen, Bayer, Boehringer Ingelheim, Pharmacosmos and CSL Vifor; payment for lectures from AstraZeneca, Bayer, Novartis, Pfizer, Pharmacosmos and CSL Vifor; and support for attending meetings from Pharmacosmos., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Resveratrol, a dietary supplement that intervenes in cellular metabolism, has been shown to reduce aortic growth rate in a mouse model of Marfan syndrome (MFS), a condition associated in humans with life-threatening aortic complications, often preceded by aortic dilatation. The primary objective of this study was to investigate the effects of resveratrol on aortic growth rate in patients with MFS ., Methods: In this investigator-initiated, single-arm open-label multicentre trial, we analysed resveratrol treatment in adults aged 18-50 years with MFS. The primary endpoint was the change in estimated annual aortic growth at five predefined levels in the thoracic aorta after 1 year of resveratrol treatment, evaluated using a linear mixed model. Aortic diameters were measured by cardiac MRI at three time points to analyse the annual aortic expansion rate before and after initiation of treatment. Additionally, annual aortic growth was compared with growth in a previously conducted losartan randomised clinical trial., Results: 898 patients were screened of which 19% (168/898) patients met the inclusion criteria.36% (61/168) patients signed informed consent and 93% (57/61) aged 37±9 years, of which 28 males (49%) were included in the final analysis of the study. 46% (26/57) had undergone aortic root replacement prior to the study. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (from 0.39±0.06 to -0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to -0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072)., Conclusion: Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with MFS. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with MFS., Trial Registration Number: NL66127.018.18., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone., Methods: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform., Results: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio., Conclusions: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs., Trial Registration Number: NCT02556450., Competing Interests: Competing interests: JS and AL are employees of Mosaiques-Diagnostics, Hanover, Germany. HM is the co-founder and co-owner of Mosaiques-Diagnostics. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally., (© 2024 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Studies comparing the safety of orexin receptor antagonists and other hypnotic types for older patients with heart failure (HF) remain lacking. This study aimed to compare orexin receptor antagonists (suvorexant) with benzodiazepines or Z-drugs for sleep treatment and investigate the risk of acute HF-related rehospitalisation in older patients with HF., Methods: This study used a cohort design to analyse data from an administrative claims database from April 2008 to December 2020. The study population was determined based on inclusion and exclusion criteria from a cohort of 1 159 937 patients aged ≥65 years, selected through random sampling. The follow-up period was censored based on multiple criteria, including outcome occurrences and hypnotic classification changes. Kaplan-Meier survival analysis and Cox proportional hazards models were conducted for risk assessment., Results: The analysis included 1858 patients, aged ≥65 years and experiencing their first HF-related hospitalisation. These patients were categorised based on the initially prescribed hypnotic classification, including suvorexant, benzodiazepines and Z-drugs in 490, 606 and 762 patients, respectively. The average age and SD were similar across all hypnotic classes at 82.7±7.6 years. Kaplan-Meier curves indicated a higher trend of rehospitalisation risk for benzodiazepines and Z-drugs than for suvorexant. The adjusted HRs were 2.77 (95% CI 1.17 to 6.52) for benzodiazepines and 2.98 (95% CI 1.33 to 6.68) for Z-drugs., Conclusions: Suvorexant administration for sleep treatment in older patients with HF shows a potentially reduced risk of acute HF-related rehospitalisation compared with benzodiazepines and Z-drugs. The results of this study provide valuable information for selecting hypnotics in older patients with HF having concurrent sleep disorders., Competing Interests: Competing interests: None declared.

Bibliometric rankings of researchers are increasingly important for academic hiring and for making grant application decisions in the biomedical sciences. As a case study, we performed a comprehensive bibliometric analysis of German pharmacology and toxicology. The 42 members of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) represented in the German 'best scientist' ranking in biology and biochemistry on www.research.com for the year 2022 were analyzed according to various aspects. The scientist ranking on Research.com is based on the Hirsch Index (h-Index). In the comparatively small field of pharmacology, which accounts for only 4.2% of the scientists in the ranking on Research.com, there are only two women. This shows that female pharmacologists are highly underrepresented in elite pharmacology. To achieve a high h-Index, a pharmacologist must publish more papers than a biochemist or biologist. Furthermore, German elite pharmacology was compared in the three sub-societies of the DGPT. There are no significant differences between elite pharmacologists and toxicologists in terms of productivity. Two large German pharmacology schools (Günter Schultz and Franz Hofmann) are similar in all bibliometric parameters except for number of total publications. Age-specific factors were also defined for the analysis: 'academic age' and the quotient of the h-Index by 'academic age'. Any given bibliometric parameter (or combination of parameters) yielded different ranking results. This became even more evident when additionally considering the highly popular and widely used Laborjournal ranking of top pharmacology and toxicology researchers with only very few DGPT members listed. We unmasked 7 types of publication patterns of pharmacologists, an age-dependent publication peak at around 55 years and different trajectories for high- and low-volume publishing pharmacologists. In the future, less emphasis should be paid to bibliometric parameters in academic hiring and grant decisions than to the authentic societal and scientific impact of the research. Bibliometric parameters are very arbitrary within a very large segment of pharmacologists. Studies according to the paradigm of this account should be made for other countries, other learned societies, and other scientific fields. The different cultures among related scientific fields must be considered in bibliometric analyses as exemplified here for pharmacology versus biochemistry. Conversely, the bibliometric similarities between pharmacology and toxicology show that both fields belong together and have a very similar culture., (© 2024. The Author(s).)

Competing Interests: Competing interests: None declared.

Abstract: Quantitative and systems pharmacology (QSP) is an innovative and integrative approach combining physiology and pharmacology to accelerate medical research. This review focuses on QSP's pivotal role in drug development and its broader applications, introducing clinical pharmacologists/researchers to QSP's quantitative approach and the potential to enhance their practice and decision-making. The history of QSP adoption reveals its impact in diverse areas, including glucose regulation, oncology, autoimmune disease, and HIV treatment. By considering receptor-ligand interactions of various cell types, metabolic pathways, signaling networks, and disease biomarkers simultaneously, QSP provides a holistic understanding of interactions between the human body, diseases, and drugs. Integrating knowledge across multiple time and space scales enhances versatility, enabling insights into personalized responses and general trends. QSP consolidates vast data into robust mathematical models, predicting clinical trial outcomes and optimizing dosing based on preclinical data. QSP operates under a "learn and confirm paradigm," integrating experimental findings to generate testable hypotheses and refine them through precise experimental designs. An interdisciplinary collaboration involving expertise in pharmacology, biochemistry, genetics, mathematics, and medicine is vital. QSP's utility in drug development is demonstrated through integration in various stages, predicting drug responses, optimizing dosing, and evaluating combination therapies. Challenges exist in model complexity, communication, and peer review. Standardized workflows and evaluation methods ensure reliability and transparency., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)

Background: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry., Methods: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA., Results: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs., Conclusion: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials., Competing Interests: Competing interests: JC reports institutional grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/BMS and Daiichi Sankyo and personal fees from Portola. KP has consultancies with Johnson & Johnson, Element Science, Artivion and Novartis. AO received a research grant from Pfizer and is Steering Committee Member and National Coordinator of the ENGAGE-AF (TIMI 48) study. BFJ received speaker honoraria from Boehringer, Sanofi, Aspen, Pfizer, Takeda and Astra Zeneca Jitendra Pal Singh Sawhney reports professional/advisory fees outside the submitted work from Pfizer, Astra Zeneca, Novartis, Sanofi, Torrent and Lupin. TWL has received research support from Bayer, Boehringer Ingelheim and Pfizer. HG received honoraria from Bayer Australia, Eli Lilly Australia, Pfizer Australia and BMS Australia Shinya Goto was a recipient of quality personal fees from Jansen and Antos, and Phillips, fees from the American Heart Association as an Associate Editor for Circulation, and Steering Committee fees from Duke University. SH received personal fees from Bayer, BMS, Daiichi Sankyo, Pfizer, Sanofi. KAAF reports grants and personal fees from Bayer/Janssen and Astra Zeneca. PJ has served as a consultant or on an advisory board for Bayer, Boehringer Ingelheim, and Novartis. FV has received grants from Bayer Healthcare, and personal fees from Bayer Healthcare, BMS/Pfizer, Daiichi-Sankyo, and Boehringer-Ingelheim. AKK received personal fees and grants from Bayer AG, Sanofi S.A. and Anthos Therapeutics. JCLH, SV and REH report no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aimed to investigate the effectiveness of fixed-dose combination therapy (polypill) for primary and secondary prevention of major cardiovascular diseases in a typical rural setting., Methods: The PolyPars Study is a two-arm pragmatic cluster-randomised trial nested within the PARS cohort study, including all residents aged over 50 years in the entire district in southern Iran. The 91 villages underwent random allocation into two arms: the control arm, encompassing 45 clusters, was subjected to non-pharmacological intervention (educational training on healthy lifestyle), whereas the intervention arm, comprising 46 clusters, received the non-pharmacological interventions in conjunction with a once-daily polypill tablet. This tablet comprised two antihypertensive agents, a statin and aspirin. The primary outcome was the first occurrence of major cardiovascular events defined as a composite of hospitalisation for acute coronary syndrome (non-fatal myocardial infarction and unstable angina), fatal myocardial infarction, non-fatal and fatal stroke, sudden death and heart failure. The Cox regression model, with shared frailty, was used to account for clustering effect., Results: During December 2015-December 2016, a total of 4415 participants aged 50-75 years were recruited (2200 participants in the intervention arm and 2215 participants in the control arm). The overall median of follow-up duration was 4.6 years (interquartile interval 4.4-4.9). The achieved adherence rate to polypill in intervention arm was 86%. In the control group, 176 (8.0%) of 2215 participants developed primary outcome, compared with 88 (4.0%) of 2200 participants in the polypill group. We found substantial reduction in risk of primary outcome both in relative and absolute scales (HR 0.50, 95% CI 0.38 to 0.65; absolute risk reduction 4.0%, 95% CI 2.5% to 5.3%). No difference in serious adverse events was observed between the two groups., Conclusions: The fixed-dose combination therapy using polypill can safely halve the risk of major cardiovascular diseases at the population level., Trial Registration Number: NCT03459560., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the heart response of Erdheim-Chester disease (ECD) through continuous follow-up within our large cohort, for which there is a lack of understanding., Methods: We conducted a retrospective analysis of clinical data from patients with ECD with cardiac involvement diagnosed at our centre between January 2010 and August 2023. We assessed the heart response by integrating pericardial effusion and metabolic responses., Results: A total of 40 patients were included, with a median age of 51.5 years (range: 29-66) and a BRAF V600E mutation rate of 56%. The most common imaging manifestations observed were pericardial effusion (73%), right atrium (70%) and right atrioventricular sulcus infiltration (58%). Among 21 evaluable patients, 18 (86%) achieved a heart response including 5 (24%) complete response (CR) and 13 (62%) partial response (PR). The CR rate of pericardial effusion response was 33%, while the PR rate was 56%. Regarding the cardiac mass response, 33% of patients showed PR. For cardiac metabolic response, 32% and 53% of patients achieved complete and partial metabolic response, respectively. There was a correlation between pericardial effusion response and cardiac metabolic response (r=0.73 (95% CI 0.12 to 0.83), p<0.001). The median follow-up was 50.2 months (range: 1.0-102.8 months). The estimated 5-year overall survival was 78.9%. The median progression-free survival was 59.4 months (95% CI 26.2 to 92.7 months). Patients who received BRAF inhibitors achieved better heart response (p=0.037) regardless of treatment lines., Conclusion: We pioneered the evaluation of heart response of ECD considering both pericardial effusion and cardiac metabolic response within our cohort, revealing a correlation between these two indicators. BRAF inhibitors may improve heart response, regardless of the treatment lines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In order to explore clinical pharmacology and therapeutics (CPT) teaching and practices across continental Europe, the European Association of Clinical Pharmacology and Therapeutics (EACPT) made a survey in 2022 amongst its 27 affiliated societies., Methods: The survey was made available online to EACPT representatives, and 47 filled-in questionnaires were received from 25 countries (one to five per country), representing all geographic areas of Europe., Results: Clinical pharmacologists (CPs) spend 25%, 30%, 15%, and 25% of their time in teaching, hospital activities, committees, and research, respectively, with large variations across and within countries. CPT courses are given at Schools of Medicine in all the countries except one, mostly organized and taught by medical doctors (MDs). In Central, Western, and Southern Europe, the teachers may have medicine or pharmacy training. Therapeutic drug monitoring and pharmacovigilance were the hospital activities most frequently reported, and clinical/forensic toxicology, rounds of visits, and pharmacogenetics the least. Two-thirds of the panel think CPs should be MDs. However, the transversal nature of CPT was underlined, with patients/diseases and drugs as gravity centres, thus calling for the complementary skills of MDs and PharmDs. Besides, most respondents reported that clinical pharmacists in their country are involved in rounds of visits, pharmacovigilance, TDM, and/or pharmacogenetic testing and that collaborations with them would be beneficial., Conclusion: CPT comes with a plurality of backgrounds and activities, all required to embrace the different pathologies and the whole lifecycle of medicinal products, but all of them being rarely performed in any given country. The willingness to use common CPT teaching material and prescribing exams at the European level is a good sign of increasing harmonisation of our discipline Europewide., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Loop diuretics are commonly prescribed in the community, not always to patients with a recorded diagnosis of heart failure (HF). The rate of HF events in patients prescribed loop diuretics without a diagnosis of HF is unknown., Methods: This was a propensity-matched cohort study using data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office of National Statistics in the UK. Patients prescribed a loop diuretic without a diagnosis of HF (loop diuretic group) between 1 January 2010 and 31 December 2015 were compared with patients with HF (HF group)-analysis A, and patients with risk factors for HF (either ischaemic heart disease, or diabetes and hypertension-at-risk group)-analysis B. The primary endpoint was an HF event (a composite of presentation with HF symptoms, HF hospitalisation, HF diagnosis (analysis B only) and all-cause mortality)., Results: From a total population of 180 384 patients (78 968 in the loop diuretic group, 28 177 in the HF group and 73 239 in the at-risk group), there were 59 694 patients, 22 352 patients and 57 219 patients in the loop diuretic, HF and at-risk groups, respectively, after exclusion criteria were applied. After propensity matching for age, sex and comorbidities, patients in the loop diuretic group had a similar rate of HF events as those in the HF group (71.9% vs 72.1%; HR=0.92 (95% CI 0.90 to 0.94); p<0.001), and twice as those in the at-risk group (59.2% vs 35.7%; HR=2.04 (95% CI 2.00 to 2.08); p<0.001)., Conclusions: Patients prescribed a loop diuretic without a recorded diagnosis of HF experience HF events at a rate comparable with that of patients with a recorded diagnosis of HF; many of these patients may have undiagnosed HF., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)