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Aims Methods Results Conclusions The aim of this study was to examine contemporary trends in the use of, time to, and type of first add‐on anti‐hyperglycaemic therapy to metformin in Australia.We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add‐on anti‐hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add‐on therapy. All analyses were stratified by metformin initiation year.Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one‐third (n = 12 946) of people received add‐on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add‐on therapy following metformin initiation, sodium‐glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase‐4 inhibitors and sulfonylureas as first add‐on therapy decreased and insulin remained stable. One‐third of people with add‐on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy.Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP‐1 RA being used as first add‐on therapy. However, the overall prevalence of add‐on therapy was low. Advocacy to promote add‐on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality. [ABSTRACT FROM AUTHOR]

Aims: The 20:1 combination of cafedrine and theodrenaline (C/T) is widely used in Germany for the treatment of arterial hypotension. Since there is little knowledge about the impact of covariates on the effect, the aim was to develop a kinetic/pharmacodynamic covariate model describing mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR) for 30 min after the administration of C/T. Methods: Data of patients receiving C/T from the HYPOTENS study (NCT02893241, DRKS00010740) were analysed using nonlinear mixed‐effects modelling techniques. Results: Overall, 16 579 measurements from 315 patients were analysed. The combination of two kinetic compartments and a delayed effect model, coupled with distinct Emax models for HR, SBP and DBP, described the data best. The model included age, sex, body mass index (BMI), antihypertensive medication, American Society of Anaesthesiologists (ASA) physical status classification grade, baseline SBP at the time of hypotension and pre‐surgery HR as covariates (all P <.001). A higher baseline SBP led to a lower absolute increase in MAP. Patients with higher age, higher BMI and lower ASA grade showed smaller increases in MAP. The initial increase was similar for male and female patients. The long‐term effect was higher in women. Concomitant antihypertensive medication caused a delayed effect and a lower maximum MAP. The HR increased only slightly (median increase 2.6 bpm, P <.001). Conclusions: Seven covariates with an impact on the effect of C/T could be identified. The results will enable physicians to optimize the dose with respect to individual patients. [ABSTRACT FROM AUTHOR]

Anticholinergic‐induced cognitive impairment may be partially reversible upon cessation. A barrier to deprescribing of anticholinergics is the unknown risk of anticholinergic adverse drug withdrawal events (ADWE), with only limited information available on the incidence, timing and severity of anticholinergic ADWE. We report the case of a 76‐year‐old woman who experienced significant cognitive improvement following deprescribing long‐term use of a strong anticholinergic drug, doxepin, and dose reduction of another possible anticholinergic agent. The patient decided to abruptly stop taking doxepin, despite a planned careful taper with twice weekly monitoring, but did not experience any severe anticholinergic ADWE and subsequently had significantly improved cognitive function. Future research should focus on better understanding the risk of anticholinergic ADWE so that anticholinergic deprescribing decisions, including how often and by how much to taper, can be made confidently and safely. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The management of patients treated with direct oral anticoagulants (DOACs) during hospitalization is a common challenge in clinical practice. Although bridging is generally not recommended, too often DOACs are switched to parenteral therapy with low molecular weight heparins. Our objectives were to update a local guideline for perioperative DOAC management and to develop a guideline for the anticoagulation management in non‐surgical patients regarding temporary DOAC discontinuation.We executed a two‐step modified Delphi study in a 1000‐bed university hospital in Belgium. The Delphi questionnaires were developed based on a literature review and a telephone survey of prescribers. Two expert panels were established: one dedicated to perioperative DOAC management and the other to DOAC management in non‐surgical patients. Both panels completed two rounds, commencing with an individual and online round, followed by a face‐to‐face group session.After the two‐round Delphi process, the updated perioperative guideline on DOAC management included reasons for delaying the resumption of DOACs following surgery, such as oral intake not possible, the probability of re‐intervention within 3 days, and insufficient haemostasis (e.g. active clinically significant haematoma, haemorrhagic drains or wounds). Furthermore, a guideline for non‐surgical hospitalized patients was developed, outlining possible reasons for interrupting DOAC therapy. Both guidelines offer clear anticoagulation therapy strategies corresponding to the identified scenarios.We have updated and developed guidelines for DOAC management in surgical and non‐surgical patients during hospitalization, which aim to support prescribers and to enhance targeted prescription review by hospital pharmacists. [ABSTRACT FROM AUTHOR]

To prepare medical students appropriately for the management of toxicological emergencies, we have developed a simulation‐based medical education (SBME) training in acute clinical toxicology. Our aim is to report on the feasibility, evaluation and lessons learned of this training. Since 2019, each year approximately 180 fifth‐year medical students are invited to participate in the SBME training. The training consists of an interactive lecture and two SBME stations. For each station, a team of students had to perform the primary assessment and management of an intoxicated patient. After the training, the students completed a questionnaire about their experiences and confidence in clinical toxicology. Overall, the vast majority of students agreed that the training provided a fun, interactive and stimulating way to teach about clinical toxicology. Additionally, they felt more confident regarding their skills in this area. Our pilot study shows that SBME training was well‐evaluated and feasible over a longer period. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion In this reflection paper, the authors, based on their experience as teachers and students of the courses of Pharmacology at the University of Bologna, reflect on their specific roles towards innovation in the teaching of Clinical Pharmacology.Strengths, weaknesses and challenges are presented as identified during the teaching and learning experience in the currently evolving medical degree programmes of the University in light of current trends in medical education.Keeping in mind the identified challenges together with the features proposed for the model prescriber (knowledgeable, contemporary, communicative and safe), we indicate some ways to improve the students' experience and make sure they develop up‐to‐date skills in Clinical Pharmacology taking advantage of recent ongoing collaborations at European level. International collaboration is indeed necessary to adequately address the current challenges of teaching clinical pharmacology.Our shared conclusion is that empowering students with a scientifically sound method to retrieve relevant information and developing their skills to communicate in an interprofessional and, wherever possible, international environment is the key to prepare future prescribers and, ultimately, to improve patient safety. [ABSTRACT FROM AUTHOR]

Aims: To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct‐acting oral anticoagulants [DOACs] and incretin‐based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care. Methods: Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin‐based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin‐based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin‐based therapies. Results: Per year, 46–424 general practices and 179 933–1 654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin‐based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin‐based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin‐based therapies. Conclusion: DOACs and incretin‐based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ. [ABSTRACT FROM AUTHOR]

Aims: CYP2C19 is a hepatic enzyme involved in the metabolism of antidepressants associated with increased gastrointestinal bleed (GIB) risk. The aim of our study was to explore a possible association between loss‐of‐function CYP2C19 genotypes and GIB in South Asian ancestry participants prescribed antidepressants. Methods: Genes & Health participants with a record in Barts Health NHS Trust (N 22 753) were studied using a cross‐sectional approach. CYP2C19 diplotypes were assessed and metabolizer type inferred from consortia guidance. Fisher's exact test was used to compare the prevalence of GIB in different metabolizer categories. Multivariable regression was used to test for association between antidepressant prescriptions and GIB, and between CYP2C19 metabolizer state and GIB in the subcohort prescribed antidepressants. Results: Antidepressants were frequently prescribed (47%, N = 10 612). A total of 864 participants (4%) had a GIB; 534 (62%) had been prescribed a CYP2C19 metabolized antidepressant. There was an independent association between antidepressant prescriptions and GIB events (odds ratio 1.8, confidence interval 1.5‐2.0, P < 0.0001). There was no relationship between CYP2C19 inferred poor (P 0.56) or intermediate (P 0.53) metabolizer status and GIB in those prescribed an antidepressant in unadjusted analysis. A multivariable logistic regression model did not show an independent association between poor (P 0.54) or intermediate (P 0.62) CYP2C19 metabolizers and GIB in the subcohort prescribed antidepressants. Conclusions: CYP2C19 dependent antidepressants are associated with increased GIB prevalence. GIB appeared independent from CYP2C19 metabolizer genotype in individuals who had been prescribed antidepressants. Precision dosing based on CYP2C19 genetic information alone is unlikely to reduce GIB prevalence. [ABSTRACT FROM AUTHOR]

Despite 2 h of daily exercise training, muscle wasting and bone loss are still present after 6‐month missions to the international space station. Some crew members lose bone much faster than others. In preparation for missions to the Moon and Mars, space agencies are therefore reviewing their countermeasure portfolios. Here, we discuss the potential of current pharmacological strategies. Bone loss in space is fuelled by bone resorption. Alendronate, an oral bisphosphonate, reduced bone losses in experimental bed rest and space. However, gastrointestinal side effects precluded its further utilization in space. Zoledronate (a potent bisphosphonate), denosumab (RANKL antagonist) and romosozumab (sclerostin antagonist) are all administered via injection. They effectively suppress bone resorption and are routinely prescribed against osteoporosis. Their serious adverse effects, namely, osteonecrosis of the jaw and atypical femur fractures occur very rarely when the usage is limited to 1 or 2 years. Hence, utilization of one of these compounds may outweigh the bone risks of space travelling, in particular in those with high bone resorption rates. Muscle wasting in space is likely due to hampered muscle protein synthesis. Even though this might theoretically be countered by the synthesis‐boosting effects of anabolic steroids, the practical grounds for such recommendation are currently weak. Moreover, they reveal their full potential only when combined with an anabolic exercise stimulus, for example, via strength training. It therefore seems that a combination of exercise and pharmacological countermeasures should be considered for musculoskeletal health on the way to the Moon and Mars and back. [ABSTRACT FROM AUTHOR]

Aims: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self‐controlled case series study was used to compare the risk before and after treatment initiation. Methods: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self‐controlled case series study with individuals aged 5–24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate‐exposed period compared with nonexposed period. Results: Six cohort studies and 2 case–control studies were included in the systematic review. For all‐cause fractures, studies found a 39–74% lower risk in treated‐attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found—significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self‐controlled case series analysis. The risks of fractures were lower by 32–41% in different treatment periods when compared with 6 months before treatment initiation. Conclusion: Methylphenidate treatment may lower the risk of all‐cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required. [ABSTRACT FROM AUTHOR]

Aims: Measuring adherence to medication is complex due to the diversity of contexts in which medications are prescribed, dispensed and used. The Timelines‐Events‐Objectives‐Sources (TEOS) framework outlined a process to operationalize adherence. We aimed to develop practical recommendations for quantification of medication adherence using self‐report (SR), electronic monitoring (EM) and electronic healthcare databases (EHD) consistent with the TEOS framework for adherence operationalization. Methods: An adherence methodology working group of the International Society for Medication Adherence (ESPACOMP) analysed implications of the process of medication adherence for all data sources and discussed considerations specific to SR, EM and EHD regarding the information available on the prescribing, dispensing, recommended and actual use timelines, the four events relevant for distinguishing the adherence phases, the study objectives commonly addressed with each type of data, and the potential sources of measurement error and quality criteria applicable. Results: Four key implications for medication adherence measurement are common to all data sources: adherence is a comparison between two series of events (recommended and actual use); it refers to one or more specific medication(s); it applies to regular repeated events coinciding with known recommended dosing; and it requires separate measurement of the three adherence phases for a complete picture of patients' adherence. We propose recommendations deriving from these statements, and aspects to be considered in study design when measuring adherence with SR, EM and EHD using the TEOS framework. Conclusion: The quality of medication adherence estimates is the result of several design choices that may optimize the data available. [ABSTRACT FROM AUTHOR]

Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells. [ABSTRACT FROM AUTHOR]

Aims: We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark. Methods: We leveraged data on opioid fills from a 20% sample of all Danes alive during 2000–2021. Results: Overall, general practitioners were responsible for most treatment initiation (74% during 2000–2021) and maintenance treatment (92%). However, while hospital prescribers initiated ≈20% of treatments during 2001–2012, this increased to 35% in 2021. Similarly, hospital prescriber's share of maintenance treatment increased from 5.9% during 2000–2012 to 13% in 2021. This change was particularly pronounced for morphine initiation (48% hospital prescribers in 2021 up from 38% during 2000– 2010) and oxycodone initiation (78% up from 41%). Regarding choice of opioids, codeine use dropped markedly, in particular among hospital prescribers. Tramadol was consistently the most common first choice opioid in general practice (33% in 2021), whereas its use among hospital prescribers decreased (54% during 2000– 2015 to 15% in 2021). Conversely, the proportion of treatment initiation by hospital prescribers composed of morphine and oxycodone increased to 38% and 42% in 2021, respectively. Conclusions: General practice prescribes most opioids; however, hospital prescribers are increasingly responsible for opioid prescribing, in particular initiation of morphine and oxycodone. [ABSTRACT FROM AUTHOR]

Aims: Prescribing errors among junior doctors are common in clinical practice because many lack prescribing competence after graduation. This is in part due to inadequate education in clinical pharmacology and therapeutics (CP&T) in the undergraduate medical curriculum. To support CP&T education, it is important to determine which drugs medical undergraduates should be able to prescribe safely and effectively without direct supervision by the time they graduate. Currently, there is no such list with broad-based consensus. Therefore, the aim was to reach consensus on a list of essential drugs for undergraduate medical education in the Netherlands. Methods: A two-round modified Delphi study was conducted among pharmacists, medical specialists, junior doctors and pharmacotherapy teachers from all eight Dutch academic hospitals. Participants were asked to indicate whether it was essential that medical graduates could prescribe specific drugs included on a preliminary list. Drugs for which ≥80% of all respondents agreed or strongly agreed were included in the final list. Results: In all, 42 (65%) participants completed the two Delphi rounds. A total of 132 drugs (39%) from the preliminary list and two (3%) newly proposed drugs were included. Conclusions: This is the first Delphi consensus study to identify the drugs that Dutch junior doctors should be able to prescribe safely and effectively without direct supervision. This list can be used to harmonize and support the teaching and assessment of CP&T. Moreover, this study shows that a Delphi method is suitable to reach consensus on such a list, and could be used for a European list. [ABSTRACT FROM AUTHOR]

Aims: Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug penetration within tissues has been argued as a potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. The aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARV regimen in HIV‐positive patients. Methods: We included ART‐experienced patients switching to three different ARV regimens. Plasma and IC ARV drug concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL‐6 and LPS were analysed. Results: Plasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL‐6 and LPS values in the three arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho = −0.79, P <.001), and between DRV IC/plasma ratio and Log10 IL‐6 concentrations (rho = −0.36, P =.040), and a borderline statistically significant positive trend between DRV plasma concentration and sCD14 (rho = 0.31, P =.070) were suggested. Furthermore, a borderline statistically significant inverse trend between DTG IC concentrations and sCD14 (rho = −0.34, P =.090) was observed in 24 patients on DTG‐based triple therapy. Conclusions: Our preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART‐treated HIV‐positive patients. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to revisit the inter‐rater reliability of drug treatment assessments according to the Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) criteria. Methods: Potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) were independently identified by two physicians in two cohorts of older people (I: 200 hip fracture patients, median age 85 years, STOPP/START version 1; II: 302 primary care patients, median age 74 years, STOPP/START version 2). Kappa statistics were used to evaluate inter‐rater agreement. Results: In cohort I, a total of 782 PIMs/PPOs, related to 68 (78%) out of 87 criteria, were identified by at least one assessor, 500 (64%) of which were discordantly identified by the assessors, that is, by one assessor but not the other. For four STOPP criteria, all PIMs (n = 9) were concordantly identified. In cohort II, 955 PIMs/PPOs, related to 80 (70%) out of 114 criteria, were identified, 614 (64%) of which were discordantly identified. For three STOPP criteria, all PIMs (n = 3) were concordantly identified. For no START criterion, with ≥1 PPO identified, were all assessments concordant. The kappa value for PIM/PPO identification was 0.52 in both cohorts. In cohort II, the kappa was 0.37 when criteria regarding influenza and pneumococcal vaccines were excluded. Further analysis of discordantly identified PIMs/PPOs revealed methodological aspects of importance, including the data source used and criteria wording. Conclusions: When the STOPP/START criteria are applied in PIM/PPO research, reliability seems to be an issue not encountered in previous reliability studies. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. Methods: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. Results: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P <.001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P =.53 and P =.56 respectively), their overall level was higher at all three assessments (all P <.05). Conclusion: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors. [ABSTRACT FROM AUTHOR]

Aims: Prescribing errors occur frequently, especially among junior doctors. Our aim was to investigate prescribing errors made by final‐year medical students. Information on these errors can help to improve education on and assessment of clinical pharmacotherapy (CPT). Methods: This was a retrospective cohort study amongst final‐year medical students at Erasmus Medical Centre, The Netherlands. Errors made in the final prescribing assessment were analysed. Errors were categorized by type, possible consequence and possibility of reaching the patient in real life. Results: A total of 381 students wrote 1502 analysable prescriptions. Forty per cent of these contained at least one error, and 54% of errors were of the inadequate information type. The rating of prescriptions for children was lower than for other question categories (P = <.001). Fifty per cent of errors were classified as "would have reached the patient but would not have had the potential to cause harm". In total, 253 (29%) errors would not have been intercepted by an electronic prescribing system or a pharmacist. Ten (4%) of these would probably have caused harm in the patient. Conclusions: There is a high rate of errors in prescriptions written by final‐year medical students. Most errors were of the inadequate information type, indicating that students had difficulties determining the content and amount of information needed to make treatment successful. Prescriptions for children contained most errors. Curricula could be improved by offering more case‐based CPT education, focusing on the practical issues of prescribing, especially for paediatric cases, and offering more practice time for prescribing during clerkships. [ABSTRACT FROM AUTHOR]

The development of specific drug therapy for children was a paradigm‐changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off‐label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child‐friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union. [ABSTRACT FROM AUTHOR]

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3‐kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA‐related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low‐dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life‐threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low‐dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease‐specific features of PROS. [ABSTRACT FROM AUTHOR]

Diabetes mellitus was considered a fatal malady until the discovery, extraction and commercial availability of insulins. Numerous other classes of drugs ranging from sulfonylureas to sodium‐glucose co‐transporter‐2 inhibitors were then marketed. However, with the prevalence of diabetes mellitus increasing every year, many more drugs and therapies are under investigation. This review article aimed to summarize the significant developments in the pharmacotherapy of diabetes mellitus and outline the progress made by the recent advances, 100 years since insulins were first extracted successfully. Insulin analogues and insulin delivery pumps have further improved glycaemic control in diabetes mellitus. Cardiovascular and renal outcome trials have changed the landscape of diabetology, with some of these drugs also efficacious in nondiabetics. Newer drug delivery systems are being evaluated to improve the efficacy and reduce the dosing frequency and adverse effects of antidiabetics. Some newer drugs with novel mechanisms of action targeting type 1 and type 2 diabetes have also shown promise in recent clinical trials. These drugs include dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide 1‐agonists, glucokinase activators, anti‐CD3 monoclonal antibodies and glimins. Their efficacy needs to be evaluated in larger studies. [ABSTRACT FROM AUTHOR]

Aims: Junior doctors write most hospital prescriptions, yet are more than twice as likely to make an error in their prescriptions compared to senior doctors. A possibility to enhance pharmacotherapy education is through the use of e‐learning modules. The aim of this study was to determine whether P‐scribe, as the chosen e‐learning resource, helps students in passing their pharmacotherapy assessments. Methods: This retrospective study was undertaken in the Erasmus Medical Center, the Netherlands. All 270 medical students who started their master's curriculum in the academic session of 2017–2018 were included. Data were analysed to identify the frequency of student's use per e‐learning module, total time students spent on e‐learning modules and timing of the use of e‐learning modules in relation to their assessments. The results of the assessments were analysed to identify possible correlations between the time students spent using P‐scribe, their timing of use and their assessment results. Results: Students who passed their knowledge‐based assessment first time had a mean practice time of five more hours than students who did not pass first time (P <.05, 95% CI: 3.4–6.6). These students practised on average six e‐learning modules more (P <.05, 95% CI: 4.1–7.0) than students who failed their first attempt. Students who passed their skill‐based prescription test first time, practised on average five more e‐learning modules (P =.006, 95% CI: 1.4–8.3) than students who failed their first attempt. Conclusion: Students who passed their pharmacotherapy assessments first time spent more time, and practised more frequently, with e‐learning modules. [ABSTRACT FROM AUTHOR]

Pharmacogenomics is increasingly moving into mainstream clinical practice. Careful consideration must be paid to inclusion of diverse populations in research, translation and implementation, in the historical and social context of population stratification, to ensure that this leads to improvements in healthcare for all rather than increased health disparities. This review takes a broad and critical approach to the current role of diversity in pharmacogenomics and addresses potential pitfalls in order to raise awareness for prescribers. It also emphasizes evidence gaps and suggests approaches that may minimize negative consequences and promote health equality. [ABSTRACT FROM AUTHOR]

The Junior Adverse Drug Event Manager (J‐ADEM) team is a multifaceted intervention focusing on real‐life education for medical students that has been shown to assist healthcare professionals in managing and reporting suspected adverse drug reactions (ADRs) to the Netherlands Pharmacovigilance Centre Lareb. The aim of this study was to quantify and describe the ADRs reported by the J‐ADEM team and to determine the clinical potential of this approach. The J‐ADEM team consisted of medical students tasked with managing and reporting ADRs in hospitalized patients. All ADRs screened and reported by J‐ADEM team were recorded anonymously, and categorized and analysed descriptively. From August 2018 through January 2020, 209 patients on two wards in an academic hospital were screened for ADR events. The J‐ADEM team reported 101 ADRs. Although most ADRs (67%) were first identified by healthcare professionals and then reported by the J‐ADEM team, the team also reported an additional 33 not previously identified serious ADRs. In 10% of all reported ADRs, the J‐ADEM team helped optimize ADR treatment. The ADR reports were largely well‐documented (78%), and ADRs were classified as type A (66%), had a moderate or severe severity (85%) and were predominantly avoidable reactions (69%). This study shows that medical students are able to screen patients for ADRs, can identify previously undetected ADRs and can help optimize ADR management. They significantly increased (by 300%) the number of ADR reports submitted, showing that the J‐ADEM team can make a valuable clinical contribution to hospital care. [ABSTRACT FROM AUTHOR]

Aims: To investigate inter‐rater agreement on the quality of drug treatment, and the relationship between the drug treatment and hospital admission. Methods: Three specialist physicians and two resident physicians determined, independently and in consensus, the quality of drug treatment from an overall medical perspective, and its association with admission, in 30 randomly selected patients (50% female, median age 72 years) admitted to Sahlgrenska University Hospital, Sweden, in April 2018. The inter‐rater agreement was evaluated with Gwet's agreement coefficient (AC1). Results: In all, 200 (95%) out of 210 drugs at admission and 238 (97%) out of 245 drugs at discharge were assessed as reasonable drug treatment by all assessors. Conversely, none of the drugs at admission, and two at discharge, were assessed as unreasonable drug treatment by all assessors (AC1: 0.88 and 0.94 [all], 0.86 and 0.95 [specialists], 0.92 and 0.92 [residents], respectively). The assessments regarding the association between the drug treatment and the hospital admission (not related or main/contributory reason) were consistent between the assessors for 16 out of 30 patients (AC1: 0.67 [all], 0.74 [specialists], 0.54 [residents]). In none of the three cases where the hospital admission was considered possibly attributable to a prescribing error did the assessors make consistent assessments. Conclusions: As the inter‐rater agreement ranged between weak and almost perfect, the reliability of assessments of drug treatment quality, as well as adverse consequences, appears to be a methodological concern. To yield acceptably reliable results regarding both drug treatment aspects at issue, specialist physicians should be involved. [ABSTRACT FROM AUTHOR]

Aims: Junior doctors frequently prescribe incorrectly and this can cause serious harm to patients. Pharmacotherapy education in most medical schools falls short in preparing their students to prescribe safely in clinical practice. According to the theory of assessment‐driven learning, a pharmacotherapy self‐assessment for junior doctors may reduce potential harmful prescriptions in clinical practice, by revealing deficits in prescribing knowledge and skills. Methods: In this single centre, prospective cohort study, the potential harmful prescriptions of junior doctors in clinical practice were compared before and after a pharmacotherapy self‐assessment with and without additional pharmacotherapy education. Results: Potential harmful prescriptions best known to cause harm to patients were studied in all the prescriptions written out by 199 junior doctors in the first 2 months of their employment in our hospital. The pharmacotherapy self‐assessment reduced the total number of potential harmful prescriptions made by junior doctors relative to those made by junior doctors in the control group (1.3 vs. 3.2%, respectively; P <.001). Additional education did not reduce potential harmful prescriptions beyond the effect of the self‐assessment alone (1.3 vs. 1.0%, P >.05). Conclusions: Pharmacotherapy self‐assessment leads to fewer potential harmful prescriptions made by junior doctors in clinical practice, thereby improving patient safety. More research is needed to investigate whether additional pharmacotherapy education strategies reduce potential harmful prescriptions further. [ABSTRACT FROM AUTHOR]

We describe the distribution of prescriber types responsible for issuing prescriptions in Denmark. Using a 20% random sample of all Danes alive during 2000–2018 (n = 1 515 025) and all their prescriptions filled at community pharmacies (n = 182 143 707), we found that general practitioners issued 88% of all prescriptions, followed by hospital physicians (7.4%) and private practicing specialists (4.2%). These values were stable over the study period. With increasing patient age, general practitioners were responsible for a larger proportion of prescriptions (e.g. 68% for patients aged 0–17 y and 89% for patients ≥51 y). General practitioners were responsible for 84% of all treatment initiation (first prescription) and 90% of all maintenance treatment. Corresponding values for hospital physicians were 9.5 and 6.3%, and for private practicing specialists 5.3 and 3.6%. In conclusion, general practitioners are responsible for the vast majority of prescribing in Denmark, including both treatment initiation and continuation, in particular among the elderly. [ABSTRACT FROM AUTHOR]

Riociguat is a first‐in‐class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT‐1 (PAH) and CHEST‐1 (CTEPH) studies, with significant improvements in the primary endpoint of 6‐minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti‐inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type‐5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Keywords: drug information; evidence-based medicine; infectious diseases; medication safety; pharmacotherapy EN drug information evidence-based medicine infectious diseases medication safety pharmacotherapy 725 729 5 03/05/21 20210301 NES 210301 INTRODUCTION Since the early days of the COVID-19 pandemic, a long range of medications have been tried in the fight against the novel coronavirus: antivirals, antimalarial drugs, antibiotics, steroids, and numerous biologicals. Drug information, infectious diseases, medication safety, pharmacotherapy, evidence-based medicine Hence, the clinical pharmacologists are necessitated to deal with every aspect of rational, safe, and effective medication use alone.1 In Russia, for over 500 000 medical doctors, there are about 800 clinical pharmacologists, who are often overloaded with clinical consultations, assessing and reporting adverse drug events, and advising the hospital medication committees. [Extracted from the article]

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle‐bound nab‐paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics‐pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3‐weekly) or optimal average dose (cabazitaxel, nab‐paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3‐weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab‐paclitaxel at present. [ABSTRACT FROM AUTHOR]

Aims: Therapeutic drug monitoring of infliximab can guide clinical decisions in patients with loss of response and in those who can benefit from a de‐intensification. The aim of this study was to determine the impact of therapeutic drug monitoring combined with Bayesian forecasting methodology on clinical response in a real‐world dataset of patients suffering from inflammatory bowel disease. Methods: We performed a single‐centre prospective study with one‐group pre‐test/post‐test design in 108 adult inflammatory bowel disease patients treated with model‐based dosing of infliximab maintenance treatment. We recorded clinical activity scores (Harvey‐Bradshaw index and partial Mayo) and inflammatory biomarkers per patient. Results: The initial infliximab regimen was maintained in 49 (45.4%) patients and was adjusted in 59 (54.6%) patients (34 treatment intensifications, 9 de‐intensifications and 16 treatment discontinuations or therapy replacements). The median time from intervention to index measurement was 126 (103–160) days. The overall proportion of patients in clinical remission increased from 65.7% to 80.4% (P <.0001) and the median infliximab trough concentrations increased from 3.21 (0.99–5.45) to 5.13 mg/L (3.57–6.53) (P <.0001). In the intensified group, the remission rate increased from 35.3% to 61.8% (P =.001) and the percentage of patients in clinical remission or with mild symptoms increased from 76.5% to 94.1%. In the de‐intensification cohort, no patients experienced an increase in the Harvey‐Bradshaw index or partial Mayo scores, and all patients maintained an infliximab trough concentration of >5 mg/L. Conclusion: In our cohort of inflammatory bowel disease patients, Bayes‐based optimized dosing improved the short‐term efficacy of infliximab treatment. [ABSTRACT FROM AUTHOR]

Ageing is associated with several changes in human organs, which result in altered medication pharmacokinetics and pharmacodynamics. Ageing is also associated with changes in human body functions, such as impaired vision, hearing, swallowing, motor and cognitive functions, which can affect the adequate intake and administration of drugs. As a consequence, older people, and especially patients older than 75 years, are the main users of many drugs and they frequently use 5 drugs or more long‐term (i.e. polypharmacy). All this increases the complexity of adequate drug intake, administration and adherence. However, there is a lack of evidence on the considerations that should be taken into account to ensure appropriate drug prescribing to older people. This review article summarizes the most clinically relevant changes in human organ and body functions and the consequential changes in pharmacokinetics and pharmacodynamics in older people, along with possible dosing consequences or alternatives for drugs frequently prescribed to this patient population. Recommendations are given on how ageing could be considered in clinical drug development, drug authorization and appropriate prescribing. [ABSTRACT FROM AUTHOR]

Increasing pharmacotherapy safety at physicians' career start - Presentation of a 10-item list with helpful hints The results of our survey indicate that the acceptance and usefulness of our 10-item list to increase pharmacotherapy safety are generally high among physicians starting in a new work environment. Keywords: adverse drug reactions; drug safety; drug - drug interactions; medical education; pharmacotherapy EN adverse drug reactions drug safety drug - drug interactions medical education pharmacotherapy 3019 3021 3 07/01/21 20210701 NES 210701 Physicians at career start face various challenges: integration into a new work environment with new colleagues and hierarchies, the assignment of hitherto unacquainted tasks and duties, and - above all - taking over full responsibility for their patients. [Extracted from the article]

Dual GIP and GLP-1 receptor agonist Tirzepatide improves Beta-cell function and insulin sensitivity in type 2 diabetes. Keywords: metabolic hormones; pharmacotherapy; systemic metabolism; tirzepatide; type 2 diabetes EN metabolic hormones pharmacotherapy systemic metabolism tirzepatide type 2 diabetes 1222 1223 2 02/16/23 20230301 NES 230301 Seetharaman et al. showed that innovations in pharmacotherapy to ameliorate the symptoms associated with type 2 diabetes promote more insightful developments in medicine. [Extracted from the article]

Aims: The prevalence of dementia is rising as life expectancy increases globally. Behavioural and psychological symptoms of dementia (BPSD), including agitation and aggression, are common, presenting a challenge to clinicians and caregivers. Methods: Following PRISMA guidelines, we systematically reviewed evidence for gabapentin and pregabalin against BPSD symptoms of agitation or aggression in any dementia, using six databases (Pubmed, CINHL, PsychINFO, HealthStar, Embase, and Web of Science). Complementing this formal systematic review, an illustrative case of a patient with BPSD in mixed Alzheimer's/vascular dementia, who appeared to derive benefits in terms of symptom control and functioning from the introduction of gabapentin titrated up to 3600 mg day−1 alongside other interventions, is presented. Results: Twenty‐four relevant articles were identified in the systematic review. There were no randomized trials. Fifteen papers were original case series/case reports of patients treated with these compounds, encompassing 87 patients given gabapentin and six given pregabalin. In 12 of 15 papers, drug treatment was effective in the majority of cases. The remaining nine papers were solely reviews, of which two were described as systematic but predated PRISMA guidelines. Preliminary low‐grade evidence based on case series and case reviews suggests possible benefit of gabapentin and pregabalin in patients with BPSD in Alzheimer's disease. These benefits cannot be confirmed until well‐powered randomized controlled trials are undertaken. Evidence in frontotemporal dementia is lacking. Conclusion: Gabapentin and pregabalin could be considered for BPSD when medications having stronger evidence bases (risperidone, other antipsychotics, carbamazepine and citalopram) have been ineffective or present unacceptable risks of adverse outcomes. [ABSTRACT FROM AUTHOR]

Aims: Prescribing is a core skill for junior doctors, yet 8–10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors. Methods: A two‐round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five‐point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases. Results: Sixty‐two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases. Conclusion: This is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence. [ABSTRACT FROM AUTHOR]

Aims: To examine the association between statin use before and after intracranial haemorrhage (ICH) and the risk of poststroke epilepsy (PSE). Methods: Patients with new‐onset ICH between 2004 and 2012 were identified from the Taiwan National Health Insurance Research Database. The main outcome was the occurrence of epilepsy after stroke. Multivariable Cox regression modelling was used to estimate the association between statin use and the risk of PSE, with poststroke medication exposures being treated as time‐dependent variables. Results: A total of 7435 patients with ICH were enrolled with a median follow‐up of 17.6 months. Within the study cohort, 709 patients developed PSE. Poststroke, but not prestroke, stain use was associated with a reduced risk of PSE (adjusted hazard ratio 0.62, 95% confidence interval 0.42–0.90, P = 0.01). In subanalyses, a trend of a dose–response relationship was observed. A significant PSE risk reduction was correlated with a higher cumulative statin dose. Moreover, the risk of PSE was lower in patients receiving moderate‐to‐high‐intensity statin therapy (adjusted hazard ratio 0.37, 95% confidence interval 0.18–0.75, P = 0.01). Lipophilic and hydrophilic statins were similar with regard to their associations with the reduced risk of PSE. Conclusions: Statin therapy may reduce the risk of PSE after ICH, especially with moderate‐to‐high therapy intensity. Further research is needed to understand the mechanisms underlying the potential protective effects of statins against PSE in this patient population. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to evaluate how critical patient involvement is in pharmacist‐led clinical medication reviews and in identifying the most significant clinical drug‐related problems (DRPs). Methods: Pharmacist‐led clinical medication reviews were conducted with 161 consenting patients aged ≥75 years with at least seven prescribed medicines, living independently at home in Finland. A pharmacist, a nurse and a physician evaluated the clinical significance of the DRPs identified during the patient interview at an interprofessional case conference. It was evaluated whether the most significant clinical DRPs could also have been identified through reviewing the medication list only or the medication list and certain patient details. Results: Altogether, the 111 most significant clinical DRPs were evaluated. Only 6% could have been identified through reviewing the medication list only, and 16% through reviewing the medication list and certain patient details. Hence, 84% of the most significant clinical DRPs could only have been identified with patient involvement. The most common DRPs were: poor therapy control (25%); nonoptimal drug (22%); intentional nonadherence (12%); and additional drug needed (11%). patient involvement was critical when identifying DRPs related to additional drug needed, unintentional nonadherence, use of over‐the‐counter medicines or dietary supplements, or contradictions in counselling. Conclusion: Patient involvement is essential when identifying clinical DRPs. Indeed, poor therapy control, nonoptimal drug use, intentional or unintentional nonadherence might otherwise be missed. [ABSTRACT FROM AUTHOR]

Aims: Prescribing errors are an important cause of patient safety incidents and are frequently caused by junior doctors. This might be because the prescribing competence of final‐year medical students is poor as a result of inadequate clinical pharmacology and therapeutic (CPT) education. We reviewed the literature to investigate which prescribing competencies medical students should have acquired in order to prescribe safely and effectively, and whether these have been attained by the time they graduate. Methods: PubMed, EMBASE and ERIC databases were searched from the earliest dates up to and including January 2017, using the terms ‘prescribing’, ‘competence’ and ‘medical students’ in combination. Articles describing or evaluating essential prescribing competencies of final‐year medical students were included. Results: Twenty‐five articles describing, and 47 articles evaluating, the prescribing competencies of final‐year students were included. Although there seems to be some agreement, we found no clear consensus among CPT teachers on which prescribing competencies medical students should have when they graduate. Studies showed that students had a general lack of preparedness, self‐confidence, knowledge and skills, specifically regarding general and antimicrobial prescribing and pharmacovigilance. However, the results should be interpreted with caution, given the heterogeneity and methodological weaknesses of the included studies. Conclusions: There is considerable evidence that final‐year students have insufficient competencies to prescribe safely and effectively, although there is a need for a greater consensus among CPT teachers on the required competencies. Changes in undergraduate CPT education are urgently required in order to improve the prescribing of future doctors. [ABSTRACT FROM AUTHOR]

Aims The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. Methods In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. Results The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children ( n = 20), was 2.4 (−8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents ( n = 20) was −0.9 (−12, 9.8) mm. Conclusion The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements. [ABSTRACT FROM AUTHOR]

Aims The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model. Methods In this double-blind, placebo-controlled, four-way cross-over trial, 12 healthy male subjects received oral mecamylamine 10 and 20 mg, intravenous scopolamine 0.5 mg and placebo. Pharmacokinetics were analysed using non-compartmental analysis. Pharmacodynamic effects were measured with a multidimensional test battery that includes neurophysiological, subjective, (visuo)motor and cognitive measurements. Results All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml−1 for the 20 mg dose. Mecamylamine had a dose-dependent effect decreasing the adaptive tracking performance and VAS alertness, and increasing the finger tapping and visual verbal learning task performance time and errors. Scopolamine significantly affected almost all pharmacodynamic tests. Conclusion This study demonstrated that mecamylamine causes nicotinic receptor specific temporary decline in cognitive functioning. Compared with the scopolamine model, pharmacodynamic effects were less pronounced at the dose levels tested; however, mecamylamine caused less sedation. The cognitive effects of scopolamine might at least partly be caused by sedation. Whether the mecamylamine model can be used for proof-of-pharmacology of nicotinic acetylcholine receptor agonists remains to be established. [ABSTRACT FROM AUTHOR]