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Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system.

CONTRIBUTORS IN THE NETWORK OF TEACHERS IN PHARMACOTHERAPY (NOTIP) (ALPHABETIZED BY COUNTRY): Atanasova, Ivanka (Sofia University St. Kliment Ohridski, Sofia, Bulgaria); Ganeva, Maria (Trakia University, Stara Zagora, Bulgaria); Gatchev, Emil (Medical University of Sofia, Sofia, Bulgaria); Kostadinova, II (Medical University Plovdiv, Plovdiv, Bulgaria); Mimica Matanovic, S (University of Osijek, Osijek, Croatia); Vitezic, D (University of Rijeka Medical School, Rijeka, Croatia); Wozniak, Greta (University of Cyprus, Nicosia, Cyprus); Kmonickova, E (Charles University, Pilsen, Czech Republic); Urbanek, Karel (Palacky University, Olomouc, Czech Republic); Damkier, P (University of Southern Denmark, Odense, Denmark); Huupponen, RK (University of Turku, Turku, Finland); Auffret, Marine (Hospices civils de Lyon, Lyon, France); Bejan-Angoulvant, T (Université de Tours, Tours, France); Chouchana, Laurent (Hospital Cochin, Paris, France); Cracowski, Jean-Luc (University Grenoble Alpes, La Tronche, France); Drici, MD (University of Nice Côte d'Azur, Nice, France); Faillie, JL (CHU Montpellier, Montpellier, France); Geniaux, Hélène (CHU de Limoges, Limoges, France); Molimard, M (Université de Bordeaux, Bordeaux, France); Orlikowski, D (Versailles Saint-Quentin-en-Yvelines University, Versailles, France); Palin, Karine (University of Bordeaux, Bordeaux, France); Pers, Y-M (CHU Montpellier, Montpellier, France); Picard, Nicolas (CHU de Limoges, Limoges, France); Simon, N (Aix-Marseille University, Marseille, France); Toussirot, E (CHU de Besancon, Besancon, France); Boger, RH (University Medical Center Hamburg-Eppendorf, Hamburg, Germany); Cascorbi, I (University of Kiel, Kiel, Germany); Mueller, SC (University Medicine Rostock, Rostock, Germany); Regenthal, R (University of Leipzig, Leipzig, Germany); Schwab, M (Eberhard Karl University of Tübingen, Tübingen, Germany); Schwaninger, MS (University of Luebeck, Luebeck, Germany); Thuermann, PA (University Witten/Herdecke, Witten, Germany); Wojnowski, L (University Medical Center Mainz, Mainz, Germany); Kouvelas, D (Aristotle University of Thessaloniki, Thessaloniki, Greece); Riba, P (Semmelweis University, Budapest, Hungary); Kerins, David M (University College, Cork, Ireland); Williams, David J (Royal College of Surgeons in Ireland, Dublin, Ireland); Cosentino, M (University of Insubria, Varese, Italy); De Ponti, Fabrizio (University of Bologna, Bologna, Italy); Filippelli, Amelia (University of Salerno, Baronissi, Italy); Leone, R (University of Verona, Verona, Italy); Locatelli, Vittorio (University of Milano - Bicocca, Monza, Italy); Jansone, Baiba (University of Latvia, Riga, Latvia); Gulbinovic, Romaldas (Vilnius University, Vilnius, Lithuania); Mifsud, Janet (University of Malta, Msida, Malta); Braszko, Jan J (Medical University of Bialystok, Bialystok, Poland); kocic, I (Medical University of Gdansk, Gdansk, Poland); Breitenfeld, Luiza (Beira Interior University, Covilh~a, Portugal); Castelo-Branco, M (University of Beira Interior, Covilh~a, Portugal); Conea, Simona (“Vasile Goldis” Western University of Arad, Arad, Romania); Magyar, Ioan (University of Oradea, Oradea, Romania); Bevc, S (University of Maribor, Maribor, Slovenia); Krzan, Mojca (University of Ljubljana, Ljubljana, Slovenia); Bernal, ML (University of Zaragoza, Zaragoza, Spain); Capellà, D (University of Girona, Girona, Spain); Carcas, A (Universidad Autónoma de Madrid, University of Maribor, Spain); De Abajo, FJ (University of Alcalá, Alcalá de Henares, Spain); Lopez-Rico, M (University of Salamanca, Salamanca, Spain); Lucena, MI (University of Malaga, Malaga, Spain); Pontes, C (Universitat Autonoma de Barcelona, Sabadell, Spain); Sanz, EJ (Universidad de La Laguna, La Laguna, Spain); Böttiger, Y (Linköping University, Linköping, Sweden); Le Grevès, Madeleine (Uppsala University, Uppsala, Sweden); de Waard-Siebinga, I (University Medical Center Groningen, Groningen, The Netherlands); Janssen, Ben JA (Maastricht University, Maastricht, The Netherlands); Knol, Wilma (University Medical Center Utrecht, Utrecht, The Netherlands); Pandit, Rahul (University Medical Center Utrecht, Utrecht, The Netherlands); van Rosse, F (Erasmus Medical Center, Rotterdam, The Netherlands); Dent, G (Keele University, Keele, United Kingdom); Ferro, Albert (King's College London, London, United Kingdom); Hitchings, AW (St George's, University of London, London, United Kingdom); Kapil, V (Queen Mary University London, London, United Kingdom); Linton, KD (University of Sheffield, Sheffield, United Kingdom); Loke, YK (University of East Anglia, Norwich, United Kingdom); Okorie, Michael (Brighton and Sussex Medical School, Brighton, United Kingdom); Plumb, Richard David (Queen's University Belfast, Belfast, United Kingdom); Pontefract, Sarah (University of Birmingham, Birmingham, United Kingdom); Ranmuthu, S (Queen Mary University London, London, United Kingdom); Sampson, AP (University of Southampton, Southampton, United Kingdom); Thanacoody, HKR (Newcastle University, Newcastle upon Tyne, United Kingdom); Whitfield, Jonathan P (University of Aberdeen, Aberdeen, United Kingdom); Wilson, Kurt (University of Manchester, Manchester, United Kingdom) Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re‐used widely across a variety of educational systems, they may be ideally suited for this purpose Methods With a cross‐sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e‐learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge‐based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in‐part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion Digital educational resources, ranging from e‐learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real‐life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials.

TRPC6 (transient receptor potential cation channels, canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC50 values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies.

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

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