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.
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In patients with COPD, self-management skills are important to reduce the impact of exacerbations. However, both detection and adequate response to exacerbations appear to be difficult for some patients. Little is known about the underlying process of exacerbation-related self-management. Therefore, the objective of this study was to identify and explain the underlying process of exacerbation-related self-management behavior. A qualitative study using semi-structured in-depth interviews was performed according to the grounded theory approach, following a cyclic process in which data collection and data analysis alternated. Fifteen patients (male n=8; age range 59–88 years) with mild to very severe COPD were recruited from primary and secondary care settings in the Netherlands, in 2015.
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Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.
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Background: COPD self-management is a complex behavior influenced by many factors. Despite scientific evidence that better disease outcomes can be achieved by enhancing self-management, many COPD patients do not respond to self-management interventions. To move toward more effective self-management interventions, knowledge of characteristics associated with activation for self-management is needed. The purpose of this study was to identify key patient and disease characteristics of activation for self-management. Methods: An explorative cross-sectional study was conducted in primary and secondary care in patients with COPD. Data were collected through questionnaires and chart reviews. The main outcome was activation for self-management, measured with the 13-item Patient Activation Measure (PAM). Independent variables were sociodemographic variables, self-reported health status, depression, anxiety, illness perception, social support, disease severity, and comorbidities. Results: A total of 290 participants (age: 67.2±10.3; forced expiratory volume in 1 second predicted: 63.6±19.2) were eligible for analysis. While poor activation for self-management (PAM-1) was observed in 23% of the participants, only 15% was activated for self-management (PAM-4). Multiple linear regression analysis revealed six explanatory determinants of activation for self-management (P,0.2): anxiety (β: -0.35; -0.6 to -0.1), illness perception (β: -0.2; -0.3 to -0.1), body mass index (BMI) (β: -0.4; -0.7 to -0.2), age (β: -0.1; -0.3 to -0.01), Global Initiative for Chronic Obstructive Lung Disease stage (2 vs 1 β: -3.2; -5.8 to -0.5; 3 vs 1 β: -3.4; -7.1 to 0.3), and comorbidities (β: 0.8; -0.2 to 1.8), explaining 17% of the variance. Conclusion: This study showed that only a minority of COPD patients is activated for self-management. Although only a limited part of the variance could be explained, anxiety, illness perception, BMI, age, disease severity, and comorbidities were identified as key determinants of activation for self-management. This knowledge enables health care professionals to identify patients at risk of inadequate self-management, which is essential to move toward targeting and tailoring of self-management interventions. Future studies are needed to understand the complex causal mechanisms toward change in self-management
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Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.
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Synthetic glucocorticoids are potent anti-inflammatory drugs but show dose-dependent metabolic side effects such as the development of insulin resistance and obesity. The precise mechanisms involved in these glucocorticoid-induced side effects, and especially the participation of adipose tissue in this are not completely understood. We used a combination of transcriptomics, antibody arrays and bioinformatics approaches to characterize prednisolone-induced alterations in gene expression and adipokine secretion, which could underlie metabolic dysfunction in 3T3-L1 adipocytes. Several pathways, including cytokine signalling, Akt signalling, and Wnt signalling were found to be regulated at multiple levels, showing that these processes are targeted by prednisolone. These results suggest that mechanisms by which prednisolone induce insulin resistance include dysregulation of wnt signalling and immune response processes. These pathways may provide interesting targets for the development of improved glucocorticoids.
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BACKGROUND: Glucocorticoids (GCs) control expression of a large number of genes via binding to the GC receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in the regulation of gene expression, we performed gene expression profiling of livers of prednisolone-treated wild type (WT) and mice that have lost the ability to form GR dimers (GRdim).RESULTS: The GR target genes identified in WT mice were predominantly related to glucose metabolism, the cell cycle, apoptosis and inflammation. In GRdim mice, the level of prednisolone-induced gene expression was significantly reduced compared to WT, but not completely absent. Interestingly, for a set of genes, involved in cell cycle and apoptosis processes and strongly related to Foxo3a and p53, induction by prednisolone was completely abolished in GRdim mice. In contrast, glucose metabolism-related genes were still modestly upregulated in GRdim mice upon prednisolone treatment. Finally, we identified several novel GC-inducible genes from which Fam107a, a putative histone acetyltransferase complex interacting protein, was most strongly dependent on GR dimerization.CONCLUSIONS: This study on prednisolone-induced effects in livers of WT and GRdim mice identified a number of interesting candidate genes and pathways regulated by GR dimers and sheds new light onto the complex transcriptional regulation of liver function by GCs.
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Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.
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