SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Farmacologische profielen van antidepressiva

Objective: To construct a model for classification of antidepressants on the basis of their binding properties to six common transporter and receptor sites. Design and methods: Receptor binding was quantified by calculating receptor/ transporter occupancy (hereafter: receptor occupancy) for the serotonin (5HT) transporter, norepinephrine (NE) transporter, 5HT2Creceptor, M3receptor, H1receptor and a, receptor. Receptor occupancy has been proven to be an appropriate measure to estimate the pharmacological effects among drugs with the same mechanism of action. To identify groups of antidepressants showing similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principal component analysis (PCA) were performed. To visualize (a)symmetry between binding profiles of antidepressants, radar plots were used. Results: On the basis of HCA, PCA and the radar plots, four clusters of antidepressants with similar pharmacological properties were identified. The first cluster (sertraline, fluvoxamine, escitalopram, paroxetine, venlafaxine, fluoxetine, Citalopram, duloxetine and clomipramine) included antidepressants with specific affinity for the 5HT transporter. The second cluster (amitriptyline, doxepin and Imipramine) included antidepressants with high affinity for all receptors Investigated. The third cluster (maprotiline, nortriptyline, mianserin and mirtazapine) included antidepressants with high affinity for the NE transporter, H1receptor and 5HT2Creceptor. The fourth cluster (trazodone, nefazodone, reboxetine and bupropion) was identified as group with no specific similarities. Conclusions: The use of the receptor occupancy theory combined with HCA, PCA and radar plots is a useful method to visualize (a)symmetry in binding profiles of antidepressants. It could be a helpful tool in evidence-based practice, selecting the right antidepressant for the right patient, and may be used in pharmacovigilance as a prediction model for adverse effects of novel drugs entering the market

Visualizing pharmacological activities of antidepressants: A novel approach

Antidepressants have different receptor binding profiles, which are related to therapeutic action and adverse drug reactions. We constructed a model to classify antidepressants on the basis of their binding properties of most common transporter- and receptor sites. Receptor binding was quantified by calculating receptor occupancy for the 5-HT (serotonin) reuptake transporter, norepinephrinic reuptake transporter, 5-HT2C-receptor, M3-receptor, H1-receptor and 1- receptor. To identify groups of antidepressants that show similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principle component analysis (PCA) were used. In addition, to visualize (a)symmetry between binding profiles of antidepressants, radar plots were constructed. On the basis of both analyses, four clusters of antidepressants which exert similar pharmacological properties were identified. Potentially, this model could be a helpful tool in medical practice and may be used as a prediction model for adverse effects of drugs entering the market

Visualizing pharmacological activities of antidepressants

Objective: To construct a model for classification of antidepressants on the basis of their binding properties to six common transporter and receptor sites. Design and methods: Receptor binding was quantified by calculating receptor/ transporter occupancy (hereafter: receptor occupancy) for the serotonin (5HT) transporter, norepinephrine (NE) transporter, 5HT2Creceptor, M3receptor, H1receptor and a, receptor. Receptor occupancy has been proven to be an appropriate measure to estimate the pharmacological effects among drugs with the same mechanism of action. To identify groups of antidepressants showing similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principal component analysis (PCA) were performed. To visualize (a)symmetry between binding profiles of antidepressants, radar plots were used. Results: On the basis of HCA, PCA and the radar plots, four clusters of antidepressants with similar pharmacological properties were identified. The first cluster (sertraline, fluvoxamine, escitalopram, paroxetine, venlafaxine, fluoxetine, Citalopram, duloxetine and clomipramine) included antidepressants with specific affinity for the 5HT transporter. The second cluster (amitriptyline, doxepin and Imipramine) included antidepressants with high affinity for all receptors Investigated. The third cluster (maprotiline, nortriptyline, mianserin and mirtazapine) included antidepressants with high affinity for the NE transporter, H1receptor and 5HT2Creceptor. The fourth cluster (trazodone, nefazodone, reboxetine and bupropion) was identified as group with no specific similarities. Conclusions: The use of the receptor occupancy theory combined with HCA, PCA and radar plots is a useful method to visualize (a)symmetry in binding profiles of antidepressants. It could be a helpful tool in evidence-based practice, selecting the right antidepressant for the right patient, and may be used in pharmacovigilance as a prediction model for adverse effects of novel drugs entering the market