Background: Collaboration between physicians and pharmacists facilitates the conduct of medication optimisation efforts. In the context of deprescribing, pharmacists' roles are often described as making deprescribing recommendations to physicians. Little is known about factors associated with pharmacists' willingness to make deprescribing recommendations and their interprofessional collaboration with physicians in Swiss primary care settings.
View Article and Find Full Text PDFSecondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development.
View Article and Find Full Text PDF(1) Introduction: Chronic insomnia (CI) reduces quality of life and may trigger depression and cardiovascular diseases. The European Sleep Research Society recommends cognitive behavioural therapy (CBT-I) as the first-line treatment. Because a recent study in Switzerland demonstrated that this recommendation was inconsistently followed by primary care physicians, we hypothesised that pharmacists also deviate from these guidelines.
View Article and Find Full Text PDFBackground: The incidence of diabetes mellitus (both pregestational and gestational) is increasing worldwide, and hyperglycemia during pregnancy is associated with adverse pregnancy outcomes. Evidence on the safety and efficacy of metformin during pregnancy has accumulated resulting in an increase in its prescription in many reports.
Aims: We aimed to determine the prevalence of antidiabetic drug use (insulins and blood glucose-lowering drugs) before and during pregnancy in Switzerland and the changes therein during pregnancy and over time.
Explor Res Clin Soc Pharm
March 2023
Switzerland is a federal country with a liberal health system built on private mandatory health insurance where the government has three different roles (health protector, guarantor of the offered care and regulator). Health is mostly considered as a responsibility that lies with the individual person. Swiss health policies do not include the term "self-care", although, the federal policy strategy established for this decade (Health2030) includes objectives and lines of action, some of which could be classified as self-care.
View Article and Find Full Text PDFIntroduction: The use of high throughput patch clamp profiling to determine mixed ion channel-mediated arrhythmia risk was assessed using profiling data generated using proprietary internal and clinical reference compounds. We define the reproducibility of the platform and highlight inherent platform issues. The data generated was used to develop predictive models for cardiac arrhythmia risk, specifically Torsades de Pointes (TdP).
View Article and Find Full Text PDFCOVID-19 is a potentially fatal infection caused by the SARS-CoV-2 virus. The SARS-CoV-2 3CL protease (Mpro) is a viral enzyme essential for replication and is the target for nirmatrelvir. Paxlovid (nirmatrelvir co-administered with the pharmacokinetic enhancer ritonavir) showed efficacy in COVID-19 patients at high risk of progressing to hospitalization and/or death.
View Article and Find Full Text PDFHuman induced pluripotent stem cell derived cardiomyocytes (hIPSC-CM's) play an increasingly important role in the safety profiling of candidate drugs. For such models to have utility a clear understanding of clinical translation is required. In the present study we examined the ability of our hIPSC-CM model to predict the clinically observed effects of a diverse set of compounds on several electrocardiogram endpoints, including changes in QT and QRS intervals.
View Article and Find Full Text PDFDefining an appropriate and efficient assessment of drug-induced corrected QT interval (QTc) prolongation (a surrogate marker of torsades de pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15 years, the nonclinical International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG current & in vivo QTc studies; E14: thorough QT study) that are used to assess the potential of drugs to cause delayed ventricular repolarization. Incorporating these assays during nonclinical or human testing of novel compounds has led to a low prevalence of QTc-prolonging drugs in clinical trials and no new drugs having been removed from the marketplace due to unexpected QTc prolongation.
View Article and Find Full Text PDFIntroduction: Building an understanding of in vivo efficacy based on the evaluation of in vitro affinity or potency is critical in expediting early decision making in drug discovery and can significantly reduce the need for animal studies. The aim of the present study was to understand the translation of in vitro to in vivo endpoints for the cannabinoid receptor 1 (CB1).
Methods: Using a selection of CB1 agonists we describe an evaluation of in vitro to in vivo translation comparing in vitro receptor affinity or functional potency, using both cAMP and β-arrestin endpoints, to various in vivo CB1 agonist-associated endpoints.
An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol).
View Article and Find Full Text PDFJ Pharmacol Toxicol Methods
September 2020
Secondary pharmacological profiling is increasingly applied in pharmaceutical drug discovery to address unwanted pharmacological side effects of drug candidates before entering the clinic. Regulators, drug makers and patients share a demand for deep characterization of secondary pharmacology effects of novel drugs and their metabolites. The scope of such profiling has therefore expanded substantially in the past two decades, leading to the implementation of broad in silico profiling methods and focused in vitro off-target screening panels, to identify liabilities, but also opportunities, as early as possible.
View Article and Find Full Text PDFAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFSignaling diversity of G protein-coupled (GPCR) ligands provides novel opportunities to develop more effective, better-tolerated therapeutics. Taking advantage of these opportunities requires identifying which effectors should be specifically activated or avoided so as to promote desired clinical responses and avoid side effects. However, identifying signaling profiles that support desired clinical outcomes remains challenging.
View Article and Find Full Text PDFJ Pharmacol Toxicol Methods
April 2019
Introduction: High throughput in vitro profiling of the cardiac Nav1.5 peak sodium current (I) is widely used in cardiac safety screening. However, there is no standardized high throughput method to measure late I.
View Article and Find Full Text PDFPredicting ligand biological activity is a key challenge in drug discovery. Ligand-based statistical approaches are often hampered by noise due to undersampling: The number of molecules known to be active or inactive is vastly less than the number of possible chemical features that might determine binding. We derive a statistical framework inspired by random matrix theory and combine the framework with high-quality negative data to discover important chemical differences between active and inactive molecules by disentangling undersampling noise.
View Article and Find Full Text PDFJ Pharmacol Toxicol Methods
January 2019
Introduction: In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules.
Methods: An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling.
We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue.
View Article and Find Full Text PDFIn this report, we describe a method whereby lead molecules can be converted into several new analogues each using liver microsomes. Less than one micromole of substrate is incubated with liver microsomes (mouse, rat, hamster, guinea pig, rabbit, dog, monkey, or human) to produce multiple products which are isolated and analyzed by quantitative cryomicroprobe NMR (qNMR) spectroscopy. The solutions from qNMR analysis were then used as stocks that were diluted into biochemical assays.
View Article and Find Full Text PDFLate-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 () with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.
View Article and Find Full Text PDFEnhancers and long noncoding RNAs (lncRNAs) are key determinants of lineage specification during development. Here, we evaluate remodeling of the enhancer landscape and modulation of the lncRNA transcriptome during mesendoderm specification. We sort mesendodermal progenitors from differentiating embryonic stem cells (ESCs) according to Eomes expression, and find that enhancer usage is coordinated with mesendoderm-specific expression of key lineage-determining transcription factors.
View Article and Find Full Text PDFIntroduction: Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process.
View Article and Find Full Text PDFRecent data demonstrated that activation of the muscarinic M receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M and M activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M PAMs that address this hypothesis.
View Article and Find Full Text PDFS-Adenosyl-L-methionine (SAM) is an enzyme cofactor used in methyl transfer reactions and polyamine biosynthesis. The biosynthesis of SAM from ATP and L-methionine is performed by the methionine adenosyltransferase enzyme family (Mat; EC 2.5.
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