Two-step screening method to identify α-synuclein aggregation inhibitors for Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson’s disease.

Management of combined oral antithrombotic therapy by an antithrombotic stewardship program: a prospective study

Aims: Given the complexity of antithrombotic therapy guidelines especially in patients with combined antithrombotic therapy, there is a risk of inappropriate prescribing and medication errors. In order to prevent this, a multidisciplinary antithrombotic stewardship (ASP) is implemented in our hospital. The primary aim of this study is to determine the efficacy of this ASP by assessing the number of patients on combined antithrombotic therapy for whom one or more interventions are needed. Methods: A prospective cohort study in a large teaching hospital is conducted. Hospitalized patients who received combined antithrombotic therapy in which an oral anticoagulant was combined with one (double therapy) or two (triple therapy) platelet aggregation inhibitors were included. The ASP proactively evaluated the appropriateness of this combined antithrombotic therapy. If needed, ASP improved the concerned therapy. Each improvement measurement by ASP was counted as one intervention. Results: A total of 460 patients were included over a period of 12 months. 251 (54.6%) patients required at least one intervention from the ASP. The most common intervention was to define and document a maximum duration of the combined antithrombotic therapy (65.5%) instead of lifetime use of the combination, to discontinue antithrombotic therapy (19.4%) as the proper indication was lacking and to adjust the dosage (8.1%). Conclusion: As intervention was needed in more than half of the patients on combined antithrombotic therapy, it seems essential to implement an ASP that dedicated evaluates antithrombotic therapy to improve and ensure optimal use and medication safety.

699Are we treating our older generations appropriately?

Background This study aims to understand the disease burden of Atrial Fibrillation (AF) and how it is treated among older Australian women. Methods Data from the oldest cohort (born 1921-26) of the Australian Longitudinal Study of Women’s Health were linked to state based hospital data to identify AF and to Pharmaceutical Benefit Scheme data for medication details. Yearly prevalence and incidence of AF was calculated, followed by calculation of proportions for different medications received. Results A total of 6671 women were eligible for the analysis. About 1827 women from were identified as having AF between 2000-2015. Despite steady incidence, prevalence of AF increased from 2.7% (95%CI=1.6%-3.8%) when women were aged 74-79 years to 24.8% (95%CI=23.2%-26.4%) in 2015 when women were 89-94 years. About 10% of women with AF did not receive any treatment for AF and another 60% did not receive any prophylaxis for thromboembolism within 3 years of AF onset. More than three quarters of women with AF received a combination of medications. Rate control with Vitamin K Inhibitors and Rate control with Platelet Aggregation Inhibitors were the most common combinations. Conclusions Older women have high prevalence of AF. These women are undertreated for the prevention of the most common and disabling complication of AF, stroke. Key messages Prevalence of AF is increasing and women receive inadequate treatment rendering them at risk of serious complications like stroke. This results in reduced quality of life for patients as well as burdens the health care system.

Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.