A novel class of ion displacement ligands as antagonists of the αIIbß3 receptor that limit conformational reorganization of the receptor.

A collection of αIIbß3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents' structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development.

Can Medical Devices Help Mitigate Global Environmental Change Effects on Human and Animal Health? A Pilot Study.

Globalization and urbanization are new challenges for the ability to protect public health. Indeed, the anthropogenic impact is changing the environment on a global scale. These changes can have direct and indirect health effects on both human and animal populations, introducing new diseases. Heat waves and floods are an example of these changes. Global Environmental Change (GEC) consequences on human health and well-being are stronger in urban areas, which are inhabited by 70% of the European population. In this context, the use of appropriate medical devices can also help mitigate the effects of climate change. Studies into lifestyle, environment quality and potential fields of application can be useful tools to identify possible types of medical device that could help to support the therapeutic needs and the prevention of health both in everyday life, and in the case of environmental alerts. A study was carried out on the potential role of medical devices (MDs) in mitigating the effects of GEC on human and animal health, by issuing two different questionnaires to specific professional clusters: the first to doctors, pharmacists, and veterinarians, the second to MD manufacturers. The data obtained from this study confirm the strong connection between GEC and the increase in the use of some MDs. Results obtained from questionnaires circulated to MD manufacturers confirmed this trend. MD manufacturers also declared that there are no longer any seasonal trends in market demand for some medical devices. This is a pilot study to consider MDs as a mitigation tool for CEGs.

Medication Reconciliation During Hospitalization and in Hospital-Home Interface: An Observational Retrospective Study.

OBJECTIVE: Medication errors are one of the leading causes of patient harms. Medication reconciliation is a fundamental process that to be effective, it should be embraced during each single care transition. Our objectives were to investigate current medication reconciliation practices in the 2 Fondazione Toscana Gabriele Monasterio hospitals and comprehensively assess the quality of medication reconciliation practices between inpatient and outpatient care by analyzing the medication patterns 6 months before admission, during hospitalization, and 9 months after discharge for a selected group of patients with cardiovascular diseases. METHODS: A retrospective observational study was conducted in the Cardiothoracic Department of the Fondazione Toscana Gabriele Monasterio hospitals. Medication history was reviewed for all the patients admitted from and discharged to the community, from January to March 2013. Patients were excluded if they had less than 4 drugs or less than 2 drugs for cardiovascular system in their prescription list at admission or if they died during follow-up. We selected 714 patients, and we obtained the clinical charts and all drug prescriptions collected during patients' hospitalization by the electronic clinical recording system. We also analyzed the list of prescriptions of this sample of patients, from 6 months before admission to 9 months after discharge, extracted from the regional prescription registry. In the resulting sample, prescriptions were analyzed to assess unintentional discrepancies. RESULTS: The study included 298 patients (mean age, 71.2 years), according to the inclusion and exclusion criteria. Among 14,573 prescriptions analyzed, we found 4363 discrepancies (14.6 discrepancies per patient). Among these discrepancies, 1310 were classified as unintentional (4.4 discrepancies per patient). Among unintentional discrepancies, only 63 (4.8%) took place during hospitalization. Although at the hospital-home interface, 33.1% of unintentional discrepancies were detected through the comparison between the patients' declared therapy and the previous medication consumption and 62.1% were identified in the comparison between the prescription at the discharge and the following medication pattern at home. CONCLUSIONS: Medication errors have important implications for patient safety, and their identification is a main target for improving clinical practice. The comparison between the medication patterns acquired through the regional prescription registry before and after hospitalization outlined critical touchpoint in the current medication reconciliation process, calling for the definition of shared medication reconciliation standards between hospitals and primary care services to minimize medication discrepancies and enhance patient safety.

[18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain, Transthyretin Amyloidosis, and Mimicking Conditions.

OBJECTIVES: This study aimed to test the diagnostic value of [18F]-florbetaben positron emission tomography (PET) in patients with suspicion of CA. BACKGROUND: Diagnosis of cardiac involvement in immunoglobulin light-chain-derived amyloidosis (AL) and transthyretin-related amyloidosis (ATTR), which holds major importance in risk stratification and decision making, is frequently delayed. Furthermore, although diphosphonate radiotracers allow a noninvasive diagnosis of ATTR, demonstration of cardiac amyloidosis (CA) in AL may require endomyocardial biopsy. METHODS: Forty patients with biopsy-proven diagnoses of CA (20 ALs, 20 ATTRs) and 20 patients referred with the initial clinical suspicion and later diagnosed with non-CA pathology underwent a cardiac PET/computed tomography scan with a 60-min dynamic [18F]-florbetaben PET acquisition, and 4 10-min static scans at 5, 30, 50, and 110 min after radiotracer injection. RESULTS: Visual qualitative assessment showed intense early cardiac uptake in all subsets. Patients with AL displayed a high, persistent cardiac uptake in all the static scans, whereas patients with ATTR and those with non-CA showed an uptake decrease soon after the early scan. Semiquantitative assessment demonstrated higher mean standardized uptake value (SUVmean) in patients with AL, sustained over the whole acquisition period (early SUVmean: 5.55; interquartile range [IQR]: 4.00 to 7.43; vs. delayed SUVmean: 3.50; IQR: 2.32 to 6.10; p = NS) compared with in patients with ATTR (early SUVmean: 2.55; IQR: 1.80 to 2.97; vs. delayed SUVmean: 1.25; IQR: 0.90 to 1.60; p < 0.001) and in patients with non-CA (early SUVmean: 3.50; IQR: 1.60 to 3.37; vs. delayed SUVmean: 1.40; IQR: 1.20 to 1.60; p < 0.001). Similar results were found comparing heart-to-background ratio and molecular volume. CONCLUSIONS: Delayed [18F]-florbetaben cardiac uptake may discriminate CA due to AL from either ATTR or other mimicking conditions. [18F]-florbetaben PET/computed tomography may represent a promising noninvasive tool for the diagnosis of AL amyloidosis, which is still often challenging and delayed. (A Prospective Triple-Arm, Monocentric, Phase-II Explorative Study on Evaluation of Diagnostic Efficacy of the PET Tracer [18F]-Florbetaben [Neuraceq] in Patients With Cardiac Amyloidosis [FLORAMICAR2]; EudraCT number: 2017-001660-38).

PCSK9 Inhibitors' New Users: Analysis of Prescription Patterns and Patients' Characteristics from an Italian Real-world Study.

BACKGROUND AND OBJECTIVE: Cardiovascular (CV) diseases represent a major cause of death and severe medical condition worldwide. Different therapeutic options are available to control low-density lipoprotein cholesterol (LDL-C) level in order to prevent CV events. In recent years, two new drugs were approved for patients who are unable to reduce circulating LDL-C with the current therapies: evolocumab and alirocumab (proprotein convertase subtilisin/kexin type nine [PCSK9] inhibitors). This study was aimed to characterise patients who started treatment with PCSK9 inhibitors in the Tuscany region of Italy during the first year of public healthcare service reimbursement and to describe the pattern of PCSK9 inhibitor use in the first 6 months of treatment. METHODS: Patients on PCSK9 inhibitor treatment in Tuscany (3.7 million inhabitants) from 07/2017 to 06/2018 were selected from regional healthcare administrative databases. Concomitant use of lipid-lowering therapies (LLTs), adherence and persistence during the 6 months preceding the first PCSK9 inhibitor dispensing, as well as comorbidities since 1996, were described. In the first 6 months of PCSK9 inhibitor treatment, adherence, persistence and concomitant LLTs were assessed. RESULTS: There were 269 (176 evolocumab, 93 alirocumab) new users of PCSK9 inhibitors. Patients (mean age of 59.1 years) were mainly male (71.0%) in secondary prevention (70.2%) and affected by familial hypercholesterolaemia (53.5%). Sixty-six patients (24.5%) had diabetes mellitus and 12 (4.5%) chronic renal failure. In the 6 months prior to the first PCSK9 inhibitor administration, 61.3% of patients received at least one prescription of ezetimibe or high-intensity statins and 45.7% were persistent to these drugs. During follow-up, 79.9% of patients were adherent to PCSK9 inhibitor and 73.3% were persistent. CONCLUSIONS: During the first year of availability, the rate of prescription of PCSK9 inhibitors appears below expectations. Patients were mainly in secondary prevention and had been slightly persistent to previous LLTs. During follow-up, the PCSK9 inhibitor monotherapy showed high levels of adherence and persistence. This real-world study sets the stage for future longer-term investigations useful to improve our knowledge on the appropriateness, drug access and public healthcare sustainability of PCSK9 inhibitors.

Platelet proteome and clopidogrel response in patients with stable angina undergoing percutaneous coronary intervention.

OBJECTIVES: We analyzed the platelet proteome of circulating platelets during the onset of clopidogrel therapy in patients with stable angina underwent percutaneous coronary intervention in order to investigate the mechanisms that control platelet reactivity and clopidogrel response in this context. DESIGN & METHODS: Twenty patients were enrolled in this study. Blood samples were collected before coronary angiography (T0), 12 h after 600 mg of clopidogrel (T1) and 24 h after percutaneous coronary intervention (PCI) (T2). Platelet reactivity, Clopidogrel response and proteomic analysis were examined. RESULTS: Clopidogrel loading dose produced a significant inhibition in all markers of platelet activation in both flow cytometry and aggregation tests. Among the proteins found differentially expressed, eighteen were identified by MS/MS analysis and they resulted involved in the cytoskeleton rearrangement (profilin-1, calpain, α-soluble NSF attachment protein, thrombospondin), in the energetic metabolism (ubiquitin-like modifier-activating enzyme 1, protein-L-isoaspartate-(D-aspartate) O-methyltransferase and nucleoside diphosphate kinase B) and in the oxidative stress (heat shock 70 kDa protein 5 and anti-stress induced phosphoprotein 1. CONCLUSIONS: The present study provides novel information on platelet proteome changes associated with platelet activation and clopidogrel response. This investigation supports the development of further proteomic studies for the identification of novel platelet biomarkers.

Risk stratification after coronary artery bypass surgery by a point-of-care test of platelet function.

BACKGROUND: Aspirin is one of the main therapeutics in prevention of cardiovascular events due to its antiplatelet activity. However, a sufficient inhibition of platelet function by aspirin is not always achieved. This means that the extent of protection from cardiovascular event is limited. Recently, several studies have introduced the concept of residual platelet reactivity during aspirin therapy and suggested that about 40% of aspirin users may not respond adequately. We sought to determine whether the profile and prevalence of residual platelet reactivity, measured with the platelet function analyzer (PFA-100; Dade/Behring, Marburg, Germany) device could predict a recurrent cardiovascular event in patients undergoing coronary artery bypass surgery. METHODS: A cohort of 202 consecutive patients receiving primary coronary artery bypass surgery during 2004 was prospectively recruited. All patients postoperatively received regular standard daily 100 mg aspirin. Platelet function was analyzed by the PFA-100 at 30 +/- 6 days after surgery. A PFA100 closure time less than 190 seconds was defined as residual platelet reactivity. Eighty-six patients (43%) showed residual platelet reactivity. The mean follow-up time was 32 +/- 10 months and was 100% complete. RESULTS: A total of 75 cardiovascular events have been registered. The majority of these events were among patients with residual platelet activity (p = 0.001). Out of this number, graft failure was documented in 25 patients. The 42-month freedom from major cardiovascular events was significantly better for patients with adequate platelet inhibition (p = 0.001). At multivariable analysis residual platelet reactivity (p = 0.012), incomplete revascularization (p = 0.029), and diabetes (p = 0.0009) were independently associated with occurrence of negative events. CONCLUSIONS: Our results demonstrate that high residual platelet reactivity independently correlates with a worst clinical outcome in patients treated by coronary artery bypass surgery. The PFA-100 point care test could cheaply and simply discover this condition and contribute to improve the outcome of this subset of patients.