A METABOLIC-LIKE CYCLE FOR SYNTHETIC APPLICATIONS

Systems Biocatalysis is a new approach consisting of organizing enzymes in vitro to generate an artificial metabolism for synthetic purposes. The interconversion of functional groups is the main objective of biocatalysis, and systems organizing a series of enzymes to achieve a multi-step reaction have been reported. The assembly of essentially the same enzymes utilized in Nature to drive the transformation of carbohydrates towards useful synthetic intermediates [1] has been referred to as an artificial metabolism. SysBiocat aims at a similar goal addressing the generalization and organization of group of enzymes (a tool-box) able to perform a series of reactions of general synthetic utility where the feasibility is connected with the obtainment of enzymes of wide substrate specificity or in a rich array of variable common catalytic functions. [2] As a demonstration of this concept, we have recently assembled a biochemical like cycle (Asp-cycle) connecting among them an unsaturated carboxylate (fumaric acid), an alpha-amino acid (L-aspartic acid), a keto acid (oxalacetic acid) and the corresponding alpha-hydroxyacid (D- or L-malic acid). [3] In this view, the obtained cycle may be exploited by coupling it with synthetically relevant reactions which are driven to completion thanks to one or more irreversible steps in the reaction sequence. ____ [1] W.D. Fessner, C. Walter, “Artificial metabolism”, Angew Chem Int Ed, 1992, 31, p. 614 [2] U. T. Bornscheuer, G. W. Huisman, R. J. Kazlauskas, S. Lutz, J. C. Moore, K. Robins, “Engineering The Third Wave Of Biocatalysis”, Nature, 2012, 485, p. 185 [3] D. Tessaro, L. Pollegioni, L. Piubelli, P. D’Arrigo, S. Servi, “Systems Biocatalysis: An Artificial Metabolism for Interconversion of Functional Groups”, ACS Catalysis, 2015, 5, p. 160

Neoatherosclerosis and plaque rupture as triggers for very late stent thrombosis in a bare-metal stent

Very late stent thrombosis has been increasingly described in the drug eluting stent era. A 56-year-old male presented with anterior ST-elevation myocardial infarction, he received a bare-metal stent in the left anterior descending artery in 2010. We obtained an optical coherence tomography scan, showing ruptured neoatherosclerotic plaque with thrombus

Integrated Analysis of Myocardial Blush and ST-Segment Elevation Recovery After Successful Primary Angioplasty

Background — ST-segment elevation (ΣSTe) recovery and the angiographic myocardial blush (MB) grade are useful markers of microvascular reperfusion after recanalization of the infarct-related artery. We investigated the ability of a combined analysis of MB grade and ΣSTe changes to identify different patterns of myocardial reperfusion shortly after primary percutaneous coronary angioplasty (PTCA) and to predict 7-day and 6-month left ventricular (LV) functional recovery. Methods and Results — MB grade and ΣSTe recovery were evaluated shortly after successful primary PTCA (restoration of TIMI grade 3 flow) in 114 consecutive patients with ΣSTe acute myocardial infarction. LV function was assessed by 2D echocardiograms before PTCA and at 7 days and 6 months thereafter. By combining MB and ΣSTe changes, 3 main groups of patients were identified. Group 1 patients (n=60) had both significant MB (grade 2 to 3) and ΣSTe recovery (>50% versus basal ΣSTe) and a high rate of 7-day (65%) and 6-month (95%) LV functional recovery. In group 2 patients (n=21), who showed MB but persistent ΣSTe, the prevalence of early LV functional recovery was low (24%) but increased up to 86% in the late phase. Group 3 patients (n=28), who had neither significant MB nor ΣSTe resolution, had poor early (18%) and late (32%) LV functional recovery. Conclusions — After successful primary PTCA, integrated analysis of MB and ΣSTe recovery allows a real-time grading of microvascular reperfusion of the infarct area and predicts the time-course and magnitude of LV functional recovery

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

Background: Platelets play a pivotal role in the pathogenesis of acute coronary syndromes (ACS) and their inhibition remains a mainstay therapy in this setting. We aimed to perform a meta-analysis of randomized trials to evaluate the benefits of new oral antiplatelet regimens to block platelet ADPreceptors compared to standard-dose clopidogrel (300 mg loading dose followed by 75 mg/daily). Methods: We obtained results from all randomized trials enrolling patients with ACS. Primary endpoint was mortality. Secondary endpoints were myocardial infarction and definite in-stent thrombosis. Safety endpoint was the risk of major bleeding complications. We prespecified subanalyses according to new antiplatelet drugs (prasugrel/ticagrelor), high-dose clopidogrel (600 mg) and patients undergoing percutaneous coronary intervention. Results: A total of seven randomized trials were finally included in the meta-analysis (n = 58 591). We observed a significant reduction in mortality (2.9% vs. 3.4%, OR= 0.87, 95% CI 0.79–0.95, P = 0.002), recurrent myocardial infarction (4.2% vs. 5.2%, OR= 0.80, 95% CI 0.74–0.87, P < 0.0001), definite in-stent thrombosis (0.9% vs. 1.7%, OR= 0.52, 95% CI 0.43–0.63, P < 0.0001). The benefits in mortality and reinfarction were driven by the treatment with prasugrel or ticagrelor, without a significant difference in terms of major bleeding complications as compared to standarddose clopidogrel (5% vs. 4.7%, OR= 1.06 95% CI 0.96–1.17, P = 0.25). Conclusions: This meta-analysis showed that new oral antiplatelet regimens are associated with a significant reduction in mortality, reinfarction and in-stent thrombosis in ACS patients without an overall increase of major bleeding when treated with new antiplatelet drugs

Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase of acute coronary syndrome and maintains its antiplatelet potency at 30-day follow-up

Background: The aim of this study was to assess antiplatelet effect of prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) on clopidogrel, undergoing percutaneous coronary intervention (PCI).Methods: A prospective, platelet reactivity-guided, parallel-group, open-label study including 71 patients pretreated with clopidogrel 600 mg and assigned either to prasugrel (30 mg loading dose, 10 mg maintenance dose; n = 46) or clopidogrel (150 mg maintenance dose for 6 days and thereafter 75 mg maintenance dose; n = 25) regimen, based on vasodilator-stimulated phosphoprotein (VASP)-assessed platelet reactivity index (PRI; &gt; 50% vs. ≤ 50%) measured next morning post-PCI.Results: Median PRI value after switch to prasugrel sharply declined at 24 h (70.0 [61.3–75.6] vs. 11.9 [6.8–25.7]%; p &lt; 0.000001) and slightly but significantly rose between 24 h and 30 days (27.9 [15.5–46.8]%; p &lt; 0.0006). In contrast, median PRI values in the clopidogrel group were similar at baseline and at 24 h (25.1 [13.7–40.2] vs. 22.0 [18.4–36.8]%; p = NS) and then modestly rose at 30 days (30.3 [20.4–45.7]%; p &lt; 0.03). The prevalence of HTPR decreased in the prasugrel group between baseline and 24 h measurements (100.0 vs. 4.3%; p &lt; 0.0001). Rates of patients with HTPR at 24 h and 30 days were similar in both groups, so were the tendencies in patterns of platelet inhibition evaluated with multiple electrode aggregometry as compared with the VASP assay.Conclusions: Our study indicates that prasugrel overcomes HTPR on clopidogrel in the acute phase of interventionally treated ACS and maintains its antiplatelet potency in 30-day follow-up. Potential clinical benefits of personalized antiplatelet prasugrel-based therapy warrant further investigation in clinical ACS trials.