Valutazione della reattività piastrinica residua in pazienti con sindrome coronarica acuta in terapia antiaggregante

RIASSUNTO Introduzione: La terapia antiaggregante con aspirina e clopidogrel, volta alla inibizione della funzione e reattività piastrinica, rappresenta il trattamento standard per la riduzione degli eventi cardiovascolari avversi maggiori (MACE) nei pazienti con sindrome coronarica acuta sottoposti ad angioplastica coronarica ed impianto di stent. Tuttavia, i MACE, inclusa la grave complicanza della trombosi su stent, si verificano, sebbene in minor percentuale, nei pazienti in duplice terapia antiaggregante. Esistono numerose evidenze che dimostrano che una residua reattività piastrinica in corso di terapia antiaggregante si associa ad un incrementato rischio di complicanze averse cardiovascolari. La tienopiridina clopidogrel necessita di assorbimento intestinale e conversione epatica a metabolita attivo a carico di numerose isoforme del citocromo P450, tra le quali la CYP2C19 gioca un ruolo fondamentale; il metabolita attivo del clopidogrel inibisce, quindi, l’attivazione piastrinica indotta da ADP legandosi irreversibilmente al recettore piastrinico P2Y12. Negli ultimi anni diversi studi hanno sottolineato la possibile interferenza dei farmaci inibitori della pompa protonica (PPI) sull'effetto antiaggregante del clopidogrel, a causa del cross-metabolismo da parte del citocromo P450. Non è ancora del tutto chiaro se questo effetto sia una proprietà dell’intera classe o se sia specifico di un farmaco, anche se per alcuni PPI (lansoprazolo, esomeprazolo) questa interazione sembra essere più influente che per altri (pantoprazolo). Materiali e metodi: 150 pazienti consecutivi con diagnosi di sindrome coronaria acuta del tipo STEMI (n=143) e NSTEMI (n=7), trattati con angioplastica coronarica percutanea (PCI), sono stati randomizzati a ricevere un inibitore di pompa protonica (n=80) o un antagonista del recettore H2 (H2-RA) (n=70). La reattività piastrinica residua (RPR) è stata valutata mediante il Platelet Function Analyzer-100 (PFA-100) utilizzando le cartucce collagene-epinefrina (CEPI) e collagene-ADP (CADP) e mediante aggregometria a trasmissione di luce (LTA) utilizzando come stimoli pro-aggreganti adenosin difosfato (ADP) 10mM e acido arachidonico (AA) 1mM. I prelievi sono stati effettuati dopo 5 giorni (T0) e dopo 30 giorni (T1) dalla procedura di rivascolarizzazione. Risultati: I dati demografici, clinici e procedurali erano simili tra i due gruppi. La prevalenza di portatori del polimorfismo CYP2C19*2 non era statisticamente differente (27% per il gruppo PPI e 40% per il gruppo H2-RA, p=0,16). I tempi di chiusura delle cartucce CEPI (CEPI-CT) non sono risultati significativamente differenti tra i due gruppi: mediana 300 sec (range 90-300, percentili 25-75: 172-300) per il gruppo H2-RA e mediana 300 sec (range 79-300, percentili 25-75: 154-300) per il gruppo PPI a T0 (p=0,31); mediana 286 sec (range 99-300, percentili 25-75: 125-300) per il gruppo H2-RA e mediana 300 sec (range 84-300, percentili 25-75: 143-300) per il gruppo PPI a T1 (p=0,29). Per i tempi di chiusura delle cartucce CADP (CADP-CT) i dati relativi alla valutazione della funzionalità piastrinica non evidenziano una differenza statisticamente significativa tra il gruppo H2-RA ed il gruppo PPI per quanto riguarda la reattività piastrinica residua misurata come CADP-CT, sia in quinta giornata (T0) che ad un mese (T1): mediana 98 sec (range 61-300, percentili 25-75: 88-300) per il gruppo H2-RA e mediana 101 sec (range 61-300, percentili 25-75: 81-300) per il gruppo PPI a T0 (p=0,95); mediana 95 sec (range 55-300, percentili 25-75: 79-138) per il gruppo H2-RA e mediana 98 sec (range 68-300, percentili 25-75: 79-144) per il gruppo PPI a T1 (p =0,84) Abbiamo osservato un aumento significativo delle mediane dei valori di massima aggregazione (MA) indotta da ADP 10μM (ADP-MA) nel gruppo PPI, sia dopo 5 giorni che dopo 30 giorni: mediana 19% (range 0-64, percentili 25-75: 10-33) nel gruppo H2-RA e mediana 28% (range 2-85, percentili 25-75: 17-41) nel gruppo PPI a T0 (p=0,0067); mediana 28% (range 2-68, percentili 25-75: 23-44) nel gruppo H2-RA e mediana 39% (range 10-71, percentili 15-75: 30-50) nel gruppo PPI a T1 (p=0,008). Non sono state invece osservate differenze statisticamente significative ad entrambi i tempi nei valori di MA indotta da AA 1mM (AA-MA) tra il gruppo PPI ed il gruppo H2-RA: mediana 4% (range 0-63, percentili 25-75: 2-12) nel gruppo H2-RA e mediana 5% (range 0-75, percentili 25-75: 2-8) nel gruppo PPI a T0 (p=0,65); mediana 4% (range 0-28, percentili 25-75: 2-8) nel gruppo H2-RA e mediana 3% (range 0-19, percentili 25-75: 2-8) nel gruppo PPI a T1 (p=0,99) All’analisi di regressione, l’età (p=0,02), l’uso di PPI (p=0,03) e l’ipertensione (p=0,02) sono risultati significativamente associati con l'ADP-MA ad un mese, mentre a 5 giorni solo l’uso di PPI (p=0,05) era significativamente associato con l’ADP-MA. Conclusioni: Questa è la prima documentazione in uno studio randomizzato che, dopo la correzione per il bias del polimorfismo CYP2C19*2, i farmaci inibitori di pompa protonica determinano un aumento del tasso di RPR misurato con test specifici di funzionalità piastrinica piastrinica, nei pazienti trattati con duplice terapia antiaggregante. ABSTRACT Background: Antiplatelet therapy with aspirin and clopidogrel, for the inhibition of platelet function and reactivity, is the standard treatment for the reduction of major adverse cardiovascular events (MACE) in patients with acute coronary syndromes undergoing coronary angioplasty and stenting. However, MACE, including the serious complication of stent thrombosis, occur, although to a lesser percentage, in patients receiving dual antiplatelet therapy. There are many evidence to show that a residual platelet reactivity in the course of antiplatelet therapy is associated with an increased risk of cardiovascular adverse events. The thienopyridine clopidogrel requires intestinal absorption and hepatic conversion to active metabolite through various cytochrome P450 isoforms, including the CYP2C19 that plays a major role; then, the active metabolite of clopidogrel inhibits the activation of platelets by binding irreversibly P2Y12 receptor on platelet surface. In the last few years several papers have pointed out the potential interference of proton pump inhibitors (PPI) on the anti-platelet effect of clopidogrel, due to the cytochrome P450 cross-metabolism. If this is a class or a drug-specific effect is not clear, although some PPI (lansoprazole, esomeprazole) seems to be more influent than others (pantoprazole). Methods: One hundred and fifty consecutive patients with ST elevation myocardial infarction (STEMI n=143) and NSTEMI (n=7), treated with percutaneous coronary angioplasty (PCI), were randomized between a PPI (n=80) or a H2-receptor antagonist (H2-RA) (n=70). High on-antiaggregant therapy Residual Platelet Reactivity (RPR) was evaluated by Platelet Function Analyzer-100 (PFA-100) with collagen-epinephrine (CEPI) and collagene-ADP (CADP) cartridge and light transmitted aggregometry with 10µM adenosin diphosphate (ADP) and 1mM arachidonic acid (AA), on 5 (T0) and 30 (T1) days after the procedure. Results: Demographic, clinical and procedural data were similar between the two groups. The prevalence of carriers of the CYP2C19*2 polymorphism was not statistically different (27% for PPI group and 40% for H2-RA group, p=0.16). CEPI-CT values on days 5 and 30 were not significantly different: median 300 sec (range 90-300, 25-75 percentiles: 172-300) for H2-RA group and median 300 sec (range 79-300, 25-75 percentiles: 154-300) for PPI group at T0 (p=0.31); median 286 sec (range 99-300, 25-75 percentiles:125-300) for H2-RA group and median 300 sec (range 84-300, 25-75 percentiles: 143-300) for PPI group at T1 (p=0.29). In a similar way CADP-CT CT values on days 5 and 30 were not significantly different: median 98 sec (range 61-300, 25-75 percentiles: 88-300) for H2-RA group and median 101 sec (range 61-300, 25-75 percentiles: 81-300) for PPI group at T0 (p=0.95); median 95 sec (range 55-300, 25-75 percentiles:79-138) for H2-RA group and median 98 sec (range68-300, 25-75 percentiles: 79-144) for PPI group at T1 (p=0.84) We observed a significant increase in maximal aggregation (MA) values induced by 10µM ADP in PPI group, on days 5 and 30: median 19% (range 0-63, 25-75 percentiles: 10-33) for H2-RA group and median 28% (range 2-85, 25-75 percentiles: 17-41) for PPI group at T0 (p=0.0067); median 28% (range 2-68, 25-75 percentiles: 23-44) for H2-RA group and median 39% (range 10-71, 25-75 percentiles: 30-50) for PPI group at T1 (p=0.008). Not statistically difference were observed at day 5 and 30 in the MA values for 1mM AA stimulus between PPI and H2-RA group: median 4% (range 0-63, 25-75 percentiles: 2-12) for H2-RA group and median 5% (range 0-75, 25-75 percentiles: 2-8) for PPI group at T0 (p=0.65); median 4% (range 0-28, 25-75 percentiles: 2-8) for H2-RA group and median 3% (range 0-19, 25-75 percentiles: 2-8) for PPI group at T1 (p=0.99). At the regression analysis, age (p=0.02), PPI use (0.03) and hypertension (p=0.02) were significantly associated with ADP-MA at one month, while at 5 days only the use of PPI (p=0.05) was significantly associated with ADP-MA. Conclusions: This is the first documentation in a randomized trial after correction for the bias of CYP 2C19 polymorphism that pantoprazole increases the rate of RPR by specific tests of platelet activity in patients treated with dual antiplatelet therapy

Guidelines for the use of contrast-enhanced ultrasound in hepatocellular carcinoma

Abstract Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) relies on ultrasound (US) examinations performed at 6-month intervals. Early detection of HCC on a cirrhotic background is a challenging issue, since the US features of the different entities in the multi-step process of hepatocarcinogenesis – such as low-grade and high-grade dysplastic nodule – do overlap. Contrast-enhanced US allows reliable detection of arterial neo-angiogenesis associated with the malignant change. Several reports have shown that the ability of contrast-enhanced US to diagnose HCC currently approaches that of optimised multidetector computed tomography (CT) or dynamic magnetic resonance (MR) imaging protocols. The use of contrast-enhanced US to characterise nodular lesions in cirrhosis has recently been recommended by the clinical practice guidelines issued by the European Federation of Societies for Ultrasound in Medicine and Biology and the American Association for the Study of Liver Diseases. Contrast-enhanced US has also been successfully used to assess response of HCC to image-guided percutaneous ablation procedures. In this article, we discuss the advantages and limitations of contrast-enhanced US with respect to the other imaging modalities in the setting of HCC

FineCat : a meeting fostering progress in frontier research and sustainable development from and within Sicily

Scientific meetings on topics of socioeconomic and environmental global relevance such as the \u201cFineCat Symposium on heterogeneous catalysis for fine chemicals\u201d held in Sicily between 2012 and 2017 may actively promote sustainable development and progress in frontier research from and within developing areas of the world

Photocatalytic and oxidative synthetic pathways for highly efficient PANI-TIO2 nanocomposites as organic and inorganic pollutant sorbents

Polyaniline (PANI)-materials have recently been proposed for environmental remediation applications thanks to PANI stability and sorption properties. As an alternative to conventional PANI oxidative syntheses, which involve toxic carcinogenic compounds, an eco-friendly procedure was here adopted starting from benign reactants (aniline-dimer and H2O2) and initiated by ultraviolet (UV)-irradiated TiO2. To unlock the full potential of this procedure, we investigated the roles of TiO2 and H2O2 in the nanocomposites synthesis, with the aim of tailoring the properties of the final material to the desired application. The nanocomposites prepared by varying the TiO2:H2O2:aniline-dimer molar ratios were characterized for their thermal, optical, morphological, structural and surface properties. The reaction mechanism was investigated via mass analyses and X-ray photoelectron spectroscopy. The nanocomposites were tested on both methyl orange and hexavalent chromium removal. A fast dye-sorption was achieved also in the presence of interferents and the recovery of the dye was obtained upon eco-friendly conditions. An efficient Cr(VI) abatement was obtained also after consecutive tests and without any regeneration treatment. The fine understanding of the reaction mechanism allowed us to interpret the pollutant-removal performances of the different materials, leading to tailored nanocomposites in terms of maximum sorption and reduction capability upon consecutive tests even in simulated drinking water

Triply green polyaniline: UV irradiation-induced synthesis of highly porous PANI/TiO2 composite and its application in dye removal

An environmentally benign procedure for the preparation of polyaniline/TiO2 composites is presented. The UV irradiation-induced synthesis leads to materials with good crystallinity and tailored morphology, showing promising sorption and recycle properties in dye removal tests. A reaction mechanism is proposed on the basis of LC-MS and FT-IR investigations

Polyaniline/TiO2 composites: green photocatalysic synthesis and application in wastewater remediation

In recent years, polyaniline (PANI) composites and nanocomposites with metal and metal-oxide materials have received growing attention for electrochemical and photoelectrochemical applications (Gu 2013). Among them, PANI/TiO2 composites are probably the most interesting systems due to synergistic effects between the conductive polymer and the oxide photocatalyst in terms of photogenerated charge separation and photocatalytic efficiency (Bae 2011). Moreover, polyaniline has been reported to possess favourable sorption properties, which can be exploited for pollutant remediation (Alcaraz-Espinoza 2015, Janaki 2012). PANI/TiO2 composites are thus promising candidates for wastewater treatment combining different pollutant remediation approaches. Polyaniline is classically synthesised via oxidative polymerization (Tran 2011), which involves noxious reagents (aniline and peroxydisulfates) and leads to toxic and carcinogenic byproducts (such as benzidine and trans-azobenzidine). In recent years, greener alternatives have been reported, such as a synthetic process starting from aniline dimer ((4-aminophenil)aniline) and using Fe3+ as catalyst and H2O2 as oxidant (Della Pina 2018). Unfortunately, this alternative procedure does not offer any control over the polymer morphology, leading to compact materials with low surface area and, as a consequence, poor dye-sorption capability. Very recently, we proposed a new photocatalytically induced green synthesis leading to stable polyaniline/TiO2 composites with porous morphology, wide surface area, high crystallinity and, most important, excellent dye removal performance and reusability (Cionti 2018). The reaction is carried out in two steps: at first, the aniline dimer is dissolved in a HCl aqueous solution and TiO2 is added while starting UV irradiation. In the second step, H2O2 is added in the dark, leading to the final product. In this work, we shed light on the photocatalytic nature of the synthetic mechanism, highlighting the different roles of TiO2 and of H2O2 on the composite structural and morphological features as well as on the composite performance for pollutant abatement. The reaction mechanism was investigated by a combination of spectrometric techniques, radical scavenger tests, and surface characterizations (Fig.1). By sampling the reaction mixture at different irradiation times, we demonstrated that under UV irradiation the growth of the oligomers occurs at the TiO2 particle surfaces. The same experiment carried out without UV irradiation showed the intrinsic photocatalytic nature of the process: in the dark, only short oligomers without appropriate chain conjugation were produced. However, even after prolonged UV irradiation, the final green product could be obtained only upon addition of H2O2, showing that, while oligomer formation is initiated by radicals produced by TiO2 photocatalysis, small amounts of an oxidant (H2O2) are still needed for the polymer chain growth. The role of the H2O2 amount proved to be especially crucial with respect to the composite properties. Increasing the H2O2 amount together with that of TiO2 led to composites with low surface area and reduced dye removal capability (Fig.2 a) due to a faster polymerization step. On the other hand, when only the photocatalyst amount was increased, neither the product morphology, nor its dye-removal ability were affected. This enables to increase the TiO2 content within the composite with the aim of enhancing its photocatalytic performance. In this respect, the composite stability was tested in water under prolonged UV irradiation, showing that the material optical, structural and morphological properties remained unchanged. The composite was tested towards the removal of anionic azo dyes in aqueous solution, evaluating the effect of the matrix composition and the composite reusability (Fig.2 b), showing promising results

Polyaniline (PANI): an innovative support for sampling and removal of VOCs in air matrices

Polyaniline (PANI)-based materials for both removal and sampling of volatile organic compounds (VOCs) from air by rapid adsorption/desorption processes have been developed. The polymer was synthesized in form of emeraldine as both salt and base using different synthetic approaches, a traditional one and a "green" one. VOCs adsorption/desorption efficiency was evaluated for all the materials analyzing the desorbed VOCs fractions by GC/MS technique and obtaining results similar to the presently adopted method employing commercial activated carbon. Most important, in this work it has been demonstrated for the first time that the use of PANI-based sorbents allowed the substitution of the toxic CS2, recommended in official methods, with the less hazardous CH3OH as the VOCs extraction solvent. Moreover, a complete regeneration of the polymers could be realized by a few rapid washing steps. Finally, the best PANI-based material was subjected to recycling tests thereby showing a high adsorption/desorption efficiency retention up to four runs

Inkjet printed doped polyaniline: navigating through physics and chemistry for the next generation devices

Innovative benzidine-free PANI-based inks for electrically conducive inkjet printed devices were developed and tested and the results compared with those obtained by traditional PANI. NMR investigations evidenced the presence of quinones and phenolic groups on the backbone of the innovative PANIs that are thought being responsible for the higher solubility in DMSO. A mechanism of reaction was proposed. The numerous characterizations (NMR, UV-Vis, FTIR, XPS and electrical investigations) allowed to compare protonation level, doping level, valence band maximum for both the type of PANI. The correlation among structural properties, printability, conductivity and solubility was discussed

Sustainable Approaches for Polyaniline and Polypyrrole Synthesis

: Among the conducting organic polymers (COPs), polyaniline (PANI) and polypyrrole (PPY) are the most investigated. Even though many efforts have been done to overcome the traditional synthetic methods typically based on the use of strong stoichiometric oxidants, the growing environmental sensitivity and the necessity of pure products, especially in medical and biological fields, make the COPs “green†synthesis a topic of the utmost importance. Herein, we report a brief overview of our results in the synthesis of PANI and PPY operating under mild conditions, using H2O2 and O2 as the oxidants in the presence of different catalysts: colloidal Au nanoparticles (AuNPs), AuNPs/TiO2, AuNPs/C, metallic Cu, Cu salts and Fe3O4 NPs