giovanni esposito - Academia.edu (original) (raw)

Papers by giovanni esposito

Research paper thumbnail of Peripheral Drug-Eluting Technology

Cardiology Clinics, 2015

This article reviews current knowledge and applications of drug-eluting devices in the treatment ... more This article reviews current knowledge and applications of drug-eluting devices in the treatment of peripheral arterial disease. The authors briefly report on the performance of plain old balloon angioplasty and bare metal stents in femoro-popliteal and below-the-knee lesions. This article explains the rationale behind the development of drug-eluting devices and describes the main technical features of currently available drug-eluting stents and drug-coated balloons. Dedicated sections discuss the results of trials investigating the potential benefits of these devices used in femoro-popliteal and infra-popliteal arterial vascular beds. Finally, ongoing studies and potential novel applications of drug-eluting technologies in other vascular beds are mentioned.

Research paper thumbnail of Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat

Neuroscience Letters, 1993

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOP... more In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12–35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was correlated to MPP+ concentrations (r = −0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = −0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.

Research paper thumbnail of Tirofiban administration and percutaneous coronary intervention with stenting of saphenous vein graft thrombosis

Journal of Cardiovascular Medicine, 2009

Distal embolization during percutaneous coronary intervention (PCI) of saphenous vein graft (SVG)... more Distal embolization during percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) lesions is associated with a high risk of myonecrosis and myocardial infarction. PCI guidelines advocate the use of distal embolic protection devices, when technically feasible, in patients undergoing PCI for SVG disease. To date, alternative management strategies are not fully investigated. We report a case of an 84-year-old male patient with acute coronary syndrome who underwent PCI for a quite occlusive stenosis of an SVG on the first diagonal branch of the left anterior descending artery complicated by wide endoluminal thrombosis with poor antegrade coronary blood flow and absent opacity of the distal first diagonal vessel. A strategy of delayed PCI after upstream, 48 h long tirofiban administration in order to obtain a thrombus burden reduction was decided. After tirofiban administration, a high-level thrombus resolution was obtained, with a significant improvement in coronary flow, and a successful PCI with stenting was performed. There was neither clinical nor instrumental periprocedural sign of ischemia, and the patient remained asymptomatic throughout his hospital stay. Preprocedural tirofiban administration followed by PCI with stenting of an SVG thrombotic lesion without a distal protection device might be a well-tolerated and feasible option for patients with degenerated SVG disease. Further studies are needed to further expand our findings.

Research paper thumbnail of Allopurinol protects against manganese-induced oxidative stress in the striatum and in the brainstem of the rat

Neuroscience Letters, 1995

Neuronal culture is capable to accumulate the ferric iron complexed to nitrilotriacetic acid (Fe-... more Neuronal culture is capable to accumulate the ferric iron complexed to nitrilotriacetic acid (Fe-NTA), resulting neurotoxicity.

Research paper thumbnail of Effect of morphine on striatal dopamine metabolism and ascorbic acid and uric acid release in freely moving rats

Brain Research, 1997

Recent ex vivo findings have shown that morphine increases dopamine (DA) and xanthine oxidative m... more Recent ex vivo findings have shown that morphine increases dopamine (DA) and xanthine oxidative metabolism and ascorbic acid (AA) oxidation in the rat striatum. In the present study, we evaluated the effects of subcutaneous daily morphine (20 mg/kg) administration on DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), AA and uric acid in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection. On the first day, morphine administration caused a significant increase in extracellular DA, DOPAC, HVA, AA and uric acid concentrations over a 3 h period after morphine. In all treated rats (n = 7), individual concentrations of DOPAC + HVA were directly correlated with individual AA and uric acid concentrations. Last morphine administration on the 4th day increased DOPAC, HVA, AA and uric acid concentrations but failed to increase those of DA. Individual DOPAC + HVA concentrations were still directly correlated with individual AA and uric acid concentrations. These results suggest that systemic morphine increases both striatal DA release and DA and xanthine oxidative metabolism. Only the former effect undergoes tolerance. The increase in DA oxidative metabolism is highly correlated with that of xanthine. The subsequent enhancement in reactive oxygen species production may account for the increase in extracellular AA.

Research paper thumbnail of On the mechanism of d-amphetamine-induced changes in glutamate, ascorbic acid and uric acid release in the striatum of freely moving rats

British Journal of Pharmacology, 2000

The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamat... more The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dialysates from the striatum of freely-moving rats were evaluated using microdialysis.d-Amphetamine (2 mg kg−1) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d-amphetamine. 5-HIAA concentrations were unaffected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated.d-Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5-HIAA, over a 2 h period after d-amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without affecting those of glutamate or AA.d-Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5-HIAA concentrations were unaffected.These results suggest that d-amphetamine-induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier-mediated uptake).The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dialysates from the striatum of freely-moving rats were evaluated using microdialysis.d-Amphetamine (2 mg kg−1) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d-amphetamine. 5-HIAA concentrations were unaffected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated.d-Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5-HIAA, over a 2 h period after d-amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without affecting those of glutamate or AA.d-Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5-HIAA concentrations were unaffected.These results suggest that d-amphetamine-induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier-mediated uptake).British Journal of Pharmacology (2000) 129, 582–588; doi:10.1038/sj.bjp.0703066

Research paper thumbnail of EFFECTS OF ALLOPURINOL ON STRIATAL DOPAMINE, ASCORBATE AND URIC ACID DURING AN ACUTE MORPHINE CHALLENGE: EX VIVO AND IN VIVO STUDIES

Pharmacological Research, 1997

In the present studyin vivoandex vivoexperiments were combined to evaluate the effects of allopur... more In the present studyin vivoandex vivoexperiments were combined to evaluate the effects of allopurinol on the neurochemical changes induced by an acute morphine challenge (2 mg kg−1, s.c.). In samples from rat striatum, levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), ascorbate (AA), dehydroascorbate (DHAA), hypoxanthine, xanthine and uric acid (UA) were measured. Brain microdialysis experiments were carried out in freely moving rats. Striatal dialysate levels were assayed for DA, DOPAC+HVA, AA and UA using liquid chromatography followed by electrochemical detection. Morphine administration increased the striatal levels of DA metabolites, UA and DHAA and the extracellular concentrations of DA, DOPAC+HVA, UA and AA. Allopurinol (50 mg kg−1by gavage), an inhibitor of xanthine oxidase which catalyses oxidation of xanthine to UA, decreased basal UA and AA concentrations and the morphine-induced increase in DA metabolites and AA oxidation. Since oxidation of DA and xanthines generates reactive oxygen species (ROS) and AA and UA are the main cellular antioxidants, these findings suggest that: (a) single morphine administration increases DA and xanthine oxidative metabolism with a consequent increase in ROS production, which may account for changes in concentrations of extracellular AA and tissue DHAA; (b) allopurinol decreases morphine-induced DA and xanthine oxidation; (c) UA and AA may act in concert to regulate levels of ROS in the brain.

Research paper thumbnail of GLUTATHIONE DEFICIENCY POTENTIATES MANGANESE TOXICITY IN RAT STRIATUM AND BRAINSTEM AND IN PC12 CELLS

Pharmacological Research, 1997

Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenali... more Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), glutathione (GSH), ascorbic acid (AA), dehydroascorbic acid (DHAA) and uric acid (UA) were determined in the striatum and/or in the brainstem of 3-month-old male Wistar rats after subchronic oral exposure to MnCl2(20 mg kg−1daily) alone or associated to buthionine(S,R)sulphoximine-ethyl ester (BSO-E), an inhibitor of GSH synthesis. The NA, DA, DOPAC, GSH and glutathione disulphide (GSSG) concentrations were also determined in PC12 cells incubated with Mn alone or associated with either BSO-E or AA. When PC12 cells were incubated with AA, cellular AA and DHAA concentrations were also determined. It was found that BSO-E: (a) decreased GSH levels in the striatum and in the brainstem; (b) potentiated the Mn-induced increase in AA oxidation and uric acid formation in both brain regions; and (c) potentiated the Mn-induced DA and NA depletion in the brainstem. Moreover, the changes in striatal DA metabolism induced by the BSO-E association with Mn (decrease in DA, DOPAC and HVA levels and in the DOPAC+HVA/DA ratio) are consistent with the hypothesis of a loss of dopaminergic neurons. In PC12 cells, BSO-E decreased GSH and GSSG levels and potentiated the Mn-induced decrease in DA and NA concentrations. On the contrary, AA antagonised the Mn-induced DA and NA depletion. AA antagonised also the Mn−and Mn+BSO-induced decrease in PC12 cells viability. In conclusion, the impairment of neuronal antioxidant system activity plays a permissive role in the oxidative stress-mediated Mn neurotoxicity.

Research paper thumbnail of Cellular defence mechanisms in the striatum of young and aged rats subchronically exposed to manganese

Neuropharmacology, 1995

A deficiency of striatal dopamine (DA) is generally accepted as an expression of manganese (Mn) t... more A deficiency of striatal dopamine (DA) is generally accepted as an expression of manganese (Mn) toxicity in experimental animals. Since compromised cellular defence mechanisms may be involved in Mn neurotoxicity, we investigated the response of the neuronal antioxidant system [ascorbic acid (AA) oxidation, glutathione (GSH) and uric acid levels]and neurochemical changes in the striatum in aged rats exposed to Mn. Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxy-tryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), AA, dehydroascorbic acid (DHAA), GSH and uric acid were determined after subchronic oral exposure to MnCl2 200 mg/kg (3-month-old rats) and 30–100–200 mg/kg (20-month-old rats). Aged rats had basal levels of striatal DA, DOPAC, HVA, 5-HT, 5-HIAA, GSH and AA lower than those of young rats. In the striatum of aged rats, Mn induced biphasic changes in the levels of DA, DOPAC, HVA (an increase at the lower dose and a decrease at the higher dose) and DHAA (opposite changes). Mn decreased GSH levels and increased uric acid levels both in the striatum and in synaptosomes in all groups of aged rats. All of these parameters were affected to a lesser extent in young rats. In conclusion, the response of cellular defence mechanisms in aged rats is consistent with a Mn-induced increase in the formation of reactive oxygen species. An age-related impairment of the neuronal antioxidant system may play an enabling role in Mn neurotoxicity.

Research paper thumbnail of Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Journal of Clinical Investigation, 2001

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber di... more Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1 -/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1 -/mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1 +/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1 +/+ and Npr1 -/mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control. J. Clin. Invest. 107:975-984 (2001).

Research paper thumbnail of Effect of naloxone on morphine-induced changes in striatal dopamine metabolism and glutamate, ascorbic acid and uric acid release in freely moving rats

Brain Research, 1998

Recent findings have shown that systemic morphine increases extracellular dopamine (DA), dihydrox... more Recent findings have shown that systemic morphine increases extracellular dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), ascorbic acid (AA) and uric acid concentrations in the striatum of freely moving rats. The morphine-induced increase in DA oxidative metabolism is highly correlated with that of xanthine. In the present study, we evaluated the effects of subcutaneous (s.c.) naloxone (1 mg/kg) on morphine-induced changes in DA, DOPAC, HVA, 5-hydroxyindoleacetic acid (5-HIAA), AA, uric acid and glutamate in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection or (glutamate) ultraviolet detection. Morphine (5–20 mg/kg) given s.c. increased DA, DOPAC+HVA, 5-HIAA, AA and uric acid and decreased glutamate dialysate concentrations over a 3 h period after morphine. Morphine (1 mM), given intrastriatally, did not affect all the above parameters, with the exception of an early short-lasting decrease in AA concentration. Naloxone antagonised all morphine-induced changes with the exception of AA increase and glutamate decrease in dialysate concentrations. Systemic or intrastrial (0.2–2 mM) naloxone increased AA and decreased glutamate dialysate concentrations. When given intranigrally, morphine (1 mM) increased DOPAC+HVA, AA and uric acid and decreased glutamate dialysate concentrations over a 2 h period after morphine; DA and 5-HIAA concentrations were unaffected. These results suggest that: (i) morphine increases striatal DA release and 5-hydroxytryptamine oxidative metabolism by a μ-opioid receptor-mediated mechanism mainly at extranigrostriatal sites; (ii) morphine increases DA and xanthine oxidative metabolism and affects glutamate and AA release by a μ-opioid receptor mediated mechanism acting also at nigral sites; and (iii) a μ-opioid receptor-mediated mechanism tonically controls at striatal sites extracellular AA and glutamate concentrations.

Research paper thumbnail of A new rat model of small vessel stenting

Basic Research in Cardiology, 2000

Objectives: Restenosis is the major complication of coronary angioplasty and stenting. In additio... more Objectives: Restenosis is the major complication of coronary angioplasty and stenting. In addition, the small vessel diameter represents a major limitation to the wide use of the technology. The aim of this study was to assess the feasibility and the vascular response of stent deployment in rat small vessels. Methods: In 40 Wistar rats (500–550 g) a Nir stent crimped on a 1.5 mm Comet angioplasty balloon catheter was deployed at high pressure in the common carotid artery. Neointimal area, neointima/media ratio and the arterial dimension were assessed immediately and at 7, 14, 21, and 28 days after stenting. Results: After stent deployment, the neointimal area and the neointima/media ratio increased progressively and peaked at 14 days (p Conclusions: The results of this study demonstrated that the balloon expandable stents can be safely placed into rat arteries and the reduction of the internal arterial lumen observed after stent deployment was only due to the neointima formation whereas remodeling did not occur.

Research paper thumbnail of Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy

Journal of The American College of Cardiology - J AMER COLL CARDIOL, 2001

OBJECTIVESWe sought to define the role of norepinephrine and epinephrine in the development of ca... more OBJECTIVESWe sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways.BACKGROUNDCardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein–coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy.METHODSWe performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh−/−, genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh−/− hearts.RESULTSCompared with the control animals, cardiac hypertrophy was significantly blunted in Dbh−/− mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun–NH2-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh−/− mice.CONCLUSIONSThese data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways.

Research paper thumbnail of Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo

Research paper thumbnail of Dopaminergic system activity and cellular defense mechanisms in the striatum and striatal synaptosomes of the rat subchronically exposed to manganese

Archives of Toxicology, 1994

In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), asc... more In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid and glutathione (GSH) were determined by HPLC in the striatum and striatal synaptosomes after subchronic oral exposure to MnCl2 50–100–150 mg/kg. Mn significantly decreased levels of DA and GSH and increased levels of DHAA and uric acid both in the striatum and synaptosomes. In synaptosomes, individual total Mn doses/rat were directly correlated with individual DOPAC/DA ratio values (r=+0.647), uric acid (r=+0.532) and DHAA levels (r=+0.889) and inversely correlated with DA (r=−0.757) and GSH levels (r=−0.608). In turn, GSH levels were inversely correlated with uric acid (r=−0.451) and DHAA levels (r=−0.460). In conclusion, the response of striatal cellular defense mechanisms (increase in AA oxidation, decrease in GSH levels) correlated well with changes in markers of dopaminergic system activity and increase in uric acid levels. The latter provides evidence of an Mn-induced oxidative stress mediated by xanthine oxidase.

Research paper thumbnail of In vivo gene transfer: prevention of neointima formation by inhibition of mitogen-activated protein kinase kinase

Basic Research in Cardiology, 1997

Background The mitogenactivated protein kinase kinase (MAPKK) is a protein downstream ras which i... more Background The mitogenactivated protein kinase kinase (MAPKK) is a protein downstream ras which is rapidly activated in cells stimulated with various extracellular signals. These proteins are believed to play a pivotal role in integrating and transmitting transmembrane signals required for cell growth. Methods and Results To study the effect of inhibition of MAPKK on smooth muscle cell (SMC) proliferationin vivo after vascular injury, we performed experimental balloon angioplasty using the standard Clowes technique in male Wistar rats 14-weeks old. The animals did not receive any treatment after vascular injury (N=6) or were randomly assigned to receive, after balloon injury, a 30% (w/v) pluronic gel solution applied to the injured carotid artery, containing respectively: 1) no plasmid DNA (n=10); 2) RSV-lacZ (encoding the β-galactosidase gene) as control gene without effects on SMC proliferation (n=10); 3) Tg-CAT (encoding cloramphenicol acetyl-transferase gene under the control of thyreoglobulin promoter) as an additional control gene without effects on SMC proliferation (n=7); 4) a negative mutant of Mitogen-Activated Protein Kinase Kinase (MAPKK) (n=13). Fourteen days after vascular injury, carotid arteries were removed and cross sections were cut and stained with hematoxylin/eosin. Morphometric analysis demonstrated, in the MAPKK-treated rats, a significant reduction of both neointima (0.096±0.018 mm2 vs. 0.184±0.019 mm2, p Conclusions The inhibition of MAPKK, by a dominant inhibitor mutant gene, prevents the SMC proliferation after vascular injuryin vivo.

Research paper thumbnail of Responsiveness to P2Y12 receptor inhibitors

Current Opinion in Cardiology, 2011

This review is aimed at describing the variability in response to P2Y12 inhibitor agents, and to ... more This review is aimed at describing the variability in response to P2Y12 inhibitor agents, and to focus on the main tests currently available to assess the responsiveness. There is high interindividual response variability to clopidogrel. Some patients do not respond to the drug; this condition can be due to patient-related factors (poor compliance, genetic factors, cardiovascular risk profile) or to drug-related factors (reduced bioavailability or absorption, drug-drug interactions). In particular, mutations of the gene encoding for cytochrome CYP2C19, responsible for clopidogrel metabolism, are associated with an increased risk of cardiovascular events. Many tools for assessing platelet function are now available, but an appropriate test able to correlate platelet function to patient clinical outcome is still far from being recognized. There is also no standardized method to address their role in clinical practice. In addition, the safety and efficacy of alternative treatments for patients with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;clopidogrel resistance&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; has not been demonstrated yet. The recent findings from the Gauging Responsiveness with a VerifyNow Assay-Impact on Thrombosis and Safety (GRAVITAS) study showed that increasing the dose of clopidogrel in patients who are resistant does not decrease the incidence of cardiovascular events. Therefore, until the results of large-scale trials of personalized antiplatelet therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended. Clopidogrel resistance is associated with higher incidence of cardiovascular events. Despite several available tools to test clopidogrel responsiveness, there is no uniform definition of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;non-responder&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; patients. The reduction of platelet reactivity in non-responder patients is not associated with reduced cardiovascular events. Current evidence suggests that higher antiplatelet regimens provide clinical benefits to the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s risk profile rather than his/her &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;platelet profile&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;.

Research paper thumbnail of MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial infarction pAtieNts-(GUARDIAN) trial: Study design and rationale

Catheterization and Cardiovascular Interventions, 2012

Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneo... more Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). In this setting, manual thrombectomy (MT) resulted in better perfusion and clinical outcomes when compared with ''conventional'' PCI (direct stenting or stenting after predilation). MGuard net protective stent (MGS, Inspire-MD, Tel-Aviv, Israel) is a new bare-metal stent (BMS) with a polyethylene theraphthalate mesh coverage anchored to the external surface of the struts aiming to minimize distal embolization during PCI. Purpose: We intend to determine whether MGS implantation is comparable with a strategy of MT pretreatment followed by BMS deployment. Study design: The MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial Infarction pAtieNts (GUARDIAN) is a multicentre, prospective, randomized, noninferiority, open-label trial with a planned inclusion of 556 STEMI patients. Patients are assigned to treatment with MGS or MT pretreatment followed by BMS implantation in the infarct-related artery. All patients are treated medically according to current international guidelines. Randomization is performed before coronary angiography. The primary endpoint is complete (!70%) ST-segment resolution at 60 min after PCI. Secondary endpoints are thrombolysis in myocardial infarction (TIMI) coronary flow grade !2, corrected TIMI frame count <23, myocardial blush grade of the infarct related area !2, and major adverse cardiac events rate at 30-day, 6-month, and 1-year follow-up. A cardiac magnetic resonance imaging substudy is planned to investigate microvascular obstruction and infarct size area reduction, at prespecified time-points, among 80 consecutive patients enrolled. Conclusions: If MGS implantation is noninferior to a strategy of MT pretreatment followed by BMS deployment, it will lend support to the use of this treatment as another possible option for STEMI patients undergoing PCI. V C 2012 Wiley Periodicals, Inc.

Research paper thumbnail of Multicentre experience with MGuard™ net protective stent in ST-elevation myocardial infarction: Safety, feasibility, and impact on myocardial reperfusion

Catheterization and Cardiovascular Interventions, 2010

Objective: To report, for the first time, angiographic and ECG results as well as in-hospital and... more Objective: To report, for the first time, angiographic and ECG results as well as in-hospital and 1-month clinical follow-up, after MGuard net protective stent (Inspire-MD, Tel-Aviv, Israel-MGS) implantation in consecutive, not randomized, STEMI patients undergoing primary or rescue PCI. Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI), in ST-elevation myocardial infarction (STEMI) setting. Methods: One-hundred consecutive patients underwent PCI, with MGS deployment for STEMI, in five different high-volume PCI centres. Sixteen patients presented cardiogenic shock at admission. Results: All patients underwent successful procedures: mean TIMI flow grade and mean corrected TIMI frame count-cTFC(n)-improved from baseline values to 2.85 6 0.40 and to 17.20 6 10.51, respectively, with a mean difference in cTFC(n) between baseline and postprocedure of 46.88 6 31.86. High-myocardial blush grade (90% MBG 3; 10% MBG 2) was also achieved in all patients. Sixty minutes post-PCI, a high rate (90%) of complete (!70%) ST-segment resolution was achieved. At in-hospital follow-up, seven deaths occurred: noteworthy, 5 of 16 patients with cardiogenic shock at admission died. After hospital discharge, no Major Adverse Cardiac Events have been reported up to 30-day follow-up. Conclusions: MGS might represent a safe and feasible option for PCI in STEMI patients, providing high perfusional and ECG improvement. Further randomized trials comparing this strategy with the conventional one are needed in the near future to assess the impact on clinical practice of this strategy. V C 2009 Wiley-Liss, Inc.

Research paper thumbnail of Peripheral Drug-Eluting Technology

Cardiology Clinics, 2015

This article reviews current knowledge and applications of drug-eluting devices in the treatment ... more This article reviews current knowledge and applications of drug-eluting devices in the treatment of peripheral arterial disease. The authors briefly report on the performance of plain old balloon angioplasty and bare metal stents in femoro-popliteal and below-the-knee lesions. This article explains the rationale behind the development of drug-eluting devices and describes the main technical features of currently available drug-eluting stents and drug-coated balloons. Dedicated sections discuss the results of trials investigating the potential benefits of these devices used in femoro-popliteal and infra-popliteal arterial vascular beds. Finally, ongoing studies and potential novel applications of drug-eluting technologies in other vascular beds are mentioned.

Research paper thumbnail of Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat

Neuroscience Letters, 1993

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOP... more In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12–35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was correlated to MPP+ concentrations (r = −0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = −0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.

Research paper thumbnail of Tirofiban administration and percutaneous coronary intervention with stenting of saphenous vein graft thrombosis

Journal of Cardiovascular Medicine, 2009

Distal embolization during percutaneous coronary intervention (PCI) of saphenous vein graft (SVG)... more Distal embolization during percutaneous coronary intervention (PCI) of saphenous vein graft (SVG) lesions is associated with a high risk of myonecrosis and myocardial infarction. PCI guidelines advocate the use of distal embolic protection devices, when technically feasible, in patients undergoing PCI for SVG disease. To date, alternative management strategies are not fully investigated. We report a case of an 84-year-old male patient with acute coronary syndrome who underwent PCI for a quite occlusive stenosis of an SVG on the first diagonal branch of the left anterior descending artery complicated by wide endoluminal thrombosis with poor antegrade coronary blood flow and absent opacity of the distal first diagonal vessel. A strategy of delayed PCI after upstream, 48 h long tirofiban administration in order to obtain a thrombus burden reduction was decided. After tirofiban administration, a high-level thrombus resolution was obtained, with a significant improvement in coronary flow, and a successful PCI with stenting was performed. There was neither clinical nor instrumental periprocedural sign of ischemia, and the patient remained asymptomatic throughout his hospital stay. Preprocedural tirofiban administration followed by PCI with stenting of an SVG thrombotic lesion without a distal protection device might be a well-tolerated and feasible option for patients with degenerated SVG disease. Further studies are needed to further expand our findings.

Research paper thumbnail of Allopurinol protects against manganese-induced oxidative stress in the striatum and in the brainstem of the rat

Neuroscience Letters, 1995

Neuronal culture is capable to accumulate the ferric iron complexed to nitrilotriacetic acid (Fe-... more Neuronal culture is capable to accumulate the ferric iron complexed to nitrilotriacetic acid (Fe-NTA), resulting neurotoxicity.

Research paper thumbnail of Effect of morphine on striatal dopamine metabolism and ascorbic acid and uric acid release in freely moving rats

Brain Research, 1997

Recent ex vivo findings have shown that morphine increases dopamine (DA) and xanthine oxidative m... more Recent ex vivo findings have shown that morphine increases dopamine (DA) and xanthine oxidative metabolism and ascorbic acid (AA) oxidation in the rat striatum. In the present study, we evaluated the effects of subcutaneous daily morphine (20 mg/kg) administration on DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), AA and uric acid in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection. On the first day, morphine administration caused a significant increase in extracellular DA, DOPAC, HVA, AA and uric acid concentrations over a 3 h period after morphine. In all treated rats (n = 7), individual concentrations of DOPAC + HVA were directly correlated with individual AA and uric acid concentrations. Last morphine administration on the 4th day increased DOPAC, HVA, AA and uric acid concentrations but failed to increase those of DA. Individual DOPAC + HVA concentrations were still directly correlated with individual AA and uric acid concentrations. These results suggest that systemic morphine increases both striatal DA release and DA and xanthine oxidative metabolism. Only the former effect undergoes tolerance. The increase in DA oxidative metabolism is highly correlated with that of xanthine. The subsequent enhancement in reactive oxygen species production may account for the increase in extracellular AA.

Research paper thumbnail of On the mechanism of d-amphetamine-induced changes in glutamate, ascorbic acid and uric acid release in the striatum of freely moving rats

British Journal of Pharmacology, 2000

The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamat... more The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dialysates from the striatum of freely-moving rats were evaluated using microdialysis.d-Amphetamine (2 mg kg−1) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d-amphetamine. 5-HIAA concentrations were unaffected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated.d-Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5-HIAA, over a 2 h period after d-amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without affecting those of glutamate or AA.d-Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5-HIAA concentrations were unaffected.These results suggest that d-amphetamine-induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier-mediated uptake).The effects of systemic, intrastriatal or intranigral administration of d-amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in dialysates from the striatum of freely-moving rats were evaluated using microdialysis.d-Amphetamine (2 mg kg−1) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d-amphetamine. 5-HIAA concentrations were unaffected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated.d-Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5-HIAA, over a 2 h period after d-amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without affecting those of glutamate or AA.d-Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5-HIAA concentrations were unaffected.These results suggest that d-amphetamine-induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier-mediated uptake).British Journal of Pharmacology (2000) 129, 582–588; doi:10.1038/sj.bjp.0703066

Research paper thumbnail of EFFECTS OF ALLOPURINOL ON STRIATAL DOPAMINE, ASCORBATE AND URIC ACID DURING AN ACUTE MORPHINE CHALLENGE: EX VIVO AND IN VIVO STUDIES

Pharmacological Research, 1997

In the present studyin vivoandex vivoexperiments were combined to evaluate the effects of allopur... more In the present studyin vivoandex vivoexperiments were combined to evaluate the effects of allopurinol on the neurochemical changes induced by an acute morphine challenge (2 mg kg−1, s.c.). In samples from rat striatum, levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), ascorbate (AA), dehydroascorbate (DHAA), hypoxanthine, xanthine and uric acid (UA) were measured. Brain microdialysis experiments were carried out in freely moving rats. Striatal dialysate levels were assayed for DA, DOPAC+HVA, AA and UA using liquid chromatography followed by electrochemical detection. Morphine administration increased the striatal levels of DA metabolites, UA and DHAA and the extracellular concentrations of DA, DOPAC+HVA, UA and AA. Allopurinol (50 mg kg−1by gavage), an inhibitor of xanthine oxidase which catalyses oxidation of xanthine to UA, decreased basal UA and AA concentrations and the morphine-induced increase in DA metabolites and AA oxidation. Since oxidation of DA and xanthines generates reactive oxygen species (ROS) and AA and UA are the main cellular antioxidants, these findings suggest that: (a) single morphine administration increases DA and xanthine oxidative metabolism with a consequent increase in ROS production, which may account for changes in concentrations of extracellular AA and tissue DHAA; (b) allopurinol decreases morphine-induced DA and xanthine oxidation; (c) UA and AA may act in concert to regulate levels of ROS in the brain.

Research paper thumbnail of GLUTATHIONE DEFICIENCY POTENTIATES MANGANESE TOXICITY IN RAT STRIATUM AND BRAINSTEM AND IN PC12 CELLS

Pharmacological Research, 1997

Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenali... more Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), glutathione (GSH), ascorbic acid (AA), dehydroascorbic acid (DHAA) and uric acid (UA) were determined in the striatum and/or in the brainstem of 3-month-old male Wistar rats after subchronic oral exposure to MnCl2(20 mg kg−1daily) alone or associated to buthionine(S,R)sulphoximine-ethyl ester (BSO-E), an inhibitor of GSH synthesis. The NA, DA, DOPAC, GSH and glutathione disulphide (GSSG) concentrations were also determined in PC12 cells incubated with Mn alone or associated with either BSO-E or AA. When PC12 cells were incubated with AA, cellular AA and DHAA concentrations were also determined. It was found that BSO-E: (a) decreased GSH levels in the striatum and in the brainstem; (b) potentiated the Mn-induced increase in AA oxidation and uric acid formation in both brain regions; and (c) potentiated the Mn-induced DA and NA depletion in the brainstem. Moreover, the changes in striatal DA metabolism induced by the BSO-E association with Mn (decrease in DA, DOPAC and HVA levels and in the DOPAC+HVA/DA ratio) are consistent with the hypothesis of a loss of dopaminergic neurons. In PC12 cells, BSO-E decreased GSH and GSSG levels and potentiated the Mn-induced decrease in DA and NA concentrations. On the contrary, AA antagonised the Mn-induced DA and NA depletion. AA antagonised also the Mn−and Mn+BSO-induced decrease in PC12 cells viability. In conclusion, the impairment of neuronal antioxidant system activity plays a permissive role in the oxidative stress-mediated Mn neurotoxicity.

Research paper thumbnail of Cellular defence mechanisms in the striatum of young and aged rats subchronically exposed to manganese

Neuropharmacology, 1995

A deficiency of striatal dopamine (DA) is generally accepted as an expression of manganese (Mn) t... more A deficiency of striatal dopamine (DA) is generally accepted as an expression of manganese (Mn) toxicity in experimental animals. Since compromised cellular defence mechanisms may be involved in Mn neurotoxicity, we investigated the response of the neuronal antioxidant system [ascorbic acid (AA) oxidation, glutathione (GSH) and uric acid levels]and neurochemical changes in the striatum in aged rats exposed to Mn. Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxy-tryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), AA, dehydroascorbic acid (DHAA), GSH and uric acid were determined after subchronic oral exposure to MnCl2 200 mg/kg (3-month-old rats) and 30–100–200 mg/kg (20-month-old rats). Aged rats had basal levels of striatal DA, DOPAC, HVA, 5-HT, 5-HIAA, GSH and AA lower than those of young rats. In the striatum of aged rats, Mn induced biphasic changes in the levels of DA, DOPAC, HVA (an increase at the lower dose and a decrease at the higher dose) and DHAA (opposite changes). Mn decreased GSH levels and increased uric acid levels both in the striatum and in synaptosomes in all groups of aged rats. All of these parameters were affected to a lesser extent in young rats. In conclusion, the response of cellular defence mechanisms in aged rats is consistent with a Mn-induced increase in the formation of reactive oxygen species. An age-related impairment of the neuronal antioxidant system may play an enabling role in Mn neurotoxicity.

Research paper thumbnail of Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Journal of Clinical Investigation, 2001

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber di... more Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1 -/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1 -/mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1 +/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1 +/+ and Npr1 -/mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control. J. Clin. Invest. 107:975-984 (2001).

Research paper thumbnail of Effect of naloxone on morphine-induced changes in striatal dopamine metabolism and glutamate, ascorbic acid and uric acid release in freely moving rats

Brain Research, 1998

Recent findings have shown that systemic morphine increases extracellular dopamine (DA), dihydrox... more Recent findings have shown that systemic morphine increases extracellular dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), ascorbic acid (AA) and uric acid concentrations in the striatum of freely moving rats. The morphine-induced increase in DA oxidative metabolism is highly correlated with that of xanthine. In the present study, we evaluated the effects of subcutaneous (s.c.) naloxone (1 mg/kg) on morphine-induced changes in DA, DOPAC, HVA, 5-hydroxyindoleacetic acid (5-HIAA), AA, uric acid and glutamate in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection or (glutamate) ultraviolet detection. Morphine (5–20 mg/kg) given s.c. increased DA, DOPAC+HVA, 5-HIAA, AA and uric acid and decreased glutamate dialysate concentrations over a 3 h period after morphine. Morphine (1 mM), given intrastriatally, did not affect all the above parameters, with the exception of an early short-lasting decrease in AA concentration. Naloxone antagonised all morphine-induced changes with the exception of AA increase and glutamate decrease in dialysate concentrations. Systemic or intrastrial (0.2–2 mM) naloxone increased AA and decreased glutamate dialysate concentrations. When given intranigrally, morphine (1 mM) increased DOPAC+HVA, AA and uric acid and decreased glutamate dialysate concentrations over a 2 h period after morphine; DA and 5-HIAA concentrations were unaffected. These results suggest that: (i) morphine increases striatal DA release and 5-hydroxytryptamine oxidative metabolism by a μ-opioid receptor-mediated mechanism mainly at extranigrostriatal sites; (ii) morphine increases DA and xanthine oxidative metabolism and affects glutamate and AA release by a μ-opioid receptor mediated mechanism acting also at nigral sites; and (iii) a μ-opioid receptor-mediated mechanism tonically controls at striatal sites extracellular AA and glutamate concentrations.

Research paper thumbnail of A new rat model of small vessel stenting

Basic Research in Cardiology, 2000

Objectives: Restenosis is the major complication of coronary angioplasty and stenting. In additio... more Objectives: Restenosis is the major complication of coronary angioplasty and stenting. In addition, the small vessel diameter represents a major limitation to the wide use of the technology. The aim of this study was to assess the feasibility and the vascular response of stent deployment in rat small vessels. Methods: In 40 Wistar rats (500–550 g) a Nir stent crimped on a 1.5 mm Comet angioplasty balloon catheter was deployed at high pressure in the common carotid artery. Neointimal area, neointima/media ratio and the arterial dimension were assessed immediately and at 7, 14, 21, and 28 days after stenting. Results: After stent deployment, the neointimal area and the neointima/media ratio increased progressively and peaked at 14 days (p Conclusions: The results of this study demonstrated that the balloon expandable stents can be safely placed into rat arteries and the reduction of the internal arterial lumen observed after stent deployment was only due to the neointima formation whereas remodeling did not occur.

Research paper thumbnail of Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy

Journal of The American College of Cardiology - J AMER COLL CARDIOL, 2001

OBJECTIVESWe sought to define the role of norepinephrine and epinephrine in the development of ca... more OBJECTIVESWe sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways.BACKGROUNDCardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein–coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy.METHODSWe performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh−/−, genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh−/− hearts.RESULTSCompared with the control animals, cardiac hypertrophy was significantly blunted in Dbh−/− mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun–NH2-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh−/− mice.CONCLUSIONSThese data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways.

Research paper thumbnail of Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo

Research paper thumbnail of Dopaminergic system activity and cellular defense mechanisms in the striatum and striatal synaptosomes of the rat subchronically exposed to manganese

Archives of Toxicology, 1994

In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), asc... more In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid and glutathione (GSH) were determined by HPLC in the striatum and striatal synaptosomes after subchronic oral exposure to MnCl2 50–100–150 mg/kg. Mn significantly decreased levels of DA and GSH and increased levels of DHAA and uric acid both in the striatum and synaptosomes. In synaptosomes, individual total Mn doses/rat were directly correlated with individual DOPAC/DA ratio values (r=+0.647), uric acid (r=+0.532) and DHAA levels (r=+0.889) and inversely correlated with DA (r=−0.757) and GSH levels (r=−0.608). In turn, GSH levels were inversely correlated with uric acid (r=−0.451) and DHAA levels (r=−0.460). In conclusion, the response of striatal cellular defense mechanisms (increase in AA oxidation, decrease in GSH levels) correlated well with changes in markers of dopaminergic system activity and increase in uric acid levels. The latter provides evidence of an Mn-induced oxidative stress mediated by xanthine oxidase.

Research paper thumbnail of In vivo gene transfer: prevention of neointima formation by inhibition of mitogen-activated protein kinase kinase

Basic Research in Cardiology, 1997

Background The mitogenactivated protein kinase kinase (MAPKK) is a protein downstream ras which i... more Background The mitogenactivated protein kinase kinase (MAPKK) is a protein downstream ras which is rapidly activated in cells stimulated with various extracellular signals. These proteins are believed to play a pivotal role in integrating and transmitting transmembrane signals required for cell growth. Methods and Results To study the effect of inhibition of MAPKK on smooth muscle cell (SMC) proliferationin vivo after vascular injury, we performed experimental balloon angioplasty using the standard Clowes technique in male Wistar rats 14-weeks old. The animals did not receive any treatment after vascular injury (N=6) or were randomly assigned to receive, after balloon injury, a 30% (w/v) pluronic gel solution applied to the injured carotid artery, containing respectively: 1) no plasmid DNA (n=10); 2) RSV-lacZ (encoding the β-galactosidase gene) as control gene without effects on SMC proliferation (n=10); 3) Tg-CAT (encoding cloramphenicol acetyl-transferase gene under the control of thyreoglobulin promoter) as an additional control gene without effects on SMC proliferation (n=7); 4) a negative mutant of Mitogen-Activated Protein Kinase Kinase (MAPKK) (n=13). Fourteen days after vascular injury, carotid arteries were removed and cross sections were cut and stained with hematoxylin/eosin. Morphometric analysis demonstrated, in the MAPKK-treated rats, a significant reduction of both neointima (0.096±0.018 mm2 vs. 0.184±0.019 mm2, p Conclusions The inhibition of MAPKK, by a dominant inhibitor mutant gene, prevents the SMC proliferation after vascular injuryin vivo.

Research paper thumbnail of Responsiveness to P2Y12 receptor inhibitors

Current Opinion in Cardiology, 2011

This review is aimed at describing the variability in response to P2Y12 inhibitor agents, and to ... more This review is aimed at describing the variability in response to P2Y12 inhibitor agents, and to focus on the main tests currently available to assess the responsiveness. There is high interindividual response variability to clopidogrel. Some patients do not respond to the drug; this condition can be due to patient-related factors (poor compliance, genetic factors, cardiovascular risk profile) or to drug-related factors (reduced bioavailability or absorption, drug-drug interactions). In particular, mutations of the gene encoding for cytochrome CYP2C19, responsible for clopidogrel metabolism, are associated with an increased risk of cardiovascular events. Many tools for assessing platelet function are now available, but an appropriate test able to correlate platelet function to patient clinical outcome is still far from being recognized. There is also no standardized method to address their role in clinical practice. In addition, the safety and efficacy of alternative treatments for patients with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;clopidogrel resistance&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; has not been demonstrated yet. The recent findings from the Gauging Responsiveness with a VerifyNow Assay-Impact on Thrombosis and Safety (GRAVITAS) study showed that increasing the dose of clopidogrel in patients who are resistant does not decrease the incidence of cardiovascular events. Therefore, until the results of large-scale trials of personalized antiplatelet therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended. Clopidogrel resistance is associated with higher incidence of cardiovascular events. Despite several available tools to test clopidogrel responsiveness, there is no uniform definition of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;non-responder&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; patients. The reduction of platelet reactivity in non-responder patients is not associated with reduced cardiovascular events. Current evidence suggests that higher antiplatelet regimens provide clinical benefits to the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s risk profile rather than his/her &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;platelet profile&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;.

Research paper thumbnail of MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial infarction pAtieNts-(GUARDIAN) trial: Study design and rationale

Catheterization and Cardiovascular Interventions, 2012

Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneo... more Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). In this setting, manual thrombectomy (MT) resulted in better perfusion and clinical outcomes when compared with ''conventional'' PCI (direct stenting or stenting after predilation). MGuard net protective stent (MGS, Inspire-MD, Tel-Aviv, Israel) is a new bare-metal stent (BMS) with a polyethylene theraphthalate mesh coverage anchored to the external surface of the struts aiming to minimize distal embolization during PCI. Purpose: We intend to determine whether MGS implantation is comparable with a strategy of MT pretreatment followed by BMS deployment. Study design: The MGUard versus bAre-metal stents plus manual thRombectomy in ST-elevation myocarDial Infarction pAtieNts (GUARDIAN) is a multicentre, prospective, randomized, noninferiority, open-label trial with a planned inclusion of 556 STEMI patients. Patients are assigned to treatment with MGS or MT pretreatment followed by BMS implantation in the infarct-related artery. All patients are treated medically according to current international guidelines. Randomization is performed before coronary angiography. The primary endpoint is complete (!70%) ST-segment resolution at 60 min after PCI. Secondary endpoints are thrombolysis in myocardial infarction (TIMI) coronary flow grade !2, corrected TIMI frame count <23, myocardial blush grade of the infarct related area !2, and major adverse cardiac events rate at 30-day, 6-month, and 1-year follow-up. A cardiac magnetic resonance imaging substudy is planned to investigate microvascular obstruction and infarct size area reduction, at prespecified time-points, among 80 consecutive patients enrolled. Conclusions: If MGS implantation is noninferior to a strategy of MT pretreatment followed by BMS deployment, it will lend support to the use of this treatment as another possible option for STEMI patients undergoing PCI. V C 2012 Wiley Periodicals, Inc.

Research paper thumbnail of Multicentre experience with MGuard™ net protective stent in ST-elevation myocardial infarction: Safety, feasibility, and impact on myocardial reperfusion

Catheterization and Cardiovascular Interventions, 2010

Objective: To report, for the first time, angiographic and ECG results as well as in-hospital and... more Objective: To report, for the first time, angiographic and ECG results as well as in-hospital and 1-month clinical follow-up, after MGuard net protective stent (Inspire-MD, Tel-Aviv, Israel-MGS) implantation in consecutive, not randomized, STEMI patients undergoing primary or rescue PCI. Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI), in ST-elevation myocardial infarction (STEMI) setting. Methods: One-hundred consecutive patients underwent PCI, with MGS deployment for STEMI, in five different high-volume PCI centres. Sixteen patients presented cardiogenic shock at admission. Results: All patients underwent successful procedures: mean TIMI flow grade and mean corrected TIMI frame count-cTFC(n)-improved from baseline values to 2.85 6 0.40 and to 17.20 6 10.51, respectively, with a mean difference in cTFC(n) between baseline and postprocedure of 46.88 6 31.86. High-myocardial blush grade (90% MBG 3; 10% MBG 2) was also achieved in all patients. Sixty minutes post-PCI, a high rate (90%) of complete (!70%) ST-segment resolution was achieved. At in-hospital follow-up, seven deaths occurred: noteworthy, 5 of 16 patients with cardiogenic shock at admission died. After hospital discharge, no Major Adverse Cardiac Events have been reported up to 30-day follow-up. Conclusions: MGS might represent a safe and feasible option for PCI in STEMI patients, providing high perfusional and ECG improvement. Further randomized trials comparing this strategy with the conventional one are needed in the near future to assess the impact on clinical practice of this strategy. V C 2009 Wiley-Liss, Inc.