Publications by authors named "Alberto Auteri"

39 Publications

Role of genetic factors in statins side-effects.

Cardiovasc Hematol Disord Drug Targets 2012 Sep;12(1):35-43

Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Centre for Atherosclerosis Research, University of Siena, Italy.

Statins are relevant drugs involved in the reduction of cardiovascular events both in primary and secondary prevention. Related muscular side-effects are the most common cause of withdrawal and statins discontinuation could induce a negative rebound effect in terms of vascular events. Among factors in association with statins side-effects the combination with other drugs and the female sex are established conditions. However recent data suggest a specific genetic influence in intolerance development, at least for some statins. Indeed a genome-wide study in patients treated with simvastatin found an impressive association between single-nucleotide polymorphisms (SNPs) located within SLCO1B1 gene on chromosome 12 and established myopathy. Furthermore, the association between the SLCO1B1*5 variant and side-effects was found also in patients treated with atorvastatin but not, apparently, with pravastatin and categorized as carriers of mild-myopathy. Recently a similar evidence has been suggested in type 2 diabetic patients treated mainly with simvastatin. However another relevant issue is that, apart from genetic influence in liver transporters influencing drug levels, the complexity of mechanisms involved in the muscular side effects of statins has been addressed by the evidence of other influencing pathways such as the variant within the COQ2 gene involved in Coenzyme Q(10) mild-asymptomatic deficiency and skeletal muscle drug transporters expression. In conclusion, the picture of putative pharmacogenetic modulation of statins safety is reaching a growing body of evidence for translation into clinical practice but more specific studies for each single statin, in different clinical settings, both from genome-wide or competitive candidate genes evaluation, are needed before describing a definitive class-risk profile.
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http://dx.doi.org/10.2174/187152912801823138DOI Listing
September 2012

Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia.

Atherosclerosis 2011 Jan 5;214(1):122-8. Epub 2010 Nov 5.

Center for Atherosclerosis Research, University of Siena, v.le Bracci, 53100 Siena, Italy.

Objectives: We examined the time-dependent effects of atorvastatin and rosuvastatin on in vivo oxidative stress and platelet activation, to assess whether these phenomena are related to any pleiotropic effect of any statin or to their LDL-lowering effect. We also asked whether the presence of specific allele frequencies in carriers of the 3'UTR/lectin-like oxidized LDL receptor-1 (LOX-1) polymorphism may influence the effect of either statin.

Methods: We included 60 hypercholesterolemic subjects, previously screened for LOX-1 3'UTR polymorphism, randomized, according to genetic profile (15 T and 15 C carriers for each arm), to atorvastatin 20mg/day or rosuvastatin 10mg/day.

Results: After 8 weeks, atorvastatin and rosuvastatin were associated with comparable, significant reductions in LDL cholesterol (40.8% and 43.6%, respectively), plasma hs-CRP (9.5% vs. 13.8%), urinary 11-dehydro-thromboxane (TX) B(2) (38.9% vs. 27.1%) and 8-iso-prostaglandin (PG) F(2α) (39.4% vs. 19.4%). The impact of rosuvastatin or atorvastatin on CRP, 8-iso-PGF(2α), and 11-dehydro-TXB(2) did not differ according to the LOX-1 haplotype. On multiple regression analyses, only CRP and LDL were independent predictors of 11-dehydro-TXB(2), and only LDL was a significant predictor of 8-iso-PGF(2α).

Conclusions: Both atorvastatin and rosuvastatin cause comparable reductions of thromboxane-dependent platelet activation, lipid peroxidation and inflammation. The presence of 3'UTR/LOX-1 polymorphism does not affect the changes induced by either statin.
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http://dx.doi.org/10.1016/j.atherosclerosis.2010.10.006DOI Listing
January 2011

Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study.

J Hypertens 2010 Nov;28(11):2342-50

Department of Internal Medicine, Ospedale L. Sacco, University of Milan, Milan, Italy.

Objective: To compare the efficacy and safety of the angiotensin II antagonist olmesartan medoxomil (O) and the ACE inhibitor ramipril (R) in elderly patients with essential arterial hypertension.

Methods: After a 2-week placebo wash-out 1102 treated or untreated elderly hypertensive patients aged 65-89 years (office sitting diastolic blood pressure, DBP, 90-109 mmHg and/or office sitting systolic blood pressure, SBP, 140-179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once-daily. After the first 2 and 6 weeks doses could be doubled in non-normalized [blood pressure (BP) < 140/90 mmHg for nondiabetic and < 130/80 mmHg for diabetic) individuals, up to 40 mg for O and 10 mg for R. Office BPs were assessed at randomization, after 2, 6 and 12 weeks of treatment, whereas 24-h ambulatory BP was recorded at randomization and after 12 weeks.

Results: In the intention-to-treat population (542 patients O and 539 R) after 12 weeks of treatment baseline-adjusted office SBP and DBP reductions were greater (P < 0.01) with O [17.8 (95% confidence interval: 16.8/18.9) and 9.2 (8.6/9.8) mmHg] than with R [15.7 (14.7/16.8) and 7.7 (7.1/8.3) mmHg]. BP normalization rate was also greater under O (52.6 vs. 46.0% R, P < 0.05). In the subgroup of patients with valid ambulatory BP recording (318 O and 312 R) the reduction in 24-h average BP was larger (P < 0.05) with O [SBP: 11.0 (12.2/9.9) and DBP: 6.5 (7.2/5.8) mmHg] than with R [9.0 (10.2/7.9) and 5.4 (6.1/4.7) mmHg]. The larger blood pressure reduction obtained with O was particularly evident in the last 6 h from the dosing interval; a better homogeneity of the 24-h BP control with O was confirmed by higher smoothness indices. The proportion of patients with drug-related adverse events was comparable in the two groups (3.6 O vs. 3.6% R), as well as the number of patients discontinuing study drug because of a side effect (14 O vs. 19 R).

Conclusion: In elderly patients with essential arterial hypertension O provides an effective, prolonged and well tolerated BP control, representing a useful option among first-line drug treatments of hypertension in this age group.
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http://dx.doi.org/10.1097/HJH.0b013e32833e116bDOI Listing
November 2010

Variations of plasma leptin and adiponectin levels in autistic patients.

Neurosci Lett 2010 Jul 15;479(1):54-7. Epub 2010 May 15.

Center of Clinical Pharmacology, University of Siena, Siena, Italy.

Autism is a neurodevelopmental disorder with pathogenesis not completely understood. Although a genetic origin has been recognized, it has been hypothesized a role for environmental factors, immune dysfunctions, and alterations of neurotransmitter systems. In young autistic patients we investigated plasma leptin and adiponectin levels over a year period. Thirty-five patients, mean age at the basal time 14.1+/-5.4 years, were enrolled. Controls were 35 healthy subjects, sex and age matched. Blood samples were withdrawn in the morning at the baseline and 1 year after. In patients leptin concentrations significantly increased, while adiponectin did not significantly change. Leptin values in patients were significantly higher than those found in controls at each time; adiponectin values did not differ at each time between patients and controls. Since patients were not obese, we could hypothesize that leptin might participate to clinical manifestations other than weight balance. The role of adiponectin in autism is still debatable.
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http://dx.doi.org/10.1016/j.neulet.2010.05.027DOI Listing
July 2010

Pro/Anti-inflammatory cytokine imbalance in postischemic left ventricular remodeling.

Mediators Inflamm 2010 9;2010:974694. Epub 2010 May 9.

Division of Internal Medicine, Department of Clinical Medicine and Immunology, University of Siena, V. le Bracci, 53100 Siena, Italy.

Objectives: Cytokines play an important role in left ventricular remodeling consequent to myocardial ischemia. The aim of this study was to correlate cytokine production and lymphocyte apoptosis to post-ischemic left ventricular remodeling in patients affected by acute myocardial infarction (AMI) undergoing primary cutaneous angioplasty (PCI).

Methods: In 40 patients, affected by AMI and undergoing PCI, we evaluated peripheral blood mononuclear cells (PBMCs), tumor necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL10) production and apoptosis on day 1, day 3, day 7, 1 month and 6 months after PCI. Patients were divided into two subgroups of remodeling or not remodeling by echocardiographic criteria.

Results: In the subgroup of remodeling patients, at each timepoint TNF-alpha production was increased significantly in comparison with the subgroup of not remodeling patients. IL10 production was statistically lower in remodeling subjects than in not remodeling ones 1 and 6 months after reperfusion. There were no differences between the two groups as regards lymphomonocyte apoptosis.

Conclusions: We found an increased production of pro-inflammatory cytokine TNF-alpha and a corresponding decrease of anti-inflammatory/regulatory cytokine IL10 in remodeling patients and we concluded that this cytokine imbalance resulted in pro-inflammatory effects which might contribute to the progression of left ventricular remodeling.
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http://dx.doi.org/10.1155/2010/974694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866240PMC
August 2010

Cardiac dysautonomia and arterial distensibility in essential hypertensives.

Auton Neurosci 2009 Mar 1;146(1-2):102-5. Epub 2009 Jan 1.

Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy.

Introduction: The central nervous system plays an important role in the regulation of blood pressure: the sympathetic nervous system may be a primary contributor to the development of some forms of essential hypertension. Hypertension is also associated with reduced distensibility of large arteries. The aim of our study is the evaluation of a correlation between cardiac dysautonomia (evaluated by means of heart rate variability [HRV]) and altered artery distensibility (evaluated by means of measurement of the time interval from the onset of the QRS wave and the detection of the last Korotkoff sound [QKD interval]).

Materials And Methods: HRV and QKD interval were evaluated in 23 patients (60.9+/-8.7 years) with untreated hypertension and in 20 control subjects (53.2+/-16.8 years). QKD interval and QKD(100-60) (that is QKD for a 100 mm Hg systolic blood pressure and 60 bpm heart rate) were measured during a 24-hours blood pressure monitoring. HRV was evaluated by means of a spectral method. Three main spectral components were distinguished: very low frequency (VLF), low frequency (LF) and high frequency (HF) component.

Results: Patients with reduced QKD(100-60) interval show reduced total power and spectral components values, with higher LF/HF ratio in basal conditions in comparison with control group. In patients with hypertension, QKD(100-60) values correlated significantly with LF/HF ratio (Spearman r=-0.551; p=0.006), HF spectral component (Spearman r=0.630; p=0.001) and total power (Spearman r=0.426; p=0.004).

Conclusions: Our results suggest that sympathetic overactivity may be the contributor of reduced arterial distensibility observed in patients with essential hypertension.
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http://dx.doi.org/10.1016/j.autneu.2008.11.009DOI Listing
March 2009

Plasma levels of asymmetric dimethylarginine in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy.

Cerebrovasc Dis 2008 4;26(6):636-40. Epub 2008 Nov 4.

Dipartimento di Scienze Neurologiche e del Comportamento, Università di Siena, Siena, Italia.

Background: Asymmetric dimethylarginine (ADMA) is a marker of endothelial dysfunction and a new independent risk factor for adverse cerebrovascular events in small vessel disease. Conversely, L-arginine (LARG) may have a protective role.

Methods: To assess ADMA, LARG levels and LARG/ADMA ratio in 16 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and normal controls, and to look for possible correlations with white matter changes. Plasma levels of ADMA and LARG were assayed by high-performance liquid chromatography in all subjects. The overall T(1) and T(2) lesion load was obtained from brain MRI of patients with CADASIL.

Results: ADMA plasma concentrations (1.5 +/- 2.0 microM) were significantly higher (p < 0.05) in CADASIL patients than in controls (0.35 +/- 0.075 microM). Analyzing only CADASIL subjects, an inverse borderline-significant correlation was found between LARG/ADMA (190 +/- 20) and T(2)-weighted lesion volumes (57.9 +/- 46.5; r = -0.578, p = 0.024).

Conclusion: Our results may indicate the possible coexistence of endothelial dysfunction in CADASIL patients, broadening the range of potentially pathogenetic mechanisms in this disease and providing insights for future therapeutic strategies.
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http://dx.doi.org/10.1159/000166840DOI Listing
March 2009

Delineation of the phenotype associated with 7q36.1q36.2 deletion: long QT syndrome, renal hypoplasia and mental retardation.

Am J Med Genet A 2008 May;146A(9):1195-9

Medical Genetics, University of Siena, Siena, Italy.

Terminal deletions of the long arm of chromosome 7 are well known and are frequently associated with hypotelorism or holoprosencephaly due to the involvement of the SHH gene located in 7q36.3. These deletions are easily detectable with routine subtelomeric MLPA analysis. Deletions affecting a more proximal part of 7q36, namely bands 7q36.1q36.2 are less common, and may be missed by subtelomeric MLPA analysis. We report a 9-year-old girl with a 5.27 Mb deletion in 7q36.1q36.2, and compare her to literature patients proposing a phenotype characterized by mental retardation, unusual facial features, renal hypoplasia and long QT syndrome due to loss of the KCNH2 gene. These characteristics are sufficiently distinct that the syndrome may be diagnosed on clinical grounds.
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http://dx.doi.org/10.1002/ajmg.a.32197DOI Listing
May 2008

Sympathetic overactivity and plasma leptin levels in Rett syndrome.

Neurosci Lett 2008 Feb 23;432(1):69-72. Epub 2007 Dec 23.

Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy.

Rett syndrome (RTT) is a severe developmental-neurological disorder, characterized by profound and progressive loss of intellectual functioning, occurring after a period (of at least 6 months) of normal development with classic stereotype hand movements, gait ataxia, jerky truncal ataxia, deceleration of brain and body organ growth and cardiac dysautonomia. Pathogenesis of sympathetic overactivity in RTT is unknown, but a previous study observed increased plasma leptin levels in Rett girls and it is well known the role of leptin in the regulation of sympathetic nervous system activity. Aim of our study is to evaluate a relationship between plasma leptin levels and sympathetic activity in RTT. Thirty-two female patients (12.1+/-6.3 years), affected by RTT were enrolled in the study. In all the subjects, we analyzed heart rate variability, QT corrected interval and plasma leptin levels. A significant correlation was found between plasma leptin levels and LF/HF (expression of sympatho-vagal balance) (Spearman r=0.44, p=0.001). There is also a significant negative correlation between HF component (expression of vagal activity) and plasma leptin levels (Spearman r=-0.037, p=0.03) and a positive correlation between LF component and plasma leptin levels (Spearman r=0.047, p=0.01). These results show that in RTT higher plasma leptin levels appear to be associated with sympathetic overactivity, suggesting a role for leptin in cardiac dysautonomia.
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http://dx.doi.org/10.1016/j.neulet.2007.12.030DOI Listing
February 2008

Pharmacogenetics of statins therapy.

Recent Pat Cardiovasc Drug Discov 2007 Nov;2(3):228-36

Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy.

Cardiovascular disease has become the global leading cause of death worldwide, representing the most frequent cause of morbidity and mortality in the developed world. Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Meta-analyses from several primary and secondary intervention studies have clearly shown that cholesterol-lowering medication, significantly reduces cardiovascular events, mortality, and morbidity, but considerable interindividual variation exists in response to statin therapy. Pharmacogenomics can provide important insights into statins therapy through elucidation of the genetic (or genomic) contribution to variable response for these drugs. The search for genetic polymorphisms may enable us to identify novel determinants of drug responsiveness by means of the study of three candidate genes groups: (1) genes encoding proteins involved in metabolism or drug transport, or both, that influence drug pharmacokinetics; (2) genes encoding proteins involved in mechanism of action and/or metabolic pathways on which drugs operate (that influence pharmacodynamics); (3) genes encoding proteins involved in the underlying disease condition or intermediate phenotype. This review briefly summarizes the recent pharmacogenomic and pharmacogenetic patents and the potential contributions of genetic variations in candidate genes related to lipid and lipoprotein metabolism and statins efficacy.
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http://dx.doi.org/10.2174/157489007782418982DOI Listing
November 2007

Brain natriuretic peptide and other risk markers for outcome assessment in patients with non-ST-elevation coronary syndromes and preserved systolic function.

Am J Cardiol 2006 Nov 28;98(10):1322-8. Epub 2006 Sep 28.

Department of Internal Medicine and Metabolic Diseases, Section of Cardiology, University of Siena, Siena, Italy.

Several emerging cardiac markers constitute strong predictors among patients with coronary artery disease. In particular, brain natriuretic peptide (BNP), troponin T (TnT), and C-reactive protein (CRP) are related to increased risk of recurrent ischemic events and death. However, little is known about the utility of these biomarkers in combination. This study examined risk assessment in patients with coronary artery disease and preserved systolic function. We studied 208 consecutive patients (138 men, 70 women) with stable angina, unstable angina, and non-Q-wave myocardial infarction whose plasma BNP, TnT, and CRP levels were measured at hospital admission. All recruited patients underwent echocardiographic examination, and selective coronary angiography was performed. After adjusting for clinical presentation, age, gender, and common risk factors, BNP was demonstrated as a strong predictor of heart failure (6 months, odds ratio [OR] 2.03, 95% confidence interval [CI] 1.24 to 2.9, p <0.01; 12 months, OR 2.65, 95% CI 1.69 to 3.5, p <0.001) and mortality at 3, 6, and 12 months (p <0.001). BNP was also significantly related to extent of coronary artery disease and left anterior descending artery involvement (p <0.01). Patients with a BNP level >80 pg/ml in all 3 groups had a significantly poorer prognosis with increased incidence of heart failure and death. CRP was related to recurrent ischemic events (infarct or recurrent angina, OR 1.4, 95% CI 1.14 to 2.08, p <0.01) and was associated with major cardiac revascularization at 12 months (OR 1.51, 95% CI 1.29 to 1.73, p <0.001). TnT demonstrated a mild correlation with recurrent infarct or angina at 12 months (OR 1.1, 95% CI 0.96 to 1.22, p <0.05) but appeared related to multivessel coronary artery disease (OR 1.47, 95% CI 1.05 to 1.99, p <0.01). In conclusion, BNP appears to be associated with a long-term increased risk of mortality and heart failure in patients with apparently mild risk. BNP is also associated with a larger extent and greater severity of myocardial ischemia. Early BNP measurement could provide incremental information to TnT and CRP, and it may be the strongest independent predictor of cardiac outcome in subjects without left ventricular dysfunction or enlargement.
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http://dx.doi.org/10.1016/j.amjcard.2006.06.023DOI Listing
November 2006

Takayasu's arteritis: a review of the literature.

Intern Emerg Med 2006 ;1(2):105-12

Division of Medicine III, Department of Clinical Medicine and Immunological Medicine, University of Siena, Siena, Italy.

Takayasu's arteritis is a rare, idiopathic, chronic inflammatory disease with cell-mediated inflammation, involving mainly the aorta and its major branches. It leads to stenosis, occlusion or aneurysmal degeneration of large arteries. The clinical presentation is characterised by an acute phase with constitutional symptoms, followed, months or years later, by a chronic phase in which symptoms relate to fibrosis or occlusion of vessels. Angiography is the gold standard for diagnosis and for topographical classification and it correlates with symptoms and prognosis. Here we focus on the pathophysiology, clinical and angiographical classification, diagnostic assessment and therapeutic approach of Takayasu's arteritis.
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http://dx.doi.org/10.1007/BF02936534DOI Listing
January 2007

Effect of iloprost on plasma asymmetric dimethylarginine and plasma and platelet serotonin in patients with peripheral arterial occlusive disease.

Prostaglandins Other Lipid Mediat 2006 Sep 18;80(3-4):175-82. Epub 2006 Jul 18.

Center of Clinical Pharmacology, University of Siena, Italy.

Background: Iloprost, a prostacyclin analogue, is used in the treatment of peripheral arterial occlusive disease at Leriche-Fontaine stages III-IV, through intravenous infusion for at least 21 days. Recently, iloprost has been shown to be safe and effective in critical limb ischemia patients when administered per 7 days. We investigated in patients at Leriche-Fontaine stages III-IV the effect of 1-week treatment with iloprost on plasma asymmetric dimethylarginine (ADMA), plasma and platelet serotonin, and on clinical response.

Methods And Results: Twenty-four critical limb ischemia patients (16 men and 8 women, mean age 76+/-9.7 years) were included in the study and treated with intravenous iloprost (titrated from 0.5 up to 1.5 ng/kg/min) for 16 h a day for seven consecutive days. Blood samples were drawn before infusion on days 1, 4 and 8 of treatment, under the same conditions. Clinical assessment was performed by clinical evaluation, ankle/brachial pressure index and treadmill exercise test. During treatment with iloprost patients clinically improved and plasma levels of ADMA significantly decreased (p<0.001). We also observed a significant increase of serotonin (p<0.01) in platelets and a significant decrease of serotonin (p<0.001) in plasma. Similar variations of ADMA and serotonin were found in two subgroups of patients, diabetics and non-diabetics.

Conclusions: One-week treatment with iloprost in critical limb ischemia patients induced changes of peripheral markers of endothelial dysfunction and atherosclerosis, such as ADMA and serotonin, associated to a clinical improvement.
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http://dx.doi.org/10.1016/j.prostaglandins.2006.06.005DOI Listing
September 2006

3'UTR/T polymorphism of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with modified anti-platelet activity of atorvastatin in hypercholesterolemic subjects.

Atherosclerosis 2005 Dec 22;183(2):322-8. Epub 2005 Apr 22.

Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Center for Atherosclerosis Research, University of Siena, Siena, Italy.

Oxidized-low density lipoproteins (ox-LDL) and the specific receptor LOX-1 are involved in atherogenesis and atherothrombosis. LOX-1 downregulation is associated with the anti-platelet action of atorvastatin. 3'UTR/T LOX-1 polymorphism has been associated with increased risk of coronary artery disease. This study was planned to determine whether LOX-1 genetic variations could affect anti-platelet action of atorvastatin. We studied by platelet P-selectin (P-sel), CD36 and LOX-1 expression (cytofluorimetric detection) whether differences in cellular activation could be suitable in 109 3'UTR/T carriers out of 201 hypercholesterolemic subjects treated with atorvastatin 20mg/day. Hyperactivated platelets (P-sel in resting cells and % variation upon thrombin activation, p<0.001) were detected at baseline in patients without significant differences between T or C carriers. P-sel and platelet-associated ox-LDL, were significantly decreased (all p<0.001) in C carriers after one week of treatment before LDL reduction. In 3'UTR/T carriers P-sel was reduced (p<0.01) after 6 weeks of treatment according to LDL and ox-LDL reduction. In 3'UTR/T carriers atorvastatin reduced platelet activity by LDL and ox-LDL lowering and not by rapid CD36 and LOX-1 downregulation as in C carriers. Such data suggest that in T carriers LDL lowering is needed to achieve anti-platelet action.
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http://dx.doi.org/10.1016/j.atherosclerosis.2005.03.012DOI Listing
December 2005

Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects.

Clin Appl Thromb Hemost 2005 Oct;11(4):417-28

Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Center for Atherosclerosis Research, University of Siena, Siena, Italy.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.
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http://dx.doi.org/10.1177/107602960501100408DOI Listing
October 2005

[Immune factors in atherosclerosis].

Ann Ital Med Int 2005 Apr-Jun;20(2):81-9

Sezione di Medicina Interna, Dipartimento di Medicina Clinica e Scienze Immunologiche, Università degli Studi di Siena.

Immune cells play an important role in atheromatous plaque formation and progression and in the phase of "active plaque" and of the consequent clinical manifestations. Endothelial dysfunction is the first determinant step in atherogenesis by inducing the alteration of vasodilating and antithrombotic properties of the endothelium and of its permeability to lipoproteins. Circulating monocytes are recruited and internalized and lipoproteins are stored in the subendothelial area where they undergo oxidation (oxidized LDL) and are removed by macrophages by means of non-autoregulated scavenger receptors (foam cells). Foam cells are able to express surface receptors and to produce soluble mediators (interleukin-1, tumor necrosis factor-alpha, monocyte chemotactic protein 1) which attract other monocytes, activate endothelial cells and smooth muscle cells. Lymphocytes too are present in these first stages of atherogenesis. If the injurious agents are not removed or nullified by the inflammatory response and the inflammation progresses, the response changes from a protective to an injurious response. Recruitment of monocytes and lymphocytes occurs as a result of the up-regulation of adhesion molecules on both the endothelium and the leukocytes and the plaque progresses to an advanced lesion. Finally the activation of monocytes and T cells induces the plaque activation and rupture in presence of inducing agents such as oxidized LDL. CD4 lymphocytes are common components of atheroma and are mainly localized at the sites of rupture in strict contact with macrophages and smooth muscle cells which express activation surface molecules and which are able to process and to present the antigen to T cells. Activated lymphocytes produce proinflammatory cytokines as interferon-gamma which is able to amplify the inflammatory response but also interleukin-10 which seems to possess a regulatory effect. Activated macrophages release metalloproteinases and other proteolytic enzymes which cause degradation of the matrix, thinning of fibrous cap and plaque destabilization. Both T cells and macrophages produce cytotoxic factors which contribute to the apoptosis. The process may be potentiated by the activation of platelets, tissue factor, coagulation-fibrinolytic system which can contribute to thrombus formation, plaque rupture and artery occlusion.
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September 2005

Activity of citalopram on adenosine and serotonin circulating levels in depressed patients.

J Clin Psychopharmacol 2005 Jun;25(3):262-6

Center of Clinical Pharmacology, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena 53100, Italy.

Citalopram is a selective serotonin reuptake inhibitor used in the treatment of depression. Recent investigations have shown that it reduces in rat brain the release of excitatory amino neurotransmitters acid glutamate and aspartate by the involvement of the inhibitory neuromodulator adenosine. In this study, we described citalopram and serotonin levels in plasma and platelets, as well as plasma adenosine levels, in depressive patients during acute and chronic administration of citalopram. Twelve patients affected by Major Depression (DSM-IV) received a single oral dose of citalopram in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day, and 20 mg from the 11th to the 40th day. Blood samples for citalopram, serotonin, and adenosine were collected at Time 0 and 4, 12 and 24 hours after drug administration on the first day of citalopram 5 mg, and on the first and the last day of citalopram 20 mg. Citalopram, serotonin, and adenosine concentrations in plasma increased after citalopram administration, and the highest levels were observed on the last day of treatment. Citalopram was detectable in platelets with concentrations showing a time variation similar to plasma values. Serotonin levels in platelets decreased after drug administration, reaching the lowest values on the last day of treatment.
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http://dx.doi.org/10.1097/01.jcp.0000161500.58266.90DOI Listing
June 2005

[Hypogammaglobulinemia and thymoma (Good's syndrome): a case report and a literature review].

Ann Ital Med Int 2005 Jan-Mar;20(1):58-61

Dipartimento di Medicina Interna e Scienze Immunologiche, Sezione di Medicina III, Università degli Studi di Siena.

Good's syndrome is a rare adult-onset immunodeficiency disease characterized by hypogammaglobulinemia and thymoma. A 61-year-old male patient was diagnosed with Good's syndrome after a 2-year history of recurrent respiratory infections. Chest X-ray and chest computed tomography scan showed a mediastinal mass which was surgically removed. Histology revealed a thymoma. Following surgery he presented with recurrent respiratory and urinary tract infections and with esophageal candidiasis, even though his overall conditions dramatically improved after starting treatment with an appropriate dosage of intravenous immunoglobulins. Laboratory tests showed hypogammaglobulinemia, mild neutropenia, lymphopenia with no B cells, decreased CD4+ lymphocytes with an inverted CD4/CD8 ratio and increased interleukin-4-producing CD4+ lymphocytes, suggestive of an excessive Th2 response.
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December 2005

Mechanisms for antiplatelet action of statins.

Curr Drug Targets Cardiovasc Haematol Disord 2005 Apr;5(2):121-6

Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Policlinico Le Scotte, University of Siena, V.le Bracci, 53100, Siena, Italy.

Hydroxymethyl-glutaryl coenzyme A reductase inhibitors (statins) offer important benefits for the large populations of individuals at high risk for coronary heart and cerebrovascular disease. the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of such drugs may extend beyond their effects on serum cholesterol. Platelet hyperactivity is a key step in atherothrombosis and experimental data suggest that statins could exert an antiplatelet effect which could be involved in their protective action. In the present review we report of the major studies in humans showing the effect of statins on platelets, especially by the more sensitive methods to explore platelet function such as cytofluorymetric detection of specific proteins. Moreover we describe the putative mechanisms involved in platelet deactivation with particular regard to the effects related to cholesterol reduction or beyond lipid-lowering. Indeed, data from several studies suggest some differences among compounds in terms of timing of action by modulation of several activating pathways which could take part either in the early, cholesterol-lowering independent, effects in the acute phase of vascular disease or during chronic treatment.
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http://dx.doi.org/10.2174/1568006043586161DOI Listing
April 2005

Plasma catecholamine levels after fluoxetine treatment in depressive patients.

Neuropsychobiology 2005 ;51(2):72-6

Center of Clinical Pharmacology, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy.

It is known that selective serotonin reuptake inhibitors, widely used as antidepressive drugs, act by inhibiting the cell reuptake of serotonin, but their effect on the catecholaminergic system is not yet completely understood. In this study, we investigated plasma concentrations of norepinephrine, epinephrine and dopamine after acute and chronic administration of fluoxetine in depressive patients. Twelve patients affected by major depression received a single oral dose of fluoxetine in the morning, 5 mg in the first 5 days, 10 mg from the 6th to the 10th day and 20 mg from the 11th to the 40th day. Twelve healthy subjects received a placebo under identical testing procedures. Blood samples were collected at baseline and 7, 10 and 24 h after drug administration on the 1st day of fluoxetine administration at a dose of 5 mg, and on the 1st and the 30th day of fluoxetine administration at a dose of 20 mg (days 11 and 40 of treatment, respectively). We found that plasma norepinephrine, epinephrine and dopamine levels significantly increased after acute and chronic treatment (p < 0.001), reaching the highest concentrations on the last day. No significant changes of these parameters were observed in control patients.
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http://dx.doi.org/10.1159/000084163DOI Listing
April 2005

Takayasu's arteritis: case report of a patient with recurrent subclavian steal syndrome.

Heart Vessels 2004 Mar;19(2):94-7

Dipartimento di Medicina Interna e Scienze Immunologiche, Policlinico Le Scotte, 53100, Siena, Italy.

Takayasu's arteritis is a chronic inflammatory disease of unknown origin in which cell-mediated inflammation involves large arteries progressing from the adventitia to the intima, until the lumen of the vessel is narrowed. Here we report a case of a 48-year-old female patient who was diagnosed with Takayasu's arteritis 6 years ago. At that time, because of severe involvement of both the right and left carotid arteries, she underwent application of a Hemashield vascular prosthesis, including the ascending aorta, left common carotid artery, and right common carotid artery. Due to the fact that there were also bilateral subclavian artery stenoses, the application of the prosthesis induced bilateral subclavian steal syndrome. This year she developed stenosis of the prosthesis and the bilateral subclavian steal syndrome disappeared until she underwent percutaneous transluminal angioplasty, which restored cerebral flow through the carotid arteries after which the subclavian steal syndrome reappeared.
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http://dx.doi.org/10.1007/s00380-003-0726-8DOI Listing
March 2004

Thymoma and immunodeficiency.

N Z Med J 2004 Jan 30;117(1188):U750. Epub 2004 Jan 30.

Department of Internal Medicine and Immunological Sciences, University of Siena, Siena, Italy.

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January 2004