Hypercholesterolemia: Paoletti R

Poli A, Marangoni F, Paoletti R, Mannarino E, Lupattelli G, Notarbartolo A, Aureli P, Bernini F, Cicero A, Gaddi A, Catapano A, Cricelli C, Gattone M, Marrocco W, Porrini M, Stella R, Vanotti A, Volpe M, Volpe R, Cannella C, Pinto A, Del Toma E, La Vecchia C, Tavani A, Manzato E, Riccardi G, Sirtori C, Zambon A, Anonymous00119. · Nutrition Foundation of Italy, Italy. · Nutr Metab Cardiovasc Dis. · Pubmed #18258418 No free full text.

Abstract: The importance of non-pharmacological control of plasma cholesterol levels in the population is increasing, along with the number of subjects whose plasma lipid levels are non-optimal, or frankly elevated, according to international guidelines. In this context, a panel of experts, organized and coordinated by the Nutrition Foundation of Italy, has evaluated the nutritional and lifestyle interventions to be adopted in the control of plasma cholesterol levels (and specifically of LDL cholesterol levels). This Consensus document summarizes the view of the panel on this topic, with the aim to provide an updated support to clinicians and other health professionals involved in cardiovascular prevention.

Katan MB, Grundy SM, Jones P, Law M, Miettinen T, Paoletti R, Anonymous00371. · Division of Human Nutrition and Epidemiology, Wageningen University, Bomenweg 2, 6703 HD Wageningen, The Netherlands. · Mayo Clin Proc. · Pubmed #12911045 links to  free full text

Abstract: Foods with plant stanol or sterol esters lower serum cholesterol levels. We summarize the deliberations of 32 experts on the efficacy and safety of sterols and stanols. A meta-analysis of 41 trials showed that intake of 2 g/d of stanols or sterols reduced low-density lipoprotein (LDL) by 10%; higher intakes added little. Efficacy is similar for sterols and stanols, but the food form may substantially affect LDL reduction. Effects are additive with diet or drug interventions: eating foods low in saturated fat and cholesterol and high in stanols or sterols can reduce LDL by 20%; adding sterols or stanols to statin medication is more effective than doubling the statin dose. A meta-analysis of 10 to 15 trials per vitamin showed that plasma levels of vitamins A and D are not affected by stanols or sterols. Alpha carotene, lycopene, and vitamin E levels remained stable relative to their carrier molecule, LDL. Beta carotene levels declined, but adverse health outcomes were not expected. Sterol-enriched foods increased plasma sterol levels, and workshop participants discussed whether this would increase risk, in view of the marked increase of atherosclerosis in patients with homozygous phytosterolemia. This risk is believed to be largely hypothetical, and any increase due to the small increase in plasma plant sterols may be more than offset by the decrease in plasma LDL. There are insufficient data to suggest that plant stanols or sterols either prevent or promote colon carcinogenesis. Safety of sterols and stanols is being monitored by follow-up of samples from the general population; however, the power of such studies to pick up infrequent increases in common diseases, if any exist, is limited. A trial with clinical outcomes probably would not answer remaining questions about infrequent adverse effects. Trials with surrogate end points such as intima-media thickness might corroborate the expected efficacy in reducing atherosclerosis. However, present evidence is sufficient to promote use of sterols and stanols for lowering LDL cholesterol levels in persons at increased risk for coronary heart disease.

Bolego C, Poli A, Cignarella A, Catapano AL, Paoletti R. · Nutrition Foundation of Italy, Via S Pietro all'Orto 17, 20121 Milan, Italy. · Cardiovasc Drugs Ther. · Pubmed #12374904 No free full text.

Abstract: Rosuvastatin (ZD4522) and pitavastatin (NK-104) are novel HMG-CoA reductase inhibitors with a peculiar pharmacological profile. In particular, they show a high potency in decreasing LDL-C and their catabolism is not mediated by the cytochrome P-450 3A4, thus reducing the potential for drug-drug interaction and improving the management of blood cholesterol. As the magnitude of LDL-C reduction is directly associated with the decrease in the incidence of myocardial infarction and mortality for CAD, statins with increased LDL-C lowering potency may ensure the achievement of target LDL-C levels and offer a more aggressive cholesterol control, further improving CAD morbidity and mortality.

Paoletti R, Corsini A, Bellosta S. · Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. · Atheroscler Suppl. · Pubmed #12044584 No free full text.

Abstract: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of coronary events, and are generally very well tolerated. However, simvastatin, lovastatin, cerivastatin and atorvastatin are biotransformed in the liver primarily by cytochrome P450 (CYP) 3A4, and clinical experience has shown that the risk of adverse effect, such as myopathy, increases with concomitant use of statins with drugs that substantially inhibit CYP 3A4 at therapeutic doses. Indeed, pharmacokinetic interactions (e.g. increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of atorvastatin, cerivastatin, simvastatin or lovastatin and cyclosporine A, mibefradil or nefazodone. In contrast, fluvastatin (mainly metabolized by CYP 2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, an increase in pravastatin bioavailability has been reported in the presence of cyclosporine A, possibly because of an interaction at the level of biliary excretion. In summary, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Bernini F, Poli A, Paoletti R. · Department of Pharmacological Sciences, University of Milano, Italy. · Cardiovasc Drugs Ther. · Pubmed #11713888 No free full text.

Abstract: Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (< or =3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase levels occur infrequently (< or = 1.5%). These are generally asymptomatic, reversible and rarely require drug withdrawal. Statins do not cause adverse endocrine effects, do not alter glycemic control in diabetic patients, and do not increase cancer risk. Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although the risk is increased by concomitant administration of cyclosporine, niacin, fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole antifungal agents etc.) with statins metabolized by this isoenzyme. The pharmacokinetics of the individual statin should be considered in patients receiving polypharmacological treatments, to minimize the risk of unfavorable drug interactions. Atorvastatin is well tolerated in long-term treatment of dyslipidemia and is characterized by a safety profile similar to the other available statins.

Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. · Institute of Pharmacological Sciences, University of Milan, Italy. · Pharmacol Ther. · Pubmed #10665838 No free full text.

Abstract: The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

Paoletti R, Fahmy M, Mahla G, Mizan J, Southworth H. · Department of Pharmacological Sciences, University of Milan, Milan, Italy. · J Cardiovasc Risk. · Pubmed #11873095 No free full text.

Abstract: BACKGROUND: Rosuvastatin (Crestor), a new, highly efficacious statin, has demonstrated dose-dependent low-density lipoprotein cholesterol (LDL-C) reductions of up to 65% in a dose-ranging programme with doses of 1 to 80 mg. DESIGN: A randomized, double-blind multicentre trial compared rosuvastatin with commonly used starting doses of pravastatin and simvastatin to determine relative efficacy in LDL-C reduction and impact on other lipid parameters in primary hypercholesterolaemia. METHODS AND RESULTS: A total of 502 patients (greater-than-or-equal 18 years; LDL-C greater-than-or-equal 4.14 mmol/l [160 mg/dl] and < 6.50 mmol/l [250 mg/dl] and triglycerides less-than-or-equal 4.52 mmol/l [400 mg/dl]) were randomized to 12 weeks of rosuvastatin 5 mg (n = 120) or 10 mg (n = 115), pravastatin 20 mg (n=]137) or simvastatin 20 mg (n = 130). Rosuvastatin 5 and 10 mg reduced LDL-C by 42 and 49%, respectively, compared with 28% for pravastatin (P < 0.001 versus both rosuvastatin doses) and 37% for simvastatin (P < 0.01 versus rosuvastatin 5 mg; P < 0.001 versus 10[?]mg). National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) goals were achieved by 87% of rosuvastatin 10[?]mg patients, 71% of rosuvastatin 5[?]mg patients, 53% of pravastatin patients, and 64% of simvastatin patients; similar proportions of patients achieved NCEP ATP III goals. European Atherosclerosis Society (EAS) goals were achieved by 83, 63, 20 and 50% of patients, respectively. All study treatments were well tolerated. CONCLUSIONS: Both doses of rosuvastatin were more effective than pravastatin and simvastatin in meeting NCEP ATP II and EAS LDL-C targets. Rosuvastatin 10 mg was more effective than pravastatin and simvastatin in meeting NCEP ATP III targets.

Atella V, Brady A, Catapano AL, Critchley J, Graham IM, Hobbs FD, Leal J, Lindgren P, Vanuzzo D, Volpe M, Wood D, Paoletti R. · Department of Economics, University of Rome Tor Vergata, Rome, Italy. · Atheroscler Suppl. · Pubmed #19497553 No free full text.

Abstract: In Europe, cardiovascular disease (CVD) represents the main cause of morbidity and mortality, costing countries euro 190 billion yearly (2006). CVD prevention remains unsatisfactory across Europe largely due to poor control of CVD risk factors (RFs), growing incidence of obesity and diabetes, and sedentary lifestyle/poor dietary habits. Hypercholesterolaemia is a proven CVD RF, and LDL-C lowering slows atherosclerotic progression and reduces major coronary events. Lipid-lowering therapy is cost-effective, and intensive treatment of high-risk patients further improves cost effectiveness. In Italy, models indicate that improved cholesterol management translates into potential yearly savings of euro 2.9-4 billion. Identifying and eliminating legislative and administrative barriers is essential to providing optimal lipid care to high-risk patients. Public health and government policy can influence clinical practice rapidly, and guideline endorsement via national health policy may reduce the CVD burden and change physician and patient behaviour. Action to reduce CVD burden should ideally include the integration of strategies to lower the incidence of major CV events, improvement in total CV risk estimation, database monitoring of CVD trends, and development of population educational initiatives on CVD prevention. Failure to bridge the gap between science and health policy, particularly in relation to lipid management, could result in missed opportunities to reverse the burgeoning epidemic of CVD in Europe.

Arnaboldi L, Guzzetta M, Pazzucconi F, Radaelli G, Paoletti R, Sirtori CR, Corsini A. · Department of Pharmacological Sciences, University of Milan, via Balzaretti, 9, 20133 Milan, Italy. <> · Pharmacol Res. · Pubmed #17959387 No free full text.

Abstract: We evaluated the pharmacological activity of whole-blood serum from atorvastatin- vs. simvastatin- (both 40 mg/day) treated hypercholesterolemic patients (n=10) on cultured smooth muscle cell (SMC) proliferation and cholesterol biosynthesis, as related to lipid-lowering effect. Patients received either single or 2-weeks repeated doses of both simvastatin and atorvastatin, following a randomised, double-blind, cross-over design. Blood samples were collected before drug administration and at the scheduled intervals after administration, and the obtained serum was separated by centrifugation, sterilized and frozen until assayed. Cultured SMC were supplemented with medium plus 15% of separate serum sampled from the patients, and grown for 72 h. Proliferation was assayed by a Coulter Counter, while cholesterol biosynthesis was measured by the incorporation of 14C-acetate into cholesterol, under the same experimental conditions. Atorvastatin was more active vs. simvastatin in reducing total- (-28.3% vs. -20.7%; p=0.045) and LDL-cholesterol (-39.8% vs. -30.1%; p=0.011) after a 2-weeks regimen. Serum from atorvastatin-treated patients inhibited SMC proliferation vs.t=0 after both single (AUC -21.6%) and repeated (AUC -26.9%) doses, while serum from simvastatin-treated patients inhibited SMC proliferation only after repeated doses (AUC -24.5%). Interestingly, in the same experimental conditions, the serum concentrations of both statins (and of their active metabolites) were constantly below the detection limits, as shown from the lack of inhibition of cholesterol biosynthesis. The absence of any significant association between the lipid-lowering effects and the inhibition of SMC proliferation, together with no detectable active statin in the serum, suggests that these effects are elicited through independent mechanisms.

Camera M, Toschi V, Comparato C, Baetta R, Rossi F, Fuortes M, Ezekowitz MD, Paoletti R, Tremoli E. · Department of Pharmacological Sciences, University of Milan, Italy. · Thromb Haemost. · Pubmed #12008961 No free full text.

Abstract: High cholesterol levels are a known risk factor for coronary events. The molecular links between high serum cholesterol and the increased thrombogenicity of the arterial wall are still matter of investigation. In the present study we investigate the relationship between plasma cholesterol, thrombus formation and TF expression in a atherosclerotic rabbit model. Hypercholesterolemic rabbits showed a pronounced TF staining as well as NF-kappaB activation in the aortic arch. A consistent vessel wall platelet deposition was also observed. Treatment with fluvastatin reduced lipid accumulation, TF overexpression (-60%), NF-kappaB activation, and platelet deposition (-56%). In vitro studies showed that the drug upregulated IkappaB alpha in unstimulated as well as in TNFalpha-stimulated cells and also impaired the TNFalpha-induced Cdc42 prenylation, indicating that fluvastatin interferes with the transcriptional activation of TF gene. These results indicate that the prothrombotic phenotype of arterial wall, associated with elevated serum cholesterol levels, is mediated by TF overexpression. Fluvastatin treatment reduces the prothrombotic tendency by inhibiting TF synthesis.