No abstract

Aims High plasma cholesterol concentration and increased platelet activity are two major risk factors for atherosclerosis. Lovastatin, the lipophilic drug was shown to inhibit platelet aggregation whereas pravastatin, the hydrophilic drug had no such effect. Analysis of the effect of fluvastatin which is both a lipophilic and hydrophilic drug, on platelet aggregation was the goal of the present study. Methods Fluvastatin 40 mg daily was administered to 25 patients with hypercholesterolaemia for up to 24 weeks. Normal subjects acted as controls. The influence of fluvastatin on plasma lipids and on platelet aggregation and fluidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins. Results Fluvastatin therapy (40 mg day −1 for a period of 4 weeks) in hypercholesterolaemic patients resulted in a 23% and 29% reduction in plasma levels of total cholesterol and LDL-cholesterol respectively. Platelet cholesterol/phospholipids molar ratio was reduced by 26% and platelet aggregation was significantly ( P<0.02) reduced by 10% after 4 weeks of fluvastatin treatment. On continuing fluvastatin therapy for additional 20 weeks, no further decrement in plasma LDL cholesterol levels or in platelet cholesterol/phospholipid ratio were noted. However, platelet aggregation was further significantly ( P<0.01) reduced by up to 15%. Incubation of platelets with increasing concentrations of fluvastatin or lovastatin, demonstrated a dose-dependent reduction in platelet aggregation, whereas pravastatin showed no effect. This inhibitory effect of fluvastatin or lovastatin on platelet aggregation (up to 34% or 22% respectively at a concentration of 1 mg statin ml −1 ) was found both in platelet rich plasma and in washed platelet suspensions. Fluvastatin and lovastatin (but not pravastatin), seem to share similar platelet binding sites, as non labelled fluvastatin or lovastatin were able to displace [ 3 H]-labeled-fluvastatin from its binding sites on platelets. Conclusions Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets. The antiatherogenicity of fluvastatin may be related, in addition to its plasma cholesterol lowering ability, to its inhibitory effect on platelet activation.Keywords: fluvastatin, pravastatin, lovastatin, hypercholesterolaemia, platelet aggregation Several hypolipidaemic drugs as well as plasmapheresis were Introduction shown to reduce platelet tendency to aggregation [19][20][21][22]. Statins are most potent hypocholesterolaemic agents which Atherosclerosis is a complicated process involving the interaction of plasma lipoproteins, blood platelets and arterial inhibit cellular hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase, the key enzyme in cholesterol wall cells [1][2][3][4]. Blood platelets have been shown to be intimately involved in atherosclerosis [5][6][7]. Activated biosynthesis [23, 24]. Althou...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Statins demonstrate a pleiotropic effect which contributes beyond the hypocholesterolaemic effect to prevent atherosclerosis. WHAT THIS STUDY ADDS• Ezetimibe has an antioxidative effect when given as monotherapy or as an add-on to the statin, simvastatin. AIMSTo investigate the effect of lowering low-density lipoproteincholesterol (LDL-C) on platelet aggregation and LDL tendency to peroxidation by ezetimibe alone or with simvastatin in hypercholesterolaemia. METHODSSixteen patients with LDL-C >3.4 mmol l -1 received ezetimibe for 3 months (Part I). Twenty-two patients on fixed simvastatin dose with LDL-C >2.6 mmol l -1 were enrolled (Part II). Part II patients continued simvastatin treatment 20 mg day -1 for 6 weeks, then received 20 mg day -1 simvastatin combined with ezetimibe 10 mg day -1 for another 6 weeks. The tendency of LDL to peroxidation measured by lag time in minutes required for initiation of LDL oxidation and by LDL oxidation at maximal point (plateau) was measured before and after ezetimibe treatment. RESULTSPart I: Ezetimibe 10 mg daily for 3 months decreased plasma LDL-C level 16% (P = 0.002), prolonged lag time to LDL oxidation from 144 Ϯ 18 min to 195 Ϯ 16 min (P < 0.001), decreasing maximal aggregation from 83 Ϯ 15% to 60 Ϯ 36% (P = 0.04). Part II: Serum level LDL-C decreased 23% (P = 0.02) and lag time in minutes to LDL oxidation was prolonged from 55.9 Ϯ 16.5 to 82.7 Ϯ 11.6 (P < 0.0001) using combined simvastatin-ezetimibe therapy. There were no differences in platelet aggregation. CONCLUSIONSEzetimibe was associated with decreased platelet aggregation and LDL tendency to peroxidation. Treatment with ezetimibe in addition to simvastatin has an additive antioxidative effect on LDL.