(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Hyperlipoproteinemias

Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.

Topics: Anticholesteremic Agents; Cholesterol, LDL; Coronary Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hyperlipoproteinemias; Indoles; Randomized Controlled Trials as Topic; Risk Factors; Simvastatin

Disorders associated with the overproduction or delayed clearance of beta-very low density lipoprotein and low density lipoprotein (LDL) are strikingly related to premature coronary artery disease. There are five recognized classes of LDL-lowering drugs, each acting through different basic mechanisms. The increased predictability, safety, and efficacy of newer lipid-lowering agents have allowed controlled clinical trials to demonstrate conclusively that reducing LDL leads to a reduction in coronary artery disease. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is almost completely absorbed, actively targeted to the liver, and secreted in the bile. It has no active circulating metabolites. The safety and efficacy of fluvastatin have been demonstrated in more than 2,500 subjects treated in the United States, Canada, and Europe, and more than 1,000 have been treated for more than 1 year. Combination of fluvastatin with cholestyramine results in additional cholesterol lowering. The Lipoprotein and Coronary Atherosclerosis Study, a randomized, double-blind trial of fluvastatin using quantitative coronary angiography to measure atherosclerotic plaque change and positron emission tomography to evaluate myocardial perfusion (myocardial flow reserve), illustrates the further exploration of lipoproteins and atherogenesis made possible by the availability of this new generation of cholesterol-lowering agents.

Topics: Anticholesteremic Agents; Coronary Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemias; Hypolipidemic Agents; Indoles

Topics: Animals; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Synthase; Hyperlipoproteinemias; Indoles; Lipoproteins

Although lowering blood pressure (BP) reduces aortic stiffness, achieving the recommended BP goal can be difficult. Recent studies have shown that short-term use of statins can reduce BP significantly. To determine the long-term effects of statins on BP and aortic stiffness, a single-blind randomized prospective study was performed on 85 hyperlipidaemic hypertensive patients whose BP was insufficiently controlled by antihypertensive therapy. Every 3 months, aortic stiffness was assessed by measuring pulse wave velocity (PWV). Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a nonstatin antihyperlipidaemic drug. No significant differences in patient characteristics, kinds of antihypertensive drugs, BP, ankle brachial index, PWV, or serum lipid, creatinine, or C-reactive protein levels were found between the four groups at the start of the study. During the 12-month treatment period, PWV did not change in the pravastatin group or nonstatin group, but it was transiently reduced in the simvastatin group and significantly decreased in the fluvastatin group, even though the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidaemic drugs significantly decreased serum cholesterol levels without affecting BP, ankle brachial index, or serum triglyceride levels. The C-reactive protein serum levels decreased significantly in the three statin groups but not in the nonstatin group. These results suggest that long-term use of fluvastatin by hyperlipidaemic hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on BP.

Topics: Anticholesteremic Agents; Arteriosclerosis; Blood Pressure; C-Reactive Protein; Cholesterol; Elasticity; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemias; Hypertension; Indoles; Male; Middle Aged; Pravastatin; Prospective Studies; Pulsatile Flow; Simvastatin; Single-Blind Method

Renal insufficiency is frequently associated with both quantitative and qualitative abnormalities in lipid and hemorheologic profiles. Although this may lead to increased risk of cardiovascular disease, a number of studies have also shown dyslipidemia to be a significant risk factor for the progression of renal insufficiency in human chronic renal disease. This double-blind, placebo-controlled trial aimed to assess the effect of fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on these parameters in dyslipidemic patients with or without chronic renal insufficiency. After a 6-week placebo run-in, 42 patients who had been previously stratified into 2 groups on the basis of creatinine clearance levels (0.5-1.0 mL/sec or > 1.0-1.5 mL/sec) were randomized to treatment with fluvastatin (40 mg daily) or matching placebo. Significant differences (on analysis of variance with repeated measures) were seen between fluvastatin and placebo treatment groups for changes in total cholesterol (-15% vs 1%, respectively; p < 0.001), low density lipoprotein cholesterol (LDL-C; -21% vs -5%; p < 0.001), very low density lipoprotein cholesterol (-14% vs 14%; p = 0.017), very low density lipoprotein triglycerides (-1% vs 29%; p = 0.014) and total triglycerides (-7% vs 24%; p < 0.001). These effects on cholesterol levels were reflected in a significant decrease in apolipoprotein B levels with fluvastatin therapy (p < 0.001). Apolipoprotein A-I levels increased (p = 0.054) despite no significant change in the levels of high density lipoprotein cholesterol. Response to therapy did not differ between the 2 renal function groups for any of the lipid, lipoprotein, and apolipoprotein variables. Hemorheologic parameters were not altered with fluvastatin therapy, regardless of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anticholesteremic Agents; Apolipoprotein A-I; Apolipoproteins B; Cholesterol; Cholesterol, LDL; Cholesterol, VLDL; Creatinine; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Hemorheology; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemias; Indoles; Kidney Failure, Chronic; Lipoproteins, VLDL; Male; Middle Aged; Placebos; Safety; Triglycerides

We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL: 57 +/- 12 versus WHHL+ fluvastatin: 150 +/- 22%; P < 0.05) and in tendency endothelium-dependent relaxation (WHHL: 26 +/- 5 versus WHHL+ fluvastatin: 83 +/- 29%; (P = 0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL: 480 (13-3821) versus WHHL+ fluvastatin: 808 (467-1595) nmol; P < 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.

Topics: Animals; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemias; Indoles; Muscle Contraction; Muscle, Smooth, Vascular; Nitrites; Rabbits

Hyperlipoproteinaemia is one of the frequent posttransplantation problems. Administration of statins is complicated in patients after transplantation by concurrent imunosuppressive treatment, in particular by possible undesirable interaction with cyclosporin. In the presented study 15 patients after transplantation of the heart with hyperlipoproteinaemia were examined who were on a standard triple combination of immunosuppressive drugs. Fluvastatin was administered, 20 mg in the evening, and in intervals of 6 weeks, 3 months and 6 months after the onset of treatment the levels of cholesterol, LDL and HDL-cholesterol, triglycerides, urea, creatinine, liver terts and cyclosporine were followed up. The mean cholesterol level declined from 7.66 mmol/l during the 6rd week (p < 0.002), to 6.01 mmol/l during 3rd month and to 5.83 mol/l after the 6rd month (p < 0.001), LDL-cholesterol declined from 4.82 mmol/l and then 3.46 mmol/l and 3.31 mmol/l (p < 0.001). In the other investigated parameters no change recorded, incl. the cyclosporin levels. No clinical signs of muscular damage were recorded Fluvastatin thus does not only reduce effectively the cholesterol and LDL-cholesterol level but is also safe combination with immunosuppressive treatment.

Topics: Anticholesteremic Agents; Fatty Acids, Monounsaturated; Fluvastatin; Heart Transplantation; Humans; Hyperlipoproteinemias; Indoles; Male; Middle Aged

To reveal the metabolic parameters of lipoproteins (L), which determine the benefits of hypolipidemic effects of simvastatin (S) and fluvastatin (F); to trace changes in the activity of lecithin-cholesterol acyltransferase (LCA) and cholesterol (C) ester transfer (CET) from high density lipoproteins to very low density lipoproteins (VLDL) and low density lipoproteins (LDL) and the levels of apoE in the blood and in some L classes during therapy with the above drugs.. Thirty six patients took S, 10 mg/day, and 25 received F, 20 mg/day, for 3 months. The levels of lipids were measured by enzyme assays, apoprotein (apo) was determined by immunoturbidimetry and immunodiffusion.. The hypocholesterolemic and hypotriglyceridemic effect of S (19.6 and 25.5, respectively) and F (19.0 and 30.5%) were similar. With S, the reduction in the blood levels of C and LDL C positively correlated with the baseline apoE levels. With F, it did with C and LDL C before treatment. Lower blood apoE was found with S and F and lower HDL apoE/(VLDL + LDL) ratio was detected only with F. F treatment significantly lowered the activity of CET and LCA; before and after S treatment, they did not differ significantly.. Analyzing the relationship between the benefits of the hypolipidemic effect and the baseline parameters of L metabolism indicates that the changes in serum C, LDL C and HDL C are due to the composition of HDL particles and the distribution of apoE among different L classes in the patient to a greater degree.

Topics: Adult; Anticholesteremic Agents; Apolipoproteins E; Cholesterol; Cholesterol Esters; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemias; Hypolipidemic Agents; Indoles; Lipoproteins, HDL; Lipoproteins, LDL; Lipoproteins, VLDL; Male; Middle Aged; Phosphatidylcholine-Sterol O-Acyltransferase; Simvastatin; Time Factors

HMG CoA (beta-hydroxy-beta-methylglutaryl coenzyme A) reductase inhibitors are very effective in lowering total and low-density lipoprotein cholesterol. Since the introduction of lovastatin for clinical use in the United States in 1987, statins have become widely available and the number of patients treated with these compounds is estimated to be over 2 million. The incidence of adverse effects is very low with elevated transaminase levels and myopathy being of greatest concern. Currently, several intervention trials demonstrated the influence of HMG CoA reductase inhibitors on total and cardiovascular morbidity and mortality and on regression of atherosclerosis as well. Fluvastatin, LESCOLR, a synthetic drug, is the most recently approved HMG CoA reductase inhibitor. PATIENTS METHODS AND STUDY DESIGN: At the lipid clinic 18 patients (8 familial hypercholesterolemia heterozygotes and 10 subjects affected with familial combined hyperlipidemia) have been treated with increasing dose of fluvastatin (20 and 40 mg/day with the evening meal) for 3 months. All patients respected AHA step I diet. The basic parameters of lipid and lipoprotein metabolism have been measured, and apo A-I, apo B levels as well.. Concentration of total cholesterol decreased after treatment with 20 and 40 mg of fluvastatin by 17% resp. 23%. The hypolipidemic effect was even more pronounced in LDL-cholesterol level, which was reduced by 21% and 29%. Decrease of LDL-cholesterol has been accompanied by reduction of apo B concentration by 16% resp. 24%. Also triglycerides levels were significantly influenced (-9%). On the other hand treatment with fluvastatin did not affect HDL-cholesterol and apo A-I concentration.. Our first results correspond to results of other authors. We also compared results with fluvastatin with our previous studies in which we used lovastatin and simvastatin. From the comparision with other statins we can conclude that the efficacy of fluvastatin is similar to lovastatin and simvastatin. On the other hand we have to notice, that the percent reduction of total and LDL-cholesterol after fluvastatin was a little bit smaller.. Fluvastatin, Lescol, seems to be a powerful hypolipidemic drug, well tolerated by the patients. In safety laboratory we did not notice any important undesirable result.

Topics: Adult; Anticholesteremic Agents; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemia, Familial Combined; Hyperlipoproteinemia Type II; Hyperlipoproteinemias; Indoles; Male; Middle Aged