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PubMed2006

Simvastatin enhances learning and memory independent of amyloid load in mice.

OBJECTIVE: Normal aging is often associated with a decline in learning and memory functions. This decline is manifested to a much greater extent in Alzheimer's disease. Recent studies have indicated statins, a class of cholesterol-lowering drugs, as a potential therapy for Alzheimer's disease. Our objective was to determine whether administering a statin drug (simvastatin) would protect against the development of behavioral deficits in an established mouse model of Alzheimer's disease. METHODS: Tg2576 mice and their nontransgenic littermates were treated with simvastatin and assessed by behavioral tests and biochemical analyses. RESULTS: Simvastatin treatment not only reversed learning and memory deficits in the Tg2576 mice, but also enhanced learning and memory in the nontransgenic mice. Moreover, levels of amyloid beta protein in the brains of treated mice did not differ from those of untreated mice. Simvastatin treatment was associated with increased expression levels of protein kinase B (Akt) and endothelial nitric oxide synthase in the mouse brain. INTERPRETATION: Our findings demonstrate that the effects of simvastatin on learning and memory are independent of amyloid beta protein levels. The mechanisms by which simvastatin exerts its beneficial effects may be related to modulation of signaling pathways in memory formation.

Alzheimer Disease↗
PubMed1995

Effect of simvastatin on Lp(a) concentrations.

The effect of HMG-CoA reductase inhibitors on Lp(a) concentrations is controversial, with some studies showing an increase and others showing no effect on Lp(a) concentrations. Many of these studies have been limited by small sample size and the lack of a prospective design. We evaluated the effect of four treatments: (1) placebo, (2) simvastatin 10 mg PO QPM, (3) simvastatin 20 mg PO QAM, and (4) simvastatin 20 mg PO QPM on Lp(a) concentrations in a prospective, randomized, controlled clinical trial of 24 weeks in 343 subjects in 28 clinical sites in the United States. Simvastatin was not associated with a change in Lp(a) concentrations relative to placebo. These results were not affected by controlling for race, initial Lp(a) level, or urinary albumin excretion. Simvastatin significantly reduced low-density lipoprotein (LDL) cholesterol levels (10 mg PO QPM: -27.6%; 20 mg PO QAM: -28.1%; and 20 mg PO QPM: -34.3%, all p < 0.001). It was concluded that in a large, randomized, controlled trial, simvastatin does not affect Lp(a) levels but markedly lowers LDL cholesterol levels.

Adolescent↗
PubMed2003

Rapid effects of simvastatin on lipid profile and C-reactive protein in patients with hypercholesterolemia.

BACKGROUND: Rapid lowering of low-density lipoprotein (LDL) cholesterol levels as well as C-reactive protein (CRP) by administration of drugs may produce early benefit to the coronary endothelium in patients with coronary heart disease and reduce angina and coronary events after revascularization. Limited information has been available in evaluating a potentially effective first 2-week therapeutic approach for the treatment of patients with hypercholesterolemia using a statin. HYPOTHESIS: The study was undertaken to investigate whether a rapid LDL cholesterol and CRP reduction can be achieved by 2-week simvastatin therapy using a common lipid-lowering protocol in patients with hypercholesterolemia. METHODS: Forty-two patients were randomly assigned to 20 or 40 mg/day of simvastatin. Blood samples were drawn at Day 0 and at Day 14 for measuring lipid profile, CRP levels, and hepatic enzymes in all patients. RESULTS: The results showed that both doses of simvastatin (20 and 40 mg) induced significant reductions in total cholesterol (TC, 25 and 38%) and LDL cholesterol (31 and 46%) compared with baseline. However, the highest dose of simvastatin (40 mg) resulted in significantly greater reductions in TC and LDL cholesterol (p = 0.04, p = 0.02, respectively) compared with the group receiving 20 mg (p < 0.04, p < 0.02, respectively). A less significant reduction was observed in mean triglycerides (TG) level (16 and 25%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in either group. In addition, both doses of simvastatin induced significant reductions in mean CRP levels on Day 14 (22.3 and 23.1%) in a non dose-dependent manner (p < 0.001, respectively. CONCLUSIONS: Our data suggest that a common daily dose of simvastatin, especially 40 mg, is an effective 2-week therapy for patients with hypercholesterolemia, and benefit to the vascular endothelium can be derived quickly by reduction of CRP levels.

Anticholesteremic Agents↗
PubMed1998

Cholesterol metabolism and serum and biliary noncholesterol sterols in gallstone patients during simvastatin and ursodeoxycholic acid treatments.

Effects of long-term high-dose ursodeoxycholic acid (UDCA) and simvastatin treatments on cholesterol metabolism and biliary lipid compositions were compared in patients with cholesterol gallstones. Absorption and synthesis of cholesterol, serum and biliary noncholesterol sterols and lipids were determined in 14 patients randomized to UDCA (23-25 mg/kg/d) or simvastatin (40 mg/d) for 1 year. Simvastatin reduced serum low-density lipoprotein cholesterol by 55%, and UDCA, by 9%. Cholesterol absorption was decreased (35%) by UDCA, but nonsignificantly increased by simvastatin (P < .05 for difference of changes caused by the two drugs). Whole-body synthesis and biliary output of cholesterol were both significantly decreased only by UDCA. In addition, UDCA inconsistently increased the proportions of serum and biliary precursor sterols of cholesterol, known to reflect cholesterol synthesis, but did not affect their biliary secretions. Simvastatin, however, dramatically reduced serum and also biliary cholesterol precursor sterol proportions and their biliary secretions and increased proportions of serum and biliary plant sterols and cholestanol, known to reflect cholesterol absorption, but had no effect on their biliary secretion. Only UDCA significantly decreased the molar percentage of cholesterol, the lithogenic index, and the cholesterol/phospholipid (CH/ PL) ratio in bile, whereas both treatments inconsistently decreased the vesicular CH/PL ratio (P < .07 in both groups). It is concluded that both drugs decreased serum cholesterol and inhibited cholesterol synthesis, but had a differing influence on precursor sterols and the absorption of cholesterol. UDCA had more beneficial effects than simvastatin on the antilithogenic properties of bile.

Anticholesteremic Agents↗
PubMed2001

Simvastatin and Ca(2+) signaling in endothelial cells: involvement of rho protein.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin is able to produce endothelium-dependent relaxation in addition to its lipid-lowering properties. The underlying mechanisms were investigated in bovine aortic endothelial cells (BAEC). Simvastatin induced an increase in cytosolic calcium ([Ca(2+)](i)) in BAEC, by releasing Ca(2+) from intracellular stores sensitive to thapsigargin and ryanodine, and increasing Ca(2+) entry. Simvastatin response was not altered by the phospholipase A(2) inhibitor ONO-RS-082, or the combination of superoxide dismutase plus catalase. However, the response to simvastatin was reduced by the product of HMG-CoA reductase, mevalonate or by the inhibitor of small G proteins of the Rho family, Clostridium botulinum C3 toxin. Thus, increase in [Ca(2+)](i) involving the activation of Rho protein through mevalonate-dependent pathway is essential for the action of simvastatin and might contribute to its beneficial effects against vascular diseases. This study helps elucidate the mechanisms of endothelial factor generation by simvastatin in BAEC.

Aminobenzoates↗
PubMed2001

Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells.

The cholesterol-lowering drug, simvastatin, is a pro-drug of a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and inhibits cholesterol synthesis in humans and animals. In addition, the bone effects of statins including simvastatin are being studied. We assessed the effects of simvastatin on osteoblastic differentiation in nontransformed osteoblastic cells (MC3T3-E1) and rat bone marrow cells. Simvastatin enhanced alkaline phosphatase (ALP) activity and mineralization in a dose- and time-dependent fashion. This stimulatory effect of the statin was observed at relatively low doses (significant at 10(-8) M and maximal at 10(-7) M). Northern blot analysis showed that the statin (10(-7) M) increased in bone morphogenetic protein-2 as well as ALP mRNA concentrations in MC3T3-E1 cells. Simvastatin (10(-7) M) slightly increased in type I collagen mRNA abundance throughout the culture period, whereas it markedly inhibited the gene expression of collagenase-1 between days 14 and 22 of culture. These results indicate that simvastatin has anabolic effects on bone through the promotion of osteoblastic differentiation, suggesting that it could be used for the treatment of common metabolic bone diseases such as osteoporosis.

3T3 Cells↗
PubMed1995

Behavior of Lp(a) and apoproteins (A1, B, C2, C3, E) during and after therapy with simvastatin.

The efficacy of simvastatin in reducing plasma cholesterol is well documented. Other molecules within the apo lipoprotein family, particularly lipoprotein (a) Lp(a), have recently been found to have a predictive and/or causative role in atherosclerosis. Based on these considerations, we studied 15 patients affected by primary hypercholesterolemia to evaluate the effect of simvastatin in Lp(a) and apoprotein plasma levels (A1, B, C2, C3, E), in addition to the classic lipid parameters. Clinical and laboratory parameters were evaluated before therapy, after 12 weeks of therapy, and after 5 weeks of drug withdrawal. Simvastatin therapy produced a significant reduction in total cholesterol (CH) and LDL-CH (p < 0.0001), and a significant increase in HDL-CH (p < 0.01); no variation was observed in triglyceride (TG) levels. Simvastatin therapy further showed a significant decrease in apoC2 (p < 0.05), the apo C2/C3 ratio (p < 0.01), and apoE (p < 0.01), as well as a significant increase in Lp(a) plasma levels (p < 0.05). All of the parameters studied returned to pretreatment values 5 weeks after drug withdrawal; only HDL-CH persisted above the values reached during therapy. Our data agree with those documenting the beneficial effect of simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies on the long-term effect of simvastatin on apoprotein molecules, such as on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.

Adult↗
PubMed1992

Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy.

The aim of this study was to assess the effect of simvastatin on plasma lipoproteins and renal function in hypercholesterolaemic Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Twenty-six hypercholesterolaemic (total cholesterol greater than or equal to 5.5 mmol/l) Type 1 diabetic patients with nephropathy were enrolled in a double-blind randomized placebo-controlled study for 12 weeks. The active treatment group (n = 14) received simvastatin (10-20 mg/day) for 12 weeks while the remaining 12 patients received treatment with placebo. The results during simvastatin treatment (baseline vs 12 weeks): total cholesterol 6.6 vs 4.8 mmol/l (p less than 0.01), LDL-cholesterol 4.25 vs 2.57 mmol/l (p less than 0.01) and apolipoprotein B 1.37 vs 1.06 mmol/l (p less than 0.01). HDL-cholesterol, and apolipoprotein A-I remained unchanged. Total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A-I, apolipoprotein B remained unchanged during placebo treatment. Albuminuria measured during the simvastatin and the placebo treatment (baseline vs 12 weeks) (the data are logarithmically transformed before analysis because of their positively skewed transformation; geometric mean (x/divided by antilog SE) is indicated) was 458 (x/divided by 1.58) vs 393 (x/divided by 1.61) and 481 (x/divided by 1.62) vs 368 (x/divided by 1.78 micrograms/min (NS). Glomerular filtration rate during simvastatin and placebo treatment (baseline vs 12 weeks) was 64 vs 63 and 72 vs 74 ml.min-1.1.73 m-2, respectively. Two patients receiving simvastatin treatment were withdrawn, one due to gastrointestinal side effects and one due to myalgia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Renal function and insulin sensitivity during simvastatin treatment in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria.

The effect of simvastatin (10-20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol > or = 5.5 mmol.l-1). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n = 8) for 36 weeks significantly reduced total cholesterol (6.7 +/- 0.3 vs 5.1 mmol.l-1 (p < 0.01)), LDL-cholesterol (4.4 +/- 0.3 vs 2.9 +/- 0.2 mmol.l-1 (p < 0.01)) and apolipoprotein B (1.05 +/- 0.04 vs 0.77 +/- 0.02 mmol.l-1 (p < 0.01)) levels as compared to placebo (n = 10). Both glomerular filtration rate (mean +/- SEM) (simvastatin: 96.6 +/- 8.0 vs 96.0 +/- 5.7 ml.min-1 x 1.73 m-2, placebo: 97.1 +/- 6.7 vs 88.8 +/- 6.0 ml.min-1 x 1.73 m-2)(NS) and urinary albumin excretion rate (geometric mean x/divided by antilog SEM) (simvastatin: 18.4 x/divided by 1.3 vs 16.2 x/divided by 1.2 microgram.min-1, placebo 33.1 x/divided by 1.3 vs 42.7 x/divided by 1.3 micrograms.min-1)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin- and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0 +/- 0.1 vs 1.9 +/- 0.1 (NS) and 3.1 +/- 0.6 vs 3.1 +/- 0.7 mg.kg-1 x min-1 (NS)) and the placebo group (1.9 +/- 0.1 vs 1.8 +/- 0.1 (NS) and 4.1 +/- 0.6 vs 3.8 +/- 0.2 mg.kg-1 x min-1 (NS)).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

The effects of simvastatin and cholestyramine, alone and in combination, on hepatic cholesterol metabolism in the male rat. off.

The influence of dietary simvastatin, cholestyramine, and the combination of simvastatin plus cholestyramine on hepatic cholesterol metabolism has been investigated in male rats. Recovery from the effects of the drugs was also investigated by refeeding normal chow for 24 h. Both drugs, alone and in combination, increased 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in vitro, but activity returned toward control values, after drug withdrawal. Acyl-CoA:cholesterol acyltransferase (ACAT) was significantly reduced (P < 0.001) by simvastain (-75%), cholestyramine (-71%), and by the drug combination (-81%), due both to a decrease in microsomal cholesterol and to nonsubstrate-dependent modulation of enzyme activity. Refeeding control diet increased ACAT activity but not to control levels. The enhanced activity arose partly from higher microsomal cholesterol and partly from increases in total enzyme activity. Cytosolic neutral cholesteryl ester hydrolase (CEH) activity was substantially elevated by simvastatin (3-fold) and by the drug combination (6-fold), whereas the effect of cholestyramine was smaller (1.5-fold). Normal chow for 24 h only partially returned cytosolic CEH activity to control values. Microsomal CEH activity was increased by simvastatin, alone and in combination with cholestyramine (1.4 to 1.7-fold), and was also enhanced, in the cholestyramine-treated animals, following drug withdrawal. Removal of simvastatin did not allow recovery of this enzyme activity, while withdrawal of the drug combination led to values 29% below controls. The results indicate that in the rat, simvastatin and cholestyramine alter both ACAT and CEH activity, as well as inhibiting HMG-CoA reductase activity.

Animals↗
PubMed2005

Cellular cholesterol efflux to plasma from moderately hypercholesterolaemic type 1 diabetic patients is enhanced, and is unaffected by simvastatin treatment.

AIM/HYPOTHESIS: Cellular cholesterol efflux to plasma is important in reverse cholesterol transport and may be affected by simvastatin in type 1 diabetes mellitus. METHODS: In 14 moderately hypercholesterolaemic type 1 diabetic and 13 healthy men we determined plasma (apo)lipoproteins, pre-beta HDL formation, cholesteryl ester transfer protein (CETP) activity, phospholipid transfer protein (PLTP) activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux out of Fu5AH cells and fibroblasts. After diet run-in, diabetic patients were randomly treated with simvastatin 10, 20, 40 mg and placebo, once daily each, for 6 weeks in a double-blind crossover design. RESULTS: Plasma very low density lipid protein (VLDL)+LDL cholesterol, LDL cholesterol, HDL phospholipids, apolipoprotein (apo) A-I, apo B, CETP activity, PLTP activity, cholesterol esterification, cholesteryl ester transfer and the capacity of plasma to induce cholesterol efflux from Fu5AH cells and fibroblasts were higher in diabetic patients. Pre-beta HDL formation was unaltered. Simvastatin treatment decreased VLDL+LDL cholesterol, LDL cholesterol, triglycerides and apo B, CETP activity, cholesterol esterification and cholesteryl ester transfer. HDL cholesterol increased and its change was correlated with the change in cholesteryl ester transfer. The ability to promote cholesterol efflux from Fu5AH cells and fibroblasts did not change after simvastatin. CONCLUSIONS/INTERPRETATION: The capacity of plasma from moderately hypercholesterolaemic type 1 diabetic patients to induce cholesterol efflux out of Fu5AH cells and fibroblasts is enhanced, probably due to higher apo A-I, HDL phospholipids and PLTP activity. Simvastatin increases HDL cholesterol in type 1 diabetic patients via lowering of plasma cholesteryl ester transfer. The HDL changes after simvastatin do not increase cellular cholesterol efflux further.

Adult↗
PubMed2005

Interaction between simvastatin and metoprolol with respect to cardiac beta-adrenoceptor density, catecholamine levels and perioperative catecholamine requirements in cardiac surgery patients.

UNLABELLED: Beta-blockade is a standard cardiovascular therapy known to induce the up-regulation of beta-adrenoceptor density. Upon ligand-binding, beta-adrenoceptors are normally internalised via the arrestin pathway, and after dissociation they are re-inserted into the membrane. This means that at high catecholamine levels the adrenoceptor density is low and under beta-blockade it is high. The insertion of receptors into the membrane is often dependent on farnesylation processes that can be inhibited by statins. We carried out a prospective, controlled, observational study to determine whether beta-blockade-induced up-regulation of beta-adrenoceptor density is attenuated by statin therapy and whether this would subsequently affect catecholamine consumption during surgery. We obtained pre-operative blood samples and intra-operative biopsies of the right atrial appendage from 39 patients (age: 65+/-5 years; BMI: 28+/-1) undergoing coronary bypass surgery with or without simvastatin (20 mg/day) therapy and with or without concomitant metoprolol therapy (50 mg/day). The atrial tissue was used for radioligand-binding studies with (-)-[125I]-iodocyanopindolol (ICYP) and for assessment of the beta-adrenoceptor subtype distribution following standard protocols. In the blood samples, plasma adrenaline and noradrenaline concentrations were determined using HPLC. In all tissue samples, we found a total beta-adrenoceptor density of 38+/-4 fmol/mg protein in untreated controls; this which was up-regulated to 55+/-5 fmol/mg protein in patients receiving metoprolol. This increase in receptor number was nearly prevented completely by simvastatin therapy (42+/-5 fmol/mg protein). The up-regulation could be attributed to increases in the beta1-adrenoceptor subtype. In contrast, simvastatin alone had no effect on beta-adrenoceptor density. Pre-operative adrenaline levels were slightly reduced in all drug therapy groups (nonsignificant differences), while the levels noradrenaline were not significantly different among the groups. With respect to the perioperative catecholamine requirements, patients on metoprolol needed significantly less dopamine than control patients, while patients undergoing simvastatin/metoprolol therapy needed as much as the controls. The post-operative total catecholamine requirements were not different among the four groups of patients. There were no differences in plasma metoprolol concentration between patients receiving metoprolol alone and those receiving a combination of metoprolol and simvastatin. IN CONCLUSION: Simvastatin therapy seems to counter-regulate the up-regulation of beta-adrenoceptor density. In the up-regulated state induced by metoprolol therapy, the patients seemed to need less catecholamines during cardiac surgery, which may be due to the higher number of beta-adrenoceptors. Additional simvastatin therapy did not reduce post-operative catecholamine consumption.

Adrenergic beta-Antagonists↗
PubMed2006

Antioxidant effects of simvastatin in primary and secondary prevention of coronary heart disease.

OBJECTIVE: The aim of the present study was to determine the effect of simvastatin on the levels of oxidized low-density lipoprotein (ox-LDL) and free radicals in hypercholesterolemic subjects undergoing primary and secondary prevention of coronary heart disease (CHD). METHODS: Fifteen subjects with hypercholesterolemia and no obvious CHD and 29 subjects with hypercholesterolemia and stable angina received 40 mg of simvastatin daily for 12 weeks. Serum total cholesterol, HDL-cholesterol and triglyceride concentrations were determined by automated enzymatic assays whereas LDL-cholesterol was calculated using the Friedwald formula. The ox-LDL levels were determined by a commercially available ELISA kit. Free radicals were assessed by the Free Radical Analytical System (FRAS). RESULTS: Both in primary and secondary prevention, subjects had borderline levels of free radicals but in neither group there was a significant reduction of free radicals after simvastatin treatment. In subjects undergoing primary prevention of CHD, ox-LDL levels were reduced by 31.1+/-5.0% (P < 0.001) whereas in secondary prevention were reduced by 6.5+/-5.2% (P < 0.02) after simvastatin treatment. The reduction of ox-LDL levels did not correlate with the reduction of total cholesterol levels in either group studied. In both groups, ox-LDL levels were not associated with free radical levels either before or after simvastatin treatment. CONCLUSION: This study demonstrates that simvastatin can significantly reduce circulating ox-LDL levels both in subjects undergoing primary and secondary prevention of CHD. These results could partly explain the slowing down of the progression of atherosclerosis caused by HMG-CoA reductase inhibitors.

Aged↗
PubMed2003

The effect of low-dose simvastatin in children with familial hypercholesterolaemia: a 1-year observation.

UNLABELLED: Familial hypercholesterolaemia (FH) is a severe disorder of lipid metabolism associated with an enhanced risk to develop cardiovascular disease later in life, with atherosclerotic lesions beginning already in childhood. These are facts which make an early diagnosis and therapy necessary to prevent or delay such complications. The aim of this study was to investigate the efficacy and safety of low-dose simvastatin, a potent HMG-CoA reductase inhibitor, in children and adolescents with FH. Therefore, 20 children and adolescents (12 females, 8 males) aged between 10 and 17 years with FH were recruited for this 1-year simvastatin study. According to baseline levels of low density lipoprotein (LDL)-C, girls and boys were divided into two groups, one group (with LDL-C <220 mg/dl) starting with a simvastatin dosage of 5 mg/day, the other (with LDL-C >220 mg/dl) 10 mg/day with the possibility to increase dosages up to a daily maximum of 20 mg, if not reaching LDL-C concentrations of <170 mg/dl within the first period. Every 4-8 weeks, weight, height, lipids, Lp(a) and routine safety parameters of all participants were determined by a paediatrician, documenting exactly all side-effects. The percentage decrease was 25% for LDL-C in the 5 mg simvastatin period (19% for total cholesterol (tChol)), 30% for LDL-C in the 10 mg period (26% for tChol) and 36% decrease for LDL-C in the 20 mg period (29% for tChol). The changes for high density lipoprotein (HDL)-C were -5.9% (5 mg), +2.9% (10 mg) and -10.9% (20 mg) the percentage decrease in triglycerides was 12.6% (5 mg), 14.3% (10 mg) and 21% (20 mg). The side-effects of simvastatin were of no clinical relevance and all disappeared after a couple of days. CONCLUSION: our results showed that simvastatin seems to be an effective and safe medical therapy even in children and adolescents with familial hypercholesterolaemia.

Adolescent↗
PubMed1990

Clinical benefits and cost-effectiveness of lowering serum cholesterol levels: the case of simvastatin and cholestyramine in The Netherlands.

To assess the cost-effectiveness of cholesterol-reducing therapy with cholestyramine and simvastatin in the primary prevention of coronary artery disease in The Netherlands, a model of coronary artery disease incidence was used based on multivariate logistic risk functions from the Framingham study. For men with initial cholesterol levels of 8 mmol/liter, the cost per year of life saved of cholestyramine, expressed in Dutch guilders (NLG; 1 NLG = $0.50), ranges from approximately NLG 208,000 to NLG 483,000, depending on the patient's age at initiation of therapy. For simvastatin, cost-effectiveness ranges from NLG 46,000 to NLG 98,000 per year of life saved among this group of men. Similar differences between simvastatin and cholestyramine therapy prevail among women, although the costs per year of life saved for both agents are considerably higher. These results suggest that (1) simvastatin is substantially more cost effective than is cholestyramine; (2) simvastatin therapy compares favorably with other generally accepted medical practices, especially if treatment is initiated at an early age; and (3) as its long-term safety record becomes more established, simvastatin may become accepted as a drug of first choice in the treatment of persons with elevated serum cholesterol levels.

Adult↗
PubMed1993

Pravastatin inhibited the cholesterol synthesis in human hepatoma cell line Hep G2 less than simvastatin and lovastatin, which is reflected in the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and squalene synthase.

The possible difference between lovastatin (mevinolin, MK-803), simvastatin (MK-733) and pravastatin (CS-514), all chemically-related competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, were tested in the human hepatoma cell line Hep G2, which is often used as a model for the human hepatocyte. After an 18-hr incubation of the cells with the drugs, pravastatin (IC50 = 1900 nM) was less potent than simvastatin and lovastatin (IC50 = 34 and 24 nM, respectively) in inhibiting the sterol synthesis. As a consequence of this inhibition, the HMG-CoA reductase mRNA levels and squalene synthase activity, both negatively-regulated by sterols, were increased equally by simvastatin and lovastatin, whereas the induction by pravastatin was much less. In contrast, there were fewer differences between the compounds in inhibiting HMG-CoA reductase activity, when assayed directly in Hep G2 cell homogenates (IC50 values = 18, 61 and 95 nM for simvastatin, lovastatin and pravastatin, respectively). Moreover, in experiments with human hepatocytes in primary culture the IC50 values for inhibition of the cholesterol synthesis by simvastatin and pravastatin were of the same order of magnitude (23 and 105 nM, respectively). The results are therefore explained as follows: the three drugs act in the same way within the Hep G2 cell in terms of inhibiting HMG-CoA reductase and their subsequent effect on the feedback regulation of the cholesterol synthesis, i.e. increasing squalene synthase and HMG-CoA reductase mRNA. However, pravastatin seems to be less able to enter the cells compared with simvastatin and lovastatin, possibly because of the higher hydrophobicity of the latter compounds. The observation with human hepatocytes suggests that in Hep G2 cells a specific hepatic transporter is missing. On one hand the human hepatoma cell line Hep G2 has proved to be a good model for the study of the feedback regulation of enzymes of the cholesterol biosynthetic pathway such as HMG-CoA reductase and squalene synthase, but, on the other hand seems to be less suitable as a model for the study of specific uptake of drugs, e.g. the vastatins, in human hepatocytes.

Cholesterol↗
PubMed1994

Simvastatin-sodium delays cell death of anoxic cardiomyocytes by inhibition of the Na+/Ca2+ exchanger.

When incubated under anoxic conditions, cultured neonatal cardiomyocytes undergo cell necrosis. Simvastatin-sodium, the bioactive metabolite of simvastatin (a potent serum cholesterol-lowering drug), delayed the anoxia-induced myocyte necrosis in a dose-dependent manner. This beneficial effect of simvastatin-sodium could not be attributed to its cholesterol-lowering properties. We found that simvastatin-sodium, at concentrations of 20 and 50 microM, attenuated the rise in intracellular Ca2+ concentration ([Ca2+]i) measured with Fura-2 in anoxic cardiomyocytes. In a test of sarcolemmal Na+/Ca2+ exchange activity, simvastatin-sodium attenuated the rise of [Ca2+]i upon incubation in sodium-free buffer, which normally causes a reversal of Na+/Ca2+ exchange and cellular calcium overload. The inhibitory action of simvastatin-sodium on the sarcolemmal Na+/Ca2+ exchanger could well explain the cardioprotective effect of the drug on myocytes subjected to anoxia.

Animals↗
PubMed1992

Comparative hypolipidemic effects of lovastatin and simvastatin in patients with heterozygous familial hypercholesterolemia.

We have compared the effects of lovastatin and simvastatin on plasma lipoproteins, fibrinogen and urinary mevalonic acid excretion in twenty-three patients with heterozygous familial hypercholesterolemia. After a baseline period patients were randomly assigned to receive lovastatin or simvastatin at doses of 10, 20 and 40 mg twice daily, for a period of 2 months each, and then, after a 4-week wash-out period, all patients received the alternate drug for a similar period of therapy. Both drugs were well-tolerated and no patients were withdrawn due to side effects. Lipid values returned to baseline after discontinuation of therapy and no carry-over effect was observed. Treatment with lovastatin resulted in decreases in LDL cholesterol concentrations from 274 mg/dl at baseline to 211, 192 and 178 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Treatment with simvastatin reduced concentrations of LDL cholesterol to 194, 168 and 156 mg/dl, respectively, on doses of 20, 40 and 80 mg/day. Concentrations of HDL cholesterol increased on both drugs, but no dose response relationship was apparent. Both drugs reduced the 24-h urinary excretion of mevalonic acid, an intermediate in cholesterol biosynthesis, but the magnitude of decrease was similar with lovastatin and simvastatin. Small, but statistically non-significant decreases in fibrinogen occurred with both drugs. Patients who showed the greatest hypolipidemic effect during treatment with lovastatin also showed an excellent therapeutic response to simvastatin and vice versa. We conclude that, on a milligram per milligram basis, simvastatin is twice as potent as lovastatin in the treatment of familial hypercholesterolemia and that with both drugs, reductions in LDL cholesterol concentrations are accompanied by decreases in the urinary excretion of mevalonic acid.

Adult↗