Regulation of HMG-CoA reductase, apoprotein-B and LDL receptor gene expression by the hypocholesterolemic drugs simvastatin and ciprofibrate in Hep G2, human and rat hepatocytes.

Infante R.

INSERM U.55, Hopital Saint-Antoine, Paris, France.

The comparative effects of simvastatin (a competitive inhibitor of HMG-CoA reductase) and ciprofibrate (another inhibitor of cholesterogenesis) on the incorporation of [14C]acetate and [3H]mevalonate into cholesterol HMG-CoA reductase activity, apo-B synthesis, LDL receptor, and their corresponding mRNAs, have been studied in the human hepatoma cell line Hep G2 and in human and rat hepatocytes in primary culture. Incubation of Hep G2 with simvastatin (0.01-1.5 microM) or ciprofibrate (25-100 microM) produced not only a marked inhibition of cholesterogenesis from [14C]acetate but also from [3H]mevalonate, an intermediate downstream of the HMG-CoA reductase reaction. However, in human and rat hepatocytes, cultured in similar conditions, simvastatin inhibited only the cholesterol synthesis from [14C]acetate, as expected. HMG-CoA reductase activity was greatly induced in Hep G2 and rat hepatocytes after incubation with simvastatin (up to 400% of controls), but not with ciprofibrate. Increased enzyme activity was accompanied by a higher cell content of reductase mRNA. Apo-B concentration in the medium of Hep G2 cells was 31% lower after 31 h incubation with simvastatin than in controls. However, neither simvastatin nor ciprofibrate modified the synthesis rate of apo-B or its mRNA level. Both LDL-receptor and its mRNA levels were raised by simvastatin at concentrations inhibiting cholesterol synthesis. Our data show that, in this human hepatoma cell line, HMG-CoA reductase competitive inhibition by simvastatin triggers a coordinate regulation of the expression of genes coding for reductase and LDL receptor but not for apo-B. Ciprofibrate, though efficient in inhibiting cholesterogenesis, did not induce the same regulatory reactions. The reason for this discrepancy is unknown.

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[Simvastatin in the treatment of hypercholesterolemia in the aged. An epidemiological and clinical study]

[Article in Italian]

Tamburrini LR.

II Cattedra di Geriatria e Gerontologia, Universita degli Studi di Trieste.

The paper review the literature on the subject and underlines the importance of hypercholesterolemia. It also reports the findings of the large trials, works and consensus studies, including the results of the Framingham Study, the Lipidic Research Clinics Program and the main international conferences. On the basis of these findings, it assesses the hypocholesterolemic effect of simvastatin in a sample group of 51 mainly geriatric outpatients following a standard period of preliminary dietary therapy. Subjects were treated with 20 mh/day simvastatin for not less than one month, after which lipidic parameters were evaluated and revealed significant variations: circulating cholesterin was reduced from 322 mg% +/- 49.4 to 225 mg% +/- 37.6 (p less than 0.001), the LDL-lipoprotein level fell from 229 mg% +/- 6.6 to 152 mg% +/- 36.3; HDL-lipoproteins showed no significant variation, nor did other tests to ascertain possible hepatic involvement or other parenchymas secondary to the use of simvastatin. Overall cholesterol levels decreased from 16423 mg% to 11511 mg%, equivalent to 29.9%. Lastly, simvastatin also proved to be clinical efficacious, and was easy to manage and well tolerated by elderly patients. All subjects responded equally well to treatment independent of their general condition and sex. Basal cholesterolemia in elderly subjects decreased from 320 mg% +/- 46.3 to 226 mg% +/- 33.2 (p less than 0.001) and in adults from 325 mg% +/- 56.6 to 224 mg% +/- 46.5 (p less than 0.001); LDL-cholesterol decreased from 232 mg% +/- 46.5 to 153 mg% +/- 35.6 (p less than 0.001) and from 224 mg% +/- 46.6 to 147 mg% +/- 38.7 (p less than 0.001) respectively.

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Simvastatin, an inhibitor of cholesterol biosynthesis, shows a synergistic effect with N,N'-bis(2-chloroethyl)-N-nitrosourea and beta-interferon on human glioma cells.

Fumagalli R.

Institute of Pharmacological Sciences, University of Milan, Italy.

The effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on human glioma cell growth was investigated. When incubated with simvastatin, cell proliferation decreased in a concentration-dependent fashion, as measured by cell number and [3H]-thymidine incorporation into DNA (concentration producing 50% inhibition, 60 nM). The effect was detectable 12 h after cells were exposed to the drug and persisted for 2 days. Addition of mevalonate to cells exposed effect of simvastatin in combination with beta-interferon and N,N'-bis(2-chloroethyl)-N-nitrosourea, both antitumoral drugs, was also evaluated by cell growth inhibition assay. The concentration producing 50% inhibition for each of these drugs was 650 units/ml and 50 nM, respectively. Subliminal concentrations of beta-interferon or N,N'-bis(2-chloroethyl)-N-nitrosourea were incubated together with 1 nM simvastatin. The data were analyzed with the aid of an isobologram using the concept of an envelope of additivity. Simultaneous cell exposure to simvastatin with either N,N'-bis(2-chloroethyl)-N-nitrosourea or beta-interferon produced a strong synergistic inhibitory effect on cell proliferation. These data provide in vitro support for the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, utilized as plasma cholesterol-lowering agents, could potentiate the effect of antiblastic drugs on tumor growth.

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Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer.

Sylven C.

Department of Cardiology, Clinical Research Center, Huddinge, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.

Statins have cardioprotective roles. We explored the cardiac angiogenic effects of simvastatin in combination with transient overexpression of vascular endothelial growth factor (VEGF). Compared with normal mice, 1-year-old ApoE(-/-) mice fed on a high-fat diet (HFD) had about 30% less myocardial capillary (P < 0.001) and arteriolar (P < 0.03) densities, associated with decreased VEGF (55%), VEGFR-1 (56%) and VEGFR-2 (78%) mRNA expressions and myocardial endothelial nitric oxide synthase (eNOS) production (58%). By contrast, angiopoietin-1 and angiopoietin-2 mRNA expressions were increased (500% P < 0.02, and 400% P < 0.01, respectively) in the ApoE(-/-) hearts. No change was observed in Tie-2 gene expression. Phosphorylation of antiapoptotic Akt was lower and proapoptotic p38 mitogen-activated protein kinase (MAPK) was higher in the ApoE(-/-) mice compared with controls. Intramyocardial VEGF gene transfer increased capillary and arteriolar densities in the ApoE(-/-) mice, and simvastatin treatment further enhanced capillary density (P < 0.03) to a level similar to that of normal mice. Simvastatin did not change the lipid profile but blocked p38 MAPK phosphorylation in the ApoE(-/-) myocardium. Concurrent with these changes, there were increased levels of expression of mVEGF (P < 0.04) and VEGFR-2 (P < 0.03) mRNAs and increased production of eNOS (P < 0.05) in the ApoE(-/-) mice, while no changes were detected in the angiopoietin system. Thus, increased myocardial angiogenesis in the ApoE(-/-) mice following transient overexpression of VEGF is further increased by additional simvastatin treatment. These effects occurred concurrently with simvastatin-induced stimulation of the VEGF system, increased eNOS production and reduction in p38 MAPK phosphorylation.

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Effect of simvastatin on receptor mediated metabolism of low density lipoprotein in guinea pigs.

Arakawa K.

Department of Internal Medicine, School of Medicine, Fukuoka University, Japan.

This study examined the effects of simvastatin, an inhibitor of HMG-CoA reductase, on the metabolism of labelled human low density lipoprotein (LDL) in animal models. Administration of 10 mg/kg per day simvastatin for 2 weeks reduced the levels of total cholesterol, LDL-cholesterol and triglycerides by 5.7 mg/dl (16%), 8.8 mg/dl (36%) and 4.9 mg/dl (13%), respectively in guinea pigs. High density lipoprotein-cholesterol levels rose 0.8 mg/dl (29%) by simvastatin treatment. Measurements of turnover of LDL were determined between simvastatin-treated guinea pigs and untreated guinea pigs using intravenous injection of 131I-labelled LDL and 125I-labelled galactose-treated LDL to quantify the LDL receptor pathway. Simvastatin significantly increased the fractional catabolic rate (FCR) of the LDL receptor-dependent pathway. In contrast, the FCR of the LDL receptor-independent pathway was not altered by simvastatin therapy. The FCR for LDL isolated from simvastatin-treated subjects compared to that from control subjects was very similar in both control and simvastatin-fed guinea pigs. These findings suggest that simvastatin mainly reduced serum cholesterol levels by accelerated FCR of LDL receptor mediated pathway.

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Simvastatin and side effects.

Wilson MJ.

Princess Margaret Hospital, Christchurch.

OBJECT: to investigate the symptomatic and biochemical side effect profile of simvastatin (a new cholesterol lowering drug) following routine use in a specialist hospital outpatient clinic. METHODS: all patients (n = 110) newly commenced on simvastatin at the lipid disorders clinic at the Princess Margaret Hospital in the first ten months of prescription availability were asked to complete a side effects questionnaire and biochemical evaluation at six months of therapy. RESULTS: 76.4% of patients reported experiencing no side effects with 8% of patients spontaneously reporting feeling better since commencing therapy. Nineteen point one percent of patients reported experiencing symptoms they attributed to simvastatin but had continued therapy, while a further 4.5% of patients had withdrawn from therapy because of side effects. The most frequently reported side effects were muscle ache (13.6%), and gastrointestinal symptoms (4.5%). No abnormalities in biochemical safety tests occurred. CONCLUSIONS: the rate of side effects reported with prescription use exceeds that previously encountered in clinical trials. Since simvastatin is considered effective and well tolerated it is likely to receive wide acceptance in the management of high risk hypercholesterolaemic patients. However, this study indicates the need for continued physician awareness of the main symptoms and their frequency amongst those treated with simvastatin.

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Effect of simvastatin on the apparent size of LDL particles in patients with type IIB hyperlipoproteinemia.

van der Laarse A.

Department of Cardiology, University Hospital, Leiden, The Netherlands.

After 15 weeks of simvastatin therapy (20 mg/day), low density lipoprotein particle size in sera of 16 patients with type IIb hyperlipoproteinemia increased significantly from 233 +/- 5.0 A to 237 +/- 7.0 A (P less than 0.05), analyzed by 2-16% polyacrylamide gradient gel electrophoresis. Under simvastatin therapy the concentrations of total cholesterol, total triglyceride, very low density lipoprotein cholesterol and triglyceride, low density lipoprotein cholesterol and apolipoprotein B in serum fell significantly by 30%, 30%, 43%, 28%, 36% and 26%, respectively, and the concentration of high density lipoprotein cholesterol rose significantly by 14%. The changes of low density lipoprotein particle size induced by simvastatin therapy were correlated best with the changes of very low density lipoprotein triglyceride concentration (r2 = 0.438, P less than 0.01). Our results suggest that simvastatin therapy, additionally to a reduction of the serum cholesterol concentration, increases low density lipoprotein particle size which may contribute to reduction of the risk of coronary heart disease in patients with type IIb hyperlipoproteinemia.

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Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.

MacDonald JS.

Department of Safety Assessment, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

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Plasma high density lipoprotein particle size alteration by simvastatin treatment in patients with hypercholesterolaemia.

Olsson AG.

Department of Internal Medicine, Karolinska Institute, Stockholm, Sweden.

Twenty-two patients with pronounced hypercholesterolaemia were treated with simvastatin in increasing doses, i.e. 10, 20 and 40 mg O.D. Each treatment regimen had a duration of 6 weeks. In addition to the expected low density lipoprotein (LDL)-lowering effect, simvastatin altered the plasma HDL particle size spectrum by selective elevation of the plasma HDL2b and HDL3a levels, as defined by polyacrylamide gradient gel electrophoresis (gge). While the reduction in LDL cholesterol by simvastatin was dose dependent, the effect on HDL was maximal already at 10 mg daily. On treatment with simvastatin 10 mg O.D., the plasma HDL2b and HDL3a concentrations increased by 30% (P less than 0.001) and 12% (P less than 0.01) respectively. On the corresponding treatment with simvastatin LDL cholesterol decreased by 31% (P less than 0.001). The very low density lipoprotein (VLDL) cholesterol to triglyceride ratio was significantly lowered by treatment with 10 mg simvastatin O.D. suggesting a compositional change in VLDL. Positive univariate correlations between treatment-induced decreases in plasma HDL3b/3c levels and VLDL triglyceride concentration were seen. It is suggested that inhibition of cholesterol synthesis in hypercholesterolaemic subjects by simvastatin treatment alters the composition of VLDL, which may affect the close relation between HDL and VLDL, in turn producing selective elevations of the plasma HDL2b and HDL3a levels.

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