Cost effectiveness of cholesterol-lowering therapy in The Netherlands. Simvastatin versus cholestyramine.

Ascoop CA.

Department of Health Economics, Limburg State University, Maastricht, The Netherlands.

Using a model of coronary heart disease incidence based on multivariate logistic regression functions from the Framingham Heart Study, the cost effectiveness of simvastatin was compared with that of cholestyramine in preventing such disease. For men with initial cholesterol levels of 310 mg/dl, the cost effectiveness of cholestyramine, expressed in Dutch guilders, ranges from approximately 220,000 to 510,000 guilders per year of life saved, depending on age at initiation of therapy. For simvastatin, cost-effectiveness ratios range from 50,000 to 110,000 guilders per year of life saved among this group of men. Results are similar for women, although the cost effectiveness of both agents is considerably less. These results suggest that simvastatin is substantially more cost effective than cholestyramine; that it compares well with other generally accepted medical practices, especially if therapy is initiated at an early age; and that simvastatin should become accepted as a drug of first choice in the treatment of persons with elevated serum cholesterol levels as its long-term safety record becomes more established.

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Tissue-selective acute effects of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase on cholesterol biosynthesis in lens.

Tanaka RD.

Department of Cellular Biology, Squibb Institute for Medical Research, Princeton, NJ 08543-4000.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis, lower serum cholesterol by increasing the activity of low density lipoprotein (LDL) receptors in the liver. In rat liver slices, the dose-response curves for inhibition of [14C]acetate incorporation into cholesterol were similar for the active acid forms of lovastatin, simvastatin, and pravastatin. The calculated IC50 values were approximately 20-50 nM for all three drugs. Interest in possible extrahepatic effects of reductase inhibitors is based on recent findings that some inhibitors of HMG-CoA reductase, lovastatin and simvastatin, can cause cataracts in dogs at high doses. To evaluate the effects of these drugs on cholesterol synthesis in the lens, we developed a facile, reproducible ex vivo assay using lenses from weanling rats explanted to tissue culture medium. [14C]Acetate incorporation into cholesterol was proportional to time and to the number of lenses in the incubation and was completely eliminated by high concentrations of inhibitors of HMG-CoA reductase. At the same time, incorporation into free fatty acids was not inhibited. In marked contrast to the liver, the dose-response curve for pravastatin in lens was shifted two orders of magnitude to the right of the curves for lovastatin acid and simvastatin acid. The calculated IC50 values were 4.5 +/- 0.7 nM, 5.2 +/- 1.5 nM, and 469 +/- 42 nM for lovastatin acid, simvastatin acid, and pravastatin, respectively. Thus, while equally active in the liver, pravastatin was 100-fold less inhibitory in the lens compared to lovastatin and simvastatin. Similar selectivity was observed with rabbit lens. Following oral dosing, ex vivo inhibition of [14C]acetate incorporation into cholesterol in rat liver was similar for lovastatin and pravastatin, but cholesterol synthesis in lens was inhibited by lovastatin by as much as 70%. This inhibition was dose-dependent and no inhibition in lens was observed with pravastatin even at very high doses. This tissue-selective inhibition of sterol synthesis by pravastatin was likely due to the inability of pravastatin to enter the intact lens since pravastatin and lovastatin acid were equally effective inhibitors of HMG-CoA reductase enzyme activity in whole lens homogenates. We conclude that pravastatin is tissue-selective with respect to lens and liver in its ability to inhibit cholesterol synthesis.

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Effects of inhibition of cholesterol synthesis by simvastatin on the production of adrenocortical steroid hormones and ACTH.

Van 'T Laar A.

Department of Medicine, University Hospital Nijmegen, The Netherlands.

Simvastatin, a derivative of lovastatin, is a potent inhibitor of cholesterol biosynthesis and may interfere with steroid hormone production, for which cholesterol is required. In a single-blind, placebo-controlled study, 24 patients with severe primary hypercholesterolaemia (mean serum cholesterol +/- SD = 10.74 +/- 1.59 mmol/l) were treated with simvastatin 40 mg per day for 8 weeks. Before and after treatment, the following parameters were evaluated: basal levels of ACTH, cortisol, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone; urinary excretion of free cortisol; the cortisol response after short-term infusion of ACTH; the ACTH and cortisol response during insulin-induced hypoglycaemia. Total serum cholesterol decreased by 35.0 +/- 8.1% (P less than 0.001) and low-density lipoprotein (LDL) cholesterol by 39.8 +/- 9.8% (P less than 0.001); high-density lipoprotein (HDL) increased by 9.2 +/- 11.1% (P less than 0.001). Basal levels of ACTH were higher after simvastatin (2.9 +/- 1.9 pmol/l vs 4.1 +/- 2.9 pmol/l; P less than 0.05) whereas basal levels of steroid hormones were not significantly changed. The excretion of free cortisol was unaltered. The peak cortisol after ACTH infusion was lower after treatment (0.87 +/- 0.23 mumol/l vs 0.78 +/- 0.10 mumol/l; P less than 0.05), but was unaltered during insulin-induced hypoglycaemia. We conclude that simvastatin lowers serum cholesterol without clinically relevant effects on the adrenocortical steroid hormone secretion and the hypothalamic-pituitary-adrenal axis.

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Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients.

Torre-Amione G.

Baylor College of Medicine, 6550 Fannin, Houston, Texas 77030, USA.

BACKGROUND: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF-alpha) expression; TNF-alpha is a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients. METHODS: We randomized 10 consecutive heart transplant recipients to receive either 20 mg/day simvastatin (n = 5) or placebo (n = 5) for 6 months after cardiac transplantation. Routine surveillance endomyocardial biopsy specimens were obtained from all patients. We analyzed tissues for myocardial TNF-alpha content, total collagen content, and myocyte size using semiquantitative immunohistochemistry. RESULTS: Myocyte size and total collagen content of placebo and simvastatin groups did not show a statistically significant difference at any biopsy time point. Myocardium TNF-alpha content (% tissue area stained) at 1 week after transplantation was similar in the simvastatin and placebo groups. At the 24(th) week after transplantation, when compared with Week 1 values, we found a significant decrease in myocardium TNF-alpha content in the simvastatin group (15.0% +/- 2.3% vs 5.8% +/- 2.4%, p = 0.02) that was not observed in the placebo group (15.0% +/- 1.5% vs 12.0% +/- 2.6%, p = not significant). CONCLUSION: Simvastatin treatment in heart transplant recipients decreased myocardium TNF-alpha expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-alpha may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

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[Efficacy and safety of simvastatin, a new cholesterol-lowering drug]

[Article in Dutch]

Stalenhoef AF.

The effects of simvastatin, an inhibitor of cholesterol synthesis, was studied in 50 patients with hypercholesterolaemia. In the first study, 24 patients with serum cholesterol levels of 10.74 +/- 1.59 mmol/l were treated with simvastatin 40 mg daily for 6 months. Serum cholesterol levels decreased within 4 to 8 weeks to stable values 30 to 36% below the basal value. Serum triglycerides decreased by 16 to 28% and high density lipoprotein (HDL) cholesterol increased by 6 to 11% on average. In the second study, 26 patients with serum cholesterol levels of 12.35 +/- 2.05 mmol/l were treated with simvastatin 40 mg daily as monotherapy or combined with a bile acid binding resin for 2 years. Cholesterol levels decreased to values which remained stable throughout the entire study period; after 2 years the decrease amounted to 43%. Compared with monotherapy, combination with a bile acid binding resin yielded a further 12% decrease of cholesterol. In the entire group, triglycerides decreased by 16% and HDL cholesterol increased by 9% on the average. Side effects were limited to slight increases in alanine aminotransferase and creatine phosphokinase occurring in some patients. Simvastatin appears to be an important asset in the treatment of hypercholesterolaemia.

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Simvastatin and L-arginine preserve renal function after ischemia/reperfusion injury.

Yoder KN.

Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio 45701, USA. inmans ohio.edu

BACKGROUND: HMG-CoA reductase inhibitors have been shown to have beneficial renal hemodynamic effects by increasing renal blood flow, independent of their lipid-lowering properties. Currently in organ transplantation, the calcineurin inhibitor cyclosporine A (CyA) is the immunosuppressant of choice. However, its use is limited by its nephrotoxic effects, namely its renal vasoconstrictor properties. The purpose of this study was to determine the effect of an HMG-CoA reductase inhibitor, simvastatin (Zocor), on renal function in rats and on urinary nitrite/nitrate production following ischemia/reperfusion injury (I/R) with concomitant cyclosporine treatment. In addition, L-NAME (N(G)-nitro-L-arginine methyl ester) and L-arginine were administered with CyA to the rats to test the hypothesis that simvastatin's beneficial effects were due to nitric oxide. METHODS: Male Wistar rats (250 g) were anesthetized and the supra-aorta clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into five groups: 1) controls, no ischemia, no treatment (CTRL, n = 8); 2) ischemia (ISCH) plus cyclosporine A only (CyA, 5 mg/kg/day i.p., n = 8); 3) ischemia plus CyA and simvastatin (SIM, 10 mg/kg/day, gavage, n = 8); 4) ischemia plus simvastatin plus L-NAME plus CyA (10 mg/kg/day, gavage, n = 8), and 5) ischemia plus simvastatin plus L-arginine (2% in drinking water, n = 7) plus CyA. Five to 7 days after I/R injury, the glomerular filtration rate (GFR) was determined using urinary iohexol clearance. Urinary nitrite/nitrate production was determined using nitrate reductase and the Greiss reaction. Data are expressed as mean +/- SEM, and intergroup comparisons were made using one-way analysis of variance. RESULTS: The GFR values (mL/min) for all five groups are as follows: 1) CTRL = 1.25 +/- 0.10; 2) ISCH plus CyA only = 0.45 +/- 0.06 (P < 0.05 versus CTRL, ISCH only and simvastatin and cyclosporine and simvastatin plus L-arginine and cyclosporine); 3) CyA and SIM = 0.78 +/- 0.09, CyA and L-NAME = 0.62 +/- 0.12, and CyA and L-arginine and SIM = 1.57 +/- 0.12. Results in the control were significantly different from results in the ischemic only and the L-NAME groups (P < 0.05). The L-arginine plus cyclosporine and simvastatin group was significantly higher than the ischemic only group, ischemic plus simvastatin and cyclosporine and the L-NAME plus cyclosporine group (P < 0.05). No significant differences could be detected in the urinary nitric oxide concentrations. CONCLUSIONS:: After I/R injury and cyclosporine treatment, simvastatin and L-arginine preserved renal function, compared with cyclosporine treatment alone, because simvastatin and L-arginine may not have a direct vasoconstrictor effect on the renal microcirculation. They may be suppressing endothelin or increasing other vasodilator mediators such as the vasodilator prostaglandins and/or nitric oxide.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15654174&dopt=Abstract simvastatin, Zocor