Effect of simvastatin treatment on plasma apolipoproteins and hepatic apolipoprotein mRNA levels in the genetically hypercholesterolemic rat (RICO).

Lutton C.

Laboratoire des Maladies Metaboliques, INRA, Theix, St Genes Champanelle, France.

The effects of long-term treatment with simvastatin on plasma lipoproteins, plasma apolipoproteins, and on hepatic apolipoprotein gene expression were evaluated in genetically hypercholesterolemic (RICO) rats. Simvastatin administration caused a decrease in plasma triglyceride and phospholipid concentrations. Plasma cholesterol concentration was not changed by simvastatin, but cholesterol distribution among plasma lipoproteins was altered. Plasma apo B, apo A-I, and apo A-IV concentrations were lowered by simvastatin treatment whereas plasma apo E concentration was not affected by this drug. In the liver, simvastatin treatment induced a significant decrease of apo E mRNA level but had no effect on apo B, apo A-I, and apo A-IV mRNA abundances. It appears that simvastatin may modify plasma apolipoprotein concentrations by influencing their hepatic synthesis at both pre- and posttranscriptional levels.

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Plasma concentration profiles of simvastatin 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin.

Karkas JD.

Department of Nephrology, University Hospital, Lund, Sweden.

A few cases of severe rhabdomyolysis have been reported in heart transplant recipients treated simultaneously with ciclosporin (CS) and the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin. When measured, plasma lovastatin HMG-CoA reductase inhibitor concentrations in these patients were higher than expected. This prompted us to study the plasma concentration profiles of simvastatin HMG-CoA reductase inhibitory activity after a single dose of simvastatin in kidney transplant recipients. Five patients treated with CS, azathioprine and prednisolone (CS patients) were compared to 5 patients treated with azathioprine and prednisolone (non-CS patients). The concentration curves had similar shapes but the mean area under the curve/24 h was almost 3 times higher (p = 0.047) and the mean peak concentration was twice as high in CS patients (p = 0.028). These results suggest a difference in the disposition of simvastatin in CS patients as compared to non-CS patients. Simvastatin should be administered in a reduced dosage to CS patients.

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3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibition modulates vasopressin-stimulated Ca2+ responses in rat A10 vascular smooth muscle cells.

Wojcikiewicz RJ.

Department of Pharmacology, Leicester Royal Infirmary, UK.

Previous evidence has indicated a role for changes in cell membrane cholesterol in the modulation of [Ca2+]i responses and smooth muscle contraction to vascular agonists. However, the actions of plasma cholesterol-lowering agents such as 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (eg, simvastatin) have not been defined. Such agents may in addition affect isoprenoid intermediates that may play a role in signal transduction pathways involving G proteins. Arginine vasopressin-induced [Ca2+]i responses in A10 rat vascular myocytes were therefore studied in vitro. Vasopressin stimulated an initial peak [Ca2+]i that was independent of extracellular Ca2+ entry and a subsequent plateau that was dependent on Ca2+ influx, mainly through receptor-operated dihydropyridine-insensitive divalent cation channels. Simvastatin-treated A10 cells (5 mg/L for 24 hours) showed a normal initial peak response to vasopressin, but the plateau phase of Ca2+ entry was significantly impaired. By use of Mn2+ quenching of intracellular fura 2 to measure divalent cation entry, the maximal rate of vasopressin-stimulated Mn2+ entry was impaired in simvastatin-treated cells by 52%. Mevalonate (1 mmol/L for 4 hours at 37 degrees C) reversed all the changes in simvastatin-treated cells. There were no associated changes in total cellular cholesterol or fluorescence anisotropy measurements with simvastatin treatment. Measurements of inositol-1,4,5-trisphosphate mass showed that simvastatin did not impair the initial peak response to vasopressin but significantly reduced the subsequent plateau phase. These changes were also reversed with mevalonate incubation. These findings suggest that simvastatin has additional effects on [Ca2+]i homeostasis that are independent of changes in total cell cholesterol.

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Determination of changes in serum lathosterol during treatment with simvastatin to evaluate the role of lathosterol as a parameter for whole body cholesterol synthesis.

Wijnandts PN.

Central Laboratory for Clinical Chemistry, University Hospital, Groningen, Netherlands.

Serum levels of cholesterol and the cholesterol precursor lathosterol were determined in five healthy volunteers who took 20 mg simvastatin daily during 1 week. During this period and for the following 5 days blood samples were collected. Five days after ingestion of simvastatin, serum lathosterol had already reached a steady-state level and its concentration decreased by 55-73%. In contrast, the cholesterol concentration decreased only by 17-29% and did not reach a steady-state level even after 7 days of treatment. After withdrawal of simvastatin, serum lathosterol quickly rose to pretreatment values. From the data a mean half-life of lathosterol could be calculated of 23.5 +/- 6.6 h during treatment with simvastatin and of 28.7 +/- 15.1 h after its withdrawal, taking, respectively, the decrease and increase of serum lathosterol into account. From these data it can be concluded that serum lathosterol is also a good parameter for determining whole body cholesterol synthesis during non-steady-state conditions, although plasma mevalonic acid, another (early) cholesterol precursor, is preferred owning to its much shorter reported half-life.

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Simvastatin and intracellular pH regulation by the Na+/H+ antiport of SV40-virus-transformed human MRC5 fibroblasts.

Ng LL.

Department of Pharmacology, Leicester Royal Infirmary, U.K.

1. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by simvastatin leads to inhibition of both cell growth and Na+/H+ antiport activity. The effect of simvastatin on intracellular pH and Na+/H+ antiport activity was therefore studied on an adherent cell line, the SV40-virus-transformed MRC5 human fibroblast. 2. Simvastatin led to a dose-dependent decrease in intracellular pH, attributed to a reduction in Na+/H+ exchange, together with a rounding of cell shape. Mevalonate (1 mmol/l) prevented these effects of simvastatin, and when added after inhibition of the antiport by simvastatin, reversed these changes within 1-2h. 3. The phenomenon of mevalonate reversal of antiport inhibition by simvastatin was not sensitive to cycloheximide, indicating its post-translational nature. This was also consistent with the short period of incubation with mevalonate leading to reversal of antiport inhibition (1-2 h). These changes in intracellular pH regulation were not due to alterations in cell cholesterol content. 4. A variety of inhibitors of post-translational processes, such as N-linked glycosylation (tunicamycin), phosphorylation (staurosporine), isoprenylation (farnesol, limonene), and of pertussis-toxin-sensitive G-proteins or calmodulin (W7), had no effect on the reversal by mevalonate of simvastatin-induced changes in Na+/H+ antiport activity. 5. N-Ethylmaleimide (50 mumol/l for 5 min) prevented mevalonate reversing the effects of simvastatin, suggesting the importance of thiol groups in the phenomenon of reversal of the inhibition of Na+/H+ antiport activity by simvastatin. Furthermore, concurrent incubation of simvastatin-treated cells with dithiothreitol (1 mmol/l) and N-ethylmaleimide restored the ability of mevalonate to reverse the inhibitory effects of simvastatin on Na+H+ antiport activity.

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The effect of simvastatin on dyslipemia in continuous ambulatory peritoneal dialysis patients.

Stangou M.

CAPD Unit, 1st Department of Internal Medicine, Aghios Dimitrios Hospital, Thessaloniki, Greece.

The efficacy of simvastatin, an inhibitor of HMG-CoA reductase, was evaluated in 14 nondiabetic hypercholesterolemic continuous ambulatory peritoneal dialysis (CAPD) patients with or without hypertriglyceridemia. Following a hypolipemic diet for 6 weeks, simvastatin was administered at a dose of 10 mg/day for 6 months. After 6 weeks on simvastatin, cholesterol was reduced by 22% (p < 0.001), triglycerides by 24% (p < 0.001), low-density lipoprotein (LDL) by 27% (p < 0.001), while high-density lipoprotein (HDL) increased by 18% (p < 0.005). These changes remained steady for 6 months. Apolipoprotein-B (Apo-B) was reduced by 17.8% (p < 0.0001), while Apo-A was stable. There were no liver function abnormalities observed. In 3 patients serum creatinine kinase (CK) was increased, and in 2 treatment was stopped. No new lens opacities or other side effects were detected. Simvastatin seems to be an effective and relatively well-tolerated drug for dyslipemias in CAPD.

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