atorvastatin Lipitor
Managed care trends in statin usage.

Bazalo GR.

gkbazalo uswest.net

PURPOSE: HMG-CoA reductase inhibitors ("statins") have become the drug class of choice for the treatment of hyperlipidemia. Six product brands encompassing 20 dosage strengths have been available during the past two years. The objective of this review is to describe dosing trends for the six statin brands and to determine if and how these trends vary among managed care plans as a function of product market share. METHODOLOGY: Utilization of HMG-CoA reductase inhibitors was examined using the NDC Health Information Services (Phoenix, Ariz.) database for the two-year period ending December 2000. This database contains unit dispensing data at the dosage-strength level for 1,079 managed care plans. Trends in market share, mean daily dose, and dosage distribution of the six current statin brands were examined. The relationship of market share to mean dose was also examined for each brand. PRINCIPAL FINDINGS: Market share decreased for all statin brands during the two-year period, except for the two newest entries, atorvastatin (up 9.7 share points) and cerivastatin (up 4.6 share points). The mean dose of all statins increased during the two-year period. A statistically significant negative correlation between market share and mean dose was found for atorvastatin and a positive correlation was found for fluvastatin (P < 0.01). Furthermore, atorvastatin share was significantly correlated to lower mean doses of all other statin brands. That is, higher use of atorvastatin was associated with lower doses of all statin products. CONCLUSION: In developing a cost-management strategy, managed care organizations should take historical and anticipated market-share changes and dose-mix changes into account along with the product's clinical efficacy and total cost of care.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11688111&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of atorvastatin on intracellular calcium uptake in coronary smooth muscle cells from diabetic pigs fed an atherogenic diet.

Hill BJ, Dixon JL, Sturek M.

Department of Physiology, School of Medicine, University of Missouri, MA415 Medical Sciences Building, Columbia, MO 65212, USA. sturekm missouri.edu

Intracellular Ca(2+) store loading has been shown to alter proliferation and apoptosis of several cell types. In addition, HMG-CoA reductase inhibitors (i.e. atorvastatin) are effective in treating diabetic dyslipidemic patients. Thus, we hypothesized that chronic atorvastatin treatment would prevent increased Ca(2+) uptake into intracellular Ca(2+) stores in vascular smooth muscle cells from diabetic dyslipidemic pigs. Male Yucatan pigs were divided into four groups for 20 weeks-- (1) low fat fed (control); (2) hyperlipidemic (F); (3) alloxan-induced diabetic dyslipidemic (DF); and (4) diabetic dyslipidemic pigs treated with atorvastatin (DFA). The F, DF, and DFA groups were fed a high fat/cholesterol diet. Cells were isolated from the coronary artery and the myoplasmic Ca(2+) (Ca(m)) response measured using single cell fura-2 imaging. The Ca(m) response to caffeine (5 mM to release Ca(2+) from the sarcoplasmic reticulum, SR) and ionomycin (10 microM; to release the total Ca(2+) store) was determined in either the presence of low Na (19Na; inhibits Na(+)-Ca(2+) exchange), thapsigargin (TSG; inhibits the SR Ca(2+) pump), and a 19Na+TSG solution. Low Na induced the uptake of Ca(2+) into both SR and non-SR Ca(2+) stores in the DF group, but not the DFA group. Furthermore, after depletion of the SR Ca(2+) store with TSG, 19Na evoked Ca(2+) uptake into non-SR Ca(2+) stores in all three groups except in the DFA group. In summary, this study demonstrates that atorvastatin prevents the enhanced uptake of Ca(2+) by SR and non-SR Ca(2+) stores in diabetic dyslipidemic pigs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11689213&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cells.

Kolyada AY, Fedtsov A, Madias NE.

Department of Medicine, Tufts University School of Medicine, Division of Nephrology and the Tupper Research Institute, New England Medical Center, Boston, Massachusetts, USA.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase ameliorate atherosclerosis by both cholesterol-dependent and cholesterol-independent mechanisms. We examined whether HMG-CoA reductase inhibitors affect the expression and activity of inducible NO synthase (iNOS) in cultured rat aortic vascular smooth muscle (VSM) cells. Atorvastatin (34 to 68 micromol/L) markedly increased nitrite production, an increase that was essentially abrogated by the NO synthase inhibitor N(G)-monomethyl-L-arginine (500 micromol/L). Activity of iNOS, determined by the conversion of L-arginine to L-citrulline, increased 9-fold after atorvastatin treatment. Western blot and semiquantitative reverse transcriptase-polymerase chain reaction revealed that atorvastatin (34 to 68 micromol/L) strongly upregulated iNOS protein and mRNA levels, respectively. These concentrations of atorvastatin did not cause cytotoxicity, as judged by the cell survival rate. Similarly, simvastatin and lovastatin (34 micromol/L) caused robust upregulation of the iNOS protein level. Transfection experiments demonstrated that the -1034- to 88-bp human iNOS promoter was strongly induced by atorvastatin (34 micromol/L). Electromobility and supershift assays using a nuclear factor-kappaB (NF-kappaB) consensus oligonucleotide and nuclear extracts from VSM cells as well as transfection studies using an NF-kappaB reporter plasmid suggested that the transcriptional activation of the iNOS gene by atorvastatin is not mediated via the NF-kappaB pathway. We conclude that HMG-CoA reductase inhibitors potently upregulate iNOS expression and activity in VSM cells, at least in part, by transcriptional mechanisms that do not depend on transcription factor NF-kappaB. These effects might have important implications for the impact of HMG-CoA reductase inhibitors on atherosclerosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11711492&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells.

Scharnagl H, Schinker R, Gierens H, Nauck M, Wieland H, Marz W.

Division of Clinical Chemistry, Department of Medicine, Albert-Ludwigs-University Freiburg, Hugstetter Strabetae 55, 79106, Freiburg, Germany. hubsch med1.ukl.uni-freiburg.de

We evaluated the effects of the hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGRI) atorvastatin, lovastatin, and simvastatin on lipid homeostasis in HepG2 cells. The drugs were almost equally effective in inhibiting cholesterol synthesis and in decreasing cellular cholesterol. Atorvastatin and lovastatin increased low-density lipoprotein receptor mRNA (2.5-fold at 3 x 10(-7) M) and the transcription rate at the promoter of the low-density lipoprotein receptor gene (>5-fold at 10(-6) M). The three compounds enhanced the activity of the low-density lipoprotein receptor at a similar magnitude (1.6-2.1- fold at 10(-6) M). Atorvastatin and lovastatin increased the nuclear form of sterol regulatory element binding protein (SREBP)-2, but not of SREBP-1. Each of the drugs increased triacylglyceride synthesis (50% at 10(-7)-10(-6) M), cellular triacylglyceride content (16% at 10(-6) M), and expression of fatty acid synthase by reporter gene and Northern blot analysis (2-fold and 2.7-fold at 10(-6) M and 3 x 10(-7) M, respectively). All compounds reduced the secretion of apo B (30% at 3 x 10(-7) M). HMGRI decreased the ratio of cholesterol to apo B in newly synthesised apo B containing particles by approximately 50% and increased the ratio of triacylglycerides to apo B by approximately 35%. We conclude that regulatory responses to HMGRI are mediated by SREBP-2 rather than by SREBP-1, that HMGRI oppositely affect the cellular cholesterol and triacylglyceride production, that HMGRI moderately decrease the release of apo B containing particles, but profoundly alter their composition, and that atorvastatin does not significantly differ from other HMGRI in these regards.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11728391&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment.

Banyai S, Banyai M, Falger J, Jansen M, Alt E, Derfler K, Koppensteiner R.

Division of Angiology, Department of Medicine, University Hospital Zurich, Raemistrasse 100, CH-8091, Zurich, Switzerland. susanne.banyai higr.ch

To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia (FH) on regular LDL apheresis, we prospectively studied the rheological variables fibrinogen, plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit and platelet aggregation in 12 patients (two homozygous, ten heterozygous) before and during treatment with atorvastatin. Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls (P<0.05), whereas fibrinogen, plasma viscosity and hematocrit were similar in the two groups. Treatment with atorvastatin reduced red cell aggregation (P<0.01), whole blood viscosity (P<0.01), plasma viscosity (P<0.01) and platelet aggregation (P<0.05), but caused a slight increase in plasma fibrinogen (by 5%; P<0.01). Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis. This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11730833&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Cellular antioxidant effects of atorvastatin in vitro and in vivo.

Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G.

Medizinische Klinik und Poliklinik-Innere Medizin III, Universitatskliniken des Saarlandes, Homburg/Saar, Germany.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may exert direct effects on vascular cells and beneficially influence endothelial dysfunction. Because reactive oxygen species (ROS) may lead to vascular damage and dysfunction, we investigated the effect of atorvastatin on ROS production and the underlying mechanisms in vitro and in vivo. Cultured rat aortic vascular smooth muscle cells were incubated with 10 micromol/L atorvastatin. Angiotensin II-induced and epidermal growth factor-induced ROS production were significantly reduced by atorvastatin (dichlorofluorescein fluorescence laser microscopy). Atorvastatin downregulated mRNA expression of the NAD(P)H oxidase subunit nox1, whereas p22phox mRNA expression was not significantly altered (reverse transcription-polymerase chain reaction, Northern analysis). Membrane translocation of rac1 GTPase, which is required for the activation of NAD(P)H oxidase, was inhibited by atorvastatin (Western blot). mRNA expression of superoxide dismutase isoforms and glutathione peroxidase was not modified by atorvastatin, whereas catalase expression was upregulated at mRNA and protein levels, resulting in an increased enzymatic activity. Effects of atorvastatin on ROS production and nox1, rac1, and catalase expression were inhibited by L-mevalonate but not by 25-hydroxycholesterol. In addition, spontaneously hypertensive rats were treated with atorvastatin for 30 days. ROS production in aortic segments was significantly reduced in statin-treated rats (lucigenin chemiluminescence). Treatment with atorvastatin reduced vascular mRNA expression of p22phox and nox1 and increased aortic catalase expression. mRNA expression of superoxide dismutases, glutathione peroxidase, and NAD(P)H oxidase subunits gp91phox, p40phox, p47phox, and p67phox remained unchanged. Translocation of rac1 from the cytosol to the cell membrane was also reduced in vivo. Thus, atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats mediated by decreased expression of essential NAD(P)H oxidase subunits and by upregulation of catalase expression. These effects of atorvastatin may contribute to the vasoprotective effects of statins.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11834532&dopt=Abstract atorvastatin Lipitor