atorvastatin Lipitor
Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin.

Llaverias G, Lacasa D, Vinals M, Vazquez-Carrera M, Sanchez RM, Laguna JC, Alegret M.

Unitat de Farmacologia, Departament de Farmacologia i Quimica Terapeutica, Facultat de Farmacia, Universitat de Barcelona, Barcelona 08028, Spain.

Rosiglitazone and atorvastatin combination therapy has beneficial effects on both glycemic control and plasma lipid levels in type 2 diabetic patients. In the present study, we sought to determine whether this combination can also exert direct antiatherosclerotic effects in macrophages. Our results show that 2 microM rosiglitazone, alone or combined with 5 microM atorvastatin, significantly upregulated the expression of the ATP-binding cassette transporter ABCA1 and of the class B scavenger receptor CLA-1 (CD36 and LIMPII analog), both involved in cholesterol efflux from macrophages. On the other hand, the combination with atorvastatin attenuated the inductive response elicited by rosiglitazone alone on CD36 mRNA (34%, P < 0.05) and protein (16%, P < 0.05), while the uptake of oxidized low density lipoprotein (LDL) remained unaffected. When we examined the effects of the drugs on acetyl-LDL-induced cholesterol accumulation, we found that only the combination of atorvastatin with rosiglitazone caused a net depletion in the cholesteryl ester content of macrophages (35%, P < 0.05). Our data suggest that this reduction was not mediated by effects on proteins that regulate cholesterol flux, but it may be related to the inhibition of cholesteryl ester formation elicited by the statin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15183127&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Anti-apoptotic effect of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardiac myocytes through protein kinase C activation.

Tanaka K, Honda M, Takabatake T.

The 4th Department of Internal Medicine, Shimane Medical University, Shimane, Japan.

Pleiotropic effects of statins, which are independent of lipid lowering, have been reported. In the present study, we examined the effect of a statin on apoptosis of adult rat cultured cardiac myocytes. We used the protein kinase C (PKC) inhibitors staurosporine (1 micro mol/L), chelerythrine (10 micro mol/L) and rottlerin (5 micro mol/L) to induce myocyte apoptosis. The effect of atorvastatin (10(-7) g/mL), a statin, on myocyte apoptosis induced by these PKC inhibitors was examined. All these PKC inhibitors markedly increased the percentage of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL)-positive myocytes. This increase was significantly suppressed by atorvastatin treatment. Both chelerythrine and rottlerin induced subcellular translocation of PKCdelta and elevated caspase-3 activity in myocytes. The changes in the subcellular distribution of PKCdelta and caspase-3 activity induced by these PKC inhibitors were suppressed by atorvastatin treatment. The results of the present study suggest that the inhibitory effect of atorvastatin on apoptosis of adult rat cardiac myocytes induced by the PKC inhibitors is through activation of PKCdelta pathway.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15191412&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
A pharmacoeconomic evaluation of aggressive cholesterol lowering in Sweden.

Olsson A, Casciano R, Stern L, Svangren P.

Department of Medicine and Care, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden.

OBJECTIVE: To estimate the short-term healthcare costs and incremental cost per event avoided, associated with aggressive atorvastatin treatment in patients with acute coronary syndrome in Sweden. METHODS: The total expected 16-week healthcare costs per patient on atorvastatin 80 mg per day and placebo were compared using clinical outcomes data from The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study and Swedish cost data sources. The incremental cost per event avoided was also assessed for. The clinical outcomes measured in this pharmacoeconomic analysis included: death, cardiac arrest, non-fatal myocardial infarction, fatal myocardial infarction, angina pectoris, non-fatal stroke, congestive heart failure, and surgical or percutaneous coronary revascularizations. All direct medical costs were taken into account. RESULTS: The probability of the occurrence of an event was 40.4% per patient in the placebo cohort and 36.6% per patient in the atorvastatin cohort. The total expected cost per patient was SEK 17,887 (1950.21 euro) in the placebo group and SEK 18,465 (2013.06 euro) in the atorvastatin group, resulting in an incremental cost of SEK 578 (63.0137 euro) per patient. The cost per event avoided was SEK 15,076 (1643.64 euro). Sixty six percent of the cost of atorvastatin treatment was offset by the cost savings obtained through the reduction in the number of events in the atorvastatin group compared to the placebo group. CONCLUSIONS: In Sweden, the clinical benefits of aggressive short-term atorvastatin treatment administered within a few days after acute coronary syndrome is associated with a substantial hospitalization cost offset secondary to the clinical benefits of atorvastatin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15203261&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke.

Rundek T, Naini A, Sacco R, Coates K, DiMauro S.

Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA.

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely used for the treatment of hypercholesterolemia and coronary heart disease and for the prevention of stroke. There have been various adverse effects, most commonly affecting muscle and ranging from myalgia to rhabdomyolysis. These adverse effects may be due to a coenzyme Q(10) (CoQ(10)) deficiency because inhibition of cholesterol biosynthesis also inhibits the synthesis of CoQ(10). OBJECTIVE: To measure CoQ(10) levels in blood from hypercholesterolemic subjects before and after exposure to atorvastatin calcium, 80 mg/d, for 14 and 30 days. DESIGN: Prospective blinded study of the effects of short-term exposure to atorvastatin on blood levels of CoQ(10). SETTING: Stroke center at an academic tertiary care hospital.Patients We examined a cohort of 34 subjects eligible for statin treatment according to National Cholesterol Education Program: Adult Treatment Panel III criteria. RESULTS: The mean +/- SD blood concentration of CoQ(10) was 1.26 +/- 0.47 micro g/mL at baseline, and decreased to 0.62 +/- 0.39 micro g/mL after 30 days of atorvastatin therapy (P<.001). A significant decrease was already detectable after 14 days of treatment (P<.001). CONCLUSIONS: Even brief exposure to atorvastatin causes a marked decrease in blood CoQ(10) concentration. Widespread inhibition of CoQ(10) synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, myalgia, and myoglobinuria.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15210526&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
[Cost-effectiveness of atorvastatin for the prevention of coronary disease. An analysis of the ASCOT study]

[Article in German]

Szucs TD, Klose G, Dusing R.

ECPM Research, University Hospital, Basel. thomas.szucs unibas.ch

BACKGROUND: Increasing health service expenditure, on the one hand, and the politically declared objective of stability of statutory contributions and restriction of public funds, on the other hand, have been central points in the political and social discussion for several years. PATIENTS AND METHODS: Cost-effectiveness of Atorvastatin in primary prevention was analysed by applying the results of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT study) to the German health system. Costs and effectiveness were subject to an extensive sensitivity analysis. RESULTS: The cost-effectiveness of Atorvastatin treatment in Germany is approximately 10,102 Euro (95% CI: 9109; 12,881) per life-year gained. Taking 2004 price reductions into consideration, these values are reduced to 7311 Euro [95% CI: 5197; 10,091) per life-year gained. The robustness of this result was substantiated through extensive sensitivity analyses. CONCLUSION: The administration of the lipid lowering compound Atorvastatin in hypertensive patients with additional coronary heart disease risk factors in Germany is cost-effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15213873&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Post-stroke atorvastatin treatment reduces neurological deficits and mortality rate in the stroke-prone spontaneously hypertensive rat.

Hayashi A, Suzuki M, Ogawa Y, Sonoda R, Sasamata M.

Applied Pharmacology Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. hayashi.asuka yamanouchi.co.jp

Several large clinical trials have demonstrated that 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors decreased the incidence of stroke independently of their cholesterol-lowering effect. We have investigated the effect of post-stroke treatment with atorvastatin on neurological deficits and mortality in stroke-prone spontaneously hypertensive rats (SHR-SP). The vehicle-treated group showed significantly aggravated neurological deficits compared with those observed on the first day of stroke. In contrast, the post-stroke oral administration of atorvastatin at 3 or 30 mg kg(-1)/day significantly ameliorated these neurological deficits. Atorvastatin improved the survival rate in a dose-dependent manner, with this effect being significant at 30 mg kg(-1)/day. Atorvastatin did not affect blood pressure, heart rate or total cholesterol in SHR-SP at either dose. In contrast, it significantly increased plasma nitric oxide (NO) levels at both doses. These results indicated that post-stroke administration of atorvastatin ameliorated neurological deficits and prolonged survival, which might have resulted from increased plasma NO, apart from its effect on cholesterol level and blood pressure in SHR-SP. In conclusion, this study demonstrated the protective effects of post-stroke administration of atorvastatin against stroke in SHR-SP.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15233868&dopt=Abstract atorvastatin Lipitor



atorvastatin Lipitor
Atorvastatin prevents end-organ injury in salt-sensitive hypertension: role of eNOS and oxidant stress.

Zhou MS, Jaimes EA, Raij L.

Nephrology-Hypertension Section, Veterans Affairs Medical Center, Renal Division and Vascular Biology Institute, University of Miami School of Medicine, Fla 33125, USA.

Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O2-) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O2- in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200+/-8 versus 150+/-2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7+/-0.2 versus 1.8+/-0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O2- (2632+/-316 versus 1176+/-112 counts/min per milligram in NS; P<0.05) and plasma 8-F2alpha isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5+/-0.3 nmol/min per gram protein) as well as the increase in O2- (1192+/-243 counts/min per milligram) and plasma 8-F2alpha isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174+/-8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15238570&dopt=Abstract atorvastatin Lipitor