Mevacor (Lovastatin)

Mevacor is the brand name for the generic substance Lovastatin and it is an antilipemic drug. It reduces the amounts of LDL cholesterol in the blood, also known as the “bad” cholesterol. It blocks its production in the body by interfering with the actions of a certain enzyme, and keeps it within the healthy limit of 200mg/dl. High blood cholesterol levels are known to be associated with many health problems and Mevacor can play a very significant role in their prevention. Especially heart disease, stroke, heart attack and peripheral vascular disease sufferers (or those at risk) can realize the benefit of Mevacor. Mevacor has exceptionally few side effects, the most common of which are gas, stomach pain, diarrhea and blurred vision.

Am J Cardiol. 2005 May 1;95(9):1025-1032.
Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A(2) in Patients With Coronary Heart Disease Versus Control Subjects.
Schaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ.
Cardiovascular Research and Lipid Metabolism Laboratories, Tufts University School of Medicine, Friedman School of Nutrition Science and Policy at Tufts University, and Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.

The effects of atorvastatin (40 mg/day) versus placebo on fasting and postprandial plasma levels of high-sensitivity C-reactive protein (hs-CRP) and lipoprotein-associated phospholipase A(2) (Lp-PLA2) were examined over 36 weeks in 84 patients who had coronary heart disease and low-density lipoprotein cholesterol levels >130 mg/dl and compared directly with the effects of fluvastatin, lovastatin, pravastatin, and simvastatin. Results were also compared with those obtained in age- and gender-matched control subjects (n = 84). Feeding increased median hs-CRP levels by 2% in patients (p = NS) and 22% in controls (p <0.01) and increased mean Lp-PLA2 values by 9% in patients (p = NS) but decreased values by 21% in controls (p <0.0001). Patients had 51% higher median hs-CRP values and 29% higher mean Lp-PLA2 values than did controls (p <0.05 for hs-CRP and Lp-PLA2) in the fasting state; however, Lp-PLA2 values were 62% higher (p <0.0001) in the fed state in patients compared with controls. Atorvastatin decreased median hs-CRP levels by 32% (p <0.01) and mean Lp-PLA2 values by 26% in patients (p <0.0001), with similar decreases in the fed state, and none of the other statins had any significant effect on these parameters. Change in Lp-PLA2 was significantly related to change in low-density lipoprotein cholesterol (p <0.01), with no significant relations with change in hs-CRP. Our data indicate greater differences in patients with coronary heart disease compared with controls in Lp-PLA2 in the fed state than in the fasting state and that atorvastatin is more effective than fluvastatin, lovastatin, pravastatin, or simvastatin for decreasing not only low-density lipoprotein cholesterol but also hs-CRP and Lp-PLA2.

Wei Sheng Yan Jiu. 2005 Jan;34(1):70-3.
[Protective effects of Lovastatin on early diabetic renal tissue and the possible mechanism]
[Article in Chinese]
Wang LH, Duan HJ, Shi YH, Liu QJ.
Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China. wanglh68@163.com

OBJECTIVE: To investigate the protective effects of Lovastatin on renal function in experimental diabetic nephropathy in rats. and the function of cAMP-responsive element binding protein (CREB1) in this duration. METHODS: Diabetes was induced in male Wistar rats by intrapetitoneal injection of STZ (65 mg/kg). Three groups were divided as: Sham group, diabetic control group and Lovastatin treatment group. Lovastatin (20 mg/kg) was administered daily by gavage from the next day of the induction diabetes for 4 weeks. Upro, ucr in urine and Glu, Scr, BUN in serum were determined. Immunohistochemistry and computer image-pattern analysis system were used to analyze expression of PCNA and p-CREB1. Western blot were performed to valuate the expression of p-CREB1 with their specific corresponding antibodies. CREB1 mRNA was measured by RT-PCR. RESULTS: After Lovastatin treatment, renal function were ameliorative in diabetic rats. Decrements were also found in the expression of and PCNA, p-CREB1 and its mRNA in the treatment group compared with the diabetic group. CONCLUSION: Inhibition of glomerular cAMP-responsive element binding protein 1 may be responsible for the Lovastatin protective function that allevate the renal proliferation and hypertrophy in diabetic rats.

CMAJ. 2005 Apr 26;172(9):1187-94.
Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: an evaluation of class effect.
Zhou Z, Rahme E, Abrahamowicz M, Tu JV, Eisenberg MJ, Humphries K, Austin PC, Pilote L.
Department of Epidemiology and Biostatistics, McGill University, Montreal, Que.

BACKGROUND: Clinical trials have shown the benefits of statins after acute myocardial infarction (AMI). However, it is unclear whether different statins exert a similar effect in reducing the incidence of recurrent AMI and death when used in clinical practice. METHODS: We conducted a retrospective cohort study (1997-2002) to compare 5 statins using data from medical administrative databases in 3 provinces (Quebec, Ontario and British Columbia). We included patients aged 65 years and over who were discharged alive after their first AMI-related hospital stay and who began statin treatment within 90 days after discharge. The primary end point was the combined outcome of recurrent AMI or death from any cause. The secondary end point was death from any cause. Adjusted hazard ratios (HRs) for each statin compared with atorvastatin as the reference drug were estimated using Cox proportional hazards regression analysis. RESULTS: A total of 18,637 patients were prescribed atorvastatin (n = 6420), pravastatin (n = 4480), simvastatin (n = 5518), lovastatin (n = 1736) or fluvastatin (n = 483). Users of different statins showed similar baseline characteristics and patterns of statin use. The adjusted HRs (and 95% confidence intervals) for the combined outcome of AMI or death showed that each statin had similar effects when compared with atorvastatin: pravastatin 1.00 (0.90-1.11), simvastatin 1.01 (0.91-1.12), lovastatin 1.09 (0.95-1.24) and fluvastatin 1.01 (0.80-1.27). The results did not change when death alone was the end point, nor did they change after adjustment for initial daily dose or after censoring of patients who switched or stopped the initial statin treatment. INTERPRETATION: Our results suggest that, under current usage, statins are equally effective for secondary prevention in elderly patients after AMI.

J Immunol. 2005 Feb 15;174(4):2327-35.
Suppression of autoimmune retinal disease by lovastatin does not require th2 cytokine induction.
Gegg ME, Harry R, Hankey D, Zambarakji H, Pryce G, Baker D, Adamson P, Calder V, Greenwood J.
Division of Cellular Therapy.

Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina. Efficacy was reversed by coadministration of mevalonolactone, the downstream product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not by squalene, which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment (20 mg/kg/day i.p.) over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 +/- 0.03 muM, did not induce splenocyte Th2 cytokine production but did cause a small reduction in Ag-induced T cell proliferation and a decrease in the production of IFN-gamma and IL-10. Thus, it is possible to dissociate the therapeutic effect of statins in experimental autoimmune uveitic mice from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration, which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment showed little efficacy in retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.

Blood. 2004 Sep 15;104(6):1816-24. Epub 2004 May 25.
Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells.
Banker DE, Mayer SJ, Li HY, Willman CL, Appelbaum FR, Zager RA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. dbanker@fhcrc.org
Cholesterol levels are abnormally increased in many acute myeloid leukemia (AML) samples exposed in vitro to chemotherapy. Blocking these acute cholesterol responses selectively sensitizes AML cells to therapeutics. Thus, defining the molecular mechanisms by which AML cells accomplish these protective cholesterol increments might elucidate novel therapeutic targets. We now report that the levels of mRNAs encoding the cholesterol synthesis-regulating enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and the cholesterol-importing low-density lipoprotein (LDL) receptor were both increased by daunorubicin (DNR) or cytarabine (ARA-C) treatments in almost three fourths of cultured AML samples. However, less than one third of AML samples significantly increased LDL accumulation during drug treatments, suggesting that de novo synthesis is the primary mechanism by which most AML cells increase cholesterol levels during drug exposures. LDL increments were not correlated with cholesterol increments in ARA-C-treated AML samples. However, LDL and cholesterol increments did correlate in DNR-treated AML samples where they were measured, suggesting that a subset of AMLs may rely on increased LDL accumulation during treatment with particular drugs. Our data suggest that cholesterol synthesis inhibitors may improve the efficacy of standard antileukemia regimens, but that for maximum benefit, therapy may need to be tailored for individual patients with leukemia.

Blood. 2004 Sep 15;104(6):1825-32. Epub 2004 May 25.
The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase.
Schmidmaier R, Baumann P, Simsek M, Dayyani F, Emmerich B, Meinhardt G.
Laboratory for Molecular Haematology, Department of Haematology and Oncology, Klinikum der Universitat Munchen, Medizinische Klinik-Innenstadt, Ziemssenstrasse 1, 80336 Munich, Germany. ralf.schmidmaier@med.uni-muenchen.de
Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR.

JAMA. 2004 Sep 15;292(11):1307-16. Epub 2004 Aug 30.
Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E; A to Z Investigators.
Donald W. Reynolds Cardiovascular Clinical Research Center, the University of Texas Southwestern Medical Center, Dallas 75390-9047, USA. james.delemos@utsouthwestern.edu).
CONTEXT: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. OBJECTIVE: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. DESIGN, SETTING, AND PARTICIPANTS: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. MAIN OUTCOME MEASURE: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. RESULTS: Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P =.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P =.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P =.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P =.02). CONCLUSIONS: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E; A to Z Investigators.
Donald W. Reynolds Cardiovascular Clinical Research Center, the University of Texas Southwestern Medical Center, Dallas 75390-9047, USA. james.delemos@utsouthwestern.edu).
CONTEXT: Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome (ACS) event affect clinical outcome. OBJECTIVE: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS. DESIGN, SETTING, AND PARTICIPANTS: International, randomized, double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial between December 29, 1999, and January 6, 2003. MAIN OUTCOME MEASURE: The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke. Follow-up was for at least 6 months and up to 24 months. RESULTS: Among the patients in the placebo plus simvastatin group, the median low-density lipoprotein (LDL) cholesterol level achieved while taking placebo was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8 months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin only group, the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L) at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%) in the placebo plus simvastatin group experienced the primary end point compared with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio [HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P =.05) but no differences were observed in other individual components of the primary end point. No difference was evident during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P =.89), but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group (HR, 0.75; 95% CI, 0.60-0.95; P =.02). Myopathy (creatine kinase >10 times the upper limit of normal associated with muscle symptoms) occurred in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving lower doses of simvastatin, and in 1 patient receiving placebo (P =.02). CONCLUSIONS: The trial did not achieve the prespecified end point. However, among patients with ACS, the early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.

Am J Cardiol. 2004 Sep 1;94(5):652-5.
Effect of simvastatin on endothelial function in cardiac syndrome X patients.
Fabian E, Varga A, Picano E, Vajo Z, Ronaszeki A, Csanady M.
Department of Cardiology, Elizabeth Hospital, Budapest, Hungary. dr.fabian.emilia@ihklinika.hu
Patients with cardiac syndrome X with mild hypercholesterolemia were randomized to placebo (n = 20) or simvastatin 20 mg/day (n = 20). In the simvastatin group, there was a significant (26%; p < 0.0001) decrease in total cholesterol, a 38% (p < 0.0001) decrease in low-density lipoprotein cholesterol levels, and 7% a (p < 0.0001) increase in high-density lipoprotein cholesterol levels, without significant changes in triglyceride levels. Brachial artery flow-mediated dilation increased significantly (52% relative increase, p < 0.0001), and the time to > 1-mm ST-segment depression during stress testing was longer by the end of the study (p < 0.0001). Copyright 2004 Excerpta Medica, Inc.

Blood Coagul Fibrinolysis. 2004 Sep;15(6):463-7.
Increased soluble CD40L levels are reduced by long-term simvastatin treatment in peritoneally dialyzed patients.
Malyszko J, Malyszko JS, Hryszko T, Mysliwiec M.
Nephrology and Transplantology Department, Medical University, 15-540 Bialystok, Zurawia 14, Poland. jolmal@poczta.onet.pl
BACKGROUND: Dyslipidemia and increased mortality due to cardiovascular events are common in peritoneally dialyzed patients [continuous ambulatory peritoneal dialysis (CAPD)]. Statins show beneficial effects on serum lipids and reduce cardiovascular mortality. The CD40-CD40 ligand (CD40L) system has proved critical for the activation of tissue structural cells that include endothelial cells, epithelial cells and fibroblasts. It has been reported that enhanced CD40L-CD40 interaction in familial hypercholesterolemia may be downregulated by statins, but prospective studies on CAPD patients are lacking. AIM: To determine the effects of 6 months treatment with simvastatin on platelet aggregation, markers of endothelial cell injury, and sCD40L in 15 hyperlipidemic CAPD patients. METHODS: Simvastatin (Zocor, Merck Sharp & Dohme) was given in a dose of 10 mg at bedtime. RESULTS: CD40L decreased significantly after 6 months of the therapy. Thrombomodulin decreased significantly after 3 months of the therapy, whereas von Willebrand factor, E-selectin and P-selectin did not change significantly during the study. CONCLUSION: Simvastatin reduced enhanced sCD40L levels together with amelioration of endothelial dysfunction. Treatment with simvastatin might downregulate enhanced CD40L-CD40 interactions in CAPD patients.

Eur J Haematol. 2004 Sep;73(3):183-90.
Microenvironment factors do not afford myeloma cell lines protection from simvastatin.
Osadchy A, Drucker L, Radnay J, Shapira H, Lishner M.
Oncogenetic Laboratory, Sapir Medical Center, Meir Hospital, Kfar Sava, Israel.
BACKGROUND: The intensive interactions of myeloma cells (multiple myeloma, MM) with microenvironmental components of the bone marrow contribute significantly to their proliferation and survival. It has been shown that these signals confer drug resistance, delineating their circumvention as a primary objective in disease treatment. This study was designed to assess the effect of some major extracellular factors on the previously established anti-neoplastic response of myeloma cells to simvastatin (Sim). STUDY DESIGN: RPMI8226, U266, and ARH77 seeded in culture plates precoated with fibronectin (FN)/agarose/none were treated with Sim, insulin-like growth factor-I (IGF-I), interleukin-6 (IL-6) or combinations for 5 d. Then we assessed cell morphology, viability (WST1), cell cycle (propidium iodide, PI, staining and flow cytometric analysis), total cell count, and cell death (trypan blue exclusion), and DNA fragmentation. RESULTS AND CONCLUSIONS: Reduced viability was demonstrated with Sim in all treated cell lines with and without co-administration of IGF-I or IL-6 (P < 0.05). The extent of inhibition did not vary between Sim only and combinations (NS). FN did not influence cell response to Sim alone or combined with IL-6/IGF-I (NS). We conclude that IL-6, IGF-I, and FN do not afford myeloma cell lines protection from Sim modulation. Copyright Blackwell Munksgard 2004.

Lancet. 2004 Aug 28;364(9436):771-7.
Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S).
Strandberg TE, Pyorala K, Cook TJ, Wilhelmsen L, Faergeman O, Thorgeirsson G, Pedersen TR, Kjekshus J; 4S Group.
Department of Medicine, University of Helsinki, Helsinki, PL 340, 00029 HUS, Finland. timo.strandberg@hus.fi
BACKGROUND: The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5-6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial. METHODS: 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5.5-8.0 mmol/L, and serum triglycerides 2.5 mmol/L or lower. The double-blind period lasted for a median of 5.4 years (range for survivors 4.9-6.3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10.4 years (range for survivors 9.9-11.3). Analysis was by intention to treat. FINDINGS: 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10.4-year follow-up (relative risk 0.85 [95% CI 0.74-0.97], p=0.02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0.76 [0.64-0.90], p=0.0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0.81 [0.60-1.08], p=0.14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0.88 [0.73-1.05], p=0.15). Incidence of any specific type of cancer did not rise in the simvastatin group. INTERPRETATION: Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.

Am J Cardiol. 2004 Aug 1;94(3):306-11.
Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study.
Rubenfire M; Impact of Medical Subspecialty on Patient Compliance to Treatment Study Group.
Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, 48109-0363, USA. mrubenfi@umich.edu
Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes.

Am J Physiol Regul Integr Comp Physiol. 2004 Aug;287(2):R342-8. Epub 2004 May 06.
Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice.
Budzyn K, Marley PD, Sobey CG.
Department of Pharmacology, University of Melbourne, Parkville, Victoria 3010, Australia.
We tested the hypothesis that endothelial nitric oxide (NO) synthase (eNOS)-derived NO modulates rho-kinase-mediated vascular contraction. Because 3-hydroxy-3-methylglutaryl (HMG)-CoA-reductase inhibition can both upregulate eNOS expression and inhibit rhoA/rho-kinase function, a second hypothesis tested was that statin treatment modulates rho-kinase-mediated contraction and that this can occur independently of eNOS. Contractile responses to the receptor-dependent agonists serotonin and phenylephrine but not to the receptor-independent agent KCl were greater in aortic rings from eNOS-null (eNOS(-/-)) vs. wild-type (eNOS(+/+)) mice. Similarly enhanced responses were seen in eNOS(+/+) rings after acute NOS inhibition. The rho-kinase inhibitor Y-27632 abolished or profoundly attenuated responses to receptor agonists in both eNOS(+/+) and eNOS(-/-) rings, but responses in eNOS(+/+) were more sensitive to Y-27632. Mevastatin treatment (20 mg/kg sc per day, 14 days) reduced responses to serotonin and phenylephrine in female mice of both strains. KCl-induced contractions were slightly smaller in eNOS(+/+)-derived aortic rings only. Levels of plasma cholesterol, and aortic expression of rhoA and rho-kinase, did not differ between groups. Thus eNOS-derived NO suppresses rhoA/rho-kinase-mediated vascular contraction. Moreover, a similar suppressive effect on rho-kinase-mediated vasoconstriction by statin therapy occurs independently of effects on eNOS or plasma cholesterol.

Blood. 2004 Aug 1;104(3):840-6. Epub 2004 Apr 08.
Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin.
Solovey A, Kollander R, Shet A, Milbauer LC, Choong S, Panoskaltsis-Mortari A, Blazar BR, Kelm RJ Jr, Hebbel RP.
Vascular Biology Center and Divisions of Hematology-Oncology-Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
Abnormal tissue factor (TF) expression has been demonstrated on blood monocytes and circulating endothelial cells in humans with sickle cell anemia. We have now studied sickle transgenic mice to help define the biology of endothelial TF expression in sickle disease. Using immunostaining of tissue sections, we find that this is confined almost exclusively to the pulmonary veins. About 15% and 13% of these exhibit TF-positive endothelium in the wild-type normal mouse and the normal human hemoglobin (HbA)-expressing control transgenic mouse, respectively. The mild sickle mouse is indistinguishable from normal (approximately 14% positive), but TF expression is significantly elevated in the moderate and severe mouse models of sickle disease (approximately 29% and approximately 41% positive, respectively). Exposure of the mild sickle mouse to hypoxia for 3 hours, followed by reoxygenation, converted its TF expression phenotype to that of the severe sickle mouse (approximately 36% positive). Pretreatment with lovastatin eliminated excessive expression of TF in the posthypoxic mild sickle mouse (approximately 16% positive) and in the more severe mouse at ambient air (approximately 21% positive). In addition to identifying tissue expression of endothelial TF in the sickle lung, these studies implicate reperfusion injury physiology in its expression and suggest a rationale for use of statins in sickle disease.

Carcinogenesis. 2004 Aug;25(8):1335-44. Epub 2004 Feb 26.
Ionizing radiation-induced E-selectin gene expression and tumor cell adhesion is inhibited by lovastatin and all-trans retinoic acid.
Nubel T, Dippold W, Kaina B, Fritz G.
University of Mainz, Institute of Toxicology, Division of Applied Toxicology, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
E-selectin mediated tumor cell adhesion plays an important role in metastasis. Here we show that ionizing radiation (IR) induces E-selectin gene and protein expression in human endothelial cells at therapeutically relevant dose level. E-selectin expression is accompanied by an increase in the adhesion of human colon carcinoma cells to primary human umbilical vein endothelial cells (HUVEC). The HMG-CoA reductase inhibitor lovastatin impairs IR-stimulated E-selectin expression as analyzed at the level of the protein, mRNA and promoter. Inactivation of Rho GTPases either by use of Clostridium difficile toxin A or by co-expression of dominant-negative Rho blocked IR-induced E-selectin gene induction, indicating Rho GTPases to be essential. Radiation-induced expression of E-selectin was also blocked by all-trans retinoic acid (at-RA), whereas 9-cis retinoic acid was ineffective. Abrogation of IR-stimulated E-selectin expression by lovastatin and at-RA reduced tumor cell adhesion in a dose-dependent manner. Combined treatment with lovastatin and at-RA exerted additive inhibitory effects on radiation-induced E-selectin expression and tumor cell adhesion. Therefore, application of statins and at-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment.

Surgery. 2004 Aug;136(2):323-8.
Aortic eNOS expression and phosphorylation in Apo-E knockout mice: differing effects of rapamycin and simvastatin.
Naoum JJ, Zhang S, Woodside KJ, Song W, Guo Q, Belalcazar LM, Hunter GC.
Department of Surgery, University of Texas Medical Branch at Galveston, TX 77555, USA.
BACKGROUND: The inhibition of nitric oxide (NO) by hypercholesterolemia may be mediated, in part, by interactions with caveolin-1 (Cav-1). Because of the facilitatory effects of statins on endothelial function and the adverse effects of rapamycin (RAPA) on plasma lipids, we compared the effects of simvastatin (SMV) and RAPA on endothelial NO synthase (eNOS) and Cav-1 protein expression and phosphorylation in the aortas of apolipoprotein E (Apo-E) knockout (-/-) mice. METHODS: Apo-E -/- mice (n = 38) fed a high-cholesterol diet were given SMV (100 mg/kg/day po), RAPA (3 mg/kg/day ip), or no treatment for 10 weeks. Blood was drawn for serum lipid analysis, and protein was extracted for Western immunoblotting. Selected aortic specimens from 2 animals in each group were examined by histology and immunohistochemistry. The data are expressed as the mean +/- SEM and compared by the Student t test and ANOVA. Significance was established as P < .05. RESULTS: Lipid levels at 10 weeks were similar in the 3 groups except for higher triglyceride levels in RAPA-treated animals. eNOS expression was highest in RAPA-treated mice, but the p-eNOS to eNOS protein expression ratio was significantly greater in the SMV treatment group compared to both RAPA and controls (P < .05). Both Cav-1 and p-Cav-1 expression was significantly lower in the SMV-treated animals (P < .05) compared to mice treated with RAPA. CONCLUSIONS: Although eNOS expression was greatest in the RAPA-treated mice, the expression of p-eNOS was similar in the RAPA- and SMV-treated animals. The increase in eNOS induced by RAPA and the inverse relationship between p-eNOS and Cav-1 protein expression observed with SMV treatment suggest different mechanisms for the regulation of aortic eNOS expression in Apo-E mice by these 2 agents. Copyright 2004 Elsevier Inc.

Life Sci. 2004 Jul 30;75(11):1287-302.
Simvastatin modulates TNFalpha-induced adhesion molecules expression in human endothelial cells.
Zapolska-Downar D, Siennicka A, Kaczmarczyk M, Kolodziej B, Naruszewicz M.
Clinical Biochemistry and Laboratory Diagnostic, Regional Center for Atherosclerosis Research, Pomeranian Medical University, ul. Powstancow Wlkp. 72, PL-70-111 Szczecin, Poland.
Adhesion and transendothelial migration of leukocytes into the vascular wall is a crucial step in atherogenesis. Expression of cell adhesion molecules by endothelial cells plays a leading role in this process. We investigated the effect of simvastatin, an inhibitor of HMG-CoA reductase administered to reduce plasma levels of LDL-cholesterol, on the expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) by human umbilical vein endothelial cells (HUVEC) stimulated with tumor necrosis factor alpha (TNFalpha). We found the expression to be significantly inhibited by the drug in a time and concentration-dependent manner and to a greater extent in the case of VCAM-1 as compared with ICAM-1. In TNFalpha-stimulated HUVEC, simvastatin decreased VCAM-1 and ICAM-1 mRNA levels, inhibited TNFalpha-induced activation of nuclear factor kappaB (NF-kappaB) and enhanced expression of peroxisome proliferator-activated receptor alpha (PPARalpha). These effects were associated with reduction of adherence of monocytes and lymphocytes to HUVEC. The present findings suggest that the benefits of statins in vascular disease may include the inhibition of expression of VCAM-1 and ICAM-1 through effects on NF-kappaB.

Biochem Biophys Res Commun. 2004 Jul 16;320(1):165-9.
Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis.
Gniadecki R.
Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark. rg01@bbh.hosp.dk
Fas is a member of the tumour necrosis factor receptor superfamily. Fas-mediated apoptosis is an essential mechanism protecting against skin cancer. Activation of Fas by specific ligand or agonistic antibodies leads to the formation of a membrane associated death-inducing signalling complex comprising aggregates of Fas, the Fas-associated death domain protein (FADD), and caspase-8. It has recently been suggested that activity of Fas is not only regulated by its cognate ligand but also by the association of this receptor with cholesterol-enriched lipid domains in the plasma membrane (lipid rafts). We report here that disruption of lipid rafts by cholesterol-depleting compounds (methyl-beta-cyclodextrin, filipin III, cholesterol oxidase, and mevastatin) leads to a spontaneous clustering of Fas in the non-raft compartment of the plasma membrane, formation of Fas-FADD complexes, activation of caspase-8, and apoptosis. We propose that in some cell types exclusion of Fas from lipid rafts leads to the spontaneous, ligand-independent activation of this death receptor, a mechanism that can potentially be utilized in anticancer therapy.

Acta Pharmacol Sin. 2004 Jul;25(7):893-901.
Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor.
Jiang JL, Jiang DJ, Tang YH, Li NS, Deng HW, Li YJ.
Department of Pharmacology, School of Pharmaceutic Sciences, Central South University, Changsha 410078, China.
AIM: To investigate the effect of simvastatin on endothelium-dependent vasorelaxation and endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) in rats and cultured ECV304 cells. METHODS: Endothelial injury was induced by a single injection of low density lipoprotein (LDL) (4 mg/kg, 48 h) in rats or incubation with LDL (300 mg/L) or oxidative-modified LDL (100 mg/L) in cultured ECV304 cells, and vasodilator responses to acetylcholine (ACh) in the aortic rings and the level of ADMA, nitrite/nitrate (NO) and tumor necrosis factor-alpha (TNF-alpha) in the serum or cultured medium were determined. And the adhesion of the monocytes to endothelial cells and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the cultured ECV304 cells were measured. RESULTS: A single injection of LDL decreased endothelium-dependent relaxation to ACh, markedly increased the serum level of endogenous ADMA and TNF-alpha, and reduced serum level of NO. Pretreatment with simvastatin (30 or 60 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, the increased level of TNF-alpha and the decreased level of NO by LDL, but no effect on serum concentration of endogenous ADMA. In cultured ECV304 cells, LDL or ox-LDL markedly increased the level of ADMA and TNF-alpha and potentiated the adhesion of monocytes to endothelial cells, concomitantly with a significantly decrease in the activity of DDAH and serum level of NO. Pretreatment with simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly decreased the level of TNF-alpha and the adhesion of monocytes to endothelial cells, but did not affect the concentration of endogenous ADMA and the activity of DDAH. CONCLUSION: Simvastatin protect the vascular endothelium against the damages induced by LDL or ox-LDL in rats or cultured ECV304 cells, and the beneficial effects of simvastatin may be related to the reduction of inflammatory cytokine TNF-alpha level.

BMJ. 2003 Nov 29;327(7426):1264.
Coronary heart disease prevention: insights from modelling incremental cost effectiveness.
Marshall T.
Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TT. T.P.
OBJECTIVE: To determine which treatments for preventing coronary heart disease should be offered to which patients by assessing their incremental cost effectiveness. DESIGN: Modelling study. DATA SOURCES: Cost estimates (for NHS) and estimates of effectiveness obtained for aspirin, antihypertensive drugs, statins and clopidogrel. DATA SYNTHESIS: Treatment effects were assumed to be independent, and cost per coronary event prevented was calculated for treatments individually and in combination across patients at a range of coronary risks. RESULTS: The most cost effective preventive treatments are aspirin, initial antihypertensive treatment (bendrofluazide and atenolol), and intensive antihypertensive treatment (bendrofluazide, atenolol and enalapril), whereas simvastatin and clopidogrel are the least cost effective (cost per coronary event prevented in a patient at 10% coronary risk over five years is 3500 pounds sterling for aspirin, 12 500 pounds sterling for initial antihypertensives, 18 300 pounds sterling for intensive antihypertensives, 60 000 pounds sterling for clopidogrel, and 61 400 pounds sterling for simvastatin). Aspirin in a patient at 5% five year coronary risk costs less than a fifth as much per event prevented (7900 pounds sterling) as simvastatin in a patient at 30% five year risk (40 800 pounds sterling). DISCUSSION: A cost effective prevention strategy would offer aspirin and initial antihypertensive treatment to all patients at greater than 7.5% five year coronary risk before offering statins or clopidogrel to patients at greater than 15% five year coronary risk. Incremental cost effectiveness analysis of treatments produces robust, practical cost effectiveness rankings that can be used to inform treatment guidelines.

Am J Cardiol. 2003 Aug 21;92(4B):3K-9K.
Current and future aims of lipid-lowering therapy: changing paradigms and lessons from the Heart Protection Study on standards of efficacy and safety.
Ballantyne CM.
Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center and Baylor College of Medicine, Houston, Texas 77030, USA
Lipid-lowering guidelines continue to evolve toward the use of (1) global risk assessment, (2) lipid measures other than or in addition to low-density lipoprotein (LDL) cholesterol in assessment of risk and treatment benefit, and (3) recommendations for more aggressive lipid lowering. Findings in the Heart Protection Study (HPS) indicate that high-risk patients benefit from statin therapy initiated at a dose that provides aggressive lowering of LDL cholesterol. Statin treatment in this trial provided consistent benefits in reducing major vascular events among a wide variety of high-risk patients, including those beginning treatment with LDL cholesterol levels <100 mg/dL. The HPS findings therefore suggest that the optimal LDL cholesterol level is well below current target levels. In addition, they provide reassurance that aggressive statin therapy is safe. Frequently, current targets for LDL cholesterol are not achieved in clinical practice, particularly among those patients who have coronary artery disease or are at high risk of disease. More intensive lipid lowering than that currently practiced is necessary to achieve current goals and to provide the aggressive reduction of LDL cholesterol shown to improve outcomes in clinical trials. New statins, such as rosuvastatin, offer the prospect of improved lipid-lowering therapy.

Drug Saf. 2003;26(11):769-86.
Benefits and risks of simvastatin in patients with familial hypercholesterolaemia.
Mata P, Alonso R, Badimon J.
Lipid Clinic, Internal Medicine Department, Fundacion Jimenez Diaz, Madrid, Spain.
Familial hypercholesterolaemia is a frequent, inherited, monogenic disorder, associated with accelerated development of atherosclerotic disease leading to coronary artery disease. Life expectancy of patients with familial hypercholesterolaemia is reduced by 15-30 years unless they are adequately treated with lipid-lowering therapy. Given the chronic nature of this disease, the selection of a therapeutic approach should be strongly based on its long-term safety and tolerability. The introduction of HMG-CoA reductase inhibitors has revolutionised the treatment of familial hypercholesterolaemia.Simvastatin 40-80 mg/day effectively reduces serum low density lipoprotein (LDL)-cholesterol levels. Furthermore, simvastatin reduces triglycerides and mildly raises high density lipoprotein-cholesterol levels. In addition to the hypolipidaemic effect, other potentially important effects, such as improvement of endothelial function and reduction of LDL oxidation and vascular inflammation, have been associated with HMG-CoA reductase inhibitor therapy. Simvastatin has also been shown to abolish the progression, and even facilitate the regression, of existing human atherosclerotic lesions.The good safety and tolerability profile of simvastatin is clearly highlighted by the low rate of therapy discontinuation observed in several population-based clinical trials. The most common adverse events leading to the discontinuation of therapy are gastrointestinal upset and headache. Asymptomatic elevations in liver transaminase levels and myopathy are uncommon.The overwhelming clinical evidence regarding the long-term use of HMG-CoA reductase inhibitor therapy in patients with familial hypercholesterolaemia together with the long-term safety data (particularly relating to simvastatin) provide support for the use of this drug as a first-line agent when pharmacological treatment is indicated. Early intervention with simvastatin treatment can be successfully implemented with favourable economic benefits.

Clin Ter. 2002 Nov-Dec;153(6):377-80
Bettini R, Gorini M.
Ospedale di Circolo, Universita degli Studi dell'Insubria, Varese, Italia.
Cell Immunol. 2003 May;223(1):52-62.
Sun D, Fernandes G.
Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Lovastatin inhibits bone marrow-derived dendritic cell maturation and upregulates proinflammatory cytokine production.
Statins are a group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors which are most effective as lipid lowering agents, and are currently extensively used clinically. Recently, it was also shown that statins affect the immune response. We investigated the effects of lovastatin on the maturation and functional changes of bone marrow-derived dendritic cells (BM-DC). Lovastatin inhibited MHC class II and CD40 expression on DC in a dose-dependent manner, but had lesser effects on CD16, CD80, CD86, and CD11b expression. Nuclear extracts of lovastatin treated DC had decreased NF-kappaB DNA binding activity. Although antigen capture capacity of DC was not affected by lovastatin, the T-cell stimulatory activity of DC was inhibited. Lovastatin up-regulated DC pro-inflammatory cytokine production induced by LPS as measured by intracellular cytokine staining, ELISA and cDNA microarrays. Mevalonate, added in vitro, prevented these effects. These results indicate that lovastatin may inhibit BM-DC maturation and up-regulate cytokine production through a mevalonate dependent pathway, and may cause adverse effects on either innate or adaptive immunity.

Prescrire Int. 2003 Aug;12(66):143-8.
Statins: new data in secondary prevention and diabetes. Pravastatin and simvastatin are the best-assessed statins.
The efficacy of pravastatin and simvastatin was first shown several years ago in patients with coronary heart disease. Other trials have since been published. In the HPS trial, which studied patients with coronary heart disease, other cardiovascular conditions, or diabetes, simvastatin significantly reduced the risk of death, coronary events and stroke when compared with placebo. In the ALLHAT-LLT trial, in patients with treated hypertension, pravastatin did not reduce overall mortality. In the PROSPER trial, in patients aged over 70 with cardiovascular disease or cardiovascular risk factors, pravastatin reduced the incidence of coronary events relative to placebo, but did not reduce overall mortality. Pharmacovigilance studies suggest there is no difference between these four statins in terms of their potential to cause rhabdomyolysis. Taken together, these trials show that statin use can be extended to patients with levels of LDL-cholesterol over 2.4 mmol/l (0.9 g/l) if they have coronary heart disease (and no hypercholesterolaemia), a history of ischaemic stroke, or lower-limb arterial disease. Statins can also be prescribed for diabetic patients with no signs of cardiovascular disease but whose LDL-cholesterol exceeds 3.4 mmol/l (1.3 g/l). Clinical trial data support the use of pravastatin or simvastatin in these situations, at a dose of 20 or 40 mg daily. Plasma creatine phosphokinase assay should be done if muscle symptoms occur or if the patient has a particular risk of rhabdomyolysis.