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PubMed2005

Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts.

Simvastatin is best known for its antilipidemic action and use in cardiovascular disease due to its inhibition of 3-hydroxy-3-methylglutaryl CoenzymeA (HMG CoA) reductase, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. Connective tissue growth factor (CTGF) and persistent myofibroblast formation are major determinants of the aggressive fibrotic disease, idiopathic pulmonary fibrosis (IPF). In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on CTGF gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited (P < 0.05) CTGF gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of CTGF. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.

ADP Ribose Transferases↗
PubMed2006

Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin.

Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1-1.0 muM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The antiproliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS, and that the level of active RhoA increased by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, but not by farnesylpyrophosphate. Because these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to prevention of geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.

ADP Ribose Transferases↗
PubMedDate not supplied

Early effects of simvastatin versus atorvastatin on oxidative stress and proinflammatory cytokines in hyperlipidemic subjects.

The authors investigated the time-dependent action of atorvastatin and simvastatin on oxidative stress and cytokine levels immediately after the start of treatment. These factors play a role in endothelial dysfunction. Hyperlipidemic patients (n = 132) were assigned to treatment with 40 mg atorvastatin, 40 mg simvastatin, or placebo. Blood samples were taken before, 2 hours, 24 hours, 7 days, and 3 weeks after the administration of the statin or placebo to evaluate serum concentrations of total peroxides (TP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and soluble intercellular vascular adhesion molecule 1 (sICAM 1). In the atorvastatin group the TP changes were significantly different at 2 hours and 24 hours (p = 0.005), whereas in the simvastatin group there was a gradual, more or less linear decline in TP until 7 days (p = 0.006) and then a plateau. Simvastatin exhibited a faster statistically significant decrease over time in IL-6 and sICAM 1 levels (at 7 days, p = 0.014 and p = 0.001, respectively). TNF-alpha demonstrated a faster linear trend in the simvastatin group, but the significant effect appeared late (p = 0.006). Both simvastatin and atorvastatin exerted early beneficial effects on oxidative stress, proinflammatory cytokines, and endothelial activation in hyperlipidemic subjects. These effects became significant 2 hours following the initiation of therapy.

Adult↗
PubMed2001

The effects of converting from simvastatin to atorvastatin on plasminogen activator inhibitor type-1.

Plasminogen activator inhibitor type-1 (PAI-1) is an important regulatory component of fibrinolysis and is elevated in the presence of endothelial dysfunction. Endothelial dysfunction and PAI-1 in patients with coronary artery disease (CAD) have been demonstrated to improve following simvastatin therapy. The effect of converting from simvastatin to atorvastatin on PAI-1 has not been reported and may be an additional consideration when making a formulary medication switch. Fourteen adult patients with hypercholesterolemia and CAD who were receiving simvastatin for a minimum of 3 months were randomized to continue on simvastatin or be converted to atorvastatin. Doses were adjusted to achieve or sustain a low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL. A fasting lipid panel and PAI-1 were obtained at baseline and following 10 weeks of treatment. Mean +/- SD LDL cholesterol at baseline (95.6 +/- 13.8 vs. 87.0 +/- 12.3 dL, p = 0.24) and following 10 weeks of simvastatin or atorvastatin (96.6 +/- 8.9 vs. 87.4 +/- 20.3 mg/dL, p = 0.29) were similar. No differences in PAI-1 were observed at baseline (47.7 +/- 19.3 vs. 64.6 +/- 22.2 ng/mL, p = 0.15) or at 10 weeks (51.1 +/- 32.5 vs. 63.9 +/- 26.9 ng/mL, p = 0.44). These data suggest that the conversion from simvastatin to atorvastatin does not adversely affect PAI-1 plasma concentrations in patients with CAD.

Aged↗
PubMed1991

Simvastatin: a review of its pharmacology and clinical use.

Simvastatin, a chemical derivative of lovastatin, is an antihyperlipidemic medication that inhibits hydroxymethylglutaryl coenzyme A reductase. Animal and clinical data suggest simvastatin is twice as potent as lovastatin. It lowers serum cholesterol by inhibiting hepatic synthesis of cholesterol and, more importantly, by increasing the number of low-density lipoprotein (LDL) receptors present on hepatic cellular membranes. Simvastatin, when used at doses of 40 mg/d in patients with heterozygous familial hypercholesterolemia, significantly reduces total cholesterol (greater than 30 percent) and LDL cholesterol (35-45 percent) and tends to reduce triglycerides and raise high-density lipoprotein (HDL) cholesterol. The agent is also effective in patients with polygenic hypercholesterolemia, familial dysbetalipoproteinemia, and nephrotic syndrome. Addition of cholestyramine to simvastatin enhances the LDL cholesterol-lowering effect to approximately 55 percent. Common clinical adverse effects reported with simvastatin use include headaches and gastrointestinal complaints. Transient elevations in serum transaminases and creatine phosphokinase have also been seen. Based on data currently available, the drug's clinical activity and adverse-effect profile are similar to those of lovastatin. Therefore, there is no need for formularies to contain both medications. To choose between the two, one needs to consider the incidence of adverse effects and the daily cost of each product when used at equally effective doses. That information is now now available and, until it is, a clear recommendation cannot be made. Simvastatin, presently marketed in several countries, is investigational in the U.S. but is expected to be available soon.

Adolescent↗
PubMed2001

Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: a randomized, double-blind study.

BACKGROUND: Rosuvastatin (Crestor), a new, highly efficacious statin, has demonstrated dose-dependent low-density lipoprotein cholesterol (LDL-C) reductions of up to 65% in a dose-ranging programme with doses of 1 to 80 mg. DESIGN: A randomized, double-blind multicentre trial compared rosuvastatin with commonly used starting doses of pravastatin and simvastatin to determine relative efficacy in LDL-C reduction and impact on other lipid parameters in primary hypercholesterolaemia. METHODS AND RESULTS: A total of 502 patients (greater-than-or-equal 18 years; LDL-C greater-than-or-equal 4.14 mmol/l [160 mg/dl] and < 6.50 mmol/l [250 mg/dl] and triglycerides less-than-or-equal 4.52 mmol/l [400 mg/dl]) were randomized to 12 weeks of rosuvastatin 5 mg (n = 120) or 10 mg (n = 115), pravastatin 20 mg (n=]137) or simvastatin 20 mg (n = 130). Rosuvastatin 5 and 10 mg reduced LDL-C by 42 and 49%, respectively, compared with 28% for pravastatin (P < 0.001 versus both rosuvastatin doses) and 37% for simvastatin (P < 0.01 versus rosuvastatin 5 mg; P < 0.001 versus 10[?]mg). National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) goals were achieved by 87% of rosuvastatin 10[?]mg patients, 71% of rosuvastatin 5[?]mg patients, 53% of pravastatin patients, and 64% of simvastatin patients; similar proportions of patients achieved NCEP ATP III goals. European Atherosclerosis Society (EAS) goals were achieved by 83, 63, 20 and 50% of patients, respectively. All study treatments were well tolerated. CONCLUSIONS: Both doses of rosuvastatin were more effective than pravastatin and simvastatin in meeting NCEP ATP II and EAS LDL-C targets. Rosuvastatin 10 mg was more effective than pravastatin and simvastatin in meeting NCEP ATP III targets.

Cholesterol, LDL↗
PubMed2002

Lowering low density lipoprotein cholesterol with simvastatin, a hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor, does not affect luteal function in premenopausal women.

In this double-blind, randomized, placebo-controlled study, normally cycling women (n = 86) with elevated low density lipoprotein cholesterol (LDL-C) levels were studied over six menstrual cycles. At the end of the screening phase, participants received placebo for the second menstrual cycle and subsequently were randomized to receive either placebo or simvastatin (40 mg/d) for the next four cycles. The second and sixth menstrual cycles were considered baseline and treatment cycles, respectively. Participants kept a menstrual diary throughout the study and provided daily first-void urine samples during cycles 2 and 6. Urine samples were assayed for LH and pregnanediol glucuronide (PdG). The primary end point was change in luteal phase duration as defined by the day of the urinary LH peak to the day preceding the onset of menstruation. Treatment with simvastatin (40 mg/d) effectively lowered LDL-C by 34.3% (P < 0.001). Simvastatin was generally well tolerated, and no meaningful difference in adverse event profile was observed between treatment groups. Compared with the placebo group, simvastatin did not have clinically relevant effects on luteal phase duration, peak PdG concentration, or integrated luteal phase PdG concentration. The results of this study demonstrate that treatment of healthy premenopausal women for approximately 4 months with simvastatin (40 mg/d) lowers LDL-C without adversely affecting reproductive gonadal function. Simvastatin should not be used during pregnancy or by nursing mothers.

Adult↗
PubMed2004

Inhibition of in-vitro simvastatin metabolism in rat liver microsomes by bergamottin, a component of grapefruit juice.

Grapefruit juice can modify the pharmacokinetic parameters of many drugs, in particular simvastatin, an orally active cholesterol-lowering agent. The exact components in grapefruit juice responsible for drug interactions are not perfectly known. However, it seems that bergamottin, a furocoumarin derivative, is one of the main active components within grapefruit juice. The objective of this paper was to quantify and to characterize in-vitro the inhibitory effect of bergamottin on simvastatin metabolism by using rat and human liver microsomes. In rat liver microsomes, the incubation conditions (+/-NADPH) of bergamottin were found to influence its inhibiting capacity. In co-incubation with simvastatin, the Ki value (the equilibrium dissociation constant for the enzyme-inhibitor complex) was higher (Ki = 174 +/- 36 microM) than in pre-incubation (Ki = 45 +/- 6 microM and 4 +/- 2 microM, without and with NADPH, respectively). It thus seems that the pre-incubation of bergamottin (in particular with NADPH) increases its inhibiting capacity on simvastatin metabolism. Bergamottin metabolism study in rat liver microsomes showed the formation of two metabolites that were CYP-450 dependent. In contrast, in human liver microsomes, the incubation conditions of bergamottin did not influence its inhibiting capacity of simvastatin metabolism (Ki = 34 +/- 5 microM, Ki = 22 +/- 5 microM, Ki = 27 +/- 11 microM in coincubation and pre-incubation without and with NADPH, respectively). In rat and man, bergamottin was found to be a mixed-type inhibitor of simvastatin hepatic metabolism. However, in rat, bergamottin was partially a mechanism-based inhibitor by involvement of either bergamottin alone or one of its metabolites. The results highlight the importance of validating in-vitro models to help verify the suitability of the in-vitro model for predicting the nature and degree of metabolic drug interactions.

Animals↗
PubMed2006

Effect of combination therapy with simvastatin and carvedilol in patients with left ventricular dysfunction complicated with acute myocardial infarction who underwent percutaneous coronary intervention.

BACKGROUND: This study assessed the effects of combination therapy with simvastatin and carvedilol on clinical outcome in patients with left ventricular (LV) dysfunction after acute myocardial infarction (AMI). METHODS AND RESULTS: The study retrospectively analyzed the data from 672 patients with LV dysfunction [LV ejection fraction (LVEF) <40%] complicated with AMI who underwent percutaneous coronary intervention (PCI). The patients were divided into 4 treatment groups: combination group (n=160), simvastatin only group (n=216), carvedilol only group (n=242), neither treatment group (n=54). At 6 months after PCI, the LVEF had improved most significantly in the combination group. During 1-year follow-up, cardiac death occurred most frequently in the neither treatment group compared with the other 3 groups (combination: 4%, simvastatin alone: 7%, carvedilol alone: 8%, neither: 17%, p<0.001 between neither treatment and other 3 groups). The results on major adverse cardiovascular events (MACE) showed that the combination of simvastatin and carvedilol was associated with a relative risk reduction of 53% (p<0.001), treatment with simvastatin alone with a relative risk reduction of 44% (p=0.001), and carvedilol alone with a relative risk reduction of 40% (p=0.003) compared with neither treatment. The independent predictors of 1-year MACE were neither treatment, elevated high sensitivity C-reactive protein (> or =0.5 mg/dl), and old age (>70 years). CONCLUSION: Combination therapy with simvastatin and carvedilol had a positive impact on the endpoints of cardiovascular death and MACE and seems to have an additive beneficial effect on these endpoints in patients with LV dysfunction complicated with AMI who underwent PCI.

Aged↗
PubMed2005

Simvastatin treatment of pulmonary hypertension: an observational case series.

BACKGROUND: Statins confer cardiovascular benefits beyond the reduction of serum cholesterol through antiproliferative and antiinflammatory mechanisms and induction of endothelial nitric oxide expression. In pneumonectomized rats injected with monocrotaline, simvastatin reversed established pulmonary hypertension and conferred a 100% survival advantage. STUDY OBJECTIVES: To evaluate the safety and efficacy of simvastatin for treatment of patients with pulmonary arterial hypertension (PAH). DESIGN: Open-label observational study performed at Stanford University Medical Center. Sixteen patients with primary and secondary causes of PAH, World Health Organization (WHO) classes I (n = 2), II (n = 4), III (n = 3), IV (n = 7), are described. Simvastatin was prescribed at 20 to 80 mg/d and continued in the absence of adverse effects. MEASUREMENTS AND RESULTS: Serial measurements of 6-min walk (6MW) performance, hemodynamics, and echocardiographic estimates of right ventricular systolic pressures (RVSPs) were recorded on each patient. Simvastatin treatment was not associated with hepatic dysfunction, muscle necrosis, or other adverse events. Individual patients demonstrated improvements in 6MW performance, improvements in cardiac output, or decreases in RVSP that may be attributable to simvastatin treatment. Overall, the rate of disease progression appeared to be attenuated, and WHO class IV patients demonstrated improved survival. CONCLUSIONS: Simvastatin treatment appears safe in patients with PAH.

Adult↗
PubMed1992

Effect of simvastatin in patients with type I (insulin-dependent) diabetes mellitus and hypercholesterolemia.

In 10 hypercholesterolemic patients with Type I (insulin-dependent) diabetes, simvastatin 10-40 mg/day was compared to placebo in a randomized, double-blind, cross-over study with treatment periods of 12 weeks. Between each treatment there was a wash-out period of 4 weeks. Compared to placebo, simvastatin reduced total cholesterol by 19% (p less than 0.001) and low density lipoprotein (LDL) cholesterol by 24% (p less than 0.001). Simvastatin therapy reduced plasma triglyceride by 8% and increased high density lipoprotein (HDL) cholesterol by 8%, but neither of these alterations was significant (p greater than 0.05). Diabetic control and daily requirement of insulin were not influenced by simvastatin. In six patients, all men, there were no alterations in the concentrations of dehydroepiandrosterone-sulphate, testosterone, estradiol, prolactin, luteinizing hormone or follicle-stimulating hormone, while sex hormone-binding globulin was significantly (19% (p less than 0.05)) reduced during therapy with simvastatin. Thus, in Type I (insulin-dependent) diabetic patients, simvastatin causes significant reductions in plasma total cholesterol and LDL cholesterol which are similar in magnitude to those observed in non-diabetics. This favourable effect can be obtained without any concomitant negative influence on glucose regulation or total gonadal steroid hormone concentrations.

Adult↗
PubMed2006

A case of simvastatin-associated pancreatitis and review of statin-associated pancreatitis.

Reduction of low-density lipoprotein cholesterol (LDL) concentration has become the primary goal and a standard of care in the practice of cholesterol management. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most frequently prescribed lipid lowering agents on the market. As more information is learned through the results of clinical trials, LDL goals become more stringent and difficult to attain. Large doses of high-potency statins, sometimes given in combination with other lipid-lowering agents, are frequently necessary to achieve these goals. As a result, the frequency of adverse effects from statin therapy may be expected to increase, and less common adverse effects may occur more often. As statins are used more aggressively, rare and possibly dangerous adverse effects must be identified, especially those that are becoming more frequently encountered. Increased awareness may lead to earlier diagnosis and management of diseases that may be caused by the statins. We describe a 58-year-old man who was hospitalized with idiopathic pancreatitis 4 months after starting simvastatin therapy. His oral drug therapy was withheld, and he was treated with bowel rest. The patient was discharged on hospital day 5, and his oral drug regimen, including simvastatin, was resumed. He was admitted again 16 months later with a second diagnosis of acute pancreatitis and was discharged after 3 days of bowel rest with no oral drug therapy. Simvastatin was restarted on discharge, but the patient stopped taking it after experiencing muscle soreness and weakness in his arms. He recalled having similar arm pain that preceded the previous episode of acute pancreatitis. All other causes of the pancreatitis had been ruled out; thus, the correlation between simvastatin-induced myalgia and onset of acute pancreatitis on two separate occasions made simvastatin the suspected instigating agent. Pancreatitis is a rare adverse effect of statin therapy, but it has been documented in several case reports involving most of the statins. Continued reporting is necessary to increase awareness of this rare adverse effect of simvastatin so that it may be promptly managed or avoided in the future.

Humans↗
PubMedDate not supplied

Frequency of simvastatin prescriptions with potentially interacting medications in a Veterans Affairs health care system.

OBJECTIVE: The primary objective of this review is to quantify the proportion of patients on simvastatin, an HMG-CoA reductase inhibitor (commonly known as statin), who received concurrent prescriptions for potentially interacting chronicuse medications. The secondary objective is to determine the frequency with which simvastatin was prescribed above its recommended dose when administered concomitantly with known interacting medications. METHODS: A retrospective review of computerized outpatient pharmacy records from a Veterans Affairs Medical Center and its associated ambulatory clinics was performed in September 2002. RESULTS: A total of 12,240 patients had an active prescription for a statin. The majority of patients (95%, N = 11,677) were on simvastatin therapy, and 1,231 (10.5%) of the patients on simvastatin were prescribed at least 1 potentially interacting medication. More than one half (57.8%) of simvastatin doses were above the maximum recommended daily dose when prescribed with potentially interacting medications. CONCLUSION: This analysis supports the need for vigilance in reviewing the dose of simvastatin in patients receiving interacting medications. Health care systems should consider strategies to educate health care professionals on prevention of drug interactions and adverse patient outcomes.

Aged↗
PubMed2003

Benefits and risks of simvastatin in patients with familial hypercholesterolaemia.

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.

Anticholesteremic Agents↗
PubMed1997

Cost effectiveness of micronised fenofibrate and simvastatin in the short-term treatment of type IIa and type IIb hyperlipidaemia.

The aim of this study was to compare the cost effectiveness of micronised fenofibrate 200 mg and simvastatin 20 mg in the treatment of type IIa and IIb hyperlipidaemia. In a retrospective analysis, data from 2 randomised controlled clinical trials were evaluated. The results show that micronised fenofibrate has a better short term cost effectiveness than simvastatin. The costs per successfully treated patient with hyperlipidaemia over a 12-week period were [in Deutschmarks (DM); DMI = $US0.66, April 1995] DM537 for fenofibrate and DM809 for simvastatin. When the data were analysed according to type of hyperlipidaemia (classification of Frederickson), there were only small differences between both test drugs (DM450 for fenofibrate, DM517 for simvastatin) in patients with type IIa because simvastatin had higher response rates which, in part, compensated for the higher acquisition cost. However, response rates in patients with type IIb hyperlipidaemia were higher for fenofibrate, which led to a substantial cost advantage for this agent (DM768 for fenofibrate, DM2080 for simvastatin). These results were confirmed by various sensitivity analyses, including the assessment of drug monitoring programmes (postmarketing surveillance) to validate response rates and the total costs of the therapy. In this study, we evaluated the total costs of a 12-week period of therapy, not the costs per day. The results are based on actual clinical data and not just on theoretical models. The study underlines the necessity to differentiate between the types of hyperlipidaemia when performing a pharmacoeconomic analysis of lipid-lowering treatments.

Anticholesteremic Agents↗
PubMed1997

A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors.

Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and also selectively inhibits the growth of leukaemic progenitor cells. The antileukaemic action of simvastatin was compared in vitro with that of lovastatin and pravastatin, chemically related compounds which are also competitive inhibitors of HMG-CoA reductase. After 18 hours incubation with 2.5-20 microM of inhibitor, no effect was observed by any of the compounds on the subsequent clonogenic growth of normal bone marrow (BM) progenitor cells from 4 donors and BM cells from one patient in remission. However, simvastatin and lovastatin produced inhibition of acute myeloid leukaemia (AML) progenitor cell growth of between 25% and 100% in 5 populations tested (4 primary AMLs and the HL60 cell line). Pravastatin showed similar growth inhibitory effects to simvastatin and lovastatin in 2 out of 3 primary AMLs but was less active against one primary AML cell population and HL60 cells. These results indicate that, in addition to simvastatin, lovastatin and pravastatin are also selective inhibitors of leukaemic cell growth, however simvastatin was chosen for clinical trial in patients with leukaemia.

Acute Disease↗
PubMed2001

The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells.

HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that have been shown to effectively decrease severe rejection periods and development of transplant coronary artery disease after heart transplantation. Precise regulation of major histocompatibility complex class II (MHC class II) gene expression plays a pivotal role in control of the immune response after transplantation. The aim of this study was to evaluate the potential role of HMG-CoA reductase inhibitors in regulating the immune response. We have examined the effects of simvastatin on MHC class II expression in primary human endothelial cells. Using RNAse protection assay and flow cytometry, we observed that simvastatin dose-dependently reduced interferon-gamma (IFN-gamma) induced MHC class II expression (mRNA and protein). In contrast, simvastatin did not affect the expression of MHC class I, pointing to specific actions in the MHC class II signalling cascade. The transcriptional coactivator CIITA is the general regulator of both constitutive and inducible MHC class II expression. After stimulation with IFN-gamma, the CIITA gene is selectively activated via one (promotor IV) of its four promoters. Interestingly, mRNA levels of CIITA were decreased after treatment with simvastatin. In addition, using transient transfections of promoter-reporter constructs we observed that the activity of CIITA promoter IV was decreased by simvastatin. In conclusion, simvastatin selectively decreases IFN-gamma-induced MHC class II expression in human primary endothelial cells through actions on the CIITA promoter IV. Thus, the beneficial effects of statins reported after heart transplantation may result from this immunosuppressive action, suggesting possible therapeutic use for other immunological disorders as well.

Cells, Cultured↗
PubMed1999

Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia.

BACKGROUND AND AIM: Impaired triglyceride-rich lipoprotein metabolism is most probably related to an enhanced cardiovascular risk, and may be associated with a pro-coagulant state. A double-blind, randomized study was undertaken to evaluate two widely utilized hypolipidemic drugs in the post-prandial phase and their impact on lipid, coagulation and fibrinolytic parameters. METHODS AND RESULTS: Thirty middle-aged men selected according to their low density lipoprotein-cholesterol (LDL-C) > or = 160 and < or = 240 mg/dl and borderline hypertriglyceridemia (110-220 mg/dl) after at least one month of a lipid-lowering diet received gemfibrozil (600 mg bid) or simvastatin (20 mg qd) and the corresponding placebo. On enrollment and after 2 months of drug treatment, they were tested with a standard oral fat load (OFL) (35 g fat/m2 body surface). On both occasions plasma total-cholesterol, LDL-C, HDL-C, triglycerides, lipoprotein[a] (Lp[a]), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), antithrombin-III (AT-III), plasminogen and fibrinogen were determined just before the meal (t0) and at times 2 hours, 4 h, 6 h, 8 h after it (t2-t8). A two-factor (time and visit) multivariate analysis for repeated measurements was performed to evaluate the data. Total cholesterol, and LDL-C were significantly diminished 2 months after both gemfibrozil and simvastatin, the latter being more active. Plasma triglycerides showed a marked reduction with gemfibrozil at all times, while simvastatin regimen yielded only minor modifications. HDL-C was only slightly increased by simvastatin; Lp[a] plasma levels were almost unaffected. Small fibrinogen (t0, t2, t6, t8), PAI-1 (t6) and AT III (t0-t8) increases were observed after gemfibrozil, while simvastatin did not significantly modify these parameters. CONCLUSIONS: In the post-prandial phase, gemfibrozil and simvastatin induce different metabolic effects that beneficially influence the lipid pattern, whereas fibrinolytic and coagulative parameters display minor variations of undetermined significance.

Adult↗