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At least 919 records · Page 51Linked to original sources
PubMed2006

Statins revert doxorubicin resistance via nitric oxide in malignant mesothelioma.

Human malignant mesothelioma (HMM) is resistant to many anticancer drugs, including doxorubicin. Mevastatin and simvastatin, 2 inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, potentiated the intracellular accumulation and the cytotoxicity of doxorubicin in HMM cells constitutively expressing P-glycoprotein and multidrug resistance-associated protein 3. This effect of statins was nitric oxide (NO)-dependent, since it was reverted by either an NO synthase inhibitor or an NO scavenging system. The NO synthase up-regulation in HMM and other cells is known to be associated with the activation of the transcription factor NF-kappaB: in HMM cells statins increased the NF-kappaB translocation into the nucleus, decreased the level of the NF-kappaB inhibitor IkBalpha and increased the phosphorylation/activation of IkB kinase alpha (IKKalpha). IKKalpha is under the negative control exerted by RhoA in its prenylated (active) form: incubation of HMM cells with statins lowered the amount of active RhoA and the level of Rho-associated kinase activity. All statins' effects were reverted by mevalonic acid, thus suggesting that they were mediated by the inhibition of HMGCoA reductase and were likely to be subsequent to the reduced availability of precursor molecules for RhoA prenylation. Both the Rho kinase inhibitor Y27632 and the RhoA inhibitor toxin B (from Clostridium difficile) mimicked the statins' effects, enhancing doxorubicin accumulation, NO synthesis and IKKalpha phosphorylation and decreasing the amount of IkBalpha in HMM cells. Simvastatin, Y27632 and toxin B elicited tyrosine nitration in the P-glycoprotein, thus providing a likely mechanism by which NO reverts the doxorubicin resistance in HMM cells.

Amides↗
PubMed2004

Induction of osteoblast differentiation indices by statins in MC3T3-E1 cells.

Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyzes conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. The present study was undertaken to understand the events of osteoblast differentiation induced by statins. Simvastatin at 10(-7) M markedly increased mRNA expression for bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (OCN) in nontransformed osteoblastic cells (MC3T3-E1), while suppressing gene expression for collagenase-1, and collagenase-3. Extracellular accumulation of proteins such as VEGF, OCN, collagenase-digestive proteins, and noncollagenous proteins was increased in the cells treated with 10(-7) M simvastatin, or 10(-8) M cerivastatin. In the culture of MC3T3-E1 cells, statins stimulated mineralization; pretreating MC3T3-E1 cells with mevalonate, or geranylgeranyl pyrophosphate (a mevalonate metabolite) abolished statin-induced mineralization. Statins stimulate osteoblast differentiation in vitro, and may hold promise drugs for the treatment of osteoporosis in the future.

Alkaline Phosphatase↗
PubMed1994

Characterization of 57 kDa statin as a true marker for growth arrest in tissue by its disappearance from regenerating liver.

Statin, a 57 kDa nuclear protein, is lost from quiescent fibroblasts in culture when they are induced to enter the cell cycle by feeding with growth factors, or by removal of contact inhibition. In order to investigate changes in statin expression during the transition from a quiescent to a cycling state in situ, we performed 70% partial hepatectomy on rats and analyzed the regenerating liver by immunofluorescence microscopy with antistatin monoclonal antibodies (S44 mAb), and by immunoblotting of liver proteins in cytoplasmic and enriched nuclear/cytoskeletal fractions. Western blot analysis showed that rat hepatocytes in situ contain a nuclear 57 kDa form of statin, as seen in cultured fibroblasts; however additional S44-immunoreactive polypeptides with molecular weights of 53 and 110 kDa are also present in both cytoplasmic and nuclear/cytoskeletal fractions. Immunofluorescence microscopy indicates that the proportion of S44-positive hepatocyte nuclei drops to approximately 60% within 24 hours after hepatectomy, a time period when re-entry of hepatocytes into the cell cycle is first observed. On Western blots of hepatocyte nuclear/cytoskeletal proteins obtained 24 hours after hepatectomy, the 57 kDa form of statin is markedly reduced. These results suggest that, although in liver the S44 antibody recognizes three proteins (53 kDa, 57 kDa, and 110 kDa), the 57 kDa in intact liver, similar to cultured fibroblasts, is the only polypeptide recognized by the statin antibody that disappears when hepatocytes are induced to re-enter the cell cycle from a quiescent state.

Animals↗
PubMed2005

Induction of macrophage elastase (MMP-12) gene expression by statins.

The statins (including mevastatin and lovastatin) are a widely prescribed class of serum-cholesterol lowering drugs that function by inhibiting 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase activity and cellular sterol synthesis. Statins are also widely being appreciated for their inhibitory effects upon inflammation, primarily mediated through direct regulation of inflammatory gene expression. Here we report that statins are also capable of increasing the expression of macrophage elastase (MMP-12). The induction of MMP-12 in mouse macrophages by statins is specific for HMG CoA reductase inhibition, rescued by mevalonate and not observed after inhibition of subsequent steps in the cholesterol biosynthetic pathway. Modulation of cholesterol metabolism may lead to changes in MMP-12 expression and subsequent impacts during physiological and pathophysiological states. We conclude that statins, in addition to their previously described anti-inflammatory properties, may promote the production of some proteinases from activated macrophages.

Animals↗
PubMed2002

Statins and progressive renal disease.

Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.

Adult↗
PubMed2005

Molecular clues into the pathogenesis of statin-mediated muscle toxicity.

The pathophysiology of statin-mediated muscle dysfunction is poorly defined. Reductions in skeletal muscle membrane cholesterol were initially thought to account for the range of myopathic reactions, e.g., myalgia, elevated serum creatine kinase, or rhabdomyolysis. This assumption however, does not consider a potential role of the isoprenoids in the pathophysiology of statin myopathy. The observation that derangements in mevalonate kinase (MK), but not more distal enzymes of cholesterologenesis, are associated with a skeletal myopathy suggests a critical role for the isoprenoids in the maintenance of muscle. Statins also deplete the isoprenoid pool by inhibiting the enzyme, beta-hydroxy-beta-methylglutaryl coenzyme A reductase, which is upstream of MK. Identifying candidate proteins that are both dependent on isoprenoid-mediated modification and associated with muscle disease, when genetically mutated, offers further insight into potential mechanisms of statin myopathy. For example, lamin A/C, selenoprotein N, alpha- and beta-dystroglycan, and cytoskeletal G-proteins all require isoprenylation for optimal function. Understanding the pleiotropic effects of protein prenylation, and the potential consequences of a generalized insufficiency of this form of protein modification, may help clarify the molecular pathogenesis of statin myopathy.

Animals↗
PubMed1996

Immunohistochemical analysis of statin in colorectal adenocarcinoma, polyps, and normal mucosa.

PURPOSE: The search for an understanding of the kinetics of the malignant cell is an ongoing focus of research. The aim of the present study was to determine whether there were any differences in the expression of statin, a nonproliferation-specific nuclear protein, among different colorectal tissues and whether there is any relationship between statin presence and neoplastic aggressivity. METHODS: The study population consisted of specimens from 19 patients who underwent resection for carcinoma, one for villous adenoma, and seven for colonoscopic polypectomies. Tissue samples were taken from the center of the specimen and from mucosa 10 cm from the lesion. RESULTS: Statin immunoreactivity was evaluated by counting stained nuclei in ten randomly chosen fields, and percent of positive cells was calculated. Average percentage of statin-positive cells was 34.33 +/- 6.81 in the normal crypt, 44.42 +/- 7.28 for polyps, and 7.74 +/- 5.67 for carcinomas (significantly lower than normal mucosa and polyps; P < 0.001). CONCLUSION: Statin expression is dramatically diminished in invasive carcinoma tissue, but it did not help determine aggressivity with respect to Dukes stage.

Adenocarcinoma↗
PubMed2007

Statin therapy in cardiovascular diseases other than atherosclerosis.

Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, thereby blocking the synthesis of cholesterol. Since being discovered in Japan in the mid 1970s, statins have been widely used to lower low-density lipoprotein cholesterol. However, analysis of cardiovascular research has revealed other important effects beyond changes in lipid parameters, referred to as pleiotropic effects. This paper focuses on the effects of statins as anti-ischemic agents with improvement in endothelial function, along with studies on valvular aortic stenosis, atrial fibrillation, heart failure, peripheral arterial disease, and cancer. As the evolution of statin research continues, there appear to be new potential benefits from statins to be found in many facets of cardiovascular disease.

Atherosclerosis↗
PubMed2003

The potential therapeutic role of statins in central nervous system autoimmune disorders.

3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, 'statins' are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their cholesterol-reducing properties. Recent studies indicate that statins have antiinflammatory and neuroprotective properties which may be beneficial in the treatment of multiple sclerosis as well as other central nervous system (CNS) neurodegenerative diseases. This article will outline current experimental evidence that may suggest potential clinical benefits for patients with CNS autoimmune disorders. Ultimately, clinical trials will have to determine the safety and efficacy of statins in this patient population.

Animals↗
PubMed2005

Statin-macrolide interaction risk: a population-based study throughout a general practice database.

INTRODUCTION: The myopathy risk associated with statin use increases in case of concomitant prescription of certain drugs, such as cytochrome P(450) (CYP) system inhibitors (i.e., macrolides). The aim of this study was to assess whether concurrent statin/macrolide prescriptions at high interaction risk are commonly written in a general practice setting. METHODS: For this study, 156 general practitioners (GPs) with a patient population of almost 200,000 individuals, and participating in the Arianna database set up by "Caserta-1" Local health-Service Agency (ASL), were recruited. Within such a study sample, subjects receiving at least one statin/macrolide concomitant prescription during the year 2003 were identified. Sensitivity analysis was performed to assess the time distribution of high-risk macrolide prescriptions written within +/-10 days from the statin prescription date. RESULTS: Among 190,124 patients included in the study, 7,176 (3.8%) received at least one statin prescription during the observation period. Of these, 228 (3.2%) were occasionally co-prescribed with any macrolide on the same date, in 153 cases (2.1% of statin users) the macrolide being of high interaction risk. In particular, 2.1% (55) of simvastatin users and 2.2% (64) of patients on atorvastatin were prescribed with high-risk macrolide on the same date versus 0.6% and 1.8% of patients prescribed with fluvastatin and pravastatin, respectively. Concerning GPs, 99 (63.5%) co-administered statin and macrolide at high interaction risk at least once. CONCLUSIONS: Most GPs occasionally prescribed statin/macrolide at high interaction risk on the same date, despite the availability of therapeutic alternatives. Prevention strategies targeted to increase awareness of health professionals about the interaction risks of widely prescribed drugs are needed.

Adolescent↗
PubMed2005

Efficacy and safety of statins in hypercholesterolemia with emphasis on lipoproteins.

Information of the effect of statin on lipoproteins such as apolipoprotein (apo) A-I, lipoprotein (a) [Lp (a)], or apolipoprotein B levels is limited. This investigation was a crossover study designed to evaluate the efficacy and safety of atorvastatin and simvastatin in patients with hyperlipidemia. Sixty-six patients were involved in the study. Group I consisted of 32 patients, who were first treated with atorvastatin (10 mg) then switched to simvastatin (10 mg). Group II consisted of 34 patients, who were first treated with simvastatin then switched to atorvastatin. Each regimen was used for 3 months (phase I), stopped for 2 months, and then restarted for another 3 months (phase II). Both statins effectively reduced total cholesterol, low-density lipoprotein cholesterol (LDL-C), apo B, and Lp (a) (P < 0.001 in all comparisons). A significant increase in the high-density lipoprotein cholesterol (HDL-C) was noted after both statin treatments (P < 0.05 in all comparisons). Both statins caused an increase in the apo A-I levels, and the extent of changes in apo A-I revealed no difference between the two drugs. Compared to the simvastatin group, there were more patients in the atorvastatin group achieving the National Cholesterol Education Program ATP-III LDL-C goal (P < 0.05) and European LDL-C goal (P < 0.001). Both treatments were well tolerated; no patient was withdrawn from the study. This study demonstrates that both statins can effectively improve lipid profiles in patients with hyperlipidemia. Atorvastatin is more effective in helping patients reach the ATP-III and European LDL-C goals than simvastatin at the same dosage.

Adult↗
PubMed2006

Prognosis at 6 months for coronary and cerebrovascular patients: impact of antiplatelet agents and statins: results from the Prevenir III study.

PURPOSE: The aim of the Prevenir III study was to assess, in secondary prevention, the risk after 6 months of subsequent coronary and cerebrovascular events in a population of patients in private practice. METHODS: A prospective observational survey, including patients diagnosed with previous myocardial infarction, unstable angina or stroke, was carried out by French general practitioners and cardiologists. RESULTS: 9556 patients were selected by 3746 physicians representative of French physicians. The medical records of 8288 were analyzed. After a 6-month follow-up, 116 patients (1.4%) had been hospitalized for coronary or cerebrovascular event i.e. cumulative incidence 3.6 per 100 person-years (95% CI 2.9-4.2). The rate of coronary events was 0.9% and the cumulative incidence 2.3% person-years (95% CI 1.8-2.8), the event rate of stroke was 0.5% and the cumulative incidence 1.3 person-years (95% CI 0.9-1.7) and all-cause mortality was 1.2% i.e. 3.1 per 100 person-years (95% CI 2.5-3.7). Patients treated with statins and antiplatelet agents, or both, were less likely to undergo subsequent events than patients not receiving statins or antiplatelet agents. All-cause mortality rate decreased dramatically (Hazard Ratio 0.4 95% CI 0.2-0.7 after adjustment for age, sex, diagnosis at inclusion, time elapsed since the index event, cardiovascular and non cardiovascular history, betablockers, angiotensin-converting enzyme inhibitors and cardiovascular risk factors) in patients treated with a combination of statins and antiplatelet agents when compared to patients treated with neither statins nor antiplatelet agents. CONCLUSION: Our survey enabled a better understanding of the prognosis at 6 months in a large sample of coronary and cerebrovascular patients. We observed the beneficial impact of the combination of statins and antiplatelet agents in cardiovascular secondary prevention.

Aged↗
PubMed2001

Statins in children: what do we know and what do we need to do?

Children have been tested and treated for hypercholesterolemia for more than 30 years. Although most treatment regimens have been limited to dietary intervention, statin use is increasing. Statins have been used in children since 1987, but published sources have only reported on small numbers of children with severe hypercholesterolemia. The available data indicates that statins can be useful and well tolerated. New data will be available in the next few years that will lead to the wider use of these drugs. Although statin drugs have proven to be safe in the adult population, physicians will be obliged to follow pediatric patients closely when these agents are widely used in the first few years. The use of highly effective safe drugs such as statins will allow for the assessment of the best time to initiate therapy in younger populations and what benefits may be found over the long term.

Atorvastatin↗
PubMed2001

Statins, hormones, and women: benefits and drawbacks for atherosclerosis and osteoporosis.

Clinical trials have shown that 3-hydoxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, known as statins, significantly reduce the risk of both primary and secondary coronary heart disease events. Although these trials have included few women, the evidence suggests that statins are as effective in women as in men. The addition of hormone replacement therapy to statin therapy augments lowering of low- density lipoprotein cholesterol, but may not increase the favorable effects on clinical events achieved with statins alone. Finally, new data suggest that statins may also reduce the risk of osteoporotic fractures, a provocative finding still in need of verification by clinical trials.

Arteriosclerosis↗
PubMed2002

A general assessment of the safety of HMG CoA reductase inhibitors (statins).

Few principles in medicine today are as well accepted as the benefits of using statins to reduce cardiovascular risk factors and to prevent cardiovascular disease. The recent withdrawal of a statin (cerivastatin) has lead to a re-examination of all statins, and an attempt to better assess the risk-benefit ratio of this class of drugs. Although the benefits of statin treatment are well known from a myriad of clinical trials, the safety of these compounds has not been an issue since lovastatin was first introduced in 1987. This report provides a brief review of statin safety, and reiterates the excellent profile of this class of drugs.

Clinical Trials as Topic↗
PubMed2005

Statins and stroke prevention.

Data from studies on the benefits of statins in coronary artery disease patients in preventing recurrent primary and secondary cardiac endpoints, as well as ischemic strokes, imply the potential value of statins in recurrent ischemic stroke prevention without coronary artery disease symptoms or, by extension, primary ischemic stroke prevention. However, data on the latter are lacking, although the ongoing Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is designed to answer that question. Until these data become available, clinicians are justified in using statins to avert recurrent ischemic strokes due to atherosclerosis, especially if elevated total cholesterol, increased low-density lipoprotein cholesterol, and/or reduced high-density lipoprotein cholesterol, as specified in the National Cholesterol Education Program Third Adult Treatment Panel, are present. This article reviews the pathophysiology of atherosclerosis, particularly the major components of atheromas of cholesterol, smooth muscle cells, inflammation, "foam cells," and connective tissue elements. Emphasis is placed on the first three and the results of statin trials in coronary artery disease, as well as the beneficial pleiotrophic effects of statins in ischemic strokes.

Atherosclerosis↗
PubMed2006

Other than potency, are all statins the same?

Statins have been shown to interact with metabolic pathways that potentially affect physiologic functions beyond cholesterol balance. We may broadly categorize non-lipid effects of statins as clinically favorable or clinically detrimental. Whether non-lipid effects of statins are of clinical significance and whether there are differences in non-lipid effects among statins remain points of major current controversy. This review evaluates the available information on potential differences among statins in non-lipid effects.

Clinical Trials as Topic↗
PubMed1999

Non-lipid-lowering effects of statins on atherosclerosis.

Lipid and nonlipid mechanisms contribute to the beneficial effects of some statins on endothelial function, plaque stability and thrombus formation. The nonlipid effects of statins may contribute to alleviation of tissue ischemia and prevention of acute cardiovascular syndromes. Endothelial dysfunction is reversed by a statin and this beneficial property results, in part, from direct actions on the endothelial vasoactive factors, nitric oxide and endothelin-1. Some statins have been shown to inhibit production of proinflammatory cytokines that regulate many key functions of the vascular wall including monocyte adhesion, chemotaxis, and metalloproteinase secretion. Vascular smooth muscle cell synthetic capacity and viability is inhibited by lipophilic agents, whereas a hydrophilic agent does not interfere with this reparative response. Some statins may impede thrombogenesis by reduced activation of the extrinsic coagulation pathway, inhibition of platelet adhesion and aggregation, and improvement in the rheologic profile.

Anticholesteremic Agents↗