Showing papers on "Lovastatin published in 2003"
TL;DR: Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17% and is corroborated by results from the nine cohort studies.
Abstract: Objectives To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment. Design Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke. Main outcome measures Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol. Results Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P Conclusions Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.
1,709 citations
TL;DR: The discovery and development of lovastatin — the first approved inhibitor of HMG-CoA reductase — and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease are described.
Abstract: In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin--the first approved inhibitor of HMG-CoA reductase--and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.
779 citations
TL;DR: Statins inhibit secretion of a several MMPs from both SMCs and macrophages, which could therefore contribute to their plaque-stabilizing effects.
Abstract: Objective— Production of several metalloproteinases (MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages. Methods and Results— We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, -3, and -9 secretion from human SMC by 52±19%, 71±18%, and 73±17%, respectively (P<0.01, n=3). Similar dose-related effects of cerivastatin (50 to 500 nmol/L), simvastatin (1 to 20 μmol/L), and lovastatin (5 to 20 μmol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, -3, and -9 and constitutive MMP-2 secretion but not TIMP-1 or -2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, -3, and ...
321 citations
TL;DR: M. oleifera possesses a hypolipidaemic effect on lipid profile of liver, heart and aorta while similar treatment of normal animals did not produce significant reduction in heart.
294 citations
TL;DR: It is demonstrated that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leukocyte migration across the blood‐brain barrier.
Abstract: Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leukocyte traffic into the central nervous system (CNS). To breach the specialized blood-brain barrier, activated leukocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling the Rho GTPase. To function correctly Rho requires posttranslational prenylation, and this can be inhibited by depleting the supply of isoprenoids through inhibition of the cholesterol synthesis pathway with 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) inhibitors (statins). Here we show that treatment of brain EC in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect can be reversed by supplementation with mevalonolactone, the downstream product of HMG-CoA reductase, or by ectopic expression of myristoylated Rho, which remains active in the absence of prenylation. In a relapsing-remitting mouse model of MS, lovastatin treatment inhibited leukocyte migration into the CNS and significantly attenuated the development of both acute and relapsing clinical disease. These studies demonstrate that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leukocyte migration across the blood-brain barrier. These studies demonstrate a novel effect of statins in modulating the immune response in neuroinflammtory diseases and may provide additional rationale for their use in the treatment of MS.
230 citations
TL;DR: A method to decipher the complex inter-relationships between metabolite production trends and gene expression events is described, and how information gleaned from such studies can be applied to yield improved production strains is shown.
Abstract: We describe a method to decipher the complex inter-relationships between metabolite production trends and gene expression events, and show how information gleaned from such studies can be applied to yield improved production strains. Genomic fragment microarrays were constructed for the Aspergillus terreus genome, and transcriptional profiles were generated from strains engineered to produce varying amounts of the medically significant natural product lovastatin. Metabolite detection methods were employed to quantify the polyketide-derived secondary metabolites lovastatin and (+)-geodin in broths from fermentations of the same strains. Association analysis of the resulting transcriptional and metabolic data sets provides mechanistic insight into the genetic and physiological control of lovastatin and (+)-geodin biosynthesis, and identifies novel components involved in the production of (+)-geodin, as well as other secondary metabolites. Furthermore, this analysis identifies specific tools, including promoters for reporter-based selection systems, that we employed to improve lovastatin production by A. terreus.
219 citations
TL;DR: Ezetimibe plus Lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo, and may offer a new treatment option in lipid management of patients with hypercholesterolemia.
Abstract: This multicenter, randomized, double-blind, placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week single-blind placebo lead-in period, 548 patients with low-density lipoprotein (LDL) cholesterol ≥145 mg/dl (3.75 mmol/L) and ≤250 mg/dl (6.47 mmol/L) and triglycerides ≤350 mg/dl (3.99 mmol/L) were randomized to one of the following, administered daily for 12 weeks: ezetimibe 10 mg; lovastatin 10, 20, or 40 mg; ezetimibe 10 mg plus lovastatin 10, 20, or 40 mg; or placebo. The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone. Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides compared with lovastatin alone (p <0.01). The coadministration of ezetimibe provided an incremental 14% LDL cholesterol decrease, a 5% HDL cholesterol increase, and a 10% decrease in triglycerides compared with pooled lovastatin alone. Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33% to 45%, median triglyceride decreases of 19% to 27%, and mean HDL cholesterol increases of 8% to 9%, depending on the statin dose. The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin (10 mg) provided comparable efficacy to high-dose lovastatin (40 mg) across the lipid profile (LDL cholesterol, HDL cholesterol, and triglycerides). Ezetimibe plus lovastatin was well tolerated, with a safety profile similar to both lovastatin alone and placebo. The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia.
217 citations
TL;DR: Production of lovastatin and microbial biomass by Aspergillus terreus ATCC 20542 were influenced by the type of the carbon source and the nitrogen source used, and the use of spores gave a more consistent inoculum in the different runs.
212 citations
TL;DR: It is shown that N‐BPs cause γ,δ‐T‐cell activation and proliferation in vitro by an indirect mechanism through inhibition of FPP synthase, an effect that can be overcome by inhibiting HMG‐CoA reductase with a statin.
Abstract: The acute phase response is the major adverse effect of intravenously administered N-BPs. In this study we show that N-BPs cause γ,δ-T-cell activation and proliferation in vitro by an indirect mechanism through inhibition of FPP synthase, an effect that can be overcome by inhibiting HMG-CoA reductase with a statin. These studies clarify the probable initial cause of the acute phase response to N-BP drugs and suggest a possible way of preventing this phenomenon.
Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of γ,δ-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of γ,δ-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known γ,δ-T-cell agonists.
Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of γ,δ-T-cells in the CD3+ population.
Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3+ γ,δ-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. γ,δ-T-cell proliferation and activation (interferon γ [IFNγ] and TNFα release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of γ,δ-T-cells by a synthetic γ,δ-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of γ,δ-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/dimethylallyl diphosphate in PBMCs. Because activation of γ,δ-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.
207 citations
TL;DR: Cholesterol-lowering statin drugs are among the most frequently prescribed agents for reducing morbidity and mortality related to coronary heart disease and a solid-phase extraction method was developed to enrich the analytes from aqueous samples.
186 citations
TL;DR: In conclusion, this data give some first insight in the mode of action of statins to reduce the prevalence of AD in clinical trials.
TL;DR: By enhancing osteoblast gene expression and by inhibiting adipogenesis, lovastatin may shunt uncommitted osteoprogenitor cells in marrow from the adipocytic to the osteoblastic differentiation pathway.
TL;DR: Findings strongly suggest that statins’ inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.
Abstract: Several prospective clinical studies have indicated that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, prevent cardiovascular events in part through their antiinflammatory properties. Because inflammation is positively and negatively regulated by T helper (Th) 1 cells and Th2 cells, respectively, we examined the effects of statins on the Th polarization in vitro and in vivo. Here we demonstrated that the statins tested, ie, cerivastatin, simvastatin, lovastatin, and atorvastatin, promoted Th2 polarization through both inhibition of Th1 development and augmentation of Th2 development of CD4+ T cells primed in vitro with anti-CD3 antibody and splenic antigen-presenting cells. Cerivastatin exerted most potent effect on modulation of Th1/Th2 development, and the effect was completely abrogated by an addition of mevalonate. Consistent with in vitro experiments, cerivastatin treatment decreased IFN-gamma production of lymph node cells from mice immunized with ovalbumin emulsified in complete Freund's adjuvant, indicating that Th1 development is also suppressed in an in vivo proinflammatory environment. In this murine model, cerivastatin significantly reduced mesangial matrix expansion of glomeruli in the kidney and attenuated proteinuria. The decrease of glomerular sclerosis by cerivastatin treatment was positively related to the suppression of interferon (IFN)-gamma-producing Th1 response in draining lymph node cells. Hence, these findings strongly suggest that statins' inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.
TL;DR: All statins with the exception of pitavastatin show very low systemic bioavailability due to an extensive first pass effect at the intestinal and/or hepatic level, and pravastatin has the lowest protein binding and shows the longest terminal half-life.
Abstract: This article reviews the pharmacokinetic properties of HMG-CoA reductase inhibitors (or statins), as reported in humans. Most data presented here refer to commercially available statins (atorvastatin, fluvastatin, lovastatin and simvastatin), although statins that have recently been withdrawn (cerivastatin) or are currently under development (glenvastatin, pitavastatin and rosuvastatin) will also be considered. All statins with the exception of pitavastatin show very low systemic bioavailability due to an extensive first pass effect at the intestinal and/or hepatic level. Such a characteristic can be advantageous, since the liver is the target organ for statins. Unlike most statins, lovastatin and simvastatin are administered as inactive lactone prodrugs. Statins differ mainly in the degree of metabolism and the number of active and inactive metabolites. All statins but pravastatin show highly active metabolites, the pharmacological activity depending on the kinetic profile of both parent compound and active metabolites. Pravastatin has the lowest protein binding (50% vs. > 90%) and is eliminated by both metabolism and renal excretion. Atorvastatin shows the longest terminal half-life (11-14 h vs. 1-3 h). Pharmacokinetic interactions with statins are very likely to occur, particularly for those statins that are CYP3A4 substrates. However, although of extreme interest in clinical practice, this subject was extensively reviewed in a previous article and therefore is not discussed here.
TL;DR: The effect of statins on LDL partially explains the reduction of plasma oxysterol level, and 3 statins and a nonstatin hypolipidemic agent on plasma levels of 24S-hydroxycholesterol and apo E in patients with AD are examined.
Abstract: Background The statin treatment of dyslipidemia is associated with a reduced risk of development of Alzheimer disease (AD). The effect may be mediated by a reduction in cholesterol biosynthesis in the brain, by lowering levels of apolipoprotein E (apo E)–containing lipoproteins, or by pleitropic effects such as reduction in β-amyloid production. In the brain, cholesterol from damaged or dying neurons is converted to 24S-hydroxycholesterol by cholesterol 24-hydroxylase (CYP46). The oxysterol is subsequently transferred across the blood-brain barrier, transported to the liver by low-density lipoproteins (LDLs), and excreted as bile acids. Most of plasma 24S-hydroxycholesterol is derived from brain cholesterol; consequently, plasma levels of the oxysterol reflect brain cholesterol catabolism. Objective To examine the effect of 3 statins and a nonstatin hypolipidemic agent on plasma levels of 24S-hydroxycholesterol and apo E in patients with AD. Study Design The study had a sequential parallel design. It was open-labeled and involved lipoprotein and 24S-hydroxycholesterol evaluations at baseline and at 6 weeks of treatment with 40 mg of lovastatin, simvastatin, or pravastatin sodium per day, or 1 g of extended-release niacin per day. Blood samples were drawn after a 12-hour fast for measurement of plasma sterols, oxysterols, lipoprotein cholesterol, and levels of apo E, plasma transaminases, and glucose. Measurements were made at baseline and during treatment. Results Statin treatment reduced levels of plasma lathosterol by 49.5%, 24S-hydroxycholesterol by 21.4%, LDL cholesterol by 34.9%, and total cholesterol by 25%. The ratios of lathosterol-campesterol and 24S-hydroxycholesterol–LDL cholesterol were reduced significantly, but the ratio of 24S-hydroxycholesterol–total cholesterol was unchanged. Extended-release niacin also significantly reduced levels of 24S-hydroxycholesterol by 10% and LDL cholesterol by 18.1%. None of the agents lowered plasma concentration of apo E. Conclusions Statins lowered levels of plasma 24S-hydroxycholesterol without affecting levels of apo E. The LDL lowering was more pronounced than 24S-hydroxycholesterol reductions. The effect of statins on LDL partially explains the reduction of plasma oxysterol level.
TL;DR: Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simVastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either ator Vastatin or simvastsatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).
Abstract: This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol <45 mg/dl in men and <50 mg/dl in women) were randomized to atorvastatin, simvastatin, or niacin ER/lovastatin for 16 weeks. The primary efficacy variables were the mean percent change in LDL cholesterol and HDL cholesterol levels from baseline. After 8 weeks, the starting dose niacin ER/lovastatin 1,000/40 mg and the 10-mg starting dose atorvastatin both lowered mean LDL cholesterol by 38%. After 12 weeks, niacin ER/lovastatin 1,000/40 mg lowered LDL cholesterol by 42% versus 34% with the 20-mg starting dose of simvastatin (p <0.001). Niacin ER/lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses (p <0.001). Niacin ER/lovastatin also provided significant improvements in triglycerides, lipoprotein(a), apolipoprotein A-1, apolipoprotein B, and HDL subfractions. A total of 6% of study subjects receiving niacin ER/lovastatin withdrew because of flushing. No significant differences were seen among study groups in discontinuance due to elevated liver enzymes. No drug-induced myopathy was observed. Niacin ER/lovastatin was comparable to atorvastatin 10 mg and more effective than simvastatin 20 mg in reducing LDL cholesterol, was more effective in increasing HDL cholesterol than either atorvastatin or simvastatin, and provided greater global improvements in non-HDL cholesterol, triglycerides, and lipoprotein(a).
TL;DR: Dietary cinnamate inhibits hepatic HMG-CoA reductase activity, resulting in lower hepatic cholesterol content, and suppresses lipid peroxidation via enhancement of hepatic antioxidant enzyme activities.
Abstract: This study investigated the effect of cinnamate, a phenolic compound found in cinnamon bark and other plant materials, on lipid metabolism and antioxidant enzyme activities in rats fed a high cholesterol diet. Three groups of rats were given a diet containing 1 g of cholesterol/kg for 6 weeks. The control group only received the high cholesterol diet, whereas the other two groups received a diet supplemented with lovastatin or cinnamate (0.1 g/100 g of diet). The plasma high-density lipoprotein-cholesterol levels were significantly higher in the cinnamate group than in either the control or lovastatin groups, and the atherogenic index was significantly lower in rats with cinnamate supplementation. Supplementation with cinnamate resulted in significantly lower hepatic cholesterol and triglyceride levels. Accumulation of hepatic lipid droplets was higher in the control group than in the rats supplemented with either cinnamate or lovastatin. Hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity...
01 Sep 2003
TL;DR: The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
Abstract: OBJECTIVE The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation. METHODS Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed. RESULTS All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression. CONCLUSIONS The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
TL;DR: It is shown that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis, and the results imply that protein Geranylgeranylation is critical for regulatingMyeloma tumor cell survival, possibly through regulating Mcl-1 expression.
TL;DR: Lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice, suggesting that low plasma cholesterol levels might be a risk factor for AD in females.
TL;DR: Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets.
Abstract: Aims High plasma cholesterol concentration and increased platelet activity are two major risk factors for atherosclerosis. Lovastatin, the lipophilic drug was shown to inhibit platelet aggregation whereas pravastatin, the hydrophilic drug had no such effect. Analysis of the effect of fluvastatin which is both a lipophilic and hydrophilic drug, on platelet aggregation was the goal of the present study.
Methods Fluvastatin 40 mg daily was administered to 25 patients with hypercholesterolaemia for up to 24 weeks. Normal subjects acted as controls. The influence of fluvastatin on plasma lipids and on platelet aggregation and fluidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins.
Results Fluvastatin therapy (40 mg day−1 for a period of 4 weeks) in hypercholesterolaemic patients resulted in a 23% and 29% reduction in plasma levels of total cholesterol and LDL-cholesterol respectively. Platelet cholesterol/phospholipids molar ratio was reduced by 26% and platelet aggregation was significantly (P 3H]-labeled-fluvastatin from its binding sites on platelets.
Conclusions Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets. The antiatherogenicity of fluvastatin may be related, in addition to its plasma cholesterol lowering ability, to its inhibitory effect on platelet activation.
TL;DR: The data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.
Abstract: Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.
TL;DR: The data suggest that lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
Abstract: Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 microM lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the lovastatin-treated ARO cells. To support this notion, we demonstrate that lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. In conclusion, our data suggest that lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
TL;DR: Data suggest that statins may have clinical significance in the primary prevention of human breast cancer beyond their cholesterol-lowering effect, however, clinical proof must be awaited before drawing any further conclusions.
Abstract: The effect of five statins, i.e. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin was investigated on the proliferation of the human breast cancer cell line MCF-7. All statins except of pravastatin were able to inhibit cell proliferation up to 90 % at a concentration of 50 micro M. Between the effective statins no significant difference was observed indicating a class-specific effect. These data suggest that statins may have clinical significance in the primary prevention of human breast cancer beyond their cholesterol-lowering effect. However, clinical proof must be awaited before drawing any further conclusions.
TL;DR: The results suggest that as lovastatin exerts an inhibitory effect on the development of early mammary lesions of mammary carcinogenesis, this compound may be useful for the chemoprevention of Mammary cancer and might have utility as an adjuvant in breast cancer therapy.
Abstract: The effects of lovastatin, a potent inhibitor of HMG CoA reductase, on experimental mammary and prostate oncogenesis, were studied in vitro and in vivo. Lovastatin inhibited cell growth in vitro in a dose-dependent manner for both mammary and prostate cancer cell lines, which was associated with p53-independent apoptosis. Flow cytometric analyses of lovastatin-treated mammary and prostate cancer cells demonstrated cell-cycle G(1) arrest, as well as decreases in S and G(2)/M fractions. p21(Waf1) and p27(Kip1) were induced by lovastatin in both types of cancer cells. Gene expression profiling of cells treated with lovastatin, however, was remarkable for a paucity of transcriptional changes induced by lovastatin. Treatment with lovastatin for 4 weeks did inhibit the formation of pre-neoplastic mammary intraepithelial neoplasias (MIN) in vivo, but not invasive carcinomas in the C3(1)/SV40 TAg transgenic model of mammary cancer. The decreased multiplicity of MIN lesions was associated with increased levels of apoptosis in these lesions. However, cell proliferation in the mammary lesions was not significantly different between lovastatin-treated and control mice 1 day after lovastatin treatment. In female mice treated with lovastatin for 12 weeks, there was a tendency for reduced tumor volume, which did not reach statistical significance. However, lovastatin did not suppress any lesion formation in the prostate of C3(1)/SV40 TAg transgenic male mice. Our results suggest that as lovastatin exerts an inhibitory effect on the development of early mammary lesions of mammary carcinogenesis, this compound may be useful for the chemoprevention of mammary cancer and might have utility as an adjuvant in breast cancer therapy. The chemopreventive effects of lovastatin in vivo, however, may be tissue-specific.
TL;DR: Seven patients with the relapsing-remitting MS after 12 months of therapy with lovastatin show that the Kurtzke Expanded Disability Status Scale (EDSS) score was unchanged in 6 patients and improved one point in another patient after treatment and lower post-treatment total cholesterol levels provide evidence of compliance with therapy.
Abstract: Sirs: In the last few years many studies have demonstrated that statins, in addition to their lipidlowering effects, have anti-inflammatory and immunomodulatory properties [1]. These properties of statins have suggested that they could have beneficial effects in immune mediated neurological disorders [2, 3]. In particular, lovastatin has been shown to inhibit the induction of inducible nitric oxide synthase and proinflammatory cytokines in rat astrocytes, microglia and macrophages [2] and to repress MHC-II mediated T-cell activation [3]. Moreover, lovastatin treatment decreased neuroinflammatory activity and clinical signs in experimental allergic encephalomyelitis, an animal model for multiple sclerosis (MS) [4]. On the basis of these findings we have begun to investigate whether lovastatin could be a treatment option for MS patients. We report the results observed on seven patients with the relapsing-remitting MS after 12 months of therapy with lovastatin. The study was designed as a one-center, open-label non placebo-controlled trial. All the subjects were recruited and treated on an outpatient basis, at the MS clinic of the Neurology Service of a general hospital. None of the patients was on any immunossuppressive or immunomodulating therapy and none received these agents during lovastatin treatment. The study was approved by the ethical committee of our Hospital and a written informed consent was provided from all patients. Our cohort consisted in women (age between 24 and 45 years) with a mean disease duration of 4.61 ± 2.16 years and clinical evidence of disease activity as measured by at least two relapses within the previous 2 years. Each subject was treated with 20 mg of lovastatin per day for one month and the dose was increased to 40 mg per day if no adverse effects were noted. A clinical examination and hematology and biochemical tests (including the plasma lipid profile and creatine kinase) were performed at baseline and every 3 months. Brain MRI was performed at baseline and every 6 months. During the follow-up, all clinical evaluations were done without knowledge of the neuroradiological results. No adverse events associated with therapy were observed. Our results (Table) show that the Kurtzke Expanded Disability Status Scale (EDSS) score was unchanged in 6 patients and improved one point in another patient after treatment. Three patients were free of relapses during therapy and for the whole group the mean annual relapse rate decreased during this period. In four patients there was a reduction of the inflammatory activity of the disease after treatment in comparison to baseline, as assessed by the number of gadolinium (Gd)-enhanced T1 lesions on MRI. One patient did not have active lesions at baseline and two enhanced lesions were seen at the end of the study. In five patients, the number of lesions on T2-weighted images increased after treatment. Lower post-treatment total cholesterol levels provide evidence of compliance with therapy. The results from this short pilot LETTER TO THE EDITORS
TL;DR: Results suggest that inhibition of iNOS gene expression by statins can be attributed to interference with protein isoprenylation, which mediates both NF-kappa B and STAT1 activation in the upstream signaling pathways for iN OS gene transcription.
Abstract: The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are potent inhibitors of cholesterol synthesis and have wide therapeutic use in cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their action on serum cholesterol levels. In this study, we investigated the effects of lovastatin, pravastatin, atorvastatin and fluvastatin on macrophage formation of nitric oxide (NO) in murine RAW 264.7 cells. Stimulation of macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) resulted in inducible NO synthase (iNOS) expression, which was accompanied by a large amount of NO formation. At concentrations of 0.1–30 µM, statins can inhibit stimuli-induced NO formation and iNOS induction to different extents. This inhibition occurs at the transcriptional level, and displays potency in the order of lovastatin > atorvastatin > fluvastatin >> pravastatin. We found that LPS-induced IκB kinase and nuclear factor-κB (NF-κB) activation, as well as IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation, were reduced by lovastatin. Moreover, inhibition by lovastatin of NO production and κB activation was reversed by mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. All these results suggest that inhibition of iNOS gene expression by statins can be attributed to interference with protein isoprenylation, which mediates both NF-κB and STAT1 activation in the upstream signaling pathways for iNOS gene transcription.
TL;DR: This 200-day treatment significantly reduced serum triglycerides and atherosclerotic index (ratio of non-HDL-cholesterol to HDL-ch cholesterol) and Severity of atherosclerosis was reduced significantly in all treatment groups.
Abstract: Long-term effects of Cholestin (Monascus purpureus rice; red yeast rice) on serum lipids and severity of atherosclerosis were examined in rabbits fed for 200 days on a semi-purified diet containing 0.25% cholesterol. Serum total cholesterol was 25 and 40% lower, respectively, in rabbits fed 0.4 or 1.35 g/kg/day of Cholestin (Monascus purpureus rice; red yeast rice) compared to controls. This treatment also lowered serum LDL cholesterol. This 200-day treatment significantly reduced serum triglycerides and atherosclerotic index (ratio of non-HDL-cholesterol to HDL-cholesterol). Although similar reductions of total, LDL-cholesterol and triglycerides were observed, a parallel group of rabbits fed lovastatin (0.0024 g/kg/day) failed to reduce the index significantly. Apolipoprotein A(1) was increased and apolipoprotein B was reduced in all treatment groups. Severity of atherosclerosis was reduced significantly in all treatment groups. The sudanophilic area of involvement was 80.6% in controls, and reduced significantly; to 30.1% on the low dose of Cholestin (Monascus purpureus rice; red yeast rice), and 17.2% on the high dose. Lovastatin reduced severity of lesions by 89% (sudanophilia) and 84% (visual). Visual grading of lesion severity showed reduction by 38% and 68%.
Journal Article•
TL;DR: In the present study, 110 fungal strains of Persian Type Culture Collection including some selected strains isolated in various screening projects were tested for their potentiality to produce lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis.
Abstract: In the present study, 110 fungal strains of Persian Type Culture Collection (PTCC) including some selected strains isolated in various screening projects were tested for their potentiality to produce lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting enzyme of cholesterol biosynthesis. The fungal strains were cultivated in a twostage submerged fermentation followed by screening by TLC. All positive results were evaluated by confirmatory HPLC. Nine species of four genera were found to be lovastatin producers. Aspergillus terreus was the best lovastatin producing strain with a level of 55 mg lovastatin per liter of screening production medium. Iran. Biomed. J. 7 (1): 29-33, 2003
Journal Article•
TL;DR: The data indicate that lovastatin inhibits osteoclast development through inhibition of geranylgeranylation of key prenylated proteins and that the bone effects of statins are at least partially due to their effects on osteoclasts numbers.
Abstract: HMG-CoA reductase inhibitor (statin) treatment is frontline therapy for lowering plasma cholesterol levels in patients with hyperlipidemia. In a few case studies, analysis of clinical data has revealed a decreased risk of fracture in patients on statin therapy. However, this reduction in the incidence of fracture is not always observed nor is it supported by an increase in bone density, which further complicates our understanding of the role of statins in bone metabolism. Thus, the precise role of statins in bone metabolism remains poorly understood. In this study, we examined the effect of statin treatment on osteoclastogenesis. Treatment with lovastatin resulted in a significant, dose-dependent decrease in the numbers of differentiated osteoclasts and decreased cholesterol biosynthesis activity with an EC(50) similar to that observed in freshly isolated rat or cultured human liver cells. Studies assessing the role of mevalonate metabolites in the development of the osteoclasts demonstrated that geranylgeraniol, but not squalene or farnesol was important for the development and differentiation of osteoclasts, implicating protein geranylgeranylation rather than protein farnesylation as a key factor in the osteoclast differentiation process. In conclusion, our data indicate that lovastatin inhibits osteoclast development through inhibition of geranylgeranylation of key prenylated proteins and that the bone effects of statins are at least partially due to their effects on osteoclast numbers.