Statins, by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decrease the synthesis not only of cholesterol but also of nonsteroidal mevalonate derivatives. While the first effect translates into plasma cholesterol reductions, the second is related to nonlipid-lowering (pleiotropic) properties. Purpose of this review is to assess the correlation between differences in statin structures and clinical effects. While the cardiovascular benefits of statin chronic therapy are achieved by lowering low-density lipoprotein cholesterol (LDL-C) and should be considered a class effect, the acute ones may reflect structure differences and pleiotropic properties of these drugs.
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Eight weeks-old apoE(-/-) mice were fed a Western-type diet. Vulnerable atherosclerotic lesions were formed in the branchiocephalic artery at the age of 30-weeks, before simvastatin administration for 8 weeks. Simvastatin did neither affect the levels of plasma glucose and lipids, nor the size of atherosclerotic lesions. Analysis of plaque composition showed that simvastatin decreased the area of lipid core and increased the amounts of macrophages and smooth muscle cells in atherosclerotic plaques of apoE(-/-) mice. In addition, simvastatin down-regulated the expression of vascular cell adhesion molecule-1 (VCAM-1) by both inhibition of nuclear factor kappa B (NF-кB) activation and suppression of the expression of the receptor for advanced glycation end products (RAGE). Moreover, we found that simvastatin administration led to reduced TUNEL-positive cells in the aortic root lesions, accompanied by up-regulation of Bcl-2 and Bcl-xL expression, and decreased P(53) expression as shown by Western blot.
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The expression of OATP2B1 was analyzed in 46 human atrial and 15 ventricular samples, including samples from hearts with dilated cardiomyopathy and hearts with ischemic cardiomyopathy.
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Statins are commonly prescribed for cardiovascular diseases which have been reported to share many contributory underlying mechanisms with erectile dysfunction (ED). However, the correlation between statin use and incident ED is uncertain.
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Vascular dementia (VaD) is a degenerative cerebrovascular disorder that leads to progressive decline in cognitive abilities and memory. Several reports demonstrated that oxidative stress and endothelial dysfunction are principal pathogenic factors in VaD. The present study was constructed to determine the possible neuroprotective effects of simvastatin in comparison with cilostazol in VaD induced by L-methionine in rats. Male Wistar rats were divided into four groups. Group I (control group), group II received L-methionine (1.7 g/kg, p.o.) for 32 days. The remaining two groups received simvastatin (50 mg/kg, p.o.) and cilostazol (100 mg/kg, p.o.), respectively, for 32 days after induction of VaD by L-methionine. Subsequently, rats were tested for cognitive performance using Morris water maze test then sacrificed for biochemical and histopathological assays. L-methionine induced VaD reflected by alterations in rats' behavior as well as the estimated neurotransmitters, acetylcholinesterase activity as well as increased brain oxidative stress and inflammation parallel to histopathological changes in brain tissue. Treatment of rats with simvastatin ameliorated L-methionine-induced behavioral, neurochemical, and histological changes in a manner comparable to cilostazol. Simvastatin may be regarded as a potential therapeutic strategy for the treatment of VaD. To the best of our knowledge, this is the first study to reveal the neuroprotective effects of simvastatin or cilostazol in L-methionine-induced VaD. Graphical Abstract ᅟ.
Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.
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An experimental randomised control study was conducted on seventy five male albino rats, divided into five groups labelled A, B, C, D and E with fifteen rats in each group. Group A was kept as normal control, groups B, C, D and E were given hyperlipidaemic diet for six weeks. In group B no further intervention was done, group C and group D were given ethanolic extract of Eugenia Jambolana and Simvastatin respectively for eight weeks. Group E was given combination of both for same duration. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were measured at zero, six and fourteen weeks.
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We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
Diabetes mellitus is associated with a variety of complications, including alterations in the central nervous system (CNS). We have recently shown that diabetes results in a reduction of cholesterol synthesis in the brain due to decreased insulin stimulation of SREBP2-mediated cholesterol synthesis in neuronal and glial cells. In the present study, we explored the effects of the decrease in cholesterol on neuronal cell function using GT1-7 hypothalamic cells subjected to cholesterol depletion in vitro using three independent methods: 1) exposure to methyl-β-cyclodextrin, 2) treatment with the HMG-CoA reductase inhibitor simvastatin, and 3) shRNA-mediated knockdown of SREBP2. All three methods produced 20-31% reductions in cellular cholesterol content, similar to the decrease in cholesterol synthesis observed in diabetes. All cholesterol-depleted neuron-derived cells, independent of the method of reduction, exhibited decreased phosphorylation/activation of IRS-1 and AKT following stimulation by insulin, insulin-like growth factor-1, or the neurotrophins (NGF and BDNF). ERK phosphorylation/activation was also decreased after methyl-β-cyclodextrin and statin treatment but increased in cells following SREBP2 knockdown. In addition, apoptosis in the presence of amyloid-β was increased. Reduction in cellular cholesterol also resulted in increased basal autophagy and impairment of induction of autophagy by glucose deprivation. Together, these data indicate that a reduction in neuron-derived cholesterol content, similar to that observed in diabetic brain, creates a state of insulin and growth factor resistance that could contribute to CNS-related complications of diabetes, including increased risk of neurodegenerative diseases, such as Alzheimer disease.
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Statins exhibit neuroprotective effects after spinal cord injury (SCI). However, the molecular mechanism underlying these effects remains unknown. This study demonstrates that the hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin (Simv) exhibits neuroprotective effects on neuronal apoptosis and supports functional recovery in a rat SCI model by activating the Wnt/β-catenin signaling pathway. In specific, Simv administration after SCI significantly up-regulated the expression of low density lipoprotein receptor-related protein 6 phosphorylation and β-catenin protein, increased the mRNA expression of lymphoid enhancer factor-1 and T-cell factor-1, and suppressed the expression of β-catenin phosphorylation in the spinal cord neurons. Simv enhanced motor neuronal survival in the spinal cord anterior horn and decreased the lesion of spinal cord tissues after SCI. Simv administration after SCI also evidently reduced the expression levels of Bax, active caspase-3, and active caspase-9 in the spinal cord neurons and the proportion of transferase UTP nick end labeling (TUNEL)-positive neuron cells, but increased the expression level of Bcl-2 in the spinal cord neurons. However, the anti-apoptotic effects of Simv were reduced in cultured spinal cord nerve cells when the Wnt/β-catenin signaling pathway was suppressed in the lipopolysaccharide-induced model. Furthermore, the Basso, Beattie, and Bresnahan scores indicated that Simv treatment significantly improved the locomotor functions of rats after SCI. This study is the first to report that Simv exerts neuroprotective effects by reducing neuronal apoptosis, and promoting functional and pathological recovery after SCI by activating the Wnt/β-catenin signaling pathway. We verified the neuroprotective properties associated with simvastatin following spinal cord injury (SCI). Simvastatin reduced neuronal apoptosis, improved the functional and pathological recovery via activating Wnt/β-catenin signal pathway, however, the anti-apoptosis effects of simvastatin were reversed following suppressing Wnt/β-catenin signaling pathway in primary spinal cord neurons. The significant findings may provide clinical therapeutic value of simvastatin for treating SCI.
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To analyze pomegranate extract (POMx) effects on serum and on human HMDM atherogenicity in simvastatin - treated hypercholesterolemic patients.
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Adopting randomized, parallel and controlled trail method, a total of 70 DM-HL patients of qi-yin deficiency and phlegm-blood stagnant syndrome type were randomized into two groups. The original medication for lowering blood sugar and blood pressure was unchanged, the trial group received oral administration of NZC 5 tablets, 3 times a day, while the control group received Lipanthgl or Simvastatin depending on their different constituents of blood lipids. After 6 months of treatment, sixty subjects completed the trail while two patients dropped out due to side effect and 8 patients lost follow-up (4 in each group). Levels of blood lipids, blood routine, liver and kidney function and symptoms in patients were detected and compared.
In the rat model of nonalcoholic fatty liver fibrosis, the extent of pathological changes in hepatic tissues correlated with severity of disease progression. The levels of serum TC, TG, ALT, AST and TNFa were increased significantly in model rats (vs. healthy controls; all, P less than 0.01). AMPKa mRNA expression and activity was significantly decreased in model rats (vs. healthy controls; P less than 0.01 and P less than 0.05, respectively). Simvastatin, treatment significantly improved all of these parameters in model rats (vs. untreated model rats; all, P less than 0.05). In vitro simvastatin treatment of human HSCs significantly increased AMPKa activity (quiescent LX-2: 0.93+/-0.10 vs. 0.72+/-0.09, activated LX-2: 0.72+/-0.10 vs. 0.54+/-0.10, q=7.00, 6.00; all, P less than 0.01), decreased a-smooth muscle actin expression (mRNA: 0.30+/-0.02 vs. 0.36+/-0.02, protein: 0.30+/-0.03 vs. 0.38+/-0.02, q=11.245, 11.216; all, P less than 0.01), and decreased collagen I expression (mRNA: 0.30+/-0.03 vs. 0.37+/-0.03, protein: 0.25+/-0.03 vs. 0.33+/-0.03, q=8.791, 11.163; all, P less than 0.01).
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Forty Kunming mice were randomized into 5 equal groups, and were given intragastric administration with distilled water (control), lipid emulsion (LE) at the daily dose of 5 ml/kg, LE plus simvastatin, LE plus DSC at 5.0 g/kg (DSC-L group), and LE plus DSC at 10.0 g/kg (DSC-H group), respectively. Serum TC, TG, and HDL-c levels and left femur hydroxyproline, calcium and phosphate contents were measured in the rats, with the right femur taken for bone biomechanical test.
The extent of reporting of adverse events to FDA varied by statin and may be influenced by publicity. For statins-associated rhabdomyolysis, the estimated extent of reporting appears to range from 5 to 30% but in the absence of stimulated reporting appears to be 5-15%.
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Simvastatin (SMV) assists in bone regeneration and has an anti-inflammatory effect when delivered or applied locally. The present clinical trial is designed to investigate the effectiveness of 1.2-mg SMV as a local drug delivery system as an adjunct to scaling and root planing (SRP) for the treatment of Class II furcation defects.
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The in vitro effect of the hydrophilic statin - pravastatin - and three hydrophobic statins - atorvastatin, lovastatin and simvastatin - on the production of IL-1beta, IL-1ra, IL-2, IL-6 and IFN-gamma by human peripheral blood mononuclear cells (PBMC) and their response to mitogens was examined. Lovastatin and simvastatin increased the production of IL-1beta in a dose dependent manner and reduced secretion of IL-1ra at high concentration. These two statins exerted a dose dependent inhibitory effect on IL-2 production and reduced the secretion of IFNgamma at high dose. Atorvastatin did not affect IL-1beta, but suppressed IL-1ra, IL-2 and IFNgamma production. Atorvastatin, lovastatin and simvastatin caused a dose dependent inhibition of mitogen-induced proliferation of PBMC. IL-6 production was not affected by any one of the statins. While pravastatin caused a slight reduction in the proliferative response of PBMC to PHA, it did not affect either their response to Con A and PWM, or the secretion of cytokines tested.
The clinical efficacy and tolerability of simvastatin and fluvastatin were compared in 432 patients with primary hypercholesterolaemia in a multinational, randomised, double-blind trial. Following at least 10 weeks on a lipid-lowering diet, patients continuing to have a total cholesterol level ≥ 6.5 mmol/L and elevated low density lipoprotein (LDL) cholesterol levels received 6 weeks of once-daily treatment with either simvastatin 5mg (n = 109), simvastatin 10mg (n =110), fluvastatin 20mg (n = 105), or fluvastatin 40mg (n = 108). The relative potency rates of simvastatin to fluvastatin in reducing LDL and total cholesterol levels were estimated to be 7.60 and 7.65, respectively. Significantly greater mean reductions in LDL cholesterol levels were found at week 6 with simvastatin 10mg (30%) compared with either fluvastatin 20mg (22%; p < 0.001) or fluvastatin 40mg (26%; p = 0.03). Similarly, LDL cholesterol was lowered more in the simvastatin 5mg group (26%) than in the fluvastatin 20mg group (22%; p = 0.03). No significant difference was seen between simvastatin 5mg and fluvastatin 40mg. Plasma total cholesterol levels were also significantly lower with simvastatin 10mg compared with fluvastatin 20mg (23 vs 16%; p < 0.001) and fluvastatin 40mg (23 vs 19%; p = 0.02), and with simvastatin 5mg compared with fluvastatin 20mg (19 vs 16%; p = 0.01). Simvastatin 5mg and fluvastatin 40mg both lowered total cholesterol levels by 19%. The percentage of patients reaching National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) target LDL cholesterol levels after 6 weeks' treatment with simvastatin 5 or 10 mg/day or fluvastatin 20 or 40 mg/day was 24, 25, 12 and 21%, respectively. Tolerability profiles were generally similar, although significantly more gastrointestinal adverse events occurred in the fluvastatin-treated patients (23 vs 11%). In conclusion, simvastatin 10 mg/day is more effective in lowering total and LDL cholesterol levels than the maximum recommended dose of fluvastatin (40 mg/day), whereas simvastatin 5 mg/day and fluvastatin 40 mg/day showed similar efficacy.
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Nonunion of fractured bones is a common clinical problem for orthopedic surgeons. This study aimed to investigate the effects of simvastatin locally applied from calcium sulfate (CS) combined with a mesenchymal stem cell (MSC) sheet on fracture healing. In vitro, the proliferation and differentiation of rat bone marrow-derived MSCs stimulated by simvastatin were investigated. In vivo, an osteotomy model was made in rat tibia, and fractured tibias were treated with CS, CS/simvastatin, CS/MSC sheet or simvastatin-loaded CS with MSC or untreated (control). Tibias were harvested at 2 or 8 weeks and underwent real-time quantitative polymerase chain reaction, x-ray, micro-CT and histological analysis. The expression levels of bone morphogenetic protein 2, alkaline phosphatase, osteocalcin, osteoprotegerin and vascular endothelial growth factor of simvastatin-induced MSCs increased with the concentrations of the simvastatin, significantly higher than those in the MSCs group. At 2 weeks, the CS/simvastatin/MSC sheet group showed significantly higher expressions of bone morphogenetic protein 2, alkaline phosphatase, osteocalcin, osteoprotegerin and vascular endothelial growth factor, with more callus formation around the fracture site compared with the other four groups. At 8 weeks, complete bone union was obtained in the CS/simvastatin/MSC sheet group. By contrast, newly regenerated bone tissue partially bridged the gap in the CS/simvastatin group and the CS/MSC sheet group; the control and CS group showed nonunion of the tibia. These results show that both simvastatin and the MSC sheet contributed to the formation of new bone and that the tibia fracture was completely healed by transplantation of the MSC sheet with locally applied simvastatin. Such MSC sheet with locally applied simvastatin might contribute to the treatment of fractures, bone delayed unions or nonunions in clinical practice.
NS398, a selective cyclooxygenase-2 inhibitor, and simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, both exert an anticancer effect on hepatocellular carcinoma cells, but the effect of co-administration of the two drugs remains unknown. We aimed to investigate the synergistic in vitro anticancer effect of co-administration of NS398 and simvastatin and its mechanism.
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Increased monocyte adherence to the vessel wall is one of the earliest events in atherosclerosis. The mechanism by which hypercholesterolemia causes alterations in endothelial adhesiveness for monocytes is unclear. This study sought to determine if monocyte adhesion molecule expression is affected by low-density lipoprotein (LDL)-cholesterol levels. Patients with hypercholesterolemia and stable coronary artery disease were compared with those without major cardiovascular risk (control). Patients with hypercholesterolemia were treated with simvastatin 20--40 mg/day for 8--10 weeks. Blood samples were examined with flow cytometry assays at baseline and after cholesterol-lowering therapy. Monocyte CD11b and CD14 adhesion molecule expression, measured as fluorescence intensity, were significantly (P<0.0001) higher in hypercholesterolemic patients before the study (176.9+/-9.8 and 138.0+/-4.8, respectively) when compared with that in control subjects (97.2+/-8.1 and 84.0+/-6.4, respectively). Both decreased markedly with treatment: to 118.8+/-6.9 and 103.1+/-3.9, respectively. Monocyte L-selectin expression was significantly lower in patients with hypercholesterolemia before treatment (43.0+/-3.0) when compared with control subjects (79.9+/-2.7), and it increased markedly with treatment (54.2+/-2.5). LDL levels correlated directly with both CD11b and CD14 expression and correlated inversely with L-selectin expression. These data show that hypercholesterolemia affects monocyte adhesion molecule expression which, in turn, decreases with statin-induced plasmatic cholesterol reduction. Such perturbations in monocyte function likely represent a proinflammatory response to hypercholesterolemia and may have a role in the early progression of atherogenesis.
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The present study aims to directly investigate the behavioral and antioxidant effects of simvastatin in a model of bipolar mania induced by lisdexamfetamine dimesylate. Wistar rats were treated for 30 days with simvastatin. On the 24th day after the start of treatment, each rat was administered lisdexamfetamine dimesylate for 7 days. The results suggest that simvastatin combined with lisdexamfetamine dimesylate induced a significant increased locomotion and lisdexamfetamine dimesylate administration causes an oxidative imbalance determined by an increment in lipid peroxidation, protein oxidation and alterations in the activities of antioxidant enzymes in brain areas; moreover, in the presence of simvastatin, most of these effects were prevented. These findings contribute to a better understanding of the critical roles of lisdexamfetamine dimesylate in the treatment of neuropsychiatric disorders, associated with increased oxidative stress and changes in antioxidant enzymatic defense. In view of the central role played by lisdexamfetamine dimesylate, the established antioxidant effect of simvastatin therapy is of major interest.
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Preclinical information on the biliary metabolites of a drug candidate is typically obtained through the collection of bile after surgical cannulation of the bile duct. In this study, we describe a novel approach using the Entero-Test, a simple device that facilitates the noninvasive sampling of duodenal bile. The Entero-Test was used to collect bile from six fasted dogs that had been dosed either orally with simvastatin (SV) or intravenously with simvastatin hydroxy acid (SVA), compounds that have been previously reported to undergo extensive metabolism and biliary secretion in the dog. The devices, consisting of a weighted gelatin capsule containing 90 cm of a highly absorbent nylon string, were swallowed by each dog with the proximal end of the string taped to the animal's face. Once the weighted string had reached the duodenum, gallbladder contraction was stimulated to release bile. Each bile-stained string was then retrieved via the mouth and, after solvent extraction, samples were analyzed for drug-related material by ultraperformance liquid chromatography-mass spectrometry and NMR spectroscopy. Numerous metabolites of SV and SVA were observed, and, in general, the major metabolites have been reported previously from studies with bile duct-cannulated animals dosed with [14C]SV or [14C]SVA. The results from this study demonstrate the utility of deploying the Entero-Test in absorption, distribution, metabolism, and elimination studies to provide information on the nature of biliary metabolites, which, on occasion, may be sufficient to negate the need for more invasive sampling techniques. The benefits and limitations of the technique are discussed.