Effects Of Simvastatin In Patients Research Articles

Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial

Immune dysregulation has been reported in schizophrenia spectrum disorders (SSD). In the past decade, several trials using anti-inflammatory agents for treatment of SSD have been completed, with so far limited success. One such anti-inflammatory agent used is simvastatin. A recent, large-scale, randomized controlled trial with simvastatin augmentation failed to show improvement in the predefined primary outcome. However, baseline inflammatory profiles were not taken into account. Here we employed a data-driven clustering approach to investigate whether patients with an inflammatory monocyte gene signature respond better to add-on simvastatin treatment than those without such a signature, over a treatment period of 2 years. In 61 patients (60 randomized, 1:1 placebo:simvastatin) and healthy controls, a previously validated monocyte gene expression signature was assessed using quantitative polymerase chain reaction. Resulting delta cycle threshold values were used to identify patient clusters. Two major patient clusters with either up- or downregulated pro-inflammatory factors were detected. Linear mixed models showed a significant three-way interaction between the inflammatory cluster, treatment, and time for psychotic symptoms. Only patients treated with simvastatin who were in the inflammatory group, showed a consistent improvement: symptom severity gradually decreased after 3 months and reached significance after 12 and 24 months compared to baseline (p.adj<0.05). The effects were small, and overall between-group effects were not significant. Here, we show that patient stratification based on inflammatory gene expression might be useful to select appropriate treatment augmentation for patients with SSD, highlighting the need for precision medicine approaches. Our findings corroborate the results of the primary analyses, showing that in the overall group, simvastatin was not effective; however, at the individual level the treatment might make a difference.

Pretreatment of simvastatin on liver trace element levels during endotoxemia

There are a number of studies investigating anti-inflammatory effects of simvastatin in patients with sepsis and animal models. There are a few studies which investigated effect of simvastatin on elements in sepsis. In the present study, the impact of pretreatment with simvastatin on element levels was evaluated in liver during endotoxemia. Rats were divided into control, LPS, simvastatin, and simvastatin + LPS. The histopathologic examination of the liver was performed using hematoxylin and eosin. Selenium, zinc, iron, manganese, magnesium, and copper were analyzed using inductively coupled plasma – optical emission spectroscopy. In the LPS, the hepatocyte cell structure was damaged. In the simvastatin + LPS, hepatocyte, and sinusoidal cord damage were partially smaller than LPS. Levels of selenium, and copper significantly decreased in both of LPS and simvastatin + LPS. In the LPS group, iron was found to increase. In the simvastatin + LPS, zinc was increased. Simvastatin partially smaller liver damage by increasing zinc levels during endotoxemia.

Anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage in an intensive care unit.

Intracerebral hemorrhage is one of the most common types of cerebrovascular disease in humans and often causes paralysis, a vegetative state and even death. Patients with acute intracerebral hemorrhage are frequently monitored in intensive care units (ICUs). Spontaneous intracerebral hemorrhage is associated with a higher rate of mortality and morbidity than other intracephalic diseases. The expression levels of inflammatory factors have important roles in inflammatory responses indicative of changes in a patient's condition and are therefore important in the monitoring and treatment of affected patients at the ICU as well as the development of therapeutic strategies for acute cerebral hemorrhage. The present study investigated the anti-inflammatory effects of Simvastatin in patients with acute intracerebral hemorrhage at an ICU, and inflammatory factors and cellular changes were systematically analyzed. The plasma concentrations of inflammatory factors, including interleukin (IL)-4, IL-6, IL-8 and IL-10, were evaluated by ELISAs. The plasma concentrations of inflammatory cellular changes were detected by using flow cytometry. The results demonstrated that after Simvastatin treatment of patients with acute cerebral hemorrhage at the ICU, the plasma concentrations of IL-4, IL-6, IL-8 and IL-10 were downregulated compared with those in placebo-treated controls. In addition, Simvastatin treatment at the ICU decreased lymphocytes, granulocytes and mononuclear cells in patients with acute cerebral hemorrhage. The levels of inflammatory factors were associated with brain edema in patients with acute cerebral hemorrhage treated at the ICU. In addition, the amount of bleeding was reduced in parallel with the inflammatory cell plasma concentration of lymphocytes, granulocytes and mononuclear cells. Importantly, Simvastatin treatment produced beneficial outcomes by improving brain edema and reducing the amount of bleeding. In conclusion, the present study demonstrated the efficacy of Simvastatin in treating acute intracerebral hemorrhage and evidenced the association between inflammatory responses and the progress of affected patients at the ICU, thereby providing insight for applying effective therapies for patients with acute intracerebral hemorrhage.

Reduced Apoptosis After Acute Myocardial Infarction by Simvastatin

To observe the effect of simvastatin in patients with acute myocardial infarction in rabbits against myocardial apoptosis, and to explore its possible mechanism. Male New Zealand white rabbits were randomized into three groups, including the myocardial infarction group (12 rabbits), the simvastatin treatment group (15 rabbits), and the sham group (12 rabbits). In the simvastatin treatment and myocardial infarction groups, the rabbits received myocardial infarction surgeries. While in the sham group, loose knots were tied in the left anterior descending coronary artery branches. The simvastatin treatment group was given simvastatin by oral gavage 24h after surgery. Parameters, which included left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left ventricular ejection fraction, and left ventricular mass index, were recorded in these three groups. Edge myocardial infarction and myocardial cell apoptosis were analyzed using TUNEL assay, and Bcl-2, Bax, and Caspase-3 protein levels were detected by Western blot. Acute myocardial infarction model was successfully established in rabbits by ligation of the left anterior descending coronary artery. Compared with the myocardial infarction group, left ventricular end-diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD) were significantly reduced and left ventricular ejection fraction (LVEF) increased in the simvastatin treatment group. Compared with the sham group, LVEDD and LVESD were significantly increased and LVEF decreased in the simvastatin treatment group. All the differences were statistically significant (P<0.05). Left ventricular mass index in the simvastatin treatment group was statistically lower than the myocardial infarction group. Compared with the sham group, left ventricular mass index in both the simvastatin treatment and myocardial infarction groups was significantly increased. The differences of the above comparisons were statistically significant (P<0.05). Compared with the sham group, the apoptosis rate of the myocardial infarction group and the simvastatin treatment groups was significantly increased as shown by TUNEL assay, however, the apoptosis rate of the simvastatin treatment group was significantly lower than that of the myocardial infarction group. All the differences among above comparisons were statistically significant (P<0.05). Bcl-2 levels significantly increased in the simvastatin treatment group compared with the myocardial infarction group, but Bcl-2 levels in both groups were significantly lower than the sham group. However, Bax protein levels showed inverse expression with Bcl-2. Meanwhile, Caspase-3 protein expression showed similar trend with Bcl-2. Simvastatin can improve cardiac function after myocardial infarction and reduce apoptosis of myocardial cells, possibly by decreasing Bax and Caspase-3 expression and increasing the expression level of Bcl-2.

Anti-inflammatory effects of simvastatin in patients with chronic heart failure.

Proinflammatory markers were evaluated in patients with chronic heart failure of ischemic origin and essential hypertension with preserved left-ventricular ejection fraction before and after a 6-month course of simvastatin therapy (20 mg/day). The study was carried out in 125 patients with diastolic dysfunction manifested as impaired relaxation and pseudonormalization. The main group received standard therapy for chronic heart failure and simvastatin, controls received only standard therapy. In addition, the results in the main group were compared in patients with different types of left-ventricular diastolic dysfunction. Simvastatin therapy significantly reduced the levels of C-reactive protein and IL-6.

Antioxidant effects of simvastatin in patients with coronary heart disease and dyslipidemia

Aim.To investigate the effects of simvastatin therapy on antioxidant enzyme activity and the correction of disturbed antioxidant status in patients with coronary heart disease (CHD) – post-infarction cardiosclerosis (PICS) – in combination with dyslipidemia (DLP).Material and methods.The study included 132 CHD patients with PICS and 20 healthy controls. All participants underwent the measurement of plasma levels of lipids, lipid peroxidation (LP) products – diene conjugates (DC) and 2-thiobarbituric acid reagents (TBAR), antioxidant enzymes – glutathione peroxidase (GP) and superoxide dismutase (SOD) in red blood cells, plasma activity of the antioxidant ceruloplasmin/transferrin system (AOS CP/TF) (electron paramagnetic resonance method), and 24-hour Holter monitoring of electrocardiogram (ECG).Results.The three-month simvastatin therapy (20 mg/day), as a component of the complex cardiac treatment, demonstrated its antioxidant effects and antiperoxidation activity in 60% of CHD patients. The subsequent therapy with 2-ethyl-6-methyl-3-hydroxypyridine sulphate (ES; 375 mg/day) and ubidecarenone (30 mg/ day) normalised the parameters of LP-antioxidant defence (AOD) and the levels of hepatic transaminases. Plasma AOS CP/TF activity inversely correlated with the duration of myocardial ischemia in CHD patients (r=-0,34; p=0,004).Conclusion.To optimise the treatment of atherogenic DLP in simvastatin-treated CHD patients, ubidecarenone and ES could be used to improve the LP-AOD parameters.

Monocyte-suppressing effects of simvastatin in patients with isolated hypertriglyceridemia

BackgroundNo previous study investigated statin action on monocyte cytokine release and systemic inflammation in patients with isolated hypertriglyceridemia. MethodsOur study included 43 subjects with isolated hypertriglyceridemia and peripheral artery stenosis randomly allocated to one of two groups, treated for 12weeks with either simvastatin (40mg twice daily) or placebo. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and monocyte cytokine release were determined on the day of allocation and at the end of the treatment period. ResultsSimvastatin, but not placebo, reduced monocyte release of tumor necrosis factor-α, interleukin-6, interleukin-1β and monocyte chemoattractant protein-1, as well decreased plasma levels of C-reactive protein. ConclusionsOur study shows that simvastatin reduces monocyte secretory function and has systemic anti-inflammatory properties in patients with isolated hypertriglyceridemia.

Effects of Simvastatin in Patients with Viral Chronic Hepatitis C

A geranyl-geranylated protein is synthesized during chronic hepatitis C virus replication; statins can inhibit this synthesis. We aimed at studying the effects of administrating simvastatin to patients who finished the standard antiviral therapy and who did not have hepatic cytolysis. A total of 101 patients were divided into 3 groups. Those without liver cytolysis were divided as follows: In group A1 patients were treated with simvastatin for 3 months and in group A2 the patients were non-treated controls. Those patients with hepatic cytolysis were placed in group B and treated for 3 months with simvastatin. The patients were biologically monitored monthly and the initial viremia was compared with the final one. The results were then statistically analysed. Significant changes of viremia were not observed in the patients from groups A1 and A2. In 24 patients in group B (58.54%) the viremia was significantly reduced (p=0.018), and in 6 patients (39.02%) it increased insignificantly. After 1 and 2 months of treatment, the cholesterolemy and the serum alkaline phosphatase significantly decreased to the patients from group B. In this study, more than half of the patients chronically infected with the hepatitis C virus, who had hepatic cytolysis and were treated with simvastatin, showed a significant reduction in the level of viremia.

The Effect of Simvastatin on Lymphocyte Secretory Function in Patients With Impaired Fasting Glucose

No previous study has determined the impact of statins on lymphocyte secretory function in patients with the early stages of glucose metabolism abnormalities. Our study aimed at assessing the strength of a lymphocyte-suppressing effect of simvastatin in patients with impaired fasting glucose with reference to its action in dyslipidemic subjects. Phytohemagglutinin-stimulated lymphocytes of impaired fasting glucose (n = 32) and hypercholesterolemic (n = 30) subjects produced more interleukin-2, interferon-g, and tumor necrosis factor-a than lymphocytes of 31 matched subjects with normal plasma lipids and glucose tolerance. Apart from lowering plasma lipids, in both treatment groups, simvastatin (40 mg daily) reduced lymphocyte cytokine release to the level observed in control subjects, which was accompanied by a decrease in plasma high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 levels. Our study shows that already at the early stages of glucose metabolism abnormalities, lymphocyte secretory function is disturbed to a similar degree as in hypercholesterolemia. Simvastatin is an effective lymphocyte-suppressing and anti-inflammatory agent irrespective of plasma lipid levels. The treatment-induced reduction in lymphocyte cytokine release and systemic inflammation may contribute to the clinical effectiveness of statins in the prevention and therapy of atherosclerosis in subjects with early glucose metabolism abnormalities and dyslipidemia.

Anti‐Inflammatory and Monocyte‐Suppressing Effects of Simvastatin in Patients with Impaired Fasting Glucose

The aim of our study was to compare the effect of simvastatin on systemic inflammation and monocyte secretory function between individuals with impaired fasting glucose (IFG) and patients with isolated hypercholesterolaemia. The study included 25 patients with IFG and 23 patients with hypercholesterolaemia. The lipid profile, fasting and 2-hr post-glucose load plasma glucose levels, homeostatic model assessment (HOMA) ratio, glycated haemoglobin, plasma high-sensitivity C-reactive protein (hsCRP) levels and monocyte release of TNF-α, interleukin-1β, interleukin-6 and MCP-1 were assessed at baseline, and after 30 and 90 days of simvastatin treatment (20 mg/daily). Compared to monocytes of the control patients (22 age-, sex- and weight-matched patients without lipid and glucose metabolism abnormalities), monocytes of the patients with hypercholesterolaemia and patients with IFG released greater amounts of all studied cytokines and exhibited higher plasma levels of hsCRP, with no difference between the two groups of patients. Although in both the patients with hypercholesterolaemia and the patients with IFG simvastatin treatment improved lipid profile, it exhibited no effect on glucose metabolism markers. The drug markedly reduced plasma hsCRP and monocyte secretion of TNF-α, interleukin-1β, interleukin-6 and MCP-1 in a lipid- and glucose-independent manner. Our results indicate that low-grade systemic inflammation and monocyte secretory function are disturbed to a similar degree in the patients with isolated hypercholesterolaemia and in the patients with IFG. They also show that simvastatin is an effective anti-inflammatory drug in patients with isolated early glucose metabolism abnormalities.

Biologic Effects of Simvastatin in Patients with Aneurysmal Subarachnoid Hemorrhage: A Double-Blind, Placebo-Controlled Randomized Trial

Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol (P<0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH.

Tissue factor +5466A>G polymorphism determines thrombin formation following vascular injury and thrombin-lowering effects of simvastatin in patients with ischemic heart disease

We examined the hypothesis that the +5466A>G variant (rs3917643) of the tissue factor (TF) gene is associated with thrombin formation following simvastatin in patients with ischemic heart disease (IHD). Prothrombin 1.2 fragments (F1.2) and thrombin-antithrombin complexes (TAT) were assessed in 95 men with stable IHD, aged 54.4+/-6.8 years, in blood collected every 60s from the bleeding-time wounds before and after a 3-month simvastatin administration (40 mg/day). We identified 16 patients with the TF +5466AG genotype and 79 subjects with the +5466AA genotype. Baseline maximum rates of F1.2 and TAT formation and their maximum levels at the site of vascular injury, but not in venous blood, were higher in +5466G allele carriers than in those with +5466AA genotype (P<0.0001). The magnitude of reduction in maximum rates of F1.2 and TAT formation following simvastatin was larger (P<0.001) in +5466G allele carriers than in +5466AA subjects. The degree of decrease in maximum local levels of F1.2 and TAT after simvastatin was similar in both genotype groups. The presence of the +5466G allele was independently associated with the maximum velocity of F1.2 and TAT generation and maximum levels of both markers before and after simvastatin in multiple regression models (P<0.01 for all analyses). Local thrombin generation, in +5466AG and +5466AA subjects, showed no significant correlations with lipid variables. Thrombin formation following vascular injury and thrombin-lowering effect of statins in patients with IHD are at least in part genetically determined by the TF +5466A>G polymorphism.

Clinical Effects of Simvastatin in Patients with Hypercholesterolemia

Background:To evaluate the clinical efficacy of Simvastatin, a HMG-CoA reductase inhibitor, we observed the changes of clinical characteristics and lipid profiles after Simvastatin administration in patients with hypercholesterolemia. Methods and Results:Simvastatin 10mg was given once daily for 12 weeks in 35 patients(60± 6.0 years;14 male, 21 female with hypercholesterolemia. High density lipoprotein-cholesterol(HDL- C was increased from 38±10 to 45±9mg/dl(p<0.05. Simvastatin significantly decreased total cho- lesterol(TC from 235±15 to 181±21mg/dl(23.0%, low-density lipoprotein cholesterol(LDL-C from 164±19 to 104±18mg/dl(36.5%, TC/HDL-C from 7.0±2.0 to 4.4±1.1, LDL-C/HDL-C from 4.9±1.7 to 2.5±0.8(p<0.01 respectively. Apo B was decreased by 31%(119±19 to 87±15mg/dl, apo B/A1 ratio was decreased by 41%(1.2±0.2 to 0.7±0.2 and lipoprotein(a decreased by 12%(33 ±22 to 29±17, while apo A1 was increased by 25%(104±18 to 130±23mg/dl, p<0.01 respectively. No patients complained of chest pain, but two had skin rashes. Creatine kinase and creatinine were not changed in all patients. Conclusions:Simvastatin is an effective and well tolerated cholesterol lowering agent in patients with hypercholesterolemia.

高コレステロール血症におけるHMG-CoA還元酵素阻害剤プラバスタチン投与時のエスケープ現象とシンバスタチンの効果

Although the hydroxymethylglutaryl coenzyme A reductase inhibitor is a powerful therapeutic agent in the treatment of hypercholesterolemia, an escape phenomenon has been reported. We sought to determine the effects of simvastatin in patients associated with the escape phenomenon following pravastatin therapy. Twenty-one patients with hypercholesterolemia (mean age:58;age range:25 to 75;seven men, 14 women) were studied. All patients had been given pravastatin (10mg/day) for at least 12 weeks. After the occurrence of the escape phenomenon, pravastatin was replaced by simvastatin (5mg/day). Serum lipids were measured periodically. Although total serum cholesterol levels showed significant decreases following pravastatin therapy (from 281±4mg/dl to 224±6mg/dl), such levels increased to 255±6mg/dl after 12 to 116 weeks. By replacing pravastatin with simvastatin, total serum cholesterol levels fell to 220±5mg/dl after 12 weeks and remained low (222±8mg/dl, n=13) even after 32 weeks. However, the total serum cholesterol levels tended to increase after 40 weeks. The serum LDL-cholesterol levels revealed changes that paralleled those of the total cholesterol levels, while serum HDL-cholesterol and the triglyceride levels did not reveal significant changes. These results suggest that simvastatin is a useful therapeutic alternative when the escape phenomenon occurs involving the use of pravastatin, although a similar phenomenon may occur even with simvastatin following long-term administration.

The Influence of Simvastatin on Adrenal Corticosteroid Production and Urinary Mevalonate during Adrenocorticotropin Stimulation in Patients with Heterozygous Familial Hypercholesterolemia*

The adrenal gland requires a continuous supply of cholesterol for the biosynthesis of adrenal corticosteroids, which can be supplied by low density lipoprotein receptor-mediated uptake or local synthesis. The present study examined whether hypolipidemic therapy with a potent HMG CoA reductase inhibitor, simvastatin, compromises the adrenal response to ACTH stimulation in adult patients with heterozygous familial hypercholesterolemia. The adrenal response to a 36-h continuous ACTH infusion was determined at baseline and after 2 months of simvastatin treatment (40 mg, twice daily) in eight patients. Simvastatin reduced total and low density lipoprotein cholesterol levels by 36% and 45%, respectively. The time course of the increase in serum cortisol concentrations with continuous ACTH infusion was the same before and during simvastatin therapy, as were the rates of urinary excretion of free cortisol, 17-hydroxycorticosteroids, and 17-ketosteroids. Urinary excretion of mevalonate, which correlates with rates of whole body cholesterol synthesis, decreased from 3.8 +/- 0.42 (+/- SEM) mu,ol/24 h at baseline to 2.75 +/- 0.56 on simvastatin; no significant changes were seen in the urinary mevalonate levels before and after simvastatin therapy during ACTH stimulation. We conclude that the hypolipidemic effects of simvastatin in patients with heterozygous familial hypercholesterolemia are paralleled by a decrease in urinary mevalonate, but that the drug does not adversely affect ACTH-stimulated adrenal corticosteroid production.