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1.
Pravastatin and Simvastatin Pretreatment in Combination with Pyrimethamine and Sulfadiazine Reduces Infection Process of Toxoplasma gondii Tachyzoites (RH Strain) in HeLa Cells.
Sanfelice, RADS, da Silva, SS, Bosqui, LR, Machado, LF, Miranda-Sapla, MM, Panagio, LA, Navarro, IT, Conchon-Costa, I, Pavanelli, WR, Almeida, RS, et al
Acta parasitologica. 2019;(3):612-616
Abstract
PURPOSE Toxoplasma gondii is a protozoan from phylum Apicomplexa, which causes the toxoplasmosis infection; this one exhibits an apicoplast organelle which assists in the metabolism of isoprenoids and other pivotal mediators for the parasite survival. Statins are drugs that inhibit cholesterol synthesis, blocking the conversion of the substrate HMG-CoA to mevalonate, thus preventing the initial processes of the biosynthesis of these precursors, both in humans and parasite. Our goal was to verify whether the Toxoplasma gondii (RH strain) tachyzoites form pretreated with pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations could affect the infection processes, suggesting direct action on protozoa intracellular proliferation through the inhibition of isoprenoids in the parasite's apicoplast. METHODS To have the adhesion, infection, and parasite proliferation during experimental infection investigated, HeLa cells (105) were subjected to a 24-hour infection by T. gondii tachyzoites forms of RH strain (5 × 105) pretreated for 30 min with pravastatin and/or simvastatin combined or not with pyrimethamine and sulfadiazine. RESULTS Combined with conventional drugs at low concentrations pravastatin and simvastatin inhibit the adhesion, invasion, and intracellular proliferation of T. gondii in HeLa cells which are similar to the positive control. CONCLUSION Pravastatin and simvastatin in association with pyrimethamine and sulfadiazine at low concentrations can be regarded as a promising, effective alternative to toxoplasmosis treatment with reduced side effects.
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2.
Statin Treatment Decreases Mitochondrial Respiration But Muscle Coenzyme Q10 Levels Are Unaltered: The LIFESTAT Study.
Dohlmann, TL, Morville, T, Kuhlman, AB, Chrøis, KM, Helge, JW, Dela, F, Larsen, S
The Journal of clinical endocrinology and metabolism. 2019;(7):2501-2508
Abstract
BACKGROUND Myalgia is a common adverse effect of statin therapy, but the underlying mechanism is unknown. Statins may reduce levels of coenzyme Q10 (CoQ10), which is an essential electron carrier in the mitochondrial electron transport system, thereby impairing mitochondrial respiratory function, potentially leading to myalgia. OBJECTIVES To investigate whether statin-induced myalgia is coupled to reduced intramuscular CoQ10 concentration and impaired mitochondrial respiratory function. METHODS Patients receiving simvastatin (i.e., statin) therapy (n = 64) were recruited, of whom 25 experienced myalgia (myalgic group) and 39 had no symptoms of myalgia (NS group). Another 20 had untreated high blood cholesterol levels (control group). Blood and muscle samples were obtained. Intramuscular CoQ10 concentration was measured, and mitochondrial respiratory function and reactive oxygen species (ROS) production were measured. Citrate synthase (CS) activity was used as a biomarker of mitochondrial content in skeletal muscle. RESULTS Intramuscular CoQ10 concentration was comparable among groups. Mitochondrial complex II-linked respiration was reduced in the statin-myalgic and -NS groups compared with the control group. When mitochondrial respiration was normalized to CS activity, respiration rate was higher in the myalgic group compared with the NS and control groups. Maximal ROS production was similar among groups. CONCLUSION Statin therapy appeared to impair mitochondrial complex-II-linked respiration, but the mitochondrial capacity for complex I+II-linked respiration remained intact. Myalgia was not coupled to reduced intramuscular CoQ10 levels. Intrinsic mitochondrial respiratory capacity was increased with statin-induced myalgia but not accompanied by increased ROS production.
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3.
Inflammatory biomarkers in patients in Simvastatin treatment: No effect of co-enzyme Q10 supplementation.
Hansen, M, Kuhlman, ACB, Sahl, RE, Kelly, B, Morville, T, Dohlmann, TL, Chrøis, KM, Larsen, S, Helge, JW, Dela, F
Cytokine. 2019;:393-399
Abstract
PURPOSE Atherosclerosis is a major risk factor for cardiovascular disease (CVD) and is known to be an inflammatory process. Statin therapy decreases both cholesterol and inflammation and is used in primary and secondary prevention of CVD. However, a statin induced decrease of plasma concentrations of the antioxidant coenzyme Q10 (CoQ10), may prevent the patients from reaching their optimal anti-inflammatory potential. Here, we studied the anti-inflammatory effect of Simvastatin therapy and CoQ10 supplementation. METHODS 35 patients in primary prevention with Simvastatin (40 mg/day) were randomized to receive oral CoQ10 supplementation (400 mg/d) or placebo for 8 weeks. 20 patients with hypercholesterolemia who received no cholesterol-lowering treatment was a control group. Plasma concentrations of lipids and inflammatory biomarkers (interleukin-6 (IL6); -8 (IL8); -10 (IL10), tumor necrosis factor-α (TNFα); high-sensitivity C reactive protein (hsCRP)) as well as glycated hemoglobin (HbA1c) were quantified before and after the intervention. RESULTS No significant change in inflammatory markers or lipids was observed after CoQ10 supplementation Patients in Simvastatin therapy had significantly (P < 0.05) lower baseline concentration of IL6 (0.31 ± 0.03 pg/ml), IL8 (1.6 ± 0.1 pg/ml) IL10 (0.16 ± 0.02 pg/ml) and borderline (P = 0.053) lower TNFα (0.88 ± 0.05 pg/ml), but not hsCRP (1.34 ± 0.19 mg/l) compared with the control group (0.62 ± 0.08, 2.6 ± 0.2, 0.25 ± 0.01, 1.07 ± 0.09, and 1.90 ± 0.35, respectively). CONCLUSIONS Simvastatin therapy has beneficial effects on inflammatory markers in plasma, but CoQ10 supplementation seems to have no additional potentiating effect in patients in primary prevention. In contrast, glucose homeostasis may improve with CoQ10 supplementation.
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4.
Effects of Simvastatin on Augmentation Index Are Transient: Outcomes From a Randomized Controlled Trial.
Gepner, AD, Lazar, K, Hulle, CV, Korcarz, CE, Asthana, S, Carlsson, CM
Journal of the American Heart Association. 2019;(20):e009792
Abstract
Background Statins improve endothelial function, but their effects on arterial stiffness and aortic blood pressure in middle-aged adults are uncertain. Methods and Results This was a prospective, randomized, double-blind, placebo-controlled trial of middle-aged (40-72 years old) adults who were randomly assigned to receive simvastatin 40 mg (n=44) or placebo (n=44) daily for 18 months to evaluate impact on dementia-related biomarkers (primary end points) and measures of vascular health (secondary end points). This analysis focuses on the predetermined secondary end points of changes in central aortic blood pressure, aortic augmentation index, and brachial artery flow-mediated dilation. Measurements were performed at baseline and after 6, 12, and 18 months. Multivariable models were used to identify predictors of these prespecified vascular end points. Study groups were similar at baseline; low-density lipoprotein cholesterol declined in the statin group but not in the placebo group (P<0.01). There were no significant differences in changes in central blood pressure parameters or flow-mediated dilation (all P>0.2). After 12 months, augmentation index decreased from baseline in the statin group compared with the placebo group (-2.3% [5.5%] versus 1.2% [5.7%], P=0.007), but by 18 months the response in both groups trend toward baseline (-1.1% [5.8%] versus 0.2% [4.8%], P=0.3). Low-density lipoprotein cholesterol was not associated with changes in augmentation index at any time point. Conclusions Statin therapy led to a short-term reduction in augmentation index after 12 months, but this effect did not persist after 18 months despite continued reduction in low-density lipoprotein cholesterol levels. These findings suggest that statins may have a transient effect on aortic stiffness. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00939822.
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Statins influence biomarkers of low grade inflammation in apparently healthy people or patients with chronic diseases: A systematic review and meta-analysis of randomized clinical trials.
Milajerdi, A, Larijani, B, Esmaillzadeh, A
Cytokine. 2019;:154752
Abstract
BACKGROUND No earlier study summarized findings on the effect of statins on inflammatory biomarkers in apparently healthy individuals or those with chronic diseases. This study was done to systematically review earlier publications on the effect of statins on serum concentrations of C-reactive protein (CRP) and Interleukin-6 (IL-6) in apparently healthy individuals or those with chronic diseases. METHODS We searched relevant publications published up to December 2018 in PubMed, MEDLINE, SCOPUS, EMBASE, and Google Scholar databases. For this purpose, suitable MESH and non-MESH keywords were used. Randomized placebo-controlled clinical trials that examined the effect of statins on serum concentrations of CRP and IL-6 in apparently healthy adults or those with chronic diseases were included. RESULTS Overall, 18 studies with 23 effect sizes, that enrolled 32,156 individuals (38% female and 62% male; mean age: 44.79 years) were included. When we combined 21 effect sizes from 16 studies, we observed a significant reduction in circulating levels of CRP following administration of statins [Weighted Mean Difference (WMD): -0.80; 95% CI: -1.05, -0.56]. Combining 12 effect sizes from 11 studies, a significant reduction was found in serum CRP concentrations following administration of Atorvastatin (WMD: -0.57; 95% CI: -0.78, -0.35). Pooling 5 effect sizes from 2 studies, we found a significant reduction in serum concentrations of CRP following administration of Simvastatin (WMD: -0.29; 95% CI: -0.49, -0.10; I2 = 88.5%). Combining 6 effect sizes from 5 studies, we found a significant reduction in serum IL-6 concentrations after Atorvastatin therapy (WMD: -2.13; 95% CI: -3.96, -0.30; I2 = 98.6%). CONCLUSIONS In conclusion, we found that statins administration in apparently healthy people or those with chronic diseases help reducing serum CRP concentrations. In addition, Atorvastatin administration resulted in reduced serum IL-6 concentrations in these people.
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6.
Kruppel-like factor 2 mediated anti-proliferative and anti-metastasis effects of simvastatin in p53 mutant colon cancer.
Lu, L, Huang, W, Hu, W, Jiang, L, Li, Y, Wu, X, Yuan, D, Li, M
Biochemical and biophysical research communications. 2019;(4):772-779
Abstract
The changes in cellular metabolism play an important role in promoting tumor progression. Recent findings suggested that the mutation of tumor suppressor gene p53 promoted lipids synthesis and mutant p53 (mutp53) was essential for regulating mevalonate pathway for cholesterol synthesis. Simvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to exhibit therapeutic effects against many types of cancers including breast cancer, colon cancer, lung cancer, etc. However, the underlying mechanism of the antitumor effect of simvastatin still needs to be further investigated. Our data demonstrated that suppression of mevalonate pathway by simvastatin significantly upregulated Kruppel-like factor 2 (KLF2) and p21WAF1/CIP1 expression in mutp53 colon cancer cells SW1116 but not in p53 wild type cells HCT116. Meanwhile, we found that overexpression of KLF2 could significantly induce p21WAF1/CIP1 expression, inhibit Wnt signaling and suppress epithelial-mesenchymal transition, indicating that KL2 might mediate antitumor effect of simvastatin in SW1116 cells. Moreover, bioinformatic analysis from The Cancer Genome Atlas (TCGA) database indicated that KLF2 were positively correlated with CDKN1A (encoding p21WAF1/CIP1), both of which were downregulated in colon cancer tissue, especially in p53 mutant colon cancer tissue. The results showed that KLF2 might be a tumor suppressor gene in colon cancer, which was in accordance with our experimental data. We also found that CDKN1A expression in mutant p53 colon cancer tissue was significant decreased when compared with p53 wild type colon cancer tissue, while Wnt ligand Wnt5a exhibited the highest level in p53 mutant colon cancer tissue. These data provide strong evidences for clinical application of simvastatin in treatment of colon cancer with p53 mutation.
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7.
Coenzyme Q10 does not improve peripheral insulin sensitivity in statin-treated men and women: the LIFESTAT study.
Kuhlman, AB, Morville, T, Dohlmann, TL, Hansen, M, Kelly, B, Helge, JW, Dela, F
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2019;(5):485-492
Abstract
Simvastatin is a cholesterol-lowering drug that is prescribed to lower the risk of cardiovascular disease following high levels of blood cholesterol. There is a possible risk of new-onset diabetes mellitus with statin treatment but the mechanisms behind are unknown. Coenzyme Q10 (CoQ10) supplementation has been found to improve glucose homeostasis in various patient populations and may increase muscle glucose transporter type 4 content. Our aim was to investigate if 8 weeks of CoQ10 supplementation can improve glucose homeostasis in simvastatin-treated subjects. Thirty-five men and women in treatment with a minimum of 40 mg of simvastatin daily were randomized to receive either 2 × 200 mg/day of CoQ10 supplementation or placebo for 8 weeks. Glucose homeostasis was investigated with fasting blood samples, oral glucose tolerance test (OGTT) and intravenous glucose tolerance test. Insulin sensitivity was assessed with the hyperinsulinemic-euglycemic clamp. Different indices were calculated from fasting samples and OGTT as secondary measures of insulin sensitivity. A muscle biopsy was obtained from the vastus lateralis muscle for muscle protein analyzes. There were no changes in body composition, fasting plasma insulin, fasting plasma glucose, or 3-h glucose with intervention, but glycated hemoglobin decreased with time. Glucose homeostasis measured as the area under the curve for glucose, insulin, and C-peptide during OGTT was unchanged after intervention. Insulin secretory capacity was also unaltered after CoQ10 supplementation. Insulin sensitivity was unchanged but hepatic insulin sensitivity increased. No changes in muscle GLUT4 content was observed after intervention. CoQ10 supplementation does not change muscle GLUT4 content, insulin sensitivity, or secretory capacity, but hepatic insulin sensitivity may improve.
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8.
Synthetic Approaches Towards Antihypercholesterolemic Drug Simvastatin.
Fattah, TA, Saeed, A, Shehzadi, SA
Current organic synthesis. 2019;(5):652-670
Abstract
Cardiovascular diseases are among the most threatening problems being faced by twenty-first century humans. The core cause of these diseases is high cholesterol level. Simvastatin (1: Synvinolin) is a well-known cholesterol-lowering drug marketed under the trade name Zocor®, which significantly reduces the risk of cardiovascular diseases related to hypercholesterolemia and is effective in lowering the total plasma cholesterol, low-density and very low-density lipoprotein cholesterol. It also enhances the high-density lipoprotein cholesterol. This review article aims to provide an overview of several chemical and biological methods utilized for the production of simvastatin in high yields and purity. Many robust and scalable methods have been described using lovastatin (2: Mevinolin) as a starting material, produced by the fungal strain of Aspergelius terreus. Enzymatic synthesis of simvastatin is also highlighted in this review. In addition, detailed experimental conditions, as well as the compatibility for industrial-scale preparations of simvastatin are also discussed.
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9.
ZNF542P is a pseudogene associated with LDL response to simvastatin treatment.
Kim, K, Theusch, E, Kuang, YL, Dose, A, Mitchel, K, Cubitt, C, Chen, YI, Krauss, RM, Medina, MW
Scientific reports. 2018;(1):12443
Abstract
Statins are the most commonly prescribed cardiovascular disease drug, but their inter-individual efficacy varies considerably. Genetic factors uncovered to date have only explained a small proportion of variation in low-density lipoprotein cholesterol (LDLC) lowering. To identify novel markers and determinants of statin response, we used whole transcriptome sequence data collected from simvastatin and control incubated lymphoblastoid cell lines (LCLs) established from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial. We looked for genes whose statin-induced expression changes were most different between LCLs derived from individuals with high versus low plasma LDLC statin response during the CAP trial. We created a classification model of 82 "signature" gene expression changes that distinguished high versus low LDLC statin response. One of the most differentially changing genes was zinc finger protein 542 pseudogene (ZNF542P), the signature gene with changes most correlated with statin-induced change in cellular cholesterol ester, an in vitro marker of statin response. ZNF542P knock-down in a human hepatoma cell line increased intracellular cholesterol ester levels upon simvastatin treatment. Together, these findings imply a role for ZNF542P in LDLC response to simvastatin and, importantly, highlight the potential significance of noncoding RNAs as a contributing factor to variation in drug response.
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10.
The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study: Protocol for a point-of-care randomized controlled trial of statin pharmacogenetics in primary care.
Vassy, JL, Brunette, CA, Majahalme, N, Advani, S, MacMullen, L, Hau, C, Zimolzak, AJ, Miller, SJ
Contemporary clinical trials. 2018;:40-50
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Abstract
BACKGROUND The association between the SLCO1B1 rs4149056 variant and statin-associated muscle symptoms (SAMS) is well validated, but the clinical utility of its implementation in patient care is unknown. DESIGN The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study is a pseudo-cluster randomized controlled trial of SLCO1B1 genotyping among statin-naïve primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients of enrolled primary care providers are aged 40-75 and have elevated risk of cardiovascular disease by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Patients give consent by telephone in advance of an upcoming appointment, but they are enrolled only if and when their provider co-signs an order for SLCO1B1 testing, performed on a blood sample already collected in clinical care. Enrolled patients are randomly allocated to have their providers receive results through the electronic health record at baseline (PGx + arm) versus after 12 months (PGx- arm). The primary outcome is the change in low-density lipoprotein cholesterol (LDL-C) after one year. Secondary outcomes are concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for simvastatin prescribing, concordance with ACC/AHA guidelines for statin use, and incidence of SAMS. With 408 patients, the study has >80% power to exclude a between-group LDL-C difference of 10 mg/dL (non-inferiority design) and to detect between-group differences of 15% in CPIC guideline concordance (superiority design). CONCLUSION The outcomes of the I-PICC Study will inform the clinical utility of preemptive SLCO1B1 testing in the routine practice of medicine, including its proposed benefits and unforeseen risks.