Improvement of Endothelial Dysfunction with Simvastatin in Patients with Autosomal Dominant Polycystic Kidney Disease

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Endothelial dysfunction (ED), which is an early manifestation of vascular injury, has been shown in patients with ADPKD. Statins have a beneficial effect in the reversal of ED. The aim of this study was to investigate the effects of a statin, simvastatin, on ED in patients with ADPKD. Sixteen patients with ADPKD having well-preserved renal function were included in the study. Endothelial function of the brachial artery was evaluated by using high-resolution vascular ultrasound. Endothelial-dependent dilatation (EDD) was expressed as the percentage change in the brachial artery diameter from baseline to reactive hyperemia. After the baseline evaluations of EDDs, patients were started treatment with simvastatin at a dose of 40 mg/day and were treated for six months. EDDs were recalculated after one and six months of therapy. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein were also measured as markers of inflammation. Baseline EDD was 11.3 ± 6.9% in patients with ADPKD. After one month of simvastatin treatment, EDD increased significantly to 14.6 ± 4.6 % (P = 0.016 versus baseline). Endothelial-dependent dilatation further increased significantly to 18.9 ± 7.5 % (P = 0.011 versus baseline, P = 0.048 versus first month) after six months of therapy. There was also a significant decrease in the level of IL-6 from 21.6 ± 21.7 pg/mL to 9.1 ± 3.5 pg/mL (P= 0.002).

Six months of simvastatin therapy resulted in a significant improvement of ED in patients with ADPKD. This finding may be in part related to the pleiotropic effects of simvastatin.     

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

BACKGROUND: As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans. MATERIAL AND METHODS: We assessed the effect of simvastatin on left ventricular function and coenzyme Q10 levels in 21 (11 male, 10 female) hypercholesterolaemic subjects (mean age = 56 years) with normal LVF, over a period of 6 months. Subjects were re-tested after a 1-month wash-out period (7 months). Echocardiography was performed on all subjects before commencement of simvastatin (20 mg day(-1)), and at 1, 3, 6 and 7 months after initiation of treatment. Fasting blood samples were also collected at these intervals to assess lipids, apoproteins, vitamin E and coenzyme Q10. RESULTS: Serum lipids showed the expected reductions. Plasma vitamin E and coenzyme Q10 levels were reduced by 17 +/- 4% (P < 0.01) and 12 +/- 4% (P < 0.03) at 6 months. However, the coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio increased significantly. Left ventricular ejection fraction (EF) decreased transiently after 1 month, while no significant change was observed at 3 and 6 months. Other markers of left ventricular function did not change significantly at any time point. CONCLUSION: Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.     

Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation

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辛伐他汀对糖尿病血脂异常的调节作用

目的　了解辛伐他汀对糖尿病血脂异常的调节作用。方法　比较 6 3例 2型糖尿病合并血脂异常采用胰岛素强化治疗 [即胰岛素泵持续皮下注射胰岛素 (CSII)或者多次 (>4次 /d)皮下注射胰岛素 (MSII) ]并连续服用辛伐他汀 2周与 4 2例 2型糖尿病合并血脂异常单纯采用胰岛素强化治疗 (CSII或者MSII) 2周后血脂的变化情况 ,同时了解治疗前后的空腹血糖 (FBS)、餐后 2小时血糖、肝功能 (LF)、肾功能 (SPS)及心肌酶学等的变化。结果　胰岛素强化治疗并连续服用辛伐他汀治疗组血脂显著变化 (P <0 .0 0 1 ) ,而单纯胰岛素强化治疗组血脂变化不明显 (P >0 .0 5 ) ,前者调节糖尿病合并血脂异常有效率达 93.6 % ,且副作用发生率低 (7.93% )而轻微。结论　辛伐他汀对 2型糖尿病合并血脂异常的调节作用疗效肯定 ,副反应小 ,可作为常用药物     

辛伐他汀对人牙髓干细胞增殖和分化的影响

目的:研究辛伐他汀对人牙髓干细胞(dental pulpstem cells,DPSCs)增殖和成骨分化的影响。方法:将第3代人DPSCs在矿化培养液中诱导培养,同时加入不同浓度的辛伐他汀(1×10-5mol/L、1×10-6mol/L、1×10-7mol/L、1×10-8mol/L),噻唑蓝(methyl thiazolyl tetrazolium,MTT)法检测细胞增殖情况,碱性磷酸酶试剂盒检测碱性磷酸酶(alkaline phosphatase,ALP)活性,茜素红染色鉴定成骨分化。结果:各浓度辛伐他汀均抑制人DPSCs增值,辛伐他汀浓度为1×10-5mol/L时,抑制作用最明显。适宜浓度辛伐他汀(1×10-6mol/L、1×10-7mol/L、1×10-8mol/L)促进人DPSCs向成骨细胞分化,其中,1×10-7mol/L的辛伐他汀促进ALP活性的作用最明显。结论:辛伐他汀抑制人DPSCs的增值,适宜浓度的辛伐他汀可有效促进人DPSCs的成骨分化。     

Montelukast modifies simvastatin-induced myopathy and hepatotoxicity

Montelukast (MNK) has prominent anti-inflammatory and antioxidant activities. It can protect the liver in different hepatotoxic models in animals. Simvastatin (SMV) is one of commonly used lipid lowering drugs for treatment of dyslipidemia in order to reduce cardiovascular disease. It has severe side effects such as myopathy and hepatotoxicity. The aim of the present study is to investigate the possible effect of MNK on SMV-induced myopathy and hepatotoxicity. Four groups of male rats: control group which received saline via stomach tube, MNK treated group (received 10 mg/kg/day MNK via stomach tube), SMV treated group (received 30 mg/kg/day SMV via stomach tube), and MNK + SMV (combination) group which received both MNK and SMV. All animals were treated for 14 days before obtaining blood and tissue samples. SMV has both hepatotoxic effects and myopathy. SMV caused a significant increase in myoglobin, creatinine kinase, ALT, AST, ALP, and bilirubin but, it decreased total proteins, globulin and albumin levels. Co-treatment of SMV and MNK increased the antioxidant activity significantly. MNK modifies partially the myopathic changes and hepatotoxic effect of SMV. Co-administration of MNK and SMV decreased their toxic potentials on the liver, skeletal muscles, and kidney. They have antioxidant activities when given together that produce muscle and hepatic protective effects.     

Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice

SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin, by subcutaneous continuous infusion. The effect of the drug was measured by subsequent colony formation of surviving HL60 cells in vitro and flow cytometry. The number of clonogenic HL60 cells was reduced in the bone marrow of mice that received simvastatin compared with control mice by 65% and 68% in two separate experiments. The number of clonogenic, normal, murine, bone marrow progenitor cells concomitantly exposed to simvastatin in vivo , was not affected in either experiment. Flow cytometric analysis of bone marrow and spleen cells confirmed these results by showing that simvastatin had reduced the percentage of human leukaemia cells in these tissues by 70% and 88% respectively.   The data show that the reported selective effect of simvastatin against acute myeloid leukaemia cells in vitro, can be extended to this in vivo model. HL60 bears an N-ras mutation. In further in vitro studies, ketoconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyrophosphate synthesis, had a similar effect to simvastatin on HL60 colony development. Furthermore, the clonogenicity of a population of N-ras mutated, primary acute myeloid leukaemia (AML) cells was no more sensitive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin may be independent of the RAS signalling pathway.     

Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group

BACKGROUND: Elevated levels of low-density lipoprotein (LDL) cholesterol promote the development of atherosclerosis and coronary heart disease. HYPOTHESIS: Simvastatin 80 mg/day will be more effective than simvastatin 40 mg/day at reducing LDL cholesterol and will be well tolerated. METHODS: Two similar, randomized, multicenter, controlled, double-blind, parallel-group, 48-week studies were performed to evaluate the long-term lipid-altering efficacy and safety of simvastatin 80 mg/day in patients with hypercholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients with LDL cholesterol levels > or = 4.2 mmol/l were enrolled. At 20 centers in the US and 19 countries world-wide, 1,105 hypercholesterolemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) once daily for 24 weeks. Those patients completing an initial 24-week base study were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the extension, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. RESULTS: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was maintained over the 48 weeks of treatment. The mean percentage reductions (95% confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 weeks of treatment (p < 0.001 between groups). Larger reductions in total cholesterol and triglycerides were also observed with the 80 mg dose compared with the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatment. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper limit of normal) occurred infrequently with both doses. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. CONCLUSIONS: Compared with the 40 mg dose, simvastatin 80 mg produced greater reductions in LDL cholesterol, total cholesterol, and triglycerides. Both doses were well tolerated.