(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Necrosis

The aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology (VH) intravascular ultrasound (IVUS).. Recent clinical trials have demonstrated a reduction of atherosclerotic plaque, yet whether statin therapy affects the change in components of plaque remains unknown.. This study was a nonrandomized and nonblinded design. Eighty patients with stable angina pectoris were divided into either the fluvastatin group (n = 40) or the control group (n = 40) according to their total or low-density lipoprotein (LDL) cholesterol level. The volume of each plaque component (dense calcium, fibrous tissue, fibro-fatty, or necrotic core) was evaluated at baseline and at 12-month follow-up.. The LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) levels in the fluvastatin group were significantly decreased at time of follow-up. In VH IVUS findings, fibro-fatty volume was significantly decreased (baseline 80.1 +/- 57.9 mm(3) vs. follow-up 32.5 +/- 27.7 mm(3), p < 0.0001) and fibrous tissue volume was increased (baseline 146.5 +/- 85.6 mm(3) vs. follow-up 163.3 +/- 94.5 mm(3), p < 0.0001) in the fluvastatin group. In the control group, the volumes of all plaque components without fibrous tissue were significantly increased. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001) and change in hsCRP level (R = 0.357, p = 0.006).. One-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume.

Topics: Aged; Biomarkers; C-Reactive Protein; Calcinosis; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fibrosis; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Japan; Male; Middle Aged; Necrosis; Predictive Value of Tests; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

The Hippo signalling pathway is involved in breast cancer and canine mammary tumour (CMT). This study sought to evaluate the efficacy of fluvastatin on the Hippo pathway and its main effectors, YAP and TAZ, in vivo in a murine CMT cell line xenograft model. On treatment day 1, mice were divided into four groups: vehicle, fluvastatin, doxorubicin or a combination therapy. Tumour volumes were monitored with callipers and tissues harvested on day 28th of treatment. Histopathological examination of tumour tissues and major organs was performed as well as tumour evaluation of necrosis, apoptosis, cellular proliferation, expression of YAP, TAZ and the mRNA levels of four of their target genes (CTGF, CYR61, ANKRD1 and RHAMM2). Results showed a statistically significant variation in tumour volumes only for the combination therapy and final tumour weight only for the doxorubicin group compared to control. There was no significant difference in tumour necrosis, expression of CC3, ki-67, YAP and TAZ measured by immunohistochemistry and in the mRNA levels of the target genes. Unexpectedly, lung metastases were found in the control group (9) and not in the fluvastatin treated group (7). In addition, mass spectrometry-based quantification of fluvastatin reveals concentrations comparable to levels reported to exert therapeutic effects. This study shows that fluvastatin tumours concentration reached therapeutic levels without having an effect on the hippo pathway or various tumour parameters. Interestingly, only the control group had lung metastases. This study is the first to explore the repurposing of statins for cancer treatment in veterinary medicine.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Dog Diseases; Dogs; Doxorubicin; Female; Fluvastatin; Heterografts; Humans; Lung Neoplasms; Mammary Glands, Human; Mammary Neoplasms, Animal; Mice; Necrosis; RNA, Messenger; Rodent Diseases; Transcription Factors

The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins.

Topics: Adenosine Triphosphatases; Animals; Atorvastatin; Blood Glucose; Cardiotonic Agents; Catalase; Cholesterol; Fatty Acids, Monounsaturated; Fluvastatin; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoproterenol; Male; Myocardial Infarction; Myocardium; Necrosis; Pravastatin; Rats, Wistar; Rosuvastatin Calcium; Simvastatin; Superoxide Dismutase; Triglycerides

This study sought to assess, by serial computed tomography angiography (CTA), the effect of statin treatment on coronary plaque morphology.. In addition to the assessment of luminal stenosis, CTA also allows characterization of plaque morphology. Large, positively remodeled plaques with large necrotic cores have been reported as indicators of plaque instability.. CTA was performed in 32 patients (26 men, ages 64.3 +/- 8.5 years). Of these, 24 received fluvastatin after the baseline study; 8 subjects who refused statin treatment were followed as the control subjects. Serial imaging was performed after a median interval of 12 months. All vessels were examined in every subject, and a 10-mm-long segment was identified for comparison before and after intervention. Total plaque volume, low attenuation plaque (LAP) volume, lumen volume, and remodeling index were calculated.. In the statin-treated patients, the total plaque volume (92.3 +/- 37.7 vs. 76.4 +/- 26.5 mm(3), p < 0.01) and LAP volume (4.9 +/- 7.8 vs. 1.3 +/- 2.3 mm(3), p = 0.01) were significantly reduced over time; however, there was no change in the lumen volume (63.9 +/- 25.3 vs. 65.2 +/- 26.2 mm(3), p = 0.59). On the other hand, no change was observed in the CTA characteristics in the control subjects, including total plaque volume (94.4 +/- 21.2 vs. 98.4 +/- 28.6 mm(3), p = 0.48), LAP volume (2.1 +/- 3.0 vs. 2.3 +/- 3.6 mm(3), p = 0.91), and lumen volume (80.5 +/- 20.7 vs. 75.0 +/- 16.3 mm(3), p = 0.26). The plaque volume change (-15.9 +/- 22.2 vs. 4.0 +/- 14.0 mm(3), p = 0.01) and LAP volume change (-3.7 +/- 7.0 vs. 0.2 +/- 1.5 mm(3), p < 0.01) were significantly greater in the statin than the control group. The lumen volume (1.3 +/- 15.6 vs. -5.5 +/- 13.1 mm(3), p = 0.24) and remodeling index (-2.4 +/- 6.8% vs. -0.3 +/- 6.5%, p = 0.53) did not show the significant differences between the 2 groups. The decrease in the plaque volume was due to reduction in the LAP volume (R = 0.83, p < 0.01), and was not related to any changes in the lumen volume (R = 0.21, p = 0.24).. This preliminary study suggests that serial CTA evaluation of coronary plaques allows for the assessment of interval change in the plaque morphology. Statin treatment results in decreases in the plaque and necrotic core volume. The features known to be associated with plaque instability.

Topics: Aged; Coronary Angiography; Coronary Stenosis; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Necrosis; Pilot Projects; Predictive Value of Tests; Prospective Studies; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Topics: Calcinosis; Coronary Artery Disease; Fatty Acids, Monounsaturated; Fibrosis; Fluorobenzenes; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Necrosis; Observer Variation; Predictive Value of Tests; Pyrimidines; Radiography; Rosuvastatin Calcium; Severity of Illness Index; Simvastatin; Sulfonamides; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

Statins have antiproliferative and anti-tumoral effects in MCF-7 cells. We determined the effect of statins upon MCF-7 cell cycle, toxicity, cell death, reactive oxygen species (ROS) production and mitochondrial membrane potential. Fluvastatin, simvastatin and atorvastatin inhibited cell proliferation. Antiproliferation was associated with a decrease in the DNA synthesis and a cell cycle arrest in the G1 and G2/M phases. A loss in the mitochondrial membrane potential was observed with fluvastatin. Statins induced increase in ROS production that was associated with cell death, which was abrogated by the antioxidant NAC. Our results suggest that the cytotoxic effect observed is mediated by an oxidative stress.

Topics: Acetylcysteine; Antineoplastic Agents; Antioxidants; Apoptosis; Atorvastatin; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Membrane; Cell Proliferation; DNA Replication; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Membrane Potential, Mitochondrial; Necrosis; Oxidative Stress; Pyrroles; Reactive Oxygen Species; Simvastatin

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been widely used in clinical practise and their efficacy in reducing cardiovascular risk has been well described.. To investigate the effect of low doses of fluvastatin (nanomolar) on H(2)O(2)-induced cell damage and the underlying mechanism.. Primary cultures of human umbilical vein endothelial cells were used, and the effects of fluvastatin on H(2)O(2)-induced apoptosis, necrosis, and proliferation were observed. H(2)O(2) at a concentration of 100 mum significantly induced apoptotic cell death after 24-h cell culture. Fluvastatin at low concentrations (10-100 nm) prevented H(2)O(2)-induced apoptosis, as determined by a DNA fragmentation assay and by cell counting with trypan blue and Hoechst 33342 nuclei staining. The protective effect of fluvastatin was mediated by the upregulation of Bcl-2 expression as probed by real-time polymerase chain reaction and Western blotting. Using siRNA to knock down the expression of Bcl-2, the protective effect of fluvastatin was abolished. Fluvastatin had no direct effect on the H(2)O(2)-sensitive TRPM2 calcium channel.. These results suggest that fluvastatin has a potent protective effect against H(2)O(2)-induced apoptosis via upregulation of Bcl-2 expression. The findings provide a new insight into the mechanism by which fluvastatin is able to modulate the influence of oxidative stress on vascular endothelial cells.

Topics: Antibodies, Monoclonal; Apoptosis; Cell Division; Cells, Cultured; DNA Damage; Endothelial Cells; Fatty Acids, Monounsaturated; Fluvastatin; Genes, bcl-2; Humans; Hydrogen Peroxide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Necrosis; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; TRPM Cation Channels; Umbilical Veins; Up-Regulation

The purpose of this study was to evaluate the apoptosis and necrosis induced by five kinds of statins in IM-9 human lymphoblasts with fluorescence-enhanced flow cytometry using avidin-biotin complex. IM-9 human lymphoblasts (2 x 10(4) cells/cm2) were seeded into tissue culture plates and incubated with five kinds of statins. Statin-treated cells were first incubated with biotin-annexin V, followed by addition of avidin-FITC and propidium iodide, and then subjected to flow cytometry. The fluorescence intensity was enhanced using an avidin-biotin complex system, resulting in successful separate determination of the statin-induced apoptosis and necrosis by flow cytometry, which enabled us to quantitatively evaluate the statin-induced cell damage. Flow cytometric analysis results in the intensity of statin-induced apoptosis in IM-9 cells as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. The intensity of statin-induced necrosis in IM-9 cells was expressed as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. The total damage of IM-9 cells induced by five kinds of statins were expressed as the sum of both percentages of apoptosis and necrosis as follows: atorvastatin cerivastatin>fluvastatin simvastatin>pravastatin. Our studies show that fluorescence enhancement with avidin-biotin complex is useful for the identification and quantitation of annexin-positive apoptosis cells and thus, the fluorescence-enhanced flow cytometry was shown to be applicable for screening of statins as new anti-leukemia agents.

Topics: Apoptosis; Atorvastatin; Avidin; Biotin; Cell Line; Cell Separation; Cells, Cultured; Drug Industry; Drug Screening Assays, Antitumor; Fatty Acids, Monounsaturated; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Leukemia; Microscopy, Fluorescence; Necrosis; Pharmaceutical Preparations; Pravastatin; Propidium; Pyridines; Pyrroles; Simvastatin; Time Factors