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

Topics: Aged; Anti-Arrhythmia Agents; Anticholesteremic Agents; Atrial Fibrillation; Blood Pressure; Cardiovascular Surgical Procedures; Chronic Disease; Cross Infection; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glycated Hemoglobin; Humans; Indoles; Male; Methicillin-Resistant Staphylococcus aureus; Metoprolol; Middle Aged; Surgical Wound Infection; Systole

The "statins," or hydroxymethylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors, are a generally safe class of drugs that are widely used throughout the world and are rarely associated with severe hepatotoxicity. In this article, two cases of severe hepatotoxicity attributed to statin use are presented. In addition, a detailed summary of previously published cases of statin hepatotoxicity and the risks and benefits of statins in patients with chronic liver disease are presented. Drug-induced liver injury (DILI) from statins typically presents with an acute hepatocellular liver injury pattern, although mixed or cholestatic injury patterns have also been reported. Nonspecific autoantibodies as well as clinical, laboratory, and histological features of an autoimmune-like hepatitis may be present in some patients with statin hepatotoxicity. Despite their widespread use, acute liver failure and death have rarely been reported in patients with statin hepatotoxicity. Multiple retrospective studies as well as a large prospective randomized controlled trial demonstrate that statins can safely be given to hyperlipidemic patients with compensated chronic liver disease.

Topics: Adult; Aged; Aged, 80 and over; Atorvastatin; Autoimmunity; Biomarkers; Biopsy; Chemical and Drug Induced Liver Injury; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Liver; Liver Diseases; Male; Middle Aged; Practice Guidelines as Topic; Pyrroles; Risk Assessment; Treatment Outcome; Young Adult

This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade.. After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat.. During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated.. In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Italy; Kidney Diseases; Lipids; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

Experimental data demonstrated that inflammatory mediators, such as pro-inflammatory and anti-inflammatory cytokines and their receptors might have important role in the development and the progression of heart failure (HF). Statins were shown to downregulate inflammatory cytokines in HF. Interleukin (IL)-10 is one of the most important anti-inflammatory cytokines. The effect of statin therapy on plasma IL-10 levels is not known in patients with HF. We conducted this study to investigate the effects of fluvastatin therapy on plasma IL-10 cytokine concentration in patients with HF.. A total of 29 patients with ischemic HF were included in this prospective uncontrolled study. Patients were assigned to fluvastatin (80 mg/day) after baseline examinations. Determination of biochemical parameters including lipids, IL-10, and tumor necrosis factor-alpha were performed at baseline and 12 weeks after the initiation of fluvastatin therapy. All participants also underwent symptom-limited exercise tolerance test at baseline and 12 weeks, and heart rate recovery (HRR) was calculated.. A significant elevation in the plasma levels of IL-10 after 12 weeks of fluvastatin treatment (4.8+ or -1.0 vs. 6.5+ or -1.3 pg/ml, P=0.002) was observed. Plasma tumor necrosis factor-alpha levels were significantly decreased after fluvastatin therapy (6.3+ or -2.3 vs. 4.8+ or -1.4 pg/ml, P=0.003). Fluvastatin therapy significantly improved HRR at 1 min after 12 weeks compared with baseline (19+ or -7 vs. 24+ or -9 bpm, P<0.001). A positive correlation between the change in the levels of IL-10 and the change in HRR at 1 min (r=0.57, P<0.001) was observed.. Fluvastatin therapy might lead to an increase in plasma IL-10 levels and an associated improvement in vagal tonus as assessed by HRR at 1 min in patients with HF. These findings might partly explain the possible benefit observed in statin trials.

Topics: Aged; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Heart Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interleukin-10; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Up-Regulation

Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study.. ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N= 1050) or placebo (N= 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N= 439).. There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean low-density lipoprotein (LDL)-cholesterol levels by 32% (95% CI -33 to -30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed.. Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.

Topics: Adult; Aged; Anticholesteremic Agents; Cholesterol; Chronic Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Incidence; Indoles; Kidney Transplantation; Male; Middle Aged

There are few reports on the safety and efficacy of long-term treatment with statins in patients with chronic renal disease and hyperlipidemia. We evaluated these subjects treated with fluvastatin.. After a 4-week run-in period, a total of 80 patients with diabetic nephropathy or chronic glomerulonephritis were randomly allocated to receive dietary therapy and fluvastatin 20 mg/day (n=39), or dietary therapy alone (n=41) for a period of 48 weeks. Lipid parameters, rhabdomyolysis-related indicators, 24-hour urinary albumin excretion and creatinine clearance were measured. The pharmacokinetics of fluvastatin was examined in 8 patients.. Creatinine clearance and 24-hour urinary albumin excretion did not differ between the two groups. The peak serum fluvastatin concentration (Cmax) was 141+/-67 microg/L and the mean AUC0-6 h was 341+/-149 microgh/L. Fluvastatin treatment significantly lowered serum total cholesterol, low-density lipoprotein (LDL) cholesterol and apo-lipoprotein B concentrations by 16%, 25%, and 22%, respectively, compared with patients receiving dietary therapy alone. There were no significant differences in serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations between the two treatment groups. Serum creatine kinase and aldolase concentrations did not change throughout treatment in both groups.. Fluvastatin treatment significantly improved lipid parameters in patients with chronic renal disease. Fluvastatin was well tolerated, with no adverse effects on renal function and no muscular toxicity. However, the drug showed no direct renoprotective effects.

Topics: Adult; Aged; Albuminuria; Chronic Disease; Creatinine; Diabetic Nephropathies; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Male; Middle Aged; Myoglobin; Prospective Studies

Topics: Anti-Inflammatory Agents; Antioxidants; Atorvastatin; Cell Proliferation; Chronic Disease; Dinoprostone; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Interleukin-1beta; Lipids; Lipopolysaccharides; Microglia; Monocytes; Nitric Oxide; Pravastatin; Quinolines; Reactive Oxygen Species; Rosuvastatin Calcium; Simvastatin; THP-1 Cells; Tumor Necrosis Factor-alpha

Chronic heart failure (CHF) is characterized by left ventricular (LV) dysfunction along with impaired autonomic control functions. Herbal drugs are increasingly being used in the treatment of cardiovascular disorders. The present study was designed to examine the protective effect of Terminalia arjuna (T arjuna) bark extract on LV and baroreflex function in CHF and to elucidate the possible mechanistic clues in its cardioprotective action. The baroreflex was evaluated by measuring the changes in heart rate (HR) with changes in arterial blood pressure induced by bolus injections of phenylephrine (vasoconstrictor) and sodium nitroprusside (vasodilator). T arjuna bark extract and fluvastatin were tested/administered therapeutically and prophylactically in isoproterenol-induced rat model of CHF. Fifteen days after isoproterenol administration, rats exhibited cardiac dysfunction, hypertrophy, and LV remodeling along with reduced baroreflex sensitivity. Prophylactic and therapeutic treatment with T arjuna improved cardiac functions and baroreflex sensitivity. It also attenuated hypertrophy and fibrosis of the LV. Fluvastatin treatment exerted a similar protective effect against myocardial remodeling and heart failure. Further, T arjuna and fluvastatin significantly reduced oxidative stress and inflammatory cytokine level in CHF rats. In conclusion, T arjuna exerts beneficial effect on LV functions, myocardial remodeling, and autonomic control in CHF possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels.

Topics: Animals; Antioxidants; Baroreflex; Chronic Disease; Cytokines; Disease Models, Animal; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoproterenol; Male; Nitroprusside; Oxidative Stress; Phenylephrine; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Terminalia; Ventricular Dysfunction, Left

Statins are widely used for primary and secondary prevention of cardiovascular disease. For this reason, knowledge of the side effects and interactions pertaining to this class of pharmaceuticals is of utmost importance to all physicians. In this text a case report is presented of an eighty year old gentleman, referred to the respiratory clinic at Mater Dei Hospital Malta after developing dry cough on being treated with simvastatin and fluvastatin. An attempt at switching over to a placebo was made with resolution of symptoms. This is the second described case in the literature of lone cough associated with statin therapy necessitating treatment discontinuation in our patient. Possible hypothesis are discussed as well as suggestions for further research to unravel the underlying mechanisms of this association.

Topics: Aged, 80 and over; Chronic Disease; Cough; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Simvastatin

The present study demonstrated prophylactic and therapeutic potential of Terminalia arjuna bark extract in isoproterenol (ISO)-induced chronic heart failure (CHF). Fifteen days after injection of ISO (85 mg/kg twice at an interval of 24 h, s.c), rats showed decline in maximal rate of rise and fall of left ventricular pressure (LV (dP/dt)(max) and LV (dP/dt)(min)), cardiac contractility index (LV (dP/dt)(max)/LVP), cardiac output and rise in LV end-diastolic pressure. CHF rats showed a significant increase in serum creatine kinase isoenzyme-MB (CK-MB) and malondialdehyde levels, as well as fall in the activities of superoxide dismutase, reduced glutathione. Altered lipid profile and increased level of cytokine tumour necrosis factor-α (TNF-α) along with histological changes in heart were also observed in CHF rats. T. arjuna bark extract (500 mg/kg, p.o) treatment prior and 15 days after ISO injection significantly attenuated cardiac dysfunction and myocardial injury in CHF rats. Cardioprotective action of T. arjuna was comparable to fluvastatin, a synthetic drug. The results suggest that T. arjuna bark extract has a significant prophylactic and therapeutic beneficial effect on protection of heart against ISO-induced CHF possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels.

Topics: Animals; Cardiac Output; Cardiotonic Agents; Chronic Disease; Creatine Kinase, MB Form; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Glutathione; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Isoproterenol; Lipids; Malondialdehyde; Myocardial Contraction; Myocardium; Plant Bark; Plant Extracts; Rats; Rats, Wistar; Superoxide Dismutase; Terminalia; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Function, Left; Ventricular Pressure

Statins may provide additional benefits in patients with cardiac failure due to their pleiotropic effects besides their cholesterol-lowering actions. In this study, we aimed to evaluate the impact of 12-week fluvastatin therapy on the inflammatory cytokines and the ventricular performance markers in patients with heart failure.. Fourty chronic heart failure patients, twenty with idiopathic dilated cardiomyopathy (DCM group) and 20 with ischemic cardiomyopathy (ICM group), for whom statin treatment was indicated according to Adult Treatment Panel III were included to this open label and prospective study. After a 12-week treatment with fluvastatin 80 mg/day; clinical functional capacity, echocardiographic indices of cardiac performance and inflammatory markers were evaluated. After the treatment, functional capacity (in DCM group: 2.05+/-0.4 versus 1.65+/-0.6, p=0.005; in ICM group: 2.25+/-0.5 versus 1.8+/-0.6, p=0.003), left ventricular ejection fraction, LVEF (from 30+/-5% to 33+/-5%, p=0.001 in DCM and 29+/-4% to 31+/-5%, p=0.001 in ICM group) and tissue Doppler mitral annular systolic velocity, Sm (5.8+/-1 cm/s to 7+/-1 cm/s, p=0.001 in DCM and 5.4+/-0.8 cm/s to 7+/-1 cm/s, p=0.001 in ICM group) improved. Tumor necrosis factor-alpha and interleukin-6 levels decreased, but no significant changes in high sensitive C-reactive protein and brain natriuretic peptide levels were detected with the fluvastatin treatment in both groups.. Fluvastatin improved cardiac functions and the clinical symptoms in HF patients with either idiopathic dilated or ischemic etiology. This positive effect of fluvastatin which might be secondary to inflammatory modulation was more marked in patients with ischemic etiology. Statins in HF deserves special attention by means of further large-scale trials.

Topics: Aged; Biomarkers; Chronic Disease; Cytokines; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Prospective Studies; Time Factors; Ventricular Function, Left

Innate immune activation mediated by myocardial Toll-like receptors (TLRs) is involved in cardiovascular disease. The function and role of TLRs on peripheral leukocytes in human chronic heart failure (CHF) are not known.. We measured whole blood TLR4 and TLR2 expressions in 28 patients with CHF (64+/-2 years, New York Heart Association [NYHA] functional class 2.2+/-0.1, left ventricular (LV) ejection fraction 32+/-2%) and 13 healthy subjects of similar age and gender.. As assessed by flow cytometry, TLR4 and TLR2 were detected on CD14+ monocytes. Unstimulated monocyte TLR4 expression was significantly higher in CHF patients compared to controls (mean fluorescence intensity, 3.57+/-0.57 vs. 1.72+/-0.32, p<0.05). TLR2 expressions were similar in CHF patients and control subjects (p=0.5). TLR4 levels correlated with the severity of CHF (NYHA class I/II: 2.66+/-0.40, and NYHA class III/IV: 5.08+/-1.24, p<0.01) and with serum lipid levels (total cholesterol, r=-0.44, p<0.01 and high-density lipoprotein, r=-0.68, p<0.001). After stimulation of monocytes by lipopolysaccharide (LPS, 10 ng/ml, 3 h), activated TLR4 was higher in CHF patients (p<0.05). Pre-incubation with fluvastatin for 24 h inhibited dose-dependently ex vivo monocyte TLR4 and TLR2 expressions (p<0.001).. This study suggests that upregulation of monocyte TLR4 may contribute to the pathophysiology of chronic heart failure. Fluvastatin may prevent excessive innate immune response in vitro in chronic heart failure by inhibition of monocyte Toll-like receptor signaling.

Topics: Aged; Analysis of Variance; Case-Control Studies; Chronic Disease; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Monocytes; Statistics, Nonparametric; Toll-Like Receptor 4

Statins reduce lipid levels, inflammation and cardiovascular events in patients with coronary artery disease; CKD patients show increased risk of cardiovascular and increased plasma levels of IL-6 and IL-8.. To evaluate the in vitro effect of simvastatin (S) or fluvastatin (F) on the lipopolysaccharide (LPS) stimulated secretion of IL-6 and IL-8 from monocytes of chronic kidney disease patients (CKD) in K-DOQI stages 3-5.. Monocytes enriched peripheral blood (PBMC) from 28 CKD (15 in K-DOQI stages 3-4, Group I, and 13 in K-DOQI stage 5 on hemodialysis, Group II) and 10 healthy subjects (HS), were isolated by Ficoll-gradient centrifugation. Cells were incubated with LPS 100 ng/ml or with LPS plus increasing doses of statins (from 10(-6) to 10(-8) M ) for 24 h. Surnatant IL-6 and IL-8 concentrations were determined by EIA.. Basally the mean concentration of IL-6 and IL-8 was higher in patients than in HS and in Group II than in Group I (IL6: HS 285 +/- 77 pg/ml, Group I 365 +/- 178 pg/ml, Group II 520 +/- 139 pg/ml- IL8 HS 180 +/- 75 pg/ml, Group I 1722 +/- 582 pg/ml, Group II 4400 +/- 1935 pg/ml). After addition of LPS the mean concentration of IL-6 and IL-8 increased in all groups (IL6: HS 1740 +/- 178 pg/ml, Group I 3754 +/- 672 pg/ml, Group II 4800 +/- 967 pg/ml; IL8: HS 450+/-132 pg/ml, Group I 9700+/-2837 pg/ml, Group II 11608 +/- 2316 pg/ml). After the addition of LPS plus increasing doses of S or F from 10(-10) to 10(-6) M, a significantly lower cytokine concentration compared to the data after LPS alone was observed (IL6: HS 45%, Group I 75%, Group II 50%; IL8: HS 100%, Group I 65%, Group II 35%).. These data confirm that cytokine release is increased in CKD patients and that is highest in the most severe patients. Furthermore they suggest that fluvastatin or simvastatin can be used in order to reduce the high cardiovascular risk.

Topics: Cardiovascular Diseases; Cells, Cultured; Chronic Disease; Cytokines; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Interleukin-6; Interleukin-8; Kidney Diseases; Lipopolysaccharides; Monocytes; Simvastatin

We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O2) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity.. Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser1177-phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment.. These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.

Topics: Animals; Blood Pressure; Caveolin 1; Chronic Disease; Cyclic GMP; Electrocardiography; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; HSP90 Heat-Shock Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Hypoxia; Indoles; Myocardium; Nitric Oxide Synthase Type III; Organ Size; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilation; Ventricular Function, Right

The study included 30 IHD patients with primary hypercholesterolemia (22 males and 8 females). 18 and 12 patients have received a single daily dose of fluvastatin 20 and 40 mg, respectively, in the evening for 12 weeks. The drug effect was assessed by changes in the clinical status, lipid spectrum, transport-metabolic and absorption-secretory functions of the liver. IHD patients with hypercholesterolemia were found to have dysfunction of the hepatobiliary system. Fluvastatin treatment reduced the level of total cholesterol (Ch), LDLP Ch, triglycerides. HDLP Ch levels remained unchanged. Atherogenic lipoproteins aggregation diminished. Positive changes occurred in hepatic metabolism: bilirubin concentrations lowered, serum albumin went up, absorption-secretory function of hepatocytes normalized, hepatic mono-oxidase system activated. Fluvastatin-related hepatic damage was not reported in the course of 12-month follow-up.

Topics: Adult; Aged; Anticholesteremic Agents; Chronic Disease; Drug Evaluation; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Lipids; Liver; Male; Middle Aged; Myocardial Ischemia; Radionuclide Imaging; Time Factors; Ultrasonography