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

Inflammation promotes acute coronary syndromes (ACS) and ensuing clinical complications. It is well known that statins decrease the risk of coronary events and may benefit the stabilization of atherosclerotic plaque with their anti-inflammatory effects. We investigated the effects of different doses of fluvastatin on serum concentrations of high-sensitive C-reaction protein (hs-CRP) and tumor necrosis factor-alpha (TNF-alpha) in the early phase of ACS.. We prospectively randomized 60 patients with ACS to 3 groups: (1) group A (n=20): were given routine therapy; (2) group B (n=20): were administrated routine therapy with 40 mg/d oral fluvastatin; (3) group C (n=20): received routine therapy with 80 mg/d oral fluvastatin. Twenty patients with stable coronary heart disease served as controls. The following-up period was 7 days. By immunoturbidimetric assay and ELISA methods the serum concentrations of hs-CRP and TNF-alpha were measured before and after therapy.. (1) The serum concentrations of hs-CRP and TNF-alpha in patients with ACS was significantly higher than those in the control group (P<0.05). (2) After 1 week of therapy, the serum concentrations of hs-CRP and TNF-alpha were significantly lower in group B and group C (all P<0.01), especially in group C. (3) The serum concentrations of hs-CRP and TNF-alpha did not correlate to the concentrations of TC, TG, LDL-C, or HDL-C.. Early fluvastatin intervention decreases dose-dependently the serum concentrations of hs-CRP and TNF-alpha of patients with ACS. The high-dose fluvastatin invention may play a stronger anti-inflammatory effect in ACS patients. The anti-inflammatory effect of fluvastatin may be beyond the lipid lowering.

Topics: Acute Disease; Biomarkers; C-Reactive Protein; Coronary Disease; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Inflammation Mediators; Lipid Metabolism; Male; Middle Aged; Syndrome; Time Factors; Tumor Necrosis Factor-alpha

Statins promptly lower rates of adverse cardiovascular events in patients with acute coronary syndromes (ACS). These therapeutic properties may be mediated by the effects of statins on key hemostatic factors. This study examined the immediate effects of fluvastatin on plasma free tissue factor pathway inhibitor (fTFPI) and soluble endothelial protein C receptor (sEPCR) concentrations in patients with unstable angina or non-ST segment elevation myocardial infarction.. We studied 57 patients consecutively admitted to our emergency department and randomly assigned to placebo (n = 29) versus fluvastatin, 80 mg, p.o. (n = 28). All patients were treated with aspirin and metoprolol p.o., nitroglycerin i.v., and subcutaneous enoxaparin. Venous blood was sampled as soon as possible upon admission, before and 6 h after administration of study drug and standard anti-ischemic therapy.. Mean sEPCR concentrations decreased significantly in patients treated with fluvastatin (-8.1 +/- 6.7% from baseline) and was unchanged in the placebo group (-2.3 +/- 14.4%, P = 0.007 vs. fluvastatin). Though fTFPI increased significantly after the administration of both fluvastatin and placebo, the mean increase after fluvastatin (450+/-436%) was significantly greater than after placebo (155+/-141%, P = 0.001).. Treatment with fluvastatin significantly modified key hemostatic factors toward an antithrombotic effect within 6 h. These properties may, in part, explain the early salutary effects of fluvastatin in patients with ACS.

Topics: Acute Disease; Adult; Aged; Antigens; Antigens, CD; Blood Coagulation Factors; Coronary Disease; Endothelial Protein C Receptor; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glycoproteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Male; Middle Aged; Receptors, Cell Surface

Statin therapy has been reported to reduce the acute rejection rate following renal transplantation in a pilot study. The present study is the first randomized, double-blind and adequately powered study to examine the effect of statins on acute rejection of renal allografts.. A total of 364 patients were randomly assigned to receive either fluvastatin 40 mg or placebo in combination with conventional cyclosporine-based immunosuppressive therapy. The primary end point was treated first acute rejection. Secondary end points included biopsy-proven rejection, histological severity of rejection, occurrence of steroid-resistant rejection, and serum creatinine at three months following transplantation.. Fluvastatin was well tolerated; no patients developed myositis or rhabdomyolysis. There was no difference in the acute rejection rate [86 (47.3%) fluvastatin vs. 87 (47.8%) placebo] and no significant difference in the severity of rejection, steroid resistant rejection or mean serum creatinine at three months (160 micromol/L vs. 160 micromol/L). Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels increased following renal transplantation. With the exception of the increase in HDL-C, which was augmented, the increases in lipid parameters were significantly reduced by fluvastatin (total cholesterol +17.5% vs. 35.7%; LDL-C +6.3% vs. 46.7%; HDL-C +43.3% vs. 38.1%; triglyceride +52.2% vs 77.6%).. Contrary to the reported effects of statins, fluvastatin had no effect on the incidence or severity of acute rejection following renal transplantation. There were no increases in adverse events. A significant and potentially beneficial alteration in the lipid profile was observed in the early post transplant period. We conclude that fluvastatin may be used safely to correct dyslipidemia in patients with end-stage renal failure through the peri-transplant period.

Topics: Acute Disease; Adult; Aged; Blood Pressure; Cholesterol, HDL; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Fluvastatin; Graft Rejection; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Transplantation; Male; Middle Aged; Research Design

Classical chemotherapy has an active, but limited, role in acute leukemia with relapse common in adult patients. Recent evidence has implicated signal transduction pathways in leukemic progression and also in resistance to cytotoxic therapy. We have used a short-term, in-vitro incubation assay with cytotoxic analysis by MTT, confirmed by histone-associated DNA fragmentation, to evaluate both classical and nonclassical combinations of drugs. Isobologram median effect analysis, confirmed by curve shift analysis, was used to identify synergy and antagonism. Fluvastatin, a prenylation inhibitor, demonstrates global enhancement of the effects of classical agents in both AML-193 and KG-1 cell lines. Similarly, the m-TOR inhibitors, RAD-001 (everolimus) and rapamycin, also cause time-dependent global enhancement of cytotoxic agents. At clinically achievable combinations, RAD-001 perturbs the AKT pathway in vitro. The unique combination of fluvastatin and an m-TOR inhibitor was synergistic in both cell lines. These effects were independent of whether or not human plasma was used in the assay system. These studies suggest several novel combinations of agents that need to be evaluated in the management of leukemia.

Topics: Acute Disease; Antineoplastic Agents; Cell Line, Tumor; Drug Synergism; Everolimus; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Leukemia; Protein Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, and is used clinically as a safe and effective approach in the control of hypercholesterolemia. We have shown previously (Dimitroulakos, J., Nohynek, D., Backway, K. L., Hedley, D. W., Yeger, H., Freedman, M. H., Minden, M D., and Penn, L. Z. Increased sensitivity of acute myelogenous leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood, 93: 1308-1318, 1999) that lovastatin, a prototypic member of the statin family, can induce apoptosis of human acute myeloid leukemia (AML) cells in a sensitive and specific manner. In the present study, we evaluated the relative potency and mechanism of action of the newer synthetic statins, fluvastatin, atorvastatin, and cerivastatin, to trigger tumor-specific apoptosis. Cerivastatin is at least 10 times more potent than the other statins at inducing apoptosis in AML cell lines. Cerivastatin-induced apoptosis is reversible with the addition of the immediate product of the HMG-CoA reductase reaction, mevalonate, or with a distal product of the pathway, geranylgeranyl pyrophosphate. This suggests protein geranylgeranylation is an essential downstream component of the mevalonate pathway for cerivastatin similar to lovastatin-induced apoptosis. The enhanced potency of cerivastatin expands the number of AML patient samples as well as the types of malignancies, which respond to statin-induced apoptosis with acute sensitivity. Cells derived from acute lymphocytic leukemia are only weakly sensitive to lovastatin cytotoxicity but show robust response to cerivastatin. Importantly, cerivastatin is not cytotoxic to nontransformed human bone marrow progenitors. These results strongly support the further testing of cerivastatin as a novel anticancer therapeutic alone and in combination with other agents in vivo.

Topics: Acute Disease; Apoptosis; Atorvastatin; Cell Division; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Leukemia, Myeloid; Lovastatin; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridines; Pyrroles; Sensitivity and Specificity; Tumor Cells, Cultured

Topics: Acute Disease; Aged; Anti-Inflammatory Agents; Anticholesteremic Agents; Cholestasis; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Male; Nephrotic Syndrome; Prednisolone