Extralipid effects of micronized fenofibrate in dyslipidemic patients.

The aim of this study was to evaluate the levels of lipid and extralipid parameters in patients with atherogenic dyslipidemia. We investigated the lipid-lowering therapeutic efficacy of fenofibrate and its extralipid influence on oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), Fibrinogen, factor VII and plasminogen activator type 1 (PAI-1) during 1-month treatment. Fourteen individuals with HLPIIb were treated with micronized fenofibrate (267 mg/d) for 1 month. The control group included twelve volunteers. Lipidograms were determined with enzymatic kits. ELISA method was used to measure oxLDL and PAI-1. Plasma CRP levels were measured spectrophotometrically. Fibrinogen and factor VII serum levels were evaluated with automatic coagulometer. After 1-month therapy with micronized fenofibrate, we observed a significant reduction of total cholesterol (TC) (277.2 to 217.8 mg/dl, p < 0.05), LDL (183.6 to 129.4 mg/dl, p < 0.05), trigliceryde (TG) (316.7 to 220.6 mg/dl, p < 0.05), oxLDL (68.7 +/- 5.5 to 39.7 +/- 3.7 U/l, p < 0.001) and increase in high-density lipoprotein (HDL) (35.1 to 41.9 mg/dl, p < 0.05). Fibrate treatment also decreased CRP(5.81 +/- 0.26 to 5.08 +/- 0.06 mg/l, p < 0.001), PAI-1 (120.4 +/- 9.7 to 84.7 +/- 5.9 ng/ml; p < 0.05), fibrinogen (3.65 +/- 0.17 to 3.44 +/- 0.16 g/l, ns) and factor VII (159.7% +/- 56.7 to 141% +/- 42.4, ns). The micronized fenofibrate at a daily dose of 267 mg demonstrated a highly beneficial effect on all lipid parameters and advantageous influence on inflammatory and thrombogenic plasma risk factors in patients with dyslipidemia HLPIIb.

Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures.

Pro-inflammatory cytokines, such as interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha have been suggested to be involved in the pathophysiology of depression and in the mechanism of action of antidepressant drugs. Until now the effect of antidepressants on cytokines has been examined only in plasma, blood mononuclear cells and spleen, which reflect the activity of peripheral cytokine network. The aim of this study was to evaluate the effect of amitriptyline and its metabolite nortriptyline on the release of IL-1beta and TNF-alpha by lipopolysaccharide (LPS)-activated rat mixed glial and microglial cell cultures. LPS stimulated the release of both cytokines. The exposure of mixed glial culture to amitriptyline and nortriptyline led to a decrease in both IL-1beta and TNF-alpha release. Moreover, amitriptyline reduced LPS-stimulated IL-1beta release by microglial cultures. Although amitriptyline reduced secretion of both cytokines, the drug did not affect IL-1beta and TNF-alpha mRNAs in mixed cell cultures. Our study has shown for the first time that amitriptyline and nortriptyline administered at concentrations which may be achieved in plasma and brain structures during treatment, inhibit the secretion of IL-1beta and TNF-alpha in rat mixed glial and microglial cell cultures. The obtained results support the previous observations that antidepressants are able to reduce peripheral release of pro-inflammatory cytokines and suggest that the cytokine network may be involved in the central mechanism of action of amitriptyline and nortriptyline.

Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates.

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.

Monocyte suppressing action of fenofibrate.

Since atherosclerosis has been proven to be an inflammatory disease, it is obvious that the proper treatment for dyslipidemia should not only correct lipid parameters but also inhibit inflammation. Monocytes and monocyte-derived proinflammatory cytokines are widely known to be involved in the formation and rupture of the atherosclerotic plaque. The aim of our study was to assess the effect of fenofibrate, a commonly used hypolipidemic drug, on the release of interleukin 1beta (IL-1beta), interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) by monocytes from patients with combined hyperlipidemia. Fourteen patients with biochemically confirmed type IIb dyslipidemia who did not respond to a low-fat diet were treated with micronized fenofibrate for 1 month. The control group included 12 healthy, normolipidemic, age-matched subjects. To accurately evaluate the levels of the inflammatory cytokines, we excluded patients with any inflammatory disease. Monocytes were isolated from peripheral blood before and after the treatment. IL-1beta, IL-6 and MCP-1 release was measured by enzyme-linked immunosorbent assay (ELISA) after lipopolysaccharide stimulation. IL-1beta, IL-6 and MCP-1 levels were significantly higher in hyperlipidemic patients compared to the control (143.9 +/- 6.5 vs. 74.4 +/- 4.4 pg/ml; 8212 +/- 285 vs. 6110 +/- 170 pg/ml; 19.6 +/- 0.9 vs. 12.3 +/- 0.6 ng/ml, respectively). Thirty-day fenofibrate treatment decreased the release of IL-1beta by 43% (143.9 +/- 6.5 vs. 86.2 +/- 5.9 pg/ml), of IL-6 by 22% (8212 +/- 285 vs. 6330 +/- 234 pg/ml), and of MCP-1 by 29% (19.6 +/- 0.9 vs. 14.0 +/- 0.8 ng/ml). The evaluated cytokines were markedly elevated in patients with type IIb dyslipidemia. Effective fenofibrate therapy had a significant inhibitory effect on the release of monocyte-derived inflammatory cytokines.

Immunophilin ligands decrease release of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-2 in rat astrocyte cultures exposed to simulated ischemia in vitro.

The aim of present study was to evaluate the effects of immunophilin ligands (cyclosporin A, FK506 and rapamycin) on the simulated ischemia-induced release of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-2) in rat primary astrocyte cell cultures. Astrocytes were exposed to cyclosporin A (CsA) (0.25, 0.5, 1, 10, 20 and 50 microM), FK506 (1, 10, 100, 1000 nM) and rapamycin (10, 100, 500 and 1000 nM). In vitro simulated ischemia significantly increased secretion of IL-1beta, TNF-alpha and IL-2 by astrocyte cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester). CsA (at concentrations of 10-50 microM), FK506 (at all used concentrations) and rapamycin (in dose-dependent manner) significantly attenuated IL-1beta release after 24 h exposure to ischemic conditions. Immunophilin ligands at all used concentrations significantly decreased TNF-alpha levels in culture media after 24 h exposure to ischemia. Moreover, significant decrease in IL-2 secretion at 0.25, 0.5, 1 and 50 microM CsA and FK506 at concentrations of 100 and 1000 nM were observed. The results suggest that immunophilin ligands may regulate glial activity during ischemia by affecting the release of pro-inflammatory cytokines.

Influence of antidepressant drugs on macrophage cytotoxic activity in rats.

The aim of the study was to evaluate the in vivo and in vitro effects of antidepressant drugs on cytotoxic activity of rat spleen macrophages. In the in vivo experiment, rats were injected subcutaneously with two different doses (2 or 10 mg/kg) of desipramine, fluvoxamine and fluoxetine. The drugs were given once, for 2, 4 or 8 weeks. In the in vitro experiment, spleen macrophages were cultured with three different concentrations of desipramine (3.75, 0.75, or 0.075 mM), fluvoxamine (3.14, 0.62, or 0.062 mM), and fluoxetine (3.23, 0.64, or 0.064 mM) for 72 h. The cytotoxic activity of macrophages was evaluated by measuring the lysis of ((51)Cr) chromate-labelled P-815 target cells. In the in vivo experiment, a single dose of fluvoxamine (2 and 10 mg/kg) and fluoxetine (10 mg/kg) significantly decreased macrophage cytotoxic activity. Fluvoxamine (2 and 10 mg/kg), fluoxetine (10 mg/kg) and desipramine (10 mg/kg) administrated for 14 days also decreased macrophage cytotoxic activity. Twenty-eight day treatment with desipramine (2 and 10 mg/kg) decreased macrophage cytotoxic activity. Desipramine, fluvoxamine and fluoxetine given for 56 days did not affect macrophage cytotoxic activity. In the in vitro experiment, antidepressant drugs did not affect the cytotoxic activity of macrophages. The results of the study indicate that the effects of antidepressant drugs on macrophage cytotoxic activity depend on the drug type, dose and duration of the treatment.

Flupentixol and trifluperidol reduce secretion of tumor necrosis factor-alpha and nitric oxide by rat microglial cells.

Tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which are produced by activated microglial cells, are involved in the neuropathogenesis of many diseases affecting the central nervous system (CNS). There is a need to develop drugs that inhibit neurotoxic processes in neurodegenerative diseases. The aim of this study was to evaluate the effect of two neuroleptics, flupentixol and trifluperidol, on the release of pro-apoptotic TNF-alpha and NO by LPS-activated rat microglial cells. Flupentixol and trifluperidol reduced the TNF-alpha and NO release by cultured microglia exposed to LPS for 6 and 24h. The results suggest that flupentixol and trifluperidol, which are well-known antipsychotic drugs, may be used in the treatment of CNS diseases associated with excessive TNF-alpha and NO release.

[Pleiotropic effects of micronized fenofibrate in patients with combined hyperlipidemia]. / Plejotropowe dzialanie fenofibratu mikronizowanego u chorych z hiperlipidemia mieszana.

More and more recent studies demonstrate the pleiotropic effects of fibrates. Except lowering plasma lipid levels they can influence blood coagulation abnormalities and stabilise atherosclerotic lesions--a frequent result of the activation of inflammatory cells within the vascular wall. The anti-inflammatory action of fibrates includes inhibiting the release of many cytokines, such as Tumor Necrosis Factor e (TNF-alpha) by these cells. The aim of this study was to evaluate the effect of fenofibrate on the plasma levels of Plasminogen Activator Inhibitor type 1 (PAI-1) and fibrinogen in patients with combined dyslipidemia. Moreover, we assessed the amount of TNF-alpha released by peripheral blood isolated monocytes before and after therapy. Fourteen patients (8 women and 6 men) with hyperlipidemia IIb were treated with micronized fenofibrate (Lipanthyl 200 m, Fournier) in a daily dose of 200 mg for one month. The control group consisted of 12 individuals matched for age with biochemical confirmation of normolipemia. Plasma PAI-1 and TNF-alpha levels were measured by the ELISA method. Fibrinogen levels were measured according to the commonly used Clauss method. Before treatment the haemostatic compounds and TNF-alpha studied were significantly higher in the group with hyperlipidaemia IIb compared to the control group. One-month therapy with fenofibrate resulted in significant decrease of triglycerides and total cholesterol. After treatment, PAI-1 and fibrinogen levels also decreased significantly: PAI-1 from 101.18 +/- 9.74 ng/mL to 81.22 +/- 6.68 ng/mL, p < 0.01 and fibrinogen from 364.5 +/- 29.6 mg/dL to 294.7 +/- 19.3 mg/dL, p < 0.01. The study also revealed that the level of produced TNF-alpha decreased significantly from 2136.0 +/- 250.8 pg/mL to 1336.8 +/- 132.0 pg/mL, p < 0.05. These results may confirm new pathways of fibrates action.