Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome.

BACKGROUND AND OBJECTIVE: Metabolic syndrome is characterized by insulin resistance (IR) as well as dyslipidemia, ventral overweight, hypertension and elevated fasting plasma glucose. Since diabetic and prediabetic states are commonly associated with hypertriglyceridemia, fenofibrates have been used in such patients. The aim of this pilot open trial was to study the influence of micronized fenofibrate on insulin resistance and plasma insulin levels in prediabetic and diabetic patients. SUBJECTS: From 114 dyslipidemic patients, 31 with dyslipidemia and insulin resistance were selected to take part in the study. Of the 31 patients, 20 were nondiabetic and only 11 had noninsulin-dependent diabetes mellitus. Eighteen dyslipidemic patients acted as controls. METHODS: Insulin resistance was assessed in a short-term insulin tolerance test. Plasma insulin, antiinsulin antibodies, lipid parameters and the insulin sensitivity index (ISI) were measured at entry and after a 3-month therapy with 200 mg micronized fenofibrate daily. RESULTS: Three-month therapy with micronized fenofibrate resulted in significant ISI increase and was accompanied by a decrease in plasma insulin levels in dyslipidemic patients with metabolic syndrome. ISI also improved in patients with type 2 diabetes mellitus and there was an unexpected increase in plasma insulin levels. Antiinsulin antibodies were unchanged throughout the trial. Reductions in plasma triglycerides and total cholesterol exceeding 50% and 20%, respectively, were observed in patients with metabolic syndrome. These changes were accompanied by an increase in mean levels of plasma high-density lipoprotein (HDL) cholesterol (above 35%). CONCLUSIONS: Micronized fenofibrate is an effective drug in normalizing lipid-lipoprotein levels in patients with metabolic syndrome. After a 3-month fenofibrate therapy, insulin resistance was reduced in a group of patients with dyslipidemia and metabolic syndrome.

Effects of fenofibrate and simvastatin on plasma sICAM-1 and MCP-1 concentrations in patients with hyperlipoproteinemia.

OBJECTIVE: The most important mechanism through which high plasma lipid levels trigger the formation of atherosclerotic lesions involves a change in the expression of adhesion molecules on endothelial and smooth muscle cells. The aim of this study was to evaluate an extralipid effect of fenofibrate and simvastatin by examination of MCP-1 and ICAM-1 plasma concentration after 1-month hypolipemic therapy as well as MCP-1 and ICAM-1 plasma concentration after 1-month therapy with low-fat diet alone. METHODS: Twenty patients with HLPIIb or HLPIIa, who did not respond to a low-fat diet, were treated with micronized fenofibrate or simvastatin, respectively, for 1 month. The control group included 18 normo-lipidemic, healthy age-matched participants; 10 patients with HLPIIa were effectively treated with a low-fat diet for 1 month. This group was compared to a control group of 10 healthy subjects. The plasma adhesion molecule levels were measured by an ELISA method before and after the treatment. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. RESULTS: sICAM-1 levels were significantly higher in HLPIIa and HLPIIb patients (331 +/- 19 ng/ml and 423 +/- 23 ng/ml, respectively) compared with the control group (236 +/- 12 mg/ml). MCP-1 levels were also significantly higher in HLPIIa and HLPIIb patients (170 +/- 9 pg/ml and 183 +/- 15 pg/ml, respectively) compared with the control group (100 +/- 4 pg/ml). Fenofibrate (200 mg daily) significantly decreased sICAM-1 (by 17%) and MCP-1 levels (by 12.5%). Simvastatin (20 mg daily) caused a significant decrease (by 10.5%) in sICAM-1 levels only. Restriction in dietary lipids resulted in a significant decrease in the levels of cholesterol (8%), LDL cholesterol (14.9%) and ApoB (12.7%), which was accompanied by a significant decrease in the levels of sICAM-1 (8.7%) and MCP-1 (16.1%). CONCLUSION: The results of this study suggest that high lipid levels are accompanied by increased levels of sICAM-1 and MCP-1 and that hypolipidemic therapy only slightly decreases the levels of these molecules compared with plasma lipids. The hypolipidemic diet-related decrease in the levels of lipids, ICAM-1 and MCP-1 suggests that it is a drug-induced decrease in lipid levels but not a direct action of the drugs on endothelial cells, smooth muscle cells or macrophages that leads to a decrease in the levels of adhesion molecules.

Effects of atorvastatin, simvastatin, and fenofibrate therapy on monocyte chemoattractant protein-1 secretion in patients with hyperlipidemia.

OBJECTIVE: Monocytes that migrate into the arterial wall participate in the development and, eventually, rupture of the atherosclerotic plaque. The aim of this study was to evaluate the secretion of monocyte chemoattractant protein-1 (MCP-1) by monocytes from hyperlipidemic patients treated with hypolipidemic drugs, namely fenofibrate, simvastatin, or atorvastatin to determine what role is played by these drugs in the development and stabilization of the atherosclerotic plaque. METHODS: Fifty-four hyperlipidemic patients, who did not respond to a low-fat diet, were treated with fenofibrate, simvastatin, or atorvastatin (18 patients in each group) for 1 month. The control group included 18 normolipidemic, healthy, age-matched participants. Ten hyperlipidemic patients were effectively treated with hypolipidemic diet alone for 1 month. This group was compared with a control group of ten healthy subjects. To accurately evaluate the adhesion molecule levels, we excluded hyperlipidemic patients and control subjects with any inflammatory disease. Before and after treatment, monocytes were isolated from peripheral blood. After stimulation with lipopolysaccharide (LPS), MCP-1 secretion was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: MCP-1 levels were significantly higher in hyperlipidemic patients than controls: 15.8+/-0.47, 16.7+/-0.23, and 14.9+/-0.45 compared with 12.36+/-0.42 ng/ml. Fenofibrate, atorvastatin, and simvastatin significantly decreased MCP-1 levels from 15.8+/-0.47 to 8.79+/-0.89, from 16.7+/-0.23 to 7.46+/-0.73, and from 14.9+/-0.45 to 10.3+/-0.8 ng/ml, respectively. In the diet-treated group of hyperlipidemic patients, the level of MCP-1 before therapy was significantly higher than in controls (16.89+/-0.31 vs 12.45+/-0.36 ng/ml). The diet therapy caused a significant decrease in levels of MCP-1 to 15.1+/-0.36 ng/ml. There was a correlation between the decreased levels of lipids and the decreased release of MCP-1 in the patients treated with hypolipemic drugs. CONCLUSION: The drug-induced decrease in MCP-1 secretion in hyperlipidemic patients suggests that, apart from acting on lipids, the hypolipidemic drugs studied may directly inhibit the activity of monocytes.

Plasma cytokines as predictors of coronary heart disease.

BACKGROUND AND OBJECTIVE: Growing body of evidence explicitly suggests the significant role of inflammatory processes in vascular diseases related to atherosclerosis. Monocytes, present in every phase of atherogenesis, are the principal cells accumulating in atherosclerotic plaque. Monocyte Chemotactic Protein 1 (MCP-1) seems to influence firm adherence of rolling monocytes and infiltration into the artery wall. Although the significant meaning of inflammation in atherogenesis has been proved, potential role of antiinflammatory cytokines remains unknown. Interleukin 10 (IL-10) is a major cytokine of pleiotropic antiinflammatory function known to exert inhibitory effects on monocytes. Recent data emerging from clinical and pathological studies suggest important role of thrombosis and fibrinolytic disorders in atherosclerosis complications especially in coronary heart disease (CHD). Individuals with greater Plasminogen Activator Inhibitor 1 (PAI-1) level are believed to be more susceptible to cardiovascular disease. METHODS: In our study we measured the plasma levels of MCP-1, IL-10 and PAI-1 in 10 patients with stable angina and 10 healthy subjects. We also estimated its mutual correlations. The plasma levels of MCP-1, IL-10 and PAI-1 were determined with R&D kits (ELISA). RESULTS: Plasma levels of MCP-1 were significantly higher (261.5+/-40.7 pg/mL vs 73.3+/-3.05 pg/mL; p<0.0002) and also levels of PAI-1 were higher (79.36+/-5.8 ng/mL vs 35.88+/-1.38 ng/mL; p<0.0001) in patients with SA compared with the healthy control subjects. Whereas plasma levels of IL-10 were lower (11.6+/-0.5 pg/mL vs 16.5+/-0.4 pg/mL; p<0.0001) compared with control group and correlated with both MCP-1 plasma level (r=-0.67; p<0.0015) and PAI-1 concentration (r=-0.69; p<0.0008). CONCLUSION: The data obtained confirm the predictive role of cytokines in patients with stable coronary heart disease. The negative correlation of anti-inflammatory IL-10 and PAI-1 was also found.

A new immunological marker of atherosclerotic injury of arterial wall.

BACKGROUND AND OBJECTIVE: The atherosclerotic arterial injuries lead to many life threatening vascular incidents. It has been well documented that inflammatory processes play an important role in atherogenesis. Intensive studies are undertaken to find a serum marker of inflammatory reaction correlated with arterial injuries. METHODS: In our study we measured the level of interleukin-6 (IL-6) in patients with dyslipidemia IIa and IIb biochemically confirmed. Control estimations were done in age-matched group. Arterial injuries were evaluated as a thickening of complex intima-media in common carotid arteries by means of Doppler ultrasonography. RESULTS: Levels of IL-6 were significantly higher in both groups of patients with dyslipidemia as compared with the healthy control persons (IIa vs control p<0.001, IIb vs control p<0.001). The plasma level of IL-6 is significantly correlated to intima-media complex thickness (r=0.68, p<0.0001). CONCLUSION: We conclude that increase of serum concentration of IL-6 may be related to arterial wall injuries in the course of the most atherogenic lipid disorders.

Recent insights into body weight control: from physiology to pathology.

Over the past several years, new modulators of feeding and body weight have been discovered, and our knowledge of the mechanisms and neurohumoral interactions between anorexigenic and orexigenic compounds has increased dramatically. This review aims to summarize the present knowledge of the role of leptin and several hypothalamic neuropeptides, such as neuropeptide Y (NPY), corticotropin-releasing hormone (CRH) and melanocortins, in the regulation of appetite and body weight. It also presents the progress made in the design of interactions between leptin and hypothalamic peptides in the regulation of feeding. The role of these compounds in the pathogenesis of obesity in animals and humans, and their potential usefulness in the treatment of this disorder, are discussed.

Augmenting effect of methionine-enkephalin on interleukin-6 production by cytokine-stimulated murine macrophages.

The effects of methionine-enkephalin on the production of interleukin-6 by activated peritoneal murine macrophages were studied. Macrophage were activated with interleukin-1beta or interferon-gamma in the presence or absence of graded concentrations of methionine-enkephalin. Methionine-enkephalin combined with interleukin-1beta or interferon-gamma caused an increase in IL-6 release from cultured macrophages. The opioid receptor antagonist naloxone did not change the stimulatory effect of methionine-enkephalin on IL-6 production by stimulated macrophages. Methionine-enkephalin added to the culture medium of resting macrophages increased IL-6 release from macrophages which were later induced with interleukin-1beta or interferon-gamma. The results of this study suggest that methionine-enkephalin can modulate the proinflammatory cytokine response by controlling, via non-opioid receptor mechanism, the production of IL-6.

In-vitro immunomodulatory effects of haloperidol and perazine in schizophrenia.

There are some reports describing concurrent changes in lymphocytic and monocytic activities in schizophrenia. In this study we investigated T cell activity in schizophrenic patients by measuring the release of interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+ and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2 levels and the percentage of CD4-cells tended to decrease and sIL-2R levels decreased significantly in schizophrenic patients. Haloperidol and perazine significantly decreased IL-2 levels and increased sIL-2R levels and the percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R levels was higher in patients with a predominance of positive symptoms compared with those in whom both positive and negative symptoms were severe. The study has shown that T-cell activity is reduced in schizophrenia and that neuroleptics may have immunomodulatory properties.

[The effect of astrocytoma cells on secretion of cytokines by autologous lymphocytes]. / Wplyw komórek gwiazdziaka na wydzielanie cytokin przez limfocyty autologiczne.

Immunotherapy is one of the experimental methods used in the treatment of brain tumours. The development of astrocytomas is accompanied by decreased activity of lymphocytes, namely inhibition of mitogen-induced proliferation and decreased cytokine secretion, which is an adverse event in the course of disease. In the present study, astrocytoma cells obtained from human tumours and cocultured with autologous lymphocytes inhibited cytokine secretion by those lymphocytes.

Influence of neuroleptics on cytotoxic activity of macrophages in rats.

The aim of the study was to evaluate the influence of neuroleptics on the in vivo and in vitro activities of rat spleen macrophages. In the in vivo study, three neuroleptics (chlorpromazine, haloperidol, and sulpiride) were given once, for 14 or 28 days. In the in vitro study, we evaluated the effects of two different concentrations of the neuroleptics on 3-day cultures of spleen macrophages. Rat spleen macrophages were isolated by the adherence method, and their cytotoxic activity was determined by measuring 51 Cr release from target cells P-815. In the in vitro study, both concentrations of all neuroleptics did not alter the cytotoxic activity of macrophages. In the in vivo study, neuroleptics (chlorpromazine 2 mg/kg, haloperidol 0.5 mg/kg, sulpiride 50 mg/kg) enhanced the cytotoxicity of macrophages both after a single injection and after 14 days. The results of the study indicate that the immunomodulatory effects of the neuroleptics depend mainly on dosage and experimental conditions.

Effects of thiorphan, bestatin and captopril on the Lewis lung carcinoma metastases in mice.

Previously we have found that administration of thiorphan alone or in combination with bestatin exerts antitumor effect in mice, including reduction of B16 melanoma tumor growth and prolongation of survival time. These data prompted us to extend our studies to estimate the effect of treatment with thiorphan, captopril and bestatin on lung metastases in mice. Administration of thiorphan alone at a dose of 25 micrograms/mouse or in combination with bestatin (50 micrograms) or captopril (5 mg/mouse) decreased the number of spontaneous metastases in lungs of Lewis lung carcinoma bearing mice. Neither the injections of bestatin, captopril nor bestatin in combination with captopril influenced the number of lung tumor colonies. Treatment with thiorphan at a dose 25 micrograms augmented cytotoxic activity of natural killer (NK) cells and macrophages. These observations explain partly the mechanism of action of thiorphan.

Bidirectional modulation of mouse natural killer cell and macrophage cytotoxic activities by enkephalins.

Stimulation of a cellular immune function as measured by splenic natural killer (NK) cell activity has been described following systemic treatment with enkephalins. In this study, we evaluated the effects of the central administration of enkephalins on the splenic NK cell activity and macrophage cytotoxicity. Intracerebroventricular injection of leucine-enkephalin (LE) or methionine-enkephalin (ME) induced bidirectional modulation of NK cell and macrophage cytotoxic activities (suppression followed by enhancement). Administration of ME or LE at doses of 100 or 10 micrograms/mouse caused inhibition of NK cell and macrophage activity 2 h after injection. Enhancement of NK cells activity was observed at 96 h and macrophages cytotoxicity at 24 h after icv injection with both enkephalins. Pretreatment with naloxone (20 micrograms/mouse) inhibited the enkephalins-induced augmentation of NK cell and macrophage cytotoxic activity. These findings demonstrate that central actions of enkephalins produce changes in cytotoxicity of NK cells and macrophages.

Antitumor activity of bestatin and thiorphan in mice.

We have investigated the effect of bestatin and thiorphan on growth of murine transplantable tumors, survival time, activity of natural killer (NK) cells and macrophages in mice. The injections of thiorphan at the does of 0.5 or 5 micrograms per mouse retarded tumor growth and prolonged survival period in B16 melanoma bearing animals. Pretreatment with naloxone (an unspecific antagonist of opioid receptors) blocked the tumor growth inhibition induced by the treatment with bestatin and thiorphan what could suggest a contribution of endogenous enkephalin in this antitumor effect. The percentage of mice bearing B16 melanoma tumor in the group treated with thiorphan at doses of 0.5, 5 or 50 micrograms per mouse was lower in comparison with control animals in a dose-dependent manner. The treatment with thiorphan at concentrations of 0.4-1.6 mg/ml inhibited growth of cultured in vitro B16 melanoma cell in comparison with control culture. Thiorphan added to the medium at concentration of 0.5 microgram/ml or administered 4 times at the dose of 0.5 microgram/mouse augmented NK lymphocyte activity.

Effect of captopril and thiorphan on the proliferation of human neoplastic cell lines and their influence on cytostatic activity of interferon alpha or cytotoxic activity of doxorubicin.

We have assessed the effect of thiorphan or captopril on proliferation of two human tumor cell lines, A549 and HL60 including their influence on the cytostatic activity of interferon alpha or doxorubicin. The results showed that captopril inhibits the proliferation of both A549 and HL60 cells lines but thiorphan has antiproliferative effect only on A549 cells in a dose-dependent manner. However, neither captopril nor thiorphan administered in combination with interferon alpha or doxorubicin enhanced cytotoxic potential of doxorubicin and cytostatic activity of interferon alpha.