OBJECTIVEThe aim of this study was to evaluate the efficacy and safety of combination therapy with simvastatin and fenofibrate in patients with combined hyperlipidemia.

METHODSA total of 221 patients with combined hyperlipidemia were randomly assigned to receive 10 mg simvastatin (n = 72) or 200 mg fenofibrate (n = 68), or a combination of 10 mg simvastatin + 200 mg fenofibrate (n = 81) for 6 months. Lipid profiles, physical and laboratory investigations for adverse effects were assessed.

RESULTS(1) Combination treatment were more effective in normalizing lipid profile than any monotherapy. Serum TC, LDL-C, and TG were reduced by 30%, 37% and 56% respectively, whilst HDL-C significantly increased by 24% (all P < 0.01). The improvement in TG and HDL-C achieved by combination treatment was superior to fenofibrate or simvastatin alone. (2) The success rate of TC, LDL-C and TG control in the combination therapy group were 51%, 55% and 61% respectively, with an overall success rate (all three together) of 45%, which was superior to either drug given as monotherapy. (3) All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy.

CONCLUSIONThe results of this study demonstrated that combination therapy with fenofibrate (200 mg/day) and low-dose simvastatin (10 mg/day) is more effective than monotherapy in patients with combined hyperlipidemia, and is generally safe and well tolerated.

Drug Therapy, Combination ; Female ; Fenofibrate ; administration & dosage ; adverse effects ; therapeutic use ; Humans ; Hyperlipoproteinemia Type V ; drug therapy ; Hypolipidemic Agents ; administration & dosage ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Simvastatin ; administration & dosage ; adverse effects ; therapeutic use

Thiazolidinediones (TZD), which are widely used as insulin sensitizers, and fibrates, which are lipid-lowering drugs, are used in the treatment of dyslipidemia that commonly accompanies diabetes. Several reports suggest elevated levels of high-density lipoprotein (HDL) cholesterol, but the paradoxical reduction of HDL cholesterol level during single or combined TZD and fibrate therapies has been occasionally reported. Herein, we report a case of paradoxical decrease in HDL cholesterol and apolipoprotein A-1 levels during rosiglitazone and fenofibrate treatment for the first time in Korea. The patient was a 56-yr-old man presenting with type 2 diabetes mellitus and dyslipidemia. His HDL cholesterol and apolipoprotein A-1 levels returned to normal after the cessation of fenofibrate therapy. Since diabetes is an established risk factor of cardiovascular diseases, low HDL cholesterol can be a key cause of concern for patients with diabetes. Therefore, HDL cholesterol level should be determined before and after starting TZD and/or fibrate therapy in diabetic patients.
Apolipoprotein A-I/metabolism ; Cholesterol, HDL/*blood ; Diabetes Mellitus, Type 2/complications/*drug therapy ; Dyslipidemias/complications/*drug therapy ; Fenofibrate/*therapeutic use ; Humans ; Hypolipidemic Agents/*therapeutic use ; Male ; Middle Aged ; Thiazolidinediones/*therapeutic use

BACKGROUNDAgeing is associated with increased incidence of dyslipidemia. To investigate potential molecular mechanisms, the effects of age and fibrate administration on peroxisome proliferator-activated receptor alpha (PPARalpha) expression in livers of young and old rats were studied.

METHODSA total of 16 young (2-month-old) and 16 old rats (24-month-old) were randomly assigned to a control group and fenofibrate group (fenofibrate in a total therapeutic dosage of 0.5% in ratio to each treated rat weight in 14 days). RT-PCR was applied to evaluate hepatic mRNA expression of PPARalpha and its target genes. Western blotting was used to determine PPARalpha protein level in liver tissue.

RESULTSWhen compared with 2-month-old rats, the liver tissue from 24-month-old rats showed reduced expression of PPARalpha mRNA (52%, P < 0.05) and protein (109%, P < 0.01). Consequently, the mRNA levels of PPAR target genes, LPL, ACO, ACS and CPT-1 were markedly lowered by 19%, 8%, 13% and 9% respectively, and apoCIII increased by 24% in livers from 24-month-old rats, compared with values obtained from 2-month-old rats (P < 0.05). Fenofibrate therapy significantly lowered plasma triglyceride and total cholesterol levels in old rats, accompanied with improvement in hepatic expression of genes, including LPL, ACO, ACS, CPT-1 and apoCIII, but no change was found in PPARalpha expression in livers from either 24-month or 2-month-old rats.

CONCLUSIONSThe decrease in the hepatic PPARalpha expression is probably directly related to the lipid metabolic disturbances observed in old animals. The beneficial effects of fenofibrate administration in old rats suggests that fibrates may be useful for treating lipid disturbances in old people.

Aging ; metabolism ; Animals ; Fenofibrate ; pharmacology ; therapeutic use ; Hyperlipidemias ; drug therapy ; etiology ; Lipids ; blood ; Liver ; metabolism ; Male ; PPAR alpha ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the anti-fibrosis effects and mechanisms of fenofibrate on hepatic fibrosis using a mouse model of fibrosis induced by carbon tetrachloride (CCl4).

METHODSTwenty-six male C57BL mice were divided into the following three groups: CCL4-induced untreated model control (n = 10), CCl4-induced fenofibrate-treated model (n = 10), and uninduced/untreated normal control (n = 6). All animals were sacrificed after the 5 weeks of induction and treatment. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA) and procollagen III amino-terminal peptide (PIIINP) were determined by routine biochemistry assays. Liver content of hydroxyproline (HYP) was measured by spectrophotometry. Liver content of malonic aldehyde (MDA) and superoxide dismutase (SOD) was measured by enzymatic assays. mRNA expression levels of liver fibrosis-associated factors were determined by PCR, and included alpha-smooth muscle actin (a-SMA), transforming growth factor-beta1 (TGFbeta1), type I collagen-alpha (Collagen1a), peroxisome proliferator-activated receptor-alpha (PPARa), and the inflammatory cytokines tumor necrosis factor alpha (TNFa) and interleukin-6 (IL-6). Finally, the degree of inflammation and fibrosis were assessed by histological analysis using hematoxylin-eosin and Sirius red staining.

RESULTSCompared to the untreated model group, the fenofibrate-treated model group showed significantly lower levels of serum ALT (55.72+/-1.20 vs. 38.72+/-1.25 IU/L), HA (236.20+/-17.57 vs. 152.9+/-13.06 mug/L) and PIIINP (41.66+/-1.89 vs. 34.32+/-1.53 mug/L) (all P less than 0.05). The fenofibrate-treated group also showed a significantly higher level of hepatic SOD content (untreated model: 67.00+/-4.65 vs. 101.1+/-5.32) but significantly lower level of hepatic MDA content (14.67+/-0.93 vs. 10.17+/-0.60 nmol/mg) and lower level of hepatic HYP content (0.67+/-0.80 vs. 0.41+/-0.50 mg/g) (all, P less than 0.05). In addition, the fenofibrate-treated group showed significantly reduced mRNA expression levels of a-SMA (6.83+/-0.88 vs. untreated model: 11.57+/-1.31), TGFbeta1 (67.83+/-4.65 vs. 112.30+/-4.81), Collagen1a (67.83+/-4.65 vs. 112.30+/-4.81), TNFa (17.43+/-2.32 vs. 37.83+/-4.69), and IL-6 (4.00+/-0.49 vs. 5.62+/-0.54), but significantly increased PPARa (0.30+/-0.03 vs. 0.18+/-0.03) (all, P less than 0.05). Finally, the degree of CCL4-induced hepatic fibrosis was attenuated by the fenofibrate treatment.

CONCLUSIONFenofibrate can reduce the degree of liver fibrosis in mice induced by CCl4. The mechanism may involve up-regulation of PPARa, inhibition of the inflammatory response, and enhancement of SOD antioxidant activity.

Animals ; Fenofibrate ; therapeutic use ; Inflammation ; drug therapy ; Liver Cirrhosis, Experimental ; drug therapy ; metabolism ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; PPAR alpha ; metabolism ; Superoxide Dismutase ; metabolism

OBJECTIVETo investigate the effect of micronized fenofibrate on vascular endothelial function in patients with hypertriglyceridemia.

METHODSUsing high-resolution ultrasound, we measured flow- and nitroglycerin-induced dilatation of the brachial artery in 30 patients with hypertriglyceridemia before and after treatment with micronized fenofibrate at a dose of 200 mg once daily for 4 weeks. Simultaneously, both serum lipid and plasma endothelin (ET) levels were determined.

RESULTSAfter micronized fenofibrate therapy, serum triglyceride (TG) levels decreased significantly (P < 0.05). Plasma ET levels also decreased markedly [(82.66 +/- 15.46) microg/L vs. (106.22 +/- 19.16) microg/L, P < 0.001]. Flow-induced vasodilatation was much improved (11.0% +/- 9.0% vs 2.7% +/- 2.0%, P < 0.01). However, no significant changes in vasodilatation occurred in response to nitroglycerin (16.2% +/- 6.0% vs 15.0% +/- 5.0%, P > 0.05) in patients with hypertriglyceridemia.

CONCLUSIONSMicronized fenofibrate can improve impaired endothelium-dependent vasodilatation in patients with hypertriglyceridemia. Improving endothelial function may also be the mechanism responsible for the beneficial effects of micronized fenofibrate.

Adult ; Endothelium, Vascular ; drug effects ; physiology ; Female ; Fenofibrate ; pharmacology ; therapeutic use ; Humans ; Hypertriglyceridemia ; drug therapy ; Male ; Middle Aged ; Vasodilation ; drug effects

OBJECTIVETo demonstrate the clinical efficacy of micronized fenofibrate on mildly-moderately elevated LDL-C levels and reduced HDL-C levels.

METHODSDuring 1998 - 1999, 2358 patients with type IIa, IIb and IV hyperlipidemia were monitored in 16 cities in China. They were treated daily with micronized fenofibrate (micronized lipanthyl) 200 mg for 8 weeks. Lipid levels before and after the treatment were measured and analyzed.

RESULTSMicronized fenofibrate significantly increased HDL-C levels by 12.7%, the effect being inversely correlated to the baseline level of HDL-C. Out of the total patient population, a baseline level of HDL-C < 1.0 mmol/L was found in 837 patients: amongst this group, 510 patients (60.9%) were observed to have an increase in the level of HDL-C to > 1.0 mmol/L with a mean of 1.3 mmol/L, after 8-week micronized fenofibrate therapy. Furthermore, the mean LDL-C level decreased by 15.9% following an 8-week treatment of micronized fenofibrate, an effect positively correlated to the baseline level of LDL. In general, all patients tolerated the drug comfortably.

CONCLUSIONSShort-term treatment of micronized fenofibrate in patients with dyslipidemia significantly increases HDL-C level and reduces mildly-moderately elevated LDL-C level. As expected, it also reduces triglyceride levels.

Adult ; Aged ; Aged, 80 and over ; Cholesterol, HDL ; blood ; Cholesterol, LDL ; blood ; Female ; Fenofibrate ; adverse effects ; therapeutic use ; Humans ; Hyperlipidemias ; blood ; drug therapy ; Hypolipidemic Agents ; therapeutic use ; Male ; Middle Aged

OBJECTIVETo explore the effect of polymorphism in codon Ala54Thr of human intestinal fatty acid-binding protein gene (IFABP) on the therapeutic efficacy of fenofibrate.

METHODSTotally 147 patients with hyperlipidemia [72 men mean age: (56.2 +/- 8.63) years; 75 women mean age: (58.4 +/- 9.12) years] were enrolled. IFABP genotypes were detected by polymerase chain reaction, Hha I digestion, and sequencing. Four weeks before and after treatment, the levels of fasting serum total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), apolipoprotein A I (apoA I) and apolipoprotein B (apoB) were detected with biochemical techniques.

RESULTSThe frequency of IFABP genotype was 0.47 for A/A, 0.37 for A/T, and 0.16 for T/T, and the allelic frequency was 0.65 for A and 0.35 for T. No significant different was found in lipid levels in every genotype before treatment (P > 0.05). After 4 weeks of treatment, the levels of TC, TG, LDL-C, and apoB significantly decreased (P < 00.01), and the levels of HDH-C and apoA I significantly increased (P < 0.01). The total therapeutic efficacy on A54A and A54T were 97% and 95%, respectively. In the patients with T54T genotype after treatment, no significant difference in lipids levels was found except TG (P < 0.05), and the total efficacy was only 38%. The total therapeutic efficacies of fenofibrate on A54A and A54T were higher than those of T54T, and there was significant different between A54A and T54T (P < 0.01).

CONCLUSIONThe polymorphism of human IFABP gene in hyperlipidemia is related with the therapeutic efficacy of fenofibrate, and the T54T IFABP genotype may have strong negative effect on such efficacy.

Aged ; Apolipoproteins ; blood ; Fatty Acid-Binding Proteins ; genetics ; Female ; Fenofibrate ; therapeutic use ; Gene Frequency ; Genotype ; Humans ; Hyperlipidemias ; blood ; drug therapy ; genetics ; Hypolipidemic Agents ; therapeutic use ; Lipids ; blood ; Male ; Middle Aged ; Polymorphism, Genetic ; Treatment Outcome

OBJECTIVETo investigate the fat decreasing effects of fenofibrate on alcoholic fatty liver and drug-induced fatty liver in rats.

METHODSAlcoholic fatty liver and drug-induced fatty liver rats models were established. The two kinds of rats with fatty liver were seperatedly divided into fenofibrate treatment group (80 mg/kg daily) and control group without treatment. Rats were killed after four weeks, then the levels of serum triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL) and malondialdehyde (MDA), hepatic lipase (HL), lipoprotein lipase (LPL) both in serum and liver tissue were measured according to the Test Kits. Histopathological changes in liver was dyed with HE and observed under light microscope.

RESULTSAfter treatment by fenofibrate, in the serum of rats with alcoholic fatty liver, the level of TG decreased significantly (1.07 mmol/L 0.06 mmol/L vs 1.56 mmol/L 0.29 mmol/L, t=5.115, p<0.001), while the level of TC had no alteration. The levels of MDA both in serum and liver tissue decreased (1.10 nmol/L 0.22 nmol/L vs 1.26 nmol/L 0.21 nmol/L, t=0.592, p<0.05; 5.92 nmol/g 1.24 nmol/g vs 7.42 nmol/g 1.22 nmol/g, t=3.477, p<0.05, respectively), while the levels of HL, LPL in serum and liver tissue increased significantly (Serum: 0.053muEq/ml/h 0.006muEq/ml/h vs 0.037 muEq/ml/h 0.006muEq/ml/h, t=-5.086, p<0.001; 0.018 muEq/ml/h 0.004 muEq/ml/h vs 0.014muEq/ml/h 0.004muEq/ml/h, t=-2.485, p<0.05. Liver tissue: 0.075muEq/ml/h 0.010muEq/ml/h vs 0.065muEq/ml/h 0.007muEq/ml/h, t=-2.437, p<0.05; 0.022 muEq/ml/h 0.014 muEq/ml/h vs 0.008 muEq/ml/h 0.002 muEq/ml/h, t=-2.876, p<0.05). Fat content in liver decreased (26.01 mg/g 1.69 mg/g vs 71.45 mg/g 2.66 mg/g, t=-43.224, p<0.001). The pathological changes of liver in fenofibrate-treated rats with alcoholic fatty liver were improved. For the drug-induced fatty liver rats, fenofibrate treatment group had no difference from the untreated control group.

CONCLUSIONFenofibrate can significantly decrease the fat content in liver tissue of rats with alcoholic fatty liver, as well as ameliorating liver pathological changes. But fenofibrate has no effect on drug-induced fatty liver.

Animals ; Carbon Tetrachloride ; toxicity ; Fatty Liver ; chemically induced ; drug therapy ; pathology ; Fatty Liver, Alcoholic ; blood ; drug therapy ; pathology ; Fenofibrate ; therapeutic use ; Hypolipidemic Agents ; therapeutic use ; Lipids ; blood ; Liver ; pathology ; Male ; Rats ; Rats, Wistar

The aim of this study was to investigate the possible beneficial effects of Fenofibrate on renal ischemia-reperfusion injury (IRI) in mice and its potential mechanism. IRI was induced by bilateral renal ischemia for 60 min followed by reperfusion for 24 h. Eighteen male C57BL/6 mice were randomly divided into three groups: sham-operated group (sham), IRI+saline group (IRI group), IRI+Fenofibrate (FEN) group. Normal saline or Fenofibrate (3 mg/kg) was intravenously injected 60 min before renal ischemia in IRI group and FEN group, respectively. Blood samples and renal tissues were collected at the end of reperfusion. The renal function, histopathologic changes, and the expression levels of pro-inflammatory cytokines [interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α) and IL-6] in serum and renal tissue homogenate were assessed. Moreover, the effects of Fenofibrate on activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling and peroxisome proliferator-activated receptor-α (PPAR-α) were also measured in renal IRI. The results showed that plasma levels of blood urea nitrogen and creatinine, histopathologic scores and the expression levels of TNF-α, IL-8 and IL-6 were significantly lower in FEN group than in IRI group. Moreover, Fenofibrate pretreatment could further induce PI3K/Akt signal pathway and PPAR-α activation following renal IRI. These findings indicated PPAR-α activation by Fenofibrate exerts protective effects on renal IRI in mice by suppressing inflammation via PI3K/Akt activation. Thus, Fenofibrate could be a novel therapeutic alternative in renal IRI.
Animals ; Base Sequence ; DNA Primers ; Enzyme Activation ; Fenofibrate ; pharmacology ; therapeutic use ; Inflammation ; drug therapy ; Kidney ; blood supply ; Male ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Real-Time Polymerase Chain Reaction ; Reperfusion Injury ; drug therapy ; Signal Transduction

OBJECTIVETo investigate the effect of PPAR alpha activator fenofibrate on left ventricular hypertrophy and myocardium PPAR alpha (peroxisome proliferator-activated receptor-alpha) expression in spontaneously hypertensive rats (SHR).

METHODSSixteen nine-week-old male spontaneously hypertensive rats were randomly divided into two groups: SHR received fenofibrate 100 mg x kg(-1) x d(-1) by oral gavage once daily for 8 weeks (SHR-F, n=8), and SHR received vechile (0.9 % saline) acted as controls (SHR, n=8). Age-matched Wistar-kyoto rats received vehicle for 8 weeks were served as negative controls (WKY, n=8). Systolic blood pressure was measured at the beginning, 2, 4, and 8 weeks of the experiment. At the end of the experiment, plasma BNP (brain natriuretic peptide)and lipid levels were measured. Left ventricular hypertrophy was accessed by pathological analysis. The expression of PPAR alpha and nuclear factor-kappa B (NF-kappa B p65) were investigated by the method of Western blotting.

RESULTCompared with SHR group, systolic blood pressure was slightly lowered in SHR-F group, but it didn't reach significant level(p>0.05). Fenofibrate administration lowered plasma BNP in SHR-F group (P<0.01). There were not much difference of plasma lipid levels between SHR-F and SHR group. Left ventricular mass index (assessed by left ventricular weight/body weight, g x kg(-1)), transdiameter of cardiomyocyte (TDM), cardiomyocyte area (CA), collagen volume fraction (CVF), and perivascular circumferential area (PVCA) decreased significantly in SHR-F group (P<0.05, P<0.01). The myocardium PPAR alpha expression increased significantly (P<0.01), and NF-kappa B p65 expression decreased significantly (P<0.01) in SHR-F group.

CONCLUSIONPPAR alpha activator fenofibrate can regress left ventricular hypertrophy and increase myocardium PPAR alpha expression in spontaneously hypertensive rats, which is perhaps independent of its lipid-lowering activity.

Animals ; Blood Pressure ; drug effects ; Blotting, Western ; Fenofibrate ; therapeutic use ; Hypertension ; drug therapy ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; blood ; drug therapy ; metabolism ; Lipids ; blood ; Male ; Myocardium ; metabolism ; Natriuretic Peptide, Brain ; blood ; PPAR alpha ; biosynthesis ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Time Factors ; Transcription Factor RelA ; biosynthesis