Estudio observacional, prospectivo, abierto, multicéntrico, post-comercialización, para evaluar la efectividad y seguridad de ácido fenofíbrico 105 mg comprimidos en pacientes con hipertrigliceridemia y/o dislipidemias mixtas / Prospective, open-label, multicenter, post-marketing observational study to evaluate the effectiveness and safety of 105 mg fenofibric acid tablets in patients with hypertriglyceridemia and/or mixed dyslipidemia

Introducción: Estudio observacional, prospectivo, abierto, multicéntrico. Se evaluaron 117 pacientes reclutados en 16 centros. Se incluyeron pacientes mayores de 18 años, con hipertrigliceridemia mayor a 200 mg/dl (asociado o no a dislipidemia mixta) que ya estén recibiendo ácido fenofíbrico 105 mg/día desde hace por lo menos 8 y no más de 12 semanas. El cronograma de visitas consistió en una visita inicial (entre 8 a 12 semanas de iniciado el tratamiento con ácido fenofíbrico) y una visita final (8 semanas después de la visita inicial). Resultados: La efectividad fue evaluada a partir de valores de laboratorio y su respuesta al tratamiento, (descenso de niveles séricos de triglicéridos principalmente y descenso de niveles séricos de LDL, y ascenso de niveles séricos de HDL), comparando valores basales y controles de laboratorio en la visita inicial y final. Efectividad: 106 pacientes evaluables. Triglicéridos: Basal: 368,44 ± 165,39 mg/dl; Día 60: 246,30 ± 171,43 mg/dl; Día 120: 180,92 ± 130,59 mg/dl. Anova: p<0,05. LDL: Basal: 144,24 ± 42,33 mg/dl; Día 60: 121,73 ± 38,24 mg/dl; Día 120: 116,08 ±39,81 mg/dl. Anova: p < 0,05. HDL: Basal 41,58 ± 14,09 mg/dl; Día 60: 43,74 ±13,78 mg/dl; Día 120: 46,43 ± 16,09 mg/dl. Anova: p: <0,05. Seguridad: 117 pacientes evaluables. Eventos adversos: 9 pacientes (7,69%) Conclusiones: En nuestro grupo de pacientes evaluados, la administración de 105 mg de Acido Fenofíbrico al día resultó efectiva para disminuir los valores séricos de Triglicéridos y LDL, además de aumentar el HDL. El perfil de seguridad fue aceptable (AU)

Introduction: Observational, prospective, open, multicenter clinical study. One hundred and seventeen (117) patients were recruited from 16 sites. Inclusion criteria: both sexes patients elder than 18 years old with bypertriglyceridemia values higher than 200 mg/dl (related or not to mixed dylipidemia), who had to be taking 105 mg/day of fenofibric acid sinde - at least - 8 weeks and no more than 12 weeks. Study schedule: Baseline visit between 8 and 12 weeks after fenofibric acid strting tretment. Last clinical trial visit: 8 weeks after the baseline one. Results: Effectiveness was evaluated considering laboratory clinical values achieved after treatment. It means: as primary outome it was considerd lower triglycerides serum levels and, as a secondary one, lower LDL and higher HDL serum levels. Laboratory values were compared between the ones from baseline visit and the ones from last visit. Effectiveness: 106 evaluable patients. Triglycerides: Baseline: 368,44 ± 165,39 mg/dl: Day 60: 246,30 ±171,43 mg/dl. Day 120: 180,92 ± 130,59 mg/dl. Anova: p< 0.05. LDL: Baseline: 144,24 ± 42,33 mg/dl: Day 60: 121,73 ± 38,24 mg/dl; Day 120: 116,08 ± 39,81 mg/dl. Anova: p<0,05. HDL: Baseline: 41,58 ± 14,09 mg/dl: Day 60: 43,74 ± 13,78 mg/dl. Day 120: 46,43 ± 16.09 mg/dl. Anova: p<0.05. Safety: 117 evaluable patients: Adverse Events: 9 patients (7,69%). Conclusion: The administration of 105 mg/day of fenofibric acid to the evaluable patients recruited for this clinical study, showed to be effective not only to decrease triglycerides and LDL serum levels, but also to increase HDL, cholesterol values. Patient safety was acceptaable (AU)

Anti-Hypertensive Action of Fenofibrate via UCP2 Upregulation Mediated by PPAR Activation in Baroreflex Afferent Pathway / 神经科学通报·英文版

Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.

Neither polyphenol-rich red wine nor fenofibrate affects the onset of type-1 diabetes mellitus in the BB rat / 한국실험동물학회지

Serum levels of the pro-inflammatory apolipoprotein CIII (apoCIII) are increased in type-1 diabetic (T1D) patients and when β-cells are exposed to apoCIII they undergo apoptosis, which can be prevented by an antibody against apoCIII. We have previously investigated the BB rat, an animal model that develops a human-like T1D at the age of around 60 days, and found that apoCIII was also increased in sera from pre-diabetic rats and this promoted β-cell death. Lowering apoCIII with an oligonucleotide antisense during a phase of the pre-diabetic period prolonged the time to onset of T1D. In order to find other ways to lower apoCIII we in this study tested non-alcoholic red wine with medium and high concentrations of polyphenols and the lipid-lowering drug, fenofibrate, both reported to decrease the expression of apoCIII by activating peroxisome proliferator-activated receptors. Pre-diabetic BB-rats were treated orally for one month prior to the expected onset of diabetes with the two different wines or fenofibrate. None of the treatments prevented or prolonged the time to onset of diabetes and the expression of apoCIII was unaffected in this animal model for T1D. However, it must be emphasized that this does not exclude that other species can show a response to these substances.

Effects of sera of rats fed with tablets on endoplasmic reticulum stress in a HepG2 cell model of nonalcoholic fatty liver disease / 南方医科大学学报

OBJECTIVE@#To investigate the effects of sera from rats fed with tablets (HGT) on endoplasmic reticulum (ER) stress in a steatotic hepatocyte model of free fatty acids (FFAs)-induced nonalcoholic fatty liver disease (NAFLD) and explore the possible mechanism.@*METHODS@#FFAs prepared by mixing oleic acid and palmitic acid at the ratio of 2:1. HepG2 cells were treated with the sera from rats fed with low-, moderate-or high-dose HGT (HGT sera) or sera of rats fed with fenofibrate (fenofibrate sera), followed by treatment with 1 mmol/L FFAs for 24 h to induce hepatic steatosis. Oil red O staining was used to observe the distribution of lipid droplets in the cells. The biochemical parameters including triglyceride (TG), lactated hydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using a commercial kit. The morphological changes of the ER in the cells were observed using transmission electron microscopy. The protein/mRNA expressions of ER stress-related signal molecules including GRP78, PERK, p-PERK, ATF6, ATF4, CASPASE-12, CHOP, XBP-1, PKC, and p-PKC-δ were detected using Western blotting and/or quantitative real-time PCR (qRT-PCR). The changes in the protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP were also detected in cells with transient transfection of PKC-δ siRNA for PKC-δ knockdown.@*RESULTS@#Compared with the control cells, the cells treated with FFAs showed significantly increased levels of TG, AST, and ALT ( < 0.05). Compared with FFAs-treated cells, the cells pretreated with HGT sera or fenofibrate sera all showed significantly decreased TG, AST and ALT levels ( < 0.05), reduced accumulation of the lipid droplets ( < 0.05), and lowered protein or mRNA expression levels of GRP78, p-PERK, ATF6, ATF4, CHOP, CASPASE-12, XBP-1 and p-PKC-δ ( < 0.05). PKC-δ knockdown caused significantly reduced protein expressions of GRP78, p-PERK, CASPASE-12 and CHOP in the cells with FFA-induced hepatic steatosis ( < 0.001); treatment with high-dose HGT serum more significantly reduced the expressions of GRP78 ( < 0.001) and P-PERK ( < 0.01) in FFAs-induced cells with PKC-δ knockdown.@*CONCLUSIONS@#HGT serum can effectively prevent FFAs-induced steatosis in HepG2 cells by alleviating ER stress, in which PKC-δ may act as an important target.

Heparin and insulin in the management of hypertriglyceridemia-associated pancreatitis: case series and literature review

SUMMARY Severe hypertriglyceridemia accounts for up to 7% of all cases of acute pancreatitis. Heparin and insulin activate lipoprotein lipase (LPL), thereby reducing plasma triglyceride levels. However, the safety and efficacy of heparin and insulin in the treatment of hypertriglyceridemia-associated acute pancreatitis have not been well established yet. We successfully used heparin and insulin as first-line therapy in four consecutive patients with acute pancreatitis secondary to hypertriglyceridemia. In a literature search, we revised almost all reports published to date of patients managed successfully with this combination. Heparin and insulin appear to be a safe, effective, and inexpensive first-line therapy for hypertriglyceridemia-associated acute pancreatitis.

Effect of Long-term Fenofibrate Therapy on Serum Creatinine and Its Reversibility in Hypertriglyceridemic Patients with Hypertension

OBJECTIVE: Previous studies have shown that fenofibrate therapy increases serum creatinine level and that there is a return of serum creatinine to baseline level after the discontinuation of the drug. We evaluated the effect of long-term fenofibrate therapy on creatinine levels and its reversibility in patients with hypertension and hypertriglyceridemia. METHODS: This retrospective study enrolled 54 hypertensive and hypertriglyceridemic patients taking fenofibrate for 3–6 years (Fenofibrate group) and 30 control patients with similar age, sex, follow-up duration, and creatinine levels (Control group). In 23 patients taking fenofibrate with low triglyceride level and/or with high creatinine levels, fenofibrate was discontinued, and creatinine levels were measured after 2 months. RESULTS: Creatinine levels increased in both the fenofibrate group (from 0.91±0.18 mg/dL to 1.09±0.23 mg/dL, p < 0.001) and the control group (from 0.94±0.16 mg/dL to 0.98±0.16 mg/dL, p=0.04) compared to baseline. However, the elevation was more pronounced in the fenofibrate group than in the control group (21.1±15.4% vs. 4.5±11.3%, p < 0.001). The discontinuation of fenofibrate lowered creatinine levels (from 1.39±0.32 mg/dL to 1.15±0.24 mg/dL, p < 0.001) which were still higher than pre-treatment levels (p=0.013). CONCLUSION: Long-term fenofibrate therapy significantly increased creatinine levels in hypertensive and hypertriglyceridemic patients. The effect of fenofibrate on creatinine level was partially reversible. This finding suggests that follow-up creatinine level is necessary with fenofibrate therapy.

Effect of Fenofibrate Medication on Renal Function / 가정의학회지

BACKGROUND: Fibrates are widely used to treat hypertriglyceridemia, a risk factor for arteriosclerosis, but these compounds have been associated with renal dysfunction. This study aimed to investigate the effects of fibrates on renal function in relatively healthy adult subjects with no cardiovascular diseases. METHODS: This retrospective study included 558 outpatients who were prescribed 160 mg fenofibrate (fenofibrate group) or 10 mg atorvastatin (control group) between August 2007 and October 2015. The groups were randomly matched using propensity scores at a 1:1 ratio. Serum creatinine levels and estimated glomerular filtration rates before and after treatment were compared between the two groups. RESULTS: Patients in the fenofibrate group showed greater changes in serum creatinine levels than those in the control group (9.73%±9.83% versus −0.89%±7.37%, P<0.001). Furthermore, 55.1% of patients in the fenofibrate group, but only 6.1% of those in the control group, exhibited a serum creatinine level increase ≥0.1 mg/dL (P<0.001). The fenofibrate group showed significantly greater declines in the estimated glomerular filtration rate than the control group (−10.1%±9.48% versus 1.42%±9.42%, P<0.001). Moreover, 34.7% of the fenofibrate group, but only 4.1% of the control group, exhibited an estimated glomerular filtration rate decrease ≥10 mL/min·1.73 m² (P<0.001). CONCLUSION: Fenofibrate treatment resulted in increased serum creatinine levels and reduced estimated glomerular filtration rates in a primary care setting. Therefore, regular renal function monitoring should be considered essential during fibrate administration.

Chemical degradation kinetics of fibrates: bezafibrate, ciprofibrate and fenofibrate

ABSTRACT Fibrates are drugs used for the treatment of hypertriglyceridemia and for the prevention of atherosclerosis. Three drugs in the fibrate class, ciprofibrate, fenofibrate and bezafibrate, were chosen for this study because their raw materials are readily available and because scientific publications on these compounds is limited. To evaluate their intrinsic stability, the drugs were exposed to a test condition (temperature, oxidation, UV light exposure, hydrolysis at different pH values and metal ions in solution) and then were subjected to analysis by HPLC. The samples were run on a C18 column, with a flow rate of 1.0 mL min-1 in a mobile phase consisting of methanol: 0.01 % phosphoric acid v/v (80:20), with variable detection wavelengths in the UV spectra. The analysis methodology showed satisfactory performance parameters. The three drugs were very unstable, degrading in each of the conditions evaluated. The test conditions of acid and basic hydrolysis showed the most significant degradation. The results demonstrated that the drugs in this class are unstable. Based on these experimentally determined degradation kinetics, it is easy to understand and emphasize the importance of the lack of liquid dosage forms on the market for fibrates because of their instability.

Role and mechanism of action of fibroblast growth factor-21 in reducing triglyceride in nonalcoholic fatty liver disease / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the role and mechanism of action of fibroblast growth factor-21 (FGF-21) in reducing triglyceride (TG) in the in vitro and in vivo models of nonalcoholic fatty liver disease (NAFLD).</p><p><b>METHODS</b>(1) A mixture of free fatty acids was used to establish a model of steatosis in L02 cells, and the cells were treated with various concentrations of FGF-21 or fenofibrate. Twenty-four hours later, oil red O staining was performed to observe the degree of steatosis, and intracellular TG content was determined. RT-PCR and Western blot were applied to measure the mRNA and protein expression of sterol regulatory element-binding protein-1c (SREBP-1c). (2) High-fat diet was used to establish a mouse model of steatosis, and these mice were intraperitoneally injected with FGF-21 or fenofibrate. Eight weeks later, whole blood and liver samples were collected, and HE staining was performed to observe steatosis. Meanwhile, the serum levels of TG, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured, and TG content in the liver was also measured. One-way analysis of variance was used for comparison of data between multiple groups, and the least significant difference t-test was used for comparison between any two groups.</p><p><b>RESULTS</b>(1) Compared with the control group, the model group showed significant steatosis, with significant increases in intracellular lipid droplets and TG content (t = -20.57, P < 0.01), while FGF-21 reduced the number of intracellular lipid droplets and TG content (F = 98.16, P < 0.01) in a dose-dependent manner. In addition, the model group had significantly increased mRNA and protein expression of SREBP-1c compared with the control group (t = -10.73 and -0.1006, both P < 0.01), while FGF-21 down-regulated the mRNA and protein expression of SREBP-1c (F = 161.35 and 36.72, both P < 0.01). (2) Compared with the mice in the control group, those in the model group showed significant steatosis and had significant increases in serum TG level and TG content in the liver (t = -18.84 and 15.71, both P < 0.01). FGF-21 relieved hepatic steatosis and reduced the serum TG level and TG content in the liver (t = 18.11 and 9.46, both P < 0.01). Moreover, FGF-21 reduced the serum levels of ALT and AST in NAFLD mice (t = 25.93 and 12.50, both P < 0.01).</p><p><b>CONCLUSION</b>FGF-21 can inhibit the synthesis of TG through suppressing the expression of SREBP-1c, which further confirms the potential therapeutic effect of FGF-21 in the treatment of NAFLD. This may provide new ideas for the treatment of NAFLD.</p>

Efficacy of fenofibrate for hepatic steatosis in rats after severe burn / 中华烧伤杂志

<p><b>OBJECTIVE</b>To observe the efficacy of fenofibrate for hepatic steatosis in rats after severe burn.</p><p><b>METHODS</b>Twenty-seven male SD rats were divided into sham injury group, burn group, and burn+ fenofibrate group according to the random number table, with 9 rats in each group. Rats in sham injury group were sham injured on the back by immersing in 37 ℃ warm water for 15 s and then remained without other treatment. Rats in burn group and burn+ fenofibrate group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back by immersing in 98 ℃ hot water for 15 s, and then they were intraperitoneally injected with lactated Ringer's solution at post injury hour (PIH) 1. From PIH 24 to post injury day (PID) 8, rats in burn+ fenofibrate group were treated with fenofibrate in the dose of 80 mg·kg(-1)·d(-1), while those in burn group were treated with equivalent volume of saline. (1) Three rats of each group were respectively selected on PID 4, 6, and 8 for the collection of inferior vena caval blood samples. Serum content of total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high density lipoprotein (HDL), and low density lipoprotein (LDL) was determined with fully automatic biochemical analyzer. Body mass of each rat was measured immediately after blood sampling, and then rats were sacrificed to collect liver tissue for weighing wet mass. The ratio of wet mass of liver tissue to body mass (liver index) was calculated. Meanwhile, gross observation of liver was performed. (2) One liver tissue sample was harvested from each rat at each time point to observe histopathologic changes with HE staining. One liver tissue slice of each rat at each time point was collected to evaluate degree of hepatic steatosis, and the number of rats in each group in each grade of hepatic steatosis was recorded. Measurement data were processed with analysis of variance of factorial design and SNK test, and enumeration data were processed with Kruskal-Wallis test and Nemenyi test.</p><p><b>RESULTS</b>(1) The content of TC, TG, FFA, and HDL of rats in burn group on PID 4 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC, TG, and FFA of rats was significantly decreased (with P values below 0.05), while the content of HDL of rats was not obviously changed in burn+ fenofibrate group on PID 4 (P>0.05). There were no obvious differences in the content of LDL of rats among 3 groups on PID 4 (with P values above 0.05). The content of TC, TG, and HDL of rats in burn group on PID 6 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC and TG of rats was significantly decreased (with P values below 0.05), while the content of HDL of rats was significantly increased in burn+ fenofibrate group on PID 6 (P<0.05). There were no obvious differences in the content of FFA and LDL of rats among 3 groups on PID 6 (with P values above 0.05). The content of TC and HDL of rats in burn group on PID 8 was obviously different from that in sham injury group (with P values below 0.05). Compared with that in burn group, the content of TC of rats was significantly decreased (P<0.05), while the content of HDL of rats was not obviously changed in burn+ fenofibrate group on PID 8 (P>0.05). There were no obvious differences in content of TG, FFA, and LDL of rats among 3 groups on PID 8 (with P values above 0.05). (2) The texture of liver tissue of rats in burn+ fenofibrate group at each time point was tender and soft, without oil or fat on the section, which was close to the gross condition of liver of rats in sham injury group. Dark yellow plaque scattered on the surface of liver tissue of rats in burn group at each time point with oil and fat on the section, which was especially obvious on PID 6. There was no obvious difference in liver index of rats among 3 groups on PID 4 (F=1.63, P>0.05). On PID 6 and 8, the liver indexes of rats in sham injury group, burn group, and burn+ fenofibrate group were 0.0416±0.0016, 0.0533±0.0054, and 0.0370±0.0069; 0.0423±0.0034, 0.0624±0.0005, and 0.0444±0.0042 respectively. The liver indexes of rats in burn group on PID 6 and 8 were significantly higher than those in the other two groups (with P values below 0.05). There were no obvious differences in the liver indexes of rats between burn+ fenofibrate group and sham injury group on PID 6 and 8 (with P values above 0.05). (3) The liver tissue structure of rats in sham injury group was normal at each time point. Hepatic steatosis of rats in burn group at each time point appeared microvesicular and disperse, which was especially obvious on PID 6. Mild hepatic steatosis was observed in rats of burn+ fenofibrate group on PID 4, and then the structure of liver tissue gradually recovered to normal level from PID 6 on. The degree of hepatic steatosis of rats in sham injury group was 0 grade. One rat in I grade, 1 rat in II grade, and 7 rats in III grade were observed in hepatic steatosis of rats in burn group. Three rats in 0 grade, 4 rats in I grade, and 2 rats in II grade were observed in hepatic steatosis of rats in burn+ fenofibrate group. The degree of hepatic steatosis of rats in burn group was more severe than that in the other two groups (with χ(2) values respectively 56.25 and 162.44, P values below 0.05). The degree of hepatic steatosis of rats in burn+ fenofibrate group was more severe than that in sham injury group (χ(2)=27.51, P<0.05).</p><p><b>CONCLUSIONS</b>Fenofibrate can ameliorate the dyslipidemia of severely burned rat, and it can alleviate the degree of hepatic steatosis in certain degree.</p>

The effect of relgulation of PPAR-α on cardiac hypertrophy and the relationship between the effect of PPAR-α with PI3K/Akt/mTOR pathway / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To investigate the effect of peroxisiome proliferator activated receptor-α (PPAR-α) on the regulation of cardiomyocyte hypertrophy and the relationship between the effect of PPAR-α with PI3K/Akt//mTOR signal pathway.</p><p><b>METHODS</b>Cardiomyocyte hypertrophy was induced by isoproterenol (ISO). The cell surface area was measured by image analysis system (Leica). The expressions of atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC) and PPAR-α mRNA were detected by qRT-PCR. The protein expressions of Akt, mTOR and P70S6K were detected by Western blot. The expression of PPAR-α was suppressed by RNAi.</p><p><b>RESULTS</b>(1) The expression of PPAR-α was significantly reduced in cardiomyocyte hypertrophy. PPAR-α activator Fenofibrate (Feno) increased the expression of PPAR-α and suppressed cardiomyocyte hypertrophy. The inhibitory effect of Feno on cardiomyocyte hypertrophy was reversed by PPAR-α RNAi. (2) Feno significantly inhibited the increase of the protein expressions of p-Akt, p-mTOR and p-p70S6K in ISO induced cardiomyocyte hypertrophy, which could be blocked by PPAR-α RNAi. (3) PI3K antagonist LY294002 (LY) or mTOR antagonist rapamycin (RAPA) markedly-inhibited cardiomyocyte hypertrophy. The inhibitory effects of LY or RAPA on cardiomyocyte hypertrophy were reversed by PPAR-α RNAi.</p><p><b>CONCLUSION</b>PPAR-α can negatively regulate cardiomyocyte hypertrophy. The effect might be associated with PPAR-α inhiting PI3K/ Akt/mTOR signal pathway.</p>

Effects of fenofibrate on hepatocyte apoptosis in nonalcoholic fatty liver / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To use a rat model of nonalcoholic liver disease (NAFLD) to observe effects of the peroxisome proliferator-activated receptor-a (PPAR-a) agonist fenofibrate on hepatic steatosis in nonalcoholic fatty liver and to investigate the underlying mechanism.</p><p><b>METHODS</b>Sixty-six Sprague-Dawley rats were given adaptive feeding for 1 week and then randomly allocated into the following three groups: unmodeled control (group C,n =18), untreated NAFLD model (group M, n =24), and fenofibrate-treated NAFLD model (group F, n =24).Group C rats were given a normal diet, while group M and group F rats were given a high-fat diet. After model establishment, the group F rats were treated with fenofibrate (10 mg/kg/d, intraperitoneal) and the group C and group M rats were given sham-treatment with cosolvent (5 mL/kg/d, intraperitoneal). At the end of treatment weeks 4, 6 and 8, one-third of rats in each group were euthanized.Liver tissues were assessed by hematoxylin-eosin (HE) staining to determine level of steatosis and inflammaion activity, and by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling to measure changes in hepatocyte apoptosis index. Changes in expression levels of the PPAR-a receptor and apoptosis factors (bcl-2, bax and caspase-3) were assessed by reverse transcription-PCR and immunohistochemistry.</p><p><b>RESULTS</b>The NAFLD modeled rats showed appropriate induction of hepatic steatosis, hepatic inflammation, and hepatocyte apoptosis. Compared to the group M rats, the group F rats showed lower expression of PPAR-and bcl-2 and higher expression of bax and caspase-3 at both the mRNA and protein level.</p><p><b>CONCLUSION</b>Fenofibrate can ameliorate hepatic steatosis in an experimental rat model of NAFLD, and the mechanism may be associated with inhibition of hepatocyte apoptosis.</p>

Fenofibrate pre-treatment suppressed inflammation by activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling in renal ischemia-reperfusion injury / 华中科技大学学报（医学）（英德文版）

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.

Fenofibrate Therapy and Change of Renal Function: Management, What and How? / 대한내과학회지

Fenofibrate is one of PPAR-alpha (peroxisome proliferator activated receptor alpha) agonists. Fenofibrate decreases effectively triglyceride and increases high density lipoprotein cholesterol level through the effect on lipoprotein lipase, hepatic production and degradation of lipoproteins. Fenofibrate was recommended as the drug for hypertriglyceridemia treatment in European guideline released in 2011. But American heart association guideline in 2013 did not recommend non-statin therapy including fibrate for the prevention of atherosclerotic cardiovascular disease. But fenofibrate is still considered as the important drug for the management of atherogenic dyslipidemia especially in patients with metabolic syndrome and diabetes to reduce the residual risk after statin therapy from the evidence of many studies. Fibrates including bezafibrate, gemfibrozil, and fenofibrate increased serum creatinine level in several studies. But the mechanism of change in renal function is not clear till now. And the reversibility of renal function with drug discontinuation is dependent on the kinds of fibrate. Fenofibrate increased serum creatinine level, decreased albuminuria and renal function was reversible with the drug discontinuation in large clinical trials. In these days renal function change with fenofibrate therapy in Korean patients with hypertriglyceridemia was investigated. Fenofibrate treatment for 2 months increased serum creatinine level significantly and old age was associated with the change of renal function in multivariate analysis. Short-term therapy significantly increased serum creatinine level even within normal range, and this change may be important in some groups especially old age.

Effect of Short-term Fenofibrate Therapy on Blood Creatinine Levels in Patients with Hypertriglyceridemia / 대한내과학회지

BACKGROUND/AIMS: Previous studies have reported that fenofibrate therapy increases blood creatinine levels. The aim of this study was to evaluate the effect of fenofibrate therapy on the renal function in patients with hypertriglyceridemia and to determine the parameters associated with changes in renal functions. METHODS: This prospective study enrolled 86 hypertriglyceridemic patients (triglycerides > or = 200 mg/dL) who were divided into two groups: the fenofibrate group (n = 43), who received 160 mg of fenofibrate, and the control group (n = 43). Lipid profiles and renal function were measured at the beginning of the study and after 2 months. RESULTS: The estimated glomerular filtration rate (eGFR) decreased in the fenofibrate group (p < 0.001), but did not change in the control group (p = 0.80). Accordingly, the decrease was more pronounced in the fenofibrate group than the control group (-18.6 +/- 8.6 vs. 0.9 +/- 9.6%, respectively; p < 0.001). Changes in serum creatinine (p < 0.001) and blood urea nitrogen (p < 0.005) levels were similar to those of eGFR. In a stepwise linear regression analysis, the percent change in creatinine was independently associated with fenofibrate therapy (r = 0.71; p < 0.001) and old age (r = 0.27; p < 0.05) in all patients. In the fenofibrate group, percent change in creatinine was associated with age (r = -0.51; p < 0.001) and smoking (r = 0.42; p < 0.005), while percent change was associated with body mass index (r = 0.31; p < 0.05) in the control group. Elevation of creatinine by 20% or more was associated with fenofibrate therapy (p < 0.001) and old age (p < 0.005) in all patients, and with old age (p < 0.001) in the fenofibrate group. CONCLUSIONS: Short-term fenofibrate therapy significantly impaired the renal function of hypertriglyceridemic patients, and this effect was more pronounced in elderly patients. This finding suggests that creatinine levels should be followed in patients receiving fenofibrate therapy.

Systemic medical management of diabetic retinopathy

Diabetes mellitus [DM] has assumed epidemic proportions and as a consequence, diabetic retinopathy is expected to be a major societal problem across the world. Diabetic retinopathy [DR] affects the vision by way of proliferative disease that results in vitreous hemorrhage and traction retinal detachment or by way of diabetic maculopathy [DME]. The present-day management of diabetic retinopathy revolves around screening the diabetics for evidence of retinopathy and treating the retinopathy with laser photocoagulation. DME is treated with laser photocoagulation and/or intra- vitreal injection of anti-vascular endothelial growth factor [VEGF] agents or steroids. Laser remains the mainstay of treatment and is potentially destructive. Systemic management aims at preventing or delaying the onset of retinopathy; reversing the early retinopathy; or delaying the progression of established retinopathy. Evidence from multiple studies has confirmed the protective role of rigid control of blood glucose and blood pressure. The evidence for lipid control versus maculopathy was less definitive. However, the use of fenofibrates [originally used for lowering serum lipids] has shown a benefit on both proliferative disease and maculopathy outside their lipid-lowering effect. Other drugs being tried are the Protein Kinase C [PKC] inhibitors, other peroxisome proliferator-activated receptors [PPAR] agonists, Forsoklin [which binds GLUT 1 receptor], minocycline [for its anti inflammatory effect], and Celecoxib [Cox-2 inhibitor]

Should we start all patients with diabetic retinopathy on fenofibrates?

There remains a need for strategies that are effective in preventing diabetic retinopathy [DR] or slowing down its progression, which is safe, well-tolerated, and more effective, have a lower risk profile, easy to perform, have more predictable results with less morbidity than the current regimens. Physicians caring for diabetic patients not only need to maximize glycemic control, but also closely monitor and treat other systemic conditions. The consistency of clinical data from the fenofibrate studies showed consistent beneficial effects with fenofibrate in slowing the progression of DR. They demonstrated significant benefit on micro-vascular [i.e., retinopathy and nephropathy] outcome, possibly independent of lipid levels. Can we combine the effectiveness of the current standard procedures with the prevention and slowing down of progression of DR that fenofibrates can offer? Knowledge of the primary mode of action of fenofibrate will be useful for both physicians and patients in determining how best to use this drug as an adjunct in the management of DR and ultimately facilitating the translation of clinical trial data to clinical practice

Anti-fibrosis effects of fenofibrate in mice with hepatic fibrosis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the anti-fibrosis effects and mechanisms of fenofibrate on hepatic fibrosis using a mouse model of fibrosis induced by carbon tetrachloride (CCl4).</p><p><b>METHODS</b>Twenty-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.</p><p><b>RESULTS</b>Compared 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.</p><p><b>CONCLUSION</b>Fenofibrate 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.</p>

Effect of Fenofibrate Therapy on Blood Creatinine Levels in Patients with Hypertension and Hypertriglyceridemia

OBJECTIVE: Previous studies have reported that fenofibrate therapy increased blood creatinine levels. We investigated the effect of fenofibrate therapy on creatinine levels in patients with hypertension and hypertriglyceridemia. METHODS: This retrospective study included 36 hypertensive patients with hypertriglyceridemia taking fenofibrate for 1-3 years (Fenofibrate group) and 36 control patients with similar age, sex, follow-up duration, creatinine levels, and lipid levels to those of fenofibrate therapy (Control group). RESULTS: Baseline parameters except lipid profiles were similar between the fenofibrate and control groups. Creatinine levels increased in the fenofibrate group (from 0.90+/-0.18 mg/dL to 1.05+/-0.22 mg/dL, p<0.001) and did not change in the control group (from 0.91+/-0.12 mg/dL to 0.92+/-0.14 mg/dL, p=0.39). The elevation was more pronounced in the fenofibrate group than in the control group (0.15+/-0.12 vs. 0.02+/-0.11 mg/dL, p<0.001). Changes in creatinine levels were only associated with fenofibrate therapy (r=0.52, p<0.001) in the stepwise linear regression analysis. CONCLUSION: Fenofibrate therapy for 1-3 years significantly increased creatinine levels in hypertensive patients with hypertriglyceridemia. This finding suggests that follow-up measurement of creatinine level is necessary with fenofibrate therapy.

Role of TRB3 in the inhibitory effect of fenofibrate against high glucose-induced proliferation of glomerular mesangial cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of TRB3 in the inhibitory effect of fenofibrate against the proliferation of glomerular mesangial cell induced by high glucose.</p><p><b>METHODS</b>Rat glomerular mesangial cells (MCs) were cultured in the presence of 5.5 mmol/L glucose (normal control), 25 mmol/L glucose (high glucose group), or high glucose along with 10, 50, or 100 µmol/L fenofibrate. Cell counting kit-8 (CCK-8) assay was used to evaluate cell proliferation, and Hoechst 33258 staining was employed to determine chromatin distribution in the MCs. Flow cytometry was performed to analyze the cell cycle changes in different groups. The expressions of TRB3 and P-AKT in different groups were detected using immunocytochemistry and Western blotting.</p><p><b>RESULTS</b>High glucose induced obvious proliferation of the MCs (P<0.001), which was significantly inhibited by fenofibrate in a concentration-dependent manner (P<0.001). The MCs exposed to fenofibrate presented with typical apoptotic morphologies and cell cycle arrest at G1/S phase. Low levels of TRB3 expression was detected in the normal control and high glucose groups, whereas in the 3 fenofibrate groups, TRB3 expression increased and P-AKT expression decreased as fenofibrate concentration increased.</p><p><b>CONCLUSION</b>Fenofibrate can promote TRB3 expression in rat MCs. TRB3 causes cell cycle arrest at G1/S phase by inhibiting AKT phosphorylation to result in suppressed proliferation of the MCs.</p>