Mitochondrial dysfunction, oxidative stress, ER stress and mitochondria-ER crosstalk alterations in a chemical rat model of Huntington's disease: Potential benefits of bezafibrate.

Redox homeostasis, mitochondrial functions, and mitochondria-endoplasmic reticulum (ER) communication were evaluated in the striatum of rats after 3-nitropropionic acid (3-NP) administration, a recognized chemical model of Huntington's disease (HD). 3-NP impaired redox homeostasis by increasing malondialdehyde levels at 28 days, decreasing glutathione (GSH) concentrations at 21 and 28 days, and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione S-transferase at 7, 21, and 28 days, catalase at 21 days, and glutathione reductase at 21 and 28 days. Impairment of mitochondrial respiration at 7 and 28 days after 3-NP administration was also observed, as well as reduced activities of succinate dehydrogenase (SDH) and respiratory chain complexes. 3-NP also impaired mitochondrial dynamics and the interactions between ER and mitochondria and induced ER-stress by increasing the levels of mitofusin-1, and of DRP1, VDAC1, Grp75 and Grp78. Synaptophysin levels were augmented at 7 days but reduced at 28 days after 3-NP injection. Finally, bezafibrate prevented 3-NP-induced alterations of the activities of SOD, GPx, SDH and respiratory chain complexes, DCFH oxidation and on the levels of GSH, VDAC1 and synaptophysin. Mitochondrial dysfunction and synaptic disruption may contribute to the pathophysiology of HD and bezafibrate may be considered as an adjuvant therapy for this disorder.

Lipid-lowering agent-triggered dermatomyositis and polymyositis: a case series and literature review.

Lipid-lowering agent-triggered dermatomyositis (DM) or polymyositis (PM) is a rare event. Therefore, the aim of the present study was to describe a series of such cases. A retrospective cohort study of 5 DM and 4 PM cases triggered by prior exposure to lipid-lowering agents between 2001 and 2017 was carried out. All patients, except for two cases, had muscle biopsy compatible with inflammatory myopathy and no serum autoantibodies positive for anti-SRP or anti-HMGCoAR. Median age of the patients at time of diagnosis was 68 years. Seven patients had previously taken simvastatin 20 mg/day (exposure period from 2 days to 4 years) and two bezafibrate 100 mg/day (3-4 months). Median time from symptom onset to disease diagnosis was 6 months. All patients with DM had a heliotrope and/or Gottron's papules. All patients had symmetrical, predominantly proximal muscle weakness of limbs, with median serum creatine phosphokinase of 3087U/L (interquartile 25-75% range 1293-13,937 U/L). All patients received glucocorticoid and immunosuppressants. Complete reversal of clinical symptoms and normalization of serum creatine phosphokinase level occurred within a median of 12 months after starting the treatment. There was disease relapse in three cases, and one case of death was unrelated to the disease (pulmonary infectious complications resulting from lymphoma). In contrast to cases described in the literature, the patients in the present study had a relatively more aggressive course, requiring glucocorticoids and immunosuppressants, in addition to a tendency for a longer period to achieve disease remission.

Extreme urinary betaine losses in type 2 diabetes combined with bezafibrate treatment are associated with losses of dimethylglycine and choline but not with increased losses of other osmolytes.

PURPOSE: Betaine deficiency is a probable cardiovascular risk factor and a cause of elevated homocysteine. Urinary betaine excretion is increased by fibrate treatment, and is also often elevated in diabetes. Does fibrate further increase betaine excretion in diabetes, and does it affect the plasma concentrations and excretions of related metabolites and of other osmolytes? METHODS: Samples from a previous study of type 2 diabetes were selected if participants were taking bezafibrate (n = 32). These samples were compared with participants matched for age and gender and not on a fibrate (comparator group, n = 64). Betaine, related metabolites, and osmolytes were measured in plasma and urine samples from these 96 participants. RESULTS: Median urinary betaine excretion in those on bezafibrate was 5-fold higher than in the comparator group (p < 0.001), itself 3.5-fold higher than the median reported for healthy populations. In the bezafibrate group, median dimethylglycine excretion was higher (9-fold, p < 0.001). Excretions of choline, and of the osmolytes myo-inositol, taurine and glycerophosphorylcholine, were not significantly different between groups. Some participants excreted more betaine than usual dietary intakes. Several betaine fractional clearances were >100 %. Betaine excretion correlated with excretions of the osmolytes myo-inositol and glycerophosphorylcholine, and also with the excretion of choline and N,N-dimethylglycine, but it was inconclusive whether these relationships were affected by bezafibrate therapy. CONCLUSIONS: Increased urinary betaine excretions in type 2 diabetes are further increased by fibrate treatment, sometimes to more than their dietary intake. Concurrent betaine supplementation may be beneficial.

Bezafibrate maintenance therapy in patients with advanced chronic hepatitis C.

BACKGROUND: Bezafibrate exerts multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-α, which modulates the expression of key genes of lipid transport, lipoprotein metabolism as well as inflammation. The aim of the present study was to assess the efficacy and safety of bezafibrate in patients with advanced chronic hepatitis C. MATERIALS AND METHODS: A total of 34 patients received oral bezafibrate treatment (400 mg/day) on the basis of a prospective observational open-label study design. Clinical, biochemical and virological data were evaluated during a mean treatment duration of 19 months. In a subpopulation (n=8), cytokine expression analysis was carried out and compared with an hepatitis C virus treatment-naive control group (n=7). RESULTS: A significant improvement in aspartate aminotransferase (P=0.007), alanine aminotransferase (P<0.0001), alkaline phosphatase (P=0.001), γ-glutamyltranspeptidase levels (P=0.001) and aspartate aminotransferase-to-platelets ratio index Score (P=0.026) could be found at the end of observation. No significant effect on viral load was observed. Bezafibrate treatment for at least 4 months markedly increased interferon-γ expression compared with the treatment-naive patients (4.81 vs. 1.63 arbitrary units; P=0.005), whereas tumour necrosis factor-α and interleukin-6 levels were not significantly influenced. CONCLUSION: This observational study provides evidence that bezafibrate is effective for patients with advanced chronic hepatitis C by reducing liver enzymes significantly and should be further evaluated as a potentially beneficial maintenance therapy.

The effect of bezafibrate and omega-3 fatty acids on lymphocyte cytokine release and systemic inflammation in patients with isolated hypertriglyceridemia.

PURPOSE: The aim of this study was to compare the effects of fibrates and omega-3 fatty acids on lymphocyte secretory function and systemic inflammation in patients with isolated hypertriglyceridemia. METHODS: The study included 107 patients with isolated hypertriglyceridemia who received bezafibrate (200 mg twice daily), omega-3 fatty acids (1 g twice daily) or placebo for 12 weeks. The lipid profile, fasting and 2-h post-glucose load plasma glucose levels, homeostasis model assessment index (HOMA), plasma high-sensitivity C-reactive protein (hsCRP) levels and lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α were assessed at baseline, on the day of randomization, and after 4 and 12 weeks of treatment. RESULTS: Both bezafibrate and omega-3 fatty acids reduced plasma triglyceride levels. Bezafibrate additionally decreased total and low-density lipoprotein-cholesterol levels and the HOMA and insignificantly decreased post-glucose load plasma glucose, as well as increased high-density lipoprotein-cholesterol. Bezafibrate treatment was associated with a reduction in lymphocyte release of interleukin-2, interferon-γ and tumor necrosis factor-α, which was accompanied by a reduction in plasma hsCRP levels. Omega-3 fatty acid did not significantly reduce lymphocyte cytokine release and plasma hsCRP. The anti-inflammatory effects of both drugs did not correlate with their action on plasma lipids, but in the case of the former the effect was related to the improvement in insulin sensitivity. CONCLUSION: Our results indicate that bezafibrate is superior to omega-3 fatty acid in inhibiting systemic inflammation and lymphocyte secretory function.

Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML).

Acute myeloid leukaemia (AML) causes life-threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two-thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at <3 months emphasizing the urgent need for anti-AML therapies that do not suppress haemopoiesis. Our laboratory studies showed combined Bezafibrate and Medroxyprogesterone acetate (BaP) had activity against AML without toxicity to normal stem cells. Here we report the safety and efficacy of BaP in 20 patients (19 AML, 1 high-risk myelodysplasia) for whom intensive chemotherapy was not an option. No patient exhibited haematological toxicity from BaP. Eleven patients took BaP alone for >4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22-30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML.

Fish oil increases bile acid synthesis in male patients with hypertriglyceridemia.

Fibrates are drugs of choice in patients with hypertriglyceridemia (HTG), but may increase the risk for gallstones by decreasing bile acid synthesis. Fish oil might be a therapeutic alternative, but its effect on bile acid metabolism in humans is unknown. We compared the effects of triglyceride-lowering therapy by fish oil or bezafibrate on cholesterol synthesis and bile acid metabolism in HTG. Cholesterol synthesis, bile acid pool sizes, and synthesis rates were compared between 9 male HTG patients and 10 normolipidemic controls matched for age, sex, and BMI. Effects of bezafibrate or fish oil were studied only in HTG patients in a randomized crossover trial. Patients had 14-fold higher serum triglyceride concentrations and greater cholesterol synthesis, as indicated by a 107% higher ratio of serum lathosterol to cholesterol (P < 0.01) than controls. The groups did not differ in bile acid metabolism. Both bezafibrate and fish oil reduced serum TG concentration (-68 and -51% vs. baseline, respectively). Compared with baseline, bezafibrate therapy was associated with reduced cholesterol synthesis (-25%, P = 0.009) without changes in bile acid synthesis rate and pool size. In contrast, fish oil increased bile acid synthesis (+31% vs. baseline, P = 0.07 and +53% vs. bezafibrate, P = 0.02) and altered bile acid distribution, as reflected by an increased ratio of the cholic acid (CA) synthesis rate to the chenodeoxycholic acid (CDCA) synthesis rate (+35% vs baseline, P = 0.05 and + 32% vs bezafibrate, P = 0.07) without effects on bile acid pool size or cholesterol synthesis. In conclusion, cholesterol synthesis is greater in HTG patients than in controls, whereas bile acid synthesis does not differ. Bezafibrate and fish oil have similar triglyceride-lowering capacities, but distinct effects on cholesterol synthesis. Bile acid synthesis is increased by fish oil, but not by bezafibrate therapy.

Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator.

Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs). Peroxisome proliferators produce a myriad of extraperoxisomal effects, which are not necessarily dependent on their interaction with PPARs. An investigation on the peculiar activities of bezafibrate could clarify some of the molecular events and the relationship with the biochemical and pharmacological properties of this class of compounds. In this view, the human acute promyelocytic leukemia HL-60 cell line and human rabdomiosarcoma TE-671 cell line were cultured in media containing bezafibrate and a number of observations such as spectrophotometric analysis of mitochondrial respiratory chain enzymes, NMR metabolite determinations, phosphofructokinase enzymatic analysis, and differentiation assays were carried on. Bezafibrate induced a derangement of NADH cytochrome c reductase activity accompanied by metabolic alterations, mainly a shift to anaerobic glycolysis and an increase of fatty acid oxidation, as shown by NMR analysis of culture supernatants where acetate, lactate, and alanine levels increased. On the whole, the present results suggest a biochemical profile and a therapeutic role of this class of PPARs ligands more complex than those previously proposed.

Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells.

The effects of a variety of fibrates on the cell viability were examined in human embryonal rhabdomyosarcoma cells (HRMSC). Five fibrates, including fenofibrate, clofibrate, gemfibrozil, bezafibrate and ciprofibrate, all concentration-dependently reduced the cell viability determined by the mitochondrial enzyme activity. The cell injury occurred time-dependently and was marked at 24-48 h. The toxic action of fibrates was specific to HRMSC, since bezafibrate did not induce any marked changes in the viability of human microvascular endothelial cells or arterial smooth muscle cells. Synergistic cell injury was observed after a combined treatment with bezafibrate and simvastatin, although simvastatin alone reduced the cell viability. The cell injury was characterized by a typical nuclear damage, as evidenced by Hoechst 33342 staining and deoxynucleotidyl transferase dUTP nick-end label-positive staining. Similar cell-specific injury was induced by 8(S)-hydroxyeicosatetraenoic acid, a potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. Consistent with these data, a marked expression for PPARalpha mRNA was observed in HRMSC but not in the endothelial or smooth muscle cells. Therefore, it is suggested that fibrates cause a cell-specific injury in HRMSC via activation of PPARalpha. Moreover, our present cell injury model using HRMSC may be useful for elucidating the mechanisms of clinical rhabdomyolysis induced by lipid-lowering agents.

Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease.

BACKGROUND: Coronary heart disease patients with low high-density lipoprotein cholesterol (HDL-C) levels, high triglyceride levels, or both are at an increased risk of cardiovascular events, but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed. METHODS AND RESULTS: In a double-blind trial, 3090 patients with a previous myocardial infarction or stable angina, total cholesterol of 180 to 250 mg/dL, HDL-C < or =45 mg/dL, triglycerides < or =300 mg/dL, and low-density lipoprotein cholesterol < or =180 mg/dL were randomized to receive either 400 mg of bezafibrate per day or a placebo; they were followed for a mean of 6.2 years. The primary end point was fatal or nonfatal myocardial infarction or sudden death. Bezafibrate increased HDL-C by 18% and reduced triglycerides by 21%. The frequency of the primary end point was 13. 6% on bezafibrate versus 15.0% on placebo (P=0.26). After 6.2 years, the reduction in the cumulative probability of the primary end point was 7.3%, (P=0.24). In a post hoc analysis in the subgroup with high baseline triglycerides (> or =200 mg/dL), the reduction in the cumulative probability of the primary end point by bezafibrate was 39.5% (P=0.02). Total and noncardiac mortality rates were similar, and adverse events and cancer were equally distributed. CONCLUSIONS: Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. An overall trend in a reduction of the incidence of primary end points was observed. The reduction in the primary end point in patients with high baseline triglycerides (> or =200 mg/dL) requires further confirmation.

Acute renal failure after cardiopulmonary bypass: a possible association with drugs of the fibrate group.

BACKGROUND: Renal failure is a recognized, but infrequent, complication following cardiac surgery. The causes for this condition are multifactorial, and a major concern is that the occurrence of postoperative acute renal failure is still associated with a high mortality rate. METHODS AND MATERIALS: We report unexpected acute renal failure occurring in 4 patients after uncomplicated cardiac surgery. Each patient was taking a fibric acid derivative at the time of surgery. Renal failure occurred rapidly within 3 days of surgery and was associated with increased concentrations of skeletal muscle-derived creatine kinase (CK). One patient developed myoglobinuria, and another developed a malignant hyperthermia-like syndrome. CONCLUSIONS: These cases show that patients receiving lipid lowering medications could be at higher risk of developing acute renal failure after cardiac surgery. This association merits careful evaluation in large prospective studies and, if proved, would suggest that patients taking either statins or fibrates should discontinue doing so before cardiac surgery.

Low total cholesterol is associated with high total mortality in patients with coronary heart disease. The Bezafibrate Infarction Prevention (BIP) Study Group.

The present non-intervention screening study was undertaken to explore the relationships between pre-existing low total cholesterol and all-cause mortality. Eleven thousand, five hundred and sixty-three patients with coronary heart disease who attended a screening visit but were not included in the Bezafibrate Infarction Prevention study were followed-up for a mean of 3.3 years after determination of baseline total cholesterol. Five hundred and ninety-five (5%) of this largely unselected population who had total cholesterol levels < or = 160 mg.dl-1 formed the study population. The remaining 10968 patients acted as controls. The relative risk of all-cause mortality among patients with low cholesterol compared to others was 1.49 (95% CI: 1.16-1.91). The relative risk of non-cardiac death was 2.27 times higher in the low cholesterol group than in the controls (95% CI: 1.49-3.45), whereas the risk of cardiac death was the same in both groups (relative risk 1.09; 95% CI: 0.76-1.56). The most frequent cause of non-cardiac death associated with low total cholesterol was cancer. These results in patients with coronary heart disease add weight to previous studies associating low total cholesterol with an increased risk of non-cardiac death. However, a longer follow-up of this cohort of patients is necessary in order to clarify this association.

High-dose fluvastatin and bezafibrate combination treatment for heterozygous familial hypercholesterolemia.

This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 800 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes > 3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term safety of statin-fibrate combination treatment in the management of hypercholesterolaemia in patients with coronary artery disease.

OBJECTIVE: To evaluate the long-term safety profile of treatment with a statin-fibrate combination in a cohort of patients with documented coronary artery disease. DESIGN: Retrospective cohort analytical study. SETTING: District general hospital. PATIENTS: 102 (81 male and 21 female) hypercholesterolaemic (total cholesterol concentration > 6.5 mmol/l) patients with documented coronary artery disease and who had been treated with a statin-fibrate combination for over 1 year. Coronary artery disease was confirmed by angiography in 93 patients and by a positive (Bruce protocol) exercise test in the remainder. Fifty eight patients had a history of previous coronary bypass graft surgery. INTERVENTIONS: Twice daily lipid lowering treatment was given, with the fibrate administered in the morning (either bezafibrate 400 mg (n = 101) or fenofibrate 200 mg (n = 1)) and the statin in the evening (either simvastatin 10 mg (n = 23), 20 mg (n = 72), or 40 mg (n = 2) or pravastatin 10 mg (n = 1) or 20 mg (n = 4)). Treatment continued for 1 (n = 9), 2 (n = 58), or 3 (n = 35) years. MAIN OUTCOME MEASURES: Selected laboratory variables (total cholesterol concentration and liver (aspartate transaminase (AST)) and muscle enzyme (creatine kinase (CK)) activities) and documented symptomatology. RESULTS: A mean (SD) total cholesterol concentration of 5.2 (0.8) mmol/l was achieved after combined treatment for 1 year which was maintained at annual follow up. Over a maximum 3 year follow up no patient reported myalgic symptoms and none had a measured CK activity > 10 times above nomal. Four men on a simvastatin-bezafibrate combination had a CK activity rise to less than three times normal. Fourteen patients with a negative history of alcohol excess (consumption < 21 units/week) had borderline raised AST values. CONCLUSIONS: Statin-fibrate combination treatment for up to 3 years in a cohort of patients with coronary artery disease was not associated with serious disturbances in biochemical markers of muscle or liver function.

Design features of a five-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).

Young survivors of myocardial infarction represent a poignant challenge to clinical research on atherogenic mechanisms and factors predisposing to and precipitating coronary thrombosis. Young male postinfarction patients are characterized by heavy smoking, dyslipoproteinaemias involving very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL), a family history of premature coronary artery disease, hyperinsulinaemic responses to oral and intravenous glucose challenges, an elevated plasma fibrinogen concentration and defective fibrinolytic function. Based on the multiplicity of metabolic and haemostatic disturbances present in these patients, a double-blind, randomized, placebo-controlled angiographic trial was initiated to determine whether bezafibrate, a clofibrate analogue, retards the progression or facilitates regression of premature coronary atherosclerosis. Men under the age of 45 years who survived a first myocardial infarction were screened for participation in the study. A fasting serum cholesterol value > or = 5.2 mmol/l and/or serum triglycerides > or = 1.6 mmol/l after three months of dietary treatment and angiographically demonstrable lesions in at least one coronary segment were required for inclusion. Treatment with diet and bezafibrate (200 mg t.i.d.) or matching placebo is continued for five years during which time re-angiography is performed after two years and at the end of the study. The primary aim of the trial is a comparison between the bezafibrate and placebo groups for change in mean minimum luminal diameter between the baseline and five-year coronary angiograms. This report presents the design features of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and a review of current knowledge of mechanisms underlying premature coronary atherosclerosis and myocardial infarction at a young age.

Bezafibrate-induced myopathy: no evidence for defects in muscle metabolism.

A 58-year-old man with chronic renal failure developed severe muscle pain and tenderness 1 week after starting bezafibrate 400 mg daily. Serum creatine kinase was 32,280 U/l. Muscle biopsy revealed scattered necrotic fibers and mild type 2b atrophy. Muscle total and free carnitine were at the upper limits of the normal range. Biochemical investigations of muscle homogenate showed normal carnitine pelmityl transferase (CPT) as well as normal individual glycolytic and mitochondrial enzyme activities. Withdrawal of the drug was followed by rapid clinical improvement. Our study casts doubt on the hypothesis that bezafibrate is able to affect muscle metabolic pathways. It is likely that the drug acts on cholesterol constituents of the muscle membrane, producing discontinuities of the sarcolemma and initiating cell necrosis.