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Biomedicines Mar 2022Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this...
Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice.
PubMed: 35327418
DOI: 10.3390/biomedicines10030616 -
Journal of Atherosclerosis and... Jun 2023
Randomized Controlled Trial
PubMed: 37150612
DOI: 10.5551/jat.ER63659 -
Annals of the Rheumatic Diseases Apr 1992The case is presented of a 70 year old woman with mild hypercholesterolaemia and hypertension who was readmitted to hospital six months after a previous admission for... (Review)
Review
The case is presented of a 70 year old woman with mild hypercholesterolaemia and hypertension who was readmitted to hospital six months after a previous admission for angina pectoris. The patient was treated with verapamil, nifedipine, and aspirin, and had been receiving bezafibrate (400 mg every 12 hours) for the previous 40 days. Twenty four hours after admission she developed podagra, which was treated with indomethacin (100 mg daily). Eight days after admission myocardial infarction was suspected, and the next day she presented with symptoms of rhabdomyolysis, which was confirmed by laboratory tests. Bezafibrate was withdrawn and the patient became asymptomatic after seven days. It is recommended that doctors should be aware of the possibility of patients, especially those with impaired renal function, developing rhabdomyolysis while being treated with bezafibrate.
Topics: Aged; Bezafibrate; Female; Humans; Hypercholesterolemia; Hypertension; Indomethacin; Rhabdomyolysis
PubMed: 1586257
DOI: 10.1136/ard.51.4.536 -
Movement Disorders : Official Journal... Mar 2014Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric... (Review)
Review
Huntington's disease (HD) is a prototypical dominantly inherited neurodegenerative disorder characterized by progressive cognitive deterioration, psychiatric disturbances, and a movement disorder. The genetic cause of the illness is a CAG repeat expansion in the huntingtin gene, which leads to a polyglutamine expansion in the huntingtin protein. The exact mechanism by which mutant huntingtin causes HD is unknown, but it causes abnormalities in gene transcription as well as both mitochondrial dysfunction and oxidative damage. Because the penetrance of HD is complete with CAG repeats greater than 39, patients can be diagnosed well before disease onset with genetic testing. Longitudinal studies of HD patients before disease onset have shown that subtle cognitive and motor deficits occur as much as 10 years before onset, as do reductions in glucose utilization and striatal atrophy. An increase in inflammation, as shown by elevated interleukin-6, occurs approximately 15 years before onset. Detection of these abnormalities may be useful in defining an optimal time for disease intervention to try to slow or halt the degenerative process. Although reducing gene expression with small interfering RNA or short hairpin RNA is an attractive approach, other approaches targeting energy metabolism, inflammation, and oxidative damage may be more easily and rapidly moved into the clinic. The recent PREQUEL study of coenzyme Q10 in presymptomatic gene carriers showed the feasibility of carrying out clinical trials to slow or halt onset of HD. We review both the earliest detectable clinical and laboratory manifestations of HD, as well as potential neuroprotective therapies that could be utilized in presymptomatic HD.
Topics: Animals; Disease Models, Animal; Genetic Testing; Humans; Huntington Disease; Mitochondria; Neuroprotective Agents; Ubiquinone
PubMed: 24573776
DOI: 10.1002/mds.25835 -
Journal of Internal Medicine May 2000To determine the efficacy and safety of a statin-fibrate combination in diabetes patients. DESIGN.: An open 21-month trial in which each patient first received the... (Clinical Trial)
Clinical Trial Comparative Study
OBJECTIVE
To determine the efficacy and safety of a statin-fibrate combination in diabetes patients. DESIGN.: An open 21-month trial in which each patient first received the single drug for 6 months and then a combination of the two for 1 year.
SETTING
Three lipid clinics in university-based tertiary care hospitals.
PATIENTS
One hundred and forty-eight patients with type 2 (non-insulin-dependent, NIDDM) diabetes mellitus under stable control for 3 months by means of diet and oral hypoglycaemic medication.
INTERVENTION
Patients from one clinic (n = 48) received bezafibrate slow release (400 mg day-1), and patients from the other two clinics (n = 100) received simvastatin 20 mg day-1. Six months later, all patients were switched to a daily combination of 400 mg bezafibrate slow release and 20 mg simvastatin for 1 year.
RESULTS
The combination of statin and fibrate led to a 23% reduction in total cholesterol, 42% reduction in triglycerides, 29% reduction in LDL-c, 25% increase in HDL-c, 10% decrease in fibrinogen and 19% reduction of Lp(a) levels, and a decrease in the cholesterol/HDL-c ratio (from 8.9 to 5.4) in all 148 patients. Cardiovascular (CV) event rate was significantly reduced from 9.5% during the first 6 months of the study to less than 2% during the last year of the study (whilst on combination Rx). Side-effects with all treatments included only two patients who developed myopathy when on the combined regimen and one on the single statin regimen. However, plasma creatinine phosphokinase (CPK) levels doubled (but remained within the normal range) in most of the patients on combination therapy, compared with only a mild increase in patients receiving a single medication.
CONCLUSIONS
The statin and fibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidaemia, as evidenced by improvement in the lipoprotein profile, reductions in Lp(a), fibrinogen and CV event rate, and almost no clinically significant side-effects.
Topics: Aged; Bezafibrate; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Simvastatin; Time Factors; Treatment Outcome
PubMed: 10809995
DOI: 10.1046/j.1365-2796.2000.00646.x -
Pharmaceuticals (Basel, Switzerland) Jan 2022Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, reportedly attenuated tau pathology in a transgenic mouse model of primary tauopathy. Since...
Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, reportedly attenuated tau pathology in a transgenic mouse model of primary tauopathy. Since tau pathology is a neuropathological hallmark of Alzheimer's disease (AD), bezafibrate may be a potential drug for the treatment of AD. However, no study has investigated its effects in AD models. Thus, we aimed to evaluate whether bezafibrate has neuroprotective effects in a sporadic AD model induced by streptozotocin (STZ) intracerebroventricular (ICV) injection. Rats were administered STZ-ICV (3 mg/kg) followed by bezafibrate (50 mg/kg/day, intraperitoneal) for 4 weeks. Behavior tests and positron emission tomography (PET) were performed to evaluate longitudinal changes in cognitive function, tau pathology, and cerebral glucose metabolism. Immunofluorescence staining was performed to assess neuronal survival and microglial accumulation. STZ-ICV administration induced significant cognitive impairment and substantial neuronal loss, tau pathology, glucose hypometabolism, and microgliosis in the cortex and hippocampus, while bezafibrate effectively attenuated these abnormalities. This study demonstrated that bezafibrate has long-lasting neuroprotective effects in a sporadic AD model. Our data indicate that the neuroprotective effects of bezafibrate might be associated with its ability to ameliorate tau pathology, brain glucose hypometabolism, and neuroinflammation. These findings suggest that bezafibrate is a potential multi-target drug candidate for the treatment of AD.
PubMed: 35215222
DOI: 10.3390/ph15020109 -
EMBO Molecular Medicine Mar 2020Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there... (Observational Study)
Observational Study
Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae.
Topics: Bezafibrate; Humans; Mitochondria; Mitochondrial Myopathies; Organelle Biogenesis
PubMed: 32107855
DOI: 10.15252/emmm.201911589 -
Heliyon Mar 2024The metabolic disorders caused by diabetes can lead to various complications, including male spermatogenesis dysfunction. Exploring effective therapeutics that attenuate...
The metabolic disorders caused by diabetes can lead to various complications, including male spermatogenesis dysfunction. Exploring effective therapeutics that attenuate diabetes mellitus (DM)-induced male subfertility is of great importance. Pharmaceuticals targeting PPARα activation such as bezafibrate have been regarded as an important strategy for patients with diabetes. In this study, we use streptozocin (STZ) injection to establish a type 1 DM mice model and use bezafibrate to treat DM mice and evaluate the effects of bezafibrate on the spermatogenic function of the DM male mice. Bezafibrate treatment exhibited protective effects on DM-induced spermatogenesis deficiency, as reflected by increased testis weight, improved histological morphology of testis, elevated sperm parameters, increased serum testosterone concentration as well as increased mRNA levels of steroidogenesis enzymes. Meanwhile, testicular cell apoptosis, inflammation accumulation and oxidative stress status were also shown to be alleviated by bezafibrate compared with the DM group. In vivo and in vitro studies, PPARα specific inhibitor and PPARα knockout mice were further used to investigate the role of PPARα in the protective effects of bezafibrate on DM-induced spermatogenesis dysfunction. Our results indicated that the protection of bezafibrate on DM-induced spermatogenesis deficiency was abrogated by PPARα inhibition or deletion. Our study suggested that bezafibrate administration could ameliorate DM-induced spermatogenesis dysfunction and may represent a novel practical strategy for male infertility.
PubMed: 38533024
DOI: 10.1016/j.heliyon.2024.e28284 -
Medicine Feb 2023Hypertriglyceridemia and chronic kidney disease (CKD) are known risk factors for cardiovascular disease. However, treatment with statins, which control low-density...
Hypertriglyceridemia and chronic kidney disease (CKD) are known risk factors for cardiovascular disease. However, treatment with statins, which control low-density lipoprotein cholesterol levels, increases the risk of estimated glomerular filtration rate (eGFR) reduction. Although conventional fibrates, such as bezafibrate (Beza-F) and fenofibrate (Feno-F), are the mainstay for hypertriglyceridemia treatment, they may be associated with a risk of increased serum creatinine level and renal dysfunction. Pemafibrate (Pema) is pharmacologically defined as a selective peroxisomal proliferator-activated receptor α modulator which is excreted in bile and not likely to cause renal dysfunction. We evaluated the efficacy and safety of switching from Beza-F or Feno-F to Pema in CKD patients with hypertriglyceridemia. We recruited 47 CKD patients with hypertriglyceridemia who were receiving Beza-F, Feno-F, or eicosapentaenoic acid (EPA) but were switched to Pema from 2018 to 2021. A retrospective analysis of renal function and lipid profiles was performed before and 24 weeks after switching. CKD patients switching from EPA to Pema were used as study control. The effect of Pema on hypertriglyceridemia was equivalent to that of Beza-F or Feno-F. However, after switching to Pema, eGFR showed a marked average improvement of 10.2 mL/min/1.73 m2 (P < .001). Improvement in eGFR and levels of n-acetyl-β-d-glucosaminidase and β-2-microglobulin was observed only in cases of switching from Beza-F or Feno-F but not from EPA. Although Beza-F and Feno-F are useful medications for the treatment of hypertriglyceridemia, these are associated with a high risk of renal dysfunction. We also found that the deterioration in eGFR due to Beza-F or Feno-F is reversible with drug withdrawal and may not increase the risk for long-term renal dysfunction. We suggest that Pema may be an effective and safe treatment for hypertriglyceridemia in CKD patients.
Topics: Humans; Fenofibrate; Hypertriglyceridemia; Renal Insufficiency; Renal Insufficiency, Chronic; Retrospective Studies; Drug Substitution; Bezafibrate
PubMed: 36800602
DOI: 10.1097/MD.0000000000032818 -
Cardiovascular Diabetology Nov 2013There are numerous reports describing the efficacy of fenofibrate in combination with ezetimibe for treating dyslipidemia. In contrast, a study combining bezafibrate and... (Observational Study)
Observational Study
BACKGROUND
There are numerous reports describing the efficacy of fenofibrate in combination with ezetimibe for treating dyslipidemia. In contrast, a study combining bezafibrate and ezetimibe has not yet been conducted. In this study, we examined the safety, including the risk of gallstone formation, and the efficacy of long-term combination therapy with bezafibrate and ezetimibe for treating dyslipidemia.
METHODS
Dyslipidemic patients treated with 400 mg/day bezafibrate in combination with 10 mg/day ezetimibe for the first time were eligible. We selected 157 institutions in Japan and conducted a 12-month prospective observational study, with patients enrolled on the day they started combination therapy. Safety of the combination was examined in terms of the type, onset, and severity of adverse drug reactions (ADRs). Efficacy was evaluated in terms of the changes in low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride (TG), and non-HDL cholesterol (non-HDL-C) levels from the start of combination therapy (baseline) to the last observation carried forward (LOCF). Lipid levels were assessed at 1, 3, 6, and 12 months after starting combination therapy.
RESULTS
We enrolled 665 patients in this observational study. Safety was evaluated in 659, and ADRs occurred in 42 patients (6.4%). The most frequent ADRs were blood creatine phosphokinase increase (1.5%) and myalgia (0.8%). Asymptomatic gallstones were observed in four patients (0.6%). Effectiveness was evaluated in 622 patients. LDL-C, HDL-C, TG, and non-HDL-C levels improved significantly from baseline to LOCF by -17.4%, 8.8%, -40.5%, and -21.6%, respectively (all, p < 0.001). Lipid levels also improved from baseline to each evaluation time-point.
CONCLUSIONS
Bezafibrate in combination with ezetimibe is safe and effective, and is potentially useful for comprehensive management of dyslipidemia.
Topics: Aged; Azetidines; Bezafibrate; Biomarkers; Cholesterol, HDL; Cholesterol, LDL; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Humans; Hypolipidemic Agents; Japan; Lipids; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Time Factors; Treatment Outcome; Triglycerides
PubMed: 24195788
DOI: 10.1186/1475-2840-12-163